Late-onset hypogammaglobulinemia after rituximab therapy

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Development and implementation into practice of biologic agents has dramatically changed the approaches to the treatment of many severe diseases. But in the light of experience of their use more and more attention is paid not only to their efficacy but also to side effects. One of such medications is rituximab - a monoclonal chimeric antibody to CD20 antigen, which is expressed on the membrane of pre-B-lymphocytes and mature B-lymphocytes. In the literature more frequently are published the data about late-onset side effects of this medication, particularly hypogammaglobulinemia. The review presents the data on its prevalence after treatment of different diseases with rituximab, its severity, risk of infection. The possible mechanisms of the development of this phenomenon are discussed. Long-term hypogammaglobulinemia was shown to significantly delay the restoration of peripheral compartment of B cells, with over 90% of B cell population presented by naive B cells and significantly decreased concentration of B cells. Literature analysis demonstrates that the risk of hypogammaglobulinemia increases in multiple rituximab courses, preceding immunosuppression, decreased baseline immunoglobulin level. The need for detection of serum level of immunoglobulins before therapy with rituximab is pointed out by many authors, as the main disease can mask primary immunodeficiency, primarily common variable immunodeficiency, which requires life-term replacement therapy with intravenous immunoglobulins. The issue of administration of this therapy in secondary antibodies deficiency is not solved but severe hypogammaglobulinemia or severe infectious and inflammatory processes definitely require it. So to effectively detect hypogammaglobulinemia it is appropriate to perform monitoring of the level of immunoglobulins not only before but also during the treatment with rituximab as well as in several years after its completion.

