The four main types of inflammatory muscle disease — dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis — are summarized. Pathogenesis, differential diagnosis, and treatment approaches are discussed.

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Inflammatory Muscle Diseases

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(13)60954-X.pdf

Immunopathogenic mechanisms of systemic autoimmune disease

Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years?

Results from clinical trials of biologic anti-TNF drugs performed in the late 1990s confirmed the biological relevance of TNF function in the pathogenesis of chronic noninfectious inflammation of joints, skin and gut, which collectively affects 2-3% of the population. Up to April 2009, more than two million patients worldwide have received the first marketed drugs, namely the monoclonal anti-TNF antibodies infliximab and adalimumab and the soluble TNF receptor etanercept. All three are equally effective in rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, but, for not clearly defined reasons, only the monoclonal antibodies are effective in inflammatory bowel disease. About 60% of patients who do not benefit from standard nonbiologic treatments for these diseases respond to TNF antagonists. Less than half of responding patients achieve complete remission of disease. Importantly, some of those patients with rheumatoid arthritis in whom long-term anti-TNF therapy induced disease remission remain disease-free after discontinuation of any kind of treatment. There are not yet reliable predictors of which patients will or will not respond on anti-TNF therapy, whereas subsequent loss of an initial clinical response occurs frequently. The spectrum of efficacy anti-TNF therapies widens to include diseases such as systemic vasculitis and sight-threatening uveitis. While paradoxical new adverse effects are recognized, i.e. exacerbation or development of new onset psoriasis, reactivation of latent tuberculosis remains the most important safety issue of anti-TNF therapies. Clinical practice guidelines and consensus statements on the criteria of introduction, duration of treatment and cessation of TNF antagonists, including safety issues, are under constant revision as data from longer periods of patient exposure accumulate. It is hoped that more efficacious drugs that will ideally target the deleterious proinflammatory properties of TNF without compromising its protective role in host defense and (auto)immunity will be available in the near future.

The First Decade of Biologic TNF Antagonists in Clinical Practice: Lessons Learned, Unresolved Issues and Future Directions

Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Objective: To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. Methods: A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1α, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon γ (IFNγ), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. Results: Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by ⩾20% in three or more variables of the disease activity core set, four were unchanged and two worsened ⩾30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. Conclusions: Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.

https://ard.bmj.com/content/annrheumdis/67/12/1670.full.pdf?67%2F12%2F1670=

A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies

Objective: To investigate serum levels of B cell activating factor (BAFF) in patients with myositis and correlate these to autoantibody profile, clinical phenotype and treatment. Methods: BAFF levels in sera from 49 patients with dermatomyositis, 44 with polymyositis, 6 with inclusion body myositis and 30 matched controls were measured by ELISA. Specific autoantibodies were detected by line blot and western blot assays. Results: Serum levels of BAFF were significantly higher in patients compared to healthy controls (p = 0.003). Patients with anti-Jo-1 autoantibodies had higher BAFF levels than control individuals (p Conclusion: Our finding of elevated serum levels of BAFF in patients with myositis with described phenotypes together with the correlations between levels of BAFF and CK and a negative correlation with dose of glucocorticoids, indicate that BAFF could be a potential therapeutic target in such cases.

https://ard.bmj.com/content/annrheumdis/68/6/836.full.pdf

Increased serum levels of B cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies

. Fathi M, Barbasso Helmers S, Lundberg IE (Karolinska University Hospital, Stockholm; Karolinska Institutet, Karolinska University Hospital, Stockholm; and Institute of Environmental Medicine, Karolinska Institutet, Stockholm; Sweden). KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis. J Intern Med 2012; 271: 589–597.

Objectives.  To investigate whether Caucasian patients with polymyositis (PM) or dermatomyositis (DM) and interstitial lung disease (ILD) have elevated serum levels of KL-6 compared with patients without ILD and whether KL-6 could be used as a marker for ILD activity and treatment efficacy of ILD in PM/DM.

Design and methods.  Thirty patients with PM/DM (seven with ILD) and 17 age- and sex-matched healthy controls were included in a retrospective, cross-sectional analysis. Twelve patients were followed for longitudinal evaluation. ILD was defined as restrictive lung function impairment with radiographic signs of ILD. Serum KL-6 levels were measured using a sandwich enzyme immunoassay kit. Groups were compared by Mann–Whitney U-test.

Results.  PM/DM patients with ILD had significantly higher median serum KL-6 levels compared with those without ILD: 995 (range 533–2318) versus 322 (range 132–1225) U mL−1 (P = 0.0002). Median serum levels of healthy controls were 225 (range 136–519) U mL−1. Serum levels of KL-6 were inversely correlated with percentages of forced expiratory volume in 1 s (FEV1), vital capacity (VC), total lung capacity (TLC), forced VC, diffusing capacity of carbon monoxide (DLco), maximal voluntary ventilation at 40 breaths min−1 and residual volume (RV). Changes in KL-6 levels showed a significant inverse correlation with changes in percentage FEV1, TLC, DLco and RV. At a cut-off level of 549 U mL−1 (mean ± 2.5 SD for controls), the sensitivity and specificity for diagnosis of ILD were 83% and 100%, respectively.

Conclusion.  The level of serum KL-6 may serve as measure of ILD in patients with PM/DM and is a promising biomarker for use in clinical practice to assess clinical response to treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2011.02459.x

KL‐6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis

Objectives: To investigate the expression of microsomal prostaglandin E (PGE) synthase 1 (mPGES-1) and cyclooxygenase (COX) in muscle biopsies from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive treatment. Methods: mPGES-1 and COX expression was evaluated by immunohistochemistry in muscle tissue from healthy individuals and from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive treatment. The number of inflammatory cell infiltrates, T lymphocytes and macrophages was estimated before and after treatment. To localise the mPGES-1 expression double immunofluorescence was performed with antibodies against mPGES-1, CD3, CD68, CD163 and a fibroblast marker. A functional index was used to assess muscle function. Results: In patients with myositis, mPGES-1, COX-2 and COX-1 expression was significantly higher compared to healthy individuals and associated with inflammatory cells. Double immunofluorescence demonstrated a predominant expression of mPGES-1 in macrophages. Conventional immunosuppressive treatment resulted in improved but still lower muscle function than normal. A decreased number of CD68-positive macrophages and reduced COX-2 expression in muscle tissue was also seen. By contrast, following the same treatment no significant changes were observed in muscle tissue regarding number of infiltrates, T lymphocytes, CD163-positive macrophages or mPGES-1 protein levels. Conclusions: Increased expression of mPGES-1, COX-1 and COX-2 at protein level was observed in muscle tissue from patients with myositis compared to healthy individuals. Conventional immunosuppressive treatment led to a significant downregulation of COX-2 in myositis muscle tissue. However, the expression of mPGES-1 and COX-1 remained unchanged indicating a role of these enzymes in the chronicity of these diseases.

https://ard.bmj.com/content/annrheumdis/67/11/1596.full.pdf

Effects of immunosuppressive treatment on microsomal prostaglandin E synthase 1 and cyclooxygenases expression in muscle tissue of patients with polymyositis or dermatomyositis

S Barbasso Helmers

Papers

A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies

Increased serum levels of B cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies

KL‐6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis

Effects of immunosuppressive treatment on microsomal prostaglandin E synthase 1 and cyclooxygenases expression in muscle tissue of patients with polymyositis or dermatomyositis