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Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma

  • Review Article
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From Nature Reviews Rheumatology

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Abstract

Autoimmune rheumatic diseases (ARD), such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SS), have consistently been associated with the development of B-cell non-Hodgkin lymphoma (BCNHL). In this Review, we focus on reports published since 2006 and summarize the data regarding the BCNHL subtypes and clinical findings associated with this increased risk. Patients with these ARD, particularly those with detectable autoantibodies and systemic involvement, are at increased risk of developing BCNHL, especially diffuse large B-cell lymphoma and marginal zone lymphoma. SS shows the strongest association with BCNHL. Male sex, advanced age, prolonged disease course and increased disease severity, but not family history of autoimmune conditions, seem to be associated with an increased risk of non-Hodgkin lymphoma. Chronic immune stimulation, genetic and environmental factors and some immunosuppressive drugs might be involved in lymphomagenesis in these patients. The reason why some ARD are associated with BCNHL and other autoimmune diseases are not remains unclear. These associations are important as they provide information about the mechanisms of lymphomagenesis, and might help identify new therapeutic targets.

Key Points

  • Patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SS) are at increased risk of developing B-cell non-Hodgkin lymphoma, with the highest risk associated with SS

  • The subtypes most strongly associated with SS and SLE are diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma, whereas DLBCL and lymphoplasmacytic lymphoma are most common in RA

  • Chronic autoimmune and pathogen-induced immune stimulation, genetic and environmental factors and some immunosuppressant therapies are likely to be involved in lymphomagenesis

  • Some drugs that target B cells have been shown to be effective against both autoimmune rheumatic diseases and lymphomas

  • The clinical benefits obtained with these drugs demonstrate the importance of B cells in the pathogenesis of these diseases, and has led to the development of new drugs of this class

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References

  1. Jaffe, E. S., Harris, N. L., Stein, H. & Isaacson, P. G. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood 112, 4384–4399 (2008).

    Article  CAS  Google Scholar 

  2. Grulich, A. E. & Vajdic, C. M. The epidemiology of non-Hodgkin lymphoma. Pathology 37, 409–419 (2005).

    Article  Google Scholar 

  3. Goldin, L. R. & Landgren, O. Autoimmunity and lymphomagenesis. Int. J. Cancer 124, 1497–1502 (2009).

    Article  CAS  Google Scholar 

  4. Bierman, P. J., Harris, N. & Armitage, J. O. in Cecil Medicine 23rd edn 1408–1420 (Saunders Elsevier, Philadelphia, 2007).

    Google Scholar 

  5. Longo, D. L. in Harrison's Principles of Internal Medicine 17th edn 687–688 (McGraw-Hill Medical, New York, 2008).

    Google Scholar 

  6. Zintzaras, E., Voulgarelis, M. & Moutsopoulos, H. M. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch. Intern. Med. 165, 2337–2344 (2005).

    Article  Google Scholar 

  7. Alexander, D. D. et al. The non-Hodgkin lymphomas: a review of the epidemiologic literature. Int. J. Cancer 120 (Suppl.), 1–39 (2007).

    Article  Google Scholar 

  8. Kiss, E., Kovacs, L. & Szodoray, P. Malignancies in systemic lupus erythematosus. Autoimmun. Rev. 9, 195–199 (2010).

    Article  CAS  Google Scholar 

  9. Hansen, A., Lipsky, P. E. & Dörner, T. B-cell lymphoproliferation in chronic inflammatory rheumatic diseases. Nat. Clin. Pract. Rheumatol. 3, 561–569 (2007).

    Article  CAS  Google Scholar 

  10. Baecklund, E. et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 54, 692–701 (2006).

    Article  Google Scholar 

  11. Smedby, K. E. et al. Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J. Natl Cancer Inst. 98, 51–60 (2006).

    Article  Google Scholar 

  12. Smedby, K. E. et al. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. Blood 111, 4029–4038 (2008).

    Article  CAS  Google Scholar 

  13. Mellemkjaer, L. et al. Autoimmune disease in individuals and close family members and susceptibility to non-Hodgkin's lymphoma. Arthritis Rheum. 58, 657–666 (2008).

    Article  Google Scholar 

  14. Anderson, L. A. et al. Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies. Int. J. Cancer 125, 398–405 (2009).

    Article  CAS  Google Scholar 

  15. Ansell, P. et al. Non-Hodgkin lymphoma and autoimmunity: does gender matter? Int J Cancer. doi: 10.1002/ijc.25680.

  16. Jemal, A. et al. Cancer statistics, 2009. CA Cancer J. Clin. 59, 225–249 (2009).

    Article  Google Scholar 

  17. Smith, A. et al. The Haematological Malignancy Research Network (HMRN): a new information strategy for population based epidemiology and health service research. Br. J. Haematol. 148, 739–753 (2010).

    Article  Google Scholar 

  18. Kristinsson, S. Y. et al. Immune-related and inflammatory conditions and risk of lymphoplasmacytic lymphoma or Waldenström macroglobulinemia. J. Natl Cancer Inst. 102, 557–567 (2010).

