Active Proliferative Lupus Nephritis Research Articles

Qualified kidney injury biomarkers demonstrate value during early clinical drug development.

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced renal tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, ii) Phase 2 rheumatoid arthritis patients (RA; n = 266) dosed with PFE-2, iii) lupus patients on standard-of-care therapies (n = 121), and iv) healthy volunteers (n = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.

Increased Urine Excretion of Neutrophil Granule Cargo in Active Proliferative Lupus Nephritis

Background: Lupus nephritis (LN) occurs in over half of patients with systemic lupus erythematosus (SLE), but the cellular and molecular events that contribute to LN are not clearly defined. We reported previously that neutrophil degranulation participates in glomerular injury in mouse models of acute LN. The current study tests the hypothesis that glomerular recruitment and subsequent activation of neutrophils results in urine excretion of neutrophil granule constituents that are predictive of glomerular inflammation in proliferative LN. Methods: Urine and serum levels of 11 neutrophil granule proteins were measured by antibody-based array in proliferative LN patients and healthy donors (HD), and results were confirmed by ELISA. Glomerular neutrophil accumulation was assessed in LN patient biopsies who contributed urine for granule cargo quantitation and normal kidney tissue by microscopy. Degranulation was measured by flow cytometry in neutrophils isolated from LN patients and HD controls by cell surface granule markers CD63 (azurophilic), CC66b (specific) and CD35 (secretory). Nonparametric statistical analyses were performed and corrected for multiple comparisons. Results: Eight granule proteins (myeloperoxidase, neutrophil elastase, azurocidin, olfactomedin-4, lactoferrin, alpha-1-acid glycoprotein 1 (α-1AG), MMP-9, and cathelicidin) were significantly elevated in urine from patients with active proliferative LN by array and/or ELISA, while only neutrophil elastase was increased in LN serum. Urine excretion of α-1AG declined in patients who achieved remission. The majority of LN glomeruli contained ≥ 3 neutrophils. Basal levels of specific granule markers were increased in neutrophils from LN patients, compared to HD controls. Serum from patients with active LN stimulated specific and secretory, but not azurophilic granule release by HD neutrophils. Conclusions: Circulating neutrophils in patients with LN are primed for enhanced degranulation. Glomerular recruitment of those primed neutrophils leads to release and urine excretion of neutrophil granule cargo that serves as a urine marker of active glomerular inflammation in proliferative LN.

Serum S100P and C4d proteins as markers for active proliferative lupus nephritis in Egyptian patients with systemic lupus erythematosus

Lupus nephritis (LN), occurring in approximately 50% of individuals with systemic lupus erythematosus (SLE), significantly influences therapy and prognosis. Proliferative LN, more prevalent than non-proliferative LN, is associated with a poorer prognosis. This study aimed to investigate the potential correlation between serum levels of the pro-inflammatory proteins human calcium-binding S100P (S100P) and Human complement Fragment 4 (C4d) and confirmed proliferative LN through biopsy. The objective was to evaluate their reliability as biomarkers for disease activity in proliferative LN.
 Methods. Serum S100P and C4d were measured using enzyme-linked immunosorbent assay in 100 female patients with established SLE. Among these, 50 had confirmed proliferative LN through biopsy, and 50 did not. A control group of 50 healthy female donors' plasma samples was included.
 Results. SLE patients with proliferative LN exhibited significantly higher serum levels of S100P (P < 0.001) and C4d (P < 0.001) compared to SLE patients without LN and controls. Serum S100P demonstrated a significantly higher positive correlation with the activity index in renal biopsies (r = 0.784) compared to serum C4d (r = 0.416). Additionally, serum S100P had a significantly higher positive correlation with SLEDAI-R than serum C4d (r = 0.651 vs. r = 0.257). Both serum S100P and C4d showed promise as reliable biomarkers for the diagnosis of active proliferative LN, as indicated by the ROC curve and AUC assessments.
 Conclusion. Serum concentrations of S100P and C4d emerge as useful indicators for identifying SLE patients with active proliferative LN.

