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Background: IKBKE is a negative regulator of T cell activation and one of the key activators of type I interferon (IFN) and NFκB signaling via non-classical pathways. The upstream single nucleotide polymorphism of IKBKE (rs2297550-G) is a genome-wide association study risk variant of systemic lupus erythematosus, and is associated with decreased IKBKE expression in T cells by expression quantitative trait locus analysis. Case presentation: A 48-year-old female had a remittent fever, arthritis, and oral ulcers for 20 years. She had a poor response to corticosteroids or disease-modifying antirheumatic drugs, including the tumor necrosis factor-α antagonist, etanercept, and the anti-interleukin-6 receptor antibody, tocilizumab. Method: She participated in the Initiative on Rare and Undiagnosed Disease (IRUD), and whole-exome sequencing (WES) was performed. Functional analyses were conducted by transfecting the identified variants into reporter cells to assess the activation of NFAT and NFκB signaling. Additionally, peripheral blood RNA- sequencing (RNA-seq) data were compared with those from healthy individuals to evaluate the gene expression profiles of immune cells. Result: WES identified a novel heterozygous c.1877G>A, p(Cys626Tyr) variant in IKBKE. Functional analysis indicated that this variant led to increased activity of NFAT (p = 0.015) and decreased activity of NFκB and type I IFN (p = 0.00068 and 0.00044, respectively). The patient had a remarkably low proportion of Naïve CD4 T cells. RNA-seq of peripheral blood immune cell subsets revealed significant differences in gene expression, especially in T cells. Conclusion: A novel functional heterozygous variant in IKBKE is described in a patient with a remittent fever and arthritis. The data suggest that IKBKE is an important negative regulator of inflammation, particularly in T cells, and this IKBKE variant might be the underlying cause of a novel autoinflammatory pathology. [ABSTRACT FROM AUTHOR]

Objectives: Anti-melanoma differentiation associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) is a representative of rapidly progressive interstitial pneumonia. However, its association with thrombotic microangiopathy (TMA), characterized by thrombocytopenia, haemolytic anaemia, and organ dysfunction, has not been defined. This study aimed to elucidate the characteristics of anti-MDA5 Ab-positive DM accompanied by TMA. Methods: We reviewed our hospital records from November 2009 to September 2022. We included patients in accordance with the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria and the criteria of Bohan and Peter. TMA was diagnosed according to the criteria for transplantation-associated TMA proposed by the International Working Group. Results: This study enrolled a total of 26 anti-MDA5 Ab-positive DM patients, four of whom developed TMA. The patients with TMA had an increased urine protein/creatinine ratio. In addition, these four of them showed significantly elevated levels of ferritin and anti-MDA5 Ab titers and were considered to have high disease activity; yet, all of them survived. Conclusions: Our study indicated that anti-MDA5 Ab-positive DM patients with hyperferritinemia, a high anti-MDA5 Ab titer, and an increased urine protein/creatinine ratio should be carefully managed, bearing in mind a complication of TMA. [ABSTRACT FROM AUTHOR]

Objectives: We evaluated the medication selection and clinical characteristics of rheumatoid arthritis patients who started treatment with/without methotrexate (MTX) (using biologic disease-modifying antirheumatic drugs or Janus kinase inhibitors instead) in Japan. Methods: Using a Japanese hospital-based administrative claims database, rheumatoid arthritis patients who received treatment [abatacept (ABA), interleukin-6 receptor inhibitor, tumor necrosis factor inhibitor, or Janus kinase inhibitor] between 1 January 2015 and 31 December 2019 were enrolled. Results: Overall, 19,301 patients were included (10,530 receiving MTX; 8771 not receiving MTX within 60 days of the first treatment). Mean ages at diagnosis were 60.7 and 65.9 years in the MTX and non-MTX groups, respectively (P < .0001). The non-MTX group had higher proportions of patients with Charlson Comorbidity Index ≥1 (P < .0001) and higher comorbidity rates. ABA was the most frequently used drug among patients with infectious/parasitic, circulatory, and respiratory diseases at baseline. Interleukin-6 receptor inhibitor had the highest use rate among patients with neoplasms; blood, gastrointestinal, and genitourinary diseases; and abnormal clinical/laboratory findings. ABA had the highest persistence probability from 6 months onward. Conclusions: MTX is used less frequently among older Japanese rheumatoid arthritis patients or those with comorbidities. In such patients, ABA is the most frequently used drug, followed by interleukin-6 receptor inhibitor, when MTX is not used at treatment start. [ABSTRACT FROM AUTHOR]

