Etanercept-associated Pulmonary Granulomatous Inflammation in Patients with Rheumatoid Arthritis
To the Editor:
We describe 4 patients with rheumatoid arthritis (RA) who developed noninfectious pulmonary granulomatous disease while treated with etanercept (Table 1). All patients improved with withdrawal of etanercept and addition of prednisone, without use of antibiotic, antifungal, or antimycobacterial medications. They were subsequently treated with adalimumab with no recurrence of pulmonary toxicity.
Patient 1. After an inadequate response to leflunomide, a 60-year-old man with 1 year of seropositive RA started etanercept, with subsequent improvement. He then experienced progressive malaise and a 40-lb weight loss. Chest radiograph and computed tomography (CT) scan revealed multiple pulmonary nodules bilaterally. Open-lung biopsy demonstrated large granulomas with palisading histiocytes and a necrotizing central zone. Tissue stains for acid-fast bacillus and fungi, routine cultures, and microscopic examination of stained specimens were negative. Polymerase chain reaction for mycobacterial infection, tests for fungal organisms, antineutrophil cytoplasmic antibodies, and antinuclear antibodies were all negative. Etanercept was discontinued and prednisone 10 mg daily was added. Serial chest CT scans showed regression of the pulmonary nodules. One year later adalimumab was added because of progression of joint symptoms. He has tolerated adalimumab well for 4 years, and followup chest CT showed further regression of the pulmonary nodules.
Patient 2. A 60-year-old woman with erosive polyarticular, rheumatoid factor (RF)-positive RA since 1982 started methotrexate (MTX) in 1994, with addition of etanercept in 1999. In January 2001 she developed left chest-wall herpes zoster and exertional dyspnea. High resolution CT (HRCT) demonstrated pleural effusions, interstitial lung disease, and scattered centrilobular nodules. Transbronchial biopsy revealed numerous confluent non-necrotic granulomas within the bronchial wall. Special stains for acid-fast bacilli (AFB) and fungi were negative. She received prednisone 30 mg/day, reduced to 10 mg daily over several months. MTX was withheld and etanercept was continued. Followup HRCT showed improvement. In September 2003 she complained of dyspnea and symptoms of an upper respiratory infection, and was treated for sinusitis with amoxicillin/clavulanate. Etanercept was stopped. Chest radiograph showed multiple reticular-nodular and ground-glass opacities throughout the lungs, more pronounced in the lower lung fields, and worse than in 2002. HRCT showed bilateral ground-glass opacity with basilar predominance, innumerable tiny nodules in the upper and mid-lungs, and thickened bands of fibrosis in both lung bases (Figure 1A). Transbronchial biopsy showed non-necrotic granulomatous inflammation (Figure 1B). Special stains for fungi and AFB were negative. Mycobacterium chelonae grown from AFB culture after 1 month was judged to be a contaminant. She started prednisone 30 mg daily for 2 weeks with a slow taper. Followup HRCT showed complete resolution of micronodules and improvement of bilateral ground-glass opacity, with minimal fibrosis. Because of persistent symptoms of RA, adalimumab was added in August 2005, without worsening of pulmonary symptoms or pulmonary function tests. Chest radiograph 3 months later showed no pulmonary nodules.
Patient 3. A 66-year-old woman with erosive polyarticular RA since 1989 started etanercept in 1999, with an excellent response. In August 2003, while receiving etanercept and leflunomide, she experienced insidious onset of dry cough, malaise, exertional dyspnea, and gastrointestinal (GI) distress. Leflunomide was discontinued and the GI symptoms resolved, but she remained ill. She had no fever, but her weight decreased by 30 lb over 3 months. Etanercept was then stopped. Chest radiograph showed diffusely hazy lung fields and thickening of fissures with normal cardiac size. CT revealed diffuse pulmonary micronodules and mild mediastinal adenopathy (Figure 1C). Pulmonary function testing (PFT) showed an obstructive ventilatory defect with impairment in gas exchange. Transbronchial biopsy showed multiple epithelioid granulomas involving the pulmonary parenchyma, without associated fibro-inflammatory reaction (Figure 1D). Special stains for acid-fast and fungal organisms were negative. She started prednisone 40 mg daily, tapered to 7.5 mg daily within 2 months. Chest CT 2 months later showed considerable improvement in ground-glass opacity and nodules with persistence of mild mediastinal adenopathy. PFT normalized, and adalimumab was started due to flaring RA. After 4 years of treatment with adalimumab, the pulmonary infiltrates have not recurred.
Patient 4. A 54-year-old woman with a history of juvenile erosive polyarticular RF-positive RA had progressive disability and deformity despite treatment with antiinflammatory agents and disease modifying antirheumatic drugs. In 1999 etanercept was begun, with significant improvement, eventually resulting in return to fulltime employment. In November 2004 she developed dyspnea and chest tightness without significant cough and with slight fever (100.1°F). Chest radiograph showed hazy opacification of both lungs. Chest CT revealed patchy ground-glass opacities in upper and mid-lung zones, slight mediastinal adenopathy, and no pleural or pericardial effusions (Figure 1E). Transbronchial biopsy revealed focal interstitial chronic inflammation and one small poorly developed granuloma (Figure 1F). Bronchoalveolar lavage (BAL) yielded a lymphocyte-predominant effluent with a CD4:CD8 T cell ratio of 0.6. Immunohistochemical staining showed the majority of lymphocytes were CD8 . Extensive studies for microbial organisms were all negative. Etanercept was discontinued and the chest radiograph normalized, along with resolution of pulmonary symptoms and normalization of PFT. Then RA flared severely and adalimumab was started, 40 mg every other week. Signs and symptoms of RA again improved and pulmonary symptoms did not recur.
