Rituximab is a safe and effective alternative treatment for patients with autoimmune hepatitis: Results from the ColHai registry.

BACKGROUND AND AIMS: Small series suggest that rituximab could be effective as treatment for autoimmune hepatitis (AIH), although data are scarce. We aimed to evaluate the efficacy and safety of rituximab in different cohorts of patients with AIH. METHODS: Multicentre retrospective analysis of the 35 patients with AIH and its variant forms treated with rituximab and included in the ColHai registry between 2015 and 2023. RESULTS: Most patients were female (83%), 10 (29%) had cirrhosis and four (11.4%) variant forms of AIH. Indication for rituximab were as follows: 14(40%) refractory AIH, 19(54%) concomitant autoimmune or haematological disorder, 2(6%) intolerance to prior treatments. In three (9%) subjects with a concomitant disorder, rituximab was the first therapy for AIH. Overall, 31 (89%) patients achieved or maintained complete biochemical response (CBR), including the three in first-line therapy. No difference in CBR was observed according to rituximab indication (refractory AIH 86% vs. concomitant disorders 90%, p = .824) or cirrhosis (80% vs. 92%, p = .319). Rituximab was associated with a significant reduction in corticosteroids (median dose: prior 20 vs. post 5 mg, p < .001) and the discontinuation of ≥1 immunosuppressant in 47% of patients. Flare-free rate at 1st, 2nd and 3rd year was 86%, 73% and 62% respectively. Flares were not associated with the development of liver failure and were successfully managed with repeated doses of rituximab and/or increased corticosteroids. Three (9%) patients experienced infusion-related adverse events (1 anaphylaxis and 2 flu-like symptoms) and five (14%) infections. CONCLUSION: Rituximab is safe and effective in patients with refractory AIH and those treated due to concomitant autoimmune or haematological disorders.

IRF8 regulates efficacy of therapeutic anti-CD20 monoclonal antibodies.

Anti-CD20 monoclonal antibodies such as Rituximab, Ofatumumab, and Obinutuzumab are widely used to treat lymphomas and autoimmune diseases. They act by depleting B cells, mainly through Fc-dependent effectors functions. Some patients develop resistance to treatment but the underlying mechanisms are poorly understood. Here, we performed a genome-wide CRISPR/Cas9 screen to identify genes regulating the efficacy of anti-CD20 antibodies. We used as a model the killing of RAJI B cells by Rituximab through complement-dependent-cytotoxicity (CDC). As expected, the screen identified MS4A1, encoding CD20, the target of Rituximab. Among other identified genes, the role of Interferon Regulatory Factor 8 (IRF8) was validated in two B-cell lines. IRF8 KO also decreased the efficacy of antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP) induced by anti-CD20 antibodies. We further show that IRF8 is necessary for efficient CD20 transcription. Levels of IRF8 and CD20 RNA or proteins correlated in normal B cells and in hundreds of malignant B cells. Therefore, IRF8 regulates CD20 expression and controls the depleting capacity of anti-CD20 antibodies. Our results bring novel insights into the pathways underlying resistance to CD20-targeting immunotherapies.

Systematic literature review of immunoglobulin trends for anti-CD20 monoclonal antibodies in multiple sclerosis.

OBJECTIVE: To exp lore changes in immunoglobulin (Ig) levels for people with relapsing-multiple sclerosis (RMS) treated with ocrelizumab or ofatumumab and the relationship between Ig levels and infections. METHODS: A systematic literature review (SLR) was conducted to identify clinical trials and real-world evidence (RWE) studies on Ig levels over time and studies on associations with infections for ocrelizumab and ofatumumab for people with RMS through 10 September 2021. Searches were conducted in Embase, MEDLINE, Cochrane Library, trial registries, and recent conference abstracts. RESULTS: Of 1,580 articles identified, 30 reporting on 11 trials and 5 RWE studies were included. Ocrelizumab trials (n = 4) had 24-336 weeks of follow-up and reported decreasing Ig G (IgG) levels, while RWE (n = 5) had 52-78 weeks of follow-up and reported IgG to be stable or decrease only slightly. IgG levels were stable in ofatumumab trials (n = 5; 104-168 weeks of follow-up), but no RWE or longer-term studies were identified. No apparent association between decreased Ig levels and infections was observed during ofatumumab treatment (ASCLEPIOS I/II), while for ocrelizumab, the only data on apparent associations between decreased IgG levels and serious infection rates were for a pooled population of people with RMS or primary progressive MS. CONCLUSION: Decreasing IgG levels have been correlated with increased infection risk over time. IgG levels appeared to decrease over time in ocrelizumab trials but remained relatively stable over time in ofatumumab trials. Additional research is needed to understand differences between ocrelizumab and ofatumumab and identify people at risk of decreasing IgG levels and infection.

