The objective of immunosuppressive treatment for lupus nephritis is to abate ongoing damage to nephrons by active disease, and to prevent disease flares during the long-term maintenance phase
Current standard of care induction therapy for active, severe proliferative or membranous lupus nephropathy is dual immunosuppression with high-dose corticosteroids and either mycophenolate mofetil or cyclophosphamide
Low-dose corticosteroids combined with either mycophenolate or azathioprine are recommended as maintenance immunosuppression; mycophenolate mofetil for a minimum of 2 years is preferred in patients with previous renal flares
The selection of immunosuppressive agent and dose should take into account ethnic variation in response to different treatments
Antimalarial treatment is associated with reductions in renal flares and accrual of renal damage, as well as improved patient survival
Holistic management of patients with lupus nephritis should include prevention of and surveillance for complications, blood pressure control, renal preservation, vascular risk minimization and attention to overall quality of life
Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus, and an important cause of both acute kidney injury and end-stage renal disease. Despite its aggressive course, lupus nephritis is amenable to treatment in the majority of patients. The paradigm of immunosuppressive treatment for lupus nephritis has evolved over the past few decades from corticosteroids alone to corticosteroids combined with cyclophosphamide. Sequential treatment regimens using various agents have been formulated for induction and long-term maintenance therapy, and mycophenolate mofetil has emerged as a standard of care option for both induction and maintenance immunosuppressive treatment. The current era has witnessed the emergence of multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents that target key pathogenetic mechanisms of lupus nephritis. Clinical outcomes have improved in parallel with these therapeutic advances. This Review discusses the evidence in support of current standard of care immunosuppressive treatments and emerging therapies, and describes their roles and relative merits in the management of patients with lupus nephritis.
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Rabbani, M. A. et al. Early renal damage assessed by the SLICC/ACR damage index is predictor of severe outcome in lupus patients in Pakistan. Lupus 19, 1573–1578 (2010).
Yap, D. Y. H., Tang, C. S. O., Ma, M. K. M., Lam, M. F. & Chan, T. M. Survival analysis and causes of mortality in patients with lupus nephritis. Nephrol. Dial. Transplant. 27, 3248–3254 (2012).
Sutton, E. J., Davidson, J. E. & Bruce, I. N. The systemic lupus international collaborating clinics (SLICC) damage index: a systematic literature review. Semin. Arthritis Rheum. 43, 352–361 (2013).
Lopez, R., Davidson, J. E., Beeby, M. D., Egger, P. J. & Isenberg, D. A. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford) 51, 491–498 (2012).
Danila, M. I. et al. Renal damage is the most important predictor of mortality within the damage index: data from LUMINA LXIV, a multiethnic cohort. Rheumatology (Oxford) 48, 542–545 (2009).
Davidson, A. & Aranow, C. Lupus nephritis: lessons from murine models. Nat. Rev. Rheumatol. 6, 13–20 (2010).
Jakes, R. W. et al. Systematic review of the epidemiology of systemic lupus erythematosus in the Asia-Pacific region: prevalence, incidence, clinical features, and mortality. Arthritis Care Res. (Hoboken) 64, 159–168 (2012).
Mok, C. C., Kwok, R. C. & Yip, P. S. Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis Rheum. 65, 2154–2160 (2013).
Chan, T. M., Tse, K. C., Tang, C. S. O., Lai, K. N. & Li, F. K. Long-term outcome of patients with diffuse proliferative lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus 14, 265–262 (2005).
Illei, G. G. et al. Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis Rheum. 46, 995–1002 (2002).
El Hachmi, M., Jadoul, M., Lefebvre, C., Depresseux, G. & Houssiau, F. A. Relapses of lupus nephritis: incidence, risk factors, serology and impact on outcome. Lupus 12, 692–696 (2003).
Weening, J. J. et al. Classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 65, 521–530 (2004).
Korbet, S. M. et al. Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am. J. Kidney. Dis. 35, 904–914 (2000).
Houssiau, F. A. et al. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis. Arthritis Rheum. 50, 3934–3940 (2004).
Chen, Y. E., Korbet, S. M., Katz, R. S., Schwartz, M. M. & Lewis, E. J. for Collaborative Study Group. Value of a complete or partial remission in severe lupus nephritis. Clin. J. Am. Soc. Nephrol. 3, 46–53 (2008).
