Key messages
Intravenous immunoglobulin (IVIg) treatment improves disability, muscle strength and skin symptoms in people with dermatomyositis. These improvements may be large enough to be meaningful in daily life, but we cannot be sure.
It is unclear whether IVIg treatment is beneficial in idiopathic inflammatory myopathies (IIMs) other than dermatomyositis.
Due to the small number of studies, it is unclear whether other non-targeted therapies, such as methotrexate and azathioprine, are beneficial in IIM.
Background
The IIMs are a group of diseases where the immune system attacks the muscles. This damages the muscles, causing progressive weakness. In some types of IIM, known as dermatomyositis, there are rashes that are very specific to this disease. Traditionally, if there is no rash, the disease has been called polymyositis, but there are many different forms of IIM that may respond differently to treatment.
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 that the immune system stops attacking the muscles. With recent advances, these treatments can be very precise, targeting very specific molecules or cells in the immune system. However, the subject of this review is non-targeted therapies, which cause a more general suppression or modulation.
What did we want to find out?
We wanted to find out the benefits and harms of non-targeted therapies in the IIMs. In particular, we were interested in three treatments that are frequently used: immunoglobulin, azathioprine and methotrexate.
What did we do?
We searched for all studies that assessed non-targeted therapies in people with IIM. People with IIM had to be selected randomly to 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 (primary) outcomes were improvement in measurements of disability or function and how many people had a meaningful improvement in muscle strength. Other (secondary) measures we looked at included the overall amount of steroid taken, serious negative effects, the number leaving the studies because the drug did not work or because of harm, the amount of steroid therapy used, skin disease activity (Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI)) and internationally agreed combined scores made up of different measures (the International Myositis Assessment and Clinical Studies Group (IMACS) definitions of improvement (DOI), or the more recent total improvement scores). For children, we reported achievement of improvement defined by the Paediatric Rheumatology International Trials Organisation (PRINTO).
What did we find?
We found 16 studies that involved 789 people with IIM.
Three studies (136 people) assessed the effect of intravenous immunoglobulin (IVIg) on disability and muscle strength and showed a probable benefit. We were moderately confident in both these results. One study (95 people) assessed the effect of IVIg on achieving an overall improvement as measured by the IMACs DOI and showed a benefit. One study (95 people) assessed the effect of IVg on skin symptoms and showed a benefit. We had moderate confidence in this result. There may be more serious harms with IVIg than with placebo and little or no difference in withdrawals for either lack of benefit or harms. We have very low confidence in these results.
Only one small study (16 people) compared azathioprine to placebo. This study found little or no benefit of azathioprine for muscle strength, but we have very little confidence in the results. The evidence for the effects on the amount of steroid used was also very uncertain. The study did not assess disability or function. We had very low confidence in all of the results. The study did not systematically report serious harms or withdrawals.
Based on one study (27 people), methotrexate showed little or no effect on function, muscle strength or overall benefit as measured by the IMACs DOI in IIM. However, we had very low confidence in the results. In juvenile dermatomyositis, the evidence from a single study (93 children) showed that more children may improve with methotrexate as measured by the PRINTO definition of improvement. Serious harms may be slightly more frequent with methotrexate and withdrawals for lack of benefit or harms slightly less frequent with methotrexate than placebo.
What are the limitations of the evidence?
There was evidence that IVIg is effective for disability, muscle strength and skin disease but the majority of the people in these assessments had dermatomyositis. As such, it is not clear that these findings can be applied to the other IIMs. We could not be confident in the results for the other interventions due to the small number of studies. Further studies are needed to decide whether these treatments are helpful.
How up-to-date is this evidence?
This summary is based on evidence available until 3 February 2023.
阅读完整摘要
Idiopathic inflammatory myopathies (IIM) are autoimmune-mediated inflammatory disorders of skeletal muscles with non-muscle involvement in some people, which carry significant morbidity and mortality. Treatment of IIM represents an area of unmet need. This review is an update of a review previously published in 2012, as new and promising data on non-targeted treatments have emerged.
研究目的
To assess the effects (benefits and harms) of non-targeted immunosuppressant and immunomodulatory treatments for IIM: dermatomyositis (DM, including juvenile dermatomyositis, jDM), immune-mediated necrotising myopathy (IMNM), anti-synthetase syndrome (ASS), overlap-myositis (OM) and polymyositis (PM). We also included cancer-related myositis and amyopathic dermatomyositis.
检索策略
On 3 February 2023, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, Embase, MEDLINE, ClinicalTrials.gov and WHO ICTRP. We intended to check references and citations, and contact experts to identify additional studies, but lacked the resources.
