370
Views
3
CrossRef citations to date
0
Altmetric
Review

Mechanism of Action and Efficacy of Immunosupressors in Lupus Nephritis

ORCID Icon, , &
Pages 441-458 | Published online: 11 Dec 2021

References

  • Pakozdi A, Pyne D, Sheaff M, Rajakariar R. Utility of a repeat renal biopsy in lupus nephritis: a single centre experience. Nephrol Dial Transplant. 2018;33(3):507–513. doi:10.1093/ndt/gfx019
  • Kon T, Yamaji K, Sugimoto K, et al. Investigation of pathological and clinical features of lupus nephritis in 73 autopsied cases with systemic lupus erythematosus. Mod Rheumatol. 2010;20(2):168–177. doi:10.3109/s10165-009-0260-3
  • Borchers AT, Leibushor N, Naguwa SM, Cheema GS, Shoenfeld Y, Gershwin ME. Lupus nephritis: a critical review. Autoimmun Rev. 2012;12(2):174–194. doi:10.1016/j.autrev.2012.08.018
  • Adler M, Chambers S, Edwards C, Neild G, Isenberg D. An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period. Rheumatology (Oxford). 2006;45(9):1144–1147. doi:10.1093/rheumatology/kel039
  • Quintana LF, Jayne D. Sustained remission in lupus nephritis: still a hard road ahead. Nephrol Dial Transplant. 2016;31(12):2011–2018. doi:10.1093/ndt/gfv381
  • Mahajan A, Amelio J, Gairy K, et al. Systemic lupus erythematosus, lupus nephritis and end-stage renal disease: a pragmatic review mapping disease severity and progression. Lupus. 2020;29(9):1011–1020. doi:10.1177/0961203320932219
  • Sabucedo AJ, Contreras G. ESKD, transplantation, and dialysis in lupus nephritis. Semin Nephrol. 2015;35(5):500–508. doi:10.1016/j.semnephrol.2015.08.011
  • Zhang L, Lee G, Liu X, et al. Long-term outcomes of end-stage kidney disease for patients with lupus nephritis. Kidney Int. 2016;89(6):1337–1345. doi:10.1016/j.kint.2016.02.014
  • Hench PS, Kendall EC, Slocumb CH, Polley HF. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24(8):181–197.
  • Scheschowitsch K, Leite JA, Assreuy J. New insights in glucocorticoid receptor signaling-more than just a ligand-binding receptor. Front Endocrinol (Lausanne). 2017;8:16. doi:10.3389/fendo.2017.00016
  • Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17(4):233–247. doi:10.1038/nri.2017.1
  • Hardy RS, Raza K, Cooper MS. Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases. Nat Rev Rheumatol. 2020;16(3):133–144. doi:10.1038/s41584-020-0371-y
  • Vandewalle J, Luypaert A, De Bosscher K, Libert C. Therapeutic mechanisms of glucocorticoids. Trends Endocrinol Metab. 2018;29(1):42–54. doi:10.1016/j.tem.2017.10.010
  • Buttgereit F, Wehling M, Burmester GR. A new hypothesis of modular glucocorticoid actions: steroid treatment of rheumatic diseases revisited. Arthritis Rheum. 1998;41(5):761–767. doi:10.1002/1529-0131(199805)41:5<761::AID-ART2>3.0.CO;2-M
  • Boumpas DT, Austin HA, Vaughn EM, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet. 1992;340(8822):741–745. doi:10.1016/0140-6736(92)92292-N
  • Gourley MF, Austin HA, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med. 1996;125(7):549–557. doi:10.7326/0003-4819-125-7-199610010-00003
  • Singh JA, Hossain A, Kotb A, Wells G. Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis. BMC Med. 2016;14(1):137. doi:10.1186/s12916-016-0673-8
  • Walsh M, Jayne D, Moist L, Tonelli M, Pannu N, Manns B. Practice pattern variation in oral glucocorticoid therapy after the induction of response in proliferative lupus nephritis. Lupus. 2010;19(5):628–633. doi:10.1177/0961203309356292
  • Fischer-Betz R, Chehab G, Sander O, et al. Renal outcome in patients with lupus nephritis using a steroid-free regimen of monthly intravenous cyclophosphamide: a prospective observational study. J Rheumatol. 2012;39(11):2111–2117. doi:10.3899/jrheum.120537
  • Zeher M, Doria A, Lan J, et al. Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis. Lupus. 2011;20(14):1484–1493. doi:10.1177/0961203311418269
  • Condon MB, Ashby D, Pepper RJ, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72(8):1280–1286. doi:10.1136/annrheumdis-2012-202844
  • Tedeschi B, Arnaud L, Hie M, Mathian A, Amoura Z. Successful treatment of combined proliferative and membranous lupus nephritis using a full corticosteroid-free regimen. Ann Rheum Dis. 2014;73(2):474–475. doi:10.1136/annrheumdis-2013-204385
  • Rovin BH, Solomons N, Pendergraft WF, et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int. 2019;95(1):219–231. doi:10.1016/j.kint.2018.08.025
  • Ruiz-Irastorza G, Danza A, Perales I, et al. Prednisone in lupus nephritis: how much is enough? Autoimmun Rev. 2014;13(2):206–214. doi:10.1016/j.autrev.2013.10.013
  • Ruiz-Arruza I, Barbosa C, Ugarte A, Ruiz-Irastorza G. Comparison of high versus low-medium prednisone doses for the treatment of systemic lupus erythematosus patients with high activity at diagnosis. Autoimmun Rev. 2015;14(10):875–879. doi:10.1016/j.autrev.2015.05.011
  • Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78(6):736–745. doi:10.1136/annrheumdis-2019-215089
  • Gordon C, Amissah-Arthur MB, Gayed M, et al. The British Society for Rheumatology guideline for the management of systemic lupus erythematosus in adults: executive summary. Rheumatology (Oxford). 2018;57(1):14–18. doi:10.1093/rheumatology/kex291
  • Hahn BH, McMahon MA, Wilkinson A, et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012;64(6):797–808. doi:10.1002/acr.21664
  • Pons-Estel BA, Bonfa E, Soriano ER, et al. First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR). Ann Rheum Dis. 2018;77(11):1549–1557. doi:10.1136/annrheumdis-2018-213512
  • Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020;79(6):713–723. doi:10.1136/annrheumdis-2020-216924
  • Lightstone L. Minimising steroids in lupus nephritis–will B cell depletion pave the way? Lupus. 2013;22(4):390–399. doi:10.1177/0961203313476155
  • Lightstone L, Doria A, Wilson H, Ward FL, Larosa M, Bargman JM. Can we manage lupus nephritis without chronic corticosteroids administration? Autoimmun Rev. 2018;17(1):4–10. doi:10.1016/j.autrev.2017.11.002
  • Tani C, Vagelli R, Stagnaro C, Carli L, Mosca M. Remission and low disease activity in systemic lupus erythematosus: an achievable goal even with fewer steroids? Real-life data from a monocentric cohort. Lupus Sci Med. 2018;5(1):e000234. doi:10.1136/lupus-2017-000234
  • Ruiz-Irastorza G, Ugarte A, Ruiz-Arruza I, Khamashta M. Seventy years after Hench’s Nobel prize: revisiting the use of glucocorticoids in systemic lupus erythematosus. Lupus. 2020;29(10):1155–1167. doi:10.1177/0961203320930099
  • Yang X, Sherwin CM, Yu T, Yellepeddi VK, Brunner HI, Vinks AA. Pharmacokinetic modeling of therapies for systemic lupus erythematosus. Expert Rev Clin Pharmacol. 2015;8(5):587–603. doi:10.1586/17512433.2015.1059751
  • Struck RF, Alberts DS, Horne K, Phillips JG, Peng YM, Roe DJ. Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial. Cancer Res. 1987;47(10):2723–2726.
  • Ntali S, Bertsias G, Boumpas DT. Cyclophosphamide and lupus nephritis: when, how, for how long? Clin Rev Allergy Immunol. 2011;40(3):181–191. doi:10.1007/s12016-009-8196-0
  • Mok CC, Ying KY, Ng WL, et al. Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide. Am J Med. 2006;119(4):355 e325–333. doi:10.1016/j.amjmed.2005.08.045
  • de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670–680. doi:10.7326/0003-4819-150-10-200905190-00004
  • Ioannidis JP, Katsifis GE, Tzioufas AG, Moutsopoulos HM. Predictors of sustained amenorrhea from pulsed intravenous cyclophosphamide in premenopausal women with systemic lupus erythematosus. J Rheumatol. 2002;29(10):2129–2135.
  • Mok CC, Wong RW, Lau CS. Ovarian failure and flares of systemic lupus erythematosus. Arthritis Rheum. 1999;42(6):1274–1280. doi:10.1002/1529-0131(199906)42:6<1274::AID-ANR26>3.0.CO;2-B
  • Takada K, Arefayene M, Desta Z, et al. Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. Arthritis Rheum. 2004;50(7):2202–2210. doi:10.1002/art.20338
  • Singh G, Saxena N, Aggarwal A, Misra R. Cytochrome P450 polymorphism as a predictor of ovarian toxicity to pulse cyclophosphamide in systemic lupus erythematosus. J Rheumatol. 2007;34(4):731–733.