Korbet, S. M. & Lewis, E. J. for Collaborative Study Group. Severe lupus nephritis: the predictive value of a ≥50% reduction in proteinuria at 6 months. Nephrol. Dial. Transplant. 28, 2313–2318 (2013).
Rovin, B. H. et al. for the LUNAR Investigator Group. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis. Arthritis Rheum. 64, 1215–1226 (2012).
Furie, R. et al. Efficacy and safety of abatacept in lupus nephritis. A twelve-month, randomized, double-blind study. Arthritis Rheumatol. 66, 379–389 (2014).
Wofsy, D., Hillson, J. L. & Diamond, B. Abatacept for lupus nephritis. Alternative definitions of complete response support conflicting conclusions. Arthritis Rheum. 64, 3660–3665 (2012).
Donadio, J. V. Jr, Holley, K. E., Ferguson, R. H. & Ilstrup, D. M. Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide. N. Engl. J. Med. 299, 1151–1155 (1978).
Austin, H. A. 3rd et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N. Engl. J. Med. 314, 614–619 (1986).
Illei, G. G. et al. Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann. Intern. Med. 135, 248–257 (2001).
Mysler, E. F. et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis. Arthritis Rheum. 65, 2368–2379 (2013).
Boumpas, D. T. et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340, 741–745 (1992).
Gourley, M. F. et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann. Intern. Med. 125, 549–557 (1996).
Lewis, E. J. et al. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. N. Engl. J. Med. 326, 1373–1379 (1992).
Mok, C. C. et al. Outcome and prognostic indicators of diffuse proliferative lupus glomerulonephritis treated with sequential oral cyclophosphamide and azathioprine. Arthritis Rheum. 46, 1003–1013 (2002).
Chan, T. M. et al. Sequential therapy for diffuse proliferative and membranous lupus nephritis: cyclophosphamide and prednisolone followed by azathioprine and prednisolone. Nephron 71, 321–327 (1995).
Houssiau, F. A. 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. 46, 2121–2131 (2002).
Houssiau, F. A. 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. 69, 61–64 (2010).
Bakir, A. A., Levy, P. S. & Dunea, G. The prognosis of lupus nephritis in African-Americans: a retrospective analysis. Am. J. Kidney Dis. 24, 159–171 (1994).
Austin, H. A. 3rd et al. High-risk features of lupus nephritis: importance of race and clinical and histological factors in 166 patients. Nephrol. Dial. Transplant. 10, 1620–1628 (1995).
Korbet, S. M., Schwartz, M. M., Evans, J. & Lewis, E. J., for Collaborative Study Group. Severe lupus nephritis: racial differences in presentation and outcome. J. Am. Soc. Nephrol. 18, 244–254 (2007).
Contreras, G. et al. Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 350, 971–980 (2004).
Mok, C. C. et al. Treatment of diffuse proliferative lupus glomerulonephritis: a comparison of two cyclophosphamide-containing regimens. Am. J. Kidney Dis. 38, 256–264 (2001).
Bernatsky, S. et al. The relationship between cancer and medication exposures in systemic lupus erythematosus: a case-cohort study. Ann. Rheum. Dis. 67, 74–79 (2008).
Baker, G. L. et al. Malignancy following treatment of rheumatoid arthritis with cyclophosphamide. Long-term case-control follow-up study. Am. J. Med. 83, 1–9 (1987).
Petri, M. Cyclophosphamide: new approaches for systemic lupus erythematosus. Lupus 13, 366–371 (2004).
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guidelines for Glomerulonephritis. Kidney Int. Suppl. 2, 139–274 (2012).
Halloran, P., et al Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized double-blind clinical studies in prevention of rejection. The International Mycophenolate Mofetil Renal Transplant Study Groups. Transplantation 63, 39–47 (1997).
McMurray, R. W., Elbourne, K. B., Lagoo, A. & Lai, S. Mycophenolate mofetil suppresses autoimmunity and mortality in the female NZBxNZW F1 mouse model of systemic lupus erythematosus. J. Rheumatol. 25, 2364–2370 (1998).
