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Published in: Rheumatology International 6/2021

01-06-2021 | ANCA-Associated Vasculitis | Observational Research

Rituximab-associated hypogammaglobulinemia in autoimmune rheumatic diseases: a single-center retrospective cohort study

Authors: Stefanie D. Wade, Vasileios C. Kyttaris

Published in: Rheumatology International | Issue 6/2021

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Abstract

B-cell targeted therapies, such as rituximab (RTX), are used widely in autoimmune rheumatic diseases (AIRD). RTX can cause hypogammaglobulinemia and predispose patients to infections. Herein, we asked whether the underlying diagnosis influences the risk for hypogammaglobulinemia in patients treated with RTX. All patients who received RTX infusions and carried a diagnosis of rheumatoid arthritis (RA), ANCA-associated vasculitis (AAV), or connective tissue disease (CTD) were included in this single-center retrospective cohort study. We used STATA® for analysis: Chi-square test was used for comparing categorical variables. Based on distribution, continuous variables were compared using the t test/ANOVA or the Wilcoxon/Kruskal–Wallis tests. Of the 163 patients who received RTX for an AIRD, 60 with pre- and post- RTX immunoglobulins were analyzed. A higher incidence of post-treatment hypogammaglobulinemia was seen in AAV (45%) compared to RA (22%) and CTD (9.1%) groups (p = 0.03). Glucocorticoid exposure of 10 mg or more was identified as a significant risk factor for hypogammaglobulinemia. Finally, we observed a higher number of clinically significant infections per person in the AAV group than in the RA and CTD groups. We observed an increased incidence of hypogammaglobulinemia in the RTX-treated AAV group, with almost half of patients developing post-RTX hypogammaglobulinemia. The rate of infections per person was highest in the AAV group. Screening immunoglobulins were not consistently measured pre- and post-RTX. Results highlight a need for increased awareness of the role of immunoglobulin measurement before maintenance doses of RTX, especially in patients with AAV and steroid exposure.
Literature
1.
go back to reference Anolik JH, Friedberg JW, Zheng B et al (2007) B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny. Clin Immunol 122(2):139–145PubMedCrossRef Anolik JH, Friedberg JW, Zheng B et al (2007) B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny. Clin Immunol 122(2):139–145PubMedCrossRef
2.
go back to reference Edwards JC, Szczepanski L, Szechinski J et al (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350(25):2572–2581PubMedCrossRef Edwards JC, Szczepanski L, Szechinski J et al (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350(25):2572–2581PubMedCrossRef
3.
go back to reference Cohen SB, Emery P, Greenwald MW et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54(9):2793–2806PubMedCrossRef Cohen SB, Emery P, Greenwald MW et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54(9):2793–2806PubMedCrossRef
4.
go back to reference Emery P, Fleischmann R, Filipowicz-Sosnowska A et al (2006) The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 54(5):1390–1400PubMedCrossRef Emery P, Fleischmann R, Filipowicz-Sosnowska A et al (2006) The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 54(5):1390–1400PubMedCrossRef
6.
go back to reference Fanouriakis A, Kostopoulou M, Alunno A et al (2019) 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 78(6):736–745PubMedCrossRef Fanouriakis A, Kostopoulou M, Alunno A et al (2019) 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 78(6):736–745PubMedCrossRef
7.
go back to reference Diaz-Lagares C, Croca S, Sangle S et al (2012) Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 11(5):357–364PubMedCrossRef Diaz-Lagares C, Croca S, Sangle S et al (2012) Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun Rev 11(5):357–364PubMedCrossRef
8.
go back to reference Boletis JN, Marinaki S, Skalioti C, Lionaki SS, Iniotaki A, Sfikakis PP (2009) Rituximab and mycophenolate mofetil for relapsing proliferative lupus nephritis: a long-term prospective study. Nephrol Dial Transplant 24(7):2157–2160PubMedCrossRef Boletis JN, Marinaki S, Skalioti C, Lionaki SS, Iniotaki A, Sfikakis PP (2009) Rituximab and mycophenolate mofetil for relapsing proliferative lupus nephritis: a long-term prospective study. Nephrol Dial Transplant 24(7):2157–2160PubMedCrossRef
9.
go back to reference Terrier B, Amoura Z, Ravaud P et al (2010) Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French autoimmunity and rituximab registry. Arthritis Rheum 62(8):2458–2466PubMedCrossRef Terrier B, Amoura Z, Ravaud P et al (2010) Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French autoimmunity and rituximab registry. Arthritis Rheum 62(8):2458–2466PubMedCrossRef
10.
11.
go back to reference Guillevin L, Pagnoux C, Karras A et al (2014) Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 371(19):1771–1780PubMedCrossRef Guillevin L, Pagnoux C, Karras A et al (2014) Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 371(19):1771–1780PubMedCrossRef
12.
go back to reference Merrill JT, Neuwelt CM, Wallace DJ et al (2010) Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 62(1):222–233PubMedPubMedCentralCrossRef Merrill JT, Neuwelt CM, Wallace DJ et al (2010) Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 62(1):222–233PubMedPubMedCentralCrossRef
13.
go back to reference Rovin BH, Furie R, Latinis K et al (2012) Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 64(4):1215–1226PubMedCrossRef Rovin BH, Furie R, Latinis K et al (2012) Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 64(4):1215–1226PubMedCrossRef
14.
go back to reference Teng YKO, Bruce IN, Diamond B et al (2019) Phase III, multicentre, randomized, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol. BMJ Open 9(3):e025687PubMedPubMedCentralCrossRef Teng YKO, Bruce IN, Diamond B et al (2019) Phase III, multicentre, randomized, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol. BMJ Open 9(3):e025687PubMedPubMedCentralCrossRef
15.
go back to reference Christou EAA, Giardino G, Worth A, Ladomenou F (2017) Risk factors predisposing to the development of hypogammaglobulinemia and infections post-Rituximab. Int Rev Immunol 36(6):352–359PubMedCrossRef Christou EAA, Giardino G, Worth A, Ladomenou F (2017) Risk factors predisposing to the development of hypogammaglobulinemia and infections post-Rituximab. Int Rev Immunol 36(6):352–359PubMedCrossRef
16.
go back to reference Buch MH, Smolen JS, Betteridge N et al (2011) Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 70(6):909–920PubMedCrossRef Buch MH, Smolen JS, Betteridge N et al (2011) Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 70(6):909–920PubMedCrossRef
17.
go back to reference Wijetilleka S, Jayne DR, Mukhtyar C et al (2019) Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted therapies in autoimmune rheumatic diseases. Rheumatology 58(5):889–896PubMedCrossRef Wijetilleka S, Jayne DR, Mukhtyar C et al (2019) Recommendations for the management of secondary hypogammaglobulinaemia due to B cell targeted therapies in autoimmune rheumatic diseases. Rheumatology 58(5):889–896PubMedCrossRef
18.
go back to reference Fernandez-Castro M, Mellor-Pita S, Citores MJ et al (2007) Common variable immunodeficiency in systemic lupus erythematosus. Semin Arthritis Rheum 36(4):238–245PubMedCrossRef Fernandez-Castro M, Mellor-Pita S, Citores MJ et al (2007) Common variable immunodeficiency in systemic lupus erythematosus. Semin Arthritis Rheum 36(4):238–245PubMedCrossRef
19.
go back to reference Thiel J, Rizzi M, Engesser M et al (2017) B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. Arthritis Res Ther 19(1):101PubMedPubMedCentralCrossRef Thiel J, Rizzi M, Engesser M et al (2017) B cell repopulation kinetics after rituximab treatment in ANCA-associated vasculitides compared to rheumatoid arthritis, and connective tissue diseases: a longitudinal observational study on 120 patients. Arthritis Res Ther 19(1):101PubMedPubMedCentralCrossRef
20.
go back to reference Marco H, Smith RM, Jones RB et al (2014) The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease. BMC Musculoskelet Disord 15:178PubMedPubMedCentralCrossRef Marco H, Smith RM, Jones RB et al (2014) The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease. BMC Musculoskelet Disord 15:178PubMedPubMedCentralCrossRef
21.
go back to reference Cortazar FB, Pendergraft WF 3rd, Wenger J, Owens CT, Laliberte K, Niles JL (2017) Effect of continuous B cell depletion with rituximab on pathogenic autoantibodies and total IgG levels in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 69(5):1045–1053PubMedPubMedCentralCrossRef Cortazar FB, Pendergraft WF 3rd, Wenger J, Owens CT, Laliberte K, Niles JL (2017) Effect of continuous B cell depletion with rituximab on pathogenic autoantibodies and total IgG levels in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 69(5):1045–1053PubMedPubMedCentralCrossRef
22.
go back to reference De La Torre I, Leandro MJ, Valor L, Becerra E, Edwards JC, Cambridge G (2012) Total serum immunoglobulin levels in patients with RA after multiple B-cell depletion cycles based on rituximab: relationship with B-cell kinetics. Rheumatology 51(5):833–840CrossRef De La Torre I, Leandro MJ, Valor L, Becerra E, Edwards JC, Cambridge G (2012) Total serum immunoglobulin levels in patients with RA after multiple B-cell depletion cycles based on rituximab: relationship with B-cell kinetics. Rheumatology 51(5):833–840CrossRef
23.
go back to reference Reddy V, Martinez L, Isenberg DA, Leandro MJ, Cambridge G (2017) Pragmatic treatment of patients with systemic lupus erythematosus with rituximab: long-term effects on serum immunoglobulins. Arthritis Care Res (Hoboken) 69(6):857–866CrossRef Reddy V, Martinez L, Isenberg DA, Leandro MJ, Cambridge G (2017) Pragmatic treatment of patients with systemic lupus erythematosus with rituximab: long-term effects on serum immunoglobulins. Arthritis Care Res (Hoboken) 69(6):857–866CrossRef
24.
go back to reference García-Fernández A, López-Gutiérrez F, Loarce-Martos J et al (2020) Cohort of rheumatic patients treated with rituximab and COVID-19: Does rituximab treatment increases the severity of SARS-COV2 Infection? [abstract]. Arthritis Rheumatol 72(suppl):10 García-Fernández A, López-Gutiérrez F, Loarce-Martos J et al (2020) Cohort of rheumatic patients treated with rituximab and COVID-19: Does rituximab treatment increases the severity of SARS-COV2 Infection? [abstract]. Arthritis Rheumatol 72(suppl):10
25.
go back to reference Md Yusof MY, Vital EM, McElvenny DM et al (2019) Predicting Severe infection and effects of hypogammaglobulinemia during therapy with rituximab in rheumatic and musculoskeletal diseases. Arthritis Rheumatol 71(11):1812–1823PubMedCrossRef Md Yusof MY, Vital EM, McElvenny DM et al (2019) Predicting Severe infection and effects of hypogammaglobulinemia during therapy with rituximab in rheumatic and musculoskeletal diseases. Arthritis Rheumatol 71(11):1812–1823PubMedCrossRef
26.
go back to reference Iversen K, Ihlemann N, Gill SU et al (2019) Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 380(5):415–424PubMedCrossRef Iversen K, Ihlemann N, Gill SU et al (2019) Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 380(5):415–424PubMedCrossRef
28.
go back to reference Duarte AC, Cordeiro A, Fernandes BM et al (2019) Rituximab in connective tissue disease-associated interstitial lung disease. Clin Rheumatol 38(7):2001–2009PubMedCrossRef Duarte AC, Cordeiro A, Fernandes BM et al (2019) Rituximab in connective tissue disease-associated interstitial lung disease. Clin Rheumatol 38(7):2001–2009PubMedCrossRef
29.
go back to reference Boleto G, Avouac J, Wipff J et al (2018) Predictors of hypogammaglobulinemia during rituximab maintenance therapy in rheumatoid arthritis: a 12-year longitudinal multi-center study. Semin Arthritis Rheum 48(2):149–154PubMedCrossRef Boleto G, Avouac J, Wipff J et al (2018) Predictors of hypogammaglobulinemia during rituximab maintenance therapy in rheumatoid arthritis: a 12-year longitudinal multi-center study. Semin Arthritis Rheum 48(2):149–154PubMedCrossRef
30.
go back to reference Gottenberg JE, Ravaud P, Bardin T et al (2010) Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 62(9):2625–2632PubMedCrossRef Gottenberg JE, Ravaud P, Bardin T et al (2010) Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 62(9):2625–2632PubMedCrossRef
31.
go back to reference Barmettler S, Ong MS, Farmer JR, Choi H, Walter J (2018) Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open 1(7):e184169PubMedPubMedCentralCrossRef Barmettler S, Ong MS, Farmer JR, Choi H, Walter J (2018) Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open 1(7):e184169PubMedPubMedCentralCrossRef
32.
go back to reference Besada E, Koldingsnes W, Nossent JC (2014) Serum immunoglobulin levels and risk factors for hypogammaglobulinaemia during long-term maintenance therapy with rituximab in patients with granulomatosis with polyangiitis. Rheumatology 53(10):1818–1824PubMedCrossRef Besada E, Koldingsnes W, Nossent JC (2014) Serum immunoglobulin levels and risk factors for hypogammaglobulinaemia during long-term maintenance therapy with rituximab in patients with granulomatosis with polyangiitis. Rheumatology 53(10):1818–1824PubMedCrossRef
33.
go back to reference Henry J, Gottenberg JE, Rouanet S et al (2018) Doses of rituximab for retreatment in rheumatoid arthritis: influence on maintenance and risk of serious infection. Rheumatology 57(3):538–547PubMedCrossRef Henry J, Gottenberg JE, Rouanet S et al (2018) Doses of rituximab for retreatment in rheumatoid arthritis: influence on maintenance and risk of serious infection. Rheumatology 57(3):538–547PubMedCrossRef
34.
go back to reference Roberts DM, Jones RB, Smith RM et al (2015) Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease. J Autoimmun 57:60–65PubMedCrossRef Roberts DM, Jones RB, Smith RM et al (2015) Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease. J Autoimmun 57:60–65PubMedCrossRef
35.
go back to reference Assala M, Groh M, Blanche P et al (2017) Pneumococcal and influenza vaccination rates in patients treated with corticosteroids and/or immunosuppressive therapies for systemic autoimmune diseases: a cross-sectional study. Jt Bone Spine 84(3):365–366CrossRef Assala M, Groh M, Blanche P et al (2017) Pneumococcal and influenza vaccination rates in patients treated with corticosteroids and/or immunosuppressive therapies for systemic autoimmune diseases: a cross-sectional study. Jt Bone Spine 84(3):365–366CrossRef
36.
go back to reference Furer V, Rondaan C, Heijstek MW et al (2020) 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 79(1):39–52CrossRefPubMed Furer V, Rondaan C, Heijstek MW et al (2020) 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 79(1):39–52CrossRefPubMed
37.
go back to reference Barmettler S, Price C (2015) Continuing IgG replacement therapy for hypogammaglobulinemia after rituximab–for how long? J Allergy Clin Immunol 136(5):1407–1409PubMedCrossRef Barmettler S, Price C (2015) Continuing IgG replacement therapy for hypogammaglobulinemia after rituximab–for how long? J Allergy Clin Immunol 136(5):1407–1409PubMedCrossRef
38.
go back to reference Papp KA, Haraoui B, Kumar D et al (2019) Vaccination guidelines for patients with immune-mediated disorders taking immunosuppressive therapies: executive summary. J Rheumatol 46(7):751–754PubMedCrossRef Papp KA, Haraoui B, Kumar D et al (2019) Vaccination guidelines for patients with immune-mediated disorders taking immunosuppressive therapies: executive summary. J Rheumatol 46(7):751–754PubMedCrossRef
40.
go back to reference Tomblyn M, Chiller T, Einsele H et al (2009) Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 15(10):1143–1238PubMedPubMedCentralCrossRef Tomblyn M, Chiller T, Einsele H et al (2009) Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 15(10):1143–1238PubMedPubMedCentralCrossRef
41.
go back to reference Wijetilleka S, Mukhtyar C, Jayne D et al (2019) Immunoglobulin replacement for secondary immunodeficiency after B-cell targeted therapies in autoimmune rheumatic disease: systematic literature review. Autoimmun Rev 18(5):535–541PubMedCrossRef Wijetilleka S, Mukhtyar C, Jayne D et al (2019) Immunoglobulin replacement for secondary immunodeficiency after B-cell targeted therapies in autoimmune rheumatic disease: systematic literature review. Autoimmun Rev 18(5):535–541PubMedCrossRef
Metadata
Title
Rituximab-associated hypogammaglobulinemia in autoimmune rheumatic diseases: a single-center retrospective cohort study
Authors
Stefanie D. Wade
Vasileios C. Kyttaris
Publication date
01-06-2021
Publisher
Springer Berlin Heidelberg
Published in
Rheumatology International / Issue 6/2021
Print ISSN: 0172-8172
Electronic ISSN: 1437-160X
DOI
https://doi.org/10.1007/s00296-021-04847-x

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