Weaning Maintenance Therapy in Lupus Nephritis: For Whom, When, and How?

Lupus nephritis (LN) is one of the main determinants severity systemic lupus erythematosus (SLE). LN flares can lead to organ damage with chronic kidney disease (CKD) or even end-stage (ESKD) and impair patients’ survival. The “treat-to-target” strategy, which aims at obtaining maintaining remission low activity SLE alleviate symptoms prevent damage, also refers control residual in kidney. But come from treatments, toxicities related long-term use treatments should be prevented. This may contribute frequent nonadherence patients SLE. de-escalation weaning whenever possible, “think-to-untreat” (T2U) considered LN. possibility treatment was explored retrospective cohorts, on basis clinical remission. It proposed prospectively a kidney-biopsy-based approach, combining pathologic secure weaning. WIN-Lupus trial first randomized controlled comparing continuation discontinuation maintenance immunosuppressive therapy (IST) after 2 3 years showed higher risk severe who discontinued treatment, but without flare some patients, need better identified. We propose here narrative review available literature discuss how T2U strategy. SLE, has major impact morbidity mortality.1Yap D.Y.H. Tang C.S.O. Ma M.K.M. et al.Survival analysis causes mortality nephritis.Nephrol Dial Transplant. 2012; 27: 3248-3254https://doi.org/10.1093/ndt/gfs073Crossref PubMed Scopus (182) Google Scholar,2Murimi-Worstell I.B. Lin D.H. Nab H. al.Association between erythematosus: systematic meta-analysis.BMJ Open. 2020; 10e031850https://doi.org/10.1136/bmjopen-2019-031850Crossref (25) Scholar induce cumulative leading CKD ESKD 15% 20% 10 years3Tektonidou M.G. Dasgupta A. Ward M.M. Risk renal nephritis, 1971–2015: Bayesian meta-analysis.Arthritis Rheumatol. 2016; 68: 1432-1441https://doi.org/10.1002/art.39594Crossref (250) Scholar). Nonadherence factor for flares4Feldman C.H. Yazdany J. Guan al.Medication associated increased subsequent acute care utilization among Medicaid beneficiaries erythematosus.Arthritis Care Res (Hoboken). 2015; 67: 1712-1721https://doi.org/10.1002/acr.22636Crossref (83) ESKD.5Costedoat-Chalumeau N. Houssiau F.A. Improving medication adherence nephritis.Kidney Int. 2021; 99: 285-287https://doi.org/10.1016/j.kint.2020.10.037Abstract Full Text PDF (3) However, burden infectious6Feldman Hiraki L.T. Winkelmayer W.C. al.Serious infections adult nephritis.Arthritis 1577-1585https://doi.org/10.1002/art.39070Crossref (141) neoplastic,7Kiss E. Kovacs L. Szodoray P. Malignancies erythematosus.Autoimmun Rev. 2010; 9: 195-199https://doi.org/10.1016/j.autrev.2009.07.004Crossref (59) metabolic8Bruce I. Lupus: new diabetes. management.Lupus. 2013; 22: 1203-1204https://doi.org/10.1177/0961203313505690Crossref (4) complications as well cardiovascular LN9Conrad Verbeke G. Molenberghs al.Autoimmune diseases risk: population-based study 19 autoimmune 12 22 million individuals UK.Lancet. 2022; 400: 733-743https://doi.org/10.1016/S0140-6736(22)01349-6Abstract (34) CKD,10Gansevoort R.T. Correa-Rotter R. Hemmelgarn B.R. al.Chronic epidemiology, mechanisms, prevention.Lancet. 382: 339-352https://doi.org/10.1016/S0140-6736(13)60595-4Abstract (1327) heavily impairs prognosis.11Thomas Mancini Jourde-Chiche al.Mortality France assessed by multiple-cause-of-death analysis.Arthritis 2014; 66: 2503-2511https://doi.org/10.1002/art.38731Crossref (135) Scholar, 12Hermansen M.L. Lindhardsen Torp-Pedersen C. al.The nephritis: Danish nationwide cohort study.Rheumatol (Oxf Engl). 2017; 56: 709-715https://doi.org/10.1093/rheumatology/kew475Crossref (71) 13Levy B. Couchoud Rougier J.-P. al.Outcome dialysis: an observational incident French National Registry 2002–2012.Lupus. 24: 1111-1121https://doi.org/10.1177/0961203315578763Crossref (14) Furthermore, drugs taken consideration.14Ali A.Y. Abdelaziz T.S. Behiry M.E. prevalence non-adherence medications flares.Curr Rheumatol 16: 245-248https://doi.org/10.2174/1573397115666190626111847Crossref (5) Scholar,15Aim M.A. Queyrel V. Tieulié al.Importance temporality context relation life habit restrictions psychosocial qualitative study.Lupus. 