About the authors

O V Moskalets

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Moscow, Russia


  1. Aleksandrova E.N., Novikov A.A., Nasonov E.L. Laboratory support for the registry of patients receiving rituximab (mabtera). Nauchno-prakticheskaya revmatologiya. 2008; S1: 21–28. (In Russ.)
  2. Kimbi E. Tolerability and safety of rituximab (Mab­tera). Cancer Treat. Rev. 2005; 1 (6): 456–463. doi: 10.1016/j.ctrv.2005.05.007.
  3. Sherstnev V.M., Lepkov S.V. Hepatitis virus B reactivation due to the use of rituximab in the therapy of lymphoproliferative disorders. Klinicheskaya onkogematologija. Fundamental'nye issledovaniya i klinicheskaya profilaktika. 2008; 2: 136–140. (In Russ.)
  4. Wolach O., Bairey O., Lahav M. Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature. Medicine. 2010; 89 (5): 308–318. doi: 10.1097/md.0b013e3181f2caef.
  5. Alekseeva Ju.A., Vobishсhevich R.I. Late-onset neutropenia after rituximab therapy. Farmateka. 2012; (18): 62–65. (In Russ.)
  6. Casulo C., Maragulia J., Zelenetz A.D. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin. Lymphoma Myeloma Leuk. 2013; 13 (2): 106–111. doi: 10.1016/j.clml.2012.11.01.
  7. Van Vollenhoven R.F., Emery P.M., Bingham C.O.3rd et al. Long-term safety of rituximab in rheumatoid arthritis: a 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann. Rheum. Dis. 2013; 72: 1496–1502. DOI: 10.1116/
  8. annrheumdis-2012-201956.
  9. Yousot M.Y., Vital E.M., Buch M.H. B cell therapies, approved and emerging: a review of infection risk and prevention during use. Curr. Rheumatol. Rep. 2015; 17 (10): 65. doi: 10.1007/s11926-015-0539-7.
  10. Gil'deeva G.N., Kudlaj D.A., Luk'yanov S.V. The mechanisms of action of rituximab. Eksperimental'naya i klinicheskaya farmakologiya. 2015; 78 (12): 51–56. (In Russ.)
  11. Roll P., Palanichami A., Kneitz C. et al. Regeneration of B cell subsets after B cell depletion using anti-CD20 antibodies in rheumatoid arthritis. Arthritis Rheum. 2006; 54 (8): 2377–2386. doi: 10.1002/art.22019.
  12. Tsanyan M.E., Solov'ev S.K., Torgashina A.V. et al. Long-term follow-up of patients with refractory systemic lupus erythematosus during rituximab treatment. Terapevticheskiy arkhiv. 2014; 86 (5): 40–49. (In Russ.)
  13. Venhoff N., Effelsberg N.M., Salzer U. et al. Impact of rituximab on immunoglobulin concentrtions and B cell numbers after cyclophosphamide treatment in patients with ANCA-associated vasculitides. PLoS ONE. 2012; 7 (5): e37626. doi: 10.1371/journal.pone.0037626.
  14. Kado R., Sanders G., McCune W.J. Supression of normal immune responses after treatment with ritu­ximab. Curr. Opin. Rheumatol. 2016; 28 (3): 251–258. doi: 10.1097/BOR0000000000000272.
  15. Roberts D.M., Jones R.B., Smith R.M. et al. Ritu­ximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease. J. Autoimmun. 2015; 57: 60–65. doi: 10.1016/j.jaut.2014.11.009.
  16. Alekseeva E.I., Deni­sova R.V., Valieva S.I. et al. Efficacy and safety of ritu­ximab in children with systemic lupus erythematosus: results of a retrospective study of the case series. Voprosy sovremennoy pediatrii. 2016; 15 (5): 497–504. (In Russ.)
  17. Mesnyakina L.A., Solov'ev S.K., Aseeva E.A., Nasonov E.L. The efficacy of biological therapy and the features of humoral immunity in patients with systemic lupus erithematosus. Nauchno-prakti­cheskaya revmatologiya. 2018; 56 (3): ­302–309. (In Russ.)
  18. Novi­kov P.I., Zykova A.S., Shchegoleva E.M. et al. Short-term efficacy and safety of biosimilar rituximab in patients with ­ANCA-associated vasculitis. Klinicheskaya farmakologiya i terapiya. 2018; 27 (2): 38–42. (In Russ.)
  19. Popa C., Leandro M.J., Cambridge G., Edwards J.C. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 years. Rheumatology (Oxford). 2007; 46 (4): 626–630. doi: 10.1093/rheumatology/kel393.
  20. Becerra E., Cambridge G., de la Torre I., Leandro M.J. Long term safety of rituximab in patients with rheumatoid arthritis. Int. J. Clin. Rheumatol. 2012; 7 (4): 383–390. doi: 10.2217/ijr.12.31.
  21. Marco H., Smith R.M., Jones R.B. et al. The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease. Mucoscelet. Dis. 2014; 15: 18. DOI: 10/1186/1471-2474-15-178.
  22. Kim S.H., Huh S.-Y., Lee S.J. et al. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 2013; 70 (9): 1110–1117. doi: 10.1001/jamaneurol.2013.3071.
  23. Patel V.L., Mahévas M., Lee S.Y. et al. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood. 2012; 119 (25): 5989–5995. doi: 10.1182/blood-2011-11-393975.
