Use of tacrolimus for managing csDMARD-failed rheumatoid arthritis: A real- time experience from a single tertiary care centre

Chandrashekara S, Sahana Nagathihalli Jayanna, Dr. Renuka Panchagnula
DOI: 10.15305/ijrci/v10i1/353

Abstract

Aim: To evaluate the efficacy of tacrolimus in achieving disease activity score-28-c-reactive protein 3 [DAS28-CRP (3)] remission in patients managed with tacrolimus at the end of 24 week in a tertiary setting.

Methodology: The retrospective study included RA patients who fulfilled American College of Rheumatology (ACR) 2010 criteria and managed by tacrolimus as an add-on to the background DMARD or as a substitute to conventional synthetic DMARD. Apart from demographic data, TJC, SJC, ESR and CRP were recorded at each visit. Subjects were grouped as those who achieved remission (DAS28-CRP (3) <2.6) and not under remission (DAS28-CRP (3)>2.6). Descriptive analysis was carried out for different variables in the classified groups, chi-square test for categorical variables and ANOVA and t-test to compare the continuous variables.

Results: The study selected 100 patients who fulfilled the criteria for analysis. The corresponding number of subjects who received 4 mg, 3 mg, 2 mg, 1.5 mg and 1 mg of tacrolimus were 3, 23, 57, 2 and 15 respectively. The corresponding number of patients evaluated at 3, 6, 9 and 12 months were 100, 86, 71 and 56. Around 20% of the patients reached a state of remission by the end of 12 months. The DAS28-CRP (3) remission (<2.6) was achieved in 7 (7%) out of 100 at the end of 3 months, which increased to 17 (20%) out of 86 by 6th month. Around 9 out of 57 maintained the remission till the end of 12 months and 11 (20%) out of 57, who were followed till 12th month, had moderate response. Discriminate function analysis showed that the age and duration of disease were strong predictors of achieving remission. Baseline DAS score and duration of illness at the time of introduction of tacrolimus negatively predicted the patients achieving remission.

Conclusion: Tacrolimus is beneficial to achieve remission by the end of 6 months in 20% of the patients with 3 or 4 DMARD-failure. It is also useful in patients who cannot use biologics.

 


Citation

Chandrashekara S, Sahana NJ, Panchagnula R. IJRCI. 2022;10(1): OR1 DOI: 10.15305/ijrci/v10i1/353

Keywords

DMARD, tacrolimus, rheumatoid arthritis

References

1. Hatanaka H, Iwami M, Kino T, Goto T, Okuhara M. FR-900520 and FR-900523, novel immunosuppressants isolated from a Streptomyces. I. Taxonomy of the producing strain. J Antibiot (Tokyo). 1988 Nov;41(11):1586–91.

2. Chandrashekara S, Shobha V, Rao V, Desai A, Jois R, Dharmanand BG, et al. Incidence of infection other than tuberculosis in patients with autoimmune rheumatic diseases treated with bDMARDs: a real-time clinical experience from India. Rheumatol Int. 2019 Mar;39(3):497–507.

3. Prabu N, Petciappan V, Anand G, A T, Nijish A. AB0268 low dose tacrolimus is an effective add on therapy for patients with active rheumatoid arthritis – a single centre experience. Annals of the Rheumatic Diseases. 2021 Jun 1;80:1160.2-1160.

4. Suzuki K, Kameda H, Amano K, Nagasawa H, Takei H, Sekiguchi N, et al. Single center prospective study of tacrolimus efficacy and safety in treatment of rheumatoid arthritis. Rheumatol Int. 2009 Feb;29(4):431–6.

5. Kanzaki T, Kawahata K, Kanda H, Fujio K, Kubo K, Akahira L, et al. Long-term therapeutic effects and safety of tacrolimus added to methotrexate in patients with rheumatoid arthritis. Rheumatol Int. 2013 Apr;33(4):871–7.

6. Kitahama M, Nakajima A, Inoue E, Taniguchi A, Momohara S, Yamanaka H. Efficacy of adjunct tacrolimus treatment in patients with rheumatoid arthritis with inadequate responses to methotrexate. Mod Rheumatol. 2013 Jul;23(4):788–93.

7. Tanaka Y, Kawai S, Takeuchi T, Yamamoto K, Miyasaka N. Prevention of joint destruction by tacrolimus in patients with early rheumatoid arthritis: a post hoc analysis of a double-blind, randomized, placebo-controlled study. Mod Rheumatol. 2013 Nov;23(6):1045–52.

8. Motomura H, Matsushita I, Seki E, Mine H, Kimura T. Inhibitory effect of tacrolimus on progression of joint damage in patients with rheumatoid arthritis. Int J Rheum Dis. 2014 Sep;17(7):749–54.

9. van Riel PLCM, Renskers L. The Disease Activity Score (DAS) and the Disease Activity Score using 28 joint counts (DAS28) in the management of rheumatoid arthritis. Clin Exp Rheumatol. 2016 Oct;34(5 Suppl 101):S40–4.

