What musculoskeletal adverse effects can occur in adult patients receiving infliximab?

Musculoskeletal Side Effects of Infliximab

Musculoskeletal pain, including myalgia and arthralgia, can occur with infliximab therapy, though these adverse effects are relatively uncommon and are primarily documented in case reports rather than being listed among the most frequent adverse reactions in major clinical trials.

Common Musculoskeletal Manifestations

The FDA drug label and clinical guidelines identify the following musculoskeletal adverse effects:

• Arthralgia occurs in approximately 7-8% of patients receiving infliximab across various indications 1
• Musculoskeletal pain is reported as a common adverse event, particularly noted in adalimumab studies (a related TNF antagonist), suggesting this is a class effect 2
• Myalgia can occur as part of serum sickness-like reactions, typically presenting early in the treatment course with fever and/or rash 1

Serious Musculoskeletal Reactions

Serum Sickness-Like Syndrome

In psoriasis studies, approximately 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash, usually early in the treatment course 1. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility 1.

Inflammatory Bursitis

• Bilateral sub-deltoid/subacromial bursitis has been documented in case reports, typically occurring 48 hours after infusion 3
• This reaction can present with acute onset muscle pain and stiffness, confirmed by musculoskeletal ultrasound showing hypoechoic widening of bursae 3
• The temporal relationship to infusion (typically 48 hours post-infusion) and rapid resolution after drug discontinuation support causality 3

Lupus-Like Reactions

Rare cases of drug-induced lupus with musculoskeletal manifestations have been reported 2. The British Association of Dermatologists guidelines note that lupus-like reactions can occur with infliximab, though these are rare 2. Two patients with rheumatoid arthritis developed drug-induced lupus in clinical trials 4.

Clinical Differentiation: Important Caveats

Distinguishing Drug-Related vs. Disease-Related Symptoms

A critical pitfall is differentiating infliximab-induced musculoskeletal symptoms from:

• Underlying disease activity: Patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis already have baseline musculoskeletal symptoms 5, 6
• Paradoxical inflammatory reactions: Some patients may develop new-onset arthralgia despite treatment for inflammatory conditions 3

Timing Patterns

• Early reactions (within 48 hours to 2 weeks): More likely to represent acute infusion-related reactions, serum sickness-like syndrome, or inflammatory bursitis 1, 3
• Late reactions (weeks to months): May represent antibody formation (ATI) with associated immune complex-mediated symptoms 7

Risk Factors and Antibody Development

Low infliximab trough concentrations during treatment initiation are associated with development of antibodies to infliximab (ATI), which increase the risk of immunological reactions including musculoskeletal symptoms 7. Approximately 19-21% of patients develop ATI, with median time to detection of 3.7 months 7.

• Concomitant methotrexate use significantly reduces ATI development (0% vs. 32% in spondyloarthritis patients) 7
• ATI presence is associated with increased infusion reactions and reduced drug maintenance 7

Management Algorithm

When Musculoskeletal Symptoms Occur:

1. Assess timing relative to infusion: Symptoms within 48-72 hours suggest acute reaction 3

2. Evaluate severity:

   • Mild arthralgia/myalgia without systemic symptoms: Consider continuing with close monitoring 1
   • Severe symptoms requiring hospitalization or with fever/rash: Strongly consider drug discontinuation 1

3. Investigate for serum sickness: Check for fever, rash, and joint swelling occurring together 1

4. Consider imaging: Musculoskeletal ultrasound can identify inflammatory bursitis if localized shoulder/joint pain is present 3

5. Check for antibody formation: Measure trough infliximab levels and ATI if symptoms persist or recur 7

6. Rule out lupus-like syndrome: Check ANA, anti-dsDNA if systemic symptoms develop 2, 4

Treatment Modifications:

• For mild symptoms: NSAIDs or analgesics may provide symptomatic relief 3
• For severe reactions: Discontinue infliximab and consider switching to a different mechanism of action (not another TNF antagonist if lupus-like syndrome) 3
• For ATI-related symptoms: Consider adding methotrexate if not already prescribed, or switching to alternative biologic 7

Monitoring Recommendations

• Educate patients to report new musculoskeletal symptoms, particularly if accompanied by fever or rash 1
• Consider baseline musculoskeletal assessment before initiating therapy to establish a reference point 8
• Monitor trough infliximab concentrations early in treatment (target >1 μg/mL) to reduce ATI development 9, 7