Can Methotrexate Cause Lung Nodules? Unraveling the Pulmonary Connection

October 12, 2025 •

4 min read

According to a review published in Herald Scholarly Open Access, methotrexate has been linked to the development of pulmonary rheumatoid nodules, a phenomenon known as accelerated nodulosis. This connection is particularly relevant for patients with conditions like rheumatoid arthritis, raising the question: Can methotrexate cause lung nodules?

Quick Summary

Methotrexate can trigger or accelerate the development of lung nodules, especially in patients with rheumatoid arthritis. Timely diagnosis is crucial to rule out other serious causes like malignancy or infection, with management typically involving medication cessation and symptom monitoring.

Key Points

Causation and Acceleration: Methotrexate can cause or accelerate the formation of lung nodules, a condition known as accelerated nodulosis, particularly in patients with rheumatoid arthritis.
Symptoms: These nodules are often asymptomatic but can cause symptoms like cough, dyspnea, and fever in some cases, especially if they are large or complicated.
Diagnosis of Exclusion: Diagnosing methotrexate-induced nodules is challenging and primarily involves excluding other causes like malignancy, infection, and the patient's underlying disease-related lung issues.
Diagnostic Tools: High-resolution computed tomography (HRCT) is the preferred imaging modality for evaluating lung nodules in patients on methotrexate.
Treatment: The cornerstone of treatment is the immediate and permanent discontinuation of methotrexate. In symptomatic cases, corticosteroids may be used.
Risk Factors: Risk factors for pulmonary toxicity include older age, underlying lung disease, and pre-existing rheumatoid factor positivity.
Distinction from RA-ILD: It is vital to differentiate methotrexate-induced nodules from the more chronic lung disease (interstitial lung disease) often associated with rheumatoid arthritis itself.

The Connection Between Methotrexate and Lung Nodules

Methotrexate (MTX) is a widely used disease-modifying antirheumatic drug (DMARD) for conditions such as rheumatoid arthritis (RA) and psoriasis. While effective, it carries a spectrum of potential side effects, including pulmonary toxicity. Among these pulmonary manifestations, the development of lung nodules is a recognized, albeit rare, complication. This phenomenon, sometimes called accelerated nodulosis, occurs when methotrexate triggers or exacerbates the growth of pulmonary nodules, particularly in patients with RA who are already prone to such formations. The nodules caused by methotrexate are histologically and clinically similar to rheumatoid nodules but can appear more rapidly and in greater numbers.

Understanding Methotrexate-Induced Nodulosis

Clinical Presentation

Methotrexate-induced lung nodules are often asymptomatic and discovered incidentally during imaging. However, in some cases, they can lead to noticeable respiratory symptoms. This is especially true if the nodules enlarge, cavitate, or rupture, which can cause significant complications.

Common symptoms of pulmonary toxicity, which may or may not accompany nodules, include:

Persistent dry, non-productive cough
Shortness of breath (dyspnea)
Fever
Fatigue
Pleuritic chest pain

Pathophysiology and Proposed Mechanisms

The exact mechanism by which methotrexate causes or accelerates the formation of lung nodules is not fully understood, but several theories exist. One prominent hypothesis suggests that methotrexate, possibly through the activation of adenosine A1 receptors, enhances the cellular fusion process, leading to the formation of multinucleated giant cells characteristic of rheumatoid nodules. It is important to note that the occurrence of these nodules does not necessarily correlate with the total cumulative dose of methotrexate, and they can appear at various points during treatment.

Distinguishing Causes of Pulmonary Nodules

Diagnosing methotrexate-induced nodulosis is challenging because it is a diagnosis of exclusion. It is crucial to differentiate drug-induced nodules from other conditions with similar presentations. The table below compares the characteristics of methotrexate-induced nodules with other common causes in patients with rheumatologic conditions.


Feature	Methotrexate-Induced Nodulosis	Rheumatoid Arthritis (RA) Lung Disease	Malignancy/Infection
Onset	Often acute or subacute, within months to a few years of starting MTX.	More typically a chronic, indolent process over months to years.	Varies; infections are often acute, while malignancy is typically subacute or chronic.
Nodule Characteristics	Can be multiple, bilateral, and sometimes cavitating. May regress or stabilize upon MTX cessation.	Can be multiple, solid, cavitating, or fibrotic. Less likely to regress immediately upon stopping MTX.	Variable; solitary or multiple. Often irregular shape, potential for rapid growth.
Associated Symptoms	Can be asymptomatic or associated with dry cough, dyspnea, and fever.	Often associated with insidious dyspnea and chronic cough; potentially other systemic RA symptoms.	Depend on the specific pathology; fever and cough are common with infections.
Key Diagnostic Tools	Imaging (CT scan) showing nodules. Ruling out infection and malignancy is critical.	Imaging (HRCT), clinical correlation with RA, pulmonary function tests.	Biopsy is often mandatory to confirm etiology.
Response to Intervention	Often regress or stabilize after stopping MTX.	Treatment depends on RA-ILD subtype; may not improve with MTX cessation alone.	Specific antimicrobial therapy for infection; chemotherapy, radiation, or surgery for malignancy.

