The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

A functional genomics approach reveals suggestive quantitative trait loci associated with combined TLR4 and BCP crystal-induced inflammation and osteoarthritis.

OBJECTIVE: Basic calcium phosphate (BCP) crystals can activate the NLRP3 inflammasome and are potentially involved in the pathogenesis of osteoarthritis (OA). In order to elucidate relevant inflammatory mechanisms in OA, we used a functional genomics approach to assess genetic variation influencing BCP crystal-induced cytokine production. METHOD: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers who were previously genotyped and stimulated with BCP crystals and/or lipopolysaccharide (LPS) after which cytokines release was assessed. Cytokine quantitative trait locus (cQTL) mapping was performed. For in vitro validation of the cQTL located in anoctamin 3 (ANO3), PBMCs were incubated with Tamoxifen and Benzbromarone prior to stimulation. Additionally, we performed co-localisation analysis of our top cQTLs with the most recent OA meta-analysis of genome-wide association studies (GWAS). RESULTS: We observed that BCP crystals and LPS synergistically induce IL-1ß in human PBMCs. cQTL analysis revealed several suggestive loci influencing cytokine release upon stimulation, among which are quantitative trait locus annotated to ANO3 and GLIS3. As functional validation, anoctamin inhibitors reduced IL-1ß release in PBMCs after stimulation. Co-localisation analysis showed that the GLIS3 locus was shared between LPS/BCP crystal-induced IL-1ß and genetic association with Knee OA. CONCLUSIONS: We identified and functionally validated a new locus, ANO3, associated with LPS/BCP crystal-induced inflammation in PBMCs. Moreover, the cQTL in the GLIS3 locus co-localises with the previously found locus associated with Knee OA, suggesting that this Knee OA locus might be explained through an inflammatory mechanism. These results form a basis for further exploration of inflammatory mechanisms in OA.

Basic calcium phosphate crystals induce the expression of extracellular matrix remodelling enzymes in tenocytes.

OBJECTIVES: Basic calcium phosphate (BCP) crystals contribute to several syndromes associated with tendon disease, including acute calcific tendinitis and Milwaukee shoulder syndrome. Interactions between BCP crystals and tenocytes (tendon cells) may contribute to these clinical syndromes. This study aimed to determine the direct effects of BCP crystals on tenocyte function and viability. METHODS: In vitro assays were used to assess changes in human tenocytes cultured with BCP crystals. Real-time PCR was used to determine changes in the expression of tendon-related genes and extracellular matrix remodelling enzymes (MMPs; a disintegrin and metalloproteases, ADAMTS; and tissue inhibitor of metalloproteinases, TIMPs). ELISA was used to measure protein concentrations in tenocyte supernatants. MTT and alamarBlue™ assays were used to determine changes in cell viability. RESULTS: BCP crystals upregulated tenocyte gene expression of MMP-1, MMP-3, ADAMTS-4 and TIMP-1 after 24 h. Time-course experiments showed expression peaked at 8 h for TIMP-1 and 48 h for MMP-1 and ADAMTS-4. Cyclooxygenase (COX)-1 gene expression was upregulated after 48 h. Tenocytes did not alter expression of scleraxis and tendon collagens, and expression of pro-inflammatory cytokines was not induced with BCP crystals. BCP crystals increased tenocyte release of prostaglandin E2 (PGE2) and MMP-1 protein after 24 h. However, neither COX-1 inhibition nor COX-2 inhibition led to consistent change in BCP crystal-induced tenocyte gene expression of extracellular matrix remodelling enzymes. BCP crystals had no effect on tenocyte viability. CONCLUSION: BCP crystals induce extracellular matrix remodelling enzymes, but not inflammatory cytokines, in tenocytes.

Temporal trends in COVID-19 outcomes in people with rheumatic diseases in Ireland: data from the COVID-19 Global Rheumatology Alliance registry.

