User login
No Benefit to High-Dose IV Vs Oral Steroids in Giant Cell Arteritis
TOPLINE:
In patients with giant cell arteritis (GCA), intravenous methylprednisolone compared with oral glucocorticoids alone does not improve visual acuity and increases the risk for diabetes within the first year. Survival rates do not differ with these two treatments.
METHODOLOGY:
- Researchers conducted a population-based retrospective study at three centers in Sweden to assess the clinical characteristics, treatment-related toxicity, and mortality in patients with GCA who were receiving high-dose intravenous methylprednisolone.
- A total of 419 patients with biopsy-confirmed GCA (mean age at diagnosis, 75 years; 69% women) diagnosed from 2004 to 2019 were included.
- Patients were treated with either intravenous methylprednisolone (n = 111) at a dose of 500-1000 mg per day for 3 consecutive days or oral glucocorticoids alone (n = 308).
- Ischemic visual complications considered to indicate visual involvement were confirmed by an ophthalmologist, and data on visual acuity were collected from ophthalmologic clinic records at initial consultations and follow-up at 3-18 months.
TAKEAWAY:
- Despite a tendency toward improvement, no significant difference in visual acuity was observed with intravenous methylprednisolone compared with oral glucocorticoids.
- Patients treated with intravenous methylprednisolone had a higher risk for newly diagnosed diabetes within a year of GCA diagnosis (odds ratio [OR], 2.59; P = .01).
- The risk for diabetes remained elevated even after adjustment for the cumulative oral glucocorticoid dose at 3 months (adjusted OR, 3.30; P = .01).
- Survival rates did not significantly differ between the treatment groups over a mean follow-up of 6.6 years.
IN PRACTICE:
“In this study on the use of intravenous methylprednisolone treatment in GCA, we found no evidence of a beneficial effect in improving visual acuity or enabling more rapid tapering of the oral glucocorticoid dose,” the authors wrote. “The use of IVMP [intravenous methylprednisolone] was associated with an increased risk of diabetes during the first year compared with oral GC [glucocorticoid], raising questions about the value of IVMP in GCA treatment.”
SOURCE:
The study, led by Hampus Henningson, Department of Clinical Sciences, Rheumatology, Lund University, Lund, Sweden, was published online in Rheumatology.
LIMITATIONS:
The retrospective nature of the study may have resulted in missing data and difficulty in accurately quantifying the cumulative glucocorticoid doses. The study did not validate the diagnoses of comorbidities but relied solely on diagnostic codes.
DISCLOSURES:
This study was supported by the Swedish Research Council, Swedish Rheumatism Association, Swedish Medical Society, Alfred Österlund’s Foundation, and King Gustaf V’s 80-year foundation. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
In patients with giant cell arteritis (GCA), intravenous methylprednisolone compared with oral glucocorticoids alone does not improve visual acuity and increases the risk for diabetes within the first year. Survival rates do not differ with these two treatments.
METHODOLOGY:
- Researchers conducted a population-based retrospective study at three centers in Sweden to assess the clinical characteristics, treatment-related toxicity, and mortality in patients with GCA who were receiving high-dose intravenous methylprednisolone.
- A total of 419 patients with biopsy-confirmed GCA (mean age at diagnosis, 75 years; 69% women) diagnosed from 2004 to 2019 were included.
- Patients were treated with either intravenous methylprednisolone (n = 111) at a dose of 500-1000 mg per day for 3 consecutive days or oral glucocorticoids alone (n = 308).
- Ischemic visual complications considered to indicate visual involvement were confirmed by an ophthalmologist, and data on visual acuity were collected from ophthalmologic clinic records at initial consultations and follow-up at 3-18 months.
TAKEAWAY:
- Despite a tendency toward improvement, no significant difference in visual acuity was observed with intravenous methylprednisolone compared with oral glucocorticoids.
- Patients treated with intravenous methylprednisolone had a higher risk for newly diagnosed diabetes within a year of GCA diagnosis (odds ratio [OR], 2.59; P = .01).
- The risk for diabetes remained elevated even after adjustment for the cumulative oral glucocorticoid dose at 3 months (adjusted OR, 3.30; P = .01).
- Survival rates did not significantly differ between the treatment groups over a mean follow-up of 6.6 years.
IN PRACTICE:
“In this study on the use of intravenous methylprednisolone treatment in GCA, we found no evidence of a beneficial effect in improving visual acuity or enabling more rapid tapering of the oral glucocorticoid dose,” the authors wrote. “The use of IVMP [intravenous methylprednisolone] was associated with an increased risk of diabetes during the first year compared with oral GC [glucocorticoid], raising questions about the value of IVMP in GCA treatment.”
SOURCE:
The study, led by Hampus Henningson, Department of Clinical Sciences, Rheumatology, Lund University, Lund, Sweden, was published online in Rheumatology.
LIMITATIONS:
The retrospective nature of the study may have resulted in missing data and difficulty in accurately quantifying the cumulative glucocorticoid doses. The study did not validate the diagnoses of comorbidities but relied solely on diagnostic codes.
DISCLOSURES:
This study was supported by the Swedish Research Council, Swedish Rheumatism Association, Swedish Medical Society, Alfred Österlund’s Foundation, and King Gustaf V’s 80-year foundation. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
In patients with giant cell arteritis (GCA), intravenous methylprednisolone compared with oral glucocorticoids alone does not improve visual acuity and increases the risk for diabetes within the first year. Survival rates do not differ with these two treatments.
METHODOLOGY:
- Researchers conducted a population-based retrospective study at three centers in Sweden to assess the clinical characteristics, treatment-related toxicity, and mortality in patients with GCA who were receiving high-dose intravenous methylprednisolone.
- A total of 419 patients with biopsy-confirmed GCA (mean age at diagnosis, 75 years; 69% women) diagnosed from 2004 to 2019 were included.
- Patients were treated with either intravenous methylprednisolone (n = 111) at a dose of 500-1000 mg per day for 3 consecutive days or oral glucocorticoids alone (n = 308).
- Ischemic visual complications considered to indicate visual involvement were confirmed by an ophthalmologist, and data on visual acuity were collected from ophthalmologic clinic records at initial consultations and follow-up at 3-18 months.
TAKEAWAY:
- Despite a tendency toward improvement, no significant difference in visual acuity was observed with intravenous methylprednisolone compared with oral glucocorticoids.
- Patients treated with intravenous methylprednisolone had a higher risk for newly diagnosed diabetes within a year of GCA diagnosis (odds ratio [OR], 2.59; P = .01).
- The risk for diabetes remained elevated even after adjustment for the cumulative oral glucocorticoid dose at 3 months (adjusted OR, 3.30; P = .01).
- Survival rates did not significantly differ between the treatment groups over a mean follow-up of 6.6 years.
IN PRACTICE:
“In this study on the use of intravenous methylprednisolone treatment in GCA, we found no evidence of a beneficial effect in improving visual acuity or enabling more rapid tapering of the oral glucocorticoid dose,” the authors wrote. “The use of IVMP [intravenous methylprednisolone] was associated with an increased risk of diabetes during the first year compared with oral GC [glucocorticoid], raising questions about the value of IVMP in GCA treatment.”
SOURCE:
The study, led by Hampus Henningson, Department of Clinical Sciences, Rheumatology, Lund University, Lund, Sweden, was published online in Rheumatology.
LIMITATIONS:
The retrospective nature of the study may have resulted in missing data and difficulty in accurately quantifying the cumulative glucocorticoid doses. The study did not validate the diagnoses of comorbidities but relied solely on diagnostic codes.
DISCLOSURES:
This study was supported by the Swedish Research Council, Swedish Rheumatism Association, Swedish Medical Society, Alfred Österlund’s Foundation, and King Gustaf V’s 80-year foundation. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Cannabis Often Used as a Substitute for Traditional Medications
Nearly two thirds of patients with rheumatic conditions switched to medical cannabis from medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, with the substitution being associated with greater self-reported improvement in symptoms than nonsubstitution.
METHODOLOGY:
- Researchers conducted a secondary analysis of a cross-sectional survey to investigate the prevalence of switching to medical cannabis from traditional medications in patients with rheumatic conditions from the United States and Canada.
- The survey included questions on current and past medical cannabis use, sociodemographic characteristics, medication taken and substituted, substance use, and patient-reported outcomes.
- Of the 1727 patients who completed the survey, 763 patients (mean age, 59 years; 84.1% women) reported current use of cannabis and were included in this analysis.
- Participants were asked if they had substituted any medications with medical cannabis and were sub-grouped accordingly.
- They also reported any changes in symptoms after initiating cannabis, the current and anticipated duration of medical cannabis use, methods of ingestion, cannabinoid content, and frequency of use.
TAKEAWAY:
- Overall, 62.5% reported substituting medical cannabis for certain medications, including NSAIDs (54.7%), opioids (48.6%), sleep aids (29.6%), muscle relaxants (25.2%), benzodiazepines (15.5%), and gabapentinoids (10.5%).
- The most common reasons given for substituting medical cannabis were fewer side effects (39%), better symptom control (27%), and fewer adverse effects (12%).
- Participants who substituted medical cannabis reported significant improvements in symptoms such as pain, sleep, joint stiffness, muscle spasms, and inflammation, and in overall health, compared with those who did not substitute it for medications.
- The substitution group was more likely to use inhalation methods (smoking and vaporizing) than the nonsubstitution group; they also used medical cannabis more frequently and preferred products containing delta-9-tetrahydrocannabinol.
IN PRACTICE:
“The changing legal status of cannabis has allowed a greater openness with more people willing to try cannabis for symptom relief. These encouraging results of medication reduction and favorable effect of [medical cannabis] require confirmation with more rigorous methods. At this time, survey information may be seen as a signal for effect, rather than sound evidence that could be applicable to those with musculoskeletal complaints in general,” the authors wrote.
SOURCE:
The study was led by Kevin F. Boehnke, PhD, University of Michigan Medical School, Ann Arbor, and was published online in ACR Open Rheumatology.
LIMITATIONS:
The cross-sectional nature of the study limited the determination of causality between medical cannabis use and symptom improvement. Moreover, the anonymous and self-reported nature of the survey at a single timepoint may have introduced recall bias. The sample predominantly consisted of older, White females, which may have limited the generalizability of the findings to other demographic groups.
DISCLOSURES:
Some authors received grant support from the National Institute on Drug Abuse and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some others received payments, honoraria, grant funding, consulting fees, and travel support, and reported other ties with pharmaceutical companies and other institutions.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Nearly two thirds of patients with rheumatic conditions switched to medical cannabis from medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, with the substitution being associated with greater self-reported improvement in symptoms than nonsubstitution.
METHODOLOGY:
- Researchers conducted a secondary analysis of a cross-sectional survey to investigate the prevalence of switching to medical cannabis from traditional medications in patients with rheumatic conditions from the United States and Canada.
- The survey included questions on current and past medical cannabis use, sociodemographic characteristics, medication taken and substituted, substance use, and patient-reported outcomes.
- Of the 1727 patients who completed the survey, 763 patients (mean age, 59 years; 84.1% women) reported current use of cannabis and were included in this analysis.
- Participants were asked if they had substituted any medications with medical cannabis and were sub-grouped accordingly.
- They also reported any changes in symptoms after initiating cannabis, the current and anticipated duration of medical cannabis use, methods of ingestion, cannabinoid content, and frequency of use.
TAKEAWAY:
- Overall, 62.5% reported substituting medical cannabis for certain medications, including NSAIDs (54.7%), opioids (48.6%), sleep aids (29.6%), muscle relaxants (25.2%), benzodiazepines (15.5%), and gabapentinoids (10.5%).
- The most common reasons given for substituting medical cannabis were fewer side effects (39%), better symptom control (27%), and fewer adverse effects (12%).
- Participants who substituted medical cannabis reported significant improvements in symptoms such as pain, sleep, joint stiffness, muscle spasms, and inflammation, and in overall health, compared with those who did not substitute it for medications.
- The substitution group was more likely to use inhalation methods (smoking and vaporizing) than the nonsubstitution group; they also used medical cannabis more frequently and preferred products containing delta-9-tetrahydrocannabinol.
IN PRACTICE:
“The changing legal status of cannabis has allowed a greater openness with more people willing to try cannabis for symptom relief. These encouraging results of medication reduction and favorable effect of [medical cannabis] require confirmation with more rigorous methods. At this time, survey information may be seen as a signal for effect, rather than sound evidence that could be applicable to those with musculoskeletal complaints in general,” the authors wrote.
SOURCE:
The study was led by Kevin F. Boehnke, PhD, University of Michigan Medical School, Ann Arbor, and was published online in ACR Open Rheumatology.
LIMITATIONS:
The cross-sectional nature of the study limited the determination of causality between medical cannabis use and symptom improvement. Moreover, the anonymous and self-reported nature of the survey at a single timepoint may have introduced recall bias. The sample predominantly consisted of older, White females, which may have limited the generalizability of the findings to other demographic groups.
DISCLOSURES:
Some authors received grant support from the National Institute on Drug Abuse and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some others received payments, honoraria, grant funding, consulting fees, and travel support, and reported other ties with pharmaceutical companies and other institutions.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Nearly two thirds of patients with rheumatic conditions switched to medical cannabis from medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, with the substitution being associated with greater self-reported improvement in symptoms than nonsubstitution.
