mrjСовременная ревматологияModern Rheumatology Journal1996-70122310-158XIMA-PRESS, LLC10.14412/1996-7012-2017-3-91-98mrj-781Research ArticleОБЗОРЫREVIEWSBiologic agents in immune-mediated inflammatory rheumatic diseases: current state of the art and clinical practice in RomaniaBiologic agents in immune-mediated inflammatory rheumatic diseases: current state of the art and clinical practice in RomaniaBalanescA.BalanescA.

Strada Dionisie Lupu, nr. 37, Sector 2, Bucharest, Romania

Strada Dionisie Lupu, nr. 37, Sector 2, Bucharest, Romania

DinuBalaD.DinuBalaD.

Strada Dionisie Lupu, nr. 37, Sector 2, Bucharest, Romania

Strada Dionisie Lupu, nr. 37, Sector 2, Bucharest, Romania

dinu.balanescu@yahoo.comDonisanT.DinuBalaD.

Strada Dionisie Lupu, nr. 37, Sector 2, Bucharest, Romania

Strada Dionisie Lupu, nr. 37, Sector 2, Bucharest, RomaniaUniversity of Medicine and Pharmacy «Carol Davila»

University of Medicine and Pharmacy «Carol Davila»РумынияUniversity of Medicine and Pharmacy «Carol Davila»RomaniaUniversity of Medicine and Pharmacy «Carol Davila»РумынияStrada Dionisie Lupu, nr. 37, Sector 2, Bucharest, RomaniaRomania2017260920171139198Copyright © Balanesc A., DinuBala D., Donisan T., 20172017Balanesc A., DinuBala D., Donisan T.Balanesc A., DinuBala D., DinuBala D.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://mrj.ima-press.net/mrj/article/view/781

The article describes a wide spectrum of biological agents for treatment of Immune-mediated inflammatory rheumatic diseases in clinical practice in EU. Pharmacological classification, main characteristics of anti-TNF agents and biologics with another modes of action, as well as the most important results of clinical trials are provided. Authors focused on the use of biological agents in clinical practice in emerging market regions such as Central and Eastern Europe, particularly in Romania, were disparity due to economic and social factors provides challenges to achieving optimal monitoring and physician’s decision making. Such very important points as an adoption of «treat to target» recommendations to local practice, consensus guidelines on the criteria for biological treatment, patient education initiatives, the development of a national patients registry, are discussed.

The article describes a wide spectrum of biological agents for treatment of Immune-mediated inflammatory rheumatic diseases in clinical practice in EU. Pharmacological classification, main characteristics of anti-TNF agents and biologics with another modes of action, as well as the most important results of clinical trials are provided. Authors focused on the use of biological agents in clinical practice in emerging market regions such as Central and Eastern Europe, particularly in Romania, were disparity due to economic and social factors provides challenges to achieving optimal monitoring and physician’s decision making. Such very important points as an adoption of «treat to target» recommendations to local practice, consensus guidelines on the criteria for biological treatment, patient education initiatives, the development of a national patients registry, are discussed.

rheumatic diseasesbiologic agentsclinical practicetreat totargetemerging marketsrheumatic diseasesbiologic agentsclinical practicetreat totargetemerging marketsReferencesBalanescu A. Progrese in tratamentul biologic al bolilor reumatice. In: Gherasim L. Actualitati in medicina interna. Bucuresti: Editura Medicala, 2015;28:739-764.Balanescu A. Progrese in tratamentul biologic al bolilor reumatice. In: Gherasim L. Actualitati in medicina interna. Bucuresti: Editura Medicala, 2015;28:739-764.Choy E, G. P. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344(12):907-916.Choy E, G. P. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344(12):907-916.Dinarelo C, L. M. Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis – a primer for clinicians. Thoussand Oaks C, editor: Amgen Inc; 2000.Dinarelo C, L. M. Proinflammatory and anti-inflammatory cytokines in rheumatoid arthritis – a primer for clinicians. Thoussand Oaks C, editor: Amgen Inc; 2000.Lam J, Abu-Amer Y, Nelson C, Fremont D, Ross F, S. T. Tumour necrosis factor superfamily cytokines and the pathogenesis of inflammatory osteolysis. Ann Rheum Dis 2002;61(suppl II):ii82-83.Lam J, Abu-Amer Y, Nelson C, Fremont D, Ross F, S. T. Tumour necrosis factor superfamily cytokines and the pathogenesis of inflammatory osteolysis. Ann Rheum Dis 2002;61(suppl II):ii82-83.Maini R, St. Clair E, Breedveld F, Furst D, Kalden J, M. W. Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999;354:1932- 1939.Maini R, St. Clair E, Breedveld F, Furst D, Kalden J, M. W. Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999;354:1932- 1939.Maini R, Breedveld F, Kalden J, Smolen J, Furst D, M. W. Sustained improvement over two years in physical function, structural damage, and signs and symotoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004;50:1051-1065.Maini R, Breedveld F, Kalden J, Smolen J, Furst D, M. W. Sustained improvement over two years in physical function, structural damage, and signs and symotoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004;50:1051-1065.Smolen J.S, Han C, Bala M, Maini R.N, Kalden J.R, van der Heijde D, et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti- tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study Arthritis Rheum. 2005;52(4):1020-1030.Smolen J.S, Han C, Bala M, Maini R.N, Kalden J.R, van der Heijde D, et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti- tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study Arthritis Rheum. 2005;52(4):1020-1030.Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2014;Online First, published on January 7, 2014 as 10.1136/annrheumdis-2013-204577.Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2014;Online First, published on January 7, 2014 as 10.1136/annrheumdis-2013-204577.van der Heijde D, Dijkmans B, P. G. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 2005;52:582-591.van der Heijde D, Dijkmans B, P. G. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 2005;52:582-591.Braun J, Landewe R, KG. H. Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: results of a multicentre, randomized, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum. 2006;54:1646-1652.Braun J, Landewe R, KG. H. Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: results of a multicentre, randomized, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum. 2006;54:1646-1652.Goh L, S. A. Update on biologic therapies in ankylosing spondylitis: a literature review. International Journal of Rheumatic Diseases. 2012;15:445-454.Goh L, S. A. Update on biologic therapies in ankylosing spondylitis: a literature review. International Journal of Rheumatic Diseases. 2012;15:445-454.Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov V, L. M. Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study. Ann Rheum Dis 2014;73:101-107.Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov V, L. M. Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study. Ann Rheum Dis 2014;73:101-107.Kavanaugh A, Antoni CE, Gladman D, Wassenberg S, Zhou B, Beutler A, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year. Ann Rheum Dis. 2006;65(8):1038-1043.Kavanaugh A, Antoni CE, Gladman D, Wassenberg S, Zhou B, Beutler A, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year. Ann Rheum Dis. 2006;65(8):1038-1043.Weinblatt M, Keystone E, Furst D, Moreland L, M. W. Adalimumab, a fully human anti- tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitent methotrexate: the ARMADA study. Arthritis Rheum 2003;48:35-45.Weinblatt M, Keystone E, Furst D, Moreland L, M. W. Adalimumab, a fully human anti- tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitent methotrexate: the ARMADA study. Arthritis Rheum 2003;48:35-45.van de Putte L, Atkins C, M. M. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic dryg treatment failed. Ann Rheum Dis. 2004;63:508-516.van de Putte L, Atkins C, M. M. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic dryg treatment failed. Ann Rheum Dis. 2004;63:508-516.Keystone E, Kavanaugh A, J. S. Radiographic, clinical and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis alpha antibody) in patients with active rheumatoid arthritis receiving concomitent methotrexate therapy: a randomised, placebo-controlled 52 week trial. Arthritis Rheum 2004;50:1400-1411.Keystone E, Kavanaugh A, J. S. Radiographic, clinical and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis alpha antibody) in patients with active rheumatoid arthritis receiving concomitent methotrexate therapy: a randomised, placebo-controlled 52 week trial. Arthritis Rheum 2004;50:1400-1411.Weinblatt M, Keystone E, Furst D, Kavanaugh A, Chartash E, O. S. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Intern Med 2006;65:753-759.Weinblatt M, Keystone E, Furst D, Kavanaugh A, Chartash E, O. S. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Intern Med 2006;65:753-759.Breedveld F, Weisman M, Kavanaugh A, S. C. The PREMIER Study: a multicentric, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54:26-37.Breedveld F, Weisman M, Kavanaugh A, S. C. The PREMIER Study: a multicentric, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54:26-37.Van der Heijde D, Kivitz A, MH. S. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, doubleblind, placebocontrolled trial. Arthritis Rheum 2006;54: 2136-2146.Van der Heijde D, Kivitz A, MH. S. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, doubleblind, placebocontrolled trial. Arthritis Rheum 2006;54: 2136-2146.Rudwaleit M, Olivieri I, KA. B. Adalimumab is effective and well tolerated in treating patients with ankylosing spondylitis who have advanced spinal fusion. Rheumatology (Oxford). 2009;48:551-557.Rudwaleit M, Olivieri I, KA. B. Adalimumab is effective and well tolerated in treating patients with ankylosing spondylitis who have advanced spinal fusion. Rheumatology (Oxford). 2009;48:551-557.Sieper J, van der Heijde D, Dougados M, Mease P, Maksymowych W, M. B. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 2013;72: 815-822.Sieper J, van der Heijde D, Dougados M, Mease P, Maksymowych W, M. B. Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 2013;72: 815-822.Keystone EC, Genovese MC, L. K. Golimumab, a human antibody to TNF-α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate:the GO-FORWARD study. Ann Rheum Dis. 2009;68:789-796.Keystone EC, Genovese MC, L. K. Golimumab, a human antibody to TNF-α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate:the GO-FORWARD study. Ann Rheum Dis. 2009;68:789-796.Kay J, M. R. Golimumab: A novel human anti-TNF-α monoclonal antibody for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Arthritis Rheum. 2008;58 (4):964-975.Kay J, M. R. Golimumab: A novel human anti-TNF-α monoclonal antibody for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. Arthritis Rheum. 2008;58 (4):964-975.Inman RD, Davis JC Jr, D. vdH. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 2008;58:3402-3412.Inman RD, Davis JC Jr, D. vdH. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 2008;58:3402-3412.Kavanaugh A, van der Heijde D, McInnes IB, Mease P, Krueger GG, Gladman DD, et al. Golimumab in psoriatic arthritis: one-year clinical efficacy, radiographic, and safety results from a phase III, randomized, placebo-controlled trial. Arthritis Rheum. 2012;64(8):2504- 2517.Kavanaugh A, van der Heijde D, McInnes IB, Mease P, Krueger GG, Gladman DD, et al. Golimumab in psoriatic arthritis: one-year clinical efficacy, radiographic, and safety results from a phase III, randomized, placebo-controlled trial. Arthritis Rheum. 2012;64(8):2504- 2517.Kavanaugh A, McInnes IB, Mease P, Krueger GG, Gladman D, van der Heijde D, et al. Clinical efficacy, radiographic and safety findings through 5 years of subcutaneous golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of a randomised, placebo-controlled trial (the GO-REVEAL study). Ann Rheum Dis. 2014;[Epub ahead of print].Kavanaugh A, McInnes IB, Mease P, Krueger GG, Gladman D, van der Heijde D, et al. Clinical efficacy, radiographic and safety findings through 5 years of subcutaneous golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of a randomised, placebo-controlled trial (the GO-REVEAL study). Ann Rheum Dis. 2014;[Epub ahead of print].McDonnell T, Ioannou Y, A. R. PEGylated drugs in rheumatology-why develop them and do they work? Rheumatology (Oxford). 