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  • Review Article
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Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology

Nature Reviews Rheumatology volume 16, pages 167–178 (2020)Cite this article

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Abstract

The introduction of biologic DMARDs into rheumatology has resulted in a substantial reduction of the burden of many rheumatic diseases. In the slipstream of the success achieved with these biologic DMARDs, some conventional immunosuppressive drugs have also found use in new indications. Notably, mycophenolate mofetil, azathioprine and tacrolimus have made their way from solid organ transplantation drugs to become useful assets in rheumatology practice. Mycophenolate mofetil and azathioprine inhibit the purine pathway and subsequently diminish cell proliferation. Both drugs have a pivotal role in the treatment of various rheumatic diseases, including lupus nephritis. Tacrolimus inhibits lymphocyte activation by inhibiting the calcineurin pathway. Mycophenolate mofetil and tacrolimus are, among other indications, increasingly being recognized as useful drugs in the treatment of interstitial lung disease in systemic rheumatic diseases and skin fibrosis in systemic sclerosis. A broad array of trials with mycophenolate mofetil, azathioprine and/or tacrolimus are ongoing within the field of rheumatology that might provide further novel avenues for the use of these drugs. In this Review, we discuss the historical perspective, pharmacodynamics, clinical indications and novel avenues for mycophenolate mofetil, azathioprine and tacrolimus in rheumatology.

Key points

  • Mycophenolate mofetil (MMF), azathioprine and tacrolimus are three conventional DMARDs that originate from the field of transplantation medicine, but have been repurposed for the treatment of rheumatic diseases.

  • MMF and azathioprine both interfere with the purine pathway to inhibit cell proliferation, whereas tacrolimus inhibits calcineurin activity and subsequent lymphocyte activation.

  • MMF and azathioprine are pivotal in the treatment of lupus nephritis.

  • MMF and tacrolimus are, among other indications, increasingly recognized as useful drugs in the treatment of interstitial lung disease in systemic rheumatic diseases and skin fibrosis in systemic sclerosis.

  • Future avenues for these drugs include the optimization of dosing schemes and investigation of novel indications and effects when co-administered with other DMARDs.

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Fig. 1: Inhibition of nucleotide synthesis by mycophenolate mofetil.
Fig. 2: Immunomodulatory effects of azathioprine.
Fig. 3: Inhibition of T cells by tacrolimus.

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References

  1. Nobel Media AB 2020. The nobel prize in physiology or medicine 1988. NobelPrize.Org. https://www.nobelprize.org/prizes/medicine/1988/summary/ (2020).

  2. Alsberg, C. L. & Black F. in Contribution to the study of maize deterioration; biochemical and toxicological investigations of Penicillium puberulum and Penicillium stoloniferum (Trieste, 1913).

  3. Gong, Z. J. et al. Mycophenolic acid, an immunosuppressive agent, inhibits HBV replication in vitro. J. Viral Hepat. 6, 229–236 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Abraham, E. P. The effect of mycophenolic acid on the growth of Staphylococcus aureus in heart broth. Biochem. J. 39, 398–404 (1945).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Allison, A. C. & Eugui, E. M. Immunosuppressive and long-acting anti-inflammatory activity of mycophenolic acid and derivative, RS-61443. Br. J. Rheumatol. 30, 57–61 (1991).

    PubMed  Google Scholar 

  6. Jones, E. L. et al. Treatment of psoriasis with oral mycophenolic acid. J. Invest. Dermatol. 65, 537–542 (1975).

    Article  CAS  PubMed  Google Scholar 

  7. Lipsky, J. J. Mycophenolate mofetil. Lancet 348, 1357–1359 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Bullingham, R. E., Nicholls, A. J. & Kamm, B. R. Clinical pharmacokinetics of mycophenolate mofetil. Clin. Pharmacokinet. 34, 429–455 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Van Hest, R. M. et al. Within-patient variability of mycophenolic acid exposure: therapeutic drug monitoring from a clinical point of view. Ther. Drug Monit. 28, 31–34 (2006).