METHODOLOGY:
- Researchers conducted a secondary analysis of a cross-sectional survey to investigate the prevalence of switching to medical cannabis from traditional medications in patients with rheumatic conditions from the United States and Canada.
- The survey included questions on current and past medical cannabis use, sociodemographic characteristics, medication taken and substituted, substance use, and patient-reported outcomes.
- Of the 1727 patients who completed the survey, 763 patients (mean age, 59 years; 84.1% women) reported current use of cannabis and were included in this analysis.
- Participants were asked if they had substituted any medications with medical cannabis and were sub-grouped accordingly.
- They also reported any changes in symptoms after initiating cannabis, the current and anticipated duration of medical cannabis use, methods of ingestion, cannabinoid content, and frequency of use.
TAKEAWAY:
- Overall, 62.5% reported substituting medical cannabis for certain medications, including NSAIDs (54.7%), opioids (48.6%), sleep aids (29.6%), muscle relaxants (25.2%), benzodiazepines (15.5%), and gabapentinoids (10.5%).
- The most common reasons given for substituting medical cannabis were fewer side effects (39%), better symptom control (27%), and fewer adverse effects (12%).
- Participants who substituted medical cannabis reported significant improvements in symptoms such as pain, sleep, joint stiffness, muscle spasms, and inflammation, and in overall health, compared with those who did not substitute it for medications.
- The substitution group was more likely to use inhalation methods (smoking and vaporizing) than the nonsubstitution group; they also used medical cannabis more frequently and preferred products containing delta-9-tetrahydrocannabinol.
IN PRACTICE:
“The changing legal status of cannabis has allowed a greater openness with more people willing to try cannabis for symptom relief. These encouraging results of medication reduction and favorable effect of [medical cannabis] require confirmation with more rigorous methods. At this time, survey information may be seen as a signal for effect, rather than sound evidence that could be applicable to those with musculoskeletal complaints in general,” the authors wrote.
SOURCE:
The study was led by Kevin F. Boehnke, PhD, University of Michigan Medical School, Ann Arbor, and was published online in ACR Open Rheumatology.
LIMITATIONS:
The cross-sectional nature of the study limited the determination of causality between medical cannabis use and symptom improvement. Moreover, the anonymous and self-reported nature of the survey at a single timepoint may have introduced recall bias. The sample predominantly consisted of older, White females, which may have limited the generalizability of the findings to other demographic groups.
DISCLOSURES:
Some authors received grant support from the National Institute on Drug Abuse and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some others received payments, honoraria, grant funding, consulting fees, and travel support, and reported other ties with pharmaceutical companies and other institutions.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Therapeutic Drug Monitoring in Rheumatology: A Promising Outlook But Many Barriers to Overcome
Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.
While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.
“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”
She noted that TDM is most acutely needed for management of systemic lupus erythematosus, where nonadherence is a major problem. “Whole blood hydroxychloroquine monitoring has proven beneficial for identifying nonadherence, but also to pinpoint patients who are on too much, a risk factor for retinopathy,” Petri said.
“The state of therapeutic drug monitoring in general has been interesting when you think about its use in autoimmune disease because it’s very much used in gastroenterology and it’s been much less used in rheumatology,” Zachary Wallace, MD, codirector of the Rheumatology & Allergy Clinical Epidemiology Research Center at Massachusetts General Hospital in Boston, told Medscape Medical News. “Some of that may have to do with the interpretation of the availability of evidence, but I think it’s something clinicians will come across more and more often in their practice and wondering what its role might be,” he added.
The movement to precision medicine also portends to grow interest in TDM in rheumatology, said Stephen Balevic, MD, PhD, a rheumatologist and pharmacologist at Duke University and director of pharmacometrics at the Duke Clinical Research Institute, Durham, North Carolina.
“It’s a very exciting time for rheumatologists to begin thinking outside box on what it means to study precision medicine, and I think pharmacology is one of the most overlooked aspects of precision medicine in our community,” he told Medscape Medical News.
That may be because older DMARDs, namely hydroxychloroquine and methotrexate, came to market when regulatory requirements were different than they are today, Balevic said. “Many of the older conventional DMARDs were discovered incidentally and never really had the traditional pharmacokinetic-pharmacodynamic trials to determine optimal dosing, or perhaps that was extrapolated from other populations,” he said.
So, the “one-size-fits-all” approach does not work for prescribing older or even some of the newer DMARDs for rheumatologic disorders, Balevic said.
Reactive vs Proactive TDM
Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.
Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”
Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”
In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.
Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.
“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
The State of the Evidence
NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.
Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.
“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.
“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”
However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.
NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.
Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.
“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”
In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.
Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
Barriers to Wider Use of TDM
“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”
The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.
“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.
“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.
That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.
Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”
Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”
Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
Cost and Patient Trust as Barriers
“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.
But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.
Patient trust could be another potential barrier, Garg said. “A lot of times there is not shared decision-making involved in why this test is being done, how those tests will help us as clinicians, and [patients’ understanding of] the use of the medicine,” Garg said.
“If the shared decision-making to build trust is not there, a lot of times patients worry that they’re being under surveillance or they’re being watched, so that might add to the lack of trust in the core issues that are critical threats to patients with chronic diseases because this is a lifelong partnership,” she said.
Convenience is another issue. “Particularly with mycophenolate levels, a lot of studies have used area under the curve, so getting an area under the curve level over a period of 12 hours would require several samples,” Garg said.
Testing protocols are also uncertain, Garg added. “A few data points ... are missing, like how we use the data over time,” she said. “If you do it for a given patient over several years, how often should you do it? How often do the levels fluctuate? How are the data used to inform dosing changes or monitoring changes?
“When those pieces are put together, then we are more likely to build up an intervention that clinicians can use in clinical practice, so they know how to order it and how frequently do it — every 6 months, 3 months, or every month. And then, over a period of time, how to adjust the dosing. That’s the big question.”
Who May Benefit Most From TDM?
In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?
“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.
“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.
The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.
While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.
She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
Potential Risks for TDM
Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”
That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.
A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
What DMARDs Are Most Suitable for TDM?
Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”
Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
Why Do TDM?
“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.
“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.
Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”
However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
What’s Next
Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.
“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.
“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”
Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
A version of this article appeared on Medscape.com.
Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.
While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.
“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”
She noted that TDM is most acutely needed for management of systemic lupus erythematosus, where nonadherence is a major problem. “Whole blood hydroxychloroquine monitoring has proven beneficial for identifying nonadherence, but also to pinpoint patients who are on too much, a risk factor for retinopathy,” Petri said.
“The state of therapeutic drug monitoring in general has been interesting when you think about its use in autoimmune disease because it’s very much used in gastroenterology and it’s been much less used in rheumatology,” Zachary Wallace, MD, codirector of the Rheumatology & Allergy Clinical Epidemiology Research Center at Massachusetts General Hospital in Boston, told Medscape Medical News. “Some of that may have to do with the interpretation of the availability of evidence, but I think it’s something clinicians will come across more and more often in their practice and wondering what its role might be,” he added.
The movement to precision medicine also portends to grow interest in TDM in rheumatology, said Stephen Balevic, MD, PhD, a rheumatologist and pharmacologist at Duke University and director of pharmacometrics at the Duke Clinical Research Institute, Durham, North Carolina.
“It’s a very exciting time for rheumatologists to begin thinking outside box on what it means to study precision medicine, and I think pharmacology is one of the most overlooked aspects of precision medicine in our community,” he told Medscape Medical News.
That may be because older DMARDs, namely hydroxychloroquine and methotrexate, came to market when regulatory requirements were different than they are today, Balevic said. “Many of the older conventional DMARDs were discovered incidentally and never really had the traditional pharmacokinetic-pharmacodynamic trials to determine optimal dosing, or perhaps that was extrapolated from other populations,” he said.
So, the “one-size-fits-all” approach does not work for prescribing older or even some of the newer DMARDs for rheumatologic disorders, Balevic said.
Reactive vs Proactive TDM
Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.
Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”
Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”
In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.
Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.
“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
The State of the Evidence
NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.
Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.
“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.
“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”
However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.
NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.
Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.
“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”
In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.
Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
Barriers to Wider Use of TDM
“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”
The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.
“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.
“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.
That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.
Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”
Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”
Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
Cost and Patient Trust as Barriers
“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.
But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.
Patient trust could be another potential barrier, Garg said. “A lot of times there is not shared decision-making involved in why this test is being done, how those tests will help us as clinicians, and [patients’ understanding of] the use of the medicine,” Garg said.
“If the shared decision-making to build trust is not there, a lot of times patients worry that they’re being under surveillance or they’re being watched, so that might add to the lack of trust in the core issues that are critical threats to patients with chronic diseases because this is a lifelong partnership,” she said.
Convenience is another issue. “Particularly with mycophenolate levels, a lot of studies have used area under the curve, so getting an area under the curve level over a period of 12 hours would require several samples,” Garg said.
Testing protocols are also uncertain, Garg added. “A few data points ... are missing, like how we use the data over time,” she said. “If you do it for a given patient over several years, how often should you do it? How often do the levels fluctuate? How are the data used to inform dosing changes or monitoring changes?
“When those pieces are put together, then we are more likely to build up an intervention that clinicians can use in clinical practice, so they know how to order it and how frequently do it — every 6 months, 3 months, or every month. And then, over a period of time, how to adjust the dosing. That’s the big question.”
Who May Benefit Most From TDM?
In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?
“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.
“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.
The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.
While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.
She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
Potential Risks for TDM
Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”
That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.
A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
What DMARDs Are Most Suitable for TDM?
Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”
Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
Why Do TDM?
“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.
“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.
Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”
However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
What’s Next
Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.
“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.
“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”
Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
A version of this article appeared on Medscape.com.
Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.
While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.
“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”
She noted that TDM is most acutely needed for management of systemic lupus erythematosus, where nonadherence is a major problem. “Whole blood hydroxychloroquine monitoring has proven beneficial for identifying nonadherence, but also to pinpoint patients who are on too much, a risk factor for retinopathy,” Petri said.
“The state of therapeutic drug monitoring in general has been interesting when you think about its use in autoimmune disease because it’s very much used in gastroenterology and it’s been much less used in rheumatology,” Zachary Wallace, MD, codirector of the Rheumatology & Allergy Clinical Epidemiology Research Center at Massachusetts General Hospital in Boston, told Medscape Medical News. “Some of that may have to do with the interpretation of the availability of evidence, but I think it’s something clinicians will come across more and more often in their practice and wondering what its role might be,” he added.
The movement to precision medicine also portends to grow interest in TDM in rheumatology, said Stephen Balevic, MD, PhD, a rheumatologist and pharmacologist at Duke University and director of pharmacometrics at the Duke Clinical Research Institute, Durham, North Carolina.
“It’s a very exciting time for rheumatologists to begin thinking outside box on what it means to study precision medicine, and I think pharmacology is one of the most overlooked aspects of precision medicine in our community,” he told Medscape Medical News.
That may be because older DMARDs, namely hydroxychloroquine and methotrexate, came to market when regulatory requirements were different than they are today, Balevic said. “Many of the older conventional DMARDs were discovered incidentally and never really had the traditional pharmacokinetic-pharmacodynamic trials to determine optimal dosing, or perhaps that was extrapolated from other populations,” he said.
So, the “one-size-fits-all” approach does not work for prescribing older or even some of the newer DMARDs for rheumatologic disorders, Balevic said.
Reactive vs Proactive TDM
Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.
Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”
Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”
In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.
Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.
“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
The State of the Evidence
NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.
Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.
“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.
“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”
However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.
NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.
Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.
“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”
In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.
Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
Barriers to Wider Use of TDM
“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”
The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.
“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.
“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.
That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.
Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”
Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”
Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
Cost and Patient Trust as Barriers
“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.
But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.
Patient trust could be another potential barrier, Garg said. “A lot of times there is not shared decision-making involved in why this test is being done, how those tests will help us as clinicians, and [patients’ understanding of] the use of the medicine,” Garg said.
“If the shared decision-making to build trust is not there, a lot of times patients worry that they’re being under surveillance or they’re being watched, so that might add to the lack of trust in the core issues that are critical threats to patients with chronic diseases because this is a lifelong partnership,” she said.
Convenience is another issue. “Particularly with mycophenolate levels, a lot of studies have used area under the curve, so getting an area under the curve level over a period of 12 hours would require several samples,” Garg said.
Testing protocols are also uncertain, Garg added. “A few data points ... are missing, like how we use the data over time,” she said. “If you do it for a given patient over several years, how often should you do it? How often do the levels fluctuate? How are the data used to inform dosing changes or monitoring changes?
“When those pieces are put together, then we are more likely to build up an intervention that clinicians can use in clinical practice, so they know how to order it and how frequently do it — every 6 months, 3 months, or every month. And then, over a period of time, how to adjust the dosing. That’s the big question.”
Who May Benefit Most From TDM?
In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?
“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.
“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.
The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.
While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.
She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
Potential Risks for TDM
Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”
That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.
A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
What DMARDs Are Most Suitable for TDM?
Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”
Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
Why Do TDM?
“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.
“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.
Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”
However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
What’s Next
Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.
“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.
“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”
Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
A version of this article appeared on Medscape.com.