Tumor necrosis factor (TNF) regulates expression of adhesion molecules responsible for leukocyte migration1, and is critical for the formation and function of granulomas2. Consequently, reactivation and acquisition of new infections that are contained by a granulomatous host response (e.g., tuberculosis and histoplasmosis) are of particular concern with anti-TNF therapy3,4. Pulmonary toxicity is not a well known side effect of etanercept, and most adverse pulmonary events during treatment with TNF antagonists are infectious5. There are 6 reported cases of noncaseating granulomatous inflammation in patients with RA treated with etanercept6-8, and one report of an individual with psoriatic arthritis developing pulmonary granulomas while taking etanercept9. Two additional reports link other TNF blockers with pulmonary granulomas in RA patients8-10. Onset of pulmonary sarcoidosis, described during treatment of ankylosing spondylitis (AS) with infliximab11, resolved with prednisone and discontinuation of the TNF blocker. Another patient with AS developed cutaneous sarcoidosis and hilar adenopathy while taking etanercept, which resolved when etanercept was discontinued12. Etanercept is not currently viewed as an attractive option for the treatment of sarcoidosis13. Other forms of pulmonary toxicities related to anti-TNF therapy have been suggested. Several reports link infliximab with worsening or new onset of interstitial pneumonia14-17. In one RA patient, adalimumab was linked to pulmonary fibrosis18. Among 39 patients who developed systemic vasculitis while receiving TNF antagonists, involvement of the lung (1 case) or the pleura (2 cases) was unusual19. The appearance of a new granulomatous process during treatment with a TNF antagonist may seem surprising, given the role of TNF in formation of granulomas during infections such as tuberculosis20. However, it appears that although TNF–/– mice can localize a full spectrum of inflammatory cells in lung tissue during tuberculous infection, the precise functional organization of the granulomas is defective21. In this model, both secreted and transmembrane TNF are essential for successful host defense22. In one case we studied the BAL fluid CD4:CD8 ratio of lymphocytes. The finding of a CD4:CD8 ratio < 1.0 is highly suggestive of hypersensitivity pneumonitis, but not sarcoidosis, which is associated with noncaseating pulmonary granulomata and a CD4:CD8 ratio > 123. It is unclear whether the pulmonary infiltrates in our patients represented a reaction to etanercept itself or to an undefined trace contaminant. All patients improved with withdrawal of etanercept and the addition of prednisone, without use of antibiotics. This observation, along with the histopathologic features of the granulomas and BAL findings in one patient, suggests a drug effect. All 4 patients were subsequently treated with adalimumab, a monoclonal anti-TNF agent, with no recurrence of pulmonary toxicity. This helps to exclude the possibility that an occult infection was overlooked, and implies a drug-specific effect rather than a class effect. It is currently unclear why these 2 drugs might differ in their potential adverse effects. In the absence of infections, drug toxicity should be considered as a cause of pulmonary granulomatous inflammation in RA patients receiving etanercept.
VLADIMIR M. OGNENOVSKI, MD, Division of Rheumatology; TAMMY CLARK OJO, MD, Division of Pulmonary and Critical Care Medicine; DAVID A. FOX, MD, Division of Rheumatology, Department of Internal Medicine and Rheumatic Diseases Core Center, University of Michigan, Ann Arbor, Michigan, USA. Address reprint requests to Dr. D.A. Fox, Room 3918 Taubman Center, SPC 5358, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5358. E-mail: firstname.lastname@example.org
2. Roach DR, Briscoe H, Saunders B, France MP, Riminton S, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002;168:4620-7. [MEDLINE]
8. Bijkerk C, De Gendt C, De Jong A, Janssen M, Traksel R, Visser H. Non-tuberculous granulomatous inflammation linked to anti-tumor necrosis factor alpha therapy [abstract]. Ann Rheum Dis 2004;63 Suppl: 306.
18. Schoe A, vander Laan-Baalbergen NE, Huizinga TW, Breedveld FC, van Laar JM. Pulmonary fibrosis in a patient with rheumatoid arthritis treated with adalimumab. Arthritis Rheum 2006;55:157-9. [MEDLINE]
21. Bean AGD, Roach D, Briscoe H, et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibilty to aerosol mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 1999;162:3504-11. [MEDLINE]
22. Saunders BM, Tran S, Ruuls S, Sedgwick JD, Briscoe H, Britton WJ. Transmembrane TNF is sufficient to initiate cell migration and granuloma formation and provide acute, but not long-term, control of mycobacterium tuberculosis infection. J Immunol 2005;174:4852-9. [MEDLINE]
J Rheumatol 2008;35:11; doi:10.3899/jrheum.080383