ObjectiveBased on a unique cohort of clinically suspect arthralgia (CSA) patients, we analysed which combinations of MRI features at onset were predictive for rheumatoid arthritis (RA) development. This was done to increase our comprehension of locations of RA onset and improve the predictive accuracy of MRI in CSA.MethodsIn the discovery cohort, 225 CSA patients were followed on clinical arthritis development. Contrast-enhanced 1.5 T MRIs were made of unilateral metacarpophalangeal (MCP) (2–5), wrist, and metatarsophalangeal (1–5) joints at baseline and scored for synovitis, tenosynovitis, and bone marrow edema. Severity, number, and combinations of locations (joint/tendon/bone) with subclinical inflammation were determined, with symptom-free controls of similar age category as reference. Cox regression was used for predictor selection. Predictive values were determined at 1 year follow-up. Results were validated in 209 CSA patients.ResultsIn both cohorts, 15% developed arthritis < 1 year. The multivariable Cox model selected presence of MCP-extensor peritendinitis (HR 4.38 (2.07–9.25)) and the number of locations with subclinical inflammation (1–2 locations HR 2.54 (1.11–5.82); ≥ 3 locations HR 3.75 (1.49–9.48)) as predictors. Severity and combinations of inflammatory lesions were not selected. Based on these variables, five risk categories were defined: no subclinical inflammation, 1–2 locations, or ≥ 3 locations, with or without MCP-extensor peritendinitis. Positive predictive values (PPVs) ranged 5% (lowest category; NPV 95%) to 67% (highest category). Similar findings were obtained in the validation cohort; PPVs ranged 4% (lowest category; NPV 96%) to 63% (highest category).ConclusionTenosynovitis, particularly MCP-extensor peritendinitis, is among the first tissues affected by RA. Incorporating this feature and number of locations with subclinical inflammation improved prediction making with PPVs up to 63–67%.

Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by heterotopic ossification (HO). The disease is caused by a mutation in the activin receptor type 1 ( ACVR1 ) gene that enhances this receptor's responsiveness to Activin‐A. Binding of Activin‐A to the mutated ACVR1 receptor induces osteogenic differentiation. Whether Activin‐A also affects osteoclast formation in FOP is not known. Therefore we investigated its effect on the osteoclastogenesis‐inducing potential of periodontal ligament fibroblasts (PLF) from teeth of healthy controls and patients with FOP. We used western blot analysis of phosphorylated SMAD3 (pSMAD3) and quantitative polymerase chain reaction to assess the effect of Activin‐A on the PLF. PLF‐induced osteoclast formation and gene expression were studied by coculturing control and FOP PLF with CD14‐positive osteoclast precursor cells from healthy donors. Osteoclast formation was also assessed in control CD14 cultures stimulated by macrophage colony‐stimulating factor (M‐CSF) and receptor activator of nuclear factor kappa‐B ligand (RANK‐L). Although Activin‐A increased activation of the pSMAD3 pathway in both control and FOP PLF, it increased ACVR1, FK binding protein 12 (FKBP12), an inhibitor of DNA binding 1 protein (ID‐1) expression only in FOP PLF. Activin‐A inhibited PLF mediated osteoclast formation albeit only significantly when induced by FOP PLF. In these cocultures, it reduced M‐CSF and dendritic cell‐specific transmembrane protein (DC‐STAMP) expression. Activin‐A also inhibited osteoclast formation in M‐CSF and RANK‐L mediated monocultures of CD14+ cells by inhibiting their proliferation. This study brings new insight on the role of Activin A in osteoclast formation, which may further add to understanding FOP pathophysiology; in addition to the known Activin‐A‐mediated HO, this study shows that Activin‐A may also inhibit osteoclast formation, thereby further promoting HO formation.