Small Bowel Dysmotility Brings Challenges to Patients With Systemic Sclerosis
TOPLINE:
Patients with systemic sclerosis (SSc) who exhibit abnormal small bowel transit are more likely to be men, experience more severe cardiac involvement, have a higher mortality risk, and show fewer sicca symptoms.
METHODOLOGY:
- Researchers enrolled 130 patients with SSc having gastrointestinal (GI) symptoms (mean age at symptom onset, 56.8 years; 90% women; 81% White) seen at the Johns Hopkins Scleroderma Center, Baltimore, from October 2014 to May 2022.
- Clinical data and serum samples were longitudinally collected from all actively followed patients at the time of enrollment and every 6 months thereafter (median disease duration, 8.4 years).
- Participants underwent whole gut transit scintigraphy for the assessment of small bowel motility.
- A cross-sectional analysis compared the clinical features of patients with (n = 22; mean age at symptom onset, 61.4 years) and without (n = 108; mean age at symptom onset, 55.8 years) abnormal small bowel transit.
TAKEAWAY:
- Men with SSc (odds ratio [OR], 3.70; P = .038) and those with severe cardiac involvement (OR, 3.98; P = .035) were more likely to have abnormal small bowel transit.
- Sicca symptoms were negatively associated with abnormal small bowel transit in patients with SSc (adjusted OR, 0.28; P = .043).
- Patients with abnormal small bowel transit reported significantly worse (P = .028) and social functioning (P = .015) than those having a normal transit.
- A multivariate analysis showed that patients with abnormal small bowel transit had higher mortality than those with a normal transit (adjusted hazard ratio, 5.03; P = .005).
IN PRACTICE:
“Our findings improve our understanding of risk factors associated with abnormal small bowel transit in SSc patients and shed light on the lived experience of patients with this GI [gastrointestinal] complication,” the authors wrote. “Overall, these findings are important for patient risk stratification and monitoring and will help to identify a more homogeneous group of patients for future clinical and translational studies,” they added.
SOURCE:
The study was led by Jenice X. Cheah, MD, University of California, Los Angeles. It was published online on October 7, 2024, in Rheumatology.
LIMITATIONS:
The study may be subject to referral bias as it was conducted at a tertiary referral center, potentially including patients with a more severe disease status. Furthermore, this study was retrospective in nature, and whole gut transit studies were not conducted in all the patients seen at the referral center. Additionally, the cross-sectional design limited the ability to establish causality between the clinical features and abnormal small bowel transit.
DISCLOSURES:
The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Patients with systemic sclerosis (SSc) who exhibit abnormal small bowel transit are more likely to be men, experience more severe cardiac involvement, have a higher mortality risk, and show fewer sicca symptoms.
METHODOLOGY:
- Researchers enrolled 130 patients with SSc having gastrointestinal (GI) symptoms (mean age at symptom onset, 56.8 years; 90% women; 81% White) seen at the Johns Hopkins Scleroderma Center, Baltimore, from October 2014 to May 2022.
- Clinical data and serum samples were longitudinally collected from all actively followed patients at the time of enrollment and every 6 months thereafter (median disease duration, 8.4 years).
- Participants underwent whole gut transit scintigraphy for the assessment of small bowel motility.
- A cross-sectional analysis compared the clinical features of patients with (n = 22; mean age at symptom onset, 61.4 years) and without (n = 108; mean age at symptom onset, 55.8 years) abnormal small bowel transit.
TAKEAWAY:
- Men with SSc (odds ratio [OR], 3.70; P = .038) and those with severe cardiac involvement (OR, 3.98; P = .035) were more likely to have abnormal small bowel transit.
- Sicca symptoms were negatively associated with abnormal small bowel transit in patients with SSc (adjusted OR, 0.28; P = .043).
- Patients with abnormal small bowel transit reported significantly worse (P = .028) and social functioning (P = .015) than those having a normal transit.
- A multivariate analysis showed that patients with abnormal small bowel transit had higher mortality than those with a normal transit (adjusted hazard ratio, 5.03; P = .005).
IN PRACTICE:
“Our findings improve our understanding of risk factors associated with abnormal small bowel transit in SSc patients and shed light on the lived experience of patients with this GI [gastrointestinal] complication,” the authors wrote. “Overall, these findings are important for patient risk stratification and monitoring and will help to identify a more homogeneous group of patients for future clinical and translational studies,” they added.
SOURCE:
The study was led by Jenice X. Cheah, MD, University of California, Los Angeles. It was published online on October 7, 2024, in Rheumatology.
LIMITATIONS:
The study may be subject to referral bias as it was conducted at a tertiary referral center, potentially including patients with a more severe disease status. Furthermore, this study was retrospective in nature, and whole gut transit studies were not conducted in all the patients seen at the referral center. Additionally, the cross-sectional design limited the ability to establish causality between the clinical features and abnormal small bowel transit.
DISCLOSURES:
The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Patients with systemic sclerosis (SSc) who exhibit abnormal small bowel transit are more likely to be men, experience more severe cardiac involvement, have a higher mortality risk, and show fewer sicca symptoms.
METHODOLOGY:
- Researchers enrolled 130 patients with SSc having gastrointestinal (GI) symptoms (mean age at symptom onset, 56.8 years; 90% women; 81% White) seen at the Johns Hopkins Scleroderma Center, Baltimore, from October 2014 to May 2022.
- Clinical data and serum samples were longitudinally collected from all actively followed patients at the time of enrollment and every 6 months thereafter (median disease duration, 8.4 years).
- Participants underwent whole gut transit scintigraphy for the assessment of small bowel motility.
- A cross-sectional analysis compared the clinical features of patients with (n = 22; mean age at symptom onset, 61.4 years) and without (n = 108; mean age at symptom onset, 55.8 years) abnormal small bowel transit.
TAKEAWAY:
- Men with SSc (odds ratio [OR], 3.70; P = .038) and those with severe cardiac involvement (OR, 3.98; P = .035) were more likely to have abnormal small bowel transit.
- Sicca symptoms were negatively associated with abnormal small bowel transit in patients with SSc (adjusted OR, 0.28; P = .043).
- Patients with abnormal small bowel transit reported significantly worse (P = .028) and social functioning (P = .015) than those having a normal transit.
- A multivariate analysis showed that patients with abnormal small bowel transit had higher mortality than those with a normal transit (adjusted hazard ratio, 5.03; P = .005).
IN PRACTICE:
“Our findings improve our understanding of risk factors associated with abnormal small bowel transit in SSc patients and shed light on the lived experience of patients with this GI [gastrointestinal] complication,” the authors wrote. “Overall, these findings are important for patient risk stratification and monitoring and will help to identify a more homogeneous group of patients for future clinical and translational studies,” they added.
SOURCE:
The study was led by Jenice X. Cheah, MD, University of California, Los Angeles. It was published online on October 7, 2024, in Rheumatology.
LIMITATIONS:
The study may be subject to referral bias as it was conducted at a tertiary referral center, potentially including patients with a more severe disease status. Furthermore, this study was retrospective in nature, and whole gut transit studies were not conducted in all the patients seen at the referral center. Additionally, the cross-sectional design limited the ability to establish causality between the clinical features and abnormal small bowel transit.
DISCLOSURES:
The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Group Aims to Better Define ‘Extraordinarily Heterogeneous’ Mast Cell Activation Syndrome
Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population.
Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading.
Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.
The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals.
Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment.
In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”
She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”
But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.”
Two Definitions Characterize the Illness Differently
One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria:
- Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
- The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
- Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.
The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples:
- Constitutional: Chronic fatigue, flushing, or sweats
- Dermatologic: Rashes or lesions
- Ophthalmologic: dry eyes
- Oral: Burning or itching in mouth
- Pulmonary: Airway inflammation at any/all levels
- Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
- Gastrointestinal: Reflux, dysphagia, or malabsorption
- Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
- Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
- Neurologic: Headaches or sensory neuropathies
- Psychiatric: Depression or anxiety
- Endocrinologic: Thyroid disease or dyslipidemia
- Hematologic: Polycythemia or anemia (after ruling out other causes)
The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition.
Underdiagnosis vs Overdiagnosis
Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”
Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted.
But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.”
Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”
Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”
During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”
He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”
At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026.
Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).
A version of this article first appeared on Medscape.com.
Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population.
Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading.
Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.
The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals.
Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment.
In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”
She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”
But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.”
Two Definitions Characterize the Illness Differently
One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria:
- Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
- The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
- Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.
The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples:
- Constitutional: Chronic fatigue, flushing, or sweats
- Dermatologic: Rashes or lesions
- Ophthalmologic: dry eyes
- Oral: Burning or itching in mouth
- Pulmonary: Airway inflammation at any/all levels
- Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
- Gastrointestinal: Reflux, dysphagia, or malabsorption
- Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
- Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
- Neurologic: Headaches or sensory neuropathies
- Psychiatric: Depression or anxiety
- Endocrinologic: Thyroid disease or dyslipidemia
- Hematologic: Polycythemia or anemia (after ruling out other causes)
The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition.
Underdiagnosis vs Overdiagnosis
Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”
Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted.
But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.”
Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”
Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”
During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”
He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”
At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026.
Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).
A version of this article first appeared on Medscape.com.
Depending on one’s perspective, “mast cell activation syndrome (MCAS)” is either a relatively rare, narrowly defined severe allergic condition or a vastly underrecognized underlying cause of multiple chronic inflammatory conditions that affect roughly 17% of the entire population.
Inappropriate activation of mast cells — now termed mast cell activation disease (MCAD) — has long been known to underlie allergic symptoms and inflammation, and far less commonly, neoplasias such as mastocytosis. The concept of chronic, persistent MCAS associated with aberrant growth and dystrophism is more recent, emerging only in the last couple of decades as a separate entity under the MCAD heading.
Observational studies and clinical experience have linked signs and symptoms of MCAS with other inflammatory chronic conditions such as hypermobile Ehlers-Danlos Syndrome (EDS), postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and recently, long COVID. However, those conditions themselves are diagnostically challenging, and as yet there is no proof of causation.
The idea that MCAS is the entity — or at least, a key one — at the center of “a confoundingly, extraordinarily heterogeneous chronic multisystem polymorbidity” was the theme of a recent 4-day meeting of a professional group informally dubbed “Masterminds.” Since their first meeting in 2018, the group has grown from about 35 to nearly 650 multidisciplinary professionals.
Stephanie L. Grach, MD, assistant professor of medicine at the Mayo Clinic, Rochester, Minnesota, gave an introductory talk about the importance of changing “the medical paradigm around complex chronic illness.” Much of the rest of the meeting was devoted to sharing approaches for managing MCAS comorbidities, including dysautonomia, hypermobility, and associated craniocervical dysfunction, and various other multi-system conditions characterized by chronic pain and/or fatigue. Several talks covered the use of agents that block mast cell activity as potential treatment.
In an interview, Grach said “the meeting was an exciting example of how not only research, but also medicine, is moving forward, and it’s really cool to see that people are independently coming to very similar conclusions about shared pathologies, and because of that, the importance of overlap amongst complex medical conditions that historically have really been poorly addressed.”
She added, “mast cell activation, or mast cell hyperactivity, is one part of the greater picture. What’s important about the mast cell component is that of the multiple different targetable pathologies, it’s one that currently has potential available therapies that can be explored, some of them relatively easily.”
But Christopher Chang, MD, PhD, chief of the Pediatric Allergy and Immunology program, Joe DiMaggio Children’s Hospital, Hollywood, Florida, sees it differently. In an interview, he noted that the reason for disagreement over what constitutes MCAS is that “it doesn’t have a lot of objective findings that we can identify. ... We know that mast cells are important immune cells, just like all immune cells are important. It seems like whenever someone has unexplained symptoms, people try to blame it on mast cells. But it’s very hard to prove that.”
Two Definitions Characterize the Illness Differently
One proposed “consensus” MCAS definition was first published in 2011 by a group led by hematologist Peter Valent, MD, of the Medical University of Vienna in Austria. It has been revised since, and similar versions adopted by medical societies, including the American Academy of Allergy, Asthma & Immunology (AAAAI). The most recent versions propose three core MCAS criteria:
- Typical clinical signs of severe, recurrent (episodic) systemic (at least two organ systems) MCA are present (often in the form of anaphylaxis).
- The involvement of mast cells (MCs) is documented by biochemical studies, preferably an increase in serum tryptase levels from the individual’s baseline to plus 20% + 2 ng/mL.
- Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production, or drugs blocking mediator release or effects of MC-derived mediators.
The following year, a separate publication authored by Gerhard J. Molderings, MD, University of Bonn in Germany, and colleagues proposed a much broader MCAS definition. Also revised since, the latest “consensus-2” was published in 2020. This definition consists of one major criterion: “A constellation of clinical complaints attributable to pathologically increased MC activity, ie, MC mediator release syndrome.” This “constellation” involves conditions of nearly every organ system that, taken together, are estimated to affect up to 17% of the entire population. These are just a few examples:
- Constitutional: Chronic fatigue, flushing, or sweats
- Dermatologic: Rashes or lesions
- Ophthalmologic: dry eyes
- Oral: Burning or itching in mouth
- Pulmonary: Airway inflammation at any/all levels
- Cardiovascular: Blood pressure lability or codiagnosis of POTS is common
- Gastrointestinal: Reflux, dysphagia, or malabsorption
- Genitourinary: Endometriosis, dysmenorrhea, or dyspareunia
- Musculoskeletal/connective tissue: Fibromyalgia or diagnosis of hypermobile EDS is common
- Neurologic: Headaches or sensory neuropathies
- Psychiatric: Depression or anxiety
- Endocrinologic: Thyroid disease or dyslipidemia
- Hematologic: Polycythemia or anemia (after ruling out other causes)
The diagnosis is made by fulfilling that major criterion, plus at least one objective assessment of pathologically increased release of MC mediators, including infiltrates, abnormal MC morphology, or MC genetic changes shown to increase MC activity. Other alternatives include evidence of above-normal levels of MC mediators, including tryptase, histamine or its metabolites, heparin, or chromatin A, in whole blood, serum, plasma, or urine. Symptomatic response to MC activation inhibitors can also be used but isn’t required as it is in the other definition.
