Abstract
The treatment of severe vasculitides, such as antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis, is associated with both short- and long-term toxicities that limit its use in paediatric patients and is complicated by refractory and relapsing disease that requires increased exposure to these toxic therapies. B cells have been implicated in the pathogenesis of autoimmune diseases, including vasculitis, and represent a potential target for new therapies that may have a more acceptable toxicity profile. The use of rituximab, a biologic therapy directed against B cells, has provided valuable insight into the potential role of B-cell targeted therapies for vasculitis. Rituximab appears to be a potentially useful treatment for vasculitis in adult patients, but randomized evidence comparing it to cyclophosphamide in terms of both efficacy and toxicity is lacking, as is long-term safety data. Several other B-cell-directed therapies are in development and may offer rational alternatives or adjunctives to traditional treatments.
Similar content being viewed by others
References
Dillon MJ, Ozen S (2006) A new international classification of childhood vasculitis. Pediatr Nephrol 21:1219–1222
Collagen Diseases and Hypersensitivity Panel (MRC) (1960) Treatment of polyarteritis nodosa with cortisone: results after three years. Br Med J 1399:1400–1400
Frohnert PF, Sheps SG (1967) Long-term follow-up study of periarteritis nodosa. Am J Med 43:8–11
Fauci AS, Wolff SM, Johnson JS (1971) Effect of cyclophosphamide upon the immune response in Wegener’s granulomatosis. N Engl J Med 285:1493–1496
Booth AD, Almond MK, Burns A, Ellis P, Gaskin G, Neild GH, Plaisance M, Pusey CD, Jayne DR (2003) Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis 41:776–784
Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group (2005) Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352:351–361
Jayne D, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, Mirapeix E, Savage C, Sinico A, Stegeman C, Westman K, Van Der Woude FJ, de Lind van Wijngaarden R, Pusey C (2007) Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 18:2180–2188
Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM (2001) T cell activation in rheumatoid synovium is B cell dependent. J Immunol 167:4710–4718
Youinou P, Devauchelle V, Hutin P, Le Berre R, Saraux A, Pers JO (2007) A conspicuous role for B cells in Sjogren’s syndrome. Clin Rev Allergy Immunol 32:231–237
Cambridge G, Stohl W, Leandro MJ, Migone TS, Hilbert DM, Edwards JC (2006) Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum 54:723–732
Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, Lipsky PE, Radbruch A, Dorner T (2000) Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 165:5970–5979
Popa ER, Franssen CF, Limburg PC, Huitema MG, Kallenberg CG, Tervaert JW (2002) In vitro cytokine production and proliferation of T cells from patients with anti-proteinase 3- and antimyeloperoxidase-associated vasculitis, in response to proteinase 3 and myeloperoxidase. Arthritis Rheum 46:1894–1904
Shlomchik MJ, Craft JE, Mamula MJ (2001) From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 1:147–153
Matsumura R, Kondo Y, Sugiyama T, Sueishi M, Koike T, Takabayashi K, Tomioka H, Yoshida S, Tsuchida H (1988) Immunohistochemical identification of infiltrating mononuclear cells in tubulointerstitial nephritis associated with Sjogren’s syndrome. Clin Nephrol 30:335–340
Cohen CD, Calvaresi N, Armelloni S, Schmid H, Henger A, Ott U, Rastaldi MP, Kretzler M (2005) CD20-positive infiltrates in human membranous glomerulonephritis. J Nephrol 18:328–333
Liossis SN, Kovacs B, Dennis G, Kammer GM, Tsokos GC (1996) B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events. J Clin Invest 98:2549–2557
Lipsky PE (2001) Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol 2:764–766
