Autoantibodies directed against Telomerase RNA Ro y-RNAs and Vault RNAs Domain Family Member 2 (TROVE2)/Ro60 and Tripartite Motif 21 (TRIM21)/Ro52 are historically related to distinct SSA/Ro autoantigens. However, despite advances facilitating separate testing, these autoantibodies remain frequently confused resulting in a lack of clarity and precision in the literature. We conducted a systematic literature review to inform a Delphi process to achieve consensus on a clearer, harmonised nomenclature. The systematic review included primary publications in systemic lupus erythematosus (SLE) and Sjögren disease (SjD) published between January 1, 2000 and May 26, 2025 that mentioned testing for anti-TROVE2/Ro60 and/or anti-TRIM21/Ro52 autoantibodies. This analysis contributed to a Delphi consensus exercise proposing preferred nomenclature by a group of 17 international expert physicians and laboratorians. Eight hundred ninety-one publications were included (301 SLE, 493 SjD, and 97 mixed SLE/SjD). Only 20.9% of studies tested and reported the autoantibodies separately; 75.0% did neither; and 4.2% tested but did not report them separately. There was considerable nomenclatural heterogeneity with 16 different terms used for anti-TROVE2/Ro60 and 11 terms for anti-TRIM21/Ro52 autoantibodies. After 2 rounds of voting, the Delphi panel reached a unanimous consensus on the terms anti-TROVE2/Ro60 and anti-TRIM21/Ro52 autoantibodies. The distinction of anti-TROVE2/Ro60 and anti-TRIM21/Ro52 autoantibodies was frequently unclear and imprecise throughout the literature. Their clinical associations also lacked clarity and precision. To clarify and strengthen the understanding of the clinical associations of these 2 important autoantibodies, the terms anti-TROVE2/Ro60 and anti-TRIM21/Ro52 are recommended for future studies and publications.

Efficacy thresholds allow interpretation of randomised clinical trials (RCTs) and establishment of treatment targets. To assess the need for more personalised treatment goals, minimal clinically important improvement (MCII) thresholds in psoriatic arthritis (PsA) clinical and patient-reported outcome measures were determined by treatment history and baseline disease activity. This post hoc analysis pooled data from 3 RCTs in participants with active PsA receiving guselkumab every 8 week (Q8W), or placebo with W24 transition to guselkumab Q8W. MCII thresholds for clinical Disease Activity Index for PsA (cDAPSA), PsA Disease Activity Score (PASDAS), and patient-reported assessments of arthritis and psoriasis, pain, fatigue, and physical function were determined using established distribution-based methods in participant subgroups defined by prior tumour necrosis factor inhibitor (TNFi) treatment and baseline cDAPSA and PASDAS disease activity (high vs moderate). In this pooled RCT population, estimated MCII thresholds for all examined measures were consistent across TNFi-experienced and biologic-naïve cohorts. However, the determined cDAPSA, but not PASDAS, MCII was more stringent among participants with high vs moderate baseline disease activity. Guselkumab-treated participants had greater odds of achieving MCII thresholds vs placebo as early as W8, irrespective of prior TNFi and baseline cDAPSA and PASDAS disease activity, supporting the known-groups validity of the estimated thresholds. Estimated MCII thresholds were consistent regardless of prior TNFi but greater for participants with higher baseline joint disease activity, indicating disease severity may impact perceived PsA improvement. These findings may aid in setting more personalised goals in shared decision‑making and treat-to-target strategies, and RCT interpretation.

IgG4-related disease (IgG4-RD) is a chronic immune-mediated disease characterised by mass-forming lesions. The smouldering tempo and often asymptomatic nature of IgG4-RD pose challenges in the monitoring of disease activity. The goal of this study is to identify novel biomarkers capable of distinguishing active disease from remission. Ninety-two inflammation-associated proteins were measured across 67 patients with IgG4-RD, 49 healthy donors (HDs), and 21 patients with sarcoidosis. Statistical analyses were adjusted for age, sex, race, and false discovery rate. Biomarkers that distinguished IgG4-RD were studied by unsupervised hierarchical clustering, receiver operator characteristic curves, and statistical analyses. Quantitative enzyme-linked immunosorbent assay (ELISA) was used to validate findings in a cohort of 80 patients with IgG4-RD, including 28 patients with paired longitudinal samples, and 80 age, sex, and race-matched HDs. Twelve inflammation-associated proteins distinguished IgG4-RD. Although most markers correlated with one another, CCL19, CCL2, and CCL13 were the most distinguishing of IgG4-RD. Among these, only CCL19 decreased during treatment-induced remission relative to active IgG4-RD. CCL19 correlated with clinical and laboratory parameters of disease activity and severity. Quantitative ELISA validated the systemic elevation of CCL19 in patients with IgG4-RD. CCL19 performed similarly to IgG4 in dynamically declining in response to treatment and increasing with subsequent relapse. Importantly, CCL19 and IgG4 supplemented one another in distinguishing active disease from remission. CCL19 is a novel and promising biomarker for the longitudinal monitoring of disease activity in patients with IgG4-RD and may provide supplemental value to IgG4 in identifying relapsing disease.

