OBJECTIVES:A systematic literature review (SLR) of publications from 2000 to 2022 identified terminology for calcium pyrophosphate crystal deposition (CPPD) and revealed substantial heterogeneity and poor adherence to recommendations. This study aimed to standardise CPPD terminology by developing an international consensus on labels and definitions. METHODS:Members of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) were invited by email to participate in a 3-round Delphi exercise. A steering committee identified key components of CPPD aetiology, pathophysiology, and clinical presentation among elements appearing in >10% of SLR papers, adding or removing items when scientifically justified. Participants selected preferred labels for each element. Respondents to the first round were invited to subsequent rounds. This paper reports the resulting G-CAN CPPD nomenclature. RESULTS:Consensus was reached for 'calcium pyrophosphate (CPP) crystal' and 'calcium pyrophosphate crystal deposition (CPPD)' to describe the deposition process. The unified term 'calcium pyrophosphate crystal deposition on imaging' was adopted across imaging modalities, whereas 'chondrocalcinosis' was redefined as conventional radiographic cartilage calcification consistent with CPPD. Four clinical manifestations were identified: 'acute CPP crystal arthritis' (with 'flare' for acute episodes), 'chronic CPP crystal arthritis', 'crowned dens syndrome', and 'osteoarthritis with CPPD'; the term 'pseudogout' received no support. The condition is now classified as 'asymptomatic CPPD' or 'CPPD disease' for symptomatic presentations. CONCLUSIONS:This G-CAN nomenclature is the first systematic effort to align CPPD terminology with contemporary biological and imaging evidence. By resolving longstanding ambiguities-particularly regarding 'chondrocalcinosis'-it provides a framework for consistent research definitions, clinical trial homogeneity, and improved patient care.

ABSTRACT Background Grip strength is increasingly recognized as a modifiable and easily measurable protective factor against chronic diseases. Lower grip strength may compromise joint stability, predisposing periarticular tissues to local inflammation, which has been implicated in hand osteoarthritis (HOA), a condition affecting approximately 189 million people globally and imposing substantial health and socio‐economic burden. Whether lower grip strength is a risk factor for clinically relevant symptomatic HOA remains unclear. We aimed to examine the association between grip strength and incident symptomatic HOA to inform targeted preventive strategies. Methods We conducted prospective cohort studies and Mendelian randomization analyses using data from the Xiangya Osteoarthritis (XO) Study and UK Biobank. Individuals without baseline symptomatic or hospital‐diagnosed HOA were included. Genetic instruments for grip strength were derived from genome‐wide association studies. Symptomatic HOA in the XO Study was defined as the presence of radiographic HOA with symptoms, whereas hospital‐diagnosed HOA in the UK Biobank was ascertained through hospital inpatient records. Results Among 2869 XO Study participants (5461 hands; 55.9% women; mean age of 63.2 years), 166 (3.0%) hands developed incident symptomatic HOA during a mean follow‐up of 3.7 years. Compared with the lowest grip strength quartile, odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) of symptomatic HOA in the second, third and highest quartiles were 0.51 (95% CI, 0.31–0.84), 0.62 (95% CI, 0.39–0.99) and 0.46 (95% CI, 0.28–0.75), respectively (p for trend = 0.003). Similar associations were observed among 481 582 UK Biobank individuals (54.2% women; mean age of 56.4 years). Mendelian randomization analyses showed ORs of genetically determined grip strength of 0.56 (95% CI, 0.40–0.78, p < 0.001) for incident symptomatic HOA in the XO Study and 0.37 (95% CI, 0.25–0.56, p < 0.001) for incident hospital‐diagnosed HOA in the UK Biobank. Conclusions Higher grip strength was associated with a lower risk of incident symptomatic HOA. These findings offer empirical evidence that interventions aimed at enhancing grip strength may help prevent symptomatic HOA and reduce its individual and societal burden.

