As more lupus nephritis (LN) medications become available, identifying treatments that are disease-modifying is critical in making treatment decisions. Based on our 2022 published working definition of LN disease modification as 'minimizing disease activity with the fewest treatment-associated toxicities and slowing progression to end-stage kidney disease' (ESKD), the objective of this review was to classify current LN treatments according to the proposed kidney disease modification criteria, excluding toxicities. Based upon a selection of LN clinical trial (n = 27) and observational study (n = 20) publications, as well as the authors' clinical experiences, we evaluated the disease modification potential for 16 LN treatments (inclusive of antimalarials, glucocorticoids, immunosuppressants, calcineurin inhibitors and biologics) according to the proposed kidney disease activity and organ damage criteria at year 1, years 2-5, and > 5-year time points. Fulfilling criteria at year 1 and years 2-5 was considered evidence for disease modification potential. Satisfying criteria at > 5 years (slowing or preventing progression in SLICC/ACR Damage Index [SDI] and ESKD, and/or doubling of serum creatinine) was used to confirm disease modification. Each treatment was designated as one of the following at each time point: (a) criterion met; (b) inconclusive; (c) no available supportive data. This review excluded an assessment of potential toxicities. All LN treatments met at least one of the potential kidney disease-modification criteria at any time point, but limited relevant data in the literature meant disease modification > 5 years could only be confirmed for cyclophosphamide. Belimumab met more criteria across the three time points than any other biologic treatment but lacked > 5-year data to confirm disease modification. Further research is needed to support the classification of LN treatments as disease modifiers, particularly for > 5 years. We discuss considerations for future studies, challenges to the classification, and possible updates to published criteria.

Aberrant B-cell function, which could arise from various underlying causes, is central to the pathogenesis of diverse autoimmune rheumatic diseases. B cells remain the only cell type to be specifically therapeutically targeted through depletion and have the only therapy with a routinely available flow cytometric biomarker of treatment. Since first use and subsequent licensing for rheumatoid arthritis, rituximab has had a transformative impact on patients globally and across the rheumatic diseases. Further insights from B-cell-activating factor (BAFF) blockade with belimumab in systemic lupus erythematosus have followed. Examination of B-cell depletion, clinical outcomes, and re-emergent disease after treatment have deepened our understanding of the identity, detailed phenotype, biology, and kinetics of the B-cell subsets that are central to disease. This Review reflects on 20 years of clinical and translational insights drawn from B-cell targeted therapies for adult autoimmune rheumatic diseases, and highlights how these therapies have informed an exciting new era of future therapeutic developments.

Lupus nephritis (LN) is a common complication in patients with systemic lupus erythematosus (SLE), where the key mechanism is the deposition of immune complexes in the kidneys, leading to renal damage. B lymphocytes play a crucial role in the pathogenesis of lupus nephritis through several pathways. These include the production of autoantibodies, which contribute to the deposition of immune complexes in the kidneys, activation of the complement system, and promotion of local inflammatory responses. Additionally, B cells act as antigen-presenting cells, facilitating T cell activation, and secrete proinflammatory cytokines that further exacerbate inflammation. Moreover, an imbalance in B cell subpopulations can worsen autoimmune damage, highlighting the complex role of B cells in the progression of LN. Targeting B cells has emerged as a promising therapeutic strategy, particularly for patients with relapsed or refractory LN. Recent advances in B cell-targeted therapies have shown significant clinical potential, offering new hope for better disease management. This review highlights the latest progress in B cell-targeted approaches for LN treatment and explores their potential to revolutionize care for this challenging condition.

Treatment of Systemic Lupus Erythematosus (SLE) remains challenging. The aim of this real-world evidence study of patients with refractory SLE treated with rituximab (RTX) was to explore for any potential long-term effect(s) of this particular B cell depletion approach. This study included patients with SLE who had i) received at least 1 cycle of RTX and had ii) an at least 10 yr of follow-up after their first RTX infusion. Outcomes were assessed at 1 year and at their latest evaluation that was ≥ 10 yr after RTX treatment initiation. In cases where the SLE Disease Activity Index 2000 (cSLEDAI-2 k) was employed, a response was defined as a cSLEDAI-2 k of less than 4 in cases where the cSLEDAI-2 k was ≥ 4. In cases where the cSLEDAI-2 k was 2-4 at baseline, a response was defined as a cSLEDAI-2 k of 0. RTX was administered in 62 patients with SLE. For this real-world evidence study 23 patients (25 cases) with SLE (all Caucasian female, age range: 14-72 yr, mean: 31 yr) with active or relapsing disease, fulfilling inclusion criteria were enrolled. RTX treatment was associated with a response rate of 68.75% after 1 yr and 75% after ≥ 10 yr. The median cSLEDAI-2 K score decreased from 5.83 ± 3.70 at baseline to 1.95 ± 2.40 (p < 0.001) at 1 yr and to 2.37 ± 3.00 (p < 0.001) at the ≥ 10 yr time-point of follow-up. Our data suggest that RTX may indeed represent an alternative therapeutic option in patients with SLE refractory to standard treatment with an acceptable safety profile.

The ubiquitin-proteasome system (UPS) is the major non-lysosomal mechanism for selective degradation of intracellular proteins that is essential for the regulation of cellular functions and survival. Modulation of the proteasomes and cereblon E3 ligase promotes degradation of polyubiquitin-tagged transcription factors and oncoproteins, leading to depletion of long-lived plasma cells, diminished autoantibody and interferon-α production, reduced T-cell polarization to the proinflammatory phenotypes and increased regulatory T-cell activity that are relevant to the therapy of systemic lupus erythematosus (SLE).

