As prenatal genetic testing and imaging have advanced, the diagnosis of genetic disorders has moved from the postnatal to the prenatal time frame. This has largely been facilitated by the increasing use of exome sequencing (ES) in the prenatal setting. Two landmark trials published in January 2019 highlighted the overall diagnostic yields of prenatal ES as 8.5% and 10% in fetuses with normal karyotype and microarray.^1,2

Although this is a huge step forward in prenatal diagnosis, ES is currently a manually curated, labor-intensive task. The process involves reviewing thousands of sequence variants for any given sample and prioritizing each variant based on bio­informatic data, prediction models, literature review, and specific patient characteristics. The patient characteristics, or phenotypic information, are critically important in prioritizing candidate variants.

To date, prenatal ES has been limited by the use of inconsistent terminology and the lack of well-understood prenatal phenotypes. In this Update, we highlight how recently published work draws attention to these critical gaps in prenatal diagnosis.

Standardizing phenotyping language in the prenatal setting

Tomar S, Sethi R, Lai PS. Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing. Eur J Hum Genet. 2019;27:1389-1397.

Clinical ES in pediatric and adult populations is enhanced by the use of standardized vocabulary to describe disorders. Standardized language ensures that identified variants are filtered correctly and in a systematic fashion based on the patient characteristics that are provided. One commonly used platform is the Human Phenotype Ontology (HPO).

Tomar and colleagues assessed the impact of HPO-based clinical information on the performance of a gene prioritization tool.³ Gene prioritization (or simulation) tools are used for interpretation of ES data to help analysts efficiently sort through the thousands of variants in an individual’s genetic sequence. The performance, or accuracy, of a prioritization tool can be assessed by looking at the location of the disease-causing gene in the suggested gene list.

Continue to: Cohort of diagnosed patients and gene prioritization...

Cohort of diagnosed patients and gene prioritization

In this experimental model, Tomar and colleagues included 50 cases with neuromuscular disorders; all had available sequencing data, fully described phenotypes, and known causal genes. The authors varied the level of available clinical information in the HPO terms used for simulated variant analysis. Using 3 web-based gene prioritization tools on the 50 cases, they varied the HPO input to include a random selection of 10%, 30%, and 50% of HPO terms derived from deep phenotyping.

The 3 prioritization tools ranked input genes based on gene-phenotype associations that were derived from gene-phenotype databases. The authors then assessed the quality of the candidate gene lists by the location of the known causative gene on the generated rank lists. They repeated this analysis 4 times with different randomly selected HPO terms. 

Inclusion of more HPO terms allowed for more accurate diagnoses in rare disorders

The authors found that the phenotype input for ES matters. When only 10% and 30% of the HPO terms were used to create a candidate gene list, the causative gene was less likely to be in the top portions of gene lists than when 50% or 100% of the available HPO terms were used.

For well-characterized disorders, use of the top 10% HPO terms performed as well as when all available HPO terms were used. For previously undescribed disease-gene associations, identification of the disease gene suffered with more limited HPO term availability.

What this study contributes

This study was a simulation of previously sequenced patients with neuromuscular disorders. It examined a small sample size for a narrow spectrum of disease. However, it clearly illustrated the principle that completeness of phenotypic information for ES pipelines is relevant for interpretation.

Detailed description of prenatal findings is essential to diagnosis

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181.

In a retrospective cohort study, Aarabi and colleagues evaluated the diagnostic utility and limitations of ES in prenatal cases with structural birth defects.⁴

A case series study

The investigators included 20 pregnancies with structural birth defects that were referred to their center for prenatal diagnosis between 12 and 20 weeks’ gestation. All pregnancies had normal karyotype and microarray analyses prior to enrollment.

ES was performed on trio samples, which included fetal and parental DNA samples (extracted from peripheral blood). Reports provided by the commercial laboratories were normal for all cases and included no pathogenic or likely pathogenic variants. The laboratory provided the investigators with the FASTQ (genetic sequence) files for reanalysis, which was performed using both prenatal and postnatal detailed phenotypic information.

Continue to: Use of postnatal information facilitated diagnoses...

Use of postnatal information facilitated diagnoses

Reanalysis of ES data using detailed postnatal findings revealed a possible diagnosis in 20% of cases. Each case in which a diagnosis was made, detailed below, highlights an important limitation in our current ability to make prenatal diagnoses.

Case 1. A fetus was diagnosed prenatally with arthrogryposis, plagiocephaly, and club feet. After birth, the infant also was found to have generalized muscle weakness, elevated creatine phosphokinase, and congenital hip dislocation.

Reanalysis of the ES data revealed compound heterozygous missense variants in the nebulin gene (NEB). Although classified as variants of uncertain significance (VUS), these are consistent with the phenotype, the authors argued, and with the diagnosis of autosomal recessive nemaline myopathy 2.

Case 2. Prenatal diagnosis was made of a right limb anomaly, tetralogy of Fallot, intrauterine growth restriction, ambiguous genitalia, and dextrocardia. Postnatal evaluation revealed absent pulmonary valve syndrome, right arm dysplasia, pectus carinatum deformity, and failure to thrive.

In this case, ES with the postnatal information revealed a VUS in the NOTCH1 gene, which has been associated with Adams-Oliver syndrome. Although by strict criteria this variant is also of uncertain significance, Adams-Oliver syndrome is characterized, in part, by transverse limb defects and congenital heart disease, as was found in the proband.

Case 3. Prenatal ultrasonography revealed microcephaly and absence of the septum pellucidum. Postnatal magnetic resonance imaging revealed semi-lobar holoprosencephaly. A holoprosencephaly-specific gene panel revealed a deletion in the ZIC2 gene, which is known to cause holoprosencephaly.

Careful re-examination of the ES data revealed some abnormality in the ZIC2 signal, which might have been studied in greater detail and thereby detected if the prenatal diagnosis of holoprosencephaly had been made.

Case 4. An ultrasound evaluation at 12 weeks’ gestation revealed a cystic hygroma, short long bones, and possible absent hand and fibula. A postnatal fetal autopsy at 14 weeks showed split-hand and split-foot malformations, which were not appreciated on ultrasonography.

In filtering the ES data with this information, a pathogenic variant in the PRCN gene was identified as causal, and the diagnosis of Goltz syndrome was made.

Challenges facing  prenatal diagnosis

A case series is inherently limited by its small sample size. Nevertheless, the authors suggest 2 major challenges in our ability to make the above diagnoses in the prenatal setting:
1) the prenatal assessment being limited to major structural abnormalities, and 2) commercial laboratories not having enough experience or volume to interpret the limited information provided by prenatal imaging.

Can AI technology be incorporated to make a genetic diagnosis?

Hsieh TC, Mensah MA, Pantel JT, et al. PEDIA: prioritization of exome data by image analysis. Genet Med. 2019;21:2807-2814.

Increasingly, ES is used in all types of undiagnosed, rare genetic diseases. Although there is a high diagnostic yield in many populations, ES’s clinical utility is limited by the labor-intensive process of interpreting each variant in the context of detailed phenotypic information. The widespread use of HPO would be one step toward standardizing the information that is entered into the analysis of ES data, but even HPO cannot capture certain visual clues.

Hsieh and colleagues attempted to use artificial intelligence (AI) for “next-generation phenotyping” to assess facial dysmorphology and integrate the information into variant classification.⁵ The authors described their approach of incorporating AI as “prioritization of exome data by image analysis” (PEDIA).

Continue to: Designing dysmorphology machine learning...

Designing dysmorphology machine learning

The cohort included 679 individuals with 105 different genetic disorders. All individuals had a previously confirmed molecular diagnosis that would be detected by ES. Each individual had a frontal facial photograph analyzed and detailed clinical features documented in HPO terms extracted by 2 clinicians.

A facial analysis software called DeepGestalt, trained on 17,000 patient images, was used to create a Gestalt score. Each individual had 4 different predicted gene scoring approaches:

• a molecular deleteriousness score
• facial analysis with the Gestalt score
• a combination of molecular deleteriousness score and HPO-based gene-prioritization tool (termed semantic similarity score)
• the PEDIA score, which included all 3 prior approaches.

A type of machine learning algorithm (support vector machine, or SVM) was applied, validated, and used to prioritize genes based on the combined scores.

AI seemed to improve diagnostic accuracy

Utilizing the combination of machine learning, HPO terms, and facial analysis software greatly improved the accuracy of variant classification predictions over any approach alone.

Using only the sequence variant and molecular deleteriousness score, the causative variant was ranked in the top 10 of all identified variants in less than 45% of cases. Adding the HPO-based gene prioritization tools increased the accuracy to 63% to 94%. Use of the PEDIA score, which incorporated all 3, increased the accuracy to 99% for the top 10 ranking.

Even more impressive improvements were made in the top 1 ranking accuracy rate, which went from 36% to 74% without facial image information to 86% to 89% with inclusion of DeepGestalt scores.

Study strengths and limitations

This study’s innovative application of facial analysis and machine learning, combined with HPO-driven variant classification, showed added benefit. To achieve this with available patient photographs and thorough phenotyping, previously diagnosed patients were used. Because complete ES information was not available for those patients, their known pathogenic variant was inserted into randomly selected exomes from the 1000 Genomes Project (healthy individuals). The authors additionally noted that the PEDIA score performance was diminished for rare disorders in which limited data were available. 

As prenatal genetic testing and imaging have advanced, the diagnosis of genetic disorders has moved from the postnatal to the prenatal time frame. This has largely been facilitated by the increasing use of exome sequencing (ES) in the prenatal setting. Two landmark trials published in January 2019 highlighted the overall diagnostic yields of prenatal ES as 8.5% and 10% in fetuses with normal karyotype and microarray.^1,2

Although this is a huge step forward in prenatal diagnosis, ES is currently a manually curated, labor-intensive task. The process involves reviewing thousands of sequence variants for any given sample and prioritizing each variant based on bio­informatic data, prediction models, literature review, and specific patient characteristics. The patient characteristics, or phenotypic information, are critically important in prioritizing candidate variants.

To date, prenatal ES has been limited by the use of inconsistent terminology and the lack of well-understood prenatal phenotypes. In this Update, we highlight how recently published work draws attention to these critical gaps in prenatal diagnosis.

Standardizing phenotyping language in the prenatal setting

Tomar S, Sethi R, Lai PS. Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing. Eur J Hum Genet. 2019;27:1389-1397.

Clinical ES in pediatric and adult populations is enhanced by the use of standardized vocabulary to describe disorders. Standardized language ensures that identified variants are filtered correctly and in a systematic fashion based on the patient characteristics that are provided. One commonly used platform is the Human Phenotype Ontology (HPO).

Tomar and colleagues assessed the impact of HPO-based clinical information on the performance of a gene prioritization tool.³ Gene prioritization (or simulation) tools are used for interpretation of ES data to help analysts efficiently sort through the thousands of variants in an individual’s genetic sequence. The performance, or accuracy, of a prioritization tool can be assessed by looking at the location of the disease-causing gene in the suggested gene list.

Continue to: Cohort of diagnosed patients and gene prioritization...

Cohort of diagnosed patients and gene prioritization

In this experimental model, Tomar and colleagues included 50 cases with neuromuscular disorders; all had available sequencing data, fully described phenotypes, and known causal genes. The authors varied the level of available clinical information in the HPO terms used for simulated variant analysis. Using 3 web-based gene prioritization tools on the 50 cases, they varied the HPO input to include a random selection of 10%, 30%, and 50% of HPO terms derived from deep phenotyping.

The 3 prioritization tools ranked input genes based on gene-phenotype associations that were derived from gene-phenotype databases. The authors then assessed the quality of the candidate gene lists by the location of the known causative gene on the generated rank lists. They repeated this analysis 4 times with different randomly selected HPO terms. 

Inclusion of more HPO terms allowed for more accurate diagnoses in rare disorders

The authors found that the phenotype input for ES matters. When only 10% and 30% of the HPO terms were used to create a candidate gene list, the causative gene was less likely to be in the top portions of gene lists than when 50% or 100% of the available HPO terms were used.

For well-characterized disorders, use of the top 10% HPO terms performed as well as when all available HPO terms were used. For previously undescribed disease-gene associations, identification of the disease gene suffered with more limited HPO term availability.

What this study contributes

This study was a simulation of previously sequenced patients with neuromuscular disorders. It examined a small sample size for a narrow spectrum of disease. However, it clearly illustrated the principle that completeness of phenotypic information for ES pipelines is relevant for interpretation.

Detailed description of prenatal findings is essential to diagnosis

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181.

In a retrospective cohort study, Aarabi and colleagues evaluated the diagnostic utility and limitations of ES in prenatal cases with structural birth defects.⁴

A case series study

The investigators included 20 pregnancies with structural birth defects that were referred to their center for prenatal diagnosis between 12 and 20 weeks’ gestation. All pregnancies had normal karyotype and microarray analyses prior to enrollment.

ES was performed on trio samples, which included fetal and parental DNA samples (extracted from peripheral blood). Reports provided by the commercial laboratories were normal for all cases and included no pathogenic or likely pathogenic variants. The laboratory provided the investigators with the FASTQ (genetic sequence) files for reanalysis, which was performed using both prenatal and postnatal detailed phenotypic information.

Continue to: Use of postnatal information facilitated diagnoses...

Use of postnatal information facilitated diagnoses

Reanalysis of ES data using detailed postnatal findings revealed a possible diagnosis in 20% of cases. Each case in which a diagnosis was made, detailed below, highlights an important limitation in our current ability to make prenatal diagnoses.

Case 1. A fetus was diagnosed prenatally with arthrogryposis, plagiocephaly, and club feet. After birth, the infant also was found to have generalized muscle weakness, elevated creatine phosphokinase, and congenital hip dislocation.

Reanalysis of the ES data revealed compound heterozygous missense variants in the nebulin gene (NEB). Although classified as variants of uncertain significance (VUS), these are consistent with the phenotype, the authors argued, and with the diagnosis of autosomal recessive nemaline myopathy 2.

Case 2. Prenatal diagnosis was made of a right limb anomaly, tetralogy of Fallot, intrauterine growth restriction, ambiguous genitalia, and dextrocardia. Postnatal evaluation revealed absent pulmonary valve syndrome, right arm dysplasia, pectus carinatum deformity, and failure to thrive.

In this case, ES with the postnatal information revealed a VUS in the NOTCH1 gene, which has been associated with Adams-Oliver syndrome. Although by strict criteria this variant is also of uncertain significance, Adams-Oliver syndrome is characterized, in part, by transverse limb defects and congenital heart disease, as was found in the proband.

Case 3. Prenatal ultrasonography revealed microcephaly and absence of the septum pellucidum. Postnatal magnetic resonance imaging revealed semi-lobar holoprosencephaly. A holoprosencephaly-specific gene panel revealed a deletion in the ZIC2 gene, which is known to cause holoprosencephaly.

Careful re-examination of the ES data revealed some abnormality in the ZIC2 signal, which might have been studied in greater detail and thereby detected if the prenatal diagnosis of holoprosencephaly had been made.

Case 4. An ultrasound evaluation at 12 weeks’ gestation revealed a cystic hygroma, short long bones, and possible absent hand and fibula. A postnatal fetal autopsy at 14 weeks showed split-hand and split-foot malformations, which were not appreciated on ultrasonography.

In filtering the ES data with this information, a pathogenic variant in the PRCN gene was identified as causal, and the diagnosis of Goltz syndrome was made.

Challenges facing  prenatal diagnosis

A case series is inherently limited by its small sample size. Nevertheless, the authors suggest 2 major challenges in our ability to make the above diagnoses in the prenatal setting:
1) the prenatal assessment being limited to major structural abnormalities, and 2) commercial laboratories not having enough experience or volume to interpret the limited information provided by prenatal imaging.

Can AI technology be incorporated to make a genetic diagnosis?

Hsieh TC, Mensah MA, Pantel JT, et al. PEDIA: prioritization of exome data by image analysis. Genet Med. 2019;21:2807-2814.

Increasingly, ES is used in all types of undiagnosed, rare genetic diseases. Although there is a high diagnostic yield in many populations, ES’s clinical utility is limited by the labor-intensive process of interpreting each variant in the context of detailed phenotypic information. The widespread use of HPO would be one step toward standardizing the information that is entered into the analysis of ES data, but even HPO cannot capture certain visual clues.

Hsieh and colleagues attempted to use artificial intelligence (AI) for “next-generation phenotyping” to assess facial dysmorphology and integrate the information into variant classification.⁵ The authors described their approach of incorporating AI as “prioritization of exome data by image analysis” (PEDIA).

Continue to: Designing dysmorphology machine learning...

Designing dysmorphology machine learning

The cohort included 679 individuals with 105 different genetic disorders. All individuals had a previously confirmed molecular diagnosis that would be detected by ES. Each individual had a frontal facial photograph analyzed and detailed clinical features documented in HPO terms extracted by 2 clinicians.

A facial analysis software called DeepGestalt, trained on 17,000 patient images, was used to create a Gestalt score. Each individual had 4 different predicted gene scoring approaches:

• a molecular deleteriousness score
• facial analysis with the Gestalt score
• a combination of molecular deleteriousness score and HPO-based gene-prioritization tool (termed semantic similarity score)
• the PEDIA score, which included all 3 prior approaches.

A type of machine learning algorithm (support vector machine, or SVM) was applied, validated, and used to prioritize genes based on the combined scores.

AI seemed to improve diagnostic accuracy

Utilizing the combination of machine learning, HPO terms, and facial analysis software greatly improved the accuracy of variant classification predictions over any approach alone.

Using only the sequence variant and molecular deleteriousness score, the causative variant was ranked in the top 10 of all identified variants in less than 45% of cases. Adding the HPO-based gene prioritization tools increased the accuracy to 63% to 94%. Use of the PEDIA score, which incorporated all 3, increased the accuracy to 99% for the top 10 ranking.

Even more impressive improvements were made in the top 1 ranking accuracy rate, which went from 36% to 74% without facial image information to 86% to 89% with inclusion of DeepGestalt scores.

Study strengths and limitations

This study’s innovative application of facial analysis and machine learning, combined with HPO-driven variant classification, showed added benefit. To achieve this with available patient photographs and thorough phenotyping, previously diagnosed patients were used. Because complete ES information was not available for those patients, their known pathogenic variant was inserted into randomly selected exomes from the 1000 Genomes Project (healthy individuals). The authors additionally noted that the PEDIA score performance was diminished for rare disorders in which limited data were available. 

As prenatal genetic testing and imaging have advanced, the diagnosis of genetic disorders has moved from the postnatal to the prenatal time frame. This has largely been facilitated by the increasing use of exome sequencing (ES) in the prenatal setting. Two landmark trials published in January 2019 highlighted the overall diagnostic yields of prenatal ES as 8.5% and 10% in fetuses with normal karyotype and microarray.^1,2

Although this is a huge step forward in prenatal diagnosis, ES is currently a manually curated, labor-intensive task. The process involves reviewing thousands of sequence variants for any given sample and prioritizing each variant based on bio­informatic data, prediction models, literature review, and specific patient characteristics. The patient characteristics, or phenotypic information, are critically important in prioritizing candidate variants.

To date, prenatal ES has been limited by the use of inconsistent terminology and the lack of well-understood prenatal phenotypes. In this Update, we highlight how recently published work draws attention to these critical gaps in prenatal diagnosis.

Standardizing phenotyping language in the prenatal setting

Tomar S, Sethi R, Lai PS. Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing. Eur J Hum Genet. 2019;27:1389-1397.

Clinical ES in pediatric and adult populations is enhanced by the use of standardized vocabulary to describe disorders. Standardized language ensures that identified variants are filtered correctly and in a systematic fashion based on the patient characteristics that are provided. One commonly used platform is the Human Phenotype Ontology (HPO).

Tomar and colleagues assessed the impact of HPO-based clinical information on the performance of a gene prioritization tool.³ Gene prioritization (or simulation) tools are used for interpretation of ES data to help analysts efficiently sort through the thousands of variants in an individual’s genetic sequence. The performance, or accuracy, of a prioritization tool can be assessed by looking at the location of the disease-causing gene in the suggested gene list.

Continue to: Cohort of diagnosed patients and gene prioritization...

Cohort of diagnosed patients and gene prioritization

In this experimental model, Tomar and colleagues included 50 cases with neuromuscular disorders; all had available sequencing data, fully described phenotypes, and known causal genes. The authors varied the level of available clinical information in the HPO terms used for simulated variant analysis. Using 3 web-based gene prioritization tools on the 50 cases, they varied the HPO input to include a random selection of 10%, 30%, and 50% of HPO terms derived from deep phenotyping.

The 3 prioritization tools ranked input genes based on gene-phenotype associations that were derived from gene-phenotype databases. The authors then assessed the quality of the candidate gene lists by the location of the known causative gene on the generated rank lists. They repeated this analysis 4 times with different randomly selected HPO terms. 

Inclusion of more HPO terms allowed for more accurate diagnoses in rare disorders

The authors found that the phenotype input for ES matters. When only 10% and 30% of the HPO terms were used to create a candidate gene list, the causative gene was less likely to be in the top portions of gene lists than when 50% or 100% of the available HPO terms were used.

For well-characterized disorders, use of the top 10% HPO terms performed as well as when all available HPO terms were used. For previously undescribed disease-gene associations, identification of the disease gene suffered with more limited HPO term availability.

What this study contributes

This study was a simulation of previously sequenced patients with neuromuscular disorders. It examined a small sample size for a narrow spectrum of disease. However, it clearly illustrated the principle that completeness of phenotypic information for ES pipelines is relevant for interpretation.

Detailed description of prenatal findings is essential to diagnosis

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181.

In a retrospective cohort study, Aarabi and colleagues evaluated the diagnostic utility and limitations of ES in prenatal cases with structural birth defects.⁴

A case series study

The investigators included 20 pregnancies with structural birth defects that were referred to their center for prenatal diagnosis between 12 and 20 weeks’ gestation. All pregnancies had normal karyotype and microarray analyses prior to enrollment.

ES was performed on trio samples, which included fetal and parental DNA samples (extracted from peripheral blood). Reports provided by the commercial laboratories were normal for all cases and included no pathogenic or likely pathogenic variants. The laboratory provided the investigators with the FASTQ (genetic sequence) files for reanalysis, which was performed using both prenatal and postnatal detailed phenotypic information.

Continue to: Use of postnatal information facilitated diagnoses...

Use of postnatal information facilitated diagnoses

Reanalysis of ES data using detailed postnatal findings revealed a possible diagnosis in 20% of cases. Each case in which a diagnosis was made, detailed below, highlights an important limitation in our current ability to make prenatal diagnoses.

Case 1. A fetus was diagnosed prenatally with arthrogryposis, plagiocephaly, and club feet. After birth, the infant also was found to have generalized muscle weakness, elevated creatine phosphokinase, and congenital hip dislocation.

Reanalysis of the ES data revealed compound heterozygous missense variants in the nebulin gene (NEB). Although classified as variants of uncertain significance (VUS), these are consistent with the phenotype, the authors argued, and with the diagnosis of autosomal recessive nemaline myopathy 2.

Case 2. Prenatal diagnosis was made of a right limb anomaly, tetralogy of Fallot, intrauterine growth restriction, ambiguous genitalia, and dextrocardia. Postnatal evaluation revealed absent pulmonary valve syndrome, right arm dysplasia, pectus carinatum deformity, and failure to thrive.

In this case, ES with the postnatal information revealed a VUS in the NOTCH1 gene, which has been associated with Adams-Oliver syndrome. Although by strict criteria this variant is also of uncertain significance, Adams-Oliver syndrome is characterized, in part, by transverse limb defects and congenital heart disease, as was found in the proband.

Case 3. Prenatal ultrasonography revealed microcephaly and absence of the septum pellucidum. Postnatal magnetic resonance imaging revealed semi-lobar holoprosencephaly. A holoprosencephaly-specific gene panel revealed a deletion in the ZIC2 gene, which is known to cause holoprosencephaly.

Careful re-examination of the ES data revealed some abnormality in the ZIC2 signal, which might have been studied in greater detail and thereby detected if the prenatal diagnosis of holoprosencephaly had been made.

Case 4. An ultrasound evaluation at 12 weeks’ gestation revealed a cystic hygroma, short long bones, and possible absent hand and fibula. A postnatal fetal autopsy at 14 weeks showed split-hand and split-foot malformations, which were not appreciated on ultrasonography.

In filtering the ES data with this information, a pathogenic variant in the PRCN gene was identified as causal, and the diagnosis of Goltz syndrome was made.

Challenges facing  prenatal diagnosis

A case series is inherently limited by its small sample size. Nevertheless, the authors suggest 2 major challenges in our ability to make the above diagnoses in the prenatal setting:
1) the prenatal assessment being limited to major structural abnormalities, and 2) commercial laboratories not having enough experience or volume to interpret the limited information provided by prenatal imaging.

Can AI technology be incorporated to make a genetic diagnosis?

Hsieh TC, Mensah MA, Pantel JT, et al. PEDIA: prioritization of exome data by image analysis. Genet Med. 2019;21:2807-2814.

Increasingly, ES is used in all types of undiagnosed, rare genetic diseases. Although there is a high diagnostic yield in many populations, ES’s clinical utility is limited by the labor-intensive process of interpreting each variant in the context of detailed phenotypic information. The widespread use of HPO would be one step toward standardizing the information that is entered into the analysis of ES data, but even HPO cannot capture certain visual clues.

Hsieh and colleagues attempted to use artificial intelligence (AI) for “next-generation phenotyping” to assess facial dysmorphology and integrate the information into variant classification.⁵ The authors described their approach of incorporating AI as “prioritization of exome data by image analysis” (PEDIA).

Continue to: Designing dysmorphology machine learning...

Designing dysmorphology machine learning

The cohort included 679 individuals with 105 different genetic disorders. All individuals had a previously confirmed molecular diagnosis that would be detected by ES. Each individual had a frontal facial photograph analyzed and detailed clinical features documented in HPO terms extracted by 2 clinicians.

A facial analysis software called DeepGestalt, trained on 17,000 patient images, was used to create a Gestalt score. Each individual had 4 different predicted gene scoring approaches:

• a molecular deleteriousness score
• facial analysis with the Gestalt score
• a combination of molecular deleteriousness score and HPO-based gene-prioritization tool (termed semantic similarity score)
• the PEDIA score, which included all 3 prior approaches.

A type of machine learning algorithm (support vector machine, or SVM) was applied, validated, and used to prioritize genes based on the combined scores.

AI seemed to improve diagnostic accuracy

Utilizing the combination of machine learning, HPO terms, and facial analysis software greatly improved the accuracy of variant classification predictions over any approach alone.

Using only the sequence variant and molecular deleteriousness score, the causative variant was ranked in the top 10 of all identified variants in less than 45% of cases. Adding the HPO-based gene prioritization tools increased the accuracy to 63% to 94%. Use of the PEDIA score, which incorporated all 3, increased the accuracy to 99% for the top 10 ranking.

Even more impressive improvements were made in the top 1 ranking accuracy rate, which went from 36% to 74% without facial image information to 86% to 89% with inclusion of DeepGestalt scores.

Study strengths and limitations

This study’s innovative application of facial analysis and machine learning, combined with HPO-driven variant classification, showed added benefit. To achieve this with available patient photographs and thorough phenotyping, previously diagnosed patients were used. Because complete ES information was not available for those patients, their known pathogenic variant was inserted into randomly selected exomes from the 1000 Genomes Project (healthy individuals). The authors additionally noted that the PEDIA score performance was diminished for rare disorders in which limited data were available. 