Van Bruggen, M. C., Walgreen, B., Rijke, T. P. & Berden, J. H. Attenuation of murine lupus nephritis by mycophenolate mofetil. J. Am. Soc. Nephrol. 9, 1407–1415 (1998).
Jonsson, C. A., Svensson, L. & Carlsten, H. Beneficial effect of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil on survival and severity of glomerulonephritis in systemic lupus erythematosus (SLE)-prone MRLlpr/lpr mice. Clin. Exp. Immunol. 116, 534–541 (1999).
Corna, D. et al. Mycophenolate mofetil limits renal damage and prolongs life in murine lupus autoimmune disease. Kidney Int. 51, 1583–1589 (1997).
Ramos, M. A. et al. Modulation of autoantibody production by mycophenolate mofetil: effects on the development of SLE in NZBxNZW F1 mice. Nephrol. Dial. Transplant. 18, 878–883 (2003).
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).
Chan, T. M., Tse, K. C., Tang, C. S., Mok, M. Y. & Li, F. K., for Hong Kong Nephrology Study Group. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J. Am. Soc. Nephrol. 16, 1076–1084 (2005).
Tse, K. C., Tang, C. S, Lio, W. I., Lam, M. F. & Chan, T. M. Quality of life comparison between corticosteroid-and-mycofenolate mofetil and corticosteroid-and-oral cyclophosphamide in the treatment of severe lupus nephritis. Lupus 15, 371–379 (2006).
Hu, W. et al. Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis. Chin. Med. J. (Engl.) 115, 705–709 (2002).
Ding, L., Zhao, M., Zou, W., Liu, Y. & Wang, H. Mycophenolate mofetil combined with prednisone for diffuse proliferative lupus nephritis: a histopathological study. Lupus 13, 113–118 (2004).
Ong, L. M. et al. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology 10, 504–510 (2005).
Ginzler, E. M. et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N. Engl. J. Med. 353, 2219–2228 (2005).
Lu, F. et al. for MMF in Induction Therapy for Active Lupus Nephritis in Mainland China Study Group. A prospective multicenter study of mycophenolate mofetil combined with prednisolone as induction therapy in 213 patients with active lupus nephritis. Lupus 17, 622–629 (2008).
Cross, J. et al. Mycophenolate mofetil for remission induction in severe lupus nephritis. Nephron Clin. Pract. 100, c92–c100 (2005).
Appel, G. B. et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J. Am. Soc. Nephrol. 20, 1103–1112 (2009).
Dooley, M. A. et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N. Engl. J. Med. 365, 1886–1895 (2011).
Isenberg, D. et al. Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study. Rheumatology (Oxford) 49, 128–140 (2010).
Walsh, M., Solomons, N., Lisk, L. & Jayne, D. R. W. 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. 61, 710–715 (2013).
Rovin, B. H. et al. Lupus Nephritis: induction therapy in severe lupus nephritis—should MMF be considered the drug of choice? Clin. J. Am. Soc. Nephrol. 8, 147–153 (2013).
Neylan, J. F. for U.S. Renal Transplant Mycophenolate Mofetil Study Group. Immunosuppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. Transplantation 64, 1277–1282 (1997).
Mathew, T. H. for Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded long-term randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Transplantation 65, 956–965 (1998).
Radhakrishnan, J. et al. Mycophenolate mofetil and intravenous cyclophosphamide are similar as induction therapy for class V lupus nephritis. Kidney Int. 77, 152–160 (2010).
Yap, D. Y. et al. Pilot 24 month study to compare mycophenolate mofetil and tacrolimus in the treatment of membranous lupus nephritis with nephrotic syndrome. Nephrology (Carlton) 17, 352–357 (2012).
Houssiau, F. A. et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann. Rheum. Dis. 69, 2083–2089 (2010).
Yap, D. Y. et al. Long-term data on corticosteroids and mycophenolate mofetil treatment in lupus nephritis. Rheumatology (Oxford) 52, 480–486 (2013).
Vincenti, F. et al. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation 73, 775–782 (2002).
Coward, R. J. et al. Nephrotic plasma alters slit diaphragm-dependent signaling and translocates nephrin, Podocin, and CD2 associated protein in cultured human podocytes. J. Am. Soc. Nephrol. 16, 629–637 (2005).