Selective immunoproteasome inhibitors and newer generation cereblon modulators have improved safety profiles compared to conventional compounds. This article summarizes the literature regarding the modulation of the UPS in murine and human SLE.

Bortezomib and the selective immunoproteasome inhibitors, ONX-0914 and zetomipzomib, ameliorate renal disease in murine lupus models. While clinically effective in refractory SLE, bortezomib is limited by its toxicities. Zetomipzomib shows promising data in phase Ib/II studies of SLE and lupus nephritis. Thalidomide and lenalidomide are effective in refractory cutaneous lupus but again limited by their off-target effects. A phase II RCT of iberdomide shows favorable results in SLE, especially chronic and subacute cutaneous lesions. These molecules should be further explored in larger clinical trials of renal and cutaneous SLE.

Obinutuzumab, a humanized type II anti-CD20 monoclonal antibody, provided significantly better renal responses than placebo in a phase 2 trial involving patients with lupus nephritis receiving standard therapy.

In a phase 3, randomized, controlled trial, we assigned adults with biopsy-proven active lupus nephritis in a 1:1 ratio to receive obinutuzumab in one of two dose schedules (1000 mg on day 1 and at weeks 2, 24, 26, and 52, with or without a dose at week 50) or placebo. All patients received standard therapy with mycophenolate mofetil, along with oral prednisone at a target dose of 7.5 mg per day by week 12 and 5 mg per day by week 24. The primary end point was a complete renal response at week 76, defined by a urinary protein-to-creatinine ratio of less than 0.5 (with protein and creatinine both measured in milligrams), an estimated glomerular filtration rate of at least 85% of the baseline value, and no intercurrent event (i.e., rescue therapy, treatment failure, death, or early trial withdrawal). Key secondary end points at week 76 included a complete renal response with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event.

A total of 271 patients underwent randomization; 135 were assigned to the obinutuzumab group (combined dose schedules) and 136 to the placebo group. A complete renal response at week 76 was observed in 46.4% of the patients in the obinutuzumab group and 33.1% of those in the placebo group (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 2.0 to 24.8; P = 0.02). A complete renal response at week 76 with a prednisone dose of 7.5 mg per day or lower between weeks 64 and 76 was observed in more patients in the obinutuzumab group than in the placebo group (42.7% vs. 30.9%; adjusted difference, 11.9 percentage points; 95% CI, 0.6 to 23.2; P = 0.04), and a urinary protein-to-creatinine ratio lower than 0.8 without an intercurrent event was more common with obinutuzumab than with placebo (55.5% vs. 41.9%; adjusted difference, 13.7 percentage points; 95% CI, 2.0 to 25.4; P = 0.02). No unexpected safety signals were identified. More serious adverse events, mainly infections and events related to coronavirus disease 2019, occurred with obinutuzumab than with placebo.

Among adults with active lupus nephritis, obinutuzumab plus standard therapy was more efficacious than standard therapy alone in providing a complete renal response. (Funded by F. Hoffmann-La Roche; REGENCY ClinicalTrials.gov number, NCT04221477.).

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.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.

Glucocorticoids (GCs) possess potent anti-inflammatory and immunosuppressive properties and are used to treat various diseases, including systemic autoimmune rheumatic diseases, rheumatoid arthritis, and systemic lupus erythematosus (SLE). However, GCs are associated with several adverse events and are considered risk factors for infections and cardiovascular disorders; furthermore, their application as therapeutics has changed with recent progress in molecular-targeted therapies. Although GCs have been the mainstay of SLE treatment for more than 50 years, the latest European Alliance of Association for Rheumatology recommendations for the management of SLE in 2023 has significantly relegated the use of GCs and recommended that these be used as "bridging therapy" during periods of SLE disease activity. They also recommended the use of GC pulse therapy followed by relatively low doses of GCs even in patients with high disease-activity lupus nephritis, with a focus on the appropriate use of hydroxychloroquine, immunosuppressive drugs, and biological agents. This combination is essential for improving renal survival, minimizing flares, and reducing the side effects of GC. The GC dose was tapered to < 5 mg/day of prednisolone within half a year, maintained for 3 years, and then discontinued with the concomitant use of combination therapies. In contrast to non-renal SLE, the development of more potent molecular targeted therapies for lupus nephritis is required.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune dysregulation and widespread inflammation. Natural killer (NK) cells, essential for immune surveillance, exhibit profound dysfunction in SLE, including impaired cytotoxicity and cytokine production. However, the mechanisms underlying these abnormalities remain poorly understood. This study investigates how the accumulation of dysfunctional mitochondria due to defective mitophagy contributes to NK cell impairment in SLE and explores strategies to restore their function.

Mitochondrial structure and function in NK cells from SLE patients (n=104) and healthy controls (n=104) were assessed using flow cytometry, transmission electron microscopy, and proteomics. Mitophagy-related gene expression was quantified by RT-qPCR. The effects of Urolithin A, a mitophagy activator, and hydroxychloroquine (HCQ) on mitochondrial recycling and NK cell function were evaluated in vitro .