Recent single-cell RNA-sequencing analysis of rheumatoid arthritis (RA) synovial tissues revealed the heterogeneity of RA synovial fibroblasts (SFs) with distinct functions such as high IL-6 production. The molecular mechanisms responsible for high IL-6 production will become a promising drug target of RASFs to treat RA. In this study, we performed siRNA screening of 65 transcription factors (TFs) differentially expressed among RASF subsets to identify TFs involved in IL-6 production. The siRNA screening identified 7 TFs including ARID5B, a RA risk gene, that affected IL-6 production. Both long and short isoforms of ARID5B were expressed and negatively regulated by TNF-α in RASFs. The siRNA knockdown and lentiviral overexpression of long and short isoforms of ARID5B revealed that the long isoform suppressed IL-6 production stimulated with TNF-α. eQTL analysis using 58 SFs demonstrated that RA risk allele, rs10821944, in intron 4 of the ARID5B gene had a trend of eQTL effects to the expression of long isoform of ARID5B in SFs treated with TNF-α. ARID5B was found to be a negative modulator of IL-6 production in RASFs. The RA risk allele of ARID5B intron may cause high IL-6 production, suggesting that ARID5B will become a promising drug target to treat RA. [ABSTRACT FROM AUTHOR]

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4+FOXP3+ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1, which led to destabilization of forkhead box P3 (FOXP3) and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregs from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and Treg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional Tregs in autoimmune diseases. Editor's summary: Regulatory T cells (Tregs) are known to be dysfunctional in autoimmune diseases, but the cause of this dysfunction has not been fully elucidated. Here, Sumida et al. found that Tregs isolated from individuals with multiple sclerosis, an autoimmune disease of the central nervous system, had increased expression of the short isoform of PR domain zinc finger protein 1 (PRDM1-S), which destabilized expression of the essential Treg transcription factor FOXP3 and induced Treg dysfunction mediated through SGK1, a salt-sensing kinase. Upstream epigenetic analysis revealed a regulatory role for AP-1 and IRF transcription factors in this circuit. The authors detected similar up-regulation of PRDM1-S in other autoimmune diseases, suggesting that PRDM1-S overexpression may be a common feature of Treg dysfunction. —Courtney Malo [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management. Egr2 plays a central role in driving the differentiation of monocytes into hLAMs in MASH liver. [ABSTRACT FROM AUTHOR]

Objective: The European League Against Rheumatism recommends that the disease activity of systemic lupus erythematosus should be stable before pregnancy because complications and disease flares increase if pregnancy occurs while disease activity is high. However, some patients have ongoing serological activity even after treatment. Herein, we investigated how physicians decide on the acceptability of pregnancy in patients showing only serological activity. Methods: A questionnaire was administered from December 2020 to January 2021. It included the characteristics of physicians, facilities, and the allowance for pregnancies of patients using vignette scenarios. Results: The questionnaire was distributed to 4946 physicians, and 9.4% responded. The median age of respondents was 46 years, and 85% were rheumatologists. Pregnancy allowance was significantly affected by the duration of the stable period and status of serological activity [duration: proportion difference 11.8 percentage points (p.p.), P < .001; mild activity: proportion difference −25.8 p.p., P < .001; high activity: proportion difference −65.6 p.p., P < .001]. For patients with high-level serological activity, 20.5% of physicians allowed pregnancy if there were no clinical symptoms for 6 months. Conclusions: Serological activity had a significant effect on the acceptability of pregnancy. However, some physicians allowed patients with serological activity alone to become pregnant. Further observational studies are required to clarify such prognoses. [ABSTRACT FROM AUTHOR]

Early diagnosis and timely therapeutic intervention are clinical challenges of rheumatoid arthritis (RA), especially for treatment-resistant or difficult-to-treat patients. Little is known about the immunological mechanisms involved in refractory RA. In this review, we summarize previous research findings on the immunological mechanisms of treatment-resistant RA. Genetic prediction of treatment-resistant RA is challenging. Patients with and without anti-cyclic citrullinated peptide autoantibodies are considered part of distinct subgroups, especially regarding long-term clinical prognosis and treatment responses. B cells, T cells and other immune cells and fibroblasts are of pathophysiological importance and are associated with treatment responses. Finally, we propose a new hypothesis that stratifies patients with RA into two subgroups with distinct immunological pathologies based on our recent immunomics analysis of RA. One RA subgroup with a favorable prognosis is characterized by increased interferon signaling. Another subgroup with a worse prognosis is characterized by enhanced acquired immune responses. Increases in dendritic cell precursors and diversified autoreactive anti-modified protein antibodies may have pathophysiological roles, especially in the latter subgroup. These findings that improve treatment response predictions might contribute to future precision medicine for RA. [ABSTRACT FROM AUTHOR]

Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4+ T cell subsets from 354 patients with autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3midCD4+ effector memory T cell subset that expands with age, which we designated "age-associated T helper (THA) cells." THA cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of THA cells, gene expression in THA cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that THA cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of THA cells may facilitate improved understanding of the relationship between aging and autoimmune diseases. Editor's summary: Pathological CD4+ T cell responses contribute to the development of autoimmunity, but whether their age-related changes affect autoimmune disease susceptibility remains unclear. By analyzing a cohort of 354 patients with autoimmune disease, Goto et al. identified a population of peripheral blood CXCR3midCD4+ T cells that is expanded during aging and conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. These age-associated helper T (THA) cells promoted antibody production by B cells and were regulated by the transcription factor ZEB2. THA cell gene signatures correlated with SLE disease activity and were observed in target organs, indicating that THA cells may represent a therapeutic target for autoimmune diseases. —Claire Olingy [ABSTRACT FROM AUTHOR]