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In this double-blind, randomized trial, mycophenolate mofetil was superior to azathioprine for maintaining a renal response and preventing relapse in patients with lupus nephritis who had had a response to induction therapy. Systemic lupus erythematosus is an autoimmune disorder often characterized by the development of glomerulonephritis. 1 Renal involvement remains the strongest predictor of morbidity and mortality among patients with lupus, 1 and despite improvements in the management of lupus, the incidence of end-stage renal disease has not declined. 2 Management of lupus nephritis consists of induction therapy to achieve remission and long-term maintenance therapy to prevent relapse, progression to end-stage renal disease, and death. 3 However, the options for long-term therapy remain controversial. Treatment options include glucocorticoids and the immunosuppressive agents cyclophosphamide, azathioprine, and mycophenolate mofetil. These drugs have considerable toxicity and are not effective . . .

Class V lupus nephritis (LN) occurs in one-fifth of biopsy-proven cases of systemic lupus erythematosus. To study the effectiveness of treatments in this group of patients, we pooled analysis of two large randomized controlled multicenter trials of patients with diverse ethnic and racial background who had pure class V disease. These patients received mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) as induction therapy for 24 weeks, with percentage change in proteinuria and serum creatinine as end points. Weighted mean differences, pooled odds ratios, and confidence intervals were calculated by using a random-effects model. A total of 84 patients with class V disease were divided into equal groups, each group had comparable entry variables but one received MMF and one received IVC. Within these groups, 33 patients on MMF and 32 patients on IVC completed 24 weeks of treatment. There were no differences between the groups in mean values for the measured end points. Similarly, no difference was found regarding the number of patients who did not complete the study or who died. In patients with nephrotic syndrome, no difference was noted between those treated with MMF and IVC regarding partial remission or change in urine protein. Hence we found that the response to MMF as induction treatment of patients with class V LN appears to be no different from that to IVC.

IntroductionHigh-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy.MethodsPropensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months.ResultsThere were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months.ConclusionsCompared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.

ObjectiveEarly reduction in proteinuria after initial treatment has been associated with improved long-term kidney outcomes in lupus nephritis (LN). The addition of voclosporin, a second generation calcineurin inhibitor, to MMF and low-dose glucocorticoids (GC)s led to greater reductions in proteinuria compared to conventional therapy in the AURA-LV and AURORA 1 studies with an acceptable safety profile. Using propensity-matched participants from the voclosporin clinical trials and ALMS, we tested the hypothesis that a voclosporin-based, triple immunosuppressive regimen results in improved safety without compromising efficacy. MethodsIn AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m2/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS vs. AURA-LV/AURORA 1) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. ResultsA total of 179 matched pairs were identified. As expected, cumulative GC exposure was 2-fold higher in ALMS at 3 and 6 months. The incidence of adverse events (AEs) was higher in IVC- and high-dose MMF-treated participants (table 1), although more voclosporin-treated participants reported AEs of GFR decrease and hypertension; the incidence of serious AEs was similar with all treatments. At 6 months, the proportion of participants achieving >50% UPCR reduction from baseline was significantly greater in the voclosporin arm (p=0.005).ConclusionA voclosporin-based triple immunosuppressive regimen (voclosporin, MMF, and low-dose GCs) has a better overall safety profile than double-therapy regimens, with specific AEs attributable to higher-dose GCs, higher-dose MMF and IVC in the latter. Triple therapy is also superior in achieving early proteinuria milestones. These data provide further support for use of combination therapy as initial treatment in patients with active LN and to minimizing patient exposure to GCs, as proposed by the 2023 EULAR guidelines. AcknowledgementThis study was funded by Aurinia Pharmaceuticals Inc. Abstract P87 Table 1Select safety outcomes % (n) 3 Months 6 Months ALMS AURA-LV/AURORA 1 ALMS AURA-LV/AURORA1 IVC N=91 MMF N=88 Voclosporin N=179 IVC N=91 MMF N=88 Voclosporin N=179 Any AE 91.2 (83) 94.3 (83) 83.2 (149) 95.6 (87) 95.5 (84) 89.9 (161) Serious AE 12.1 (11) 22.7 (20) 14.5 (26) 15.4 (14) 25.0 (22) 19.6 (35) AEs by System Organ Class,% (n) Gastrointestinal disorders 59.3 (54) 52.3 (46) 34.6 (62) 65.9 (60) 61.4 (54) 38.5 (69) Infections and infestations 46.2 (42) 60.2 (53) 41.9 (75) 58.2 (53) 72.7 (64) 54.2 (97) Skin and subcutaneous tissue disorders 47.3 (43) 28.4 (25) 19.6 (35) 56.0 (51) 37.5 (33) 24.0 (43) Musculoskeletal/connective tissue disorders 34.1 (31) 29.5 (26) 19.6 (35) 44.0 (40) 37.5 (33) 24.6 (44) Blood and lymphatic system disorders 20.9 (19) 13.6 (12) 11.7 (21) 40.7 (37) 23.9 (21) 18.4 (33) Psychiatric disorders 13.2 (12) 17.0 (15) 2.2 (4) 15.4 (14) 17.0 (15) 3.4 (6) Endocrine disorders 11.0 (10) 8.0 (7) 1.1 (2) 11.0 (10) 8.0 (7) 1.1 (2) Reproductive system and breast disorders 9.9 (9) 6.8 (6) 2.2 (4) 12.1 (11) 8.0 (7) 2.2 (4) Renal and urinary disorders 6.6 (6) 4.5 (4) 7.3 (13) 8.8 (8) 9.1 (8) 10.6 (19) AEs by Preferred Term,% (n) GFR decreased 0 (0) 0 (0) 18.4 (33) 0 (0) 0 (0) 24.6 (44) Hypertension 8.8 (8) 10.2 (9) `15.6 (28) 12.1 (11) 14.8 (13) 17.3 (31) In AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m2/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate two groups of matched patients (n=179) from the ALMS (IVC and MMF) and AURA-LV/AURORA 1 (voclosporin) studies based on the following parameters: age, duration of lupus nephritis, duration of SLE, albumin, C3, C4, creatinine, anti-dsDNA, eGFR, UPCR, biopsy class, sex, and geographical region. Adverse events (AEs) occurred on or after the first dose of study drug up to either 3 or 6 months of treatment and coded by System Organ Class and Preferred Term using MedDRA v9.1 (ALMS), v17.0 (AURA-LV) and v20.0 (AURORA 1). AEs were selected for inclusion in this table to evaluate the impact of IVC, MMF, voclosporin, and glucocorticoids on these organ systems. Assignation of AEs of ‘GFR decreased’ were based on the clinical discretion of the study investigator and were not characterized by a specified drop in eGFR from baseline. GFR, glomerular filtration rate; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil.