Incidence, Clinical Presentation, Relapses and Outcome of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Patients Treated With Anti-CD20 Monoclonal Antibodies.

BACKGROUND: Our objective is to describe the presentation and complications, including relapses, of coronavirus disease 2019 (COVID-19) in patients under anti-CD20 treatments. In addition, to describe viral clearance and determine the safety of reintroducing anti-CD20 treatment. METHODS: Retrospective cohort study of 422 patients under anti-CD20 treatment that was administered from 1 January 2019 to 31 December 2020. RESULTS: Fifty-seven patients were diagnosed with COVID-19 (13.5%). Twenty-five patients (43.9%) required hospital admission. Five patients died (8.8%), and 10 developed severe COVID-19 and acute respiratory distress syndrome. Mortality rate was higher among patients infected during the first 3 months following the last dose of anti-CD20 (14.7% vs 0%, P = .046). The median time of persistence of positive reverse transcription polymerase chain reaction (RT-PCR) was 22 days (IQR 13-40).Nine out of 52 survivors (17.3%) presented relapses. All of them received the last dose of anti-CD20 less than 6 months before the COVID-19 episode. Clinical presentation was fever (n = 8; 88.9%), dyspnea (n = 7; 77.8%), cough (n = 7; 77.8%), worsening of previous infiltrates (n = 5; 55.6%) and new pulmonary infiltrates (n = 8; 88.9%). An increase in lymphocytes with CD4/CD8 ratio inversion was observed in all cases. Among the 25 patients who resumed anti-CD20 drug, 4 (16.0%) presented relapses vs 5/28 among those who did not (17.9%), (P = .857). CONCLUSIONS: Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the 6 months after anti-CD20 administration had a worse outcome and a higher mortality rate. The duration of infectivity may be longer. Relapses of COVID-19 occurred in more than 15% and were associated with viral replication. Once the infection is resolved, it is safe to restart treatment with anti-CD20.

Pembrolizumab treatment of inflammatory progressive multifocal leukoencephalopathy: a report of two cases.

Progressive multifocal leukoencephalopathy (PML) is a rare but devastating neurological disease caused by reactivation of the JC virus in susceptible individuals. The illness has classically been associated with the human immunodeficiency virus (HIV) and multiple sclerosis (MS) patients who are treated with natalizumab. It is also associated with haematological malignancies, organ transplantation, autoimmune disease and immunodeficiency. Aside from natalizumab, a range of other immunomodulators including obinutuzumab and rituximab have been associated with PML. The nature of these associations is unclear due to the overall low incidence of PML associated with these drugs and the fact that most patients will have other confounding risk factors for developing the disease. There is no known effective treatment available for PML in the non-HIV, non-MS cohort. Recent case studies and series have proposed that pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, may be a potentially efficacious option for these patients. We present two cases of non-HIV, non-MS patients with PML who were treated with pembrolizumab with little clinical benefit. The literature surrounding pembrolizumab use in PML is discussed, with a focus on potential indicators of successful outcomes for patients who receive this therapy.

Human or Chimeric Monoclonal Anti-CD20 Antibodies for Children with Nephrotic Syndrome: A Superiority Randomized Trial.

BACKGROUND: The chimeric anti-CD20 monoclonal antibody rituximab is effective in steroid-dependent and calcineurin inhibitor-dependent forms of nephrotic syndrome, but many patients relapse at 1 year. Because ofatumumab, a fully human anti-CD20 monoclonal antibody, has a more extended binding site and higher affinity to CD20 compared with rituximab, it might offer superior efficacy in these patients. METHODS: We designed a single-center randomized clinical trial to compare the long-term efficacy of ofatumumab versus rituximab in children and young adults with nephrotic syndrome maintained in remission with prednisone and calcineurin inhibitors. We randomized 140 children and young adults (aged 2-24 years) to receive intravenous ofatumumab (1.50 mg/1.73 m2) or rituximab (375 mg/m2). After infusions, oral drugs were tapered and withdrawn within 60 days. The primary outcome was relapse at 1 year, which was analyzed following the intent-to-treat principle. The secondary endpoint was relapse within 24 months from infusion, on the basis of urine dipstick and confirmed by a urine protein-to-creatinine ratio <200. RESULTS: At 12 months, 37 of 70 (53%) participants who received ofatumumab experienced relapse versus 36 of 70 (51%) who received rituximab (odds ratio [OR], 1.06; 95% confidence interval [95% CI], 0.55 to 2.06). At 24 months, 53 of 70 (76%) participants who received ofatumumab experienced relapse, versus 46 of 70 (66%) who received rituximab (OR, 1.6; 95% CI, 0.8 to 3.3). The two groups exhibited comparable B cell subpopulation reconstitution and did not differ in adverse events. CONCLUSIONS: A single dose of ofatumumab was not superior to a single dose of rituximab in maintaining remission in children with steroid-dependent and calcineurin inhibitor-dependent nephrotic syndrome. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT02394119) and https://www.clinicaltrialsregister.eu/ctr-search/search (2015-000624-28).

