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New findings raise questions about the role of ANAs in SLE
Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.
“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.
However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.
He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.
For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.
A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.
“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”
The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.
It appears an important problem relates to test kit variability, he said.
“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.
In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).
Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.
Anti–double-stranded DNA assays
Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.
For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.
The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.
Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.
Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”
Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.
Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.
“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.
However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.
He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.
For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.
A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.
“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”
The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.
It appears an important problem relates to test kit variability, he said.
“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.
In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).
Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.
Anti–double-stranded DNA assays
Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.
For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.
The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.
Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.
Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”
Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.
Antinuclear antibodies (ANAs) have long been considered an important marker in rheumatologic conditions, particularly for the diagnosis and classification of patients with systemic lupus erythematosus, but recent findings are raising new questions about their role.
“We’ve measured ANAs for a long time – it’s a very important test in rheumatology,” David S. Pisetsky, MD, PhD, explained in an interview.
However, even though this test has been around for decades, “some interesting things have developed around it that have made a lot of people, including me, take a second look,” said Dr. Pisetsky, professor of medicine and immunology at Duke University, Durham, N.C.
He elaborated on those recent findings, which relate to the findings of ANA negativity in patients with an established diagnosis of systemic lupus erythematosus (SLE) and to variability among ANA test kit findings, during a presentation at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“Screening of patients during clinical trials for new treatments of SLE suggest that a significant number of people with lupus – 20%-30%, in fact – are ANA negative despite disease activity at the time the test is done,” he said.
For example, unpublished (but recently submitted) data from a phase 2 trial looking at the efficacy and safety of an interleukin-6 monoclonal antibody for the treatment of SLE showed that 23.8% of baseline samples from 183 SLE patients with positive historical ANA and clinically active lupus prior to randomization were ANA negative.
A particular concern with respect to such findings is that ANA positivity is typically a criterion for entry into clinical trials of therapies for lupus and prescription of medications approved for active lupus, Dr. Pisetsky said.
“On the other hand, about 20% of otherwise healthy people – especially women – can be ANA positive, so it’s always been problematic as a screening test due to these false positives, but these new findings suggest that in lupus a real concern is false negatives,” he said. “It’s quite a surprise.”
The findings raise questions about whether ANA negativity in SLE reflects the natural history of the disease, an effect of treatments, or a problem with the assays.
It appears an important problem relates to test kit variability, he said.
“There are lots of different ANA test kits. Their performance characteristics are very different. The performance of ANA tests is much more variable than people realize,” he said, citing data from an analysis that he and his colleagues conducted using 103 samples from a cohort of patients with established SLE.
In that 2017 study, an ANA enzyme-linked immunosorbent assay showed an ANA-negativity rate of 11.7% with zero indeterminate tests, whereas three different test kits showed ANA-negativity rates of 22.3% (with 8.7% of samples reported as indeterminate), 9.7% (with another 9.7% indeterminate), and 4.9% (with another 1.9% indeterminate), respectively. Multiplex testing showed a 13.6% ANA-negativity rate and an indeterminate rate of 7.8% (Ann Rheum Dis. 2018;77:911-3).
Only one sample tested negative for ANA on all three test kits, and disagreement about ANA negativity occurred in one-third of the samples, he said.
Anti–double-stranded DNA assays
Recent findings also raise questions about the use of assays that specifically assess for anti–double-stranded DNA (anti-dsDNA) antibodies, which are highly associated with SLE and have been used as a biomarker for the disease, Dr. Pisetsky said.
For example, a comparison of two anti-dsDNA assays showed discordant results with respect to negativity for anti-dsDNA antibodies in 64 of 181 samples from SLE patients. One assay showed a 70.7% rate of anti-dsDNA negativity and the other showed a 37.6% rate.
The concern regarding test variability relates to the issue of ANA positivity and eligibility for study enrollment and certain treatments; test variability can affect the diagnosis of patients with SLE because ANA positivity is an important finding in routine clinical care, and for anti-dsDNA, test variability can affect assessment of disease activity, he explained.
Tests may differ in a number of ways, such as in their specificity, sensitivity, avidity, and range of epitopes detected. Unfortunately, not enough is known at this point to make specific recommendations regarding best test kits, and while there are alternative technologies that could be useful for ANA testing, none has been validated for particular use in the assessment of trial eligibility, Dr. Pisetsky said.
Nonetheless, awareness of the test variability is important, especially when it comes to assessing patients for trial eligibility and prescribing medications, he added. “For practical, real-world utilization, people need to know about this.”
Dr. Pisetsky reported receiving ANA-related research support from Pfizer, conducting collaborative research with Bio-Rad and EuroImmun, and serving as an adviser to ImmunArray.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
New SLE disease activity measure beats SLEDAI-2K
, according to investigators.
In terms of identifying clinically significant changes, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) was superior to the SLE Disease Activity Index 2000 (SLEDAI-2K), said the authors of a longitudinal cohort study comparing the two instruments.
The SLE-DAS maintained high specificity compared with the SLEDAI-2K and had a similar clinical workup time requirement, according to Diogo Jesus, MD, of the rheumatology department at Centro Hospitalar e Universitário de Coimbra, Portugal, and his colleagues.
“Such a performance can have major implications in the interpretation of clinical trials applying the disease activity as the primary endpoint, and in daily clinical practice, where SLE-DAS could provide robust guidance for treatment in the individual patient,” Dr. Jesus and his coauthors wrote in Annals of the Rheumatic Diseases.
The longitudinal cohort study by Dr. Jesus and his colleagues included 520 patients with SLE from tertiary care centers in Coimbra, Portugal, and Padova, Italy. These included a derivation cohort of 324 patients and an external validation cohort of 196 patients (the Padova Lupus Cohort).
A cutoff value of 1.72 for change in the 17-item SLE-DAS had significantly higher sensitivities to detect a clinical meaningful improvement in both the derivation (82.1%) and external validation (89.5%) cohorts, compared with a cutoff value of 4 or higher in the SLEDAI-2K at 44.8% and 47.4%, respectively, the investigators reported. Likewise, ability to detect clinically meaningful worsening was significantly higher with SLE-DAS, with sensitivities of 93.1% in the derivation cohort and 95.5% in the external validation group versus a respective 46.6% and 59.1% for SLEDAI-2K. Both clinical improvement and worsening were defined by a change in the Physician Global Assessment score of 0.3 or more.
Specificity was high for both instruments, with values around 98%-99% in both cohorts for clinically meaningful worsening and about 97%-100% for clinically meaningful improvement, the report shows.
Further analyses showed that disease activity tracked over time with SLE-DAS had a higher predictive value for damage accrual versus the SLEDAI-2K, according to the investigators.
The SLE-DAS formula, published in the journal by Dr. Jesus and his colleagues, includes a total of 17 weighted and mostly binary variables: presence or absence of alopecia, arthritis, cardiac/pulmonary involvement, generalized cutaneous rash, hemolytic anemia, hypocomplementemia, increased anti-dsDNA levels, leukopenia, localized cutaneous rash, mucocutaneous vasculitis, mucosal ulcers, myositis, neuropsychiatric involvement, proteinuria, serositis, systemic vasculitis, and thrombocytopenia.
Next, the researchers plan to define SLE-DAS cutoff values for remission, low disease activity, and moderate or high disease activity. An online calculator is also in the works, they said.
Dr. Jesus and his coauthors did not report any outside funding for the study and said they had no competing interests related to their research.
SOURCE: Jesus D et al. Ann Rheum Dis. 2019 Jan 9. doi: 10.1136/annrheumdis-2018-214502.
, according to investigators.
In terms of identifying clinically significant changes, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) was superior to the SLE Disease Activity Index 2000 (SLEDAI-2K), said the authors of a longitudinal cohort study comparing the two instruments.
The SLE-DAS maintained high specificity compared with the SLEDAI-2K and had a similar clinical workup time requirement, according to Diogo Jesus, MD, of the rheumatology department at Centro Hospitalar e Universitário de Coimbra, Portugal, and his colleagues.
“Such a performance can have major implications in the interpretation of clinical trials applying the disease activity as the primary endpoint, and in daily clinical practice, where SLE-DAS could provide robust guidance for treatment in the individual patient,” Dr. Jesus and his coauthors wrote in Annals of the Rheumatic Diseases.
The longitudinal cohort study by Dr. Jesus and his colleagues included 520 patients with SLE from tertiary care centers in Coimbra, Portugal, and Padova, Italy. These included a derivation cohort of 324 patients and an external validation cohort of 196 patients (the Padova Lupus Cohort).
A cutoff value of 1.72 for change in the 17-item SLE-DAS had significantly higher sensitivities to detect a clinical meaningful improvement in both the derivation (82.1%) and external validation (89.5%) cohorts, compared with a cutoff value of 4 or higher in the SLEDAI-2K at 44.8% and 47.4%, respectively, the investigators reported. Likewise, ability to detect clinically meaningful worsening was significantly higher with SLE-DAS, with sensitivities of 93.1% in the derivation cohort and 95.5% in the external validation group versus a respective 46.6% and 59.1% for SLEDAI-2K. Both clinical improvement and worsening were defined by a change in the Physician Global Assessment score of 0.3 or more.
Specificity was high for both instruments, with values around 98%-99% in both cohorts for clinically meaningful worsening and about 97%-100% for clinically meaningful improvement, the report shows.
Further analyses showed that disease activity tracked over time with SLE-DAS had a higher predictive value for damage accrual versus the SLEDAI-2K, according to the investigators.
The SLE-DAS formula, published in the journal by Dr. Jesus and his colleagues, includes a total of 17 weighted and mostly binary variables: presence or absence of alopecia, arthritis, cardiac/pulmonary involvement, generalized cutaneous rash, hemolytic anemia, hypocomplementemia, increased anti-dsDNA levels, leukopenia, localized cutaneous rash, mucocutaneous vasculitis, mucosal ulcers, myositis, neuropsychiatric involvement, proteinuria, serositis, systemic vasculitis, and thrombocytopenia.
Next, the researchers plan to define SLE-DAS cutoff values for remission, low disease activity, and moderate or high disease activity. An online calculator is also in the works, they said.
Dr. Jesus and his coauthors did not report any outside funding for the study and said they had no competing interests related to their research.
SOURCE: Jesus D et al. Ann Rheum Dis. 2019 Jan 9. doi: 10.1136/annrheumdis-2018-214502.
, according to investigators.
In terms of identifying clinically significant changes, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) was superior to the SLE Disease Activity Index 2000 (SLEDAI-2K), said the authors of a longitudinal cohort study comparing the two instruments.
The SLE-DAS maintained high specificity compared with the SLEDAI-2K and had a similar clinical workup time requirement, according to Diogo Jesus, MD, of the rheumatology department at Centro Hospitalar e Universitário de Coimbra, Portugal, and his colleagues.
“Such a performance can have major implications in the interpretation of clinical trials applying the disease activity as the primary endpoint, and in daily clinical practice, where SLE-DAS could provide robust guidance for treatment in the individual patient,” Dr. Jesus and his coauthors wrote in Annals of the Rheumatic Diseases.
The longitudinal cohort study by Dr. Jesus and his colleagues included 520 patients with SLE from tertiary care centers in Coimbra, Portugal, and Padova, Italy. These included a derivation cohort of 324 patients and an external validation cohort of 196 patients (the Padova Lupus Cohort).
A cutoff value of 1.72 for change in the 17-item SLE-DAS had significantly higher sensitivities to detect a clinical meaningful improvement in both the derivation (82.1%) and external validation (89.5%) cohorts, compared with a cutoff value of 4 or higher in the SLEDAI-2K at 44.8% and 47.4%, respectively, the investigators reported. Likewise, ability to detect clinically meaningful worsening was significantly higher with SLE-DAS, with sensitivities of 93.1% in the derivation cohort and 95.5% in the external validation group versus a respective 46.6% and 59.1% for SLEDAI-2K. Both clinical improvement and worsening were defined by a change in the Physician Global Assessment score of 0.3 or more.
Specificity was high for both instruments, with values around 98%-99% in both cohorts for clinically meaningful worsening and about 97%-100% for clinically meaningful improvement, the report shows.
Further analyses showed that disease activity tracked over time with SLE-DAS had a higher predictive value for damage accrual versus the SLEDAI-2K, according to the investigators.
The SLE-DAS formula, published in the journal by Dr. Jesus and his colleagues, includes a total of 17 weighted and mostly binary variables: presence or absence of alopecia, arthritis, cardiac/pulmonary involvement, generalized cutaneous rash, hemolytic anemia, hypocomplementemia, increased anti-dsDNA levels, leukopenia, localized cutaneous rash, mucocutaneous vasculitis, mucosal ulcers, myositis, neuropsychiatric involvement, proteinuria, serositis, systemic vasculitis, and thrombocytopenia.
Next, the researchers plan to define SLE-DAS cutoff values for remission, low disease activity, and moderate or high disease activity. An online calculator is also in the works, they said.
Dr. Jesus and his coauthors did not report any outside funding for the study and said they had no competing interests related to their research.