31: 1423-1433https://doi.org/10.1177/09612033221115966Crossref (1) In addition continued efforts achieve maintain and/or SLE16Zen M. Iaccarino Gatto al.Lupus state decrease progression Caucasian overlaps remission.Ann Rheum Dis. 2018; 77: 104-110https://doi.org/10.1136/annrheumdis-2017-211613Crossref (103) 17Ugarte-Gil M.F. Hanly Urowitz al.Remission (LDA) accrual results Systemic International Collaborating Clinics (SLICC) inception cohort.Ann 81: 1541-1548https://doi.org/10.1136/ard-2022-222487Crossref (6) 18Gatto Zen Doria New therapeutic strategies management.Nat Rev 2019; 15: 30-48https://doi.org/10.1038/s41584-018-0133-2Crossref (84) 19van Vollenhoven R.F. Bertsias al.2021 DORIS definition SLE: final recommendations international task force.Lupus Sci Med. 8e000538https://doi.org/10.1136/lupus-2021-000538Crossref (45) development modern therapeutics, prevention damages optimized nephroprotection priority repeat biopsy assess reliably differentiate persistent evolution lesions20Tamirou F. Management nephritis.J Clin 10: 670https://doi.org/10.3390/jcm10040670Crossref (9) now being routine evaluation LN, pending robust noninvasive biomarkers. cohorts WIN-Lupus.21Jourde-Chiche Costedoat-Chalumeau Baumstarck K. al.WIN-Lupus group. Weaning (WIN-Lupus): multicentre randomised trial.Ann 1420-1427https://doi.org/10.1136/annrheumdis-2022-222435Crossref position biopsy, algorithm this name it "think-to-untreat" strategy,22Chiche Jousse-Joulin S. From “Treat Target” “Think Untreat”: de-implementation paradigm erythematosus.Rev Med Intern. 44: 101-104https://doi.org/10.1016/j.revmed.2022.12.001Crossref (0) reference its opposite pole, strategy; following treat-to-target sustained guidelines management have been updated 2019 Joint European League Against Rheumatism Renal Association–European Dialysis Transplant Association (EULAR/ERA-EDTA)23Fanouriakis Kostopoulou Cheema al.2019 Update Association-European (EULAR/ERA-EDTA) nephritis.Ann 79: 713-723https://doi.org/10.1136/annrheumdis-2020-216924Crossref (321) 2021 Kidney Disease–Improving Global Outcomes (KDIGO) guidelines.24Rovin B.H. Adler S.G. Barratt al.Executive summary KDIGO Guideline Glomerular Diseases.Kidney 100: 753-779https://doi.org/10.1016/j.kint.2021.05.015Abstract (144) After initial (or induction phase) proliferative IST must (maintenance treatment) least 5 years, consolidate relapses. relies mycophenolate mofetil (MMF) preferably (KDIGO), MMF azathioprine (AZA) (EULAR/ERA-EDTA), AZA pregnancy wish. Calcineurin inhibitors belimulab considered. A dose corticosteroids targeted (<5–7.5 mg/d per KDIGO, extrarenal activity; 2.5–5 EULAR/ERA-EDTA) weaned (in case complete 1 year KDIGO; EULAR/ERA-EDTA). Hydroxychloroquine (HCQ) all regular ophthalmologic monitoring25Jorge A.M. Zhou al.Hydroxychloroquine ophthalmology flares.JAMA. 328: 1458-1460https://doi.org/10.1001/jama.2022.13591Crossref (8) 50% reduction estimated glomerular filtration rate (eGFR) <30 ml/min.23Fanouriakis duration not less than 36 months KDIGO,24Rovin progressive discussed quiescence EULAR/ERA-EDTA,23Fanouriakis years. individualized according speed quality remission, flare-free activity, patient wishes. Of note, these were level evidence. They are summarized Table 1. wish either adapt (azathioprine, calcineurin prescribed during pregnancy) wean while continuing HCQ considering favored hormonal environment.26Fakhouri Schwotzer Cabiddu al.Glomerular pregnancy: pragmatic management.Kidney 103: 264-281https://doi.org/10.1016/j.kint.2022.10.029Abstract ScholarTable 1Current class III IV definitionsRecommendationsEULAR/ERA-EDTA [Faniourakis, ARD 2020]KDIGO [Rovin, Int 2021]Maintenance ISTMMF 1–2 g/d (especially induction) mg/kg/d if wish)MMF (preferably) AZAor CNI (if tolerated)Maintenance CS2.5–5 SLE< 5–7.5 extrarenalWeaning possible CCR ≥ moWeaning treatmentAfter > 3–5 yr CCRGradual taperingCS first, then (continue HCQ)Total moOnly controlled+/− Repeat (pathologic remission?)AZA, azathioprine; CCR, response; CNI, inhibitor; CS, corticosteroids; EULAR/ERA-EDTA, Association; HCQ, hydroxychloroquine IST, therapy; lobal Outcomes; nephritis; MMF, mofetil; PCR, partial remission; UPCR, urinary protein/creatinine ratio. Open table tab AZA, reached ESKD, immunosuppression guided manifestations SLE.23Fanouriakis These often reduced dialysis, tapered majority.27Coplon N.S. Diskin C.J. Petersen Swenson R.S. course disease.N Engl J 1983; 308: 186-190https://doi.org/10.1056/NEJM198301273080403Crossref (137) Scholar,28Nossent H.C. Swaak T.J. Berden J.H. 55 failure treated hemodialysis continuous ambulatory peritoneal dialysis. Dutch working party SLE.Am 1990; 89: 169-174https://doi.org/10.1016/0002-9343(90)90295-oAbstract Conversely, relapse progressing EKSD flare, particular caution regarding tapering patients. earlier trials Institute Health short-course pulses cyclophosphamide (6 monthly pulses) long-course (2 additional quarterly pulses).29Boumpas D.T. Austin 3rd, H.A. Vaughn E.M. al.Controlled pulse methylprednisolone versus two regimens nephritis.Lancet. 1992; 340: 741-745https://doi.org/10.1016/0140-6736(92)92292-nAbstract Scholar,30Illei G.G. Crane al.Combination plus improves outcome adding toxicity Intern 2001; 135: 248-257https://doi.org/10.7326/0003-4819-135-4-200108210-00009Crossref (426) 45% observed 145 (with cyclophosphamide, methylprednisolone, both).31Illei Takada Parkin D. al.Renal common therapy: followup participating studies.Arthritis Rheum. 2002; 46: 995-1002https://doi.org/10.1002/art.10142Crossref (266) data justified question optimal remained unresolved.32Moroni Raffiotta al.Can we withdraw immunosuppressants remission? An expert debate.Autoimmun 17: 11-18https://doi.org/10.1016/j.autrev.2017.11.003Crossref (15) Moroni al. 33Moroni Gallelli Quaglini al.Withdrawal follow-up.Nephrol 2006; 21: 1541-1548https://doi.org/10.1093/ndt/gfk073Crossref (82) reported Milan 2006, 201334Moroni Longhi Giglio al.What happens withdrawal nephritis.Clin Exp S75-S81PubMed 73 161 (45%) To eligible discontinuation, had stable (normal serum creatinine, proteinuria <0.5 g/d, absence hematuria, clinically quiescent ≥12 months). 21 (29%) reduction, successfully retreated. other 52 (71%) completely stopped subsequently corticosteroids, whom 32 did resume follow-up, 20 temporarily. Patients likely they longer before HCQ. authors concluded that ≥5 ≥3 years.35Moroni Frontini Ponticelli When stop nephritis. review.Clin Am Soc Nephrol. 1909-1917https://doi.org/10.2215/CJN.04830421Crossref Recently, al.36Zen Fuzzi Loredo Martinez al.Immunosuppressive achievement nephritis.Rheumatology (Oxford). 61: 688-695https://doi.org/10.1093/rheumatology/keab373Crossref (2) 83 238 (34.8%) biopsy-proven 1980 2020 period Padova, Italy. (23%) including 8 retreated, most 64 (77%) experience flare. older, more WIN-Lupus21Jourde-Chiche multicenter included presented (class +/− V, active lesions), ≥1 year, year. desire become pregnant within eGFR ml/min 1.73 m2, 6 required >20 7 days >10 mg/d, included. (1:1) into groups follows: (AZA MMF) over months. primary end point 24 secondary endpoints (renal extrarenal), survival adverse events, eGFR, corticosteroid consumption, health-related life. designed noninferiority trial. Between 2011 2016, 96 48 group, per-protocol population 84 patients: 40 group 44 Biopsy-proven relapses occurred (12.5%) (27.3%) (difference 14.8% [95% CI −1.9 31.5]). Therefore, demonstrated. superiority statistically significant, probably because underpowered. Relapse-free differ groups. (5/40 vs. 14/44 patients; P = 0.035). Adverse life, factors inclusion proteinuria-to-creatinuria ratio (P 0.001), C3 0.003), index 0.025), antiphospholipid syndrome 0.041), 0.046). Lower levels albumin, hemoglobin, leukocytes, lymphocytes, eosinophils relapse. limitations, lack power (96 out 200 planned), open-label design, no requirement off possibly too short identify late delayed side effects, selection bias (noninclusion relapsing patients). strengths include homogeneity terms involvement (biopsy-proven LN), (2–3 years), (≥1 year), prescription, relapse), standard period. Overall, stopping demonstrated, majority relapse, confirms identified, help stratification through identification biological factors. there high identifying needed. follow-up ongoing describe management, toxicities, provide information longer-term function. trial, down until zero months, viewed abrupt could (up mg/d) relapses, investigator’s discretion. No flared discontinuation. There discrepancy LN.37Malvar Pirruccio Alberton al.Histologic 32: 1338-1344https://doi.org/10.1093/ndt/gfv296Crossref (108) Not only persisting lesions, significant lesions. Persistent shown discontinuation,38De Rosa Azzato Toblli J.E. al.A prospective highlights findings therapy.Kidney 94: 788-794https://doi.org/10.1016/j.kint.2018.05.021Abstract (74) Malvar al.39Malvar Lococo al.Kidney biopsy–based safe ameliorate 97: 156-162https://doi.org/10.1016/j.kint.2019.07.018Abstract (47) strategy Among 220 75 (35%) ≥42 underwent activity. infraclinical 24-months rechallenged same procedure (9%) median lower 23% 29% rates previously when