BACKGROUND:IgG4-related disease is a chronic fibroinflammatory condition that can affect virtually any organ system. Glucocorticoid agents are a cornerstone of therapy but are limited by toxic effects, and relapse is common after discontinuation. Obexelimab is a bifunctional monoclonal antibody that inhibits B-cell activity through coengagement of CD19 and FcγRIIb without inducing B-cell depletion. METHODS:In this phase 3, double-blind, randomized, placebo-controlled trial, patients with active IgG4-related disease received subcutaneous obexelimab at a dose of 250 mg or placebo once weekly for 52 weeks. For patients in both groups, glucocorticoids were tapered in a standardized schedule to discontinuation at week 8. The primary end point was the time to the first flare of IgG4-related disease for which rescue therapy was required, as determined by both the investigator and the independent adjudication committee. Key secondary end points included complete remission at week 52 and the cumulative dose of glucocorticoid rescue therapy through week 52. RESULTS:From January 2023 through November 2024, a total of 194 patients underwent randomization (with 97 assigned to each group). The time to the first disease flare that required rescue therapy was significantly longer with obexelimab than with placebo (hazard ratio, 0.44; 95% confidence interval, 0.28 to 0.71; P<0.001); flares were reported in 26 patients (26.8%) in the obexelimab group and in 53 patients (54.6%) in the placebo group. Obexelimab showed a significant benefit over placebo with respect to all the key secondary end points, including complete remission (37.1% vs. 19.6%, P = 0.005) and the cumulative dose of glucocorticoid rescue therapy (329.5 mg vs. 929.8 mg, P = 0.004). Adverse events included arthralgias (in 19.6% of the patients in the obexelimab group vs. 11.3% of those in the placebo group), hypersensitivity (in 16.5% vs. 11.3%), and diarrhea (in 11.3% vs. 6.2%). Serious adverse events occurred in 10.3% of the patients in the obexelimab group and in 18.6% of those in the placebo group. CONCLUSIONS:Among patients with active IgG4-related disease, weekly obexelimab treatment led to a significantly lower risk of disease flare and significantly less glucocorticoid exposure than placebo. (Funded by Zenas BioPharma; INDIGO ClinicalTrials.gov number, NCT05662241.).

Objectives Evidence supporting an occupational hypothesis for sarcoidosis remains limited. The hypothesis of the present study was that some occupational exposures might be more prevalent among sarcoidosis patients than in the French population.Methods A cross-sectional observational study design was used to collect occupational data from patients enrolled in the Epidemiology ofSarcoidosis (EpiSarc) cohort study with documented sarcoidosis. The data were initiallyclassified according to the occupational classification of the French National Institute ofStatistics and Economic Studies and then compared to employment data fromthe French population for the reference year 2016.Results Among the 1,512 sarcoidosis patients included, occupational data were avail- able for 1,177 patients (78%). Of these, 1,086 (92%) were employed at time of sarcoidosis diagnosis. Notably, manual workers were significantly overrepresented compared to the general French population (40% versus 20%, p < 0.0001). Among the 471 manual workers, the distribution of occupations was as follows: construction workers (n = 165, 35%), domestic helpers and cleaners (n = 109, 23%), transportation and handling workers (n = 82, 17.5%), manufacturing labourers and industrial operators (n = 67, 14%), textile indus- try workers (n = 25, 5.5%), and other occupations (n = 23, 5%). The frequency of patients with manual working occupations varied depending on the organ involvement, being the highest in patients with lung involvement.Conclusion We found that manual workers occupations with exposure to various environmental hazards that may trigger inflammation promoting an abnormal granulomatous immune response, including dust, were associated with sarcoidosis.

Objectives The objective of the article is to assess the efficacy and safety of rilzabrutinib, an oral, reversible inhibitor of Bruton’s tyrosine kinase, in participants with IgG4-related disease. Methods This Phase 2a (NCT04520451) open-label, 52-week study enrolled 2 cohorts of participants with IgG4-related disease: Cohort A (participants who had failed or were intolerant to rituximab) and Cohort B (participants enrolled agnostic to rituximab history). Participants received rilzabrutinib plus a 2-to-4-week glucocorticoid (GC) taper followed by rilzabrutinib alone for up to 52 weeks. Primary endpoints were the proportion of participants without disease flare following first rilzabrutinib dose until the end of treatment and safety. Results This study included 27 participants (Cohort A: 13; Cohort B: 14). At the end of treatment, 70.4% (19/27) of participants were flare-free and off GCs/immunosuppressants. Disease activity (mean [SD]), measured by IgG4-related disease Responder Index, decreased by 8.3 (5.8) at week 12 in both cohorts and by 10.7 (6.3) in participants who completed 52 weeks of rilzabrutinib (14/17). Serious treatment-emergent adverse events (TEAEs) occurred in 2 participants, 1 resulting in death, but both events were judged unrelated to the study drug. The most frequent TEAEs were diarrhoea, 40.7% (11/27); coronavirus disease 2019, 18.5% (5/27); and dizziness, 18.5% (5/27). Conclusions Rilzabrutinib had an acceptable safety profile in patients with IgG4-related disease who had failed/ intolerant to rituximab and who were rituximab-naïve. Most participants discontinued GCs successfully without disease flares and exhibited sustained disease activity reduction. Further investigation of this potential alternative to B-cell–depleting therapies is needed in larger, long-term, placebo-controlled trials.