Bensman, A. & Niaudet, P. Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies. Pediatr. Nephrol. 25, 1197–1199 (2010).
Faul, C. et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat. Med. 14, 931–938 (2008).
Hofstra, J. M., Fervenza, F. C. & Wetzels, J. F. M. Treatment of idiopathic membranous nephropathy. Nat. Rev. Nephrol. 9, 443–458 (2013).
Coppo, R. Different targets for treating focal segmental glomerulosclerosis. Contrib. Nephrol. 181, 84–90 (2013).
Morton, S. J. & Powell, R. J. An audit of cyclosporin for systemic lupus erythematosus and related overlap syndromes: limitations of its use. Ann. Rheum. Dis. 59, 487–489 (2000).
Ishiguro, N., Iwasaki, T., Kawashima, M. & Kawakami, M. Intractable ulceration in a patient with lupus erythematosus profundus successfully treated with cyclosporine. Int. J. Dermatol. 51, 1131–1133 (2012).
Margreiter, R. for European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study. Lancet 359, 741–746 (2002).
Zavada, J. et al. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the CYCLOFA-LUNE study. Lupus 19, 1281–1289 (2010).
Zavada, J. 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 23, 69–74 (2014).
Kamijo, Y. et al. Treatment with cyclosporine A improves SLE disease activity of Japanese patients with diffuse proliferative lupus nephritis. Clin. Nephrol. 76, 136–143 (2011).
Bao, H. et al. Successful treatment of class V+IV lupus nephritis with multitarget therapy. J. Am. Soc. Nephrol. 19, 2001–2010 (2008).
Tanaka, H. et al. Management of young patients with lupus nephritis using tacrolimus administered as a single daily dose. Clin. Nephrol. 72, 430–436 (2009).
Moroni, G. et al. A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years. Clin. J. Am. Soc. Nephrol. 1, 925–932 (2006).
Chen, W. et al. Short-term outcomes of induction therapy with tacrolimus versus cyclophosphamide for active lupus nephritis: a multicenter randomized clinical trial. Am. J. Kidney Dis. 57, 235–244 (2011).
Li, X. et al. Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis. Nephrol. Dial. Transplant. 27, 1467–72 (2012).
Lee, Y. H., Lee, H. S., Choi, S. J., Dai Ji, J. & Song, G. G. Efficacy and safety of tacrolimus therapy for lupus nephritis: a systematic review of clinical trials. Lupus 20, 636–640 (2011).
Tanaka, H. et al. Long-term tacrolimus-based immunosuppressive treatment for young patients with lupus nephritis: a prospective study in daily clinical practice. Nephron Clin. Pract. 121, c165–c173 (2012).
Austin, H. A. 3rd et al. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J. Am. Soc. Nephrol. 20, 901–911 (2009).
Tse, K. C. et al. A pilot study on tacrolimus treatment in membranous or quiescent lupus nephritis with proteinuria resistant to angiotensin inhibition or blockade. Lupus 16, 46–51 (2007).
Szeto, C. C. et al. Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis. Rheumatology (Oxford) 47, 1678–1681 (2008).
Gaston, R. S. Chronic calcineurin inhibitor nephrotoxicity: reflections on an evolving paradigm. Clin. J. Am. Soc. Nephrol. 4, 2029–2034 (2009).
Westhoff, T. H. & van der Giet, M. Tacrolimus in the treatment of idiopathic nephrotic syndrome. Expert Opin. Investig. Drugs. 16, 1099–1110 (2007).
Yap, D. Y. et al. Long-term data on tacrolimus treatment in lupus nephritis. Rheumatology (Oxford). http://dx.doi.org/10.1093/rheumatology/keu265.
Grootscholten, C. et al. for Dutch Working Party on Systemic Lupus Erythematosus. Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial. Kidney Int. 70, 732–742 (2006).
Grootscholten, C. et al. for Dutch Working Party on Systemic Lupus Erythematosus. Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than does treatment with azathioprine plus methylprednisolone in patients with proliferative lupus nephritis. Arthritis Rheum. 56, 924–937 (2007).