Researchers have been studying the use of exogenous progestins for prevention of preterm delivery (PTD) for almost 60 years, but conflicting results contribute to an ongoing debate. Interpretation of the available data is particularly difficult because different forms and doses of progestins have been used in disparate study populations.

Based on available data, progesterone supplementation is not effective as a primary prevention strategy for PTD in the general low-risk obstetric population. PTD is a complex problem with varied and incompletely elucidated pathogenic pathways, making it unlikely that one interventional approach would be effective for all pregnant women. As a result, emerging indications for the use of progesterone are based on risk factors for PTD (ie, prior PTD and/or short cervix). However, this secondary prevention approach is a limiting factor in itself because 50% of women destined to have a PTD have no identifiable risk factors.¹ In addition, researchers have found that progestins are ineffective at delaying delivery for women with multiple gestation, suggesting that a distinct underlying mechanism of early parturition is present in these women, and that this mechanism is unresponsive to progestins.²

The formulations used in the study of progestin supplementation for PTD prevention have been almost exclusively either the synthetic 17 alpha-hydroxyprogesterone caproate (17-OHPC) or natural progesterone administered orally or vaginally. In 2003, the American College of Obstetricians and Gynecologists (ACOG) supported the use of progesterone to reduce the rate of PTD,³ and in 2011, the US Food and Drug Administration (FDA) approved 17-OHPC for use as prophylaxis against recurrent PTD. As a result, in recent years, the perceived standard of care for a majority of practitioners in the United States had been that all women with a previous preterm birth should be offered 17-OHPC. It may be interesting to note that in other parts of the world, the same enthusiastic adoption did not occur. For example, in Australia and New Zealand in 2007, only 5% of practitioners were using progesterone for this indication.⁴ Further, 17-OHPC is not recommended by professional guidelines in the United Kingdom and has remained unavailable in Germany.

The publication in 2019 of the PROLONG trial called into question the use of 17-OHPC for the prevention of PTD.⁵ In the December 2019 issue of OBG Management (“Managing preterm birth in those at risk: Expert strategies”), I expressed the opinion that with only rare exceptions, 17-OHPC is no longer a viable option for recurrent PTD prevention.⁶ In light of these developments, what scientific evidence is relevant and applicable to the care of women at risk for PTD?

Continue to: Case 1 Previous spontaneous PTD at 31 weeks...

Case 1 Previous spontaneous PTD at 31 weeks

MC is an asymptomatic 32-year-old woman with a singleton pregnancy at 13 weeks’ gestation. You see her for a maternal-fetal medicine consultation because 2 years ago she had a spontaneous PTD at 31 weeks’ gestation. What management recommendations can you make to decrease her risk of recurrent PTD?

Cervical length measurement narrows in on risk

The indication “previous preterm birth” is largely meaningless because of the heterogeneity in preterm birth pathways (preterm birth as a syndrome⁷) and inadequate risk characterization. Among women who experience a spontaneous PTD, 70% to 80% do not deliver prematurely in subsequent pregnancies.⁸ To better characterize the risk of PTD recurrence, ultrasound assessment of cervical length should be used. Research has shown that among women with a prior spontaneous PTD who maintain a normal cervical length until 24 weeks’ gestation, more than 90% will deliver at 35 weeks or after without intervention.⁹ Such an approach not only identifies the subgroup of women at significantly increased risk of recurrence but also eliminates unnecessary interventions.

Cervical ultrasound surveillance should be initiated at 16 weeks’ gestation. A short cervix before 16 weeks is not associated with a statistically significant increase in risk for PTD.¹⁰ Shortening of the cervix begins approximately 10 weeks before delivery in any gestational age group.¹¹ Therefore, ultrasound assessment of the cervix at 28 weeks and after is irrelevant. In addition, after 28 weeks, cervical length varies greatly leading to loss in the predictive power of the cervical measurement.¹² Based on these considerations, cervical surveillance may be extended up to 26 weeks. Although cervical cerclage is not an option in the United States in cases in which a short cervix is detected between 24 and 26 weeks, vaginal progesterone supplementation may still be considered.

Case 1 Continued

MC was started on ultrasound cervical surveillance at 16 weeks’ gestation. Her cervical length was initially normal (> 2.5 cm), but at 18 weeks the measurement was 2.2 cm. What is your recommendation?

The value of vaginal progesterone

There appears to be increasing consensus on the value of vaginal progesterone for women with a midtrimester short cervix on sonography, with or without a history of PTD. An individual patient data meta-analysis demonstrated the benefits of vaginal progesterone.¹³ Although there was no evidence of an effect on PTD at less than 37 weeks, the rates of PTD at less than 36 weeks and spontaneous PTD at less than 34 weeks were significantly reduced (by 20% and 28%, respectively). Also, there was a significant reduction in the risk of respiratory distress syndrome (53%) and composite neonatal morbidity and mortality (41%), with no significant impact on infant development up to the second year of life.¹³

The lack of generalizable evidence of benefit on childhood outcomes, combined with considerable uncertainty about the exact role and mechanism of action of exogenous progestins, contribute to the ongoing debate. Vaginal progesterone dosage regimens have been based on extrapolations from experience with progesterone in nonpregnant women, and recent pharmacokinetic studies have revealed how precarious such extrapolations may be. As an example, in nonpregnant women, the bioavailability of oral and vaginal progesterone is similar.¹⁴ In pregnancy, however, while daily oral progesterone doubles a pregnant woman’s serum progesterone level,¹⁵ daily vaginal administration of progesterone results in only a modest rise in serum progesterone, with a coefficient of variation among individuals that is double that outside of pregnancy.¹⁶ It is, therefore, considered that vaginal progesterone in pregnancy may have a local action secondary to the uterine first-pass effect. The uterine first-pass effect for vaginal progesterone was described in nonpregnant women and is only assumed to occur in pregnancy as well. ¹⁷

After evaluating the data from the largest available study of vaginal progesterone,¹⁸ the FDA concluded in 2012 that the study did not meet the statistical significance generally expected to support the approval of a new product. However, according to a more comprehensive evidence review developed in 2019 by the National Guideline Alliance in the United Kingdom, women with a history of PTD and women with a short cervix derive an important benefit from the use of vaginal progesterone; thus, this intervention should be offered to them.¹⁹ At this time, a short cervix and PTD prevention are not considered FDA-approved indications for progesterone supplementation in pregnancy. However, vaginal progesterone is FDA approved for use in pregnant women with a history of infertility.

Continue to: Case 1 Continued...

Case 1 Continued

MC initiated treatment with daily vaginal progesterone at 18 weeks’ gestation and returned for ultrasound cervical length examination weekly instead of every other week. At 20 weeks’ gestation, cervical length was 2.0 cm; the following week it was 1.4 cm. What would you recommend at this point?

When to consider cerclage

If cervical shortening progresses to about 1.5 cm while a woman is being treated with vaginal progesterone, cerclage may be considered. The benefit of cerclage in patients with prior PTD and a short cervix was highlighted in a 2018 Cochrane Review.²⁰ In this stepwise management approach to a short cervix, waiting for a cervix to be less than 1.5 cm may be unadvisable. Under conditions of a very short cervix that is frequently dilated with exposure of fetal membranes, ascending subclinical intra-amniotic infection may already be present, reducing the efficacy of any preventive measures. Preferential consideration for cerclage from the start over initial vaginal progesterone also may be appropriate when there is a history of 2 spontaneous PTDs or mid-trimester losses, a history of a successful cerclage, or with a very short cervix (< 1.0 cm) at the initial evaluation. As for the latter, a 2018 individual patient data meta-analysis of vaginal progesterone found no benefit when the cervix was less than 1.0 cm.¹³

Progesterone plus cerclage likely to add benefit

The results of an adjusted indirect comparison meta-analysis suggest that both interventions—vaginal progesterone and cerclage—are equally effective.²¹ Assuming that there is no clinically meaningful difference in benefit associated with these 2 treatments, the next logical question is whether combining the 2 therapies provides any added benefit; limited observational data seem to suggest that it does. In a retrospective cohort of 86 consecutive singleton pregnancies among women who underwent ultrasound-indicated cerclage, those who used vaginal progesterone after cerclage (n = 45) had a lower rate of PTD.²² Also, a small (66 cases) case-control study demonstrated the benefit of administration of vaginal progesterone as a rescue intervention in women with cerclage and progressive cervical shortening despite cerclage.²³

Case 2 Woman experiences adverse effects from vaginal progesterone

MS is a 25-year-old G2P0101 who was started on vaginal progesterone as prophylaxis for recurrent PTD. She is now at 20 weeks’ gestation, with a stable remnant cervical length of 2.0 cm. She is reporting an increasing vaginal burning sensation and vaginal discharge caused by the nightly vaginal progesterone applications, to the point that she is unwilling to continue the treatment. She asks if any alternatives to vaginal progesterone are available to decrease her risk of PTD.

Continue to: Is oral progesterone an option?...

Is oral progesterone an option?

In the 1980s and 1990s, oral micronized progesterone was widely used in France at doses of 900 to 1,200 mg/d for women at risk for PTD. The practice was stopped when secondary hepatic effects, including cholestasis of pregnancy, were reported at a higher rate in treated women.²⁴ A rise in the serum concentration of progesterone metabolites has been associated with impaired biliary excretion and subsequent accumulation of bile acids.²⁵ In other reports, elevated serum transaminase activity was found in pregnant women treated with oral micronized progesterone, and withdrawal of treatment frequently has led to improvement in transaminase levels.²⁶ The synthesis of endogenous progesterone during normal pregnancy is between 250 and 500 mg/d,²⁶ and experts have expressed concern that exogenous progesterone supplementation may impose an additional load on the hepatic transport of sulfated metabolites. Unlike orally administered progesterone, progestins given by the vaginal route avoid the hepatic first-pass effect. For this reason, they may be associated with less hepatic dysfunction.

Although not recommended by professional guidelines, oral progesterone administration for the prevention of PTD has been used in the United States. A 2015 survey of Wisconsin prenatal care providers found that of those who prescribed any progesterone for PTD prevention, oral progesterone was prescribed by 13.1% of obstetricians, 24.4% of midwives, and 40.7% of family medicine practitioners.²⁷

Some limited recent evidence from a meta-analysis of 3 trials investigating oral progesterone versus placebo suggests effectiveness in the prevention of recurrent PTD and reduction in perinatal morbidity and mortality.¹⁵ However, the number of cases included in the meta-analysis (386) was too small to support definitive clinical recommendations. Furthermore, questions have been raised in the literature about the reliability of the largest trial included in that meta-analysis.²⁸

Case 3 Two previous spontaneous PTDs

A 29-year-old G3P0201 presents for her first prenatal appointment at 10 weeks’ gestation. With her first pregnancy she had a spontaneous PTD at 23 weeks, and the neonate did not survive. In her second pregnancy, she was treated with 17-OHPC from 16 weeks’ gestation. She had a spontaneous PTD at 29 weeks, and that child is developing normally by her report. She believes that 17-OHPC helped her in her last pregnancy and is anxious about the risk for still another PTD. Consistent with the concept of shared decision-making, you inform her of the results of the recent PROLONG trial and statements on the subject released by professional organizations such as ACOG and the Society for Maternal-Fetal Medicine (SMFM). What options does she have?

17-OHPC may be a possibility in very high-risk women

According to a SMFM statement released in the wake of the PROLONG trial publication, “. . . SMFM believes that it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial”.²⁹ Only a few women will have a recurrence risk of PTD over 50%, as was the background event rate in the Meis trial.³⁰ Such a risk level may be suspected, as an example, in women with 2 or more prior early (before 34 weeks) PTDs without intervening term deliveries. Even in those cases, if treatment with 17-OHPC is decided upon, ultrasound cervical surveillance should be added as an additional safety measure. ●

Researchers have been studying the use of exogenous progestins for prevention of preterm delivery (PTD) for almost 60 years, but conflicting results contribute to an ongoing debate. Interpretation of the available data is particularly difficult because different forms and doses of progestins have been used in disparate study populations.

Based on available data, progesterone supplementation is not effective as a primary prevention strategy for PTD in the general low-risk obstetric population. PTD is a complex problem with varied and incompletely elucidated pathogenic pathways, making it unlikely that one interventional approach would be effective for all pregnant women. As a result, emerging indications for the use of progesterone are based on risk factors for PTD (ie, prior PTD and/or short cervix). However, this secondary prevention approach is a limiting factor in itself because 50% of women destined to have a PTD have no identifiable risk factors.¹ In addition, researchers have found that progestins are ineffective at delaying delivery for women with multiple gestation, suggesting that a distinct underlying mechanism of early parturition is present in these women, and that this mechanism is unresponsive to progestins.²

The formulations used in the study of progestin supplementation for PTD prevention have been almost exclusively either the synthetic 17 alpha-hydroxyprogesterone caproate (17-OHPC) or natural progesterone administered orally or vaginally. In 2003, the American College of Obstetricians and Gynecologists (ACOG) supported the use of progesterone to reduce the rate of PTD,³ and in 2011, the US Food and Drug Administration (FDA) approved 17-OHPC for use as prophylaxis against recurrent PTD. As a result, in recent years, the perceived standard of care for a majority of practitioners in the United States had been that all women with a previous preterm birth should be offered 17-OHPC. It may be interesting to note that in other parts of the world, the same enthusiastic adoption did not occur. For example, in Australia and New Zealand in 2007, only 5% of practitioners were using progesterone for this indication.⁴ Further, 17-OHPC is not recommended by professional guidelines in the United Kingdom and has remained unavailable in Germany.

The publication in 2019 of the PROLONG trial called into question the use of 17-OHPC for the prevention of PTD.⁵ In the December 2019 issue of OBG Management (“Managing preterm birth in those at risk: Expert strategies”), I expressed the opinion that with only rare exceptions, 17-OHPC is no longer a viable option for recurrent PTD prevention.⁶ In light of these developments, what scientific evidence is relevant and applicable to the care of women at risk for PTD?

Continue to: Case 1 Previous spontaneous PTD at 31 weeks...

Case 1 Previous spontaneous PTD at 31 weeks

MC is an asymptomatic 32-year-old woman with a singleton pregnancy at 13 weeks’ gestation. You see her for a maternal-fetal medicine consultation because 2 years ago she had a spontaneous PTD at 31 weeks’ gestation. What management recommendations can you make to decrease her risk of recurrent PTD?

Cervical length measurement narrows in on risk

The indication “previous preterm birth” is largely meaningless because of the heterogeneity in preterm birth pathways (preterm birth as a syndrome⁷) and inadequate risk characterization. Among women who experience a spontaneous PTD, 70% to 80% do not deliver prematurely in subsequent pregnancies.⁸ To better characterize the risk of PTD recurrence, ultrasound assessment of cervical length should be used. Research has shown that among women with a prior spontaneous PTD who maintain a normal cervical length until 24 weeks’ gestation, more than 90% will deliver at 35 weeks or after without intervention.⁹ Such an approach not only identifies the subgroup of women at significantly increased risk of recurrence but also eliminates unnecessary interventions.

Cervical ultrasound surveillance should be initiated at 16 weeks’ gestation. A short cervix before 16 weeks is not associated with a statistically significant increase in risk for PTD.¹⁰ Shortening of the cervix begins approximately 10 weeks before delivery in any gestational age group.¹¹ Therefore, ultrasound assessment of the cervix at 28 weeks and after is irrelevant. In addition, after 28 weeks, cervical length varies greatly leading to loss in the predictive power of the cervical measurement.¹² Based on these considerations, cervical surveillance may be extended up to 26 weeks. Although cervical cerclage is not an option in the United States in cases in which a short cervix is detected between 24 and 26 weeks, vaginal progesterone supplementation may still be considered.

Case 1 Continued

MC was started on ultrasound cervical surveillance at 16 weeks’ gestation. Her cervical length was initially normal (> 2.5 cm), but at 18 weeks the measurement was 2.2 cm. What is your recommendation?

The value of vaginal progesterone

There appears to be increasing consensus on the value of vaginal progesterone for women with a midtrimester short cervix on sonography, with or without a history of PTD. An individual patient data meta-analysis demonstrated the benefits of vaginal progesterone.¹³ Although there was no evidence of an effect on PTD at less than 37 weeks, the rates of PTD at less than 36 weeks and spontaneous PTD at less than 34 weeks were significantly reduced (by 20% and 28%, respectively). Also, there was a significant reduction in the risk of respiratory distress syndrome (53%) and composite neonatal morbidity and mortality (41%), with no significant impact on infant development up to the second year of life.¹³

The lack of generalizable evidence of benefit on childhood outcomes, combined with considerable uncertainty about the exact role and mechanism of action of exogenous progestins, contribute to the ongoing debate. Vaginal progesterone dosage regimens have been based on extrapolations from experience with progesterone in nonpregnant women, and recent pharmacokinetic studies have revealed how precarious such extrapolations may be. As an example, in nonpregnant women, the bioavailability of oral and vaginal progesterone is similar.¹⁴ In pregnancy, however, while daily oral progesterone doubles a pregnant woman’s serum progesterone level,¹⁵ daily vaginal administration of progesterone results in only a modest rise in serum progesterone, with a coefficient of variation among individuals that is double that outside of pregnancy.¹⁶ It is, therefore, considered that vaginal progesterone in pregnancy may have a local action secondary to the uterine first-pass effect. The uterine first-pass effect for vaginal progesterone was described in nonpregnant women and is only assumed to occur in pregnancy as well. ¹⁷

After evaluating the data from the largest available study of vaginal progesterone,¹⁸ the FDA concluded in 2012 that the study did not meet the statistical significance generally expected to support the approval of a new product. However, according to a more comprehensive evidence review developed in 2019 by the National Guideline Alliance in the United Kingdom, women with a history of PTD and women with a short cervix derive an important benefit from the use of vaginal progesterone; thus, this intervention should be offered to them.¹⁹ At this time, a short cervix and PTD prevention are not considered FDA-approved indications for progesterone supplementation in pregnancy. However, vaginal progesterone is FDA approved for use in pregnant women with a history of infertility.

Continue to: Case 1 Continued...

Case 1 Continued

MC initiated treatment with daily vaginal progesterone at 18 weeks’ gestation and returned for ultrasound cervical length examination weekly instead of every other week. At 20 weeks’ gestation, cervical length was 2.0 cm; the following week it was 1.4 cm. What would you recommend at this point?

When to consider cerclage

If cervical shortening progresses to about 1.5 cm while a woman is being treated with vaginal progesterone, cerclage may be considered. The benefit of cerclage in patients with prior PTD and a short cervix was highlighted in a 2018 Cochrane Review.²⁰ In this stepwise management approach to a short cervix, waiting for a cervix to be less than 1.5 cm may be unadvisable. Under conditions of a very short cervix that is frequently dilated with exposure of fetal membranes, ascending subclinical intra-amniotic infection may already be present, reducing the efficacy of any preventive measures. Preferential consideration for cerclage from the start over initial vaginal progesterone also may be appropriate when there is a history of 2 spontaneous PTDs or mid-trimester losses, a history of a successful cerclage, or with a very short cervix (< 1.0 cm) at the initial evaluation. As for the latter, a 2018 individual patient data meta-analysis of vaginal progesterone found no benefit when the cervix was less than 1.0 cm.¹³

Progesterone plus cerclage likely to add benefit

The results of an adjusted indirect comparison meta-analysis suggest that both interventions—vaginal progesterone and cerclage—are equally effective.²¹ Assuming that there is no clinically meaningful difference in benefit associated with these 2 treatments, the next logical question is whether combining the 2 therapies provides any added benefit; limited observational data seem to suggest that it does. In a retrospective cohort of 86 consecutive singleton pregnancies among women who underwent ultrasound-indicated cerclage, those who used vaginal progesterone after cerclage (n = 45) had a lower rate of PTD.²² Also, a small (66 cases) case-control study demonstrated the benefit of administration of vaginal progesterone as a rescue intervention in women with cerclage and progressive cervical shortening despite cerclage.²³

Case 2 Woman experiences adverse effects from vaginal progesterone

MS is a 25-year-old G2P0101 who was started on vaginal progesterone as prophylaxis for recurrent PTD. She is now at 20 weeks’ gestation, with a stable remnant cervical length of 2.0 cm. She is reporting an increasing vaginal burning sensation and vaginal discharge caused by the nightly vaginal progesterone applications, to the point that she is unwilling to continue the treatment. She asks if any alternatives to vaginal progesterone are available to decrease her risk of PTD.

Continue to: Is oral progesterone an option?...

Is oral progesterone an option?

In the 1980s and 1990s, oral micronized progesterone was widely used in France at doses of 900 to 1,200 mg/d for women at risk for PTD. The practice was stopped when secondary hepatic effects, including cholestasis of pregnancy, were reported at a higher rate in treated women.²⁴ A rise in the serum concentration of progesterone metabolites has been associated with impaired biliary excretion and subsequent accumulation of bile acids.²⁵ In other reports, elevated serum transaminase activity was found in pregnant women treated with oral micronized progesterone, and withdrawal of treatment frequently has led to improvement in transaminase levels.²⁶ The synthesis of endogenous progesterone during normal pregnancy is between 250 and 500 mg/d,²⁶ and experts have expressed concern that exogenous progesterone supplementation may impose an additional load on the hepatic transport of sulfated metabolites. Unlike orally administered progesterone, progestins given by the vaginal route avoid the hepatic first-pass effect. For this reason, they may be associated with less hepatic dysfunction.

Although not recommended by professional guidelines, oral progesterone administration for the prevention of PTD has been used in the United States. A 2015 survey of Wisconsin prenatal care providers found that of those who prescribed any progesterone for PTD prevention, oral progesterone was prescribed by 13.1% of obstetricians, 24.4% of midwives, and 40.7% of family medicine practitioners.²⁷

Some limited recent evidence from a meta-analysis of 3 trials investigating oral progesterone versus placebo suggests effectiveness in the prevention of recurrent PTD and reduction in perinatal morbidity and mortality.¹⁵ However, the number of cases included in the meta-analysis (386) was too small to support definitive clinical recommendations. Furthermore, questions have been raised in the literature about the reliability of the largest trial included in that meta-analysis.²⁸

Case 3 Two previous spontaneous PTDs

A 29-year-old G3P0201 presents for her first prenatal appointment at 10 weeks’ gestation. With her first pregnancy she had a spontaneous PTD at 23 weeks, and the neonate did not survive. In her second pregnancy, she was treated with 17-OHPC from 16 weeks’ gestation. She had a spontaneous PTD at 29 weeks, and that child is developing normally by her report. She believes that 17-OHPC helped her in her last pregnancy and is anxious about the risk for still another PTD. Consistent with the concept of shared decision-making, you inform her of the results of the recent PROLONG trial and statements on the subject released by professional organizations such as ACOG and the Society for Maternal-Fetal Medicine (SMFM). What options does she have?

17-OHPC may be a possibility in very high-risk women

According to a SMFM statement released in the wake of the PROLONG trial publication, “. . . SMFM believes that it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial”.²⁹ Only a few women will have a recurrence risk of PTD over 50%, as was the background event rate in the Meis trial.³⁰ Such a risk level may be suspected, as an example, in women with 2 or more prior early (before 34 weeks) PTDs without intervening term deliveries. Even in those cases, if treatment with 17-OHPC is decided upon, ultrasound cervical surveillance should be added as an additional safety measure. ●

Researchers have been studying the use of exogenous progestins for prevention of preterm delivery (PTD) for almost 60 years, but conflicting results contribute to an ongoing debate. Interpretation of the available data is particularly difficult because different forms and doses of progestins have been used in disparate study populations.

Based on available data, progesterone supplementation is not effective as a primary prevention strategy for PTD in the general low-risk obstetric population. PTD is a complex problem with varied and incompletely elucidated pathogenic pathways, making it unlikely that one interventional approach would be effective for all pregnant women. As a result, emerging indications for the use of progesterone are based on risk factors for PTD (ie, prior PTD and/or short cervix). However, this secondary prevention approach is a limiting factor in itself because 50% of women destined to have a PTD have no identifiable risk factors.¹ In addition, researchers have found that progestins are ineffective at delaying delivery for women with multiple gestation, suggesting that a distinct underlying mechanism of early parturition is present in these women, and that this mechanism is unresponsive to progestins.²

The formulations used in the study of progestin supplementation for PTD prevention have been almost exclusively either the synthetic 17 alpha-hydroxyprogesterone caproate (17-OHPC) or natural progesterone administered orally or vaginally. In 2003, the American College of Obstetricians and Gynecologists (ACOG) supported the use of progesterone to reduce the rate of PTD,³ and in 2011, the US Food and Drug Administration (FDA) approved 17-OHPC for use as prophylaxis against recurrent PTD. As a result, in recent years, the perceived standard of care for a majority of practitioners in the United States had been that all women with a previous preterm birth should be offered 17-OHPC. It may be interesting to note that in other parts of the world, the same enthusiastic adoption did not occur. For example, in Australia and New Zealand in 2007, only 5% of practitioners were using progesterone for this indication.⁴ Further, 17-OHPC is not recommended by professional guidelines in the United Kingdom and has remained unavailable in Germany.

The publication in 2019 of the PROLONG trial called into question the use of 17-OHPC for the prevention of PTD.⁵ In the December 2019 issue of OBG Management (“Managing preterm birth in those at risk: Expert strategies”), I expressed the opinion that with only rare exceptions, 17-OHPC is no longer a viable option for recurrent PTD prevention.⁶ In light of these developments, what scientific evidence is relevant and applicable to the care of women at risk for PTD?

Continue to: Case 1 Previous spontaneous PTD at 31 weeks...

Case 1 Previous spontaneous PTD at 31 weeks

MC is an asymptomatic 32-year-old woman with a singleton pregnancy at 13 weeks’ gestation. You see her for a maternal-fetal medicine consultation because 2 years ago she had a spontaneous PTD at 31 weeks’ gestation. What management recommendations can you make to decrease her risk of recurrent PTD?

Cervical length measurement narrows in on risk

The indication “previous preterm birth” is largely meaningless because of the heterogeneity in preterm birth pathways (preterm birth as a syndrome⁷) and inadequate risk characterization. Among women who experience a spontaneous PTD, 70% to 80% do not deliver prematurely in subsequent pregnancies.⁸ To better characterize the risk of PTD recurrence, ultrasound assessment of cervical length should be used. Research has shown that among women with a prior spontaneous PTD who maintain a normal cervical length until 24 weeks’ gestation, more than 90% will deliver at 35 weeks or after without intervention.⁹ Such an approach not only identifies the subgroup of women at significantly increased risk of recurrence but also eliminates unnecessary interventions.

Cervical ultrasound surveillance should be initiated at 16 weeks’ gestation. A short cervix before 16 weeks is not associated with a statistically significant increase in risk for PTD.¹⁰ Shortening of the cervix begins approximately 10 weeks before delivery in any gestational age group.¹¹ Therefore, ultrasound assessment of the cervix at 28 weeks and after is irrelevant. In addition, after 28 weeks, cervical length varies greatly leading to loss in the predictive power of the cervical measurement.¹² Based on these considerations, cervical surveillance may be extended up to 26 weeks. Although cervical cerclage is not an option in the United States in cases in which a short cervix is detected between 24 and 26 weeks, vaginal progesterone supplementation may still be considered.

Case 1 Continued

MC was started on ultrasound cervical surveillance at 16 weeks’ gestation. Her cervical length was initially normal (> 2.5 cm), but at 18 weeks the measurement was 2.2 cm. What is your recommendation?

The value of vaginal progesterone

There appears to be increasing consensus on the value of vaginal progesterone for women with a midtrimester short cervix on sonography, with or without a history of PTD. An individual patient data meta-analysis demonstrated the benefits of vaginal progesterone.¹³ Although there was no evidence of an effect on PTD at less than 37 weeks, the rates of PTD at less than 36 weeks and spontaneous PTD at less than 34 weeks were significantly reduced (by 20% and 28%, respectively). Also, there was a significant reduction in the risk of respiratory distress syndrome (53%) and composite neonatal morbidity and mortality (41%), with no significant impact on infant development up to the second year of life.¹³

The lack of generalizable evidence of benefit on childhood outcomes, combined with considerable uncertainty about the exact role and mechanism of action of exogenous progestins, contribute to the ongoing debate. Vaginal progesterone dosage regimens have been based on extrapolations from experience with progesterone in nonpregnant women, and recent pharmacokinetic studies have revealed how precarious such extrapolations may be. As an example, in nonpregnant women, the bioavailability of oral and vaginal progesterone is similar.¹⁴ In pregnancy, however, while daily oral progesterone doubles a pregnant woman’s serum progesterone level,¹⁵ daily vaginal administration of progesterone results in only a modest rise in serum progesterone, with a coefficient of variation among individuals that is double that outside of pregnancy.¹⁶ It is, therefore, considered that vaginal progesterone in pregnancy may have a local action secondary to the uterine first-pass effect. The uterine first-pass effect for vaginal progesterone was described in nonpregnant women and is only assumed to occur in pregnancy as well. ¹⁷

After evaluating the data from the largest available study of vaginal progesterone,¹⁸ the FDA concluded in 2012 that the study did not meet the statistical significance generally expected to support the approval of a new product. However, according to a more comprehensive evidence review developed in 2019 by the National Guideline Alliance in the United Kingdom, women with a history of PTD and women with a short cervix derive an important benefit from the use of vaginal progesterone; thus, this intervention should be offered to them.¹⁹ At this time, a short cervix and PTD prevention are not considered FDA-approved indications for progesterone supplementation in pregnancy. However, vaginal progesterone is FDA approved for use in pregnant women with a history of infertility.

Continue to: Case 1 Continued...

Case 1 Continued

MC initiated treatment with daily vaginal progesterone at 18 weeks’ gestation and returned for ultrasound cervical length examination weekly instead of every other week. At 20 weeks’ gestation, cervical length was 2.0 cm; the following week it was 1.4 cm. What would you recommend at this point?

When to consider cerclage

If cervical shortening progresses to about 1.5 cm while a woman is being treated with vaginal progesterone, cerclage may be considered. The benefit of cerclage in patients with prior PTD and a short cervix was highlighted in a 2018 Cochrane Review.²⁰ In this stepwise management approach to a short cervix, waiting for a cervix to be less than 1.5 cm may be unadvisable. Under conditions of a very short cervix that is frequently dilated with exposure of fetal membranes, ascending subclinical intra-amniotic infection may already be present, reducing the efficacy of any preventive measures. Preferential consideration for cerclage from the start over initial vaginal progesterone also may be appropriate when there is a history of 2 spontaneous PTDs or mid-trimester losses, a history of a successful cerclage, or with a very short cervix (< 1.0 cm) at the initial evaluation. As for the latter, a 2018 individual patient data meta-analysis of vaginal progesterone found no benefit when the cervix was less than 1.0 cm.¹³

Progesterone plus cerclage likely to add benefit

The results of an adjusted indirect comparison meta-analysis suggest that both interventions—vaginal progesterone and cerclage—are equally effective.²¹ Assuming that there is no clinically meaningful difference in benefit associated with these 2 treatments, the next logical question is whether combining the 2 therapies provides any added benefit; limited observational data seem to suggest that it does. In a retrospective cohort of 86 consecutive singleton pregnancies among women who underwent ultrasound-indicated cerclage, those who used vaginal progesterone after cerclage (n = 45) had a lower rate of PTD.²² Also, a small (66 cases) case-control study demonstrated the benefit of administration of vaginal progesterone as a rescue intervention in women with cerclage and progressive cervical shortening despite cerclage.²³

Case 2 Woman experiences adverse effects from vaginal progesterone

MS is a 25-year-old G2P0101 who was started on vaginal progesterone as prophylaxis for recurrent PTD. She is now at 20 weeks’ gestation, with a stable remnant cervical length of 2.0 cm. She is reporting an increasing vaginal burning sensation and vaginal discharge caused by the nightly vaginal progesterone applications, to the point that she is unwilling to continue the treatment. She asks if any alternatives to vaginal progesterone are available to decrease her risk of PTD.

Continue to: Is oral progesterone an option?...

Is oral progesterone an option?

In the 1980s and 1990s, oral micronized progesterone was widely used in France at doses of 900 to 1,200 mg/d for women at risk for PTD. The practice was stopped when secondary hepatic effects, including cholestasis of pregnancy, were reported at a higher rate in treated women.²⁴ A rise in the serum concentration of progesterone metabolites has been associated with impaired biliary excretion and subsequent accumulation of bile acids.²⁵ In other reports, elevated serum transaminase activity was found in pregnant women treated with oral micronized progesterone, and withdrawal of treatment frequently has led to improvement in transaminase levels.²⁶ The synthesis of endogenous progesterone during normal pregnancy is between 250 and 500 mg/d,²⁶ and experts have expressed concern that exogenous progesterone supplementation may impose an additional load on the hepatic transport of sulfated metabolites. Unlike orally administered progesterone, progestins given by the vaginal route avoid the hepatic first-pass effect. For this reason, they may be associated with less hepatic dysfunction.

Although not recommended by professional guidelines, oral progesterone administration for the prevention of PTD has been used in the United States. A 2015 survey of Wisconsin prenatal care providers found that of those who prescribed any progesterone for PTD prevention, oral progesterone was prescribed by 13.1% of obstetricians, 24.4% of midwives, and 40.7% of family medicine practitioners.²⁷

Some limited recent evidence from a meta-analysis of 3 trials investigating oral progesterone versus placebo suggests effectiveness in the prevention of recurrent PTD and reduction in perinatal morbidity and mortality.¹⁵ However, the number of cases included in the meta-analysis (386) was too small to support definitive clinical recommendations. Furthermore, questions have been raised in the literature about the reliability of the largest trial included in that meta-analysis.²⁸

Case 3 Two previous spontaneous PTDs

A 29-year-old G3P0201 presents for her first prenatal appointment at 10 weeks’ gestation. With her first pregnancy she had a spontaneous PTD at 23 weeks, and the neonate did not survive. In her second pregnancy, she was treated with 17-OHPC from 16 weeks’ gestation. She had a spontaneous PTD at 29 weeks, and that child is developing normally by her report. She believes that 17-OHPC helped her in her last pregnancy and is anxious about the risk for still another PTD. Consistent with the concept of shared decision-making, you inform her of the results of the recent PROLONG trial and statements on the subject released by professional organizations such as ACOG and the Society for Maternal-Fetal Medicine (SMFM). What options does she have?

17-OHPC may be a possibility in very high-risk women

According to a SMFM statement released in the wake of the PROLONG trial publication, “. . . SMFM believes that it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial”.²⁹ Only a few women will have a recurrence risk of PTD over 50%, as was the background event rate in the Meis trial.³⁰ Such a risk level may be suspected, as an example, in women with 2 or more prior early (before 34 weeks) PTDs without intervening term deliveries. Even in those cases, if treatment with 17-OHPC is decided upon, ultrasound cervical surveillance should be added as an additional safety measure. ●

The rapid spread of COVID-19 forced Seemal Desai, MD, to make an excruciating choice; he could either shutter his busy dermatology practice in Plano, Tex., or switch most patient consults to telemedicine, which he’d never used.

But as soon as he learned that telehealth regulations had been relaxed by the Centers for Medicare & Medicaid Services and that reimbursement had been broadened, Dr. Desai, a dermatologist in private practice and his staff began to mobilize.

“Kaboom! We made the decision to start doing it,” he said in an interview. “We drafted a consent form, uploaded it to our website, called patients, changed our voice greeting, and got clarity on insurance coverage. We’ve been flying by the seat of our pants.”

“I’m doing it because I don’t have a choice at this point,” said Dr. Desai, who is a member of the American Academy of Dermatology board of directors and its coronavirus task force. “I’m very worried about continuing to be able to meet our payroll expenses for staff and overhead to keep the office open.”
 

“Flying by the seat of our pants” to see patients virtually

Dermatologists have long been considered pioneers in telemedicine. They have, since the 1990s, capitalized on the visual nature of the specialty to diagnose and treat skin diseases by incorporating photos, videos, and virtual-patient visits. But the pandemic has forced the hands of even holdouts like Dr. Desai, who clung to in-person consults because of confusion related to HIPAA compliance issues and the sense that teledermatology “really dehumanizes patient interaction” for him.

In fact, as of 2017, only 15% of the nation’s 11,000 or so dermatologists had implemented telehealth into their practices, according to an AAD practice survey. In the wake of COVID-19, however, that percentage has likely more than tripled, experts estimate.

Now, dermatologists are assuming the mantle of educators for other specialists who never considered telehealth before in-person visits became fraught with concerns about the spread of the virus. And some are publishing guidelines for colleagues on how to prioritize teledermatology to stem transmission and conserve personal protective equipment (PPE) and hospital beds.

User-friendly technology and the relaxed telehealth restrictions have made it fairly simple for patients and physicians to connect. Facetime and other once-prohibited platforms are all currently permissible, although physicians are encouraged to notify patients about potential privacy risks, according to an AAD teledermatology tool kit.
 

Teledermatology innovators

“We’ve moved 10 years in telemedicine policy in 2 weeks,” said Karen Edison, MD, of the University of Missouri, Columbia. “The federal government has really loosened the reins.”

At least half of all dermatologists in the United States have adopted telehealth since the pandemic emerged, she estimated. And most, like Dr. Desai, have done so in just the last several weeks.

“You can do about 90% of what you need to do as a dermatologist using the technology,” said Dr. Edison, who launched the first dermatology Extension for Community Healthcare Outcomes, or ECHO, program in the Midwest. That telehealth model was originally developed to connect rural general practitioners with specialists at academic medical centers or large health systems.

“People are used to taking pictures with their phones. In some ways, this crisis may change the face of our specialty,” she said in an interview.

“As we’re all practicing social distancing, I think physicians and patients are rethinking how we can access healthcare without pursuing traditional face-to-face interactions,” said Ivy Lee, MD, from the University of California, San Francisco, who is past chair of the AAD telemedicine task force and current chair of the teledermatology committee at the American Telemedicine Association. “Virtual health and telemedicine fit perfectly with that.”

Even before the pandemic, the innovative ways dermatologists were using telehealth were garnering increasing acclaim. All four clinical groups short-listed for dermatology team of the year at the BMJ Awards 2020 employed telehealth to improve patient services in the United Kingdom.

In the United States, dermatologists are joining forces to boost understanding of how telehealth can protect patients and clinicians from some of the ravages of the virus.

The Society of Dermatology Hospitalists has developed an algorithm – built on experiences its members have had caring for hospitalized patients with acute dermatologic conditions – to provide a “logical way” to triage telemedicine consults in multiple hospital settings during the coronavirus crisis, said President-Elect Daniela Kroshinsky, MD, from Massachusetts General Hospital in Boston.

Telemedicine consultation is prioritized and patients at high risk for COVID-19 exposure are identified so that exposure time and resource use are limited and patient and staff safety are maximized.

“We want to empower our colleagues in community hospitals to play a role in safely providing care for patients in need but to be mindful about preserving resources,” said Dr. Kroshinsky, who reported that the algorithm will be published imminently.

“If you don’t have to see a patient in person and can offer recommendations through telederm, you don’t need to put on a gown, gloves, mask, or goggles,” she said in an interview. “If you’re unable to assess photos, then of course you’ll use the appropriate protective wear, but it will be better if you can obtain the same result” without having to do so.
 

Sharing expertise

After the first week of tracking data to gauge the effectiveness of the algorithm at Massachusetts General, Dr. Kroshinsky said she is buoyed.

Of the 35 patients assessed electronically – all of whom would previously have been seen in person – only 4 ended up needing a subsequent in-person consult, she reported.

“It’s worked out great,” said Dr. Kroshinsky, who noted that the pandemic is a “nice opportunity” to test different telehealth platforms and improve quality down the line. “We never had to use any excessive PPE, beyond what was routine, and the majority of patients were able to be staffed remotely. All patients had successful outcomes.”

With telehealth more firmly established in dermatology than in most other specialties, dermatologists are now helping clinicians in other fields who are rapidly ramping up their own telemedicine offerings.

These might include obstetrics and gynecology or “any medical specialty where they need to do checkups with their patients and don’t want them coming in for nonemergent visits,” said Carrie L. Kovarik, MD, of the University of Pennsylvania, Philadelphia.

In addition to fielding many recent calls and emails from physicians seeking guidance on telehealth, Dr. Kovarik, Dr. Lee, and colleagues have published the steps required to integrate the technology into outpatient practices.

“Now that there’s a time for broad implementation, our colleagues are looking to us for help and troubleshooting advice,” said Dr. Kovarik, who is also a member of the AAD COVID-19 response task force.

Various specialties “lend themselves to telehealth, depending on how image- or data-dependent they are,” Dr. Lee said in an interview. “But all specialists thinking of limiting or shutting down their practices are thinking about how they can provide continuity of care without exposing patients or staff to the risk of contracting the coronavirus.”
 

After-COVID goals

In his first week of virtual patient consults, Dr. Desai said he saw about 50 patients, which is still far fewer than the 160-180 he sees in person during a normal week.

“The problem is that patients don’t really want to do telehealth. You’d think it would be a good option,” he said, “but patients hesitate because they don’t really know how to use their device.” Some have instead rescheduled in-person appointments for months down the line.

Although telehealth has enabled Dr. Desai to readily assess patients with acne, hair loss, psoriasis, rashes, warts, and eczema, he’s concerned that necessary procedures, such as biopsies and dermoscopies, could be dangerously delayed. It’s also hard to assess the texture and thickness of certain skin lesions in photos or videos, he said.

“I’m trying to stay optimistic that this will get better and we’re able to move back to taking care of patients the way we need to,” he said.

Like Dr. Desai, other dermatologists who’ve implemented telemedicine during the pandemic have largely been swayed by the relaxed CMS regulations. “It’s made all the difference,” Dr. Kovarik said. “It has brought down the anxiety level and decreased questions about platforms and concentrated them on how to code the visits.”

And although it’s difficult to envision post-COVID medical practice in the thick of the pandemic, dermatologists expect the current strides in telemedicine will stick.

“I’m hoping that telehealth use isn’t dialed back all the way to baseline” after the pandemic eases, Dr. Kovarik said. “The cat’s out of the bag, and now that it is, hopefully it won’t be put back in.”

“If there’s a silver lining to this,” Dr. Kroshinsky said, “I hope it’s that we’ll be able to innovate around health care in a fashion we wouldn’t have seen otherwise.”

A version of this article originally appeared on Medscape.com.

The rapid spread of COVID-19 forced Seemal Desai, MD, to make an excruciating choice; he could either shutter his busy dermatology practice in Plano, Tex., or switch most patient consults to telemedicine, which he’d never used.

But as soon as he learned that telehealth regulations had been relaxed by the Centers for Medicare & Medicaid Services and that reimbursement had been broadened, Dr. Desai, a dermatologist in private practice and his staff began to mobilize.

“Kaboom! We made the decision to start doing it,” he said in an interview. “We drafted a consent form, uploaded it to our website, called patients, changed our voice greeting, and got clarity on insurance coverage. We’ve been flying by the seat of our pants.”

“I’m doing it because I don’t have a choice at this point,” said Dr. Desai, who is a member of the American Academy of Dermatology board of directors and its coronavirus task force. “I’m very worried about continuing to be able to meet our payroll expenses for staff and overhead to keep the office open.”
 

“Flying by the seat of our pants” to see patients virtually

Dermatologists have long been considered pioneers in telemedicine. They have, since the 1990s, capitalized on the visual nature of the specialty to diagnose and treat skin diseases by incorporating photos, videos, and virtual-patient visits. But the pandemic has forced the hands of even holdouts like Dr. Desai, who clung to in-person consults because of confusion related to HIPAA compliance issues and the sense that teledermatology “really dehumanizes patient interaction” for him.

In fact, as of 2017, only 15% of the nation’s 11,000 or so dermatologists had implemented telehealth into their practices, according to an AAD practice survey. In the wake of COVID-19, however, that percentage has likely more than tripled, experts estimate.

Now, dermatologists are assuming the mantle of educators for other specialists who never considered telehealth before in-person visits became fraught with concerns about the spread of the virus. And some are publishing guidelines for colleagues on how to prioritize teledermatology to stem transmission and conserve personal protective equipment (PPE) and hospital beds.

User-friendly technology and the relaxed telehealth restrictions have made it fairly simple for patients and physicians to connect. Facetime and other once-prohibited platforms are all currently permissible, although physicians are encouraged to notify patients about potential privacy risks, according to an AAD teledermatology tool kit.
 

Teledermatology innovators

“We’ve moved 10 years in telemedicine policy in 2 weeks,” said Karen Edison, MD, of the University of Missouri, Columbia. “The federal government has really loosened the reins.”

At least half of all dermatologists in the United States have adopted telehealth since the pandemic emerged, she estimated. And most, like Dr. Desai, have done so in just the last several weeks.

“You can do about 90% of what you need to do as a dermatologist using the technology,” said Dr. Edison, who launched the first dermatology Extension for Community Healthcare Outcomes, or ECHO, program in the Midwest. That telehealth model was originally developed to connect rural general practitioners with specialists at academic medical centers or large health systems.

“People are used to taking pictures with their phones. In some ways, this crisis may change the face of our specialty,” she said in an interview.

“As we’re all practicing social distancing, I think physicians and patients are rethinking how we can access healthcare without pursuing traditional face-to-face interactions,” said Ivy Lee, MD, from the University of California, San Francisco, who is past chair of the AAD telemedicine task force and current chair of the teledermatology committee at the American Telemedicine Association. “Virtual health and telemedicine fit perfectly with that.”

Even before the pandemic, the innovative ways dermatologists were using telehealth were garnering increasing acclaim. All four clinical groups short-listed for dermatology team of the year at the BMJ Awards 2020 employed telehealth to improve patient services in the United Kingdom.

In the United States, dermatologists are joining forces to boost understanding of how telehealth can protect patients and clinicians from some of the ravages of the virus.

The Society of Dermatology Hospitalists has developed an algorithm – built on experiences its members have had caring for hospitalized patients with acute dermatologic conditions – to provide a “logical way” to triage telemedicine consults in multiple hospital settings during the coronavirus crisis, said President-Elect Daniela Kroshinsky, MD, from Massachusetts General Hospital in Boston.

Telemedicine consultation is prioritized and patients at high risk for COVID-19 exposure are identified so that exposure time and resource use are limited and patient and staff safety are maximized.

“We want to empower our colleagues in community hospitals to play a role in safely providing care for patients in need but to be mindful about preserving resources,” said Dr. Kroshinsky, who reported that the algorithm will be published imminently.

“If you don’t have to see a patient in person and can offer recommendations through telederm, you don’t need to put on a gown, gloves, mask, or goggles,” she said in an interview. “If you’re unable to assess photos, then of course you’ll use the appropriate protective wear, but it will be better if you can obtain the same result” without having to do so.
 

Sharing expertise

After the first week of tracking data to gauge the effectiveness of the algorithm at Massachusetts General, Dr. Kroshinsky said she is buoyed.

Of the 35 patients assessed electronically – all of whom would previously have been seen in person – only 4 ended up needing a subsequent in-person consult, she reported.

“It’s worked out great,” said Dr. Kroshinsky, who noted that the pandemic is a “nice opportunity” to test different telehealth platforms and improve quality down the line. “We never had to use any excessive PPE, beyond what was routine, and the majority of patients were able to be staffed remotely. All patients had successful outcomes.”

With telehealth more firmly established in dermatology than in most other specialties, dermatologists are now helping clinicians in other fields who are rapidly ramping up their own telemedicine offerings.

These might include obstetrics and gynecology or “any medical specialty where they need to do checkups with their patients and don’t want them coming in for nonemergent visits,” said Carrie L. Kovarik, MD, of the University of Pennsylvania, Philadelphia.

In addition to fielding many recent calls and emails from physicians seeking guidance on telehealth, Dr. Kovarik, Dr. Lee, and colleagues have published the steps required to integrate the technology into outpatient practices.

“Now that there’s a time for broad implementation, our colleagues are looking to us for help and troubleshooting advice,” said Dr. Kovarik, who is also a member of the AAD COVID-19 response task force.

Various specialties “lend themselves to telehealth, depending on how image- or data-dependent they are,” Dr. Lee said in an interview. “But all specialists thinking of limiting or shutting down their practices are thinking about how they can provide continuity of care without exposing patients or staff to the risk of contracting the coronavirus.”
 

After-COVID goals

In his first week of virtual patient consults, Dr. Desai said he saw about 50 patients, which is still far fewer than the 160-180 he sees in person during a normal week.

“The problem is that patients don’t really want to do telehealth. You’d think it would be a good option,” he said, “but patients hesitate because they don’t really know how to use their device.” Some have instead rescheduled in-person appointments for months down the line.

Although telehealth has enabled Dr. Desai to readily assess patients with acne, hair loss, psoriasis, rashes, warts, and eczema, he’s concerned that necessary procedures, such as biopsies and dermoscopies, could be dangerously delayed. It’s also hard to assess the texture and thickness of certain skin lesions in photos or videos, he said.

“I’m trying to stay optimistic that this will get better and we’re able to move back to taking care of patients the way we need to,” he said.

Like Dr. Desai, other dermatologists who’ve implemented telemedicine during the pandemic have largely been swayed by the relaxed CMS regulations. “It’s made all the difference,” Dr. Kovarik said. “It has brought down the anxiety level and decreased questions about platforms and concentrated them on how to code the visits.”

And although it’s difficult to envision post-COVID medical practice in the thick of the pandemic, dermatologists expect the current strides in telemedicine will stick.

“I’m hoping that telehealth use isn’t dialed back all the way to baseline” after the pandemic eases, Dr. Kovarik said. “The cat’s out of the bag, and now that it is, hopefully it won’t be put back in.”

“If there’s a silver lining to this,” Dr. Kroshinsky said, “I hope it’s that we’ll be able to innovate around health care in a fashion we wouldn’t have seen otherwise.”

A version of this article originally appeared on Medscape.com.

The rapid spread of COVID-19 forced Seemal Desai, MD, to make an excruciating choice; he could either shutter his busy dermatology practice in Plano, Tex., or switch most patient consults to telemedicine, which he’d never used.

But as soon as he learned that telehealth regulations had been relaxed by the Centers for Medicare & Medicaid Services and that reimbursement had been broadened, Dr. Desai, a dermatologist in private practice and his staff began to mobilize.

“Kaboom! We made the decision to start doing it,” he said in an interview. “We drafted a consent form, uploaded it to our website, called patients, changed our voice greeting, and got clarity on insurance coverage. We’ve been flying by the seat of our pants.”

“I’m doing it because I don’t have a choice at this point,” said Dr. Desai, who is a member of the American Academy of Dermatology board of directors and its coronavirus task force. “I’m very worried about continuing to be able to meet our payroll expenses for staff and overhead to keep the office open.”
 

“Flying by the seat of our pants” to see patients virtually

Dermatologists have long been considered pioneers in telemedicine. They have, since the 1990s, capitalized on the visual nature of the specialty to diagnose and treat skin diseases by incorporating photos, videos, and virtual-patient visits. But the pandemic has forced the hands of even holdouts like Dr. Desai, who clung to in-person consults because of confusion related to HIPAA compliance issues and the sense that teledermatology “really dehumanizes patient interaction” for him.

In fact, as of 2017, only 15% of the nation’s 11,000 or so dermatologists had implemented telehealth into their practices, according to an AAD practice survey. In the wake of COVID-19, however, that percentage has likely more than tripled, experts estimate.

Now, dermatologists are assuming the mantle of educators for other specialists who never considered telehealth before in-person visits became fraught with concerns about the spread of the virus. And some are publishing guidelines for colleagues on how to prioritize teledermatology to stem transmission and conserve personal protective equipment (PPE) and hospital beds.

User-friendly technology and the relaxed telehealth restrictions have made it fairly simple for patients and physicians to connect. Facetime and other once-prohibited platforms are all currently permissible, although physicians are encouraged to notify patients about potential privacy risks, according to an AAD teledermatology tool kit.
 

Teledermatology innovators

“We’ve moved 10 years in telemedicine policy in 2 weeks,” said Karen Edison, MD, of the University of Missouri, Columbia. “The federal government has really loosened the reins.”

At least half of all dermatologists in the United States have adopted telehealth since the pandemic emerged, she estimated. And most, like Dr. Desai, have done so in just the last several weeks.

“You can do about 90% of what you need to do as a dermatologist using the technology,” said Dr. Edison, who launched the first dermatology Extension for Community Healthcare Outcomes, or ECHO, program in the Midwest. That telehealth model was originally developed to connect rural general practitioners with specialists at academic medical centers or large health systems.

“People are used to taking pictures with their phones. In some ways, this crisis may change the face of our specialty,” she said in an interview.

“As we’re all practicing social distancing, I think physicians and patients are rethinking how we can access healthcare without pursuing traditional face-to-face interactions,” said Ivy Lee, MD, from the University of California, San Francisco, who is past chair of the AAD telemedicine task force and current chair of the teledermatology committee at the American Telemedicine Association. “Virtual health and telemedicine fit perfectly with that.”

Even before the pandemic, the innovative ways dermatologists were using telehealth were garnering increasing acclaim. All four clinical groups short-listed for dermatology team of the year at the BMJ Awards 2020 employed telehealth to improve patient services in the United Kingdom.

In the United States, dermatologists are joining forces to boost understanding of how telehealth can protect patients and clinicians from some of the ravages of the virus.

The Society of Dermatology Hospitalists has developed an algorithm – built on experiences its members have had caring for hospitalized patients with acute dermatologic conditions – to provide a “logical way” to triage telemedicine consults in multiple hospital settings during the coronavirus crisis, said President-Elect Daniela Kroshinsky, MD, from Massachusetts General Hospital in Boston.

Telemedicine consultation is prioritized and patients at high risk for COVID-19 exposure are identified so that exposure time and resource use are limited and patient and staff safety are maximized.

“We want to empower our colleagues in community hospitals to play a role in safely providing care for patients in need but to be mindful about preserving resources,” said Dr. Kroshinsky, who reported that the algorithm will be published imminently.

“If you don’t have to see a patient in person and can offer recommendations through telederm, you don’t need to put on a gown, gloves, mask, or goggles,” she said in an interview. “If you’re unable to assess photos, then of course you’ll use the appropriate protective wear, but it will be better if you can obtain the same result” without having to do so.
 

Sharing expertise

After the first week of tracking data to gauge the effectiveness of the algorithm at Massachusetts General, Dr. Kroshinsky said she is buoyed.