SOURCE: Jesus D et al. Ann Rheum Dis. 2019 Jan 9. doi: 10.1136/annrheumdis-2018-214502.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point: The Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) had better performance in detecting clinically significant changes, compared with the commonly used SLE Disease Activity Index 2000 (SLEDAI-2K).
Major finding: In a validation cohort, the SLE-DAS (vs. SLEDAI-2K) had a significantly higher sensitivity to detect a clinical meaningful improvement (89.5% vs. 47.4%) and clinically meaningful worsening (95.5% vs. 59.1%), with comparably high specificity for both tools.
Study details: Longitudinal cohort study including 520 patients with SLE from two tertiary care centers.
Disclosures: The study authors did not report any outside funding for the study and said they had no competing interests related to the research.
Source: Jesus D et al. Ann Rheum Dis. 2019 Jan 9. doi: 10.1136/annrheumdis-2018-214502.
Primary Sjögren’s syndrome: New research and new resources improve outlook
Recent findings, new classification criteria and treatment guidelines, and concerted efforts by various organizations to provide educational resources are among a number of factors improving the outlook for patients with primary Sjögren’s syndrome, according to Judith James, MD, PhD.
Additionally, the number of studies of primary Sjögren’s syndrome (pSS) is increasing, albeit slowly, and ongoing studies of biologics are showing promise, Dr. James said during a clinical update at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Classification criteria
The ACR in conjunction with the European League Against Rheumatism (EULAR) published new criteria for pSS classification in 2016 based on the available evidence and expert consensus. Inclusion criteria include daily, persistent, troublesome dry eyes for more than 3 months, recurrent sensation of sand or gravel in the eyes, use of tear substitutes more than three times each day, frequent drinking of liquids to aid in swallowing dry food, or at least one EULAR Sjögren’s syndrome disease activity index (ESSDAI) domain with a positive item. Exclusion criteria include prior head and neck radiation treatment, polymerase chain reaction–confirmed active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, or IgG4-related disease, said Dr. James, professor and chair of the arthritis and clinical immunology research program at the University of Oklahoma, Oklahoma City (Arthritis Rheumatol. Jan 2017;69[1]:35-45).
- A score of 4 or higher in patients who meet the inclusion criteria and do not have any of the exclusion criteria leads to classification with pSS, based on the following findings:
- Labial salivary gland with focal lymphocytic sialadenitis and focus score of at least 1 foci/4 mm2 (weight/score = 3).
- Anti-SSA/Ro-positivity (weight/score = 3).
- Ocular Staining Score of at least 5, or van Bijsterveld score of at least 4, in at least one eye (weight/score = 1).
- Schirmer’s test of no more than 5 mm/5 min in at least one eye (weight/score = 1).
- Unstimulated whole saliva flow rate of no more than 0.1 mL/min (weight/score = 1).
Clinical pearls for detection and management
In Dr. James’ experience, the three symptoms (taken together) with the highest predictive value for diagnosing pSS are dry mouth, sore mouth/tongue, and dry eyes. About 25% of Sjögren’s patients may have no detectable salivary flow, she said.
Dry, cracked skin that can lead to secondary infections is another common issue affecting about 55% of patients.
“So we always have to talk to our Sjögren’s patients about skin,” she said. “We also have recurrent sinusitis, chronic cough, dyspepsia, constipation, and other symptoms.”
Concurrent autoimmune diseases are another concern in Sjögren’s patients, she said. One to particularly keep in mind, in addition to lupus and rheumatoid arthritis, is autoimmune thyroid disease.
Data suggest that up to 45% of Sjögren’s patients have thyroid dysfunction, and if you look at just those with autoimmune thyroiditis, their risk of Sjögren’s is increased 10-fold vs. those without autoimmune thyroiditis, she said.
Other conditions to keep in mind when it comes to diagnosing and managing patients, as has been shown in numerous studies over the years, include Raynaud’s phenomenon, which affects at least 13% of patients, and subclinical muscle inflammation, which affects more than 50% of patients, Dr. James said.
“Depression ... as well as anxiety, is quite common in Sjögren’s patients, and fatigue is profound,” she added, noting that fatigue is “the No. 1 issue” for many patients.
Another area of particular concern in Sjögren’s is the increased risk of lymphoma, she said.
Studies show varying rates of lymphoma in Sjögren’s, with one suggesting a 44-fold increased risk, but this is likely only among those at very high risk. Other studies suggest the increase is risk overall is in the range of 4- to 10-fold, she said.
Mortality in Sjögren’s patients
A 2015 study by Soledad Retamozo et al. showed that the presence of cryoglobulinemic vasculitis (CV) at diagnosis is associated with increased mortality risk.
Of 515 consecutive pSS patients with a mean follow-up of 110 months, 65 (12%) had cryoglobulins detected, and 21 of those (32%) fulfilled CV criteria. The patients with cryoglobulins had higher cumulative mean disease activity, 45 (9%) developed B-cell lymphoma, and 33 (6%) died (Arthritis Rheumatol. 2015;67[suppl 10]. Abstract 628).
Additionally, both CV-positive and CV-negative patients had higher risk of B-cell lymphoma, but the risk was greatest in the CV-positive group (hazard ratios, 7.47 and 2.56, respectively), and the CV-positive patients had a higher risk of death (HR, 11.68).
“This actually has changed practice in our Sjögren’s clinic because we didn’t used to do cryos on everybody unless they had leukocytoclastic vasculitis, because they also have a higher risk of death,” Dr. James said.
Systemic activity also predicts pSS mortality, according to findings published in 2016 by Pilar Brito-Zerón et al. Of 1,045 patients who were part of the Spanish Group of Autoimmune Disease-SS Study Group and who were followed for a mean of 117 months, mortality was 11%. Survival was 96% at 5 years, 90% at 10 years, 81% at 20 years, and 60% at 30 years (Ann Rheum Dis. 2016;75:348-55).
Baseline factors associated with increased mortality on multivariate analysis included male gender, cryoglobulins, and low complement levels; the strongest model for death included high activity in at least one ESSDAI domain, baseline ESSDAI of at least 14, more than one laboratory predictive marker such as lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4, and/or cryoglobulins.
Predicting progression to pSS
Progress has also been made with respect to predicting progression to pSS among patients who present with some related symptoms but don’t meet Sjögren’s criteria, Dr. James noted.
A 2017 study by Caroline Shiboski et al. looked at 771 patients from the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry who had previously had objective measures of salivary hypofunction, dry eyes, focal lymphocytic sialadenitis or anti-Ro/anti-La. When these patients were recalled 2-3 years after their baseline evaluation, 28 (9%) of 308 patients who did not meet pSS criteria at baseline had then progressed to pSS (Arthritis Care Res. 2017;70[2]:284-94).
Those with baseline hypergammaglobulinemia were four times more likely to progress, and those with baseline low complement levels were six times more likely to progress.
Many patients will present with symptoms, but won’t ever develop Sjögren’s, but the subset of patients with these baseline characteristics may be at greater risk, she said.
Autoantibodies and pathogenesis
Up to 90% of pSS patients will have one or more of anti-Ro, anti-La, or rheumatoid factor, and many will have a positive antinuclear antibody (ANA) level of at least 1:320, Dr. James said, adding that anti-Ro and anti-La are linked with earlier disease onset, increased disease severity, longer disease duration, and extraglandular involvement.
Ro52, a target of Sjögren’s autoantibodies, may also confer more severe disease, and autoantibodies to muscarinic acetylcholine receptors appear to contribute to pathogenesis in Sjögren’s patients “above and beyond what we see with lymphocytic infiltrates and other things that are happening in the salivary gland,” she said.
Other exciting progress with respect to disease pathogenesis includes an increased focus on genetics and genetic predisposition beyond human leukocyte antigen associations.
Mutations in genes that overlap with Sjögren’s and lupus or Sjögren’s and RA, such as IRF5, Blk, and STAT4 appear to contribute to Sjögren’s syndrome development.
“And then there’s also some new genetics looking at Sjögren’s-specific genes, and these may help us as we think about new targetable pathways in this disorder,” she said.
Genomics and gene-environment interactions, such as interactions with viral infections or “other things that lead to molecular mimicry that get the disease process started,” are also getting increased attention; gene-expression profiling has shown overlap between Sjögren’s and lupus (shared genetics, autoantibodies, and similarly strong interferon signatures, for example), which isn’t surprising.
“But we’re also seeing NF-kB [NF-kappa B] activation, antigen presentation, and migration pathways that are being found in Sjögren’s that aren’t necessarily the ones that we see in lupus,” she added.
Clinical practice guidelines
A number of practice guidelines addressing various symptoms and issues associated with pSS have been released in the last few years, including several from EULAR, the United States, Brazil, and the United Kingdom, are summarized and reviewed in a recent paper by Vasco Romão et al. (RMD Open. 2018;4:e000789. doi: 10.1136/rmdopen-2018-000789).
The British Society of Rheumatology guideline, which came out about a year ago, has particularly practical guidance on the management of dryness and systemic disease, she said (Rheumatology. 2017;56[10]:1643-7).
The increasing focus on pSS research has important implications both for trial design and patient care, especially in light of the new classification criteria, practice guidelines, and educational resources provided by organizations such as the Sjögren’s Syndrome Foundation (including videos, health care provider information, and downloadable brochures and resource sheets) and the European Research Network’s ReCONNET Disease Info Toolbox for Sjögren’s, Dr. James concluded.
Dr. James reported having no disclosures.
Recent findings, new classification criteria and treatment guidelines, and concerted efforts by various organizations to provide educational resources are among a number of factors improving the outlook for patients with primary Sjögren’s syndrome, according to Judith James, MD, PhD.
Additionally, the number of studies of primary Sjögren’s syndrome (pSS) is increasing, albeit slowly, and ongoing studies of biologics are showing promise, Dr. James said during a clinical update at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Classification criteria
The ACR in conjunction with the European League Against Rheumatism (EULAR) published new criteria for pSS classification in 2016 based on the available evidence and expert consensus. Inclusion criteria include daily, persistent, troublesome dry eyes for more than 3 months, recurrent sensation of sand or gravel in the eyes, use of tear substitutes more than three times each day, frequent drinking of liquids to aid in swallowing dry food, or at least one EULAR Sjögren’s syndrome disease activity index (ESSDAI) domain with a positive item. Exclusion criteria include prior head and neck radiation treatment, polymerase chain reaction–confirmed active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, or IgG4-related disease, said Dr. James, professor and chair of the arthritis and clinical immunology research program at the University of Oklahoma, Oklahoma City (Arthritis Rheumatol. Jan 2017;69[1]:35-45).
- A score of 4 or higher in patients who meet the inclusion criteria and do not have any of the exclusion criteria leads to classification with pSS, based on the following findings:
- Labial salivary gland with focal lymphocytic sialadenitis and focus score of at least 1 foci/4 mm2 (weight/score = 3).
- Anti-SSA/Ro-positivity (weight/score = 3).
- Ocular Staining Score of at least 5, or van Bijsterveld score of at least 4, in at least one eye (weight/score = 1).
- Schirmer’s test of no more than 5 mm/5 min in at least one eye (weight/score = 1).
- Unstimulated whole saliva flow rate of no more than 0.1 mL/min (weight/score = 1).
Clinical pearls for detection and management
In Dr. James’ experience, the three symptoms (taken together) with the highest predictive value for diagnosing pSS are dry mouth, sore mouth/tongue, and dry eyes. About 25% of Sjögren’s patients may have no detectable salivary flow, she said.
Dry, cracked skin that can lead to secondary infections is another common issue affecting about 55% of patients.
“So we always have to talk to our Sjögren’s patients about skin,” she said. “We also have recurrent sinusitis, chronic cough, dyspepsia, constipation, and other symptoms.”
Concurrent autoimmune diseases are another concern in Sjögren’s patients, she said. One to particularly keep in mind, in addition to lupus and rheumatoid arthritis, is autoimmune thyroid disease.
Data suggest that up to 45% of Sjögren’s patients have thyroid dysfunction, and if you look at just those with autoimmune thyroiditis, their risk of Sjögren’s is increased 10-fold vs. those without autoimmune thyroiditis, she said.
Other conditions to keep in mind when it comes to diagnosing and managing patients, as has been shown in numerous studies over the years, include Raynaud’s phenomenon, which affects at least 13% of patients, and subclinical muscle inflammation, which affects more than 50% of patients, Dr. James said.
“Depression ... as well as anxiety, is quite common in Sjögren’s patients, and fatigue is profound,” she added, noting that fatigue is “the No. 1 issue” for many patients.
Another area of particular concern in Sjögren’s is the increased risk of lymphoma, she said.
Studies show varying rates of lymphoma in Sjögren’s, with one suggesting a 44-fold increased risk, but this is likely only among those at very high risk. Other studies suggest the increase is risk overall is in the range of 4- to 10-fold, she said.
Mortality in Sjögren’s patients
A 2015 study by Soledad Retamozo et al. showed that the presence of cryoglobulinemic vasculitis (CV) at diagnosis is associated with increased mortality risk.
