Pulmonary sarcoidosis developing during infliximab therapy

Authors

  • Finbar D. O'shea,

    1. Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
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    • Dr. O'Shea is cosponsored by a Wyeth Pharmaceuticals Travelling Fellowship (more than $10,000). Dr. Inman has received consultancy fees and/or honoraria (less than $10,000 each) from Amgen, Abbott, Schering, and Centocor.

  • Theodore K. Marras,

    1. Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
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  • Robert D. Inman

    Corresponding author
    1. Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
    • Arthritis Center of Excellence, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada
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    • Dr. O'Shea is cosponsored by a Wyeth Pharmaceuticals Travelling Fellowship (more than $10,000). Dr. Inman has received consultancy fees and/or honoraria (less than $10,000 each) from Amgen, Abbott, Schering, and Centocor.


Introduction

The use of anti–tumor necrosis factor (anti-TNF) agents is expanding rapidly in many different areas of medical practice. With this increasing use and longer followup periods, a wider range of possible adverse effects may be encountered. We report the development of pulmonary sarcoidosis occurring in the context of 5 years of successful infliximab treatment for ankylosing spondylitis (AS). Current evidence supports the efficacy of infliximab for the treatment of granulomatous inflammation such as Crohn's disease, therefore our finding seems paradoxical and highlights the need for vigilance in long-term monitoring of anti-TNF therapy.

Case History

The patient was a 34-year-old man with a 15-year history of seronegative arthritis with both peripheral and axial features. The early clinical course was characterized by recurrent knee effusions and subsequently by inflammatory back pain. Optimal disease control was never achieved despite a range of treatments, which included sulfasalazine, methotrexate, oral and intraarticular corticosteroids, and multiple nonsteroidal antiinflammatory drugs. In addition to joint symptoms, the patient had intermittent plaques of psoriasis on the extensor surfaces of the arms and legs.

In July 2000, the back pain worsened significantly. Radiographs showed bilateral erosive sacroiliitis consistent with AS. The patient was found to be HLA–B27 positive. Infliximab was initiated at 5 mg/kg every 8 weeks intravenously. A baseline chest radiograph and tuberculosis (TB) skin test results were negative. There was a prompt and dramatic improvement in both axial and peripheral manifestations of the patient's disease, and for the ensuing 5 years he was in remission with infliximab infusions, without adverse effects of treatment. In May 2005, although his disease was well controlled from a joint and skin point of view, the patient developed pleuritic chest pain, a productive cough, and dyspnea. A chest radiograph was normal. The patient was treated for a presumptive lower respiratory tract infection with azithromycin. A week later his symptoms persisted, and a repeat chest radiograph revealed a small left pleural effusion with some airspace opacification in the left lower lobe. Computed tomography (CT) scan of the chest was performed, which showed mediastinal and hilar adenopathy, a small left pleural effusion, compressive atelectasis, and left pleural thickening (Figure 1).

Figure 1.

Chest computed tomography scan showing A, extensive subcarinal mediastinal and hilar adenopathy and a small left pleural effusion (mean density 40 Hounsfield units [HU], window width 400 HU), and B, basal atelectasis or consolidation near the left pleural effusion (mean density –600 HU, window width 1,600 HU).

The patient's symptoms gradually improved. A followup chest radiograph 10 days later showed some fullness of the inferior aspect of the right hilum, but the left pleural effusion and pulmonary opacity had improved. The differential diagnosis at this stage included resolving bacterial pneumonia, TB, lymphoma, and sarcoidosis. At this stage, all laboratory findings were within normal limits with the exception of a modest elevation in erythrocyte sedimentation rate (ESR; 30 mm/hour, normal <12 mm/hour) and C-reactive protein level (CRP; 35 mg/dl, normal <10 mg/dl). A TB skin test result was negative.