Late-onset neutropenia after anti-CD20 therapy for multiple sclerosis, neuromyelitis optica spectrum disorders and MOG antibody-associated disease: A prospective study.

Late-onset neutropenia (LON) after anti-CD20 therapy is a poorly described side effect in inflammatory disorders of the CNS. In this prospective study, patients treated with Rituximab or Ocrelizumab for MS, neuromyelitis optica spectrum disorders or MOG antibody-associated disease (MOGAD) were asked to perform complete blood count (CBC) every two weeks for six months, with the aim of identifying LON. Out of 152 patients, two (1,32%) had an absolute neutrophil count <1,000/mm3: one patient with MOGAD had agranulocytosis and one patient with MS had grade 3 neutropenia. Both were asymptomatic. These results confirm that LON after anti-CD20 therapy in inflammatory disorders of the CNS is not exceptional. Nevertheless, this biological complication remains too infrequent to justify close systematic CBC follow-up.

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia.

In the last decade, the treatment of chronic lymphocytic leukemia (CLL) has shifted away from chemoimmunotherapy toward targeted novel agents such as small molecule inhibitors and antibodies. Here, we give an overview of the pharmacology of venetoclax and obinutuzumab and the evidence from early phase to Phase III trials that have shaped how they are used in the treatment of CLL. Venetoclax, an oral anti-apoptotic BCL-2 inhibitor, in combination with a CD20 antibody has shown superiority to chemoimmunotherapy in treatment-naive and relapsed/refractory CLL. Obinutuzumab is a novel anti-CD20 monoclonal antibody that has been safely combined with novel agents including venetoclax and Bruton tyrosine kinase inhibitors and has shown superiority over rituximab when combined with chlorambucil.

A five-year follow-up of untreated patients with chronic lymphocytic leukaemia treated with ofatumumab and chlorambucil: final analysis of the Complement 1 phase 3 trial.

The Complement 1 trial investigated the efficacy and safety of ofatumumab + chlorambucil with chlorambucil monotherapy in patients with previously untreated chronic lymphocytic leukaemia (CLL). On long-term follow-up in the chemoimmunotherapy arm vs. the chemotherapy arm there was an estimated 12% (not significant) and 39% risk reduction in overall survival and progression-free survival, respectively. A high rate (61%) of treatment with next-line therapies in both the treatment arms may dilute any potential OS difference and confound the interpretation of the OS results. Addition of ofatumumab to chlorambucil demonstrated clinical benefit and tolerability as a frontline treatment option in patients unfit for fludarabine-containing therapy, with no new safety concerns.

[Advances in antibody therapy for B cell lymphoma].

Almost 20 years have passed after rituximab, an anti-CD20 mouse-human chimeric monoclonal antibody therapeutic, was introduced in the clinical setting for the treatment of CD20-positive B cell malignancies. Although the prognosis has significantly improved in most B cell malignancies, resistance to rituximab with/without chemotherapies is also widely recognized. With this background, newer generation antibody therapeutics and other molecular targeting drugs that show more effectiveness especially to refractory patients are critically required. In this review, molecular mechanisms of the second/third generation anti-CD20 antibodies (ofatumumab and obinutuzumab), anti-CD19 chimeric antigen-receptor T-cells (CAR-T-CD19; tisagenlecleucel, axicabtagene ciloleucel), and the anti-PD-1 antibodies (nivolumab and pembrolizumab) are presented. The therapeutic effectiveness of those drugs as monotherapy and/or combined therapy with conventional chemotherapy (immunochemotherapy) and another molecular targeting therapeutics (so-called "chemo-free" regimens) are also reviewed.

