Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy
- Stanley Cohen, MD
Stanley Cohen, MD
- Clinical Professor of Medicine
- University of Texas Southwestern Medical School
- Amy Cannella, MD, MS, RhMSUS
Amy Cannella, MD, MS, RhMSUS
- Associate Professor of Internal Medicine
- Rheumatology Fellowship Program Director
- University of Nebraska Medical Center
The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint injury. In patients with disease resistant to methotrexate (MTX) monotherapy, and whose condition is also resistant to treatment with an initial course of biologic disease-modifying antirheumatic drug (DMARD), usually a tumor necrosis (TNF) inhibitor, typically administered in combination with MTX, timely adjustments in the treatment regimen are required to achieve effective disease control and to prevent damage to the joints. The achievement and maintenance of tight control of disease by use of DMARDs is associated with improved outcomes, as these medications and strategies have the potential to control synovitis and to slow or even stop radiographic progression [1-11]. (See "General principles of management of rheumatoid arthritis in adults", section on 'Tight control'.)
The treatment of active RA in adults who are resistant to initial therapy with a biologic DMARD, usually a TNF inhibitor in the context of ongoing treatment with MTX, will be reviewed here. The general principles of the management of RA, the initial treatment of RA, the treatment of patients resistant to initial therapy with nonbiologic DMARDs (eg, MTX monotherapy), and the approach to RA patients with severe structural damage are presented separately. (See "General principles of management of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "Total joint replacement for severe rheumatoid arthritis" and "Evaluation and medical management of end-stage rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
GENERAL PRINCIPLES AND APPROACH
Principles of management — There are several general principles that are important in the management of all patients with rheumatoid arthritis (RA). Briefly, these include:
●Achievement and maintenance of tight control of disease activity, defined as remission or a state of low disease activity, without compromising safety
●Treatment of all patients diagnosed with RA with disease-modifying antirheumatic drug (DMARD) therapy
- Schoels M, Knevel R, Aletaha D, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis 2010; 69:638.
- Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005; 52:3381.
- Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007; 146:406.
- de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, et al. Progression of joint damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies. Arthritis Rheum 2008; 58:1293.
- Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 1999; 353:1568.
- Puolakka K, Kautiainen H, Möttönen T, et al. Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis: a five-year randomized followup trial. Arthritis Rheum 2004; 50:55.
- Rantalaiho V, Korpela M, Hannonen P, et al. The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial. Arthritis Rheum 2009; 60:1222.
- Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004; 364:263.
- Verstappen SM, Jacobs JW, van der Veen MJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis 2007; 66:1443.
- Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001; 358:903.
- Sokka T, Kautiainen H, Häkkinen A, Hannonen P. Radiographic progression is getting milder in patients with early rheumatoid arthritis. Results of 3 cohorts over 5 years. J Rheumatol 2004; 31:1073.
- O'Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med 2013; 369:307.
- Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012; 64:625.
- van Vollenhoven RF. Switching between anti-tumour necrosis factors: trying to get a handle on a complex issue. Ann Rheum Dis 2007; 66:849.
- 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; 374:210.
- Furst DE, Gaylis N, Bray V, et al. Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study. Ann Rheum Dis 2007; 66:893.
- Hyrich KL, Lunt M, Watson KD, et al. Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum 2007; 56:13.
- Karlsson JA, Kristensen LE, Kapetanovic MC, et al. Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology (Oxford) 2008; 47:507.
- Finckh A, Ciurea A, Brulhart L, et al. Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent? Ann Rheum Dis 2010; 69:387.
- Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005; 353:1114.
- 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; 54:2793.
- 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; 67:1516.
- 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; 54:1390.
- Emery P. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment. Rheumatology (Oxford) 2012; 51 Suppl 5:v22.
- Salliot C, Finckh A, Katchamart W, et al. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumour necrosis factor agent: a meta-analysis. Ann Rheum Dis 2011; 70:266.
- Schoels M, Aletaha D, Smolen JS, Wong JB. Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: systematic review and indirect pairwise meta-analysis. Ann Rheum Dis 2012; 71:1303.
- Emery P, Gottenberg JE, Rubbert-Roth A, et al. Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis who failed to respond to a single previous TNF inhibitor: SWITCH-RA, a global, observational, comparative effectiveness study. Ann Rheum Dis 2015; 74:979.