FC 049A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS

Abstract Background and Aims In patients (pts) with SLE, activation of the CD40–CD40L pathway results in stimulation and proliferation of B cells and other inflammatory cell types. The subsequent generation of autoantibodies and their deposition in the kidney, as well as activation of myeloid and resident kidney cells, result in local inflammation and eventually, kidney injury. Thus, CD40 is an appealing therapeutic target in lupus nephritis (LN). BI 655064 is a humanised anti-CD40 monoclonal antibody that blocks the CD40 pathway in a nanomolar range and downregulates activated B cells. This study assessed the efficacy and safety over 52 weeks (wks) of three doses of subcutaneous BI 655064 compared with placebo, as add-on to mycophenolate and steroids, in pts with active proliferative LN (ClinicalTrials.gov number: NCT02770170). Method Overall, 121 pts with LN were randomised, double blind, in a 2:1:1:2 ratio to placebo or BI 655064 120 mg, 180 mg or 240 mg, and received a weekly loading dose for the first 3 wks, followed by dosing every 2 wks for the 120 and 180 mg doses, and weekly (120 mg) for the 240 mg group. Key inclusion criteria included an active ISN/RPS class III or IV (±V) renal biopsy within 3 months prior to screening and a screening protein/creatinine ratio of ≥1 mg/mg. Randomisation was stratified based on race (Asian vs non-Asian) and screening protein/creatine (UP/UC) ratio (<3 vs ≥3). The primary efficacy endpoint was complete renal response (CRR), defined as 24 h proteinuria <0.5 g/day and stable eGFR at Wk 52. Results The placebo response in this trial was higher than expected (48.3%; Table 1); none of the BI 655064 doses increased rates of CRR at Wk 52 compared with placebo. However, CRR at Wk 52 based on creatinine-adjusted proteinuria, assessed using spot urine, showed a better response in the 180 mg group (50%) vs placebo (42.5%), and the 180 mg dose showed a greater change from baseline over time vs placebo from Wk 4. Time to CRR was shorter in the 180 mg group (17.3 wks) vs placebo (20.4 wks). The 180 mg group also showed improvement vs placebo in total SLEDAI (SELENA) and its subscores. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR), whereby confirmation of the endpoint was required at both Wks 46 (penultimate visit on treatment) and 52. A 15.2% higher cCRR in the 180 mg group (44.3%) vs placebo (29.1%) was observed (p=0.26). While based on a small sample size, there were more reports of infection-related severe and serious adverse events and neutropenia in the 240 mg group compared with placebo. Of note, in those who experienced neutropenia, a clinical impact (e.g. increase in infections) was not established. Aside from these observations, safety data were comparable across treatment groups. Larger decreases from baseline were observed in the percentage of CD27−IgD−CD95+, CD27−IgD+CD95+, CD27+IgD+CD95+ and CD27+IgD−CD95+ B-cell subsets in the 180 and 240 mg groups compared with placebo. Treatment-emergent anti-drug antibodies (ADAs) were detected in five pts treated with BI 655054, all at low titre, and in one who received placebo; ADAs had no impact on pharmacokinetics or safety. Conclusion The trial did not meet its primary CRR endpoint. However, when confirmation of CRR was required at both Wks 46 and 52, the resultant decrease in the placebo response generated an effect size of 15.2% and 9.1% in favour of 180 mg and 240 mg BI 655064, respectively.

POS0695 KZR-616, A SELECTIVE IMMUNOPROTEASOME INHIBITOR FOR THE TREATMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS FROM THE COMPLETED DOSE ESCALATION PHASE 1B PORTION OF THE MISSION STUDY

