BackgroundInterstitial Lung Disease (ILD) is the most common cause of mortality in myositis and t... more BackgroundInterstitial Lung Disease (ILD) is the most common cause of mortality in myositis and there is lack of randomized clinical trials for myositis-associated ILD (MA-ILD). A T-cell mediated pathogenesis has been postulated for MA-ILD, and abatacept (ABA) is a T cell co-stimulatory modulator.ObjectivesOur primary objective was to evaluate the efficacy, safety and tolerability of ABA (125 mg SQ weekly) combined with standard of care (SOC) vs. placebo/SOC in MA-ILD patients in a multi-center, double-blind, randomized placebo-controlled proof of concept clinical trial.Methods20 patients (pts) with anti-synthetase antibody (Anti-Syn Ab) were enrolled across 5 centers for 24 weeks in a randomized placebo-controlled phase (RCT) followed by an open label extension (OLE) for 24 weeks. Active myositis was not required but pts must have had active ILD (new onset or worsening requiring treatment) and previously failed ≥1 SOC drug for ILD. Pts were required to be on stable SOC [glucocorticoids (GC)/1 immunosuppressive (IS) agent (azathioprine or mycophenolate) prior to the trial as well as stable SOC IS throughout the trial]. A recommended GC taper was instituted. The primary endpoint was the change in Force Vital Capacity (FVC) (in ml) change from baseline to week 24. Secondary endpoints included FVC changes over 48 weeks, patient reported outcomes (PRO) of dyspnea (UCSD-shortness of breath questionnaire; range 0-120, MCID of 8) and DLCO corrected % predicted (DLCO) at 24 and 48 weeks. Mixed effect modeling was used for analysis and the study was not powered for primary or secondary outcomes.ResultsA total of 20 anti-Syn Ab positive pts (mean age of 57, 45% female and 85% Caucasian, Jo-1, 55%) were randomized to ABA (n=9) and placebo (n=11). All but 1 pts completed 48 weeks of the trial. There was no significant or clinically relevant difference in median FVC (ml) from baseline to week 24 between ABA (-40 ml) and placebo (30 ml), p = 0.97. However, the median FVC (ml) change from baseline to week 48 was 140 ml and -40 ml, in ABA vs. placebo (p=0.15), with a 180 ml difference in favor of the ABA group. FVC% predicted remained stable (±5%) or improved (>5%) without death or drug rescue in 75% (6/8) and 45% (5/11) at week 24 and week 48, in ABA vs. placebo, respectively. The median DLCO change from baseline was -4.5 and -10.5 at week 24; 6.5 and -2.7 at week 48, in ABA vs. placebo group, respectively. DLCO remained stable (±5%) or improved (>5%) without death or rescue in 57% (4/7) and 45% (5/11) at week 24; 62.5% (5/8) and 40% (4/10) at week 48, in ABA vs. placebo, respectively. Dyspnea improved by median of 1 and 3 at week 24; 13 and 5 at week 48 in ABA vs. placebo, respectively. Dyspnea improved by an MCID of 8 without requiring drug rescue or death in 22% (2/9) and 45.5% (5/11) at week 24; 50% (4/8) and 18% (2/11) pts at week 48 in ABA vs. placebo, respectively. There were 3 severe adverse events (1 in RCT, 2 in OLE) in 2 pts requiring hospitalization in the ABA group for progressive respiratory failure and 1 died (at 24 weeks). There were 36 and 23 adverse events among 9 placebo and 9 treatment group pts. ABA was well tolerated.ConclusionMA-ILD ABA-treated subjects showed similar FVC, DLCO and dyspnea PRO trends compared to placebo at 24 weeks but clinically and numerically meaningful trends were observed in ABA-treated subjects at week 48. These results suggest the need for a larger randomized study of ABA in MA-ILD. Abatacept was relatively safe and well tolerated in the cohort.Figure 1: Change from baseline in Forced Vital Capacity (FVC) in ml by treatment groups.Table 1.Baseline demographics and clinical variables by treatment groups:Clinical variablePlacebo (N=11)Abatacept (N=9)Age57.7 [47.8-64.5]49.7 [46.6-59.3]Female4 (36)5 (56)Non-Hispanic11 (100)9…
