Winter 2026 Press Review – Annals of Rheumatic Diseases

August 2025 to November 2025

Author: Giovanni Fulvio

Transcriptomic profiling of Sjögren’s disease salivary glands identifies signatures associated with both follicular and extrafollicular responses linked to rheumatoid factor and anti-La/SSB seropositivity

Pontarini et al. (10.1016/j.ard.2025.07.021) investigated salivary gland (SG) transcriptomic signatures to support stratification in Sjögren’s disease (SjD). Unsupervised gene clustering confirmed clear transcriptome segregation between sicca and SjD. Transcriptomes of SjD-SG with ELS showed mainly genes associated with germinal centre formation. Conversely, SG without ELS from patients displayed a unique extrafollicular B-cell gene set associated with type-I interferon (IFN). The identified IFN genes showed strong positive correlations with serum RF levels in 2 independent cohorts (QMUL and TRACTISS).

Matrix stiffness regulates profibrotic fibroblast differentiation and fibrotic niche activation in systemic sclerosis

Ueberall et al. (10.1016/j.ard.2025.05.016) investigated how matrix stiffness alters fibroblast transcriptional state. Fibroblasts subjected to increased matrix stiffness exhibited a distinct transcriptional signature, amplified in SSc patients and enriched in PI16+ progenitor-like cells within the SFRP2+ fibrotic compartment. Further analysis indicated that PI16+ fibroblasts are predisposed to SFRP2+COMP+ PU.1+ myofibroblasts differentiation, whereas blocking mechanotransduction by focal adhesion kinase inhibition disrupts this process, suggesting that matrix stiffness is a key driver of this lineage transition. Spatial mapping revealed colocalisation of the PI16+ and COMP+ subsets in extracellular matrix-dense regions, highlighting the functional relevance of this relationship in fibrotic progression.

Osteoarthritis risk associated with romosozumab compared with teriparatide in individuals with osteoporosis: a target trial emulation study

Hatano et al. (10.1016/j.ard.2025.06.2124) compared osteoarthritis among individuals with osteoporosis initiating romosozumab vs an active comparator. A total of 22,145 individuals were included in the study (87% female; mean age, 80 years) .After IPTW-IPCW adjustment, romosozumab was associated with a lower risk of osteoarthritis compared with teriparatide (ARR, 1.1% [95% CI, 0.5%-1.8%]; RR, 0.79 [0.66, 0.89]). Joint-specific analyses showed the following results: knee osteoarthritis: ARR, 0.8% (95% CI, 0.3%-1.5%), RR, 0.79 (0.66, 0.92); hip osteoarthritis: ARR, 0.2% (95% CI, 0.0%-0.5%), RR, 0.68 (0.37, 1.05); and hand osteoarthritis: ARR, 0.2% (95% CI, 0.0%-0.4%), RR, 0.61 (0.35, 1.06).

Chondrocalcinosis and incident knee osteoarthritis: findings from 2 large prospective cohorts with 20 years of follow-up

Wu, Yahong et al. (10.1016/j.ard.2025.07.009) investigated the role of chondrocalcinosis as a potential risk factor for incident knee osteoarthritis and knee pain in 2 large longitudinal cohorts: the Rotterdam Study (RS) and the Multicenter Osteoarthritis Study (MOST). Chondrocalcinosis was present in 5% of osteoarthritis-free participants at baseline. It was significantly associated with incident knee osteoarthritis in both cohorts (pooled odds ratio [OR]: 1.75, 95% CI: 1.35-2.27, P < .001), with significance maintained in Kellgren and Lawrence grade = 0 participants (pooled OR: 1.77, 95% CI: 1.04-3.01, P = .035). No consistent association with incident knee pain was observed.

Antimitochondrial antibodies in systemic sclerosis target enteric neurons and are associated with GI dysmotility

McMahan et al. (10.1016/j.ard.2025.06.2119) investigated whether M2 is expressed by specific ENS cells, and if AM2A are associated with GI dysmotility in SSc patients. Nineteen of 147 patients (12.9%) were AM2A-positive. AM2A positivity was significantly associated with slower transit in the oesophagus (β -14.4, 95%CI, -26.2, -2.6) and stomach (β -7.9, 95% CI, -14.1, -1.6). Immunostaining demonstrated pan-mitochondrial antigens TOM-20 and M2 enrichment in human ENS neurons, specifically in mesoderm-derived enteric neurons (MENS). Autoantibodies in SSc sera penetrated live adult murine MENs and HepG2 cells. Upon penetrating live cells, AM2A localised to mitochondria, and immunoprecipitation demonstrated binding to the M2 antigen. Seahorse assays show that penetration of HepG2 cells with SSc-AM2A altered cellular respiration suggesting that penetrating AM2A is pathogenic.