  • van Casteren NJ, van der Linden GH, Hakvoort-Cammel FG, Hahlen K, Dohle GR, van den Heuvel-eibrink MM. Effect of childhood cancer treatment on fertility markers in adult male long-term survivors. Pediatr Blood Cancer. 2009;52(1):108–112. doi:10.1002/pbc.21780
  • Sabbour MS, Osman LM. Comparison of chlorambucil, azathioprine or cyclophosphamide combined with corticosteroids in the treatment of lupus nephritis. Br J Dermatol. 1979;100(2):113–125. doi:10.1111/j.1365-2133.1979.tb05548.x
  • Austin HA, Klippel JH, Balow JE, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med. 1986;314(10):614–619. doi:10.1056/NEJM198603063141004
  • Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121–2131. doi:10.1002/art.10461
  • Houssiau FA, Vasconcelos C, D’Cruz D, et al. The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Ann Rheum Dis. 2010;69(1):61–64. doi:10.1136/ard.2008.102533
  • Attia DHS, Eissa M, Samy LA, Khattab RA. Influence of glutathione S transferase A1 gene polymorphism (−69C > T, rs3957356) on intravenous cyclophosphamide efficacy and side effects: a case-control study in Egyptian patients with lupus nephritis. Clin Rheumatol. 2021;40(2):753–762. doi:10.1007/s10067-020-05276-0
  • Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14(Suppl 1):s2–8. doi:10.1191/0961203305LU2109OA
  • Joy MS, Hilliard T, Hu Y, et al. Pharmacokinetics of mycophenolic acid in patients with lupus nephritis. Pharmacotherapy. 2009;29(1):7–16. doi:10.1592/phco.29.1.7
  • Mino Y, Naito T, Matsushita T, et al. Comparison of pharmacokinetics of mycophenolic acid and its glucuronide between patients with lupus nephritis and with kidney transplantation. Ther Drug Monit. 2008;30(6):656–661. doi:10.1097/FTD.0b013e31818b8244
  • Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011;365(20):1886–1895. doi:10.1056/NEJMoa1014460
  • Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103–1112. doi:10.1681/ASN.2008101028
  • Chan TM, Li FK, Tang CS, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. 2000;343(16):1156–1162. doi:10.1056/NEJM200010193431604
  • Kapitsinou PP, Boletis JN, Skopouli FN, Boki KA, Moutsopoulos HM. Lupus nephritis: treatment with mycophenolate mofetil. Rheumatology (Oxford). 2004;43(3):377–380. doi:10.1093/rheumatology/keh012
  • Glicklich D, Acharya A. Mycophenolate mofetil therapy for lupus nephritis refractory to intravenous cyclophosphamide. Am J Kidney Dis. 1998;32(2):318–322. doi:10.1053/ajkd.1998.v32.pm9708620
  • Henderson LK, Masson P, Craig JC, et al. Induction and maintenance treatment of proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis. 2013;61(1):74–87. doi:10.1053/j.ajkd.2012.08.041
  • Touma Z, Gladman DD, Urowitz MB, Beyene J, Uleryk EM, Shah PS. Mycophenolate mofetil for induction treatment of lupus nephritis: a systematic review and metaanalysis. J Rheumatol. 2011;38(1):69–78. doi:10.3899/jrheum.100130
  • Mak A, Cheak AA, Tan JY, Su HC, Ho RC, Lau CS. Mycophenolate mofetil is as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis: a meta-analysis and meta-regression. Rheumatology (Oxford). 2009;48(8):944–952. doi:10.1093/rheumatology/kep120
  • Zhu B, Chen N, Lin Y, et al. Mycophenolate mofetil in induction and maintenance therapy of severe lupus nephritis: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2007;22(7):1933–1942. doi:10.1093/ndt/gfm066
  • Rovin BH, Parikh SV, Hebert LA, et al. Lupus nephritis: induction therapy in severe lupus nephritis–should MMF be considered the drug of choice? Clin J Am Soc Nephrol. 2013;8(1):147–153. doi:10.2215/CJN.03290412
  • Walsh M, Solomons N, Lisk L, Jayne DR. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis with poor kidney function: a subgroup analysis of the Aspreva Lupus Management Study. Am J Kidney Dis. 2013;61(5):710–715. doi:10.1053/j.ajkd.2012.11.042
