What is the best course of action for a patient with a long history of connective tissue disorder on methotrexate (MTX), Humira (adalimumab), and Plaquenil (hydroxychloroquine) experiencing worsening muscle pain and stiffness?

Evaluation and Management of Worsening Muscle Pain in a Patient on Methotrexate, Adalimumab, and Hydroxychloroquine

This patient requires immediate laboratory evaluation including CK, aldolase, inflammatory markers (ESR, CRP), and a comprehensive rheumatologic assessment to distinguish between drug-induced myositis, inflammatory arthritis flare, or polymyalgia-like syndrome, with urgent rheumatology referral if CK is elevated or symptoms are severe.

Initial Diagnostic Workup

The clinical presentation—pain worse with standing, improving with movement initially but worsening with prolonged activity, and stiffness—suggests either inflammatory arthritis, polymyalgia-like syndrome, or potentially drug-induced myositis. The diagnostic approach must differentiate these entities:

Essential Laboratory Tests

• CK and aldolase to evaluate for myositis, as muscle weakness (not just pain) is more typical of true myositis 1
• Inflammatory markers (ESR and CRP) to assess systemic inflammation 1
• Transaminases (AST, ALT) and LDH, which can be elevated in myositis 1
• Troponin and ECG to exclude myocardial involvement if myositis is suspected 1
• ANA, RF, and anti-CCP if inflammatory arthritis is being considered 1

Clinical Examination Priorities

• Complete rheumatologic examination of all joints for tenderness, swelling, and range of motion 1
• Muscle strength testing to distinguish true weakness from pain-limited movement 1
• Skin examination for dermatomyositis findings 1

Differential Diagnosis and Management Strategy

If CK is Normal: Likely Inflammatory Arthritis or Polymyalgia-Like Syndrome

For moderate symptoms (Grade 2):

• Initiate prednisone 20 mg daily for 2-4 weeks 1
• Continue current immunosuppressive regimen (methotrexate, adalimumab, hydroxychloroquine) 1
• Add NSAIDs (naproxen 500 mg BID or meloxicam 7.5-15 mg daily) if no contraindications 1
• Taper corticosteroids over 4-8 weeks if symptoms improve 1
• Refer to rheumatology for ongoing management 1

If no improvement after 4 weeks:

• Escalate to prednisone 40 mg daily 1
• Consider adding a steroid-sparing agent such as methotrexate dose optimization (already on therapy, so consider increasing to 25 mg weekly if not at maximum dose) 2
• Consider triple therapy optimization if not already maximized 3, 4, 5

If CK is Elevated (≥3x ULN): Drug-Induced Myositis

This is a medical urgency requiring:

• Hold adalimumab temporarily 1
• Continue methotrexate and hydroxychloroquine as these may be needed for maintenance 1
• Initiate prednisone 0.5-1 mg/kg daily (approximately 30-60 mg for a 60-year-old) 1
• Urgent rheumatology and/or neurology referral 1

For severe symptoms (Grade 3-4) or very high CK:

• Consider hospitalization if severe weakness, respiratory involvement, or rhabdomyolysis 1
• Methylprednisolone 1-2 mg/kg IV for severe compromise 1
• Consider IVIG or plasmapheresis for acute severe disease 1
• May require permanent discontinuation of adalimumab 1

Critical Considerations for This Patient

Methotrexate-Related Concerns

Methotrexate can cause myopathy, though this is uncommon at standard doses 6. However, methotrexate should generally be continued during evaluation unless severe myositis is confirmed, as it remains a cornerstone of connective tissue disease management 1, 2.

Statin Interaction

Hold statins if the patient is taking them, as they can contribute to myopathy and confound the diagnosis 1.

Disease Activity Assessment

The pattern described (pain on standing, improvement with movement, worsening with prolonged activity) is more consistent with inflammatory arthritis or polymyalgia-like syndrome rather than true myositis, where weakness would be the predominant feature 1.

Monitoring and Follow-Up

• Serial CK and inflammatory markers every 2-4 weeks initially 1
• Functional assessment at each visit 1
• Do not restart adalimumab until CK normalizes and symptoms resolve if myositis is confirmed 1
• Consider EMG, MRI, or muscle biopsy only if diagnosis remains uncertain after initial workup 1

Common Pitfalls to Avoid

• Do not assume this is simply disease progression without excluding drug-induced myositis, particularly given the combination of immunosuppressive agents 1
• Do not stop all immunosuppression abruptly, as this could trigger a disease flare; corticosteroids should be maintained or initiated 1
• Do not delay rheumatology referral if symptoms are moderate to severe, as early intervention prevents irreversible damage 1, 2