The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease

BMC Musculoskeletal Disorders

David RW Jayne²  Kenneth GC Smith³  Afzal N Chaudhry²  Stella Burns²  Fausta Catapano²  Mary-Jane Guerry²  Rachel B Jones²  Rona M Smith²  Helena Marco¹ 

[1] Nephrology Division, Fundació Puivert, Universitat Autònoma de Barcelona, Barcelona, Spain. Currently working on Nephrology Division, Germans Trias I Pujol, Badalona, Spain;Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK;Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge, UK

关键词: Autoimmune;    Infection;    IgG;    Systemic lupus erythematosus (SLE);    Vasculitis;    B cell;    Hypogammaglobulinaemia;    Rituximab;   

Others  :  1125662
DOI  :  10.1186/1471-2474-15-178

 received in 2014-01-23, accepted in 2014-05-15,  发布年份 2014

【 摘 要 】

Background

Rituximab is a B cell depleting anti-CD20 monoclonal antibody. CD20 is not expressed on mature plasma cells and accordingly rituximab does not have immediate effects on immunoglobulin levels. However, after rituximab some patients develop hypogammaglobulinaemia.

Methods

We performed a single centre retrospective review of 177 patients with multisystem autoimmune disease receiving rituximab between 2002 and 2010. The incidence, severity and complications of hypogammaglobulinaemia were investigated.

Results

Median rituximab dose was 6 g (1–20.2) and total follow-up was 8012 patient-months. At first rituximab, the proportion of patients with IgG <6 g/L was 13% and remained stable at 17% at 24 months and 14% at 60 months. Following rituximab, 61/177 patients (34%) had IgG <6 g/L for at least three consecutive months, of whom 7/177 (4%) had IgG <3 g/L. Low immunoglobulin levels were associated with higher glucocorticoid doses during follow up and there was a trend for median IgG levels to fall after ≥ 6 g rituximab. 45/115 (39%) with IgG ≥6 g/L versus 26/62 (42%) with IgG <6 g/L experienced severe infections (p = 0.750). 6/177 patients (3%) received intravenous immunoglobulin replacement therapy, all with IgG <5 g/L and recurrent infection.

Conclusions

In multi-system autoimmune disease, prior cyclophosphamide exposure and glucocorticoid therapy but not cumulative rituximab dose was associated with an increased incidence of hypogammaglobulinaemia. Severe infections were common but were not associated with immunoglobulin levels. Repeat dose rituximab therapy appears safe with judicious monitoring.