Arends, S. et al. for Dutch Working Party on Systemic Lupus Erythematosus. Long-term follow-up of a randomised controlled trial of azathioprine/methylprednisolone versus cyclophosphamide in patients with proliferative lupus nephritis. Ann. Rheum. Dis. 71, 966–973 (2012).
Smith, R. M., Clatworthy, M. R. & Jayne, D. R. W. Biological therapy for lupus nephritis—tribulations and trials. Nat. Rev. Rheumatol. 6, 547–552 (2010).
Gregersen, J. W. & Jayne, D. R. W. B-cell depletion in the treatment of lupus nephritis. Nat. Rev. Nephrol. 8, 505–514 (2012).
Garcia-Carrasco, M. et al. Anti-CD20 therapy in patients with refractory systemic lupus erythematosus: a longitudinal analysis of 52 Hispanic patients. Lupus 19, 213–219 (2010).
Catapano, F., Chaudhry, A. N., Jones, R. B., Smith, K. G. & Jayne, D. W. Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol. Dial. Transplant. 25, 3586–3592 (2010).
Lu, T. Y. et al. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients. Arthritis Rheum. 61, 482–487 (2009).
Lindholm, C. et al. Longterm clinical and immunological effects of anti-CD20 treatment in patients with refractory systemic lupus erythematosus. J. Rheumatol. 35, 826–833 (2008).
Jónsdóttir, T. et al. Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response. Ann. Rheum. Dis. 67, 330–334 (2008).
Díaz-Lagares, C. et al. The UK-BIOGEAS Registry. Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun. Rev. 11, 357–364 (2012).
Pepper, R. et al. Rituximab is an effective treatment for lupus nephritis and allows a reduction in maintenance steroids. Nephrol. Dial. Transplant. 24, 3717–3723 (2009).
Moroni, G. et al. Rituximab vs mycophenolate and vs cyclophosphamide pulses for induction therapy of active lupus nephritis: a clinical observational study. Rheumatology (Oxford) 53, 1570–1577 (2014).
Furie, R. et al. for the BLISS-76 Study Group. 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. 63, 3918–3930 (2011).
Navarra, S. V. et al. for the BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomized placebo-controlled phase 3 trial. Lancet 377, 721–731 (2011).
Dooley, M. A. et al. for the BLISS-52 and -76 Study Groups. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus 22, 63–72 (2013).
Condon, M. B. 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. 72, 1280–1286 (2013).
Kawasaki, Y. Mizoribine: a new approach in the treatment of renal disease. Clin. Dev. Immunol. (2009). http://dx.doi.org/10.1155/2009/681482.
Tanaka, Y. et al. for Japanese Study Group for Renal Disease in Children. Combination therapy with steroids and mizoribine in juvenile SLE: a randomized controlled trial. Pediatr. Nephrol. 25, 877–882 (2010).
Fuke, T. et al. Mizoribine requires individual dosing due to variation of bioavailability. Pediatr. Int. 54, 885–891 (2012).
Nozu, K. et al. High-dose mizoribine treatment for adolescents with systemic lupus erythematosus. Pediatr. Int. 48, 152–157 (2006).
Kondo, T. et al. Efficacy of weekly mizoribine pulse therapy in refractory lupus nephritis. Mod. Rheumatol. 23, 97–103 (2013).
Zhang, M., Xing, C. Y. & Liu, J. Study of the efficacy of mizoribine in lupus nephritis in Chinese patients. Rheumatol. Int. 33, 2737–2742 (2013).
Tanaka, H. et al. Efficacy of mizoribine-tacrolimus based induction therapy for pediatric lupus nephritis. Lupus 23, 813–818 (2014)
Meier, F. M., Frerix, M., Hermann, W. & Muller-Ladner, U. Current immunotherapy in rheumatoid arthritis. Immunotherapy 5, 955–974 (2013).
Tam, L. S., Li, E. K., Wong, C. K., Lam, C. W. K. & Szeto, C. C. Double-blind randomized placebo-controlled pilot study of leflunomide in systemic lupus erythematosus. Lupus 13, 601–604 (2004).
Wang, H. Y. et al, China Leflunomide Lupus Nephritis Study Group. Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study. Lupus 17, 638–644 (2008).
