Summary
Since the introduction of tumor necrosis factor (TNF)-α inhibitors, the treatment of rheumatoid arthritis (RA) has been revolutionized. The approach of targeting TNF-α has considerably improved the success in the treatment of RA. Over the last 3 decades five different TNF-α inhibitors have been administered: infliximab, etanercept, adalimumab, golimumab, and certolizumab-pegol. All of them show excellent efficacy with similar rates of clinical response and prevention of radiographic disease progression. With improved therapies, treatment strategies have also changed, with the aims now being to achieve and maintain remission. Most recently, the discussion expands to the issue of treatment reduction in patients who have achieved sustained remission; here, the discontinuation of TNF-α inhibitor therapy has become an area of interest, given obvious economic and risk-benefit evaluations. However, only little is known if “biologic free” remission is possible in patients with sustained remission following intensive TNF-α inhibitor therapy.
Zusammenfassung
Die Entdeckung und Einführung von Tumor-Nekrosis-Faktor Alpha (TNF-α) Blockern hat die Therapie der Rheumatoiden Arthritis (RA) revolutioniert. Der direkte Therapieansatz am Zytokine TNF-α führte zu beachtlichen Erfolgen und Ansteigen von Remissionsraten. Innerhalb der letzten drei Dekaden wurden fünf verschiedene TNF-α Blocker entwickelt und am Markt eingeführt: Infliximab (IFX), Adalimumab (ADA), Etanercept (ETN), Golimumab (GLM) und Certolizumab Pegol (CZP). Alle diese Medikamente zeigen ausgezeichnete Effektivität mit vergleichbaren Erfolgsraten betreffend klinischer Aktivität und radiologischer Progression. Durch Verbesserung der Therapeutika kam es schlussendlich zu Adaptierung und Optimierung von Therapiestrategien, mit Erreichen und Erhalten von Remission als oberstes Therapieziel. Da dauerhafte Remission mittlerweile ein realistisches Szenario darstellt, und in Anbetracht sozio-ökonomischer und Nutzen-Risiko Überlegungen beschäftigen sich neuere Arbeiten mit dem Thema der Therapiereduktion in dieser Patientenpopulation. Bis dato ist allerdings nur wenig darüber bekannt, ob „biologika- freie“ Remission in Patienten mit vorangegangener intensiver TNF-α Therapie eine Möglichkeit darstellt.
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References
Spector TD. Rheumatoid arthritis. Rheum Dis Clin North Am. 1990;16(3):513–37.
Kobelt G, Woronoff AS, Richard B, et al. Disease status, costs and quality of life of patients with rheumatoid arthritis in France: the ECO-PR Study. Joint Bone Spine. 2008;75(4):408–15.
Pugner KM, Scott DI, Holmes JW, et al. The costs of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum. 2000;29(5):305–20.
Bluml S, Scheinecker C, Smolen JS, et al. Targeting TNF receptors in rheumatoid arthritis. Int Immunol. 2012;24(5):275–81.
Feldmann M, Maini RN. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med. 2003;9(10):1245–50.
Di Giovine FS, Nuki G, Duff GW. Tumour necrosis factor in synovial exudates. Ann Rheum Dis. 1988;47(9):768–72.
Tracey D, Klareskog L, Sasso EH, et al. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244–79.
Azuma Y, Kaji K, Katogi R, et al. Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem. 2000;275(7):4858–64.
Smolen JS, Han C, Bala M, 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):1020–30.
Maini RN, Breedveld FC, Kalden JR, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004;50(4):1051–65.
Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594–602.
Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, 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(1):26–37.
Kavanaugh A, Fleischmann RM, Emery P, et al. Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis. 2013;72(1):64–71.
Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50(5):1400–11.
Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337(3):141–7.
Weinblatt ME, Schiff MH, Ruderman EM, et al. Efficacy and safety of etanercept 50 mg twice a week in patients with rheumatoid arthritis who had a suboptimal response to etanercept 50 mg once a week: results of a multicenter, randomized, double-blind, active drug-controlled study. Arthritis Rheum. 2008;58(7):1921–30.
Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363(9410):675–81.
Smolen JS, Nash P, Durez P, et al. Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet. 2013;381(9870):918–29.
Emery P, Fleischmann RM, Moreland LW, et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum. 2009;60(8):2272–83.
Keystone E, Genovese MC, Klareskog L, et al. Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52-week results of the GO-FORWARD study. Ann Rheum Dis. 2010;69(6):1129–35.
Smolen JS, Kay J, Doyle MK, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet. 2009;374(9685):210–21.
Pasut G. Pegylation of biological molecules and potential benefits: pharmacological properties of certolizumab pegol. BioDrugs. 2014;28(Suppl 1):15–23.
Keystone E, Heijde D, Mason D, Jr. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 2008;58(11):3319–29.
Smolen J, Landewe RB, Mease P, et al. 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(6):797–804.
Fleischmann R, Vencovsky J, van Vollenhoven RF, et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis. 2009;68(6):805–11.
Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370(9602):1861–74.
Hetland ML, Christensen IJ, Tarp U, et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum. 2010;62(1):22–32.
Singh JA, Christensen R, Wells GA. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2009(4):CD007848.
Aaltonen KJ, Virkki LM, Malmivaara A, et al. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One. 2012;7(1):e30275.
Schiff M, Weinblatt ME, Valente R, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann Rheum Dis. 2014;73(1):86–94.
Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541–50.
Pascual-Salcedo D, Plasencia C, Ramiro S, et al. Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology. 2011;50(8):1445–52.
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;54(3):711–5.
Krieckaert C, Rispens T, Wolbink G. Immunogenicity of biological therapeutics: from assay to patient. Curr Opin Rheumatol. 2012;24(3):306–11.
Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr Opin Rheumatol. 2009;21(3):211–5.
Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631–7.
Felson DT, Smolen JS, Wells G. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70(3):404–13.
Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492–509.
Allaart CF, Breedveld FC, Dijkmans BA. Treatment of recent-onset rheumatoid arthritis: lessons from the BeSt study. J Rheumatol Suppl. 2007;80:25–33.
van der Kooij SM, le Cessie S, Goekoop-Ruiterman YP, et al. Clinical and radiological efficacy of initial vs delayed treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis. Ann Rheum Dis. 2009;68(7):1153–8.
Cohen SB, Emery P, Greenwald MW, et al. 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):2793–806.
Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353(11):1114–23.
Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–23.
Nam JL, Winthrop KL, van Vollenhoven RF, et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis. 2010;69(6):976–86.
Rendas-Baum R, Wallenstein GV, Koncz T, et al. Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-alpha inhibitors. Arthritis Res Ther. 2011;13(1):R25.
Tanaka Y, Hirata S, Kubo S, et al. Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. Ann Rheum Dis. 2015;74:389–95.
Herrak P, Gortz B, Hayer S, et al. Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis. Arthritis Rheum. 2004;50(7):2327–37.
Ji H, Pettit A, Ohmura K, et al. Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis. J Exp Med. 2002;196(1):77–85.
Tanaka Y, Hirata S, Saleem B, et al. Discontinuation of biologics in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2013;31(4 Suppl 78):S22–7.
Brocq O, Millasseau E, Albert C, et al. Effect of discontinuing TNFalpha antagonist therapy in patients with remission of rheumatoid arthritis. Joint Bone Spine. 2009;76(4):350–5.
Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72(10):1613–20.
Todoerti M, De Nard F, Boffini N, et al. Biosimilars: lights and shadows in rheumatology. Rheumatology Reports. 2014;6:5518–21.
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Radner, H., Aletaha, D. Anti-TNF in rheumatoid arthritis: an overview. Wien Med Wochenschr 165, 3–9 (2015). https://doi.org/10.1007/s10354-015-0344-y
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DOI: https://doi.org/10.1007/s10354-015-0344-y