Abstract
Several neurological disorders have been associated with the use of monoclonal antibodies (mAbs), especially those targeting tumor necrosis factor (TNF) and its receptors. These disorders include, among others, multiple sclerosis, optic neuritis, and various forms of peripheral demyelinating neuropathy. Progressive multifocal leukoencephalopathy, the natural course of which is lethal within months, has been mainly associated with the anti-α4-integrin mAb natalizumab and, to a lesser extent, with rituximab, alemtuzumab and efalizumab. The prevalence of demyelinating disease induced by biological therapies, as reported in randomized controlled trials and postmarketing studies, has been estimated to range from 0.02–0.20%. Peripheral neuropathies can occur early or late after initiation of therapy. Short-term follow-up indicates relatively good outcomes, sometimes after mAb discontinuation alone, although corticosteroids or intravenous immunoglobulin may be necessary to reverse and stabilize the condition. Definitive cessation of the biological therapy should be discussed on a case-by-case basis. Prospective postmarketing studies in which the control group includes patients with rheumatic autoimmune diseases—most notably rheumatoid arthritis—treated with conventional therapies could help us to evaluate the real risks and outcomes in patients receiving mAbs who develop neurological diseases.
Key Points
-
Several studies have suggested a potential role for tumor necrosis factor (TNF) in the pathogenesis of inflammatory demyelinating CNS disease
-
Demyelinating disorders have been described in both postmarketing surveillance and isolated case reports for the main anti-TNF agents
-
As of July 2009, over 140 cases had been reported of demyelinating CNS processes, including multiple sclerosis and optic neuritis, after starting biological therapies
-
Progressive multifocal leukoencephalopathy has been mainly associated with natalizumab and, to a lesser extent, with rituximab, alemtuzumab and efalizumab
-
Anti-TNF-related peripheral neuropathies, including multifocal motor neuropathy with conduction block, chronic inflammatory demyelinating polyradiculoneuropathy, axonal polyneuropahy, and Lewis–Sumner syndrome, have recently been associated with TNF-targeted therapies
-
In anti-TNF-associated neuropathies, discontinuation of treatment does not always resolve the disorder, and long-term immune treatment may be required to control the condition and ensure better results
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Novak, J. C., Lovett-Rache, A. E. & Rache, M. K. Monoclonal antibody therapies and neurologic disorders. Arch. Neurol. 65, 1162–1165 (2008).
Ramos-Casals, M., Brito-Zerón, P., Soto, M. J., Cuadrado, M. J. & Khamashta, M. A. Autoimmune diseases induced by TNF-targeted therapies. Best Pract. Res. Clin. Rheumatol. 22, 847–861 (2008).
Faivre, A. et al. Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy. J. Neurol. Sci. 291, 103–106 (2010).
BIOGEAS [online], (2007).
Ramos-Casals, M. et al. Autoimmune diseases induced by biological agents. A double-edged sword? Autoimmun. Rev. 9, 188–193 (2010).
Ramos-Casals, M. et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 86, 242–251 (2007).
Ramos-Casals, M., Brito-Zerón, P., Cuadrado, M. J. & Khamashta, M. A. Vasculitis induced by tumor necrosis factor-targeted therapies. Curr. Rheumatol. Rep. 10, 442–448 (2008).
Weissert, R. Progressive multifocal leukoencephalopathy. J. Neuroimmunol. doi:10.1016/j.jneuroim.2010.09.021.
Tyler, K. L. Progressive multifocal leukoencephalopathy: can we reduce risk in patients receiving biological immunomodulatory therapies? Ann. Neurol. 68, 271–274 (2010).
Bielekova, B. & Becker, B. L. Monoclonal antibodies in MS. Mechanisms of action. Neurology 74 (Suppl. 1), S31–S40 (2010).
The CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801 (2008).
Paolillo, A. et al. Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath 1H. Neurology 53, 751–757 (1999).
Moreau, T. et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 344, 298–301 (1994).
Piccinni, C. et al. Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents. Eur. J. Clin. Pharmacol. 66, 199–206 (2010).
Allen, J. A., Adlakha, A. & Bergethon, P. R. Reversible posterior leukoencephalopathy syndrome after bevacizumab/FOLFIRI regimen for metastatic colon cancer. Arch. Neurol. 63, 1475–1478 (2006).
Glusker, P., Recht, L. & Lane, B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N. Engl. J. Med. 354, 980–981 (2006).
van Oosten, B. W. et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47, 1531–1534 (1996).
[No authors listed] TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 53, 457–465 (1999).
Chung, J. H. et al. Adalimumab-associated optic neuritis. J. Neurol. Sci. 244, 133–136 (2006).
Bernatsky, S., Renoux, C. & Suissa, S. Demyelinating events in rheumatoid arthritis after drug exposures. Ann. Rheum. Dis. 69, 1691–1693 (2010).
Stübgen, J. P. Tumor necrosis factor-α antagonists and neuropathy. Muscle Nerve 37, 281–292 (2008).
Tracey, D., Klareskog, L., Sasso, E. H., Salfeld, J. G. & Tak, P. P. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol. Ther. 117, 244–279 (2008).
Shin, I. S., Baer, A., Kwon, H., Papadopoulos, E. & Siegel, J. Guillain–Barré and Miller Fisher syndromes occurring with tumor necrosis factor α antagonist therapy. Arthritis Rheum. 54, 1429–1434 (2006).
Lozeron, P., Denier, C., Lacroix, C. & Adams, D. Long-term course of demyelinating neuropathies occurring during tumor necrosis factor-α-blocker therapy. Arch. Neurol. 66, 490–497 (2009).
Alshekhlee, A., Basiri, K., Miles, J. D., Ahmad, S. A. & Katirji, B. Chronic inflammatory demyelinating polyneuropathy associated with tumor necrosis factor-α antagonists. Muscle Nerve 41, 723–727 (2010).
Birnbaum, J. Infliximab associated neuropathy in RA patients—the importance of considering the diagnosis of mononeuritis multiplex. Clin. Rheumatol. 26, 281–282 (2007).
Singer, O. C., Otto, B., Steinmetz, H. & Ziemann, U. Acute neuropathy with multiple conduction blocks after TNFα monoclonal antibody therapy. Neurology 63, 1754 (2004).
Gondim, F. A., Brannagan, T. H. 3rd, Sander, H. W., Chin, R. I. & Latov, N. Peripheral neuropathy in patients with inflammatory bowel disease. Brain 128, 867–879 (2005).
Miller, F. W. et al. Approaches for identifying and defining environmentally associated rheumatic disorders. Arthritis Rheum. 43, 243–249 (2000).
Tektonidou, M. G., Serelis, J. & Skopouli, F. M. Peripheral neuropathy in two patients with rheumatoid arthritis receiving infliximab treatment. Clin. Rheumatol. 26, 258–260 (2007).
Jarrett, S. J. et al. Anti-tumor necrosis factor-alpha therapy-induced vasculitis: case series. J. Rheumatol. 30, 2287–2291 (2003).
Richette, P. et al. Sensory neuropathy revealing necrotizing vasculitis during infliximab therapy for rheumatoid arthritis. J. Rheumatol. 31, 2079–2081 (2004).
Cisternas, M., Gutiérrez, M. & Jacobelli, S. Successful rechallenge with anti-tumor necrosis factor α for psoriatic arthritis after development of demyelinating nervous system disease during initial treatment. Arthritis Rheum. 46, 3107–3108 (2002).
Richez, C. Blanco, P., Lagueny, A., Schaeverbeke, T. & Dehais, J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-α blockers. Neurology 64, 1468–1470 (2005).
Hooper, D. R., Tarnopolsky, M. A. & Baker, S. K. Lewis–Sumner syndrome associated with infliximab therapy in rheumatoid arthritis. Muscle Nerve 38, 1318–1325 (2008).
Chen, Y. et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N. Engl. J. Med. 361, 1067–1074 (2009).
Major, E. O. Reemergence of PML in natalizumab-treated patients—new cases, same concerns. N. Engl. J. Med. 361, 1041–1043 (2009).
Xu, L. et al. The polymorphisms of the TNF-α gene in multiple sclerosis?—a meta-analysis. Mol. Biol. Rep. doi: 10.1007/s11033-010-053320130.
Bachmann, R., Eugster, H. P., Frei, K., Fontana, A. & Lassmann, H. Impairment of TNF-receptor-1 signaling but not Fas signaling diminishes T-cell apoptosis in myelin oligodendrocyte glycoprotein peptide-induced chronic demyelinating autoimmune encephalomyelitis in mice. Am. J. Pathol. 154, 1417–1422 (1999).
Wenning, W. et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N. Engl. J. Med. 361, 1075–1080 (2009).
Schiff, M. H. et al. Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann. Rheum. Dis. 65, 889–894 (2006).
Burmester, G. R. et al. Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial. Ann. Rheum. Dis. 66, 732–739 (2007).
Colombel, J. F. et al. Adalimumab safety in global clinical trials of patients with Crohn's disease. Inflamm. Bowel Dis. 15, 1308–1319 (2009).
Magnano, M. D., Robinson, W. H. & Genovese, M. C. Demyelination and inhibition of tumor necrosis factor (TNF). Clin. Exp. Rheumatol. 22 (Suppl. 35), S134–S140 (2004).
Author information
Authors and Affiliations
Consortia
Contributions
X. Bosch, A. Saiz and M. Ramos-Casals researched data for the article, made substantial contributions to discussions of the content, wrote the text and reviewed and/or edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Bosch, X., Saiz, A., Ramos-Casals, M. et al. Monoclonal antibody therapy-associated neurological disorders. Nat Rev Neurol 7, 165–172 (2011). https://doi.org/10.1038/nrneurol.2011.1
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneurol.2011.1
This article is cited by
-
Demyelinating plaque-associated uveitis
Graefe's Archive for Clinical and Experimental Ophthalmology (2024)
-
Neuromyelitis Optica: Pathogenesis Overlap with Other Autoimmune Diseases
Current Allergy and Asthma Reports (2023)
-
Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
Nature Immunology (2023)
-
Adverse drug reactions of Rituximab in patients suffering from autoimmune neurological diseases
DARU Journal of Pharmaceutical Sciences (2022)
-
Neuromyelitis Optica Spectrum Disorders (NMOSD) and Connective Tissue Disease (CTD): an Update for the Rheumatologist
Current Rheumatology Reports (2021)