Evidence for the Presence of Synovial Sheaths Surrounding the Extensor Tendons at the Metacarpophalangeal Joints

Background. MRI-detected inflammation around the metacarpophalangeal (MCP-)joints is prevalent in RA and poses a markedly increased risk of RA-development when present in arthralgia patients. Such inflammation is called ‘peritendinitis’, since anatomy literature reports no presence of a tenosynovial sheath at these tendons. However, the presence or absence of a synovial sheath at these extensor tendons has never been studied. Methods. A macroscopy and microscopy study of extensor-tendons at the MCP-joints of two embalmed human hands was performed. Routine histology was performed with Haematoxylin-Eosin staining. Results. We found evidence for the presence of synovial lining around extensor-tendons at MCP-joints. A delimited space surrounding the extensor digitorum tendon was observed, which was lined with an epithelium representing fibroblast-like synoviocytes. Conclusion. Contrast-enhancement around extensor tendons at MCP joints observed on MRI in RA represents tenosynovitis and thus inflammation of synovial tissue. Further studies with larger numbers of specimen are warranted to study anatomic variants. In addition, the molecular composition of the tenosynovium remains to be characterized.

OP0036 IL-6 ACTIVATES YES-ASSOCIATED PROTEIN (YAP) IN FIBROBLASTS AND INDUCES YAP-SNAIL COMPLEX FORMATION TO DRIVE SYNOVIAL LINING PATHOLOGY IN INFLAMMATORY ARTHRITIS

Background:In rheumatoid arthritis (RA), the fibroblast-like synoviocytes (FLS) in synovial lining become invasive and cause joint destruction. The molecular mechanisms underpinning this pathogenic FLS phenotype are incompletely understood. The FLS descend from Growth differentiation factor 5 (Gdf5)-expressing joint interzone cells in the embryo, and we showed that conditional ablation of the transcriptional co-activator Yes associated protein (Yap) in Gdf5-lineage cells prevents synovial lining hyperplasia after traumatic cartilage injury in mice [1].Objectives:Here, we investigated a potential role for Yap in pathogenic FLS in immune-mediated inflammatory arthritis.Methods:Immunohistochemistry was used to detect Yap in human RA synovium and Yap, Snail and Ctgf in mouse synovium following antigen-induced arthritis (AIA). To determine the effect of Yap knockout (KO) in synovial stromal cells, AIA was induced in Gdf5-Cre;tdTomato;Yapfl/fl (Yap cKO) and Gdf5-Cre;tdTomato;Yapwt/wt (control) mice, or in Pdgfrα-CreER;Yapfl/fl (Yap ciKO, targeting Pdgfrα-expressing fibroblasts) and Yapfl/fl or YapWT/fl (control) mice after adult tamoxifen induction. Yap KO in both models was confirmed by immunohistochemistry. After nine days, arthritis severity was determined by histological scoring of synovial lining hyperplasia, immune infiltrates, cellular exudate, and marginal erosions. TdTomato+ Gdf5-lineage cells in synovium were quantified. In vitro, Yap reporter cells were treated with inflammatory cytokines to evaluate their ability to stimulate Yap-induced GFP expression by flow cytometry. Snail overexpression, siRNA-mediated Yap knockdown, and IL-6/sIL-6R stimulation were performed on normal mouse FLS, AIA-FLS or human RA-FLS, and cell invasion through a matrigel-coated transwell was quantified. A proximity ligation assay was utilised to detect Yap/Snail complex formation.Results:Average expression levels of Yap (p<0.0001), its transcription factor partner Snail (p=0.002), and their downstream target Ctgf (p=0.0003), were increased in mouse synovium after AIA (n=5), and Yap was highly expressed by FLS in human RA synovium. Yap cKO mice (n=24) showed a significantly decreased arthritis severity (p=0.002) after AIA compared to controls (n=22), with significant reductions in synovial lining hyperplasia (p<0.001), synovial immune cell infiltrates (p=0.026) and marginal erosions (p=0.002). Similarly, Yap ciKO mice (n=6) showed a significant decrease in arthritis score (p=0.039) after AIA compared to controls (n=9). However, both control mice (p<0.001) and Yap cKO mice (p<0.001) showed an extensive expansion of tdTomato+ Gdf5-lineage synovial cells after AIA, with no significant difference between control and Yap cKO mice. In vitro, Yap knockdown prevented IL-6/sIL-6R-induced invasion of normal mouse FLS (p=0.037) and decreased the invasiveness of AIA-FLS (p=0.0057). Using Yap reporter cells, we found that Yap was activated by IL-6/sIL-6R (p=0.016), but not TNFα or IL-1β. Finally, IL-6/sIL-6R treatment of normal mouse FLS (p=0.033) or human RA-FLS (p=0.036) induced Yap-Snail complex formation, and Yap knockdown prevented FLS invasion induced by Snail overexpression (p=0.027).Conclusion:These data demonstrate that via activation by IL-6, and co-operation with the transcription factor Snail, Yap acts as a key modulator of the invasive and destructive phenotype of FLS in inflammatory arthritis. Therapeutic targeting of Yap could reduce joint destruction in RA.References:[1]A. J. Roelofs et al., “Joint morphogenetic cells in the adult mammalian synovium,” Nat. Commun., vol. 8, no. May, p. 15040, 2017. DOI: 10.1136/annrheumdis-2018-213799Acknowledgements:This work was funded by the Medical Research Council (MR/L020211/1 and MR/L022893/1) and Versus Arthritis (20775 and 21156).Disclosure of Interests:None declared