Llorente L, Zou W, Levy Y, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, Morel-Fourrier B, Brouet JC, Alarcon-Segovia D, Galanaud P, Emilie D (1995) Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med 181:839–844
Mohan C (2001) Murine lupus genetics: lessons learned. Curr Opin Rheumatol 13:352–360
Izui S, McConahey PJ, Dixon FJ (1978) Increased spontaneous polyclonal activation of B lymphocytes in mice with spontaneous autoimmune disease. J Immunol 121:2213–2219
Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ (1999) A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 189:1639–1648
Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR (1994) Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435–445
Anolik JH, Campbell D, Felgar RE, Young F, Sanz I, Rosenblatt J, Looney RJ (2003) The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum 48:455–459
Pers JO, Devauchelle V, Daridon C, Bendaoud B, Le Berre R, Bordron A, Hutin P, Renaudineau Y, Dueymes M, Loisel S, Berthou C, Saraux A, Youinou P (2007) BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjogren’s syndrome. Arthritis Rheum 56:1464–1477
Smolen JS, Keystone EC, Emery P, Breedveld FC, Betteridge N, Burmester GR, Dougados M, Ferraccioli G, Jaeger U, Klareskog L, Kvien TK, Martin-Mola E, Pavelka K (2007) Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 66:143–150
Sfikakis PP, Souliotis VL, Fragiadaki KG, Moutsopoulos HM, Boletis JN, Theofilopoulos AN, Sfikakis PP, Souliotis VL, Fragiadaki KG, Moutsopoulos HM, Boletis JN, Theofilopoulos AN (2007) Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin Immunol 123:66–73
Vallerskog T, Gunnarsson I, Widhe M, Risselada A, Klareskog L, van Vollenhoven R, Malmstrom V, Trollmo C (2007) Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE. Clin Immunol 122:62–74
Gong Q, Ou Q, Ye S, Lee WP, Cornelius J, Diehl L, Lin WY, Hu Z, Lu Y, Chen Y, Wu Y, Meng YG, Gribling P, Lin Z, Nguyen K, Tran T, Zhang Y, Rosen H, Martin F, Chan AC (2005) Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol 174:817–826
Cambridge G, Isenberg DA, Edwards J, Leandro MJ, Migone TS, Teodorescu M, Stohl W (2008) B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response. Ann Rheum Dis 67:1011–6
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 (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825–2833
Chaiwatanatorn K, Lee N, Grigg A, Filshie R, Firkin F (2003) Delayed-onset neutropenia associated with rituximab therapy. Br J Haematol 121:913–918
Arnold DM, Dentali F, Crowther MA, Meyer RM, Cook RJ, Sigouin C, Fraser GA, Lim W, Kelton JG (2007) Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 146:25–33
Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572–2581
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 (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 54:2793–2806
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 (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 54:1390–1400
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 (2007) Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum 56:3896–3908
Salliot C, Dougados M, Gossec L (2008) Risk of serious infections during rituximab, abatacept and anakinra therapies for rheumatoid arthritis: meta-analyses of randomized placebo-controlled trials. Ann Rheum Dis doi:https://doi.org/10.1136/ard.2007.083188
Aries PM, Hellmich B, Voswinkel J, Both M, Nolle B, Holl-Ulrich K, Lamprecht P, Gross WL (2006) Lack of efficacy of rituximab in Wegener’s granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis 65:853–858
Brihaye B, Aouba A, Pagnoux C, Cohen P, Lacassin F, Guillevin L, Brihaye B, Aouba A, Pagnoux C, Cohen P, Lacassin F, Guillevin L (2007) Adjunction of rituximab to steroids and immunosuppressants for refractory/relapsing Wegener’s granulomatosis: a study on 8 patients. Clin Exp Rheumatol 25:S23–S27
Eriksson P (2005) Nine patients with anti-neutrophil cytoplasmic antibody-positive vasculitis successfully treated with rituximab. J Intern Med 257:540–548