Over the following month, the patient continued to have intermittent chest pains unaccompanied by fever or weight loss. He underwent mediastinoscopy and video-assisted thoroscopy with pleural biopsy. The lymph node biopsy sample demonstrated numerous tight, well-formed granulomas surrounded by a thin rim of fibrosis (Figure 2). The granulomas were judged to be nonnecrotizing. The pleural biopsy sample demonstrated chronic inflammation, fibrosis, and reactive mesothelial hyperplasia without granulomas or malignant cells. Stains of the pleural fluid and lymph node were negative for acid-fast bacilli, fungi, and bacteria, as were all subsequent cultures. Cytology of the pleural fluid was negative for malignant cells. In light of the pathologic findings, a diagnosis of sarcoidosis was made.

Figure 2.

Hematoxylin and eosin stained lymph node biopsy sample showing numerous tight, well-formed granulomas surrounded by a thin rim of fibrosis. A, Low power (original magnification × 5) and B, high power (original magnification × 100).

The patient continued to have a productive cough and some chest discomfort. A followup chest radiograph revealed persistent mediastinal hilar adenopathy with clear lung fields, and he was treated with prednisone 40 mg/day. This promptly resulted in complete resolution of his pulmonary symptoms. CRP level and ESR normalized. The patient's infliximab infusions were not reinstituted. A flare in his axial and peripheral joint disease resolved with the initiation of steroid therapy. He has been maintained on a slowly tapering dose of prednisone over the last 6 months (currently taking 15 mg on alternate days) with no recurrence of his respiratory symptoms. A followup thorax CT after 4 months of steroid therapy showed that the left pleural effusion had resolved but the mediastinal lymphadenopathy was unchanged.

Discussion

This case raises 2 interesting and unusual points: the rare association of psoriatic arthritis and sarcoidosis, and the unexpected development of a chronic granulomatous disease during the course of infliximab treatment. The development of sarcoidosis is unusual in the context of any of the spondylarthropathies. A recent report presented the case of a 40-year-old man with longstanding AS who developed sarcoidosis (1). The authors' review of the literature identified 13 other cases of sarcoidosis associated with AS. This association can raise diagnostic dilemma because spine involvement in sarcoidosis can mimic AS. A possible pathophysiologic link between the diseases was proposed, invoking possible common pathogenetic pathways (1).

Sarcoidosis has rarely been associated with psoriasis or psoriatic arthritis. A recent review of 517 patients with sarcoidosis collected over a 36-year period identified only 4 patients who also had a diagnosis of psoriasis (2). No reference was made to any of these patients having psoriatic arthritis. Although this association may be a chance event, the authors point to the fact that because 3 of the 4 patients were female, with the same blood group and HLA profiles, genetic factors may predispose some individuals to these 2 distinct diseases.

Sarcoidosis is an immune-mediated inflammatory disorder characterized by the formation of granulomas. TNFα is thought to be important in the initiation and perpetuation of inflammation in sarcoidosis, contributing to the granuloma formation and to the progression of fibrosis (3). It would be predicted that specific anti-TNF agents, such as infliximab and etanercept, would therefore be effective in the treatment of sarcoidosis. The results to date, however, have been mixed. Etanercept has been reported to improve chronic sarcoid arthropathy and lupus pernio (4). Intraarticular etanercept has actually been used successfully to treat chronic, refractory sarcoid arthritis of the wrist (5). Infliximab has also been shown to improve refractory sarcoidosis (6, 7). With respect to ocular sarcoidosis, the results have been complex. In one study, etanercept has been shown to be ineffective in the treatment of refractory ocular sarcoidosis (8). One report documented sarcoid-related uveitis occurring during the course of etanercept therapy for polyarticular juvenile idiopathic arthritis (9). Recently, a randomized multicenter trial has failed to demonstrate the efficacy of etanercept in treating Wegener's granulomatosis, another pulmonary granulomatous disease (10).

Phillips and Weinblatt recently reported the first case of a culture-negative granulomatous pulmonary lesion occurring in a patient receiving etanercept therapy for psoriatic arthritis (11). In that case, chest radiograph and CT identified a bilateral reticulonodular interstitial pattern, which was worse in the upper lobes. No hilar lymphadenopathy was demonstrated. Transbronchial lung biopsy showed noncaseating granulomas, and all cultures were negative. The authors thought sarcoidosis was unlikely because of the absence of interstitial thickening and the loosely cohesive granulomas. It was believed that the granulomatous pulmonary reaction was associated with etanercept and not the anti-TNF therapies in general, because the patient was subsequently treated with adalimumab without recurrence of the pulmonary reaction. Our case is similar in some respects, with a patient with psoriatic arthritis developing a pulmonary granulomatous process while receiving another anti-TNFα agent, infliximab. We have judged this to be sarcoidosis, as shown by the distinctive histologic findings, bilateral hilar lymhadenopathy, negative mycobacterial cultures, and clinical response to steroid therapy.

