Myositis-specific or myositis-associated antibodies can be found in most patients with myositis and are associated with distinct disease phenotypes. These antibodies also provide valuable insights into the pathogenesis of myositis and can help guide treatment. The discovery of novel autoantigen systems related to idiopathic inflammatory myopathies (collectively referred to as myositis) in adults and children has had major implications for the diagnosis and management of this group of diseases across a wide range of medical specialties. Traditionally, autoantibodies found in patients with myositis are described as being myositis-specific autoantibodies (MSAs) or myositis-associated autoantibodies (MAAs), depending on their prevalence in other, related conditions. However, certain MSAs are more closely associated with extramuscular manifestations, such as skin and lung disease, than with myositis itself. It is very rare for more than one MSA to coexist in the same individual, underpinning the potential to use MSAs to precisely define genetic and disease endotypes. Each MSA is associated with a distinctive pattern of disease or phenotype, which has implications for diagnosis and a more personalized approach to therapy. Knowledge of the function and localization of the autoantigenic targets for MSAs has provided key insights into the potential immunopathogenic mechanisms of myositis. In particular, evidence suggests that the alteration of expression of a myositis-related autoantigen by certain environmental influences or oncogenesis could be a pivotal event linking autoantibody generation to the development of disease.

Autoantibodies in myositis

Objective The aim was to study the prevalence, rate of appearance and severity of clinical features in patients with different anti-synthetase syndrome (ASyS) autoantibodies. Methods All Johns Hopkins Myositis Longitudinal Cohort subjects positive for any ASyS autoantibodies were included. Clinical information, including symptoms, signs, strength, creatine kinase concentrations and pulmonary function tests, were prospectively collected. The standardized mortality and cancer rates and the rate of appearance and intensity of the different organ manifestations were assessed using univariate and multivariate analysis and compared between ASyS autoantibodies. Results One hundred and twenty-four (73.4%) patients were positive for anti-Jo1, 23 (13.6%) for anti-PL12, 16 for anti-PL7 (9.5%) and 3 (1.8%) for anti-EJ or anti-OJ, respectively. The mean length of follow-up was 4.1 years. Anti-PL12 was more frequent in black subjects. Anti-PL12 and anti-PL7 were associated with more prevalent and severe lung involvement, often without muscle involvement. Anti-Jo1 displayed more severe muscle involvement compared with anti-PL12 patients. Concurrent anti-Ro52 was more prevalent in anti-Jo1 patients and was associated with earlier development of mechanic's hands, DM-specific skin findings and arthritis. Independent of ASyS antibody status, black patients demonstrated more severe lung involvement than white patients. There was no significant increase in mortality or cancer risk in ASyS patients compared with the general US population. Conclusion Different ASyS autoantibodies are associated with phenotypically distinct subgroups within the ASyS spectrum. Anti-PL7 and anti-PL12 are characterized by more severe lung involvement, whereas anti-Jo1 is associated with more severe muscle involvement. Black race is a major prognostic factor associated with lung disease severity.

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A longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies.

OBJECTIVE To identify initial predictors of poor survival in patients with PM/DM-associated interstitial lung disease (ILD). METHODS We established a multicentre retrospective cohort of incident cases of PM/DM-associated ILD from 44 institutions across Japan (Multicentre Retrospective Cohort of Japanese Patients with Myositis-associated ILD, JAMI). Inclusion criteria were an onset age ⩾16 years; PM/DM or clinically amyopathic DM according to the published criteria; imaging evidence of ILD; and availability of serum samples for assays of autoantibodies such as anti-melanoma differentiation-associated gene 5 and anti-aminoacyl tRNA synthetase. We collected demographic data and clinical characteristics recorded at the time of diagnosis, as well as follow-up survival data. Predictors of ILD-related mortality were identified by univariate and multivariate analyses. RESULTS JAMI enrolled a cohort of 497 patients with PM (15%), classic DM (32%) and clinically amyopathic DM (53%). During the observation period (median 20 months), 76 died of respiratory insufficiency directly related to ILD. Univariate analysis revealed several initial parameters associated with ILD mortality, including demographic, clinical, laboratory, imaging and autoantibody variables. We used multivariate analysis with a stepwise selection of parameters to generate an appropriate predictive model, and identified the following independent risk factors for ILD mortality: age at onset ⩾60 years [hazard ratio (HR) = 4.3, 95% CI: 2.4, 7.5], CRP ⩾1 mg/dl (HR = 2.6, 95% CI: 1.5, 4.8), peripheral capillary oxygen saturation <95% (HR = 2.0, 95% CI: 1.2, 3.4) and anti-melanoma differentiation-associated gene 5 antibody (HR = 7.5, 95% CI: 2.8, 20.2). CONCLUSION We established a large cohort of incident cases of PM/DM-associated ILD, and successfully identified independent predictors of short-term ILD mortality.