OBJECTIVES: Although evidence is accumulating globally, data on outcomes in rheumatic disease and COVID-19 in Ireland are limited. We used data from the COVID-19 Global Rheumatology Alliance (C19-GRA) to describe time-varying COVID-19 outcomes for people with rheumatic disease in Ireland. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24 March 2020 and 9 July 2021 were analysed. Differences in the likelihood of hospitalization and mortality according to demographic and clinical variables were investigated using Chi-squared test or Fisher's exact test, as appropriate. Trends in odds of hospitalization and mortality over time were investigated using logistic regression with the time period as a categorical variable. RESULTS: Of 212 cases included, 59.4% were female and median age was 58.0 years (range 13-96). Of the 212 cases, 92 (43%) were hospitalized and 22 (10.4%) died. Increasing age, a diagnosis of gout, ever smoking, glucocorticoid use, having comorbidities and specific comorbidities of cancer, cardiovascular and pulmonary disease were more common in those hospitalized. A diagnosis of inflammatory arthritis, csDMARD and/or b/tsDMARD use were less frequent in those hospitalized. Increasing age, a diagnosis of gout, ever smoking, having comorbidities and specific comorbidities of obesity, cardiovascular and pulmonary disease were more common in those who died. Odds of hospitalization or mortality did not change over time. CONCLUSION: No temporal trend was observed in either COVID-19-related hospitalization or mortality outcomes for people with rheumatic disease in Ireland.

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

Plasma levels of the soluble form of the FcγRIIa receptor vary with receptor polymorphisms and are elevated in rheumatoid arthritis.

Soluble forms of the low-affinity immunoglobulin receptor FcγRIIa (sFcγRIIa) lacking the cytoplasmic tail have been reported in plasma however the mechanism and functional consequences are unknown. This study aimed to evaluate mechanisms of FcγRIIa release compared to GPVI release from platelets, and examine whether genetic polymorphisms at positions 27 and 131 within FcγRIIa correlate with platelet FcγRIIa stability and function. Enzyme-linked immunosorbent assays (ELISAs) were used to measure plasma sFcγRIIa and sGPVI levels. FcγRIIa genotype at positions 27 and 131 was evaluated. sFcγRIIa levels were not significantly different between non-131HH and 131HH but were significantly lower in 27W than non-27W. Treatment of platelets with aggregated immunoglobulin (Ig) G induced release of FcγRIIa and GPVI, but only sGPVI release was statistically significant, required functional FcγRIIa, and was blocked by inhibitors of signaling pathways and metalloproteinases. This indicated that sFcγRIIa was not released from platelets by metalloproteolysis. sFcγRIIa levels were not correlated with sGPVI levels in healthy individuals however levels of sFcγRIIa and sGPVI in plasma from patients with rheumatoid arthritis (RA) were significantly elevated above levels found in healthy individuals. Elevated level of sFcγRIIa in RA patients may reflect active immune-based arthritis and be predictive of active inflammation.

Basic Calcium Phosphate Crystals Induce Osteoarthritis-Associated Changes in Phenotype Markers in Primary Human Chondrocytes by a Calcium/Calmodulin Kinase 2-Dependent Mechanism.

Chondrocytes in osteoarthritis undergo a phenotype shift leading to increased production of cartilage-degrading enzymes. There are similarities between the phenotype of osteoarthritic chondrocytes and those of growth plate chondrocytes. Hydroxyapatite can promote chondrocyte differentiation in the growth plate. Basic calcium phosphate (BCP) crystals (which consist of hydroxyapatite, octacalcium apatite and tricalcium phosphate) are frequently found in osteoarthritic joints. The objective of this study was to determine whether BCP crystals induce disease-associated changes in phenotypic marker expression in chondrocytes. Primary human chondrocytes isolated from macroscopically normal cartilage were treated with BCP for up to 48 h. Expression of indian hedgehog (IHH), matrix metalloproteinase 13 (MMP13), interleukin-6 (IL-6) and type X collagen (COLX) were higher, and expression of sry-box 9 (SOX9) lower, in BCP-treated chondrocytes (50 µg/mL) compared to untreated controls. COLX protein was also present in BCP-treated chondrocytes. Intracellular calcium and levels of phosphorylated and total calcium/calmodulin kinase 2 (CaMK2) were elevated following BCP treatment due to BCP-induced release of calcium from intracellular stores. CaMK2 inhibition or knockdown ameliorated the BCP-induced changes in SOX9, IHH, COLX, IL-6 and MMP13 expression. BCP crystals induce osteoarthritis-associated changes in phenotypic marker expression in chondrocytes by calcium-mediated activation of CaMK2. The presence of BCP crystals in osteoarthritic joints may contribute to disease progression.

Performance characteristics and predictors of temporal artery ultrasound for the diagnosis of giant cell arteritis in routine clinical practice in a prospective cohort.

OBJECTIVES: The diagnosis of giant cell arteritis (GCA) is primarily a clinical one. Temporal artery (TA) ultrasound (US) has been proposed as a new diagnostic tool. We aimed to assess the performance characteristics of TA US in routine clinical practice. METHODS: All patients presenting with suspected GCA to our institution are recruited to a prospective registry. Patients who had both a TA US and biopsy (TAB) performed at the time of presentation were included in the current study. The performance characteristics of TA US was compared to physician diagnosis at six months following presentation. Predictive factors for a positive TA US were explored in univariate and multivariable logistic regression analyses. RESULTS: 162 patients were included, 123 (76%) with GCA. Mean (SD) duration of glucocorticoid therapy was 6.6 days (19.4) at the time of TA US. TA US had a sensitivity of 52.8% (95%CI 43.7, 61.9) and specificity of 71.8% (95%CI 54.9, 84.5) for the diagnosis of GCA. Glucocorticoid duration did not significantly impact the results. A sequential strategy of TA US followed by TAB in the case of a negative US had a sensitivity of 78.9% (95%CI 70.1, 85.5) and specificity of 71.8% (95%CI 54.9, 84.5), equivalent to a simultaneous testing strategy. The only factor independently predictive of a positive TA US was male sex (OR 5.53, 95% CI 2.72 to 11.22, p<0.001). CONCLUSIONS: TA US is potentially useful in the diagnosis of GCA; however, interpretation of its results requires knowledge of the performance characteristics in the target population.

Interleukin 12 and interleukin 23 play key pathogenic roles in inflammatory and proliferative pathways in giant cell arteritis.

OBJECTIVES: The pathogenesis of giant cell arteritis (GCA) remains unclear. TH1 and TH17 pathways are implicated, but the proximal initiators and effector cytokines are unknown. Our aim was to assess the role of interleukin 12 (IL-12) and interleukin 23 (IL-23) in GCA pathogenesis. METHODS: IL-12 and IL-23 expression were quantified by immunohistochemistry in temporal artery biopsies (TABs). Temporal artery (TA) explant, peripheral blood mononuclear cell (PBMC) and myofibroblast outgrowth culture models were established. PBMCs and TA explants were cultured for 24 hours in the presence or absence of IL-12 (50 ng/mL) or IL-23 (10 ng/mL). Gene expression in TA was quantified by real-time PCR and cytokine secretion by ELISA. Myofibroblast outgrowths were quantified following 28-day culture. RESULTS: Immunohistochemistry demonstrated increased expression of interleukin 12p35 (IL-12p35) and interleukin 23p19 (IL-23p19) in biopsy-positive TAs, localised to inflammatory cells. IL-12p35 TA expression was significantly increased in those with cranial ischaemic complications (p=0.026) and large vessel vasculitis (p=0.006). IL-23p19 TA expression was increased in those with two or more relapses (p=0.007). In PBMC cultures, exogenous IL-12 significantly increased interleukin 6 (IL-6) (p=0.009), interleukin 22 (IL-22) (p=0.003) and interferon γ (IFN-γ) (p=0.0001) and decreased interleukin 8 (IL-8) (p=0.0006) secretion, while exogenous IL-23 significantly increased IL-6 (p=0.029), IL-22 (p=0.001), interleukin 17A (IL-17A) (p=0.0003) and interleukin 17F (IL-17F) (p=0.012) secretion. In ex vivo TA explants, IL-23 significantly increased gene expression of IL-8 (p=0.0001) and CCL-20 (p=0.027) and protein expression of IL-6 (p=0.002) and IL-8 (p=0.004). IL-12 (p=0.0005) and IL-23 (p<0.0001) stimulation increased the quantity of myofibroblast outgrowths from TABs. CONCLUSION: IL-12 and IL-23 play central and distinct roles in stimulating inflammatory and proliferative pathways relevant to GCA pathogenesis.