Underdiagnosis vs Overdiagnosis
Lawrence B. Afrin, MD, senior consultant in hematology/oncology at the AIM Center for Personalized Medicine, Westchester, New York, and lead author of the 2020 update of the broader “consensus-2” criteria, said in an interview, “we now know MCAS exists, and it’s prevalent, even though, for understandable and forgivable reasons, we’ve been missing it all along. ... If you see a patient who has this chronic, multisystem unwellness with general themes of inflammation plus or minus allergic issues and you can’t find some other rational explanation that better accounts for what’s going on ... then it’s reasonable to think to include MCAS in the differential diagnosis. If the patient happens not to fit the diagnostic criteria being advanced by one group, that doesn’t necessarily rule out the possibility that this is still going on.”
Afrin, along with his coauthors, faulted the narrower “consensus-1” definition for lacking data to support the “20% + 2” criteria for requiring the difficult determination of a patient’s “baseline” and for requiring evidence of response to treatment prior to making the diagnosis. Not all patients will respond to a given histamine blocker, he noted.
But Lawrence B. Schwartz, MD, PhD, an author on both the Valent and AAAAI criteria, disagreed, noting that the narrower criteria “appear to have a high degree of specificity and sensitivity when the reaction is systemic and involves hypotension. Less severe clinical events, particularly involving the gastrointestinal or central nervous systems, do not have precise clinical or biomarker criteria for identifying mast cell involvement.”
Added Schwartz, who is professor of medicine and chair of the Division of Rheumatology, Allergy, and Immunology and program director of Allergy and Immunology, Virginia Commonwealth University (VCU), Richmond, “when mast cell activation events occur only in the skin, we refer to it as chronic urticaria and in the airways or conjunctiva of allergic individuals as allergic asthma, rhinitis, and/or conjunctivitis. The absence of specific criteria for mast cell activation in the GI [gastrointestinal] tract or CNS [central nervous system] neither rules in mast cell involvement nor does it rule out mast cell involvement. Thus, more research is needed to find better diagnostic criteria.”
Schwartz also pointed to a recent paper reporting the use of artificial intelligence models to “quantify diagnostic precision and specificity” of “alternative” MCAS definitions. The conclusion was a “lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.”
During the meeting, Afrin acknowledged that the broader view risks overdiagnosis of MCAS. However, he also referenced Occam’s razor, the principle that the simplest explanation is probably the best one. “Which scenario is more likely? Multiple diagnoses and problems that are all independent of each other vs one diagnosis that’s biologically capable of causing most or all of the findings, ie, the simplest solution even if it’s not the most immediately obvious solution?”
He said in an interview: “Do we have any proof that MCAS is what’s underlying hypermobile Ehlers-Danlos or POTS or chronic fatigue? No, we don’t have any proof, not because anybody has done studies that have shown there to be no connection but simply because we’re so early in our awareness that the disease even exists that the necessary studies haven’t even been done yet.”
At the meeting, Afrin introduced proposals to turn the “Masterminds” group into a formal professional society and to launch a journal. He also gave an update on progress in developing a symptom assessment tool both for clinical use and to enable clinical trials of new drugs to target mast cells or their mediators. The plan is to field test the tool in 2025 and publish those results in 2026.
Grach, Afrin, and Chang had no disclosures. Schwartz discovered tryptase and invented the Thermo Fisher tryptase assay, for which his institution (VCU) receives royalties that are shared with him. He also invented monoclonal antibodies used for detecting mast cells or basophils, for which VCU receives royalties from several companies, including Millipore, Santa Cruz, BioLegend, and Hycult Biotech, that are also shared with him. He is a paid consultant for Blueprint Medicines, Celldex Therapeutics, Invea, Third Harmonic Bio, HYCOR Biomedical, Jasper, TerSera Therapeutics, and GLG. He also serves on an AstraZeneca data safety monitoring board for a clinical trial involving benralizumab treatment of hypereosinophilic syndrome and receives royalties from UpToDate (biomarkers for anaphylaxis) and Goldman-Cecil Medicine (anaphylaxis).
A version of this article first appeared on Medscape.com.
Avoid Too Low or High Vitamin D Levels for Best Pregnancy Outcomes in Lupus
TOPLINE:
Both low and high levels of maternal 25-hydroxy [25(OH)] vitamin D are linked to an increased risk for adverse pregnancy outcomes in women with systemic lupus erythematosus (SLE), with levels of 40-59 ng/mL being associated with the lowest risk.
METHODOLOGY:
- Researchers analyzed 260 pregnancies in the Hopkins Lupus Cohort to examine the association between 25(OH) vitamin D levels and adverse pregnancy outcomes in women with SLE.
- The participants were required to have serum vitamin D levels measured during pregnancy and pregnancy-related outcomes data.
- The 25(OH) vitamin D levels were measured at visits every 6 weeks, and the participants were divided into six subgroups on the basis of the mean 25(OH) vitamin D levels: < 20 ng/dL, 20-29 ng/dL, 30-39 ng/dL, 40-49 ng/dL, 50-59 ng/dL, and ≥ 60 ng/dL.
- The adverse pregnancy outcomes included miscarriage, preterm delivery, and restricted intrauterine growth of the fetus.
- This study used a time-to-event analysis to assess the association between time-varying 25(OH) vitamin D levels and adverse pregnancy outcomes.
TAKEAWAY:
- Adverse pregnancy outcomes were observed in 45.3% of pregnancies; the risks for miscarriage and preterm delivery were significantly different across the six subgroups with varying vitamin D levels (P = .0045 and P = .0007, respectively).
- A U-shaped curve association was observed between vitamin D levels and adverse pregnancy outcomes, with the highest risk seen in patients with the lowest or highest levels of vitamin D during pregnancy, while the lowest risk was seen in those with vitamin D levels between 40 and 59 ng/mL.
- Low 25(OH) vitamin D levels during the second trimester resulted in premature delivery in 9 out of 10 pregnancies; however, a relationship between vitamin D levels in the first trimester and pregnancy outcomes was not observed.
- The time-to-event analysis showed that the U-shaped association between vitamin D levels and adverse pregnancy outcomes was still observed even after accounting for lupus disease activity; however, the elevated risk seen in individuals with the highest levels of vitamin D was no longer statistically significant.
IN PRACTICE:
“We recommend monitoring of maternal serum 25(OH) vitamin D levels throughout SLE pregnancies and supplementing patients with vitamin D insufficiency or deficiency, aiming for 25(OH) vitamin D range of 40-59 ng/mL. Over supplementation should be avoided,” the authors wrote.
SOURCE:
The study was led by Nima Madanchi, MD, Johns Hopkins University, Baltimore, and was published online on September 23, 2024, in Arthritis Care & Research.
LIMITATIONS:
This study could not prove a cause-and-effect relationship between vitamin D levels and adverse pregnancy outcomes. This study included only clinically identified pregnancies, potentially missing very early miscarriages. It also could not adjust for parity due to the unknown parity of the index pregnancy.
DISCLOSURES:
This Hopkins Lupus Cohort was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
Both low and high levels of maternal 25-hydroxy [25(OH)] vitamin D are linked to an increased risk for adverse pregnancy outcomes in women with systemic lupus erythematosus (SLE), with levels of 40-59 ng/mL being associated with the lowest risk.
METHODOLOGY:
- Researchers analyzed 260 pregnancies in the Hopkins Lupus Cohort to examine the association between 25(OH) vitamin D levels and adverse pregnancy outcomes in women with SLE.
- The participants were required to have serum vitamin D levels measured during pregnancy and pregnancy-related outcomes data.
- The 25(OH) vitamin D levels were measured at visits every 6 weeks, and the participants were divided into six subgroups on the basis of the mean 25(OH) vitamin D levels: < 20 ng/dL, 20-29 ng/dL, 30-39 ng/dL, 40-49 ng/dL, 50-59 ng/dL, and ≥ 60 ng/dL.
- The adverse pregnancy outcomes included miscarriage, preterm delivery, and restricted intrauterine growth of the fetus.
- This study used a time-to-event analysis to assess the association between time-varying 25(OH) vitamin D levels and adverse pregnancy outcomes.
TAKEAWAY:
- Adverse pregnancy outcomes were observed in 45.3% of pregnancies; the risks for miscarriage and preterm delivery were significantly different across the six subgroups with varying vitamin D levels (P = .0045 and P = .0007, respectively).
- A U-shaped curve association was observed between vitamin D levels and adverse pregnancy outcomes, with the highest risk seen in patients with the lowest or highest levels of vitamin D during pregnancy, while the lowest risk was seen in those with vitamin D levels between 40 and 59 ng/mL.
- Low 25(OH) vitamin D levels during the second trimester resulted in premature delivery in 9 out of 10 pregnancies; however, a relationship between vitamin D levels in the first trimester and pregnancy outcomes was not observed.
- The time-to-event analysis showed that the U-shaped association between vitamin D levels and adverse pregnancy outcomes was still observed even after accounting for lupus disease activity; however, the elevated risk seen in individuals with the highest levels of vitamin D was no longer statistically significant.
IN PRACTICE:
“We recommend monitoring of maternal serum 25(OH) vitamin D levels throughout SLE pregnancies and supplementing patients with vitamin D insufficiency or deficiency, aiming for 25(OH) vitamin D range of 40-59 ng/mL. Over supplementation should be avoided,” the authors wrote.
SOURCE:
The study was led by Nima Madanchi, MD, Johns Hopkins University, Baltimore, and was published online on September 23, 2024, in Arthritis Care & Research.
LIMITATIONS:
This study could not prove a cause-and-effect relationship between vitamin D levels and adverse pregnancy outcomes. This study included only clinically identified pregnancies, potentially missing very early miscarriages. It also could not adjust for parity due to the unknown parity of the index pregnancy.
DISCLOSURES:
This Hopkins Lupus Cohort was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
Both low and high levels of maternal 25-hydroxy [25(OH)] vitamin D are linked to an increased risk for adverse pregnancy outcomes in women with systemic lupus erythematosus (SLE), with levels of 40-59 ng/mL being associated with the lowest risk.
METHODOLOGY:
- Researchers analyzed 260 pregnancies in the Hopkins Lupus Cohort to examine the association between 25(OH) vitamin D levels and adverse pregnancy outcomes in women with SLE.
- The participants were required to have serum vitamin D levels measured during pregnancy and pregnancy-related outcomes data.
- The 25(OH) vitamin D levels were measured at visits every 6 weeks, and the participants were divided into six subgroups on the basis of the mean 25(OH) vitamin D levels: < 20 ng/dL, 20-29 ng/dL, 30-39 ng/dL, 40-49 ng/dL, 50-59 ng/dL, and ≥ 60 ng/dL.
- The adverse pregnancy outcomes included miscarriage, preterm delivery, and restricted intrauterine growth of the fetus.
- This study used a time-to-event analysis to assess the association between time-varying 25(OH) vitamin D levels and adverse pregnancy outcomes.
TAKEAWAY:
- Adverse pregnancy outcomes were observed in 45.3% of pregnancies; the risks for miscarriage and preterm delivery were significantly different across the six subgroups with varying vitamin D levels (P = .0045 and P = .0007, respectively).
- A U-shaped curve association was observed between vitamin D levels and adverse pregnancy outcomes, with the highest risk seen in patients with the lowest or highest levels of vitamin D during pregnancy, while the lowest risk was seen in those with vitamin D levels between 40 and 59 ng/mL.
- Low 25(OH) vitamin D levels during the second trimester resulted in premature delivery in 9 out of 10 pregnancies; however, a relationship between vitamin D levels in the first trimester and pregnancy outcomes was not observed.
- The time-to-event analysis showed that the U-shaped association between vitamin D levels and adverse pregnancy outcomes was still observed even after accounting for lupus disease activity; however, the elevated risk seen in individuals with the highest levels of vitamin D was no longer statistically significant.
IN PRACTICE:
“We recommend monitoring of maternal serum 25(OH) vitamin D levels throughout SLE pregnancies and supplementing patients with vitamin D insufficiency or deficiency, aiming for 25(OH) vitamin D range of 40-59 ng/mL. Over supplementation should be avoided,” the authors wrote.
SOURCE:
The study was led by Nima Madanchi, MD, Johns Hopkins University, Baltimore, and was published online on September 23, 2024, in Arthritis Care & Research.
LIMITATIONS:
This study could not prove a cause-and-effect relationship between vitamin D levels and adverse pregnancy outcomes. This study included only clinically identified pregnancies, potentially missing very early miscarriages. It also could not adjust for parity due to the unknown parity of the index pregnancy.