Of the 35 patients assessed electronically – all of whom would previously have been seen in person – only 4 ended up needing a subsequent in-person consult, she reported.

“It’s worked out great,” said Dr. Kroshinsky, who noted that the pandemic is a “nice opportunity” to test different telehealth platforms and improve quality down the line. “We never had to use any excessive PPE, beyond what was routine, and the majority of patients were able to be staffed remotely. All patients had successful outcomes.”

With telehealth more firmly established in dermatology than in most other specialties, dermatologists are now helping clinicians in other fields who are rapidly ramping up their own telemedicine offerings.

These might include obstetrics and gynecology or “any medical specialty where they need to do checkups with their patients and don’t want them coming in for nonemergent visits,” said Carrie L. Kovarik, MD, of the University of Pennsylvania, Philadelphia.

In addition to fielding many recent calls and emails from physicians seeking guidance on telehealth, Dr. Kovarik, Dr. Lee, and colleagues have published the steps required to integrate the technology into outpatient practices.

“Now that there’s a time for broad implementation, our colleagues are looking to us for help and troubleshooting advice,” said Dr. Kovarik, who is also a member of the AAD COVID-19 response task force.

Various specialties “lend themselves to telehealth, depending on how image- or data-dependent they are,” Dr. Lee said in an interview. “But all specialists thinking of limiting or shutting down their practices are thinking about how they can provide continuity of care without exposing patients or staff to the risk of contracting the coronavirus.”
 

After-COVID goals

In his first week of virtual patient consults, Dr. Desai said he saw about 50 patients, which is still far fewer than the 160-180 he sees in person during a normal week.

“The problem is that patients don’t really want to do telehealth. You’d think it would be a good option,” he said, “but patients hesitate because they don’t really know how to use their device.” Some have instead rescheduled in-person appointments for months down the line.

Although telehealth has enabled Dr. Desai to readily assess patients with acne, hair loss, psoriasis, rashes, warts, and eczema, he’s concerned that necessary procedures, such as biopsies and dermoscopies, could be dangerously delayed. It’s also hard to assess the texture and thickness of certain skin lesions in photos or videos, he said.

“I’m trying to stay optimistic that this will get better and we’re able to move back to taking care of patients the way we need to,” he said.

Like Dr. Desai, other dermatologists who’ve implemented telemedicine during the pandemic have largely been swayed by the relaxed CMS regulations. “It’s made all the difference,” Dr. Kovarik said. “It has brought down the anxiety level and decreased questions about platforms and concentrated them on how to code the visits.”

And although it’s difficult to envision post-COVID medical practice in the thick of the pandemic, dermatologists expect the current strides in telemedicine will stick.

“I’m hoping that telehealth use isn’t dialed back all the way to baseline” after the pandemic eases, Dr. Kovarik said. “The cat’s out of the bag, and now that it is, hopefully it won’t be put back in.”

“If there’s a silver lining to this,” Dr. Kroshinsky said, “I hope it’s that we’ll be able to innovate around health care in a fashion we wouldn’t have seen otherwise.”

A version of this article originally appeared on Medscape.com.

Many emergency room workers remove their clothes as soon as they get home – some before they even enter. Does that mean you should worry about COVID-19 transmission from your own clothing, towels, and other textiles?

While researchers found that the virus can remain on some surfaces for up to 72 hours, the study didn’t include fabric. “So far, evidence suggests that it’s harder to catch the virus from a soft surface (such as fabric) than it is from frequently touched hard surfaces like elevator buttons or door handles,” wrote Lisa Maragakis, MD, senior director of infection prevention at the Johns Hopkins Health System.

One thing experts do know: At this point, transmission happens mostly through close contact, not from touching hard surfaces or clothing. The best thing you can do to protect yourself is to stay home. And if you do go out, practice social distancing.

“This is a very powerful weapon,” Robert Redfield, MD, director of the CDC, told National Public Radio. “This virus cannot go from person to person that easily. It needs us to be close. It needs us to be within 6 feet.”

And don’t forget to use hand sanitizer while you’re out, avoid touching your face, and wash your hands when you get home.

If nobody in your home has symptoms of COVID-19 and you’re all staying home, the CDC recommends routine cleaning, including laundry. Even if you go out and maintain good social distancing – at least 6 feet from anyone who’s not in your household – you should be fine.

But if you suspect you got too close for too long, or someone coughed on you, there’s no harm in changing your clothing and washing it right away, especially if there are hard surfaces like buttons and zippers where the virus might linger. Wash your hands again after you put everything into the machine. Dry everything on high, since the virus dies at temperatures above 133 F. File these steps under “abundance of caution”: They’re not necessary, but if it gives you peace of mind, it may be worth it.

Using the laundromat

Got your own washer and dryer? You can just do your laundry. But for those who share a communal laundry room or visit the laundromat, some extra precautions make sense:

• Consider social distancing. Is your building’s laundry room so small that you can’t stand 6 feet away from anyone else? Don’t enter if someone’s already in there. You may want to ask building management to set up a schedule for laundry, to keep everyone safe.
• Sort your laundry before you go, and fold clean laundry at home, to lessen the amount of time you spend there and the number of surfaces you touch, suggests a report in The New York Times.
• Bring sanitizing wipes or hand sanitizer with you to wipe down the machines’ handles and buttons before you use them. Or, since most laundry spaces have a sink, wash your hands with soap right after loading the machines.
• If you have your own cart, use it. A communal cart shouldn’t infect your clothes, but touching it with your hands may transfer the virus to you.
• Don’t touch your face while doing laundry. (You should be getting good at this by now.)
• Don’t hang out in the laundry room or laundromat while your clothes are in the machines. The less time you spend close to others, the better. Step outside, go back to your apartment, or wait in your car.

Courtesy WebMD

If someone is sick

The guidelines change when someone in your household has a confirmed case or symptoms. The CDC recommends:

• Wear disposable gloves when handling dirty laundry, and wash your hands right after you take them off.
• Try not to shake the dirty laundry to avoid sending the virus into the air.
• Follow the manufacturers’ instructions for whatever you’re cleaning, using the warmest water possible. Dry everything completely.
• It’s fine to mix your own laundry in with the sick person’s. And don’t forget to include the laundry bag, or use a disposable garbage bag instead.

Wipe down the hamper, following the appropriate instructions.

This article first appeared on WebMD.

Many emergency room workers remove their clothes as soon as they get home – some before they even enter. Does that mean you should worry about COVID-19 transmission from your own clothing, towels, and other textiles?

While researchers found that the virus can remain on some surfaces for up to 72 hours, the study didn’t include fabric. “So far, evidence suggests that it’s harder to catch the virus from a soft surface (such as fabric) than it is from frequently touched hard surfaces like elevator buttons or door handles,” wrote Lisa Maragakis, MD, senior director of infection prevention at the Johns Hopkins Health System.

One thing experts do know: At this point, transmission happens mostly through close contact, not from touching hard surfaces or clothing. The best thing you can do to protect yourself is to stay home. And if you do go out, practice social distancing.

“This is a very powerful weapon,” Robert Redfield, MD, director of the CDC, told National Public Radio. “This virus cannot go from person to person that easily. It needs us to be close. It needs us to be within 6 feet.”

And don’t forget to use hand sanitizer while you’re out, avoid touching your face, and wash your hands when you get home.

If nobody in your home has symptoms of COVID-19 and you’re all staying home, the CDC recommends routine cleaning, including laundry. Even if you go out and maintain good social distancing – at least 6 feet from anyone who’s not in your household – you should be fine.

But if you suspect you got too close for too long, or someone coughed on you, there’s no harm in changing your clothing and washing it right away, especially if there are hard surfaces like buttons and zippers where the virus might linger. Wash your hands again after you put everything into the machine. Dry everything on high, since the virus dies at temperatures above 133 F. File these steps under “abundance of caution”: They’re not necessary, but if it gives you peace of mind, it may be worth it.

Using the laundromat

Got your own washer and dryer? You can just do your laundry. But for those who share a communal laundry room or visit the laundromat, some extra precautions make sense:

• Consider social distancing. Is your building’s laundry room so small that you can’t stand 6 feet away from anyone else? Don’t enter if someone’s already in there. You may want to ask building management to set up a schedule for laundry, to keep everyone safe.
• Sort your laundry before you go, and fold clean laundry at home, to lessen the amount of time you spend there and the number of surfaces you touch, suggests a report in The New York Times.
• Bring sanitizing wipes or hand sanitizer with you to wipe down the machines’ handles and buttons before you use them. Or, since most laundry spaces have a sink, wash your hands with soap right after loading the machines.
• If you have your own cart, use it. A communal cart shouldn’t infect your clothes, but touching it with your hands may transfer the virus to you.
• Don’t touch your face while doing laundry. (You should be getting good at this by now.)
• Don’t hang out in the laundry room or laundromat while your clothes are in the machines. The less time you spend close to others, the better. Step outside, go back to your apartment, or wait in your car.

Courtesy WebMD

If someone is sick

The guidelines change when someone in your household has a confirmed case or symptoms. The CDC recommends:

• Wear disposable gloves when handling dirty laundry, and wash your hands right after you take them off.
• Try not to shake the dirty laundry to avoid sending the virus into the air.
• Follow the manufacturers’ instructions for whatever you’re cleaning, using the warmest water possible. Dry everything completely.
• It’s fine to mix your own laundry in with the sick person’s. And don’t forget to include the laundry bag, or use a disposable garbage bag instead.

Wipe down the hamper, following the appropriate instructions.

This article first appeared on WebMD.

Many emergency room workers remove their clothes as soon as they get home – some before they even enter. Does that mean you should worry about COVID-19 transmission from your own clothing, towels, and other textiles?

While researchers found that the virus can remain on some surfaces for up to 72 hours, the study didn’t include fabric. “So far, evidence suggests that it’s harder to catch the virus from a soft surface (such as fabric) than it is from frequently touched hard surfaces like elevator buttons or door handles,” wrote Lisa Maragakis, MD, senior director of infection prevention at the Johns Hopkins Health System.

One thing experts do know: At this point, transmission happens mostly through close contact, not from touching hard surfaces or clothing. The best thing you can do to protect yourself is to stay home. And if you do go out, practice social distancing.

“This is a very powerful weapon,” Robert Redfield, MD, director of the CDC, told National Public Radio. “This virus cannot go from person to person that easily. It needs us to be close. It needs us to be within 6 feet.”

And don’t forget to use hand sanitizer while you’re out, avoid touching your face, and wash your hands when you get home.

If nobody in your home has symptoms of COVID-19 and you’re all staying home, the CDC recommends routine cleaning, including laundry. Even if you go out and maintain good social distancing – at least 6 feet from anyone who’s not in your household – you should be fine.

But if you suspect you got too close for too long, or someone coughed on you, there’s no harm in changing your clothing and washing it right away, especially if there are hard surfaces like buttons and zippers where the virus might linger. Wash your hands again after you put everything into the machine. Dry everything on high, since the virus dies at temperatures above 133 F. File these steps under “abundance of caution”: They’re not necessary, but if it gives you peace of mind, it may be worth it.

Using the laundromat

Got your own washer and dryer? You can just do your laundry. But for those who share a communal laundry room or visit the laundromat, some extra precautions make sense:

• Consider social distancing. Is your building’s laundry room so small that you can’t stand 6 feet away from anyone else? Don’t enter if someone’s already in there. You may want to ask building management to set up a schedule for laundry, to keep everyone safe.
• Sort your laundry before you go, and fold clean laundry at home, to lessen the amount of time you spend there and the number of surfaces you touch, suggests a report in The New York Times.
• Bring sanitizing wipes or hand sanitizer with you to wipe down the machines’ handles and buttons before you use them. Or, since most laundry spaces have a sink, wash your hands with soap right after loading the machines.
• If you have your own cart, use it. A communal cart shouldn’t infect your clothes, but touching it with your hands may transfer the virus to you.
• Don’t touch your face while doing laundry. (You should be getting good at this by now.)
• Don’t hang out in the laundry room or laundromat while your clothes are in the machines. The less time you spend close to others, the better. Step outside, go back to your apartment, or wait in your car.

Courtesy WebMD

If someone is sick

The guidelines change when someone in your household has a confirmed case or symptoms. The CDC recommends:

• Wear disposable gloves when handling dirty laundry, and wash your hands right after you take them off.
• Try not to shake the dirty laundry to avoid sending the virus into the air.
• Follow the manufacturers’ instructions for whatever you’re cleaning, using the warmest water possible. Dry everything completely.
• It’s fine to mix your own laundry in with the sick person’s. And don’t forget to include the laundry bag, or use a disposable garbage bag instead.

Wipe down the hamper, following the appropriate instructions.

This article first appeared on WebMD.

The US Food and Drug Administration has approved luspatercept (Reblozyl, Bristol-Myers Squibb/Acceleron) for the treatment of anemia in patients with myelodysplastic syndromes (MDS).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The green light represents the first treatment advancement in MDS in more than a decade, says an expert in the field.

Luspatercept is the first and so far only erythroid maturation agent (EMA), and was launched last year when it was approved for the treatment of anemia in adults with beta thalassemia, who require regular red blood cell transfusions.

The new approval is for the treatment of anemia in adult patients with very low- to intermediate-risk MDS with ring sideroblasts and patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, after they have progressed on treatment with an erythropoiesis-stimulating agent and who require two or more red blood cell (RBC) units over 8 weeks.

Luspatercept is not a substitute for RBC transfusions in patients who require immediate correction of anemia.

The FDA approval in MDS is based on results from the pivotal, placebo-controlled, phase 3 MEDALIST trial, conducted in 229 patients with very-low–, low- and intermediate-risk non-del(5q) MDS with ring sideroblasts. All patients were RBC transfusion-dependent and had disease that was refractory to, or unlikely to respond to, erythropoiesis-stimulating agents. Results were published in January in the New England Journal of Medicine. The study was funded by Acceleron Pharma and Celgene, which was later acquired by Bristol-Myers Squibb.

These results were first presented at the 2018 annual meeting of the American Society of Hematology (ASH), as reported by Medscape Medical News. At the time, ASH President Alexis Thompson, MD, said it appears that luspatercept can improve the production of endogenous RBCs by enhancing the maturation of these cells in the bone marrow. The drug significantly reduced the need for RBC transfusions, and “this is a very exciting advance for patients who would have few other treatment options,” she said.

“Anemia and the chronic need for transfusions is a very big issue for these patients,” commented lead study author Pierre Fenaux, MD, PhD, from Hôpital Saint-Louis in Paris, France. “With low hemoglobin levels, patients are tired all the time and have an increased risk of falls and cardiovascular events. When you can improve hemoglobin levels, you really see a difference in quality of life.”

The MEDALIST trial is an important milestone for patients with lower-risk, transfusion-dependent MDS, commented Elizabeth Griffiths, MD, associate professor of oncology and director of MDS, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

“No new agents have been approved for MDS in the last 10 years, highlighting this development as a substantial step forward for the MDS community,” she told Medscape Medical News. “Current therapies are time-intensive and only modestly beneficial.”

“The availability of a new, effective drug — particularly relevant to those harboring SF3B1 mutations — is an exciting development and is likely to offer meaningful improvements in quality of life,” Griffiths said. “Since these patients tend to live longer than others with MDS, there are many patients in my clinical practice who would have fit the enrollment criteria for this study. Such patients are eagerly awaiting the opportunity for a decrease in transfusion burden.”
 

Study Details

In the trial, luspatercept reduced the severity of anemia — 38% of the 153 patients who received luspatercept achieved transfusion independence for 8 weeks or longer compared with 13% of the 76 patients receiving placebo (P < .001).

In the study, patients received luspatercept at a starting dose of 1.0 mg/kg with titration up to 1.75 mg/kg, if needed, or placebo, subcutaneously every 3 weeks for at least 24 weeks.

During the 16 weeks before the initiation of treatment, study patients had received a median of 5 RBC units transfusions during an 8-week period (43.2% of patients had ≥ 6 RBC units, 27.9% had ≥ 4 to < 6 RBC units, and 28.8% had < 4 RBC units). At baseline, 138 (60.3%), 58 (25.3%), and 32 (14%) patients had serum erythropoietin levels less than 200 IU/L, 200-500 IU/L, and greater than 500 IU/L, respectively.

The most common luspatercept-associated adverse events (any grade) in the trial were fatigue, diarrhea, asthenia, nausea, and dizziness. Grade 3 or 4 treatment-emergent adverse events were reported in 42.5% of patients who received luspatercept and 44.7% of patients who received placebo. The incidence of adverse events decreased over time, according to the study authors.

This article first appeared on Medscape.com.

The US Food and Drug Administration has approved luspatercept (Reblozyl, Bristol-Myers Squibb/Acceleron) for the treatment of anemia in patients with myelodysplastic syndromes (MDS).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The green light represents the first treatment advancement in MDS in more than a decade, says an expert in the field.

Luspatercept is the first and so far only erythroid maturation agent (EMA), and was launched last year when it was approved for the treatment of anemia in adults with beta thalassemia, who require regular red blood cell transfusions.

The new approval is for the treatment of anemia in adult patients with very low- to intermediate-risk MDS with ring sideroblasts and patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, after they have progressed on treatment with an erythropoiesis-stimulating agent and who require two or more red blood cell (RBC) units over 8 weeks.

Luspatercept is not a substitute for RBC transfusions in patients who require immediate correction of anemia.

The FDA approval in MDS is based on results from the pivotal, placebo-controlled, phase 3 MEDALIST trial, conducted in 229 patients with very-low–, low- and intermediate-risk non-del(5q) MDS with ring sideroblasts. All patients were RBC transfusion-dependent and had disease that was refractory to, or unlikely to respond to, erythropoiesis-stimulating agents. Results were published in January in the New England Journal of Medicine. The study was funded by Acceleron Pharma and Celgene, which was later acquired by Bristol-Myers Squibb.

These results were first presented at the 2018 annual meeting of the American Society of Hematology (ASH), as reported by Medscape Medical News. At the time, ASH President Alexis Thompson, MD, said it appears that luspatercept can improve the production of endogenous RBCs by enhancing the maturation of these cells in the bone marrow. The drug significantly reduced the need for RBC transfusions, and “this is a very exciting advance for patients who would have few other treatment options,” she said.

“Anemia and the chronic need for transfusions is a very big issue for these patients,” commented lead study author Pierre Fenaux, MD, PhD, from Hôpital Saint-Louis in Paris, France. “With low hemoglobin levels, patients are tired all the time and have an increased risk of falls and cardiovascular events. When you can improve hemoglobin levels, you really see a difference in quality of life.”

The MEDALIST trial is an important milestone for patients with lower-risk, transfusion-dependent MDS, commented Elizabeth Griffiths, MD, associate professor of oncology and director of MDS, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

“No new agents have been approved for MDS in the last 10 years, highlighting this development as a substantial step forward for the MDS community,” she told Medscape Medical News. “Current therapies are time-intensive and only modestly beneficial.”

“The availability of a new, effective drug — particularly relevant to those harboring SF3B1 mutations — is an exciting development and is likely to offer meaningful improvements in quality of life,” Griffiths said. “Since these patients tend to live longer than others with MDS, there are many patients in my clinical practice who would have fit the enrollment criteria for this study. Such patients are eagerly awaiting the opportunity for a decrease in transfusion burden.”
 

Study Details

In the trial, luspatercept reduced the severity of anemia — 38% of the 153 patients who received luspatercept achieved transfusion independence for 8 weeks or longer compared with 13% of the 76 patients receiving placebo (P < .001).

In the study, patients received luspatercept at a starting dose of 1.0 mg/kg with titration up to 1.75 mg/kg, if needed, or placebo, subcutaneously every 3 weeks for at least 24 weeks.

During the 16 weeks before the initiation of treatment, study patients had received a median of 5 RBC units transfusions during an 8-week period (43.2% of patients had ≥ 6 RBC units, 27.9% had ≥ 4 to < 6 RBC units, and 28.8% had < 4 RBC units). At baseline, 138 (60.3%), 58 (25.3%), and 32 (14%) patients had serum erythropoietin levels less than 200 IU/L, 200-500 IU/L, and greater than 500 IU/L, respectively.

The most common luspatercept-associated adverse events (any grade) in the trial were fatigue, diarrhea, asthenia, nausea, and dizziness. Grade 3 or 4 treatment-emergent adverse events were reported in 42.5% of patients who received luspatercept and 44.7% of patients who received placebo. The incidence of adverse events decreased over time, according to the study authors.

This article first appeared on Medscape.com.

The US Food and Drug Administration has approved luspatercept (Reblozyl, Bristol-Myers Squibb/Acceleron) for the treatment of anemia in patients with myelodysplastic syndromes (MDS).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The green light represents the first treatment advancement in MDS in more than a decade, says an expert in the field.

Luspatercept is the first and so far only erythroid maturation agent (EMA), and was launched last year when it was approved for the treatment of anemia in adults with beta thalassemia, who require regular red blood cell transfusions.

The new approval is for the treatment of anemia in adult patients with very low- to intermediate-risk MDS with ring sideroblasts and patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, after they have progressed on treatment with an erythropoiesis-stimulating agent and who require two or more red blood cell (RBC) units over 8 weeks.

Luspatercept is not a substitute for RBC transfusions in patients who require immediate correction of anemia.

The FDA approval in MDS is based on results from the pivotal, placebo-controlled, phase 3 MEDALIST trial, conducted in 229 patients with very-low–, low- and intermediate-risk non-del(5q) MDS with ring sideroblasts. All patients were RBC transfusion-dependent and had disease that was refractory to, or unlikely to respond to, erythropoiesis-stimulating agents. Results were published in January in the New England Journal of Medicine. The study was funded by Acceleron Pharma and Celgene, which was later acquired by Bristol-Myers Squibb.

These results were first presented at the 2018 annual meeting of the American Society of Hematology (ASH), as reported by Medscape Medical News. At the time, ASH President Alexis Thompson, MD, said it appears that luspatercept can improve the production of endogenous RBCs by enhancing the maturation of these cells in the bone marrow. The drug significantly reduced the need for RBC transfusions, and “this is a very exciting advance for patients who would have few other treatment options,” she said.

“Anemia and the chronic need for transfusions is a very big issue for these patients,” commented lead study author Pierre Fenaux, MD, PhD, from Hôpital Saint-Louis in Paris, France. “With low hemoglobin levels, patients are tired all the time and have an increased risk of falls and cardiovascular events. When you can improve hemoglobin levels, you really see a difference in quality of life.”

The MEDALIST trial is an important milestone for patients with lower-risk, transfusion-dependent MDS, commented Elizabeth Griffiths, MD, associate professor of oncology and director of MDS, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

“No new agents have been approved for MDS in the last 10 years, highlighting this development as a substantial step forward for the MDS community,” she told Medscape Medical News. “Current therapies are time-intensive and only modestly beneficial.”

“The availability of a new, effective drug — particularly relevant to those harboring SF3B1 mutations — is an exciting development and is likely to offer meaningful improvements in quality of life,” Griffiths said. “Since these patients tend to live longer than others with MDS, there are many patients in my clinical practice who would have fit the enrollment criteria for this study. Such patients are eagerly awaiting the opportunity for a decrease in transfusion burden.”
 

Study Details

In the trial, luspatercept reduced the severity of anemia — 38% of the 153 patients who received luspatercept achieved transfusion independence for 8 weeks or longer compared with 13% of the 76 patients receiving placebo (P < .001).

In the study, patients received luspatercept at a starting dose of 1.0 mg/kg with titration up to 1.75 mg/kg, if needed, or placebo, subcutaneously every 3 weeks for at least 24 weeks.

During the 16 weeks before the initiation of treatment, study patients had received a median of 5 RBC units transfusions during an 8-week period (43.2% of patients had ≥ 6 RBC units, 27.9% had ≥ 4 to < 6 RBC units, and 28.8% had < 4 RBC units). At baseline, 138 (60.3%), 58 (25.3%), and 32 (14%) patients had serum erythropoietin levels less than 200 IU/L, 200-500 IU/L, and greater than 500 IU/L, respectively.

The most common luspatercept-associated adverse events (any grade) in the trial were fatigue, diarrhea, asthenia, nausea, and dizziness. Grade 3 or 4 treatment-emergent adverse events were reported in 42.5% of patients who received luspatercept and 44.7% of patients who received placebo. The incidence of adverse events decreased over time, according to the study authors.

This article first appeared on Medscape.com.

Since the Centers for Disease Control and Prevention (CDC) confirmed the first US case of novel coronavirus infection on January 20, much of the clinical focus has naturally centered on the virus’ prodromal symptoms and severe respiratory effects.

However, US neurologists are now reporting that COVID-19 symptoms may also include encephalopathy, ataxia, and other neurologic signs.

“I am hearing about strokes, ataxia, myelitis, etc,” Stephan Mayer, MD, a neurointensivist in Troy, Michigan, posted on Twitter on March 26.

Other possible signs and symptoms include subtle neurologic deficits, severe fatigue, trigeminal neuralgia, complete/severe anosmia, and myalgia as reported by clinicians who responded to the tweet.

On March 31, the first presumptive case of encephalitis linked to COVID-19 was documented in a 58-year-old woman treated at Henry Ford Health System in Detroit.

Physicians who reported the acute necrotizing hemorrhagic encephalopathy case in the journal Radiology counseled neurologists to suspect the virus in patients presenting with altered levels of consciousness.

Researchers in China also reported the first presumptive case of Guillain-Barre syndrome (GBS) associated with COVID-19. A 61-year-old woman initially presented with signs of the autoimmune neuropathy GBS, including leg weakness, and severe fatigue after returning from Wuhan, China. She did not initially present with the common COVID-19 symptoms of fever, cough, or chest pain.

Her muscle weakness and distal areflexia progressed over time. On day 8, the patient developed more characteristic COVID-19 signs, including ‘ground glass’ lung opacities, dry cough, and fever. She was treated with antivirals, immunoglobulins, and supportive care, recovering slowly until discharge on day 30.

“Our single-case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have causal relationship. More cases with epidemiological data are necessary,” said senior author Sheng Chen, MD, PhD.

However, “we still suggest physicians who encounter acute GBS patients from pandemic areas protect themselves carefully and test for the virus on admission. If the results are positive, the patient needs to be isolated,” added Dr. Chen, a neurologist at Shanghai Ruijin Hospital and Shanghai Jiao Tong University School of Medicine in China.

Neurologic presentations of COVID-19 “are not common, but could happen,” Dr. Chen added. Headache, muscle weakness, and myalgias have been documented in other patients in China, he said.
 

Early days

Despite this growing number of anecdotal reports and observational data documenting neurologic effects, the majority of patients with COVID-19 do not present with such symptoms.

“Most COVID-19 patients we have seen have a normal neurological presentation. Abnormal neurological findings we have seen include loss of smell and taste sensation, and states of altered mental status including confusion, lethargy, and coma,” said Robert Stevens, MD, who focuses on neuroscience critical care at the Johns Hopkins School of Medicine in Baltimore, Maryland.

Other groups are reporting seizures, spinal cord disease, and brain stem disease. It has been suggested that brain stem dysfunction may account for the loss of hypoxic respiratory drive seen in a subset of patients with severe COVID-19 disease, he added.

However, Dr. Stevens, who plans to track neurologic outcomes in COVID-19 patients, also cautioned that it’s still early and these case reports are preliminary.