POS0385 DURING DEVELOPMENT OF RHEUMATOID ARTHRITIS, INTERMETATARSAL BURSITIS MAY OCCUR BEFORE CLINICAL JOINT SWELLING: A LARGE MRI STUDY IN PATIENTS WITH CLINICALLY SUSPECT ARTHRALGIA

Background:Inflammation of the synovial lining is a hallmark of rheumatoid arthritis (RA). A synovial lining is not only present at synovial joints and tendon sheaths but also at bursae. Inflammation of the synovium-lined intermetatarsal bursae in the forefoot, intermetatarsal bursitis (IMB), was recently identified with MRI. It is specific for early RA and present in the majority of RA patients at diagnosis. During development of RA, MRI-detectable subclinical synovitis and tenosynovitis often occur before clinical arthritis presents. Whether IMB is also present in a pre-arthritis stage is unknown.Objectives:To assess the occurrence of IMB in patients with clinically suspect arthralgia (CSA) and its association with progression to clinical arthritis in a large MRI-study.Methods:We studied 524 consecutive patients presenting with CSA. CSA was defined as recent-onset arthralgia of small joints that is likely to progress to RA based on the clinical expertise of the rheumatologist. Participants underwent unilateral contrast-enhanced 1.5T MRI of the forefoot, metacarpophalangeal (MCP) joints and wrist at baseline. Thereafter patients were followed for detection of clinical arthritis, as identified at physical joint examination by the rheumatologist. Baseline MRIs were evaluated for IMB at all 4 intermetatarsal spaces. Also synovitis, tenosynovitis and osteitis were assessed in line with the RA MRI scoring system (summed as RAMRIS-inflammation). Both IMB and RAMRIS-inflammation were dichotomised into positive/negative using data from age-matched symptom-free controls as a reference. Cox regression analysed the association of IMB with progression to clinical arthritis; multivariable analyses were used to adjust for RAMRIS-inflammation which is known to associate with progression to clinical arthritis. Analyses were repeated stratified for ACPA-status, since ACPA-positive and ACPA-negative RA are considered separate entities with differences in pathophysiology.Results:The baseline MRIs showed ≥1 IMB in 35% of CSA-patients. Patients with IMB were more likely to also have synovitis (OR 2.5 (95%CI 1.2–4.9)) and tenosynovitis (8.9 (3.4–22.9)) on forefoot MRI, but not osteitis (0.9 (0.5–1.8)). Patients were followed for median 25 months (IQR 19–27). IMB-positive patients developed clinical arthritis more often than IMB-negative patients (HR 3.0 (1.9-4.8)). This association was independent of RAMRIS-inflammation (adjusted HR 2.2 (1.4–3.6)). In stratified analyses, IMB was more frequent in ACPA-positive than in ACPA-negative CSA (68% vs. 30%, p<0.001). Moreover IMB predicted clinical arthritis development in ACPA-positive CSA (HR 2.5 (1.1–5.7)) but not in ACPA-negative CSA patients (1.0 (0.5–2.2)).Conclusion:One-third of CSA patients have IMB. IMB is frequently present in conjunction with subclinical synovitis and tenosynovitis. It precedes the development of clinical arthritis, and in particular the development of ACPA-positive RA. These results reinforce the notion that not only intra- but also juxta-articular synovial inflammation is involved in the development of RA.Disclosure of Interests:None declared

POS0021 INTERMETATARSAL BURSITIS, A NOVEL FEATURE OF JUXTA-ARTICULAR INFLAMMATION IN EARLY RHEUMATOID ARTHRITIS: RESULTS FROM A LONGITUDINAL MRI-STUDY

