The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted in favor of changes to the current recommendations that would remove the permissive language for the hepatitis B birth dose to be administered after discharge from the hospital.

The revised language will state that for all medically stable infants weighing greater than or equal to 2,000 g at birth and born to hepatitis B surface antigen–negative mothers, the first dose of vaccine should be administered within 24 hours of birth. Originally, the recommendations were to state that vaccination should take place before hospital discharge, but this language was changed via a unanimously approved amendment to broaden the scope of the guidelines. Furthermore, the recommendations state that only single-antigen hepatitis B vaccine should be used for the birth dose.

©luiscar/Thinkstockphotos

dchitnis@frontlinemedcom.com

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted in favor of changes to the current recommendations that would remove the permissive language for the hepatitis B birth dose to be administered after discharge from the hospital.

The revised language will state that for all medically stable infants weighing greater than or equal to 2,000 g at birth and born to hepatitis B surface antigen–negative mothers, the first dose of vaccine should be administered within 24 hours of birth. Originally, the recommendations were to state that vaccination should take place before hospital discharge, but this language was changed via a unanimously approved amendment to broaden the scope of the guidelines. Furthermore, the recommendations state that only single-antigen hepatitis B vaccine should be used for the birth dose.

©luiscar/Thinkstockphotos

dchitnis@frontlinemedcom.com

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted in favor of changes to the current recommendations that would remove the permissive language for the hepatitis B birth dose to be administered after discharge from the hospital.

The revised language will state that for all medically stable infants weighing greater than or equal to 2,000 g at birth and born to hepatitis B surface antigen–negative mothers, the first dose of vaccine should be administered within 24 hours of birth. Originally, the recommendations were to state that vaccination should take place before hospital discharge, but this language was changed via a unanimously approved amendment to broaden the scope of the guidelines. Furthermore, the recommendations state that only single-antigen hepatitis B vaccine should be used for the birth dose.

©luiscar/Thinkstockphotos

dchitnis@frontlinemedcom.com

BALTIMORE – Performing computed tomography angiography (CTA) following noncontrast computed tomography (NCCT) to obtain a high-resolution image of the large-vessel occlusion significantly delays the time to thrombectomy.

In clinical practice, omitting CTA in patients whose middle cerebral artery visualized on NCCT reveals the hyperdense sign may speed the time to thrombectomy and improve outcome. The findings of a retrospective cohort study of prospectively collected data were presented by Kunakorn Atchaneeyasakul, MD, of the University of Miami, as a poster and a brief oral presentation at the annual meeting of the American Neurological Association.

BALTIMORE – Performing computed tomography angiography (CTA) following noncontrast computed tomography (NCCT) to obtain a high-resolution image of the large-vessel occlusion significantly delays the time to thrombectomy.

In clinical practice, omitting CTA in patients whose middle cerebral artery visualized on NCCT reveals the hyperdense sign may speed the time to thrombectomy and improve outcome. The findings of a retrospective cohort study of prospectively collected data were presented by Kunakorn Atchaneeyasakul, MD, of the University of Miami, as a poster and a brief oral presentation at the annual meeting of the American Neurological Association.

BALTIMORE – Performing computed tomography angiography (CTA) following noncontrast computed tomography (NCCT) to obtain a high-resolution image of the large-vessel occlusion significantly delays the time to thrombectomy.

In clinical practice, omitting CTA in patients whose middle cerebral artery visualized on NCCT reveals the hyperdense sign may speed the time to thrombectomy and improve outcome. The findings of a retrospective cohort study of prospectively collected data were presented by Kunakorn Atchaneeyasakul, MD, of the University of Miami, as a poster and a brief oral presentation at the annual meeting of the American Neurological Association.

WASHINGTON – Antibiotics given in advance of gastric bypass surgery preferentially alter the microbiome, nudging it toward a more “lean” physiologic profile.

Given before a sleeve gastrectomy, vancomycin, which has little gut penetration, barely shifted the high ratio of Firmicutes to Bacteroidetes, a profile typically associated with obesity and insulin resistance. But cefazolin, which has much higher gut penetration, suppressed the presence of Firmicutes, which metabolize fat, and allowed the expansion of carbohydrate-loving Bacteroidetes – a profile generally seen in lean people.

