Treatment efficacy and methotrexate-related toxicity in patients with rheumatoid arthritis receiving methotrexate in combination with adalimumab

Gerd R Burmester, Gurjit S Kaeley, Arthur F Kavanaugh, Cem Gabay, Daryl K MacCarter, Peter Nash, Tsutomu Takeuchi, Sandra L Goss, Ramona Rodila, Kun Chen, Hartmut Kupper, Jasmina Kalabic, Gerd R Burmester, Gurjit S Kaeley, Arthur F Kavanaugh, Cem Gabay, Daryl K MacCarter, Peter Nash, Tsutomu Takeuchi, Sandra L Goss, Ramona Rodila, Kun Chen, Hartmut Kupper, Jasmina Kalabic

Abstract

Background: Treatment of rheumatoid arthritis (RA) with a combination of methotrexate (MTX)+adalimumab (ADA) is more effective than ADA monotherapy. We assessed the toxicity of different doses of MTX and treatment efficacy of ADA+MTX in two trials.

Methods: Data originated from CONCERTO, in patients with early RA initiating ADA+ 2.5, 5, 10 or 20 mg/week MTX for 26 weeks; and MUSICA, in patients with an inadequate response to MTX initiating ADA+ 7.5 or 20 mg/week MTX for 24 weeks. Efficacy was assessed by the American College of Rheumatology 50 (ACR50). Patient-reported MTX-related toxicity information was collected at each visit on 18 prespecified MTX-related adverse events (AE) in the MTX label.

Results: In CONCERTO, ACR50 rates increased over time, ranging from 54% to 68% at week 26, while AE rates remained steady, ranging from 2.4% to 17.8% at week 26. Of 395 patients, 113 (28.6%) reported 345 MTX-related AEs, including one serious AE (SAE, excessive fatigue and/or malaise); 10 AEs (in two patients) led to study discontinuation. In MUSICA, ACR50 rates increased over time, and were 32.3% and 37.5% at week 24, while MTX-related AE rates remained steady and were 6.5% at week 24. Of 309 patients, 71 (23%) reported 185 MTX-related AEs, including 5 SAEs (four infections and one fever/chills); six AEs (in four patients) led to study discontinuation.

Conclusion: In patients with RA initiating ADA+MTX combination, treatment efficacy was achieved and increased throughout both trials, while rates of MTX-related AEs remained steady. MTX-related AEs were observed in up to 30% of patients and most were mild. MTX was discontinued by 0.5%-1.3% of patients.

Trial registration number: MUSICA (NCT01185288), CONCERTO (NCT01185301), Post results.

Keywords: adalimumab; combination treatment; efficacy; methotrexate; rheumatoid arthritis; toxicity.

Conflict of interest statement

Competing interests: GRB has received research grants and consulting fees or other remuneration from, and served on speakers’ bureaus on behalf of AbbVie, Bristol-Myers Squibb, Merck, Roche, Pfizer and UCB. GSK is a consultant for AbbVie. AK has received grant/research and/or provided expert advice to AbbVie, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche and UCB. CG has received research grants and/or provided expert advice to AbbVie, Amgen, BMS, MSD, Pfizer, Roche, Celgene, Sanofi, Debiopharm, AB2 Bio and Regeneron. DKM has served on speakers’ bureaus and is a consultant for AbbVie. PN received funding for clinical trials, research grants, and honoraria for lectures and advice from AbbVie, BMS, Roche, Pfizer, Janssen, Amgen, Sanofi-Aventis, UCB, Eli Lilly, Novartis and Celgene. TT has received grants from Astellas, AbbVie GK, Asahi Kasei Pharma, BMS KK, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Pfizer Japan, Santen Pharmaceutical, SymBio Pharmaceuticals, Taisho Toyama, Takeda Pharmaceutical, Teijin Pharma; speaking fees from Astellas, AbbVie GK, Asahi Kasei Pharma, BMS KK, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Pfizer Japan, Santen Pharmaceutical, SymBio Pharmaceuticals, Taisho Toyama, Takeda and Teijin Pharma; and consultant fees from AbbVie GK, Asahi Kasei Medical KK, Astra-Zeneca, Bristol-Myers KK, Daiichi Sankyo, Eli Lilly Japan, Mitsubishi Tanabe, Nippon Kayaku and Novartis KK. SLG, RR, KC, HK and JK are employees of AbbVie and may own stock/options of AbbVie.