  • Radhakrishnan J, Moutzouris DA, Ginzler EM, Solomons N, Siempos II, Appel GB. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney Int. 2010;77(2):152–160. doi:10.1038/ki.2009.412
  • Chan TM, Tse KC, Tang CS, Mok MY, Li FK. Hong Kong Nephrology Study G. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol. 2005;16(4):1076–1084. doi:10.1681/ASN.2004080686
  • Laskari K, Mavragani CP, Tzioufas AG, Moutsopoulos HM. Mycophenolate mofetil as maintenance therapy for proliferative lupus nephritis: a long-term observational prospective study. Arthritis Res Ther. 2010;12(6):R208. doi:10.1186/ar3184
  • Fassbinder T, Saunders U, Mickholz E, et al. Differential effects of cyclophosphamide and mycophenolate mofetil on cellular and serological parameters in patients with systemic lupus erythematosus. Arthritis Res Ther. 2015;17:92. doi:10.1186/s13075-015-0603-8
  • Mejia-Vilet JM, Arreola-Guerra JM, Cordova-Sanchez BM, Morales-Buenrostro LE, Uribe-Uribe NO, Correa-Rotter R. Comparison of lupus nephritis induction treatments in a Hispanic population: a single-center cohort analysis. J Rheumatol. 2015;42(11):2082–2091. doi:10.3899/jrheum.150395
  • Dall’Era M, Solomons N, Federico R, Truman M. Comparison of standard of care treatment with a low steroid and mycophenolate mofetil regimen for lupus nephritis in the ALMS and AURA studies. Lupus. 2019;28(5):591–596. doi:10.1177/0961203319842924
  • Kittanamongkolchai W, Rukrung C, Supasiri T, et al. Therapeutic drug monitoring of mycophenolate mofetil for the treatment of severely active lupus nephritis. Lupus. 2013;22(7):727–732. doi:10.1177/0961203313486949
  • Luszczynska P, Pawinski T. Therapeutic drug monitoring of mycophenolic acid in lupus nephritis: a review of current literature. Ther Drug Monit. 2015;37(6):711–717. doi:10.1097/FTD.0000000000000223
  • Yap DYH, Tam CH, Yung S, et al. Pharmacokinetics and pharmacogenomics of mycophenolic acid and its clinical correlations in maintenance immunosuppression for lupus nephritis. Nephrol Dial Transplant. 2020;35(5):810–818. doi:10.1093/ndt/gfy284
  • Luszczynska P, Pawinski T, Kunicki PK, Durlik M, Augustyniak-Bartosik H, Hurkacz M. Pharmacokinetics of free and total mycophenolic acid in adult lupus nephritis patients-implications for therapeutic drug monitoring. Eur J Clin Pharmacol. 2019;75(3):371–379. doi:10.1007/s00228-018-2599-x
  • Alexander S, Fleming DH, Mathew BS, et al. Pharmacokinetics of concentration-controlled mycophenolate mofetil in proliferative lupus nephritis: an observational cohort study. Ther Drug Monit. 2014;36(4):423–432. doi:10.1097/FTD.0000000000000031
  • Pourafshar N, Karimi A, Wen X, et al. The utility of trough mycophenolic acid levels for the management of lupus nephritis. Nephrol Dial Transplant. 2019;34(1):83–89. doi:10.1093/ndt/gfy026
  • Kiyokawa T, Hanaoka H, Iida H, et al. High plasma mycophenolate acid concentration in the early phase of induction therapy predicts good renal outcome in lupus nephritis. Mod Rheumatol. 2020;30(3):517–524. doi:10.1080/14397595.2019.1623435
  • Sahasranaman S, Howard D, Roy S. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008;64(8):753–767. doi:10.1007/s00228-008-0478-6
  • Kaballo BG, Ahmed AE, Nur MM, Khalid IO, Abu-Aisha H. Mycophenolate mofetil versus azathioprine for maintenance treatment of lupus nephritis. Saudi J Kidney Dis Transpl. 2016;27(4):717–725. doi:10.4103/1319-2442.185233
  • Tamirou F, D’Cruz D, Sangle S, et al. Long-term follow-up of the MAINTAIN nephritis trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis. Ann Rheum Dis. 2016;75(3):526–531. doi:10.1136/annrheumdis-2014-206897
  • Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos. 2001;29(4 Pt 2):601–605.