  24. Levy R., Mahévas M., Galicier L. et al. Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the li­terature. Autoimmun. Rev. 2014; 13 (10): 1055–1063. DOI: 10/1016/j.autrev.2014.08.036.
  25. Makatsori M., Kiani-Alikhan S., Manson A.L. et al. Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. QJM. 2014; 107 (10): 821–828. doi: 10.1093/qjmed/hcu094.
  26. Barmettler S., Ong M.-S., Farmer J.R. et al. Association of immunoglobulin levels, infectious risk and mor­tality with rituximab. JAMA Netw. Open. 2018; 1 (7): e184169. DOI: 10/1001/jamanetworkopen.2018.4169.
  27. Duraisingham S.S., Bucklnd M., Dempster J. et. al. Primary vs secondary antibody deficiency: clinical features and infection outcomes of immunoglobulin replacement. PLoS ONE. 2014. doi: 10.1371/journal,pone.0100324.
  28. Shortt J., Spencer A. Adjuvant rituximab causes prolonged hypogammaglobulinemia following autologous stem cell transplant for non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2006; 38 (6): 433–436. doi: 10.1038/sj.bmt.1705436.
  29. Walker A.R., Kleiner A., Rich L. et al. Profound hypogammaglobulinemia 7 years after treatment for indolent lymphoma. Cancer Invest. 2008; 26 (4): 431–433. DOI: 10.1080.07357900701809068.
  30. Kaplan B., Kopylltsova Y., Khokhar A. et al. Ri­tuximab and immune deficiency: case series and review of the literature. J. Allergy Clin. Immunol. Pract. 2014; 2 (5): 594–600. doi: 10.1016/j.jaip.2014.06.003.
  31. Kado R., Sanders G., McCune W.J. Diagnostic and therapeutic considerations in patients with hypogammaglobulinemia after rituximab therapy. Curr. Opin. Rheumatol. 2017; 29 (3): 228–233. doi: 10.1097/BOR. 0000000000000377.
  32. Irie E., Shirota Y., Suzuki C. et al. Severe hypogammaglobulinemia persisting for 6 years after treatment with rituximab combined chemotherapy due to arrest of B lymphocyte differentiation together with alteration of T lymphocyte homeostasis. Int. J. Hematol. 2010; 91 (3): ­501–508. DOI: 10/1007/s12185-010-0528-6.
  33. Cooper N., Davies E.G., Thrasher A.J. ­Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinemia requi­ring replacement intravenous immunoglobulin. Br. J. Hematol. 2009; 146 (1): 120–122. doi: 10.1111/j.1365-2141.2009.07715.x.
  34. De La Torre I., Leandro M.J., Valor L. et al. Total serum immunoglobulin levels in patients with RA after multiple B-cell depletion cycles based on rituximab: relationship with B-cell kinetics. Rheumatology (Oxford). 2012; 51 (5): 833–840. doi: 10.1093/rheumatology/ker417.
  35. Christou E.A.A., Giardino G., Worth A., Ladomenou F. Risk factors predisposing to the development of hypogammaglobulinemia and infections post-ritu­ximab. Int. Rev. Immunol. 2017; 36 (6): 352–359. doi: 10.1080/08830185.2017.1346092.
  36. Einarsson J.T., Evert M., Geborek P. et al. Ritu­ximab in clinical practice: dosage, drug adhehrnce, Ig le­vels, infections and drug antibodies. Clin. Rheum. 2017; 36 (12): 2743–2750. doi: 10.1007/s10067-017-3848-6.
  37. Diwakar L., Gorrie S., Richter A. et al. Does ritu­ximab aggravate pre-existing hypogammaglobulinemia? J. Clin. Pathol. 2010; 63 (3): 275–277. DOI: 10/1136/jcp.2009.068940.
  38. Cunningham-Rundles C. Autoimmune manifestation in common variable immunodeficiency. J. Clin. Immunol. 2008; 28 (1): S42–S45. doi: 10.1007/s10875-008-9182-7.
  39. Salliot C., Dougados M., Gossec L. Risk of serious infections during rituximab, abatocept and anakirna treatments for rheumatoid arthritis: meta-analyses of randomized placebo-controlled trials. Ann. Rheum. Dis. 2009; 68 (1): 25–32. doi: 10.1136/ard.2007.083188.
  40. Сohen S.B., Emery P., Greenwald M.W. et al. Ritu­ximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of multicenter, randomized, double-blind, placebo-controlled phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthr. Rheum. 2006; 54 (9): 2793–2806. doi: 10.1002/art.22025.
  41. Freeman J.A., Crassini K.R., Best O.G. et al. Immunoglobulin G subclass deficiency and infection risk in 150 patients with chronic lymphoid leukemia. Leuk. Lymphoma. 2013; 54 (1): 99–104. doi: 10.3109/10428194.­2012.706285.
  42. Rozenberg-Berzalel S., Asher I., Sthoeger Z. Recurrent infections in an ITP patient treated with rituximab. Harefuah. 2012; 151 (11): 617–619, 655. PMID: 23367730.



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© 2019 Moskalets O.V.

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