IgG4-related disease (IgG4-RD) is a recently described entity comprising pseudo-tumoral and inflammatory conditions that were previously considered separately. It is characterised by specific histological abnormalities, including polyclonal lymphoplasmacytic infiltration, fibrosis and contingent of IgG4+ plasma cells, often associated with elevated serum IgG4 levels and a good response to glucocorticoids. The clinical presentation is highly heterogeneous and requires a multidisciplinary assessment. The diagnosis is based on the identification of suggestive clinical or radiological signs, such as pancreatic, salivary or lacrimal gland involvement, retroperitoneal fibrosis, cholangitis, aortitis, lymphadenopathy or interstitial nephritis. It is also based on the search for laboratory evidence of abnormalities such as polyclonal gammopathy, elevated serum IgG4 levels and complement consumption, and is most often confirmed by organ biopsy. The disease progresses slowly, with gradual symptoms and a risk of sequelae related to fibrosis, particularly pancreatic or renal failure. Management is based on providing the patient with comprehensive information about symptoms, warning signs, adverse events of treatments, vaccination, diet and physical activity. Initial treatment consists of oral glucocorticoids at a dose of 0.4 to 0.6mg/kg/day for two to four weeks, followed by a gradual tapering until discontinuation at three months if possible. This treatment induces remission in more than 90% of cases, but relapses are common, sometimes requiring treatment with immunosuppressants. Follow-up includes regular consultations, imaging tests and laboratory workups, in particular serum IgG4 measurement, in order to monitor disease activity, predict relapses and prevent complications.

Acquired hemophilia A during pregnancy is exceptionally rare and poses significant risks to both mother and fetus, including maternal hemorrhage and neonatal bleeding due to transplacental transfer of factor (F)VIII inhibitors. We report four cases of antenatally diagnosed acquired hemophilia A to provide insights into management and outcomes. All patients received corticosteroids during pregnancy, with individualized peripartum hemostatic strategies using bypassing agents when indicated. Transplacental FVIII inhibitor transfer occurred in three neonates, leading to transient low FVIII levels; only one mild bleeding event was observed, and all infants achieved spontaneous remission within weeks. Postpartum escalation of immunosuppressive therapy, including rituximab, was required in selected mothers to achieve remission. Our series highlights the critical importance of prepartum diagnosis, allowing optimized maternal hemostatic management, avoidance of traumatic delivery, and structured neonatal surveillance to prevent severe bleeding complications.

OBJECTIVES:Anti-MDA5 dermatomyositis (anti-MDA5 DM) is the most severe subtype of dermatomyositis, due to its pulmonary involvement. Current treatment involves corticosteroids and immunosuppressants, but variability in responses exists. This study aims to evaluate the efficacy and safety of Janus kinase (JAK)- and calcineurin-inhibitor combination (JAK-CNI) in anti-MDA5 DM patients. METHODS:A nested case-control study was conducted within a retrospective cohort of 234 anti-MDA5 DM patients. Patients receiving JAK-CNI were matched 1:2 with comparators. All-cause mortality or transplant within a year was compared using Cox proportional hazards models. Infectious and noninfectious side effects were also assessed. RESULTS:Twenty-seven patients receiving JAK-CNI were compared to 52 matched controls. Almost all these patients had pulmonary involvement. Thirty-nine (49%) died or were transplanted during follow-up. No significant improvement in survival or transplant-free survival was observed with JAK-CNI compared with comparators (hazard ratios 1.02, 95% confidence intervals [0.48-2.16]). Results were consistent regardless of intensive care unit (ICU) admission status and when analyses were restricted to patients with rapidly progressive interstitial lung disease. A trend toward a beneficial effect of the JAK-CNI combination was observed in non-ICU patients. Infectious complications were frequent (n = 49, 62%), with no excess risk in patients receiving JAK-CNI. CONCLUSION:JAK-CNI showed a similar outcome to other immunosuppressive combinations. However, as the study included the most severe cases, the potential benefit of early JAK-CNI introduction in less severe forms cannot be dismissed, as suggested by the nonsignificant trend in non-ICU patients. Future studies are needed to clarify the optimal timing and patient selection for JAK-CNI therapy in anti-MDA5 DM.

