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Systemic Nocardiosis in a Case of Rheumatoid Arthritis Treated with Tumor Necrosis Factor Blockers

To the Editor:

Increasing severe or opportunistic infection risk is a major concern with the use of tumor necrosis factor (TNF-a) blockers in chronic inflammatory diseases¹. Among granulomatous infections, cases of nocardiosis are rarely reported. Systemic nocardiosis may have a poor prognosis. We describe such a case in a patient with longstanding rheumatoid arthritis (RA) treated with anti-TNF agents.

A 63-year-old Caucasian man, without concomitant disease, was diagnosed with erosive, rheumatoid factor-positive RA in 1990, and then treated with continuous prednisone (12 to 20 mg/day). After failure of several conventional disease modifying antirheumatic drugs, he was treated with methotrexate (MTX; 10 to 15 mg/wk) for 7 years, starting in 2000 (in association with cyclosporine for 2 years). In November 2006, lack of efficacy of this regimen (Disease Activity Score 28: 6.2) prompted initiation of anti-TNF therapy (etanercept, 3 mo treatment, and then adalimumab, 4 mo), in combination with MTX, without response (DAS 28: 6.5). Skin tuberculin test was negative and chest radiograph was normal before start of anti-TNF therapy. This treatment (anti-TNF and MTX) was stopped in July 2007 due to occurrence of subcutaneous nodules of the trunk (a biopsy of one nodule revealed a pyogenic granuloma), pulmonary nodules (Figure 1), and above all neurological signs: headache, vertigo, and cerebellar dysarthria. Investigations with computed tomography (CT) and magnetic resonance imaging led to discovery of 2 lesions, one in the right parietal region of brain, the other in the cerebellum, both with edema and mass effect (Figure 2). No motor deficiency was noted. Fever was 38°C. C-reactive protein (CRP) was 122 mg/l, white blood cell count 6/l. Cerebrospinal fluid was normal; investigations for tuberculosis, viruses (HIV, hepatitis B and C, herpes virus, picornavirus, enterovirus), cysticercosis, bilharziosis, and toxoplasmosis were negative. There were no antinuclear antibodies. Surgical brain biopsy revealed a pyogenic abscess and presence of Nocardia farcinica. CT scan revealed several abdominal nodules. He was then treated with antibiotics (amikacin, imipenem, and cilastatine), initially combined with high-dose, short-term steroid therapy (3 mg/kg/day) for management of cerebral edema. At 3 months, a moderate flare of RA prompted reintroduction of prednisone 10 mg/day, while antibiotics (linezolide, then sulfamethoxazole and trimethoprim) were continued. At this time, he exhibited progressive and moderate improvement of diplopia and dysarthria, while CT scan showed disappearance of the thoracic and abdominal nodules, and reduction of the cerebral tumoral mass. CRP had diminished to 44 mg/l.

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Figure 1. Thoracic CT scan shows multiple dense nodules in the pulmonary fields.

A B

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Figure 2. Brain MRI. A. T1-weighted sequence shows right temporoparietal lesion with peripheral contrast uptake. B. T2-weighted sequence shows circular lesion with significant edema, and mass effect on the fourth ventricle.

In this patient with longstanding RA under prolonged immunosuppressive treatment (prednisone 17 yrs, MTX 7 yrs, anti-TNF agents 7 months), the diagnosis was determined of systemic nocardiosis (lung, skin, abdomen, and brain). Nocardiosis is caused by an opportunistic aerobic, Gram-positive, filamentous bacteria of the order of Actinomycetales. The most common Nocardia species are N. asteroides, N. brasiliensis, and N. otitidis-caviatum, with long incubation periods². Contamination is mostly due to inhalation or through the skin. This rare infection occurs mainly in immunocompromised patients (immunosuppressive therapy, autoimmune diseases, transplanted patients, HIV infection)^2-5. Systemic nocardiosis is defined by the presence of 2 or more foci of infection², as in our case. The lung is the most frequent primary site of systemic nocardiosis (60% to 80% of cases)², and cerebral or other locations may occur in 20% to 40% of cases. Central nervous system (CNS) involvement is responsible for the worst prognosis, with a 75% rate of mortality in lupus patients³. Septic arthritis² and vertebral osteomyelitis⁶ have also been described.

TNF plays a role in the clearance of Nocardia in animal models⁷. Thus, anti-TNF therapy may favor Nocardia infection and dissemination. Nocardiosis under anti-TNF treatment has been rarely reported. In the US survey, 8 cases were identified among about 300,000 patients treated with anti-TNF agents^8,9. Cutaneous Nocardia was also described in a case of RA treated with infliximab, MTX, and corticosteroids¹⁰.

Nevertheless, it must be pointed out that nocardiosis may be diagnosed in RA patients treated with only corticosteroids and MTX^11-13 or corticosteroids alone¹⁴. Due to the slow growth of Nocardia, it is possible that anti-TNF agents in our case acted as an accelerating and disseminating factor within a previously undiagnosed nocardiosis, favored by the combination of longstanding corticosteroid and MTX therapy.

The occurrence of CNS disease in a case of a chronic inflammatory condition treated with immunosuppressive agents may be related to various diagnoses. This emphasizes the need for a precise diagnostic procedure¹⁵. The goal is the isolation of the microorganism, which may require cerebral biopsy.

DANIEL WENDLING, MD, PhD, Department of Rheumatology; MUHSEN MURAD, MD, Department of Neurology; SANDRA MATHIEU, MD, Department of Rheumatology; ERIC BERGER, MD; LUCIEN RUMBACH, MD, Department of Neurology, University Teaching Hospital Minjoz, and University of Franche-Comté, 25030 Besançon, France. Address reprint requests to Prof. D. Wendling, e-mail: dwendling@chu-besancon.fr

We thank Patrick Boiron, Laboratoire de Mycologie appliquée, faculté de Pharmacie, Lyon, who performed typing of the nocardia.

REFERENCES

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