Henes JC, Fritz J, Koch S, Klein R, Horger M, Risler T, Kanz L, Koetter I, Henes JC, Fritz J, Koch S, Klein R, Horger M, Risler T, Kanz L, Koetter I (2007) Rituximab for treatment-resistant extensive Wegener’s granulomatosis–additive effects of a maintenance treatment with leflunomide. Clin Rheumatol 26:1711–1715
Keogh KA, Wylam ME, Stone JH, Specks U (2005) Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52:262–268
Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, Specks U (2006) Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 173:180–187
Omdal R, Wildhagen K, Hansen T, Gunnarsson R, Kristoffersen G (2005) Anti-CD20 therapy of treatment-resistant Wegener’s granulomatosis: favourable but temporary response. Scand J Rheumatol 34:229–232
Smith KG, Jones RB, Burns SM, Jayne DR (2006) Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. Arthritis Rheum 54:2970–2982
Stasi R, Stipa E, Del Poeta G, Amadori S, Newland AC, Provan D (2006) Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology 45:1432–1436
Jones RB, Ferraro A, Chaudhry AN, Brogan P, Salama A, Savage COS, Short A, Jayne DRW (2007) Multi-Centre Survey of Rituximab for Refractory ANCA Associated Vasculitis. J Am Soc Nephrol 18:FC061
Rituximab Information: FDA alert. U.S.Food and Drug Administration (2006) Available at https://doi.org/www.fda.gov/cder/drug/InfoSheets/HCP/rituximab.htm. Accessed 15 March 2008. Last updated 18 December 2006
Harris HE, Harris HE (2008) Progressive multifocal leucoencephalopathy in a patient with systemic lupus erythematosus treated with rituximab. Rheumatology 47:224–225
Tahir H, Rohrer J, Bhatia A, Wegener WA, Isenberg DA (2005) Humanized anti-CD20 monoclonal antibody in the treatment of severe resistant systemic lupus erythematosus in a patient with antibodies against rituximab. Rheumatology 44:561–562
Koukoulaki M, Smith KG, Jayne DR, Koukoulaki M, Smith KGC, Jayne DRW (2006) Rituximab in Churg-Strauss syndrome. Ann Rheum Dis 65:557–559
Pepper RJ, Fabre MA, Pavesio C, Gaskin G, Jones RB, Jayne D, Pusey CD, Salama AD (2008) Rituximab is effective in the treatment of refractory Churg-Strauss syndrome and is associated with diminished T-cell interleukin-5 production. Rheumatology (Oxford) 47:1104–1105
Bhatia A, Ell PJ, Edwards JC (2005) Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis. Ann Rheum Dis 64:1099–1100
Parodi E, Nobili B, Perrotta S, Rosaria Matarese SM, Russo G, Licciardello M, Zecca M, Locatelli F, Cesaro S, Bisogno G, Giordano P, De Mattia D, Ramenghia U (2006) Rituximab (anti-CD20 monoclonal antibody) in children with chronic refractory symptomatic immune thrombocytopenic purpura: efficacy and safety of treatment. Int J Hematol 84:48–53
Giulino LB, Bussel JB, Neufeld EJ (2007) Treatment with rituximab in benign and malignant hematologic disorders in children. J Pediatr 150:338–344
El-Hallak M, Binstadt BA, Leichtner AM, Bennett CM, Neufeld EJ, Fuhlbrigge RC, Zurakowski D, Sundel RP (2007) Clinical effects and safety of rituximab for treatment of refractory pediatric autoimmune diseases. J Pediatr 150:376–382
Willems M, Haddad E, Niaudet P, Kone-Paut I, Bensman A, Cochat P, Deschenes G, Fakhouri F, Leblanc T, Llanas B, Loirat C, Pillet P, Ranchin B, Salomon R, Ulinski T, Bader-Meunier B (2006) Rituximab therapy for childhood-onset systemic lupus erythematosus. J Pediatr 148:623–627
Podolskaya A, Stadermann M, Pilkington C, Marks SD, Tullus K (2008) B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus. Arch Dis Child 93:401–406
Acknowledgments
MW is supported by the Kidney Research Scientist Core Education National Training (KRESCENT) Program and the Alberta Heritage Foundation for Medical Research.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Walsh, M., Jayne, D. Targeting the B cell in vasculitis. Pediatr Nephrol 24, 1267–1275 (2009). https://doi.org/10.1007/s00467-008-1010-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-008-1010-z