OBJECTIVE:Although gut microbiome dysbiosis is associated with symptomatic hand osteoarthritis (SHOA), the role of bile acids (BAs), key metabolites in host-microbiota interactions, in SHOA pathogenesis remains unexplored. We investigated the association between plasma BA metabolism and SHOA. METHODS:The associations between plasma BAs and SHOA were examined in the Xiangya Osteoarthritis (XO) Study and validated in an independent cohort through logistic regression models. Gut microbiome data from a previous study conducted within the XO Study were integrated to explore associations between SHOA-related gut microbes and key BAs. As an exploratory analysis, gene-based meta-analyses evaluated associations between genes encoding key BA receptors and hand OA. RESULTS:In the discovery cohort (n = 1,359, mean age ± SD 63.1 ± 9.0 years, 58.4% women, SHOA prevalence 5.2%, all participants being Asian), elevated levels of deoxycholic acid (DCA) species (odds ratio [OR] 1.75, 95% confidence interval [CI] 1.03-2.96) and DCA (OR 2.14, 95% CI 1.24-3.70) were positively associated with SHOA presence and severity. These associations were replicated in an independent cohort (n = 142). Multiomics analyses revealed significant correlations of DCA species, DCA, and the DCA species-to-total BAs ratio with SHOA-related gut microbes. DCA interacted with SHOA-related gut microbes and was associated with SHOA. Gene-based meta-analyses identified significant associations between genes encoding the Farnesoid X receptor and the pregnane X receptor and hand OA. CONCLUSION:Dysregulated BA metabolism, particularly elevated DCA levels, is associated with SHOA. The observation that DCA interacts with SHOA-related gut microbes, together with genes encoding DCA receptors, may help guide future biologically and clinically relevant studies.

Objectives The oral microbiome plays a critical role in modulating systemic inflammation, partly through its interactions with the gut microbiome. Although gut microbiome dysbiosis has been implicated in symptomatic hand osteoarthritis (SHOA), the role of oral microbiome dysbiosis in SHOA and its relationship with gut microbiome dysbiosis remain unclear. Elucidating these associations could provide novel insights into SHOA pathogenesis.Methods Participants were recruited from the Xiangya Osteoarthritis (XO) Study, an ongoing community-based observational study. Saliva samples were analysed using 16S ribosomal RNA gene sequencing. Oral microbial richness, composition and relative abundance of specific taxa were compared between SHOA participants and controls without SHOA. Correlations within the oral-gut microbiome network were also assessed and compared between groups.Results Compared with controls (n=712), participants with SHOA (n=52) exhibited significantly lower oral microbial richness (p=0.007) and altered composition (p=0.007). The relative abundance of the genus Trichococcus was significantly higher in SHOA participants (β=0.437 (95% CI 0.174 to 0.699), p=0.001, Q=0.073) and positively associated with SHOA severity. Furthermore, the number of significant correlations within the oral-gut microbiome network was markedly reduced in SHOA participants compared with controls. Notably, Trichococcus abundance in the oral microbiome correlated positively with the gut microbial KEGG pathway of tyrosine metabolism (r=0.137, p=0.001, Q=0.047), both linked to SHOA.Conclusion Oral microbiome dysbiosis and disruption of the oral-gut microbiome network are associated with prevalent SHOA. These findings suggest a potential role of the oral-gut microbiome axis in SHOA pathogenesis. Larger studies are needed to confirm these associations.Trial registration number NCT04033757.