2014;53(3):391-396.McDonnell T, Ioannou Y, A. R. PEGylated drugs in rheumatology-why develop them and do they work? Rheumatology (Oxford). 2014;53(3):391-396.Keystone E, van den Heijde D, D M. Certolizumab Pegol Plus Methotrexate Is Significantly More Effective Than Placebo Plus Methotrexate In Active Rheumatoid Arthritis. Arthritis & Rheum. 2008;58;11: 3319-3329.Keystone E, van den Heijde D, D M. Certolizumab Pegol Plus Methotrexate Is Significantly More Effective Than Placebo Plus Methotrexate In Active Rheumatoid Arthritis. Arthritis & Rheum. 2008;58;11: 3319-3329.Smolen J, Landewe R, P. M. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis. 2009;68:797-804.Smolen J, Landewe R, P. M. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis. 2009;68:797-804.Fleischmann R, Vencovsky J, RF. vV. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous diseasemodifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis. 2009;68:805-811.Fleischmann R, Vencovsky J, RF. vV. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous diseasemodifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis. 2009;68:805-811.Landewe R, J B, Deodhar A, Dougados M, Maksymowych W, P. M. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled phase 3 study. Ann Rheum Dis 2014;73:39-47.Landewe R, J B, Deodhar A, Dougados M, Maksymowych W, P. M. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled phase 3 study. Ann Rheum Dis 2014;73:39-47.Mease PJ, Fleischmann R, Deodhar AA, Wollenhaupt J, Khraishi M, Kielar D, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24 week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA). Ann Rheum Dis. 2014;73(1): 48-55.Mease PJ, Fleischmann R, Deodhar AA, Wollenhaupt J, Khraishi M, Kielar D, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24 week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA). Ann Rheum Dis. 2014;73(1): 48-55.Klareskog L, van der Heijde D, J. dJ. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized trial. Lancet 2004;363:675-681.Klareskog L, van der Heijde D, J. dJ. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized trial. Lancet 2004;363:675-681.Emery P, Breedveld F, van der Heijde D, Ferraccioli G, Dougados M, Robertson D, et al. Two-Year Clinical and Radiographic Results With Combination Etanercept- Methotrexate Therapy Versus Monotherapy in Early Rheumatoid Arthritis. Arthritis & Rheum. 2010;62:674- 682.Emery P, Breedveld F, van der Heijde D, Ferraccioli G, Dougados M, Robertson D, et al. Two-Year Clinical and Radiographic Results With Combination Etanercept- Methotrexate Therapy Versus Monotherapy in Early Rheumatoid Arthritis. Arthritis & Rheum. 2010;62:674- 682.Canete J, J. P. Biologic Therapy in Rheumatoid Arthritis. Current Topics in Medicinal Chemistry. 2013;13:752-759.Canete J, J. P. Biologic Therapy in Rheumatoid Arthritis. Current Topics in Medicinal Chemistry. 2013;13:752-759.Dougados M, Braun J, S. S. Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised doubleblind placebo-controlled study (SPINE). Ann Rheum Dis 2011;70(799-804).Dougados M, Braun J, S. S. Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised doubleblind placebo-controlled study (SPINE). Ann Rheum Dis 2011;70(799-804).Song I, Weib A, Hermann K, Haibel H, Althoff C, D. P. Similar response rates in patients with ankylosing spondylitis and nonradiographic axial spondyloarthritis after 1 year of treatment with etanercept: results from the ESTHER trial. Ann Rheum Dis 2013;7:823-825.Song I, Weib A, Hermann K, Haibel H, Althoff C, D. P. Similar response rates in patients with ankylosing spondylitis and nonradiographic axial spondyloarthritis after 1 year of treatment with etanercept: results from the ESTHER trial. Ann Rheum Dis 2013;7:823-825.Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, DJ. B. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000;29;356(9227): 385-390.Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, DJ. B. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000;29;356(9227): 385-390.Sterry W, Ortonne JP, B. K. Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis: PRESTA randomized double blind multicentre trial. BMJ 2010;340:C147.Sterry W, Ortonne JP, B. K. Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis: PRESTA randomized double blind multicentre trial. BMJ 2010;340:C147.Bruner V, Atteno M, Spano A, Scarpa R, R. P. Biological therapies for spondyloarthritis. Ther Adv Musculoskel Dis. 2014; 6(3) 92-101.Bruner V, Atteno M, Spano A, Scarpa R, R. P. Biological therapies for spondyloarthritis. Ther Adv Musculoskel Dis. 2014; 6(3) 92-101.Miserocchi E, Modorati G, Pontikaki I, Meroni P, V. G. Long-term treatment with golimumab for severe uveitis. Ocul Immunol Inflamm. 2013:(Epub ahead of print).Miserocchi E, Modorati G, Pontikaki I, Meroni P, V. G. Long-term treatment with golimumab for severe uveitis. Ocul Immunol Inflamm. 2013:(Epub ahead of print).Ramiro S, Gaujoux-Viala C, Nam J, Smolen J, Buch M, Gossec L, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2014;73:529- 535.Ramiro S, Gaujoux-Viala C, Nam J, Smolen J, Buch M, Gossec L, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2014;73:529- 535.Rueda Gotor J, R. BA. Tocilizumab in rheumatoid arthritis. Reumatol Clin. 2011;6S3: S29-32.Rueda Gotor J, R. BA. Tocilizumab in rheumatoid arthritis. Reumatol Clin. 2011;6S3: S29-32.Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010; 69(1):88-96.Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010; 69(1):88-96.Kaufmann J, Feist E, Roske AE, WA. S. Monotherapy with tocilizumab or TNF-alpha inhibitors in patients with rheumatoid arthritis: efficacy, treatment satisfaction, and persistence in routine clinical practice. Clin Rheumatol. 2013;May 24. [Epub ahead of print].Kaufmann J, Feist E, Roske AE, WA. S. Monotherapy with tocilizumab or TNF-alpha inhibitors in patients with rheumatoid arthritis: efficacy, treatment satisfaction, and persistence in routine clinical practice. Clin Rheumatol. 2013;May 24. [Epub ahead of print].Smolen J, Landewe R, F B. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73:492-509.Smolen J, Landewe R, F B. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73:492-509.Meier F, Frerix M, Hermann M, U. Ml-L. Current immunotherapy in rheumatoid arthritis. Immunotherapy. 2013;5(9):955-974.Meier F, Frerix M, Hermann M, U. Ml-L. Current immunotherapy in rheumatoid arthritis. Immunotherapy. 2013;5(9):955-974.Baeten D, Sieper J, Braun J, et al. Secukinumab, interleukin-17A inhibition in ankylosing spondylitis. N Engl J Med. 2015; 373:2534-48.Baeten D, Sieper J, Braun J, et al. Secukinumab, interleukin-17A inhibition in ankylosing spondylitis. N Engl J Med. 2015; 373:2534-48.Mease PJ, McInnes IB, Kirkham B, et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med. 2015; 373(14):1329-39.Mease PJ, McInnes IB, Kirkham B, et al. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med. 2015; 373(14):1329-39.Ritchlin C, Rahman P, Kavanaugh A, McInnes IB, Puig L, Li S, et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional nonbiological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo- controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014;73(6):990-999.Ritchlin C, Rahman P, Kavanaugh A, McInnes IB, Puig L, Li S, et al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional nonbiological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo- controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. 2014;73(6):990-999.Caporali R, Bugatti S, Cavagna L, Antivalle M, P. S-P. Modulating the co-stimulatory signal for T cell activation in rheumatoid arthritis: Could it be the first step of the treatment? Autoimmunity Reviews 2014; 13:49-53.Caporali R, Bugatti S, Cavagna L, Antivalle M, P. S-P. Modulating the co-stimulatory signal for T cell activation in rheumatoid arthritis: Could it be the first step of the treatment? Autoimmunity Reviews 2014; 13:49-53.Weinblatt ME, Schiff M, R. V. Headto-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a Phase IIIb, multinational, prospective, randomized study. Arthritis Rheum. 2013;65(1):28-38.Weinblatt ME, Schiff M, R. V. Headto-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a Phase IIIb, multinational, prospective, randomized study. Arthritis Rheum. 2013;65(1):28-38.Edwards J, G. C. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocyte. Rheumatology (Oxford) 2001;40:205-211.Edwards J, G. C. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocyte. Rheumatology (Oxford) 2001;40:205-211.Edwards J, Szczepanski A, P. E. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-2581.Edwards J, Szczepanski A, P. E. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-2581.Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, A. K. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIb double-blind, placebo-controlled, doseranging trial (DANCER). Arthritis Rheum 2006;54:1390-1400.Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, A. K. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIb double-blind, placebo-controlled, doseranging trial (DANCER). Arthritis Rheum 2006;54:1390-1400.Ding HJ, C. G. New biologic therapy for systemic lupus erythematosus. Current Opinion in Pharmacology 2013;13:405-412.Ding HJ, C. G. New biologic therapy for systemic lupus erythematosus. Current Opinion in Pharmacology 2013;13:405-412.FDA. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm251946.htm. 2011.FDA. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm251946.htm. 2011.Stone JH, Merkel PA, R. S. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363: 221-232.Stone JH, Merkel PA, R. S. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363: 221-232.Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, et al. Efficacy of remission-induction regimens for ANCAassociated vasculitis. N Engl J Med. 2013; 369(5):417-427.Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, et al. Efficacy of remission-induction regimens for ANCAassociated vasculitis. N Engl J Med. 2013; 369(5):417-427.FDA. "FDA approves Benlysta to treat lupus" (Press release). U.S. Food and Drug Administration (FDA). March 9, 2011. 2011.FDA. "FDA approves Benlysta to treat lupus" (Press release). U.S. Food and Drug Administration (FDA). March 9, 2011. 2011.Schneider P. The role of APRIL and BAFF in lymphocyte activation. Curr Opin Immunol. 2005;17 (3):282-289.Schneider P. The role of APRIL and BAFF in lymphocyte activation. Curr Opin Immunol. 2005;17 (3):282-289.Navarra SV, Guzma RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:721-731.Navarra SV, Guzma RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011;377:721-731.Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, 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.Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, 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.Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;0:1-18. doi:10.1136/annrheumdis-2016-210715Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological diseasemodifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;0:1-18. doi:10.1136/annrheumdis-2016-210715Balanescu A, Wiland P. Maximizing early treatment with biologics in patients with rheumatoid arthritis: the ultimate breakthrough in joints preservation. Rheumatol Int. 2013 Jun;33(6):1379-86.Balanescu A, Wiland P. Maximizing early treatment with biologics in patients with rheumatoid arthritis: the ultimate breakthrough in joints preservation. Rheumatol Int. 2013 Jun;33(6):1379-86.Codreanu C, Mogosanu C, Ionescu R, Ancuta I, Opris, D. Biologic Therapy In Rheumatoid Arthritis: Results From The Romanian Registry Of Rheumatic Diseases One Year After Initiation. Farmacia. 2014; 62(6):1089-96.Codreanu C, Mogosanu C, Ionescu R, Ancuta I, Opris, D. Biologic Therapy In Rheumatoid Arthritis: Results From The Romanian Registry Of Rheumatic Diseases One Year After Initiation. Farmacia. 2014; 62(6):1089-96.Ionescu R. Oral communication, «The Romanian Registry Of Rheumatic Diseases» Annual Meeting, Bucharest, 2 March 2017.Ionescu R. Oral communication, «The Romanian Registry Of Rheumatic Diseases» Annual Meeting, Bucharest, 2 March 2017.Ordinul MSP/ CNAS nr. 1301/ 500/ 2008 pentru aprobarea protocoalelor terapeutice privind prescrierea medicamentelor. Retrieved from http://www.cnas.ro/casnt/post/ordinul-msp-cnas-nr-1301-500-2008-pentru-aprobarea-protocoalelor-terapeuticeprivind-prescrierea-med.html.Ordinul MSP/ CNAS nr. 1301/ 500/ 2008 pentru aprobarea protocoalelor terapeutice privind prescrierea medicamentelor. Retrieved from http://www.cnas.ro/casnt/post/ordinul-msp-cnas-nr-1301-500-2008-pentru-aprobarea-protocoalelor-terapeuticeprivind-prescrierea-med.html.Ordinul nr 141/2017. Retrieved from http://amfms.ro/ordinul-nr-1412017/.Ordinul nr 141/2017. Retrieved from http://amfms.ro/ordinul-nr-1412017/.Retrieved from http://www.ms.ro/wpcontent/uploads/2017/02/Ordin-protocoale-2017Anexa.pdf.Retrieved from http://www.ms.ro/wpcontent/uploads/2017/02/Ordin-protocoale-2017Anexa.pdf.Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force Ann Rheum Dis 2016;75:3-15.Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force Ann Rheum Dis 2016;75:3-15.

The authors declare that there are no conflicts of interest present.