ABSTRACT Background Lack of reliable and valid measures of disease activity and clinical response... more ABSTRACT Background Lack of reliable and valid measures of disease activity and clinical response in patients with CTD-ILD makes clinical trial design difficult. From a multi-tiered investigation to develop consensus on provisional criteria in both CTD-ILD and idiopathic pulmonary fibrosis (IPF), we report the results of expert voting from a 3-tiered Delphi exercise to identify domains “important” to measure in a one year randomized controlled trial (RCT) in IPF and CTD-ILD. Methods Using the international consensus organization, Outcome Measures in Rheumatology (OMERACT) methodology, 270 experts nominated 23 “domains” and 616 “instruments” that were assembled into an initial voting survey for a 3-tiered Delphi exercise with survey items anchored by degree of importance on a 9-point Likert scale with as a voting option. All stages of data collection used a custom-designed secure web-site that included related articles and opportunities for participants to upload commentary supporting or refuting importance of each item. Tier 1 Analysis: A cut-off median <4 was applied to the results. Final review demanded 100% consensus agreement for dismissal of an item based on lack of: 1. Face validity, 2. Content validity (more suited to diagnostic, demographic, or inclusion criteria) and 3. Feasibility in a multicenter trial. Tiers 2 and 3 Analysis: To protect against bias introduced by using an arbitrary cut-off, cluster analysis was implemented to identify patterns of consensus within the data. Results 90% of invited experts: 137 pulmonary, 102 rheumatology and 4 cardiology specialists from 32 countries/6 continents participated. 74% and 69% of participants considered ILD and rheumatologic lung disease respectively as their primary field of research or clinical interest. Recidivism after Tier 1 was <1% with each subsequent Tier. Five common domains were identified for CTD-ILD and IPF: DYSPNEA, HEALTH RELATED QUALITY OF LIFE, LUNG IMAGING, LUNG PHYSIOLOGY/FUNCTION and SURVIVAL. Conclusions Development of valid, discriminatory and feasible outcome measures to assess disease progression and therapeutic responses is essential for performing RCTs in CTD-ILD. This is the first comprehensive, multi-disciplinary, international effort to assess domains for study of ILD. Experts identified a core set of measures focused on radiographic, physiologic and patient-reported outcomes culled from a large number of candidate items. A research agenda focusing on candidate biomarkers and domains requiring instrument development has emerged. Broad participation from a multidisciplinary ILD research community reflects the high perceived need in this area. Disclosure of Interest L. A. Saketkoo Grant/Research support from: Actelion, United Therapeutics, D. Khanna Speakers Bureau: Actelion, Fibrogen, Gilead, Novartis, Pfizer, Sanofi, Unitied Therapeutics, D. Huscher: None Declared, P. Dellaripa Grant/Research support from: Biogen IDEC, Genentech, K. Flaherty: None Declared, E. Matteson Grant/Research support from: Biogen IDEC, Genentech, C. Oddis Consultant for: Biogen IDEC, Genentech, A. Wells: None Declared, C. Denton Consultant for: Actelion, Glaxo Smith Kline, Pfizer, United Therapeutics, O. Distler Consultant for: Actelion, Active BiotechBristol-Myers Squibb, Fibrogen, Ergonex, Genentech, Novartis, Pfizer, Sanofi, Unitied Therapeutics, 4D Therapeutics, O. Kowal-Bielecka Consultant for: Bayer, Pfizer, N. Sandorfi: None Declared, R. Christmann: None Declared, K. Phillips Grant/Research support from: Actelion, Amgen, Centocor, Merck, Pfizer, Unitied Therapeutics, D. Pittrow Consultant for: Actelion, Pfizer, MSD, Novartis, Bayer, MBiotec, Baxter, V. Strand Consultant for: Actelion, Amgen, Bristol Myers Squibb, Celgene, Fibrogen, Genentech, Novartis, Pfizer, Sanofi, UCB, K. Brown Consultant for: Actelion, Fibrogen, Gilead, Amgen, Genentech, Celgene, J. Seibold Consultant for: Actelion, Fibrogen, Gilead, Genentech, Celgene, MedImmune, Boerhringer-Ingelheim, Sigma Tau
Objectives Patient-reported global disease activity (patient-global) is a myositis core set measu... more Objectives Patient-reported global disease activity (patient-global) is a myositis core set measure. Understanding the drivers of patient-global is important in patient assessment, and disagreements between physician and patient perception of disease activity may negatively impact shared decision making. We examined the determinants of patient-global and discordance between patient-global and physician-reported global disease activity (physician-global) in idiopathic inflammatory myopathies (IIMs). Methods Adults with IIM were enrolled in a prospective observational cross-sectional study. The following myositis outcome measures were collected: patient-global, physician-global, extramuscular and muscle disease activity, manual muscle testing, HAQ, creatine kinase, fatigue, pain, Patient-Reported Outcomes Measurement Information System physical function, 36-item Short Form, sit to stand, timed up and go, 6-minute walk and Actigraph steps/min/day count. A linear regression model was us...
Background:Dermatomyositis (DM) is a rare chronic systemic autoimmune disease with characteristic... more Background:Dermatomyositis (DM) is a rare chronic systemic autoimmune disease with characteristic skin rash and progressive proximal muscle weakness. Current therapies encompass corticosteroids and other immunosuppressants and intravenous immunoglobulins (IVIg), however, none of these therapies are proven by randomized controlled phase 3 studies. There have been no large randomized clinical trials supporting the efficacy and safety of IVIg in DM.Objectives:The ProDERM study aimed to evaluate the efficacy and safety/tolerability of IVIg in DM patients in a double-blind, randomized, placebo-controlled, international multi-center, phase III clinical trial.Methods:The trial consisted of a double-blind, placebo-controlled First Period (16 weeks), in which adult patients with definite or probable DM (according to Bohan and Peter criteria) were randomized 1:1 to either high dose IVIg (2g/kg every 4 weeks) or placebo. Patients on placebo and patients without clinical worsening while on IVIg...
ObjectiveTo assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, dou... more ObjectiveTo assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double‐blind, placebo‐controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM).MethodsThirty‐six subjects with probable or definite DM/PM were enrolled in a 6‐month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis‐associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)‐8 score of less than 136/150. If the MMT‐8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcom...
ObjectivesIn dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes.... more ObjectivesIn dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with an increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.MethodsPhage ImmunoPrecipitation Sequencing using sera from 43 patients with DM suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins patients with myositis (255 with DM, 28 with antisynthetase syndrome, 40 with immune-mediated necrotising myopathy, 29 with inclusion body myositis and 19 with polymyositis), 80 rheumatological disease controls (25 with Sjogren’s syndrome, 25 with systemic lupus erythematosus and 30 with rheumatoid arthritis (RA)) and 200 healthy comparators were screened for anti-SP4 autoantibodies by ELISA. A validation cohort of 46 anti-TIF1γ-positive patient sera from the University of Pit...
Idiopathic immune myopathies (IIM) represent a group of disorders causing chronic inflammation an... more Idiopathic immune myopathies (IIM) represent a group of disorders causing chronic inflammation and significant damage to skeletal muscle due to an unchecked autoimmune response. The main challenge slowing study of IIM is an understanding of the pathogenic mechanism responsible for initiation and progression of skeletal muscle inflammation. Two mouse models of IIM have recently provided new insights into the pathogenesis of the disease. The synaptotagmin VII null (Syt VII−/−) mouse is characterized by defects in membrane resealing and presents with a mild form myositis at 2 months of age. A more robust model of IIM combines knock‐out of Syt VII with a FoxP3 mutation resulting in a mouse with impaired membrane resealing and regulatory T‐cell deficiency. Adoptive transfer of lymphocyte preparations isolated from this double mutant mouse model to recombination‐activating gene 1 (RAG‐1) null mice results in severe skeletal muscle inflammation. Plasma membrane resealing is a highly conser...
Glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myop... more Glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myopathy (IIM); however, they have significant limitations including lack of complete response and long-term adverse events. Glucocorticoid-sparing agents are often given concomitantly with other immunosuppressive agents, particularly in patients with moderate or severe disease. First-line conventional immunosuppressive drugs include either methotrexate or azathioprine, and second-line immunosuppressive therapy includes mycophenolate mofetil, tacrolimus or cyclosporine, intravenous immunoglobulin, or rituximab, used alone or in various combinations. As treatment of refractory cases of idiopathic inflammatory myopathies (IIM) has been challenging, there is growing interest in assessing novel biologics that target various pathways implicated in the pathogenesis of IIM. Rituximab is being used off-label with increasing evidence in refractory myositis and associated interstitial lung disease. Antitumor necrosis factor (anti-TNF) is currently not being used in IIM due to uncertain efficacy data. Further research is currently ongoing to evaluate the role of other novel therapies such as tocilizumab (anti-IL6), abatacept (inhibition of T-cell co-stimulation), sifalimumab (anti-IFNα), or tofacitinib (Janus kinase (JAK) inhibitor) given their biological plausibility and encouraging recent small case series results. IVIG is being used either as monotherapy or as combination therapy especially for necrotizing myopathies, and there is an ongoing randomized controlled trial in dermatomyositis (DM).
OBJECTIVE The Outcome Measures in Rheumatology (OMERACT) is a research organization focused on im... more OBJECTIVE The Outcome Measures in Rheumatology (OMERACT) is a research organization focused on improving health care outcomes for patients with autoimmune and musculoskeletal diseases. The Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) Working Group on Lung Physiology is a group within OMERACT charged with identifying outcome measures that should be implemented in studies of patients with CTD-ILD. The OMERACT Filter 2.1 is an evidence-based algorithm used to identify outcome measures that are truthful, feasible, and able to discriminate between groups of interest. Our objective was to summate evidence (published literature, key opinion leader input, patient perspectives) that would influence the CTD-ILD Working Group's vote to accept or reject the use of two measures of lung physiology, the forced vital capacity (FVC) and the diffusion capacity of carbon monoxide (DLco) for use in randomized controlled trials (RTCs) and longitudinal observational studies (LOSs) involving patients with systemic sclerosis associated ILD (SSc-ILD). METHODS Patient Research Partners (those afflicted with SSc-ILD) and the CTD-ILD Working Group on Lung Physiology were polled to assess their opinion on the FVC and DLco in terms of feasibility; the CTD-ILD Working Group was also queried on these instruments' face and content validity. We then conducted a systematic literature review to identify articles in the SSc-ILD population that assessed the following measurement properties of FVC and DLco: (1) construct validity, (2) test-retest reliability, (3) longitudinal construct validity, (4) clinical trial discrimination/sensitivity to detect change in clinical trials, and (5) thresholds of meaning. Results were summarized in a Summary of Measurement Properties (SOMP) table for each instrument. OMERACT CTD-ILD Working Group members discussed and voted on the strength of evidence supporting these two instruments and voted to endorse, provisionally endorse, or not endorse either instrument. RESULTS Forty Patient Research Partners reported these two measures are feasible (are not an unnecessary burden or represent an infeasible longitudinal assessment of their disease). A majority of the 18 CTD-ILD Working Group members voted that both the FVC and DLco are feasible and have face and content validity. The systematic literature review returned 1,447 non-duplicated articles, of which 177 met eligibility for full text review. Forty-eight studies (13 RCTs, 35 LOSs) were included in the qualitative analysis. The FVC SOMP table revealed high quality, consistent data with evidence of good performance for all five measurement properties, suggesting requisite published evidence to proceed with endorsement. The DLco SOMP table showed a lack of data to support test-retest reliability and inadequate evidence to support clinical trial discrimination. There was unanimous agreement (15 [100%]) among voting CTD-ILD Working Group members to endorse the FVC as an instrument for lung physiology in RCTs and LOSs in SSc-ILD. Based on currently available evidence, DLco did not meet the OMERACT criteria and is not recommended for use in RCTs to represent lung physiology of SSc-ILD. The OMERACT Technical Advisory Group agreed with these decisions. CONCLUSION The OMERACT Filter 2.1 was successfully applied to the domain of lung physiology in patients with SSc-ILD. The FVC was endorsed for use in RCTs and LOSs based on the Working Group's vote; DLco was not endorsed.