Cyrus Jahansouz, MD, of the University of Minnesota, Minneapolis, and his colleagues wanted to examine whether a shift in preoperative antibiotics might affect the way the microbiome re-establishes itself in the wake of vertical sleeve gastrectomy. They enrolled 32 patients who were candidates for the procedure. None had undergone prior gastrointestinal surgery, and none had been exposed to antibiotics in the 3 months prior to bariatric surgery. They were similar in age, weight, body mass index, and fasting glucose. The mean HbA1c was about 6%.

Patients were randomized to three groups: maximal diet therapy (800 calories per day) without surgery; vertical sleeve gastrectomy with the usual preoperative antibiotic cefazolin and the postsurgical diet; and vertical sleeve gastrectomy with preoperative vancomycin and the postsurgical diet. All patients gave a fecal sample immediately before surgery and another one 6 days after surgery.

Preoperative cluster analysis of bacterial DNA showed that all of the samples had a similar composition, predominated by Firmicutes species (60%-70%). Bacteroidetes species made up about 20%-30%, with Proteobacteriae, Actinobacteriae, Verrucomicrobia, and other phyla comprising the remainder of the microbiome.

At the second sampling, the diet-only group showed no microbiome changes at all. The vancomycin group showed a very small but not significant expansion of Bacteroidetes and reduction of Firmicutes.

Patients in the cefazolin group showed a significant shift in the ratio – and it was quite striking, Dr. Jahansouz said. Among these patients, Firmicutes had decreased from 70% to 40% of the community. Bacteroidetes showed a corresponding shift, increasing from 20% of the community to 45%. The findings are quite surprising, he noted, considering that only one dose of antibiotic was associated with the changes and that they were evident within just a few days.

Although “a little hard to interpret” because of its small size and short follow-up, the study suggests that antibiotic choice might contribute to the success of weight-loss surgery, Dr. Jahansouz said at the annual clinical congress of the American College of Surgeons.

“There are still several factors in the perioperative period that we have to study to be able to identify what other things might have also influenced the shift,” he said in an interview. “But I do think that, in the future, these changes can be manipulated to benefit metabolic outcomes.”

Two phyla – Bacteroidetes and Firmicutes – dominate the human gut microbiome in a dynamic ratio that is highly associated with the way energy is extracted from food. Bacteroidetes species specialize in carbohydrate digestion and Firmicutes in fat digestion. “In a lean, insulin-sensitive state, Bacteroidetes dominates the human gut microbiome,” Dr. Jahansouz said. “With the progression of obesity and insulin resistance, there is a subsequent shift in the microbiome phenotype, favoring the growth of Firmicutes at the expense and reduction of Bacteroidetes. This is a significant change, because this obesity-associated phenotype has an increased capacity to harvest energy. It’s not the same for a lean person to consume 1,000 calories as it is for an obese person to consume them.”

Bariatric surgery has been shown to alter the gut microbiome, shifting it toward this more “lean” profile (Cell Metab. 2015 Aug 4;22[2]:228-38). This shift may be an important component of the still not fully elucidated mechanisms by which bariatric surgery causes weight loss and normalizes insulin signaling, Dr. Jahansouz said.

Dr. Jahansouz is following this group of patients to explore whether there are differences in weight loss and insulin signaling. He also will track whether the microbiome stabilizes at its early postsurgical profile, or continues to shift, either toward an even higher Bacteroidetes to Firmicutes ratio, or back to a more “obese” profile.

He and his colleagues are also investigating the effect of antibiotics and gastric bypass surgery in mouse models. “I can say that antibiotics seem to have a remarkable impact on the effect of mouse sleeve gastrectomy. We’re not quite there yet with humans,” but the data are compelling.

Dr. Jahansouz said that he had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

WASHINGTON – Antibiotics given in advance of gastric bypass surgery preferentially alter the microbiome, nudging it toward a more “lean” physiologic profile.

Given before a sleeve gastrectomy, vancomycin, which has little gut penetration, barely shifted the high ratio of Firmicutes to Bacteroidetes, a profile typically associated with obesity and insulin resistance. But cefazolin, which has much higher gut penetration, suppressed the presence of Firmicutes, which metabolize fat, and allowed the expansion of carbohydrate-loving Bacteroidetes – a profile generally seen in lean people.

Cyrus Jahansouz, MD, of the University of Minnesota, Minneapolis, and his colleagues wanted to examine whether a shift in preoperative antibiotics might affect the way the microbiome re-establishes itself in the wake of vertical sleeve gastrectomy. They enrolled 32 patients who were candidates for the procedure. None had undergone prior gastrointestinal surgery, and none had been exposed to antibiotics in the 3 months prior to bariatric surgery. They were similar in age, weight, body mass index, and fasting glucose. The mean HbA1c was about 6%.