Initial predictors of poor survival in myositis-associated interstitial lung disease: a multicentre cohort of 497 patients

Patients with idiopathic inflammatory myopathies (IIMs) suffer an increased burden of comorbidities, but data on mortality in recently diagnosed IIM are conflicting. Also, little is known when, if ever, in relation to IIM diagnosis, mortality is increased. Methods A population-based IIM cohort of patients diagnosed between 2002 and 2011 and general population comparators were identified using healthcare registers. They were linked to the cause of death register for follow-up. Results 224 (31%) of the 716 patients with IIM and 870 (12%) of the 7100 general population died during follow-up. This corresponded to a mortality rate of 60/1000 person-years in IIM and 20/1000 person-years in the general population. The cumulative mortality at 1 year after diagnosis was 9% in IIM and 1% in the general population, and increased in both IIM and the general population with time. The overall hazard ratio (HR) 95%CI of death comparing IIM with the general population was 3.7 (3.2 to 4.4). When we stratified on time since diagnosis, we noted an increase in mortality already within the first year of diagnosis compared with the general population, HR 9.6 (95% CI 6.9 to 13.5). This HR then plateaued around 2 after >10 years with the disease, although the estimates were not statistically significant. Malignancies, diseases of the circulatory and respiratory system were common causes of death. Conclusion Mortality is increased in patients with contemporary IIM. The increased mortality was noted within a year of diagnosis, which calls for extra vigilance during the first year of IIM diagnosis.

https://ard.bmj.com/content/annrheumdis/77/1/40.full.pdf

Mortality in idiopathic inflammatory myopathy: results from a Swedish nationwide population-based cohort study

Interstitial Lung Disease in Polymyositis and Dermatomyositis.

Among patients with autoimmune myositis, associated interstitial lung disease (MA-ILD) is a known contributor of excess morbidity and mortality. Recent data on survival in idiopathic inflammatory myopathies originate primarily in Asia and Europe and vary widely. We sought to examine mortality in a large U.S. myositis cohort focusing in particular on the impact of associated ILD. A cross-sectional analysis of participants from the Johns Hopkins Myositis Center with autoimmune myositis (polymyositis [PM], dermatomyositis [DM], or clinically amyopathic dermatomyositis [CADM]) was conducted. The primary outcome assessed was all-cause mortality. Cumulative mortality rates were estimated using the Kaplan–Meier test; the Cox proportional hazards model was used to compare group differences in survival. Eight hundred and thirty-one participants were included with a median follow-up time of 4.5 years. Four hundred thirty-eight (53 %) had PM, 362 (43 %) had DM, and 31 (4 %) had CADM. Ninety-four (11 %) participants had clinically evident ILD. Overall, 51 participants died (6 %). In those without ILD, the survival rates at 1, 5, and 10 years were 99, 95, and 90 %, respectively. In those with ILD, the survival rates at 1, 5, and 10 years were 97, 91, and 81 %, respectively. The risk of death was statistically significantly higher among participants with ILD compared to those without ILD (HR 2.13. 95 % CI 1.06–4.25; p = 0.03). We analyzed one of the largest known cohorts of patients with autoimmune myositis and found significantly higher mortality rates among those with clinically evident ILD compared to those without clinically evident ILD. Our results suggest that ILD remains an important and significant source of mortality in patients with inflammatory myopathies and as such should be screened for and treated aggressively.

Assessment of Mortality in Autoimmune Myositis With and Without Associated Interstitial Lung Disease.


 Introduction:
 Observational evidence from real world data suggests that providing cardiac rehabilitation (CR) to older patients with incident atrial fibrillation (AF) is associated with lower risk of all-cause mortality and re-hospitalization. We leveraged these data to estimate cost-effectiveness of extending Medicare coverage for exercise based CR to older AF patients.
 
 
 Hypotheses:
 Exercise based CR for older patients with incident AF is cost-effective at a conventional willingness to pay threshold of $50,000 per quality adjusted life year (QALY).
 
 
 Methods:
 A cost-utility analysis was conducted using a decision tree to compare initiation of exercise-based CR with standard care versus standard care alone for older patients with incident AF. Outcomes considered were re-hospitalization and all-cause mortality. A systematic review was conducted to obtain inputs for model parameters. Paucity of research did not allow meta-analyses. Estimated risks & related uncertainty intervals for re-hospitalization and death were obtained from a published propensity score matched analysis of electronic health records data pooled from 41 health care organizations in the United States of America and the United Kingdom. In this study, CR + standard care versus standard care alone was associated with lower odds of all-cause mortality (odds ratio, 0.32, 95% uncertainty interval 0.29, 0.35) and re-hospitalization (odds ratio, 0.56, 95% uncertainty interval, 0.53, 0.59) over 18 months of follow-up. Estimations for costs and QALY were obtained from USA based, peer-reviewed, published studies. Probabilistic sensitivity analysis was conducted to account for uncertainty in estimates. Data analysis was performed from healthcare perspective using Microsoft Excel software.
 
 
 Results:
 In a hypothetical cohort of 10,000 older patients with incident AF (mean age, 68 years, 71% male, 84% White), estimated costs per QALY gained for CR + standard care was about $2659 and standard care alone was about $2455. Providing CR was associated with an estimated incremental cost of $10,374 per incremental QALY gained. Probabilistic sensitivity analysis showed that CR had a >75% chance of being cost-effective at a willingness to pay threshold of $50,000 per QALY.
 
 
 Conclusions:
 Findings from our simulation study based on real world evidence suggest that extending Medicare coverage for exercise based CR to older patients with incident AF may be potentially cost-effective. Implementing such a policy change requires evidence from a large randomized controlled trial that overcomes design-related limitations identified in previous observational and small, randomized interventional research studies.


Radhika Parikh

Papers

Assessment of Mortality in Autoimmune Myositis With and Without Associated Interstitial Lung Disease.

Abstract P371: Estimating Cost-Effectiveness of Exercise Based Cardiac Rehabilitation for Older Patients With Atrial Fibrillation