OBJECTIVE:The objective of this study was to examine whether foot/ankle injury and injection contribute to the risk of foot/ankle OA in retired UK male professional footballers. METHODS:This was a case-control study among retired UK male footballers, in which cases reported General Practitioner-diagnosed foot/ankle OA or forefoot/ankle surgery after retirement, and controls reported neither. Injury was defined as significant foot/ankle injury with pain for most days over 3 months during their career. Injection was defined as injection of corticosteroids or other agents into foot/ankle joints during their career. Adjusted odds ratios (aORs) with 95% confidence interval (CIs) were calculated using logistic regression. Areas Under the Curve (AUCs) and 95% CIs were estimated to examine the contribution of injury and/or injection in the context of other available risk factors. RESULTS:Of 424 footballers studied, 63 had foot/ankle OA and 361 had neither. Cases had similar mean age (63.2 vs 63.0, P = 0.457) and BMI (27.7 vs 27.0, P = 0.240) to those of controls, but more foot/ankle injury (73.3% vs 42.5%, P < 0.001) and injections (75.0% vs 48.4%, P < 0.001), with aORs of 4.23 (95% CI 1.88-9.48) and 2.62 (95% CI 1.19-5.78), respectively. The AUC was 0.69 (95% CI 0.62-0.77) for injury, 0.74 (95% CI 0.66-0.81) for injury and injection, and 0.78 (95% CI 0.70-0.85) for all risk factors. Similar results were observed in footballers with ankle OA only. CONCLUSION:Injury was a major risk factor for foot/ankle OA in retired UK male professional footballers. The role of injection needs cautious interpretation due to potential confounding by indication.

OBJECTIVE:Hand synovitis affects over 20% middle-aged and older adults. Although the roles of synovitis in hand pain and osteoarthritis are well established, its relationship with serious outcomes such as mortality remains uncertain. We investigated the association between hand synovitis and all-cause mortality. METHODS:In the population-based Xiangya Osteoarthritis Study (XO Study), participants underwent bilateral hand ultrasonography at baseline to assess synovitis (grades 0-3; ≥2 defined as positive). Mortality data were obtained from local registries. Cox proportional hazards models were employed to examine the association between hand synovitis and all-cause mortality, adjusting for age, age squared, sex, body mass index, educational level, alcohol consumption, smoking status, hand injury, physical activity level, radiographic hand osteoarthritis status, hypertension, hyperlipidemia, and the age-adjusted Charlson Comorbidity Index. RESULTS:Among 3,552 participants (mean ± SD age 64.4 ± 9.3 years, 57.9% women), 393 deaths occurred over a mean follow-up of 5.72 years. Ultrasound-detected hand synovitis was significantly associated with higher all-cause mortality (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.01-1.58). Compared with no synovitis, bilateral involvement conferred a higher mortality than unilateral involvement (aHR 1.42 [95% CI 1.03-1.96] versus 1.20 [95% CI 0.93-1.54]). Mortality risk also increased with the number of affected joints (aHRs: 1.19 [95% CI 0.91-1.57] for one joint; 1.35 [95% CI 1.02-1.80] for more than one joint; P for trend < 0.05). In the exploratory analyses, the strongest association was observed for distal interphalangeal joint synovitis (aHR 1.82 [95% CI 1.14-2.91]). CONCLUSION:Hand synovitis, especially when bilateral or polyarticular, may serve as a marker of increased all-cause mortality risk, though future studies are needed to confirm and investigate this further. Ultrasound assessment offers a noninvasive and accessible approach to identify this potential biomarker for mortality risk.

OBJECTIVE:To evaluate associations between constitutional morphological features and specific radiographic phenotypes of hip osteoarthritis (OA). METHOD:A cross-sectional study of 566 symptomatic unilateral hip OA cases referred for joint replacement was conducted using the Genetics of Osteoarthritis and Lifestyle (GOAL) database. Unaffected hips of cases were assumed to reflect pre-OA innate constitutional morphology of the contralateral affected hip. Radiographic OA phenotypes in affected hips were classified by the site of minimum joint space width (JSW). Tertiles were used to examine dose response. Odds ratios (ORs) with 95% confidence intervals (CI) adjusted for confounding factors were calculated using logistic regression. RESULTS:Among the 14 morphological features studied, the odds of superolateral, superior intermediate, and superior indeterminate hip OA decreased as the tertiles for acetabular depth (AD) and centre-edge angle (CEA) increased. In contrast, higher mid-centre distance (MCD) showed a positive dose response with all superior hip OA patterns, especially the superolateral and superior intermediate patterns (OR 5.17 [95% CI 2.18-12.23] and OR 5.05 [95% CI 1.98-12.90], respectively). Sourcil angle (SA) associated with superolateral (OR 3.27 [95% CI 1.47-7.26]), and superior intermediate patterns (OR 2.39 [95% CI 1.01-5.68]). Neck shaft angle (NSA) associated with superolateral patterns (OR 2.14 [95% CI 1.01-4.71]. Femoral head to femoral neck ratio (FHNR) associated with the superomedial pattern (OR 4.22 [95% CI 1.49-11.89]). CONCLUSIONS:Person-specific pre-OA morphological features associate with different phenotypes of hip OA based on the site of minimum JSW. Further prospective studies are required to confirm these findings.