DISCLOSURES:
This Hopkins Lupus Cohort was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Frailty, Not Just Advanced Age, Affects ANCA Vasculitis Outcomes
TOPLINE:
Older adults with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis face a higher risk for end-stage renal disease or mortality and severe infections. However, frailty, more than age, predicts severe infections within 2 years of diagnosis.
METHODOLOGY:
- Researchers conducted a retrospective cohort study using data from the Mass General Brigham ANCA-associated vasculitis cohort in the United States.
- They included 234 individuals (median age, 75 years) with incident ANCA-associated vasculitis who were treated from January 2002 to December 2019.
- Baseline frailty was measured using a claims-based frailty index, with data collected in the year before treatment initiation; individuals were categorized as those who were nonfrail, prefrail, mildly frail, and moderately to severely frail.
- Frailty, either mild or moderate to severe, was noted in 44 of 118 individuals aged ≥ 75 years and in 25 of 116 individuals aged 65-74 years.
- The outcomes of interest were the incidences of end-stage renal disease or death and severe infections within 2 years of diagnosis. The association of age and frailty with clinical outcomes was assessed in those aged 65-74 years and ≥ 75 years.
TAKEAWAY:
- Frailty was a significant predictor of severe infections within 2 years of ANCA-associated vasculitis diagnosis (adjusted hazard ratio [aHR], 8.46; 95% CI, 3.95-18.14), showing a stronger association than seen for chronological age ≥ 75 years (aHR, 2.52; 95% CI, 1.26-5.04).
- The incidence of severe infections was higher in those with vs without frailty in the age groups 65-74 years (38.9 vs 0.8 cases per 100 person-years) and ≥ 75 years (61.9 vs 12.3 cases per 100 person-years).
- Older age (≥ 75 years) was associated with an increased risk for end-stage renal disease or death (aHR, 4.50; 95% CI, 1.83-11.09); however, frailty was not.
- The effect of frailty on end-stage renal disease or death varied by age, with a larger difference observed in individuals aged 65-74 years (frail vs nonfrail, 7.5 vs 2.0 cases per 100 person-years) than in those aged ≥ 75 years (13.5 vs 16.0 cases per 100 person-years).
IN PRACTICE:
“Our results highlight the fact that assessment of frailty in the care of older adults with ANCA-associated vasculitis can distinguish a group of patients at increased risk of severe infections who might benefit from interventions to minimize infection risk and optimize outcomes,” the authors wrote.
“Incorporating frailty screening into the management of ANCA-associated vasculitis provides an opportunity to offer personalized, evidence-based care to frail older adults,” Alexandra Legge, MD, Dalhousie University, Halifax, Nova Scotia, Canada, wrote in an associated comment published online in The Lancet Rheumatology.
SOURCE:
This study was led by Sebastian E. Sattui, MD, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh in Pennsylvania. It was published online on September 18, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study’s observational design and single-center setting limited the generalizability of the findings. Residual confounding may have been possible despite adjustments for relevant baseline factors. The requirement of at least one healthcare encounter before baseline may have underrepresented individuals without frailty. Differences in treatment patterns after the baseline period were not controlled for.
DISCLOSURES:
The study was supported by the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors reported receiving grants, research support, consulting fees, honoraria, or royalties or serving on advisory boards of pharmaceutical companies and other sources outside of the submitted work.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
Older adults with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis face a higher risk for end-stage renal disease or mortality and severe infections. However, frailty, more than age, predicts severe infections within 2 years of diagnosis.
METHODOLOGY:
- Researchers conducted a retrospective cohort study using data from the Mass General Brigham ANCA-associated vasculitis cohort in the United States.
- They included 234 individuals (median age, 75 years) with incident ANCA-associated vasculitis who were treated from January 2002 to December 2019.
- Baseline frailty was measured using a claims-based frailty index, with data collected in the year before treatment initiation; individuals were categorized as those who were nonfrail, prefrail, mildly frail, and moderately to severely frail.
- Frailty, either mild or moderate to severe, was noted in 44 of 118 individuals aged ≥ 75 years and in 25 of 116 individuals aged 65-74 years.
- The outcomes of interest were the incidences of end-stage renal disease or death and severe infections within 2 years of diagnosis. The association of age and frailty with clinical outcomes was assessed in those aged 65-74 years and ≥ 75 years.
TAKEAWAY:
- Frailty was a significant predictor of severe infections within 2 years of ANCA-associated vasculitis diagnosis (adjusted hazard ratio [aHR], 8.46; 95% CI, 3.95-18.14), showing a stronger association than seen for chronological age ≥ 75 years (aHR, 2.52; 95% CI, 1.26-5.04).
- The incidence of severe infections was higher in those with vs without frailty in the age groups 65-74 years (38.9 vs 0.8 cases per 100 person-years) and ≥ 75 years (61.9 vs 12.3 cases per 100 person-years).
- Older age (≥ 75 years) was associated with an increased risk for end-stage renal disease or death (aHR, 4.50; 95% CI, 1.83-11.09); however, frailty was not.
- The effect of frailty on end-stage renal disease or death varied by age, with a larger difference observed in individuals aged 65-74 years (frail vs nonfrail, 7.5 vs 2.0 cases per 100 person-years) than in those aged ≥ 75 years (13.5 vs 16.0 cases per 100 person-years).
IN PRACTICE:
“Our results highlight the fact that assessment of frailty in the care of older adults with ANCA-associated vasculitis can distinguish a group of patients at increased risk of severe infections who might benefit from interventions to minimize infection risk and optimize outcomes,” the authors wrote.
“Incorporating frailty screening into the management of ANCA-associated vasculitis provides an opportunity to offer personalized, evidence-based care to frail older adults,” Alexandra Legge, MD, Dalhousie University, Halifax, Nova Scotia, Canada, wrote in an associated comment published online in The Lancet Rheumatology.
SOURCE:
This study was led by Sebastian E. Sattui, MD, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh in Pennsylvania. It was published online on September 18, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study’s observational design and single-center setting limited the generalizability of the findings. Residual confounding may have been possible despite adjustments for relevant baseline factors. The requirement of at least one healthcare encounter before baseline may have underrepresented individuals without frailty. Differences in treatment patterns after the baseline period were not controlled for.
DISCLOSURES:
The study was supported by the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors reported receiving grants, research support, consulting fees, honoraria, or royalties or serving on advisory boards of pharmaceutical companies and other sources outside of the submitted work.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
Older adults with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis face a higher risk for end-stage renal disease or mortality and severe infections. However, frailty, more than age, predicts severe infections within 2 years of diagnosis.
METHODOLOGY:
- Researchers conducted a retrospective cohort study using data from the Mass General Brigham ANCA-associated vasculitis cohort in the United States.
- They included 234 individuals (median age, 75 years) with incident ANCA-associated vasculitis who were treated from January 2002 to December 2019.
- Baseline frailty was measured using a claims-based frailty index, with data collected in the year before treatment initiation; individuals were categorized as those who were nonfrail, prefrail, mildly frail, and moderately to severely frail.
- Frailty, either mild or moderate to severe, was noted in 44 of 118 individuals aged ≥ 75 years and in 25 of 116 individuals aged 65-74 years.
- The outcomes of interest were the incidences of end-stage renal disease or death and severe infections within 2 years of diagnosis. The association of age and frailty with clinical outcomes was assessed in those aged 65-74 years and ≥ 75 years.
TAKEAWAY:
- Frailty was a significant predictor of severe infections within 2 years of ANCA-associated vasculitis diagnosis (adjusted hazard ratio [aHR], 8.46; 95% CI, 3.95-18.14), showing a stronger association than seen for chronological age ≥ 75 years (aHR, 2.52; 95% CI, 1.26-5.04).
- The incidence of severe infections was higher in those with vs without frailty in the age groups 65-74 years (38.9 vs 0.8 cases per 100 person-years) and ≥ 75 years (61.9 vs 12.3 cases per 100 person-years).
- Older age (≥ 75 years) was associated with an increased risk for end-stage renal disease or death (aHR, 4.50; 95% CI, 1.83-11.09); however, frailty was not.
- The effect of frailty on end-stage renal disease or death varied by age, with a larger difference observed in individuals aged 65-74 years (frail vs nonfrail, 7.5 vs 2.0 cases per 100 person-years) than in those aged ≥ 75 years (13.5 vs 16.0 cases per 100 person-years).
IN PRACTICE:
“Our results highlight the fact that assessment of frailty in the care of older adults with ANCA-associated vasculitis can distinguish a group of patients at increased risk of severe infections who might benefit from interventions to minimize infection risk and optimize outcomes,” the authors wrote.
“Incorporating frailty screening into the management of ANCA-associated vasculitis provides an opportunity to offer personalized, evidence-based care to frail older adults,” Alexandra Legge, MD, Dalhousie University, Halifax, Nova Scotia, Canada, wrote in an associated comment published online in The Lancet Rheumatology.
SOURCE:
This study was led by Sebastian E. Sattui, MD, Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh in Pennsylvania. It was published online on September 18, 2024, in The Lancet Rheumatology.
LIMITATIONS:
The study’s observational design and single-center setting limited the generalizability of the findings. Residual confounding may have been possible despite adjustments for relevant baseline factors. The requirement of at least one healthcare encounter before baseline may have underrepresented individuals without frailty. Differences in treatment patterns after the baseline period were not controlled for.
DISCLOSURES:
The study was supported by the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Some authors reported receiving grants, research support, consulting fees, honoraria, or royalties or serving on advisory boards of pharmaceutical companies and other sources outside of the submitted work.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Dermatomyositis Cancer Screening Guidelines Get Real-World Validation
Newly issued guidelines for cancer screening in patients with dermatomyositis had 100% sensitivity in a single institution’s cohort, though most of the cancers found would have been detected with standard cancer screenings recommended for the general population, according to a research letter published in JAMA Dermatology.
“These early results emphasize the continued need to refine risk assessment and cancer screening for patients with dermatomyositis while balancing resource use and outcomes,” concluded Caroline J. Stone and her colleagues at the Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Patients with dermatomyositis have approximately a 4.7 times greater risk for cancer than those without it, according to a 2016 meta-analysis. Despite the well-established link between cancer and dermatomyositis, cancer in people with idiopathic inflammatory myopathies is commonly diagnosed at a later stage and is the leading cause of death in people with these conditions.
Guidelines First Presented in 2022 and Published in 2023
A wide variability in screening practices eventually led the International Myositis Assessment & Clinical Studies Group (IMACS) to present the first evidence-based and consensus-based guidelines for cancer screening of patients with idiopathic inflammatory myopathies, including those with dermatomyositis, at the 2022 annual meeting of the American College of Rheumatology and publish them in 2023 in Nature Reviews Rheumatology. The guidelines advise low-risk patients to undergo basic cancer screening with routine blood and urine studies, liver function tests, plain chest radiography, and age- and sex-appropriate cancer screening.
Intermediate- and high-risk patients are recommended to undergo enhanced screening that can include mammography, Pap tests, endoscopy/colonoscopy, pelvic and transvaginal ultrasonography, prostate-specific antigen or cancer antigen 125 blood tests, fecal occult blood tests, and CT of the neck, thorax, abdomen, and pelvis.
But because the guidelines are new, little evidence exists regarding their validation in real-world cohorts. Researchers, therefore, assessed the IMACS guidelines in 370 patients, aged 18-80 years, who visited the University of Pennsylvania rheumatology-dermatology specialty clinic between July 2008 and January 2024. All participants had dermatomyositis and at least 3 years of follow-up and were an average 48 years old. The vast majority were women (87%) and White participants (89%).
Most (68.6%) had myositis-specific autoantibody test results, one of the factors included in the guidelines for determining whether the patient should be classified as low, intermediate, or high risk. Other factors for risk stratification included myositis subtype, age at disease onset, and clinical features. About half (49.2%) had classic dermatomyositis, 42.4% had amyopathic dermatomyositis, 3.8% had juvenile dermatomyositis, 3.2% had hypomyopathic dermatomyositis, 0.8% had antisynthetase syndrome, and 0.5% had immune-mediated necrotizing myopathy.
Just over half the patients (54%) were classified as high risk, while 37.3% were classified as intermediate risk and 8.9% as low risk using the guidelines. Among the 18 patients (4.9%) with paraneoplastic dermatomyositis, 15 were classified as high risk and 3 as intermediate risk.
Of the patients diagnosed with cancer, 55% of cases were diagnosed about a year before their dermatomyositis diagnosis. In three patients, symptoms “suggestive of cancer at the time of dermatomyositis diagnosis, including lymphadenopathy and unexplained weight loss,” led to diagnostic testing that found an underlying cancer.
In the eight patients diagnosed with cancer after their dermatomyositis diagnosis, 75% of the cancers were identified during the first year of follow-up and 25% in the second year. Five were identified based on basic cancer screening and three on enhanced screening.
A total of 11 patients (3%) developed intravenous contrast allergies, and no other adverse events were reported to be associated with cancer screening, but the study was not designed to capture other types of adverse screening effects, such as cost, quality of life, or risk from radiation exposure.