Of 515 consecutive pSS patients with a mean follow-up of 110 months, 65 (12%) had cryoglobulins detected, and 21 of those (32%) fulfilled CV criteria. The patients with cryoglobulins had higher cumulative mean disease activity, 45 (9%) developed B-cell lymphoma, and 33 (6%) died (Arthritis Rheumatol. 2015;67[suppl 10]. Abstract 628).
Additionally, both CV-positive and CV-negative patients had higher risk of B-cell lymphoma, but the risk was greatest in the CV-positive group (hazard ratios, 7.47 and 2.56, respectively), and the CV-positive patients had a higher risk of death (HR, 11.68).
“This actually has changed practice in our Sjögren’s clinic because we didn’t used to do cryos on everybody unless they had leukocytoclastic vasculitis, because they also have a higher risk of death,” Dr. James said.
Systemic activity also predicts pSS mortality, according to findings published in 2016 by Pilar Brito-Zerón et al. Of 1,045 patients who were part of the Spanish Group of Autoimmune Disease-SS Study Group and who were followed for a mean of 117 months, mortality was 11%. Survival was 96% at 5 years, 90% at 10 years, 81% at 20 years, and 60% at 30 years (Ann Rheum Dis. 2016;75:348-55).
Baseline factors associated with increased mortality on multivariate analysis included male gender, cryoglobulins, and low complement levels; the strongest model for death included high activity in at least one ESSDAI domain, baseline ESSDAI of at least 14, more than one laboratory predictive marker such as lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4, and/or cryoglobulins.
Predicting progression to pSS
Progress has also been made with respect to predicting progression to pSS among patients who present with some related symptoms but don’t meet Sjögren’s criteria, Dr. James noted.
A 2017 study by Caroline Shiboski et al. looked at 771 patients from the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry who had previously had objective measures of salivary hypofunction, dry eyes, focal lymphocytic sialadenitis or anti-Ro/anti-La. When these patients were recalled 2-3 years after their baseline evaluation, 28 (9%) of 308 patients who did not meet pSS criteria at baseline had then progressed to pSS (Arthritis Care Res. 2017;70[2]:284-94).
Those with baseline hypergammaglobulinemia were four times more likely to progress, and those with baseline low complement levels were six times more likely to progress.
Many patients will present with symptoms, but won’t ever develop Sjögren’s, but the subset of patients with these baseline characteristics may be at greater risk, she said.
Autoantibodies and pathogenesis
Up to 90% of pSS patients will have one or more of anti-Ro, anti-La, or rheumatoid factor, and many will have a positive antinuclear antibody (ANA) level of at least 1:320, Dr. James said, adding that anti-Ro and anti-La are linked with earlier disease onset, increased disease severity, longer disease duration, and extraglandular involvement.
Ro52, a target of Sjögren’s autoantibodies, may also confer more severe disease, and autoantibodies to muscarinic acetylcholine receptors appear to contribute to pathogenesis in Sjögren’s patients “above and beyond what we see with lymphocytic infiltrates and other things that are happening in the salivary gland,” she said.
Other exciting progress with respect to disease pathogenesis includes an increased focus on genetics and genetic predisposition beyond human leukocyte antigen associations.
Mutations in genes that overlap with Sjögren’s and lupus or Sjögren’s and RA, such as IRF5, Blk, and STAT4 appear to contribute to Sjögren’s syndrome development.
“And then there’s also some new genetics looking at Sjögren’s-specific genes, and these may help us as we think about new targetable pathways in this disorder,” she said.
Genomics and gene-environment interactions, such as interactions with viral infections or “other things that lead to molecular mimicry that get the disease process started,” are also getting increased attention; gene-expression profiling has shown overlap between Sjögren’s and lupus (shared genetics, autoantibodies, and similarly strong interferon signatures, for example), which isn’t surprising.
“But we’re also seeing NF-kB [NF-kappa B] activation, antigen presentation, and migration pathways that are being found in Sjögren’s that aren’t necessarily the ones that we see in lupus,” she added.
Clinical practice guidelines
A number of practice guidelines addressing various symptoms and issues associated with pSS have been released in the last few years, including several from EULAR, the United States, Brazil, and the United Kingdom, are summarized and reviewed in a recent paper by Vasco Romão et al. (RMD Open. 2018;4:e000789. doi: 10.1136/rmdopen-2018-000789).
The British Society of Rheumatology guideline, which came out about a year ago, has particularly practical guidance on the management of dryness and systemic disease, she said (Rheumatology. 2017;56[10]:1643-7).
The increasing focus on pSS research has important implications both for trial design and patient care, especially in light of the new classification criteria, practice guidelines, and educational resources provided by organizations such as the Sjögren’s Syndrome Foundation (including videos, health care provider information, and downloadable brochures and resource sheets) and the European Research Network’s ReCONNET Disease Info Toolbox for Sjögren’s, Dr. James concluded.
Dr. James reported having no disclosures.
Recent findings, new classification criteria and treatment guidelines, and concerted efforts by various organizations to provide educational resources are among a number of factors improving the outlook for patients with primary Sjögren’s syndrome, according to Judith James, MD, PhD.
Additionally, the number of studies of primary Sjögren’s syndrome (pSS) is increasing, albeit slowly, and ongoing studies of biologics are showing promise, Dr. James said during a clinical update at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Classification criteria
The ACR in conjunction with the European League Against Rheumatism (EULAR) published new criteria for pSS classification in 2016 based on the available evidence and expert consensus. Inclusion criteria include daily, persistent, troublesome dry eyes for more than 3 months, recurrent sensation of sand or gravel in the eyes, use of tear substitutes more than three times each day, frequent drinking of liquids to aid in swallowing dry food, or at least one EULAR Sjögren’s syndrome disease activity index (ESSDAI) domain with a positive item. Exclusion criteria include prior head and neck radiation treatment, polymerase chain reaction–confirmed active hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, or IgG4-related disease, said Dr. James, professor and chair of the arthritis and clinical immunology research program at the University of Oklahoma, Oklahoma City (Arthritis Rheumatol. Jan 2017;69[1]:35-45).
- A score of 4 or higher in patients who meet the inclusion criteria and do not have any of the exclusion criteria leads to classification with pSS, based on the following findings:
- Labial salivary gland with focal lymphocytic sialadenitis and focus score of at least 1 foci/4 mm2 (weight/score = 3).
- Anti-SSA/Ro-positivity (weight/score = 3).
- Ocular Staining Score of at least 5, or van Bijsterveld score of at least 4, in at least one eye (weight/score = 1).
- Schirmer’s test of no more than 5 mm/5 min in at least one eye (weight/score = 1).
- Unstimulated whole saliva flow rate of no more than 0.1 mL/min (weight/score = 1).
Clinical pearls for detection and management
In Dr. James’ experience, the three symptoms (taken together) with the highest predictive value for diagnosing pSS are dry mouth, sore mouth/tongue, and dry eyes. About 25% of Sjögren’s patients may have no detectable salivary flow, she said.
Dry, cracked skin that can lead to secondary infections is another common issue affecting about 55% of patients.
“So we always have to talk to our Sjögren’s patients about skin,” she said. “We also have recurrent sinusitis, chronic cough, dyspepsia, constipation, and other symptoms.”
Concurrent autoimmune diseases are another concern in Sjögren’s patients, she said. One to particularly keep in mind, in addition to lupus and rheumatoid arthritis, is autoimmune thyroid disease.
Data suggest that up to 45% of Sjögren’s patients have thyroid dysfunction, and if you look at just those with autoimmune thyroiditis, their risk of Sjögren’s is increased 10-fold vs. those without autoimmune thyroiditis, she said.
Other conditions to keep in mind when it comes to diagnosing and managing patients, as has been shown in numerous studies over the years, include Raynaud’s phenomenon, which affects at least 13% of patients, and subclinical muscle inflammation, which affects more than 50% of patients, Dr. James said.
“Depression ... as well as anxiety, is quite common in Sjögren’s patients, and fatigue is profound,” she added, noting that fatigue is “the No. 1 issue” for many patients.
Another area of particular concern in Sjögren’s is the increased risk of lymphoma, she said.
Studies show varying rates of lymphoma in Sjögren’s, with one suggesting a 44-fold increased risk, but this is likely only among those at very high risk. Other studies suggest the increase is risk overall is in the range of 4- to 10-fold, she said.
Mortality in Sjögren’s patients
A 2015 study by Soledad Retamozo et al. showed that the presence of cryoglobulinemic vasculitis (CV) at diagnosis is associated with increased mortality risk.
Of 515 consecutive pSS patients with a mean follow-up of 110 months, 65 (12%) had cryoglobulins detected, and 21 of those (32%) fulfilled CV criteria. The patients with cryoglobulins had higher cumulative mean disease activity, 45 (9%) developed B-cell lymphoma, and 33 (6%) died (Arthritis Rheumatol. 2015;67[suppl 10]. Abstract 628).
Additionally, both CV-positive and CV-negative patients had higher risk of B-cell lymphoma, but the risk was greatest in the CV-positive group (hazard ratios, 7.47 and 2.56, respectively), and the CV-positive patients had a higher risk of death (HR, 11.68).
“This actually has changed practice in our Sjögren’s clinic because we didn’t used to do cryos on everybody unless they had leukocytoclastic vasculitis, because they also have a higher risk of death,” Dr. James said.
Systemic activity also predicts pSS mortality, according to findings published in 2016 by Pilar Brito-Zerón et al. Of 1,045 patients who were part of the Spanish Group of Autoimmune Disease-SS Study Group and who were followed for a mean of 117 months, mortality was 11%. Survival was 96% at 5 years, 90% at 10 years, 81% at 20 years, and 60% at 30 years (Ann Rheum Dis. 2016;75:348-55).
Baseline factors associated with increased mortality on multivariate analysis included male gender, cryoglobulins, and low complement levels; the strongest model for death included high activity in at least one ESSDAI domain, baseline ESSDAI of at least 14, more than one laboratory predictive marker such as lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4, and/or cryoglobulins.
Predicting progression to pSS
Progress has also been made with respect to predicting progression to pSS among patients who present with some related symptoms but don’t meet Sjögren’s criteria, Dr. James noted.
A 2017 study by Caroline Shiboski et al. looked at 771 patients from the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry who had previously had objective measures of salivary hypofunction, dry eyes, focal lymphocytic sialadenitis or anti-Ro/anti-La. When these patients were recalled 2-3 years after their baseline evaluation, 28 (9%) of 308 patients who did not meet pSS criteria at baseline had then progressed to pSS (Arthritis Care Res. 2017;70[2]:284-94).
Those with baseline hypergammaglobulinemia were four times more likely to progress, and those with baseline low complement levels were six times more likely to progress.
Many patients will present with symptoms, but won’t ever develop Sjögren’s, but the subset of patients with these baseline characteristics may be at greater risk, she said.
Autoantibodies and pathogenesis
Up to 90% of pSS patients will have one or more of anti-Ro, anti-La, or rheumatoid factor, and many will have a positive antinuclear antibody (ANA) level of at least 1:320, Dr. James said, adding that anti-Ro and anti-La are linked with earlier disease onset, increased disease severity, longer disease duration, and extraglandular involvement.
Ro52, a target of Sjögren’s autoantibodies, may also confer more severe disease, and autoantibodies to muscarinic acetylcholine receptors appear to contribute to pathogenesis in Sjögren’s patients “above and beyond what we see with lymphocytic infiltrates and other things that are happening in the salivary gland,” she said.
Other exciting progress with respect to disease pathogenesis includes an increased focus on genetics and genetic predisposition beyond human leukocyte antigen associations.
Mutations in genes that overlap with Sjögren’s and lupus or Sjögren’s and RA, such as IRF5, Blk, and STAT4 appear to contribute to Sjögren’s syndrome development.
“And then there’s also some new genetics looking at Sjögren’s-specific genes, and these may help us as we think about new targetable pathways in this disorder,” she said.
Genomics and gene-environment interactions, such as interactions with viral infections or “other things that lead to molecular mimicry that get the disease process started,” are also getting increased attention; gene-expression profiling has shown overlap between Sjögren’s and lupus (shared genetics, autoantibodies, and similarly strong interferon signatures, for example), which isn’t surprising.
“But we’re also seeing NF-kB [NF-kappa B] activation, antigen presentation, and migration pathways that are being found in Sjögren’s that aren’t necessarily the ones that we see in lupus,” she added.
Clinical practice guidelines
A number of practice guidelines addressing various symptoms and issues associated with pSS have been released in the last few years, including several from EULAR, the United States, Brazil, and the United Kingdom, are summarized and reviewed in a recent paper by Vasco Romão et al. (RMD Open. 2018;4:e000789. doi: 10.1136/rmdopen-2018-000789).
The British Society of Rheumatology guideline, which came out about a year ago, has particularly practical guidance on the management of dryness and systemic disease, she said (Rheumatology. 2017;56[10]:1643-7).