“An important caveat is that our knowledge of the different neurological presentations reported in association with COVID-19 is purely descriptive. We know almost nothing about the potential interactions between COVID-19 and the nervous system,” he noted.

He added it’s likely that some of the neurologic phenomena in COVID-19 are not causally related to the virus.

“This is why we have decided to establish a multisite neuro–COVID-19 data registry, so that we can gain epidemiological and mechanistic insight on these phenomena,” he said.

Nevertheless, in an online report February 27 in the Journal of Medical Virology, Yan-Chao Li, MD, and colleagues wrote that “increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system, inducing neurological diseases.”

Dr. Li is affiliated with the Department of Histology and Embryology, College of Basic Medical Sciences, Norman Bethune College of Medicine, Jilin University, Changchun, China.
 

A global view

Scientists observed SARS-CoV in the brains of infected people and animals, particularly the brainstem, they noted. Given the similarity of SARS-CoV to SARS-CoV-2, the virus that causes COVID-19, the researchers suggest a similar invasive mechanism could be occurring in some patients.

Although it hasn’t been proven, Dr. Li and colleagues suggest COVID-19 could act beyond receptors in the lungs, traveling via “a synapse‐connected route to the medullary cardiorespiratory center” in the brain. This action, in turn, could add to the acute respiratory failure observed in many people with COVID-19.

Other neurologists tracking and monitoring case reports of neurologic symptoms potentially related to COVID-19 include Dr. Mayer and Amelia Boehme, PhD, MSPH, an epidemiologist at Columbia University specializing in stroke and cardiovascular disease.

Dr. Boehme suggested on Twitter that the neurology community conduct a multicenter study to examine the relationship between the virus and neurologic symptoms/sequelae.

Medscape Medical News interviewed Michel Dib, MD, a neurologist at the Pitié Salpêtrière hospital in Paris, who said primary neurologic presentations of COVID-19 occur rarely – and primarily in older adults. As other clinicians note, these include confusion and disorientation. He also reports cases of encephalitis and one patient who initially presented with epilepsy.

Initial reports also came from neurologists in countries where COVID-19 struck first. For example, stroke, delirium, epileptic seizures and more are being treated by neurologists at the University of Brescia in Italy in a dedicated unit designed to treat both COVID-19 and neurologic syndromes, Alessandro Pezzini, MD, reported in Neurology Today, a publication of the American Academy of Neurology.

Dr. Pezzini noted that the mechanisms behind the observed increase in vascular complications warrant further investigation. He and colleagues are planning a multicenter study in Italy to dive deeper into the central nervous system effects of COVID-19 infection.

Clinicians in China also report neurologic symptoms in some patients. A study of 221 consecutive COVID-19 patients in Wuhan revealed 11 patients developed acute ischemic stroke, one experienced cerebral venous sinus thrombosis, and another experienced cerebral hemorrhage.

Older age and more severe disease were associated with a greater likelihood for cerebrovascular disease, the authors reported.

Drs. Chen and Li have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Since the Centers for Disease Control and Prevention (CDC) confirmed the first US case of novel coronavirus infection on January 20, much of the clinical focus has naturally centered on the virus’ prodromal symptoms and severe respiratory effects.

However, US neurologists are now reporting that COVID-19 symptoms may also include encephalopathy, ataxia, and other neurologic signs.

“I am hearing about strokes, ataxia, myelitis, etc,” Stephan Mayer, MD, a neurointensivist in Troy, Michigan, posted on Twitter on March 26.

Other possible signs and symptoms include subtle neurologic deficits, severe fatigue, trigeminal neuralgia, complete/severe anosmia, and myalgia as reported by clinicians who responded to the tweet.

On March 31, the first presumptive case of encephalitis linked to COVID-19 was documented in a 58-year-old woman treated at Henry Ford Health System in Detroit.

Physicians who reported the acute necrotizing hemorrhagic encephalopathy case in the journal Radiology counseled neurologists to suspect the virus in patients presenting with altered levels of consciousness.

Researchers in China also reported the first presumptive case of Guillain-Barre syndrome (GBS) associated with COVID-19. A 61-year-old woman initially presented with signs of the autoimmune neuropathy GBS, including leg weakness, and severe fatigue after returning from Wuhan, China. She did not initially present with the common COVID-19 symptoms of fever, cough, or chest pain.

Her muscle weakness and distal areflexia progressed over time. On day 8, the patient developed more characteristic COVID-19 signs, including ‘ground glass’ lung opacities, dry cough, and fever. She was treated with antivirals, immunoglobulins, and supportive care, recovering slowly until discharge on day 30.

“Our single-case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have causal relationship. More cases with epidemiological data are necessary,” said senior author Sheng Chen, MD, PhD.

However, “we still suggest physicians who encounter acute GBS patients from pandemic areas protect themselves carefully and test for the virus on admission. If the results are positive, the patient needs to be isolated,” added Dr. Chen, a neurologist at Shanghai Ruijin Hospital and Shanghai Jiao Tong University School of Medicine in China.

Neurologic presentations of COVID-19 “are not common, but could happen,” Dr. Chen added. Headache, muscle weakness, and myalgias have been documented in other patients in China, he said.
 

Early days

Despite this growing number of anecdotal reports and observational data documenting neurologic effects, the majority of patients with COVID-19 do not present with such symptoms.

“Most COVID-19 patients we have seen have a normal neurological presentation. Abnormal neurological findings we have seen include loss of smell and taste sensation, and states of altered mental status including confusion, lethargy, and coma,” said Robert Stevens, MD, who focuses on neuroscience critical care at the Johns Hopkins School of Medicine in Baltimore, Maryland.

Other groups are reporting seizures, spinal cord disease, and brain stem disease. It has been suggested that brain stem dysfunction may account for the loss of hypoxic respiratory drive seen in a subset of patients with severe COVID-19 disease, he added.

However, Dr. Stevens, who plans to track neurologic outcomes in COVID-19 patients, also cautioned that it’s still early and these case reports are preliminary.

“An important caveat is that our knowledge of the different neurological presentations reported in association with COVID-19 is purely descriptive. We know almost nothing about the potential interactions between COVID-19 and the nervous system,” he noted.

He added it’s likely that some of the neurologic phenomena in COVID-19 are not causally related to the virus.

“This is why we have decided to establish a multisite neuro–COVID-19 data registry, so that we can gain epidemiological and mechanistic insight on these phenomena,” he said.

Nevertheless, in an online report February 27 in the Journal of Medical Virology, Yan-Chao Li, MD, and colleagues wrote that “increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system, inducing neurological diseases.”

Dr. Li is affiliated with the Department of Histology and Embryology, College of Basic Medical Sciences, Norman Bethune College of Medicine, Jilin University, Changchun, China.
 

A global view

Scientists observed SARS-CoV in the brains of infected people and animals, particularly the brainstem, they noted. Given the similarity of SARS-CoV to SARS-CoV-2, the virus that causes COVID-19, the researchers suggest a similar invasive mechanism could be occurring in some patients.

Although it hasn’t been proven, Dr. Li and colleagues suggest COVID-19 could act beyond receptors in the lungs, traveling via “a synapse‐connected route to the medullary cardiorespiratory center” in the brain. This action, in turn, could add to the acute respiratory failure observed in many people with COVID-19.

Other neurologists tracking and monitoring case reports of neurologic symptoms potentially related to COVID-19 include Dr. Mayer and Amelia Boehme, PhD, MSPH, an epidemiologist at Columbia University specializing in stroke and cardiovascular disease.

Dr. Boehme suggested on Twitter that the neurology community conduct a multicenter study to examine the relationship between the virus and neurologic symptoms/sequelae.

Medscape Medical News interviewed Michel Dib, MD, a neurologist at the Pitié Salpêtrière hospital in Paris, who said primary neurologic presentations of COVID-19 occur rarely – and primarily in older adults. As other clinicians note, these include confusion and disorientation. He also reports cases of encephalitis and one patient who initially presented with epilepsy.

Initial reports also came from neurologists in countries where COVID-19 struck first. For example, stroke, delirium, epileptic seizures and more are being treated by neurologists at the University of Brescia in Italy in a dedicated unit designed to treat both COVID-19 and neurologic syndromes, Alessandro Pezzini, MD, reported in Neurology Today, a publication of the American Academy of Neurology.

Dr. Pezzini noted that the mechanisms behind the observed increase in vascular complications warrant further investigation. He and colleagues are planning a multicenter study in Italy to dive deeper into the central nervous system effects of COVID-19 infection.

Clinicians in China also report neurologic symptoms in some patients. A study of 221 consecutive COVID-19 patients in Wuhan revealed 11 patients developed acute ischemic stroke, one experienced cerebral venous sinus thrombosis, and another experienced cerebral hemorrhage.

Older age and more severe disease were associated with a greater likelihood for cerebrovascular disease, the authors reported.

Drs. Chen and Li have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Since the Centers for Disease Control and Prevention (CDC) confirmed the first US case of novel coronavirus infection on January 20, much of the clinical focus has naturally centered on the virus’ prodromal symptoms and severe respiratory effects.

However, US neurologists are now reporting that COVID-19 symptoms may also include encephalopathy, ataxia, and other neurologic signs.

“I am hearing about strokes, ataxia, myelitis, etc,” Stephan Mayer, MD, a neurointensivist in Troy, Michigan, posted on Twitter on March 26.

Other possible signs and symptoms include subtle neurologic deficits, severe fatigue, trigeminal neuralgia, complete/severe anosmia, and myalgia as reported by clinicians who responded to the tweet.

On March 31, the first presumptive case of encephalitis linked to COVID-19 was documented in a 58-year-old woman treated at Henry Ford Health System in Detroit.

Physicians who reported the acute necrotizing hemorrhagic encephalopathy case in the journal Radiology counseled neurologists to suspect the virus in patients presenting with altered levels of consciousness.

Researchers in China also reported the first presumptive case of Guillain-Barre syndrome (GBS) associated with COVID-19. A 61-year-old woman initially presented with signs of the autoimmune neuropathy GBS, including leg weakness, and severe fatigue after returning from Wuhan, China. She did not initially present with the common COVID-19 symptoms of fever, cough, or chest pain.

Her muscle weakness and distal areflexia progressed over time. On day 8, the patient developed more characteristic COVID-19 signs, including ‘ground glass’ lung opacities, dry cough, and fever. She was treated with antivirals, immunoglobulins, and supportive care, recovering slowly until discharge on day 30.

“Our single-case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have causal relationship. More cases with epidemiological data are necessary,” said senior author Sheng Chen, MD, PhD.

However, “we still suggest physicians who encounter acute GBS patients from pandemic areas protect themselves carefully and test for the virus on admission. If the results are positive, the patient needs to be isolated,” added Dr. Chen, a neurologist at Shanghai Ruijin Hospital and Shanghai Jiao Tong University School of Medicine in China.

Neurologic presentations of COVID-19 “are not common, but could happen,” Dr. Chen added. Headache, muscle weakness, and myalgias have been documented in other patients in China, he said.
 

Early days

Despite this growing number of anecdotal reports and observational data documenting neurologic effects, the majority of patients with COVID-19 do not present with such symptoms.

“Most COVID-19 patients we have seen have a normal neurological presentation. Abnormal neurological findings we have seen include loss of smell and taste sensation, and states of altered mental status including confusion, lethargy, and coma,” said Robert Stevens, MD, who focuses on neuroscience critical care at the Johns Hopkins School of Medicine in Baltimore, Maryland.

Other groups are reporting seizures, spinal cord disease, and brain stem disease. It has been suggested that brain stem dysfunction may account for the loss of hypoxic respiratory drive seen in a subset of patients with severe COVID-19 disease, he added.

However, Dr. Stevens, who plans to track neurologic outcomes in COVID-19 patients, also cautioned that it’s still early and these case reports are preliminary.

“An important caveat is that our knowledge of the different neurological presentations reported in association with COVID-19 is purely descriptive. We know almost nothing about the potential interactions between COVID-19 and the nervous system,” he noted.

He added it’s likely that some of the neurologic phenomena in COVID-19 are not causally related to the virus.

“This is why we have decided to establish a multisite neuro–COVID-19 data registry, so that we can gain epidemiological and mechanistic insight on these phenomena,” he said.

Nevertheless, in an online report February 27 in the Journal of Medical Virology, Yan-Chao Li, MD, and colleagues wrote that “increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system, inducing neurological diseases.”

Dr. Li is affiliated with the Department of Histology and Embryology, College of Basic Medical Sciences, Norman Bethune College of Medicine, Jilin University, Changchun, China.
 

A global view

Scientists observed SARS-CoV in the brains of infected people and animals, particularly the brainstem, they noted. Given the similarity of SARS-CoV to SARS-CoV-2, the virus that causes COVID-19, the researchers suggest a similar invasive mechanism could be occurring in some patients.

Although it hasn’t been proven, Dr. Li and colleagues suggest COVID-19 could act beyond receptors in the lungs, traveling via “a synapse‐connected route to the medullary cardiorespiratory center” in the brain. This action, in turn, could add to the acute respiratory failure observed in many people with COVID-19.

Other neurologists tracking and monitoring case reports of neurologic symptoms potentially related to COVID-19 include Dr. Mayer and Amelia Boehme, PhD, MSPH, an epidemiologist at Columbia University specializing in stroke and cardiovascular disease.

Dr. Boehme suggested on Twitter that the neurology community conduct a multicenter study to examine the relationship between the virus and neurologic symptoms/sequelae.

Medscape Medical News interviewed Michel Dib, MD, a neurologist at the Pitié Salpêtrière hospital in Paris, who said primary neurologic presentations of COVID-19 occur rarely – and primarily in older adults. As other clinicians note, these include confusion and disorientation. He also reports cases of encephalitis and one patient who initially presented with epilepsy.

Initial reports also came from neurologists in countries where COVID-19 struck first. For example, stroke, delirium, epileptic seizures and more are being treated by neurologists at the University of Brescia in Italy in a dedicated unit designed to treat both COVID-19 and neurologic syndromes, Alessandro Pezzini, MD, reported in Neurology Today, a publication of the American Academy of Neurology.

Dr. Pezzini noted that the mechanisms behind the observed increase in vascular complications warrant further investigation. He and colleagues are planning a multicenter study in Italy to dive deeper into the central nervous system effects of COVID-19 infection.

Clinicians in China also report neurologic symptoms in some patients. A study of 221 consecutive COVID-19 patients in Wuhan revealed 11 patients developed acute ischemic stroke, one experienced cerebral venous sinus thrombosis, and another experienced cerebral hemorrhage.

Older age and more severe disease were associated with a greater likelihood for cerebrovascular disease, the authors reported.

Drs. Chen and Li have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The vast majority of patients with tendon problems are successfully treated nonoperatively. But which treatments should you try (and when), and which are not quite ready for prime time? This review presents the evidence for the treatment options available to you. But first, it’s important to get our terminology right.

Tendinitis vs tendinosis vs paratenonitis: Words matter

The term “tendinopathy” encompasses many issues related to tendon pathology including tendinitis, tendinosis, and paratenonitis.^1,2 The clinical syndrome consists of pain, swelling, and functional impairment associated with activities of daily living or athletic performance.³ Tendinopathy may be acute or chronic, but most cases result from overuse.¹

In healthy tendons, the collagen fibers are packed tightly and organized in a linear pattern (FIGURE 1A). However, tendons that are chronically overused develop cumulative microtrauma that leads to a degenerative process within the tendon that is slow (typically measured in months) to heal. This is due to the relative lack of vasculature and the slow rate of tissue turnover in tendons.^2,4,5

Sports and manual labor are the most common causes of tendinopathy, but medical conditions including obesity, high blood pressure, diabetes, and high cholesterol are associated risk factors. Medications, particularly fluoroquinolones and statins, can cause tendon problems, and steroids, particularly those injected intratendinously, have been implicated in tendon rupture.^4,6

The term “tendinitis” has long been used for all tendon disorders although it is best reserved for acute inflammatory conditions. For most tendon conditions resulting from overuse, the term “tendinosis” is now more widely recognized and preferred.^7,8 Family physicians (FPs) should recognize that tendinitis and tendinosis differ greatly in pathophysiology and treatment.³

Tendinitis: Not as common as you think

Tendinitis is an acute inflammatory condition that accounts for only about 3% of all tendon disorders.³ Patients presenting with tendinitis usually have acute onset of pain and swelling typically either from a new activity or one to which they are unaccustomed (eg, lateral elbow pain after painting a house) or from an acute injury. Partial tearing of the affected tendon is likely, especially following injury.^2,3

Tendinosis: A degenerative condition

In contrast to the acute inflammation of tendinitis, tendinosis is a degenerative condition induced by chronic overuse. It is typically encountered in athletes and laborers.^2,5,8,9 Tendinotic tissue is generally regarded as noninflammatory, but recent research supports inflammation playing at least a small role, especially in closely associated tissues such as bursae and the paratenon tissue.¹⁰

Continue to: Histologically, tendinosis shows...

Histologically, tendinosis shows loss of the typical linear collagen fiber organization, increased mucoid ground substance, hypercellularity, and increased growth of nerves and vessels (FIGURE 1B).

Tendinosis is not always symptomatic.^5,11 When pain is present, experts have proposed that it is neurogenically derived rather than from local chemical inflammation. This is supported by evidence of increases in the excitatory neurotransmitter glutamate and its receptor N-methyl-D-aspartate in tendinotic tissue with nerve ingrowth. Tendinotic tissue also contains substance P and calcitonin gene-related peptide, neuropeptides that are associated with pain and nociceptive nerve endings.^2,3,6,10

Patients with tendinosis typically present with an insidious onset of a painful, thickened tendon.¹¹ The most common tendons affected include the Achilles, the patellar, the supraspinatus, and the common extensor tendon of the lateral elbow.² Lower extremity tendinosis is common in athletes, while upper extremity tendinopathies are more often work-related.³

Paratenonitis: Inflammation surrounding the tendon

Occasionally, tendinosis may be associated with paratenonitis, which is inflammation of the paratenon (tissue surrounding some tendons).^2,5,10 Paratendinous tissue contains a higher concentration of sensory nerves than the tendon itself and may generate significant discomfort.^10,11

The clinical presentation of paratenonitis includes a swollen and erythematous tendon.⁵ The classic example—de Quervain disease—involves the first dorsal wrist compartment, in which the abductor pollicis longus and extensor pollicis brevis tendons are encased in a synovial sheath. The term tenosynovitis is commonly used to indicate inflammation of both the paratenon and synovial sheath (TABLE 1^2,3,5,6,9-11).⁵

Continue to: Treatment demands time and patience

 

 

Treatment demands time and patience

Treating tendon conditions is challenging for both the patient and the clinician. Improvement takes time and several different treatment strategies may be required for success. Given the large number of available treatment options and the often weak or limited supporting evidence of their efficacy, designing a treatment plan can be difficult. TABLE 2 summarizes the information detailed below about specific treatment options.

First-line treatments. The vast majority of patients with tendon problems are successfully treated nonoperatively. Reasonable first-line treatments, especially for inflammatory conditions like tendinitis, tenosynovitis, and paratenonitis, include relative rest, activity modification, cryotherapy, and bracing.^12-14

Nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control are somewhat controversial. At best, they provide pain relief in the short term (7-14 days); at worst, some studies suggest potential detrimental effects to the tendon.¹⁴ If considered, NSAIDs should be used for no longer than 2 weeks. They are ideally reserved for pain control in patients with acute injuries when an inflammatory condition is likely. An alternative for pain control in inflammatory cases is a short course of oral steroids, but the adverse effects of these medications may be challenging for some patients.

Other options. If these more conservative treatments fail, or the patient is experiencing significant and debilitating pain, FPs may consider a corticosteroid injection. If this fails, or the condition is clearly past an inflammatory stage, then physical therapy should be considered. More advanced treatments, such as platelet-rich plasma injections and percutaneous needle tenotomies, are typically reserved for chronic, recalcitrant cases of tendinosis. Various other treatment options are detailed below and can be used on a case-by-case basis. Surgical management should be considered only as a last resort.

Reserve use of NSAIDs for pain control in patients with acute injuries when an inflammatory condition is likely.

Realize that certain barriers may exist to some of these treatments. With extracorporeal shockwave therapy, for example, access to a machine can be challenging, as they are typically only found in major metropolitan areas. Polidocanol, used during sclerotherapy, can be difficult to obtain in the United States. Another challenge is cost. Not all of these procedures are covered by insurance, and they can be expensive when paying out of pocket.

Continue to: Rehabilitation...

 

 

Rehabilitation: Eccentric exercises and deep-friction massage

Studies show that eccentric exercises (EEs) help to decrease vascularity and nerve presence in affected tendons, modulate expression of neuronal substances, and may stimulate formation of load-tolerant fibroblasts.^2,3

Plateletrich plasma injections are typically expensive; whole blood is less expensive because there's no manipulation of the blood product.

For Achilles tendinosis, EE is a well-­established treatment supported by multiple randomized controlled trials (RCTs). Improvements in patient satisfaction and pain range from 60% to 90%; evidence suggests greater success in midsubstance vs insertional Achilles tendinosis.¹⁵ The addition of deep-friction massage (DFM), which we’ll discuss in a moment, to EE appears to improve outcomes even more than EE alone.¹⁶

EE is also a beneficial treatment for patellar tendinosis,^3,14 and it appears to benefit rotator cuff tendinosis,³ but research has shown EE for lateral epicondylosis to be no more effective than stretching alone.¹⁷

Recommend deep-friction massage for tendinosis—not inflammatory conditions.

DFM is for treating tendinosis—not inflammatory conditions. Mechanical stimulation of the tissue being massaged releases cell mediators and growth factors that activate fibroblasts. It is typically performed with plastic or metal tools.¹⁶ DFM appears to be a reliable treatment option for the lateral elbow.¹⁸

Extracorporeal shockwave therapy appears promising; evidence is limited

Research has shown that extracorporeal shockwave therapy (ESWT) promotes the production of TGF-β1 and IGF-1 in rat models,² and it is believed to be able to disintegrate calcium deposits and stimulate tissue repair.¹⁴ Research is generally supportive of its effectiveness in treating tendinosis; however, evidence is limited by great variability in studies in terms of treatment intensity, frequency, duration, timing, number of treatments, and use of a local anesthetic.¹⁴ ESWT appears to be useful in augmenting treatment with EE, particularly with regard to the rotator cuff.¹⁹

Continue to: A review of 10 RCTs...

A review of 10 RCTs demonstrated the effectiveness of ESWT for tennis elbow.² ESWT for greater trochanteric pain syndrome (GTPS, formerly known as trochanteric bursitis) appears to be more effective than corticosteroids and home exercises for outcomes at 4 months and equivalent to home exercises at 15 months.²⁰ In patellar tendinosis, ESWT has been shown to be an effective treatment, especially under ultrasound guidance.¹² Studies involving the use of ESWT for Achilles tendinosis have had mixed results for midsubstance tendinosis, and more positive results for insertional tendinosis.¹⁵ For a video on how the therapy is administered, see https://www.youtube.com/watch?v=Fq5yqiWByX4.

Glyceryl trinitrate patches: Mixed results

Basic science studies have shown that nitric oxide modulates tendon healing by enhancing fibroblast proliferation and collagen synthesis,^2,14 but that it should be used with caution in cardiac patients and in those who take PDE-5 inhibitors. Common adverse effects include rash, headache, and dizziness.

Use glyceryl trinitrate patches with caution in cardiac patients and in those who take PDE-5 inhibitors.

In clinical studies, glyceryl trinitrate (GTN) patches show mixed results. For the upper extremity, GTN appears to be helpful for pain in the short term when combined with physical therapy, but long-term positive outcomes have been absent.²¹ In one Level 1 study for patellar tendinosis comparing GTN patches with EE to a placebo patch with EE, no significant difference was noted at 24 weeks.²² Benefit for Achilles tendinosis also appears to be lacking.^3,23

Corticosteroid injections: Mechanism unknown

The mechanism for the beneficial effects of corticosteroid injections (CSIs) for tendinosis remains controversial. Proposed mechanisms include lysis of peritendinous adhesions, disruption of the nociceptors in the region of the injection, and decreased vascularization.^10,15 Given tendinosis is generally regarded as a noninflammatory condition, and the fact that these medications have demonstrated potential negative effects on tendon healing, exercise caution when considering CSIs.^2,24

Although steroids can effectively reduce pain in the short term, intermediate- and long-term studies generally show no difference or worse outcomes when they are compared to no treatment, placebo, or other treatment modalities. In fact, strong evidence exists for negative effects of steroids on lateral epicondylosis in both the intermediate (6 months) and long (1 year) term.²⁴ Particular care is required when administering a CSI for medial epicondylosis, as the ulnar nerve is immediately posterior to the medial epicondyle.²⁵

Continue to: In contrast...

In contrast, CSIs appear to be a reliable treatment option for de Quervain disease.²⁶ Landmark-guided injections for GTPS can improve pain in the short term (< 1 month), but are inferior to either home exercises or ESWT beyond a few months. Thus, CSIs are a reasonable option for pain control in GTPS, but should not be the sole treatment modality.²⁰

Studies regarding corticosteroid use for Achilles and patellar tendinosis have had mixed results. Patients can hope for mild improvement in pain at best, and the risk for relapse and tendon rupture is ever present.²⁷ This is especially concerning given the significant load-bearing of the patellar and Achilles tendons.^14,15 If you are considering a CSI for these purposes, use imaging guidance to ensure the injection is not placed intratendinously.

Platelet-rich plasma and whole blood: Inducing an anabolic healing response

Platelet-rich plasma (PRP) and whole blood injections both aim to deliver autologous growth factors (eg, VEGF, PDGF, and IGF-1) and bioactive mediators to the site of tendinosis to induce an anabolic healing response. PRP therapy differs from whole blood therapy in that it is withdrawn and then concentrated in a centrifuge before being injected. Patients are typically injected under ultrasound guidance. The great variation in PRP preparation, platelet concentration, use of adjunctive treatments, leukocyte concentration, and number and technique of injections makes it difficult to determine the optimal PRP treatment protocol.^10,28,29

In 1 prospective RCT comparing subacromial PRP injections to CSI for the shoulder, the PRP group had better outcomes at 3 months, but similar outcomes at 6 months. The suggestion was made that PRP therapy could be an alternative treatment for individuals with a contraindication to CSIs.³⁰

PRP therapy appears to be an effective treatment option for patellar tendinopathy.^28,31 A Level 1 study comparing dry needle tenotomy and EE to dry needle tenotomy with both PRP therapy and EE found faster recovery in the PRP group.³² In another patellar tendon study comparing ESWT to PRP therapy, both were found to be effective, but PRP performed better in terms of pain, function, and satisfaction at 6 and 12 months.¹² For Achilles tendons, however, the evidence is mixed; case series have had generally positive outcomes, but the only double-blind RCT found no benefit.^28,31

Continue to: In lateral epicondylosis...

In lateral epicondylosis, the use of auto-logous whole blood or PRP injections appears to help both pain and function, with several studies failing to demonstrate superiority of 1 modality over the other.^24,25,28,33 This raises the issue of whether PRP therapy is any more effective than whole blood for the treatment of other tendinopathies. Unfortunately, there is a paucity of studies comparing the effectiveness of 1 modality to the other, apart from those for lateral epicondylosis.