    Article  PubMed  Google Scholar 

  10. Kuypers, D. R. et al. The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin. Pharmacol. Ther. 78, 351–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Kees, M. G. et al. Omeprazole impairs the absorption of mycophenolate mofetil but not of enteric-coated mycophenolate sodium in healthy volunteers. J. Clin. Pharmacol. 52, 1265–1272 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Meier-Kriesche, H. U. et al. Pharmacokinetics of mycophenolic acid in renal insufficiency. Ther. Drug Monit. 22, 27–30 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Daleboudt, G. M. et al. Concentration-controlled treatment of lupus nephritis with mycophenolate mofetil. Lupus 22, 171–179 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Alexander, S. et al. Pharmacokinetics of concentration-controlled mycophenolate mofetil in proliferative lupus nephritis: an observational cohort study. Ther. Drug Monit. 36, 423–432 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Ransom, J. T. Mechanism of action of mycophenolate mofetil. Ther. Drug Monit. 17, 681–684 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Suthanthiran, M. & Strom, T. B. Immunoregulatory drugs: mechanistic basis for use in organ transplantation. Pediatr. Nephrol. 11, 651–657 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Tang, Q. et al. Mycophenolic acid upregulates miR-142-3P/5P and miR-146a in lupus CD4+T cells. Lupus 24, 935–942 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Li, L., Chen, X. P. & Li, Y. J. MicroRNA-146a and human disease. Scand. J. Immunol. 71, 227–231 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Yang, Y. et al. The effect of mycophenolic acid on epigenetic modifications in lupus CD4+T cells. Clin. Immunol. 158, 67–76 (2015).

    Article  CAS  PubMed  Google Scholar 

  20. Zhang, B. et al. The CD40/CD40L system: a new therapeutic target for disease. Immunol. Lett. 153, 58–61 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Morales-Cárdenas, A. et al. Pulmonary involvement in systemic sclerosis. Autoimmun. Rev. 15, 1094–1108 (2016).

    Article  PubMed  Google Scholar 

  22. Morath, C. et al. Effects of mycophenolic acid on human fibroblast proliferation, migration and adhesion in vitro and in vivo. Am. J. Transplant. 8, 1786–1797 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Badid, C. et al. Mycophenolate mofetil reduces myofibroblast infiltration and collagen III deposition in rat remnant kidney. Kidney Int. 58, 51–61 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Johnsson, C., Gerdin, B. & Tufveson, G. Effects of commonly used immunosuppressants on graft-derived fibroblasts. Clin. Exp. Immunol. 136, 405–412 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Azzola, A. et al. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation. Transplantation 77, 275–280 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Ozgen, M. et al. Mycophenolate mofetil and daclizumab targeting T lymphocytes in bleomycin-induced experimental scleroderma. Clin. Exp. Dermatol. 37, 48–54 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Piera-Velazquez, S., Li, Z. & Jimenez, S. A. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders. Am. J. Pathol. 179, 1074–1080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wright, R. D., Dimou, P., Northey, S. J. & Beresford, M. W. Mesangial cells are key contributors to the fibrotic damage seen in the lupus nephritis glomerulus. J. Inflamm. 14, 22 (2019).

    Article  CAS  Google Scholar 

  29. Wang, W., Mo, S. & Chan, L. Mycophenolic acid inhibits PDGF-induced osteopontin expression in rat mesangial cells. Transpl. Proc. 31, 1176–1177 (1999).

    Article  CAS  Google Scholar 

  30. Dubus, I. et al. Mycophenolic acid antagonizes the activation of cultured human mesangial cells. Kidney Int. 62, 857–867 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Zhou, X., Workeneh, B., Hu, Z. & Li, R. Effect of immunosuppression on the human mesangial cell cycle. Mol. Med. Rep. 11, 910–916 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Hinchcliff, M. et al. Mycophenolate mofetil treatment of systemic sclerosis reduces myeloid cell numbers and attenuates the inflammatory gene signature in skin. J. Invest. Dermatol. 138, 1301–1310 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chan, T. M. et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N. Engl. J. Med. 343, 1156–1162 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Derk, C. T. et al. A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis. Rheumatology 48, 1595–1599 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Langford, C. A., Talar-Williams, C. & Sneller, M. C. Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis. Arthritis Rheum. 51, 278–283 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Majithia, V. & Harisdangkul, V. Mycophenolate mofetil (CellCept): an alternative therapy for autoimmune inflammatory myopathy. Rheumatology 44, 386–389 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Rowin, J. et al. Mycophenolate mofetil in dermatomyositis: is it safe? Neurology. 66, 1245–1247 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Ginzler, E. M. et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N. Engl. J. Med. 353, 2219–2228 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Touma, Z. et al. Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and meta-analysis. J. Rheumatol. 38, 39–78 (2011).

