Does methotrexate cause rheumatoid nodules?

October 12, 2025 •

4 min read

Though a cornerstone in treating rheumatoid arthritis (RA), methotrexate has a paradoxical side effect, known as methotrexate-induced accelerated nodulosis (MIAN), which can cause or accelerate the formation of rheumatoid nodules in susceptible individuals. This condition is notable because it can occur even when the medication is effectively controlling joint inflammation.

Quick Summary

Methotrexate can cause a condition called accelerated nodulosis, where new or existing rheumatoid nodules grow rapidly. This paradoxical reaction occurs in a subset of rheumatoid arthritis patients, even when their joint symptoms are well-controlled by the medication. Risk factors include genetics, seropositivity, and smoking, with management often involving adjusting or discontinuing the drug.

Key Points

Accelerated Nodulosis: Methotrexate can paradoxically cause the rapid growth of rheumatoid nodules in a subset of patients with rheumatoid arthritis, known as methotrexate-induced accelerated nodulosis (MIAN).
Not a Sign of Disease Activity: Unlike typical rheumatoid nodules that often indicate severe disease, MIAN can develop even when the medication is effectively controlling joint inflammation.
Adenosine Pathway Mechanism: The reaction is likely caused by methotrexate's effect on adenosine receptors, specifically the A1 receptor, which promotes giant cell formation.
Genetic Predisposition: Certain individuals, particularly those with the HLA-DRB1*0401 allele, are more susceptible to developing MIAN.
Discontinuation as Treatment: The standard treatment for MIAN is to stop the methotrexate, which often leads to the nodules shrinking or disappearing.
Alternative Medications: If methotrexate is discontinued, other DMARDs or treatments like hydroxychloroquine, colchicine, or sulfasalazine may be used to manage RA and nodules.
Clinical Differences: MIAN-related nodules are often smaller, grow more rapidly, and appear in different locations (e.g., fingers, hands, ears) compared to classic rheumatoid nodules.

Understanding the Link: Methotrexate and Nodulosis

Methotrexate (MTX) is a first-line therapy for many individuals with rheumatoid arthritis (RA) due to its effectiveness in controlling joint inflammation and preventing disease progression. However, in a perplexing turn, a well-documented but rare side effect of the drug is the accelerated development of rheumatoid nodules, a phenomenon known as methotrexate-induced accelerated nodulosis (MIAN). This adverse reaction is considered 'paradoxical' because it can occur even while the drug successfully suppresses the inflammatory joint disease. For healthcare providers and patients alike, recognizing and managing MIAN is crucial for optimizing treatment outcomes.

The Mechanism Behind the Paradox

The precise mechanism by which methotrexate can cause nodules remains under investigation, but research points to its influence on adenosine pathways. While methotrexate is known to increase levels of extracellular adenosine to produce its anti-inflammatory effects via A2a receptors, studies suggest that in some individuals, the same process may also stimulate A1 receptors on monocytes. This stimulation of A1 receptors is thought to promote the formation of multinucleated giant cells, which are a key component of nodule pathology.

Potential Pathogenic Pathways

Adenosine Receptor Modulation: As mentioned, the paradoxical stimulation of A1 receptors on macrophages, leading to giant cell formation, is a leading hypothesis.
Genetic Predisposition: Specific genetic markers have been linked to an increased risk of MIAN. For example, some individuals carrying the HLA-DRB1*0401 allele appear to have a significantly higher risk of developing accelerated nodulosis.
Immune System Interactions: Some evidence suggests that methotrexate-induced immunosuppression, combined with other factors like Epstein-Barr virus (EBV) infection, could trigger nodule formation.

Risk Factors and Clinical Features

Not all patients with RA taking methotrexate will develop nodules. Certain factors can increase a patient's risk of MIAN:

Seropositivity: The vast majority of patients who develop MIAN are seropositive, meaning they test positive for rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (anti-CCP).
Pre-existing Rheumatoid Nodules: Patients who already have nodules before starting methotrexate may experience accelerated growth and appearance of new nodules.
Smoking: Cigarette smoking is a known risk factor for developing rheumatoid nodules in general, and it can also contribute to nodule formation in patients on methotrexate.
Genetics: As noted, carriers of the HLA-DRB1*0401 allele have a higher susceptibility.

