Immunobiological drugs in the treatment of rheumatic diseases

O.O. Melnyk


Rheumatic diseases (RD) are among the most common chronic diseases of the musculoskeletal system and connective tissue which are found in both adults and children. The cause of these pathological conditions can be changes in the functioning of the immune system, inflammation, infections and other factors. In some cases, they lead to disability and have a significant impact on the quality of life and lifetime. There are non-pharmacological and pharmacological treatments for RD. The first line (non-pharmacological) treatment of most RDs consists in changing the lifestyle (exercises, correct diet, smoking cessation). Standard pharmacological treatment includes non-steroidal anti-inflammatory drugs, glucocorticoids, anti-inflammatory drugs that suppress acute phase response, help reduce the level of autoantibodies. Unfortunately, although non-steroidal anti-inflammatory drugs help control RD symptoms reducing pain, swelling and inflammation, they do not slow down the disease progression. This also refers to glucocorticoids which are anti-inflammatory hormones associated with cortisol, a steroid produced naturally in the body. Despite their advantages, glucocorticoids have significant side effects including diabetes, osteoporosis, hypertension, cataract and susceptibility to infections. In recent years, new data on the pathogenesis of rheumatic diseases has been obtained that has contributed to the possibility of creating innovative immunobiological drugs. The development of such drugs has revolutionized the therapeutic approach to chronic rheumatic diseases, especially in patients who are resistant to standard treatment. The mechanism of action of these immunobiological drugs is based on the inhibition of specific or molecular targets directly involved in the disease pathogenesis. They include tumor necrosis factor blockers, interleukin-1, -6, 17A receptor antagonists, CD20, CD80/CD86 blockers and T-cell costimulation blocker. Their use allows us to improve the prognosis and achieve clinical remission in a significant number of patients.


rheumatic diseases; immunobiological drugs; tumor necrosis factor blockers; interleukin-1, -6, 17A receptor antagonists; CD20, CD80/CD86 blockers; T-cell соstimulation blocker; review


Deshpande S. History of rheumatology. Med J DY Patil UnivSP. 2014;7(2):119-123. doi: 10.4103/0975-2870.126307.

Entezami P, Fox DA, Clapham PJ, Chung KC. Historical perspective on the etiology of rheumatoid arthritis. Hand Clin 2011 Feb;27(1):1- 10. 

Sakkas LI, Tronzas P. The Greek (Hellenic) rheumatology over the years: from ancient to modern times. Rheumatol Int. 2019 Jun;39(6):947-955. doi: 10.1007/s00296-019-04261-4.

Parish LC. An historical approach to the nomenclature of rheumatoid arthritis. Arthritis Rheum. 1963 Apr;6:138-58. doi: 10.1002/art.1780060206.

Hollander JL, Comroe BI. Arthritis and allied conditions, 4th edn. Philadelphia, PA: Lea & Febiger; 1949.

Conley CL, Hartmann RC. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Clin Invest 1952;152:621-2.

Pereira Da Silva JA, Woolf AD, eds. Rheumatology in Practice. London: Springer- Verlag; 2010. 516 p. doi: 10.1007/978-1-84882-581-9.

Branco JC, Rodrigues AM, Gouveia N, et al. Prevalence of rheumatic and musculoskeletal diseases and their impact on health-related quality of life, physical function and mental health in Portugal: results from EpiReumaPt– a national health survey. RMD Open. 2016 Jan 19;2(1):e000166. doi: 10.1136/rmdopen-2015-000166.

Barbour KE, Helmick CG, Boring M, Brady TJ. Vital Signs: Prevalence of Doctor-Diagnosed Arthritis and Arthritis-Attributable Activity Limitation – United States, 2013-2015. MMWR Morb Mortal Wkly Rep. 2017 Mar 10;66(9):246-253. doi: 10.15585/mmwr.mm6609e1.

Andersson Gare B. Juvenile arthritis: who gets it, where and when? A review of current data on incidence and prevalence. Clin Exp Rheumatol. 1999 May-Jun;17(3):367-74.

Dougados A, Radbruch A. Rheumatic Diseases: a Major Challenge for European Research and Health Care. European Science Foundation. Project Number SPB N°26. 2006.

Stoerk A. An essay on the use and effects of the root of the colchicum autumnale, or Meadow Saffron, Translated from the Latin. London: T Becket and PA de Honet; 1764.

Jacques Jean, Beer JJ. The Emergence of the German Dye Industry. In: Revue d'histoire des sciences et de leurs applications. 1963;16(4):400-401.

Zündorf U. Aspirin, 100 Years: The Future Has Just Begun. Leverkusen, Germany: Bayer AG, Consumer Care Business Group; 1997.

Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: Compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949 Apr 13;24(8):181-97.

Rundles RW, Wyngaarden JB, Hitchings GH, Elion GB, Silberman. HR. Effects of a xanthine oxidase inhibitor on thiopurine metabolism, hyperuricaemia and gout. Trans Assoc Am Physicians. 1963;76:126-40.

Malavyia AN, Many A, Schwartz RS. Treatment of dermatomyositis with methotrexate. Lancet 1968;292(7556):485-488.

Kaltsonoudis E, Papagoras C, Drosos AD. Current and Future Role of Methotrexate in the Therapeutic Armamentarium for Rheumatoid Arthritis. Int J Clin Rheumatol. 2012;7:179-89.

Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971 Jun 23;231(25):232-5.

Page F. Treatment of lupus erythematosus with mepacrine. Lancet. 1951 Oct 27;2(6687):755-8. doi: 10.1016/s0140-6736(51)91643-1.

Bagnall AW. The value of chloroquine in rheumatoid disease:A four-year study of continuous therapy. Can Med Assoc J. 1957 Aug 1;77(3):182-94.

Kumar P, Banik S. Pharmacotherapy options in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2013 Aug 8;6:35-43. doi: 10.4137/CMAMD.S5558.

Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993 Dec;36(12):1681-90. doi: 10.1002/art.1780361206.

Conti F, Ceccarelli F, Massaro L, et al. Biological therapies in rheumatic diseases. Clin Ter. 2013;164(5):e413-428. doi: 10.7417/CT.2013.1622.

Pennica D, Nedwin GE, Hayflick JS, et al. Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20-1985 Jan 2;312(5996):724-9. doi: 10.1038/312724a0.

Chan FK-M, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science. 2000 Jun 30;288(5475):2351-4. doi: 10.1126/science.288.5475.2351.

Prajapati R, Plant D, Barton A. Genetic and genomic predictors of anti-TNF response. Pharmacogenomics. 2011 Nov;12(11):1571-85. doi: 10.2217/pgs.11.114.

Mitoma H, Horiuchi T, Hatta N, et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-a. Gastroenterology. 2005 Feb;128(2):376-92. doi: 10.1053/j.gastro.2004.11.060.

Ringheanu M, Daum F, Markowitz J, et al. Effects of infliximab on apoptosis and reverse signaling of monocytes from healthy individuals and patients with Crohn’s disease. Inflamm Bowel Dis. 2004 Nov;10(6):801-10. doi:10.1097/00054725-200411000-00015.

Bachmann F, Nast A, Sterry W, Philipp S. Safety and efficacy of the tumor necrosis factor antagonists. Semin Cutan Med Surg. 2010 Mar;29(1):35-47. doi: 10.1016/j.sder.2010.02.002.

Gardam MA, Keystone EC, Menzies R, et al. Anti-tumor necrosis factor agents and tuberculosis risk: mechanism of action and clinical management. Lancet Infect Dis. 2003 Mar;3(3):148-55.

Scrivo R, Sauzullo I, Mengoni F, et al. Serial interferon-γ release assays for screening and monitoring of tuberculosis infection during treatment with biologic agents. Clin Rheumatol. 2012 Nov;31(11):1567-75. doi: 10.1007/s10067-012-2049-6.

Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 2009 Feb 18;301(7):737-44. doi: 10.1001/jama.2009.146.

Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Safety of anti-TNF-alpha therapy in rheumatoid arthritis and spondylarthropathies with concurrent B or C chronic hepatitis. Rheumatology (Oxford). 2006 Oct;45(10):1294-7. doi:10.1093/rheumatology/kel123.

Rodgers M, Epstein D, Bojke L, et al. Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis: a systematic review and economic evaluation. Health Technol Assess. 2011 Feb;15(10):i-xxi, 1-329. doi: 10.3310/hta15100.

Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf. 2011 Feb;20(2):119-30. doi: 10.1002/pds.2046.

Moulis G, Sommet A, Bene J, et al. Cancer risk of anti-TNF-α at recommended doses in adult rheumatoid arthritis: a meta-analysis with intention to treat and per protocol analyses. PLoS One. 2012;7(11):e48991. doi: 10.1371/journal.pone.0048991.

Moulis G, Sommet A, Lapeyre-Mestre M. Mortality rates among patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: comment on the article by Simard et al. Arthritis Rheum. 2013 Jun;65(6):1670-1. doi: 10.1002/art.37931.

The Lenercept Multiple Sclerosis Study Group; The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized placebo-controlled multicenter study. Neurology. 1999 Aug 11;53(3):457-65.

Ramos-Casals M, Brito-Zerуn P, Muсoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore). 2007 Jul;86(4):242-51.

Stallmach A, Hagel S, Bruns T. Adverse effects of biologics used for treating IBD. Best Pract Res Clin Gastroenterol. 2010 Apr;24(2):167-82. doi: 10.1016/j.bpg.2010.01.002.

Katz JA, Antoni C, Keenan GF, Smith DE, Jacobs SJ, Lichtenstein GR. Outcome of pregnancy in women receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis. Am J Gastroenterol. 2004 Dec;99(12):2385-92. doi: 10.1111/i.1572-0241.2004.30186.x.

Verstappen SMM, King Y, Watson KD, Symmons DPM, Hyrich KL; BSRBR Control Centre Consortium, BSR Biologics Register. Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011 May;70(5):823-6. doi: 10.1136/ard.2010.140822.

Cheifetz A, Mayer L. Monoclonal antibodies, immunogenicity, and associated infusion reactions. Mt Sinai J Med. 2005 Jul;72(4):250-6.

Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol. 2003 Jun;98(6):1315-24. doi:10.1111/i.1572-0241.2003.07457.x.

Wolbink GJ, Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006 Mar;54(3):711-5. doi: 10.1002/art.21671.

Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2572-81. doi: 10.1056/NEJMoa032534.

Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. 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 May;54(5):1390-400. doi: 10.1002/art.21778.

Rubbert-Roth A, Tak PP, Zerbini C, et al. Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a phase III randomized study (MIRROR). Rheumatology (Oxford). 2010 Sep;49(9):1683-93. doi: 10.1093/rheumatology/keq116.

Cohen SB, Keystone E, Genovese MC, et al. Continued inhibi­tion of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate. Ann Rheum Dis. 2010 Jun;69(6):1158-61. doi: 10.1136/ard.2009.119222.

Haraoui B, Bokarewa M, Kallmeyer I, Bykerk VP; RESET Investigators. Safety and effectiveness of rituximab in patients with rheumatoid arthri­tis following an inadequate response to 1 prior tumor necrosis factor inhibitor: the RESET Trial. J Rheumatol. 2011 Dec;38(12):2548-56. doi: 10.3899/jrheum.110444.

Gomez-Reino JJ, Maneiro JR, Ruiz J, et al. Comparative effectiveness of switching to alternative tumour necrosis factor (TNF) antagonists versus switching to rituximab in patients with rheumatoid arthritis who failed previous TNF antagonists: the MIRAR Study. Ann Rheum Dis. 2012 Nov;71(11):1861-4. doi: 10.1136/annrheumdis-2012-201324.

Tak PP, Rigby W, Rubbert-Roth A, et al. Sustained inhibition of pro­gressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE. Ann Rheum Dis. 2012 Mar;71(3):351-7. doi: 10.1136/annrheumdis-2011-200170.

Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nat Rev Rheumatol. 2010 Jun;6(6):326-37. doi: 10.1038/nrrheum.2010.68.

Lu TY, Ng KP, Cambridge G, et al. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythemato­sus at University College London Hospital: the first fifty patients. Arthritis Rheum. 2009 Apr 15;61(4):482-7. doi: 10.1002/art.24341.

Albert D, Dunham J, Khan S, et al. Variability in the biological response to anti-CD20 B cell depletion in systemic lupus erythaematosus. Ann Rheum Dis. 2008 Dec;67(12):1724-31. doi: 10.1136/ard.2007.083162.

Fernandez-Nebro A, de la Fuente JL, Carreno L, et al. Multicenter lon­gitudinal study of B-lymphocyte depletion in refractory systemic lupus erythematosus: the LESIMAB study. Lupus. 2012 Sep;21(10):1063-76. doi: 10.1177/0961203312446627.

Wang CR, Liu MF. Rituximab usage in systemic lupus erythematosus-associated antiphospholipid syndrome: a single-center experience. Semin Arthritis Rheum. 2016 Aug;46(1):102-8. doi: 10.1016/j.semarthrit.2016.02.002.

Ryden-Aulin M, Boumpas D, Bultink I, et al. Off-label use of rituximab for systemic lupus erythematosus in Europe. Lupus Sci Med. 2016 Sep 6;3(1):e000163. doi: 10.1136/lupus-2016-000163.

Bosello S, De Luca G, Tolusso B, et al. B cells in systemic sclerosis: a possible target for therapy. Autoimmun Rev. 2011 Aug;10(10):624-30. doi: 10.1016/j.autrev.2011.04.013.

McGonagle D, Tan AL, Madden J, et al. Successful treatment of resis­tant scleroderma-associated interstitial lung disease with rituximab. Rheumatology (Oxford). 2008 Apr;47(4):552-3. doi: 10.1093/rheumatology/kem357.

Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009 Feb;60(2):578-83. doi: 10.1002/art.24249.

Cornec D, Devauchelle-Pensec V, Tobon GJ, Pers JO, Jousse-Joulin S, Saraux A. B cells in Sjogren’s syndrome: from pathophysiology to diagnosis and treatment. J Autoimmun. 2012 Sep;39(3):161-7. doi: 10.1016/j.jaut.2012.05.014.

Carsons SE, Vivino FB, Parke A, et al. Treatment guidelines for rheumatologic manifestations of Sjogren’s syndrome: use of biologic agents, management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res (Hoboken). 2017 Apr;69(4):517-527. doi: 10.1002/acr.22968.

Ostensen M, Forger F. How safe are anti-rheumatic drugs during pregnancy? Curr Opin Pharmacol. 2013 Jun;13(3):470-5. doi: 10.1016/j.coph.2013.03.004.

Klink DT, van Elburg RM, Schreurs MW, van Well GT. Rituximab administration in third trimester of pregnancy suppresses neonatal B-cell development. Clin Dev Immunol. 2008;2008:271363. doi: 10.1155/2008/271363.

Dubey AK, Handu SS, Dubey S, Sharma P, Sharma KK, Ahmed QM. Belimumab: First targeted biological treatment for systemic lupus erythematosus. J Pharmacol Pharmacother. 2011 Oct;2(4):317-9. doi: 10.4103/0976-500X.85930.

Stohl W, Hilbert DM. The discovery and development of belimumab: the anti-BLyS-lupus connection. Nat Biotechnol. 2012 Jan 9;30(1):69-77. doi: 10.1038/nbt.2076.

Kim SS, Kirou KA, Erkan D. Belimumab in systemic lupus erythematosus: an update for clinicians. Ther Adv Chronic Dis. 2012 Jan;3(1):11-23. doi: 10.1177/2040622311424806.

Dhaun N, Kluth DC. Belimumab for systemic lupus erythematosus. Lancet. 2011 Jun 18;377(9783):2079-80; author reply 2080-1. doi: 10.1016/S0140-6736(11)60911-2.

Taylor P, Quattrocchi E, Maletti S, Kurrash R, Peterson J, Chang D. Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial. Ann Rheum Dis. 2011 Dec;70(12):2119-25. doi: 10.1136/ard.2011.151522.

Rigby W, Tony HP, Oelke K, et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a forty-eight-week randomized, doubleblind, placebo-controlled, parallel-group phase III trial. Arthritis Rheum. 2012 Feb;64(2):350-9. doi: 10.1002/art.33317.

Manetta J, Bina H, Ryan P, Fox N, Witcher DR, Kikly K. Generation and characterization of tabalumab, a human monoclonal antibody that neutralizes both soluble and membrane-bound B-cell activating factor. J Inflamm Res. 2014 Aug 20;7:121-31. doi: 10.2147/JIR.S67751.