The increasing focus on pSS research has important implications both for trial design and patient care, especially in light of the new classification criteria, practice guidelines, and educational resources provided by organizations such as the Sjögren’s Syndrome Foundation (including videos, health care provider information, and downloadable brochures and resource sheets) and the European Research Network’s ReCONNET Disease Info Toolbox for Sjögren’s, Dr. James concluded.
Dr. James reported having no disclosures.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Precision medicine in rheumatology: Enormous opportunity exists
Advances in precision medicine present enormous opportunity for rheumatology, but optimizing its benefits requires more input from the specialty and a sharper focus on related training for rheumatologists, according to Judith A. James, MD, PhD.
Precision medicine is getting a great deal of attention and is an exciting area, but it is already widely used in the field; think treat-to-target in rheumatoid arthritis, autoantibody testing for patient stratification across various conditions, and individual monitoring and dose escalation to achieve optimal uric acid levels in gout patients, Dr. James, professor of medicine and associate vice provost of clinical and translational science at the University of Oklahoma, Oklahoma City, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We have historically ... actually had the highest number of FDA approved biomarker tests in rheumatology compared to all other specialties until this last couple of years where we’re starting to see this explosion of genetic testing in oncology – and we’ve been doing genetic testing,” she said.
However, there is a great deal more work to be done.
“We still have a long way to go to go to get the right drug at the right dose at the right time in the right patient in order to optimize outcomes in all of these diseases that we are responsible for as rheumatologists,” she said.
The fields of oncology and hematology have been intensely focused on precision medicine – the development of unique therapies based on specific genetic abnormalities in an individual’s tumor – and this focus is apparent in practice patterns: A recent survey of 132 medical oncologists and hematologists/oncologists showed that nearly 90% had ordered DNA sequencing, about 65% do so monthly, and 25% do so weekly.
“Those numbers are just going to continue to climb, and I think will see this in other disciplines as well,” she said.
The possibilities for improved outcomes in rheumatologic conditions using tailored treatments based on individual characteristics are practically limitless, she said, noting the heterogeneity of many rheumatologic conditions.
This is particularly true for systemic lupus erythematosus (SLE) patients, she said.
Identifying patient subsets based on organ involvement, demographics, and biomarkers, for example, could lead to personalized treatments with different doses, routes of administration, and concurrent medications, she explained.
Genetics in SLE
Dr. James highlighted the role of genetics and the value of precision medicine in the SLE setting in a large transancestral association study published in 2017. The investigators analyzed Immunochip genotype data from 27,574 SLE cases and controls and identified 58 distinct non–human leukocyte antigen (HLA) regions in Americans with European ancestry, 9 in those with African ancestry, and 16 in those with Hispanic ancestry. The investigators found that these non-HLA regions included 24 novel to SLE, and in their analysis the researchers were able to refine association signals in previously established regions, extend associations to additional ancestries, and reveal a complex multigenic effect just outside of the HLA region (Nature Commun. 2017;8:16021).
The findings led to a “cumulative hit hypothesis” for autoimmune disease, and help to clarify genetic architecture and ethnic disparities in SLE, they concluded.
“So we now have over a hundred genetic regions that have been associated with lupus, compared to healthy controls,” Dr. James said.
A frustration with genetic data such as these, however, is the challenge of “getting it into the clinic,” she noted.
“I think that looking at individual [single nuclear polymorphisms] is probably not what we’re going to be doing, but we’re seeing a lot of interest in the idea of genetic load,” she said, explaining that it may soon be possible to use genetic load information to evaluate patient risk.
A recent study at her institution looked at lupus risk from another angle: She and her colleagues recontacted family members from Oklahoma Lupus Genetics studies to look more closely at which blood relatives of SLE patients transitioned to SLE, and what factors were associated with that transition when compared with relatives who remained unaffected (Arthritis Rheumatol. 2017;69[3]:630-42).
Among the findings was a higher risk of transitioning among family members with both a positive antinuclear antibody test and a baseline Connective Tissue Disease Screening Questionnaire score indicative of connective tissue disease.
“We also found, of course, biomarkers, or blood markers, that helped us identify the individuals who were at the highest risk of transitioning, so we think a blood test might really be helpful,” she said.
That study also suggested that there may be ways to intervene in SLE patients’ relatives at increased risk for also developing lupus. For example, those who transitioned had increased levels of soluble tumor necrosis factor receptors and the interferon-driven chemokine MCP-3; a prevention trial is now underway, she noted.
Beyond genetics
Genetics are just one piece of the precision medicine puzzle, and other areas of investigation that may help to divide patients into subgroups for more precise treatment include genomics, soluble mediators, and immunophenotyping, Dr. James said.
“It may be that we need different pieces of all of these things to help guide our treatment in lupus patients,” she said.
Longitudinal clinical and blood transcriptional profiling of patients in the Dallas Pediatric SLE cohort, for example, identified a molecular classification system for SLE patients. The analysis of 972 samples from 158 SLE patients and 48 healthy controls, which were collected for up to 4 years, showed that an interferon response signature was present in 784 of the samples.
The investigators found that a plasmablast signature, which is found more in African-American patients than in other populations, best correlates with disease activity and that a neutrophil-related signature is associated with progression to active lupus nephritis (Cell. 2016;165[3]:551-65).
“This is something that will potentially be helpful [in the clinic], and we need to test this in the adult population,” Dr. James said.
The investigators also were able to stratify patients, based on individual immunoprofiling, into seven major groups based on molecular correlates. They concluded that such stratification could help improve the outcomes of clinical trials in SLE.
In another study, researchers looked at longitudinal gene expression in SLE patients by stratifying each of two independent sets of patients (a pediatric cohort and an adult cohort) into three clinically differentiated disease clusters defined by mechanisms of disease progression (Arthritis Rheumatol. Dec 2018;70[12]:2025-35).
The clusters included one showing a correlation between the percentage of neutrophils and disease activity progression, one showing a correlation between the percentage of lymphocytes and disease activity progression, and a third for which the percentage of neutrophils correlated to a lesser degree with disease activity but was functionally more heterogeneous. Patients in the two neutrophil‐driven clusters had an increased risk of developing proliferative nephritis.
The results have implications for treatment, trial design, and understanding of disease etiology, the investigators concluded.
“This may help us in the future as we think about which medicine to start patients on, and which medicines to start patients on first,” Dr. James said.
It is clear that precision medicine will play an increasingly important role in rheumatology, Dr. James said, when considering the context of other findings in recent years, such as those from studies looking at soluble mediators of inflammation associated with disease flare, as well as those that involved extensive immunophenotyping and showed widely divergent transcriptional patterns based on ancestral backgrounds. Other research, such as the BOLD (Biomarkers of Lupus Disease) study, looked at various mechanisms of disease flare.
Numerous types of personalized therapies are being considered in rheumatology, ranging from expanded regulatory T cells to chimeric antigen receptor T cell therapy to risk profiling for disease prevention, just to name a few. Going forward it will be important to perform more systems biology analyses to assemble precision medicine–related data that can inform clinical diagnosis, prognosis, and therapy selection and optimization, she said.
The future of personalized therapies in rheumatology will require more input from rheumatologists on large-scale precision medicine projects such as the National Institutes of Health’s All of Us Research Project and the Million Veteran Program, as well as other similar programs of major health systems, she noted, adding that different types of training and interaction with molecular pathologists, genetic counselors, health coaches, and other key players also are needed.
Dr. James reported having no relevant disclosures.
Advances in precision medicine present enormous opportunity for rheumatology, but optimizing its benefits requires more input from the specialty and a sharper focus on related training for rheumatologists, according to Judith A. James, MD, PhD.
Precision medicine is getting a great deal of attention and is an exciting area, but it is already widely used in the field; think treat-to-target in rheumatoid arthritis, autoantibody testing for patient stratification across various conditions, and individual monitoring and dose escalation to achieve optimal uric acid levels in gout patients, Dr. James, professor of medicine and associate vice provost of clinical and translational science at the University of Oklahoma, Oklahoma City, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We have historically ... actually had the highest number of FDA approved biomarker tests in rheumatology compared to all other specialties until this last couple of years where we’re starting to see this explosion of genetic testing in oncology – and we’ve been doing genetic testing,” she said.
However, there is a great deal more work to be done.
“We still have a long way to go to go to get the right drug at the right dose at the right time in the right patient in order to optimize outcomes in all of these diseases that we are responsible for as rheumatologists,” she said.
The fields of oncology and hematology have been intensely focused on precision medicine – the development of unique therapies based on specific genetic abnormalities in an individual’s tumor – and this focus is apparent in practice patterns: A recent survey of 132 medical oncologists and hematologists/oncologists showed that nearly 90% had ordered DNA sequencing, about 65% do so monthly, and 25% do so weekly.
“Those numbers are just going to continue to climb, and I think will see this in other disciplines as well,” she said.
The possibilities for improved outcomes in rheumatologic conditions using tailored treatments based on individual characteristics are practically limitless, she said, noting the heterogeneity of many rheumatologic conditions.
This is particularly true for systemic lupus erythematosus (SLE) patients, she said.
Identifying patient subsets based on organ involvement, demographics, and biomarkers, for example, could lead to personalized treatments with different doses, routes of administration, and concurrent medications, she explained.
Genetics in SLE
Dr. James highlighted the role of genetics and the value of precision medicine in the SLE setting in a large transancestral association study published in 2017. The investigators analyzed Immunochip genotype data from 27,574 SLE cases and controls and identified 58 distinct non–human leukocyte antigen (HLA) regions in Americans with European ancestry, 9 in those with African ancestry, and 16 in those with Hispanic ancestry. The investigators found that these non-HLA regions included 24 novel to SLE, and in their analysis the researchers were able to refine association signals in previously established regions, extend associations to additional ancestries, and reveal a complex multigenic effect just outside of the HLA region (Nature Commun. 2017;8:16021).
The findings led to a “cumulative hit hypothesis” for autoimmune disease, and help to clarify genetic architecture and ethnic disparities in SLE, they concluded.
“So we now have over a hundred genetic regions that have been associated with lupus, compared to healthy controls,” Dr. James said.
A frustration with genetic data such as these, however, is the challenge of “getting it into the clinic,” she noted.
“I think that looking at individual [single nuclear polymorphisms] is probably not what we’re going to be doing, but we’re seeing a lot of interest in the idea of genetic load,” she said, explaining that it may soon be possible to use genetic load information to evaluate patient risk.
A recent study at her institution looked at lupus risk from another angle: She and her colleagues recontacted family members from Oklahoma Lupus Genetics studies to look more closely at which blood relatives of SLE patients transitioned to SLE, and what factors were associated with that transition when compared with relatives who remained unaffected (Arthritis Rheumatol. 2017;69[3]:630-42).
Among the findings was a higher risk of transitioning among family members with both a positive antinuclear antibody test and a baseline Connective Tissue Disease Screening Questionnaire score indicative of connective tissue disease.
“We also found, of course, biomarkers, or blood markers, that helped us identify the individuals who were at the highest risk of transitioning, so we think a blood test might really be helpful,” she said.
That study also suggested that there may be ways to intervene in SLE patients’ relatives at increased risk for also developing lupus. For example, those who transitioned had increased levels of soluble tumor necrosis factor receptors and the interferon-driven chemokine MCP-3; a prevention trial is now underway, she noted.
Beyond genetics
Genetics are just one piece of the precision medicine puzzle, and other areas of investigation that may help to divide patients into subgroups for more precise treatment include genomics, soluble mediators, and immunophenotyping, Dr. James said.
“It may be that we need different pieces of all of these things to help guide our treatment in lupus patients,” she said.
Longitudinal clinical and blood transcriptional profiling of patients in the Dallas Pediatric SLE cohort, for example, identified a molecular classification system for SLE patients. The analysis of 972 samples from 158 SLE patients and 48 healthy controls, which were collected for up to 4 years, showed that an interferon response signature was present in 784 of the samples.
The investigators found that a plasmablast signature, which is found more in African-American patients than in other populations, best correlates with disease activity and that a neutrophil-related signature is associated with progression to active lupus nephritis (Cell. 2016;165[3]:551-65).
“This is something that will potentially be helpful [in the clinic], and we need to test this in the adult population,” Dr. James said.
The investigators also were able to stratify patients, based on individual immunoprofiling, into seven major groups based on molecular correlates. They concluded that such stratification could help improve the outcomes of clinical trials in SLE.
In another study, researchers looked at longitudinal gene expression in SLE patients by stratifying each of two independent sets of patients (a pediatric cohort and an adult cohort) into three clinically differentiated disease clusters defined by mechanisms of disease progression (Arthritis Rheumatol. Dec 2018;70[12]:2025-35).
The clusters included one showing a correlation between the percentage of neutrophils and disease activity progression, one showing a correlation between the percentage of lymphocytes and disease activity progression, and a third for which the percentage of neutrophils correlated to a lesser degree with disease activity but was functionally more heterogeneous. Patients in the two neutrophil‐driven clusters had an increased risk of developing proliferative nephritis.
The results have implications for treatment, trial design, and understanding of disease etiology, the investigators concluded.