SLE NK cells exhibited accumulation of enlarged, dysfunctional mitochondria, impaired lysosomal acidification, and increased cytosolic mitochondrial DNA leakage, consistent with defective mitophagy. Proteomic and transcriptional analyses revealed downregulation of key mitophagy-related genes. These abnormalities were associated with diminished NK cell effector functions, including reduced degranulation and cytokine production. In vitro , treatment with Urolithin A enhanced mitophagy, improved mitochondrial and lysosomal function, and restored NK cell effector responses. HCQ was also associated with partial recovery of mitochondrial recycling and NK cell function.

These findings identify mitochondrial dysfunction and impaired mitophagy as major contributors to NK cell abnormalities in SLE. By uncovering a novel immunometabolic mechanism, this offers new insight into SLE pathogenesis and highlights potential therapeutic strategies targeting mitochondrial quality control.

Chimeric antigen receptor (CAR)-based therapies developed for the treatment of haematological malignancies have recently been repurposed to treat refractory systemic autoimmune diseases. In this Review we critically discuss the current data available on the use of CAR-based therapy in systemic autoimmune diseases, the current challenges, and the potential next steps toward their implementation into clinical practice. Beyond the targeting of B cells via CD19, we discuss the advantages and potential pitfalls of targeting plasma cells (B-cell Maturation Antigen or CD138) and other non-immune targets, such as fibroblast activated protein, and of aiming to restore immune homeostasis using CAR T regulatory cells. Crucial points need to be addressed for CAR-based therapy to become a viable treatment option for patients with systemic autoimmune diseases.

PURPOSE OF REVIEW: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), significantly impacting patient outcomes. Despite advances in immunosuppressive therapies, many patients progress to end-stage renal disease (ESRD), and kidney transplantation becomes essential for improving survival. However, the unique characteristics of autoimmune diseases make the timing of kidney transplantation and post-transplant management challenging. This review evaluates authoritative guidelines and recent studies to identify optimal timing for kidney transplantation and effective pre- and post-transplant management measures for patients with LN. RECENT FINDINGS: Advancements in immunosuppressive therapies, including calcineurin inhibitors, Voclosporin, and biologic agents such as belimumab, have significantly improved LN management. Emerging biomarkers, such as urinary MCP-1 and BAFF, offer promising tools for monitoring LN activity and predicting recurrence risk post-transplantation. Current guidelines emphasize the importance of achieving disease quiescence before transplantation, while new evidence supports the benefits of preemptive transplantation and personalized immunosuppressive regimens in improving patient and graft survival. This review highlights the latest evidence and strategies for optimizing kidney transplantation outcomes in LN patients, focusing on timing, immunosuppression, and disease monitoring.

Renal involvement in systemic lupus erythematosus (SLE), lupus nephritis (LN), is common and can result in significant morbidity, including progressive renal dysfunction, and even ultimately leading to death. LN is heterogeneous complicated by the immunologic component, and it is critical to accurately classify LN to direct optimal therapy. Accordingly, identification of objective markers is paramount in reflecting disease stage and monitoring treatment response. In part two of this series, we comprehensively examine LN disease classification, therapies and potential markers to guide therapeutic options.

Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.

Evans syndrome (ES) is characterized by the development of autoimmune hemolytic anemia and immune thrombocytopenic purpura and is often linked to autoimmune diseases, such as systemic lupus erythematosus (SLE). Standard treatment includes prednisolone and intravenous immunoglobulin; however, relapse commonly occurs when prednisolone is tapered or stopped. Rituximab is increasingly used for refractory ES with SLE, although its efficacy in new-onset cases remains unclear. We herein report a 67-year-old woman with new-onset ES and SLE with lupus nephritis class IV-G whose condition improved with rituximab after prednisolone, hydroxychloroquine, and mycophenolate mofetil. The patient remained relapse-free for one year, suggesting that rituximab is a potentially viable first-line therapy.

Childhood-onset systemic lupus erythematosus (cSLE) is a severe lifelong and life-threatening autoimmune disease with multi-organ involvement. Compared to those with adult-onset disease, cSLE patients have more aggressive disease with a higher prevalence of early lupus nephritis (LN) causing worse kidney and patient outcomes. The transfer of adolescent patients to adult healthcare poses several major challenges, from a disease as well as a psychosocial perspective. Transitional care even in tertiary centers can be heterogenous, suboptimal, and often even non-existent. In this comprehensive review of the literature, we synthesize the obstacles adolescents and young adults (AYA) with systemic lupus erythematosus (SLE) and LN face and how these challenges impact the transfer to adult health care. Finally, we propose a framework for a structured and individually modifiable transitional care plan, tailored to the unique needs of this population and taking into account their social and cultural background. This framework includes suggestions for the timing of the preparatory phase and the transfer itself, the composition of the transitional care team, increasing transition readiness and treatment adherence, and establishing a supportive network of peers. Efficient transitional care will optimize long-term patient outcomes.

Rheumatic diseases encompass a wide range of autoimmune and inflammatory disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), and systemic sclerosis (SSc). These conditions often result in chronic pain, disability, and reduced quality of life, with unpredictable disease courses that may lead to joint destruction, organ damage, or systemic complications. Biomarkers, defined as measurable indicators of biological processes or conditions, have the potential to transform clinical practice by improving disease diagnosis, monitoring, prognosis, and treatment decisions. While significant strides have been made in identifying and validating biomarkers in rheumatic diseases, challenges remain in their standardization, clinical utility, and integration into routine practice. This review provides an overview of the current state of biomarkers in rheumatic diseases, their roles in clinical settings, and the emerging advancements in the field.

