Management of accelerated pulmonary nodulosis following etanercept therapy in a patient with rheumatoid arthritis

Sir, Pulmonary nodulosis is an unusual extra-articular manifestation of rheumatoid disease. We report a case of a patient with seropositive erosive RA who developed cavitating pulmonary nodulosis during the first few months of treatment with the recombinant soluble TNF-α-receptor, etanercept. To our knowledge, it is the fifth reported case of pulmonary nodulosis in rheumatoid patients treated with etanercept. In all previous cases, etanercept was stopped when pulmonary nodulosis was diagnosed. As far as we are aware this is the first reported case of continuing etanercept treatment and shows that the condition does not necessarily progress. This case also illustrates the utility of T-spot screening in excluding Mycobacterium tuberculosis (TB) during anti-TNF treatment. A 57-yr-old female with a 20-yr history of seropositive erosive RA was reviewed in December 2005. Previous treatments with MTX, SSZ, and penicillamine had been poorly tolerated or ineffective. Ongoing treatment with LEF (20 mg/day) and oral prednisolone (7.5 mg/day) was of limited efficacy (DAS28 score in December 2005 was 5.97). There was no significant past medical history. The patient was a non-smoker with no previous exposure to TB and had been given a Bacille Calmette-Guerin (BCG) inoculation as part of her childhood immunizations. Routine pre-treatment screening involved a chest radiograph (normal) and a Heaf test (negative). Due to ongoing disease activity, etanercept was commenced in June 2006 (25 mg subcutaneously twice weekly) in combination with LEF and prednisolone. A significant clinical response to treatment was seen during the first 3 months of treatment [DAS 28 score at 12 weeks 4.87 (reduction of 1.88)]. A monitoring chest radiograph in March 2007 (9 months into treatment) showed a new area of opacity at the left lung base. The patient reported feeling well although direct questioning revealed a feeling of pressure around the left lower ribs and an occasional dry cough. There was no weight loss, malaise or fever. A high-resolution CT scan of the chest was performed (Fig. 1). The appearance was suggestive of cavitating pulmonary nodulosis secondary to rheumatoid disease, although TB remained an important differential. An enzyme-linked immunospot assay for IFN-γ release from T cells (T-spot test) was undertaken to exclude recent or previous TB exposure. This was conclusively negative. High-resolution CT image through the lower lung zones demonstrates multiple peripheral nodules, some with central cavitation. After discussion with the patient, etanercept was continued in combination with LEF and prednisolone. The decision not to discontinue etanercept was influenced by the rheumatological response to treatment and the fact that the nodules were relatively asymptomatic. With regular clinical and radiographic follow-up the patient remains well; there is no evidence of progression of the lung nodules and the minor respiratory symptoms have resolved. Rheumatoid nodules occur in ∼25% of the patients with RA [1]. They are associated with seropositivity, severe articular disease, smoking and a genetic predisposition (HLA-DRB1). Commonly occurring subcutaneously at sites of external pressure (frequently the elbow), they may also involve internal tissues especially at sites of mechanical stress (lung or heart valves). Accelerated pulmonary nodulosis is a recognized complication of MTX [1, 2] and LEF [3] therapy in RA patients. There are to our knowledge four previously reported cases of accelerated pulmonary nodulosis following treatment with etanercept. Interestingly, in two of the other cases the patient was on combination treatment with LEF [4, 5]. In each case, etanercept was withdrawn after the discovery of pulmonary nodulosis. In two, a conservative approach was adopted, while the remaining two were treated with prednisolone and AZA. In the three cases where the outcome is known, the nodules regressed within 3 months [4–6]. This is the first report of continued treatment with etanercept and shows that progressive nodulosis is not inevitable. Pulmonary tuberculosis is an important differential diagnosis in cavitating lung disease and since anti-TNF treatment is recognized as causing reactivation of latent TB [7], exclusion of tuberculosis is a key component of management. Tuberculin skin testing is associated with a significant incidence of false-negative results, particularly in those who are immunosuppressed [8]. It also shows reactivity in patients exposed to non-tuberculous Mycobacterium (including BCG). The enzyme-linked immunospot assay for IFN-γ release from T cells (the T-spot test) is a recently developed technique that detects IFN-γ release from activated T cells in vitro, in response to M. tuberculosis-specific antigen. It has a greater sensitivity than tuberculin skin testing and a greater specificity (since it does not cross-react with non-tuberculous Mycobacterium) [9]. In conclusion, this case highlights a number of important issues: first, pulmonary nodulosis is recognized with etanercept treatment, but it may not be necessary to discontinue etanercept, particularly in patients such as ours who are relatively asymptomatic and whose musculoskeletal disease is responding. The case also demonstrates the need for careful monitoring during treatment with biologics, as well as the utility of the T-spot test in eliminating the important differential diagnosis of TB. Disclosure statement: The authors have declared no conflicts of interest.