The most common neoplasm identified was breast cancer, found in nine (50%) of the patients using mammography. Two patients had lung cancer identified with chest radiography and two had ovarian cancer identified with abdominal radiography and CT. The remaining five patients included one each with bladder cancer, papillary thyroid cancer, renal cell carcinoma, non-Hodgkin lymphoma, and adenocarcinoma with unknown primary.
The sensitivity of the guidelines in detecting cancer related to dermatomyositis was 100%, though the authors noted that the “IMACS risk-stratification scheme may overestimate cancer risk and encourage enhanced screening protocols of unclear benefit.” Most of the cancers found after dermatomyositis diagnosis were detected with routine age- and sex-related screening that already falls under basic cancer screening recommendations for the general population. Nonetheless, 90% of the participants fell into the intermediate- and high-risk groups, warranting a more comprehensive and costly enhanced screening protocol.
Will the Guidelines Lead to Overscreening?
The 4.9% cancer prevalence is considerably lower than the typical 15%-25% prevalence among patients with dermatomyositis, but the findings, regardless, suggest the guidelines will lead to overscreening, wrote Andrea D. Maderal, MD, University of Miami Miller School of Medicine in Florida, and Alisa Femia, MD, New York University Grossman School of Medicine, New York City, in an accompanying editorial. Given that the median age in patients with cancer in the study was 58 years — 18 years older than the age cutoff for high-risk criteria — one way to refine the guidelines may be to increase the age for the high-risk category, they suggested.
“While these guidelines led to many ultimately unnecessary screening tests based on currently recommended designations of intermediate-risk and high-risk patients, these guidelines reflect a more conservative approach to screening than was previously performed,” Dr. Maderal and Dr. Femia wrote.
Jeff Gehlhausen, MD, PhD, an assistant professor of dermatology at Yale School of Medicine, New Haven, Connecticut, said he is not concerned about overscreening in patients, however, and is “very enthusiastic” about the findings.
“Patients are very anxious for good reason,” given the typical cancer prevalence of 25% in this population, he said in an interview. “I think therein lies the challenge — with that risk, what is ‘enough’ screening?” Yet this “incredibly impressive” study “provides real insights into the applicability of the IMACS screenings to our dermatomyositis management,” including relevance to his own patients. “Their findings are instructive for how to better evaluate these patients in a more mindful fashion,” he said, and they are particularly welcome, given how widely variable practice has historically been before the guidelines were issued.
“This question has been an outstanding one for decades, and nearly every doctor has a different answer,” Dr. Gehlhausen said. “The introduction of the guidelines alone are now much more actionable with this study, and that’s why it’s such an important one for our community.”
Benedict Wu, DO, PhD, director of Inpatient Dermatology and an assistant professor at Montefiore Einstein and a member of the Montefiore Einstein Comprehensive Cancer Center in New York City, similarly regarded the findings as reassuring, though he was surprised at the low prevalence of cancer in the patients.
“The most reassuring finding was that the detection of most malignancies was possible by using routine age- and sex-related screening combined with basic cancer screening,” Wu said in an interview. “Basic cancer screening can reduce costs while keeping patients safe.”
He also found it reassuring that all the paraneoplastic dermatomyositis was in intermediate- or high-risk patients, and while he does not see the IMACS guidelines as overestimating cancer risk, he does think “the risk stratification and recommended screening tests could be revised to be less ‘aggressive.’ ”
The overall low rate of cancer in the group “calls into question the need for stringent and annual cancer screening,” he said. “In this large cohort of patients, the fact that malignancy was detected within 2 years of dermatomyositis diagnosis will help guide us with long-term screening recommendations.”
Despite the study’s small size and single-center design, the demographics of the patients nearly represents exactly what is found in the United States more broadly, Wu noted. He also drew attention to how many patients lacked the myositis antibody profile performed, and he agreed with the authors that more extensive and prospective studies need to be conducted. He also emphasized the need to keep in mind that “the primary goal of dermatomyositis management should focus on controlling/reducing the disease burden.”
The research was funded by the National Institutes of Health and the US Department of Veterans Affairs. The authors had no disclosures. Dr. Maderal reported personal fees from argenx. No disclosures were noted for Dr. Gehlhausen and Dr. Wu.
A version of this article appeared on Medscape.com.
Newly issued guidelines for cancer screening in patients with dermatomyositis had 100% sensitivity in a single institution’s cohort, though most of the cancers found would have been detected with standard cancer screenings recommended for the general population, according to a research letter published in JAMA Dermatology.
“These early results emphasize the continued need to refine risk assessment and cancer screening for patients with dermatomyositis while balancing resource use and outcomes,” concluded Caroline J. Stone and her colleagues at the Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Patients with dermatomyositis have approximately a 4.7 times greater risk for cancer than those without it, according to a 2016 meta-analysis. Despite the well-established link between cancer and dermatomyositis, cancer in people with idiopathic inflammatory myopathies is commonly diagnosed at a later stage and is the leading cause of death in people with these conditions.
Guidelines First Presented in 2022 and Published in 2023
A wide variability in screening practices eventually led the International Myositis Assessment & Clinical Studies Group (IMACS) to present the first evidence-based and consensus-based guidelines for cancer screening of patients with idiopathic inflammatory myopathies, including those with dermatomyositis, at the 2022 annual meeting of the American College of Rheumatology and publish them in 2023 in Nature Reviews Rheumatology. The guidelines advise low-risk patients to undergo basic cancer screening with routine blood and urine studies, liver function tests, plain chest radiography, and age- and sex-appropriate cancer screening.
Intermediate- and high-risk patients are recommended to undergo enhanced screening that can include mammography, Pap tests, endoscopy/colonoscopy, pelvic and transvaginal ultrasonography, prostate-specific antigen or cancer antigen 125 blood tests, fecal occult blood tests, and CT of the neck, thorax, abdomen, and pelvis.
But because the guidelines are new, little evidence exists regarding their validation in real-world cohorts. Researchers, therefore, assessed the IMACS guidelines in 370 patients, aged 18-80 years, who visited the University of Pennsylvania rheumatology-dermatology specialty clinic between July 2008 and January 2024. All participants had dermatomyositis and at least 3 years of follow-up and were an average 48 years old. The vast majority were women (87%) and White participants (89%).
Most (68.6%) had myositis-specific autoantibody test results, one of the factors included in the guidelines for determining whether the patient should be classified as low, intermediate, or high risk. Other factors for risk stratification included myositis subtype, age at disease onset, and clinical features. About half (49.2%) had classic dermatomyositis, 42.4% had amyopathic dermatomyositis, 3.8% had juvenile dermatomyositis, 3.2% had hypomyopathic dermatomyositis, 0.8% had antisynthetase syndrome, and 0.5% had immune-mediated necrotizing myopathy.
Just over half the patients (54%) were classified as high risk, while 37.3% were classified as intermediate risk and 8.9% as low risk using the guidelines. Among the 18 patients (4.9%) with paraneoplastic dermatomyositis, 15 were classified as high risk and 3 as intermediate risk.
Of the patients diagnosed with cancer, 55% of cases were diagnosed about a year before their dermatomyositis diagnosis. In three patients, symptoms “suggestive of cancer at the time of dermatomyositis diagnosis, including lymphadenopathy and unexplained weight loss,” led to diagnostic testing that found an underlying cancer.
In the eight patients diagnosed with cancer after their dermatomyositis diagnosis, 75% of the cancers were identified during the first year of follow-up and 25% in the second year. Five were identified based on basic cancer screening and three on enhanced screening.
A total of 11 patients (3%) developed intravenous contrast allergies, and no other adverse events were reported to be associated with cancer screening, but the study was not designed to capture other types of adverse screening effects, such as cost, quality of life, or risk from radiation exposure.
The most common neoplasm identified was breast cancer, found in nine (50%) of the patients using mammography. Two patients had lung cancer identified with chest radiography and two had ovarian cancer identified with abdominal radiography and CT. The remaining five patients included one each with bladder cancer, papillary thyroid cancer, renal cell carcinoma, non-Hodgkin lymphoma, and adenocarcinoma with unknown primary.
The sensitivity of the guidelines in detecting cancer related to dermatomyositis was 100%, though the authors noted that the “IMACS risk-stratification scheme may overestimate cancer risk and encourage enhanced screening protocols of unclear benefit.” Most of the cancers found after dermatomyositis diagnosis were detected with routine age- and sex-related screening that already falls under basic cancer screening recommendations for the general population. Nonetheless, 90% of the participants fell into the intermediate- and high-risk groups, warranting a more comprehensive and costly enhanced screening protocol.
Will the Guidelines Lead to Overscreening?
The 4.9% cancer prevalence is considerably lower than the typical 15%-25% prevalence among patients with dermatomyositis, but the findings, regardless, suggest the guidelines will lead to overscreening, wrote Andrea D. Maderal, MD, University of Miami Miller School of Medicine in Florida, and Alisa Femia, MD, New York University Grossman School of Medicine, New York City, in an accompanying editorial. Given that the median age in patients with cancer in the study was 58 years — 18 years older than the age cutoff for high-risk criteria — one way to refine the guidelines may be to increase the age for the high-risk category, they suggested.
“While these guidelines led to many ultimately unnecessary screening tests based on currently recommended designations of intermediate-risk and high-risk patients, these guidelines reflect a more conservative approach to screening than was previously performed,” Dr. Maderal and Dr. Femia wrote.
Jeff Gehlhausen, MD, PhD, an assistant professor of dermatology at Yale School of Medicine, New Haven, Connecticut, said he is not concerned about overscreening in patients, however, and is “very enthusiastic” about the findings.
“Patients are very anxious for good reason,” given the typical cancer prevalence of 25% in this population, he said in an interview. “I think therein lies the challenge — with that risk, what is ‘enough’ screening?” Yet this “incredibly impressive” study “provides real insights into the applicability of the IMACS screenings to our dermatomyositis management,” including relevance to his own patients. “Their findings are instructive for how to better evaluate these patients in a more mindful fashion,” he said, and they are particularly welcome, given how widely variable practice has historically been before the guidelines were issued.
“This question has been an outstanding one for decades, and nearly every doctor has a different answer,” Dr. Gehlhausen said. “The introduction of the guidelines alone are now much more actionable with this study, and that’s why it’s such an important one for our community.”
Benedict Wu, DO, PhD, director of Inpatient Dermatology and an assistant professor at Montefiore Einstein and a member of the Montefiore Einstein Comprehensive Cancer Center in New York City, similarly regarded the findings as reassuring, though he was surprised at the low prevalence of cancer in the patients.
“The most reassuring finding was that the detection of most malignancies was possible by using routine age- and sex-related screening combined with basic cancer screening,” Wu said in an interview. “Basic cancer screening can reduce costs while keeping patients safe.”
He also found it reassuring that all the paraneoplastic dermatomyositis was in intermediate- or high-risk patients, and while he does not see the IMACS guidelines as overestimating cancer risk, he does think “the risk stratification and recommended screening tests could be revised to be less ‘aggressive.’ ”
The overall low rate of cancer in the group “calls into question the need for stringent and annual cancer screening,” he said. “In this large cohort of patients, the fact that malignancy was detected within 2 years of dermatomyositis diagnosis will help guide us with long-term screening recommendations.”
Despite the study’s small size and single-center design, the demographics of the patients nearly represents exactly what is found in the United States more broadly, Wu noted. He also drew attention to how many patients lacked the myositis antibody profile performed, and he agreed with the authors that more extensive and prospective studies need to be conducted. He also emphasized the need to keep in mind that “the primary goal of dermatomyositis management should focus on controlling/reducing the disease burden.”
The research was funded by the National Institutes of Health and the US Department of Veterans Affairs. The authors had no disclosures. Dr. Maderal reported personal fees from argenx. No disclosures were noted for Dr. Gehlhausen and Dr. Wu.
A version of this article appeared on Medscape.com.
Newly issued guidelines for cancer screening in patients with dermatomyositis had 100% sensitivity in a single institution’s cohort, though most of the cancers found would have been detected with standard cancer screenings recommended for the general population, according to a research letter published in JAMA Dermatology.
“These early results emphasize the continued need to refine risk assessment and cancer screening for patients with dermatomyositis while balancing resource use and outcomes,” concluded Caroline J. Stone and her colleagues at the Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Patients with dermatomyositis have approximately a 4.7 times greater risk for cancer than those without it, according to a 2016 meta-analysis. Despite the well-established link between cancer and dermatomyositis, cancer in people with idiopathic inflammatory myopathies is commonly diagnosed at a later stage and is the leading cause of death in people with these conditions.
Guidelines First Presented in 2022 and Published in 2023
A wide variability in screening practices eventually led the International Myositis Assessment & Clinical Studies Group (IMACS) to present the first evidence-based and consensus-based guidelines for cancer screening of patients with idiopathic inflammatory myopathies, including those with dermatomyositis, at the 2022 annual meeting of the American College of Rheumatology and publish them in 2023 in Nature Reviews Rheumatology. The guidelines advise low-risk patients to undergo basic cancer screening with routine blood and urine studies, liver function tests, plain chest radiography, and age- and sex-appropriate cancer screening.
Intermediate- and high-risk patients are recommended to undergo enhanced screening that can include mammography, Pap tests, endoscopy/colonoscopy, pelvic and transvaginal ultrasonography, prostate-specific antigen or cancer antigen 125 blood tests, fecal occult blood tests, and CT of the neck, thorax, abdomen, and pelvis.
