Objective

Recent clinical trials in lupus nephritis have all used different criteria to assess complete response. The objective of this analysis was to compare several previously proposed criteria, using the same data set from a large trial of abatacept in lupus nephritis (IM101075). In so doing, we sought to determine which criteria are most sensitive to differences among treatment groups and to further examine the potential of abatacept in lupus nephritis.

Methods

Patients in the IM101075 trial received abatacept at 1 of 2 different dose regimens or placebo, both on a background of mycophenolate mofetil and corticosteroids. Using data from this trial, we assessed rates of complete response at 12 months according to 5 sets of criteria, from 1) the trial protocol, 2) the Aspreva Lupus Management Study (ALMS) trial of mycophenolate mofetil, 3) the Lupus Nephritis Assessment with Rituximab (LUNAR) trial of rituximab, 4) an ongoing National Institutes of Health trial of abatacept (Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study [ACCESS]), and 5) published recommendations of the American College of Rheumatology.

Results

According to the complete response definition from the IM101075 study protocol, there was no difference among treatment groups in the IM101075 study. In contrast, according to the ALMS, LUNAR, and ACCESS criteria, rates of complete response among patients in the IM101075 study were higher in both treatment groups relative to control. The largest differences were obtained with use of the LUNAR criteria (complete response rate of 6% in the control group, compared to 22% and 24% in the 2 abatacept groups).

Conclusion

The choice of definition of complete response can determine whether a lupus nephritis trial is interpreted as a success or a failure. The results of this analysis provide an evidence-based rationale for choosing among alternative definitions and offer a strong rationale for conducting further studies of abatacept in lupus nephritis.

Objective

Clinical trials of therapies for lupus nephritis have used many different primary outcome measures, ranging from complete response to time to end-stage renal disease. The objective of this study was to compare several possible outcome measures, using data from a large, multicenter trial of abatacept in lupus nephritis, to gain insight into which outcome measure, if any, was best able to discern differences among treatment groups.

Methods

Study patients received either abatacept or placebo, on a background of mycophenolate mofetil and glucocorticoids. Using data from this trial, the following primary outcome measures at 24 and 52 weeks were compared: complete response rate, major clinical response rate, total response rate (complete plus partial response), improvement in proteinuria, improvement in estimated glomerular filtration rate, and frequency of treatment failure. Time to complete response was also evaluated.

Results

Complete response rate, major clinical response rate, and time to complete response were the measures that best discriminated between the abatacept groups and placebo, and the sensitivities of these 3 measures were comparable. For these measures, sample sizes of 50 patients would have been sufficient to demonstrate a statistically significant difference between treatment and control at 52 weeks. Each of the other measures also discriminated between treatment and control, but much larger group sizes would have been required to determine statistical significance.

Conclusion

The choice of primary outcome measure can substantially influence the ability to detect therapeutic benefit in lupus nephritis trials. This study suggests that complete response rate, major clinical response rate at 52 weeks, and time to complete response may be the most sensitive outcome measures for detecting differences among therapeutic regimens.

The immune mechanisms that cause tissue injury in lupus nephritis have been challenging to define. The advent of high-dimensional cellular analyses, such as single-cell RNA sequencing, has enabled detailed characterization of the cell populations present in small biopsy samples of kidney tissue. In parallel, the development of methods that cryopreserve kidney biopsy specimens in a manner that preserves intact, viable cells, has enabled the uniform analysis of tissue samples collected at multiple sites and across many geographic areas and demographic cohorts with high-dimensional platforms. The application of these methods to kidney biopsy samples from patients with lupus nephritis has begun to define the phenotypes of both infiltrating and resident immune cells, as well as parenchymal cells, present in nephritic kidneys. The detection of similar immune cell populations in urine suggests that it might be possible to non-invasively monitor immune activation in kidneys. Once applied to large patient cohorts, these high-dimensional studies might enable patient stratification according to patterns of immune cell activation in the kidney or identify disease features that can be used as surrogate measures of efficacy in clinical trials. Applied broadly across multiple inflammatory kidney diseases, these studies promise to enormously expand our understanding of renal inflammation in the next decade.

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 m(2) 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.

Objective

To assess the relationship between treatment response, baseline biomarker levels, and atacicept exposure in patients with systemic lupus erythematosus (SLE) in the phase II/III APRIL-SLE study.

Methods

We performed a post hoc analysis of patients who received placebo, atacicept 75 mg, or atacicept 150 mg in a randomized, controlled, 52-week trial. Serum levels of BlyS and APRIL were measured at baseline, and serum levels of Ig and the numbers of naive B cells and plasma cells were measured at baseline and during treatment. Atacicept exposure was determined by assessment of the serum trough concentrations throughout the 52-week trial period. Associations between these parameters, treatment response (reduction in British Isles Lupus Assessment Group A or B flare), and infection rates were explored.

