Rheumatology Advance Access originally published online on June 21, 2008
Rheumatology 2008 47(8):1256-1257; doi:10.1093/rheumatology/ken234
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Fatal Pneumocystis pneumonia following rituximab administration for rheumatoid arthritis
1Department of Internal Medicine I and 2Institute of Pathology, University of Regensburg, Regensburg, Germany
Correspondence to: L. L. Teichmann, Department of Internal Medicine I, University of Regensburg, 93042 Regensburg, Germany. E-mail: lino.teichmann{at}klinik.uni-regensburg.de
SIR, The widespread use of immunosuppressive drugs for the treatment of inflammatory disorders puts a growing number of non-HIV patients at risk for opportunistic infections including Pneumocystis pneumonia [1]. In RA, Pneumocystis pneumonia is a rare but serious complication. Here, we describe the first case of Pneumocystis pneumonia in a patient with RA after B-cell depleting therapy with rituximab. Beforehand, the patient was treated with traditional DMARDs and prednisolone for several years without any major complications.
A 53-yr-old man with RA presented with a 7-day history of shortness of breath, dizziness, loss of appetite and fever. Until 4 months earlier, the patient was treated with a combination DMARD-therapy consisting of MTX (20 mg s.c. weekly) and LEF (20 mg daily) together with low-dose prednisolone. A severe arthritis flare necessitated an adjustment of this therapy, which had been in place for 4 yrs without side-effects. As the patient had a past history of pleural tuberculosis, we decided against administration of a TNF-
-inhibitor at that time. Instead, treatment with LEF was discontinued and rituximab (1000 mg i.v. on days 1 and 15) was administered in combination with MTX (20 mg s.c. weekly). In addition, the patient received low-dose prednisolone at 5–7.5 mg/day. The patient had been diagnosed with emphysema due to cigarette smoking in the past. On examination, an oropharyngeal candidiasis and bronchial breathing was noted. Heart rate was 110/min and blood pressure 150/60 mmHg. Leucocytes were within the normal range (6.1 x 109/l) but lymphocytes were considerably decreased (183 x 106/l). The concentration of CRP was 282 mg/l and lactate dehydrogenase was 747 U/l. The HIV test was negative. A chest radiograph showed patchy or confluent infiltrates spread over both lungs (Fig. 1). The patient was immediately transferred to the intensive care unit and a flexible bronchoscopy with bronchoalveolar lavage was performed. After the procedure, the patient developed respiratory failure and had to be intubated and mechanically ventilated. Bronchoalveolar lavage fluid was negative for Mycobacteria (Ziehl–Neelsen stain, culture and PCR analysis) and Pneumocystis (Grocott's methenamine silver stain). However, Acinetobacter baumannii was detected and the bronchoaleveolar lavage contained 106 copies/ml of Herpes simplex virus DNA. Treatment with piperacillin/sulbactam, ciprofloxacin, aciclovir and voriconazole was initiated. One week after admission, antibiotics were empirically switched to meropenem and vancomycin due to clinical worsening. Bronchoalveolar lavage was repeated on day 14. Again, microscopy for Pneumocystis was negative but this time PCR analysis revealed Pneumocystis DNA at high concentrations (106 copies/ml). Cotrimoxazol was added to the antibiotic regimen immediately but eventually the patient died from septic multi-organ failure. Post-mortem histology of the lungs revealed alveoli filled with amorphous PAS-positive material. Pneumocystis cysts were found in the Grocott's methenamine silver stain. These findings confirmed the diagnosis of septic multi-organ failure due to Pneumocystis pneumonia.
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The patient demonstrated here was treated with a complex immunosuppressive drug scheme for RA. In this scenario, it is impossible to determine the contribution of single drugs to the development of Pneumocystis pneumonia. Prednisolone and MTX are both risk factors for Pneumocystis pneumonia [2, 3]. RA itself has been discussed to cause suppression of cellular immunity [4]. However, our patient with long-standing RA was treated with MTX, LEF and low-dose prednisolone for 4 yrs without any major complications but contracted Pneumocystis pneumonia 4 months after LEF was stopped and rituximab was administered. The strong temporal relationship between the rituximab infusions and the onset of the disease suggests that rituximab played a decisive role in the development of the opportunistic infection.