Background:KZR-616 is a first-in-class selective inhibitor of the immunoproteasome, which is active in >15 autoimmune disease models, including murine models of systemic lupus erythematosus (SLE)/lupus nephritis (LN).1,2,3 Selective inhibition of the immunoproteasome modulates both innate and adaptive immune effector cells, resulting in reduced inflammatory T helper cell subsets (Th1 and Th17), increased regulatory T cells, and decreased plasma cells and autoantibodies. KZR-616 was well tolerated in two healthy volunteer studies of 100 subjects receiving up to 75 mg subcutaneously (SC). Target levels of immunoproteasome inhibition were observed at doses ≥30 mg.3,4 KZR-616 is currently in Phase 2 studies for several autoimmune indications, including the ongoing Phase 2 portion of the MISSION Study (KZR-616-002; NCT0339013) in patients with LN.Objectives:Results of the completed MISSION Phase 1b dose escalation portion of the study are reported.Methods:In the open-label, multicenter, dose escalation Phase 1b portion, SLE patients (per SLICC Classification Criteria) with SLEDAI ≥4 despite stable background immunosuppressant, anti-malarial, and/or corticosteroid therapy were administered weekly KZR-616 subcutaneously at doses of 45 mg (cohort 1), 60 mg (cohort 2), 60 mg following step-up doses of 30 mg and 45 mg (cohort 2a), 60 mg following a step-up dose of 30 mg (cohorts 2b, 2c) or 75 mg following a step-up dose of 30 mg (cohort 3) for 13 weeks with follow-up through Week 25 (W25); a lyophilized formulation was used for cohorts 2b, 2c and 3. The disease activity measures assessed were: SLEDAI-2K, Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), 28 tender and swollen joint counts, Physician and Patient Global Assessments, and Patient Assessment of Pain. Safety and tolerability were assessed in the safety population (patients receiving at least one dose of KZR-616).Results:The Phase 1b portion of MISSION enrolled 47 SLE patients, including 2 patients with active proliferative LN. The most common treatment-emergent adverse events (TEAE) were injection site reactions, which were mostly mild. Infections occurred at a low rate, and there were no reports of peripheral neuropathy, prolonged hematologic AEs, or clinically significant laboratory abnormalities. No discontinuations were observed in cohorts 2b and 2c; no serious AEs were reported in cohort 3 and TEAEs were consistent with those reported in earlier cohorts. Mean values of all measures of disease activity improved in evaluable patients who completed the 13-week treatment period, and improvements were generally maintained at W25. All patients with elevated anti-double-stranded DNA antibody (anti-dsDNA) levels at baseline (n=7) had a reduction in levels with 3 of 7 experiencing a >50% reduction in their levels. Two of two patients with active proliferative LN had a >50% reduction in UPCR and experienced reductions in SLEDAI-2K scores as well as anti-dsDNA levels. Exposure to KZR-616, similar to that reported in healthy volunteers, was dose-proportional across doses, and no accumulation was observed.Conclusion:KZR-616 SC, once weekly for 13 weeks up to 75 mg, appears to be safe and well-tolerated in patients with active SLE on stable background therapy in the MISSION Phase 1b. At doses ≥45mg, efficacy was noted, including improvements in proteinuria in two of two patients with LN and serologic improvement in all 7 patients with quantifiable levels of anti-dsDNA antibodies at baseline. KZR-616 60 mg SC weekly for 24 weeks is currently being evaluated in the MISSION Phase 2 in patients with LN. Based on the results of MISSION, inhibition of the immunoproteasome with KZR-616 represents a novel strategy to treat autoimmune diseases.

POS0687 A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS

POS0687 A RANDOMISED DOSE RANGING, PLACEBO-CONTROLLED, PHASE II STUDY ASSESSING THE EFFICACY AND SAFETY OF BI 655064, AN ANTAGONISTIC ANTI-CD40 ANTIBODY, IN PATIENTS WITH LUPUS NEPHRITIS

The association between active proliferative lupus nephritis during pregnancy and small for gestational age newborns.

To analyse maternal variables associated with occurrence of small for gestational age (SGA) newborns in pregnancies of women with systemic lupus erythematosus (SLE), considering clinical and laboratory characteristics prior to conception, during gestation and comorbidities. Retrospective cohort study with SLE pregnant patients and singleton deliveries after 22 weeks. SGA newborn was defined as birth weight below 10th percentile and SLE activity at conception and during gestation was measured using the SLE Pregnancy Disease Activity Index (SLEPDAI). Univariate analysis was employed to evaluate individual influence of demographic and clinical variables on the SGA newborn outcome, while variables with p<0.20 were included in multivariate regression. Among 151 pregnancies, 28 (18.5%) had SGA newborns. History of proliferative nephritis (RR=3.84, CI 1.63-9.3) and positivity for anti-RNP and anti-Sm antibodies (RR=2.67, CI 1.11-6.43; 2.78, CI 1.44-5.32) were more frequent in the study group. Active proliferative nephritis at conception (RR=3.29, CI 1.75-6.18) and during gestation (RR=3.63, CI 1.97-6.71), as well as complement C3 consumption (RR=2.70, CI 1.09-6.67) and venous pulse therapy with methylprednisolone (RR=20.3, CI 2.18-190), were also associated with SGA newborns, the latter being independently associated in multivariate regression. Adverse perinatal outcomes, such as stillbirths (4.3 times) and neonatal intensive care unit admissions (3.2 times), were more frequent among SGA infants. Active proliferative lupus nephritis during pregnancy was associated with SGA newborns, while its treatment with venous pulse therapy with methylprednisolone may play a significant role in this context. Presence of previous proliferative nephritis, SLEPDAI ≥4, C3 consumption and presence of anti-RNP and anti-Sm antibodies were additional variables associated with SGA newborns in this population.

Complements as a Predictive Biomarker of Lupus Nephritis in Female Patients with Systemic Lupus Erythematosus

Background: Lupus nephritis (LN) has been demonstrated in about 40–50 percent of all systemic lupus erythematosus (SLE) patients. Patients having renal flares are at risk from suffering serious kidney damage, and usually have a poor prognosis. Unfortunately, renal flare pathogenesis in LN patients remains unclear, and no known predictions of an impending renal flare exist. Aim: The present study aims to measure circulating levels of anti-C1q antibodies, C3, C4, TNF-α and soluble TNF-α receptor, serum creatinine and blood urea nitrogen (BUN) as biomarkers for active LN. Materials and methods: The study included 180 SLE female patients meeting the revised classification requirements of the modified American College of Rheumatology (ACR); 90 female patients with active proliferative LN (biopsy-proven) and other 90 patients with inactive LN. Patients were receiving mycophenolate mofetil; and the study was conducted between 2018 and 2019. Results: We found that low levels of complement C3 and C4 in combination with high levels of BUN, creatinine, anti-C1q antibodies and positive anti-dsDNA antibodies were more likely to be associated with lupus nephritis development in SLE patients. Also, high levels of TNF-α and its soluble receptor can be used as an indication of active disease activity and flare development. Conclusion: Monitoring of Anti-C1q antibodies, C3, C4, serum creatinine, and BUN levels in SLE patients can improve LN prognosis. TNF-α can also be used as an indicator for active LN and concomitant flare. This early diagnosis combined with prompt care would help decrease morbidity and mortality in LN patients.

AB0373 TREATMENT OF SLE WITH THE IMMUNOPROTEASOME INHIBITOR KZR-616: RESULTS FROM THE FIRST 4 COHORTS OF THE MISSION STUDY, AN OPEN-LABEL PHASE 1B DOSE ESCALATION TRIAL

Background:Non-specific proteasome inhibitors, such as bortezomib (BTZ), target the constitutive proteasome and immunoproteasome and are approved treatments for multiple myeloma1. BTZ has also been used to treat systemic lupus erythematosus (SLE) and lupus nephritis (LN); however, treatment emergent adverse events (TEAEs), such as gastrointestinal (GI) effects, hematologic abnormalities, asthenia and peripheral neuropathy, limit its use as a long-term treatment option for chronic autoimmune disease2. KZR-616 is a first-in-class selective immunoproteasome inhibitor and is highly active in murine SLE3. Subcutaneous (SC) administration of KZR-616 (30 and 45 mg weekly [QW]) was demonstrated as safe and well-tolerated, and successfully achieved target levels of immunoproteasome inhibition in healthy volunteers4, 5.Objectives:We report the preliminary safety and efficacy of KZR-616 in the first 4 cohorts of the Phase 1b portion of Study KZR-616-002 in patients with active SLE (NCT03393013).Methods:SLE patients (per SLICC Classification Criteria) with SLEDAI ≥4 despite stable background immunosuppressant, anti-malarial, and/or corticosteroid (≤20 mg prednisone equivalent) therapy in this open-label multicentric dose-escalation trial received KZR-616 at doses of 45mg (Cohort 1), 60mg (Cohort 2), or 30mg with escalation to 60mg (Cohorts 2a and 2b) SC weekly through Week 13 (W13) with 12 weeks of follow-up. Efficacy measures included SLEDAI, Cutaneous Lupus Erythematous Disease Area and Severity Index, 28 tender and swollen joint counts, Physicians Global Assessment, Patient Global Assessment, and Patient Assessment of Pain, in evaluable patients (those who received ≥1 month of KZR-616).Results:As of 16 January 2020, 33 patients had enrolled and received at least 1 dose of KZR-616. The majority of TEAEs have been mild or moderate with no reported peripheral neuropathy, prolonged GI-related AEs, and no clinically significant laboratory AEs. There were 3 treatment emergent SAEs, one each of thrombotic microangiopathy (Cohort 2), localized herpes zoster (Cohort 2a), and systemic inflammatory response syndrome (Cohort 2a) with the latter 2 patients completing the full 13 weeks of treatment after resolution. When compared to baseline, improvement in all measures of disease activity were seen at W13 and maintained or improved during the follow-up period, and 94% of evaluable patients had improvements on at least 2 measures/assessments of disease activity. A single patient with active class IV/V nephritis was enrolled on prednisone 10 mg, leflunomide 10 mg, and hydroxychloroquine 200mg/day; nephrotic-range proteinuria at baseline (3.85 g/day) decreased to 0.6 g/day 4 weeks after the last dose of KZR-616.Conclusion:Weekly subcutaneous administration of KZR-616 at 45 and 60 mg was safe and well-tolerated. Evidence of disease suppression at W13 in active SLE patients on stable background therapy was observed. In addition, one study participant with active proliferative nephritis was enrolled with significant reduction in proteinuria. The Phase 2 portion of this study in active proliferative LN is open for enrollment.