But because the guidelines are new, little evidence exists regarding their validation in real-world cohorts. Researchers, therefore, assessed the IMACS guidelines in 370 patients, aged 18-80 years, who visited the University of Pennsylvania rheumatology-dermatology specialty clinic between July 2008 and January 2024. All participants had dermatomyositis and at least 3 years of follow-up and were an average 48 years old. The vast majority were women (87%) and White participants (89%).
Most (68.6%) had myositis-specific autoantibody test results, one of the factors included in the guidelines for determining whether the patient should be classified as low, intermediate, or high risk. Other factors for risk stratification included myositis subtype, age at disease onset, and clinical features. About half (49.2%) had classic dermatomyositis, 42.4% had amyopathic dermatomyositis, 3.8% had juvenile dermatomyositis, 3.2% had hypomyopathic dermatomyositis, 0.8% had antisynthetase syndrome, and 0.5% had immune-mediated necrotizing myopathy.
Just over half the patients (54%) were classified as high risk, while 37.3% were classified as intermediate risk and 8.9% as low risk using the guidelines. Among the 18 patients (4.9%) with paraneoplastic dermatomyositis, 15 were classified as high risk and 3 as intermediate risk.
Of the patients diagnosed with cancer, 55% of cases were diagnosed about a year before their dermatomyositis diagnosis. In three patients, symptoms “suggestive of cancer at the time of dermatomyositis diagnosis, including lymphadenopathy and unexplained weight loss,” led to diagnostic testing that found an underlying cancer.
In the eight patients diagnosed with cancer after their dermatomyositis diagnosis, 75% of the cancers were identified during the first year of follow-up and 25% in the second year. Five were identified based on basic cancer screening and three on enhanced screening.
A total of 11 patients (3%) developed intravenous contrast allergies, and no other adverse events were reported to be associated with cancer screening, but the study was not designed to capture other types of adverse screening effects, such as cost, quality of life, or risk from radiation exposure.
The most common neoplasm identified was breast cancer, found in nine (50%) of the patients using mammography. Two patients had lung cancer identified with chest radiography and two had ovarian cancer identified with abdominal radiography and CT. The remaining five patients included one each with bladder cancer, papillary thyroid cancer, renal cell carcinoma, non-Hodgkin lymphoma, and adenocarcinoma with unknown primary.
The sensitivity of the guidelines in detecting cancer related to dermatomyositis was 100%, though the authors noted that the “IMACS risk-stratification scheme may overestimate cancer risk and encourage enhanced screening protocols of unclear benefit.” Most of the cancers found after dermatomyositis diagnosis were detected with routine age- and sex-related screening that already falls under basic cancer screening recommendations for the general population. Nonetheless, 90% of the participants fell into the intermediate- and high-risk groups, warranting a more comprehensive and costly enhanced screening protocol.
Will the Guidelines Lead to Overscreening?
The 4.9% cancer prevalence is considerably lower than the typical 15%-25% prevalence among patients with dermatomyositis, but the findings, regardless, suggest the guidelines will lead to overscreening, wrote Andrea D. Maderal, MD, University of Miami Miller School of Medicine in Florida, and Alisa Femia, MD, New York University Grossman School of Medicine, New York City, in an accompanying editorial. Given that the median age in patients with cancer in the study was 58 years — 18 years older than the age cutoff for high-risk criteria — one way to refine the guidelines may be to increase the age for the high-risk category, they suggested.
“While these guidelines led to many ultimately unnecessary screening tests based on currently recommended designations of intermediate-risk and high-risk patients, these guidelines reflect a more conservative approach to screening than was previously performed,” Dr. Maderal and Dr. Femia wrote.
Jeff Gehlhausen, MD, PhD, an assistant professor of dermatology at Yale School of Medicine, New Haven, Connecticut, said he is not concerned about overscreening in patients, however, and is “very enthusiastic” about the findings.
“Patients are very anxious for good reason,” given the typical cancer prevalence of 25% in this population, he said in an interview. “I think therein lies the challenge — with that risk, what is ‘enough’ screening?” Yet this “incredibly impressive” study “provides real insights into the applicability of the IMACS screenings to our dermatomyositis management,” including relevance to his own patients. “Their findings are instructive for how to better evaluate these patients in a more mindful fashion,” he said, and they are particularly welcome, given how widely variable practice has historically been before the guidelines were issued.
“This question has been an outstanding one for decades, and nearly every doctor has a different answer,” Dr. Gehlhausen said. “The introduction of the guidelines alone are now much more actionable with this study, and that’s why it’s such an important one for our community.”
Benedict Wu, DO, PhD, director of Inpatient Dermatology and an assistant professor at Montefiore Einstein and a member of the Montefiore Einstein Comprehensive Cancer Center in New York City, similarly regarded the findings as reassuring, though he was surprised at the low prevalence of cancer in the patients.
“The most reassuring finding was that the detection of most malignancies was possible by using routine age- and sex-related screening combined with basic cancer screening,” Wu said in an interview. “Basic cancer screening can reduce costs while keeping patients safe.”
He also found it reassuring that all the paraneoplastic dermatomyositis was in intermediate- or high-risk patients, and while he does not see the IMACS guidelines as overestimating cancer risk, he does think “the risk stratification and recommended screening tests could be revised to be less ‘aggressive.’ ”
The overall low rate of cancer in the group “calls into question the need for stringent and annual cancer screening,” he said. “In this large cohort of patients, the fact that malignancy was detected within 2 years of dermatomyositis diagnosis will help guide us with long-term screening recommendations.”
Despite the study’s small size and single-center design, the demographics of the patients nearly represents exactly what is found in the United States more broadly, Wu noted. He also drew attention to how many patients lacked the myositis antibody profile performed, and he agreed with the authors that more extensive and prospective studies need to be conducted. He also emphasized the need to keep in mind that “the primary goal of dermatomyositis management should focus on controlling/reducing the disease burden.”
The research was funded by the National Institutes of Health and the US Department of Veterans Affairs. The authors had no disclosures. Dr. Maderal reported personal fees from argenx. No disclosures were noted for Dr. Gehlhausen and Dr. Wu.
A version of this article appeared on Medscape.com.
FROM JAMA DERMATOLOGY
Severe Autoimmune Diseases Linked to Premature Ovarian Insufficiency
TOPLINE:
Women with premature ovarian insufficiency (POI) have a 2.6 times higher prevalence of severe autoimmune diseases before diagnosis and a 2- to 3-fold increased risk for these diseases after diagnosis.
METHODOLOGY:
- Researchers conducted a population-based registry study including 3972 women diagnosed with spontaneous POI between 1988 and 2017.
- A total of 15,708 female population controls matched by age and municipality of residence were included for comparison.
- Autoimmune disease diagnoses were evaluated from childhood until the end of 2017 using the Hospital Discharge Registry.
- Women with a history of cancer or bilateral oophorectomy were excluded from the study.
TAKEAWAY:
- Women with POI had a 2.6 times higher prevalence of severe autoimmune diseases before diagnosis compared to controls (odds ratio [OR], 2.6; 95% CI, 2.2-3.1).
- The prevalence of specific autoimmune diseases such as polyglandular autoimmune diseases (OR, 25.8; 95% CI, 9.0-74.1) and Addison disease (OR, 22.9; 95% CI, 7.9-66.1) was significantly higher in women with POI.
- The standardized incidence ratios for being diagnosed with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI, 2.3-3.4) during the first 3 years, decreasing to 1.3 (95% CI, 1.1-1.6) after 12 years.
- No significant difference was found in the prevalence of diabetes type 1 and ankylosing spondylitis between women with POI and the reference cohort.
IN PRACTICE:
“The study results strengthen the hypothesis that autoimmune mechanisms play an important role in the pathogenesis of POI. Future studies should focus on the immunological mechanism of POI from preventative and curative perspectives,” wrote the authors of the study.
SOURCE:
The study was led by Susanna M. Savukoski, Oulu University Hospital in Finland. It was published online in Human Reproduction.
LIMITATIONS:
The study included only autoimmune disorders diagnosed in specialized health care, which may underestimate the overall prevalence of autoimmune disorders in women with POI. Additionally, the study did not account for confounders such as body mass index and smoking, which are associated with the risk for autoimmune disease and POI.
DISCLOSURES:
Ms. Savukoski received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Women with premature ovarian insufficiency (POI) have a 2.6 times higher prevalence of severe autoimmune diseases before diagnosis and a 2- to 3-fold increased risk for these diseases after diagnosis.
METHODOLOGY:
- Researchers conducted a population-based registry study including 3972 women diagnosed with spontaneous POI between 1988 and 2017.
- A total of 15,708 female population controls matched by age and municipality of residence were included for comparison.
- Autoimmune disease diagnoses were evaluated from childhood until the end of 2017 using the Hospital Discharge Registry.
- Women with a history of cancer or bilateral oophorectomy were excluded from the study.
TAKEAWAY:
- Women with POI had a 2.6 times higher prevalence of severe autoimmune diseases before diagnosis compared to controls (odds ratio [OR], 2.6; 95% CI, 2.2-3.1).
- The prevalence of specific autoimmune diseases such as polyglandular autoimmune diseases (OR, 25.8; 95% CI, 9.0-74.1) and Addison disease (OR, 22.9; 95% CI, 7.9-66.1) was significantly higher in women with POI.
- The standardized incidence ratios for being diagnosed with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI, 2.3-3.4) during the first 3 years, decreasing to 1.3 (95% CI, 1.1-1.6) after 12 years.
- No significant difference was found in the prevalence of diabetes type 1 and ankylosing spondylitis between women with POI and the reference cohort.
IN PRACTICE:
“The study results strengthen the hypothesis that autoimmune mechanisms play an important role in the pathogenesis of POI. Future studies should focus on the immunological mechanism of POI from preventative and curative perspectives,” wrote the authors of the study.
SOURCE:
The study was led by Susanna M. Savukoski, Oulu University Hospital in Finland. It was published online in Human Reproduction.
LIMITATIONS:
The study included only autoimmune disorders diagnosed in specialized health care, which may underestimate the overall prevalence of autoimmune disorders in women with POI. Additionally, the study did not account for confounders such as body mass index and smoking, which are associated with the risk for autoimmune disease and POI.
DISCLOSURES:
Ms. Savukoski received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
TOPLINE:
Women with premature ovarian insufficiency (POI) have a 2.6 times higher prevalence of severe autoimmune diseases before diagnosis and a 2- to 3-fold increased risk for these diseases after diagnosis.
METHODOLOGY:
- Researchers conducted a population-based registry study including 3972 women diagnosed with spontaneous POI between 1988 and 2017.
- A total of 15,708 female population controls matched by age and municipality of residence were included for comparison.
- Autoimmune disease diagnoses were evaluated from childhood until the end of 2017 using the Hospital Discharge Registry.
- Women with a history of cancer or bilateral oophorectomy were excluded from the study.
TAKEAWAY:
- Women with POI had a 2.6 times higher prevalence of severe autoimmune diseases before diagnosis compared to controls (odds ratio [OR], 2.6; 95% CI, 2.2-3.1).
- The prevalence of specific autoimmune diseases such as polyglandular autoimmune diseases (OR, 25.8; 95% CI, 9.0-74.1) and Addison disease (OR, 22.9; 95% CI, 7.9-66.1) was significantly higher in women with POI.
- The standardized incidence ratios for being diagnosed with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI, 2.3-3.4) during the first 3 years, decreasing to 1.3 (95% CI, 1.1-1.6) after 12 years.
- No significant difference was found in the prevalence of diabetes type 1 and ankylosing spondylitis between women with POI and the reference cohort.
IN PRACTICE:
“The study results strengthen the hypothesis that autoimmune mechanisms play an important role in the pathogenesis of POI. Future studies should focus on the immunological mechanism of POI from preventative and curative perspectives,” wrote the authors of the study.
SOURCE:
The study was led by Susanna M. Savukoski, Oulu University Hospital in Finland. It was published online in Human Reproduction.
LIMITATIONS:
The study included only autoimmune disorders diagnosed in specialized health care, which may underestimate the overall prevalence of autoimmune disorders in women with POI. Additionally, the study did not account for confounders such as body mass index and smoking, which are associated with the risk for autoimmune disease and POI.
DISCLOSURES:
Ms. Savukoski received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. Additional disclosures are noted in the original article.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.
Could Eyelid Imaging Aid Early Diagnosis of Sjögren Disease?
A noninvasive eye test could help people with Sjögren disease — a disorder that can go undiagnosed for years — get relief sooner, suggested a pilot study published in Therapeutic Advances in Musculoskeletal Disease.
Researchers led by Jing Wu, Department of Ophthalmology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and colleagues used infrared imaging to detect atrophy of the oil-producing meibomian glands, which lubricate the eyelids and eyes, in 56 patients with suspected Sjögren disease. The test can be administered by an eye care practitioner using a Keratograph 5M machine. Patients also underwent salivary gland biopsies to detect Sjögren disease.
A total of 34 patients diagnosed with primary Sjögren disease had more significant atrophy and shortening of the meibomian glands in their upper eyelids than 22 patients with other types of dry eye who served as control patients. The accuracy of temporal and total meibomian gland dysfunction dropout rates in the upper eyelids to predict primary Sjögren disease classification was good, with an area under the curve of 0.94 and 0.91, respectively.