    Google Scholar 

  40. Henderson L. et al. Treatment for lupus nephritis. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD002922.pub3 (2012).

  41. Maneiro, J. R. et al. Maintenance therapy of lupus nephritis with mycophenolate or azathioprine: a systematic review and meta-analysis. Rheumatology 53, 834–838 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Stoenoiu, M. S. et al. Repeat kidney biopsies fail to detect differences between azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN Nephritis Trial. Nephrol. Dial. Transpl. 27, 1924–1930 (2012).

    Article  CAS  Google Scholar 

  43. Ordi-Ros, J. et al. Enteric-coated mycophenolate sodium versus azathioprine in patients with active systemic lupus erythematosus: a randomised clinical trial. Ann. Rheum. Dis. 76, 1575–1582 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Palmer, S. C. et al. Induction and maintenance immunosuppression treatment of proliferative lupus nephritis: a network mata-analysis of randomized trials. Am. J. Kidney Dis. 70, 324–336 (2017).

    Article  PubMed  Google Scholar 

  45. Ntatsaki, E. et al. BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology 53, 2306–2309 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Hiemstra, T. F. et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA 304, 2381–2388 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Draibe, J. et al. Use of mycophenolate in ANCA-associated renal vasculitis: 13 years of experience at a university hospital. Nephrol. Dial. Transpl. 30, i132–i137 (2015).

    Article  CAS  Google Scholar 

  48. Morganroth, P. A., Kreider, M. E. & Werth, V. P. Mycophenolate mofetil for interstitial lung disease in dermatomyositis. Arthritis Care Res. 62, 1496–1501 (2010).

    Article  Google Scholar 

  49. Saketkoo, L. A. & Espinoza, L. R. Rheumatoid arthritis interstitial lung disease: mycophenolate mofetil as an antifibrotic and disease-modifying antirheumatic drug. Arch. Intern. Med. 168, 1718–1719 (2008).

    Article  PubMed  Google Scholar 

  50. Gerbino, A. J., Goss, C. H. & Molitor, J. A. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest 133, 455–460 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Tashkin, D. P. et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLE II): a randomized controlled, double-blind, parallel group trial. Lancet Respir. Med. 4, 708–719 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Volkmann, E. R. et al. Mycophenolate mofetil versus placebo for systemic sclerosis-related interstitial lung disease: an analysis of scleroderma lung studies I and II. Arthritis Rheumatol. 69, 1451–1460 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Namas, R. et al. Efficacy of mycophenolate mofetil and oral cyclophosphamide on skin thickness: post-hoc analyses from two randomized placebo-controlled trials. Arthritis Care Res. 70, 439–444 (2018).

    Article  CAS  Google Scholar 

  54. Herrick, A. L. et al. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Ann. Rheum. Dis. 76, 1207–1218 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov (2020).

  56. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03444805 (2019).

  57. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03678987 (2018).

  58. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02954939 (2019).

  59. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01946880 (2019).

  60. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02453997 (2017).

  61. Ganson, N. J. et al. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res. Ther. 8, R12 (2005).

    Article  CAS  PubMed Central  Google Scholar 

  62. Hershfield, M. S. et al. Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Res. Ther. 16, R63 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03303989 (2019).

  64. Feturi, F. G. et al. Mycophenolic acid for topical immunosuppression in vascularized composite allotransplantation: optimizing formulation and preliminary evaluation of bioavailability and pharmacokinetics. Front. Surg. 9, 5–20 (2018).

    Google Scholar 

  65. Dugas, H. L., Peters, J. I. & Williams, R. O. III Nebulization of mycophenolate mofetil inhalation suspension in rats: comparison with oral and pulmonary administration of Cellcept®. Int. J. Pharm. 441, 19–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Elion, G. B. The purine path to chemotherapy. Science 244, 41–47 (1989).

    Article  CAS  PubMed  Google Scholar 

  67. Elion, G. B., Callahan, S. W. & Hitchings, G. H. The metabolism of 2-amino-6-[(1-methyl-4-nitro-5-imidazolyl)thio]purine (B.W. 57–323) in man. Cancer Chemother. Rep. 8, 47–52 (1960).

    CAS  PubMed  Google Scholar 

  68. Schwartz, R., Stack, J. & Dameshek, W. Effect of 6-mercaptopurine on antibody production. Proc. Soc. Exp. Biol. Med. 99, 164–167 (1958).

    Article  CAS  PubMed  Google Scholar 

  69. Starzl, T. E. et al. Extended survival in 3 cases of orthotopic homotransplantation of the human liver. Surgery. 63, 549–563 (1968).

    CAS  PubMed  Google Scholar 

  70. MacKay, I. R., Weiden, S. & Ungar, B. Treatment of active chronic hepatitis and lupoid hepatitis with 6-mercaptopurine and azathioprine. Lancet 1, 899–902 (1964).

    Article  CAS  PubMed  Google Scholar 

  71. Van Scoik, K. G., Johnson, C. A. & Porter, W. R. The pharmacology and metabolism of the thiopurine drugs 6-mercaptopurine and azathioprine. Drug Metab. Rev. 16, 157–174 (1985).

    Article  PubMed  Google Scholar 

  72. Van Os, E. C. et al. Azathioprine pharmacokinetics after intravenous, oral, delayed release oral and rectal foam administration. Gut 39, 63–68 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Stolk, J. N. et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 41, 1858–1866 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. Bergan, S. et al. Kinetics of mercaptopurine and thioguanine nucleotides in renal transplant recipients during azathioprine treatment. Ther. Drug Monit. 16, 13–20 (1994).

    Article  CAS  PubMed  Google Scholar 

  75. Chocair, P. R. et al. The importance of thiopurine methyltransferase activity for the use of azathioprine in transplant recipients. Transplantation 53, 1051–1056 (1992).

    Article  CAS  PubMed  Google Scholar 

  76. Jung, E. J. et al. Oral administration of 1,4-aryl-2-mercaptoimidazole inhibits T-cell proliferation and reduces clinical severity in the murine experimental autoimmune encephalomyelitis model. J. Pharmacol. Exp. Ther. 331, 1005–1013 (2009).

    Article  CAS  PubMed  Google Scholar 

  77. Tiede, I. et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J. Clin. Invest. 111, 1133–1145 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Faroudi, M. et al. Critical roles for Rac GTPases in T-cell migration to and within lymph nodes. Blood. 116, 5536–5547 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bertini, I. et al. The anti-apoptotic Bcl-x(L) protein, a new piece in the puzzle of cytochrome c interactome. PLoS One 6, e18329 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Maltzman, J. S. & Koretzky, G. A. Azathioprine: old drug, new actions. J. Clin. Invest. 111, 1122–1124 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Marinkovic´, G. et al. 6-Mercaptopurine reduces macrophage activation and gut epithelium proliferation through inhibition of GTPase Rac1. Inflamm. Bowel Dis. 20, 1487–1495 (2014).

    Article  PubMed  Google Scholar 

  82. Marinkovic´, G. et al. Inhibition of GTPase Rac1 in endothelium by 6-mercaptopurine results in immunosuppression in nonimmune cells: new target for an old drug. J. Immunol. 192, 4370–4378 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Hessels, A. C. et al. Thiopurine methyltransferase genotype and activity cannot predict outcomes of azathioprine maintenance therapy for antineutrophil cytoplasmic antibody associated vasculitis: a retrospective cohort study. PLoS One 13, e0195524 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Tareyeva, I. E., Shilov, E. M. & Gordovskaya, N. B. The effects of azathioprine and prednisolone on T- and B-lymphocytes in patients with lupus nephritis and chronic glomerulonephritis. Clin. Nephrol. 14, 233–237 (1980).

    CAS  PubMed  Google Scholar 

  85. Glas, J. et al. The leukocyte count predicts the efficacy of treatment with azathioprine in inflammatory bowel disease. Eur. J. Med. Res. 10, 535–538 (2005).

    CAS  PubMed  Google Scholar 

  86. Fraser, A. G., Orchard, T. R. & Jewell, D. P. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 50, 485–489 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Suarez-Almazor, M. E., Spooner, C. & Belseck, E. Azathioprine for treating rheumatoid arthritis. Cochrane Database Syst. Rev. 4, CD001461 (2000).

    Google Scholar 

  88. Grootscholten, C. et al. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis: a randomized controlled trial. Kidney Int. 70, 732–742 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Jayne, D. et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N. Engl. J. Med. 349, 36–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Mukhtyar, C. et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann. Rheum. Dis. 68, 310–317 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Contreras, G. et al. Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 350, 971–980 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Rahman, P. et al. Cytotoxic therapy in systemic lupus erythematosus: experience from a single center. Medicine 76, 432–437 (1997).

    Article  CAS  PubMed  Google Scholar 

  93. Hamuryudan, V. et al. Azathioprine in Behçet’s syndrome: effects on long-term prognosis. Arthritis Rheum. 40, 769–774 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Jones, G., Crotty, M. & Brooks, P. Psoriatic arthritis: a quantitative overview of therapeutic options. The Psoriatic Arthritis Meta-Analysis Study Group. Br. J. Rheumatol. 36, 95–99 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Benenson, E. et al. High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener’s granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide. Clin. Rheumatol. 24, 251–257 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Bérezné, A. et al. Therapeutic strategy combining intravenous cyclophosphamide followed by oral azathioprine to treat worsening interstitial lung disease associated with systemic sclerosis: a retrospective multicenter open-label study. J. Rheumatol. 35, 1064–1072 (2008).

    PubMed  Google Scholar 

  97. Hoyles, R. K. et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 54, 3962–3970 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03770663 (2018).

  99. Vuillard, C. et al. Clinical features and outcome of patients with acute respiratory failure revealing anti-synthetase or anti-MDA-5 dermato-pulmonary syndrome: a French multicenter retrospective study. Ann. Intensive Care 11, 87 (2018).

    Article  CAS  Google Scholar 

  100. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03543527 (2018).

  101. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02356445 (2017).

  102. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02954939 (2016).

  103. Dugué, P. A. et al. Risk of cervical cancer in women with autoimmune diseases, in relation with their use of immunosuppressants and screening: population-based cohort study. Int. J. Cancer. 136, E711–E719 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Jiyad, Z. et al. Azathioprine and risk of skin cancer in organ transplant recipients: systematic review and meta-analysis. Am. J. Transplant. 16, 3490–3503 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. Hagen, J. W. & Pugliano-Mauro, M. A. Nonmelanoma skin cancer risk in patients with inflammatory bowel disease undergoing thiopurine therapy: a systematic review of the literature. Dermatol. Surg. 44, 469–480 (2018).

    Article  CAS  PubMed  Google Scholar 

  106. Lim, S. Z. & Chua, E. W. Revisiting the role of thiopurines in inflammatory bowel disease through pharmacogenomics and use of novel methods for therapeutic drug monitoring. Front. Pharmacol. 9, 1107 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kino, T. et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J. Antibiot. 40, 1256–1265 (1987).

    Article  CAS  Google Scholar 

  108. Kino, T. et al. Effect of FK-506 on human mixed lymphocyte reaction in vitro. Transpl. Proc. 19, 36–39 (1987).

    CAS  Google Scholar 

  109. Ochiai, T. et al. Comparative studies on the immunosuppressive activity of FK506, 15-deoxyspergualin, and cyclosporine. Transpl. Proc. 21, 829–832 (1989).

    CAS  Google Scholar 

  110. Starzl, T. E. et al. FK 506 for liver, kidney, and pancreas transplantation. Lancet 2, 1000–1004 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Spencer, C. M., Goa, K. L. & Gillis, J. C. Tacrolimus: an update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 54, 925–975 (1997).

    Article  CAS  PubMed  Google Scholar 

  112. Peters, D. H. et al. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 46, 746–794 (1993).

    Article  CAS  PubMed  Google Scholar 

  113. Yu, M. et al. Pharmacokinetics, pharmacodynamics and pharmacogenetics of tacrolimus in kidney transplantation. Curr. Drug Metab. 19, 513–522 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lemahieu, W. et al. Cytochrome P450 3A4 and P-glycoprotein activity and assimilation of tacrolimus in transplant patients with persistent diarrhea. Am. J. Transplant. 5, 1383–1391 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Matsuda, S. et al. Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation. EMBO Rep. 1, 428–434 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Cardenas, M. E. et al. Immunophilins interact with calcineurin in the absence of exogenous immunosuppressive ligands. EMBO J. 13, 5944–5957 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Clipstone, N. A. & Crabtree, G. R. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357, 695–697 (1992).

    Article  CAS  PubMed  Google Scholar 

  118. Shaw, K. T. et al. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc. Natl Acad. Sci. USA 92, 11205–11209 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Hoyos, B. et al. Kappa B-specific DNA binding proteins: role in the regulation of human interleukin-2 gene expression. Science 244, 457–460 (1989).

    Article  CAS  PubMed  Google Scholar 

  120. Frantz, B. et al. Calcineurin acts in synergy with PMA to inactivate I κ B/MAD3, an inhibitor of NF-κ B. EMBO J. 13, 861–870 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Matsuda, S. et al. T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A. J. Biol. Chem. 273, 12378–12382 (1998).

    Article  CAS  PubMed  Google Scholar 

  122. Khanna, A. et al. Tacrolimus induces increased expression of transforming growth factor-β1 in mammalian lymphoid as well as nonlymphoid cells. Transplantation 67, 614–619 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Shin, G. T. et al. In vivo expression of transforming growth factor-β1 in humans: stimulation by cyclosporine. Transplantation 65, 313–318 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. Khanna, A. et al. Expression of TGF-β and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity. Kidney Int. 62, 2257–2263 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Sasaki, T. et al. Characteristic features of tacrolimus-induced lung disease in rheumatoid arthritis patients. Clin. Rheumatol. 35, 541–545 (2016).

    Article  PubMed  Google Scholar 

  126. Koike, R. et al. Tacrolimus-induced pulmonary injury in rheumatoid arthritis patients. Pulm. Pharmacol. Ther. 24, 401–406 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Issa, N. et al. Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence. Am. J. Nephrol. 37, 602–612 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Morteau, O. et al. Renal transplant immunosuppression impairs natural killer cell function in vitro and in vivo. PLoS One 5, e13294 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Tiefenthaler, M. et al. In vitro treatment of dendritic cells with tacrolimus: impaired T-cell activation and IP-10 expression. Nephrol. Dial. Transplant. 19, 553–560 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Ren, Y. et al. Tolerogenic dendritic cells modified by tacrolimus suppress CD4+ T-cell proliferation and inhibit collagen-induced arthritis in mice. Int. Immunopharmacol. 21, 247–254 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Kannegieter, N. M. et al. The effect of tacrolimus and mycophenolic acid on CD14+ monocyte activation and function. PLoS One 12, e0170806 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Lampropoulos, C. E. et al. Topical tacrolimus therapy of resistant cutaneous lesions in lupus erythematosus: a possible alternative. Rheumatology 43, 1383–1385 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Mok, C. C. et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann. Rheum. Dis. 75, 30–36 (2016).

    Article  PubMed  Google Scholar 

  134. Liu, Z. et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann. Intern. Med. 162, 18–26 (2015).

    Article  PubMed  Google Scholar 

  135. Choi, C. B. et al. Outcomes of multitarget therapy using mycophenolate mofetil and tacrolimus for refractory or relapsing lupus nephritis. Lupus 27, 1007–1011 (2018).

    Article  CAS  PubMed  Google Scholar 

  136. Barba, T. et al. Treatment of idiopathic inflammatory myositis associated interstitial lung disease: A systematic review and meta-analysis. Autoimmun. Rev. 18, 113–122 (2019).

    Article  PubMed  Google Scholar 

  137. Kurita, T. et al. The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. Rheumatology 54, 39–44 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03865888 (2019).

  139. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT00504348 (2017).

