Case reports [8] Bal AM, Bharadwaj RS, Gita N, Joshi SA, Thakare JP. Guillain-Barre syndrome in a paediatric patient following infection due to Leptospira. Jpn J Infect Dis 2003;56:29 31. [9] Odaka M, Yuki N, Yamada M, Koga M, Takemi T, Hirata K, et al. Bickerstaff brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barre syndrome. Brain 2003;126:2279 90. [10] Hahn AF. Guillain-Barre syndrome. Lancet 1998;353:635 41. /
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[11] Paparounas K, O’Hanlon GM, O’Leary CP, Rowan EG, Willison HJ. Anti-ganglioside antibodies can bind peripheral nerve nodes of Ranvier and activate the complement cascade without inducing acute conduction block in vitro. Brain 1999;122:807 16. [12] Goodfellow JA, Bowes T, Sheikh K, Odaka M, Halstead SK, Humphreys PD, et al. Overexpression of GD1a ganglioside sensitizes motor nerve terminals to anti-GD1a antibodymediated injury in a model of acute motor axonal neuropathy. J Neurosci 2005;25:1620 8. /
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Pneumocystis carinii pneumonia in a rheumatoid arthritis patient treated with adalimumab UMUT KALYONCU1, OMER KARADAG1, ALI AKDOGAN1, BUNYAMIN KISACIK1, MUSTAFA ERMAN2, SIBEL ERGUVEN3 & A. IHSAN ERTENLI1 From the 1Department of Internal Medicine Division of Rheumatology, 2Department of Preventive Oncology, Institute of Oncology, and 3Department of Microbiology and Clinical Microbiology Hacettepe University Faculty of Medicine, Ankara, Turkey
Abstract Patients with rheumatoid arthritis (RA) have an increased risk of infection as a result of alterations in immune regulation, debility, and comorbid illnesses. TNF-a is of central importance in the pathophysiological responses to infection and inflammation, and plays a crucial role in host defence. Pneumocystis carinii is an opportunistic pathogen that commonly affects individuals with inadequate T-cell mediated immune response. Patients with acquired immune deficiency, as well as those receiving immunosuppressive drugs for various conditions have an increased risk of P. carinii pneumonia (PCP). We report the development of PCP in a woman with RA shortly after the initiation of anti-TNF-a treatment with adalimumab.
Introduction TNF-a is of central importance in the pathophysiological responses to infection and inflammation, and plays a crucial role in host defence. It stimulates the production of other pro-inflammatory cytokines and promotes the maturation of inflammatory cells. The importance of TNF-a in the pathogenesis of rheumatoid arthritis (RA) is now well known and treatment with TNF antagonists is highly effective. However, the safety profile of this new class of agents is not yet fully established [1]. Pneumocystis carinii is an opportunistic pathogen that commonly affects individuals with inadequate T-cell mediated immune response. Patients with acquired immune deficiency, as well as those receiving immunosuppressive drugs for various conditions
have an increased risk of P. carinii pneumonia (PCP) [2]. We report the development of PCP in a woman with RA shortly after the initiation of anti-TNF-a treatment with adalimumab. Case report A 59-y-old female with the diagnosis of RA fulfilling the ACR criteria was followed up from May 1998. Until March 2004, her treatment consisted of methotrexate 7.5 15 mg per week, sulfasalazine 1.5 3.0 g/d, and deflazacort 3 6 mg/d. She could not tolerate leflunomide, and although hydroxychloroquine 100 mg was also given, it had to be discontinued due to ocular toxicity. Between March 2004 and October 2005, the treatment regimen was
Correspondence: O. Karadag, Hacettepe Universitesi Romatoloji Unitesi, 06100 Sihhiye- Ankara, Turkey. Tel: /90 312 3100194. Fax: /90 312 3100194. E-mail:
[email protected]
(Received 5 October 2006; accepted 9 October 2006) ISSN 0036-5548 print/ISSN 1651-1980 online # 2007 Taylor & Francis DOI: 10.1080/00365540601071867
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switched to methotrexate 15 mg per week, sulfasalazine 2.5 g/d and azathioprine 100 mg/d. Because of persistent disease activity (DAS-28 score: 6.02), adalimumab 40 mg subcutaneously q14 d in combination with methotrexate 15 mg per week was started. Two months later, the patient felt better and DAS-28 score fell to 4.73. However, after 3 months of adalimumab treatment, she was admitted to hospital with non-productive cough, shortness of breath, and fever. Physical examination revealed low-grade fever (37.88C), tachycardia (110/min), and tachypnoea (28/min). There were fine crepitations in both lung bases. There was no evidence of exacerbation of arthritis. The erythrocyte sedimentation rate was 73 mm/h, white blood cell count 7600/mm3, and lymphocyte count 980/ mm3. Arterial blood gas revealed hypoxia with a partial oxygen pressure of 48 mmHg. Urinalysis and renal function tests were normal. On chest X-ray, there were bilateral lower and middle zone infiltrates (Figure 1). High resolution computed tomography of the thorax showed bilateral, diffuse ground-glass opacifications and thickened interlobular septa (Figure 2). The patient was hospitalized and empirical treatment with intravenous trimethoprim-sulfamethoxazole, prednisone, supplemental 40% oxygen via ventimask and levofloxacin 500 mg/d was started with the presumptive diagnoses of PCP or atypical pneumonia. Methotrexate and adalimumab were discontinued. The next d, her vital signs normalized and on the fourth d of hospitalization, oxygen supplementation could be discontinued. On the fifth d, bronchoscopy with bronchoalveolar lavage was performed. The lavage material revealed the presence of P. carinii when stained with direct fluorescent antibody for PCP-direct fluorescent antibody (PCP-DFA), with no mycobacteria on
Figure 1. Bilateral lower and middle zone infiltrates on chest x-ray.
Figure 2. HRCT revealed bilateral, diffuse ground-glass opacifications and thickened interlobular septa.
Ziehl-Neelsen stain or bacteria on Gram stain (Figure 3). Levofloxacin was discontinued and intravenous cotrimoxazole was given for 8 d followed by high dose oral therapy for 2 additional weeks. Chest X-ray taken on the ninth d was normal. Discussion Patients with RA have an increased risk of infection as a result of alterations in immune regulation, debility, and comorbid illnesses. Immunosuppressive medications further augment this risk, and anti-TNF agents are no exception. Although safety information is less extensive than with the older agents, many cases of opportunistic infections including invasive pulmonary aspergillosis, pulmonary cryptococcosis, disseminated sporotrichosis, cerebral toxoplasmosis, disseminated CMV infection, and herpes zoster have been described in patients receiving this group of drugs [3,4].
Figure 3. Presence of P. carinii with direct fluorescent antibody.
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Case reports Secretion of TNF-a by alveolar macrophages is an important host response and defence against P. carinii infection, and higher TNF-a production is associated with lower counts of microorganisms. Patients with RA treated with TNF-a inhibitors show decreased production of interferon-g and decreased expression of Toll-like receptor-4 (TLR4), which are necessary for the recognition of microorganisms by phagocytes and dendritic cells. This causes an increased susceptibility to intracellular bacterial and fungal pathogens such as P. carinii. TNF-a activity has also been shown to be critical in animal PCP models and administration of anti-TNF-a IgG to reconstituted SCID mice with PCP results in impaired clearance of P. carinii in the lung [57]. Adalimumab is a fully humanized IgG I anti-TNF monoclonal antibody that is used in the treatment of refractory RA. It is considered to be a relatively safe drug. Safety Trial of Adalimumab in RA (STAR) revealed a higher number of injection site reactions with adalimumab than with placebo (8.8% vs 0.6%, respectively). However, adalimumab and placebo arms were comparable in terms of serious adverse events (5.3% vs 6.9%, respectively), infections (52.2% vs 49.4%) and serious infections (1.3% vs 1.9%) [8]. Although PCP was once viewed as a problem of patients with AIDS, it is now known to affect patients receiving glucocorticoids or intensive immunosuppressive therapies for cancer or organ transplantation. As our case demonstrates, patients receiving biological agents for inflammatory conditions such as RA are also at risk. The Food and Drug Administration database up to June 2001 has identified 44 patients receiving infliximab and 5 receiving etanercept for RA or Crohn’s disease who had PCP in association with these drugs. The onset of PCP averaged between 1 and 2 months following the initiation of treatment and 6 of the 49 patients died (12%) [9]. However, there have been no reports of PCP associated with adalimumab treatment. Our patient was receiving adalimumab in combination with methotrexate, an agent that she had been receiving for the last 7 y. Methotrexate is also known to increase the risk of infection in RA patients and PCP is 1 of the opportunistic infections in patients taking this drug. PCP has been reported to develop at any time between 1 month and several y of methotrexate treatment [10]. In our patient, the timing of PCP favours an association with adalimumab, rather than with methotrexate. However, the concomitant use of methotrexate may have at least contributed to the development of this complication.
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Diagnosis of PCP can be challenging because signs and symptoms may mimic communityacquired bacterial infections. A high degree of suspicion appears to be the first prerequisite for a diagnosis of PCP. Not infrequently, hypoxia mandates that bronchoscopy be delayed, and it may not always be possible to obtain satisfactory sputum samples, even with induction with 3% NaCl. Our patient was given empirical PCP treatment because of severe hypoxia and she improved quickly. Moderate to severe episodes of PCP cause severe morbidity and, even with the best management, up to 20% of patients die. We think that patients on immunosuppressive and/or anti-TNF drugs with bilateral pulmonary infiltrates and severe hypoxia should immediately be given empirical anti-PCP treatment. There are no evidence-based guidelines for the prevention of fungal infections in the setting of anti-TNF-a therapy. However, a low CD4 count may be taken as a warning sign and PCP prophylaxis may be considered, especially for patients who have a history of serious infections. Although anti-TNF agents represent an effective treatment alternative for patients with refractory RA, their use may be associated with serious opportunistic infections. We have presented a patient with RA who developed PCP while receiving adalimumab in combination with methotrexate. To the best of our knowledge, this case represents the first case of PCP associated with adalimumab. We suggest that physicians should be particularly vigilant for signs and symptoms of opportunistic infections, including PCP, especially during the first 3 to 6 months of anti-TNF-a therapy.
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