This review provides an update on the rapidly growing field of engineered cellular therapies for autoimmune disorders, primarily focusing on clinical experience and correlative studies with chimeric antigen receptor (CAR) T-cells.

To date, two case series describing treatment with CAR T-cell therapy for systemic lupus erythematosus (SLE) suggest that drug-free remission can be sustained in patients with previously treatment-refractory disease. The outcomes of these studies are similar, despite the use of different CAR constructs and lymphodepletion regimens. Although it is not yet clear whether the patients described have truly been cured, the majority of remissions have remained durable up to last follow-up at 1-2 years from treatment. Meanwhile, mechanistic studies are providing a window into how transient B-cell depletion mediates lasting benefit. With the encouraging data in SLE, CAR T-cells and other novel B-cell-depleting agents (e.g. bispecific T-cell engagers) are now being evaluated as treatment for other autoimmune conditions, with the goal of durable response.

Recent reports highlight cellular therapies as a promising strategy for patients with treatment-refractory autoimmune conditions; however, there is still limited experience, and better insight into this therapeutic approach is expected to emerge rapidly.

Chimeric antigen receptor (CAR) T cells have recently shown remarkable promise in treating rheumatic diseases, including systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies, and systemic sclerosis. Currently, there are 37 clinical trials registered for CAR T-cell therapy in rheumatic diseases and many more are being planned. Much of this enthusiasm is justifiable, but widespread adoption of CAR T-cell therapy in rheumatology faces several barriers. The trajectory of autoimmune diseases differs from malignancies and a surprisingly narrow population could be eligible for CAR T-cell therapy. Current CAR T-cell approaches rely on B-cell depletion, which has a mixed record of success for many diseases. The high cost of CAR T-cell therapy and potential safety concerns, such as cytokine release syndrome and long-term infection risks, also pose substantial challenges. Moving forward, more targeted CAR T-cell approaches, such as antigen-specific chimeric autoantibody receptors or chimeric autoantigen T-cell receptors, could offer greater efficacy and safety in treating rheumatic diseases.

Lupus nephritis (LN) can occur as an isolated component of disease activity or be accompanied by diverse extrarenal manifestations. Whether isolated renal disease is sufficient to decrease health-related quality of life (HRQOL) remains unknown. This study compared Patient-Reported Outcomes Measurement Information System 29-Item (PROMIS-29) scores in LN patients with isolated renal disease to those with extrarenal symptoms to evaluate the burden of LN on HRQOL and inform future LN clinical trials incorporating HRQOL outcomes.

A total of 181 LN patients consecutively enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership completed PROMIS-29 questionnaires at the time of a clinically indicated renal biopsy. Raw PROMIS-29 scores were converted to standardized T scores.

Seventy-five (41%) patients had extrarenal disease (mean age 34, 85% female) and 106 (59%) had isolated renal (mean age 36, 82% female). Rash (45%), arthritis (40%) and alopecia (40%) were the most common extrarenal manifestations. Compared with isolated renal, patients with extrarenal disease reported significantly worse pain interference, ability to participate in social roles, physical function, and fatigue. Patients with extrarenal disease had PROMIS-29 scores that significantly differed from the general population by >0.5 SD of the reference mean in pain interference, physical function, and fatigue. Arthritis was most strongly associated with worse scores in these three domains.

Most patients had isolated renal disease and extrarenal manifestations associated with worse HRQOL. These data highlight the importance of comprehensive disease management strategies that address both renal and extrarenal manifestations to improve overall patient outcomes.

Increasing frequency of autoimmune diseases is one of the major problems in modern societies. Despite the introduction of new therapeutic agents for autoimmunity over the past several decades, more progress is needed. Synthetic receptor-based cell therapies are being adopted as an option for treating autoimmune diseases from the field of oncology. Currently evaluated strategies can be summarized into two approaches. The first one is the elimination of autoreactive cells by targeting them, for example, with CAR-T or CAAR-T cells. The second is based on rebalancing the proinflammatory milieu with engineered immunosuppressive cells, for example, CAR-Treg. Both approaches can be supplemented with the use of synthetic systems such as Split-CAR, SynNotch, MESA, GEMS, and SNIPR, or prospective off-the-shelf approaches, for example, in situ use of the in vitro transcribed mRNA, ultimately allowing for enhanced efficacy and safety. The primary goal of our review is to provide some perspective on both strategies in basic, translational, and clinical studies with all their advantages and disadvantages to allow for informed future design of adoptive cell therapies for autoimmune diseases.

To describe intravenous (IV) belimumab's clinical effectiveness in patients with systemic lupus erythematosus (SLE) in real-world practice in Saudi Arabia.

This retrospective, observational OBSErve study (GSK Study 215349) analyzed medical record data for adults with SLE receiving IV belimumab. Index date was the date of belimumab initiation. The primary endpoint was overall clinical response per physician judgement (categorized as worse, no improvement, improvement of <20%, 20-49%, 50-79%, ≥80%) at 6 months post-index. The secondary endpoints included changes from index in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score and corticosteroid dose at 6 months post-index; and healthcare resource utilization (HCRU) 6 months pre- and post-index.

Of 47 patients enrolled, 44 patients completed ≥6 months of IV belimumab treatment and were included in the analysis. Most patients were female (91.5%) and the mean (standard deviation [SD]) age was 33.1 (8.1) years. At 6 months post-index, overall physician-assessed clinical improvements of ≥20% and ≥50% were reported for 97.7% (n=43) and 79.5% (n=35) of patients, respectively; 2.3% (n=1) of patients had no improvement, and no patient worsened. Mean SELENA-SLEDAI score decreased by 7.8 points during the 6 months post-index. Mean (SD) corticosteroid dose decreased from 10.2 (7.5) mg/day at index to 6.2 (3.4) mg/day at 6 months post-index. Reductions in unscheduled physician office and emergency room visits were observed during the post-index versus pre-index periods.

Real-world data from patients with SLE treated with IV belimumab in Saudi Arabia demonstrated clinical improvements and reductions in corticosteroid dose and HCRU. Although the low number of patients and lack of a control group limit interpretation, the similar findings to the other OBSErve studies support the effectiveness of belimumab for patients with SLE in Saudi Arabia.

Limited data exists on clinical predictors of kidney outcomes in children with lupus nephritis (LN).

Children aged below 18 years with biopsy-proven LN followed from January 2010 to February 2024 in a tertiary-care center were enrolled in order to characterize their clinical presentations, flares, infections, histology and determine Major Adverse Kidney Events (MAKE) (defined as eGFR < 60 mL/min/1.73 m2 and/or death). Data was analysed to identify predictive factors of adverse outcomes.

Seventy-five children (20% boys) with median (IQR) age at diagnosis 11.2 (9,13) years, were studied. Clinical presentations were nephritic syndrome, mixed nephritic-nephrotic features, rapidly progressive glomerulonephritis (RPGN), and nephrotic syndrome in 24 (32%), 15 (20%), 11 (14.7%) and 5 (6.7%) patients, respectively. Proliferative LN was the major (70.6%) histological subtype. In total, 75 kidney flares (21.3% nephritic) with incidence rate (IR) of 0.48 flares per person-year were noted in 31 (41.3%) children. Infections occurred in 32 (42.6%), with IR of 0.58 episodes per person-year. Bacterial pneumonia 14 (22.9%), sepsis 10 (16.3%) and tropical infections 6 (9.8%) were most common. At median last follow-up of 2.3 (1.3, 5.6) years with 85.4% kidney-survival rate, 41 (54.6%), and 21 (28%) were in complete-response (CR), and partial-response (PR), respectively. Proliferative LN and those in PR or NR were at significantly higher risk of kidney flares and infections, regardless of initial induction therapy. RPGN at presentation, non-responders at 6 months and severe kidney flare ever predicted MAKE in 11 (14.6%) children.

Multiple kidney flares and infections constitute a significant morbidity in LN. RPGN, non-responders and severe kidney flare predict adverse kidney outcomes.

B-cell targeting chimeric antigen receptor (CAR) T-cell therapies, which lead to profound B-cell depletion, have been well-established in hematology-oncology. This deep B-cell depletion mechanism has prompted the exploration of their use in B-cell driven autoimmune diseases. We herein report on the manufacturing of KYV-101, a fully human anti-CD19 CAR T-cell therapy, derived from patients who were treated across a spectrum of autoimmune diseases.

KYV-101 was manufactured from peripheral blood-derived mononuclear cells of 20 patients across seven autoimmune disease types (neurological autoimmune diseases, n = 13; rheumatological autoimmune diseases, n = 7). Patients ranged from 18 to 75 years of age. Duration of disease ranged from <1 to 23 years since diagnosis. Patients were heavily pretreated, and most were refractory to prior immunosuppressive treatments. Apheresis was collected across nine sites, cryopreserved, and shipped to the manufacturing facility. Healthy donor apheresis samples were collected for manufacturing comparison. Manufacturing was performed using the CliniMACS Prodigy system. Cells were enriched for CD4+/CD8+ T cells, transduced with a third generation lentiviral vector encoding the CAR, expanded in vitro, and harvested. Percent cell viability, T-cell purity, cellular expansion, and transduction efficiency were assessed. Activity was assessed using cytokine release assays for KYV-101 CAR T cells co-cultured with different CD19+/- target cell lines.

KYV-101 was successfully manufactured for 100% of patients. Transduced cell populations were highly viable, with expansion ranging from 11 to 66 fold at Day 8, and were comparable across disease types. Healthy donor-derived controls displayed similar expansion ranges. High CAR expression and transduction rates were observed, ranging between 37 and 77% with low variation in transgene copy number (two to four per cell). Cell viability of the final KYV-101 drug product ranged from 87 to 97%. KYV-101 displayed robust CD19-dependent and effector dose-related release of the pro-inflammatory cytokine IFN-γ.

KYV-101 manufacturing yielded a CAR T-cell product with high viability and consistent composition and functionality, regardless of disease indication, pre-treatment, and heterogeneity of the incoming material. Cryopreservation of the apheresis and final drug product enabled widespread distribution. These results support the robustness of the manufacturing process for the fully human KYV-101 anti-CD19 CAR T-cell therapy drug product for patients across diverse autoimmune disease types.