There are few reports of nontuberculous granulomatous disease with anti-TNF therapy. During a clinical trial of infliximab, a patient with AS was reported as developing allergic bronchiocentric granulomatous lesions after the second infusion; these lesions resolved within 8 weeks (12). A patient with rheumatoid arthritis developed bilateral pulmonary necrotizing granulomas after 6 months of treatment with adalimumab. The findings in that case were consistent with TB, but all cultures, stains, and polymerase chain reaction analyses were negative, and the lesions were unresponsive to a 6-month course of antituberculosis medication (13).

Another example of the development of pulmonary side effects while receiving anti-TNF agents has been reported by Cunnane et al (14). They reported 3 patients with rheumatoid arthritis who developed nodulosis and, in 2 cases, an associated vasculitis shortly after the initiation of etanercept. One patient, who had asymptomatic pulmonary nodules on chest radiograph prior to treatment, developed a cough and exertional dyspnea 2 months after starting etanercept. Several cavitating lung lesions were identified on CT. Lung biopsy demonstrated multiple necrotizing pulmonary nodules with a marked inflammatory cell infiltrate and evidence of vasculitis.

It has been well established that TNFα plays an important role in the formation and maintenance of granulomas (15). It has been shown that TNF receptor-deficient (TNFR-p55−/−) mice succumb to infection with Mycobacterium avium because of deranged T cell–macrophage interaction. The resulting granulomas are immature and malorganized and become necrotic, which causes severe tissue damage (16). With the therapeutic use of potent anti-TNF agents, normal cell-mediated host defenses may be expected to be compromised. This has become particularly evident in lymphotoxin α (TNFβ)–deficient mice, where recruitment and activation of mononuclear cells in response to bacillus Calmette-Guérin infection are significantly delayed and reduced, resulting in immature granulomas incapable of controlling the mycobacterial infection (17). It should be recognized that the current concepts of the mechanism of action of infliximab propose that inhibition of TNFα is the primary event, without inhibition of lymphotoxin α. Studies of these 2 members of the TNF family have concluded that it is TNFα, rather than lymphotoxin α, that is most critical for control of mycobacterial infection (15).

From the earliest clinical trials with infliximab, it was evident that the use of this anti-TNF monoclonal antibody was associated with an increased risk of reactivation of TB. This is thought to be due to the failure of granulomas to effectively compartmentalize viable M tuberculosis bacilli, as well as failure of macrophage apoptosis after bacillary infection. The median interval from the start of treatment with infliximab until the development of TB was 12 weeks (range 1–52 weeks) (18).

The relationship between infliximab and granulomatous inflammatory conditions remains a controversial one. A recent case has been reported documenting the successful use of infliximab in the treatment of the severe granulomatous disease in common variable immunodeficiency (19). One fundamental paradox is evident in this context. The monoclonal anti-TNF antibodies carry a greater risk of TB reactivation than soluble TNF receptors (20, 21); however, they are the superior agents for effectively treating the chronic granulomatous inflammation underlying Crohn's disease. Highlighting these complex interactions is the fact that our patient was clinically in remission for his arthritis while receiving infliximab therapy, implying that he had achieved effective TNF suppression at the time the sarcoidosis developed. Cytokines in addition to TNF almost certainly play an important role in the pathogenesis of sarcoidosis. There has been a recent publication of a case of pulmonary sarcoidosis occurring during interferon-α therapy in a patient with chronic hepatitis C (22).

These reports should occasion vigilance in monitoring patients receiving anticytokine agents, both for infectious and noninfectious complications. These unusual events may also shed new light on the pathogenesis of idiopathic inflammatory diseases such as sarcoidosis.

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