Diekmann, F. & Campistol, J. M. Conversion from calcineurin inhibitors to sirolimus in chronic allograft nephropathy: benefits and risks. Nephrol. Dial. Transplant. 21, 562–568 (2006).
Gabardi, S. & Baroletti, S. A. Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology. Pharmacotherapy 30, 1044–1056 (2010).
Lui, S. L. et al. Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice. Nephrol. Dial. Transplant. 23, 2768–2776 (2008).
Lui, S. L. et al. Rapamycin prevents the development of nephritis in lupus-prone NZB/W F1 mice. Lupus 17, 305–313 (2008).
Yap, D. Y. H. et al. Proliferation signal inhibitors in the treatment of lupus nephritis: preliminary experience. Nephrology (Carlton) 17, 676–680 (2012).
Hahn, B. H. et al. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res. (Hoboken) 64, 797–808 (2012).
Bertsias, G. K. et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann. Rheum. Dis. 71, 1771–1782 (2012).
Ruiz-Irastorza, G., Ramos-Casals, M., Brito-Zeron, P. & Khamashta, M. A. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann. Rheum. Dis. 69, 20–28 (2010).
Alarcón, G. S. et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann. Rheum. Dis. 66, 1168–1172 (2007).
Fessler, B. J. et al. Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum. 52, 1473–1480 (2005).
Karres, I. et al. Chloroquine inhibits proinflammatory cytokine release into human whole blood. Am. J. Physiol. 274, R1058–R1064 (1998).
Wozniacka, A., Lesiak, A., Narbutt, J., McCauliffe, D. P. & Sysa-Jedrzejowska, A. Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus 15, 268–275 (2006).
Wallace, D. J., Linker-Israeli, M., Metzger, A. L. & Stecher, V. J. The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. Lupus 2, S13–S15 (1993).
Toubi, E. et al. The reduction of serum B-lymphocyte activating factor levels following quinacrine add-on therapy in systemic lupus erythematosus. Scand. J. Immunol. 63, 299–303 (2006).
Ben-Zvi, I., Kivity, S., Langevitz, P. & Shoenfeld, Y. Hydroxychloroquine: from malaria to autoimmunity. Clin. Rev. Allergy Immunol. 42, 145–153 (2012).
Ermann, J. & Bermas, B. L. The biology behind the new therapies for SLE. Int. J. Clin. Pract. 61, 2113–2119 (2007).
Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N. Engl. J. Med. 324, 150–154 (1991).
Tsakonas, E. et al. for The Canadian Hydroxychloroquine Study Group. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. Lupus 7, 80–85 (1998).
Shinjo, S. K. et al. Antimalarial treatment may have a time-dependent effect on lupus survival: data from a multinational Latin American inception cohort. Arthritis Rheum. 62, 855–862 (2010).
Pons-Estel, G. J. et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Care Res. 61, 830–839 (2009).
Pokroy-Shapira, E., Gelernter, I. & Molad, Y. Evolution of chronic kidney disease in patients with systemic lupus erythematosus over a long-period follow-up: a single-center inception cohort study. Clin. Rheumatol. 33, 649–657 (2014).
Kasitanon, N., Fine, D. M., Haas, M., Magder, L. S. & Petri, M. Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus 15, 366–370 (2006).
Hodis, H. N., Quismorio, F. P. Jr, Wickham, E. & Blankenhorn, D. H. The lipid, lipoprotein, and apolipoprotein effects of hydroxychloroquine in patients with systemic lupus erythematosus. J. Rheumatol. 20, 661–665 (1993).
Petri, M., Lakatta, C., Magder, L. & Goldman, D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am. J. Med. 96, 254–259 (1994).
Borba, E. F. & Bonfá, E. Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy. J. Rheumatol. 28, 780–785 (2001).
Song, D. et al. The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res. Ther. 15, R12. http://dx.doi.org/10.1186/ar4142 (2013).
Chen, S. et al. Significance of histological crescent formation in patients with diffuse proliferative lupus nephritis. Am. J. Nephrol. 38, 445–452 (2013).
Najafi, C. C. et al. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int. 59, 2156–2163 (2001).
Hill, G. S. et al. Class IV-S versus class IV-G lupus nephritis: clinical and morphologic differences suggesting different pathogenesis. Kidney Int. 68, 2288–2297 (2005).
