Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis

ObjectivesTo integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis.MethodsIn this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed.ResultsWe identified four SF clusters with respective marker genes: PRG4+ SF (CD55, MMP3, PRG4, THY1neg); CXCL12+ SF (CXCL12, CCL2, ADAMTS1, THY1low); POSTN+ SF (POSTN, collagen genes, THY1); CXCL14+ SF (CXCL14, C3, CD34, ASPN, THY1) that correspond to lining (PRG4+ SF) and sublining (CXCL12+ SF, POSTN+ + and CXCL14+ SF) SF subsets. CXCL12+ SF and POSTN+ + were most prominent in the fibroid while PRG4+ SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. PRG4+ SF correlated positively with disease severity parameters in the fibroid, POSTN+ SF in the lymphoid pathotype whereas CXCL14+ SF showed negative association with disease severity in all pathotypes.ConclusionThis study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments.

The Neuropeptide VIP Limits Human Osteoclastogenesis:Clinical Associations with Bone Metabolism Markers in Patients with Early Arthritis

We aimed to evaluate the direct action of VIP on crucial molecules involved in human osteoclast differentiation and function. We also investigated the relationship between VIP serum levels and bone remodeling mediators in early arthritis patients. The expression of VIP receptors and osteoclast gene markers in monocytes and in vitro differentiated osteoclasts was studied by real-time PCR. NFATc1 activity was measured using a TransAM® kit. Osteoclastogenesis was confirmed by quantification of tartrate-resistant acid phosphatase positive multinucleated cells. OsteoAssay® Surface Multiple Well Plate was used to evaluate bone-resorbing activity. The ring-shaped actin cytoskeleton and the VPAC1 and VPAC2 expression were analyzed by immunofluorescence. We described the presence of VIP receptors in monocytes and mature osteoclasts. Osteoclasts that formed in the presence of VIP showed a decreased expression of osteoclast differentiation gene markers and proteolytic enzymes involved in bone resorption. VIP reduced the resorption activity and decreased both β3 integrin expression and actin ring formation. Elevated serum VIP levels in early arthritis patients were associated with lower BMD loss and higher serum OPG concentration. These results demonstrate that VIP exerts an anti-osteoclastogenic action impairing both differentiation and resorption activity mainly through the negative regulation of NFATc1, evidencing its bone-protective effects in humans.

Early arthritis as a rheumatological chameleon: a description of a clinical case

The article discusses the difficulties of differential diagnosis of early arthritis and inflammatory bowel diseases with a predominant clinical picture of extraintestinal manifestations, in particular, articular syndrome. The clinical observation demonstrates features of the course of such conditions, a long diagnostic search and a wide list of diseases included in differential diagnostics range.

Very low prevalence of ultrasound-detected tenosynovial abnormalities in healthy subjects throughout the age range: OMERACT ultrasound minimal disease study

ObjectivesThis study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range.MethodsAdult HS (age 18–80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1–5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort.Results939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups.ConclusionsUltrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA.

“From Where I Stand”: Using Multiple Anchors Yields Different Benchmarks for Meaningful Improvement and Worsening in the Rheumatoid Arthritis Flare Questionnaire (RA-FQ)

Purpose The Rheumatoid Arthritis Flare Questionnaire (RA-FQ) is a patient-reported measure of disease activity in RA. We estimated minimal and meaningful change from the perspective of RA patients, physicians, and using a disease activity index. Methods Data were from 3- and 6-month visits of adults with early RA enrolled in the Canadian Early Arthritis Cohort. Participants completed the RA-FQ, the Patient Global Assessment of RA, and Patient Global Change Impression at consecutive visits. Rheumatologists recorded joint counts and MD Global. Clinical Disease Activity Index (CDAI) scores were computed. We compared mean RA-FQ change across categories using patients, physicians, and CDAI anchors. Results The 808 adults were mostly white (84%) women (71%) with a mean age of 55 and moderate-high disease activity (85%) at enrollment. At V2, 79% of patients classified their RA as changed; 59% were better and 20% were worse. Patients reporting they were a lot worse had a mean RA-FQ increase of 8.9 points whereas those who were a lot better had a -6.0 decrease. Minimal worsening and improvement were associated with a mean 4.7 and -1.8 change in RA-FQ, respectively, while patients rating their RA unchanged had stable scores. Physician and CDAI classified more patients as worse than patients, and minimal and meaningful RA-FQ thresholds differed by group. Conclusion Thresholds to identify meaningful change vary by anchor used. These data offer new evidence demonstrating robust psychometric properties of the RA-FQ and offer guidance about improvement or worsening, supporting its use in RA care, research and decision-making.

A Prospective Study of Management of Fracture Dislocation of Hip (PIPKIN) by Safe Surgical Dislocation (2 Years 6 Months Follow-Up in a Tertiary Hospital at Visakhapatnam)

BACKGROUND High velocity motor vehicle injuries are associated with hip fracture dislocations especially dash board injuries. Most commonly posterior hip dislocations are associated with occasional femoral head fractures. Computerized tomographic imaging is done to look at the congruency of the hip joint. Safe surgical dislocation or Ganz approach was described in 2001 for exposing the hip in a 360-degree view without damaging the vascularity of the femoral head. In this study, we wanted to evaluate the radiological and functional outcome using modified Merle d' Aubigne-Postel and Harris hip scoring. METHODS The current study is a prospective study in a tertiary referral centre where 8 young adult males were followed up for a period of 2 years 6 months from August 2018 to February 2021 after safe surgical dislocation and reduction with headless Herbert screws to maintain congruent hip surface. RESULTS We had 1 patient with associated chest injury requiring intercostal tube placement, while none of them had developed avascular necrosis or early arthritis. We had used modified Merle d'Aubigne-Postel and Harris hip scoring to assess the functional outcome. We had six patients with excellent results and two patients with good outcome due to occasional pain. We followed all the patients for more than 2 years. We evaluated the radiological and functional outcomes. The results are comparable to other researcher’s studies. CONCLUSIONS Safe surgical dislocation is a very good choice for fixation of femoral head fractures where the complications like early arthritis of femoral head and acetabulum are less along with preserving the vascularity of the femoral head and preventing the chances of avascular necrosis of femoral head. It also provides a good intraoperative view for handling the fracture reduction. KEYWORDS Pipkin Fracture, Ganz Approach, Safe Surgical Dislocation Hip, Herbert Screw

Smoking and Methotrexate Inefficacy in Rheumatoid Arthritis: What About Underlying Molecular Mechanisms?

The study by Safy-Khan, et al in the current issue of The Journal of Rheumatology1 reports that in a methotrexate (MTX)-based treatment regimen for patients with early arthritis, current smoking was significantly associated with a smaller reduction of Disease Activity Score in 28 joints (DAS28) over time compared to noncurrent smoking. This negative effect of current smoking on DAS28 was dose-dependent: patients who smoked 10–19 cigarettes per day did worse than patients who smoked 1–9 cigarettes per day.