Accelerated nodulosis during low dose methotrexate therapy for rheumatoid arthritis. An analysis of ten cases

J Rheumatol. 1992 Jun;19(6):867-71.


Objective: To obtain information on the occurrence of accelerated nodulosis during methotrexate (MTX) for rheumatoid arthritis (RA), localization, size and presence in heart and lungs of these nodules, predisposing factors, relationship with other extraarticular manifestations (EAM) and their histological features.

Methods: Ten patients with accelerated nodulosis were studied. Four participated in a double blind study of MTX and azathioprine. Patient characteristics, localization, size and histopathology of new nodules were determined. Echocardiography and chest roentgenograms were performed.

Results: Accelerated nodulosis occurred exclusively during treatment with MTX in our double blind study. The estimated incidence was 8%. One patient reported was rheumatoid factor negative. Newly developed nodules were small, and located in the fingers in all patients and in additional sites in 7. Pretreatment nodules were not found in the fingers. In one patient nodules on the mitral valve were found, but this was not likely to be associated with the use of MTX. No new pulmonary nodules were found. Other EAM developed concurrently in 4 patients. Histopathology revealed typical rheumatoid nodules. In 3 patients nodulosis regressed after MTX was stopped. In 2 of them they recurred after a rechallenge.

Conclusions: Accelerated nodulosis during MTX for RA is not rare, and occurs despite good clinical response of polyarthritis. Rheumatoid factor positivity is not a prerequisite. New nodules are small and preferentially located in the fingers. Recurrence after rechallenge with MTX suggests causality.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / drug therapy*
  • Azathioprine / therapeutic use
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Echocardiography
  • Female
  • Humans
  • Lung / pathology
  • Male
  • Methotrexate / administration & dosage*
  • Methotrexate / adverse effects*
  • Methotrexate / therapeutic use
  • Middle Aged
  • Myocardium / pathology
  • Radiography, Thoracic
  • Rheumatoid Nodule / chemically induced*
  • Rheumatoid Nodule / diagnostic imaging
  • Rheumatoid Nodule / pathology
  • Skin / pathology


  • Azathioprine
  • Methotrexate