ObjectivesTo identify predictors of overall lupus and lupus nephritis (LN) responses in patients with LN.MethodsData from the Aspreva Lupus Management Study (ALMS) trial cohort was used to identify baseline predictors of response at 6 months. Endpoints were major clinical response (MCR), improvement, complete renal response (CRR) and partial renal response (PRR). Univariate and multivariate logistic regressions with least absolute shrinkage and selection operator (LASSO) and cross-validation in randomly split samples were utilised. Predictors were ranked by the percentage of times selected by LASSO and prediction performance was assessed by the area under the receiver operating characteristics (AUROC) curve.ResultsWe studied 370 patients in the ALMS induction trial. Improvement at 6 months was associated with older age (OR=1.03 (95% CI: 1.01 to 1.05) per year), normal haemoglobin (1.85 (1.16 to 2.95) vs low haemoglobin), active lupus (British Isles Lupus Assessment Group A or B) in haematological and mucocutaneous domains (0.61 (0.39 to 0.97) and 0.50 (0.31 to 0.81)), baseline damage (SDI>1 vs =0) (0.38 (0.16 to 0.91)) and 24-hour urine protein (0.63 (0.50 to 0.80)). LN duration 2–4 years (0.43 (0.19 to 0.97) vs <1 year) and 24-hour urine protein (0.63 (0.45 to 0.89)) were negative predictors of CRR. LN duration 2–4 years (0.45 (0.24 to 0.83) vs <1 year) negatively predicted PRR. The AUROCs of models for improvement, CRR and PRR were 0.56, 0.55 and 0.51 respectively.ConclusionsBaseline variables predicted 6-month outcomes in patients with SLE. While the modest performance of models emphasises the need for new biomarkers to advance this field, the factors identified can help identify those patients who may require novel treatment strategies.

Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis. This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m2 or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499. Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64–4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments. Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis. Aurinia Pharmaceuticals.

Non-blinded trials of pemphigus vulgaris suggest that mycophenolate mofetil (MMF) may be beneficial. In a prospective, multicenter trial, outpatients with mild or moderate pemphigus vulgaris were randomized to MMF (2 or 3gday−1) plus oral corticosteroids or placebo plus oral corticosteroids for 52 weeks. The primary end point was the proportion of patients in the placebo and combined MMF groups responding to treatment (absence of new, persistent oral or cutaneous lesions, and prednisone dose ≤10mgday−1 from weeks 48 to 52). Of 96 randomized patients, 94 were given treatment and 75 completed the study. Treatment responses occurred in 40 of 58 patients (69.0%) in the combined MMF group and 23 of 36 (63.9%) in the placebo group (P=0.6558, 95% confidence interval –17.4 to 27.6). MMF-treated patients showed faster and more durable responses. In post hoc analyses, more patients taking MMF showed sustained responses for 3 or 6 months than did placebo patients. MMF was well tolerated. Although MMF did not show an advantage on the primary end point, there seemed to be a beneficial treatment effect on several secondary end points, including time to response and duration of response. Thus, MMF may be a potentially useful agent in patients with mild or moderate pemphigus vulgaris. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to

Objective To identify factors associated with clinical outcome in patients with lupus nephritis. Methods Data from the Aspreva Lupus Management Study (ALMS) were analysed. Using multivariate analysis, we assessed the prognostic value of demographic, clinical, laboratory and histopathological features on the frequency of either complete remission (CR) or treatment failure (TF) during the maintenance phase. Results Among the 370 subjects who entered the trial (complete population), non-Hispanic ethnicity was associated with a higher likelihood of CR (OR=2.0). Several factors were independently associated with a greater likelihood of TF, including: (1) anti-double-stranded DNA (anti-dsDNA) at trial entry (OR=12.7), (2) failure to reduce anti-dsDNA within 8 weeks (OR=2.9) and (3) failure to reduce urine protein:creatinine ratio (UP/C) by ≥25% within 8 weeks (OR=2.6). Among the 227 subjects who entered the maintenance phase (maintenance population), baseline estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m2 was associated with a greater likelihood of CR (OR=2.0), and UP/C >1 at the end of induction was associated with a lower likelihood of CR (OR=0.3). Induction treatment with intravenous cyclophosphamide (IVC) was associated with a lower likelihood of TF (OR=0.5), while lack of treatment with antimalarials (OR=2.4), failure to reduce anti-dsDNA during the first 8 weeks of induction (OR=3.5), failure to reduce UP/C during the first 8 weeks of induction (OR=2.1) and anti-dsDNA positivity at the end of induction (OR=8.3) were independently associated with a greater likelihood of TF. Conclusions This analysis demonstrates that levels of anti-dsDNA and UP/C during induction treatment are independently associated with renal outcome over the ensuing 3 years in both the complete and maintenance populations. Ethnicity is associated with renal outcome in just the complete population, and eGFR, induction treatment and treatment with antimalarials are associated with renal outcome in just the maintenance population.

The Phase III Aspreva Lupus Management Study (ALMS) will investigate mycophenolate mofetil (MMF) therapy for lupus nephritis (LN). Eligibility criteria include: 12—75 years of age; diagnosis of systemic lupus erythematosus according to revised American College of Rheumatology criteria; and biopsy-demonstrated LN (Class III—V). Randomized patients will receive open-label induction therapy with MMF or cyclophosphamide in combination with corticosteroids for 24 weeks. The primary efficacy endpoint is treatment response [decreased proteinuria and stabilized (within 25% of baseline) or improved serum creatinine level]. Patients achieving response or complete remission (normalization of all parameters) will be rerandomized to double-blind, placebo-controlled maintenance treatment with MMF or azathioprine, both plus corticosteroids. The maintenance phase primary endpoint is time to treatment failure. To detect a 15% rate improvement in the MMF group compared with cyclophosphamide, and to provide 90% power, a total of 358 patients will be required for the induction phase. On the basis of a projected 278 rerandomized patients, the maintenance phase will have 90% power to detect a difference between treatment groups assuming azathioprine and MMF three-year failure rates of 59.5% and 40.7%, respectively. Aspreva Lupus Management Study may provide invaluable comparative data on the efficacy and safety of MMF as LN induction and maintenance therapy. Lupus (2007) 16, 972—980.

To the Editor: Dooley et al. (Nov. 17 issue) 1 report the efficacy of mycophenolate mofetil versus azathioprine as maintenance therapy for lupus nephritis and declare mycophenolate superior. Yet azathioprine was prescribed according to body weight, despite overwhelming evidence favoring the use of thiopurine methyltransferase (TPMT) testing for pharmacogenetic guidance in administration. 2 By omitting previous TPMT assessment, the study was conducted contrary to the recommendations of the Food and Drug Administration (FDA), the Clinical Pharmacogenetics Implementation Consortium, 2 and the drug's labeling. 3 Monitoring of thiopurine metabolites is frequently performed in practice, including for the treatment of lupus, 4 since underdosing is common. However, . . .