Patients were randomized to three groups: maximal diet therapy (800 calories per day) without surgery; vertical sleeve gastrectomy with the usual preoperative antibiotic cefazolin and the postsurgical diet; and vertical sleeve gastrectomy with preoperative vancomycin and the postsurgical diet. All patients gave a fecal sample immediately before surgery and another one 6 days after surgery.

Preoperative cluster analysis of bacterial DNA showed that all of the samples had a similar composition, predominated by Firmicutes species (60%-70%). Bacteroidetes species made up about 20%-30%, with Proteobacteriae, Actinobacteriae, Verrucomicrobia, and other phyla comprising the remainder of the microbiome.

At the second sampling, the diet-only group showed no microbiome changes at all. The vancomycin group showed a very small but not significant expansion of Bacteroidetes and reduction of Firmicutes.

Patients in the cefazolin group showed a significant shift in the ratio – and it was quite striking, Dr. Jahansouz said. Among these patients, Firmicutes had decreased from 70% to 40% of the community. Bacteroidetes showed a corresponding shift, increasing from 20% of the community to 45%. The findings are quite surprising, he noted, considering that only one dose of antibiotic was associated with the changes and that they were evident within just a few days.

Although “a little hard to interpret” because of its small size and short follow-up, the study suggests that antibiotic choice might contribute to the success of weight-loss surgery, Dr. Jahansouz said at the annual clinical congress of the American College of Surgeons.

“There are still several factors in the perioperative period that we have to study to be able to identify what other things might have also influenced the shift,” he said in an interview. “But I do think that, in the future, these changes can be manipulated to benefit metabolic outcomes.”

Two phyla – Bacteroidetes and Firmicutes – dominate the human gut microbiome in a dynamic ratio that is highly associated with the way energy is extracted from food. Bacteroidetes species specialize in carbohydrate digestion and Firmicutes in fat digestion. “In a lean, insulin-sensitive state, Bacteroidetes dominates the human gut microbiome,” Dr. Jahansouz said. “With the progression of obesity and insulin resistance, there is a subsequent shift in the microbiome phenotype, favoring the growth of Firmicutes at the expense and reduction of Bacteroidetes. This is a significant change, because this obesity-associated phenotype has an increased capacity to harvest energy. It’s not the same for a lean person to consume 1,000 calories as it is for an obese person to consume them.”

Bariatric surgery has been shown to alter the gut microbiome, shifting it toward this more “lean” profile (Cell Metab. 2015 Aug 4;22[2]:228-38). This shift may be an important component of the still not fully elucidated mechanisms by which bariatric surgery causes weight loss and normalizes insulin signaling, Dr. Jahansouz said.

Dr. Jahansouz is following this group of patients to explore whether there are differences in weight loss and insulin signaling. He also will track whether the microbiome stabilizes at its early postsurgical profile, or continues to shift, either toward an even higher Bacteroidetes to Firmicutes ratio, or back to a more “obese” profile.

He and his colleagues are also investigating the effect of antibiotics and gastric bypass surgery in mouse models. “I can say that antibiotics seem to have a remarkable impact on the effect of mouse sleeve gastrectomy. We’re not quite there yet with humans,” but the data are compelling.

Dr. Jahansouz said that he had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

WASHINGTON – Antibiotics given in advance of gastric bypass surgery preferentially alter the microbiome, nudging it toward a more “lean” physiologic profile.

Given before a sleeve gastrectomy, vancomycin, which has little gut penetration, barely shifted the high ratio of Firmicutes to Bacteroidetes, a profile typically associated with obesity and insulin resistance. But cefazolin, which has much higher gut penetration, suppressed the presence of Firmicutes, which metabolize fat, and allowed the expansion of carbohydrate-loving Bacteroidetes – a profile generally seen in lean people.

Cyrus Jahansouz, MD, of the University of Minnesota, Minneapolis, and his colleagues wanted to examine whether a shift in preoperative antibiotics might affect the way the microbiome re-establishes itself in the wake of vertical sleeve gastrectomy. They enrolled 32 patients who were candidates for the procedure. None had undergone prior gastrointestinal surgery, and none had been exposed to antibiotics in the 3 months prior to bariatric surgery. They were similar in age, weight, body mass index, and fasting glucose. The mean HbA1c was about 6%.