OP0163 2019 UPDATE OF THE JOINT EUROPEAN LEAGUE AGAINST RHEUMATISM AND EUROPEAN RENAL ASSOCIATION–EUROPEAN DIALYSIS AND TRANSPLANT ASSOCIATION (EULAR/ERA-EDTA) RECOMMENDATIONS FOR THE MANAGEMENT OF LUPUS NEPHRITIS

Background:Up to 40% of systemic lupus erythematosus (SLE) patients develop kidney disease, which represents a major cause of morbidity.Objectives:To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN).Methods:We followed the EULAR standardised operating procedures for the publication of treatment recommendations. Delphi-based methodology led to 15 questions for systematic literature review (SLR), which was undertaken by three fellows.Results:The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNI), and management of end-stage-kidney-disease (ESKD). The target of therapy is complete response (proteinuria &lt;0.5-0.7gr/24h with [near-]normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3g/day, or mycophenolic acid at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500mg x6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (&lt;7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria &gt;1g/24h despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations.Conclusion:The updated recommendations intend to inform rheumatologists, nephrologists, patients, national professional societies, hospital officials, social security agencies and regulators about the treatment of LN based on most recent evidence.Disclosure of Interests:Antonis Fanouriakis Paid instructor for: Paid instructor for Enorasis, Amgen, Speakers bureau: Paid speaker for Roche, Genesis Pharma, Mylan, Myrto Kostopoulou: None declared, Kim Cheema: None declared, Hans-Joachim Anders: None declared, Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche, Ingeborg Bajema Consultant of: GSK, John N. Boletis Grant/research support from: GSK, Pfizer, Paid instructor for: GSK, Abbvie, UCB, Enorasis, Eleni Frangou: None declared, Frederic Houssiau Grant/research support from: UCB, Consultant of: GSK, Jane Hollis: None declared, Alexandre Karras: None declared, Francesca Marchiori: None declared, Stephen Marks: None declared, Gabriela Moroni: None declared, Marta Mosca: None declared, Ioannis Parodis: None declared, Manuel Praga: None declared, Matthias Schneider Grant/research support from: GSK, UCB, Abbvie, Consultant of: Abbvie, Alexion, Astra Zeneca, BMS, Boehringer Ingelheim, Gilead, Lilly, Sanofi, UCB, Speakers bureau: Abbvie, Astra Zeneca, BMS, Chugai, GSK, Lilly, Pfizer, Sanofi, Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Vladimir Tesar: None declared, Maria Trachana: None declared, Ronald van Vollenhoven Grant/research support from: AbbVie, Amgen, Arthrogen, Bristol-Myers Squibb, GlaxoSmithKline (GSK), Janssen Research &amp; Development, LLC, Lilly, Pfizer, Roche, and UCB, Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo Bioscience, GSK, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, UCB and Vertex, Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo Bioscience, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Vertex, Alexandre Voskuyl: None declared, Y.K. Onno Teng Grant/research support from: GSK, Consultant of: GSK, Aurinia Pharmaceuticals, Novartis, Bernadette van Leeuw: None declared, George Bertsias Grant/research support from: GSK, Consultant of: Novartis, David Jayne Grant/research support from: ChemoCentryx, GSK, Roche/Genentech, Sanofi-Genzyme, Consultant of: Astra-Zeneca, ChemoCentryx, GSK, InflaRx, Takeda, Insmed, Chugai, Boehringer-Ingelheim, Dimitrios Boumpas: None declared

MO007A PHASE 1B MULTIPLE ASCENDING-DOSE STUDY OF A CD6 TARGETED THERAPY, ITOLIZUMAB, IN SUBJECTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS WITH OR WITHOUT ACTIVE PROLIFERATIVE LUPUS NEPHRITIS

Abstract Background and Aims Lupus nephritis (LN) is a leading cause of morbidity and mortality in systemic lupus erythematosus (SLE) patients. T cells are believed to play a central role in the pathogenesis of both SLE and LN. CD6 is a co-stimulatory receptor, predominantly expressed on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen presenting cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation, proliferation, differentiation and trafficking, and is central to immune mediated inflammation. Itolizumab (EQ001) is a humanized IgG1 monoclonal antibody that binds CD6, blocks the interaction between CD6 and ALCAM, and inhibits both the activation and trafficking of T cells. Inhibiting the CD6-ALCAM pathway with itolizumab potentially represents a promising therapeutic approach for the treatment of LN. The aim of this study is to assess the safety and tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of subcutaneously administered itolizumab in patients with SLE with and without active proliferative lupus nephritis (apLN). Method This cohort-based dose escalation study includes two types of patients: The Type A cohort will enroll ∼24 patients with SLE without apLN (all treated with itolizumab) and the Type B cohort will randomize in a blinded manner ∼36 patients (3:1, itolizumab:placebo) with biopsy-proven ISN/RPS class III or IV (+ V) apLN who have had inadequate response to induction and/or post-induction maintenance treatment, exhibiting urine protein to creatinine ratio [UPCR] ≥1 g/g and active serology. Within both the Type A and Type B cohorts, up to 4 dose groups will be tested (Figure). Background treatments for SLE or LN are allowed. Following 4 weeks of treatment in a new higher dose Type A cohort and recommendation by an independent safety data review committee (DRC), the dose studied in the Type A cohort may then be studied in a Type B Cohort for a 12-week treatment duration (Figure). The primary endpoint is the safety and tolerability of itolizumab. Efficacy endpoints (in the Type B cohorts) include UPCR, estimated glomerular filtration rate, prednisone dose requirements, renal response, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), FACIT Fatigue Scale, serologic markers, and other patient reported outcomes. In Type A cohort patients, clinical responses and pharmacologic activity will be assessed based on changes in serologic markers, SLEDAI-2K, FACIT Fatigue Scale. Pharmacodynamic markers, including markers that may allow future risk stratification, urinary ALCAM and CD6, will be examined in both cohort types. Results The study is ongoing. Six patients have been enrolled in Type A Cohort 1 (0.4 mg/kg dose) and completed both treatment and 4 weeks of post-treatment follow-up. The mean age was 59.5 (12.9) years, 100% were female; 67% were Hispanic/Latino; and 50% were White, and 50% were Black. Duration of SLE ranged from 3 years to 31 years. Concomitant medications for lupus included prednisone (83%, dose range 2.5 mg – 10 mg), methotrexate (33%), and anti-malarials (33%). Baseline SLEDAI-2K (mean 7.5 [2.2]) was based on findings of alopecia (83%); arthritis (67%); mucosal ulcers and rash (50% each); fever, increased dsDNA, and low complement (17% each). There were no adverse events. Additional data from this ongoing study will be presented. Conclusion Itolizumab, a monoclonal antibody blocking the CD6-ALCAM pathway, is a novel experimental treatment for LN. This is the first trial of itolizumab in patients with SLE and apLN. Data from the first cohort of patients suggest that the drug is safe and well-tolerated at a dose of 0.4 mg/kg over a 4-week treatment period. Additional cohorts of patients with SLE and apLN are currently being enrolled.

2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis

ObjectiveTo update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force...

Corticosteroids combined with doublet or single-agent immunosuppressive therapy for active proliferative lupus nephritis.

We performed a meta-analysis to assess whether corticosteroids (C) plus (+) doublet immunosuppressive therapy (IT) is superior to the classical combination of C with single-agent IT in active proliferative lupus nephritis (LN). Randomized trials evaluating the benefits and risks of C+doublet versus single-agent IT in active proliferative LN were obtained by searching PubMed, EMBASE, and Cochrane Central Register. The primary outcome was overall response rate (ORR). The secondary outcomes were the change from baseline in Systemic Lupus Erythematosus Disease Activity Index (SLE-DAI) score, negative conversion ratio of anti-double-stranded DNA (anti-dsDNA), and adverse events. The PROSPERO registry number is CRD42017068491. Eleven trials with 1855 patients were included. Compared with C+single-agent IT, C+doublet IT had a significantly higher ORR (relative risk [RR], 1.22; 95% confidence interval [CI], 1.09 to 1.35; P < 0.01). In a subgroup analysis, C+doublet IT without biologics had a significantly higher ORR than C+single-agent IT (RR, 1.30; 95% CI, 1.13 to 1.50; P < 0.01), while C+doublet IT including biologics improved ORR only for refractory severe LN (RR, 1.46; 95% CI, 1.09 to 1.96; P = 0.012). A larger change from baseline in SLE-DAI scores (standardized mean difference, - 0.49; 95% CI, - 0.68 to - 0.30; P < 0.01) and a higher negative conversion ratio of anti-dsDNA (RR, 1.34; 95% CI, 1.06 to 1.69; P = 0.014) were observed with C+doublet IT than with C+single-agent IT. The rates of adverse events were similar between the two regimens. Compared with single-agent IT, the combination of C and doublet IT without biologics improved clinical outcomes in active proliferative LN. Key Points • Compared with corticosteroids + single-agent immunosuppressive therapy, corticosteroids + doublet immunosuppressive therapy without biologics had a significantly higher overall response rate in active proliferative lupus nephritis. • Compared with corticosteroids + single-agent immunosuppressive therapy, corticosteroids + doublet immunosuppressive therapy including biologics improved overall response rate only for refractory severe lupus nephritis. • A larger change from baseline in SLE-DAI scores and a higher negative conversion ratio of anti-dsDNA were observed with corticosteroids + doublet immunosuppressive therapy than with corticosteroids + single-agent immunosuppressive therapy.

