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Review

Emerging B-Cell Therapies in Systemic Lupus Erythematosus

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Pages 39-54 | Published online: 14 Jan 2021

References

  • Costenbader KH, Feskanich D, Stampfer MJ, et al. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum. 2007;56:1251–1262. doi:10.1002/art.22510
  • Choi J, Kim ST, Craft J. The pathogenesis of systemic lupus erythematosus – an update. Curr Opin Immunol. 2012;24:651–657. doi:10.1016/j.coi.2012.10.004
  • D’Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. 2007;369:587–596. doi:10.1016/S0140-6736(07)60279-7
  • Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med. 2008;358:929–939. doi:10.1056/NEJMra071297
  • Askanase AD, Wallace DJ, Weisman MH, et al. Use of pharmacogenetics, enzymatic phenotyping and metabolite monitoring to guide treatment with azathioprine in patients with systemic lupus erythematosus. J Rheumatol. 2009;36:89–95. doi:10.3899/jrheum.070968
  • Carneiro JR, Sato EI. Double blind, randomized, placebo-controlled clinical trial of methotrexate in systemic lupus erythematosus. J Rheumatol. 1999;26:1275–1279.
  • Nashi E, Wang Y, Diamond B. The role of B cells in lupus pathogenesis. J Biochem Cell Biol. 2010;42:543–550. doi:10.1016/j.biocel.2009.10.011
  • Hahn BH. Belimumab for systemic lupus erythematosus. N Engl J Med. 2013;368:1528–1535. doi:10.1056/NEJMct1207259
  • Navarra S, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized, placebo-controlled, Phase 3 trial. Lancet. 2011;377:721–731. doi:10.1016/S0140-6736(10)61354-2
  • Furie R, Petri M, Zamani O, et al. A Phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63:3918–3930. doi:10.1002/art.30613
  • Merrill JT, van Vollenhoven RF, Buyon JF, et al. Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicenter, randomized, double blind, placebo-controlled study. Ann Rheum Dis. 2016;75:332–340. doi:10.1136/annrheumdis-2015-207654
  • Isenberg DA, Gordon C, Licu D, et al. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus: 52-week data (APRIL-SLE randomized trial). Ann Rheum Dis. 2015;74:2006–2015. doi:10.1136/annrheumdis-2013-205067
  • Merrill JT, Shanahan WR, Scheinberg M, et al. Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus: results from a randomized, double blind, placebo-controlled trial. Ann Rheum Dis. 2018;77:883–889. doi:10.1136/annrheumdis-2018-213032
  • Clowse MEB, Wallace DJ, Furie RA, et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus. Arthritis Rheumatol. 2017;69:362–375. doi:10.1002/art.39856
  • Mysler EF, Spindler AJ, Guzman R, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis. Arthritis Rheum. 2013;65:2368–2379. doi:10.1002/art.38037
  • Furie RA, Aroca G, Alvarez A, et al. A phase II randomized, double blind, placebo-controlled study to evaluate the efficacy and safety of obinutuzumab or placebo in combination with mycophenolate mofetil in patients with active class III or IV lupus nephritis (abstract). Arthritis Rheumatol. 2019;71:1125–1134.
  • Masoud S, McAdoo SP, Bedi R, et al. Ofatumumab for B cell depletion in patients with systemic lupus erythematosus who are allergic to rituximab. Rheumatol. 2018;57:1156–1161. doi:10.1093/rheumatology/key042
  • Merrill JT, June J, Koumpouras F, et al. Top-line results of a Phase 2, double blind, randomized, placebo-controlled study of a reversible B cell inhibitor, XmAb5871, in systemic lupus erythematosus (abstract). Arthritis Rheumatol. 2018;70:266–276.
  • Isenberg DA, Furie RA, Jones N, et al. Efficacy, safety, and pharmacodynamics effects of the Bruton’s tyrosine kinase inhibitor, fenebrutinib (GDC-0853), in moderate to severe systemic lupus erythematosus: results of a phase 2 randomized controlled trial (abstract). Arthritis Rheumatol. 2019;71.
  • Ishii T, Tanaka Y, Kawakami A, et al. Multicenter double blind randomized controlled trial to evaluate the effectiveness and safety of bortezomib as a treatment for refractory systemic lupus erythematosus. Mod Rheumatol. 2018;28:986–992. doi:10.1080/14397595.2018.1432331
  • Vincent FB, Morand EF, Schneider R, et al. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol. 2014;10:365–373. doi:10.1038/nrrheum.2014.33
  • Ritterhouse LL, Crowe ST, Niewold TB, et al. B lymphocyte stimulator levels in systemic lupus erythematosus: higher circulating levels in African American patients and increased production after influenza vaccination in patients with low baseline levels. Arthritis Rheum. 2011;63:3931–3941. doi:10.1002/art.30598
  • Petri M, Stohl W, Chatham W, et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008;58:2453–2459. doi:10.1002/art.23678
  • Alexander T, Cheng Q, Klotsche J, et al. Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors. Eur J Immunol. 2018;48:1573–1579. doi:10.1002/eji.201847492
  • Isenberg DA, Rahman A, Allen E, et al. BILAG 2004. Development and initial validation of an updated version of the British Isles lupus assessment group’s disease activity index for patients with systemic lupus erythematosus. Rheumatol. 2005;44:902–906. doi:10.1093/rheumatology/keh624
  • Galarza C, Valencia D, Tobon GJ, et al. Should rituximab be considered as the first-choice treatment for severe autoimmune rheumatic diseases? Clin Rev Allergy Immunol. 2008;34:124–128. doi:10.1007/s12016-007-8028-z
  • Jonsdottir T, Gunnarsson I, Risselada A, et al. Treatment of refractor SLE with rituximab plus cyclophosphamide: clinical effects, serological changes and predictors of response. Ann Rheum Dis. 2007;67:330–334. doi:10.1136/ard.2007.079095
  • Lindholm C, Borjesson-Asp K, Zendjanchi K, et al. Long term clinical and immunological effects of anti-CD20 treatment in patients with refractory systemic lupus erythematosus. J Rheumatol. 2008;35:826–833.
  • Albert D, Dunham J, Khan S, et al. Varibility in the biological response to anti-CD20 B cell depletion in systemic lupus erythematosus. Ann Rheum Dis. 2008;67:1724–1731. doi:10.1136/ard.2007.083162
  • Kamburova EG, Koenen HJPM, Boon L, et al. In vitro effects of rituximab on the proliferation, activation and differentiation of human B cells. Am J Transplant. 2012;12:341–350. doi:10.1111/j.1600-6143.2011.03833.x
  • Narvaez J, Rios-Rodriguez V, de la Fuente D, et al. Rituximab therapy in refractory neuropsychiatric lupus: current clinical evidence. Semin Arthritis Rheum. 2011;41:364–372. doi:10.1016/j.semarthrit.2011.06.004
  • Tokunaga M, Saito K, Kawabata D, et al. Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis. 2007;66:470–475. doi:10.1136/ard.2006.057885
  • Moroni G, Raffiotta F, Trezzi B, et al. Rituximab vs mycophenolate vs cyclophosphamide for induction therapy of active lupus nephritis: a clinical observational study. Rheumatol. 2014;53:1570–1577. doi:10.1093/rheumatology/ket462
  • Ramos-Casals M, Soto MJ, Cuadrado MJ, et al. Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases. Lupus. 2009;18:767–776. doi:10.1177/0961203309106174
  • Merrill JT, Neuwelt CM, Wallace DJ, et al. 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 (EXPLORER). Arthritis Rheum. 2010;62:222–233. doi:10.1002/art.27233
  • Rovin B, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study (LUNAR). Arthritis Rheum. 2012;64:1215–1226. doi:10.1002/art.34359
  • Hui-Yuen JS, Nguyen SC, Askanase AD. Targeted B cell therapies in the treatment of adult systemic lupus erythematosus. Lupus. 2016;25:1086–1096. doi:10.1177/0961203316652491
  • Coco-Ibanez T, Loza-Santamaria E, Peg-Reigosa JM, et al. Efficacy and safety of rituximab in the treatment of non-renal systemic lupus erythematosus: a systematic review. Semin Arthritis Rheum. 2014;44:175–185. doi:10.1016/j.semarthrit.2014.04.002
  • Fernandez-Nebro A, de la Fuente J, Carreno L, et al. Multicenter longitudinal study of B lymphocyte depletion in refractory systemic lupus erythematosus: the LESIMAB study. Lupus. 2012;21:1063–1076. doi:10.1177/0961203312446627
  • Pinto LF, Velasquez CJ, Prieto C, et al. Rituximab induces a rapid and sustained remission in Colombian patients with severe and refractory systemic lupus erythematosus. Lupus. 2011;20:1219–1226. doi:10.1177/0961203311409273
  • Henegar CE, Eudy AM, Kharat V, et al. Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review. Lupus. 2016;25:617–626. doi:10.1177/0961203315622819
  • Guzman M, Hui-Yuen JS. Management of pediatric systemic lupus erythematosus: focus on belimumab. Drug Design Dev Ther. 2020;14:2503–2513. doi:10.2147/DDDT.S216193
  • Van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012;71:1343–1349. doi:10.1136/annrheumdis-2011-200937
  • Strand V, Levy RA, Cervera R, et al. Improvements in health-related quality of life with belimumab, a B lymphocyte stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus from the randomized controlled BLISS trials. Ann Rheum Dis. 2014;73:838–844. doi:10.1136/annrheumdis-2012-202865
  • Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a 52-week randomized, double blind, placebo controlled study. Arthritis Rheumatol. 2017;69:1016–1027. doi:10.1002/art.40049
  • Brunner HI, Abud-Mendoza C, Viola DO, et al. Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus: results from a randomized, placebo-controlled trial. Ann Rheum Dis. 2020;79:1340–1348. doi:10.1136/annrheumdis-2020-217101
  • D’Cruz D, Maksimowicz-McKinnon K, Oates J, et al. Efficacy and safety of belimumab in patients of black race with systemic lupus erythematosus: results from the EMBRACE study. Lupus Sci Med. 2019;6.
  • Dooley A, Houssiau F, Aranow C, et al. Effect of belimumab treatment on renal outcomes: results from the phase III belimumab clinical trials in patients with SLE. Lupus. 2013;22:63–72. doi:10.1177/0961203312465781
  • Furie RA, Rovin BH, Joussai F, et al. Two-year, randomized controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383:1117–1128. doi:10.1056/NEJMoa2001180
  • Atisha F, Malkiel S, Harris KM, et al. CALIBRATE: a phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis. Arthritis Rheumatol. 2020. doi:10.1002/art.41466.
  • Ehrenstein MR, Wing C. The BAFFling effects of rituximab in lupus: danger ahead? Nat Rev Rheumatol. 2016;12:367–372. doi:10.1038/nrrheum.2016.18
  • Collins CE, Dall’Era M, Kan H, et al. Response to belimumab among patients with systemic lupus erythematosus in clinical practice settings: 24 month results from the OBSErve study in the USA. Lupus Sci Med. 2016;3:e000118. doi:10.1136/lupus-2015-000118
  • Wallace DJ, Ginzler EM, Merrill JT, et al. Safety and efficacy of belimumab plus standard-of-care therapy for up to 13 years in patients with systemic lupus erythematosus. Arthritis Rheum. 2019;71:1125–1134. doi:10.1002/art.40861
  • Hui-Yuen JS, Reddy A, Taylor J, et al. Safety and efficacy of belimumab to treat systemic lupus erythematosus in academic clinical practices. J Rheumatol. 2015;42:2288–2295. doi:10.3899/jrheum.150470
  • A study to evaluate the efficacy and safety of belimumab administered in combination with rituximab to adult subjects with systemic lupus erythematosus (SLE) – BLISS-BELIEVE. Clinicaltrials.gov identifier: NCT 03312907, accessed 30 August 2020. 2020.
  • A study of subcutaneous (sc) belimumab in pediatric participants with systemic lupus erythematosus (SLE). Clinicaltrials.gov identifier: NCT 04179032, accessed 30 August 2020. 2020.