“This may help us in the future as we think about which medicine to start patients on, and which medicines to start patients on first,” Dr. James said.
It is clear that precision medicine will play an increasingly important role in rheumatology, Dr. James said, when considering the context of other findings in recent years, such as those from studies looking at soluble mediators of inflammation associated with disease flare, as well as those that involved extensive immunophenotyping and showed widely divergent transcriptional patterns based on ancestral backgrounds. Other research, such as the BOLD (Biomarkers of Lupus Disease) study, looked at various mechanisms of disease flare.
Numerous types of personalized therapies are being considered in rheumatology, ranging from expanded regulatory T cells to chimeric antigen receptor T cell therapy to risk profiling for disease prevention, just to name a few. Going forward it will be important to perform more systems biology analyses to assemble precision medicine–related data that can inform clinical diagnosis, prognosis, and therapy selection and optimization, she said.
The future of personalized therapies in rheumatology will require more input from rheumatologists on large-scale precision medicine projects such as the National Institutes of Health’s All of Us Research Project and the Million Veteran Program, as well as other similar programs of major health systems, she noted, adding that different types of training and interaction with molecular pathologists, genetic counselors, health coaches, and other key players also are needed.
Dr. James reported having no relevant disclosures.
Advances in precision medicine present enormous opportunity for rheumatology, but optimizing its benefits requires more input from the specialty and a sharper focus on related training for rheumatologists, according to Judith A. James, MD, PhD.
Precision medicine is getting a great deal of attention and is an exciting area, but it is already widely used in the field; think treat-to-target in rheumatoid arthritis, autoantibody testing for patient stratification across various conditions, and individual monitoring and dose escalation to achieve optimal uric acid levels in gout patients, Dr. James, professor of medicine and associate vice provost of clinical and translational science at the University of Oklahoma, Oklahoma City, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
“We have historically ... actually had the highest number of FDA approved biomarker tests in rheumatology compared to all other specialties until this last couple of years where we’re starting to see this explosion of genetic testing in oncology – and we’ve been doing genetic testing,” she said.
However, there is a great deal more work to be done.
“We still have a long way to go to go to get the right drug at the right dose at the right time in the right patient in order to optimize outcomes in all of these diseases that we are responsible for as rheumatologists,” she said.
The fields of oncology and hematology have been intensely focused on precision medicine – the development of unique therapies based on specific genetic abnormalities in an individual’s tumor – and this focus is apparent in practice patterns: A recent survey of 132 medical oncologists and hematologists/oncologists showed that nearly 90% had ordered DNA sequencing, about 65% do so monthly, and 25% do so weekly.
“Those numbers are just going to continue to climb, and I think will see this in other disciplines as well,” she said.
The possibilities for improved outcomes in rheumatologic conditions using tailored treatments based on individual characteristics are practically limitless, she said, noting the heterogeneity of many rheumatologic conditions.
This is particularly true for systemic lupus erythematosus (SLE) patients, she said.
Identifying patient subsets based on organ involvement, demographics, and biomarkers, for example, could lead to personalized treatments with different doses, routes of administration, and concurrent medications, she explained.
Genetics in SLE
Dr. James highlighted the role of genetics and the value of precision medicine in the SLE setting in a large transancestral association study published in 2017. The investigators analyzed Immunochip genotype data from 27,574 SLE cases and controls and identified 58 distinct non–human leukocyte antigen (HLA) regions in Americans with European ancestry, 9 in those with African ancestry, and 16 in those with Hispanic ancestry. The investigators found that these non-HLA regions included 24 novel to SLE, and in their analysis the researchers were able to refine association signals in previously established regions, extend associations to additional ancestries, and reveal a complex multigenic effect just outside of the HLA region (Nature Commun. 2017;8:16021).
The findings led to a “cumulative hit hypothesis” for autoimmune disease, and help to clarify genetic architecture and ethnic disparities in SLE, they concluded.
“So we now have over a hundred genetic regions that have been associated with lupus, compared to healthy controls,” Dr. James said.
A frustration with genetic data such as these, however, is the challenge of “getting it into the clinic,” she noted.
“I think that looking at individual [single nuclear polymorphisms] is probably not what we’re going to be doing, but we’re seeing a lot of interest in the idea of genetic load,” she said, explaining that it may soon be possible to use genetic load information to evaluate patient risk.
A recent study at her institution looked at lupus risk from another angle: She and her colleagues recontacted family members from Oklahoma Lupus Genetics studies to look more closely at which blood relatives of SLE patients transitioned to SLE, and what factors were associated with that transition when compared with relatives who remained unaffected (Arthritis Rheumatol. 2017;69[3]:630-42).
Among the findings was a higher risk of transitioning among family members with both a positive antinuclear antibody test and a baseline Connective Tissue Disease Screening Questionnaire score indicative of connective tissue disease.
“We also found, of course, biomarkers, or blood markers, that helped us identify the individuals who were at the highest risk of transitioning, so we think a blood test might really be helpful,” she said.
That study also suggested that there may be ways to intervene in SLE patients’ relatives at increased risk for also developing lupus. For example, those who transitioned had increased levels of soluble tumor necrosis factor receptors and the interferon-driven chemokine MCP-3; a prevention trial is now underway, she noted.
Beyond genetics
Genetics are just one piece of the precision medicine puzzle, and other areas of investigation that may help to divide patients into subgroups for more precise treatment include genomics, soluble mediators, and immunophenotyping, Dr. James said.
“It may be that we need different pieces of all of these things to help guide our treatment in lupus patients,” she said.
Longitudinal clinical and blood transcriptional profiling of patients in the Dallas Pediatric SLE cohort, for example, identified a molecular classification system for SLE patients. The analysis of 972 samples from 158 SLE patients and 48 healthy controls, which were collected for up to 4 years, showed that an interferon response signature was present in 784 of the samples.
The investigators found that a plasmablast signature, which is found more in African-American patients than in other populations, best correlates with disease activity and that a neutrophil-related signature is associated with progression to active lupus nephritis (Cell. 2016;165[3]:551-65).
“This is something that will potentially be helpful [in the clinic], and we need to test this in the adult population,” Dr. James said.
The investigators also were able to stratify patients, based on individual immunoprofiling, into seven major groups based on molecular correlates. They concluded that such stratification could help improve the outcomes of clinical trials in SLE.
In another study, researchers looked at longitudinal gene expression in SLE patients by stratifying each of two independent sets of patients (a pediatric cohort and an adult cohort) into three clinically differentiated disease clusters defined by mechanisms of disease progression (Arthritis Rheumatol. Dec 2018;70[12]:2025-35).
The clusters included one showing a correlation between the percentage of neutrophils and disease activity progression, one showing a correlation between the percentage of lymphocytes and disease activity progression, and a third for which the percentage of neutrophils correlated to a lesser degree with disease activity but was functionally more heterogeneous. Patients in the two neutrophil‐driven clusters had an increased risk of developing proliferative nephritis.
The results have implications for treatment, trial design, and understanding of disease etiology, the investigators concluded.
“This may help us in the future as we think about which medicine to start patients on, and which medicines to start patients on first,” Dr. James said.
It is clear that precision medicine will play an increasingly important role in rheumatology, Dr. James said, when considering the context of other findings in recent years, such as those from studies looking at soluble mediators of inflammation associated with disease flare, as well as those that involved extensive immunophenotyping and showed widely divergent transcriptional patterns based on ancestral backgrounds. Other research, such as the BOLD (Biomarkers of Lupus Disease) study, looked at various mechanisms of disease flare.
Numerous types of personalized therapies are being considered in rheumatology, ranging from expanded regulatory T cells to chimeric antigen receptor T cell therapy to risk profiling for disease prevention, just to name a few. Going forward it will be important to perform more systems biology analyses to assemble precision medicine–related data that can inform clinical diagnosis, prognosis, and therapy selection and optimization, she said.
The future of personalized therapies in rheumatology will require more input from rheumatologists on large-scale precision medicine projects such as the National Institutes of Health’s All of Us Research Project and the Million Veteran Program, as well as other similar programs of major health systems, she noted, adding that different types of training and interaction with molecular pathologists, genetic counselors, health coaches, and other key players also are needed.
Dr. James reported having no relevant disclosures.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM
Four distinct IgG4-related disease groups described in study
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
IgG4-related disease can be grouped into four distinct clusters based on the distribution of organs involved, according to researchers who analyzed a large, multicenter cohort of patients with this heterogeneous, autoimmune-mediated condition.
The four groups also varied by age, race, sex, time to diagnosis, and concentration of serum IgG4, according to the investigators, led by Zachary S. Wallace, MD, of the division of rheumatology, allergy, and immunology at Massachusetts General Hospital and Harvard Medical School, both in Boston.
“These phenotypes may be used by clinicians to improve recognition of IgG4-related disease,” Dr. Wallace and his coauthors wrote in a report on the study that appears in the Annals of the Rheumatic Diseases.
First described in a Japanese population, IgG4-related disease has been subsequently seen in all racial and ethnic groups, according to the researchers. It is associated with organ failure and can affect nearly any organ or anatomic site, most notably the lungs, kidneys, lymph nodes, salivary glands, pancreatobiliary structures, and retroperitoneum.
In the present study, Dr. Wallace and his coinvestigators used a novel cluster analysis method, called latent class analysis, to categorize 765 cases of IgG4-related disease submitted by 52 investigators from 17 countries. The investigators included 493 of those cases in a primary study population, and the remaining 272 in a smaller cohort used to replicate the results.
In the larger, primary study cohort, about 65% of cases were male, 58% were non-Asian and 40% were white, and the mean age at diagnosis was 59.5 years. The replication cohort had similar characteristics, according to the investigators.
The clustering analysis revealed four distinct subgroups, characterized by pancreato-hepatobiliary, accounting for 31% of cases; retroperitoneal fibrosis and/or aortitis in 24%; disease generally limited to head and neck structures in 24%, and head and neck disease consistent with Mikulicz syndrome plus systemic involvement in 22%.
The highest IgG4 concentrations were seen in the group of patients with Mikulicz syndrome and systemic involvement, according to Dr. Wallace and his coauthors. The serum concentration was 1,170 mg/dL in that group, compared with 445 mg/dL in the group of patients with head and neck-limited disease, 316 mg/dL in the pancreato-hepatobiliary group, and just 178 mg/dL in the retroperitoneal fibrosis/aorta group.
Female and Asian patients were overrepresented in the group characterized by head and neck involvement, investigators also found. Moreover, that group had a significantly lower mean age at diagnosis than did the other groups.
Those variations suggested differences in genetic or environmental risk factors between clusters, according to the investigators.
“Given the similar distribution of subspecialists among investigators in this study practicing in Asian and non-Asian countries, the observed differences are unlikely to be the result of detection or selection biases,” they said in their report.
The findings of this study help to inform subsequent investigations intended to evaluate those factors in more detail, they said.
Dr. Wallace and his coauthors reported no conflicts of interest related to their work, which was previously presented at the American College of Rheumatology annual meeting.
SOURCE: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: The highest IgG4 concentrations (1,170 mg/dL) were seen in a group of patients with Mikulicz syndrome and systemic involvement. Females and Asian patients were overrepresented in a group characterized by head and neck involvement.
Study details: Two cross-sectional studies including a total of 765 cases of IgG4-related disease submitted by 52 investigators in 17 countries.
Disclosures: Authors reported no conflicts of interest.
Source: Wallace ZS et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214603.
Renal transplant improves survival in lupus nephritis patients
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
This research by Jorge et al is “strong” and has two key implications for clinical practice, said authors of an accompanying editorial in the Annals of Internal Medicine.
The first is that transplantation should be incorporated into the treatment plan for lupus nephritis patients and is particularly important before kidney failure onset, according to Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD.
“This will allow patients, families, and clinicians to devote sufficient resources to completing the transplant evaluation and searching for living donors, the preferred donor source to maximize patient and allograft survival,” they wrote.
Secondly, the evidence to date suggests wider implementation of preemptive kidney transplants would be warranted in patients with lupus nephritis, they said.
Currently, only about 9% of lupus nephritis patients with kidney failure related to lupus nephritis undergo preemptive transplants, versus 17% of patients undergoing kidney transplants for other reasons, according to the authors.
Recent studies, however, suggest preemptive transplants and early kidney transplants in lupus nephritis are indeed linked to improved patient and allograft survival, just as in other conditions, they added.
Taken together, the findings of those studies and the current study by Dr. Jorge and colleagues underscore the pronounced survival advantage attributable to kidney transplant in patients with kidney failure due to lupus nephritis, they concluded.
“It is essential that transplant be considered as promptly as possible for patients with lupus nephritis and that barriers to early transplant be surmounted,” they wrote.
The editorial was authored by Nitender Goyal, MD, Daniel E. Weiner, MD, MS, and Andrew S. Levey, MD, of Tufts Medical Center, Boston. Dr. Goyal and Dr. Levey reported no conflicts of interest. Dr. Weiner provided disclosures related to Keryx Biopharmaceuticals, Relypsa, Inc., Janssen Biopharmaceuticals, Akebia Therapeutics, and others.