BackgroundInterstitial Lung Disease (ILD) is the most common cause of mortality in myositis and t... more BackgroundInterstitial Lung Disease (ILD) is the most common cause of mortality in myositis and there is lack of randomized clinical trials for myositis-associated ILD (MA-ILD). A T-cell mediated pathogenesis has been postulated for MA-ILD, and abatacept (ABA) is a T cell co-stimulatory modulator.ObjectivesOur primary objective was to evaluate the efficacy, safety and tolerability of ABA (125 mg SQ weekly) combined with standard of care (SOC) vs. placebo/SOC in MA-ILD patients in a multi-center, double-blind, randomized placebo-controlled proof of concept clinical trial.Methods20 patients (pts) with anti-synthetase antibody (Anti-Syn Ab) were enrolled across 5 centers for 24 weeks in a randomized placebo-controlled phase (RCT) followed by an open label extension (OLE) for 24 weeks. Active myositis was not required but pts must have had active ILD (new onset or worsening requiring treatment) and previously failed ≥1 SOC drug for ILD. Pts were required to be on stable SOC [glucocorticoids (GC)/1 immunosuppressive (IS) agent (azathioprine or mycophenolate) prior to the trial as well as stable SOC IS throughout the trial]. A recommended GC taper was instituted. The primary endpoint was the change in Force Vital Capacity (FVC) (in ml) change from baseline to week 24. Secondary endpoints included FVC changes over 48 weeks, patient reported outcomes (PRO) of dyspnea (UCSD-shortness of breath questionnaire; range 0-120, MCID of 8) and DLCO corrected % predicted (DLCO) at 24 and 48 weeks. Mixed effect modeling was used for analysis and the study was not powered for primary or secondary outcomes.ResultsA total of 20 anti-Syn Ab positive pts (mean age of 57, 45% female and 85% Caucasian, Jo-1, 55%) were randomized to ABA (n=9) and placebo (n=11). All but 1 pts completed 48 weeks of the trial. There was no significant or clinically relevant difference in median FVC (ml) from baseline to week 24 between ABA (-40 ml) and placebo (30 ml), p = 0.97. However, the median FVC (ml) change from baseline to week 48 was 140 ml and -40 ml, in ABA vs. placebo (p=0.15), with a 180 ml difference in favor of the ABA group. FVC% predicted remained stable (±5%) or improved (>5%) without death or drug rescue in 75% (6/8) and 45% (5/11) at week 24 and week 48, in ABA vs. placebo, respectively. The median DLCO change from baseline was -4.5 and -10.5 at week 24; 6.5 and -2.7 at week 48, in ABA vs. placebo group, respectively. DLCO remained stable (±5%) or improved (>5%) without death or rescue in 57% (4/7) and 45% (5/11) at week 24; 62.5% (5/8) and 40% (4/10) at week 48, in ABA vs. placebo, respectively. Dyspnea improved by median of 1 and 3 at week 24; 13 and 5 at week 48 in ABA vs. placebo, respectively. Dyspnea improved by an MCID of 8 without requiring drug rescue or death in 22% (2/9) and 45.5% (5/11) at week 24; 50% (4/8) and 18% (2/11) pts at week 48 in ABA vs. placebo, respectively. There were 3 severe adverse events (1 in RCT, 2 in OLE) in 2 pts requiring hospitalization in the ABA group for progressive respiratory failure and 1 died (at 24 weeks). There were 36 and 23 adverse events among 9 placebo and 9 treatment group pts. ABA was well tolerated.ConclusionMA-ILD ABA-treated subjects showed similar FVC, DLCO and dyspnea PRO trends compared to placebo at 24 weeks but clinically and numerically meaningful trends were observed in ABA-treated subjects at week 48. These results suggest the need for a larger randomized study of ABA in MA-ILD. Abatacept was relatively safe and well tolerated in the cohort.Figure 1: Change from baseline in Forced Vital Capacity (FVC) in ml by treatment groups.Table 1.Baseline demographics and clinical variables by treatment groups:Clinical variablePlacebo (N=11)Abatacept (N=9)Age57.7 [47.8-64.5]49.7 [46.6-59.3]Female4 (36)5 (56)Non-Hispanic11 (100)9…
