Search

Objective: Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies., Methods: Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2., Results: A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab., Conclusions: Improved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified., Trial Registration Number: NCT02550652., Competing Interests: Competing interests: RAF reports personal fees from Genentech/Roche during the conduct of the study and outside the submitted work and grants from Genentech/Roche. MDC and JPG are employees and shareholders of Genentech/Roche. BHR reports personal fees from Genentech, during the conduct of the study; personal fees from Aurinia, personal fees from Bristol Myers Squibb, personal fees from Biogen, personal fees from Pfizer, personal fees from Lilly, personal fees from GlaxoSmithKline, personal fees from Mallinckrodt, personal fees from EMD Serono, personal fees from Omeros, personal fees from Calliditas, personal fees from Retrophin, personal fees from BioMarin, outside the submitted work. PB was an employee and shareholder of Genentech during the design and enrolment period. TS and IH are employees and shareholders of Roche. GA, AA, HF-L, EZ-S and AM have nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Systemic lupus erythematosus is an autoimmune disease in which the severity varies according to race, sex and age of onset. This variation is also observed in the genetic markers associated with the disease, including PTPN22, VDR and TNF genes. The genetic stratification in different populations worldwide can influence the variability., Objective: To analyze the heritability of PTPN22, VDR and TNF genetic variants and their association with pediatric lupus nephritis in Colombian families., Materials and Methods: We conducted a family-based study including 46 triads (case, father and mother). The variants rs2476601 of PTPN22; rs361525 and rs1800629 of TNF, and TaqI [rs731236], ApaI [rs7975232], BsmI [rs1544410] and FokI [rs2228570] of VDR were genotyped by qPCR. The effects of overtransmission of the risk allele from parents to children and linkage disequilibrium at the VDR and TNF loci were estimated., Results: We found that allele A of rs2476601 in PTPN22 was distributed among 8.69 % (n=16) of the parents and 19.5 % (n=18) of the cases; this allele was overtransmitted from parents to children 17 times more often than the G allele (p=0.028). TNF and VDR polymorphisms did not exhibit transmission disequilibrium. VDR TaqI, ApaI and BsmI variants exhibited linkage disequilibrium., Conclusion: These findings showed an association between the PTPN22 rs2476601 polymorphism and pediatric lupus nephritis due to its overtransmission in the group of families studied.

Renal involvement is one of the most severe manifestations of systemic lupus erythematosus (SLE). Renal biopsy is the gold standard when it comes to knowing whether a patient has lupus nephritis, and the degree of renal disease present. However, the biopsy has various complications, bleeding being the most common. Therefore, the development of alternative, non-invasive diagnostic tests for kidney disease in patients with SLE is a priority. Micro RNAs (miRNAs) are differentially expressed in various tissues, and changes in their expression have been associated with several pathological processes. The aim of this study was to identify changes in the abundance of miRNAs in plasma samples from patients with lupus nephritis that could potentially allow the diagnosis of renal damage in SLE patients. This is an observational case-control cross-sectional study, in which we characterized the differential abundance profiles of miRNAs among patients with different degrees of lupus compared with SLE patients without renal involvement and healthy control individuals. We found 89 miRNAs with changes in their abundance between lupus nephritis patients and healthy controls, and 17 miRNAs that showed significant variations between SLE patients with or without renal involvement. Validation for qPCR of a group of miRNAs on additional samples from lupus patients with or without nephritis, and from healthy individuals, showed that five miRNAs presented an average detection sensitivity of 97%, a specificity of 70.3%, a positive predictive value of 82.5%, a negative predictive value of 96% and a diagnosis efficiency of 87.9%. These results strongly suggest that miR-221-5p, miR-380-3p, miR-556-5p, miR-758-3p and miR-3074-3p are potential diagnostic biomarkers of lupus nephritis in patients with SLE. The observed differential pattern of miRNA abundance may have functional implications in the pathophysiology of SLE renal damage., Competing Interests: The authors have declared that no competing interests exist.

Mycophenolic acid, in combination with glucocorticoids, has been shown in a series of trials to be safe and effective for treatment of lupus nephritis. Regimens that permit glucocorticoid dose reduction without loss of efficacy would be advantageous. MyLupus was a 24-week, multicentre, open-label, study in patients with active proliferative lupus nephritis treated with enteric-coated mycophenolate sodium (EC-MPS), randomized to standard-dose (n = 42) or reduced-dose (n = 39) glucocorticoids. Complete response at week 24, the primary endpoint, was achieved in 19.8% (16/81) of patients (19.0% standard-dose, 20.5% reduced-dose; lower limit of 97.5% CI for the difference -15.9%, p = 0.098, i.e. non-inferiority was not shown). Partial response occurred in 42.0% of patients (34/81). From baseline to week 24, the mean global British Isles Lupus Assessment Group (BILAG) score decreased from 14.0 ± 5.4 to 5.0 ± 3.8 (p < 0.001). The incidence of adverse events was 80.2% (65/81), most frequently gastrointestinal complications (31/81, 38.3%). Infections were reported in 57.1% and 35.9% of standard- and reduced-dose glucocorticoid patients, respectively (p = 0.056), with herpes zoster in 16.7% and 0% (p = 0.012). Three patients discontinued study medication due to adverse events. This exploratory study suggests that EC-MPS may facilitate glucocorticoid reduction without loss of efficacy in patients with active lupus nephritis, but results require confirmation in a controlled, longer-term study versus the current standard of care.

Background: In clinical practice, it is sometimes difficult to diagnose a relapse in patients suffering from systemic lupus erythematosus (SLE) and lupus nephritis (LN) having potential complications, including renal failure and death. Some immunological markers can help to determine their association with LN and, therefore, diagnose the early onset of complications., Objectives: Evaluating the association between systemic and/or kidney activity and anti-P ribosomal and anti-dsDNA antibodies in patients suffering from active SLE., Methods: 389 patients were evaluated, 140 of whom were subsequently included in the study. The patients were divided into two groups by means of case-control studies, including Colombian patients having American College of Rheumatology (ACR) classification criteria for SLE (1997). The SLE disease activity index (SLEDAI) was applied and all patients presenting an increase of 5 or more compared to their last evaluation, as well as presenting renal manifestations, were considered to be cases; all patients had an activity score. An ELISA kit and the indirect immunofluorescence method with Crithidia luciliae were used for determining the presence of anti-P ribosomal and anti-dsDNA antibodies, respectively., Results: No association was found between anti-P ribosomal antibodies and LN (p=0.2971) but anti-P ribosomal antibodies showed association with a >5 SLEDAI score (OR=4.87; 1.32-17.98 95% CI; p=0.008). The coexistence of anti-P ribosomal and anti-dsDNA antibodies was associated with LN (OR=3.52; 1.07-13.42 95% CI; p=0.019) and anti-dsDNA was associated with LN (p=0.001)., Conclusion: There was no association between anti-P ribosomal antibodies and LN but anti-P ribosomal antibodies coexisting with anti-dsDNA antibodies was associated with LN, thereby suggesting that the coexistence of two antibodies is nephritogenic to a greater extent. Additional studies are needed to evaluate the coexistence of kidney-specific antibodies in SLE to determine the biological nature of LN., (Copyright 2010 Elsevier B.V. All rights reserved.)