  • Ginzler EM, Wallace DJ, Merrill JT, et al. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol. 2014;41:300–309. doi:10.3899/jrheum.121368
  • Wallace DJ, Navarra SV, Petri MA, et al. Safety profile of belimumab: pooled data from placebo-controlled phase II and III studies in patients with systemic lupus erythematosus. Lupus. 2013;22:144–154. doi:10.1177/0961203312469259
  • Bruce IN, Urowitz M, van Vollenhoven R, et al. Long-term organ damage accrual and safety in patients with SLE treated with belimumab plus standard of care. Lupus. 2016;25:699–709. doi:10.1177/0961203315625119
  • Leblanc-Trudeau C, Masetto A, Bocti C. Progressive multifocal encephalopathy associated with belimumab in a patient with systemic lupus erythematosus. J Rheumatol. 2015;42:551–552. doi:10.3899/jrheum.140577
  • Raisch DW, Rafi JA, Chen C, et al. Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA’s adverse reporting system. Expert Opin Drug Saf. 2016;15:1003–1011. doi:10.1080/14740338.2016.1198775
  • Bernatksy S, BOivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54:2550–2557. doi:10.1002/art.21955
  • Isenberg DA, Petri M, Kalunian K, et al. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52 week, phase III, multicenter, randomized, double blind, placebo-controlled study. Ann Rheum Dis. 2016;75:323–331. doi:10.1136/annrheumdis-2015-207653
  • Rovin B, Dooley MA, Radhakrishnan J, et al. The impact of tabalumab on the kidney in systemic lupus erythematosus: results from two phase III randomized, clinical trials. Lupus. 2016;25:1597–1601. doi:10.1177/0961203316650734
  • Merrill JT, Wallace DJ, Wax S, et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a 24 week, multicenter, randomized, double blind, placebo-controlled, parallel-arm, phase IIb study. Arthritis Rheumatol. 2018;70:266–276. doi:10.1002/art.40360
  • Morand E, Isenberg DA, Wallace DJ, et al. Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase IIb ADDRESS II study. Rheumatol. 2020;59:2930–2938. doi:10.1093/rheumatology/keaa029.
  • Gordon C, Wofsy D, Wax S, et al. Post hoc analysis of the phase II/III APRIL-SLE study: association between response to atacicept and serum biomarkers including BLyS and APRIL. Arthritis Rheumatol. 2017;69:122–130. doi:10.1002/art.39809
  • Furie RA, Leon G, Thomas M, et al. A phase II, randomized, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis. 2015;74:1667–1675. doi:10.1136/annrheumdis-2013-205144
  • Wallace DJ, Gordon C, Strand V, et al. Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double blind, placebo-controlled, multicenter studies (ALLEVIATE) and follow-up. Rheumatol. 2013;52:1313–1322. doi:10.1093/rheumatology/ket129
  • Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nat Rev Rheumatol. 2010;6:326–337. doi:10.1038/nrrheum.2010.68
  • Ostendorf L, Burns M, Durek P, et al. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. N Engl J Med. 2020;383:1149–1155. doi:10.1056/NEJMoa2023325
  • DiLillo DJ, Hamaguchi Y, Ueda Y, et al. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J Immunol. 2008;180:361–371. doi:10.4049/jimmunol.180.1.361
  • Sorensen PS, Blinkenberg M. The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord. 2016;9:44–52. doi:10.1177/1756285615601933
  • A study to evaluate two doses of ocrelizumab in patients with active systemic lupus erythematosus (BEGIN). Clinicaltrials.gov identifier: NCT00539838, accessed 30 August 2020. 2020.
  • A study of ocrelizumab in children and adolescents with relapsing-remitting multiple sclerosis. Clinicaltrials.gov identifier: NCT 04075266, accessed 30 August 2020. 2020.
  • A study to evaluate the efficacy and safety of ocrelizumab in adults with primary progressive multiple sclerosis (O’HAND). Clinicaltrials.gov identifier: NCT04035005, accessed 30 August 2020. 2020.