纳入排除标准
We included all randomised controlled trials (RCTs) or quasi-RCTs involving participants (adults and children) with IIM according to defined criteria. We included non-targeted immunosuppressants and immunomodulatory treatments alone or in combination, compared with a placebo, no treatment or another non-targeted immunosuppressant or immunomodulatory treatment. Our two primary outcomes were improvement of function or disability and improvement of muscle strength compared with baseline. By preference, we used the Health Assessment Questionnaire Disability Index (HAQ-DI) for disability and the Manual Muscle Test-8 (MMT8) score (adults or children) for muscle strength. Other outcomes were achievement of definitions of improvement (DOI) (the International Myositis Assessment and Clinical Studies (IMACS) Group or the more recent total improvement scores (TIS); for children, we reported achievement of improvement defined by the Paediatric Rheumatology International Trials Organisation (PRINTO)), cumulative corticosteroid dose, change in skin disease activity, serious adverse event and withdrawals for lack of benefit or adverse events.
资料收集与分析
We followed standard Cochrane methodology. To assess the risk of bias, we used the domain-based Cochrane risk of bias 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 prioritised comparisons of the following with placebo, no treatment or standard care: immunoglobulin, azathioprine and methotrexate. We included other comparisons as additional tables. We assessed the certainty of evidence using the GRADE approach.
主要结果
We identified 16 studies (789 participants). The risk of bias in all but one study was high or unclear.
Intravenous immunoglobulin (IVIg), compared to placebo, probably improves disability and muscle strength in participants with refractory IIM (standardised mean difference (SMD) 0.86, 95% confidence interval (CI) 0.51 to 1.21 (disability) and 0.78, 95% CI 0.43 to 1.13 (muscle strength); 3 RCTs, 136 participants; both moderate-certainty evidence). IVIg has a higher response rate based on American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria than placebo (risk ratio (RR) 1.80, 95% CI 1.26 to 2.56; 1 RCT, 95 participants; moderate-certainty evidence). IVIg, compared to placebo, improves skin symptoms (Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) total activity score 0 to 100; higher worse) in people with refractory DM (mean difference (MD) -8.20, 95% CI -11.91 to -4.49; 1 RCT, 95 participants; moderate-certainty evidence). There may be more serious adverse events with IVIg than with placebo (RR 1.91, 95% CI 0.50 to 7.30; 2 RCTs, 144 participants; very low-certainty evidence), but little or no difference between IVIg and placebo in withdrawals for either lack of benefit or adverse events (RR 1.02, 95% CI 0.24 to 4.33; 3 RCTs, 154 participants; very low-certainty evidence).
For azathioprine versus placebo, one study showed little or no effect of azathioprine on improvement in muscle strength, but the evidence was very uncertain (RR 1.33, 95% CI 0.43 to 4.13; 1 RCT; 16 participants; very low-certainty evidence). The evidence was also very uncertain for cumulative steroid dose (MD 12.06 mg/kg, 95% CI -6.09 to 30.21; 1 RCT, 16 participants; very low-certainty evidence). This early study did not assess IMACS DOI or CDASI or measure function or disability. Serious adverse events and withdrawals for either lack of benefit or adverse events were not systematically reported.
For methotrexate, there may be little or no improvement in adults with DM or PM in function (Amyotrophic Lateral Sclerosis Functional Rating Scale 0 to 40, higher better) (MD 1.24, 95% CI -1.60 to 4.08; 1 RCT, 27 participants; very low-certainty evidence), muscle strength (MMT scale 0 to 80, higher better) (MD -5.68, 95% CI -12.94 to 1.58; 1 RCT, 27 participants; very low-certainty evidence), achievement of IMACS DOI (RR 1.01, 95% CI 0.74 to 1.39; 1 RCT, 27 participants; very low-certainty evidence). Cumulative steroid dose was measured, but the data could not be analysed, and change in CDASI was not measured. In children with new-onset jDM on a background therapy of prednisone, a higher proportion may achieve minimal improvement according to the PRINTO criteria with methotrexate than with placebo (RR 1.40, 95% CI 1.01 to 1.96; 1 RCT, 93 participants; low-certainty evidence). Serious adverse events may occur slightly more frequently with methotrexate (RR 1.48, 95% CI 0.54 to 4.07; 2 RCTs, 124 participants; low-certainty evidence). There may be fewer withdrawals for lack of benefit or adverse events with methotrexate (RR 0.62, 95% CI 0.37 to 1.05; 3 RCTs, 151 participants; low-certainty evidence).
作者结论
Our review shows improvement in disability, muscle strength and skin symptoms following IVIg in people with refractory DM (for PM, these data are not reliable; other subtypes have not been investigated in RCTs). The improvements related to IVIg in DM may be clinically meaningful, but the absence of established minimal clinically important differences (MCIDs) for both disability and muscle strength in IIM does not facilitate interpretation. For the other agents, the small number of trials of immunosuppressive and immunomodulatory therapies is inadequate to decide whether these agents are beneficial in IIM (excluding IBM). Our review shows room for improvement in the conduct and reporting of clinical trials in IIM, as well as the need to further investigate MCIDs for important outcome measures in IIM.