Prolotherapy: An option for these 3 conditions

Prolotherapy involves the injection of hypertonic dextrose and local anesthetic, which is believed to lead to an upregulation of inflammatory mediators and growth factors. This treatment usually involves several injections spaced 2 to 6 weeks apart over several months. High-quality studies are not available to clarify the optimal dextrose concentration or number of injections required. The few high-quality studies available support prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease. Lesser-quality studies support its use for refractory pain of the Achilles, hip adductors, and plantar fascia.^24,34

Sclerotherapy: Not just for veins

As discussed earlier, tendinotic tissue can have neovascularization that is easily detected on Doppler ultrasound. Sensory nerves typically grow alongside the new vessels. Sclerosing agents, such as polidocanol, can be injected with ultrasound guidance into areas of neovascularization, with the intention of causing denervation and pain relief.¹⁵ Neovascularization does not always correlate with pathology, so careful patient selection is necessary.³⁵

Exercise caution when considering corticosteroid injections for tendinosis.

Studies of sclerotherapy for patellar tendinopathy are generally favorable. One comparing sclerotherapy to arthroscopic debridement showed improvement in pain from both treatments at 6 and 12 months, but the arthroscopy group had less pain, better satisfaction scores, and a faster return to sport.¹⁴ Sclerotherapy is also effective for Achilles tendinosis.¹⁵

Stem cells: Not at this time

Stem cell use for tendinosis is based on the theory that these cells possess the capability to differentiate into tenocytes to produce new, healthy tendon tissue. Additionally, stem cell injections are believed to create a local immune response, recruiting local growth factors and cytokines to aide in tendon repair. A recent systematic review failed to identify any high-quality studies (Level 4 data at best) supporting the use of stem cells in tendinopathy, and the researchers did not recommend stem cell use outside of clinical trials at this time.³⁶

Continue to: Percutaneous needle tenotomy...

 

 

Percutaneous needle tenotomy: Consider it for difficult cases

Percutaneous needle tenotomy is thought to benefit tendinosis by disrupting the tendinotic tissue via needling, while simultaneously causing bleeding and the release of growth factors to aid in healing. Unlike surgical ­tenotomy, the procedure is typically performed with ultrasound guidance in the office or other ambulatory setting. After local anesthesia is administered, a needle is passed multiple times through the entire region of abnormality noted on ultrasound. Generally, around 20 to 30 needle fenestrations are performed.^37,38

Consider prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease.

In one retrospective study evaluating 47 patellar tendons, 81% had excellent or good results.³⁸ In a retrospective study for lateral epicondylosis, 80% had good to excellent results.³⁹

CORRESPONDENCE
Kyle Goerl, MD, CAQSM, Lafene Health Center, 1105 Sunset Avenue, Manhattan, KS, 66502-3761; kvg3355@ksu.edu.

The vast majority of patients with tendon problems are successfully treated nonoperatively. But which treatments should you try (and when), and which are not quite ready for prime time? This review presents the evidence for the treatment options available to you. But first, it’s important to get our terminology right.

Tendinitis vs tendinosis vs paratenonitis: Words matter

The term “tendinopathy” encompasses many issues related to tendon pathology including tendinitis, tendinosis, and paratenonitis.^1,2 The clinical syndrome consists of pain, swelling, and functional impairment associated with activities of daily living or athletic performance.³ Tendinopathy may be acute or chronic, but most cases result from overuse.¹

In healthy tendons, the collagen fibers are packed tightly and organized in a linear pattern (FIGURE 1A). However, tendons that are chronically overused develop cumulative microtrauma that leads to a degenerative process within the tendon that is slow (typically measured in months) to heal. This is due to the relative lack of vasculature and the slow rate of tissue turnover in tendons.^2,4,5

Sports and manual labor are the most common causes of tendinopathy, but medical conditions including obesity, high blood pressure, diabetes, and high cholesterol are associated risk factors. Medications, particularly fluoroquinolones and statins, can cause tendon problems, and steroids, particularly those injected intratendinously, have been implicated in tendon rupture.^4,6

The term “tendinitis” has long been used for all tendon disorders although it is best reserved for acute inflammatory conditions. For most tendon conditions resulting from overuse, the term “tendinosis” is now more widely recognized and preferred.^7,8 Family physicians (FPs) should recognize that tendinitis and tendinosis differ greatly in pathophysiology and treatment.³

Tendinitis: Not as common as you think

Tendinitis is an acute inflammatory condition that accounts for only about 3% of all tendon disorders.³ Patients presenting with tendinitis usually have acute onset of pain and swelling typically either from a new activity or one to which they are unaccustomed (eg, lateral elbow pain after painting a house) or from an acute injury. Partial tearing of the affected tendon is likely, especially following injury.^2,3

Tendinosis: A degenerative condition

In contrast to the acute inflammation of tendinitis, tendinosis is a degenerative condition induced by chronic overuse. It is typically encountered in athletes and laborers.^2,5,8,9 Tendinotic tissue is generally regarded as noninflammatory, but recent research supports inflammation playing at least a small role, especially in closely associated tissues such as bursae and the paratenon tissue.¹⁰

Continue to: Histologically, tendinosis shows...

Histologically, tendinosis shows loss of the typical linear collagen fiber organization, increased mucoid ground substance, hypercellularity, and increased growth of nerves and vessels (FIGURE 1B).

Tendinosis is not always symptomatic.^5,11 When pain is present, experts have proposed that it is neurogenically derived rather than from local chemical inflammation. This is supported by evidence of increases in the excitatory neurotransmitter glutamate and its receptor N-methyl-D-aspartate in tendinotic tissue with nerve ingrowth. Tendinotic tissue also contains substance P and calcitonin gene-related peptide, neuropeptides that are associated with pain and nociceptive nerve endings.^2,3,6,10

Patients with tendinosis typically present with an insidious onset of a painful, thickened tendon.¹¹ The most common tendons affected include the Achilles, the patellar, the supraspinatus, and the common extensor tendon of the lateral elbow.² Lower extremity tendinosis is common in athletes, while upper extremity tendinopathies are more often work-related.³

Paratenonitis: Inflammation surrounding the tendon

Occasionally, tendinosis may be associated with paratenonitis, which is inflammation of the paratenon (tissue surrounding some tendons).^2,5,10 Paratendinous tissue contains a higher concentration of sensory nerves than the tendon itself and may generate significant discomfort.^10,11

The clinical presentation of paratenonitis includes a swollen and erythematous tendon.⁵ The classic example—de Quervain disease—involves the first dorsal wrist compartment, in which the abductor pollicis longus and extensor pollicis brevis tendons are encased in a synovial sheath. The term tenosynovitis is commonly used to indicate inflammation of both the paratenon and synovial sheath (TABLE 1^2,3,5,6,9-11).⁵

Continue to: Treatment demands time and patience

 

 

Treatment demands time and patience

Treating tendon conditions is challenging for both the patient and the clinician. Improvement takes time and several different treatment strategies may be required for success. Given the large number of available treatment options and the often weak or limited supporting evidence of their efficacy, designing a treatment plan can be difficult. TABLE 2 summarizes the information detailed below about specific treatment options.

First-line treatments. The vast majority of patients with tendon problems are successfully treated nonoperatively. Reasonable first-line treatments, especially for inflammatory conditions like tendinitis, tenosynovitis, and paratenonitis, include relative rest, activity modification, cryotherapy, and bracing.^12-14

Nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control are somewhat controversial. At best, they provide pain relief in the short term (7-14 days); at worst, some studies suggest potential detrimental effects to the tendon.¹⁴ If considered, NSAIDs should be used for no longer than 2 weeks. They are ideally reserved for pain control in patients with acute injuries when an inflammatory condition is likely. An alternative for pain control in inflammatory cases is a short course of oral steroids, but the adverse effects of these medications may be challenging for some patients.

Other options. If these more conservative treatments fail, or the patient is experiencing significant and debilitating pain, FPs may consider a corticosteroid injection. If this fails, or the condition is clearly past an inflammatory stage, then physical therapy should be considered. More advanced treatments, such as platelet-rich plasma injections and percutaneous needle tenotomies, are typically reserved for chronic, recalcitrant cases of tendinosis. Various other treatment options are detailed below and can be used on a case-by-case basis. Surgical management should be considered only as a last resort.

Reserve use of NSAIDs for pain control in patients with acute injuries when an inflammatory condition is likely.

Realize that certain barriers may exist to some of these treatments. With extracorporeal shockwave therapy, for example, access to a machine can be challenging, as they are typically only found in major metropolitan areas. Polidocanol, used during sclerotherapy, can be difficult to obtain in the United States. Another challenge is cost. Not all of these procedures are covered by insurance, and they can be expensive when paying out of pocket.

Continue to: Rehabilitation...

 

 

Rehabilitation: Eccentric exercises and deep-friction massage

Studies show that eccentric exercises (EEs) help to decrease vascularity and nerve presence in affected tendons, modulate expression of neuronal substances, and may stimulate formation of load-tolerant fibroblasts.^2,3

Plateletrich plasma injections are typically expensive; whole blood is less expensive because there's no manipulation of the blood product.

For Achilles tendinosis, EE is a well-­established treatment supported by multiple randomized controlled trials (RCTs). Improvements in patient satisfaction and pain range from 60% to 90%; evidence suggests greater success in midsubstance vs insertional Achilles tendinosis.¹⁵ The addition of deep-friction massage (DFM), which we’ll discuss in a moment, to EE appears to improve outcomes even more than EE alone.¹⁶

EE is also a beneficial treatment for patellar tendinosis,^3,14 and it appears to benefit rotator cuff tendinosis,³ but research has shown EE for lateral epicondylosis to be no more effective than stretching alone.¹⁷

Recommend deep-friction massage for tendinosis—not inflammatory conditions.

DFM is for treating tendinosis—not inflammatory conditions. Mechanical stimulation of the tissue being massaged releases cell mediators and growth factors that activate fibroblasts. It is typically performed with plastic or metal tools.¹⁶ DFM appears to be a reliable treatment option for the lateral elbow.¹⁸

Extracorporeal shockwave therapy appears promising; evidence is limited

Research has shown that extracorporeal shockwave therapy (ESWT) promotes the production of TGF-β1 and IGF-1 in rat models,² and it is believed to be able to disintegrate calcium deposits and stimulate tissue repair.¹⁴ Research is generally supportive of its effectiveness in treating tendinosis; however, evidence is limited by great variability in studies in terms of treatment intensity, frequency, duration, timing, number of treatments, and use of a local anesthetic.¹⁴ ESWT appears to be useful in augmenting treatment with EE, particularly with regard to the rotator cuff.¹⁹

Continue to: A review of 10 RCTs...

A review of 10 RCTs demonstrated the effectiveness of ESWT for tennis elbow.² ESWT for greater trochanteric pain syndrome (GTPS, formerly known as trochanteric bursitis) appears to be more effective than corticosteroids and home exercises for outcomes at 4 months and equivalent to home exercises at 15 months.²⁰ In patellar tendinosis, ESWT has been shown to be an effective treatment, especially under ultrasound guidance.¹² Studies involving the use of ESWT for Achilles tendinosis have had mixed results for midsubstance tendinosis, and more positive results for insertional tendinosis.¹⁵ For a video on how the therapy is administered, see https://www.youtube.com/watch?v=Fq5yqiWByX4.

Glyceryl trinitrate patches: Mixed results

Basic science studies have shown that nitric oxide modulates tendon healing by enhancing fibroblast proliferation and collagen synthesis,^2,14 but that it should be used with caution in cardiac patients and in those who take PDE-5 inhibitors. Common adverse effects include rash, headache, and dizziness.

Use glyceryl trinitrate patches with caution in cardiac patients and in those who take PDE-5 inhibitors.

In clinical studies, glyceryl trinitrate (GTN) patches show mixed results. For the upper extremity, GTN appears to be helpful for pain in the short term when combined with physical therapy, but long-term positive outcomes have been absent.²¹ In one Level 1 study for patellar tendinosis comparing GTN patches with EE to a placebo patch with EE, no significant difference was noted at 24 weeks.²² Benefit for Achilles tendinosis also appears to be lacking.^3,23

Corticosteroid injections: Mechanism unknown

The mechanism for the beneficial effects of corticosteroid injections (CSIs) for tendinosis remains controversial. Proposed mechanisms include lysis of peritendinous adhesions, disruption of the nociceptors in the region of the injection, and decreased vascularization.^10,15 Given tendinosis is generally regarded as a noninflammatory condition, and the fact that these medications have demonstrated potential negative effects on tendon healing, exercise caution when considering CSIs.^2,24

Although steroids can effectively reduce pain in the short term, intermediate- and long-term studies generally show no difference or worse outcomes when they are compared to no treatment, placebo, or other treatment modalities. In fact, strong evidence exists for negative effects of steroids on lateral epicondylosis in both the intermediate (6 months) and long (1 year) term.²⁴ Particular care is required when administering a CSI for medial epicondylosis, as the ulnar nerve is immediately posterior to the medial epicondyle.²⁵

Continue to: In contrast...

In contrast, CSIs appear to be a reliable treatment option for de Quervain disease.²⁶ Landmark-guided injections for GTPS can improve pain in the short term (< 1 month), but are inferior to either home exercises or ESWT beyond a few months. Thus, CSIs are a reasonable option for pain control in GTPS, but should not be the sole treatment modality.²⁰

Studies regarding corticosteroid use for Achilles and patellar tendinosis have had mixed results. Patients can hope for mild improvement in pain at best, and the risk for relapse and tendon rupture is ever present.²⁷ This is especially concerning given the significant load-bearing of the patellar and Achilles tendons.^14,15 If you are considering a CSI for these purposes, use imaging guidance to ensure the injection is not placed intratendinously.

Platelet-rich plasma and whole blood: Inducing an anabolic healing response

Platelet-rich plasma (PRP) and whole blood injections both aim to deliver autologous growth factors (eg, VEGF, PDGF, and IGF-1) and bioactive mediators to the site of tendinosis to induce an anabolic healing response. PRP therapy differs from whole blood therapy in that it is withdrawn and then concentrated in a centrifuge before being injected. Patients are typically injected under ultrasound guidance. The great variation in PRP preparation, platelet concentration, use of adjunctive treatments, leukocyte concentration, and number and technique of injections makes it difficult to determine the optimal PRP treatment protocol.^10,28,29

In 1 prospective RCT comparing subacromial PRP injections to CSI for the shoulder, the PRP group had better outcomes at 3 months, but similar outcomes at 6 months. The suggestion was made that PRP therapy could be an alternative treatment for individuals with a contraindication to CSIs.³⁰

PRP therapy appears to be an effective treatment option for patellar tendinopathy.^28,31 A Level 1 study comparing dry needle tenotomy and EE to dry needle tenotomy with both PRP therapy and EE found faster recovery in the PRP group.³² In another patellar tendon study comparing ESWT to PRP therapy, both were found to be effective, but PRP performed better in terms of pain, function, and satisfaction at 6 and 12 months.¹² For Achilles tendons, however, the evidence is mixed; case series have had generally positive outcomes, but the only double-blind RCT found no benefit.^28,31

Continue to: In lateral epicondylosis...

In lateral epicondylosis, the use of auto-logous whole blood or PRP injections appears to help both pain and function, with several studies failing to demonstrate superiority of 1 modality over the other.^24,25,28,33 This raises the issue of whether PRP therapy is any more effective than whole blood for the treatment of other tendinopathies. Unfortunately, there is a paucity of studies comparing the effectiveness of 1 modality to the other, apart from those for lateral epicondylosis.

Prolotherapy: An option for these 3 conditions

Prolotherapy involves the injection of hypertonic dextrose and local anesthetic, which is believed to lead to an upregulation of inflammatory mediators and growth factors. This treatment usually involves several injections spaced 2 to 6 weeks apart over several months. High-quality studies are not available to clarify the optimal dextrose concentration or number of injections required. The few high-quality studies available support prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease. Lesser-quality studies support its use for refractory pain of the Achilles, hip adductors, and plantar fascia.^24,34

Sclerotherapy: Not just for veins

As discussed earlier, tendinotic tissue can have neovascularization that is easily detected on Doppler ultrasound. Sensory nerves typically grow alongside the new vessels. Sclerosing agents, such as polidocanol, can be injected with ultrasound guidance into areas of neovascularization, with the intention of causing denervation and pain relief.¹⁵ Neovascularization does not always correlate with pathology, so careful patient selection is necessary.³⁵

Exercise caution when considering corticosteroid injections for tendinosis.

Studies of sclerotherapy for patellar tendinopathy are generally favorable. One comparing sclerotherapy to arthroscopic debridement showed improvement in pain from both treatments at 6 and 12 months, but the arthroscopy group had less pain, better satisfaction scores, and a faster return to sport.¹⁴ Sclerotherapy is also effective for Achilles tendinosis.¹⁵

Stem cells: Not at this time

Stem cell use for tendinosis is based on the theory that these cells possess the capability to differentiate into tenocytes to produce new, healthy tendon tissue. Additionally, stem cell injections are believed to create a local immune response, recruiting local growth factors and cytokines to aide in tendon repair. A recent systematic review failed to identify any high-quality studies (Level 4 data at best) supporting the use of stem cells in tendinopathy, and the researchers did not recommend stem cell use outside of clinical trials at this time.³⁶

Continue to: Percutaneous needle tenotomy...

 

 

Percutaneous needle tenotomy: Consider it for difficult cases

Percutaneous needle tenotomy is thought to benefit tendinosis by disrupting the tendinotic tissue via needling, while simultaneously causing bleeding and the release of growth factors to aid in healing. Unlike surgical ­tenotomy, the procedure is typically performed with ultrasound guidance in the office or other ambulatory setting. After local anesthesia is administered, a needle is passed multiple times through the entire region of abnormality noted on ultrasound. Generally, around 20 to 30 needle fenestrations are performed.^37,38

Consider prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease.

In one retrospective study evaluating 47 patellar tendons, 81% had excellent or good results.³⁸ In a retrospective study for lateral epicondylosis, 80% had good to excellent results.³⁹

CORRESPONDENCE
Kyle Goerl, MD, CAQSM, Lafene Health Center, 1105 Sunset Avenue, Manhattan, KS, 66502-3761; kvg3355@ksu.edu.

The vast majority of patients with tendon problems are successfully treated nonoperatively. But which treatments should you try (and when), and which are not quite ready for prime time? This review presents the evidence for the treatment options available to you. But first, it’s important to get our terminology right.

Tendinitis vs tendinosis vs paratenonitis: Words matter

The term “tendinopathy” encompasses many issues related to tendon pathology including tendinitis, tendinosis, and paratenonitis.^1,2 The clinical syndrome consists of pain, swelling, and functional impairment associated with activities of daily living or athletic performance.³ Tendinopathy may be acute or chronic, but most cases result from overuse.¹

In healthy tendons, the collagen fibers are packed tightly and organized in a linear pattern (FIGURE 1A). However, tendons that are chronically overused develop cumulative microtrauma that leads to a degenerative process within the tendon that is slow (typically measured in months) to heal. This is due to the relative lack of vasculature and the slow rate of tissue turnover in tendons.^2,4,5

Sports and manual labor are the most common causes of tendinopathy, but medical conditions including obesity, high blood pressure, diabetes, and high cholesterol are associated risk factors. Medications, particularly fluoroquinolones and statins, can cause tendon problems, and steroids, particularly those injected intratendinously, have been implicated in tendon rupture.^4,6

The term “tendinitis” has long been used for all tendon disorders although it is best reserved for acute inflammatory conditions. For most tendon conditions resulting from overuse, the term “tendinosis” is now more widely recognized and preferred.^7,8 Family physicians (FPs) should recognize that tendinitis and tendinosis differ greatly in pathophysiology and treatment.³

Tendinitis: Not as common as you think

Tendinitis is an acute inflammatory condition that accounts for only about 3% of all tendon disorders.³ Patients presenting with tendinitis usually have acute onset of pain and swelling typically either from a new activity or one to which they are unaccustomed (eg, lateral elbow pain after painting a house) or from an acute injury. Partial tearing of the affected tendon is likely, especially following injury.^2,3

Tendinosis: A degenerative condition

In contrast to the acute inflammation of tendinitis, tendinosis is a degenerative condition induced by chronic overuse. It is typically encountered in athletes and laborers.^2,5,8,9 Tendinotic tissue is generally regarded as noninflammatory, but recent research supports inflammation playing at least a small role, especially in closely associated tissues such as bursae and the paratenon tissue.¹⁰

Continue to: Histologically, tendinosis shows...

Histologically, tendinosis shows loss of the typical linear collagen fiber organization, increased mucoid ground substance, hypercellularity, and increased growth of nerves and vessels (FIGURE 1B).

Tendinosis is not always symptomatic.^5,11 When pain is present, experts have proposed that it is neurogenically derived rather than from local chemical inflammation. This is supported by evidence of increases in the excitatory neurotransmitter glutamate and its receptor N-methyl-D-aspartate in tendinotic tissue with nerve ingrowth. Tendinotic tissue also contains substance P and calcitonin gene-related peptide, neuropeptides that are associated with pain and nociceptive nerve endings.^2,3,6,10

Patients with tendinosis typically present with an insidious onset of a painful, thickened tendon.¹¹ The most common tendons affected include the Achilles, the patellar, the supraspinatus, and the common extensor tendon of the lateral elbow.² Lower extremity tendinosis is common in athletes, while upper extremity tendinopathies are more often work-related.³

Paratenonitis: Inflammation surrounding the tendon

Occasionally, tendinosis may be associated with paratenonitis, which is inflammation of the paratenon (tissue surrounding some tendons).^2,5,10 Paratendinous tissue contains a higher concentration of sensory nerves than the tendon itself and may generate significant discomfort.^10,11

The clinical presentation of paratenonitis includes a swollen and erythematous tendon.⁵ The classic example—de Quervain disease—involves the first dorsal wrist compartment, in which the abductor pollicis longus and extensor pollicis brevis tendons are encased in a synovial sheath. The term tenosynovitis is commonly used to indicate inflammation of both the paratenon and synovial sheath (TABLE 1^2,3,5,6,9-11).⁵

Continue to: Treatment demands time and patience

 

 

Treatment demands time and patience

Treating tendon conditions is challenging for both the patient and the clinician. Improvement takes time and several different treatment strategies may be required for success. Given the large number of available treatment options and the often weak or limited supporting evidence of their efficacy, designing a treatment plan can be difficult. TABLE 2 summarizes the information detailed below about specific treatment options.

First-line treatments. The vast majority of patients with tendon problems are successfully treated nonoperatively. Reasonable first-line treatments, especially for inflammatory conditions like tendinitis, tenosynovitis, and paratenonitis, include relative rest, activity modification, cryotherapy, and bracing.^12-14

Nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control are somewhat controversial. At best, they provide pain relief in the short term (7-14 days); at worst, some studies suggest potential detrimental effects to the tendon.¹⁴ If considered, NSAIDs should be used for no longer than 2 weeks. They are ideally reserved for pain control in patients with acute injuries when an inflammatory condition is likely. An alternative for pain control in inflammatory cases is a short course of oral steroids, but the adverse effects of these medications may be challenging for some patients.

Other options. If these more conservative treatments fail, or the patient is experiencing significant and debilitating pain, FPs may consider a corticosteroid injection. If this fails, or the condition is clearly past an inflammatory stage, then physical therapy should be considered. More advanced treatments, such as platelet-rich plasma injections and percutaneous needle tenotomies, are typically reserved for chronic, recalcitrant cases of tendinosis. Various other treatment options are detailed below and can be used on a case-by-case basis. Surgical management should be considered only as a last resort.

Reserve use of NSAIDs for pain control in patients with acute injuries when an inflammatory condition is likely.

Realize that certain barriers may exist to some of these treatments. With extracorporeal shockwave therapy, for example, access to a machine can be challenging, as they are typically only found in major metropolitan areas. Polidocanol, used during sclerotherapy, can be difficult to obtain in the United States. Another challenge is cost. Not all of these procedures are covered by insurance, and they can be expensive when paying out of pocket.

Continue to: Rehabilitation...

 

 

Rehabilitation: Eccentric exercises and deep-friction massage

Studies show that eccentric exercises (EEs) help to decrease vascularity and nerve presence in affected tendons, modulate expression of neuronal substances, and may stimulate formation of load-tolerant fibroblasts.^2,3

Plateletrich plasma injections are typically expensive; whole blood is less expensive because there's no manipulation of the blood product.

For Achilles tendinosis, EE is a well-­established treatment supported by multiple randomized controlled trials (RCTs). Improvements in patient satisfaction and pain range from 60% to 90%; evidence suggests greater success in midsubstance vs insertional Achilles tendinosis.¹⁵ The addition of deep-friction massage (DFM), which we’ll discuss in a moment, to EE appears to improve outcomes even more than EE alone.¹⁶

EE is also a beneficial treatment for patellar tendinosis,^3,14 and it appears to benefit rotator cuff tendinosis,³ but research has shown EE for lateral epicondylosis to be no more effective than stretching alone.¹⁷

Recommend deep-friction massage for tendinosis—not inflammatory conditions.

DFM is for treating tendinosis—not inflammatory conditions. Mechanical stimulation of the tissue being massaged releases cell mediators and growth factors that activate fibroblasts. It is typically performed with plastic or metal tools.¹⁶ DFM appears to be a reliable treatment option for the lateral elbow.¹⁸

Extracorporeal shockwave therapy appears promising; evidence is limited

Research has shown that extracorporeal shockwave therapy (ESWT) promotes the production of TGF-β1 and IGF-1 in rat models,² and it is believed to be able to disintegrate calcium deposits and stimulate tissue repair.¹⁴ Research is generally supportive of its effectiveness in treating tendinosis; however, evidence is limited by great variability in studies in terms of treatment intensity, frequency, duration, timing, number of treatments, and use of a local anesthetic.¹⁴ ESWT appears to be useful in augmenting treatment with EE, particularly with regard to the rotator cuff.¹⁹

Continue to: A review of 10 RCTs...

A review of 10 RCTs demonstrated the effectiveness of ESWT for tennis elbow.² ESWT for greater trochanteric pain syndrome (GTPS, formerly known as trochanteric bursitis) appears to be more effective than corticosteroids and home exercises for outcomes at 4 months and equivalent to home exercises at 15 months.²⁰ In patellar tendinosis, ESWT has been shown to be an effective treatment, especially under ultrasound guidance.¹² Studies involving the use of ESWT for Achilles tendinosis have had mixed results for midsubstance tendinosis, and more positive results for insertional tendinosis.¹⁵ For a video on how the therapy is administered, see https://www.youtube.com/watch?v=Fq5yqiWByX4.

Glyceryl trinitrate patches: Mixed results

Basic science studies have shown that nitric oxide modulates tendon healing by enhancing fibroblast proliferation and collagen synthesis,^2,14 but that it should be used with caution in cardiac patients and in those who take PDE-5 inhibitors. Common adverse effects include rash, headache, and dizziness.

Use glyceryl trinitrate patches with caution in cardiac patients and in those who take PDE-5 inhibitors.

