Etanercept or Methotrexate Withdrawal in Rheumatoid Arthritis Patients in Sustained Remission
Jeffrey R Curtis, Paul Emery, Elaine Karis, Boulos Haraoui, Vivian Bykerk, Priscilla K Yen, Greg Kricorian, James B Chung, Jeffrey R Curtis, Paul Emery, Elaine Karis, Boulos Haraoui, Vivian Bykerk, Priscilla K Yen, Greg Kricorian, James B Chung
Abstract
Objective: Patients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination.
Methods: Of the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24-week open-label period. These 253 patients then entered a 48-week, double-blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease-worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run-in period. The primary end point was the proportion of patients in whom SDAI-defined remission was maintained without disease-worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease-worsening, and the proportion of patients in whom SDAI-defined remission was recaptured after initiation of rescue therapy.
Results: Baseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI-defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI-defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease-worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI-defined remission was recaptured in 70-80% in each treatment group. No new safety signals were reported.
Conclusion: The efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI-defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision-making when withdrawal of therapy is being considered to reduce treatment burden in patients with well-controlled RA.
Trial registration: ClinicalTrials.gov NCT02373813.
© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
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References
- Hamann P, Holland R, Hyrich K, Pauling JD, Shaddick G, Nightingale A, et al. Factors associated with sustained remission in rheumatoid arthritis in patients treated with anti–tumor necrosis factor. Arthritis Care Res (Hoboken) 2017;69:783–93.
- Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA 2018;320:1360–72.
- Edwards CJ, Galeazzi M, Bellinvia S, Ringer A, Dimitroulas T, Kitas G. Can we wean patients with inflammatory arthritis from biological therapies? [review]. Autoimmun Rev 2019;18:102399.
- Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, 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;363:675–81.
- Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, 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;54:26–37.
- Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al, on behalf of the Anti‐Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group . Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594–602.
- Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2016; 68:1–26.
- Smolen JS, Landewe RB, Bijlsma JW, Burmester GR, Dougados M, Kerschbaumer A, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease‐modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020;79:685–99.
- Treharne GJ, Douglas KM, Iwaszko J, Panoulas VF, Hale ED, Mitton DL, et al. Polypharmacy among people with rheumatoid arthritis: the role of age, disease duration and comorbidity. Musculoskeletal Care 2007;5:175–90.
- Wang W, Zhou H, Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur J Med Chem 2018;158:502–16.
- Pope JE, Haraoui B, Thorne JC, Vieira A, Poulin‐Costello M, Keystone EC. The Canadian Methotrexate and Etanercept Outcome Study: a randomised trial of discontinuing versus continuing methotrexate after 6 months of etanercept and methotrexate therapy in rheumatoid arthritis. Ann Rheum Dis 2014;73:2144–51.
- Smolen JS, Nash P, Durez P, Hall S, Ilivanova E, Irazoque‐Palazuelos F, 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;381:918–29.
- Van Vollenhoven RF, Ostergaard M, Leirisalo‐Repo M, Uhlig T, Jansson M, Larsson E, et al. Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis 2016;75:52–8.
- Emery P, Hammoudeh M, FitzGerald O, Combe B, Martin‐Mola E, Buch MH, et al. Sustained remission with etanercept tapering in early rheumatoid arthritis. N Engl J Med 2014;371:1781–92.
- Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double‐blind, parallel treatment trial. Lancet 2008;372:375–82.
- 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: a two‐year, double‐blind, randomized study. Arthritis Rheum 2010;62:674–82.
- Prince FH, Bykerk VP, Shadick NA, Lu B, Cui J, Frits M, et al. Sustained rheumatoid arthritis remission is uncommon in clinical practice. Arthritis Res Ther 2012;14:R68.
- Ajeganova S, Huizinga T. Sustained remission in rheumatoid arthritis: latest evidence and clinical considerations. Ther Adv Musculoskelet Dis 2017;9:249–62.
- Curtis JR, Trivedi M, Haraoui B, Emery P, Park GS, Collier DH, et al. Defining and characterizing sustained remission in patients with rheumatoid arthritis. Clin Rheumatol 2018;37:885–93.
- Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003;42:244–57.
- Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 2011;63:573–86.
- Enbrel (etanercept) prescribing information. Thousand Oaks (CA): Immunex; 2017.
- Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569–81.
- Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23:137–45.
- Van der Heijde D. Radiographic progression in rheumatoid arthritis: does it reflect outcome? Does it reflect treatment? Ann Rheum Dis 2001;60 Suppl 3:iii47–50.
- Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two‐year radiographic and clinical outcomes. Arthritis Rheum 2002;46:1443–50.
- Van der Heijde D, Klareskog L, Landewé R, Bruyn GA, Cantagrel A, Durez P, et al. Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 2007;56:3928–39.
- US Food and Drug Administration . Guidance document: rheumatoid arthritis–developing drug products for treatment. May 2013. URL: .
- Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al. Low‐dose methotrexate for the prevention of atherosclerotic events. N Engl J Med 2019;380:752–62.
- Jani M, Barton A, Warren RB, Griffiths CE, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford) 2014; 53:213–22.
- Fagerli KM, Lie E, van der Heijde D, Heiberg MS, Lexberg AS, Rodevand E, et al. The role of methotrexate co‐medication in TNF‐inhibitor treatment in patients with psoriatic arthritis: results from 440 patients included in the NOR‐DMARD study. Ann Rheum Dis 2014;73:132–7.
- Favalli EG, Pregnolato F, Biggioggero M, Becciolini A, Penatti AE, Marchesoni A, et al. Twelve‐year retention rate of first‐line tumor necrosis factor inhibitors in rheumatoid arthritis: real‐life data from a local registry. Arthritis Care Res (Hoboken) 2016;68:432–9.
- Emery P, Vlahos B, Szczypa P, Thakur M, Jones HE, Woolcott J, et al. Longterm drug survival of tumor necrosis factor inhibitors in patients with rheumatoid arthritis. J Rheumatol 2020;47:493–501.
- Pappas DA, Litman HJ, Lesperance T, Kricorian G, Karis E, Rebello S, et al. Persistence on biologic DMARD monotherapy after achieving rheumatoid arthritis disease control on combination therapy: retrospective analysis of CORRONA registry data. Rheumatol Int 2021;41:381–90.
Source: PubMed