【 授权许可】

   
2014 Marco et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR, European Vasculitis Study Group: Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010, 363(3):211-220. PubMed PMID: 20647198
• [2]Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U, RAVE-ITN Research Group: Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010, 363(3):221-232. PubMed PMID: 20647199. Pubmed Central PMCID: 3137658
• [3]Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, Savage CO, Jayne DR: A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2009, 60(7):2156-2168. PubMed PMID: 19565480
• [4]Guerry MJ, Brogan P, Bruce IN, D’Cruz DP, Harper L, Luqmani R, Pusey CD, Salama AD, Scott DG, Savage CO, Watts RA, Jayne DR: Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology 2012, 51(4):634-643. PubMed PMID: 21613248
• [5]Smith RM, Jones RB, Guerry MJ, Laurino S, Catapano F, Chaudhry A, Smith KG, Jayne DR: Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2012, 64(11):3760-3769. PubMed PMID: 22729997
• [6]Cartin-Ceba R, Golbin JM, Keogh KA, Peikert T, Sanchez-Menendez M, Ytterberg SR, Fervenza FC, Specks U: Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener’s): ten-year experience at a single center. Arthritis Rheum 2012, 64(11):3770-3778. PubMed PMID: 22730028
• [7]Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hseih HJ, Zhang D, Brunetta PG: 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 2010, 62(1):222-233. PubMed PMID: 20039413
• [8]Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, Maciuca R, Zhang D, Garg JP, Brunetta P, Appel G, LUNAR Investigator Group: Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012, 64(4):1215-1226. PubMed PMID: 22231479
• [9]Smith RM, Clatworthy MR, Jayne DR: Biological therapy for lupus nephritis-tribulations and trials. Nat Rev Rheumatol 2010, 6(9):547-552. PubMed PMID: 20647994
• [10]McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998, 16(8):2825-2833. PubMed PMID: 9704735
• [11]Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004, 350(25):2572-2581. PubMed PMID: 15201414
• [12]Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, Keystone EC, Loveless JE, Burmester GR, Cravets MW, Hessey EW, Shaw T, Totoritis MC, REFLEX Trial Group: 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 2006, 54(9):2793-2806. PubMed PMID: 16947627
• [13]Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh A, Racewicz AJ, van Vollenhoven RF, Li NF, Agarwal S, Hessey EW, Shaw TM, DANCER Study Group: 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 2006, 54(5):1390-1400. PubMed PMID: 16649186
• [14]Eisenberg RA, Jawad AF, Boyer J, Maurer K, McDonald K, Prak ET, Sullivan KE: Rituximab-treated patients have a poor response to influenza vaccination. J Clin Immunol 2013, 33(2):388-396. PubMed PMID: 23064976. Pubmed Central PMCID: 3565069
• [15]Lim SH, Zhang Y, Wang Z, Esler WV, Beggs D, Pruitt B, Hancock P, Townsend M: Maintenance rituximab after autologous stem cell transplant for high-risk B-cell lymphoma induces prolonged and severe hypogammaglobulinemia. Bone Marrow Transplant 2005, 35(2):207-208. PubMed PMID: 15531902
• [16]Nishio M, Fujimoto K, Yamamoto S, Endo T, Sakai T, Obara M, Kumano K, Minauchi K, Yamaguchi K, Takeda Y, Sato N, Koizumi K, Mukai M, Koike T: Hypogammaglobulinemia with a selective delayed recovery in memory B cells and an impaired isotype expression after rituximab administration as an adjuvant to autologous stem cell transplantation for non-Hodgkin lymphoma. Eur J Haematol 2006, 77(3):226-232. PubMed PMID: 16923109
• [17]Hicks LK, Woods A, Buckstein R, Mangel J, Pennell N, Zhang L, Imrie K, Spaner D, Cheung MC, Boudreau A, Reis M, Crump M, Berinstein NL: Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma. Bone Marrow Transplant 2009, 43(9):701-708. PubMed PMID: 19029963
• [18]Irie E, Shirota Y, Suzuki C, Tajima Y, Ishizawa K, Kameoka J, Harigae H, Ishii T: 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. PubMed PMID: 20217285
• [19]van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann RM, Furst DE, Tyson N, Collinson N, Lehane PB: Long-term safety of rituximab in rheumatoid arthritis: 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(9):1496-1502. PubMed PMID: 23136242
• [20]Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, Specks U: Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 2006, 173(2):180-187. PubMed PMID: 16224107. Pubmed Central PMCID: 2662987
• [21]Rees F, Yazdani R, Lanyon P: Long-term follow-up of different refractory systemic vasculitides treated with rituximab. Clin Rheumatol 2011, 30(9):1241-1245. PubMed PMID: 21523362
• [22]Venhoff N, Effelsberg NM, Salzer U, Warnatz K, Peter HH, Lebrecht D, Schlesier M, Voll RE, Thiel J: Impact of rituximab on immunoglobulin concentrations and B cell numbers after cyclophosphamide treatment in patients with ANCA-associated vasculitides. PLoS One 2012, 7(5):e37626. PubMed PMID: 22629432. Pubmed Central PMCID: 3357389
• [23]Holle JU, Dubrau C, Herlyn K, Heller M, Ambrosch P, Noelle B, Reinhold-Keller E, Gross WL: Rituximab for refractory granulomatosis with polyangiitis (Wegener’s granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis 2012, 71(3):327-333. PubMed PMID: 22021864
• [24]Furst DE: Serum immunoglobulins and risk of infection: how low can you go? Semin Arthritis Rheum 2009, 39(1):18-29. PubMed PMID: 18620738
• [25]Smith KG, Jones RB, Burns SM, Jayne DR: Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. Arthritis Rheum 2006, 54(9):2970-2982. PubMed PMID: 16947528
• [26]Catapano F, Chaudhry AN, Jones RB, Smith KG, Jayne DW: Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol Dial Transplant 2010, 25(11):3586-3592. PubMed PMID: 20466686
• [27]Martinez Del Pero M, Chaudhry A, Jones RB, Sivasothy P, Jani P, Jayne D: B-cell depletion with rituximab for refractory head and neck Wegener’s granulomatosis: a cohort study. Clin Otolaryngol 2009, 34(4):328-335. PubMed PMID: 19673980
• [28]de Groot K, Gross WL, Herlyn K, Reinhold-Keller E: Development and validation of a disease extent index for Wegener’s granulomatosis. Clin Nephrol 2001, 55(1):31-38. PubMed PMID: 11200865
• [29]Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, Bonnet C, Cacoub P, Cantagrel A, de Bandt M, Fain O, Fautrel B, Gaudin P, Godeau B, Harlé JR, Hot A, Kahn JE, Lambotte O, Larroche C, Léone J, Meyer O, Pallot-Prades B, Pertuiset E, Quartier P, Schaerverbeke T, Sibilia J, Somogyi A, Soubrier M, Vignon E, Bader-Meunier B, et al.: Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010, 62(8):2458-2466. PubMed PMID: 20506527
• [30]Casulo C, Maragulia J, Zelenetz AD: 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. PubMed PMID: 23276889
• [31]Roubaud-Baudron C, Pagnoux C, Meaux-Ruault N, Grasland A, Zoulim A, LE Guen J, Prud'homme A, Bienvenu B, de Menthon M, Camps S, LE Guern V, Aouba A, Cohen P, Mouthon L, Guillevin L, French Vasculitis Study Group: Rituximab maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. J Rheumatol 2012, 39(1):125-130. PubMed PMID: 22089465
• [32]Lim SH, Zhang Y, Wang Z, Varadarajan R, Periman P, Esler WV: Rituximab administration following autologous stem cell transplantation for multiple myeloma is associated with severe IgM deficiency. Blood 2004, 103(5):1971-1972. PubMed PMID: 14976066
• [33]van Vollenhoven RF, Emery P, Bingham CO 3rd, Keystone EC, Fleischmann R, Furst DE, Macey K, Sweetser M, Kelman A, Rao R: Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol 2010, 37(3):558-567. PubMed PMID: 20110520
• [34]Gottenberg JE, Ravaud P, Bardin T, Cacoub P, Cantagrel A, Combe B, Dougados M, Flipo RM, Godeau B, Guillevin L, Le Loët X, Hachulla E, Schaeverbeke T, Sibilia J, Baron G, Mariette X, AutoImmunity and Rituximab registry and French Society of Rheumatology: Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 2010, 62(9):2625-2632. PubMed PMID: 20506353
• [35]van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006, 108(10):3295-3301. PubMed PMID: 16873669
• [36]Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, Dougados M, Baldassare A, Ferraccioli G, Chubick A, Udell J, Cravets MW, Agarwal S, Cooper S, Magrini F: Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum 2007, 56(12):3896-3908. PubMed PMID: 18050221
• [37]Walsh M, Chaudhry A, Jayne D: Long-term follow-up of relapsing/refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Ann Rheum Dis 2008, 67(9):1322-1327. PubMed PMID: 18055469
• [38]Flossmann O, Baslund B, Bruchfeld A, Tervaert JW, Hall C, Heinzel P, Hellmich B, Luqmani RA, Nemoto K, Tesar V, Jayne DR: Deoxyspergualin in relapsing and refractory Wegener’s granulomatosis. Ann Rheum Dis 2009, 68(7):1125-1130. PubMed PMID: 18713783