Background:Rheumatoid arthritis (RA) is characterised by inflammation of the synovial lining. In addition to synovitis, the tendon sheaths of small hand and foot joints are also frequently inflamed. This results in tenosynovitis, which is often missed at clinical evaluation in early RA but visible on imaging, such as MRI. A third anatomical structure surrounded by a synovial lining is formed by the intermetatarsal bursae in the forefeet. Inflammation of these bursae (intermetatarsal bursitis; IMB) was recently identified at MRI-studies and shown to be specific for early RA.[1] This suggests that IMB is also a feature of early RA.Objectives:We hypothesised that if IMB is indeed an RA-feature, then (1) at diagnosis its presence associates with other measures of local inflammation (synovitis, tenosynovitis and osteitis) and (2) it responds to DMARD therapy similarly as these other local inflammatory measures. These hypotheses were tested in a comprehensive MRI-study.Methods:157 consecutive early RA patients underwent unilateral contrast-enhanced 1.5T MRI of the forefoot at diagnosis. MRIs were evaluated for presence of IMB and for synovitis, tenosynovitis and osteitis in line with the RA MRI scoring system (summed as RAMRIS-inflammation). MRIs at 4, 12 and 24 months were evaluated for presence and size of IMB-lesions in patients who had IMB at baseline and received early DMARD-therapy. Logistic regression was used for analyses at patient-level; generalised estimating equations were used for bursa-level analyses. Stratification for ACPA was performed.Results:69% of RA patients had ≥1 IMB. In multivariable analyses on bursa-level, presence of IMB was independently associated with local presence of synovitis and tenosynovitis (OR 1.69 (95%CI 1.12–2.57) and 2.83 (1.80–4.44), respectively), but not with osteitis. On patient-level, presence of IMB was most strongly associated with tenosynovitis (OR 2.92 (1.62–5.24)). During treatment with DMARDs, the average size of IMB-lesions decreased (Figure 1). This decrease was associated with decrease in RAMRIS-inflammation scores; most strongly with a decrease in synovitis but not in osteitis. Within ACPA-positive and ACPA-negative RA similar results were obtained.Conclusion:IMB particularly accompanies inflammation of the synovial lining of joints and tendon-sheaths, both regarding simultaneous occurrence at diagnosis and simultaneous treatment-response. These findings suggest that IMB represents juxta-articular synovial inflammation and indeed is a hallmark of early RA.References:[1]Dakkak YJ et al. Increased frequency of intermetatarsal and submetatarsal bursitis in early rheumatoid arthritis: a large case-controlled MRI study. Arthritis Res Ther 22, 277 (2020).Disclosure of Interests:None declared.

Post-traumatic tenosynovial chondromatosis following a triquetrum fracture: a case report

ABSTRACT Tenosynovial chondromatosis (TC) is a rare progressive benign tumor from the synovial lining of tendon sheath. The TC mostly affects males between the ages 30 to 50 years old at the ventral side of wrist. There are two different forms of TC that have been proposed in previous studies: an idiopathic cause (primary TC) and a joint related diseases cause (secondary TC). Even though trauma has been written to be a common reason for TC, a case of a secondary TC affecting the dorsal wrist following a triquetrum fracture has never been written before. The aim of this report is to present a rare case of a solitary post-traumatic TC at the dorsal wrist following a triquetrum fracture. We describe the clinical presentation, imaging modalities, histopathological and treatment challenges to manage this difficult lesion.

Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis

ObjectivesOsteophytes are highly prevalent in osteoarthritis (OA) and are associated with pain and functional disability. These pathological outgrowths of cartilage and bone typically form at the junction of articular cartilage, periosteum and synovium. The aim of this study was to identify the cells forming osteophytes in OA.MethodsFluorescent genetic cell-labelling and tracing mouse models were induced with tamoxifen to switch on reporter expression, as appropriate, followed by surgery to induce destabilisation of the medial meniscus. Contributions of fluorescently labelled cells to osteophytes after 2 or 8 weeks, and their molecular identity, were analysed by histology, immunofluorescence staining and RNA in situ hybridisation. Pdgfrα-H2BGFP mice and Pdgfrα-CreER mice crossed with multicolour Confetti reporter mice were used for identification and clonal tracing of mesenchymal progenitors. Mice carrying Col2-CreER, Nes-CreER, LepR-Cre, Grem1-CreER, Gdf5-Cre, Sox9-CreER or Prg4-CreER were crossed with tdTomato reporter mice to lineage-trace chondrocytes and stem/progenitor cell subpopulations.ResultsArticular chondrocytes, or skeletal stem cells identified by Nes, LepR or Grem1 expression, did not give rise to osteophytes. Instead, osteophytes derived from Pdgfrα-expressing stem/progenitor cells in periosteum and synovium that are descendants from the Gdf5-expressing embryonic joint interzone. Further, we show that Sox9-expressing progenitors in periosteum supplied hybrid skeletal cells to the early osteophyte, while Prg4-expressing progenitors from synovial lining contributed to cartilage capping the osteophyte, but not to bone.ConclusionOur findings reveal distinct periosteal and synovial skeletal progenitors that cooperate to form osteophytes in OA. These cell populations could be targeted in disease modification for treatment of OA.

Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase–mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.

Current Pharmaceutical Options for the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis is an inflammatory and autoimmune disease that describes the joints persistent inflammation and tendon sheets synovial lining. The primary symptoms of rheumatoid arthritis are stiffness, pain, and swelling of peripheral joints. Persistent inflammation results in many systemic and extra-articular manifestations involving many organ systems. Rheumatoid arthritis treatment goals are symptomatic management of pain, stiffness and restricted mobility. NSAIDs are commonly prescribed for people with rheumatoid arthritis. Analgesic effects of NSAIDs are based mainly on the inhibition of COX-enzyme and consequently the production of prostaglandins.