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
, according to researchers who conducted a nationwide cohort study encompassing nearly all such patients treated in the United States over a 20-year period.
Transplant conferred a 70% reduction in overall death risk in these lupus nephritis end-stage renal disease (ESRD) patients, largely due to reduced deaths caused by infection and cardiovascular disease, according to the researchers, led by April Jorge, MD, and Zachary Wallace, MD, of Massachusetts General Hospital, Harvard Medical School, Boston.
Those findings suggest that patients with lupus nephritis ESRD should routinely be considered for renal transplant in a timely manner, the investigators wrote in Annals of Internal Medicine.
“Improved access to renal transplantation for this population may considerably improve outcomes,” they said.
The study was based on an analysis of 9,659 patients who had lupus nephritis ESRD between 1995 and 2014 and were waitlisted for renal transplant. The data came from the United States Renal Data System, which includes most ESRD patients treated in the country. Of those 9,659 patients, 5,738 (59%) underwent kidney transplant.
Mortality rates were 22.5 per 1,000 person-years for lupus nephritis ESRD patients who underwent transplant, and 56.3 per 1,000 person-years for those patients who did not receive transplant, the investigators found.
Renal transplant reduced risk of death by 70% in results of multivariate analysis (hazard ratio, 0.30; 95% CI, 0.27-0.33).
That lower risk of all-cause mortality was consistent across racial groups and for other characteristics, such as sex, age at ESRD onset, and Medicare enrollment status.
Risk of cardiovascular death was 74% lower with renal transplant (adjusted hazard ratio, 0.26; 95% CI, 0.23-0.30), and risk of death from infection was also markedly lower among those who underwent transplant (adjusted hazard ratio, 0.41; 95% CI, 0.32-0.52), investigators found in a cause-specific mortality analysis.
While transplant has been associated with improved survival in patients with ESRD from all causes, there are “unique concerns” regarding the potential for infections or other post-transplant complications from transplant in lupus nephritis patients with ESRD, Dr. Jorge and colleagues wrote.
“To that end, our study provides evidence for a substantial survival benefit of renal transplant among patients with lupus nephritis ESRD,” they noted.
Dr. Jorge reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. One co-author provided additional disclosures related to Teva Pharmaceuticals and Gilead Sciences outside of the study conduct.
SOURCE: Jorge A, et al. Ann Intern Med 2019 Jan 21. doi: 10.7326/M18-1570.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point: Renal transplant is associated with a substantial survival benefit in patients with end-stage renal disease (ESRD) due to lupus nephritis,
Major finding: Transplant conferred a 70% reduction in overall death risk in these lupus nephritis ESRD patients, largely due to reduced deaths caused by infection and cardiovascular disease,
Study details: Analysis of 9,659 patients with lupus nephritis ESRD in the United States Renal Data System.
Disclosures: Support for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One co-author provided disclosures related to Teva Pharmaceuticals and Gilead Sciences.
Source: Jorge A, et al. Ann Intern Med. 2019 Jan 21. doi: 10.7326/M18-1570.
MMF proves viable as alternative option in moderate ANCA-associated vasculitis
Mycophenolate mofetil was noninferior to pulsed cyclophosphamide for remission induction in ANCA-associated vasculitis, but there were more relapses, in a randomized, unblinded trial of 140 patients with non–life-threatening disease.
“Our results demonstrate that MMF [mycophenolate mofetil] represents an alternative to CYC [cyclophosphamide] for remission induction in AAV [ANCA-associated vasculitis],” said investigators led by Rachel B. Jones, MD, of the department of renal medicine at Addenbrooke’s Hospital, Cambridge, England.
“While treatment with MMF may be associated with a higher risk of relapse compared with pulsed CYC, this increased risk may be acceptable to avoid the potential adverse effects of CYC” – infections, malignancies, and infertility – “particularly when the baseline risk of relapse is low,” as with the elderly or myeloperoxidase (MPO)-ANCA disease, “or if rituximab is unavailable,” Dr. Jones and her colleagues wrote in Annals of the Rheumatic Diseases.
Since enrollment began in 2007, they also noted that “it has become common to use rituximab as an alternative to CYC induction therapy ... However, rituximab is expensive, and its use is restricted in many countries ... Alternative effective low-cost induction therapies” – such as MMF – “may be required in some cases.”
The work, which was done on behalf of the European Vasculitis Study Group, was the largest randomized trial to date of MMF for AAV remission induction, and the first to include children; patients were enrolled at 21 sites in Europe, Australia, and New Zealand.
They were randomly assigned to MMF or pulsed CYC, with 66 adults and 4 children ranging in age from 10 to 16 years in each group. In addition to those with life-threatening disease, patients younger than 6 years old and those on dialysis or with an estimated glomerular filtration rate below 15 mL/min/m2 were excluded. Following remission, subjects were switched to oral azathioprine and a prednisone taper.
The primary outcome was remission by 6 months, defined as the absence of disease activity on two consecutive occasions at least 1 month apart, plus adherence to the taper. Baseline ANCA subtype, disease activity, and organ involvement were similar between the groups.
Overall, 47 patients in the in the MMF group (67%), including 1 child, reached the primary endpoint, versus 43 patients (61%), again including 1 child, in the CYC group (risk difference = 5.7%; 90% confidence interval, –7.5% to 19%), which established noninferiority. The median time to remission was about 90 days in both arms. “Compliance was a contributory factor to the lower remission rate[s] in children,” the authors noted.
More relapses occurred in the MMF group (33% vs. 19% with CYC). Among MPO-ANCA patients, the relapse rate was 15% versus 12% with CYC. In proteinase 3 (PR3)-ANCA patients, almost half in the MMF group relapsed (48% versus 24%).
There were no significant differences in serious infections (26% with MMF versus 17% with CYC; P = .3), malignancies, thromboembolisms, or death (four CYC patients and five MMF patients at 6 months).
Adult patients in the MMF group received MMF 2 g/day, with dose increases to 3 g/day permitted for uncontrolled disease at 4 weeks. Patients younger than 17 years old were dosed according to body surface area. The CYC group received intravenous pulsed CYC 15 mg/kg every 2-3 weeks with reductions for age and renal function. A total of 58 CYC patients (83%) received at least six pulses.
After remission, azathioprine was dosed at 2 mg/kg per day. Oral prednisolone started at 1 mg/kg per day and was reduced to 5 mg/day by 6 months.
Plasma exchange or additional methylprednisolone were allowed at entry; there were no differences in their use between the groups.
The trial was sponsored by Cambridge University Hospitals NHS Foundation Trust. Vifor Pharma provided a research grant to cover the trial and MMF costs. Dr. Jones and the other investigators reported ties to several companies, including GlaxoSmithKline, Genentech/Roche, ChemoCentryx, and Genzyme/Sanofi. Vifor holds an equity stake in ChemoCentryx.
SOURCE: Jones RB et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214245.
We sometimes encounter patients for whom access to rituximab is a problem, for financial, logistical, or tolerability reasons. Also, some patients are really reluctant about an infusion, and there is still some skittishness about rituximab. I have had some patients who, despite my having strongly reiterated how rare progressive multifocal leukoencephalopathy is, have been unable to get past the fact that that’s in the package insert. It’s helpful to me as a clinician to know that mycophenolate is something we can turn to in these situations. As I discuss the ups and down of different potential strategies with patients, this is something that can be part of the discussion.
This was a really well done study, and they were honest about the limitations. They excluded patients with the most severe disease, so you are still not talking about your patients on dialysis getting mycophenolate. Also, there are questions in terms of it’s not being as effective at sustaining remission, but that’s a bridge you can cross once they are in remission, in terms of how vigilant you are about follow-up. You also can re-induce remission with mycophenolate if you have to.
Robert F. Spiera, MD, is director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York. He had no relevant disclosures, and is on the editorial advisory board of MDedge Rheumatology.
We sometimes encounter patients for whom access to rituximab is a problem, for financial, logistical, or tolerability reasons. Also, some patients are really reluctant about an infusion, and there is still some skittishness about rituximab. I have had some patients who, despite my having strongly reiterated how rare progressive multifocal leukoencephalopathy is, have been unable to get past the fact that that’s in the package insert. It’s helpful to me as a clinician to know that mycophenolate is something we can turn to in these situations. As I discuss the ups and down of different potential strategies with patients, this is something that can be part of the discussion.
This was a really well done study, and they were honest about the limitations. They excluded patients with the most severe disease, so you are still not talking about your patients on dialysis getting mycophenolate. Also, there are questions in terms of it’s not being as effective at sustaining remission, but that’s a bridge you can cross once they are in remission, in terms of how vigilant you are about follow-up. You also can re-induce remission with mycophenolate if you have to.
Robert F. Spiera, MD, is director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York. He had no relevant disclosures, and is on the editorial advisory board of MDedge Rheumatology.
We sometimes encounter patients for whom access to rituximab is a problem, for financial, logistical, or tolerability reasons. Also, some patients are really reluctant about an infusion, and there is still some skittishness about rituximab. I have had some patients who, despite my having strongly reiterated how rare progressive multifocal leukoencephalopathy is, have been unable to get past the fact that that’s in the package insert. It’s helpful to me as a clinician to know that mycophenolate is something we can turn to in these situations. As I discuss the ups and down of different potential strategies with patients, this is something that can be part of the discussion.
This was a really well done study, and they were honest about the limitations. They excluded patients with the most severe disease, so you are still not talking about your patients on dialysis getting mycophenolate. Also, there are questions in terms of it’s not being as effective at sustaining remission, but that’s a bridge you can cross once they are in remission, in terms of how vigilant you are about follow-up. You also can re-induce remission with mycophenolate if you have to.
Robert F. Spiera, MD, is director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York. He had no relevant disclosures, and is on the editorial advisory board of MDedge Rheumatology.
Mycophenolate mofetil was noninferior to pulsed cyclophosphamide for remission induction in ANCA-associated vasculitis, but there were more relapses, in a randomized, unblinded trial of 140 patients with non–life-threatening disease.
“Our results demonstrate that MMF [mycophenolate mofetil] represents an alternative to CYC [cyclophosphamide] for remission induction in AAV [ANCA-associated vasculitis],” said investigators led by Rachel B. Jones, MD, of the department of renal medicine at Addenbrooke’s Hospital, Cambridge, England.
“While treatment with MMF may be associated with a higher risk of relapse compared with pulsed CYC, this increased risk may be acceptable to avoid the potential adverse effects of CYC” – infections, malignancies, and infertility – “particularly when the baseline risk of relapse is low,” as with the elderly or myeloperoxidase (MPO)-ANCA disease, “or if rituximab is unavailable,” Dr. Jones and her colleagues wrote in Annals of the Rheumatic Diseases.
Since enrollment began in 2007, they also noted that “it has become common to use rituximab as an alternative to CYC induction therapy ... However, rituximab is expensive, and its use is restricted in many countries ... Alternative effective low-cost induction therapies” – such as MMF – “may be required in some cases.”
The work, which was done on behalf of the European Vasculitis Study Group, was the largest randomized trial to date of MMF for AAV remission induction, and the first to include children; patients were enrolled at 21 sites in Europe, Australia, and New Zealand.
They were randomly assigned to MMF or pulsed CYC, with 66 adults and 4 children ranging in age from 10 to 16 years in each group. In addition to those with life-threatening disease, patients younger than 6 years old and those on dialysis or with an estimated glomerular filtration rate below 15 mL/min/m2 were excluded. Following remission, subjects were switched to oral azathioprine and a prednisone taper.
The primary outcome was remission by 6 months, defined as the absence of disease activity on two consecutive occasions at least 1 month apart, plus adherence to the taper. Baseline ANCA subtype, disease activity, and organ involvement were similar between the groups.
Overall, 47 patients in the in the MMF group (67%), including 1 child, reached the primary endpoint, versus 43 patients (61%), again including 1 child, in the CYC group (risk difference = 5.7%; 90% confidence interval, –7.5% to 19%), which established noninferiority. The median time to remission was about 90 days in both arms. “Compliance was a contributory factor to the lower remission rate[s] in children,” the authors noted.
More relapses occurred in the MMF group (33% vs. 19% with CYC). Among MPO-ANCA patients, the relapse rate was 15% versus 12% with CYC. In proteinase 3 (PR3)-ANCA patients, almost half in the MMF group relapsed (48% versus 24%).
There were no significant differences in serious infections (26% with MMF versus 17% with CYC; P = .3), malignancies, thromboembolisms, or death (four CYC patients and five MMF patients at 6 months).
Adult patients in the MMF group received MMF 2 g/day, with dose increases to 3 g/day permitted for uncontrolled disease at 4 weeks. Patients younger than 17 years old were dosed according to body surface area. The CYC group received intravenous pulsed CYC 15 mg/kg every 2-3 weeks with reductions for age and renal function. A total of 58 CYC patients (83%) received at least six pulses.
