A Modern Scheme for Joint Destruction in Rheumatoid Arthritis1

Background: Melittin, the major medicinal component of honeybee venom, exerts antiinflammatory, analgesic, and anti-arthritic effects in patients with Rheumatoid Arthritis (RA). RA is an inflammatory autoimmune joint disease that leads to irreversible joint destruction and functional loss. Fibroblast-Like Synoviocytes (FLS) are dominant, special mesenchymal cells characterized by the structure of the synovial intima, playing a crucial role in both the initiation and progression of RA. Objective: In this study, we evaluated the effects of melittin on the viability and apoptosis of FLS isolated from patients with RA. Methods: Cell viability was determined using CCK-8 assays; apoptosis was evaluated by flow cytometry, and the expression levels of apoptosis-related proteins (caspase-3, caspase-9, BAX, and Bcl-2) were also determined. To explore whether melittin alters inflammatory processes in RA-FLS, IL-1β levels were determined using an enzyme-linked immunosorbent assay (ELISA). Furthermore, we performed GFP-LC3 punctate fluorescence dot assays and western blotting (for LC3, ATG5, p62, and Beclin 1) to assess autophagy in RA-FLS. Results: Our results show that melittin can significantly impair viability, promote apoptosis and autophagy, and inhibit IL-1β secretion in RA-FLS. Conclusion: Melittin may be useful in preventing damage to the joints during accidental local stimulation.

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SAT0086 Receptor Activator of Nuclear Factor Kappa-B Ligand (Rankl) and Sclerostin are Related to Joint Destruction in Early Rheumatoid Arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-eular.3338 ◽

2015 ◽

Vol 74 (Suppl 2) ◽

pp. 679.3-680

Author(s):

S. Rantapää-Dahlqvist ◽

A. Boman ◽

H. Kokkonen ◽

E. Berglin

Keyword(s):

Rheumatoid Arthritis ◽

Early Rheumatoid Arthritis ◽

Nuclear Factor Kappa B ◽

Joint Destruction ◽

Nuclear Factor ◽

Nuclear Factor Kappa ◽

Receptor Activator

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FRI0127 Suppression of radiographic progression after gradual methotrexate tapering in patients with rheumatoid arthritis patients maintaining low disease activity - Prospective multicenter study-

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1415 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 645.1-645

Author(s):

K. Katayama ◽

K. Yujiro ◽

T. Okubo ◽

R. Fukai ◽

T. Sato ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Joint Destruction ◽

Reduction Rate ◽

Bone Destruction ◽

High Response ◽

Continuation Rate ◽

Low Disease Activity ◽

One Year ◽

Response Group

Background:Many studies have been reported to reduce/discontinue Biologics in the treatment of rheumatoid arthritis (RA). In contrast, study for tapering methotrexate (MTX) has been limited (1,2).Objectives:We prospectively examined whether bone destruction will progress at 48 weeks after tapering or discontinuing MTX (UMIN000028875).Methods:The subjects were RA patients who have maintained low disease activity or lower for 24 weeks or more in DAS28-CRP after MTX administration. Patients having PDUS Grade 2 or 3 per site by bilateral hand ultrasonography (26 area) were excluded in this study owing to risk for joint destruction. The joint destruction was evaluated by the joint X-ray evaluation by modified total Sharp scoring (mTSS) at 1 year after the start of tapering MTX. Evaluation of clinical disease activities, severe adverse events, the continuation rate during MTX tapering were also evaluated. According to tapering response, prognostic factor for good response for tapering, joint destruction was determined. Predictors for successful tapering MTX and progression of bone destruction were determined. Statistical analysis was performed by t-test or Wilcoxon rank sum test using SAS .13.2 software.Results:The subjects were 79 (16 males, 63 females). Age average 60.9 years, disease duration 4 years 4 months, MTX dose 8.43 mg / w, DAS28-CRP 1.52, DMARDs (24.3%), ACPA 192.7 U / ml (70.5%), RF 55.6 IU / ml (65.4%).MTX was tapered from an average of 8.43 mg / w before study to 5.46 mg / w one year later. In the treatment evaluation, DAS28-CRP increased from 1.52 to 1.84. 89.7% of subjects did not progress joint damage. Other disease activities significantly increased (Table 1). The one-year continuation rate was 78.2%. Since tapering effects were varied widely, we divided patients into three groups; Flared group (N=14, initial MTX dose 8.71mg/w, final MTX dose 8.42mg/w), Low response group (N=31, final MTX reduction rate< 50%, initial MTX dose 8.93mg/w, final MTX dose 6.22mg/w), High response group (N=34, final MTX reduction rate≥ 50%, initial MTX dose 8.5mg/w, final MTX dose 3.15mg/w)(Table 2).Higher RF value at baseline and higher MTX dose at 3M, 6M were predictors of whether a subject was in Low response group or High Response group. Higher RF value and mTSS at baseline and higher MTX dose at 6M were predictors whether a subject was in Flared group or High response group. Lower age was predictor of whether a subject was in Flared group or Low responder group. Finally, mean ΔmTSS /y in Flared group (0.36) was not significantly higher than in low response group (0.07) and in high response group (0.01).Table 1Table 2.Predictors for successful tapering MTX and progression of bone destructionConclusion:Patients with MTX-administered low disease activity and finger joint echo PDUS grade 1 satisfy almost no joint destruction even after MTX reduction. For tapering, predictors may be helpful for maintaining patient’s satisfaction.References:[1]Baker KF, Skelton AJ, Lendrem DW et al. Predicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study. J. Autoimmunity. 2019;105: 102298.[2]Lillegraven S, Sundlisater N, Aga A et al. Tapering of Conventional Synthetic Disease Modifying Anti-Rheumatic Drugs in Rheumatoid Arthritis Patients in Sustained Remission: Results from a Randomized Controlled Trial. American College of Rheumatology. 2019; Abstract L08.Disclosure of Interests:None declared

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

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2530 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 19.1-19

Author(s):

R. Symons ◽

F. Colella ◽

F. Collins ◽

A. Roelofs ◽

C. De Bari

Keyword(s):

Transcription Factor ◽

Complex Formation ◽

Inflammatory Arthritis ◽

Normal Mouse ◽

Joint Destruction ◽

Proximity Ligation Assay ◽

Synovial Lining ◽

Arthritis Severity ◽

Marginal Erosions

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

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Metonyms of destruction: Death, ruination, and the bombing of Rotterdam in the Second World War

Journal of Material Culture ◽

10.1177/13591835211016488 ◽

2021 ◽

pp. 135918352110164

Author(s):

Antonius CGM Robben

Keyword(s):

Built Environment ◽

Joint Destruction ◽

Second World War ◽

City Centre ◽

Post Mortem ◽

Port City ◽

World War ◽

The Dead ◽

Second World ◽

Insight Into

The German and Allied bombing of Rotterdam in the Second World War caused thousands of dead and hundreds of missing, and severely damaged the Dutch port city. The joint destruction of people and their built environment made the ruins and rubble stand metonymically for the dead when they could not be mentioned in the censored press. The contiguity of ruins, rubble, corpses and human remains was not only semantic but also material because of the intermingling and even amalgamation of organic and inorganic remains into anthropomineral debris. The hybrid matter was dumped in rivers and canals to create broad avenues and a modern city centre. This article argues that Rotterdam’s semantic and material metonyms of destruction were generated by the contiguity, entanglement, and post-mortem and post-ruination agencies of the dead and the destroyed city centre. This analysis provides insight into the interaction and co-constitution of human and material remains in war.

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