Abstract
To assess the long-term safety and efficacy of tacrolimus (TAC) used in combination with oral methotrexate (MTX) in patients with rheumatoid arthritis (RA) whose disease remains active despite treatment with MTX alone. The clinical courses of 24 RA patients who received TAC added to MTX from a single center were analyzed retrospectively. The disease activity was evaluated by the DAS28-ESR(3) every 12 months after the addition of TAC, and side effects were evaluated for 3 years. At 3 years after starting the treatment, TAC was still being used by 19 patients (79 %). The causes of discontinuation were an inadequate response (3 cases), oral ulcers and elevation of creatinine (1 case), and worsening of interstitial pneumonia (1 case). No death was registered. The DAS28-ESR(3) was decreased from 4.81 to 3.41 after 3 years of treatment. The doses of prednisolone were decreased from 5.1 mg/day to 3.2 mg/day after 3 years. In patients whose active RA persists despite treatment with MTX, TAC in combination with MTX is safe and well tolerated and provided clinical benefit for a long time in this single-center retrospective study. Further studies are required to confirm the safety and efficacy of this combination therapy.
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References
Combe B, Landewe R, Lukas C, Bolosiu HD, Breedveld F, Dougados M et al (2007) EULAR recommendations for the management of early arthritis: report of a task force of the European standing committee for international clinical studies including therapeutics (eSCISIT). Ann Rheum Dis 66:34–45
Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C et al (2010) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 69:964–975
Bijlsma JW, Jacobs JW (2009) Methotrexate: still the anchor drug in RA treatment. Joint Bone Spine 76:452–454
Salliot C, Finckh A, Katchamart W, Lu Y, Sun Y, Bombardier C et al (2011) 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 70:266–271
Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361
Cope AP (2008) T cells in rheumatoid arthritis. Arthritis Res Ther 10:S1
Yocum DE, Furst DE, Bensen WG, Burch FX, Borton MA, Mengle-Gaw LJ et al (2004) Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience. Rheumatology (Oxford) 43:992–999
Kawai S, Tanaka K, Ohno I, Utsunomiya K, Seino Y (2008) Safety of long-term tacrolimus therapy for rheumatoid arthritis: an open-label, uncontrolled study in non-elderly patients. Mod Rheumatol 18:345–353
Furst DE, Saag K, Fleischmann MR, Sherrer Y, Block JA, Schnitzer T et al (2002) Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study. Arthritis Rheum 46:2020–2028
Kremer JM, Habros JS, Kolba KS, Kaine JL, Borton MA, Mengle-Gaw LJ et al (2003) Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate: a six-month, open-label study. Arthritis Rheum 48:2763–2768
Morita Y, Sasae Y, Sakuta T, Satoh M, Sasaki T, Kashihara N (2008) Efficacy of low-dose tacrolimus added to methotrexate in patients with rheumatoid arthritis in Japan: a retrospective study. Mod Rheumatol 18:379–384
Hesselink DA, Bouamar R, van Gelder T (2010) The pharmacogenetics of calcineurin inhibitor-related nephrotoxicity. Ther Drug Monit 32:387–393
Suzuki K, Kameda H, Amano K, Nagasawa H, Takei H, Sekiguchi N et al (2009) Single center prospective study of tacrolimus efficacy and safety in treatment of rheumatoid arthritis. Rheumatol Int 29:431–436
McCurry J (2004) Japan deaths spark concerns over arthritis drug. Lancet 363:461
Sato T, Inokuma S, Sagawa A, Matsuda T, Takemura T, Otsuka T et al (2009) Factors associated with fatal outcome of leflunomide-induced lung injury in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford) 48:1265–1268
Kinder AJ, Hassell AB, Brand J, Brownfield A, Grove M, Shadforth MF (2005) The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology (Oxford) 44:61–66
Shidara K, Hoshi D, Inoue E, Yamada T, Nakajima A, Taniguchi A et al (2010) Incidence of and risk factors for interstitial pneumonia in patients with rheumatoid arthritis in a large Japanese observational cohort, IORRA. Mod Rheumatol 20:280–286
Isnard Bagnis C, Tezenas du Montcel S, Beaufils H, Jouanneau C, Jaudon MC, Maksud P et al (2002) Long-term renal effects of low-dose cyclosporine in uveitis-treated patients: follow-up study. J Am Soc Nephrol 13:2962–2968
Richaud-Patin Y, Soto-Vega E, Jakez-Ocampo J, Llorente L (2004) P-glycoprotein in autoimmune diseases. Autoimmun Rev 3:188–192
Suzuki K, Saito K, Tsujimura S, Nakayamada S, Yamaoka K, Sawamukai N et al (2010) Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis. J Rheumatol 37:512–520
Tsujimura S, Saito K, Nawata M, Nakayamada S, Tanaka Y (2008) Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis. Ann Rheum Dis 67:380–388
Diamanti AP, Rosado M, Germano V, Scarsella M, Giorda E, Podesta E et al (2011) Reversion of resistance to immunosuppressive agents in three patients with psoriatic arthritis by cyclosporine A: modulation of P-glycoprotein function. Clin Immunol 138:9–13
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Kanzaki, T., Kawahata, K., Kanda, H. et al. Long-term therapeutic effects and safety of tacrolimus added to methotrexate in patients with rheumatoid arthritis. Rheumatol Int 33, 871–877 (2013). https://doi.org/10.1007/s00296-012-2465-6
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DOI: https://doi.org/10.1007/s00296-012-2465-6