What is the role of Immune Response Modifiers (IRM) in the treatment of myositis?

Role of Immune Response Modifiers in Myositis Treatment

Context-Dependent Treatment Approach

The role of immune response modifiers (IRMs) in myositis depends critically on the underlying etiology: for immune checkpoint inhibitor-induced myositis, immediate ICI discontinuation with high-dose corticosteroids (1-2 mg/kg/day) is mandatory, with IVIG and/or plasmapheresis added for severe cases; for idiopathic inflammatory myopathies, corticosteroids remain first-line with conventional immunosuppressants (methotrexate, azathioprine) as steroid-sparing agents, while biologics like rituximab are reserved for refractory disease. 1

Immune Checkpoint Inhibitor-Induced Myositis

Immediate Management by Severity Grade

Grade 2 (Moderate Weakness):

• Discontinue checkpoint inhibitor immediately and initiate prednisone 0.5-1 mg/kg/day 2
• If CK is elevated ≥3 times upper limit of normal, this dosing is mandatory 2
• Permanent discontinuation may be required if objective findings persist (elevated enzymes, abnormal EMG, abnormal MRI or biopsy) 2
• Refer to rheumatology or neurology before or concurrent with corticosteroid initiation 1

Grade 3-4 (Severe Weakness or Life-Threatening Features):

• Hold ICI permanently if any myocardial involvement is present 2
• Administer methylprednisolone IV 1-2 mg/kg or higher-dose bolus for severe compromise (weakness severely limiting mobility, cardiac involvement, respiratory compromise, dysphagia) 2
• Add IVIG and/or plasmapheresis for life-threatening manifestations including dysphagia, dyspnea, or myocarditis 1
• Consider hospitalization for severe weakness 2

Critical Cardiac Assessment

• Obtain cardiac troponin I (not troponin T, which can be elevated from skeletal muscle alone) and ECG for all suspected myositis cases 1
• Perform cardiac MRI if troponin is elevated, ECG abnormal, or clinical suspicion exists, as myocarditis drives the 20% mortality rate in checkpoint inhibitor-induced myositis 1
• Continue cardiac monitoring as myocarditis can develop or worsen even during treatment 1

Refractory ICI-Induced Myositis

If no improvement or worsening after 4-6 weeks of corticosteroids:

• IL-6 receptor inhibitors (tocilizumab) are the preferred biologic agent 1
• Conventional DMARDs including mycophenolate mofetil, methotrexate, or azathioprine can be used as steroid-sparing agents 2, 1
• TNF-α inhibitors may be considered specifically if associated fasciitis is present 1
• Abatacept and alemtuzumab have shown success in glucocorticoid-refractory myocarditis and may be considered as rescue therapy 1
• Caution: Rituximab is used in primary myositis but exercise caution given its long biologic duration 2

Idiopathic Inflammatory Myopathies (Dermatomyositis, Polymyositis, IMNM, Antisynthetase Syndrome)

First-Line Treatment

• Glucocorticoids remain the mainstay of initial treatment 3, 4
• High-dose corticosteroids are standard, though this results in relatively slow improvement of muscle strength 5

Add-On Immunosuppression

Early conventional immunosuppressants:

• Methotrexate and azathioprine are often used early in the treatment course 4
• These agents can be used alone or in combination 4
• Other options include mycophenolate mofetil, tacrolimus, cyclosporine, and cyclophosphamide 4

Evidence for IVIG:

• One placebo-controlled trial showed statistically significant improvement in muscle strength scores with IVIg over three months 6
• Early add-on IVIg may lead to faster clinical response in newly diagnosed myositis compared to prednisone monotherapy 5
• IVIg improved symptoms and muscle strength in refractory myositis patients 5

Biologic Agents for Refractory Disease

• Rituximab has more mechanistic rationale and is used for refractory manifestations 4
• Etanercept showed some evidence of steroid-sparing effect but no improvement in other outcomes 6
• Novel agents are being tried for refractory manifestations beyond established therapies 3

Negative Evidence

• Plasma exchange and leukapheresis, eculizumab, and infliximab showed no benefit in placebo-controlled trials 6
• Comparative studies of azathioprine versus methotrexate, ciclosporin versus methotrexate, and intramuscular methotrexate versus oral methotrexate plus azathioprine showed no statistically significant differences in efficacy 6

Monitoring and Tapering Strategy

• Monitor CK levels, ESR, and CRP regularly to assess treatment response 2, 1
• Perform muscle strength examination at each follow-up visit 1
• Once improvement is achieved, taper corticosteroids progressively to the lowest effective dose, targeting ≤10 mg/day prednisone equivalent when possible 1

Critical Pitfalls to Avoid

• Do not delay treatment while awaiting biopsy confirmation in ICI-induced myositis, as over 80% achieve favorable outcomes with prompt ICI discontinuation and immunomodulatory treatment 1
• Do not miss concurrent myasthenia gravis, which occurs in 12.5% of checkpoint inhibitor myositis cases and contributes to bulbar and respiratory symptoms 1
• Do not use IL-6 inhibition (tocilizumab) in patients with colitis or GI metastases due to rare but serious risk of intestinal perforation 2
• Do not rechallenge with checkpoint inhibitors, as caution is strongly advised given the potentially fatal nature of recurrent myositis 1
• Recognize that immunosuppressants are associated with significant side effects requiring careful monitoring 6