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Demyelinating Disease in a Patient with Psoriatic Arthritis and Family History
of Multiple Sclerosis Treated with Infliximab To the Editor: Anti-tumor necrosis factor (anti-TNF) therapies represent a major advance in the treatment of inflammatory arthropathies, with an adequate safety profile, as shown in clinical trials. However, several potential risks such as predisposition to some infections (especially tuberculosis), heart failure, or development of lymphomas1 have been uncovered in postmarketing reports. In addition, the development of demyelinating complications has been reported, although a definitive causal relationship has not been established2-4. Current guidelines recommend avoiding this therapy in patients with previous demyelinating disease. The question remains whether such caution should be extended to patients with first-degree relatives with multiple sclerosis (MS). We describe a patient with a family history of MS who developed central nervous system (CNS) demyelinating disease after commencing therapy with infliximab for psoriatic arthritis (PsA). A 47-year-old woman with PsA presented to our hospital for the first time in March 2002. She had previously been treated with methotrexate and leflunomide but both had been discontinued because of intolerance. In October 2003 she developed a flare, with arthritis in multiple joints and a high level of functional impairment. Methotrexate 10 mg weekly and folic acid were started but there was inadequate response and poor tolerance; therapy with infliximab was then begun. One month later, she was completely asymptomatic. By June 2004, however, she reported paresthesias in the right side of the face. Over the ensuing days she developed bilateral decreased visual acuity, progressive paraparesis, paresthesias in the right upper limb, and clumsiness in the left upper limb. At that time she revealed that she had a sister with MS. Magnetic resonance imaging (MRI) studies showed several white matter lesions, hyperintense on T2 weighted scans, 2 of them located in the brain stem and 4 in the spinal cord; the majority of these lesions enhanced gadolinium and were felt to be consistent with demyelinating lesions (Figure 1). The cerebrospinal fluid (CSF) analysis yielded normal levels of glucose and proteins, with mild pleocytosis (10 lymphocytes/mm3), intrathecal synthesis of IgG, and presence of oligoclonal bands. She was treated with boluses of methylprednisolone plus intravenous immunoglobulins (IVIG) with great improvement, although partial visual impairment and upper left limb clumsiness remained. In January 2005 she developed a new flare, with truncal ataxia and unstable gait; MRI revealed a new, enhancing lesion on the cervical spinal cord. She was again treated with high-dose steroids and IVIG, but this time with no improvement. She is now undergoing therapy with mitroxantone. Although TNF-a may play a pathogenic role in MS, therapy with anti-TNF has not demonstrated any benefit, and indeed disease worsening has been reported5. The reasons underlying this paradox are unclear, but it has been suggested that as anti-TNF blockers cross the blood-brain barrier with difficulty, peripheral TNF blockade might in fact result in higher levels of TNF in the CNS6. The development of sporadic cases of demyelinating disorders in the context of anti-TNF therapy may relate to the presence of latent MS (patients with silent demyelinating plaques in the MRI). In addition, some investigators have pointed out the existence of a trait for MS. This would be a premorbid state in which predisposition for the development of this disease exists, although in contrast with latent MS, no demyelinating plaques would be observed in MRI; such patients, however, would have increased levels of antibodies against viral antigens, oligoclonal bands in the CSF, and increased vulnerability of the blood-brain barrier7. Although no definitive genetic markers have been described in MS, familial aggregation in this disease is well known, suggesting a genetic basis; siblings of patients with MS, therefore, carry a higher risk of predisposition for this disease8,9. Our patient developed a white matter disease, with CSF and MRI findings and a clinical course consistent with definite MS (there was time and space dissemination) in the context of a positive family history for the disease. Whether or not she had latent MS cannot be said, given that no imaging or CSF studies were carried out prior to the institution of infliximab therapy. At present, the risk for this type of complication in patients treated with anti-TNF therapy and a family history of demyelinating diseases cannot be estimated. Although it is probably not very high, and indeed no similar cases have been reported so far, we suggest that family history of demyelinating disorders be carefully ascertained as a part of the pretreatment evaluation of patients considered for anti-TNF therapy, and that patients be properly informed of this potential risk; indeed, the British guidelines on the use of anti-TNF therapy have incorporated this concern in a recent update of the guidelines published in 200110. Whether MRI examination should be undertaken in this type of patient before starting this therapy remains a matter of debate, but more data are needed to obtain a definitive answer. TERESA RUIZ-JIMENO, MD, Rheumatology Section; ALEJANDRA CARVAJAL, MD, Neurology Section; CRISTINA MATA, MD; ELENA AURRECOECHEA, MD, Rheumatology Section, Hospital Sierrallana, Av. Manuel Teira s/n, 39300 Torrelavega, Cantabria, Spain. E-mail: teresaguille@ono.com REFERENCES 1. Hyrich KL, Silman AJ, Watson KD, Symmons DPM. Anti-tumor necrosis factor a therapy in rheumatoid arthritis: an update on safety. Ann Rheum Dis 2004;63:1538-43. 2. 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. 3. Cisternas M, Gutiérrez M, Jacobelli S. Successful rechallenge with anti-tumor necrosis factor alpha for psoriatic arthritis after development of demyelinating nervous system disease during initial treatment: comment on the article by Mohan, et al. Arthritis Rheum 2002;46:3107-8. 4. van der Laken CJ, Lems WF, van Soesbergen RM, van der Sande JJ, Dijkmans BAC. Paraplegia in a patient receiving anti-tumor necrosis factor therapy for rheumatoid arthritis: comment on the article by Mohan, et al. Arthritis Rheum 2003;48:269-70. 5. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS. Results of a randomized, placebo-controlled multicenter study. Neurology 1999;53:457-65. 6. Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism. By what mechanisms could tumor necrosis factor a antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 2001;44:1977-83. 7. Poser CM. Multiple sclerosis trait: the premorbid stage of multiple sclerosis. A hypothesis. Acta Neurol Scand 2004;109:239-43. 8. Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Nat Acad Sci USA 2003;100:12877-82. 9. Becanovic K, Jagodic M, Wallstrom E, Olsson T. Current gene-mapping strategies in experimental models of multiple sclerosis. Scand J Immunol 2004;60:39-51. 10. Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Ann Rheum Dis 2005;44:157-63. |