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:

Biologic therapies in non-rheumatic diseases: lessons for rheumatologists?

Nature Reviews Rheumatology volume 7, pages 507–516 (2011)Cite this article

Subjects

Abstract

Biologic therapies have been licensed to treat rheumatic diseases for more than a decade. In parallel, they have gained acceptance in a variety of non-rheumatic diseases, where their impact has been no less revolutionary. In this Review, we examine the application of biologics in a number of non-rheumatic autoimmune and inflammatory disorders—psoriasis, inflammatory bowel disease, uveitis, asthma, diabetes, congestive cardiac failure and multiple sclerosis. In particular, we have sought information, or lessons, that could influence their application in rheumatic diseases. For example, we highlight the potential to stratify asthma into groups that might require different targeted approaches, and focus on some of the less common adverse events associated with biologic therapies in multiple sclerosis. Similarly, we examine type 1 diabetes mellitus in the context of potential therapeutic induction of immune tolerance. Working collaboratively, across specialties, there is significant synergy to be gained in regard to understanding how biologic therapies work, how best to use them, and the adverse effects we should be conscious of.

Key Points

  • Biologic therapies are increasingly used in non-rheumatic diseases

  • As in rheumatic disease, biologics might provide a therapeutic option for otherwise refractory non-rheumatic disease

  • These agents may also provide proof-of-concept for proposed mechanisms of immunopathology, such as IL-1β blockade in type 2 diabetes mellitus

  • In other situations their effects can be paradoxical, such as worsening of heart failure and occasional induction of psoriasis and uveitis during tumor necrosis factor blockade

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The structure and function of the cytokines IL-12 and IL-23.
Figure 2: Pathogenesis of asthma and the potential role of biologics.
Figure 3: The potential for tolerogenic therapy in practice.

Similar content being viewed by others

References

  1. Strand, V., Kimberly, R. & Isaacs, J. D. Biologic therapies in rheumatology: lessons learned, future directions. Nat. Rev. Drug Discov. 6, 75–92 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Kircik, L. H. & Del Rosso, J. Q. Anti-TNF agents for the treatment of psoriasis. J. Drugs Dermatol. 8, 546–559 (2009).

    PubMed  Google Scholar 

  3. Brimhall, A. K. et al. Safety and efficacy of alefacept, efalizumab, etanercept and infliximab in treating moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials. Br. J. Dermatol. 159, 274–285 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Reich, K. et al. Comparative effects of biological therapies on the severity of skin symptoms and health-related quality of life in patients with plaque-type psoriasis: a meta-analysis. Curr. Med. Res. Opin. 24, 1237–1254 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Saad, A. A. et al. Efficacy and safety of anti-TNF therapies in psoriatic arthritis: an observational study from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 49, 697–705 (2010).

    Article  CAS  Google Scholar 

  6. Harrison, M. J. et al. Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor α therapy: results from the British Society for Rheumatology Biologics Register. Ann. Rheum. Dis. 68, 209–215 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Ko, J. M., Gottlieb, A. B. & Kerbleski, J. F. Induction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J. Dermatolog. Treat. 20, 100–108 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Malaviya, R. et al. Etanercept induces apoptosis of dermal dendritic cells in psoriatic plaques of responding patients. J. Am. Acad. Dermatol. 55, 590–597 (2006).

    Article  PubMed  Google Scholar 

  9. Goedkoop, A. Y. et al. Early effects of tumour necrosis factor α blockade on skin and synovial tissue in patients with active psoriasis and psoriatic arthritis. Ann. Rheum. Dis. 63, 769–773 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Purvis, H. A. et al. Low-strength T-cell activation promotes Th17 responses. Blood 116, 4829–4837 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chan, J. R. et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J. Exp. Med. 203, 2577–2587 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ma, H. L. et al. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J. Clin. Invest. 118, 597–607 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Leonardi, C. L. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371, 1665–1674 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Papp, K. A. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371, 1675–1684 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Griffiths, C. E. et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N. Engl. J. Med. 362, 118–128 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Kimball, A. B. et al. Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial. Arch. Dermatol. 144, 200–207 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. National Electronic Library for Medicines. Marketing authorisation application for briakinumab (Ozespa®) withdrawn [online], (2011).

  18. Hanauer, S. B. et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 359, 1541–1549 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Rutgeerts, P. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 353, 2462–2476 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Sands, B. E. et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N. Engl. J. Med. 350, 876–885 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Hanauer, S. B. et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology 130, 323–333 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Sandborn, W. J. et al. Certolizumab pegol for the treatment of Crohn's disease. N. Engl. J. Med. 357, 228–238 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Sandborn, W. J. et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121, 1088–1094 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Taylor, P. C. Pharmacology of TNF blockade in rheumatoid arthritis and other chronic inflammatory diseases. Curr. Opin. Pharmacol. 10, 308–315 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Nesbitt, A. et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm. Bowel Dis. 13, 1323–1332 (2007).

    Article  PubMed  Google Scholar 

  26. ten Hove, T. et al. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease. Gut 50, 206–211 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Di Sabatino, A. et al. Defective mucosal T cell death is sustainably reverted by infliximab in a caspase dependent pathway in Crohn's disease. Gut 53, 70–77 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Stallmach, A., Hagel, S. & Bruns, T. Adverse effects of biologics used for treating IBD. Best Pract. Res. Clin. Gastroenterol. 24, 167–182 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. FDA. Questions and Answers—TNF Blockers [online], (2009).

  30. Siegel, C. A. et al. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn's disease: a meta-analysis. Clin. Gastroenterol. Hepatol. 7, 874–881 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Van Assche, G. et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 134, 1861–1868 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Dick, A. D. et al. Neutralizing TNF-alpha activity modulates T-cell phenotype and function in experimental autoimmune uveoretinitis. J. Autoimmun. 11, 255–264 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Robertson, M. et al. Neutralizing tumor necrosis factor-α activity suppresses activation of infiltrating macrophages in experimental autoimmune uveoretinitis. Invest. Ophthalmol. Vis. Sci. 44, 3034–3041 (2003).

    Article  PubMed  Google Scholar 

  34. Sharma, S. M., Nestel, A. R., Lee, R. W. & Dick, A. D. Clinical review: Anti-TNFα therapies in uveitis: perspective on 5 years of clinical experience. Ocul. Immunol. Inflamm. 17, 403–414 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Braun, J. et al. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum. 52, 2447–2451 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Rudwaleit, M. et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann. Rheum. Dis. 68, 696–701 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Smith, J. A. et al. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum. 53, 18–23 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Lim, L. L., Fraunfelder, F. W. & Rosenbaum, J. T. Do tumor necrosis factor inhibitors cause uveitis? A registry-based study. Arthritis Rheum. 56, 3248–3252 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Reddy, A. R. & Backhouse, O. C. Does etanercept induce uveitis? Br. J. Ophthalmol. 87, 925 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wenzel, S. E. Asthma: defining of the persistent adult phenotypes. Lancet 368, 804–813 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Miranda, C. et al. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J. Allergy Clin. Immunol. 113, 101–108 (2004).

    Article  PubMed  Google Scholar 

  42. Moffatt, M. F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Walker, S., Monteil, M., Phelan, K., Lasserson, T. J. & Walters, E. H. Anti-IgE for chronic asthma in adults and children. Cochrane Database of Systematic Reviews, Issue 2, Art. No.: CD003559. doi:10.1002/14651858.CD003559.pub3 (2006).

  44. Holgate, S. et al. Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality. Curr. Med. Res. Opin. 17, 233–240 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Holgate, S. T. et al. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin. Exp. Allergy 34, 632–638 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Busse, W. W. et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N. Engl. J. Med. 364, 1005–1015 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bousquet, J. et al. Indirect evidence of bronchial inflammation assessed by titration of inflammatory mediators in BAL fluid of patients with asthma. J. Allergy Clin. Immunol. 88, 649–660 (1991).

    Article  CAS  PubMed  Google Scholar 

  48. Broide, D. H. et al. Evidence of ongoing mast cell and eosinophil degranulation in symptomatic asthma airway. J. Allergy Clin. Immunol. 88, 637–648 (1991).

    Article  CAS  PubMed  Google Scholar 

  49. Sanderson, C. J. Interleukin-5, eosinophils, and disease. Blood 79, 3101–3109 (1992).

    CAS  PubMed  Google Scholar 

  50. Collins, P. D., Marleau, S., Griffiths-Johnson, D. A., Jose, P. J. & Williams, T. J. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J. Exp. Med. 182, 1169–1174 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Büttner, C., Lun, A., Splettstoesser, T., Kunkel, G. & Renz, H. Monoclonal anti-interleukin-5 treatment suppresses eosinophil but not T-cell functions. Eur. Respir. J. 21, 799–803 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Flood-Page, P. T. et al. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am. J. Respir. Crit. Care Med. 167, 199–204 (2003).

    Article  PubMed  Google Scholar 

  53. Leckie, M. J. et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144–2148 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Green, R. H. et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 360, 1715–1721 (2002).

    Article  PubMed  Google Scholar 

  55. ten Brinke, A. et al. Factors associated with persistent airflow limitation in severe asthma. Am. J. Respir. Crit. Care Med. 164, 744–748 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Haldar, P. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N. Engl. J. Med. 360, 973–984 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Nair, P. et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 360, 985–993 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Howarth, P. H. et al. Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 60, 1012–1018 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Berry, M. et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 62, 1043–1049 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wenzel, S. E. et al. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am. J. Respir. Crit. Care Med. 156, 737–743 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Erin, E. M. et al. The effects of a monoclonal antibody directed against tumor necrosis factor-α in asthma. Am. J. Respir. Crit. Care Med. 174, 753–762 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Morjaria, J. B. et al. The role of a soluble TNFα receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 63, 584–591 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Wenzel, S. E. et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-α blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med. 179, 549–558 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Aujla, S. J. & Alcorn, J. F. TH17 cells in asthma and inflammation. Biochim. Biophys. Acta doi:10.1016/j.bbagen.2011.02.002.

  65. Isaacs, J. D. & Ferraccioli, G. The need for personalised medicine for rheumatoid arthritis. Ann. Rheum. Dis. 70, 4–7 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Chatenoud, L. & Bluestone, J. A. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat. Rev. Immunol. 7, 622–632 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Chatenoud, L., Primo, J. & Bach, J. F. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J. Immunol. 158, 2947–2954 (1997).

    CAS  PubMed  Google Scholar 

  68. Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692–1698 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Herold, K. C. et al. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54, 1763–1769 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Herold, K. C. et al. Treatment of patients with new onset Type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years. Clin. Immunol. 132, 166–173 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Keymeulen, B. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352, 2598–2608 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Keymeulen, B. et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 53, 614–623 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Keymeulen, B. et al. Transient Epstein–Barr virus reactivation in CD3 monoclonal antibody-treated patients. Blood 115, 1145–1155 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Diabetes.co.uk Diabetes drug teplizumab fails in tests [online], (2010).

  75. Diabetes.co.uk Diabetes drug otelixizumab fails in late trials [online], (2011).

  76. Cooles, F. A. & Isaacs, J. D. Treating to re-establish tolerance in inflammatory arthritis—lessons from other diseases. Best Pract. Res. Clin. Rheumatol. 24, 497–511 (2010).

    Article  PubMed  Google Scholar 

  77. Isaacs, J. D. The changing face of rheumatoid arthritis: sustained remission for all? Nat. Rev. Immunol. 10, 605–611 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Maedler, K., Dharmadhikari, G., Schumann, D. M. & Størling, J. Interleukin-1 beta targeted therapy for type 2 diabetes. Expert Opin. Biol. Ther. 9, 1177–1188 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Sauter, N. S., Schulthess, F. T., Galasso, R., Castellani, L. W. & Maedler, K. The antiinflammatory cytokine interleukin 1 receptor antagonist protects from high-fat diet-induced hyperglycemia. Endocrinology 149, 2208–2218 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Pickersgill, L. M. & Mandrup-Poulsen, T. R. The anti-interleukin-1 in type 1 diabetes action trial—background and rationale. Diabetes Metab. Res. Rev. 25, 321–324 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Deswal, A. et al. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 99, 3224–3226 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Chung, E. S. et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107, 3133–3140 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Mann, D. L. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109, 1594–1602 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Listing, J. et al. Does tumor necrosis factor α inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum. 58, 667–677 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Arnett, H. A., Wang, Y., Matsushima, G. K., Suzuki, K. & Ting, J. P. Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. J. Neurosci. 23, 9824–9832 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Boyko, A. N. Clinical effects and tolerability of high-dose, high-frequency recombinant interferon β-1a in patients with multiple sclerosis: maximizing therapy through long-term adherence. Expert Opin. Biol. Ther. 10, 653–666 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Carter, N. J. & Keating, G. M. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. Drugs 70, 1545–1577 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Polman, C. H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Kleinschmidt-DeMasters, B. K. & Tyler, K. L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N. Engl. J. Med. 353, 369–374 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Langer-Gould, A., Atlas, S. W., Green, A. J., Bollen, A. W. & Pelletier, D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N. Engl. J. Med. 353, 375–381 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Van Assche, G. et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N. Engl. J. Med. 353, 362–368 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. FDA. FDA Drug Safety Communication: Safety update on Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab) [online], (2011).

  94. Khalili, K., Gordon, J. & White, M. K. The polyomavirus, JCV and its involvement in human disease. Adv. Exp. Med. Biol. 577, 274–287 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Major, E. O. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu. Rev. Med. 61, 35–47 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Lindå, H. et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N. Engl. J. Med. 361, 1081–1087 (2009).

    Article  PubMed  Google Scholar 

  97. Tan, C. S. & Koralnik, I. J. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 9, 425–437 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Carson, K. R. et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113, 4834–4840 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Buch, M. H. et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 70, 909–920 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hauser, S. L. et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Coles, A. J. et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801 (2008).

    Article  PubMed  Google Scholar 

  103. Coles, A. J. et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354, 1691–1695 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Isaacs, J. D. & Thiel, A. Stem cell transplantation for autoimmune disorders. Immune reconstitution. Best Pract. Res. Clin. Haematol. 17, 345–358 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Jones, J. L. et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J. Clin. Invest. 119, 2052–2061 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

  1. Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Gillian M. Bell, Gary Reynolds & John D. Isaacs

Authors
  1. Gillian M. Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gary Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John D. Isaacs
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to researching data for the article, discussing content, writing the article and review/editing of the manuscript before submission.

Corresponding author

Correspondence to John D. Isaacs.

Ethics declarations

Competing interests

J. D. Isaacs has acted as a consultant to Pfizer and Roche, received speakers bureau/honoraria from Abbott and Roche, received grant/research support from Biogen Idec, GlaxoSmithKline, Pfizer, Roche and UCB, and is a patent holder/applicant with GlaxoSmithKline. The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bell, G., Reynolds, G. & Isaacs, J. Biologic therapies in non-rheumatic diseases: lessons for rheumatologists?. Nat Rev Rheumatol 7, 507–516 (2011). https://doi.org/10.1038/nrrheum.2011.106

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2011.106

Search

Advanced 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