B cell depletion with rituximab, a chimeric monoclonal antibody that selectively targets B cells by binding CD20, has been used off label in severe and resistant systemic lupus erythematosus (SLE) for over two decades. Several biological mechanisms limit the efficacy of rituximab, including immunological reactions towards the chimeric molecule, increased numbers of residual B cells, including plasmablasts and plasma cells, and a post-treatment surge in B cell-activating factor (BAFF) levels. Consequently, rituximab induces remission in only a proportion of patients, and safety issues limit its use. However, the use of rituximab has established the value of B cell depletion strategies in SLE and has guided the development of several improved B cell depletion therapies for SLE. These include enhanced monoclonal antibodies, modalities that redirect the specificity of patient T cells using chimeric antigen receptor T cells or bispecific T cell engagers, and combination treatment that simultaneously inhibits the BAFF pathway. In this Review, we consider evidence gathered from over two decades of using rituximab in SLE and examine how B cell depletion therapies could be further optimized to achieve immunological and clinical efficacy. In addition, we discuss the prospects of B cell depletion strategies for personalized treatment in SLE based on genetic research and studies in pre-symptomatic individuals.

Lupus nephritis (LN), present in 30%-50% of systemic lupus erythematosus (SLE) patients, often necessitates standard immunosuppressive therapy (glucocorticoids, MMF, CYC) as suggested by the European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines. However, a subset of subjects remains refractory. Recent findings suggested the efficacy of targeting CD38-long-lived plasma cells in LN and SLE refractory to standard treatment. However, previous experiences were limited to adult patients and described different therapeutical schemes based on daratumumab, with the addition or absence of belimumab. Moreover, the minimal effective dose of daratumumab has yet to be fully defined. In this report, we describe two cases of juvenile-onset refractory LN/SLE successfully managed with a combination of a single infusion of rituximab (targeting CD20 on B cells) and daratumumab (targeting CD38 on long-lived plasma cells), unlike prior regimens requiring prolonged daratumumab infusions. Our approach was safe and effective and may potentially reduce adverse effects and costs, providing a novel therapeutic option for juvenile refractory LN.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with diverse clinical manifestations that can lead to severe organ damage. The complex pathophysiology of SLE makes treatment selection difficult. This review examines the current evidence for biological therapies in SLE, including the anti-B cell activating factor antibody belimumab; the type I interferon receptor antagonist anifrolumab; the novel calcineurin inhibitor voclosporin; and rituximab, which targets CD20 on B cells. We also describe emerging therapies, including novel agents in development and CD19-directed chimeric antigen receptor (CAR) T cell therapy, which has shown promise in early clinical experience. Recent advances in biomarker research, including interferon signatures and transcriptomic profiles, may facilitate patient stratification and treatment selection. This review offers insights into current and future treatment strategies for patients with SLE by analyzing clinical trial results and recent immunological findings.

Systemic lupus erythematosus (SLE) is a chronic, inflammatory, and progressive autoimmune disease. The unclear pathogenesis, high heterogeneity, and prolonged course of the disease present significant challenges for effective clinical management of lupus patients. Dysregulation of the immune system and disruption of immune tolerance, particularly through the abnormal activation of B lymphocytes and the production of excessive autoantibodies, lead to widespread inflammation and tissue damage, resulting in multi-organ impairment. Currently, there is no systematic review that examines the specificity of B cell characteristics and pathogenic mechanisms across various organs. This paper reviews current research on B cells in lupus patients and summarizes the distinct characteristics of B cells in different organs. By integrating clinical manifestations of organ damage in patients with a focus on the organ-specific features of B cells, we provide a new perspective on enhancing the efficacy of lupus-targeted B cell therapy strategies.

To identify the percentage of patients with incident lupus nephritis who achieved primary efficacy renal response (PERR) and complete renal response (CRR) after 2 years of treatment at a university hospital.

An observational study including patients with lupus with a first renal biopsy with nephritis class III, IV, or V, or combined, performed between years 2000 and 2018 and follow-up for over 2 years at a university hospital in Argentina. The proportion of patients with PERR and CRR at 1 and 2 years and the proportion of patients requiring rescue therapy were calculated. Comparison with clinical trials and observational studies was done through literature search.

Seventy-five patients were included; 85.3% were female and 36.5 years in average at the time of biopsy, with lupus nephritis class III (n = 7), class IV (n = 59), combination of IV + V (n = 4), and pure V (n = 5). At 1 and 2 years, PERR was achieved in 57 patients (76.0%; 95% confidence interval [CI], 64.8%-84.5%), whereas CRR was achieved in 44 patients (58.7%; 95% CI, 46.9%-69.4%). A proteinuria level <0.7 g/24 hours was observed in 80.0% (95% CI, 69.2%-87.7%) of patients at 2 years and <0.5 g/24 hours in 76.0% (95% CI, 64.8%-84.5%). Fifteen patients (20.0%; 95% CI, 12.3%-30.8%) needed rescue therapy during the first 2 years after biopsy.

We found higher PERR (76.0%) and CRR (58.7%) at 2 years after the first renal biopsy than those reported in many randomized trials, similar to those reported in observational studies.

Lupus nephritis is one of the most severe manifestations of systemic lupus erythematosus, affecting roughly 40% of all lupus patients. With the introduction of cyclophosphamide and mycophenolate mofetil, outcomes have dramatically improved. However, 10% of patients still progress towards end-stage kidney disease, which carries an elevated mortality rate. In recent years, several novel agents have been approved for use or have shown preliminary evidence of efficacy in lupus nephritis. These agents include belimumab, voclosporin, and obinutuzumab, among others. Efficacy has also been demonstrated in recent trials combining older drugs. However, determining which patients would benefit the most from novel agents or combined drug regimens and whether these drugs might serve as an alternative to current remission-induction drug regimens rather than as add-on therapies remain unresolved issues. In this review, we will explore the current evidence regarding the efficacy of novel agents.

