We report the case of a 77-year-old woman with metastatic gallbladder cancer who initially received adjuvant capecitabine following surgery. During this period, she developed a facial rash, associated with a positive antinuclear antibody (ANA) with a titer of 1:320. Six months later, disease recurrence prompted treatment with gemcitabine, cisplatin, and durvalumab. Shortly after completing six cycles of chemo-immunotherapy, she presented with rapidly progressive dyspnea, severe hypertension, thrombotic microangiopathy (TMA; confirmed on renal pathology), and multiorgan dysfunction, including hepatic and muscular involvement. Laboratory workup revealed a strongly positive ANA titer (1:1280) corresponding to strongly positive anti-Th/To antibodies. Although the clinical presentation was highly suggestive of scleroderma renal crisis (SRC), it remained challenging to determine whether this was an immune-related adverse event, a paraneoplastic manifestation, or an exacerbation of a pre-existing autoimmune condition. This case illustrates the diagnostic and therapeutic complexity of autoimmune phenomena in oncology and highlights the importance of thorough autoimmune screening and multidisciplinary collaboration before and during immunotherapy.

Within the frame of the Lupus Nephritis Trials Network (LNTN), we conducted a systematic literature review (SLR) to propose kidney tissue-based definitions of treatment outcomes in lupus nephritis (LN). Given the limitations of clinical markers like proteinuria in predicting immunological, histological, and long-term outcomes, our work emphasises the importance of repeat kidney biopsies. Such biopsies help identify discordance between clinical and histological response, which has implications for long-term kidney outcomes. The research objectives of this SLR focused on defining repeat biopsy-based treatment response and histological remission, and their associations with long-term outcomes. The SLR reviewed studies published from 2000 to 2022, identifying 20 eligible works. Histological response was commonly defined by changes in the National Institutes of Health (NIH) Activity Index (AI), with response indicated by a decrease of ≥50 % and to ≤3. Remission was most commonly defined as an AI score of 0. These benchmarks were associated with improved long-term renal outcomes, such as reduced flare rates and preserved kidney function. Conversely, NIH AI scores ≥4 and NIH Chronicity Index (CI) scores ≥4 were associated with poor prognosis, highlighting their predictive utility. Consensus definitions were established through expert panel deliberation, setting a foundation for standardising LN treatment evaluation in clinical trials and observational studies. These definitions are not intended for routine clinical decisions but aim to enhance uniformity and comparability in research, especially when repeat kidney biopsies are performed, an approach strongly advocated by our work. Further validation through ongoing initiatives and molecular characterisation efforts will refine these criteria, fostering advances in LN management and patient outcomes.

Lupus nephritis is the most common severe manifestation of systemic lupus erythematosus. B cells are key drivers of the disease as they produce autoantibodies that deposit in the kidneys, triggering inflammatory response and damage. The REGENCY trial1 demonstrates that addition of the anti-CD20 monoclonal antibody obinutuzumab on top of standard-of-care significantly improves complete renal remission rate.

Lupus nephritis remains the most frequent severe complication of systemic lupus erythematosus, leading to chronic renal impairment in 20 to 25% of cases. Current treatment is based on the combined use of immunosuppressive treatment and targeted biotherapies to optimize the chances of promptly obtaining and maintaining a complete renal response over the long term. The author discusses these recent advances.

Objective:To optimise the organisation of care and encourage the adoption of good clinical practices, the RarERN Path© methodology was designed within ERN ReCONNET. The aim of our work was to report the application of RarERN Path© on systemic sclerosis within the ERN ReCONNET centres, providing a feasible and flexible organisational reference model for optimising the systemic sclerosis care pathway in different countries. Methods:RarERN Path© is a six-phase methodology which enables the creation of a reference organisational model co-designed on the basis of the expertise of different stakeholders. It foresees six phases, ranging from the map of existing patients' care pathways and patients' stories, to the consensus on a common organisational patient care pathways, and its key performance indicators definition. Results:The agreed reference model highlights the importance of having an organisational flow for referrals that foresees how patients may access directly the specialised unit from the different referrals. Specific specialised visits were considered as mandatory to be organised and they included cardiologist, pneumologist, gastroenterologist, psychologist, nephrologist, dermatologist, wound care specialist/nurses and other healthcare professionals (such as nurses, social workers and nutritional counselling). Moreover, specific services related to therapy were highlighted as strongly recommended to be organised, mainly represented by infusion therapy and wound care, as well as occupation therapy and physiotherapy. Conclusion:The organisational model emerged from our investigation emphasises that the organisation of specific services for systemic sclerosis treatment should be organised as a solid support for implementing the existing recommendations on systemic sclerosis management in real life.

OBJECTIVE:Our objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN). METHODS:We performed a systematic review and meta-analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy-proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta-analysis of proportions, meta-regression, and subgroup meta-analysis were performed at 6 and 12 months for all outcomes. RESULTS:Fifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3-31.5), 3.2% (95% CI 2.4-4.0), and 0.2% (95% CI 0.0-0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9-52.3), 12.1% (95% CI 9.3-14.9), and 2.7% (95% CI 0.0-5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose-response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria. CONCLUSION:A higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

Objective To determine whether immune deposit (ID) resorption in per-protocol repeat kidney biopsies in patients with proliferative lupus nephritis (PLN) correlates with histological response and/or predicts renal relapse. Methods Twenty-eight patients with PLN (class III/IV±V) who underwent a per-protocol repeat kidney biopsy after a median time of 18.4 [11.5–29.2] months (i.e., performed irrespectively of the clinical response) were included in this retrospective study. We assessed IgG, IgA, IgM, C3, and C1q IDs by direct immunofluorescence using a semi-quantitative scale (0–3) at three sites (mesangial, subendothelial, subepithelial). We computed a total Ig score (0–27; 3 Ig subclasses x 3 sites x score 0–3) and a total C score (0–18; 2 C molecules x 3 sites x score 0–3). Activity index (AI) was measured according to the NIH scoring system. Renal relapse was defined as the reappearance of a urinary protein/creatinine ratio (uPCR) >1 g/g, following a clinical response with uPCR <0.5 g/g, prompting a biopsy and/or therapy modification. Results Total Ig and C scores substantially decreased from the diagnostic (median [IQR]: 7.25 [5.00–10.00] and 6.00 [5.00–9.25], respectively) to the repeat biopsy (3.50 [0.75–6.00] and 2.50 [0.00–4.62]; p<0.001), with significant reductions for IgG, IgA, C3, and C1q (table 1). Significant resorption was observed in the mesangial (from 3.25 [0.00–5.25] to 0.00 [0.00–2.00]; p=0.005 for Ig and from 4.75 [3.00–6.00] to 0.00 [0.00–2.00]; p<0.001 for C) and subendothelial (from 0.00 [0.00–4.62] to 0.00 [0.00–0.00]; p=0.006 for Ig and from 0.00 [0.00–4.25] to 0.00 [0.00–0.00]; p=0.027 for C) sites, but not in the subepithelial site. There was no significant correlation between the decrease in AI and total Ig and C. Of seven relapsing patients, none had achieved a decrease of ≥75% in the total Ig ID score (table 2). Conclusions Resorption of mesangial and subendothelial Ig and C IDs is attainable upon treatment and does not necessarily correlate with AI score reductions. Assessment of ID scores could serve as a valuable tool for determining the early treatment response and informing subsequent treatment adjustments. Conflicts of interest IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia, Bristol Myers Squibb, Elli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Otsuka, and Roche. The other authors declare that they have no conflicts of interest related to this work. The funders had no role in the design of the study, the analyses or interpretation of data, or the writing of the manuscript.