ABSTRACT Background Lack of reliable and valid measures of disease activity and clinical response... more ABSTRACT Background Lack of reliable and valid measures of disease activity and clinical response in patients with CTD-ILD makes clinical trial design difficult. From a multi-tiered investigation to develop consensus on provisional criteria in both CTD-ILD and idiopathic pulmonary fibrosis (IPF), we report the results of expert voting from a 3-tiered Delphi exercise to identify domains “important” to measure in a one year randomized controlled trial (RCT) in IPF and CTD-ILD. Methods Using the international consensus organization, Outcome Measures in Rheumatology (OMERACT) methodology, 270 experts nominated 23 “domains” and 616 “instruments” that were assembled into an initial voting survey for a 3-tiered Delphi exercise with survey items anchored by degree of importance on a 9-point Likert scale with as a voting option. All stages of data collection used a custom-designed secure web-site that included related articles and opportunities for participants to upload commentary supporting or refuting importance of each item. Tier 1 Analysis: A cut-off median <4 was applied to the results. Final review demanded 100% consensus agreement for dismissal of an item based on lack of: 1. Face validity, 2. Content validity (more suited to diagnostic, demographic, or inclusion criteria) and 3. Feasibility in a multicenter trial. Tiers 2 and 3 Analysis: To protect against bias introduced by using an arbitrary cut-off, cluster analysis was implemented to identify patterns of consensus within the data. Results 90% of invited experts: 137 pulmonary, 102 rheumatology and 4 cardiology specialists from 32 countries/6 continents participated. 74% and 69% of participants considered ILD and rheumatologic lung disease respectively as their primary field of research or clinical interest. Recidivism after Tier 1 was <1% with each subsequent Tier. Five common domains were identified for CTD-ILD and IPF: DYSPNEA, HEALTH RELATED QUALITY OF LIFE, LUNG IMAGING, LUNG PHYSIOLOGY/FUNCTION and SURVIVAL. Conclusions Development of valid, discriminatory and feasible outcome measures to assess disease progression and therapeutic responses is essential for performing RCTs in CTD-ILD. This is the first comprehensive, multi-disciplinary, international effort to assess domains for study of ILD. Experts identified a core set of measures focused on radiographic, physiologic and patient-reported outcomes culled from a large number of candidate items. A research agenda focusing on candidate biomarkers and domains requiring instrument development has emerged. Broad participation from a multidisciplinary ILD research community reflects the high perceived need in this area. Disclosure of Interest L. A. Saketkoo Grant/Research support from: Actelion, United Therapeutics, D. Khanna Speakers Bureau: Actelion, Fibrogen, Gilead, Novartis, Pfizer, Sanofi, Unitied Therapeutics, D. Huscher: None Declared, P. Dellaripa Grant/Research support from: Biogen IDEC, Genentech, K. Flaherty: None Declared, E. Matteson Grant/Research support from: Biogen IDEC, Genentech, C. Oddis Consultant for: Biogen IDEC, Genentech, A. Wells: None Declared, C. Denton Consultant for: Actelion, Glaxo Smith Kline, Pfizer, United Therapeutics, O. Distler Consultant for: Actelion, Active BiotechBristol-Myers Squibb, Fibrogen, Ergonex, Genentech, Novartis, Pfizer, Sanofi, Unitied Therapeutics, 4D Therapeutics, O. Kowal-Bielecka Consultant for: Bayer, Pfizer, N. Sandorfi: None Declared, R. Christmann: None Declared, K. Phillips Grant/Research support from: Actelion, Amgen, Centocor, Merck, Pfizer, Unitied Therapeutics, D. Pittrow Consultant for: Actelion, Pfizer, MSD, Novartis, Bayer, MBiotec, Baxter, V. Strand Consultant for: Actelion, Amgen, Bristol Myers Squibb, Celgene, Fibrogen, Genentech, Novartis, Pfizer, Sanofi, UCB, K. Brown Consultant for: Actelion, Fibrogen, Gilead, Amgen, Genentech, Celgene, J. Seibold Consultant for: Actelion, Fibrogen, Gilead, Genentech, Celgene, MedImmune, Boerhringer-Ingelheim, Sigma Tau
Objectives Patient-reported global disease activity (patient-global) is a myositis core set measu... more Objectives Patient-reported global disease activity (patient-global) is a myositis core set measure. Understanding the drivers of patient-global is important in patient assessment, and disagreements between physician and patient perception of disease activity may negatively impact shared decision making. We examined the determinants of patient-global and discordance between patient-global and physician-reported global disease activity (physician-global) in idiopathic inflammatory myopathies (IIMs). Methods Adults with IIM were enrolled in a prospective observational cross-sectional study. The following myositis outcome measures were collected: patient-global, physician-global, extramuscular and muscle disease activity, manual muscle testing, HAQ, creatine kinase, fatigue, pain, Patient-Reported Outcomes Measurement Information System physical function, 36-item Short Form, sit to stand, timed up and go, 6-minute walk and Actigraph steps/min/day count. A linear regression model was us...