[Modern view on treatment of membranous nephropathy].

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Since the moment of animal model creation and the recognition of podocytes damage as a key mechanism of MN development, the identification of antigens, first of all the phospholipase A2 receptor (PLA2R), and the development of methods of PLA2R autoantibodies detection and its monitoring opened a new era in the idiopathic MN (iMN) diagnosis, treatment and prognosis evaluation. MN continues to be actively studied in the new millennium, since a number of aspects of its pathogenesis still need to be clarified, and there is still no clear opinion on the iMN treatment optimal approach. Comprehensive clinical and serological assessment of patients with iMN can be the key to individual choice of treatment protocols. In patients with aPLA2R-positive iMN, the predictor of disease remission is the aPLA2R titer decrease or aPLA2R disappearance in the blood serum, and disease relapse is associated with the aPLA2R appearance ore increase of aPLA2R titer in the circulation. Studies which were conducted by today (GEMRITUX, MENTOR, STARMEN, NICE, etc.) confirmed the acceptable safety profile and effectiveness of iMN therapy by anti-CD20 monoclonal antibodies (rituximab): more than half of of iMN patients had remission of nephrotic syndrome or proteinuria decrease, remissions in anti-CD20 monoclonal antibodies treated patients were longer compared to traditional therapy. The obtained data allows us to consider rituximab and anti-CD20 antibody therapy of a new generation not only as an alternative to the more toxic treatment with cyclophosphane and calcineurin inhibitors, but as an independent promising direction of therapy for patients with IMN, which completely changes the paradigm of treatment of this glomerulopathy.

Anti-CD20 monoclonal antibody-dependent phagocytosis of chronic lymphocytic leukaemia cells by autologous macrophages.

Unconjugated monoclonal antibodies (mAbs) are an important component of effective combination therapies for chronic lymphocytic leukaemia (CLL). Antibody-dependent phagocytosis (ADP) is a major mediator of mAb cytotoxicity, but there is limited knowledge of the determinants of ADP efficacy. We used macrophages derived in vitro from autologous circulating monocytes to test the effects of mAb structure and concentration, target : effector cell ratio, duration of co-incubation and CLL cell CD20 expression on ADP. Next-generation anti-CD20 mAbs (ofatumumab, ublituximab, obinutuzumab, ocaratuzumab) were significantly more effective at inducing ADP compared to rituximab, but none were as effective as the anti-CD52 mAb alemtuzumab. Ofatumumab (10 µg/ml) used as a representative next-generation anti-CD20 mAb achieved an ADP plateau at 3 h co-incubation with a target : effector ratio of 10 : 1 (mean = 2.1 CLL cells/macrophage, range = 1.5-3.5). At 0.156 µg/ml (the lowest concentration tested) ofatumumab ADP was significantly higher than alemtuzumab. However, ofatumumab-induced ADP did not increase significantly at higher mAb concentrations. We show that anti-CD20 mAb ADP efficacy is determined by the mAb characteristics, target : effector ratio and incubation time. We suggest that preclinical evaluation of anti-CD20 mAbs to understand the determinants of ADP could be useful in designing future combination therapies for CLL.

An international multicenter study comparing COVID-19 omicron outcomes in patients with hematological malignancies treated with obinutuzumab versus rituximab.

OBJECTIVES: Hematological malignancy (HM) patients treated with anti-CD20 monoclonal antibodies are at higher risk for severe COVID-19. A previous single-center study showed worse outcomes in patients treated with obinutuzumab compared to rituximab. We examined this hypothesis in a large international multicenter cohort. METHODS: We included HM patients from 15 centers, from five countries treated with anti-CD20, comparing those treated with obinutuzumab (O-G) to rituximab (R-G) between December 2021 and June 2022, when Omicron lineage was dominant. RESULTS: We collected data on 1048 patients. Within the R-G (n = 762, 73%), 191 (25%) contracted COVID-19 compared to 103 (36%) in the O-G. COVID-19 patients in the O-G were younger (61 ± 11.7 vs. 64 ± 14.5, p = 0.039), had more indolent HM diagnosis (aggressive lymphoma: 3.9% vs. 67.0%, p < 0.001), and most were on maintenance therapy at COVID-19 diagnosis (63.0% vs. 16.8%, p < 0.001). Severe-critical COVID-19 occurred in 31.1% of patients in the O-G and 22.5% in the R-G. In multivariable analysis, O-G had a 2.08-fold increased risk for severe-critical COVID-19 compared to R-G (95% CI 1.13-3.84), adjusted for Charlson comorbidity index, sex, and tixagevimab/cilgavimab (T-C) prophylaxis. Further analysis comparing O-G to R-G demonstrated increased hospitalizations (51.5% vs. 35.6% p = 0.008), ICU admissions (12.6% vs. 5.8%, p = 0.042), but the nonsignificant difference in COVID-19-related mortality (n = 10, 9.7% vs. n = 12, 6.3%, p = 0.293). CONCLUSIONS: Despite younger age and a more indolent HM diagnosis, patients receiving obinutuzumab had more severe COVID-19 outcomes than those receiving rituximab. Our findings underscore the need to evaluate the risk-benefit balance when considering obinutuzumab therapy for HM patients during respiratory viral outbreaks.