Approximately one in five patients with systemic lupus erythematosus (SLE) has disease-onset during childhood (cSLE). Lupus nephritis is more common in cSLE than adult-onset SLE and is associated with significant and increased morbidity and mortality. In this article, we review lupus nephritis in cSLE, including pathogenesis, diagnosis, biomarkers, and management through PUBMED search between July and December 2024. Diagnosis of lupus nephritis is made in 93% of cSLE patients during the first 2 years of disease. The majority of patients have active disease in other organs, and nephrotic range proteinuria and hypertension is frequently observed at diagnosis. Class III and IV are observed in over 50% of renal biopsies and progression to end-stage renal disease varies across cohorts. Major progress made in recent years includes adjustment of the proportion of fibrous crescents when scoring nephritis in cSLE to better discriminate kidney disease outcomes, and development of non-invasive biomarkers to identify renal disease activity and damage. It is anticipated that accurate non-invasive biomarkers will foster multicenter studies and help identify new treatment approaches to improve outcomes in cSLE nephritis.

Traditional initial treatment regimens for lupus nephritis (LN) used oral glucocorticoids (GC) in starting doses up to 1.0 mg/kg/day prednisone equivalent with or without a preceding intravenous methylprednisolone pulse. More recent management guidelines recommend lower starting oral GC doses following intravenous pulse therapy. As there have been no large studies directly comparing patients receiving low versus high initial oral GC doses, this pooled analysis of high-quality randomised controlled trials (RCTs) aims to evaluate differences in efficacy and safety.

Published data were analysed from RCTs that assessed variable GC doses in the standard of care (SOC) treatment arms. Patients receiving starting prednisone doses up to 0.5 mg/kg/day (low dose) were compared with 1.0 mg/kg/day (high dose). Complete renal response requiring urine protein-creatinine ratio <0.5 mg/mg (CRR 0.5), CRR or partial renal response (PRR), serious adverse events (SAE) and SAE due to infections at 12 months of treatment were compared between groups.

417 patients from SOC arms of five studies were exposed to low-dose initial GC after intravenous pulse, while 521 patients from four studies were treated with high-dose oral GC. In patients with low-dose oral GC, 25.2% achieved CRR 0.5 at 12 months compared with 27.2% in high-dose groups, p=0.54. CRR or PRR was attained in 48.7% low-dose vs 43.6% high-dose patients, p=0.14. SAEs and infection SAEs were less common in the low-dose GC group (19.4% vs 31.6%, p<0.001 and 9.8% vs 16.5%, p=0.012, respectively).

Based on pooled RCT data, there was no significant difference in 12-month renal responses between patients receiving low-dose prednisone following intravenous GC compared with those receiving initial high doses. SAEs were less frequent in patients receiving low-dose initial GC. These findings support the use of lower oral GC doses in LN treatment.

Both belimumab and telitacicept are recognised blockers for B lymphocyte activation, both of which have been approved as add-on therapies for SLE in China. The aim of this study is to compare the efficacy of rituximab (RTX) followed by belimumab or telitacicept in a real-world cohort.

A total of 49 refractory lupus nephritis patients were enrolled from four independent centres, subsequently categorised into two treatment groups: belimumab group (n=35) and telitacicept group (n=14) based on their treatment following RTX. The outcomes of renal response rates were evaluated.

In this study cohort, 63.3% presented with anti-dsDNA antibody positivity and 79.6% exhibited hypocomplementemia, with a mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) Score of 13±6, estimated glomerular filtration rate (eGFR) of 76.2 (30.2, 113.7) mL/min and urinary protein creatinine ratio (uPCR) of 2.45 (0.77, 5.19) g/g. There was no significant differences between groups. After a follow-up duration of 26±12 months, renal objective remission rate was 80.0% (28 patients) in belimumab group and 85.7% (12 patients) in telitacicept group (difference, 5.7 percentage points, 95% CI, -25.8 to 26.8, p=1.000). Renal complete response was 54.3% (19 patients) in belimumab group and 78.6% (11 patients) in telitacicept group (difference, 24.3 percentage points, 95% CI, 9.7 to 47.8, p=0.194). The anti-dsDNA antibody, complement, eGFR, uPCR and SLEDAI-2K Score were improved in both groups with a significant reduction in prednisone dose. Major adverse effects included immunoglobulin deficiency, respiratory tract infection and urinary tract infection. No death occurred.

The sequential treatment of belimumab or telitacicept following RTX may represent a promising therapeutic approach in the management of refractory lupus nephritis. Further investigation is necessary to establish optimal protocols and long-term benefits.

Paediatric Systemic lupus erythematosus (SLE) constitutes 10 to 20% of cases of SLE with more severe disease and higher mortality. We report a case of an adolescent girl with SLE with multisystem involvement who was started on hydroxychloroquine and oral prednisolone. However, due to persistent worsening of skin lesions and falling cell counts, pulsed dexamethasone was initiated which showed improvement in the skin lesions, cell counts, proteinuria and pleural effusion but there was a persistent fall in the haemoglobin. The patient was diagnosed with refractory autoimmune hemolytic anemia (AIHA) and treated with Rituximab which showed marked improvement in AIHA. Therefore, Rituximab can be considered in managing childhood SLE with refractory AIHA.

