The majority of patients who develop methotrexate nodulosis are over age 50, although much younger individuals may be affected as well. Predilection for sex is unclear. Nodules have developed in patients on a wide range of doses of methotrexate, as well as after various durations of therapy; thus, it is difficult to determine whether a dose-dependent phenomenon or a minimum cumulative dose exists.

The frequency of rheumatoid arthritis-associated methotrexate nodulosis has been estimated at 2–11 % in rheumatoid arthritis patients treated with methotrexate. In comparison, about 20 % of all patients with rheumatoid arthritis develop rheumatoid nodules, and they tend to be associated with increased disease severity. Approximately 90 % of rheumatoid arthritis patients with rheumatoid nodules are seropositive for rheumatoid factor; most patients (78 % in one study) with methotrexate-induced accelerated nodulosis have also been found to be seropositive.

Controversy exists regarding the incidence of methotrexate nodulosis with simultaneous vasculitis. Some theories suggest that the two occur more frequently in combination, while other studies have found a low proportion of patients who developed methotrexate nodulosis with concomitant vasculitis.

The nodules appear histologically like those of classical rheumatoid nodules or vasculitis. They contain multinodular foci of necrobiosis and collagen degeneration, neutrophils, and fibrin deposits with surrounding palisading histiocytes. Scarring in adjacent soft tissue or subcutaneous fat is present. In the reticular dermis, histiocytes often form rosettes around collagen bundles. Multinucleated giant cells may be noted.

Although much less common, accelerated development of nodules may also develop after administering methotrexate to treat diseases other than rheumatoid arthritis. For this reason, some authors prefer the term “methotrexate nodulosis” over “methotrexate-induced accelerated nodulosis.” For example, the nodules have appeared in patients treated with methotrexate for dermatomyositis, psoriatic arthritis, juvenile idiopathic arthritis, and mixed connective tissue disease. In these diseases, histopathology of the nodules may differ from traditional rheumatoid nodules, including variations such as septal panniculitis. However, the onset of lesions after initiation of methotrexate and resolution with its cessation are still characteristic.

The exact mechanism of the expedited development of rheumatoid nodules has not yet been elicited. However, the stimulation of adenosine receptors by methotrexate may play a role. Methotrexate is an agonist at the A1 and A2 adenosine receptors. In vitro binding to the A2 receptor produces anti-inflammatory effects. Activation of the A1 receptors, however, results in formation of giant cells and spindle-shaped arrangements of monocytes, congruent with those seen in nodules.

Genetics may play a factor in the accelerated development of rheumatoid nodules. The DRB1*0401 allele has been recognized as an HLA-class II gene linked with formation of nodules in Caucasian patients. Furthermore, methionine synthase reductase gene polymorphism has been discovered to be increased in rheumatoid arthritis patients compared to the population overall. The polymorphism was also associated with methotrexate nodulosis.

While classically occurring after methotrexate administration, accelerated rheumatoid nodule development has also been observed in patients treated with etanercept, infliximab, and azathioprine. Etanercept and infliximab are both tumor necrosis factor inhibitors, while azathioprine blocks purine synthesis using a different mechanism. Some have suggested that “therapy-induced accelerated rheumatoid nodulosis” may be a more accurate term in describing the condition, as these newer agents exhibit a similar phenomenon to methotrexate.

In some instances, patients have continued taking methotrexate and experienced regression of nodules after the addition of drugs such as hydroxychloroquine, colchicine, sulfasalazine, azathioprine, cyclosporine, or D-penicillamine. Consensus has not been established regarding whether methotrexate should be discontinued with the development of accelerated nodulosis. Some recommend stopping the drug and others recommend adding hydroxychloroquine or another agent. Reducing the dose or discontinuing methotrexate, or adding hydroxychloroquine, generally results in the clearing of nodules in 1 week to 2 years. If methotrexate therapy is initiated again, the nodules tend to reappear.

Of note, hydroxychloroquine may decrease the likelihood of accelerated nodulosis in patients with the DRB1*0401 allele. Observing the patient while continuing methotrexate is an option if the lesions are mild and tolerable, as is the case in the majority of patients. Some patients may even experience disappearance of nodules while continuing methotrexate therapy at the same or lower doses.

Another reaction to distinguish from methotrexate nodulosis is methotrexate-induced papular eruption, which has been observed in patients with acute flares of collagen vascular diseases who received low-dose methotrexate. These lesions appear as clusters of erythematous papules to patches, similar in appearance to insect bites. Distribution most commonly involves proximal extremities and buttocks. Histologically, biopsy shows histiocytes and collagen bundles in the dermis, with smaller rosettes of thick collagen bundles and surrounding histiocytes in the deeper reticular dermis. Onset is after initiation of methotrexate therapy (usually within 12–24 h), and resolution generally occurs quickly after tapering methotrexate and increasing doses of corticosteroids.