The host's defence against Pneumocystis is thought to be critically dependent on the activity of CD4+ T cells. There is growing evidence supporting the notion that rituximab not only depletes B cells but also influences T-cell immunity. Remarkably, the occurrence of infectious diseases generally considered to be associated with T-cell immunosuppression has been reported after rituximab administration. On 18 December 2006, the US Food and Drug Administration (FDA) issued a safety information warning that two patients receiving rituximab for the treatment of SLE had developed progressive multi-focal leucoencephalopathy caused by reactivated JC virus [5]. Furthermore, there are 15 published cases of CMV infections after rituximab administration [6]. In context with our case, we wish to highlight a recent publication [7] reporting six cases of Pneumocystis pneumonia in a group of 46 B-cell lymphoma patients treated with the rituximab-CHOEP-14 regimen [Cyclophosphamide 750 mg/m2 IV on day 1, Doxorubicin 50 mg/m2 IV on day 1, Vincristine 1.4 mg/m2 (max 2 mg) on day 1, Etoposide 100 mg/m2 day 1 to day 3, Prednisolone 100 mg PO on days 1-5; Repeat cycle every 15 days], compared with one out of 25 patients in the CHOEP-14 group without rituximab (13% vs 4%).
The underlying mechanisms involved in the aforementioned clinical observations are ill defined. Interestingly, B-cell deficient mice fail to clear Pneumocystis infection probably due to inefficient generation of protective CD4+ memory and effector T cells [8]. Sfikakis and colleagues [9] reported that clinical remission of lupus nephritis following B-cell depletion with rituximab is associated with a decrease in T helper cell activation. Moreover, mRNA levels of the regulatory T-cell marker FoxP3 in peripheral blood lymphocytes increased significantly in patients with lupus nephritis after rituximab therapy [10].
Whether rituximab modulates T-cell immunity and predisposes to Pneumocystis pneumonia remains to be clarified.
Disclosure statement: M.F. received speaker fees and obtained research support from Roche. B.S. received travel grants from and has participated on advisory boards for Roche. Roche is the manufacturer of rituximab. All other authors have declared no conflicts of interest.
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References |
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 Top References |
|---|
- Sepkowitz KA. Opportunistic infections in patients with and patients without acquired immunodeficiency syndrome. Clin Infect Dis (2002) 34:1098–107.[CrossRef][Web of Science][Medline]
- Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc (1996) 71:5–13.[Abstract]
- Kaneko Y, Suwa A, Ikeda Y, Hirakata M. Pneumocystis jiroveci pneumonia associated with low-dose methotrexate treatment for rheumatoid arthritis: report of two cases and review of the literature. Mod Rheumatol (2006) 16:36–8.[CrossRef][Medline]
- Prekates A, Kyprianou T, Paniara O, Roussos C. Pneumocystis carinii pneumonia in a HIV-seronegative patient with untreated rheumatoid arthritis and CD4+ T-lymphocytopenia. Eur Respir J (1997) 10:1184–6.[Abstract]
- US Food and Drug Administration. FDA alert: rituximab (marketed as Rituxan). (2006) December.
- Aksoy S, Harputluoglu H, Kilickap S, et al. Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma (2007) 48:1307–12.[CrossRef][Web of Science][Medline]
- Kolstad A, Holte H, Fossa A, Lauritzsen GF, Gaustad P, Torfoss D. Pneumocystis jirovecii pneumonia in B-cell lymphoma patients treated with the rituximab-CHOEP-14 regimen. Haematologica (2007) 92:139–40.
[Abstract/Free Full Text] - Lund FE, Hollifield M, Schuer K, Lines JL, Randall TD, Garvy BA. B cells are required for generation of protective effector and memory CD4 cells in response to Pneumocystis lung infection. J Immunol (2006) 176:6147–54.
[Abstract/Free Full Text] - Sfikakis PP, Boletis JN, Lionaki S, et al. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum (2005) 52:501–13.[CrossRef][Web of Science][Medline]
- Sfikakis PP, Souliotis VL, Fragiadaki KG, Moutsopoulos HM, Boletis JN, Theofilopoulos AN. Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin Immunol (2007) 123:66–73.[CrossRef][Web of Science][Medline]
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