Diagnosis and Management

The Diagnostic Approach

Prompt evaluation of any new respiratory symptoms in patients on methotrexate is essential. The diagnostic process is systematic and often requires a collaborative approach between rheumatologists and pulmonologists.

Steps in diagnosis include:

Patient History and Symptom Evaluation: A detailed history is taken, noting the onset, duration, and nature of respiratory symptoms.
Imaging Studies: A chest radiograph can identify pulmonary abnormalities, but a high-resolution computed tomography (HRCT) scan is more definitive for visualizing and characterizing lung nodules.
Exclusion of Other Etiologies: Extensive testing is needed to rule out infections, especially opportunistic ones given the immunosuppressive nature of MTX.
Lung Biopsy: In cases where infection or malignancy cannot be ruled out, a transbronchial or surgical lung biopsy may be necessary for a definitive histological diagnosis.
Response to Cessation: A positive response, such as stabilization or regression of nodules after discontinuing MTX, can support the diagnosis.

Management Strategies

The primary treatment for methotrexate-induced lung nodules is the immediate and permanent discontinuation of the medication. Re-introducing methotrexate after a pulmonary toxicity event carries a significant risk of recurrence.

Medication Cessation: Stopping MTX is the most critical step and often leads to the spontaneous regression or stabilization of the nodules.
Corticosteroid Therapy: In severe or symptomatic cases, high-dose corticosteroids may be administered to help reduce inflammation.
Alternative Treatments: After discontinuing MTX, alternative DMARDs may be considered to manage the underlying rheumatoid arthritis. Some evidence suggests that drugs like rituximab or tocilizumab may be effective in managing RA in patients who have experienced methotrexate pulmonary toxicity.
Surgical Intervention: In rare instances, if a nodule grows significantly, ruptures, or becomes otherwise complicated, surgical resection may be necessary.

Conclusion

While a rare complication, the formation or acceleration of lung nodules is a well-documented adverse effect of methotrexate, particularly in patients with rheumatoid arthritis. Distinguishing these drug-induced nodules from those caused by the underlying disease, infection, or malignancy is a complex but crucial process that relies on a combination of clinical assessment, advanced imaging, and sometimes, biopsy. Patients receiving methotrexate must be educated on the potential for pulmonary toxicity and report any new or worsening respiratory symptoms immediately. For those affected, the primary treatment involves stopping the medication, which often leads to resolution or stabilization of the nodules. This highlights the importance of vigilant monitoring and a comprehensive differential diagnosis when prescribing and managing methotrexate therapy.

For more detailed information on methotrexate-induced pneumonitis, please consult the PubMed article here: Methotrexate-induced pulmonary toxicity.

Frequently Asked Questions

Methotrexate-induced accelerated nodulosis is a condition where methotrexate treatment leads to the rapid development or worsening of rheumatoid nodules, including those in the lungs. These nodules are histologically similar to typical rheumatoid nodules but appear more quickly and sometimes in greater numbers.

No, methotrexate-induced lung nodules are often asymptomatic and are sometimes discovered incidentally during a routine chest CT or X-ray. However, if they become large, cavitate, or rupture, they can cause symptoms like cough, shortness of breath, and fever.

Diagnosis is based on a patient's clinical history, symptoms, and imaging findings, typically a high-resolution CT scan. Crucially, the process is a diagnosis of exclusion, meaning other potential causes, such as infections and malignancies, must first be ruled out through thorough investigation, which may include a lung biopsy.

Risk factors for pulmonary toxicity from methotrexate include older age (over 60), underlying lung disease, and diabetes mellitus. Smoking and pre-existing rheumatoid factor positivity also appear to increase the risk.

The primary treatment is the immediate and permanent discontinuation of methotrexate. In severe cases, supportive therapy and corticosteroids may be necessary. Sometimes, the nodules will regress or stabilize spontaneously after the medication is stopped.

Yes, it is crucial to differentiate methotrexate-induced lung nodules from other conditions like underlying rheumatoid arthritis lung disease, various infections, and lung malignancy. A lung biopsy is often required to achieve a definitive diagnosis and rule out malignancy.

No, once methotrexate-induced pulmonary toxicity is diagnosed, the medication should be discontinued immediately and permanently. Re-introducing the drug carries a significant risk of recurrence and is generally not recommended.