Clinically, MIAN often presents with a distinctive pattern when compared to typical RA nodules:

Rapid onset and growth: Nodules can appear and grow more quickly than traditional rheumatoid nodules.
Smaller size: MTX-induced nodules are often smaller.
Atypical locations: While RA nodules favor pressure points like elbows, MIAN often appears in unusual locations such as the hands (especially fingers), feet, and ears.
Active disease state: Unlike classic rheumatoid nodules, which are often a sign of more severe and active RA, MIAN can occur during periods of low disease activity, with the medication controlling joint inflammation.

Rheumatoid Nodules vs. Methotrexate-Induced Nodulosis

Distinguishing between typical rheumatoid nodules and those caused by methotrexate is important for treatment planning. The following table highlights the key differences:


Characteristic	Rheumatoid Nodules (Typical)	Methotrexate-Induced Nodulosis (MIAN)
Onset & Growth	Slow growth over months or years.	Rapid onset and growth, often appearing months after starting MTX.
Correlation with RA Activity	Often indicates more severe, active disease.	Can occur even when RA joint activity is well-controlled by MTX.
Common Location	Pressure points, such as elbows and knuckles.	Atypical locations like fingers, hands, feet, and ears.
Size	Can vary but tends to be larger on average.	Typically smaller than classic rheumatoid nodules.
RF/Anti-CCP Status	Nearly all cases are seropositive for RF.	Strong association with seropositivity.
Histopathology	Fibrinoid necrosis surrounded by palisading macrophages.	Histologically similar to typical nodules, with palisading granulomas.

Management and Treatment Options

For patients who develop bothersome or problematic MIAN, the primary management strategy is to discontinue the methotrexate. In many cases, stopping the drug leads to the regression or complete disappearance of the nodules. The rheumatologist will then consider switching to an alternative disease-modifying anti-rheumatic drug (DMARD). Some options include:

Hydroxychloroquine
Colchicine
Sulfasalazine
D-Penicillamine
Anti-TNF biologics, though some have also been associated with accelerated nodulosis

In some instances, adding another medication like hydroxychloroquine or colchicine may help shrink the nodules, potentially allowing the continuation of methotrexate if necessary. Surgical removal is an option for very large or symptomatic nodules, but it carries a risk of complications and recurrence. Regular monitoring is key to detect changes and determine the most appropriate course of action.

Conclusion

While methotrexate is a highly effective treatment for rheumatoid arthritis, it can paradoxically cause or accelerate the development of rheumatoid nodules in a subgroup of patients, a condition known as methotrexate-induced accelerated nodulosis. This reaction can occur even when the drug is successfully controlling other RA symptoms. Distinct from typical rheumatoid nodules in its onset, growth, and location, MIAN is thought to be linked to genetic susceptibility and the drug's effect on adenosine receptors. Prompt recognition and consultation with a rheumatologist are essential. The primary management involves discontinuing methotrexate, leading to nodule regression in many cases, and exploring alternative treatment strategies for managing RA. For more information, consult authoritative medical resources like those at UpToDate and the National Institutes of Health.

Frequently Asked Questions

Rheumatoid nodules are firm, benign lumps of tissue that form under the skin or, rarely, in internal organs of some people with rheumatoid arthritis (RA). They are composed of immune and inflammatory cells.

Classic rheumatoid nodules are often a sign of more severe RA and appear over pressure points, while methotrexate-induced nodules (MIAN) are a paradoxical side effect. MIAN nodules tend to be smaller, appear more rapidly, and form in atypical locations like fingers and hands, even when the RA is well-controlled.

Accelerated nodulosis is a rare side effect. Studies suggest it occurs in a small percentage of methotrexate-treated patients, with some reports estimating it at around 8-12%.

Yes, this is one of the key paradoxical features of methotrexate-induced accelerated nodulosis. Patients can develop new or worsening nodules while their joint inflammation is effectively managed by the drug.

You should promptly consult your rheumatologist. They will confirm the diagnosis and determine the appropriate management plan, which may include discontinuing or adjusting your medication.

In many cases, discontinuing methotrexate leads to the regression or resolution of the nodules. However, some nodules may not completely disappear.

Yes, your rheumatologist can discuss other treatment options for rheumatoid arthritis, including other DMARDs like hydroxychloroquine, sulfasalazine, or newer biologics.