BACKGROUND:The burden of cardiovascular events remains substantial with current care, highlighting the clinical importance of identifying high-risk populations. Sarcopenia, which affects 10%-27% of older adults worldwide, is modifiable but under-recognized in cardiovascular prevention because of unclear risk associations. We aimed to clarify the association between sarcopenia and cardiovascular events risk. METHODS:PubMed, Embase, and Web of Science were searched for longitudinal studies that reported on associations between sarcopenia or its related traits with cardiovascular events risk until January 2024. The primary outcome was a composite of cardiovascular events, encompassing cardiovascular diseases (such as coronary heart disease, heart failure, and stroke) and cardiovascular mortality. Data pooled using random-effects models are presented as risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS:One hundred longitudinal studies (approximately 2.3 million participants) were included. Sarcopenia was associated with higher risk of cardiovascular events (unadjusted RR [uRR] = 1.92; 95% CI, 1.59-2.32; adjusted RR [aRR] = 1.63; 95% CI, 1.30-2.04) and cardiovascular diseases (uRR = 1.69; 95% CI, 1.39-2.04; aRR = 1.28; 95% CI, 1.12-1.46), whereas the association with cardiovascular mortality was significant only in unadjusted analyses (uRR = 2.28; 95% CI, 1.56-3.33; aRR = 1.61; 95% CI, 0.98-2.64). Similar associations with cardiovascular events were observed for low muscle mass (uRR = 1.61; 95% CI, 1.32-1.97; aRR = 1.43; 95% CI, 1.23-1.68) and low grip strength (uRR = 2.04; 95% CI, 1.72-2.44; aRR = 1.46; 95% CI, 1.37-1.56). CONCLUSIONS:Sarcopenia, defined using heterogeneous criteria, was associated with an increased risk of cardiovascular events later in life. These findings suggest that sarcopenia and related traits might serve as markers of elevated subsequent cardiovascular risk. PROSPERO REGISTRATION:CRD42023400266.

OBJECTIVES:To examine whether retired male professional footballers have a higher risk of foot/ankle osteoarthritis (OA) and pain than general population male controls. METHODS:In this cross-sectional study, questionnaires for self-reported foot/ankle OA outcomes were posted to 878 footballers and 1060 controls, and subsequently a sample of responders per group underwent assessment for radiographic OA (ROA) irrespective of symptoms. ROA was defined using the La Trobe atlas when definite osteophyte (score ≥ 2) or definite joint space narrowing (score ≥ 2) was observed at any assessed foot/ankle joint. Symptomatic ROA (sROA) was defined as presence of ROA and pain in the same region of the foot for most days of the past month. Adjusted relative risks (aRRs) with 95% CI were calculated using robust Poisson regression. RESULTS:Questionnaires were completed by 468 footballers (53%) and 619 controls (58%), of whom 113 footballers and 319 controls underwent radiographic assessment. Compared with controls, footballers were more likely to: (i) report general practitioner-diagnosed foot/ankle OA (aRR 1.77; 95% CI: 1.22, 2.57), forefoot/ankle surgery (aRR 2.80; 95% CI: 2.04, 3.84), and current foot/ankle pain (aRR 1.33; 95% CI: 1.09, 1.62); and (ii) have foot/ankle ROA (aRR 1.04; 95% CI: 1.01, 1.07) and sROA (aRR 1.63; 95% CI: 1.21, 2.19). CONCLUSION:Retired male professional footballers were more likely to have self-reported and radiographic foot/ankle OA than general population male controls. The ankle appeared the joint most affected by OA in footballers compared with controls. Further study is needed in female footballers and to determine specific risk factors related to this increased risk.