Though the stem cell properties of tooth-derived periodontal ligament and gingival cells have been widely documented, surprisingly little is known about both the osteogenic and osteoclastogenic differentiation capacities of the more clinically relevant jaw bone-derived cells. These cells could be considered being recruited during bone healing such as after tooth extraction, after placing an implant, or after surgical or traumatic injury. Here, we compared the osteoblast and osteoclastogenesis features of four consecutive bone outgrowths with periodontal ligament and gingiva cells. For osteogenesis assay, cells were cultured in osteogenic medium, whereas in osteoclastogenesis assays, cells were cultured in the presence of human peripheral blood mononuclear cells (PBMCs) as a source of osteoclast precursors. After osteogenic stimulus, all six cell types responded by an increased expression of osteoblast markers RUNX2 and DMP1. Periodontal ligament cells expressed significantly higher levels of RUNX2 compared to all bone outgrowths. Alkaline phosphatase enzyme levels in periodontal ligament cells reached earlier and higher peak expression. Mineral deposits were highest in periodontal ligament, gingiva and the first bone outgrowth. Osteoclastogenesis revealed a stepwise increase of secreted pro-osteoclastogenesis proteins M-CSF, IL-1β, and TNF-α in the last three consecutive bone cultures. OPG mRNA showed the opposite: high expression in periodontal and gingiva cells and the first outgrowth. Osteoclast numbers were similar between the six cultures, both on bone and on plastic. This first study reveals that jaw bone outgrowths contain bone remodelling features that are slightly different from tooth-associated cells.

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ObjectivesThe human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis.MethodsWe performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA).ResultsMeta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not.ConclusionsHLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.

Objectives Intermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI studies identified IMB as feature of early RA, but whether IMB already occurs in the pre-arthritic phase is unknown. We performed a large MRI study in clinically suspect arthralgia (CSA) to assess the occurrence and prognostic value of IMB. Methods A total of 577 consecutive CSA patients underwent contrast-enhanced MRI of the forefoot, metacarpophalangeal joints and wrist. MRIs were evaluated for subclinical synovitis/tenosynovitis/osteitis in line with the RA MRI scoring system (summed as RAMRIS inflammation) and for IMB. IMB was considered present if uncommon in the general population at the same location (i.e. size scored above the 95th percentile in age-matched symptom-free controls). The relation of IMB with other MRI-detected subclinical inflammation (synovitis/tenosynovitis/osteitis) was studied. Cox-regression assessed the association with clinical arthritis development during median 25 months follow-up. ACPA stratification was performed. Results At presentation with CSA, 23% had IMB. IMB was more frequent in ACPA-positive than ACPA-negative CSA (47% vs 19%, P &lt; 0.001). Patients with IMB were more likely to also have subclinical synovitis [OR 3.4 (95% CI 1.8, 6.5)] and tenosynovitis [5.9(2.8, 12.6)]. IMB conferred higher risk of developing arthritis [HR 1.6(1.0–2.7) adjusted for other subclinical inflammation]. IMB-presence predicted arthritis development in ACPA-positive CSA [adjusted HR 2.2(1.0–4.7)], but not in ACPA-negative CSA-patients [0.8(0.4–1.7)]. Conclusion Approximately a quarter of CSA patients have IMB, which is frequently accompanied by subclinical synovitis and tenosynovitis. IMB precedes development of clinical arthritis, particularly in ACPA-positive CSA. These results reinforce the notion that juxta-articular synovial inflammation is involved in the earliest phases of RA development.