Patients were randomized to three groups: maximal diet therapy (800 calories per day) without surgery; vertical sleeve gastrectomy with the usual preoperative antibiotic cefazolin and the postsurgical diet; and vertical sleeve gastrectomy with preoperative vancomycin and the postsurgical diet. All patients gave a fecal sample immediately before surgery and another one 6 days after surgery.

Preoperative cluster analysis of bacterial DNA showed that all of the samples had a similar composition, predominated by Firmicutes species (60%-70%). Bacteroidetes species made up about 20%-30%, with Proteobacteriae, Actinobacteriae, Verrucomicrobia, and other phyla comprising the remainder of the microbiome.

At the second sampling, the diet-only group showed no microbiome changes at all. The vancomycin group showed a very small but not significant expansion of Bacteroidetes and reduction of Firmicutes.

Patients in the cefazolin group showed a significant shift in the ratio – and it was quite striking, Dr. Jahansouz said. Among these patients, Firmicutes had decreased from 70% to 40% of the community. Bacteroidetes showed a corresponding shift, increasing from 20% of the community to 45%. The findings are quite surprising, he noted, considering that only one dose of antibiotic was associated with the changes and that they were evident within just a few days.

Although “a little hard to interpret” because of its small size and short follow-up, the study suggests that antibiotic choice might contribute to the success of weight-loss surgery, Dr. Jahansouz said at the annual clinical congress of the American College of Surgeons.

“There are still several factors in the perioperative period that we have to study to be able to identify what other things might have also influenced the shift,” he said in an interview. “But I do think that, in the future, these changes can be manipulated to benefit metabolic outcomes.”

Two phyla – Bacteroidetes and Firmicutes – dominate the human gut microbiome in a dynamic ratio that is highly associated with the way energy is extracted from food. Bacteroidetes species specialize in carbohydrate digestion and Firmicutes in fat digestion. “In a lean, insulin-sensitive state, Bacteroidetes dominates the human gut microbiome,” Dr. Jahansouz said. “With the progression of obesity and insulin resistance, there is a subsequent shift in the microbiome phenotype, favoring the growth of Firmicutes at the expense and reduction of Bacteroidetes. This is a significant change, because this obesity-associated phenotype has an increased capacity to harvest energy. It’s not the same for a lean person to consume 1,000 calories as it is for an obese person to consume them.”

Bariatric surgery has been shown to alter the gut microbiome, shifting it toward this more “lean” profile (Cell Metab. 2015 Aug 4;22[2]:228-38). This shift may be an important component of the still not fully elucidated mechanisms by which bariatric surgery causes weight loss and normalizes insulin signaling, Dr. Jahansouz said.

Dr. Jahansouz is following this group of patients to explore whether there are differences in weight loss and insulin signaling. He also will track whether the microbiome stabilizes at its early postsurgical profile, or continues to shift, either toward an even higher Bacteroidetes to Firmicutes ratio, or back to a more “obese” profile.

He and his colleagues are also investigating the effect of antibiotics and gastric bypass surgery in mouse models. “I can say that antibiotics seem to have a remarkable impact on the effect of mouse sleeve gastrectomy. We’re not quite there yet with humans,” but the data are compelling.

Dr. Jahansouz said that he had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

Researchers from Comenius University in Bratislava, Slovakia, have shown for the first time that fibrillin-1 (FBN-1) is overexpressed in testicular germ cell tumors (TGCTs). Their data suggest that progression of germ cell neoplasia in situ (GCNIS) to overt germ cell tumor is connected with decreased FBN-1 production. Fibrillin is a glycoprotein essential in forming the elastic fibers in connective tissue.

Related: Tracking a Tumor

The researchers evaluated 350 tumor specimens and 85 adjacent nonneoplastic testicular tissues in 203 patients. They detected FBN-1 expression in 68 (97%) GCNIS, 21 (96%) yolk sac tumors, 85 (87%) seminomas, 78 (83%) embryonal carcinomas, 35 (71%) teratomas, 3 (18%) choriocarcinomas, and 1 (1%) nonneoplastic tissue. The highest FBN-1 positivity was found in GCNIS, with overexpression of FBN-1 in 77% of cases. The fact that the highest expression was observed in seminomas and the lowest in choriocarcinomas, the researchers say, suggests a reduction of FBN-1 expression with the process of differentiation.

