Targeted immunosuppressive and immunomodulatory therapies for idiopathic inflammatory myopathies.

Background: Idiopathic inflammatory myopathies (IIM) are autoimmune-mediated inflammatory disorders of skeletal muscles with non-muscle involvement in some people. Treatment of IIM represents an area of unmet need; a previous Cochrane review (2012) found little or no evidence to guide treatment. Since then, potentially promising treatments targeting B and T cells and complement inhibitors have been investigated.

Objectives: To assess the effects (benefits and harms) of targeted immunosuppressant and immunomodulatory treatments for the idiopathic inflammatory myopathies: dermatomyositis (DM, including juvenile dermatomyositis (JDM) and amyopathic dermatomyositis), immune-mediated necrotising myopathy (IMNM), anti-synthetase syndrome (ASS), overlap-myositis (OM), polymyositis (PM) and cancer-related myositis.

Search methods: We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase and clinical trial registers until February 2023. We intended to check references and citations, and contact experts to identify additional studies, but lacked the resources.

Selection criteria: We included randomised controlled trials (RCTs) or quasi-RCTs of targeted immunosuppressive and immunomodulatory therapies in adults and children with IIM. Primary outcomes were improvement of function or disability and improvement of muscle strength. Secondary outcomes were achievement of definitions of improvement, cumulative corticosteroid dose, change in skin disease activity, serious adverse event and withdrawals for lack of benefit or adverse events. Our preferred follow-up was six months, although we accepted three months.

Data collection and analysis: We followed standard Cochrane methodology. To assess risk of bias we used the domain-based Cochrane tool (RoB 1). We used fixed-effect models, and, when needed, random-effects models for meta-analysis. We created summary of findings tables for any comparison for which data were available, but chose in advance to prioritise comparisons of rituximab, abatacept or complement inhibitors with placebo, no treatment or standard care. We assessed the certainty of evidence using GRADE.

Main results: We included 16 studies (830 participants). All studies were at risk of bias (10/16 high risk in at least one domain; four studies with unclear risk in ≥ 2 domains judged as high risk). Selective reporting was the most frequent reason for high risk of bias (37%). None of the treatments assessed showed moderate or high-certainty evidence of response compared to placebo for any of the primary or secondary outcomes. Improvement of function or disability For rituximab, function or disability improvement was not reported separately. Abatacept may have little or no effect on disability measured as change on the Health Assessment Questionnaire Disability Index (HAQ-DI) (range 0 to 3, lower scores better) (mean difference (MD) -0.14, 95% confidence interval (CI) -0.29 to 0.02; 2 RCTs, 147 participants; low certainty). For complement inhibitors, the evidence for change on the HAQ-DI is very uncertain (MD -0.15, 95% CI -0.61 to 0.32; 1 RCT, 26 participants; very low certainty). Improvement of muscle strength Muscle strength was not reported separately in the rituximab study. Abatacept may have little or no effect on muscle strength (Manual Muscle Test-8 (MMT8): range 0 to 150 bilateral, 0 to 80 unilateral; higher scores better) (MD 3.6, 95% CI -0.15 to 7.35; 2 RCTs, number of participants unclear; low certainty). For complement inhibitors, there was no clear difference in muscle strength (proximal muscle strength score, range 0 to 140, 140 equates to full strength) (MD 3.89, 95% CI -6.17 to 13.95; 1 RCT, 25 participants; very low certainty). Achievement of definitions of improvement International Myositis Assessment and Clinical Studies Group definitions of improvement (IMACS DOI) In the rituximab study, the evidence for the effect on the IMACS DOI is very uncertain and could favour rituximab or placebo (risk ratio (RR) 0.72, 95% CI 0.39 to 1.34; 1 RCT, 200 participants; very low certainty). Response was measured at eight weeks (shorter than our preferred time point) and was considered indirect. Abatacept may improve achievement of IMACS DOI after three to six months (RR 1.42, 95% CI 1.02 to 1.98; 2 RCTs, 167 participants; low certainty). Myositis Response Criteria Total Improvement Score (TIS) Achievement of moderate or major TIS was reported for abatacept but could favour abatacept or placebo (RR 1.12, 95% CI 0.81 to 1.57; 1 RCT, 120 participants). TIS minimal improvement was reported for complement inhibitors and could favour treatment or placebo (RR 1.09, 95% CI 0.51 to 2.31; 1 RCT, 25 participants; very low certainty). Cumulative corticosteroid dose Cumulative steroid dose was not measured or reported separately in the selected studies. Change in skin disease activity Change in Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) was not measured in the selected studies. Serious adverse event We were unable to extract serious adverse event data for the randomised period of the rituximab study. For abatacept, the evidence was very uncertain because of study limitations and serious imprecision (RR 0.97, 95% CI 0.25 to 3.75; 2 RCTs, 167 participants; very low certainty). For complement inhibitors, the evidence was very uncertain (RR 0.18, 95% CI 0.01 to 3.11; 2 RCTs, 40 participants; very low certainty). Withdrawals for either lack of benefit or adverse events For rituximab, the evidence was very uncertain (RR 1.47, 95% CI 0.25 to 8.59; 1 RCT, 190 participants; very low certainty). The evidence was very uncertain for abatacept (RR 0.63, 95% CI 0.19 to 2.14; 2 RCTs, 167 participants; very low certainty). For complement inhibitors, one study reported no withdrawals (27 participants) and the other did not provide data (very low certainty).

Authors' conclusions: The evidence for the use of rituximab, abatacept and complement inhibitors in IIM is largely uncertain. Abatacept may improve achievement of IMACS DOI at three or six months, although the evidence is of low certainty. More research is needed to investigate the benefits and harms of targeted immunosuppressive and immunomodulatory therapies in IIM. Ideally, studies should be sufficiently powered to ensure detection of effects in subgroups (e.g. IMNM, DM, ASS). Because of the rarity of IIM, international collaborative efforts should be encouraged to embark on multicentre trials.