  140. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01410747 (2019).

  141. Suzuki, M. et al. Clinical effectiveness and safety of additional administration of tacrolimus in rheumatoid arthritis patients with an inadequate response to abatacept: a retrospective cohort study. Int. J. Rheum. Dis. 22, 2199–2205 (2019).

    Article  CAS  PubMed  Google Scholar 

  142. Shin, K. et al. Efficacy and safety of add-on tacrolimus versus leflunomide in rheumatoid arthritis patients with inadequate response to methotrexate. Int. J. Rheum. Dis. 22, 1115–1122 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Dutta, S. & Ahmad, Y. The efficacy and safety of tacrolimus in rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis. 3, 283–291 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03737708 (2019).

  145. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02837978 (2019).

  146. Krämer, B. K. et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am. J. Transplant. 10, 2632–2643 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. Cattral, M. et al. Randomized open-label crossover assessment of Prograf vs Advagraf on immunosuppressant pharmacokinetics and pharmacodynamics in simultaneous pancreas-kidney patients. Clin. Transplant. https://doi.org/10.1111/ctr.13180 (2018).

  148. Marquet, P. et al. Pharmacokinetic therapeutic drug monitoring of advagraf in more than 500 adult renal transplant patients, using an expert system online. Ther. Drug Monit. 40, 285–291 (2018).

    Article  CAS  PubMed  Google Scholar 

  149. Anghel, L. A. et al. Medication adherence and persistence in patients with autoimmune rheumatic diseases: a narrative review. Patient Prefer. Adherence 12, 1151–1166 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yap, D. Y. H. et al. Longterm data on sirolimus treatment in patients with Lupus Nephritis. J. Rheumatol. 45, 1663–1670 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Bruyn, G. A. et al. Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study. Ann. Rheum. Dis. 67, 1090–1095 (2008).

    Article  CAS  PubMed  Google Scholar 

  152. Solazzo, A. et al. Interstitial lung disease after kidney transplantation and the role of everolimus. Transpl. Proc. 48, 349–351 (2016).

    Article  CAS  Google Scholar 

  153. Woodcock, H. V. et al. The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis. Nat. Commun. 10, 6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Blokland, S. L. M. et al. Increased mTORC1 activation in salivary gland B cells and T cells from patients with Sjögren’s syndrome: mTOR inhibition as a novel therapeutic strategy to halt immunopathology? RMD Open 5, e000701 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Vazirpanah, N. et al. mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy? Ann. Rheum. Dis. 78, 663–671 (2019).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Regional Rheumatology Center, Máxima Medical Center, Eindhoven and Veldhoven, Eindhoven, the Netherlands

    Jasper C. A. Broen

  2. Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

    Jacob M. van Laar

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The authors contributed equally to all aspects of the article.

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Correspondence to Jacob M. van Laar.

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Competing interests

J.M.v.-L. declares that he has received honoraria from Arxx Tx, Eli Lilly, Gesyntha, Leadiant, Roche and Sanofi-Genzyme, and grants from Astra Zeneca, MSD, Roche and Thermofisher, unrelated to the topic of this work. J.C.A.B. declares that he has no competing interests.

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Nature Reviews Rheumatology thanks H. Lorenz, J. Pope, M. Wiese and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Bioavailability

The proportion of a drug that reaches the circulation unchanged, and so has an active effect, when introduced into the body.

Pro-drug

A biologically inactive compound that, after administration, is metabolized into a pharmacologically active drug.

Tmax

The time taken for a drug to reach its maximum serum concentration in the body.

Area under the concentration–time curve

The area under a plot of plasma concentration of a drug versus time after dosage; this time curve reflects the actual body exposure to a drug after administration of a dose of the drug.

Therapeutic index

A ratio that denotes the margin of safety of a drug, comparing the dose of a drug that produces the desired effect and the dose that produces unwanted adverse effects.

Mixed lymphocyte reaction

A test used to measure how T cells function in the presence of external stimuli; in this assay, populations of T cells from different individuals are mixed to measure the reaction that occurs.

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Broen, J.C.A., van Laar, J.M. Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol 16, 167–178 (2020). https://doi.org/10.1038/s41584-020-0374-8

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