  • Coenen MJ, de Jong DJ, van Marrewijk CJ, et al. Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology. 2015;149(4):907–917 e907. doi:10.1053/j.gastro.2015.06.002
  • Roy LM, Zur RM, Uleryk E, Carew C, Ito S, Ungar WJ. Thiopurine S-methyltransferase testing for averting drug toxicity in patients receiving thiopurines: a systematic review. Pharmacogenomics. 2016;17(6):633–656. doi:10.2217/pgs.16.12
  • Velo-Garcia A, Ntatsaki E, Isenberg D. The safety of pharmacological treatment options for lupus nephritis. Expert Opin Drug Saf. 2016;15(8):1041–1054. doi:10.1080/14740338.2016.1182496
  • McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3(1):89–98. doi:10.1517/14622416.3.1.89
  • Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75(5):795–810. doi:10.1136/annrheumdis-2015-208840
  • Houssiau FA, D’Cruz D, Sangle S, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN nephritis trial. Ann Rheum Dis. 2010;69(12):2083–2089. doi:10.1136/ard.2010.131995
  • Tian SY, Feldman BM, Beyene J, Brown PE, Uleryk EM, Silverman ED. Immunosuppressive therapies for the maintenance treatment of proliferative lupus nephritis: a systematic review and network metaanalysis. J Rheumatol. 2015;42(8):1392–1400. doi:10.3899/jrheum.141650
  • Nee R, Rivera I, Little DJ, Yuan CM, Abbott KC. Cost-utility analysis of mycophenolate mofetil versus azathioprine based regimens for maintenance therapy of proliferative lupus nephritis. Int J Nephrol. 2015;2015:917567. doi:10.1155/2015/917567
  • Barbarino JM, Staatz CE, Venkataramanan R, Klein TE, Altman RB. PharmGKB summary: cyclosporine and tacrolimus pathways. Pharmacogenet Genomics. 2013;23(10):563–585. doi:10.1097/FPC.0b013e328364db84
  • Scalea JR, Levi ST, Ally W, Brayman KL. Tacrolimus for the prevention and treatment of rejection of solid organ transplants. Expert Rev Clin Immunol. 2016;12(3):333–342. doi:10.1586/1744666X.2016.1123093
  • Ho S, Clipstone N, Timmermann L, et al. The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol. 1996;80(3 Pt 2):S40–45. doi:10.1006/clin.1996.0140
  • Kato A, Chustz RT, Ogasawara T, et al. Dexamethasone and FK506 inhibit expression of distinct subsets of chemokines in human mast cells. J Immunol. 2009;182(11):7233–7243. doi:10.4049/jimmunol.0801375
  • Moroni G, Ponticelli C. Synthetic pharmacotherapy for lupus nephritis. Expert Opin Pharmacother. 2017;18(2):175–186. doi:10.1080/14656566.2016.1276563
  • Hesselink DA, Bouamar R, Elens L, van Schaik RH, van Gelder T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014;53(2):123–139. doi:10.1007/s40262-013-0120-3
  • Zavada J, Sinikka Pesickova S, Rysava R, et al. Extended follow-up of the CYCLOFA-LUNE trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or on cyclosporine A. Lupus. 2014;23(1):69–74. doi:10.1177/0961203313511555
  • Bao H, Liu ZH, Xie HL, Hu WX, Zhang HT, Li LS. Successful treatment of class V+IV lupus nephritis with multitarget therapy. J Am Soc Nephrol. 2008;19(10):2001–2010. doi:10.1681/ASN.2007121272
  • Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: a randomized trial. Ann Intern Med. 2015;162(1):18–26. doi:10.7326/M14-1030
  • Sakai R, Kurasawa T, Nishi E, et al. Efficacy and safety of multitarget therapy with cyclophosphamide and tacrolimus for lupus nephritis: a prospective, single-arm, single-centre, open label pilot study in Japan. Lupus. 2018;27(2):273–282. doi:10.1177/0961203317719148
  • Li X, Ren H, Zhang Q, et al. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol Dial Transplant. 2012;27(4):1467–1472. doi:10.1093/ndt/gfr484
  • Yap DY, Yu X, Chen XM, et al. Pilot 24 month study to compare mycophenolate mofetil and tacrolimus in the treatment of membranous lupus nephritis with nephrotic syndrome. Nephrology (Carlton). 2012;17(4):352–357. doi:10.1111/j.1440-1797.2012.01574.x
  • Ikeuchi H, Hiromura K, Takahashi S, et al. Efficacy and safety of multi-target therapy using a combination of tacrolimus, mycophenolate mofetil and a steroid in patients with active lupus nephritis. Mod Rheumatol. 2014;24(4):618–625. doi:10.3109/14397595.2013.844397
  • Mok CC, Ying KY, Yim CW, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis. 2016;75(1):30–36. doi:10.1136/annrheumdis-2014-206456
  • Kamanamool N, Ingsathit A, Rattanasiri S, et al. Comparison of disease activity between tacrolimus and mycophenolate mofetil in lupus nephritis: a randomized controlled trial. Lupus. 2018;27(4):647–656. doi:10.1177/0961203317739131
  • Zhang H, Liu Z, Zhou M, et al. Multitarget therapy for maintenance treatment of lupus nephritis. J Am Soc Nephrol. 2017;28(12):3671–3678. doi:10.1681/ASN.2017030263
  • Cortes-Hernandez J, Torres-Salido MT, Medrano AS, Tarres MV, Ordi-Ros J. Long-term outcomes–mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial Transplant. 2010;25(12):3939–3948. doi:10.1093/ndt/gfq322
  • Mok CC, To CH, Yu KL, Ho LY. Combined low-dose mycophenolate mofetil and tacrolimus for lupus nephritis with suboptimal response to standard therapy: a 12-month prospective study. Lupus. 2013;22(11):1135–1141. doi:10.1177/0961203313502864
  • Choi CB, Won S, Bae SC. Outcomes of multitarget therapy using mycophenolate mofetil and tacrolimus for refractory or relapsing lupus nephritis. Lupus. 2018;27:961203318758505.