Genovese MC, Bojin S, Biagini IM, et al. Tabalumab in rheumatoid arthritis patients with an inadequate response to methotrexate and naive to biologic therapy: a phase II, randomized, placebo-controlled trial. Arthritis Rheum. 2013 Apr;65(4):880-9. doi: 10.1002/art.37820.

Schiff M, Combe B, Dörner T, et al. Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-tosevere rheumatoid arthritis and inadequate response to TNF inhibitors: results of a randomised, doubleblind, placebo-controlled, phase 3 study. RMD Open. 2015 Aug 12;1(1):e000037. doi: 10.1136/rmdopen-2014-000037.

Munafo A, Priestley A, Nestorov I, Visich J, Rogge M. Safety, pharmacokinetics and pharmacodynamics of atacicept in healthy volunteers. Eur J Clin Pharmacol. 2007 Jul;63(7):647-56. doi: 10.1007/s00228-007-0311-7.

Stohl W, Chatham W, Weisman M, Furie R, Weinstein A, Mishra N; LBRA01 Study Group. Belimumab (BmAb), a novel fully human monoclonal antibody to B-lymphocyte stimulator (BLyS), selectively modulates B cell subpopulations and immunoglobulins in a heterogeneous rheumatoid arthritis population. Arthritis Rheum. 2005;52 Suppl:S444.

van Vollenboven RF, Kinnman N, Vincent E, Wax S, Bathon J. Atacicept in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate Results of a Phase II, Randomized, Placebo-Controlled Trial. Arthritis Rheum. 2011 Jul;63(7):1782-92. doi: 10.1002/art.30372.

Korhonen R and Moilanen E. Abatacept, a Novel CD80/86–CD28 T Cell Co-stimulation Modulator, in the Treatment of Rheumatoid Arthritis. Basic Clin Pharmacol Toxicol. 2009 Apr;104(4):276-84. doi: 10.1111/j.1742-7843.2009.00375.x.

Cavalli G, Dinarello CA. Anakinra Therapy for Non-cancer Inflammatory Diseases. Front Pharmacol. 2018 Nov 6;9:1157. doi: 10.3389/fphar.2018.01157.

Dayer JM, Feige U, Edwards CK 3rd, Burger D. Anti-interleukin-1 therapy in rheumatic diseases. Curr Opin Rheumatol. 2001 May;13(3):170-6.

Eder C. Mechanisms of interleukin-1beta release. Immunobiology. 2009;214(7):543-53. doi: 10.1016/j.imbio.2008.11.007.

Dhimolea E. Canakinumab. MAbs. 2010 Jan-Feb;2(1):3-13. doi:10.4161/mabs.2.1.10328.

Kishimoto T. IL-6: from laboratory to bedside. Clin Rev Allergy Immunol. 2005 Jun;28(3):177-86. doi: 10.1385/CRIAI:28:3:177.

Cosentyx (secukinumab) highlights of prescribing information. East Hanover (NJ): Novartis Pharmaceuticals Corporation; 2015. Available from:

Leonardi C, Matheson R, Zachariae C, et al. Anti–Interleukin-17 Monoclonal Antibody Ixekizumab in Chronic Plaque Psoriasis. N Engl J Med. 2012 Mar 29;366(13):1190-9. doi: 10.1056/NEJMoa1109997.

Beck KM, Koo J. Brodalumab for the treatment of plaque psoriasis: up-to-date. Expert Opin Biol Ther. 2019 Apr;19(4):287-292. doi: 10.1080/14712598.2019.1579794.

Pinter A, Wilsmann-Theis D, Peitsch WK, Mössner R. Interleukin-17 receptor A blockade with brodalumab in palmoplantar pustular psoriasis: Report on four cases. J Dermatol. 2019 May;46(5):426-430. doi: 10.1111/1346-8138.14815.

Pavelka K, Chon Y, Newmark R, Lin SL, Baumgarther S, Erondu. A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and an inadequate response to methotrexate. J Rheumatol. 2015 Jun;42(6):912-9. doi: 10.3899/jrheum.141271.

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