Lupus nephritis is a severe and common complication of systemic lupus erythematosus (SLE). The pathogenesis of lupus nephritis is characterized by B-cell activation and autoantibody formation. Rituximab and belimumab, as well as telitacicept, target B cells through different mechanisms, potentially exerting a synergistic effect in the treatment of lupus nephritis. This study aims to investigate the efficacy and safety of treatment with rituximab followed by belimumab or telitacicept in the management of refractory lupus nephritis.

We conducted a single-center, open-label, retrospective study, including 25 patients with refractory lupus nephritis. All patients received combination therapy with rituximab in individualized dosages to achieve peripheral B-cell depletion, and then followed by belimumab or telitacicept. The follow-up period was at least 12 months, and the primary end point was renal remission rate at the last follow-up.

During a median follow-up of 19 (13, 29) months, 20 of 25 (80%) patients achieved objective remission (OR), including 19 (76%) patients achieved complete renal response (CRR). After rituximab (712 ± 416mg in average), 18 patients received belimumab and seven patients received telitacicept. In the rituximab plus telitacicept group, all patients achieved CRR; while in the rituximab plus belimumab group, 12 (66.7%) patients achieved CRR and 13 (72.2%) patients achieved OR. The mean SLEDAI-2K score decreased from 15 ± 6 to 6 ± 6, representing an average reduction of 60%. At the last follow-up, 18/25 (72%) had prednisone ≤ 5 mg/d or even discontinued prednisone use. Adverse effects were mainly immunoglobulin deficiency, respiratory tract infection, urinary tract infections, and rash. No death occurred.

Rituximab followed by belimumab or telitacicept may be effective in inducing remission in refractory lupus nephritis, with tolerable adverse effects.

Chimeric antigen receptor (CAR) T-cell therapy, initially successful in treating hematological malignancies, is emerging as a potential treatment for autoimmune diseases, including rheumatic conditions. CAR T cells, engineered to target and eliminate autoreactive B cells, offer a novel approach to managing diseases like systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and inflammatory myopathies, where B cells play a pivotal role in disease pathology. Early case reports have demonstrated promising results, with patients achieving significant disease remission, normalization of serological markers, and the ability to discontinue traditional immunosuppressive therapies, which supported the initiation of several clinical trials. However, the application of CAR T-cell therapy in chronic inflammatory rheumatic disorders poses unique challenges, including patient heterogeneity, the risk of adverse effects such as cytokine release syndrome, and the high costs associated with the therapy. Despite these challenges, the potential for CAR T cells to provide long-term remission or even a cure in refractory autoimmune diseases is significant. Ongoing research aims to optimize CAR T-cell constructs and improve safety profiles, paving the way for broader application in rheumatic diseases. If these challenges can be addressed, CAR T-cell therapy could revolutionize the treatment landscape for chronic inflammatory rheumatic disorders, offering new hope for patients with severe, treatment-resistant conditions.

The development of targeted drugs for the treatment of systemic lupus erythematosus (SLE) is a promising area of research because targeted drugs are associated with a lower risk of severe side effects than systemic drugs. There are only two approved drugs based on monoclonal antibodies (a group of targeted drugs) for the treatment of SLE, so there is an unmet need for the development of new and improved antibody analogs. This review analyzes the effectiveness and safety of both already approved antibodies (anifrolumab and belimumab) for the treatment of SLE and antibodies under development with an assessment of their future prospects for entering the pharmaceutical market. In addition to the antibodies themselves, the choice of their therapeutic targets and what role the targets can play in the effectiveness and safety of the antibodies are analyzed here.

To provide evidence-based clinical practice recommendations for managing Systemic Lupus Erythematosus (SLE) in Saudi Arabia.

This EULAR-adapted national guideline in which a multidisciplinary task force utilized the modified Delphi method to develop 31 clinical key questions. A systematic literature review was conducted to update the evidence since the EULAR publication. After reaching a consensus agreement, two rounds of voting and group discussion were conducted to generate consolidated recommendations/ statements.

A significant number of patients in Saudi Arabia experience delays in accessing rheumatologists, highlighting the significance of timely referral to SLE specialists or rheumatologists to ensure accurate diagnosis and prompt treatment. The primary goal of Glucocorticoid (GC) therapy in SLE patients is to establish disease control with a minimum dose and duration. Steroid-sparing agent utilization facilitates steroid-sparing goals. Hydroxychloroquine is recommended for all SLE patients, though physicians must carefully monitor toxicity and prioritize regular medication adherence assessment. SLE management during pregnancy starts from preconception time by assessing disease activity, major organ involvement, hypercoagulability status, and concomitant diseases that may negatively impact maternal and fetal outcomes. Multidisciplinary care with close monitoring may optimize both maternal and fetal outcomes. For patients with antiphospholipid antibodies, low-dose aspirin prophylaxis is recommended. Also, Long-term anticoagulant medications are fundamental to prevent secondary antiphospholipid syndrome due to high thrombosis recurrence.

This Saudi National Clinical Practice guidelines for SLE management provide evidence- based recommendations and guidance for healthcare providers in Saudi Arabia who are managing patients with SLE. These guidelines will help to standardize healthcare service, improve provider education, and perhaps lead to better treatment outcomes for SLE patients.