OBJECTIVE:To characterise the safety and efficacy of anifrolumab in active lupus nephritis (LN) through year 2 of the phase II randomised, double-blind Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-LN trial (NCT02547922) of 2 anifrolumab dosing regimens versus placebo. METHODS:Patients received intravenous anifrolumab 900 mg for the first 3 doses followed by 300 mg anifrolumab (intensified regimen (IR)), 300 mg anifrolumab (basic regimen (BR)) or placebo every 4 weeks throughout. To continue into Year 2, patients must have achieved at least partial renal response and a glucocorticoid tapering target. RESULTS:Of 147 randomised patients, 101 completed Year 1 study treatment; of these, 75 (74%) continued into Year 2 (anifrolumab IR: n=29, BR: n=23 and placebo: n=23). During Year 2, 72% of patients reported ≥1 adverse event (AE); serious AEs were reported in 6.9%, 8.7% and 8.7% of patients (anifrolumab IR, BR and placebo, respectively); 3 patients discontinued treatment due to an AE (anifrolumab IR: n=2 and placebo: n=1) and herpes zoster was reported in 2 patients (anifrolumab IR: n=1 and BR: n=1). The study was ongoing at the start of the pandemic, but no COVID-19 cases were reported. Of the 145 patients receiving treatment, more patients on the IR attained complete renal response at Week 104 compared with those on BR or placebo (27.3% vs 18.6% and 17.8%) and simultaneously achieved sustained glucocorticoid tapering (IR: 25.0%; BR: 18.6% and placebo: 17.8%). The improvements in estimated glomerular filtration rate were numerically larger in both anifrolumab groups versus placebo. CONCLUSIONS:The safety and tolerability profile through Year 2 of TULIP-LN was generally consistent with Year 1, with promising efficacy results for the anifrolumab IR regimen. Collectively, the results support further investigation of an anifrolumab intensified dosing regimen in larger populations of patients with active proliferative LN. TRIAL REGISTRATION NUMBER:NCT02547922.

Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance against nuclear and cytoplasmic self-antigens, induction of immunity and tissue inflammation. Lupus nephritis (LN), the most important predictor of morbidity in SLE, develops in almost 30% of SLE patients at disease onset and in up to 50-60% within the first 10 years. Firstly, in this review, we put the pathogenic mechanisms of the disease into a conceptual frame, giving emphasis to the role of the innate immune system in this loss of self-tolerance and the induction of the adaptive immune response. In this aspect, many mechanisms have been described such as dysregulation and acceleration of cell-death pathways, an aberrant clearance and overload of immunogenic acid-nucleic-containing debris and IC, and the involvement of antigen-presenting cells and other innate immune cells in the induction of this adaptive immune response. This result in a clonal expansion of autoreactive lymphocytes with generation of effector T-cells, memory B-cells and plasma cells that produce autoantibodies that will cause kidney damage. Secondly, we review the immunological pathways of damage in the kidney parenchyma, initiated by autoantibody binding and immune complex deposition, and followed by complement-mediated microvascular injury, activation of kidney stromal cells and the recruitment of leukocytes. Finally, we summarize the rationale for the treatment of LN, from conventional to new targeted therapies, focusing on their systemic immunologic effects and the minimization of podocytary damage.

Introduction:Belimumab was recently approved for treating lupus nephritis (LN), yet de novo LN cases during belimumab treatment given for nonrenal causes have been reported. Identification of reliable signals of impending flare is imperative. Methods:We evaluated belimumab efficacy in preventing de novo renal flares and factors associated with renal flare occurrence in nephritis-naïve patients with systemic lupus erythematosus (SLE) who are receiving add-on belimumab or placebo in 5 phase 3 clinical trials using Cox regression analysis. Results:Of 1844 eligible patients, 136 (7.4%) developed a de novo renal flare during a 52-week long follow-up. Asian origin (Adjusted Hazard Ratio [HRadj]: 1.97; 95% confidence interval [CI]: 1.32-2.94; P = 0.001), positive baseline anti-double stranded DNA (anti-dsDNA) levels (HRadj: 1.32; 95% CI: 1.07-1.63; P = 0.008), and increasing mean prednisone dose during follow-up (HRadj: 1.03; 95% CI: 1.02-1.04; P < 0.001) were associated with de novo renal flares. Low-dose intravenous (IV) belimumab (1 mg/kg monthly) yielded a nearly 3-fold lower hazard of de novo renal flare (HRadj: 0.38; 95% CI: 0.20-0.73; P = 0.004). Subcutaneous (SC) belimumab (200 mg weekly) also yielded a lower hazard (HRadj.: 0.69; 95% CI: 0.54-0.88; P = 0.003). The labeled IV dose (10 mg/kg monthly) conferred no clear protection (HRadj.: 0.74; 95% CI: 0.50-1.09; P = 0.127). Conclusion:We corroborated the substantial vulnerability of the Asian SLE population to renal affliction. Add-on low-dose IV belimumab (1 mg/kg) and SC belimumab appeared protective against renal flares in nephritis-naïve patients with SLE. The approved IV dose (10 mg/kg) yielded no clear protection.

Background Each lupus nephritis (LN) flare causes nephron loss that equals a decade or more of reduction in renal function lifespan, making prompt initiation of therapy imperative and prevention of flares even more desirable. Identification of readily available signals of imminent flare is therefore expected to improve prognosis. Objectives In light of observed cases of de novo LN during belimumab treatment (1), we evaluated predictors of de novo renal flare occurrence in patients with systemic lupus erythematosus (SLE) and no prior history of renal disease undergoing standard therapy (ST) with or without add-on belimumab in clinical trial settings. Methods Data from five clinical trials of belimumab in SLE (BLISS-52 NCT00424476; BLISS-76 NCT00410384; BLISS-NEA NCT01345253; BLISS-SC NCT01484496; EMBRACE NCT01632241) were utilised. The study population comprised 1932 patients with a baseline renal British Isles Lupus Assessment Group (BILAG) score E. De novo renal flares were defined as a change from renal BILAG E to A or B within a 52-week follow-up. Comparisons of baseline data were made using the Mann-Whitney U test, Pearson’s chi-squared (χ2) test or Fisher’s exact test as appropriate. Predictors of renal flare occurrence were investigated using univariable and multivariable Cox regression analysis. p values <0.05 were considered statistically significant. Results De novo renal flares were documented in 146 (7.6%) patients. Among patients who developed at least one renal flare, greater proportions were Asians (30.8% versus 20.2%; p<0.003), had positive baseline anti-dsDNA levels (74.0% versus 61.3%; p=0.003), and had low baseline levels of C3 (51.4% versus 38.2%; p=0.002) and C4 (45.2% versus 35.8%; p=0.030) compared with patients who did not flare. In univariable Cox regression analysis, azathioprine use was protective against renal flares (HR: 0.70; 95% CI: 0.49–0.99; p=0.047), while anti-Sm positivity at baseline showed a trend towards an association with imminent renal flare (HR: 1.68; 95% CI: 0.99–2.85; p=0.057). In multivariable Cox regression analysis adjusting for age, sex, ethnicity, serum creatinine, and variables that differed significantly in univariable analysis, Asian ancestry (HR: 1.60; 95% CI: 1.03–2.49; p=0.036), high mean prednisone dose from baseline until renal flare occurrence or throughout the follow-up (HR: 1.03; 95% CI: 1.02–1.05; p<0.001), and baseline serum creatinine (HR: 1.02; 95% CI: 1.01–1.03; p=0.001) were associated with imminent de novo renal flare, while extra-renal clinical SLE Disease Activity Index 2000 (cSLEDAI) showed a negative association (HR: 0.92; 95% CI: 0.86–0.98; p=0.007). Notably, use of belimumab 1 mg/kg by intravenous (IV) infusion yielded a nearly 3 times decreased hazard of renal flare (HR: 0.37; 95% CI: 0.20–0.68; p=0.001), whereas IV belimumab 10 mg/kg and belimumab 200 mg administered subcutaneously (SC) displayed no clear protection. Conclusion Asian patients appeared particularly susceptible to new-onset renal involvement, corroborating the substantial vulnerability of Asian SLE populations to renal affliction. Add-on low-dose IV belimumab on top of ST appeared protective against renal flares in SLE patients with no prior history of nephritis, while addition of the approved 10 mg/kg IV belimumab dose and SC belimumab yielded no clear protection. Discrepant results between low and high/approved belimumab doses warrant in-depth mechanistic exploration of underlying reasons e.g., potential effects of belimumab on B cell subsets that acquire regulatory properties. Reference [1]Parodis I, Vital EM, et al. Rheumatology (Oxford). 2021;60(9):4348-54. Acknowledgements The authors would like to thank GlaxoSmithKline for providing data through the CSDR consortium as well as all patients with SLE who participated in the trials. Disclosure of Interests Ioannis Parodis Grant/research support from: I.P. has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia Pharmaceuticals, Elli Lilly and Company, Gilead Sciences, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Otsuka Pharmaceutical, and F. Hoffmann-La Roche AG., Julius Lindblom: None declared, Nursen Çetrez: None declared, Leonardo Palazzo: None declared, Henri Ala: None declared, Frederic Houssiau: None declared, Christopher Sjowall: None declared, Brad H Rovin: None declared.

La néphrite lupique (NL) est une manifestation fréquente et sévère du lupus érythémateux systémique. L’objectif principal de la prise en charge de la NL est d’éviter l’insuffisance rénale chronique (IRC). Les stratégies de traitement actuelles restent insatisfaisantes en termes de réponse rénale complète, de prévention des rechutes, d’IRC et de progression vers l’insuffisance rénale terminale. Pour améliorer le pronostic de la NL, des données récentes suggèrent que nous devrions : (i) inclure une cible pathologique en plus de la cible clinique traditionnelle ; et (ii) remplacer la thérapie immunosuppressive séquentielle conventionnelle par une thérapie combinée.

In the last few years, several studies have provided new evidence for the diagnosis, management, and follow-up of patients with lupus nephritis. Evidence showing dissociation between clinical and histological findings has prompted reevaluation of the role of the kidney biopsy as a tool for diagnosis and follow-up. In therapeutics, four immunosuppressive schemes now have supporting evidence for use as initial therapy. Current challenges include individualized selection of the best immunosuppressive regimen, an unmet need for non-invasive biomarkers of disease activity to inform treatment responses and guide subsequent therapy, holistic patient management in this complex, multisystem disease, and ultimately the development of more targeted therapies directed at specific effector pathways driving glomerular inflammation and damage in order to improve treatment response. In this communication, we review the diagnostic and therapeutic approach to lupus nephritis, as well as evaluation of response to therapy and disease control.

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

La norme de soins actuelle de la néphrite lupique (LN) est basée sur un traitement immunosuppresseur séquentiel destiné à induire une réponse (traitement d’induction) et à éviter les récidives (traitement d’entretien). Force est de constater que les résultats de cette approche sont loin d’être satisfaisants, avec seulement 20–30 % de réponse rénale complète à 6–12mois, au moins 20 % de patients souffrant d’insuffisance rénale chronique et 5–20 % d’insuffisance rénale terminale 10ans après le diagnostic. Nous discutons notamment de deux nouveaux traitements, la voclosporine et le belimumab, récemment enregistrés par les agences des médicaments suite à d’essais contrôlés qui ont démontré leur supériorité en ajout d’un traitement immunosuppresseur standard. D’autres traitements combinés, avec de l’obinutuzumab ou de l’anifrolumab sont actuellement testés en Phase III. Il fait peu de doute que le paradigme thérapeutique évolue vers des combinaisons. L’étape suivante consistera à choisir avec discernement la plus appropriée chez un patient donné. Il est probable que la réponse viendra de l’analyse de biomarqueurs, en particulier étudiés sur les biopsies rénales elles-mêmes (initiales et répétées), permettant de développer une médecine de précision. L’horizon semble enfin se dégager pour les patients souffrant de NL.

