Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Monoclonal antibody therapy-associated neurological disorders

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

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

  1. Novak, J. C., Lovett-Rache, A. E. & Rache, M. K. Monoclonal antibody therapies and neurologic disorders. Arch. Neurol. 65, 1162–1165 (2008).

    Article  Google Scholar 

  2. 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).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. BIOGEAS [online], (2007).

  5. Ramos-Casals, M. et al. Autoimmune diseases induced by biological agents. A double-edged sword? Autoimmun. Rev. 9, 188–193 (2010).

    Article  CAS  Google Scholar 

  6. Ramos-Casals, M. et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 86, 242–251 (2007).

    Article  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. Weissert, R. Progressive multifocal leukoencephalopathy. J. Neuroimmunol. doi:10.1016/j.jneuroim.2010.09.021.

  9. Tyler, K. L. Progressive multifocal leukoencephalopathy: can we reduce risk in patients receiving biological immunomodulatory therapies? Ann. Neurol. 68, 271–274 (2010).

    Article  Google Scholar 

  10. Bielekova, B. & Becker, B. L. Monoclonal antibodies in MS. Mechanisms of action. Neurology 74 (Suppl. 1), S31–S40 (2010).

    Article  CAS  Google Scholar 

  11. The CAMMS223 Trial Investigators. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801 (2008).

  12. Paolillo, A. et al. Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath 1H. Neurology 53, 751–757 (1999).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. 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).

    Article  Google Scholar 

  16. Glusker, P., Recht, L. & Lane, B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N. Engl. J. Med. 354, 980–981 (2006).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. [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).

  19. Chung, J. H. et al. Adalimumab-associated optic neuritis. J. Neurol. Sci. 244, 133–136 (2006).

    Article  CAS  Google Scholar 

  20. Bernatsky, S., Renoux, C. & Suissa, S. Demyelinating events in rheumatoid arthritis after drug exposures. Ann. Rheum. Dis. 69, 1691–1693 (2010).

    Article  CAS  Google Scholar 

  21. Stübgen, J. P. Tumor necrosis factor-α antagonists and neuropathy. Muscle Nerve 37, 281–292 (2008).

    Article  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. 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).

    Article  Google Scholar 

  25. 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).

    Article  Google Scholar 

  26. Birnbaum, J. Infliximab associated neuropathy in RA patients—the importance of considering the diagnosis of mononeuritis multiplex. Clin. Rheumatol. 26, 281–282 (2007).

    Article  CAS  Google Scholar 

  27. Singer, O. C., Otto, B., Steinmetz, H. & Ziemann, U. Acute neuropathy with multiple conduction blocks after TNFα monoclonal antibody therapy. Neurology 63, 1754 (2004).

    Article  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Miller, F. W. et al. Approaches for identifying and defining environmentally associated rheumatic disorders. Arthritis Rheum. 43, 243–249 (2000).

    Article  CAS  Google Scholar 

  30. 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).

    Article  Google Scholar 

  31. Jarrett, S. J. et al. Anti-tumor necrosis factor-alpha therapy-induced vasculitis: case series. J. Rheumatol. 30, 2287–2291 (2003).

    PubMed  Google Scholar 

  32. Richette, P. et al. Sensory neuropathy revealing necrotizing vasculitis during infliximab therapy for rheumatoid arthritis. J. Rheumatol. 31, 2079–2081 (2004).

    PubMed  Google Scholar 

  33. 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).

    Article  Google Scholar 

  34. 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).

    Article  CAS  Google Scholar 

  35. 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).

    Article  CAS  Google Scholar 

  36. Chen, Y. et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N. Engl. J. Med. 361, 1067–1074 (2009).

    Article  CAS  Google Scholar 

  37. Major, E. O. Reemergence of PML in natalizumab-treated patients—new cases, same concerns. N. Engl. J. Med. 361, 1041–1043 (2009).

    Article  CAS  Google Scholar 

  38. 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.

  39. 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).

    Article  CAS  Google Scholar 

  40. Wenning, W. et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N. Engl. J. Med. 361, 1075–1080 (2009).

    Article  CAS  Google Scholar 

  41. 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).

    Article  CAS  Google Scholar 

  42. 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).

    Article  CAS  Google Scholar 

  43. Colombel, J. F. et al. Adalimumab safety in global clinical trials of patients with Crohn's disease. Inflamm. Bowel Dis. 15, 1308–1319 (2009).

    Article  Google Scholar 

  44. 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).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

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

Correspondence to Xavier Bosch.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints 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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2011.1

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing