Which conventional synthetic disease-modifying antirheumatic drug (csDMARD) is most associated with an increased risk of accelerated rheumatoid nodule formation?

Methotrexate is Most Associated with Accelerated Rheumatoid Nodule Formation

Among conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), methotrexate is most strongly associated with an increased risk of accelerated rheumatoid nodule formation. 1

Evidence for Methotrexate and Nodulosis

The 2021 American College of Rheumatology (ACR) guidelines specifically address the relationship between methotrexate and rheumatoid nodules:

• The guidelines acknowledge that "accelerated nodulosis has been observed in patients starting methotrexate" 1
• For patients with progressive subcutaneous nodules who are taking methotrexate, the ACR conditionally recommends "switching to a non-methotrexate DMARD over continuation of methotrexate" 1
• This recommendation is "based on the premise that methotrexate is a contributing factor to progressive nodulosis" 1

Paradoxical Effect of Methotrexate

This presents a clinical paradox because:

• Methotrexate is considered the anchor drug and first-line csDMARD for rheumatoid arthritis treatment 2
• Despite effectively controlling joint inflammation, methotrexate can simultaneously accelerate nodule formation 3
• This accelerated nodulosis occurs despite good clinical response of the polyarthritis 3

Characteristics of Methotrexate-Induced Nodulosis

Research has identified specific patterns of methotrexate-induced nodulosis:

• The estimated incidence is approximately 8% of patients on methotrexate 3
• Newly developed nodules are typically small and preferentially located in the fingers 3
• Nodules can develop in patients who did not have pre-existing nodules in those locations 3
• Nodulosis may regress after methotrexate is discontinued and recur after rechallenge, suggesting causality 3
• Rheumatoid factor positivity is not a prerequisite for developing methotrexate-induced nodulosis 3

Management Algorithm for Patients with Rheumatoid Nodules

1. For patients with stable subcutaneous nodules initiating therapy:

   • Methotrexate is still conditionally recommended as first-line therapy if moderate-to-high disease activity is present 1

2. For patients on methotrexate who develop progressive nodulosis:

   • Switch to a non-methotrexate csDMARD (such as leflunomide or sulfasalazine) 1
   • Monitor for regression of nodules after discontinuation of methotrexate

3. For patients with high risk of nodulosis or history of accelerated nodulosis:

   • Consider initial therapy with alternative csDMARDs
   • If biologic therapy is indicated, methotrexate may still be used as co-therapy if benefits outweigh risks

Other csDMARDs and Nodulosis

While methotrexate is specifically identified as causing accelerated nodulosis, the evidence does not suggest that other csDMARDs like leflunomide, sulfasalazine, or hydroxychloroquine have a similar association with accelerated nodule formation.

Clinical Implications

The paradoxical effect of methotrexate on nodule formation highlights the importance of:

• Regular monitoring for the development or progression of subcutaneous nodules in patients on methotrexate
• Recognizing that good control of joint inflammation does not preclude the development of this extraarticular manifestation
• Considering alternative csDMARDs when nodulosis is a significant clinical concern
• Understanding that the decision to switch from methotrexate should balance the risk of nodulosis against methotrexate's established efficacy in controlling joint disease

This phenomenon demonstrates that different disease manifestations in rheumatoid arthritis may respond differently to the same therapeutic intervention, requiring clinicians to tailor therapy based on the predominant disease features in each patient.