We aimed to study the serologic, genetic, and immunologic underpinnings associated with cytotoxic T lymphocytes (CTLs) in rheumatoid arthritis (RA), using T-large granular lymphocytic leukaemia with comorbid RA (T-LGLL/RA) as a model of CTL-linked RA. We used blood samples and paired clinical data from patients with RA, T-LGLL/RA, T-LGLL and healthy controls. Serological characterisation was performed using anti-cyclic citrullinated peptide 3.1 (anti-CCP3.1) enzyme-linked immunosorbent assay, multiplex RA autoantigen array, and radiolabelled peptidylarginine deiminase type III and IV (PAD4) immunoprecipitations. Genetic characterisation was performed using PADI4 single nucleotide polymorphism TaqMan genotyping assays and droplet digital polymerase chain reaction for signal transducer and activator of transcription 3 (STAT3) mutations. Multiparameter flow cytometry and pentamer binding assays were performed to immunophenotype CTLs and characterise PAD4-specific CTLs, respectively. Patients with T-LGLL/RA had enhanced anticitrullinated protein antibody responses compared with RA, and a strikingly higher frequency of anti-PAD4 antibodies (60% vs 27%, P < .0001). Among patients with T-LGLL, PADI4 single nucleotide polymorphisms were associated with anti-PAD4-positive RA (20% vs 3%, P = .02), and anti-PAD4 antibody levels were inversely correlated with absolute neutrophil count (Spearman's rho = -0.236; P = .02). Activating STAT3 mutations were associated with anti-PAD4 antibodies in both T-LGLL/RA (90% vs 74%, P = .047) and RA (39% vs 9%, P = .002). Flow cytometric characterisation of CTLs showed that anti-PAD4-positive RA was enriched for CD57+, CD7 low, T effector memory cells re-expressing CD45RA (TEMRA) CTLs. Furthermore, PAD4-specific CTLs were detected in anti-PAD4+ patients with RA and expressed elevated levels of CD69, CD57, and KLRG1, and a TEMRA phenotype. These data demonstrate a mechanistic link between autoimmunity to PAD4 and CTL-associated disease in RA.

To further understand the mechanism of action of deucravacitinib, an oral, selective tyrosine kinase 2 inhibitor, in patients with systemic lupus erythematosus (SLE) in the phase 2 PAISLEY SLE trial. RNA sequencing (RNA-seq) was performed on samples collected from baseline to week 32 in 363 patients and 56 healthy volunteers. Pharmacodynamics of differentially expressed genes (DEGs) were analysed with linear mixed-effects models using the statistical software package DREAM (differential expression for repeated measures). Single-sample gene set enrichment analysis (ssGSEA) was performed using MSigDB Hallmark and BloodGen3 gene modules. The xCell R package was used to digitally portray the blood cellular heterogeneity landscape. At baseline, 527 DEGs were identified in patients with SLE vs healthy volunteers (log2 fold change >1; adjusted P < .05). Deucravacitinib modulated up to 2529 genes and SLE-relevant gene sets, including interferon-regulated genes. ssGSEA showed that plasma cell gene sets decreased and myeloid cell gene sets reverted towards normal levels with deucravacitinib; xCell deconvolution revealed significant enrichment of dendritic cell populations with deucravacitinib vs placebo. At baseline, regulatory T-cell gene sets were increased in patients with SLE vs healthy volunteers and further increased with deucravacitinib. There were some variable, dose-dependent increases in naïve and memory B lymphocytes. Whole blood transcriptome profiling via RNA-seq revealed both expected and novel gene expression changes with deucravacitinib across multiple pathogenic pathways. These data demonstrate successful targeting of pathophysiologic immune mechanisms that should be validated in future studies and support continued evaluation of deucravacitinib in the phase 3 POETYK SLE trials.

Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy characterised by type 1 inflammation, driven by muscle-infiltrating KLRG1+ and TBX21+ cytotoxic T cells. However, the cellular sources of the stimuli that trigger this effector response in the muscle of patients with IBM remain unclear. Given their role as antigen-presenting cells, we hypothesised that these may be myeloid dendritic cells (mDCs), which have previously been reported in skeletal muscle of patients with IBM. We used immunohistochemistry, immunofluorescence, single-nucleus RNA-sequencing (snRNA-seq) and bulk RNA-sequencing (RNA-seq) data from skeletal muscle of patients with IBM, other myositis, and controls to identify mDCs and characterise their contribution to IBM inflammation. We first analysed snRNA-seq data from 3 datasets to identify, quantify, and characterise 3 mDC subsets: type 1 conventional dendritic (cDC1) cells, type 2 conventional dendritic (cDC2) cells, and mature immunoregulatory dendritic (mregDC) cells. We then analysed RNA-seq data from 2 datasets to correlate specific markers of these subsets with markers of IBM disease activity. We used immunohistochemistry and immunofluorescence to confirm mDC presence. All 3 mDC subsets, and especially cDC1 cells, are relatively increased in the muscle of patients with IBM and correlate strongly with IBM-specific inflammatory markers, including KLRG1 and TBX21. In particular, cDC1 cells specifically express the KLRG1 ligands, CDH1 and CDH2, and, along with mregDC cells, IL12B, representing possible juxtacrine and paracrine signals for effector T cells in IBM. Skeletal muscle of patients with IBM is specifically characterised by mDC subsets that correlate with markers of cytotoxic T cells and type 1 inflammation.

IκBα controls the canonical activation of NFκB. IκBα gain-of-function due to NFKBIA variants affecting the N-terminus of IκBα-especially residues 32 and 36-manifests with combined immunodeficiency. The role of NFKBIA variants affecting other IκBα domains has not been described. Variants in NFKBIA were identified using whole-exome sequencing. IκBα expression has been quantified by flow cytometry and Western blotting. Activation-induced IκBα degradation, NFκB1 activation, and nuclear translocation as well as inflammasome activity were evaluated. The p.Gln228* variant in NFKBIA, identified in a family with a history of arthritis and psoriasis, did not affect induced degradation of IκBα. Its expression in HEK293T cells confirmed its truncating effect and revealed reduced NFκB activation. Similar to transfected HEK293T cells, peripheral blood mononuclear cells from patients harbouring the p.Gln228* variant displayed substantially reduced nuclear levels of NFκB1 p50. The latter findings suggest that the p.Gln228* variant causes a functional insufficiency of NFκB1. Similar to patients with NFκB1 haploinsufficiency, high serum levels of interleukin (IL)-18, as well as enhanced induced apoptosis-associated speck-like protein containing a caspase recruitment domain speck formation and IL-1β secretion in vitro, suggest enhanced inflammasome activation. NFKBIA variants not localising to the signal reception domain can affect IκBα function and consequently restrict the canonical activation of NFκB. In contrast to the phenotype of N-terminal variants, which is dominated by combined immunodeficiency, the here-reported C-terminal deletion of IκBα was identified in patients with autoinflammatory arthritis and psoriasis.

The objective of the study is to evaluate the safety and immunogenicity of the recombinant zoster vaccine (RZV) in patients with rheumatoid arthritis (RA) using abatacept. We randomised 70 participants to receive 2 doses of RZV or placebo 8 weeks apart. The primary immunologic endpoint was the proportion of participants developing a ≥4-fold increase in anti-glycoprotein E (gE) immunoglobulin (Ig)G antibodies (humoral responders) and those developing a ≥2-fold increase in interferon gamma (IFN-γ)+ or interleukin-2 (IL-2)+ gE-specific spot-forming cells (cellular responders), at week 12 (ie, 4 weeks post-second RZV dose). The secondary immunologic endpoint was the geometric mean fold rise (GMFR) in cellular and humoral vaccine responses. For safety, we solicited adverse events following each dose, serious adverse events (SAEs) during the 52-week study period, and evaluated the potential for RA flares by assessing pre- and postvaccination Disease activity score-28 for rheumatoid arthritis with erythrocyte sedimentation rate, Clinical Disease Activity Index (CDAI), and Outcome Measures in Rheumatology (OMERACT) rheumatoid arthritis flare questionnaire (RA-FQ) scores. Fifty-six (75%) participants received RZV, and 14 (25%) received a placebo. Among those receiving RZV, only 22 (42.3%) of participants surpassed the 4-fold threshold for humoral response, and anti-gE IgG GMFR at week 12 was 4.55 (3.16, 6.47). Only 5 (10.2%) patients with RZV mounted cellular responses. Six SAEs were noted, and the proportion of patients with RA flare was similar between RZV and placebo groups (38 [68%] vs 9 [64%]). Our data suggest that RZV is safe in patients with RA using abatacept, but that the vaccine response is attenuated in such patients. Further studies should be undertaken to evaluate whether holding abatacept around the time of vaccination would improve vaccine response.