“Sjögren’s-related dry eye is definitely inflammatory,” said Esen Akpek, MD, director of the Ocular Surface Disease and Dry Eye Clinic at Johns Hopkins Medicine, Baltimore, who was not involved with the study. “It starts as inflammation, and then the inflammation spreads to the meibomian glands, to the conjunctiva, cornea, and there will be other findings, like corneal ulcers, corneal melts, cyclitis, retinitis, optic neuritis, uveitis, all these inflammatory diseases of the eye could happen with Sjögren’s.”
With other types of dry eye, such as blepharitis or even meibomian gland dysfunction without Sjögren disease, inflammation is usually confined to the ocular surface, Akpek said. As a result, symptoms tend to be less severe and progressive.
The results of this small study need validation in a larger cohort, said Steven Carsons, MD, chief of the Division of Rheumatology at NYU Langone Hospital–Long Island, who was not involved with the study. In general, however, noninvasive alternatives to today’s tests for Sjögren disease could be useful for patients and physicians.
“The definitive diagnosis is a minor salivary glandular biopsy, which is invasive and isn’t really appealing to a lot of patients,” Dr. Carsons said. This test can also be difficult to access if patients don’t live near a medical center that specializes in Sjögren disease, he said.
“I think it’s everybody’s goal to have a noninvasive test be able, at some point, to replace biopsy,” Dr. Carsons said.
Then there are blood tests. “The other more objective test, the SSA antibodies, are not very specific for Sjögren’s syndrome,” he said. “They’re fairly sensitive, but can also be seen in other autoimmune conditions, particularly lupus.”
With existing tools, however, optometrists and ophthalmologists can do more to diagnose Sjögren disease early, Dr. Akpek said.
“The issue with Sjögren’s is not that there are no earlier diagnostic aids or anything like that,” Dr. Akpek said.
Lissamine green, a dye that stains degraded cells on the eye’s surface, can reveal clues in young adult patients before other signs. “In my opinion, the earliest clinical finding that indicates presence of the disease is lissamine green staining of conjunctiva,” Akpek said.
Meibomian gland imaging would detect the disease at a later point. “By the time you get meibomian gland dysfunction, there has been longer-standing inflammation,” she said.
Two challenges hold back diagnoses, she said. One is that many practitioners mistakenly believe Sjögren disease is just a nuisance even though it can threaten vision through ocular complications and have more far-reaching effects, too.
“There are a lot of extraglandular systemic manifestations of Sjögren’s that cause morbidity in these patients,” Dr. Akpek said. For example, Sjögren disease is associated with lymphoma and other malignancies, interstitial nephritis, autoimmune hepatitis, and interstitial lung disease with fibrosis.
The second challenge, she said, is that many ophthalmologists and optometrists assume rheumatologists will make the Sjögren disease diagnosis first and then refer patients to them. But eye doctors are well positioned to spot the first signs — if they look for them.
“When you complain of dry eye, unless the doctor puts certain dyes and takes a look at the surface with the dye staining, they can’t see that you are dry,” Dr. Akpek said.
Unfortunately, these tests are underutilized. “I’m sorry to say, dry eye testing, like clinical testing, is not very commonly done,” she said. “Dry eye is managed according to patient symptoms. A lot of the time, Sjögren’s patients have such severe dry eye that they don’t complain of dryness anymore because their corneas become numb.”
Another way to prevent diagnostic delay is to collaborate, communicate, and carefully review patient records shared by other specialists.
“Particularly because of the wide involvement of different organ systems, such as the eyes, the mouth with dental problems, and then systemic features, including joints, it really does need the cooperation of ophthalmologists, dental specialists, and rheumatologists — immunologists sometimes — to come together and make this diagnosis,” Dr. Carsons said.
The study was supported by grants from the National Natural Science Foundation of China. The authors had no relevant disclosures.
A version of this article appeared on Medscape.com.
A noninvasive eye test could help people with Sjögren disease — a disorder that can go undiagnosed for years — get relief sooner, suggested a pilot study published in Therapeutic Advances in Musculoskeletal Disease.
Researchers led by Jing Wu, Department of Ophthalmology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and colleagues used infrared imaging to detect atrophy of the oil-producing meibomian glands, which lubricate the eyelids and eyes, in 56 patients with suspected Sjögren disease. The test can be administered by an eye care practitioner using a Keratograph 5M machine. Patients also underwent salivary gland biopsies to detect Sjögren disease.
A total of 34 patients diagnosed with primary Sjögren disease had more significant atrophy and shortening of the meibomian glands in their upper eyelids than 22 patients with other types of dry eye who served as control patients. The accuracy of temporal and total meibomian gland dysfunction dropout rates in the upper eyelids to predict primary Sjögren disease classification was good, with an area under the curve of 0.94 and 0.91, respectively.
“Sjögren’s-related dry eye is definitely inflammatory,” said Esen Akpek, MD, director of the Ocular Surface Disease and Dry Eye Clinic at Johns Hopkins Medicine, Baltimore, who was not involved with the study. “It starts as inflammation, and then the inflammation spreads to the meibomian glands, to the conjunctiva, cornea, and there will be other findings, like corneal ulcers, corneal melts, cyclitis, retinitis, optic neuritis, uveitis, all these inflammatory diseases of the eye could happen with Sjögren’s.”
With other types of dry eye, such as blepharitis or even meibomian gland dysfunction without Sjögren disease, inflammation is usually confined to the ocular surface, Akpek said. As a result, symptoms tend to be less severe and progressive.
The results of this small study need validation in a larger cohort, said Steven Carsons, MD, chief of the Division of Rheumatology at NYU Langone Hospital–Long Island, who was not involved with the study. In general, however, noninvasive alternatives to today’s tests for Sjögren disease could be useful for patients and physicians.
“The definitive diagnosis is a minor salivary glandular biopsy, which is invasive and isn’t really appealing to a lot of patients,” Dr. Carsons said. This test can also be difficult to access if patients don’t live near a medical center that specializes in Sjögren disease, he said.
“I think it’s everybody’s goal to have a noninvasive test be able, at some point, to replace biopsy,” Dr. Carsons said.
Then there are blood tests. “The other more objective test, the SSA antibodies, are not very specific for Sjögren’s syndrome,” he said. “They’re fairly sensitive, but can also be seen in other autoimmune conditions, particularly lupus.”
With existing tools, however, optometrists and ophthalmologists can do more to diagnose Sjögren disease early, Dr. Akpek said.
“The issue with Sjögren’s is not that there are no earlier diagnostic aids or anything like that,” Dr. Akpek said.
Lissamine green, a dye that stains degraded cells on the eye’s surface, can reveal clues in young adult patients before other signs. “In my opinion, the earliest clinical finding that indicates presence of the disease is lissamine green staining of conjunctiva,” Akpek said.
Meibomian gland imaging would detect the disease at a later point. “By the time you get meibomian gland dysfunction, there has been longer-standing inflammation,” she said.
Two challenges hold back diagnoses, she said. One is that many practitioners mistakenly believe Sjögren disease is just a nuisance even though it can threaten vision through ocular complications and have more far-reaching effects, too.
“There are a lot of extraglandular systemic manifestations of Sjögren’s that cause morbidity in these patients,” Dr. Akpek said. For example, Sjögren disease is associated with lymphoma and other malignancies, interstitial nephritis, autoimmune hepatitis, and interstitial lung disease with fibrosis.
The second challenge, she said, is that many ophthalmologists and optometrists assume rheumatologists will make the Sjögren disease diagnosis first and then refer patients to them. But eye doctors are well positioned to spot the first signs — if they look for them.
“When you complain of dry eye, unless the doctor puts certain dyes and takes a look at the surface with the dye staining, they can’t see that you are dry,” Dr. Akpek said.
Unfortunately, these tests are underutilized. “I’m sorry to say, dry eye testing, like clinical testing, is not very commonly done,” she said. “Dry eye is managed according to patient symptoms. A lot of the time, Sjögren’s patients have such severe dry eye that they don’t complain of dryness anymore because their corneas become numb.”
Another way to prevent diagnostic delay is to collaborate, communicate, and carefully review patient records shared by other specialists.
“Particularly because of the wide involvement of different organ systems, such as the eyes, the mouth with dental problems, and then systemic features, including joints, it really does need the cooperation of ophthalmologists, dental specialists, and rheumatologists — immunologists sometimes — to come together and make this diagnosis,” Dr. Carsons said.
The study was supported by grants from the National Natural Science Foundation of China. The authors had no relevant disclosures.
A version of this article appeared on Medscape.com.
A noninvasive eye test could help people with Sjögren disease — a disorder that can go undiagnosed for years — get relief sooner, suggested a pilot study published in Therapeutic Advances in Musculoskeletal Disease.
Researchers led by Jing Wu, Department of Ophthalmology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and colleagues used infrared imaging to detect atrophy of the oil-producing meibomian glands, which lubricate the eyelids and eyes, in 56 patients with suspected Sjögren disease. The test can be administered by an eye care practitioner using a Keratograph 5M machine. Patients also underwent salivary gland biopsies to detect Sjögren disease.
A total of 34 patients diagnosed with primary Sjögren disease had more significant atrophy and shortening of the meibomian glands in their upper eyelids than 22 patients with other types of dry eye who served as control patients. The accuracy of temporal and total meibomian gland dysfunction dropout rates in the upper eyelids to predict primary Sjögren disease classification was good, with an area under the curve of 0.94 and 0.91, respectively.
“Sjögren’s-related dry eye is definitely inflammatory,” said Esen Akpek, MD, director of the Ocular Surface Disease and Dry Eye Clinic at Johns Hopkins Medicine, Baltimore, who was not involved with the study. “It starts as inflammation, and then the inflammation spreads to the meibomian glands, to the conjunctiva, cornea, and there will be other findings, like corneal ulcers, corneal melts, cyclitis, retinitis, optic neuritis, uveitis, all these inflammatory diseases of the eye could happen with Sjögren’s.”
With other types of dry eye, such as blepharitis or even meibomian gland dysfunction without Sjögren disease, inflammation is usually confined to the ocular surface, Akpek said. As a result, symptoms tend to be less severe and progressive.
The results of this small study need validation in a larger cohort, said Steven Carsons, MD, chief of the Division of Rheumatology at NYU Langone Hospital–Long Island, who was not involved with the study. In general, however, noninvasive alternatives to today’s tests for Sjögren disease could be useful for patients and physicians.
“The definitive diagnosis is a minor salivary glandular biopsy, which is invasive and isn’t really appealing to a lot of patients,” Dr. Carsons said. This test can also be difficult to access if patients don’t live near a medical center that specializes in Sjögren disease, he said.
“I think it’s everybody’s goal to have a noninvasive test be able, at some point, to replace biopsy,” Dr. Carsons said.
Then there are blood tests. “The other more objective test, the SSA antibodies, are not very specific for Sjögren’s syndrome,” he said. “They’re fairly sensitive, but can also be seen in other autoimmune conditions, particularly lupus.”
With existing tools, however, optometrists and ophthalmologists can do more to diagnose Sjögren disease early, Dr. Akpek said.
“The issue with Sjögren’s is not that there are no earlier diagnostic aids or anything like that,” Dr. Akpek said.
Lissamine green, a dye that stains degraded cells on the eye’s surface, can reveal clues in young adult patients before other signs. “In my opinion, the earliest clinical finding that indicates presence of the disease is lissamine green staining of conjunctiva,” Akpek said.
Meibomian gland imaging would detect the disease at a later point. “By the time you get meibomian gland dysfunction, there has been longer-standing inflammation,” she said.
Two challenges hold back diagnoses, she said. One is that many practitioners mistakenly believe Sjögren disease is just a nuisance even though it can threaten vision through ocular complications and have more far-reaching effects, too.
“There are a lot of extraglandular systemic manifestations of Sjögren’s that cause morbidity in these patients,” Dr. Akpek said. For example, Sjögren disease is associated with lymphoma and other malignancies, interstitial nephritis, autoimmune hepatitis, and interstitial lung disease with fibrosis.
The second challenge, she said, is that many ophthalmologists and optometrists assume rheumatologists will make the Sjögren disease diagnosis first and then refer patients to them. But eye doctors are well positioned to spot the first signs — if they look for them.
“When you complain of dry eye, unless the doctor puts certain dyes and takes a look at the surface with the dye staining, they can’t see that you are dry,” Dr. Akpek said.
Unfortunately, these tests are underutilized. “I’m sorry to say, dry eye testing, like clinical testing, is not very commonly done,” she said. “Dry eye is managed according to patient symptoms. A lot of the time, Sjögren’s patients have such severe dry eye that they don’t complain of dryness anymore because their corneas become numb.”
Another way to prevent diagnostic delay is to collaborate, communicate, and carefully review patient records shared by other specialists.
“Particularly because of the wide involvement of different organ systems, such as the eyes, the mouth with dental problems, and then systemic features, including joints, it really does need the cooperation of ophthalmologists, dental specialists, and rheumatologists — immunologists sometimes — to come together and make this diagnosis,” Dr. Carsons said.
The study was supported by grants from the National Natural Science Foundation of China. The authors had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM THERAPEUTIC ADVANCES IN MUSCULOSKELETAL DISEASE