Predictors and prognostic factors influencing outcomes of anti-CD20 monoclonal antibodies in systemic lupus erythematosus: A systematic review update.

BACKGROUND: Anti-C20 monoclonal antibodies (MAb), such as rituximab, are commonly used for the treatment of patients with severe or refractory systemic lupus erythematosus (SLE) but clinical outcomes are highly variable. We aimed to provide an update of a systematic review of predictive and prognostic factors of anti-CD20 MAb treatment in SLE. METHODS: A systematic literature search was undertaken to identify predictive and prognostic factors of clinical response following treatment with anti-CD20 therapies in SLE patients. Studies examining rituximab published prior to 2015 were excluded. Risk of bias was assessed for randomized controlled trials (RCTs) using the Cochrane Collaboration (RoB2) tool for RCTs and the Quality In Prognosis Studies Tool (QUIPS) for cohort studies. A narrative synthesis of the evidence was undertaken and quality of evidence (QoE) was assessed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: From 850 studies identified, 17 studies met the inclusion criteria. A further 8 studies were identified and included through search updates. There were two post-hoc analyses of RCTs of rituximab, one RCT of ocrelizumab and one of obinutuzumab; and 16 cohort studies examining rituximab treatment. The overall QoE was low or very low. There was wide heterogeneity in definitions of clinical disease activity and outcome measures, non-standardized laboratory cut-offs, failure to account for confounders and multiple subgroup analyses of differing outcomes. B cell depletion as well as novel biomarkers, such as S100 proteins, FCGR genotype, anti-vimentin and anti-drug antibodies showed some evidence of prognostic value but QoE was limited due to moderate to high risk of bias, early phase of investigation and imprecision of results. CONCLUSION: There has been no validation of previously identified prognostic factors to guide outcome in anti-CD20 treated lupus patients. Hypothesis-driven studies of several novel markers however, demonstrate prognostic value and require replication and validation to support their use in routine clinical practice. PROSPERO REGISTRATION NUMBER: CRD42020220339.

A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset. METHODS: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use. RESULTS: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)]. CONCLUSIONS: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges.

Cytomegalovirus Occurrence and Time-to-onset Analysis Under Bendamustine With Anti-CD20 Antibodies Using the JADER Database.

BACKGROUND/AIM: Patients with malignant lymphoma, in a latent state of weakened immune function, are at risk of chemotherapy-induced immunosuppression and cytomegalovirus (CMV) infection. Concomitant therapy with bendamustine and rituximab or obinutuzumab intensifies immunosuppression, potentially affecting CMV onset. This study aimed to assess CMV onset differences between bendamustine monotherapy and combination therapy with rituximab or obinutuzumab using the Japanese Adverse Drug Event Report database (JADER). PATIENTS AND METHODS: A JADER analysis dataset (April 2004 to September 2022) defined CMV infection using 31 preferred term (PT) words from MedDRA 25.1J HLT "Cytomegalovirus infection (10011827)". Reporting odds ratios (ROR) calculated CMV infection signals for bendamustine monotherapy, rituximab, obinutuzumab, bendamustine+rituximab (BR), and bendamustine+obinutuzumab (GB). ROR confidence intervals exceeding 1 indicated a CMV signal. Days of CMV infection were calculated based on adverse event onset and administration start. RESULTS: CMV signals were confirmed for monotherapy and combination therapies. CMV infection durations (median, interquartile range) were 41.0 days (23.5-69.5) for bendamustine monotherapy, 63.5 days (35.2-95.0) for BR, and 61.0 days (33.0-102.5) for GB, with cases exceeding 200 days. CONCLUSION: JADER analysis detected significant CMV signals for rituximab, obinutuzumab, and bendamustine. Caution may be warranted 7-9 months post-bendamustine administration, necessitating further investigation, including cell-mediated immunity suppression assessment.