Comparison of Renal Responses to Cyclophosphamide and Mycophenolate Mofetil used as Induction Therapies in Korean Patients with Lupus Nephritis

Objective Although intravenous cyclophosphamide (IVC) is generally accepted as the standard therapy for induction treatment of active proliferative lupus nephritis (LN), several clinical trials have suggested that mycophenolate mofetil (MMF) is at least as effective as IVC. Because few Asian studies have compared the two treatment modalities, we compared the efficacies of MMF and IVC as LN remission induction treatments in Korean patients. Methods We enrolled 39 patients with class III and IV LN who received MMF or IVC as LN induction therapy. The renal outcomes (i.e., complete response [CR], partial response [PR], and no response [NR]) at 6 and 12 months were defined using the ACR 2006 response criteria. Results Of 39 patients, 23 (59.0%) were treated with IVC, and 16 (41.0%) were treated with MMF. Demographics, clinical characteristics, laboratory data, and adverse events did not significantly differ between the two groups. However, C3 levels were lower and activity scores in renal biopsy were higher in IVC-treated patients. CRs were achieved by 11 (47.8%) of the patients receiving IVC and 7 (43.8%) of the patients receiving MMF after 6 months of treatment (p=0.961) and by 11 (47.8%) of those who received IVC and 9 (56.2%) of those who received MMF at 12 months of treatment (p=0.713). Neither the PR rate nor the NR rate differed significantly at 6 or 12 months between the two groups. Conclusion The efficacy of MMF does not differ from that of IVC in terms of induction of LN remission in Korean patients.

An Update on Therapies for Proliferative Lupus Nephritis: How Certain Can We Be About the Evidence?

An Update on Therapies for Proliferative Lupus Nephritis: How Certain Can We Be About the Evidence?

Effect of induction therapy on circulating T-helper 17 and T-regulatory cells in active proliferative lupus nephritis.

T-helper 17 (Th17) cells and T-regulatory (Treg) cells have been suggested to play pathogenic roles in lupus nephritis. The in vivo effects of current therapies for lupus nephritis (LN) on these cells have not been adequately studied. We conducted a prospective observational study among patients with active proliferative lupus nephritis (LN) who received Eurolupus induction therapy and assessed them as per the European League Against Rheumatism criteria for renal response. Peripheral circulatory Th17 and Treg cell numbers were enumerated at start of therapy, at 3 and 6 months follow-up periods using flow cytometry. Baseline values were compared with inactive lupus patients (iSLE) and healthy controls (HC). Thirty patients with LN, 20 iSLE and 22 HC were enrolled into the study. In LN, Th17 frequency was significantly higher compared to HC, and Treg frequency significantly lower compared to both iSLE and HC. Nineteen patients fulfilled criteria for response (partial or complete) at 6 months. Responder group showed a significant decline in Th17 frequency and an increasing trend in Treg frequency compared to baseline after 6 months of therapy. Circulating Th17 cells were significantly raised in patients with active proliferative LN and showed a significant reduction in responder patients following therapy.

Circulating serum anti-C1q antibody: correlation with clinical and histopathological activity in patients with proliferative lupus nephritis

In systemic lupus erythematosus (SLE) the prevalence of anti-C1q antibodies (Abs) varies from 30 to 50% and is associated with high clinical activity and, particularly, with renal involvement. Moreover, in the absence of anti-C1q auto-Abs, no lupus nephritis occurs, whereas at least 50% of patients with anti-C1q auto-Abs have or develop lupus nephritis. For lupus nephritis, anti-C1q Abs are as specific as high-avidity dsDNA Ab and capable of closing a diagnostic gap in some cases. The present study was conducted on 40 patients with SLE. Patients were classified into group I (20 patients with active proliferative lupus nephritis (LN)), group II (10 patients with inactive LN), and group III (10 patients without nephritis). Laboratory investigations were carried out, including complete blood picture, renal functions (blood urea, serum creatinine, and creatinine clearance), complete urine analysis and urine analysis for dysmorphic red blood cells (RBCs), measurement of 24 h urinary proteins, erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and anti-dsDNA, and measurement of serum anti-C1q. Renal biopsy was taken from all patients of group I. Anti-C1q Abs were significantly higher in group I than in other groups. There were statistically significant positive correlations between anti-C1q Ab level, anti-dsDNA, and percentage of dysmorphic RBCs in urine in group I. There was also a statistically significant positive correlation between anti-C1q Ab level and cellular crescents, leukocyte infiltration, and endocapillary cellularity in the activity index. Anti-C1q Ab can be used as an indicator of renal activity in patients with lupus nephritis.

