Understanding Drug-Induced Rheumatoid Nodulosis
Rheumatoid nodules are firm lumps that can develop under the skin, most often in patients with rheumatoid arthritis (RA) [1.2.1]. They typically form over bony pressure points like the elbows, hands, and feet [1.3.3]. However, some medications used to treat RA can paradoxically cause a condition known as "accelerated nodulosis," characterized by the rapid development of multiple, often smaller nodules [1.3.3]. This drug-induced variant can appear even when the underlying arthritis is in remission or has low disease activity [1.3.9, 1.4.3]. The estimated incidence of methotrexate-induced accelerated nodulosis (MIAN) among RA patients receiving the drug is around 8% to 11.6% [1.3.4, 1.3.9]. These nodules can appear in different distributions than classic rheumatoid nodules, often affecting the hands, feet, and even ears [1.3.3]. In some rare cases, these nodules can also form internally in organs like the lungs [1.2.3, 1.3.5].
The Primary Culprits: Medications That Trigger Nodulosis
A range of disease-modifying antirheumatic drugs (DMARDs) has been linked to accelerated nodulosis. Identifying the specific agent is crucial for management.
Methotrexate (MTX)
Methotrexate is the most common drug associated with accelerated nodulosis, a condition often abbreviated as MIAN (Methotrexate-Induced Accelerated Nodulosis) [1.2.2, 1.2.4]. The onset can be unpredictable, occurring anywhere from a few months to over a decade after starting therapy [1.2.4, 1.3.4]. The exact mechanism is not fully understood, but one leading hypothesis involves the drug's effect on adenosine. MTX increases adenosine levels, which has anti-inflammatory effects through A2 receptors. However, its stimulation of adenosine A1 receptors on monocytes is thought to promote the formation of the multinucleated giant cells that are a key feature of these nodules [1.3.1, 1.4.3].
Leflunomide
Leflunomide is another DMARD that has been reported to cause accelerated nodulosis, though less frequently than methotrexate [1.2.1, 1.4.3]. Cases have been reported where nodules developed after leflunomide was added to a patient's treatment regimen [1.4.5]. The proposed mechanism for leflunomide-induced nodulosis differs from that of methotrexate. It's thought that leflunomide may reduce monocyte activity, impairing the clearance of rheumatoid factor (RF). This accumulation of RF in certain macrophages could then act as a starting point for nodule formation [1.4.1, 1.4.2].
TNF-alpha Inhibitors and Other Biologics
Paradoxically, some biologic drugs, including anti-tumor necrosis factor (anti-TNF) agents like etanercept and adalimumab, can also induce or worsen nodulosis [1.2.1, 1.5.3]. This is counterintuitive because TNF-α is a pro-inflammatory cytokine. However, the concentration of TNF-α is significantly lower in rheumatoid nodules compared to the inflamed joint lining [1.5.1]. It is hypothesized that excessive suppression of TNF-α by these drugs may allow other inflammatory pathways to become dominant, leading to nodule formation [1.5.1]. Other biologics, such as tocilizumab (an IL-6 receptor inhibitor), have also been associated with worsening subcutaneous nodulosis [1.5.9].
Comparison of Common Drug Inducers
| Drug Class | Common Examples | Proposed Mechanism of Nodulosis | Frequency |
|---|---|---|---|
| Antimetabolite | Methotrexate | Stimulation of adenosine A1 receptors, leading to giant cell formation [1.3.1, 1.4.3]. | Most Common [1.2.4] |
| Pyrimidine Synthesis Inhibitor | Leflunomide | Reduced monocyte function leading to impaired clearance of rheumatoid factor [1.4.2]. | Rare [1.2.1, 1.4.3] |
| TNF-alpha Inhibitors | Etanercept, Adalimumab, Infliximab | Paradoxical effect; excessive TNF-α suppression may allow other inflammatory pathways to drive nodule formation [1.5.1]. | Occasional [1.2.1] |
| IL-6 Receptor Inhibitors | Tocilizumab | Associated with worsening of pre-existing nodulosis; mechanism not fully clear [1.5.9]. | Reported Cases [1.5.9] |
Diagnosis and Management
Diagnosis of drug-induced nodulosis relies heavily on clinical history, specifically the recent introduction or change in DMARD therapy, coupled with the rapid appearance of nodules [1.3.7]. Histologically, these nodules are generally indistinguishable from classic rheumatoid nodules, showing features like a central area of necrosis surrounded by palisading immune cells [1.3.7, 1.4.3]. A biopsy is sometimes necessary to rule out other causes like infection or malignancy, especially for internal nodules [1.2.3].
The primary management strategy is to identify and discontinue the causative drug [1.6.9]. In many cases, stopping the medication leads to the partial or complete regression of the nodules, although this is not guaranteed [1.3.4, 1.4.3]. If the underlying RA requires ongoing treatment, a rheumatologist will switch the patient to an alternative DMARD from a different class.
Other treatments have been used with varying success:
- Alternative DMARDs: Drugs like hydroxychloroquine, sulfasalazine, and D-penicillamine have been used to help reduce nodule size [1.2.4, 1.4.3].
- Colchicine: This medication has been shown to inhibit nodulosis in some patients on methotrexate [1.6.7].
- JAK Inhibitors: Recent reports suggest that Janus Kinase (JAK) inhibitors, such as baricitinib and filgotinib, may be effective in treating accelerated nodulosis [1.3.7, 1.6.6].
- Corticosteroid Injections: Injecting steroids directly into a nodule can help reduce its size but carries a risk of infection [1.6.2, 1.6.3].
- Surgical Excision: For nodules that are particularly painful, infected, or limit function, surgical removal is an option. However, recurrence at the excision site is possible [1.6.2].
Conclusion
Drug-induced rheumatoid nodulosis is a notable side effect of several key medications used to manage rheumatoid arthritis. While methotrexate is the most well-known cause, other agents like leflunomide and TNF-alpha inhibitors can also be responsible. The appearance of rapidly developing nodules, especially when arthritis is otherwise controlled, should prompt a discussion with a healthcare provider. The main treatment involves stopping the offending drug and selecting an alternative therapy, which often leads to the resolution of the nodules.
For more information, a good resource is the American College of Rheumatology.