Related: Is Chemotherapy a Good Choice for Neuroendocrine Tumors?

GCNIS represents the preinvasive stage of most TGCTs in adults. GCNIS cells are believed to be germ cells that have failed to mature normally, the researchers note. The appearance of FBN-1 expression in germ cells in the stage of GCNIS, they suggest, can be an early event in the process of malignant transformation.

Source:
Cierna Z, Mego M,  Jurisica I, et al. BMC Cancer. 2016;16:597
doi: 10.1186/s12885-016-2644-z.

Researchers from Comenius University in Bratislava, Slovakia, have shown for the first time that fibrillin-1 (FBN-1) is overexpressed in testicular germ cell tumors (TGCTs). Their data suggest that progression of germ cell neoplasia in situ (GCNIS) to overt germ cell tumor is connected with decreased FBN-1 production. Fibrillin is a glycoprotein essential in forming the elastic fibers in connective tissue.

Related: Tracking a Tumor

The researchers evaluated 350 tumor specimens and 85 adjacent nonneoplastic testicular tissues in 203 patients. They detected FBN-1 expression in 68 (97%) GCNIS, 21 (96%) yolk sac tumors, 85 (87%) seminomas, 78 (83%) embryonal carcinomas, 35 (71%) teratomas, 3 (18%) choriocarcinomas, and 1 (1%) nonneoplastic tissue. The highest FBN-1 positivity was found in GCNIS, with overexpression of FBN-1 in 77% of cases. The fact that the highest expression was observed in seminomas and the lowest in choriocarcinomas, the researchers say, suggests a reduction of FBN-1 expression with the process of differentiation.

Related: Is Chemotherapy a Good Choice for Neuroendocrine Tumors?

GCNIS represents the preinvasive stage of most TGCTs in adults. GCNIS cells are believed to be germ cells that have failed to mature normally, the researchers note. The appearance of FBN-1 expression in germ cells in the stage of GCNIS, they suggest, can be an early event in the process of malignant transformation.

Source:
Cierna Z, Mego M,  Jurisica I, et al. BMC Cancer. 2016;16:597
doi: 10.1186/s12885-016-2644-z.

Researchers from Comenius University in Bratislava, Slovakia, have shown for the first time that fibrillin-1 (FBN-1) is overexpressed in testicular germ cell tumors (TGCTs). Their data suggest that progression of germ cell neoplasia in situ (GCNIS) to overt germ cell tumor is connected with decreased FBN-1 production. Fibrillin is a glycoprotein essential in forming the elastic fibers in connective tissue.

Related: Tracking a Tumor

The researchers evaluated 350 tumor specimens and 85 adjacent nonneoplastic testicular tissues in 203 patients. They detected FBN-1 expression in 68 (97%) GCNIS, 21 (96%) yolk sac tumors, 85 (87%) seminomas, 78 (83%) embryonal carcinomas, 35 (71%) teratomas, 3 (18%) choriocarcinomas, and 1 (1%) nonneoplastic tissue. The highest FBN-1 positivity was found in GCNIS, with overexpression of FBN-1 in 77% of cases. The fact that the highest expression was observed in seminomas and the lowest in choriocarcinomas, the researchers say, suggests a reduction of FBN-1 expression with the process of differentiation.

Related: Is Chemotherapy a Good Choice for Neuroendocrine Tumors?

GCNIS represents the preinvasive stage of most TGCTs in adults. GCNIS cells are believed to be germ cells that have failed to mature normally, the researchers note. The appearance of FBN-1 expression in germ cells in the stage of GCNIS, they suggest, can be an early event in the process of malignant transformation.

Source:
Cierna Z, Mego M,  Jurisica I, et al. BMC Cancer. 2016;16:597
doi: 10.1186/s12885-016-2644-z.

Exacerbations in bronchodilator-responsive asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS) were more frequent and severe than in COPD with emphysema, but only a minority of patients were treated to prevent them, in a review of 1,005 patients from the Annals of the American Thoracic Society.

All the subjects were current or former smokers culled from the COPDGene Study, a multicenter observational study looking for the genetic roots of COPD susceptibility; 385 patients met the investigators’ criteria for ACOS with bronchodilator response (ACOS-BDR), which included a history of asthma or hay fever, airway obstruction with significant bronchodilator responsiveness, and less then 15% emphysema on chest CT.