Background:Dermatomyositis (DM) is a rare chronic systemic autoimmune disease with characteristic... more Background:Dermatomyositis (DM) is a rare chronic systemic autoimmune disease with characteristic skin rash and progressive proximal muscle weakness. Current therapies encompass corticosteroids and other immunosuppressants and intravenous immunoglobulins (IVIg), however, none of these therapies are proven by randomized controlled phase 3 studies. There have been no large randomized clinical trials supporting the efficacy and safety of IVIg in DM.Objectives:The ProDERM study aimed to evaluate the efficacy and safety/tolerability of IVIg in DM patients in a double-blind, randomized, placebo-controlled, international multi-center, phase III clinical trial.Methods:The trial consisted of a double-blind, placebo-controlled First Period (16 weeks), in which adult patients with definite or probable DM (according to Bohan and Peter criteria) were randomized 1:1 to either high dose IVIg (2g/kg every 4 weeks) or placebo. Patients on placebo and patients without clinical worsening while on IVIg...
ObjectiveTo assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, dou... more ObjectiveTo assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double‐blind, placebo‐controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM).MethodsThirty‐six subjects with probable or definite DM/PM were enrolled in a 6‐month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis‐associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)‐8 score of less than 136/150. If the MMT‐8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcom...
ObjectivesIn dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes.... more ObjectivesIn dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with an increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.MethodsPhage ImmunoPrecipitation Sequencing using sera from 43 patients with DM suggested that transcription factor Sp4 is a novel autoantigen; this was confirmed by showing that patient sera immunoprecipitated full-length Sp4 protein. Sera from 371 Johns Hopkins patients with myositis (255 with DM, 28 with antisynthetase syndrome, 40 with immune-mediated necrotising myopathy, 29 with inclusion body myositis and 19 with polymyositis), 80 rheumatological disease controls (25 with Sjogren’s syndrome, 25 with systemic lupus erythematosus and 30 with rheumatoid arthritis (RA)) and 200 healthy comparators were screened for anti-SP4 autoantibodies by ELISA. A validation cohort of 46 anti-TIF1γ-positive patient sera from the University of Pit...
Idiopathic immune myopathies (IIM) represent a group of disorders causing chronic inflammation an... more Idiopathic immune myopathies (IIM) represent a group of disorders causing chronic inflammation and significant damage to skeletal muscle due to an unchecked autoimmune response. The main challenge slowing study of IIM is an understanding of the pathogenic mechanism responsible for initiation and progression of skeletal muscle inflammation. Two mouse models of IIM have recently provided new insights into the pathogenesis of the disease. The synaptotagmin VII null (Syt VII−/−) mouse is characterized by defects in membrane resealing and presents with a mild form myositis at 2 months of age. A more robust model of IIM combines knock‐out of Syt VII with a FoxP3 mutation resulting in a mouse with impaired membrane resealing and regulatory T‐cell deficiency. Adoptive transfer of lymphocyte preparations isolated from this double mutant mouse model to recombination‐activating gene 1 (RAG‐1) null mice results in severe skeletal muscle inflammation. Plasma membrane resealing is a highly conser...
Glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myop... more Glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myopathy (IIM); however, they have significant limitations including lack of complete response and long-term adverse events. Glucocorticoid-sparing agents are often given concomitantly with other immunosuppressive agents, particularly in patients with moderate or severe disease. First-line conventional immunosuppressive drugs include either methotrexate or azathioprine, and second-line immunosuppressive therapy includes mycophenolate mofetil, tacrolimus or cyclosporine, intravenous immunoglobulin, or rituximab, used alone or in various combinations. As treatment of refractory cases of idiopathic inflammatory myopathies (IIM) has been challenging, there is growing interest in assessing novel biologics that target various pathways implicated in the pathogenesis of IIM. Rituximab is being used off-label with increasing evidence in refractory myositis and associated interstitial lung disease. Antitumor necrosis factor (anti-TNF) is currently not being used in IIM due to uncertain efficacy data. Further research is currently ongoing to evaluate the role of other novel therapies such as tocilizumab (anti-IL6), abatacept (inhibition of T-cell co-stimulation), sifalimumab (anti-IFNα), or tofacitinib (Janus kinase (JAK) inhibitor) given their biological plausibility and encouraging recent small case series results. IVIG is being used either as monotherapy or as combination therapy especially for necrotizing myopathies, and there is an ongoing randomized controlled trial in dermatomyositis (DM).
OBJECTIVE The Outcome Measures in Rheumatology (OMERACT) is a research organization focused on im... more OBJECTIVE The Outcome Measures in Rheumatology (OMERACT) is a research organization focused on improving health care outcomes for patients with autoimmune and musculoskeletal diseases. The Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) Working Group on Lung Physiology is a group within OMERACT charged with identifying outcome measures that should be implemented in studies of patients with CTD-ILD. The OMERACT Filter 2.1 is an evidence-based algorithm used to identify outcome measures that are truthful, feasible, and able to discriminate between groups of interest. Our objective was to summate evidence (published literature, key opinion leader input, patient perspectives) that would influence the CTD-ILD Working Group's vote to accept or reject the use of two measures of lung physiology, the forced vital capacity (FVC) and the diffusion capacity of carbon monoxide (DLco) for use in randomized controlled trials (RTCs) and longitudinal observational studies (LOSs) involving patients with systemic sclerosis associated ILD (SSc-ILD). METHODS Patient Research Partners (those afflicted with SSc-ILD) and the CTD-ILD Working Group on Lung Physiology were polled to assess their opinion on the FVC and DLco in terms of feasibility; the CTD-ILD Working Group was also queried on these instruments' face and content validity. We then conducted a systematic literature review to identify articles in the SSc-ILD population that assessed the following measurement properties of FVC and DLco: (1) construct validity, (2) test-retest reliability, (3) longitudinal construct validity, (4) clinical trial discrimination/sensitivity to detect change in clinical trials, and (5) thresholds of meaning. Results were summarized in a Summary of Measurement Properties (SOMP) table for each instrument. OMERACT CTD-ILD Working Group members discussed and voted on the strength of evidence supporting these two instruments and voted to endorse, provisionally endorse, or not endorse either instrument. RESULTS Forty Patient Research Partners reported these two measures are feasible (are not an unnecessary burden or represent an infeasible longitudinal assessment of their disease). A majority of the 18 CTD-ILD Working Group members voted that both the FVC and DLco are feasible and have face and content validity. The systematic literature review returned 1,447 non-duplicated articles, of which 177 met eligibility for full text review. Forty-eight studies (13 RCTs, 35 LOSs) were included in the qualitative analysis. The FVC SOMP table revealed high quality, consistent data with evidence of good performance for all five measurement properties, suggesting requisite published evidence to proceed with endorsement. The DLco SOMP table showed a lack of data to support test-retest reliability and inadequate evidence to support clinical trial discrimination. There was unanimous agreement (15 [100%]) among voting CTD-ILD Working Group members to endorse the FVC as an instrument for lung physiology in RCTs and LOSs in SSc-ILD. Based on currently available evidence, DLco did not meet the OMERACT criteria and is not recommended for use in RCTs to represent lung physiology of SSc-ILD. The OMERACT Technical Advisory Group agreed with these decisions. CONCLUSION The OMERACT Filter 2.1 was successfully applied to the domain of lung physiology in patients with SSc-ILD. The FVC was endorsed for use in RCTs and LOSs based on the Working Group's vote; DLco was not endorsed.
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Papers by Chester Oddis