Treatment outcomes from a multiethnic lupus cohort with proliferative nephritis

Objective: To assess treatment responses and long-term outcomes in a multiethnic lupus cohort with proliferative lupus nephritis (LN) from a single United Kingdom (UK) center. Methods: 86 lupus patients were diagnosed with active proliferative LN between 1995 and 2015 at Barts Health, a large inner city hospital in London, UK. They were grouped by ethnicity into South Asians (Bangladeshi, Indian, Pakistani, and Sri Lankan), blacks (African Blacks and Afro-Caribbeans), and Caucasians. Remission rates were analyzed at 6 and 24 months after induction treatment with cyclophosphamide (CYC) or mycophenolate mofetil (MMF). Prognostic factors for the treatment response were identified by regression analysis. Kaplan-Meier method was applied to assess long-term renal survival and Cox proportional hazards model for risk factors for developing end-stage renal disease. Results: MMF achieved a higher remission rate in blacks compared to CYC (70% vs. 16.7%, P = 0.005) at 6 months, showed a trend in Asians (77.8% vs. 38.9%, P = 0.057), and comparable response in Caucasians (42.9% vs. 55.6%, P = 0.614). Low baseline serum creatinine was the strongest predictor for favorable treatment response (odds ratio 0.98, 95% confidence interval [95% CI]: 0.97-0.99, P = 0.045). Renal survival glomerular filtration rate (GFR >15 ml/min/1.73 m 2 ) was 79.8% and 75.6% at 5 and 10 years, lowest in blacks (60.5%) followed by Asians (86.7%) then Caucasians (88.9%) (P = 0.030). Low GFR (GFR Conclusions: MMF appears to be at least as effective as CYC as an induction agent in this multiethnic cohort but there were important differences in long-term renal outcomes based on ethnic group and baseline GFR and creatinine.

Anti-dsDNA antibody induces soluble fibronectin secretion by proximal renal tubular epithelial cells and downstream increase of TGF-β1 and collagen synthesis

The level of anti-dsDNA antibodies correlates with disease activity in lupus nephritis, but their role in pathogenic mechanisms remains to be defined. We investigated the effect of anti-dsDNA antibodies isolated from lupus nephritis patients on fibronectin synthesis and downstream fibrogenesis in proximal renal tubular epithelial cells (PTEC). Kidney biopsies were obtained from patients with active severe proliferative lupus nephritis. In vitro studies with cultured PTEC were performed to investigate the effect of human polyclonal IgG anti-dsDNA antibodies and mycophenolic acid (MPA). The role of IL-6, IL-8, MCP-1, TNF-α, TGF-β1, and MAPK and PKC signaling pathways on soluble and cell-associated fibronectin synthesis was investigated using neutralizing antibodies or specific inhibitors. The effect of exogenous endotoxin-free soluble fibronectin on downstream fibrotic processes was also examined. Fibronectin expression was markedly increased in the tubulo-interstitium of lupus nephritis renal biopsies and it co-localized with IgG deposition. Anti-dsDNA antibodies significantly increased both secreted and cell-associated fibronectin, through prior activation of ERK, p38 MAPK, JNK, PKC-α and PKC-βII. There was downstream induction of IL-6, IL-8, MCP-1, TNF-α and TGF-β1. MPA inhibited the induction of inflammatory and fibrotic processes by anti-dsDNA antibody. Exogenous soluble fibronectin induced TGF-β1 secretion and type I collagen synthesis in PTEC in a dose-dependent manner. Our data demonstrate that anti-dsDNA antibody contributes to tubulo-interstitial fibrosis in lupus nephritis through its action on PTEC. Anti-dsDNA antibody induces both cell-associated and soluble fibronectin secretion in PTEC, the former adds to extracellular matrix deposition while the latter amplifies the fibrotic process through induction of TGF-β1 and collagen type I. The pro-fibrotic effects of anti-dsDNA antibody are ameliorated by MPA.

Effect of induction therapy on circulating Th17 and T-regulatory cells in active proliferative lupus nephritis

and 22.2 %( 9) respectively, with seizures being the common neuropsychiatric feature at presentation. Renal biopsy done in 35 %( 14) with active urinary sediments/proteinuria showed nephritis of either of these threeeclass III, IV or V. Three of them died, one before and two after 5 years follow-up. One without renal involvement at presentation developed lupus nephritis within 1 year of presentation. Mean SDI score at presentation was 1±1.3. Sixty percent (24) crossed 5 year follow-up and their mean SDI score was 0.5±1.45. Twenty-five percent (10) crossed 10 year follow-up and two died later due to sepsis. Mean SDI score at 10 years was 0.5±1.94. Conclusion: Renal involvement was striking at presentation. Organ damagewas high at presentation as evidenced by SDI score. Sepsis can be avoided with meticulous precautions, vaccinations and careful choice of immunosuppressants. Early diagnosis and treatment can improve survival rates.