A 64-yr-old male with a longstanding history of psoriatic arthritis presented with a 6-week history of dry cough without other respiratory symptoms. His other past medical history showed hypertension and type II diabetes mellitus. He took methotrexate 12.5 mg weekly (commenced 9 yrs previously), folic acid, aspirin, nortriptyline, metformin, valsartan and insulin. The patient was an ex-smoker of 5 pack-yrs, having stopped smoking 32 yrs earlier. He kept no pets and there was no significant occupational exposure or travel history. On examination his chest was clear. There was no lymphadenopathy or clubbing.
A chest radiograph (fig. 1⇓) showed multiple pulmonary nodules. C-reactive protein was 6 mg·L−1, erythrocyte sedimentation rate was 17 mm·h−1 and white blood cell count was 13×109 cells·L−1. Other routine blood tests were unremarkable and treatment with methotrexate was stopped. Further investigation showed normal tumour markers. Antinuclear antibody and antinuclear cytoplasmic antibody were negative, as was rheumatoid factor. Spirometry was normal. A chest/abdomen and pelvis computed tomography showed multiple pulmonary soft tissue nodules (fig. 2⇓). There were no other abnormalities. Infarcted tissue with some viable lung parenchyma showing mild chronic inflammation was obtained from a percutaneous needle biopsy of a soft tissue nodule. There were no granulomas or dysplastic or malignant cells. All viral serology testing was normal. Due to the patient being completely asymptomatic bronchoalveolar lavage was not performed.
Chest radiograph showing nodulosis prior to cessation of methotrexate.
Computed tomography scan showing nodulosis prior to cessation of methotrexate.
Following review of the biopsy a chest radiograph was performed which showed partial resolution of the nodules. A radiograph performed 3 months later showed complete resolution.
The patient received no specific therapy. He remained well and his cough resolved. However, his psoriatic arthritis worsened and he was started on sulphasalazine.
We believe that methotrexate nodulosis is the most likely cause of the pulmonary nodules seen in our patient.
The differential diagnosis of multiple pulmonary nodules is vast and includes infection, malignancy, granulomatous diseases, autoimmune diseases, rheumatoid nodules and drug reactions. A causal relationship between methotrexate and the nodules is supported by a number of factors. First, the nodules resolved spontaneously after methotrexate was stopped. Secondly, there was no histological evidence of malignancy or granulomatous disease. Finally, there was no evidence of either infection or rheumatoid arthritis.
Methotrexate nodulosis is an unusual adverse effect of low-dose methotrexate in patients with rheumatoid arthritis. In this condition methotrexate triggers or accelerates the formation of nodules which are clinically and histologically indistinguishable from rheumatoid nodules [1]. The nodules usually occur on the fingers, elbows or joints. More rarely they can appear in the lung, heart, larynx and Achilles tendon [2]. Methotrexate nodulosis is rare in patients with rheumatoid arthritis who are negative for rheumatoid factor [3]. Nodules often, but not always, regress or disappear on discontinuing the drug [3].
Methotrexate nodulosis in conditions other than rheumatoid arthritis is very rare. It has been reported in a patient with systemic lupus erythematosus and Jaccoud's arthropathy [4], a patient with juvenile arthritis who was rheumatoid factor negative [5], and a patient with psoriatic arthritis and negative rheumatoid factor [6]. Only the patient with juvenile arthritis had pulmonary nodules. However, a recent case report describes a patient similar to ours with psoriatic arthritis and negative rheumatoid factor who developed accelerated pulmonary nodulosis and a sterile pleural effusion after treatment with methotrexate [7]. Open lung biopsy showed histology compatible with a rheumatoid nodule. The nodules resolved on stopping methotrexate treatment.
Statement of interest
None declared.
Provenance
Submitted article, peer reviewed.
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