In clinical studies, glyceryl trinitrate (GTN) patches show mixed results. For the upper extremity, GTN appears to be helpful for pain in the short term when combined with physical therapy, but long-term positive outcomes have been absent.²¹ In one Level 1 study for patellar tendinosis comparing GTN patches with EE to a placebo patch with EE, no significant difference was noted at 24 weeks.²² Benefit for Achilles tendinosis also appears to be lacking.^3,23

Corticosteroid injections: Mechanism unknown

The mechanism for the beneficial effects of corticosteroid injections (CSIs) for tendinosis remains controversial. Proposed mechanisms include lysis of peritendinous adhesions, disruption of the nociceptors in the region of the injection, and decreased vascularization.^10,15 Given tendinosis is generally regarded as a noninflammatory condition, and the fact that these medications have demonstrated potential negative effects on tendon healing, exercise caution when considering CSIs.^2,24

Although steroids can effectively reduce pain in the short term, intermediate- and long-term studies generally show no difference or worse outcomes when they are compared to no treatment, placebo, or other treatment modalities. In fact, strong evidence exists for negative effects of steroids on lateral epicondylosis in both the intermediate (6 months) and long (1 year) term.²⁴ Particular care is required when administering a CSI for medial epicondylosis, as the ulnar nerve is immediately posterior to the medial epicondyle.²⁵

Continue to: In contrast...

In contrast, CSIs appear to be a reliable treatment option for de Quervain disease.²⁶ Landmark-guided injections for GTPS can improve pain in the short term (< 1 month), but are inferior to either home exercises or ESWT beyond a few months. Thus, CSIs are a reasonable option for pain control in GTPS, but should not be the sole treatment modality.²⁰

Studies regarding corticosteroid use for Achilles and patellar tendinosis have had mixed results. Patients can hope for mild improvement in pain at best, and the risk for relapse and tendon rupture is ever present.²⁷ This is especially concerning given the significant load-bearing of the patellar and Achilles tendons.^14,15 If you are considering a CSI for these purposes, use imaging guidance to ensure the injection is not placed intratendinously.

Platelet-rich plasma and whole blood: Inducing an anabolic healing response

Platelet-rich plasma (PRP) and whole blood injections both aim to deliver autologous growth factors (eg, VEGF, PDGF, and IGF-1) and bioactive mediators to the site of tendinosis to induce an anabolic healing response. PRP therapy differs from whole blood therapy in that it is withdrawn and then concentrated in a centrifuge before being injected. Patients are typically injected under ultrasound guidance. The great variation in PRP preparation, platelet concentration, use of adjunctive treatments, leukocyte concentration, and number and technique of injections makes it difficult to determine the optimal PRP treatment protocol.^10,28,29

In 1 prospective RCT comparing subacromial PRP injections to CSI for the shoulder, the PRP group had better outcomes at 3 months, but similar outcomes at 6 months. The suggestion was made that PRP therapy could be an alternative treatment for individuals with a contraindication to CSIs.³⁰

PRP therapy appears to be an effective treatment option for patellar tendinopathy.^28,31 A Level 1 study comparing dry needle tenotomy and EE to dry needle tenotomy with both PRP therapy and EE found faster recovery in the PRP group.³² In another patellar tendon study comparing ESWT to PRP therapy, both were found to be effective, but PRP performed better in terms of pain, function, and satisfaction at 6 and 12 months.¹² For Achilles tendons, however, the evidence is mixed; case series have had generally positive outcomes, but the only double-blind RCT found no benefit.^28,31

Continue to: In lateral epicondylosis...

In lateral epicondylosis, the use of auto-logous whole blood or PRP injections appears to help both pain and function, with several studies failing to demonstrate superiority of 1 modality over the other.^24,25,28,33 This raises the issue of whether PRP therapy is any more effective than whole blood for the treatment of other tendinopathies. Unfortunately, there is a paucity of studies comparing the effectiveness of 1 modality to the other, apart from those for lateral epicondylosis.

Prolotherapy: An option for these 3 conditions

Prolotherapy involves the injection of hypertonic dextrose and local anesthetic, which is believed to lead to an upregulation of inflammatory mediators and growth factors. This treatment usually involves several injections spaced 2 to 6 weeks apart over several months. High-quality studies are not available to clarify the optimal dextrose concentration or number of injections required. The few high-quality studies available support prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease. Lesser-quality studies support its use for refractory pain of the Achilles, hip adductors, and plantar fascia.^24,34

Sclerotherapy: Not just for veins

As discussed earlier, tendinotic tissue can have neovascularization that is easily detected on Doppler ultrasound. Sensory nerves typically grow alongside the new vessels. Sclerosing agents, such as polidocanol, can be injected with ultrasound guidance into areas of neovascularization, with the intention of causing denervation and pain relief.¹⁵ Neovascularization does not always correlate with pathology, so careful patient selection is necessary.³⁵

Exercise caution when considering corticosteroid injections for tendinosis.

Studies of sclerotherapy for patellar tendinopathy are generally favorable. One comparing sclerotherapy to arthroscopic debridement showed improvement in pain from both treatments at 6 and 12 months, but the arthroscopy group had less pain, better satisfaction scores, and a faster return to sport.¹⁴ Sclerotherapy is also effective for Achilles tendinosis.¹⁵

Stem cells: Not at this time

Stem cell use for tendinosis is based on the theory that these cells possess the capability to differentiate into tenocytes to produce new, healthy tendon tissue. Additionally, stem cell injections are believed to create a local immune response, recruiting local growth factors and cytokines to aide in tendon repair. A recent systematic review failed to identify any high-quality studies (Level 4 data at best) supporting the use of stem cells in tendinopathy, and the researchers did not recommend stem cell use outside of clinical trials at this time.³⁶

Continue to: Percutaneous needle tenotomy...

 

 

Percutaneous needle tenotomy: Consider it for difficult cases

Percutaneous needle tenotomy is thought to benefit tendinosis by disrupting the tendinotic tissue via needling, while simultaneously causing bleeding and the release of growth factors to aid in healing. Unlike surgical ­tenotomy, the procedure is typically performed with ultrasound guidance in the office or other ambulatory setting. After local anesthesia is administered, a needle is passed multiple times through the entire region of abnormality noted on ultrasound. Generally, around 20 to 30 needle fenestrations are performed.^37,38

Consider prolotherapy for lateral epicondylosis, rotator cuff tendinopathy, and Osgood Schlatter disease.

In one retrospective study evaluating 47 patellar tendons, 81% had excellent or good results.³⁸ In a retrospective study for lateral epicondylosis, 80% had good to excellent results.³⁹

CORRESPONDENCE
Kyle Goerl, MD, CAQSM, Lafene Health Center, 1105 Sunset Avenue, Manhattan, KS, 66502-3761; kvg3355@ksu.edu.

As of 2015, an estimated 30.2 million adults in the United States—12.2% of the population— had diabetes mellitus (DM). During that year, approximately 1.5 million new cases (6.7 cases for every 1000 people) were diagnosed in adults (≥ 18 years of age).¹

As the number of people with DM increases, so will the number of cases of diabetic retinopathy, the main cause of new cases of blindness in adults in the United States² and the leading cause of blindness among US working-age (20 to 74 years) adults.³ It is estimated that 4.1 million Americans have diabetic retinopathy³; it is projected that prevalence will reach 6 million this year.⁴

Blindness related to DM costs the United States approximately $500 million each year,⁵ including health care utilization: physician office visits, diagnostic testing, medication and other treatments, and hospitalization.⁶ Impairment of vision also results in social isolation, dependence on others to perform daily functions, and a decline in physical activity.

Several professional organizations, including the American Diabetes Association and the American Academy of Ophthalmology, have developed practice guidelines for diabetic retinopathy screening. Guidelines notwithstanding, only about 55% of people with DM in the United States receive the recommended dilated eye examination at established intervals.^2,3 In addition to screening by an ophthalmologist or optometrist, adherence to clinical guidelines for risk assessment, prevention, and early referral helps reduce the incidence and severity of retinopathy.⁵

The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had diabetes mellitus (DM) for < 5 years to 77.8% in people who had DM for ≥ 15 years.

This article describes how to assess the risk of diabetic retinopathy in your patients, details the crucial role that you, the primary care physician, can play in prevention, and emphasizes the importance of referral to an eye specialist for screening, evaluation, treatment (when indicated), and follow-up.

Pathophysiology and classification

Diabetic retinopathy, the result of progressive blood vessel damage to the retina, has 2 major forms: nonproliferative and proliferative. Those forms are distinguished by the absence or presence of new growth of blood vessels (retinal neovascularization).^3,7 To improve communication and coordination among physicians who care for patients with DM worldwide, the International Clinical Diabetic Retinopathy Disease Severity Scale for diabetic retinopathy was developed,^8-10 comprising 5 levels of severity that are based on findings on dilated ophthalmoscopy (Table 1^8-10):

• Level 1. No apparent retinopathy. Funduscopic abnormalities are absent.
• Level 2. Mild nonproliferative diabetic retinopathy (NPDR). Only a few microaneurysms are seen.
• Level 3: Moderate NPDR. Characterized by microaneurysms and by intraretinal hemorrhage and venous beading, but less severe than what is seen in Level 4.
• Level 4. Severe NPDR. More than 20 intraretinal hemorrhages in each quadrant of the retina, definite venous beading in > 2 quadrants, intraretinal microvascular abnormalities in > 1 quadrant, or any combination of these findings.
• Level 5. Proliferative diabetic retinopathy. Characterized by neovascularization of the disc, retina, iris, or angle; vitreous hemorrhage; retinal detachment; or any combination of these findings. Further classified as “mild,” “moderate,” or “severe” if macular edema is present; severity is dependent on the distance of thickening and exudates from the center of the macula.⁹

Be attentive to risk factors

There are several risk factors for diabetic retinopathy, including duration of disease, type 1 DM, male gender, black race (non-Hispanic), elevated hemoglobin A1C(HbA1C) level, elevated systolic and diastolic blood pressure (BP), and insulin therapy. ^4,5,11,12

Continue to: Time since diagnosis

Time since diagnosis. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had DM for < 5 years to 77.8% in people who had DM for ≥ 15 years. The rate of proliferative diabetic retinopathy was 2% in people who had DM for < 5 years and 15.5% in those who had DM for ≥ 15 years.¹¹

Diabetic retinopathy can deteriorate during pregnancy but generally reverts to the pre-pregnancy level; long-term progression of retinopathy is not affected.

Demographic variables. The prevalence of diabetic retinopathy is higher in men, non-Hispanic blacks (38.8%), and ­people with type 1 DM.^4,5,11-13 The Veterans ­Affairs Diabetes Trial found a higher prevalence of moderate-to-severe diabetic retinopathy in Hispanics (36%) and African Americans (29%) than in non-Hispanic whites (22%).¹⁴

Among people with DM who have ­diabetic retinopathy, systolic and diastolic BP and the HbA1C level tend to be higher. They are more likely to use insulin to control disease.^4,5,13 In a recent cross-sectional analysis, the prevalence of vision-threatening retinopathy was higher among people ≥ 65 years of age (1%; 95% confidence interval [CI], 0.7%-1.5%) than among people 40 to 64 years of age (0.4%; 95% CI, 0.3%-0.7%) (P = .009).⁵

Does pregnancy exacerbate retinopathy? Controversy surrounds the role of pregnancy in the development and progression of diabetic retinopathy. The Diabetes Control and Complications Trial found a short-term increase in the level of retinopathy during pregnancy that persisted into the first postpartum year. A 1.63-fold greater risk of any deterioration of retinopathy was observed in women who received intensive DM treatment from before to during pregnancy (P < .05); pregnant women who received conventional treatment had a 2.48-fold greater risk than nonpregnant women with DM who received conventional treatment (P < .001).

Deterioration of retinopathy during pregnancy had no long-term consequences, however, regardless of type of treatment.¹⁵ More importantly, in most cases, changes in the level of retinopathy revert to the pre-­pregnancy level after 1 year or longer, and pregnancy does not appear to affect long-term progression of retinopathy.¹⁵

Continue to: Proven primary prevention strategies

 

 

Proven primary prevention strategies

Glycemic control. Optimal glycemic control is an essential component of prevention of diabetic retinopathy. From 1983 to 1993, the Diabetes Control and Complications Trial randomized 1441 patients with type 1 DM to receive intensive therapy (median HbA1C level, 7.2%) or conventional therapy (median HbA1C level, 9.1%). During a mean of 6 years of follow-up, intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% CI, 62%-85%).^16,17 A 2007 systematic review of 44 studies of the treatment of diabetic retinopathy found that strict glycemic control was beneficial in reducing the incidence and progression of retinopathy.¹⁷

The American Diabetes Association’s Standards of Medical Care in Diabetes—2019 Abridged for Primary Care Providers recommends that most nonpregnant adults maintain an HbA1Clevel < 7%. For patients with a history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular disease, other significant comorbid conditions, or longstanding DM in which it is difficult to achieve the optimal goal, a higher HbA1clevel (< 8%) might be appropriate.¹⁸

Control of BP. Strict control of BP is a major modifier of the incidence and progression of diabetic retinopathy.^17,19 In the United Kingdom Prospective Diabetes Study, 1148 patients with type 2 DM and a mean BP of 160/94 mm Hg at the onset of the study were randomly assigned to either (1) a “tight” blood pressure group (< 150/85 mm Hg) or (2) a “less-tight” group (< 180/105 mm Hg). The primary therapy for controlling BP was captopril or atenolol. After 9 years of follow-up, the tight-control group had a 34% mean reduction in risk in the percentage of patients with deterioration of retinopathy (99% CI, 11%-50%; P = .0004) and a 47% reduction in risk (99% CI, 7%-70%; P = .004) of deterioration in visual acuity.²⁰

Most patients with DM and hypertension should be treated to maintain a BP < 140/90 mm Hg. Although there is insufficient evidence to recommend a specific antihypertensive agent for preventing diabetic retinopathy, therapy should include agents from drug classes that have a demonstrated reduction in cardiovascular events in patients with DM. These include angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, thiazide diuretics, and dihydropyridine calcium channel blockers.¹⁸

Lipid management. The benefit of targeted therapy for lowering lipids for the prevention of diabetic retinopathy is not well established.¹⁷ In the Collaborative Atorvastatin Diabetes Study, 2838 patients with type 2 DM were randomized to atorvastatin (10 mg) or placebo; microvascular endpoint analysis demonstrated that patients taking atorvastatin needed less laser therapy (P = .14); however, progression of diabetic retinopathy was not reduced.²¹ Similarly, in the Action to Control Cardiovascular Risk in Diabetes Eye Study, slowing of progression to retinopathy was observed in patients with type 2 DM who were treated with fenofibrate (ie, progression in 6.5%, compared with progression in 10.2% of untreated subjects [odds ratio = 0.60 (95% CI, 0.42-0.87); P = .0056]).²²

Continue to: Despite limited data on...

Nonpregnant adults with diabetes should maintain an HbA1C level < 7%; a higher level (< 8%) might be appropriate in patients with various complicating factors.

Despite limited data on the impact of ­lipid-lowering agents on patients with diabetic retinopathy, those with type 2 DM (especially) and those who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.¹⁸

Aspirin therapy. Aspirin has not been found to be beneficial for slowing progression of diabetic retinopathy. However, aspirin did not cause further deterioration of disease, specifically in patients with vitreous hemorrhages⁴; patients with diabetic retinopathy who require aspirin therapy for other medical reasons can therefore continue to take it without increasing the risk of damage to the retina.^4,18

When should you refer patients for screening?

Screening for diabetic retinopathy is important because affected patients can be asymptomatic but have significant disease. Early detection also helps determine which patients need treatment when it is most beneficial: early in its course.⁴

Type 1 DM. Retinopathy can become apparent as early as 6 or 7 years after the onset of disease, and is rare in children prior to puberty.^4,11 As a result, patients with type 1 DM should first be screened with a comprehensive eye examination by an ophthalmologist or optometrist within 5 years of DM onset.^4,18

Type 2 DM. Because of the insidious onset of type 2 DM, patients who are given a diagnosis of DM after 30 years of age might already have high-risk features of retinopathy.⁹ In patients with type 2 DM, therefore, initial screening for diabetic retinopathy should begin at the time of diagnosis and include a comprehensive eye examination by an ophthalmologist or optometrist.^4,18,23

Continue to: Components of the exam

Components of the exam. Initial evaluation by the ophthalmologist or optometrist should include a detailed history and comprehensive eye exam with pupil dilation. Table 2⁴ lists elements of the initial physical exam, which should assess for features that often lead to visual impairment. These features include macular edema, retinal hemorrhage, venous beading, neovascularization, and vitreous hemorrhage.⁴

Frequency of follow-up. The interval between subsequent examinations should be individualized, based on the findings of the initial assessment. Consider that:

• Screening should occur every 1 or 2 years in patients without evidence of retinopathy and with adequate glycemic control.^4,18,23
• Screening every 1 or 2 years appears to be cost-effective in patients who have had 1 or more normal eye exams.
• A 3-year screening interval does not appear to present a risk in well-controlled patients with type 2 DM.²⁴
• Women with type 1 or type 2 DM who are planning pregnancy or who are pregnant should have an eye exam prior to pregnancy or early in the first trimester.^4,18,23 They should then be monitored each trimester and at the end of the first postpartum year, depending on the severity of retinopathy.¹⁸

Alternative screening modalities

Seven-field stereoscopic fundus photography is an alternative screening tool that compares favorably to ophthalmoscopy when performed by an experienced ophthalmologist, optometrist, or ophthalmologic technician.²⁵ Nonmydriatic digital stereoscopic retinal imaging has been shown to be a cost-effective method of screening patients for diabetic retinopathy.²⁶ In a study that compared digital imaging with dilated funduscopic examination, investigators reported that, of 311 eyes evaluated, there was agreement between the methods in 86% of cases. Disagreement was mostly related to the greater frequency of finding mild-to-moderate NPDR when using digital imaging.²⁷

Screening in primary care

Programs that use telemedicine-based fundus photography to screen for diabetic retinopathy during primary care visits, followed by remote interpretation by an ophthalmologist, have been shown to increase the rate of retinal screening by offering an option other than direct referral to an ophthalmologist or optometrist.²⁸ However, telemedicine-based retinal photography can be successful as a screening tool for retinopathy only if timely referral to an eye specialist is arranged when indicated by findings.¹⁸

What therapy will your referred patients receive?

Patients found to have signs of diabetic retinopathy should be referred to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy. Care will be managed according to the severity of the patient’s diabetic retinopathy.

Continue to: Patients with mild-to-moderate NPDR but without macular edema

Patients with mild-to-moderate NPDR but without macular edema. Treatment is generally not recommended. Patients should be reevaluated every 6 to 12 months because they have an increased risk of progression.⁵

Patients with mild-to-moderate NPDR and clinically significant macular edema (CSME). It is important for the eye specialist to assess for edema at the center of the macula because the risk of vision loss and need for treatment is greater when the center is involved. Vascular–endothelial growth factor (VEGF) is an important mediator of neovascularization and macular edema in diabetic retinopathy. For patients with center-­involving CSME, intravitreous injection of an anti-VEGF agent provides significant benefit and is first-line treatment in these cases.^4,29

Patients with DM (especially those with type 2 disease) who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.

The Early Treatment for Diabetic Retinopathy Study evaluated the efficacy of focal photocoagulation, a painless laser therapy, for CSME and demonstrated that this modality reduces the risk of moderate visual loss; increases the likelihood of improvement in vision; and decreases the frequency of persistent macular edema.³⁰ Focal photocoagulation has been found effective in both non-center-involving CSME and center-involving CSME.⁵

Patients with severe NPDR. The recommendation is to initiate full panretinal photocoagulation prior to progression to proliferative diabetic retinopathy PDR. Researchers noted a 50% reduction in vision loss and vitrectomy when patients with type 2 DM were treated with panretinal photocoagulation early, compared with those in whom treatment was deferred until PDR developed.^4,31 The role of anti-VEGF treatment of severe NPDR is under investigation.⁴

Patients with high-risk and severe PDR. Panretinal photocoagulation is the recommended treatment for patients with high-risk and severe PDR, and usually induces regression of retinal neovascularization. In patients with CSME and high-risk PDR, the combination of anti-VEGF therapy and panretinal photocoagulation should be considered. Vitrectomy should be considered for patients who have failed panretinal photocoagulation or are not amenable to photocoagulation.⁴

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224; Farford.Bryan@mayo.edu.

As of 2015, an estimated 30.2 million adults in the United States—12.2% of the population— had diabetes mellitus (DM). During that year, approximately 1.5 million new cases (6.7 cases for every 1000 people) were diagnosed in adults (≥ 18 years of age).¹

As the number of people with DM increases, so will the number of cases of diabetic retinopathy, the main cause of new cases of blindness in adults in the United States² and the leading cause of blindness among US working-age (20 to 74 years) adults.³ It is estimated that 4.1 million Americans have diabetic retinopathy³; it is projected that prevalence will reach 6 million this year.⁴

Blindness related to DM costs the United States approximately $500 million each year,⁵ including health care utilization: physician office visits, diagnostic testing, medication and other treatments, and hospitalization.⁶ Impairment of vision also results in social isolation, dependence on others to perform daily functions, and a decline in physical activity.

Several professional organizations, including the American Diabetes Association and the American Academy of Ophthalmology, have developed practice guidelines for diabetic retinopathy screening. Guidelines notwithstanding, only about 55% of people with DM in the United States receive the recommended dilated eye examination at established intervals.^2,3 In addition to screening by an ophthalmologist or optometrist, adherence to clinical guidelines for risk assessment, prevention, and early referral helps reduce the incidence and severity of retinopathy.⁵

The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had diabetes mellitus (DM) for < 5 years to 77.8% in people who had DM for ≥ 15 years.

This article describes how to assess the risk of diabetic retinopathy in your patients, details the crucial role that you, the primary care physician, can play in prevention, and emphasizes the importance of referral to an eye specialist for screening, evaluation, treatment (when indicated), and follow-up.

Pathophysiology and classification

Diabetic retinopathy, the result of progressive blood vessel damage to the retina, has 2 major forms: nonproliferative and proliferative. Those forms are distinguished by the absence or presence of new growth of blood vessels (retinal neovascularization).^3,7 To improve communication and coordination among physicians who care for patients with DM worldwide, the International Clinical Diabetic Retinopathy Disease Severity Scale for diabetic retinopathy was developed,^8-10 comprising 5 levels of severity that are based on findings on dilated ophthalmoscopy (Table 1^8-10):

• Level 1. No apparent retinopathy. Funduscopic abnormalities are absent.
• Level 2. Mild nonproliferative diabetic retinopathy (NPDR). Only a few microaneurysms are seen.
• Level 3: Moderate NPDR. Characterized by microaneurysms and by intraretinal hemorrhage and venous beading, but less severe than what is seen in Level 4.
• Level 4. Severe NPDR. More than 20 intraretinal hemorrhages in each quadrant of the retina, definite venous beading in > 2 quadrants, intraretinal microvascular abnormalities in > 1 quadrant, or any combination of these findings.
• Level 5. Proliferative diabetic retinopathy. Characterized by neovascularization of the disc, retina, iris, or angle; vitreous hemorrhage; retinal detachment; or any combination of these findings. Further classified as “mild,” “moderate,” or “severe” if macular edema is present; severity is dependent on the distance of thickening and exudates from the center of the macula.⁹

Be attentive to risk factors

There are several risk factors for diabetic retinopathy, including duration of disease, type 1 DM, male gender, black race (non-Hispanic), elevated hemoglobin A1C(HbA1C) level, elevated systolic and diastolic blood pressure (BP), and insulin therapy. ^4,5,11,12

Continue to: Time since diagnosis

Time since diagnosis. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had DM for < 5 years to 77.8% in people who had DM for ≥ 15 years. The rate of proliferative diabetic retinopathy was 2% in people who had DM for < 5 years and 15.5% in those who had DM for ≥ 15 years.¹¹

Diabetic retinopathy can deteriorate during pregnancy but generally reverts to the pre-pregnancy level; long-term progression of retinopathy is not affected.

Demographic variables. The prevalence of diabetic retinopathy is higher in men, non-Hispanic blacks (38.8%), and ­people with type 1 DM.^4,5,11-13 The Veterans ­Affairs Diabetes Trial found a higher prevalence of moderate-to-severe diabetic retinopathy in Hispanics (36%) and African Americans (29%) than in non-Hispanic whites (22%).¹⁴

Among people with DM who have ­diabetic retinopathy, systolic and diastolic BP and the HbA1C level tend to be higher. They are more likely to use insulin to control disease.^4,5,13 In a recent cross-sectional analysis, the prevalence of vision-threatening retinopathy was higher among people ≥ 65 years of age (1%; 95% confidence interval [CI], 0.7%-1.5%) than among people 40 to 64 years of age (0.4%; 95% CI, 0.3%-0.7%) (P = .009).⁵

Does pregnancy exacerbate retinopathy? Controversy surrounds the role of pregnancy in the development and progression of diabetic retinopathy. The Diabetes Control and Complications Trial found a short-term increase in the level of retinopathy during pregnancy that persisted into the first postpartum year. A 1.63-fold greater risk of any deterioration of retinopathy was observed in women who received intensive DM treatment from before to during pregnancy (P < .05); pregnant women who received conventional treatment had a 2.48-fold greater risk than nonpregnant women with DM who received conventional treatment (P < .001).

Deterioration of retinopathy during pregnancy had no long-term consequences, however, regardless of type of treatment.¹⁵ More importantly, in most cases, changes in the level of retinopathy revert to the pre-­pregnancy level after 1 year or longer, and pregnancy does not appear to affect long-term progression of retinopathy.¹⁵

Continue to: Proven primary prevention strategies

 

 

Proven primary prevention strategies

Glycemic control. Optimal glycemic control is an essential component of prevention of diabetic retinopathy. From 1983 to 1993, the Diabetes Control and Complications Trial randomized 1441 patients with type 1 DM to receive intensive therapy (median HbA1C level, 7.2%) or conventional therapy (median HbA1C level, 9.1%). During a mean of 6 years of follow-up, intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% CI, 62%-85%).^16,17 A 2007 systematic review of 44 studies of the treatment of diabetic retinopathy found that strict glycemic control was beneficial in reducing the incidence and progression of retinopathy.¹⁷

The American Diabetes Association’s Standards of Medical Care in Diabetes—2019 Abridged for Primary Care Providers recommends that most nonpregnant adults maintain an HbA1Clevel < 7%. For patients with a history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular disease, other significant comorbid conditions, or longstanding DM in which it is difficult to achieve the optimal goal, a higher HbA1clevel (< 8%) might be appropriate.¹⁸

Control of BP. Strict control of BP is a major modifier of the incidence and progression of diabetic retinopathy.^17,19 In the United Kingdom Prospective Diabetes Study, 1148 patients with type 2 DM and a mean BP of 160/94 mm Hg at the onset of the study were randomly assigned to either (1) a “tight” blood pressure group (< 150/85 mm Hg) or (2) a “less-tight” group (< 180/105 mm Hg). The primary therapy for controlling BP was captopril or atenolol. After 9 years of follow-up, the tight-control group had a 34% mean reduction in risk in the percentage of patients with deterioration of retinopathy (99% CI, 11%-50%; P = .0004) and a 47% reduction in risk (99% CI, 7%-70%; P = .004) of deterioration in visual acuity.²⁰

Most patients with DM and hypertension should be treated to maintain a BP < 140/90 mm Hg. Although there is insufficient evidence to recommend a specific antihypertensive agent for preventing diabetic retinopathy, therapy should include agents from drug classes that have a demonstrated reduction in cardiovascular events in patients with DM. These include angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, thiazide diuretics, and dihydropyridine calcium channel blockers.¹⁸

Lipid management. The benefit of targeted therapy for lowering lipids for the prevention of diabetic retinopathy is not well established.¹⁷ In the Collaborative Atorvastatin Diabetes Study, 2838 patients with type 2 DM were randomized to atorvastatin (10 mg) or placebo; microvascular endpoint analysis demonstrated that patients taking atorvastatin needed less laser therapy (P = .14); however, progression of diabetic retinopathy was not reduced.²¹ Similarly, in the Action to Control Cardiovascular Risk in Diabetes Eye Study, slowing of progression to retinopathy was observed in patients with type 2 DM who were treated with fenofibrate (ie, progression in 6.5%, compared with progression in 10.2% of untreated subjects [odds ratio = 0.60 (95% CI, 0.42-0.87); P = .0056]).²²

Continue to: Despite limited data on...