After remission, azathioprine was dosed at 2 mg/kg per day. Oral prednisolone started at 1 mg/kg per day and was reduced to 5 mg/day by 6 months.
Plasma exchange or additional methylprednisolone were allowed at entry; there were no differences in their use between the groups.
The trial was sponsored by Cambridge University Hospitals NHS Foundation Trust. Vifor Pharma provided a research grant to cover the trial and MMF costs. Dr. Jones and the other investigators reported ties to several companies, including GlaxoSmithKline, Genentech/Roche, ChemoCentryx, and Genzyme/Sanofi. Vifor holds an equity stake in ChemoCentryx.
SOURCE: Jones RB et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214245.
Mycophenolate mofetil was noninferior to pulsed cyclophosphamide for remission induction in ANCA-associated vasculitis, but there were more relapses, in a randomized, unblinded trial of 140 patients with non–life-threatening disease.
“Our results demonstrate that MMF [mycophenolate mofetil] represents an alternative to CYC [cyclophosphamide] for remission induction in AAV [ANCA-associated vasculitis],” said investigators led by Rachel B. Jones, MD, of the department of renal medicine at Addenbrooke’s Hospital, Cambridge, England.
“While treatment with MMF may be associated with a higher risk of relapse compared with pulsed CYC, this increased risk may be acceptable to avoid the potential adverse effects of CYC” – infections, malignancies, and infertility – “particularly when the baseline risk of relapse is low,” as with the elderly or myeloperoxidase (MPO)-ANCA disease, “or if rituximab is unavailable,” Dr. Jones and her colleagues wrote in Annals of the Rheumatic Diseases.
Since enrollment began in 2007, they also noted that “it has become common to use rituximab as an alternative to CYC induction therapy ... However, rituximab is expensive, and its use is restricted in many countries ... Alternative effective low-cost induction therapies” – such as MMF – “may be required in some cases.”
The work, which was done on behalf of the European Vasculitis Study Group, was the largest randomized trial to date of MMF for AAV remission induction, and the first to include children; patients were enrolled at 21 sites in Europe, Australia, and New Zealand.
They were randomly assigned to MMF or pulsed CYC, with 66 adults and 4 children ranging in age from 10 to 16 years in each group. In addition to those with life-threatening disease, patients younger than 6 years old and those on dialysis or with an estimated glomerular filtration rate below 15 mL/min/m2 were excluded. Following remission, subjects were switched to oral azathioprine and a prednisone taper.
The primary outcome was remission by 6 months, defined as the absence of disease activity on two consecutive occasions at least 1 month apart, plus adherence to the taper. Baseline ANCA subtype, disease activity, and organ involvement were similar between the groups.
Overall, 47 patients in the in the MMF group (67%), including 1 child, reached the primary endpoint, versus 43 patients (61%), again including 1 child, in the CYC group (risk difference = 5.7%; 90% confidence interval, –7.5% to 19%), which established noninferiority. The median time to remission was about 90 days in both arms. “Compliance was a contributory factor to the lower remission rate[s] in children,” the authors noted.
More relapses occurred in the MMF group (33% vs. 19% with CYC). Among MPO-ANCA patients, the relapse rate was 15% versus 12% with CYC. In proteinase 3 (PR3)-ANCA patients, almost half in the MMF group relapsed (48% versus 24%).
There were no significant differences in serious infections (26% with MMF versus 17% with CYC; P = .3), malignancies, thromboembolisms, or death (four CYC patients and five MMF patients at 6 months).
Adult patients in the MMF group received MMF 2 g/day, with dose increases to 3 g/day permitted for uncontrolled disease at 4 weeks. Patients younger than 17 years old were dosed according to body surface area. The CYC group received intravenous pulsed CYC 15 mg/kg every 2-3 weeks with reductions for age and renal function. A total of 58 CYC patients (83%) received at least six pulses.
After remission, azathioprine was dosed at 2 mg/kg per day. Oral prednisolone started at 1 mg/kg per day and was reduced to 5 mg/day by 6 months.
Plasma exchange or additional methylprednisolone were allowed at entry; there were no differences in their use between the groups.
The trial was sponsored by Cambridge University Hospitals NHS Foundation Trust. Vifor Pharma provided a research grant to cover the trial and MMF costs. Dr. Jones and the other investigators reported ties to several companies, including GlaxoSmithKline, Genentech/Roche, ChemoCentryx, and Genzyme/Sanofi. Vifor holds an equity stake in ChemoCentryx.
SOURCE: Jones RB et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214245.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: Overall, 47 patients in the in the MMF group (67%), including 1 child, reached remission by 6 months, versus 43 subjects (61%), again including 1 child, in the CYC group (risk difference = 5.7%; 90% CI, –7.5% to 19%), which established noninferiority.
Study details: Randomized, multisite trial with 140 patients.
Disclosures: The Cambridge University Hospitals NHS Foundation Trust sponsored the study. Vifor Pharma provided a research grant to cover the trial and MMF costs. Dr. Jones and the other investigators reported ties to several companies, including GlaxoSmithKline, Genentech/Roche, and ChemoCentryx, which is owned in part by Vifor.
Source: Jones RB et al. Ann Rheum Dis. 2019 Jan 5. doi: 10.1136/annrheumdis-2018-214245.
Anticoagulation shows promise in concurrent lupus nephritis, thrombotic microangiopathy
The use of anticoagulation in patients with comorbid lupus nephritis and thrombotic microangiopathy was linked with a greater rate of clinical response after 12 months of therapy, according to results from a study published in Annals of the Rheumatic Diseases.
“The purpose of this multicenter retrospective study was to analyze the impact of anticoagulation (vitamin K antagonists and/or heparins), in addition to conventional immunosuppression on kidney outcomes, according to the Kidney Disease: Improving Global Outcomes guidelines,” wrote first author Savino Sciascia, MD, PhD, of the University of Turin (Italy), along with his colleagues.
The researchers analyzed data from 97 patients with biopsy-confirmed lupus nephritis (LN) and thrombotic microangiopathy (TMA) who were diagnosed during 2007-2017. The entire cohort was administered standard immunosuppressive agents, including corticosteroids, cyclophosphamide, and mycophenolate, among others. After 12 months of therapy, the patients were assessed for degree of clinical response, measured using complete, partial, or no response to therapy.
“Sixty-one patients (62.9%) were [antiphospholipid antibody] positive and 37 (38.1%) of these patients received anticoagulation with a vitamin K antagonist and/or heparins,” the investigators wrote. “Mean duration of anticoagulation therapy after TMA and LN diagnosis was 7.7 months,” they added.
After statistical analysis, the researchers found that patients treated with anticoagulation therapy experienced a greater rate of clinical response, compared with those not treated. The investigators saw a complete response to therapy in 22 (59.5%) patients given anticoagulation, compared with 15 (25.0%) patients without anticoagulation. Partial treatment responses were comparable, occurring in 7 (18.9%) with anticoagulation and 15 (25.0%) without. Without anticoagulation, 30 (50%) had no response to therapy, compared with 8 (21.6%) patients given anticoagulation.
“When limiting the analysis to patients with antiphospholipid antibodies, we observed a rate of any response (either complete response [or] partial response) as high as 66% in patients receiving anticoagulant treatment compared with those receiving immunosuppression alone (34%),” they added.
The authors acknowledged a major limitation of the study was the short duration of follow-up, which limited the ability to evaluate relapse rate.
“Despite its limitations, this study represents the largest available multicenter cohort of real-life systemic lupus erythematosus patients,” said Dr. Sciascia and his colleagues. “The use of anticoagulation appeared protective and warrants further investigation as a therapeutic tool,” they concluded.
The authors reported no conflicts of interest, and no specific study funding was declared.
SOURCE: Sciascia S et al. Ann Rheum Dis. 2018 Dec 14. doi: 10.1136/annrheumdis-2018-214559.
The use of anticoagulation in patients with comorbid lupus nephritis and thrombotic microangiopathy was linked with a greater rate of clinical response after 12 months of therapy, according to results from a study published in Annals of the Rheumatic Diseases.
“The purpose of this multicenter retrospective study was to analyze the impact of anticoagulation (vitamin K antagonists and/or heparins), in addition to conventional immunosuppression on kidney outcomes, according to the Kidney Disease: Improving Global Outcomes guidelines,” wrote first author Savino Sciascia, MD, PhD, of the University of Turin (Italy), along with his colleagues.
The researchers analyzed data from 97 patients with biopsy-confirmed lupus nephritis (LN) and thrombotic microangiopathy (TMA) who were diagnosed during 2007-2017. The entire cohort was administered standard immunosuppressive agents, including corticosteroids, cyclophosphamide, and mycophenolate, among others. After 12 months of therapy, the patients were assessed for degree of clinical response, measured using complete, partial, or no response to therapy.
“Sixty-one patients (62.9%) were [antiphospholipid antibody] positive and 37 (38.1%) of these patients received anticoagulation with a vitamin K antagonist and/or heparins,” the investigators wrote. “Mean duration of anticoagulation therapy after TMA and LN diagnosis was 7.7 months,” they added.
After statistical analysis, the researchers found that patients treated with anticoagulation therapy experienced a greater rate of clinical response, compared with those not treated. The investigators saw a complete response to therapy in 22 (59.5%) patients given anticoagulation, compared with 15 (25.0%) patients without anticoagulation. Partial treatment responses were comparable, occurring in 7 (18.9%) with anticoagulation and 15 (25.0%) without. Without anticoagulation, 30 (50%) had no response to therapy, compared with 8 (21.6%) patients given anticoagulation.
“When limiting the analysis to patients with antiphospholipid antibodies, we observed a rate of any response (either complete response [or] partial response) as high as 66% in patients receiving anticoagulant treatment compared with those receiving immunosuppression alone (34%),” they added.
The authors acknowledged a major limitation of the study was the short duration of follow-up, which limited the ability to evaluate relapse rate.
“Despite its limitations, this study represents the largest available multicenter cohort of real-life systemic lupus erythematosus patients,” said Dr. Sciascia and his colleagues. “The use of anticoagulation appeared protective and warrants further investigation as a therapeutic tool,” they concluded.
The authors reported no conflicts of interest, and no specific study funding was declared.
SOURCE: Sciascia S et al. Ann Rheum Dis. 2018 Dec 14. doi: 10.1136/annrheumdis-2018-214559.
The use of anticoagulation in patients with comorbid lupus nephritis and thrombotic microangiopathy was linked with a greater rate of clinical response after 12 months of therapy, according to results from a study published in Annals of the Rheumatic Diseases.
“The purpose of this multicenter retrospective study was to analyze the impact of anticoagulation (vitamin K antagonists and/or heparins), in addition to conventional immunosuppression on kidney outcomes, according to the Kidney Disease: Improving Global Outcomes guidelines,” wrote first author Savino Sciascia, MD, PhD, of the University of Turin (Italy), along with his colleagues.
The researchers analyzed data from 97 patients with biopsy-confirmed lupus nephritis (LN) and thrombotic microangiopathy (TMA) who were diagnosed during 2007-2017. The entire cohort was administered standard immunosuppressive agents, including corticosteroids, cyclophosphamide, and mycophenolate, among others. After 12 months of therapy, the patients were assessed for degree of clinical response, measured using complete, partial, or no response to therapy.
“Sixty-one patients (62.9%) were [antiphospholipid antibody] positive and 37 (38.1%) of these patients received anticoagulation with a vitamin K antagonist and/or heparins,” the investigators wrote. “Mean duration of anticoagulation therapy after TMA and LN diagnosis was 7.7 months,” they added.
After statistical analysis, the researchers found that patients treated with anticoagulation therapy experienced a greater rate of clinical response, compared with those not treated. The investigators saw a complete response to therapy in 22 (59.5%) patients given anticoagulation, compared with 15 (25.0%) patients without anticoagulation. Partial treatment responses were comparable, occurring in 7 (18.9%) with anticoagulation and 15 (25.0%) without. Without anticoagulation, 30 (50%) had no response to therapy, compared with 8 (21.6%) patients given anticoagulation.
“When limiting the analysis to patients with antiphospholipid antibodies, we observed a rate of any response (either complete response [or] partial response) as high as 66% in patients receiving anticoagulant treatment compared with those receiving immunosuppression alone (34%),” they added.
The authors acknowledged a major limitation of the study was the short duration of follow-up, which limited the ability to evaluate relapse rate.
“Despite its limitations, this study represents the largest available multicenter cohort of real-life systemic lupus erythematosus patients,” said Dr. Sciascia and his colleagues. “The use of anticoagulation appeared protective and warrants further investigation as a therapeutic tool,” they concluded.
The authors reported no conflicts of interest, and no specific study funding was declared.
SOURCE: Sciascia S et al. Ann Rheum Dis. 2018 Dec 14. doi: 10.1136/annrheumdis-2018-214559.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: A greater proportion of patients given anticoagulation achieved partial or complete response (78.4%) versus those not given anticoagulation (50.0%).
Study details: A retrospective analysis of 97 patients with biopsy-confirmed lupus nephritis and thrombotic microangiopathy.