Objectives: (1) To compare cytokine levels in participants with serum urate (SU) < 360 µmol/L, SU ≥ 360 µmol/L with and without monosodium urate (MSU) crystal deposition, respectively, and inter-critical gout. (2) To explore the association of IL-1β, IL-6 and high-sensitivity (hs) CRP with disease duration and the frequency of self-reported gout flares. Methods: Samples and data from 184 participants from studies conducted at Academic Rheumatology, Nottingham City Hospital, were included. Serum high-sensitivity CRP and cytokines involved in the pathogenesis of gouty inflammation were measured. MANCOVA and multivariate linear regression were used, as appropriate, and were adjusted for age, sex, body mass index and self-reported comorbidities. p values were adjusted for multiple testing using a 5% false-discovery rate. Results: Participants with inter-critical gout had greater levels of IL-1β (pcorr = 0.009), IL-18 (pcorr = 0.02), IL-6 (pcorr < 0.0001), IP-10 (pcorr < 0.0001), TNF-α (pcorr < 0.0001), GRO-α (pcorr = 0.0006) and hsCRP (pcorr = 0.009) compared to other groups in multivariate analyses and after correcting for multiple testing. There were no differences in cytokine and hsCRP levels in participants with SU < 360 µmol/L and in participants with SU ≥ 360 µmol/L with or without MSU crystal deposition. There was a statistically non-significant trend for association between IL-6 levels and number of self-reported gout flares. Conclusions: Our findings suggest that gout is a chronic inflammatory condition. The pre-clinical phases of gout were not associated with systemic inflammation, potentially due to the modest sample size. Further research is required to understand whether treating gout by targeting the complete dissolution of MSU crystals would reduce systemic inflammation in inter-critical gout.

OBJECTIVES:Erosive hand osteoarthritis (EHOA) is an aggressive subtype of hand osteoarthritis (HOA) with unclear pathogenesis. Since gut dysbiosis and related metabolite alterations may exacerbate inflammation and accelerate bone destruction, we investigated whether these abnormalities were involved in EHOA. METHODS:Participants were drawn from the Xiangya Osteoarthritis Study. We compared gut microbial α-diversity and β-diversity between EHOA and controls (neither EHOA nor non-erosive HOA), and analyzed associations between microbial species abundance, functions, and EHOA. Targeted blood metabolomics were performed to identify microbiome-associated metabolites in EHOA. The associations between EHOA-related microbial species and blood metabolites were examined through multi-omics analyses. RESULTS:Among 1324 participants, significant differences in α-diversity (EHOA: median=4.53, non-HOA control: median=4.16; median difference=0.37 [95%CI: 0.09-0.57], P=0.016) and β-diversity (R²=0.002 [95%CI: 0.0018-0.006], P=0.015) were observed at the species level between EHOA and controls. Participants with EHOA had a higher relative abundance of Alistipes senegalensis (β coefficient: 0.17 [95%CI: 0.07-0.26]) and Fournierella massiliensis (β coefficient:0.39 [95%CI: 0.28-0.49]). Tryptophan metabolism was the main altered metabolic pathway. Targeted blood metabolomics showed higher levels of L-5-hydroxytryptophan (β coefficient:0.38 [95%CI: 0.15-0.61]), 3-indoleglyoxylic acid (β coefficient:0.35 [95%CI: 0.01-0.69]), 5-hydroxyindoleacetic acid (β coefficient: 0.27 [95%CI: 0.09-0.45]), indoleacrylic acid (IA) (β coefficient: 0.23 [95%CI: 0.001-0.46]), and serotonin (β coefficient: 0.20 [95%CI: 0.004-0.40]), alongside lower levels of L-tryptophan (β coefficient:-0.41 [95%CI: -0.75 to -0.06]) and indole-3-acetyl-aspartate (β coefficient:-1.05 [95%CI: -1.79 to -0.32]) in EHOA. IA was positively correlated with EHOA-related microbial species, particularly Alistipes senegalensis (β coefficient: 0.20 [95%CI: 0.14-0.27]). CONCLUSIONS:A higher relative abundance of Alistipes senegalensis and alterations in tryptophan metabolites, particularly higher levels of IA, are associated with EHOA.