Spatial transcriptomic analysis of muscle biopsy from patients with treatment-naive juvenile dermatomyositis reveals mitochondrial abnormalities despite disease-related interferon-driven signature

Syntakas et al. (10.1016/j.ard.2025.07.015) investigated the spatial transcriptomic landscape of muscle tissue from patients with treatment-naive juvenile dermatomyositis (JDM) in comparison to healthy paediatric muscle tissue. JDM muscle tissues exhibited significant interferon pathway activation and mitochondrial dysfunction compared to controls. A 15-gene interferon signature was significantly elevated in JDM muscle and macrophage-enriched regions, correlating with clinical weakness. In contrast, mitochondrial dysregulation, characterised by downregulated respiratory chain pathways, was present regardless of interferon activity or muscle strength. The interferon-driven and mitochondrial signatures were replicated in an independent RNAseq dataset from JDM muscle; the lack of association between interferon signature and mitochondrial dysregulation was validated in 19 cases by conventional staining methods. Clustering analysis revealed distinct transcriptomic profiles between JDM and control tissues, as well as between patients with JDM with varying clinical phenotypes.

Pulmonary arterial hypertension in adults with Still’s disease: another pulmonary manifestation associated with HLA-DRB1*15

Boucly et al. (10.1016/j.ard.2025.04.016) investigated the largest adult cohort of pulmonary arterial hypertension (PAH) occurring in the context of Still’s disease (SD). PAH+ and PAH- groups differed: 100% versus 69.4% female (P = .006), 75% versus 17.1% Black (P < .0001), more active SD both at diagnosis and throughout the disease course, more macrophage activation syndrome (62.5% vs 14.4%, P < .0001) and exhibit eosinophilia during the disease course (68.7% vs 7.2%, P < .0001). The HLA-DRB1*15 allele was more prevalent in PAH+ than PAH- patients (8/11 [72.7%] vs 22/73 [30.1%], P = .014). PAH+ patients more frequently received canakinumab and immunosuppressants than did PAH- patients and had higher frequency of drug reactions to interleukin 1 (IL-1) and/or IL-6 inhibitors (37.5% vs 7.2%, P = .002). Mortality was higher in PAH+ than PAH- patients (37.5% vs 0.9%, P < .0001), and all deaths were related to SD flare.

Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

Wiley et al. (10.1016/j.ard.2025.04.023) performed a genetic meta-analysis and fine-mapping of the common single nucleotide polymorphisms (SNPs) spanning the DDX6-CXCR5 association in Sjögren’s disease (SjD) and systemic lupus erythematosus (SLE). Subsequent deep bioinformatic interrogation identified five shared SNPs as likely functional: rs57494551, rs4936443, rs4938572, rs7117261, and rs4938573. Mapping of chromatin-chromatin interactions revealed a chromatin regulatory network that expanded beyond DDX6 and CXCR5 to include PHLDB1, lnc-PHLDB1-1, BCL9L, TRAPPC4, among others. Shared genetic susceptibly at the DDX6-CXCR5 locus in SjD and SLE likely alters common mechanisms of autoimmunity, including interferon signalling (DDX6), autophagy (TRAPPC4), and lymphocytic infiltration of disease-target tissues (CXCR5).

Anti-TFAM antibodies link mitochondrial damage with antiphospholipid syndrome and thrombosis in SLE

Gómez-Bañuelos et al. (10.1016/j.ard.2025.04.015) characterised the clinical and transcriptional phenotypes linked to anti-TFAM (transcription factor A, mitochondrial) antibodies in SLE. One-third of SLE patients (48/158) were positive for anti-TFAM antibodies. Unlike anti-dsDNA antibodies, anti-TFAM antibodies were not associated with disease activity or the IFN signature. Instead, anti-TFAM antibodies were associated with thrombosis, antiphospholipid syndrome (APS) (odds ratio [OR], 2.9 and 5.4, respectively), thrombosis-associated transcriptional profiles, and elevated IFN-III. Anti-TFAM antibodies were also found in PAPS, supporting their role in APS but not SLE pathogenesis. Lupus anticoagulant increased the risk of thrombosis associated with anti-TFAM antibodies (OR, 8.71), indicating they are markers of independent prothrombotic pathways.

EULAR/ACR risk stratification criteria for development of rheumatoid arthritis in the risk stage of arthralgia

Van Steenbergen et al. (10.1016/j.ard.2025.01.021) developed a risk stratification method for persons presenting with arthralgia considered to be at risk of RA. Using data from 2293 symptomatic at-risk individuals, a stratification method was derived consisting of 6 variables (morning stiffness, patient-reported joint swelling, difficulty making a fist, C-reactive protein, rheumatoid factor, and anti-citrullinated peptide antibody) yielding an area under the curve (AUC) of 0.80 (95% CI, 0.77-0.83) for inflammatory arthritis development. The inclusion of US variables did not increase the discriminative ability. When MRI were included, the AUC was 0.87 (95% CI, 0.82-0.90). In the presence of clinical, serologic, and MRI variables, a sensitivity and specificity of >75% was achieved. For RA development, the AUC of the criteria with MRI was 0.93 (95% CI, 0.90-0.97).