Calcium-Containing Crystals and Osteoarthritis: an Unhealthy Alliance.

PURPOSE OF REVIEW: Osteoarthritis (OA) is the most common form of joint disease globally and is associated with significant morbidity and disability. Increasing evidence points to an important inflammatory component in the development and progression of OA. The precise pathways involved in OA inflammatory processes remain to be clarified. Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPP) crystals can induce inflammation and arthritis and recent studies point to a potential pathogenic role in OA. In the light of this evidence, we explore the relationship and potential mechanistic pathways linking calcium-containing crystals and OA. RECENT FINDINGS: CPP crystals induce inflammation through the NLRP3 inflammasome while BCP crystals mediate both NLRP3 dependent and independent effects. BCP crystals have been demonstrated to induce key mitogenic and inflammatory pathways and contribute to cartilage degradation. Calcium-containing crystals induce key inflammatory pathways and may represent an attractive novel target in OA, a condition devoid of effective treatments.

Increased platelet reactivity as measured by plasma glycoprotein VI in gout.

Patients with gout have an increased risk of cardiovascular events. The glycoprotein VI (GPVI) receptor is found exclusively on platelets and megakaryocytes, is proteolytically cleaved upon platelet activation, and detectable in plasma as soluble GPVI (sGPVI). Therefore, elevated sGPVI is a marker of platelet activation and a risk marker for cardiovascular events. The aim of this study was to assess platelet activation, as measured by plasma sGPVI level in gout. Blood samples were taken from patients with gout or osteoarthritis, and from healthy volunteers. Demographic and clinical data were collected for all participants. Blood samples were processed as double-spun platelet-poor plasma. Plasma sGPVI levels were measured using enzyme-linked immunosorbent assay. Mann-Whitney U test was used to compare groups. In total, 91 patients were included, 27 during gout flare, 41 with intercritical gout, 23 with osteoarthritis, and 53 healthy controls. Median (interquartile range) sGPVI levels were 6.51 ng/mL (4.52, 8.41) in gout flare, 3.58 ng/mL (2.11, 5.55) in intercritical gout, 2.73 ng/mL (2.17, 3.72) in osteoarthritis, and 2.19 ng/mL (1.72, 3.31) in healthy controls. Plasma sGPVI levels in both gout groups were significantly increased compared to healthy controls (p < 0.005 for each), in gout flare compared to osteoarthritis (p < 0.005), and in gout flare compared to intercritical gout (p = 0.001). There was no significant difference in sGPVI levels in gout patients with and without tophi or in those prescribed colchicine. We conclude that patients with gout exhibit platelet hyperactivity as demonstrated by elevated sGPVI levels. Platelet activation is exacerbated in gout, especially during gout flares.

Features associated with different inflammatory phenotypes of calcium pyrophosphate deposition (CPPD) disease: study using data from the international ACR/EULAR CPPD classification criteria cohort.

