Abatacept in IgG4-related disease: a prospective, open-label, single-arm, single-centre, proof-of-concept study.

Background: There is strong rationale for interference with T cell co-stimulation in IgG4-related disease (IgG4-RD), but the literature to evaluate this is limited to a single case report. Methods: We conducted a ten-subject proof-of-concept trial of abatacept in active IgG4-RD. All subjects met the ACR/EULAR Classification Criteria for IgG4-RD. Subjects received subcutaneous abatacept 125 mg weekly for 24 weeks. Concurrent glucocorticoid treatment was permitted but if used had to be discontinued by week four. The primary endpoint, complete remission at 24 weeks, was defined as an IgG4-RD Responder Index score of 0. Peripheral blood mononuclear cells were collected at baseline, four weeks, and 12 weeks. B and T cell subsets were quantified using a 25-parameter flow cytometry panel. Findings: The subjects' median age was 68 years; seven subjects were male and nine were Caucasian. Baseline organ involvement was diverse with a median of 5 organs affected at the time of enrollment. The median serum IgG4 concentration was 597 mg/dL (IQR 304-913 mg/dL). Three subjects received concomitant prednisone at baseline. Six subjects (60%) had a disease response by week 12, five of whom maintained this response at week 24. Abatacept was stopped in the remaining five subjects (50%) due to flare (N = 1) or lack of response by week 12 (N = 4). Three subjects (30%) achieved the primary endpoint.Baseline proportions of unswitched memory B cells predicted responsiveness to abatacept. Reductions in serum IgE, circulating plasmablasts, and activated type 2 T follicular helper (TFH2) cells correlated with response to treatment. One adverse event (grade two thrombocytopenia) was attributed to abatacept. Interpretation: Abatacept was associated with variable treatment responses in IgG4-RD. Half of the subjects achieved sustained treatment responses to abatacept alone, without glucocorticoids. Correlates of clinical response included reductions in serum IgE, circulating plasmablasts, and activated TFH2 cells. Response to abatacept was predicted by higher proportions of unswitched memory B cells at baseline.

Lifetime Allergy Symptoms in IgG4-Related Disease: A Case-Control Study.

OBJECTIVE: The etiology of IgG4-related disease (IgG4-RD) is unknown, and there has been controversy over the significance of allergic conditions in IgG4-RD. We examined the prevalence of lifetime allergy symptoms in IgG4-RD and the association between these and IgG4-RD. METHODS: We identified IgG4-RD patients and non-IgG4-RD controls without autoimmune conditions seen at a single center. IgG4-RD patients were classified using the American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria. Allergy symptoms were ascertained by questionnaire. We assessed the association of IgG4-RD features with allergy symptoms. We compared the proportion of cases and controls with allergy symptoms using conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) after matching cases and controls 1:1 by age and sex. RESULTS: Lifetime allergy symptoms were reported by 165 (71%) of 231 IgG4-RD patients. Aeroallergen symptoms were most commonly reported (n = 135, 58%), followed by skin allergy symptoms (n = 97, 42%) and food allergy symptoms (n = 47, 20%). IgG4-RD cases with a history of allergy symptoms were more likely to have head and neck involvement (OR 2.0 [95% CI 1.1-3.6]) and peripheral eosinophilia (OR 3.3 [95% CI 1.2-9.0]) than those without allergy symptoms. The prevalence of any allergy symptoms was similar between cases and controls (OR 0.7 [95% CI 0.4-1.1]); this remained consistent after stratifying by head and neck involvement. CONCLUSION: Lifetime allergy symptoms are common in IgG4-RD but are not reported more often in IgG4-RD compared to non-IgG4-RD patients without autoimmune conditions. These findings suggest that allergies are not uniquely associated with the pathogenesis or presentation of IgG4-RD.

CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated fibrotic disorder that has been linked to CD4+ cytotoxic T lymphocytes (CD4+CTLs). The effector phenotype of CD4+CTLs and the relevance of both CD8+ cytotoxic T lymphocytes (CD8+CTLs) and apoptotic cell death remain undefined in IgG4-RD. OBJECTIVE: We sought to define CD4+CTL heterogeneity, characterize the CD8+CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG4-RD. METHODS: Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data. RESULTS: We establish that among circulating CD4+CTLs in IgG4-RD, CD27loCD28loCD57hi cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8+CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8+ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR. CONCLUSIONS: CD4+CTLs and CD8+CTLs may induce apoptotic cell death in tissues of patients with IgG4-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.

Prostate and pancreas involvement are linked in IgG4-related disease.

OBJECTIVE: Prostate involvement by IgG4-related disease (IgG4-RD) is a rarely described organ manifestation and knowledge regarding its frequency and clinical features is limited. METHODS: From a single-center cohort, 168 male patients were examined who satisfied the 2019 ACR/EULAR classification criteria or 2012 consensus histopathologic criteria for IgG4-RD. RESULTS: Prostate involvement were identified in 25 (15%) of these cases. The majority of patients with IgG4-RD involving the prostate gland (80%) were symptomatic at presentation with incomplete voiding (64%), urinary frequency (52%), and urinary hesitancy (48%) being the most common complaints. The radiologic presentation of prostate disease is most often a focal abnormality suggesting inflammation rather than a mass lesion. While most patients with IgG4-related prostate disease (89%) experienced recurrence after or during glucocorticoid tapering, patients treated with B cell targeted therapy in this series experienced clinical improvement and were tapered off of glucocorticoids. Additionally, patients with IgG4-RD involving the pancreas (p = < 0.001) were more likely to have prostate involvement than were those with other types of organ involvement. CONCLUSION: This report provides the first comprehensive clinical description of IgG4-RD involving the prostate gland and links this manifestation with pancreatic involvement.

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).