Objectives Walking offers numerous health benefits, yet its association with symptomatic knee osteoarthritis (SKOA) remains uncertain. The conflation of purposeful walking and unintentional walking could contribute to this uncertainty. Therefore, we aimed to examine the association between daily purposeful walking steps, daily unintentional walking steps, and total daily steps with incident SKOA. Methods We conducted a population-based cohort study using data from the UK Biobank. Of the participants who had valid accelerometer data at baseline but no history of SKOA (identified through primary care or hospitalisation records), 89,969 were included. Hazard ratios (HRs) for categories of daily purposeful walking steps (cadence ≥60 steps/min), daily unintentional walking steps (cadence <60 steps/min), and total daily steps were estimated using a Cox proportional hazard model. The dose-response relationship was assessed using restricted cubic spline regression. Results During a mean follow-up of 6.85 (SD, 1.14) years, 2711 participants developed SKOA. For daily purposeful walking steps, HRs (95% CIs) of incident SKOA were 0.84 (0.76-0.92), 0.81 (0.71-0.90), and 0.74 (0.64-0.85) for those walking 4000 to 5999, 6000 to 7999, and ≥8000 steps/d, respectively, compared with those walking <4000 steps/d. Restricted cubic spline regression analysis revealed a declining curve with a potential threshold near 8000 steps/d. Conversely, more daily unintentional walking steps were significantly associated with higher incident SKOA. No significant association was observed for total daily steps. Conclusions More daily purposeful walking steps were associated with lower incident SKOA, suggesting that purposeful walking may promote musculoskeletal health and help inform future guidelines for knee osteoarthritis prevention.

OBJECTIVE:Intramuscular fat infiltration (IMFI) in the thigh is linked to metabolic inflammation and muscle dysfunction, which could contribute to osteoarthritis development. However, no longitudinal studies have examined the associations between thigh IMFI and incident knee and hip osteoarthritis. METHODS:We conducted a cohort study using UK Biobank data, including participants with baseline IMFI in thigh muscle assessed by magnetic resonance imaging and no history of knee or hip osteoarthritis. A total of 24,224 and 24,221 participants were included in analyses of IMFI of anterior and posterior thigh muscle with knee osteoarthritis, respectively, whereas 24,767 and 24,764 were included in analyses of IMFI of anterior and posterior thigh muscle for hip osteoarthritis, respectively. Cox Proportional-hazard models were used to estimate hazard ratios (HRs) for incident clinically diagnosed knee or hip osteoarthritis, adjusting for potential confounders. RESULTS:During a mean follow-up of 4.9 years, 472 participants developed knee osteoarthritis, and 387 developed hip osteoarthritis. IMFI in the anterior thigh was significantly associated with incident knee osteoarthritis, with adjusted HRs of 1.78 (95% confidence interval [CI] 1.19-2.65), 2.00 (95% CI 1.34-2.99), and 2.34 (95% CI 1.53-3.59) across the second to fourth quartiles, respectively (P for trend <0.01). Both anterior and posterior thigh IMFI were significantly associated with hip osteoarthritis (P for both trends <0.01). Dose-response relationships were observed in restricted spline models. The interaction and subgroup analyses support that the effect of IMFI is independent of body mass index and sex. CONCLUSION:Elevated thigh IMFI is significantly associated with increased incidence of both knee and hip osteoarthritis. Interventions targeting IMFI reduction may help prevent osteoarthritis and mitigate its impact.