Another 620 subjects met criteria for COPD with emphysema, including airway obstruction without bronchodilator reversibility, and more than 15% emphysema on chest CT (Ann Am Thorac Soc. 2016 Sep;13(9):1483-9).

Although the ACOS patients had better lung function, they had similar severity and frequency of exacerbations, compared with the COPD group. After adjustment for forced expiratory volume in 1 second percent predicted and other factors, the patients with ACOS-BDR were actually more likely to have severe and frequent exacerbations. Possible explanations for this are that they were more likely to smoke and have gastroesophageal reflux disease and obstructive sleep apnea, all of which increase the risk of exacerbations.

Even so, ACOS-BDR patients were less likely to be on a long-acting beta-agonist (6.8% versus 13.9%); a long-acting muscarinic antagonist (20% versus 60.8%); or a combination long-acting beta-agonist/inhaled corticosteroid (29.9% versus 55.6%).

“Only a small percentage of them were being treated ... Early and aggressive treatment with combination therapy may help alleviate symptoms and decrease exacerbations,” said investigators led by James Cosentino, DO, of Temple University School of Medicine, Philadelphia. Patients with ACOS “are a particularly high-risk group.” They deserve “special attention, and practitioners need to be diligent in evaluation of them.”

ACOS is being increasingly recognized as a distinct clinical entity with perhaps a worse prognosis than either asthma or COPD alone. The goal of the study was to better characterize the disease.

To that end, the team found four features that seemed to distinguish ACOS-BDR from COPD with emphysema: ACOS-BDR patients were younger (60.6 versus 65.9 years old); heavier (body mass index 29.6 versus 25.1 kg/m²; more likely to be African American (26.8% versus 14.4%); and more likely to be current smokers (50.9% versus 20.7%).

It’s “likely that current smoking in subjects with ACOS, coupled with the long duration of asthma, leads to inflammation and small airway remodeling with development of symptoms earlier in the disease course than that seen in those with COPD with emphysema,” the investigators said.

“Early and aggressive treatment with combination therapy may help alleviate symptoms and decrease exacerbations. Recognition and treatment of comorbidities and aggressive smoking cessation may also play a key role in preventing exacerbations and alleviating the morbidity associated with ACOS; however, future studies on the treatment of ACOS are needed,” they said.

The majority of subjects with ACOS-BDR met criteria for Global Initiative for Chronic Obstructive Lung Disease grade B, indicating a high degree of symptoms despite less severe airflow obstruction.

The funding source wasn’t reported. Dr. Cosentino had no conflicts. Other authors disclosed personal fees from Concert Pharmaceuticals, CSA Medical, CSL Behring, Gala Therapeutics, and Novartis.

aotto@frontlinemedcom.com

Exacerbations in bronchodilator-responsive asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS) were more frequent and severe than in COPD with emphysema, but only a minority of patients were treated to prevent them, in a review of 1,005 patients from the Annals of the American Thoracic Society.

All the subjects were current or former smokers culled from the COPDGene Study, a multicenter observational study looking for the genetic roots of COPD susceptibility; 385 patients met the investigators’ criteria for ACOS with bronchodilator response (ACOS-BDR), which included a history of asthma or hay fever, airway obstruction with significant bronchodilator responsiveness, and less then 15% emphysema on chest CT.

Another 620 subjects met criteria for COPD with emphysema, including airway obstruction without bronchodilator reversibility, and more than 15% emphysema on chest CT (Ann Am Thorac Soc. 2016 Sep;13(9):1483-9).

Although the ACOS patients had better lung function, they had similar severity and frequency of exacerbations, compared with the COPD group. After adjustment for forced expiratory volume in 1 second percent predicted and other factors, the patients with ACOS-BDR were actually more likely to have severe and frequent exacerbations. Possible explanations for this are that they were more likely to smoke and have gastroesophageal reflux disease and obstructive sleep apnea, all of which increase the risk of exacerbations.

Even so, ACOS-BDR patients were less likely to be on a long-acting beta-agonist (6.8% versus 13.9%); a long-acting muscarinic antagonist (20% versus 60.8%); or a combination long-acting beta-agonist/inhaled corticosteroid (29.9% versus 55.6%).

“Only a small percentage of them were being treated ... Early and aggressive treatment with combination therapy may help alleviate symptoms and decrease exacerbations,” said investigators led by James Cosentino, DO, of Temple University School of Medicine, Philadelphia. Patients with ACOS “are a particularly high-risk group.” They deserve “special attention, and practitioners need to be diligent in evaluation of them.”

