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Neurological Complications of Infliximab To the Editor: In a recent case report1, Jarand, et al consider the diagnosis of progressive multifocal leukoencephalopathy (PML) in their patient with apparent demyelination following treatment with infliximab (Case 1). As this diagnosis entails a very poor prognosis, it is important to rule out active infection with the causative agent — JC virus — at an early stage. This cannot be done on magnetic resonance imaging (MRI) evidence alone. Although PML lesions usually appear hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, it was recently reported that PML can present atypically on MRI as a ring-enhancing lesion with mass effect2. The diagnosis is readily missed3 and has probably been underreported as a complication of treatment with anti-tumor necrosis factor-a (TNF-a) agents4: in 18 cases of apparent demyelination reported to the US Food and Drug Administration following treatment with etanercept or infliximab, brain biopsy was performed in only two5. Histopathology — the definitive way of establishing a diagnosis of PML — was consistent with encephalopathy rather than demyelination in one of these 2 brains. Furthermore, that patient's symptoms and progressive lesions on MRI were in keeping with PML rather than multiple sclerosis6. Corroborative evidence that anti-TNF-a therapy may predispose to PML also comes from experience with natalizumab, a recombinant humanized antibody directed to the a4 integrin molecule. Use of this agent was suspended last year after it was associated with a number of cases of PML3. Genain, et al7 found retrospectively that the number of T cells, and in particular regulatory T cells, was profoundly depleted in those patients who developed PML following treatment with natalizumab (< 0.2% compared to healthy control, levels of 1–4%). This suggests that T cell lymphopenia may account for the increased risk of PML infection seen in patients taking natalizumab. Wachi, et al8 recently described a similar depletion of T cells following treatment with infliximab, suggesting a possible mechanism for how anti-TNF-a therapy may predispose patients to JC virus infection and PML. We recommend that any patient presenting with new central nervous system symptoms following treatment with anti-TNF-a agents be evaluated for JC virus infection by polymerase chain reaction on cerebrospinal fluid. This test is more than 90% sensitive and almost 100% specific9 but should be used in conjunction with MRI to rule out PML. The wait-and-see approach adopted by Jarand, et al is suboptimal when potentially dealing with a rapidly fatal disease. Early detection is critical. JONATHAN C.P. ROOS, MA, AMIBiol; ANDREW J.K. OSTOR, MBBS, FRACP, University of Cambridge, Cambridge, UK. Address reprint requests to J. Roos, Department of Medicine, Box 157, Level 5, Addenbrooke's Hospital, University of Cambridge, Hills Road, Cambridge, CB2 2QQ, UK. E-mail: jcpr2@cam.ac.uk Andrew Ostor has received honoraria and grants for attending meetings from Schering-Plough and Abbott Immunology. REFERENCES 1. Jarand J, Zochodne DW, Martin LO, Voll C. Neurological complications of infliximab. J Rheumatol 2006;33:1018-20. Epub 2006 Mar 1. 2. Lima MA, Hanto DW, Curry MP, et al. Atypical radiological presentation of progressive multifocal leukoencephalopathy following liver transplantation. J Neurovirol 2005;11:46-50. 3. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-8. 4. Roos JC, Ostor AJ. Anti-tumor necrosis factor alpha therapy and the risk of JC virus infection. Arthritis Rheum 2006;54:381-2. 5. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001;44:2862-9. 6. Imperato AK, Bingham CO 3rd, Abramson SA. Overview of benefit/risk of biological agents. Clin Exp Rheumatol 2004;22 Suppl 35:S108-S114. 7. Genain CP, Islar J, Morgan K, et al. Natalizumab-induced immunosuppression in a case of progressive multifocal leukoencephalopathy (PML). Ann Neurol 2005;58 Suppl 9:S25. 8. Wachi K, Prasertsuntarasai T, Kishimoto M, Uramoto K. T-cell lymphopenia associated with infliximab and cyclophosphamide. Am J Med Sci 2005;330:48-51. 9. Yousry TA, Major EO, Ryshkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924-33. |