Resume La norme de soins actuelle de la nephrite lupique (LN) est basee sur un traitement immunosuppresseur sequentiel destine a induire une reponse (traitement d'induction) et a eviter les recidives (traitement d'entretien). Force est de constater que les resultats de cette approche sont loin d'etre satisfaisants, avec seulement 20-30 % de reponse renale complete a 6-12 mois, au moins 20 % de patients souffrant d'insuffisance renale chronique et 5-20 % d'insuffisance renale terminale 10 ans apres le diagnostic. Nous discutons notamment de deux nouveaux traitements, la voclosporine et le belimumab, recemment enregistres par les agences des medicaments suite a d'essais controles qui ont demontre leur superiorite en ajout d'un traitement immunosuppresseur standard. D'autres traitements combines, avec de l'obinutuzumab ou de l'anifrolumab sont actuellement testes en Phase III. Il fait peu de doute que le paradigme therapeutique evolue vers des combinaisons. L'etape suivante consistera a choisir avec discernement la plus appropriee chez un patient donne. Il est probable que la reponse viendra de l'analyse de biomarqueurs, en particulier etudies sur les biopsies renales elles-memes (initiales et repetees), permettant de developper une medecine de precision. L'horizon semble enfin se degager pour les patients souffrant de NL. (c) 2021 l'Academie nationale de medecine. Publie par Elsevier Masson SAS. Tous droits reserves.

Visual Abstract Background and objectives In the BLISS-LN study, belimumab improved kidney outcomes in adult patients with active lupus nephritis. This 28-week open-label extension of BLISS-LN assessed belimumab’s safety and efficacy. Design, setting, participants, & measurements Eligible patients completing BLISS-LN received monthly intravenous belimumab 10 mg/kg plus standard therapy. End points included safety, open-label week 28 primary efficacy renal response (urine protein-creatinine ratio [UPCR] ≤0.7, eGFR no more than 20% below open-label baseline value or ≥60 ml/min per 1.73 m2, no prohibited medications) and complete renal response (UPCR <0.5, eGFR no more than 10% below open-label baseline value or ≥90 ml/min per 1.73 m2, no prohibited medications), and UPCR and eGFR by visit. Responses were also analyzed post hoc using the double-blind phase criteria. Results Of 257 enrolled patients, 255 were treated (safety population: n=123 switched from placebo-to-belimumab; n=132 remained on belimumab); 245 (97%) patients completed the study. Adverse events and serious adverse events were experienced by 62% and 4% of placebo-to-belimumab patients, respectively, and by 70% and 8% of belimumab-to-belimumab patients, respectively. One death occurred in the placebo-to-belimumab group. From open-label baseline to week 28, increases occurred in the proportions of patients achieving primary efficacy renal response (placebo-to-belimumab: from 60% to 67%; belimumab-to-belimumab: from 70% to 75%) and complete renal response (placebo-to-belimumab: from 36% to 48%; belimumab-to-belimumab: from 48% to 62%). Based on double-blind phase criteria, changes also occurred in the proportions achieving primary efficacy renal response (placebo-to-belimumab: from 54% to 53%; belimumab-to-belimumab: from 66% to 52%) and complete renal response (placebo-to-belimumab: from 34% to 35%; belimumab-to-belimumab: from 46% to 41%). The seeming decrease in response rates in the belimumab-to-belimumab groups was attributed to discontinuations/administration of glucocorticoids for non-SLE reasons as opposed to nephritis. Median UPCR and eGFR values were similar at open-label baseline and week 28. Conclusions No new safety signals were identified, and efficacy was generally maintained throughout the open-label phase. Clinical Trial registry name and registration number: BLISS-LN, NCT01639339

Objective 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. Methods 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. Results 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. Conclusion 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. Trial registration number NCT02547922 .