Schwartz, M. M., Korbet, S. M. & Lewis, E. J. The prognosis and pathogenesis of severe lupus glomerulonephritis. Nephrol. Dial. Transplant. 23, 1298–1306 (2008).
Behara, V. Y. et al. Pathogenetic features of severe segmental lupus nephritis. Nephrol. Dial. Transplant. 25, 153–159 (2010).
Mok, C. C. et al. for Asian Lupus Nephritis Network (ALNN). Overview of lupus nephritis management guidelines and perspective from Asia. Nephrology (Carlton) 19, 11–20 (2014).
Lertdumrongluk, P. et al. Pharmacokinetics of mycophenolic acid in severe lupus nephritis. Kidney Int. 78, 389–395 (2010).
Chiarelli, L. R. et al. Inosine monophosphate dehydrogenase variability in renal transplant patients on long-term mycophenolate mofetil therapy. Br. J. Clin. Pharmacol. 69, 38–50 (2010).
Punyawudho, B. et al. Population pharmacokinetics of mycophenolate mofetil in Thai lupus nephritis patients. Int. J. Clin. Pharmacol. Ther. 50, 272–280 (2012).
Kittanamongkolchai, W. et al. Therapeutic drug monitoring of mycophenolate mofetil for the treatment of severely active lupus nephritis. Lupus 22, 727–732 (2013).
Neumann, I. et al. Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil. Nephrol. Dial. Transplant. 23, 3514–3520 (2008).
van Gelder, T., Berden, J. H. M. & Berger, S. P. To TDM or not to TDM in lupus nephritis patients treated with MMF? Nephrol. Dial. Transplant. http://dx.doi.org/10.1093/ndt/gfu184.
Bultink, I. E. et al. Prevalence of and risk factors for low bone mineral density and vertebral fractures in patients with systemic lupus erythematosus. Arthritis Rheum. 52, 2044–2050 (2005).
Austin, H. A. 3rd, Illei, G. G. & Balow, J. E. in Lupus Nephritis 2nd edn (ed. Lewis, E. J., Schwartz, M. M., Korbet, S. M. & Chan, D. T. M.) 169–197 (Oxford University Press, 2011).
Pasquali, S. et al. Lupus membranous nephropathy: Long-term outcome. Clin. Nephrol. 39, 175–182 (1993).
Sun, H. O. et al. Long-term outcome of Chinese patients with membranous lupus nephropathy. Lupus 17, 56–61 (2008).
Honkanen, E. et al. Long-term survival in idiopathic membranous glomerulonephritis: can the course be clinically predicted? Clin. Nephrol. 41, 127–134 (1994).
Mercadal, L. et al. Factors affecting outcome and prognosis in membranous lupus nephropathy. Nephrol. Dial. Transplant. 17, 1771–1778 (2002).
Tse, K. C. et al. Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria. Lupus 14, 947–952 (2005).
Sloan, R. P. et al. Long-term outcome in systemic lupus erythematosus membranous glomerulonephritis. Lupus Nephritis Collaborative Study Group. J. Am. Soc. Nephrol. 7, 299–305 (1996).
Swan, J. T. et al. Systematic review and meta-analysis of immunosuppressant therapy clinical trials in membranous lupus nephritis. J. Investig. Med. 59, 246–258 (2011).
Mok, C. C. et al. Treatment of pure membranous lupus nephropathy with prednisone and azathioprine: an open-label trial. Am. J. Kidney Dis. 43, 269–276 (2004).
Chan, T. M. et al. Treatment of membranous lupus nephritis with nephrotic syndrome by sequential immunosuppression. Lupus 8, 545–551 (1999).
The author thanks the Wai Hung Charitable Foundation Limited, Mr G King, and the Yu Chiu Kwong Endowed Professorship in Medicine of The University of Hong Kong for their funding support of clinical research projects in lupus nephritis conducted at Queen Mary Hospital, Hong Kong.
T.M.C. declares that he has acted as a consultant for the following companies: Astellas, Teva and Vifor Pharma.
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Chan, T. Treatment of severe lupus nephritis: the new horizon. Nat Rev Nephrol 11, 46–61 (2015). https://doi.org/10.1038/nrneph.2014.215
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