Advances in the treatment of IgA nephropathy with biological agents.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease, and the "four-hit" theory represents its currently accepted pathogenic mechanism. Mucosal immunity triggered by infections in the respiratory tract, intestines, or other areas leads to antigen presentation, T cell stimulation, B cell maturation, and the production of IgA-producing plasma cells. The proteins B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are involved in this process, and alternative complement and lectin pathway activation are also part of the pathogenic mechanism. Kidney Disease Improving Global Outcomes guidelines indicate that a specific effective treatment for IgAN is lacking, with renin-angiotensin-aldosterone system inhibitors being the primary therapy. Recent research shows that biological agents can significantly reduce proteinuria, stabilize the estimated glomerular filtration rate, and reverse some pathological changes, such as endocapillary proliferation and crescent formation. There are four main categories of biological agents used to treat IgA nephropathy, specifically anti-CD20 monoclonal antibodies, anti-BLyS or APRIL monoclonal antibodies, monoclonal antibodies targeting both BLyS and APRIL (telitacicept and atacicept), and monoclonal antibodies inhibiting complement system activation (narsoplimab and eculizumab). However, further research on the dosages, treatment duration, long-term efficacy, and safety of these biological agents is required.

Hypogammaglobulinemia secondary to B-cell depleting therapies in neuroimmunology: Comparing management strategies.

Background: Anti-CD20 agents are commonly used in MS, NMOSD, and MOGAD. Few studies have compared strategies to address hypogammaglobulinemia. Objective: To compare strategies to manage secondary hypogammaglobulinemia in neuroimmunology patients, including reducing anti-CD20 dose and dosing frequency, IVIG/SCIG, anti-CD20 cessation, and DMT switches. Methods: All MS, NMOSD, and MOGAD patients at our institution with hypogammaglobulinemia on anti-CD20 agents from 2001 to 2022 were analyzed. The median change in IgG, infection frequency, and infection severity before and after the treatment was calculated. Results: In total, 257 patients were screened, and 30 had a treatment for hypogammaglobulinemia. IVIG/SCIG yielded the largest increase in IgG per year (674.0 mg/dL), followed by B-cell therapy cessation (34.7 mg/dL), and DMT switch (5.9 mg/dL). Dose reduction had the largest decrease in yearly infection frequency (2.7 fewer infections), followed by IVIG/SCIG (2.5 fewer), DMT switch (2 fewer), and reduced dosing frequency (0.5 fewer). Infection grade decreased by 1.9 for reduced dosing frequency (less severe infections), by 1.3 for IVIG/SCIG, and by 0.6 for DMT switch. Conclusion: This data suggests that IVIG/SCIG may yield the greatest recovery in IgG while also reducing infection frequency and severity. Stopping anti-CD20 therapy and/or switching DMTs also increase IgG and may lower infection risk.

Health-economic benefits of anti-CD20 treatments in relapsing multiple sclerosis estimated using a treatment-sequence model.

Background: In high-income countries, four anti-CD20 monoclonal antibodies (mAbs) are used or in the pipeline for relapsing MS: ocrelizumab, ofatumumab (both registered), ublituximab (awaiting registration) and rituximab (off-label). List prices differ significantly between registered and off-label drugs. Objective: Comparing differences in benefits between anti-CD20 mAbs from a health-economic and societal perspective. Methods: To reflect lifetime use of DMTs, we used a treatment-sequence model to compare ocrelizumab/ofatumumab and eight other drug classes in terms of health (lifetime relapses, time to Expanded Disability Status Scale [EDSS] 6, lifetime quality-adjusted life years) and cost-effectiveness (net health benefit). To become cost-effective compared to ocrelizumab, we modelled the list price of ublituximab and desired effect on EDSS progression of rituximab. Results: Although drug sequences with ocrelizumab in first- and second-line were more cost-effective than ofatumumab, our probabilistic analysis suggests this outcome was very uncertain. To be more cost-effective than ocrelizumab, ublituximab needs to be about 25% cheaper whilst rituximab needs to equal the effect on disability progression seen with first-line treatments. Conclusions: Our model showed no clear difference in cost-effectiveness between ocrelizumab and ofatumumab. Hence, prescribing the least costly anti-CD20 mAb can democratise MS care without a loss in health benefits.