Disclosures: The authors reported no conflicts of interest, and no specific study funding was declared.
Source: Sciascia S et al. Ann Rheum Dis. 2018 Dec 14. doi: 10.1136/annrheumdis-2018-214559.
Aspirin appears underused to prevent preeclampsia in SLE patients
Women with systemic lupus erythematosus (SLE) were not more likely to take aspirin during pregnancy than when not pregnant, despite the potential to reduce preeclampsia risk, based on data from 300 women.
Although aspirin is recommended to reduce preeclampsia risk in pregnant SLE patients, data on current practice patterns are limited, wrote Arielle Mendel, MD, of McGill University, Montreal, and colleagues in Annals of the Rheumatic Diseases.
The researchers identified 475 pregnancies among 300 women aged 18-45 years who were pregnant during the study period from 2000 to 2017. The average duration of SLE duration at the time of pregnancy was 5.6 years, and approximately half (51%) of pregnancies had one or more traditional preeclampsia risk factors. In addition, 33% of the women had positive antiphospholipid antibodies (aPL).
Overall, 25% of the pregnancies included aspirin use, with no significant difference among those with one or more risk factors, any individual risk factor, or nephritis.
The study population was 44% white, 19% black, 14% Asian, 13% Hispanic, 5% from the Indian subcontinent, 1% Native American, and 5% other ethnicities.
Approximately 34% of white patients and 32% of Hispanic patients were exposed to aspirin, compared with 18% and 20% of black and Asian patients, respectively. Aspirin use did not increase over the study period, although there was a trend for increased use in patients with a positive aPL, compared with those with no aPL.
“The low aspirin use among black SLE subjects is noteworthy given the worse reproductive outcomes observed in this population,” the researchers wrote.
The findings were limited by several factors, including a lack of data on gestational age and pregnancy outcomes, the researchers noted. However, the results highlight the gap between recommendations and practice, and the need for additional research on aspirin use in pregnant SLE patients.
The study was supported in part by a McGill University Health Centre Research Award; the researchers reported no financial conflicts.
SOURCE: Mendel A et al. Ann Rheum Dis. 2018 Dec 20. doi: 10.1136/annrheumdis-2018-214434.
Women with systemic lupus erythematosus (SLE) were not more likely to take aspirin during pregnancy than when not pregnant, despite the potential to reduce preeclampsia risk, based on data from 300 women.
Although aspirin is recommended to reduce preeclampsia risk in pregnant SLE patients, data on current practice patterns are limited, wrote Arielle Mendel, MD, of McGill University, Montreal, and colleagues in Annals of the Rheumatic Diseases.
The researchers identified 475 pregnancies among 300 women aged 18-45 years who were pregnant during the study period from 2000 to 2017. The average duration of SLE duration at the time of pregnancy was 5.6 years, and approximately half (51%) of pregnancies had one or more traditional preeclampsia risk factors. In addition, 33% of the women had positive antiphospholipid antibodies (aPL).
Overall, 25% of the pregnancies included aspirin use, with no significant difference among those with one or more risk factors, any individual risk factor, or nephritis.
The study population was 44% white, 19% black, 14% Asian, 13% Hispanic, 5% from the Indian subcontinent, 1% Native American, and 5% other ethnicities.
Approximately 34% of white patients and 32% of Hispanic patients were exposed to aspirin, compared with 18% and 20% of black and Asian patients, respectively. Aspirin use did not increase over the study period, although there was a trend for increased use in patients with a positive aPL, compared with those with no aPL.
“The low aspirin use among black SLE subjects is noteworthy given the worse reproductive outcomes observed in this population,” the researchers wrote.
The findings were limited by several factors, including a lack of data on gestational age and pregnancy outcomes, the researchers noted. However, the results highlight the gap between recommendations and practice, and the need for additional research on aspirin use in pregnant SLE patients.
The study was supported in part by a McGill University Health Centre Research Award; the researchers reported no financial conflicts.
SOURCE: Mendel A et al. Ann Rheum Dis. 2018 Dec 20. doi: 10.1136/annrheumdis-2018-214434.
Women with systemic lupus erythematosus (SLE) were not more likely to take aspirin during pregnancy than when not pregnant, despite the potential to reduce preeclampsia risk, based on data from 300 women.
Although aspirin is recommended to reduce preeclampsia risk in pregnant SLE patients, data on current practice patterns are limited, wrote Arielle Mendel, MD, of McGill University, Montreal, and colleagues in Annals of the Rheumatic Diseases.
The researchers identified 475 pregnancies among 300 women aged 18-45 years who were pregnant during the study period from 2000 to 2017. The average duration of SLE duration at the time of pregnancy was 5.6 years, and approximately half (51%) of pregnancies had one or more traditional preeclampsia risk factors. In addition, 33% of the women had positive antiphospholipid antibodies (aPL).
Overall, 25% of the pregnancies included aspirin use, with no significant difference among those with one or more risk factors, any individual risk factor, or nephritis.
The study population was 44% white, 19% black, 14% Asian, 13% Hispanic, 5% from the Indian subcontinent, 1% Native American, and 5% other ethnicities.
Approximately 34% of white patients and 32% of Hispanic patients were exposed to aspirin, compared with 18% and 20% of black and Asian patients, respectively. Aspirin use did not increase over the study period, although there was a trend for increased use in patients with a positive aPL, compared with those with no aPL.
“The low aspirin use among black SLE subjects is noteworthy given the worse reproductive outcomes observed in this population,” the researchers wrote.
The findings were limited by several factors, including a lack of data on gestational age and pregnancy outcomes, the researchers noted. However, the results highlight the gap between recommendations and practice, and the need for additional research on aspirin use in pregnant SLE patients.
The study was supported in part by a McGill University Health Centre Research Award; the researchers reported no financial conflicts.
SOURCE: Mendel A et al. Ann Rheum Dis. 2018 Dec 20. doi: 10.1136/annrheumdis-2018-214434.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point: Aspirin use was low among pregnant systemic lupus erythematosus patients despite risk factors for preeclampsia.
Major finding: Approximately 25% of women with systemic lupus erythematosus took aspirin during pregnancy.
Study details: The data come from a prospective study of 300 women and 475 pregnancies.
Disclosures: The study was supported in part by a McGill University Health Centre Research Award; the researchers reported no financial conflicts.
Source: Mendel A et al. Ann Rheum Dis. 2018 Dec 20. doi: 10.1136/annrheumdis-2018-214434.
Tofacitinib tackles cutaneous sarcoidosis
Tofacitinib significantly improved skin lesions associated with cutaneous sarcoidosis, according to a case report published in the New England Journal of Medicine.
Treatment options for cutaneous sarcoidosis are limited, as are data on the effectiveness of alternatives to prednisone, which is often the first choice despite adverse effects, wrote William Damsky, MD, of Yale University in New Haven, Conn., and his colleagues.
Previous studies have suggested involvement of the JAK-STAT pathway in sarcoidosis; therefore, the researchers treated a patient who had refractory cutaneous sarcoidosis with oral tofacitinib. The treatment significantly improved the patient’s skin lesions both clinically and histologically.
The patient was a 48-year-old woman with a history of cutaneous and pulmonary sarcoidosis and treatment-resistant skin lesions. At the time of the case report, she had no pulmonary symptoms and no ophthalmologic issues, but presented with pink-brown indurated papules and plaques, and some alopecia on her scalp (N Engl J Med. 2018;379:2540-6).
The patient had not responded to other medications including glucocorticoids, minocycline, hydroxychloroquine, methotrexate, adalimumab, tacrolimus, and apremilast. With her consent, the patient received off-label tofacitinib at 5 mg twice daily. The lesions began to improve, but treatment was discontinued because of insurance issues. When treatment resumed, the patient’s Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) score, used to assess disease activity, was 85 on a scale of 0 to 165; this score dropped to 53 after 4 months of treatment.
In addition, two samples collected after 10 months of treatment showed histologic resolution of granulomas.
Although the findings must be replicated in other patients, the results suggest that “the dysregulation of JAK-STAT–dependent cytokines (e.g., interferon-gamma) is pathogenically involved in cutaneous sarcoidosis and, probably, in sarcoidosis in general,” the researchers said.
Dr. Damsky disclosed a financial relationship with Eli Lilly, and research funding from the Dermatology Foundation and the National Institutes of Health. The study was supported by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research, the National Institutes of Health, and the Dermatology Foundation.
SOURCE: Damsky W et al. N Engl J Med. 2018;379:2540-6.
Tofacitinib significantly improved skin lesions associated with cutaneous sarcoidosis, according to a case report published in the New England Journal of Medicine.
Treatment options for cutaneous sarcoidosis are limited, as are data on the effectiveness of alternatives to prednisone, which is often the first choice despite adverse effects, wrote William Damsky, MD, of Yale University in New Haven, Conn., and his colleagues.
Previous studies have suggested involvement of the JAK-STAT pathway in sarcoidosis; therefore, the researchers treated a patient who had refractory cutaneous sarcoidosis with oral tofacitinib. The treatment significantly improved the patient’s skin lesions both clinically and histologically.
The patient was a 48-year-old woman with a history of cutaneous and pulmonary sarcoidosis and treatment-resistant skin lesions. At the time of the case report, she had no pulmonary symptoms and no ophthalmologic issues, but presented with pink-brown indurated papules and plaques, and some alopecia on her scalp (N Engl J Med. 2018;379:2540-6).
The patient had not responded to other medications including glucocorticoids, minocycline, hydroxychloroquine, methotrexate, adalimumab, tacrolimus, and apremilast. With her consent, the patient received off-label tofacitinib at 5 mg twice daily. The lesions began to improve, but treatment was discontinued because of insurance issues. When treatment resumed, the patient’s Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) score, used to assess disease activity, was 85 on a scale of 0 to 165; this score dropped to 53 after 4 months of treatment.
In addition, two samples collected after 10 months of treatment showed histologic resolution of granulomas.
Although the findings must be replicated in other patients, the results suggest that “the dysregulation of JAK-STAT–dependent cytokines (e.g., interferon-gamma) is pathogenically involved in cutaneous sarcoidosis and, probably, in sarcoidosis in general,” the researchers said.
Dr. Damsky disclosed a financial relationship with Eli Lilly, and research funding from the Dermatology Foundation and the National Institutes of Health. The study was supported by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research, the National Institutes of Health, and the Dermatology Foundation.
SOURCE: Damsky W et al. N Engl J Med. 2018;379:2540-6.
Tofacitinib significantly improved skin lesions associated with cutaneous sarcoidosis, according to a case report published in the New England Journal of Medicine.
Treatment options for cutaneous sarcoidosis are limited, as are data on the effectiveness of alternatives to prednisone, which is often the first choice despite adverse effects, wrote William Damsky, MD, of Yale University in New Haven, Conn., and his colleagues.
Previous studies have suggested involvement of the JAK-STAT pathway in sarcoidosis; therefore, the researchers treated a patient who had refractory cutaneous sarcoidosis with oral tofacitinib. The treatment significantly improved the patient’s skin lesions both clinically and histologically.
The patient was a 48-year-old woman with a history of cutaneous and pulmonary sarcoidosis and treatment-resistant skin lesions. At the time of the case report, she had no pulmonary symptoms and no ophthalmologic issues, but presented with pink-brown indurated papules and plaques, and some alopecia on her scalp (N Engl J Med. 2018;379:2540-6).
The patient had not responded to other medications including glucocorticoids, minocycline, hydroxychloroquine, methotrexate, adalimumab, tacrolimus, and apremilast. With her consent, the patient received off-label tofacitinib at 5 mg twice daily. The lesions began to improve, but treatment was discontinued because of insurance issues. When treatment resumed, the patient’s Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) score, used to assess disease activity, was 85 on a scale of 0 to 165; this score dropped to 53 after 4 months of treatment.
In addition, two samples collected after 10 months of treatment showed histologic resolution of granulomas.
Although the findings must be replicated in other patients, the results suggest that “the dysregulation of JAK-STAT–dependent cytokines (e.g., interferon-gamma) is pathogenically involved in cutaneous sarcoidosis and, probably, in sarcoidosis in general,” the researchers said.
Dr. Damsky disclosed a financial relationship with Eli Lilly, and research funding from the Dermatology Foundation and the National Institutes of Health. The study was supported by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research, the National Institutes of Health, and the Dermatology Foundation.
SOURCE: Damsky W et al. N Engl J Med. 2018;379:2540-6.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: A 48-year-old woman with sarcoidosis showed significant improvement in her skin on treatment with tofacitinib.
Major finding: The patient’s disease activity score on the CSAMI went from 85 to 53 after 4 months of therapy.
Study details: Case report of a 48-year-old woman with cutaneous and pulmonary sarcoidosis and treatment-resistant skin lesions.
Disclosures: Dr. Damsky disclosed a financial relationship with Eli Lilly, and research funding from the Dermatology Foundation and the National Institutes of Health. The study was supported by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research, the National Institutes of Health, and the Dermatology Foundation.
Source: Damsky W et al. N Engl J Med. 2018;379:2540-6.