Background:The hypothesis that initiation of DMARD-treatment before arthritis becomes apparent could permanently modulate the disease process, such that persistent RA is prevented, is being studied in several ongoing trials. Essential for such studies is the ability to accurately predict clinically apparent inflammatory arthritis (IA). However there are two hurdles: first, it is insufficiently known whether it is possible to obtain high positive predictive values (PPV) in patients presenting with clinically suspect arthralgia (CSA). Second, none of current predictive models is validated in independent cohorts. We here aimed to evaluate the first question, incorporating improved markers of MRI-detected subclinical inflammation that were recently identified but have not yet been combined with other known predictors.[1]Objectives:To assess the feasibility of achieving high PPVs in prediction of IA-development in patients with CSA by combining clinical, laboratory and imaging parameters.Methods:580 patients with CSA were consecutively included in the Clinically Suspect Arthralgia (CSA)-cohort and followed on the development of IA, determined by physical examination of joints. Unilateral contrast-enhanced 1.5 Tesla MRIs were made of MCP(2-5), wrist and MTP(1-5)-joints at baseline and scored in line with the RAMRIS. The number of locations with subclinical inflammation (0/1-2/≥3) and the presence of MCP peritendinitis were defined as described previously.[1] Other studied clinical and laboratory variables were based on the literature: initial localisation of complaints (small/large joints), functional disability (health assessment questionnaire (HAQ) ≥1), ACPA-positivity (Anti-CCP2), RF-positivity (IgM-RF) and elevated CRP.[2,3] LASSO Cox regression with a 10-fold cross-validated shrinkage parameter was used for predictor selection. Regression coefficients were rounded to the nearest number ending in .5 or .0 and multiplied by two, resulting in a weighted score. Kaplan Meijer curves were used to obtain PPVs of this weighted score and the area under the curve (AUC) was determined at 2-year follow-up.Results:Mean age was 44, 78% was female, and 18% progressed to IA within 2 years. The following parameters were selected with LASSO: RF-positivity, ACPA-positivity, HAQ≥1, >2 locations of subclinical inflammation and presence of MCP-extensor peritendinitis. Based on the beta of LASSO-regression, patients were assigned 2 points for the risk-factors ACPA-positivity and >2 locations of subclinical inflammation, 1 point for RF-positivity and presence of MCP-extensor peritendinitis and 0 points for HAQ≥1. Kaplan Meijer curves show PPVs of 8%, 9%, 30%, 54%, 73%, 79% and 86% at two years (Figure 1). This model yielded an AUC of 0.79.Figure 1.Kaplan Meijer curves on inflammatory arthritis development stratified for number of points based on LASSO regression. Legend: Points were based on the regression coefficients yielded by Cox LASSO-regression. 2 points were assigned for the risk factors ACPA-positivity and >2 locations of subclinical inflammation and 1 point was assigned for RF-positivity and presence of MCP-extensor peritendinitis.Conclusion:High PPVs for IA-development can be achieved in patients with CSA by weighting a combination of known predictors. Although encouraging, these data are based on one observational cohort study and have not been validated in independent cohorts, limiting the relevance. To support future research in the field of arthralgia, it is needed that different research groups work together to come to risk estimations that are validated and accepted.References:[1] Matthijssen XME et al. ART 2019;21(1):249-.[2] van Steenbergen HW et al. ART 2014;16(2):R92.[3] ten Brinck RM et al. RMD Open 2017;3(1):e000419.Disclosure of Interests:None declared

Several nested case-control studies have shown that autoantibody-response maturation in rheumatoid arthritis (RA) precedes clinical arthritis-development. [1][2][3] This suggests a role in disease triggering. However, nested case-control studies have, similar to case control studies, the disadvantage that controls are selected and that prospective data from non-progressing patients in a similar pre-disease stage are absent. The phase preceding clinically apparent inflammatory arthritis (IA) can be distinguished into an asymptomatic and symptomatic (i.e. clinically suspect arthralgia, CSA) sub-phase. It is unknown whether autoantibody-response maturation occurs in the symptomatic phase. Likewise, its role in progression to clinical arthritis is undetermined; if autoantibody-response maturation relates to disease-development, maturation is expected to be more pronounced in CSA-patients that progress compared to CSA-patients that do not. To better understand the relation between autoantibody-response maturation in time and development of clinical arthritis (RA/IA), we performed a longitudinal study on autoantibody-response maturation in CSA-patients that did and did not progress.In serum from 147 CSA-patients, we determined with in-house ELISAs the presence and levels of IgM, IgG, IgA anti-citrullinated, anti-carbamylated and anti-acetylated protein