ACOS is being increasingly recognized as a distinct clinical entity with perhaps a worse prognosis than either asthma or COPD alone. The goal of the study was to better characterize the disease.

To that end, the team found four features that seemed to distinguish ACOS-BDR from COPD with emphysema: ACOS-BDR patients were younger (60.6 versus 65.9 years old); heavier (body mass index 29.6 versus 25.1 kg/m²; more likely to be African American (26.8% versus 14.4%); and more likely to be current smokers (50.9% versus 20.7%).

It’s “likely that current smoking in subjects with ACOS, coupled with the long duration of asthma, leads to inflammation and small airway remodeling with development of symptoms earlier in the disease course than that seen in those with COPD with emphysema,” the investigators said.

“Early and aggressive treatment with combination therapy may help alleviate symptoms and decrease exacerbations. Recognition and treatment of comorbidities and aggressive smoking cessation may also play a key role in preventing exacerbations and alleviating the morbidity associated with ACOS; however, future studies on the treatment of ACOS are needed,” they said.

The majority of subjects with ACOS-BDR met criteria for Global Initiative for Chronic Obstructive Lung Disease grade B, indicating a high degree of symptoms despite less severe airflow obstruction.

The funding source wasn’t reported. Dr. Cosentino had no conflicts. Other authors disclosed personal fees from Concert Pharmaceuticals, CSA Medical, CSL Behring, Gala Therapeutics, and Novartis.

aotto@frontlinemedcom.com

Exacerbations in bronchodilator-responsive asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS) were more frequent and severe than in COPD with emphysema, but only a minority of patients were treated to prevent them, in a review of 1,005 patients from the Annals of the American Thoracic Society.

All the subjects were current or former smokers culled from the COPDGene Study, a multicenter observational study looking for the genetic roots of COPD susceptibility; 385 patients met the investigators’ criteria for ACOS with bronchodilator response (ACOS-BDR), which included a history of asthma or hay fever, airway obstruction with significant bronchodilator responsiveness, and less then 15% emphysema on chest CT.

Another 620 subjects met criteria for COPD with emphysema, including airway obstruction without bronchodilator reversibility, and more than 15% emphysema on chest CT (Ann Am Thorac Soc. 2016 Sep;13(9):1483-9).

Although the ACOS patients had better lung function, they had similar severity and frequency of exacerbations, compared with the COPD group. After adjustment for forced expiratory volume in 1 second percent predicted and other factors, the patients with ACOS-BDR were actually more likely to have severe and frequent exacerbations. Possible explanations for this are that they were more likely to smoke and have gastroesophageal reflux disease and obstructive sleep apnea, all of which increase the risk of exacerbations.

Even so, ACOS-BDR patients were less likely to be on a long-acting beta-agonist (6.8% versus 13.9%); a long-acting muscarinic antagonist (20% versus 60.8%); or a combination long-acting beta-agonist/inhaled corticosteroid (29.9% versus 55.6%).

“Only a small percentage of them were being treated ... Early and aggressive treatment with combination therapy may help alleviate symptoms and decrease exacerbations,” said investigators led by James Cosentino, DO, of Temple University School of Medicine, Philadelphia. Patients with ACOS “are a particularly high-risk group.” They deserve “special attention, and practitioners need to be diligent in evaluation of them.”

ACOS is being increasingly recognized as a distinct clinical entity with perhaps a worse prognosis than either asthma or COPD alone. The goal of the study was to better characterize the disease.

To that end, the team found four features that seemed to distinguish ACOS-BDR from COPD with emphysema: ACOS-BDR patients were younger (60.6 versus 65.9 years old); heavier (body mass index 29.6 versus 25.1 kg/m²; more likely to be African American (26.8% versus 14.4%); and more likely to be current smokers (50.9% versus 20.7%).

It’s “likely that current smoking in subjects with ACOS, coupled with the long duration of asthma, leads to inflammation and small airway remodeling with development of symptoms earlier in the disease course than that seen in those with COPD with emphysema,” the investigators said.

“Early and aggressive treatment with combination therapy may help alleviate symptoms and decrease exacerbations. Recognition and treatment of comorbidities and aggressive smoking cessation may also play a key role in preventing exacerbations and alleviating the morbidity associated with ACOS; however, future studies on the treatment of ACOS are needed,” they said.