Figures

Figure 1
Figure 1
Rates of ACR50 response and prespecified MTX-related adverse events in patients in the (A) CONCERTO study over 26 weeks and (B) MUSICA study over 24 weeks. ACR50, American College of Rheumatology 50; MTX, methotrexate.
Figure 2
Figure 2
Proportion of patients who achieved ACR50 response and/or experienced MTX-related toxicity over time. ACR50, American College of Rheumatology 50; AE, adverse event; MTX, methotrexate.
Figure 3
Figure 3
Time to the first ACR50 response and MTX-related toxicity event in (A) CONCERTO (B) MUSICA. ACR50, American College of Rheumatology 50; MTX, methotrexate.
Figure 4
Figure 4
Mean concentrations (mM) of PG1+2, PG3 and PG4+5 in patients with or without MTX-related toxicity at baseline, week 4 and week 24/26 in (A) CONCERTO and (B) MUSICA. N was determined from patients with available MTX PG1+2 data at the time points. AE, adverse event; MTX, methotrexate; PG, polyglutamate; pts, patients.

References

    1. Smolen JS, Landewé 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;73:492–509. 10.1136/annrheumdis-2013-204573
    1. Singh JA, Saag KG, Bridges SL, et al. . American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2015;2016:1–26.
    1. 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;50:1400–11. 10.1002/art.20217
    1. 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;54:26–37. 10.1002/art.21519
    1. Schnabel A, Herlyn K, Burchardi C, et al. . Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid arthritis. Rheumatol Int 1996;15:195–200. 10.1007/BF00290521
    1. Furst DE, Koehnke R, Burmeister LF, et al. . Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol 1989;16:313–20.
    1. Yamanaka H, Inoue E, Tanaka E, et al. . Influence of methotrexate dose on its efficacy and safety in rheumatoid arthritis patients: evidence based on the variety of prescribing approaches among practicing Japanese rheumatologists in a single institute-based large observational cohort (IORRA). Mod Rheumatol 2007;17:98–105. 10.3109/s10165-006-0546-7
    1. Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis 2009;68:1094–9. 10.1136/ard.2008.092668
    1. de Rotte MC, den Boer E, de Jong PH, et al. . Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis. Ann Rheum Dis 2015;74:408–14. 10.1136/annrheumdis-2013-203725
    1. Dervieux T, Furst D, Lein DO, et al. . Pharmacogenetic and metabolite measurements are associated with clinical status in patients with rheumatoid arthritis treated with methotrexate: results of a multicentred cross sectional observational study. Ann Rheum Dis 2005;64:1180–5. 10.1136/ard.2004.033399
    1. Hornung N, Ellingsen T, Attermann J, et al. . Patients with rheumatoid arthritis treated with methotrexate (MTX): concentrations of steady-state erythrocyte MTX correlate to plasma concentrations and clinical efficacy. J Rheumatol 2008;35:1709–15.
    1. Takahashi C, Kaneko Y, Okano Y, et al. . Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study. RMD Open 2017;3:e000363 10.1136/rmdopen-2016-000363
    1. Burmester GR, Kivitz AJ, Kupper H, et al. . Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial. Ann Rheum Dis 2015;74:1037–44. 10.1136/annrheumdis-2013-204769
    1. Kaeley GS, Evangelisto AM, Nishio MJ, et al. . Methotrexate dosage reduction upon adalimumab initiation: clinical and ultrasonographic outcomes from the randomized noninferiority MUSICA trial. J Rheumatol 2016;43:1480–9. 10.3899/jrheum.151009
    1. 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;363:675–81. 10.1016/S0140-6736(04)15640-7
    1. Maini RN, Breedveld FC, Kalden JR, et al. . Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552–63. 10.1002/1529-0131(199809)41:9<1552::AID-ART5>;2-W
    1. Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 2012;71:1914–5. 10.1136/annrheumdis-2012-201544
    1. Radstake TR, Svenson M, Eijsbouts AM, et al. . Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 2009;68:1739–45. 10.1136/ard.2008.092833
    1. 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;54:711–5. 10.1002/art.21671
    1. Johnson TB, Nair MG, Galivan J. Role of folylpolyglutamate synthetase in the regulation of methotrexate polyglutamate formation in H35 hepatoma cells. Cancer Res 1988;48:2426–31.
    1. Koizumi S, Curt GA, Fine RL, et al. . Formation of methotrexate polyglutamates in purified myeloid precursor cells from normal human bone marrow. J Clin Invest 1985;75:1008–14. 10.1172/JCI111761
    1. Dervieux T, Furst D, Lein DO, et al. . Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004;50:2766–74. 10.1002/art.20460
    1. Emery P, Burmester GR, Bykerk VP, et al. . Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis 2015;74:19–26. 10.1136/annrheumdis-2014-206106
    1. Dougados M, Kissel K, Conaghan PG, et al. . Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study. Ann Rheum Dis 2014;73:803–9. 10.1136/annrheumdis-2013-204761

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere