Key messages
Due to a lack of robust evidence, the benefits and risks of rituximab, abatacept and complement inhibitor treatment in people with idiopathic inflammatory myopathies (IIMs) are unclear.
Improvement in IIM activity, as measured by the International Myositis Assessment and Clinical Studies Group (IMACS) definitions of improvement (DOI), may be more likely with abatacept treatment compared to placebo.
Large studies are needed to see if targeted therapies work in the different types of IIM. As IIM is rare, this would best be done by many centres working together internationally.
Background
The IIMs are a group of diseases where your immune system attacks the muscles. This damages the muscles, causing progressive weakness. In some types of IIM, known as dermatomyositis (DM), there are rashes that are very specific to this disease. Traditionally, if there is no rash, the disease has been called polymyositis (PM), but we now understand that there are many different forms of IIM, which may respond differently to treatment. This review does not include 'inclusion body myositis', which does not appear to respond to immunosuppression.
IIMs are treated with 'immunosuppressive' treatments that dampen down the immune system and 'immunomodulatory' drugs that alter the immune system. The aim of these therapies is to stop the immune system attacking the muscles. These treatments can be very precise, targeting very specific molecules or cells in the immune system; others are less precise. We assessed this first group of treatments (the targeted therapies) in this review.
What did we want to find out?
We wanted to find out the benefits and harms of targeted therapies in the IIMs. In particular, we were interested in the treatments rituximab, abatacept and complement inhibitors.
What did we do?
We searched for all studies that assessed targeted therapies in people with IIM. We only included studies where people with IIM were selected randomly for two or more treatment groups.
We compared and summarised the study results, and rated our confidence in the evidence, based on factors such as study methods and sizes.
There are different ways to measure whether a treatment is helpful. We looked for specific measures that we felt were important for people with IIM. Our two most important outcomes were improvement in measurements of disability or function and improvement in muscle strength (considered an improvement of 15% or more in the score). Other measures assessed included internationally agreed scores made up from a combination of different measures, the IMACS DOI and total improvement score (TIS), the total amount of steroids taken, serious negative effects and the number leaving the studies because the drug did not work or because of a medical problem.
What did we find?
We found 16 studies that involved 830 people with IIM. The biggest study was in 200 people, the smallest in 13 people. All included centres in the USA (14) or Europe (10), or both; six included centres in other countries. Pharmaceutical companies provided funding for 15 of the studies and drugs for the one remaining study. The studies lasted from 8 to 52 weeks.
One study assessed rituximab therapy in 200 participants. We looked at the eight-week results as after that, all the participants were on rituximab. This is earlier than we would have liked - we wanted results from six months and no less than three months, as treatments usually take this long to take effect. This makes us less confident in the reliability of the results. The evidence for the effect of rituximab on overall improvement assessed by the IMACS DOI and withdrawals for lack of benefit or adverse events is very uncertain. The other measurements were not available at eight weeks.
For abatacept, we included two studies with 168 participants. Abatacept may improve IIM as measured by the IMACs DOI, but we have very low confidence in this result. Abatacept may lead to little or no difference in muscle strength, measures of disability, serious negative effects or withdrawals.
We found two studies (40 participants) that compared complement inhibitors (eculizumab and zilucoplan) to placebo. The total amount of steroids taken was not reported, but for the other outcomes, complement inhibitors may have little or no effect on IIM.
What are the limitations of the evidence?
There was not enough information to be certain if the treatments worked or not. We need more studies to decide whether the treatments are helpful.
How up-to-date is this evidence?
This summary is based on evidence available until 3 February 2023.
閱讀完整摘要
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.
目的
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.
搜尋策略
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.
選擇標準
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.
資料收集與分析
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.
主要結果
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).
作者結論
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.