Nonpregnant adults with diabetes should maintain an HbA1C level < 7%; a higher level (< 8%) might be appropriate in patients with various complicating factors.

Despite limited data on the impact of ­lipid-lowering agents on patients with diabetic retinopathy, those with type 2 DM (especially) and those who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.¹⁸

Aspirin therapy. Aspirin has not been found to be beneficial for slowing progression of diabetic retinopathy. However, aspirin did not cause further deterioration of disease, specifically in patients with vitreous hemorrhages⁴; patients with diabetic retinopathy who require aspirin therapy for other medical reasons can therefore continue to take it without increasing the risk of damage to the retina.^4,18

When should you refer patients for screening?

Screening for diabetic retinopathy is important because affected patients can be asymptomatic but have significant disease. Early detection also helps determine which patients need treatment when it is most beneficial: early in its course.⁴

Type 1 DM. Retinopathy can become apparent as early as 6 or 7 years after the onset of disease, and is rare in children prior to puberty.^4,11 As a result, patients with type 1 DM should first be screened with a comprehensive eye examination by an ophthalmologist or optometrist within 5 years of DM onset.^4,18

Type 2 DM. Because of the insidious onset of type 2 DM, patients who are given a diagnosis of DM after 30 years of age might already have high-risk features of retinopathy.⁹ In patients with type 2 DM, therefore, initial screening for diabetic retinopathy should begin at the time of diagnosis and include a comprehensive eye examination by an ophthalmologist or optometrist.^4,18,23

Continue to: Components of the exam

Components of the exam. Initial evaluation by the ophthalmologist or optometrist should include a detailed history and comprehensive eye exam with pupil dilation. Table 2⁴ lists elements of the initial physical exam, which should assess for features that often lead to visual impairment. These features include macular edema, retinal hemorrhage, venous beading, neovascularization, and vitreous hemorrhage.⁴

Frequency of follow-up. The interval between subsequent examinations should be individualized, based on the findings of the initial assessment. Consider that:

• Screening should occur every 1 or 2 years in patients without evidence of retinopathy and with adequate glycemic control.^4,18,23
• Screening every 1 or 2 years appears to be cost-effective in patients who have had 1 or more normal eye exams.
• A 3-year screening interval does not appear to present a risk in well-controlled patients with type 2 DM.²⁴
• Women with type 1 or type 2 DM who are planning pregnancy or who are pregnant should have an eye exam prior to pregnancy or early in the first trimester.^4,18,23 They should then be monitored each trimester and at the end of the first postpartum year, depending on the severity of retinopathy.¹⁸

Alternative screening modalities

Seven-field stereoscopic fundus photography is an alternative screening tool that compares favorably to ophthalmoscopy when performed by an experienced ophthalmologist, optometrist, or ophthalmologic technician.²⁵ Nonmydriatic digital stereoscopic retinal imaging has been shown to be a cost-effective method of screening patients for diabetic retinopathy.²⁶ In a study that compared digital imaging with dilated funduscopic examination, investigators reported that, of 311 eyes evaluated, there was agreement between the methods in 86% of cases. Disagreement was mostly related to the greater frequency of finding mild-to-moderate NPDR when using digital imaging.²⁷

Screening in primary care

Programs that use telemedicine-based fundus photography to screen for diabetic retinopathy during primary care visits, followed by remote interpretation by an ophthalmologist, have been shown to increase the rate of retinal screening by offering an option other than direct referral to an ophthalmologist or optometrist.²⁸ However, telemedicine-based retinal photography can be successful as a screening tool for retinopathy only if timely referral to an eye specialist is arranged when indicated by findings.¹⁸

What therapy will your referred patients receive?

Patients found to have signs of diabetic retinopathy should be referred to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy. Care will be managed according to the severity of the patient’s diabetic retinopathy.

Continue to: Patients with mild-to-moderate NPDR but without macular edema

Patients with mild-to-moderate NPDR but without macular edema. Treatment is generally not recommended. Patients should be reevaluated every 6 to 12 months because they have an increased risk of progression.⁵

Patients with mild-to-moderate NPDR and clinically significant macular edema (CSME). It is important for the eye specialist to assess for edema at the center of the macula because the risk of vision loss and need for treatment is greater when the center is involved. Vascular–endothelial growth factor (VEGF) is an important mediator of neovascularization and macular edema in diabetic retinopathy. For patients with center-­involving CSME, intravitreous injection of an anti-VEGF agent provides significant benefit and is first-line treatment in these cases.^4,29

Patients with DM (especially those with type 2 disease) who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.

The Early Treatment for Diabetic Retinopathy Study evaluated the efficacy of focal photocoagulation, a painless laser therapy, for CSME and demonstrated that this modality reduces the risk of moderate visual loss; increases the likelihood of improvement in vision; and decreases the frequency of persistent macular edema.³⁰ Focal photocoagulation has been found effective in both non-center-involving CSME and center-involving CSME.⁵

Patients with severe NPDR. The recommendation is to initiate full panretinal photocoagulation prior to progression to proliferative diabetic retinopathy PDR. Researchers noted a 50% reduction in vision loss and vitrectomy when patients with type 2 DM were treated with panretinal photocoagulation early, compared with those in whom treatment was deferred until PDR developed.^4,31 The role of anti-VEGF treatment of severe NPDR is under investigation.⁴

Patients with high-risk and severe PDR. Panretinal photocoagulation is the recommended treatment for patients with high-risk and severe PDR, and usually induces regression of retinal neovascularization. In patients with CSME and high-risk PDR, the combination of anti-VEGF therapy and panretinal photocoagulation should be considered. Vitrectomy should be considered for patients who have failed panretinal photocoagulation or are not amenable to photocoagulation.⁴

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224; Farford.Bryan@mayo.edu.

As of 2015, an estimated 30.2 million adults in the United States—12.2% of the population— had diabetes mellitus (DM). During that year, approximately 1.5 million new cases (6.7 cases for every 1000 people) were diagnosed in adults (≥ 18 years of age).¹

As the number of people with DM increases, so will the number of cases of diabetic retinopathy, the main cause of new cases of blindness in adults in the United States² and the leading cause of blindness among US working-age (20 to 74 years) adults.³ It is estimated that 4.1 million Americans have diabetic retinopathy³; it is projected that prevalence will reach 6 million this year.⁴

Blindness related to DM costs the United States approximately $500 million each year,⁵ including health care utilization: physician office visits, diagnostic testing, medication and other treatments, and hospitalization.⁶ Impairment of vision also results in social isolation, dependence on others to perform daily functions, and a decline in physical activity.

Several professional organizations, including the American Diabetes Association and the American Academy of Ophthalmology, have developed practice guidelines for diabetic retinopathy screening. Guidelines notwithstanding, only about 55% of people with DM in the United States receive the recommended dilated eye examination at established intervals.^2,3 In addition to screening by an ophthalmologist or optometrist, adherence to clinical guidelines for risk assessment, prevention, and early referral helps reduce the incidence and severity of retinopathy.⁵

The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had diabetes mellitus (DM) for < 5 years to 77.8% in people who had DM for ≥ 15 years.

This article describes how to assess the risk of diabetic retinopathy in your patients, details the crucial role that you, the primary care physician, can play in prevention, and emphasizes the importance of referral to an eye specialist for screening, evaluation, treatment (when indicated), and follow-up.

Pathophysiology and classification

Diabetic retinopathy, the result of progressive blood vessel damage to the retina, has 2 major forms: nonproliferative and proliferative. Those forms are distinguished by the absence or presence of new growth of blood vessels (retinal neovascularization).^3,7 To improve communication and coordination among physicians who care for patients with DM worldwide, the International Clinical Diabetic Retinopathy Disease Severity Scale for diabetic retinopathy was developed,^8-10 comprising 5 levels of severity that are based on findings on dilated ophthalmoscopy (Table 1^8-10):

• Level 1. No apparent retinopathy. Funduscopic abnormalities are absent.
• Level 2. Mild nonproliferative diabetic retinopathy (NPDR). Only a few microaneurysms are seen.
• Level 3: Moderate NPDR. Characterized by microaneurysms and by intraretinal hemorrhage and venous beading, but less severe than what is seen in Level 4.
• Level 4. Severe NPDR. More than 20 intraretinal hemorrhages in each quadrant of the retina, definite venous beading in > 2 quadrants, intraretinal microvascular abnormalities in > 1 quadrant, or any combination of these findings.
• Level 5. Proliferative diabetic retinopathy. Characterized by neovascularization of the disc, retina, iris, or angle; vitreous hemorrhage; retinal detachment; or any combination of these findings. Further classified as “mild,” “moderate,” or “severe” if macular edema is present; severity is dependent on the distance of thickening and exudates from the center of the macula.⁹

Be attentive to risk factors

There are several risk factors for diabetic retinopathy, including duration of disease, type 1 DM, male gender, black race (non-Hispanic), elevated hemoglobin A1C(HbA1C) level, elevated systolic and diastolic blood pressure (BP), and insulin therapy. ^4,5,11,12

Continue to: Time since diagnosis

Time since diagnosis. The Wisconsin Epidemiologic Study of Diabetic Retinopathy found that the prevalence of diabetic retinopathy varied from 28.8% in people who had DM for < 5 years to 77.8% in people who had DM for ≥ 15 years. The rate of proliferative diabetic retinopathy was 2% in people who had DM for < 5 years and 15.5% in those who had DM for ≥ 15 years.¹¹

Diabetic retinopathy can deteriorate during pregnancy but generally reverts to the pre-pregnancy level; long-term progression of retinopathy is not affected.

Demographic variables. The prevalence of diabetic retinopathy is higher in men, non-Hispanic blacks (38.8%), and ­people with type 1 DM.^4,5,11-13 The Veterans ­Affairs Diabetes Trial found a higher prevalence of moderate-to-severe diabetic retinopathy in Hispanics (36%) and African Americans (29%) than in non-Hispanic whites (22%).¹⁴

Among people with DM who have ­diabetic retinopathy, systolic and diastolic BP and the HbA1C level tend to be higher. They are more likely to use insulin to control disease.^4,5,13 In a recent cross-sectional analysis, the prevalence of vision-threatening retinopathy was higher among people ≥ 65 years of age (1%; 95% confidence interval [CI], 0.7%-1.5%) than among people 40 to 64 years of age (0.4%; 95% CI, 0.3%-0.7%) (P = .009).⁵

Does pregnancy exacerbate retinopathy? Controversy surrounds the role of pregnancy in the development and progression of diabetic retinopathy. The Diabetes Control and Complications Trial found a short-term increase in the level of retinopathy during pregnancy that persisted into the first postpartum year. A 1.63-fold greater risk of any deterioration of retinopathy was observed in women who received intensive DM treatment from before to during pregnancy (P < .05); pregnant women who received conventional treatment had a 2.48-fold greater risk than nonpregnant women with DM who received conventional treatment (P < .001).

Deterioration of retinopathy during pregnancy had no long-term consequences, however, regardless of type of treatment.¹⁵ More importantly, in most cases, changes in the level of retinopathy revert to the pre-­pregnancy level after 1 year or longer, and pregnancy does not appear to affect long-term progression of retinopathy.¹⁵

Continue to: Proven primary prevention strategies

 

 

Proven primary prevention strategies

Glycemic control. Optimal glycemic control is an essential component of prevention of diabetic retinopathy. From 1983 to 1993, the Diabetes Control and Complications Trial randomized 1441 patients with type 1 DM to receive intensive therapy (median HbA1C level, 7.2%) or conventional therapy (median HbA1C level, 9.1%). During a mean of 6 years of follow-up, intensive therapy reduced the adjusted mean risk of retinopathy by 76% (95% CI, 62%-85%).^16,17 A 2007 systematic review of 44 studies of the treatment of diabetic retinopathy found that strict glycemic control was beneficial in reducing the incidence and progression of retinopathy.¹⁷

The American Diabetes Association’s Standards of Medical Care in Diabetes—2019 Abridged for Primary Care Providers recommends that most nonpregnant adults maintain an HbA1Clevel < 7%. For patients with a history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular disease, other significant comorbid conditions, or longstanding DM in which it is difficult to achieve the optimal goal, a higher HbA1clevel (< 8%) might be appropriate.¹⁸

Control of BP. Strict control of BP is a major modifier of the incidence and progression of diabetic retinopathy.^17,19 In the United Kingdom Prospective Diabetes Study, 1148 patients with type 2 DM and a mean BP of 160/94 mm Hg at the onset of the study were randomly assigned to either (1) a “tight” blood pressure group (< 150/85 mm Hg) or (2) a “less-tight” group (< 180/105 mm Hg). The primary therapy for controlling BP was captopril or atenolol. After 9 years of follow-up, the tight-control group had a 34% mean reduction in risk in the percentage of patients with deterioration of retinopathy (99% CI, 11%-50%; P = .0004) and a 47% reduction in risk (99% CI, 7%-70%; P = .004) of deterioration in visual acuity.²⁰

Most patients with DM and hypertension should be treated to maintain a BP < 140/90 mm Hg. Although there is insufficient evidence to recommend a specific antihypertensive agent for preventing diabetic retinopathy, therapy should include agents from drug classes that have a demonstrated reduction in cardiovascular events in patients with DM. These include angiotensin-­converting enzyme inhibitors, angiotensin receptor blockers, thiazide diuretics, and dihydropyridine calcium channel blockers.¹⁸

Lipid management. The benefit of targeted therapy for lowering lipids for the prevention of diabetic retinopathy is not well established.¹⁷ In the Collaborative Atorvastatin Diabetes Study, 2838 patients with type 2 DM were randomized to atorvastatin (10 mg) or placebo; microvascular endpoint analysis demonstrated that patients taking atorvastatin needed less laser therapy (P = .14); however, progression of diabetic retinopathy was not reduced.²¹ Similarly, in the Action to Control Cardiovascular Risk in Diabetes Eye Study, slowing of progression to retinopathy was observed in patients with type 2 DM who were treated with fenofibrate (ie, progression in 6.5%, compared with progression in 10.2% of untreated subjects [odds ratio = 0.60 (95% CI, 0.42-0.87); P = .0056]).²²

Continue to: Despite limited data on...

Nonpregnant adults with diabetes should maintain an HbA1C level < 7%; a higher level (< 8%) might be appropriate in patients with various complicating factors.

Despite limited data on the impact of ­lipid-lowering agents on patients with diabetic retinopathy, those with type 2 DM (especially) and those who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.¹⁸

Aspirin therapy. Aspirin has not been found to be beneficial for slowing progression of diabetic retinopathy. However, aspirin did not cause further deterioration of disease, specifically in patients with vitreous hemorrhages⁴; patients with diabetic retinopathy who require aspirin therapy for other medical reasons can therefore continue to take it without increasing the risk of damage to the retina.^4,18

When should you refer patients for screening?

Screening for diabetic retinopathy is important because affected patients can be asymptomatic but have significant disease. Early detection also helps determine which patients need treatment when it is most beneficial: early in its course.⁴

Type 1 DM. Retinopathy can become apparent as early as 6 or 7 years after the onset of disease, and is rare in children prior to puberty.^4,11 As a result, patients with type 1 DM should first be screened with a comprehensive eye examination by an ophthalmologist or optometrist within 5 years of DM onset.^4,18

Type 2 DM. Because of the insidious onset of type 2 DM, patients who are given a diagnosis of DM after 30 years of age might already have high-risk features of retinopathy.⁹ In patients with type 2 DM, therefore, initial screening for diabetic retinopathy should begin at the time of diagnosis and include a comprehensive eye examination by an ophthalmologist or optometrist.^4,18,23

Continue to: Components of the exam

Components of the exam. Initial evaluation by the ophthalmologist or optometrist should include a detailed history and comprehensive eye exam with pupil dilation. Table 2⁴ lists elements of the initial physical exam, which should assess for features that often lead to visual impairment. These features include macular edema, retinal hemorrhage, venous beading, neovascularization, and vitreous hemorrhage.⁴

Frequency of follow-up. The interval between subsequent examinations should be individualized, based on the findings of the initial assessment. Consider that:

• Screening should occur every 1 or 2 years in patients without evidence of retinopathy and with adequate glycemic control.^4,18,23
• Screening every 1 or 2 years appears to be cost-effective in patients who have had 1 or more normal eye exams.
• A 3-year screening interval does not appear to present a risk in well-controlled patients with type 2 DM.²⁴
• Women with type 1 or type 2 DM who are planning pregnancy or who are pregnant should have an eye exam prior to pregnancy or early in the first trimester.^4,18,23 They should then be monitored each trimester and at the end of the first postpartum year, depending on the severity of retinopathy.¹⁸

Alternative screening modalities

Seven-field stereoscopic fundus photography is an alternative screening tool that compares favorably to ophthalmoscopy when performed by an experienced ophthalmologist, optometrist, or ophthalmologic technician.²⁵ Nonmydriatic digital stereoscopic retinal imaging has been shown to be a cost-effective method of screening patients for diabetic retinopathy.²⁶ In a study that compared digital imaging with dilated funduscopic examination, investigators reported that, of 311 eyes evaluated, there was agreement between the methods in 86% of cases. Disagreement was mostly related to the greater frequency of finding mild-to-moderate NPDR when using digital imaging.²⁷

Screening in primary care

Programs that use telemedicine-based fundus photography to screen for diabetic retinopathy during primary care visits, followed by remote interpretation by an ophthalmologist, have been shown to increase the rate of retinal screening by offering an option other than direct referral to an ophthalmologist or optometrist.²⁸ However, telemedicine-based retinal photography can be successful as a screening tool for retinopathy only if timely referral to an eye specialist is arranged when indicated by findings.¹⁸

What therapy will your referred patients receive?

Patients found to have signs of diabetic retinopathy should be referred to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy. Care will be managed according to the severity of the patient’s diabetic retinopathy.

Continue to: Patients with mild-to-moderate NPDR but without macular edema

Patients with mild-to-moderate NPDR but without macular edema. Treatment is generally not recommended. Patients should be reevaluated every 6 to 12 months because they have an increased risk of progression.⁵

Patients with mild-to-moderate NPDR and clinically significant macular edema (CSME). It is important for the eye specialist to assess for edema at the center of the macula because the risk of vision loss and need for treatment is greater when the center is involved. Vascular–endothelial growth factor (VEGF) is an important mediator of neovascularization and macular edema in diabetic retinopathy. For patients with center-­involving CSME, intravitreous injection of an anti-VEGF agent provides significant benefit and is first-line treatment in these cases.^4,29

Patients with DM (especially those with type 2 disease) who have, or are at risk of, atherosclerotic cardiovascular disease should receive statin therapy.

The Early Treatment for Diabetic Retinopathy Study evaluated the efficacy of focal photocoagulation, a painless laser therapy, for CSME and demonstrated that this modality reduces the risk of moderate visual loss; increases the likelihood of improvement in vision; and decreases the frequency of persistent macular edema.³⁰ Focal photocoagulation has been found effective in both non-center-involving CSME and center-involving CSME.⁵

Patients with severe NPDR. The recommendation is to initiate full panretinal photocoagulation prior to progression to proliferative diabetic retinopathy PDR. Researchers noted a 50% reduction in vision loss and vitrectomy when patients with type 2 DM were treated with panretinal photocoagulation early, compared with those in whom treatment was deferred until PDR developed.^4,31 The role of anti-VEGF treatment of severe NPDR is under investigation.⁴

Patients with high-risk and severe PDR. Panretinal photocoagulation is the recommended treatment for patients with high-risk and severe PDR, and usually induces regression of retinal neovascularization. In patients with CSME and high-risk PDR, the combination of anti-VEGF therapy and panretinal photocoagulation should be considered. Vitrectomy should be considered for patients who have failed panretinal photocoagulation or are not amenable to photocoagulation.⁴

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224; Farford.Bryan@mayo.edu.

Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.

“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.

The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.

“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.

The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.

Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.

“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.

The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.

“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.

Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”

The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.

mzoler@mdedge.com

SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.

Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.

“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.

The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.

“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.

The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.

Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.

“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.

The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.

“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.

Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”

The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.

mzoler@mdedge.com

SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.

Coronary bypass surgery patients who received a radial artery as their second bypass conduit had significantly better 10-year survival than did patients who received a saphenous vein graft in a combined analysis of more than 1,000 randomized patients who had originally been enrolled in any of five independent studies.

“This is the first report of a survival benefit for CABG [coronary artery bypass grafting] using multiple arterial conduits based on randomized data,” Mario F.L. Gaudino, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Dr. Gaudino acknowledged several limitations of the finding. First, the analysis included studies that enrolled patients during 1997-2009 in five diverse sites worldwide and, therefore, involved varying surgical methods. Second, the sample size was “relatively low and underpowered, even after 10-year follow-up.” And third, the survival analysis was post hoc, although the statistically significant 27% relative reduction in mortality during follow-up with radial artery bypass, compared with saphenous vein bypass, was fully consistent with both the primary endpoint of the five studies and also with the combined hard endpoint of death and myocardial infarction.

The primary outcome of all-cause death, MI, and repeat revascularization also fell by a relative 27% with radial artery bypass, compared with saphenous vein bypass, and the combined rate of death and MI fell by 23% with radial artery bypass, both statistically significant differences, reported Dr. Gaudino, professor of cardiothoracic surgery at Weill Cornell Medicine, New York.

“The overall message is that radial bypass is associated with better long-term outcomes and potentially better survival,” he concluded.

The left interior thoracic artery (also known as the left internal mammary artery) is well established as the primary CABG conduit, usually used for bypassing the left anterior descending coronary artery, but when a second conduit is needed, several options exist: a saphenous vein, the left radial artery, or possibly the right internal thoracic artery (RITA) as a different arterial option.

Dr. Gaudino claimed that his new results placed the left radial artery clearly superior to the RITA as the second arterial conduit of choice for CABG. Not only does the RITA lack a similar efficacy evidence base from randomized trials, but the method poses a higher risk for surgical wound infections, he noted. The most recent society recommendations on conduit choice for CABG, issued less than 2 years ago by the European Society of Cardiology and European Association for Cardio-Thoracic Surgery, tapped the left radial artery as a level I recommendation over a saphenous vein graft when patients have high-grade coronary stenosis, while the RITA trailed as a level IIa recommendation specified only for patients with a low risk for sternal-wound infection.

“This was a great study that brings home the point that, in general, the radial artery is better than a saphenous vein graft,” commented Marc R. Moon, MD, a designated discussant and a professor of surgery and chief of cardiac surgery at Washington University, St. Louis.

The long-term follow-up that Dr. Gaudino reported came from extended, patient-level data collection for all 1,036 patients included in the original RADIAL (Radial Artery Database International Alliance) analysis of 5-year outcomes and reported in 2018. Dr. Gaudino and his associates tracked down survival information for all those patients, with outcome records out to at least 10 years for 91% of the original participants and with a mean follow-up that was also 10 years. The prior 2018 report based on 5-year results had also shown a statistically significant reduction in the primary endpoint with radial artery grafting, but at that point, follow-up had not yet collected enough mortality endpoints to produce a statistically significant between-group difference in death from any cause, a shortcoming that may have limited the ability of the prior report to influence U.S. practice.

“In the United States, there has been very little uptake of multiarterial grafting,” commented Frederick G.P. Welt, MD, a designated discussant, interventional cardiologist, professor of medicine, and associate chief of cardiovascular medicine at the University of Utah, Salt Lake City. The results from several earlier studies did not show much benefit for graft patency using radial arteries, but more recently clinicians have made advances in radial artery harvesting methods, implantation techniques, and adjunctive medications including antispasmodic treatments, Dr. Welt noted. Improved methods for using radial artery grafts and the risk of wound infection with RITA grafts were summarized in an editorial that accompanied the report of the 5-year RADIAL findings.

Dr. Welt said that, among the new findings reported by Dr. Gaudino, “the mortality effect is the most impressive.” Despite the limitations of the post hoc survival analysis, the reduced mortality finding is “nevertheless really important. The patient-level data lend it more credence.”

The study received no commercial funding. Dr. Gaudino had no disclosures. Dr. Moon has been a consultant to Medtronic. Dr. Welt has been an adviser to Medtronic.

mzoler@mdedge.com

SOURCE: Gaudino MFL et al. ACC 20, Abstract 410-11.

LAHAINA, HAWAII – Clascoterone cream, a first-in-class topical selective androgen receptor inhibitor for the treatment of acne now under review by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.

Bruce Jancin/MDedge News

“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.

“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.

The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.

The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.

Dr. Sprague reported having no financial conflicts regarding her presentation.

The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

LAHAINA, HAWAII – Clascoterone cream, a first-in-class topical selective androgen receptor inhibitor for the treatment of acne now under review by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.

Bruce Jancin/MDedge News

“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.

“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.

The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.

The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.

Dr. Sprague reported having no financial conflicts regarding her presentation.

The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com

LAHAINA, HAWAII – Clascoterone cream, a first-in-class topical selective androgen receptor inhibitor for the treatment of acne now under review by the Food and Drug Administration, is already generating considerable buzz in the patient-advocacy community even though the agency won’t issue its decision until August.

Bruce Jancin/MDedge News

“I’ve actually had a lot of interest in this already from parents, especially regarding girls who have very hormonal acne but the parents are really not interested in starting them on a systemic hormonal therapy at their age,” Jessica Sprague, MD, said at the SDEF Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Education Foundation.

Clascoterone targets androgen receptors in the skin in order to reduce cutaneous 5-alpha dihydrotestosterone.

“It’s being developed for use in both males and females, which is great because at this point there’s no hormonal treatment for males,” noted Dr. Sprague, a pediatric dermatologist at Rady Children’s Hospital and the University of California, both in San Diego.

The manufacturer’s application for marketing approval of clascoterone cream 1% under FDA review includes evidence from two identical phase-3, double-blind, vehicle-controlled, 12-week, randomized trials. The two studies included a total of 1,440 patients aged 9 years through adulthood with moderate to severe facial acne vulgaris who were randomized to twice-daily application of clascoterone or its vehicle.

The primary outcome was the reduction in inflammatory lesions at week 12: a 46.2% decline from baseline with clascoterone 1% cream, which was a significantly greater improvement than the 32.7% reduction for vehicle. The secondary outcome – change in noninflammatory lesion counts at week 12 – was also positive for the topical androgen receptor inhibitor, which achieved a 29.8% reduction, compared with 18.9% for vehicle. Clascoterone exhibited a favorable safety and tolerability profile, with numerically fewer treatment-emergent adverse events than in the vehicle control group. A stronger formulation of the topical agent is in advanced clinical trials for the treatment of androgenetic alopecia in both males and females.

Dr. Sprague reported having no financial conflicts regarding her presentation.

The SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.

bjancin@mdedge.com