OBJECTIVE: To examine the disease, demographic, and imaging features associated with different inflammatory phenotypes of calcium pyrophosphate deposition (CPPD) disease i.e., recurrent acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and crowned dens syndrome (CDS). METHODS: Data from an international cohort assembled from 25 sites in 7 countries for the development and validation of the 2023 ACR/EULAR CPPD classification criteria, that met the criteria were included. Three cross-sectional studies were conducted to determine the phenotypic characteristics of recurrent acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and CDS. Multivariable logistic regression analysis was used to calculate the adjusted odds ratios (aOR) and 95% confidence intervals (CIs) to examine the association between potential risk factors and the inflammatory phenotype. RESULTS: Among the 618 people included ((56% female), mean age (standard deviation (S.D.)) 74.0 (11.9) years), 602 (97.4%) had experienced acute CPP crystal arthritis, 332 (53.7%) had recurrent acute arthritis, 158 (25.6%) had persistent inflammatory arthritis, and 45 (7.3%), had had CDS. Recurrent acute CPP crystal arthritis associated with longer disease duration (aOR 2.88 (95%CI 2.00;4.14)). Chronic CPP crystal inflammatory arthritis was associated with ). acute wrist arthritis (aOR(95%CI) 2.92(1.81-4.73)), metacarpophalangeal (aOR(95% CI) 1.87(1.17-2.97)) and scapho-trapezio-trapezoid (STT) joint osteoarthritis (aOR(95% CI) 1.83(1.15-2.91)), and negatively associated with either metabolic or familial risk for CPPD (aOR(95% CI) 0.60(0.37-0.96). CDS was associated with male sex (aOR(95% CI) 2.35(1.21-4.59)), STT joint osteoarthritis (aOR(95% CI) 2.71(1.22-6.05)), and more joints affected with chondrocalcinosis (aOR(95% CI) 1.46(1.15-1.85)). CONCLUSIONS: CPPD disease encompasses acute and chronic inflammatory phenotypes, each with specific clinical and imaging features which need to be considered in the diagnostic workup.

Plasma fibrinogen is an accurate marker of disease activity in patients with polymyalgia rheumatica.

OBJECTIVE: The overall aim of this study was to establish whether plasma fibrinogen was a superior biomarker of disease activity in active PMR than the standard biomarkers, ESR and CRP. METHODS: Sixty patients with PMR were divided into active (n = 25) or inactive (n = 35) disease groups based on symptoms, physician assessment and biomarkers ESR and CRP. Plasma fibrinogen was assayed. Groups underwent assessment at baseline and 6 weeks. Disease activity as per the PMR activity score (PMR-AS) was recorded at all visits. Receiver operator curves (ROCs), predictive values and likelihood ratios were calculated for all biomarkers. RESULTS: Disease activity measures improved significantly in the active group between weeks 1 and 6 (P < 0.001). There was no significant difference between the activity scores at week 6 in the active group and the inactive group. Mean fibrinogen decreased from 5.2 to 3.5 g/l (normal <4 g/l) between weeks 1 and 6 in the active group. Mean ESR and CRP decreased from 59.6 to 24.3 mm/h (normal <30 mm/h) and 45.9 to 12.66 mg/l (normal <5 mg/l), respectively. Receiver operator curve analysis revealed fibrinogen to be more specific than either ESR or CRP for the detection of response to treatment in active PMR, with an overall sensitivity and specificity of 92% and 96%, respectively. Values above the upper limit of normal for fibrinogen, CRP and ESR were associated with likelihood ratios for active disease of 20.53, 2.9 and 2.8, respectively (P < 0.001). CONCLUSION: Plasma fibrinogen is at least as useful as CRP and ESR for the diagnosis of active PMR and more specific for confirmation of response to treatment than either ESR or CRP.

Exercise and manual physiotherapy arthritis research trial (EMPART) for osteoarthritis of the hip: a multicenter randomized controlled trial.

OBJECTIVES: To determine the effectiveness of exercise therapy (ET) compared with ET with adjunctive manual therapy (MT) for people with hip osteoarthritis (OA); and to identify if immediate commencement of treatment (ET or ET+MT) was more beneficial than a 9-week waiting period for either intervention. DESIGN: Assessor-blind randomized controlled trial with a 9-week and 18-week follow-up. SETTING: Four academic teaching hospitals in Dublin, Ireland. PARTICIPANTS: Patients (N=131) with hip OA recruited from general practitioners, rheumatologists, orthopedic surgeons, and other hospital consultants were randomized to 1 of 3 groups: ET (n=45), ET+MT (n=43), and waitlist controls (n=43). INTERVENTIONS: Participants in both the ET and ET+MT groups received up to 8 treatments over 8 weeks. Control group participants were rerandomized into either ET or ET+MT groups after 9 week follow-up. Their data were pooled with original treatment group data: ET (n=66) and ET+MT (n=65). MAIN OUTCOME MEASURES: The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function (PF) subscale. Secondary outcomes included physical performance, pain severity, hip range of motion (ROM), anxiety/depression, quality of life, medication usage, patient-perceived change, and patient satisfaction. RESULTS: There was no significant difference in WOMAC PF between the ET (n=66) and ET+MT (n=65) groups at 9 weeks (mean difference, .09; 95% confidence interval [CI] -2.93 to 3.11) or 18 weeks (mean difference, .42; 95% CI, -4.41 to 5.25), or between other outcomes, except patient satisfaction with outcomes, which was higher in the ET+MT group (P=.02). Improvements in WOMAC, hip ROM, and patient-perceived change occurred in both treatment groups compared with the control group. CONCLUSIONS: Self-reported function, hip ROM, and patient-perceived improvement occurred after an 8-week program of ET for patients with OA of the hip. MT as an adjunct to exercise provided no further benefit, except for higher patient satisfaction with outcome.

An EDucation and eXercise intervention for gluteal tendinopathy in an Irish setting: a protocol for a feasibility randomised clinical trial (LEAP-Ireland RCT).

Background: Gluteal tendinopathy (GT) is a degenerative tendon condition characterised by pain over the greater trochanter of the hip. A randomised controlled trial (RCT) in Australia found that 14 sessions of EDucation on load management plus eXercise (EDX) delivered over 8 weeks resulted in greater improvements in global rating of change and pain outcomes at 8 and 52 weeks, compared with corticosteroid injection or 'wait and see'. Typically, 5-6 physiotherapy sessions are provided in public and private physiotherapy settings in Ireland, therefore, the aim of this study is to examine the feasibility of conducting a future definitive RCT to investigate effectiveness of 6 sessions of the EDX programme compared to usual care. Methods: We will randomly allocate 64 participants with GT to physiotherapist-administered EDX or usual care. The EDX intervention (EDX-Ireland) will be delivered in 6 sessions over 8 weeks.To determine feasibility of an RCT, we will assess recruitment and retention and outcome measure completion. The health status outcomes to be assessed at baseline, 8 weeks and 3 months include: Global Rating of Change, pain severity, the Victorian Institute of Sport Assessment-Gluteal Questionnaire (VISA-G), the Patient-Specific Functional Scale, the Pain Catastrophizing Scale, Patient Health Questionnaire (PHQ), Pain Self-Efficacy Questionnaire, the EQ-5D-5L, the Central Sensitisation Inventory and hip abductor muscle strength. We will explore acceptability of the EDX-Ireland intervention from the perspective of patients and treatment providers, and the perspective of referrers to the trial. A Study Within A Trial will be also applied to compare recording of exercise adherence using app-based technology to paper diaries. Discussion: There is a need to establish effective treatments for GT that potentially can be implemented into existing health systems. The findings of this feasibility trial will inform development of a future definitive RCT. Registration: The trial is registered prospectively on ClinicalTrials.gov ( NCT05516563, 27/10/2022).

Outcomes of COVID-19 in people with rheumatic and musculoskeletal disease in Ireland over the first 2 years of the pandemic.

BACKGROUND: Poor COVID-19 outcomes occur with higher frequency in people with rheumatic and musculoskeletal diseases (RMD). Better understanding of the factors involved is crucial to informing patients and clinicians regarding risk mitigation. AIM: To describe COVID-19 outcomes for people with RMD in Ireland over the first 2 years of the pandemic. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24th March 2020 and 31st March 2022 were analysed. Differences in the likelihood of hospitalisation and mortality according to demographic and clinical variables were investigated. RESULTS: Of 237 cases included, 59.9% were female, 95 (41.3%) were hospitalised, and 22 (9.3%) died. Hospitalisation was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular and pulmonary disease, and cancer. Hospitalisation was less frequent in people with inflammatory arthritis and conventional synthetic or biologic disease-modifying antirheumatic drug use. Hospitalisation had a U-shaped relationship with disease activity, being more common in both high disease activity and remission. Mortality was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular disease, pulmonary disease, and obesity. Inflammatory arthritis was less frequent in those who died. CONCLUSION: Hospitalisation or death were more frequently experienced by RMD patients with increasing age, certain comorbidities including potentially modifiable ones, and certain medications and diagnoses amongst other factors. These are important 'indicators' that can help risk-stratify and inform the management of RMD patients.

Colchicine twice a day for hand osteoarthritis (COLOR): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Colchicine has been suggested for osteoarthritis treatment, but evidence is contradictory. We aimed to investigate colchicine's efficacy and safety compared with placebo in people with hand osteoarthritis. METHODS: In this single-centre, double-blind, randomised, placebo-controlled trial we recruited adults with symptomatic hand osteoarthritis and finger pain of at least 40 mm on a 100 mm visual analogue scale from an outpatient clinic in Denmark. The hand with the most severe finger pain at inclusion was the target hand. Participants were randomly assigned (1:1) to 0·5 mg colchicine or placebo taken orally twice a day for 12 weeks, stratified by BMI (≥30 kg/m2), sex, and age (≥75 years). Participants, outcome assessors, and data analysts were masked to treatment allocation. The primary endpoint was change from baseline to week 12 in target hand finger pain, assessed on a 100 mm visual analogue scale with a pre-specified minimal clinically important difference of 15 mm, in the intention-to-treat population. Safety was assessed at week 12 in the intention-to-treat population. The study was registered with ClinicalTrials.gov, NCT04601883, and with EudraCT, 2020-002803-20. FINDINGS: Between Jan 15, 2021, and March 3, 2022, 186 people were screened for eligibility, and 100 were randomly assigned to receive colchicine (n=50) or placebo (n=50). Participants had a mean age of 70·9 (SD 7·5) years, 69 (69%) of 100 were women and 31 (31%) were men. All participants completed the study. The mean change from baseline to week 12 in finger pain were -13·9 mm (SE 2·8) in the colchicine group and -13·5 mm (2·8) in the placebo group, with a between-group difference (colchicine vs placebo) of -0·4 mm (95% CI -7·6 to 6·7; p=0·90). In the colchicine group, there were 76 adverse events in 36 (72%) of 50 participants and one serious adverse advent (migraine attack leading to hospital admission). In the placebo group, there were 42 adverse events in 22 (44%) of 50 participants and two serious adverse events (cholecystitis and elevated alanine aminotransferase concentrations, in the same patient). INTERPRETATION: In people with painful hand osteoarthritis, treatment with 0·5 mg of colchicine twice day for 12 weeks did not effectively relieve pain, and treatment with colchicine was associated with more adverse events. FUNDING: The Oak Foundation, IMK Almene Fond, Minister Erna Hamilton's Scholarship for Science and Art, AP Moller and Wife Chastine McKinney Moller's Foundation for Medical Science Advancement, The Danish Medical Association, the Velux Foundation, Aase and Ejnar Danielsen's Foundation, and Director Emil C Hertz and Wife Inger Hertz's foundation.

Association of Gout Polygenic Risk Score With Age at Disease Onset and Tophaceous Disease in European and Polynesian Men With Gout.

OBJECTIVE: To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. METHODS: A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. RESULTS: The PRS was associated with earlier age at gout onset in men (ß = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; ß = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; ß = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (ß = 0.07 [95% CI -2.32, 2.45] in European women; ß = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; ß -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (ß = -2.42 [95% CI -3.37, -1.46] and ß = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (ß = -1.79 [95% CI -4.74, 1.16]). CONCLUSION: Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.