BACKGROUND:Eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophilic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Rituximab has emerged as the standard of care in other types of ANCA-associated vasculitis, but controlled studies on its use in EGPA are yet lacking. OBJECTIVE:To compare rituximab with conventional strategy for the induction of remission in patients with EGPA. DESIGN:Phase 3, multicenter, randomized, controlled, double-blind, superiority trial. (ClinicalTrials.gov: NCT02807103). SETTING:France. PARTICIPANTS:Patients with a diagnosis of EGPA, newly diagnosed or relapsing disease at the time of screening, with active disease defined as a Birmingham Vasculitis Activity Score (BVAS) of 3 or greater. INTERVENTION:Glucocorticoids plus rituximab (1 g 2 weeks apart) compared with the conventional strategy (glucocorticoids alone or in combination with cyclophosphamide in severe forms) for induction of remission. MEASUREMENTS:The primary end point was remission defined as a BVAS, version 3, of 0 and a prednisone dose of 7.5 mg/d or less at day 180. Secondary end points included duration of remission during the study, average daily glucocorticoid dose, and safety. RESULTS:A total of 105 participants were randomly assigned. Thirty-three (63.5%) patients in the rituximab group achieved the primary end point compared with 32 (60.4%) in the control group (relative risk, 1.05 [95% CI, 0.78 to 1.42]; P = 0.75). Results were similar at day 360. The mean duration of remission was 48.5 ± 6.51 weeks in the rituximab group and 49.1 ± 7.42 weeks in the conventional strategy group (P = 0.41). All relapse and major relapse rates were similar between the 2 groups. There was no statistically significant difference in the average daily glucocorticoid dose and no statistically significant differences in the rates of adverse events between the treatment groups. LIMITATION:Design not appropriate to answer the question of equivalence between rituximab and cyclophosphamide in patients with severe EGPA. CONCLUSIONS:Rituximab was not superior to a conventional remission induction strategy in EGPA. PRIMARY FUNDING SOURCE:French Ministry of Health.

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder usually characterized by multi-organ involvement. Its pathogenesis is complex and involves genetic and environmental factors, while immune responses usually mediate organ damage and promote fibrosis, which is a key feature of the disease. IgG4 responses, however, are not exclusive to IgG4-RD and can be encountered in other diseases with phenotypes that partially overlap that of IgG4-RD. Although IgG4-RD has clinical and histological hallmarks, the lack of validated diagnostic criteria often makes the diagnosis challenging, requiring a multi-dimensional approach that integrates clinical, radiological and serological data. The present Review covers recent advances in the understanding of disease drivers and its clinical phenotypes, mainly focusing on the differential diagnosis with potential IgG4-RD mimickers, namely histiocytoses, lymphoproliferative disorders, systemic vasculitides and other immune-mediated conditions. The Review also provides a schematic approach to IgG4-RD treatment, including a brief overview of glucocorticoid-sparing agents and emerging therapies, from B cell-depleting monoclonal antibodies to cytokine-targeting drugs, the majority of which are currently under investigation in randomized clinical trials. IgG4-related disease is a fibro-inflammatory disorder with a complex pathogenesis. Herein the authors review the latest developments in IgG4-related disease clinical phenotyping, pathophysiology and management, with a focus on the main mimics of this disease and how to approach issues related to differential diagnosis.

Clinical laboratories searching for pathogenic variants focus mostly on the protein-coding region and corresponding essential splicing sites. Screening for variants in intronic regions requires dedicated bioinformatics tools and detailed experimental studies to confirm deleteriousness and pathogenicity. We report intronic variants in a cohort of eight patients from seven kindreds with unexplained inborn errors of immunity (IEI). Using ad hoc bioinformatics tools, we identified seven kindreds carrying three branchpoint variants at three loci (BTK, SH2D1A, and WAS) and four AG-gain acceptor site variants at another four loci (DOCK8, NFKB1, STXBP2, and UNC13D). The variants were located between positions −9 and −49 relative to the wild-type acceptor site. The deleteriousness and, thus, pathogenicity of these variants were confirmed by exon-captured transcriptome studies and flow cytometry analyses of protein production or function. Our findings indicate that intronic variants should be systematically screened and investigated, even in clinical laboratory settings.