- Soliman MM, Hyrich KL, Lunt M, et al. Rituximab or a second anti-tumor necrosis factor therapy for rheumatoid arthritis patients who have failed their first anti-tumor necrosis factor therapy? Comparative analysis from the British Society for Rheumatology Biologics Register. Arthritis Care Res (Hoboken) 2012; 64:1108.
- Blake T, Rao V, Hashmi T, et al. The perplexity of prescribing and switching of biologic drugs in rheumatoid arthritis: a UK regional audit of practice. BMC Musculoskelet Disord 2014; 15:290.
- Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev 2011; :CD008794.
- Yun H, Xie F, Delzell E, et al. Comparative Risk of Hospitalized Infection Associated With Biologic Agents in Rheumatoid Arthritis Patients Enrolled in Medicare. Arthritis Rheumatol 2016; 68:56.
- Isaacs JD, Cohen SB, Emery P, et al. Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis. Ann Rheum Dis 2013; 72:329.
- Chatzidionysiou K, Lie E, Nasonov E, et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann Rheum Dis 2011; 70:1575.
- Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev 2009; :CD007848.
- Cohen S, Radominski SC, Gomez-Reino JJ, et al. Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol 2014; 66:2924.
- Singh JA, Christensen R, Wells GA, et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 2009; 181:787.
- Schiff M, Pritchard C, Huffstutter JE, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis 2009; 68:1708.
- Burmester GR, Rubbert-Roth A, Cantagrel A, et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis 2014; 73:69.
- 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; 381:1541.
- Gabay C, Riek M, Hetland ML, et al. Effectiveness of tocilizumab with and without synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis: results from a European collaborative study. Ann Rheum Dis 2016; 75:1336.
- Mease PJ, Cohen S, Gaylis NB, et al. Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors: results from the SUNRISE trial. J Rheumatol 2010; 37:917.
- Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012; 367:495.
- van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367:508.
- van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum 2013; 65:559.
- Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 2013; 381:451.
- Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 2013; 159:253.
- Charles-Schoeman C, Burmester G, Nash P, et al. Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2016; 75:1293.
- Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014; 370:2377.
- Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009; 60:1895.
- Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken) 2011; 63:1150.
- Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012; 64:617.
- Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol 2014; 66:2675.
- Jain R, Lipsky PE. Treatment of rheumatoid arthritis. Med Clin North Am 1997; 81:57.
- Guidelines for the management of rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39:713.
- Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39:723.
- ten Wolde S, Breedveld FC, Hermans J, et al. Randomised placebo-controlled study of stopping second-line drugs in rheumatoid arthritis. Lancet 1996; 347:347.
- Tiippana-Kinnunen T, Paimela L, Kautiainen H, et al. Can disease-modifying anti-rheumatic drugs be discontinued in long-standing rheumatoid arthritis? A 15-year follow-up. Scand J Rheumatol 2010; 39:12.
- Goekoop-Ruiterman YP, Huizinga TW. Rheumatoid arthritis: can we achieve true drug-free remission in patients with RA? Nat Rev Rheumatol 2010; 6:68.
- O'Mahony R, Richards A, Deighton C, Scott D. Withdrawal of disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2010; 69:1823.
- Berthelot JM, Varin S. Is dosage reduction appropriate in patients who respond well to anti-TNF-alpha agents? Joint Bone Spine 2004; 71:257.
- McCarty DJ, Harman JG, Grassanovich JL, et al. Combination drug therapy of seropositive rheumatoid arthritis. J Rheumatol 1995; 22:1636.
- GENERAL PRINCIPLES AND APPROACH
- Principles of management
- Definition of resistance to DMARDs
- Nonpharmacologic and preventive therapies
- PRETREATMENT INTERVENTIONS
- Approach to pharmacotherapy
- Resistant to one TNF inhibitor
- Resistant to two TNF inhibitors
- - Choice of therapy
- - Drug dosing, efficacy, and safety
- Resistant to standard therapies
- REEVALUATION AND MONITORING
- SYMPTOMATIC DRUG THERAPY
- Antiinflammatory therapy
- Drug therapy for flares
- DURATION OF THERAPY
- SPECIAL POPULATIONS
- Resource-poor settings
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS