The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy

A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy tacrolimus and rituximab superior to alternating treatment corticosteroids cyclophosphamide in inducing persistent remission these patients. This was tested a randomized, open-label controlled trial 86 nephrotic syndrome after six-months observation assigned 43 each receive six-month corticosteroid or (full-dose six months tapering another three months) (one gram month six). The outcome complete partial 24 months. composite occurred 36 (83.7%) the group 25 (58.1%) tacrolimus-rituximab (relative 1.44; 95% confidence interval 1.08 1.92). Complete 26 (60%) 11 (26%) (2.36; 1.34 4.16). Anti-PLA2R titers showed significant decrease both groups but proportion anti-PLA2R-positive who achieved immunological response (depletion anti-PLA2R antibodies) significantly higher (77% 92%, respectively), as compared (45% 70%, respectively). Relapses one patient group, group. Serious adverse events were similar groups. Thus, induced greater number than tacrolimus-rituximab. Primary (PMN) most common causes adults.1Couser W. nephropathy.Clin J Am Soc Nephrol. 2017; 12: 983-997Crossref PubMed Scopus (245) Google Scholar In 70%–80% cases, disease mediated by autoantibodies targeting phospholipase A2 receptor (PLA2R) expressed podocytes 3%–5% thrombospondin type 1 domain–containing 7A (THSD7A).2Beck Jr., L.H. Bonegio R.G. Lambeau G. et al.M-Type target antigen idiopathic nephropathy.N Engl Med. 2009; 361: 11-21Crossref (1419) Scholar, 3Ronco P. Debiec H. Molecular pathogenesis nephropathy.Annu Rev Pathol. 2020; 15: 287-313Crossref (42) 4Tomas N.M. Beck Meyer-Schwesinger C. al.Thrombospondin type-1 2014; 371: 2277-2287Crossref (496) Spontaneous occurs one-third patients,5Polanco N. Gutiérrez E. Covarsí A. al.Spontaneous nephropathy.J 2010; 21: 697-704Crossref (248) therefore an observational period least 6 recommended.6Waldman M. Austin H.A. Treatment 2012; 23: 1617-1630Crossref (62) 7Hofstra J.M. Fervenza F.C. Wetzels J.F.M. nephropathy.Nat 2013; 9: 443-458Crossref (88) 8Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guidelines glomerulonephritis.Kidney Int Suppl. 2 (139–27)Google Conversely, about 50% cases eventually progress end-stage kidney disease, immunosuppressive Controversy persists effective regimen. 2012 Kidney glomerulonephritis 6-month cyclic alkylating agents (usually cyclophosphamide) plus progression, since it only shown be preventing disease.8Kidney 9Ponticelli Zucchelli Passerini al.A randomized methylprednisolone chlorambucil 1989; 320: 8-13Crossref (240) 10Ponticelli 10-year follow-up study nephropathy.Kidney Int. 1995; 48: 1600-1604Abstract Full Text PDF (336) 11Ponticelli Altieri Scolari F. comparing versus 1998; 444-450Crossref 12Jha V. Ganguli Saha T.K. steroids adults caused 2007; 18: 1899-1904Crossref (215) However, given important serious associated cumulative doses agents, alternatives introduced. Calcineurin inhibitors (both cyclosporine tacrolimus) have efficacy 70% patients.13Cattran D.C. Appel G.B. Hebert L.A. al.Cyclosporine steroid-resistant nephropathy: trial.Kidney 2001; 59: 1484-1490Abstract (297) Scholar,14Praga Barrio Juárez G.F. Luño J. Tacrolimus monotherapy 71: 924-930Abstract (216) main limitation drugs rate relapse discontinuation. An found reduction rates when administered time off tacrolimus,15Segarra Praga Ramos al.Successful calcineurin inhibitor-dependent patients.Clin 4: 1083-1088Crossref (82) pilot reported encouraging results combined high-risk PMN patients.16Waldman Braun al.Membranous novel combining Rituximab.Kidney Rep. 2016; 1: 73-84Abstract (23) More recently, has received great attention.17Ruggenenti Cravedi Chianca al.Rituximab 1416-1425Crossref (188) single dose suggested induction cohort,18Cravedi Ruggenenti Sghirlanzoni M.C. Remuzzi Titrating circulating B cells optimize lymphocytolytic 2: 932-937Crossref (124) although recent trials, needed optimal efficacy.19Dahan K. Plaisier severe extended follow-up.J 28: 348-358Crossref (177) 20Fervenza Barbour S.J. 2019; 381: 36-46Crossref (157) 21Seitz-Polski B. Dahan al.High-dose early pla2r1-related 14: 1173-1182Crossref (43) Indeed, MENTOR (Membranous Nephropathy Trial Rituximab) using total 4 g rituximab.20Fervenza need head-to-head trials newer therapeutic (calcineurin inhibitors, rituximab) stressed KDIGO conference.22Floege Cattran al.Management glomerular diseases (part 1): conclusions from Controversies Conference.Kidney 95: 268-280Abstract (139) designed STARMEN (Sequential Rituximab Versus Alternating Corticosteroids Cyclophosphamide PMN) compare maintenance up addition, we studied occurrence relapses role over course treatment. From June 2014 through 2017, 130 assessed eligibility, whom 44 (33%) excluded study. Main reasons screening failure not meeting eligibility criteria (21 patients), unwillingness participate (14 diagnosis secondary cause (9 patients). remaining met randomly (43 patients) (Figure 1). As presented Table 1, no differences between observed baseline. Baseline stored serum samples available 69 patients, positive 53 (77%). Sensitivity analyses baseline anti-PLA2R–positive anti-PLA2R–negative nor without determinations (Supplementary Tables S1 S2). One anti-THSD7A positive. biopsies performed 8 (range, 6–18) before randomization. Seventy-three (85%) had de novo 13 (15%) relapsing (Table 1).Table 1Baseline characteristics according groupCharacteristicAll (n = 86)Corticosteroid-cyclophosphamide 43)Tacrolimus-rituximab 43)P valueAge, yr55.7 ± 11.456.2 12.055.2 10.81Male sex55 (64)24 (55)31 (72)0.12De novo/relapsing PMN73 (85) / (15)36 (83)/7 (17)37 (86)/6 (14)0.70Weight, kg78.5 16.076.9 17.080.0 15.00.37Blood pressure, mm Hg Systolic128.3 15.9129.4 17.7127.1 14.00.25 Diastolic76.0 9.875.1 10.777.0 8.80.37Serum creatinine, mg/dl1.0 0.31.0 0.280.48eGFR, ml/min per 1.73 m2aeGFR calculated Chronic Disease Epidemiology Collaboration equation.79.8 23.579.1 25.580.5 21.60.78Serum albumin, g/dl2.6 (2.2–2.9)2.6 (2.3–2.9)2.6 (2.0–2.9)0.47Serum cholesterol, mg/dl263.9 64.0264.1 57.8263.8 70.20.34Anti-PLA2R–positive patientsbAnti-PLA2R positivity defined >14 RU/ml.53 (77)29 37 (78)cIn (16%) determined baseline.24 32 (75)dIn (25.5%) baseline.0.38Anti-PLA2R, RU/ml80 (44–149)59 (37–150)113 (61–151)0.1Urinary protein, g/24 h7.4 (5.2–11.5)7.4 (4.8–11.3)7.4 (6.7–11.6)0.22Concomitant ACEis and/or ARBs82 83 (99)39 (91)43 (100)0.48 Diuretics70 (84)35 (81)35 (81)0.45ACEis, angiotensin-converting enzyme inhibitors; Anti-PLA2R, anti–phospholipase autoantibodies; ARBs, angiotensin II blockers; eGFR, estimated filtration rate; RU, relative units.Values are mean SD, n (%), median (interquartile range).a eGFR equation.b RU/ml.c baseline.d Open table new tab ACEis, units. Values range). All intervention. Two (4.6%) (13.9%) discontinued intervention 41 group) Patients oral 0.49 0.05 mg/kg/day 3, 5, 3.4 0.9 g. intravenous 8.2 1.4 10 3.5 Doses blood levels Supplementary S3. Three this second (0.5 patient) 12, 18, respectively, others additional beyond 9. During end intervention, 5 switched nonstudy owing lack treated 14, 16. 12 (2 14 21 (1 patient). considered nonresponders Follow-up all enrolled Thirty-six complete/partial [RR] 1.44, [CI] 1.92) 2; Figure 2a). per-protocol analysis confirmed groups: 35 22 (59%) (RR CI 1.07 1.93) 2). difference already 3 maintained throughout 2a).Table 2Composite monthsIntention-to-treat analysisTime randomizationCorticosteroid- 43)Relative (95% CI)3 mo22 (51)12 (28)1.83 (1.04–3.22)6 mo32 (74)19 (44)1.68 (1.15–2.46)12 mo34 (79)22 (51)1.55 (1.11–2.15)18 mo36 (84)23 (53)1.57 (1.15–2.13)24 (84)25 (58)1.44 (1.08–1.92)Per-protocol 41)Tacrolimus-rituximab 37)Relative (32)1.65 (0.96–2.85)6 mo31 (75)18 (48)1.55 (1.07–2.26)12 mo33 (80)20 (54)1.49 (1.07–2.08)18 mo35 (85)20 (54)1.58 (1.14–2.18)24 (85)22 (59)1.44 (1.07–1.93)CI, interval.The intention-to-treat included underwent randomization, whereas full medications. analyses, months.Data (%) CI. CI, interval. Data 2b, 2.36, 4.16).Table 3Complete mo1 (2)0 (0)6 mo6 (14)0 (0)12 mo14 (33)4 (9)3.50 (1.25–9.78)18 mo19 (44)7 (16)2.71 (1.27–5.78)24 mo26 (60)11 (26)2.36 (1.34–4.16)Per-protocol mo5 (13)0 mo13 (32)4 (11)2.93 (1.05–8.21)18 mo18 (19)2.31 (1.09–4.92)24 mo25 (61)10 (27)2.26 (1.26–4.04)CI, tendency across different non-prespecified subgroups values proteinuria, levels. age, female S1). When those response, men (80% vs. 57%) proteinuria among S4). Proteinuria decreased 7.4 h range 4.8–11.3) 0.35 (0.2–9) (6.7–11.6) (0.3–3.3) (between-group P 0.005) 3a; S5). Serum albumin increased 2.6 0.1 g/dl 3.9 0.2) 3b; There nonsignificant trend (eGFR) 3c; S6). At months, numbers ≥50% increases creatinine (2%) (12%) (P 0.2). preserved renal function (eGFR ≥45 m2) 40 (93%) (86%) 0.48). developed 73-year-old man been completion he because massive declining g, 15 days apart). No observed, chronic dialysis initiated 16 4; 3a). proportions immunologic respectively) 4). Most (80%) during Immunologic 0.036) Nonresponding slower decline lower responses, S7).Table 4Evolution antibodies percentage groupTime randomizationAnti-PLA2R, RU/ml, (IQR)Immunologic %All patientsCorticosteroid-cyclophosphamideTacrolimus-rituximabP valueCorticosteroid-cyclophosphamideTacrolimus-rituximabP valueBaseline80 (61–151)0.13 mo2.3 (1.3–65)1.4 (0.7–14)33 (2.6–76)0.00377450.036 mo1.4 (0.7–7.4)1.4 (0–1.7)2.6 (1.4–30)0.0292700.0412 mo1.6 (0–8.1)1.5 (0–5)2.1 (0–15)0.588790.3118 mo1.5 (0–2)1.3 (0–2.3)1.6 (0–15)0.388830.8824 (1.3–5.1)1.4 (0.9–3.2)1.9 (1.7–14)0.0688830.91IQR, interquartile range; PLA2R, receptor; units.Differences Mann-Whitney test. IQR, Differences out (2.7%) S8). them reached accompanied reappearance antibodies. measured restarted other rituximab. 9 3. case, tacrolimus. except event 5). low (345, 84%) medium (56, 13%) severity, 17 (4%) serious. more 0.04). leukopenia Cushing syndrome, while acute injury, hyperkalemia, diarrhea, distal tremor statistically association presence development infections, cohort < 0.0001 0.041 tacrolimus/rituximab group). within first (304 409, 74%), period.Table 5Adverse groupEventCorticosteroid-cyclophosphamide valueaP groups.PatientsEventsPatientsEventsAny event42 (98)239 (411)39 (91)170 (280)0.04Serious events8 (19)10 (17)6 (14)7 (12)0.93 Fatal0 (0)0 (0)1.00 Nonfatal8 (12)0.56Nonserious events34 (79)229 (394)33 (77)163 (268)0.04Adverse 5% any eventSystemic/general Headache3 (7)5 (9)5 (12)7 (12)0.48 Asthenia7 (16)9 (16)4 (10)4 (7)0.52 Depression3 (7)3 (5)1 (2)2 (3)0.62 Anxiety8 (19)14 (24)4 (7)0.35Metabolic syndrome7 (16)8 (0)0.01 Hyperglycemia4 (9)4 (7)2 (5)2 (3)0.68 Hyperlipidemia5 (12)2 (3)0.43Gastrointestinal Diarrhea4 (7)13 (31)13 (21)0.02 Abdominal complaint7 (16)7 (12)3 (7)4 (7)0.31Infections Upper respiratory infection10 (23)14 (24)10 (24)14 (23)1.00 Pneumonia4 Urinary tract infection4 (7)1 (2)1 (2)0.36 Tuberculosis1 (0)1.00Musculoskeletal Bone pain10 (23)12 (21)9 (21)12 (20)1.00 Myalgia7 (16)2 (3)0.16 Cramps5 (12)6 (10)5 (12)5 (8)1.00 fracture1 (1)2 (3)0.62Neurologic Tremor2 (3)7 (17)7 (12)0.09 Paresthesia2 (3)2 (3)1.00Hematologic Anemia13 (30)17 (29)9 (21)10 (17)0.46 Leukopenia13 (30)22 (38)2 (3)0.003Cardiovascular pressure Acute coronary syndrome1 (2)1.00 Venous thrombosis5 (9)2 (3)0.43 Hypertension5 (14)6 (10)0.76 Hypotension4 (7)0 (0)0.12Renal injury8 (19)8 (14)14 (33)16 (26)0.14 Hyperkalemia1 (2)6 (10)0.06 Edema6 (8)0.74Dermatologic Skin eruption4 (0)0.12Miscellaneous Drug infusion reaction1 (2)4 (7)0.36 Cancer2 (3)1 (2)0.62 Gastric adenocarcinoma1 (0) Breast carcinoma1 Rectal carcinoma0 (0)1 (2)Results (rate 100 patient-years).a Results patient-years). significan