The majority of subjects with ACOS-BDR met criteria for Global Initiative for Chronic Obstructive Lung Disease grade B, indicating a high degree of symptoms despite less severe airflow obstruction.

The funding source wasn’t reported. Dr. Cosentino had no conflicts. Other authors disclosed personal fees from Concert Pharmaceuticals, CSA Medical, CSL Behring, Gala Therapeutics, and Novartis.

aotto@frontlinemedcom.com

The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.

Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.

koakes@frontlinemedcom.com

On Twitter @karioakes

The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.

Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.

koakes@frontlinemedcom.com

On Twitter @karioakes

The novel oral osteoporosis drug odanacatib significantly reduced fractures in postmenopausal women but was also associated with a significantly higher risk for stroke, according to data from a 5-year extension of a large phase III clinical trial.

Based on an independent analysis and verification of the risk for stroke, the drug’s sponsor, Merck, has withdrawn odanacatib from review by the Food and Drug Administration. “We are disappointed that the overall benefit-risk profile for odanacatib does not support filing or further development,” Roger M. Perlmutter, MD, president of Merck Research Laboratories, said in a statement.

koakes@frontlinemedcom.com

On Twitter @karioakes

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

SALT LAKE CITY – Low serum levels of anti-Müllerian hormone predicted miscarriage after in vitro fertilization and embryo transfer, according to a single-center prospective study of more than 2,000 women.

This relationship remained statistically significant after the study controlled for age and response to controlled ovarian hyperstimulation, which suggests that AMH is a marker of the reproductive potential of oocytes, not just of oocyte quantity, Bruno Tarasconi, MD, said at the annual meeting of the American Society for Reproductive Medicine.

“Low” serum AMH was defined as less than 1.61 ng per mL, but specific levels vary by test type, so “this is not a definite cutoff,” Dr. Tarasconi emphasized. “What we need to know is that patients with low AMH are probably experiencing some problems in the ovary that affect oocyte quality.”

iStock

SALT LAKE CITY – Low serum levels of anti-Müllerian hormone predicted miscarriage after in vitro fertilization and embryo transfer, according to a single-center prospective study of more than 2,000 women.

This relationship remained statistically significant after the study controlled for age and response to controlled ovarian hyperstimulation, which suggests that AMH is a marker of the reproductive potential of oocytes, not just of oocyte quantity, Bruno Tarasconi, MD, said at the annual meeting of the American Society for Reproductive Medicine.

“Low” serum AMH was defined as less than 1.61 ng per mL, but specific levels vary by test type, so “this is not a definite cutoff,” Dr. Tarasconi emphasized. “What we need to know is that patients with low AMH are probably experiencing some problems in the ovary that affect oocyte quality.”

iStock

SALT LAKE CITY – Low serum levels of anti-Müllerian hormone predicted miscarriage after in vitro fertilization and embryo transfer, according to a single-center prospective study of more than 2,000 women.

This relationship remained statistically significant after the study controlled for age and response to controlled ovarian hyperstimulation, which suggests that AMH is a marker of the reproductive potential of oocytes, not just of oocyte quantity, Bruno Tarasconi, MD, said at the annual meeting of the American Society for Reproductive Medicine.

“Low” serum AMH was defined as less than 1.61 ng per mL, but specific levels vary by test type, so “this is not a definite cutoff,” Dr. Tarasconi emphasized. “What we need to know is that patients with low AMH are probably experiencing some problems in the ovary that affect oocyte quality.”

iStock

VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.

It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com

VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.

It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com

VIENNA – The investigational interleukin-23 p-19 subunit inhibitor tildrakizumab achieved PASI 90 improvement rates approaching 60% in patients with moderate to severe plaque psoriasis at week 28 of the pivotal phase III reSURFACE 1 and reSURFACE 2 trials, Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Moreover, the PASI 100 rate at week 28 in the two clinical trials was 24% with tildrakizumab, a humanized monoclonal antibody, at the 100-mg dose and 30% at 200 mg.

It was at these highest efficacy thresholds that the p-19 inhibitor really separated itself from etanercept (Enbrel) in reSURFACE 2, where the two biologics went head-to-head in randomized fashion. Patients on etanercept had a PASI 90 rate at week 28 of 31%, roughly only half that of tildrakizumab at the higher dose.

Bruce Jancin/Frontline Medical News

bjancin@frontlinemedcom.com