10. Fransen J, van Riel PLCM. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol. 2005 Oct;23(5 Suppl 39):S93-99.

11. Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol. 2017 Dec 6;17(1):162.

12. Smolen JS, Landewé RBM, Bijlsma JWJ, et alEULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update Annals of the Rheumatic Diseases 2020;79:685-699.

13. Aramaki T, Kawakami A, Iwamoto N, Fujikawa K, Kawashiri S, Tamai M, et al. Prediction of DAS28-CRP remission in patients with rheumatoid arthritis treated with tacrolimus at 6 months by baseline variables. Mod Rheumatol. 2009;19(6):652–6.

14. Ishida K, Shiraki K, Yoshiyasu T. Evaluation of the Safety and Effectiveness of Add-On Tacrolimus in Patients with Rheumatoid Arthritis Who Failed to Show an Adequate Response to Biological DMARDs: The Interim Results of a Specific Drug Use-Results Survey of Tacrolimus. Drugs R D. 2015 Dec;15(4):307–17.

15. Furst DE, Saag K, Fleischmann MR, Sherrer Y, Block JA, Schnitzer T, et al. 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. 2002 Aug;46(8):2020–8.

16. Kremer JM, Habros JS, Kolba KS, Kaine JL, Borton MA, Mengle-Gaw LJ, et al. Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate: a six-month, open-label study. Arthritis Rheum. 2003 Oct;48(10):2763–8.

17. Sheen DH, Hong SJ, Lee SH, Lee HS, Chung WT, Jiang H, et al. Effectiveness and Safety of Tacrolimus in Patients with Active Rheumatoid Arthritis with Inadequate Response to Disease-modifying Anti-rheumatic Drugs: The TREASURE Study. J Rheum Dis. 2018 Dec 20;26(1):20–30.

18. Yocum DE, Furst DE, Bensen WG, Burch FX, Borton MA, Mengle-Gaw LJ, et al. Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience. Rheumatology (Oxford). 2004 Aug;43(8):992–9.

19. Yocum DE, Furst DE, Kaine JL, Baldassare AR, Stevenson JT, Borton MA, et al. Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial. Arthritis Rheum. 2003 Dec;48(12):3328–37.

20. Lee YH, Woo J-H, Choi SJ, Ji JD, Bae S-C, Song GG. Tacrolimus for the treatment of active rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. Scand J Rheumatol. 2010 Aug;39(4):271–8.

21. Kitahama M, Okamoto H, Koseki Y, Inoue E, Kaneko H, Taniguchi A, et al. Efficacy and safety of tacrolimus in 101 consecutive patients with rheumatoid arthritis. Mod Rheumatol. 2010 Oct;20(5):478–85.

22. Isozaki T, Sato M, Takahashi R, Wakabayashi K, Yajima N, Miwa Y, et al. Effects of low-dose tacrolimus therapy in combination with methotrexate in patients with methotrexate-refractory rheumatoid arthritis. Open Access Rheumatol. 2010;2:29–34.

23. Naniwa T, Watanabe M, Banno S, Maeda T. Adding low dose tacrolimus in rheumatoid arthritis patients with an inadequate response to tumor necrosis factor inhibitor therapies. Rheumatol Int. 2009 Sep;29(11):1287–91.

24. Fujibayashi T, Takahashi N, Kida D, Kaneko A, Hirano Y, Fukaya N, et al. Comparison of efficacy and safety of tacrolimus and methotrexate in combination with abatacept in patients with rheumatoid arthritis; a retrospective observational study in the TBC Registry. Mod Rheumatol. 2015;25(6):825–30.

25. Ishida K, Shiraki K, Yoshiyasu T. Evaluation of the Safety and Effectiveness of Add-On Tacrolimus in Patients with Rheumatoid Arthritis Who Failed to Show an Adequate Response to Biological DMARDs: The Interim Results of a Specific Drug Use-Results Survey of Tacrolimus. Drugs R D. 2015 Dec;15(4):307–17.

26. Shin K, Baek HJ, Kang YM, Cha H-S, Kang SW, Park S-H, et al. Efficacy and safety of add-on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate. Int J Rheum Dis. 2019 Jun;22(6):1115–22.

27. Azuma T, Oishi M, Takei M, Sawada S. Tacrolimus-related nocturnal myoclonus of the lower limbs in elderly patients with rheumatoid arthritis. Mod Rheumatol. 2007;17(3):247–50.

28. Park E-Y, Lee S-G, Park E-K, Koo D-W, Park J-H, Kim G-T, et al. Drug survival and the associated predictors in South Korean patients with rheumatoid arthritis receiving tacrolimus. Korean J Intern Med. 2018 Jan;33(1):193–202.

29. Post-hoc Power Calculator [Internet]. [cited 2021 Aug 30]. Available from: https://clincalc.com/stats/Power.aspx