    Article  CAS  Google Scholar 

  19. Bernatsky, S. et al. An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum. 52, 1481–1490 (2005).

    Article  CAS  Google Scholar 

  20. Tincani, A., Taraborelli, M. & Cattaneo, R. Antiphospholipid antibodies and malignancies. Autoimmun. Rev. 9, 200–202 (2010).

    Article  CAS  Google Scholar 

  21. Hellgren, K., Smedby, K. E., Feltelius, N., Baecklund, E. & Askling, J. Do rheumatoid arthritis and lymphoma share risk factors? A comparison of lymphoma and cancer risks before and after diagnosis of rheumatoid arthritis. Arthritis Rheum. 62, 1252–1258 (2010).

    Article  Google Scholar 

  22. Lazarus, M. N., Robinson, D., Mak, V., Moller, H. & Isenberg, D. A. Incidence of cancer in a cohort of patients with primary Sjögren's syndrome. Rheumatology 45, 1012–1015 (2006).

    Article  CAS  Google Scholar 

  23. Geborek, P. et al. Tumor necrosis factor do not increase overall risk in patient with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann. Rheum. Dis. 64, 657–658 (2005).

    Article  Google Scholar 

  24. De Vita, S. & Quartuccio, L. Treatment of rheumatoid arthritis with rituximab: an update and possible indications. Autoimmun. Rev. 5, 443–448 (2006).

    Article  CAS  Google Scholar 

  25. Mariette, X. et al. Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann. Rheum. Dis. 69, 400–408 (2010).

    Article  CAS  Google Scholar 

  26. Askling, J. et al. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol. Drug Saf. 20, 119–130 (2011).

    Article  CAS  Google Scholar 

  27. Kovács, L., Szodoray, P. & Kiss, E. Secondary tumours in Sjögren's Syndrome. Autoimmun. Rev. 9, 203–206 (2010).

    Article  Google Scholar 

  28. Bende, R. J., van Maldegem, F. & van Noesel, C. J. Chronic inflammatory disease, lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas. Haematologica 94, 1109–1123 (2009).

    Article  CAS  Google Scholar 

  29. Kristinsson, S. Y. et al. Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies. Haematologica 94, 1581–1589 (2009).

    Article  Google Scholar 

  30. Goodnow, C. C. Multistep pathogenesis of autoimmune disease. Cell 130, 25–35 (2007).

    Article  CAS  Google Scholar 

  31. Youinou, P. Is BAFF the murderer in lupus? Lupus 17, 613–614 (2008).

    Article  CAS  Google Scholar 

  32. Tangye, S. G., Bryant, V. L., Cuss, A. K. & Good, K. L. BAFF, APRIL and human B cell disorders. Semin. Immunol. 18, 305–317 (2006).

    Article  CAS  Google Scholar 

  33. Cellier, C. et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet 356, 203–208 (2000).

    Article  CAS  Google Scholar 

  34. Suarez, F., Lortholary, O., Hermine, O. & Lecuit, M. Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood 107, 3034–3044 (2006).

    Article  CAS  Google Scholar 

  35. Bernatsky, S., Ramsey-Goldman, R. & Clarke, A. E. Malignancy in systemic lupus erythematosus: what have we learned? Best Pract. Res. Clin. Rheumatol. 23, 539–547 (2009).

    Article  Google Scholar 

  36. Ramos-Casals, M. et al. Characterization of B cell lymphoma in patients with Sjogren's syndrome and hepatitis C virus infection. Arthritis Rheum 57, 161–170 (2007).

    Article  Google Scholar 

  37. Brady, G., Macarthur, G. J. & Farrell, P. J. Epstein–Barr virus and Burkitt lymphoma. Postgrad. Med. J. 84, 372–377 (2008).

    Article  CAS  Google Scholar 

  38. Calza, L. et al. Systemic and discoid lupus erythematosus in HIV-infected patients treated with highly active antiretroviral therapy. Int. J. STD AIDS 14, 356–359 (2003).

    Article  Google Scholar 

  39. Reyes, S. L. I. et al. BAFF: a regulatory cytokine of B lymphocytes involved in autoimmunity and lymphoid cancer [Spanish]. Rev. Med. Chil. 134, 1175–1184 (2006).

    CAS  Google Scholar 

  40. Wang, S. S. et al. Immune mechanisms in non-Hodgkin lymphoma: joint effects of the TNF G308A and IL10 T3575A polymorphisms with non-Hodgkin lymphoma risk factors. Cancer Res. 67, 5042–5054 (2007).

    Article  CAS  Google Scholar 

  41. Bayley, J. P., Ottenhoff, T. H. & Verweij, C. L. Is there a future for TNF promoter polymorphisms? Genes Immun. 5, 315–329 (2004).

    Article  CAS  Google Scholar 

  42. Gibson, A. W. et al. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J. Immunol. 166, 3915–3922 (2001).

    Article  CAS  Google Scholar 

  43. Balkwill, F. & Coussens, L. M. Cancer: an inflammatory link. Nature 431, 405–406 (2004).

    Article  CAS  Google Scholar 

  44. Wang, S. S. et al. Common genetic variants in proinflammatory and other immunoregulatory genes and risk for non-Hodgkin lymphoma. Cancer Res. 66, 9771–9780 (2006).

    Article  CAS  Google Scholar 

  45. Chen, Y. et al. Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index and risk of non-Hodgkin lymphoma. Blood 117, 585–589 (2011).

    Article  CAS  Google Scholar 

  46. Toussirot, E. & Wendling, D. The use of TNF-α blocking agents in rheumatoid arthritis: an update. Expert Opin. Pharmacother. 8, 2089–2107 (2007).

    Article  CAS  Google Scholar 

  47. Bernatsky, S. et al. The relationship between cancer and medication exposures in systemic lupus erythematosus: a case–cohort study. Ann. Rheum. Dis. 67, 74–79 (2008).

    Article  CAS  Google Scholar 

  48. Dörner, T. & Lipsky, P. E. B-cell targeting: a novel approach to immune intervention today and tomorrow. Expert Opin. Biol. Ther. 7, 1287–1299 (2007).

    Article  Google Scholar 

  49. Dörner, T. et al. Current status on B-cell depletion therapy in autoimmune diseases other than rheumatoid arthritis. Autoimmun. Rev. 9, 82–89 (2009).

    Article  Google Scholar 

  50. Dörner, T., Kinnman, N. & Tak, P. P. Targeting B cells in immune-mediated inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol. Ther. 125, 464–475 (2010).

    Article  Google Scholar 

  51. Quartuccio, L. et al. Controversies on rituximab therapy in Sjögren syndrome-associated lymphoproliferation. Int. J. Rheumatol. 2009, 424935 (2009).

    Article  Google Scholar 

  52. Edwards, J. C., Leandro, M. J. & Cambridge, G. Repeated B lymphocyte depletion therapy in rheumatoid arthritis: 5 year follow-up. Arthritis Rheum. 52 (Suppl.), S133–S134 (2005).

    Google Scholar 

  53. Popa, C., Leandro, M. J., Cambridge, G. & Edwards, J. C. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs. Rheumatology (Oxford) 46, 626–630 (2007).

    Article  CAS  Google Scholar 

  54. Watanabe, T. Treatment strategies for nodal and gastrointestinal follicular lymphoma: current status and future development. World J. Gastroenterol. 16, 5543–5554 (2010).

    Article  Google Scholar 

  55. Voulgarelis, M., Giannouli, S., Tzioufas, A. G. & Moutsopoulos, H. M. Long term remission of Sjögren's syndrome associated aggressive B cell non-Hodgkin's lymphomas following combined B cell depletion therapy and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Ann. Rheum. Dis. 65, 1033–1037 (2006).

    Article  CAS  Google Scholar 

  56. Voulgarelis, M., Giannouli, S., Anagnostou, D. & Tzioufas, A. G. Combined therapy with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjögren's syndrome-associated B-cell aggressive non-Hodgkin's lymphomas. Rheumatology (Oxford) 43, 1050–1053 (2004).

    Article  CAS  Google Scholar 

  57. Pijpe, J. et al. Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study. Arthritis Rheum. 52, 2740–2750 (2005).

    Article  CAS  Google Scholar 

  58. Favas, C. & Isenberg, D. A. B-cell depletion therapy in SLE—what are the current prospects for its acceptance? Nat. Rev. Rheumatol. 5, 711–716 (2009).

    Article  CAS  Google Scholar 

  59. Morschhauser, F. et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: phase I/II results. J. Clin. Oncol. 27, 3346–3353 (2009).

    Article  CAS  Google Scholar 

  60. Milani, C. & Castillo, J. Veltuzumab, an anti-CD20 mAb for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and immune thrombocytopenic purpura. Curr. Opin. Mol. Ther. 11, 200–207 (2009).

    CAS  PubMed  Google Scholar 

  61. Steinfeld, S. D. et al. Epratuzumab (humanized anti-CD22 antibody) in primary Sjögren's syndrome: an open-label phase I/II study. Arthritis Res. Ther. 8, R129 (2006).

    Article  Google Scholar 

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  1. Centre for Rheumatology, Windeyer Building, University College London, 46 Cleveland Street, London W1T 4JF, UK

Authors and Affiliations

  1. Internal Medicine Department, Funchal Central Hospital, Estrada dos Marmeleiros, Funchal, 9054-535, Madeira Island, Portugal

    Catarina Dias & David A. Isenberg

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  1. Catarina Dias
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C. Dias researched data for and wrote the article. D. A. Isenberg discussed the content of the article and performed review/editing of the manuscript before submission.

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Correspondence to Catarina Dias.

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Dias, C., Isenberg, D. Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma. Nat Rev Rheumatol 7, 360–368 (2011). https://doi.org/10.1038/nrrheum.2011.62

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