<b>OBJECTIVE: </b>To assess the efficacy and safety of the type I interferon receptor antibody, anifrolumab, in patients with active, biopsy-proven, Class III/IV lupus nephritis.<b>METHODS: </b>This phase II double-blinded study randomised 147 patients (1:1:1) to receive monthly intravenous anifrolumab basic regimen (BR, 300 mg), intensified regimen (IR, 900 mg ×3, 300 mg thereafter) or placebo, alongside standard therapy (oral glucocorticoids, mycophenolate mofetil). The primary endpoint was change in baseline 24-hour urine protein-creatinine ratio (UPCR) at week (W) 52 for combined anifrolumab versus placebo groups. The secondary endpoint was complete renal response (CRR) at W52. Exploratory endpoints included more stringent CRR definitions and sustained glucocorticoid reductions (≤7.5 mg/day, W24-52). Safety was analysed descriptively.<b>RESULTS: </b>Patients received anifrolumab BR (n=45), IR (n=51), or placebo (n=49). At W52, 24-hour UPCR improved by 69% and 70% for combined anifrolumab and placebo groups, respectively (geometric mean ratio=1.03; 95% CI 0.62 to 1.71; p=0.905). Serum concentrations were higher with anifrolumab IR versus anifrolumab BR, which provided suboptimal exposure. Numerically more patients treated with anifrolumab IR vs placebo attained CRR (45.5% vs 31.1%), CRR with UPCR ≤0.5 mg/mg (40.9% vs 26.7%), CRR with inactive urinary sediment (40.9% vs 13.3%) and sustained glucocorticoid reductions (55.6% vs 33.3%). Incidence of herpes zoster was higher with combined anifrolumab vs placebo (16.7% vs 8.2%). Incidence of serious adverse events was similar across groups.<b>CONCLUSION: </b>Although the primary endpoint was not met, anifrolumab IR was associated with numerical improvements over placebo across endpoints, including CRR, in patients with active lupus nephritis.<b>Trial Registration Number: </b>NCT02547922.
<b>BACKGROUND: </b>In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown.<b>METHODS: </b>In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m2 of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2, and no use of rescue therapy). The time to a renal-related event or death was assessed.<b>RESULTS: </b>A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials.<b>CONCLUSIONS: </b>In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).
The objective of this study was to analyze and compare the effects of rituximab (RTX) and cyclophosphamide (CTX) on the serum levels of anti-C1q antibodies and antineutrophil cytoplasmic autoantibodies (ANCA) in assessing the prognosis of severe and refractory lupus nephritis (LN). Eighty-four cases of severe and refractory LN were randomly divided into two groups of 42 cases each: CTX group and RTX group (CTX+RTX) during February 2010 to February 2014 in our hospital. Changes in serum levels of anti-C1q antibodies and ANCA in the two groups were examined, and efficacies of the drugs were compared. The total efficacy of RTX group was found to be 83.3 %, which was significantly higher than that of the CTX group, 57.1 % (p < 0.05). The serum anti-C1q antibodies and ANCA were decreased to 11.9 and 26.2 % in the RTX-treated group, which was significantly lower than those observed in the CTX-treated patients (21.4 and 69.0 % respectively) (p < 0.05). The clinical indices of LN were significantly improved in the two groups after the treatment. However, the urinary protein, albumin, complement C3, the percentage of CD19(+)B cells, and SLEDAI scores in the RTX group were significantly lower than those in the CTX group (p < 0.05). RTX plus with CTX showed a better therapeutic efficacy compared to CTX, and it significantly improved the prognosis of refractory and severe LN. The improvement in disease prognosis was directly related to the reduced serum levels of anti-C1q and ANCA measured during the course of treatment suggesting that they can serve to be valuable biomarkers of LN prognosis. Moreover, the measurement can assist in the judgment of RTX efficacy guiding the adjustment of the drug dose to improve the quality of life.
OBJECTIVE: To assess the efficacy and safety of a 24-week course of abatacept in the treatment of active lupus nephritis and to assess the potential of abatacept to induce "clinical tolerance," defined as sustained clinical quiescence of lupus nephritis after discontinuation of immunosuppressive therapy.
METHODS: Patients with active lupus nephritis (n = 134) were enrolled in a randomized, double-blind phase II add-on trial in which they received either abatacept or placebo in conjunction with the Euro-Lupus Nephritis Trial regimen of low-dose cyclophosphamide (CYC) followed by azathioprine (AZA). The primary efficacy outcome was the frequency of complete response at week 24. Thereafter, patients who met either complete or partial response criteria continued blinded treatment through week 52. During this phase of the study, subjects in the abatacept treatment group in whom a complete response was achieved at week 24 discontinued immunosuppressive therapy other than prednisone (10 mg/day).
RESULTS: There were no statistically significant differences between groups with respect to the primary outcome or any of the secondary outcomes, including measures of safety. A complete response was achieved in 33% of the subjects in the treatment group and in 31% of the subjects in the control group at week 24. Fifty percent of the subjects in the treatment group who met complete response criteria and therefore discontinued immunosuppressive therapy at week 24 maintained their complete response status through week 52.
CONCLUSION: The addition of abatacept to a regimen of CYC followed by AZA did not improve the outcome of lupus nephritis at either 24 or 52 weeks. No worrisome safety signals were encountered.
OBJECTIVE: To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, when used on a background of mycophenolate mofetil and glucocorticoids.
METHODS: This was a 12-month, randomized, phase II/III, multicenter, international, double-blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight-tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight-tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52-week treatment period.
RESULTS: There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti-double-stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic-range proteinuria, treatment with abatacept resulted in an ∼20-30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment.
CONCLUSION: Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.
Objective To investigate the efficacy and safety of ocrelizumab in patients with class III/IV lupus nephritis (LN). Methods Patients were randomized 1:1:1 to receive placebo, 400 mg ocrelizumab, or 1,000 mg ocrelizumab given as an intravenous infusion on days 1 and 15, followed by a single infusion at week 16 and every 16 weeks thereafter, accompanied by background glucocorticoids plus either mycophenolate mofetil (MMF) or the Euro-Lupus Nephritis Trial (ELNT) regimen (cyclophosphamide followed by azathioprine). The study was terminated early due to an imbalance in serious infections in ocrelizumab-treated patients versus placebo-treated patients. We report week 48 efficacy data for patients receiving ≥32 weeks of treatment (n = 223) and safety results for all treated patients (n = 378). Results The overall renal response rate was 54.7%, 66.7%, 67.1%, and 66.9% in the placebo-treated, 400 mg ocrelizumab-treated, 1,000 mg ocrelizumab-treated, and combined ocrelizumab-treated groups, respectively. The associated treatment difference versus placebo for the combined ocrelizumab-treated groups was 12.7% (95% confidence interval [95% CI] −0.8, 26.1) ( P = 0.065), with similar differences observed for both ocrelizumab-treated groups. Ocrelizumab versus placebo treatment differences were apparent in patients receiving the background ELNT regimen, but not in those receiving background MMF. A numerically greater proportion of ocrelizumab-treated patients had a ≥50% reduction in the urinary protein:urinary creatinine ratio at 48 weeks compared with placebo-treated patients (placebo-treated patients, 58.7%; 400 mg ocrelizumab-treated patients, 70.7%; 1,000 mg ocrelizumab-treated patients, 68.5%). Serious adverse events occurred in 27.2% of placebo-treated patients, 35.7% of 400 mg ocrelizumab-treated patients, and 22.0% of 1,000 mg ocrelizumab-treated patients. Corresponding serious infection rates (events/100 patient-years) were 18.7 (95% CI 12.2, 28.7), 28.8 (95% CI 20.6, 40.3), and 25.1 (95% CI 17.4, 36.1), respectively. The imbalance in serious infections with ocrelizumab occurred with background MMF but not with the background ELNT regimen. Conclusion In patients with active LN, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo. Ocrelizumab treatment was associated with a higher rate of serious infections in the subgroup receiving background MMF.
OBJETIVO: Evaluar la eficacia y seguridad de rituximab en un estudio doble ciego, aleatorizado, controlado con placebo de fase III en pacientes con nefritis lúpica tratados concomitantemente con micofenolato mofetil (MMF) y corticosteroides.
MÉTODOS: Los pacientes (n = 144) con clase III o clase IV lupus nefritis fueron aleatorizados 1: 1 para recibir rituximab (1.000 mg) o placebo en los días 1, 15, 168, y 182. El punto final primario fue el estado de respuesta renal en la semana 52.
RESULTADOS: Rituximab agotan las células CD19 + B periféricas en 71 de 72 pacientes. Las tasas globales (completas y parciales) de respuesta renales fueron 45,8% entre los 72 pacientes que recibieron placebo y el 56,9% entre los 72 pacientes que recibieron rituximab (P = 0,18); respuestas parciales representaron la mayor parte de la diferencia. No se logró el objetivo primario (tasa de respuesta superior con rituximab). Ocho pacientes tratados con placebo y ninguno de los pacientes tratados con rituximab requieren terapia de rescate ciclofosfamida hasta la semana 52. Mejoras estadísticamente significativas en el complemento del suero C3, C4 y anti-DNA de doble cadena niveles (los anti-dsDNA) se observaron entre los pacientes tratados con rituximab. En ambos grupos de tratamiento, una reducción en los niveles de anti-dsDNA mayores que la mediana de la reducción se asoció con una reducción de proteinuria. Las tasas de eventos adversos graves, como infecciones, fueron similares en ambos grupos. La neutropenia, leucopenia, e hipotensión fueron más frecuentes en el grupo de rituximab.
CONCLUSIÓN: A pesar de que la terapia con rituximab llevó a más respondedores y mayores reducciones en los niveles de C3 / C4 anti-ADN de doble cadena y, no mejoró los resultados clínicos después de 1 año de tratamiento. La combinación de rituximab con MMF y corticosteroides no dio lugar a ningún señales nuevas o inesperadas en la seguridad.