Results

Recurrent high baseline levels of both BLyS (≥1.6 ng/ml) and APRIL (≥2.2 ng/ml) correlated with a greater treatment response (flare rate 75.7% with placebo, and 50.0% and 32.0% with atacicept 75 mg and atacicept 150 mg, respectively) compared with lower baseline levels of both. Increased atacicept exposure correlated with reduced flare rates (60.5% with placebo; 63.4%, 61.0%, 48.8%, and 29.3% in the 4 quartiles, from lowest to highest atacicept exposure). Greater pharmacodynamic responses (reduced Ig levels and naive B cell and plasma cell numbers) were associated with greater reductions in the flare rate. Infection rates were similar regardless of biomarker levels at baseline or at the time of atacicept exposure.

Conclusion

These post hoc analyses demonstrate a dose-response relationship between atacicept concentrations, reduced Ig levels, and reduced flare rates and suggest that baseline biomarkers such as elevated serum levels of BLyS and APRIL may help to identify the patients who are most likely to benefit from atacicept treatment.

Introduction

Cross-sectional studies document that the spot protein/creatinine ratio (PCR) is often an inaccurate estimate of proteinuria magnitude compared with the 24-hour PCR, which is the gold standard. However, the extent to which the inaccuracy of the spot PCR varies over time and between individuals has not previously been reported. We address these crucial questions using a unique database, an National Institutes of Health trial in which lupus nephritis (LN) patients (N = 103) provided spot PCR testing each month and 24-hour PCR testing every 3 months for up to 15 months after induction therapy.

Methods

A gold standard proteinuria trend line was constructed for each patient by joining the points that represented the serial 24-hour PCR values of the patient. The spot PCR values of the patient were then plotted in relationship to the 24-hour PCR trend line. Using our previous work, which estimated the 95% confidence intervals for the 24-hour PCR at specific levels, we determined in each patient whether the spot PCR values were "reliable," "problematic," or "unreliable." The sequential spot PCR of the patients deviated widely and often from the 24-hour PCR trend line, to the extent that, if the spot PCR results were used in real time for clinical decision-making, it was likely management errors would occur.

Results

Spot PCRs were reliable in 41%, problematic in 24%, and unreliable in 35% of patients. Those with unreliable spot PCRs could not be predicted and were more likely to respond poorly to treatment.

Conclusion

The spot PCR should not be used for management of LN, and perhaps, other glomerulopathies.

Objectives: Despite advances in systemic lupus erythematosus (SLE) treatment, many patients suffer from the disease and side effects. Atacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferationinducing ligand, which are increased

Objective

To characterize the overall safety profile of atacicept, we conducted an integrated analysis of pooled safety data from all 17 clinical studies to date.

Methods

Three data sets were used to investigate safety endpoints: a double-blind placebo-controlled set (n = 1568), an SLE set (n = 761) and a full analysis set (n = 1845; including all 17 studies).

Results

Of 1568 patients in the double-blind placebo-controlled-set, 30.8% received placebo, and 8.2, 24.5 and 36.5% received atacicept 25, 75 and 150 mg, respectively. Treatment-emergent adverse event (TEAE) rates (adjusted by treatment-exposure) were generally higher with atacicept vs placebo, but no consistent association was found between atacicept dose and specific TEAEs or mortality. Serious infection and serious TEAE rates were similar for atacicept and placebo. The TEAE-related discontinuation rates were higher with atacicept vs placebo (16.1 vs 10.9/100 patient-years). In the full analysis set, 11 deaths occurred during treatment. Across indications, exposure-adjusted mortality rates/100 patient-years (95% CI) were 3.60 (0.90, 14.38), 0.34 (0.05, 2.43) and 1.18 (0.49, 2.82) with atacicept 25, 75 and 150 mg, respectively, and 0.44 (0.06, 3.12) with placebo. In SLE patients, exposure-adjusted mortality rates were 1.45 (0.54, 3.87) with atacicept 150 mg and 0.78 (0.29, 2.07) across all atacicept-treated patients. No deaths occurred with atacicept 75 mg or placebo. In the SLE and double-blind placebo-controlled sets, pharmacodynamic effects of atacicept were not associated with increased infection rates.

Conclusion

The results of this integrated safety analysis support further development and evaluation of atacicept in selected patients for whom potential benefits might outweigh risks.

BACKGROUND:Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4. OBJECTIVES:To evaluate the efficacy and safety of blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity. METHODS:442 patients with SLE with antinuclear antibodies or anti-dsDNA and Safety of Estrogen in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥10 on standard-of-care medications were randomised to receive weekly subcutaneous blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from week 8. The primary end point was the week 52 SLE Responder Index-6 (SRI-6). RESULTS:The SRI-6 primary end point was not met. There was a statistically significant steroid-sparing effect, and significantly more blisibimod-treated subjects achieved corticosteroid taper. Increased blisibimod treatment effect on SRI-6 was observed in subjects who achieved a concomitant decrease in corticosteroid dose from baseline. In subjects with baseline urinary protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, significantly higher proportions of blisibimod subjects achieved >50% reduction in UPCR and/or UPCR <56.5 mg/mmol. Reductions in SLE autoantibodies and B cells, and increases in complement C3 and C4 were observed with blisibimod.Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection, urinary tract infection, injection site erythema/reaction and diarrhoea. CONCLUSIONS:Although the SRI-6 end point was not met, blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses. TRIAL REGISTRATION NUMBER:NCT01395745.