Background: A number of studies have reported an association between the occurrence of immune-related adverse events (irAEs) and clinical efficacy in patients undergoing treatment with immune checkpoint inhibitors (ICIs), but the results remain controversial. Methods: Under the guidance of a predefined protocol and Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, this meta-analysis included cohort studies investigating the association of irAEs and efficacy of ICIs in patients with cancer. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Subgroup analyses involving the cancer type, class of ICIs, combination therapy, sample size, model, landmark analysis, and approach used to extract the data were performed. Specific analyses of the type and grade of irAEs were also performed. Results: This meta-analysis included 30 studies including 4971 individuals. Patients with cancer who developed irAEs experienced both an OS benefit and a PFS benefit from ICI therapy compared to patients who did not develop irAEs (OS: hazard ratio (HR), 0.54, 95% confidence interval (CI), 0.45-0.65; p < 0.001; PFS: HR, 0.52, 95% CI, 0.44-0.61, p < 0.001). Subgroup analyses of the study quality characteristics and cancer types recapitulated these findings. Specific analyses of endocrine irAEs (OS: HR, 0.52, 95% CI, 0.44-0.62, p < 0.001), dermatological irAEs (OS: HR, 0.45, 95% CI, 0.35-0.59, p < 0.001), and low-grade irAEs (OS: HR, 0.57, 95% CI, 0.43-0.75; p < 0.001) yielded similar results. The association between irAE development and a favorable benefit on survival was significant in patients with cancer who were undergoing treatment with programmed cell death-1 inhibitors (OS: HR, 0.51, 95% CI, 0.42-0.62; p < 0.001), but not cytotoxic T-lymphocyte antigen-4 inhibitors (OS: HR, 0.89, 95% CI, 0.49-1.61; p = 0.706).

IgG4-related disease (IgG4-RD) is characterized by lymphoplasmacytic infiltration enriched in IgG4-positive plasma cells and variable degrees of fibrosis with a characteristic storiform pattern. Since fibrosis is an important feature of IgG4-RD, we performed a prospective cohort study to evaluate the performance of 68 Ga-FAPI, a recently introduced PET agent targeting fibroblast activation protein, in IgG4-RD. Methods: Twenty-six patients with IgG4-RD were recruited. All patients underwent both 68 Ga-FAPI and 18 F-FDG PET/CT. The positive rates of the PET/CT scans in the involved organs and the uptake values were compared. Results: In a total of 136 organ involvements in the 26 patients, 68 Ga-FAPI PET/CT additionally detected 18/136 (13.2%) organ involvements in 13/26 (50.0%) patients compared with 18 F-FDG PET/CT. 68 Ga-FAPI PET/CT had a higher positive rate than 18 F-FDG PET/CT in detecting involvement in the pancreas, bile duct/liver, and lacrimal gland. 68 Ga-FAPI also demonstrated significantly higher uptake than 18 F-FDG in the matched disease in the pancreas, bile duct/liver, and salivary gland (p < 0.01). However, lymph node involvements with flip-flop uptake of 18 F-FDG were not accumulating 68 Ga-FAPI. Conclusions: 68 Ga-FAPI might be a promising imaging agent for the assessment of IgG4-RD.

The presence or absence of anti-citrullinated peptide antibodies (ACPA) and associated disparities in patients with rheumatoid arthritis (RA) implies disease heterogeneity with unknown diverse immunopathological mechanisms. Here we profile CD45+ hematopoietic cells from peripheral blood or synovial tissues from both ACPA+ and ACPA- RA patients by single-cell RNA sequencing and identify subsets of immune cells that contribute to the pathogenesis of RA subtypes. We find several synovial immune cell abnormalities, including up-regulation of CCL13, CCL18 and MMP3 in myeloid cell subsets of ACPA- RA compared with ACPA+ RA. Also evident is a lack of HLA-DRB5 expression and lower expression of cytotoxic and exhaustion related genes in the synovial tissues of patients with ACPA- RA. Furthermore, the HLA-DR15 haplotype (DRB1/DRB5) conveys an increased risk of developing active disease in ACPA+ RA in a large cohort of patients with treatment-naive RA. Immunohistochemical staining shows increased infiltration of CCL13 and CCL18-expressing immune cells in synovial tissues of ACPA- RA. Collectively, our data provide evidence of the differential involvement of cellular and molecular pathways involved in the pathogenesis of seropositive and seronegative RA subtypes and reveal the importance of precision therapy based on ACPA status.