  • Jesus D, Rodrigues M, da Silva JAP, Ines L. Multitarget therapy of mycophenolate mofetil and cyclosporine A for induction treatment of refractory lupus nephritis. Lupus. 2018;27:961203318758508.
  • Richaud-Patin Y, Soto-Vega E, Jakez-Ocampo J, Llorente L. P-glycoprotein in autoimmune diseases. Autoimmun Rev. 2004;3(3):188–192. doi:10.1016/j.autrev.2003.08.002
  • Garcia-Carrasco M, Mendoza-Pinto C, Macias Diaz S, et al. P-glycoprotein in autoimmune rheumatic diseases. Autoimmun Rev. 2015;14(7):594–600. doi:10.1016/j.autrev.2015.02.006
  • Ragab SM, Soliman MA. P-glycoprotein-1 functional activity in CD5+CD7+ and CD20+ lymphocytes in systemic lupus erythematosus children: relation to disease activity, complications and steroid response. Egypt J Immunol. 2013;20(2):101–115.
  • Kansal A, Tripathi D, Rai MK, Agarwal V. Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus. Clin Rheumatol. 2016;35(2):341–349. doi:10.1007/s10067-015-3079-7
  • Picchianti-Diamanti A, Rosado MM, Scarsella M, Lagana B, D’Amelio R. P-glycoprotein and drug resistance in systemic autoimmune diseases. Int J Mol Sci. 2014;15(3):4965–4976. doi:10.3390/ijms15034965
  • Singh JA, Hossain A, Kotb A, et al. Treatments for lupus nephritis: a systematic review and network metaanalysis. J Rheumatol. 2016;43(10):1801–1815. doi:10.3899/jrheum.160041
  • Lee YH, Song GG. Relative efficacy and safety of tacrolimus, mycophenolate mofetil, and cyclophosphamide as induction therapy for lupus nephritis: a Bayesian network meta-analysis of randomized controlled trials. Lupus. 2015;24(14):1520–1528. doi:10.1177/0961203315595131
  • Tian J, Luo Y, Wu H, Long H, Zhao M, Lu Q. Risk of adverse events from different drugs for SLE: a systematic review and network meta-analysis. Lupus Sci Med. 2018;5(1):e000253. doi:10.1136/lupus-2017-000253
  • Hannah J, Casian A, D’Cruz D. Tacrolimus use in lupus nephritis: a systematic review and meta-analysis. Autoimmun Rev. 2016;15(1):93–101. doi:10.1016/j.autrev.2015.09.006
  • Kraaij T, Bredewold OW, Trompet S, et al. TAC-TIC use of tacrolimus-based regimens in lupus nephritis. Lupus Sci Med. 2016;3(1):e000169. doi:10.1136/lupus-2016-000169
  • Kuglstatter A, Mueller F, Kusznir E, et al. Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr. 2011;67(Pt 2):119–123. doi:10.1107/S0907444910051905
  • Stalder M, Birsan T, Hubble RW, Paniagua RT, Morris RE. In vivo evaluation of the novel calcineurin inhibitor ISATX247 in non-human primates. J Heart Lung Transplant. 2003;22(12):1343–1352. doi:10.1016/S1053-2498(03)00033-0
  • Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus. 1996;5(Suppl 1):S11–15. doi:10.1177/0961203396005001041
  • Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. 2015;23(5):231–269. doi:10.1007/s10787-015-0239-y
  • Lee SJ, Silverman E, Bargman JM. The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat Rev Nephrol. 2011;7(12):718–729. doi:10.1038/nrneph.2011.150
  • Wu SF, Chang CB, Hsu JM, et al. Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res Ther. 2017;19(1):183. doi:10.1186/s13075-017-1393-y
  • Wallace DJ, Gudsoorkar VS, Weisman MH, Venuturupalli SR. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev Rheumatol. 2012;8(9):522–533. doi:10.1038/nrrheum.2012.106
  • An N, Chen Y, Wang C, et al. Chloroquine autophagic inhibition rebalances Th17/Treg-mediated immunity and ameliorates systemic lupus erythematosus. Cell Physiol Biochem. 2017;44(1):412–422. doi:10.1159/000484955
  • Gao R, Wu W, Wen Y, Li X. Hydroxychloroquine alleviates persistent proteinuria in IgA nephropathy. Int Urol Nephrol. 2017;49(7):1233–1241. doi:10.1007/s11255-017-1574-2
  • Yang YZ, Liu LJ, Shi SF, et al. Effects of hydroxychloroquine on proteinuria in immunoglobulin A nephropathy. Am J Nephrol. 2018;47(3):145–152. doi:10.1159/000487330
  • Floris A, Piga M, Mangoni AA, Bortoluzzi A, Erre GL, Cauli A. Protective effects of hydroxychloroquine against accelerated atherosclerosis in systemic lupus erythematosus. Mediators Inflamm. 2018;2018:3424136. doi:10.1155/2018/3424136
  • Lopez P, Gomez J, Mozo L, Gutierrez C, Suarez A. Cytokine polymorphisms influence treatment outcomes in SLE patients treated with antimalarial drugs. Arthritis Res Ther. 2006;8(2):R42. doi:10.1186/ar1897
  • Lopez P, Gomez J, Prado C, Gutierrez C, Suarez A. Influence of functional interleukin 10/tumor necrosis factor-alpha polymorphisms on interferon-alpha, IL-10, and regulatory T cell population in patients with systemic lupus erythematosus receiving antimalarial treatment. J Rheumatol. 2008;35(8):1559–1566.
  • Ponticelli C, Moroni G. Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin Drug Saf. 2017;16(3):411–419. doi:10.1080/14740338.2017.1269168
  • Tsujimura S, Tanaka Y. Treatment strategy based on targeting P-glycoprotein on peripheral lymphocytes in patients with systemic autoimmune disease. Clin Exp Nephrol. 2012;16(1):102–108. doi:10.1007/s10157-011-0520-3
  • Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386–1394. doi:10.1016/j.ophtha.2016.01.058
  • Mahon GJ, Anderson HR, Gardiner TA, McFarlane S, Archer DB, Stitt AW. Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy. Curr Eye Res. 2004;28(4):277–284. doi:10.1076/ceyr.28.4.277.27835
  • Shulman S, Wollman J, Brikman S, Padova H, Elkayam O, Paran D. Implementation of recommendations for the screening of hydroxychloroquine retinopathy: poor adherence of rheumatologists and ophthalmologists. Lupus. 2017;26(3):277–281. doi:10.1177/0961203316660204
  • Putney JW. TRP, inositol 1,4,5-trisphosphate receptors, and capacitative calcium entry. Proc Natl Acad Sci U S A. 1999;96(26):14669–14671. doi:10.1073/pnas.96.26.14669
  • Kuijpers TW, Bende RJ, Baars PA, et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest. 2010;120(1):214–222. doi:10.1172/JCI40231
  • Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83(2):435–445. doi:10.1182/blood.V83.2.435.435
  • Pescovitz MD. Rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action. Am J Transplant. 2006;6(5 Pt 1):859–866. doi:10.1111/j.1600-6143.2006.01288.x
  • Montalvao F, Garcia Z, Celli S, et al. The mechanism of anti-CD20-mediated B cell depletion revealed by intravital imaging. J Clin Invest. 2013;123(12):5098–5103. doi:10.1172/JCI70972
  • Vieira CA, Agarwal A, Book BK, et al. Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics. Transplantation. 2004;77(4):542–548. doi:10.1097/01.TP.0000112934.12622.2B
  • Kronbichler A, Windpessl M, Pieringer H, Jayne DRW. Rituximab for immunologic renal disease: what the nephrologist needs to know. Autoimmun Rev. 2017;16(6):633–643. doi:10.1016/j.autrev.2017.04.007
  • Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012;64(4):1215–1226. doi:10.1002/art.34359
  • Weidenbusch M, Rommele C, Schrottle A, Anders HJ. Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial Transplant. 2013;28(1):106–111. doi:10.1093/ndt/gfs285
  • Salama AD, Pusey CD. Drug insight: rituximab in renal disease and transplantation. Nat Clin Pract Nephrol. 2006;2(4):221–230. doi:10.1038/ncpneph0133
  • Gomez Mendez LM, Cascino MD, Garg J, et al. Peripheral blood B cell depletion after rituximab and complete response in lupus nephritis. Clin J Am Soc Nephrol. 2018;13(10):1502–1509. doi:10.2215/CJN.01070118
  • Trivin C, Tran A, Moulin B, et al. Infectious complications of a rituximab-based immunosuppressive regimen in patients with glomerular disease. Clin Kidney J. 2017;10(4):461–469. doi:10.1093/ckj/sfw101
  • Gkrania-Klotsas E, Kumararatne DS. Serious infectious complications after rituximab therapy in patients with autoimmunity: is this the final word? Clin Infect Dis. 2021;72(5):738–742. doi:10.1093/cid/ciaa131
  • Md Yusof MY, Vital EM, Buch MH. B cell therapies, approved and emerging: a review of infectious risk and prevention during use. Curr Rheumatol Rep. 2015;17(10):65. doi:10.1007/s11926-015-0539-7
  • Dyson JK, Jopson L, Ng S, et al. Improving testing for hepatitis B before treatment with rituximab. Eur J Gastroenterol Hepatol. 2016;28(10):1172–1178. doi:10.1097/MEG.0000000000000689
  • Clifford DB, Ances B, Costello C, et al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol. 2011;68(9):1156–1164. doi:10.1001/archneurol.2011.103
  • Stabler S, Giovannelli J, Launay D, et al. Serious infectious events and immunoglobulin replacement therapy in patients with autoimmune disease receiving rituximab: a retrospective cohort study. Clin Infect Dis. 2021;72(5):727–737. doi:10.1093/cid/ciaa127
  • Dominguez-Mozo MI, Toledano-Martinez E, Rodriguez-Rodriguez L, Garcia-Montojo M, Alvarez-Lafuente R, Fernandez-Gutierrez B. JC virus reactivation in patients with autoimmune rheumatic diseases treated with rituximab. Scand J Rheumatol. 2016;45(6):507–511. doi:10.3109/03009742.2015.1135980
  • Nurmohamed MT. Newer biological agents in the treatment of rheumatoid arthritis: do the benefits outweigh the risks? Drugs. 2009;69(15):2035–2043. doi:10.2165/11318290-000000000-00000
  • Sato M, Yamada M, Nakajima M, Miyama Y, Kitayama H. The case of Kawasaki disease after rituximab infusion triggered by human anti-chimeric antibodies. CEN Case Rep. 2020;9(4):392–394. doi:10.1007/s13730-020-00492-8
  • Tahir H, Rohrer J, Bhatia A, Wegener WA, Isenberg DA. Humanized anti-CD20 monoclonal antibody in the treatment of severe resistant systemic lupus erythematosus in a patient with antibodies against rituximab. Rheumatology (Oxford). 2005;44(4):561–562. doi:10.1093/rheumatology/keh533
  • Furie R, Stohl W, Ginzler EM, et al. Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus. Arthritis Res Ther. 2008;10(5):R109. doi:10.1186/ar2506
  • Chen Y, Yang M, Long D, et al. Abnormal expression of BAFF and its receptors in peripheral blood and skin lesions from systemic lupus erythematosus patients. Autoimmunity. 2020;53(4):192–200. doi:10.1080/08916934.2020.1736049
  • Marcondes F, Scheinberg M. Belimumab in the treatment of systemic lupus erythematous: an evidence based review of its place in therapy. Autoimmun Rev. 2018;17(2):103–107. doi:10.1016/j.autrev.2017.11.013
  • Wallace DJ, Navarra S, Petri MA, et al. Safety profile of belimumab: pooled data from placebo-controlled Phase 2 and 3 studies in patients with systemic lupus erythematosus. Lupus. 2013;22(2):144–154. doi:10.1177/0961203312469259
  • Hui-Yuen JS, Li XQ, Askanase AD. Belimumab in systemic lupus erythematosus: a perspective review. Ther Adv Musculoskelet Dis. 2015;7(4):115–121. doi:10.1177/1759720X15588514
  • Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721–731. doi:10.1016/S0140-6736(10)61354-2
  • Furie R, Petri M, Zamani O, et al. A Phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918–3930. doi:10.1002/art.30613
  • Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020;383(12):1117–1128. doi:10.1056/NEJMoa2001180
  • Atisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II randomized trial of rituximab plus cyclophosphamide followed by belimumab for the treatment of lupus nephritis. Arthritis Rheumatol. 2021;73(1):121–131. doi:10.1002/art.41466
  • Ward M, Tektonidou MG. Belimumab as add-on therapy in lupus nephritis. N Engl J Med. 2020;383(12):1184–1185. doi:10.1056/NEJMe2027516
  • Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005;353(21):2219–2228. doi:10.1056/NEJMoa043731
  • Tsakonas E, Joseph L, Esdaile JM, et al. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus. 1998;7(2):80–85. doi:10.1191/096120398678919778
  • Fessler BJ, Alarcon GS, McGwin G, et al. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum. 2005;52(5):1473–1480. doi:10.1002/art.21039
  • Ruiz-Irastorza G, Egurbide MV, Pijoan JI, et al. Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus. Lupus. 2006;15(9):577–583. doi:10.1177/0961203306071872
  • Siso A, Ramos-Casals M, Bove A, et al. Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival. Lupus. 2008;17(4):281–288. doi:10.1177/0961203307086503
  • Pons-Estel GJ, Alarcon GS, McGwin G, et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum. 2009;61(6):830–839. doi:10.1002/art.24538
  • Shinjo SK, Bonfa E, Wojdyla D, et al. Antimalarial treatment may have a time-dependent effect on lupus survival: data from a multinational Latin American inception cohort. Arthritis Rheum. 2010;62(3):855–862. doi:10.1002/art.27300
  • Pons-Estel GJ, Alarcon GS, Hachuel L, et al. Anti-malarials exert a protective effect while Mestizo patients are at increased risk of developing SLE renal disease: data from a Latin-American cohort. Rheumatology (Oxford). 2012;51(7):1293–1298. doi:10.1093/rheumatology/ker514