  • Reddy V, Klein C, Isenberg DA, et al. Obinutuzumab induces superior B cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatol. 2017;56:1227–1237. doi:10.1093/rheumatology/kex067
  • Montillo M, O’Brien S, Tedeschi A, et al. Autoimmune haemolytic anaemia and immune mediated thrombocytopenia in the phase III RESONATE study of Ibrutinib vs Ofatumumab in relapsed/refractory chronic lymphocytic leukemia, including a case report. Blood. 2014;124:565. doi:10.1182/blood.V124.21.5654.5654
  • Haarhaus ML, Svenungsson E, Gunnarsson I. Ofatumumab treatment in lupus nephritis patients. Clin Kidney J. 2016;9:552–555. doi:10.1093/ckj/sfw022
  • Thornton CC, Ambrose N, Ioannou Y. Ofatumumab: a novel treatment for severe systemic lupus erythematosus. Rheumatol (Oxford). 2015;54:559–560. doi:10.1093/rheumatology/keu475
  • A study to evaluate the effect of XmAb5871 on disease activity in patients with IgG4-related disease. Clinicaltrials.gov identifier: NCT 02725476, accessed 30 August 2020. 2020.
  • Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361:226–233. doi:10.1038/361226a0
  • Satterthwaite AB. Bruton’s Tyrosine Kinase, a component of B cell signaling pathways, has multiple roles in the pathogenesis of lupus. Front Immunol. 2018;8:1986. doi:10.3389/fimmu.2017.01986
  • Chalmers SA, Glynn E, Garcia SJ, et al. BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis. Clin Immunol. 2018;197:205–218. doi:10.1016/j.clim.2018.10.008
  • Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–2437. doi:10.1056/NEJMoa1509388
  • Hutcheson J, Vanarsa K, Bashmakov A, et al. Modulating proximal cell signaling by targeting Btk ameliorates humoral autoimmunity and end-organ disease in murine lupus. Arthritis Res Ther. 2012;14:R243. doi:10.1186/ar4086.
  • MSC2364447C phase Ib in systemic lupus erythematosus. Clinicaltrials.gov identifier: NCT02537028, accessed 30 August 2020. 2020.
  • A study of AC0058TA in patients with systemic lupus erythematosus. Clinicaltrials.gov identifier: NCT03878303, accessed 30 August 2020. 2020.
  • Richardson PG, Sonnevald P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487–2498. doi:10.1056/NEJMoa043445
  • Obeng EA, Carlson LM, Gutman DM, et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107:4907–4916. doi:10.1182/blood-2005-08-3531
  • Neubert K, Meister S, Moser K, et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med. 2008;14:748–755. doi:10.1038/nm1763
  • Ichikawa HT, Conley T, Muchamuel T, et al. Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum. 2012;64:493–503. doi:10.1002/art.33333
  • Seavey MM, Lu LD, Stump KL, et al. Novel, orally active, proteasome inhibitor, delanzomib (CEP-18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE. Int Immunopharmacol. 2012;12:257–270. doi:10.1016/j.intimp.2011.11.019
  • Segarra A, Arredondo KV, Jaramillo J, et al. Efficacy and safety of bortezomib in refractory lupus nephritis: a single-center experience. Lupus. 2020;29:118–125. doi:10.1177/0961203319896018
  • Alexander T, Sarfert R, Klotsche J, et al. The proteasome inhibitor bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis. 2015;74:1474–1478. doi:10.1136/annrheumdis-2014-206016
  • Chamberlain C, Colman PJ, Ranger AM, et al. Repeated administration of dapirolizumab pegol in a randomized phase I study is well tolerated and accompanied by improvements in several composite measures of systemic lupus erythematosus disease activity and changes in whole blood transcriptomic profiles. Ann Rheum Dis. 2017;76:1837–1844. doi:10.1136/annrheumdis-2017-211388
  • Marino E, Grey ST. B cells as effectors and regulators of autoimmunity. Autoimmunity. 2012;45:377–387. doi:10.3109/08916934.2012.665527
  • Louis Bridges S, White DW, Worthing AB, et al. The science behind biosimilars: entering a new era of biologic therapy. Arthritis Rheumatol. 2018. doi:10.1002/art.40388.