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INTRODUCTION: The central biochemical cause of gout is hyperuricemia (elevated serum urate levels). Ultrasound features of monosodium urate (MSU) crystal deposition are common in people with asymptomatic hyperuricemia. However, it is unclear whether this is a precondition for the development of gout. This study aims to determine whether ultrasound imaging evidence of MSU crystal deposition predicts development of symptomatic gout over 5 years, in people who already have an increased risk of gout due to elevated serum urate concentrations (≥8 mg/dL). METHODS AND ANALYSIS: This is a prospective, international, multicentre study. The study population comprises over 250 participants with asymptomatic hyperuricemia (serum urate ≥8.0 mg/dL). After the baseline assessments, participants are followed for 5 years or until the development of gout, defined by the 2015 American College of Rheumatology/European Alliance of Associations for Rheumatology gout classification criteria. Baseline assessments include anthropomorphic measures, laboratory tests, questionnaires, blood and urine specimen collection, plain radiographs of the feet and standardised ultrasound scans of the lower limbs, scored according to the Outcomes in Rheumatology (OMERACT) gout ultrasound scoring system. The primary outcomes are the development of gout and time course for development of gout in people with and without ultrasound evidence of MSU crystal deposition. Exploratory analyses will examine clinical, genetic and biological factors associated with development of MSU crystal deposition and gout. ETHICS AND DISSEMINATION: This study protocol was approved by the New Zealand Ministry of Health Southern Health and Disability Ethics Committee (MEC/05/10/130/AM16) on 18 December 2018. The findings from this study will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12619000915156.

OBJECTIVE: To determine i) pain phenotypes (PP) in people with early-stage knee osteoarthritis (EKOA); ii) the longitudinal association between the phenotypes and pain worsening at two years. DESIGN: We studied participants with EKOA from the Multicenter Osteoarthritis Study defined as pain intensity ≤3/10, Kellgren and Lawrence grade ≤2, intermittent pain none to sometimes, and no constant pain. Two models of PP were explored. Model A included pressure pain thresholds, temporal summation, conditioned pain modulation, pain catastrophizing, sleep quality, depression, and widespread pain (WSP). In Model B, gait characteristics, quadriceps strength, comorbidities, and magnetic resonance imaging features were added to Model A. Latent Class Analysis was used to create phenotypes, and logistic regression was used to determine their association with pain worsening. RESULTS: 750 individuals (60% females), mean age [standard deviation (SD)]: 60.3 (9.4) were included in Model A and 333 individuals (60% females), mean age (SD): 59.4 (8.1) in Model B. 3-class and 4-class solutions were chosen for Model A and Model B. In Model A, the most severe phenotype was dominated by psychosocial factors, WSP, and measures of nervous system sensitization. Similarly in Model B, the Model A phenotype plus gait variables, quadriceps strength, and comorbidities were dominant. Surprisingly, none of the phenotypes in either model had a significant relationship with pain worsening. CONCLUSION: Phenotypes based upon various factors thought to be important for the pain experience were identified in those with EKOA but were not significantly related to pain worsening. These phenotypes require validation with clinically relevant endpoints.

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.

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.

OBJECTIVE: We aimed to explore the cross-sectional relation of unilateral knee pain severity and temporal asymmetry during walking and to determine relations of temporal asymmetry during walking to 2-year changes in ipsilateral and contralateral knee pain in those with mild-to-moderate unilateral knee pain. METHODS: The Multicenter Osteoarthritis Study is a prospective cohort study of adults with or at risk for knee osteoarthritis. The current study included participants with unilateral knee pain. Gait was assessed during self-selected and fast walking at baseline. Knee pain was assessed at baseline and 2 years. We calculated limb symmetry indices (LSIs; nonpainful limb/painful limb × 100) for stance, single-limb support time, and double-limb support time, then examined their relations to unilateral knee pain severity, incident contralateral knee pain, and persistent ipsilateral knee pain. RESULTS: Unilateral knee pain severity was not associated with temporal asymmetry during self-selected or fast walking. At 2 years, 17.1% of participants had incident contralateral knee pain and 51.4% had persistent ipsilateral knee pain. For self-selected walking, greater LSIs (i.e., longer time on the nonpainful limb) for stance and single-limb support time were associated with decreased odds of incident contralateral knee pain. Measures of temporal asymmetry were not associated with persistent ipsilateral knee pain, except for single-limb support time during fast walking. CONCLUSION: For those with unilateral knee pain, temporal asymmetry during walking is not associated with pain severity. However, select measures of stance and single-limb support time during self-selected and fast walking relate to longitudinal knee pain outcomes.

ObjectivePain persistence following knee replacement (KR) occurs in ∼20-30% of patients. Although several studies have identified preoperative risk factors for persistent post-KR pain, few have focused on post-KR contributing factors. We sought to determine whether altered nociceptive signaling and other peripheral nociceptive drivers present post-operatively contribute to post-KR pain.DesignWe included participants from the Multicenter Osteoarthritis Study who were evaluated ∼12 months after KR. We evaluated the relation of measures of pain sensitivity [pressure pain threshold (PPT), temporal summation (TS), and conditioned pain modulation (CPM)] and the number of painful body sites to post-KR WOMAC knee pain, and of the number of painful sites to altered nociceptive signaling using linear or logistic regression models, as appropriate.Results171 participants (mean age 69 years, 62% female) were included. TS was associated with worse WOMAC pain post-KR (β ​= ​0.77 95% CI:0.19-1.35) and reduced odds of achieving patient acceptable symptom state (aOR ​= ​0.54 95%CI:0.34-0.88). Inefficient CPM was also associated with worse WOMAC pain post-KR (β ​= ​1.43 95% CI:0.15-2.71). In contrast, PPT was not associated with these outcomes. The number of painful body sites present post-KR was associated with TS (β ​= ​0.05, 95% CI:0.01, 0.05).ConclusionsPost-KR presence of central sensitization and inefficient descending pain modulation was associated with post-KR pain. We also noted that presence of other painful body sites contributes to altered nociceptive signaling, and this may thus also contribute to the experience of knee pain post-KR. Our findings provide novel insights into central pain mechanisms and other peripheral pain sources contributing to post-KR persistent knee pain.

OBJECTIVE: Classification criteria for calcium pyrophosphate deposition (CPPD) disease will facilitate clinical research on this common crystalline arthritis. Our objective was to report on the first 2 phases of a 4-phase process for developing CPPD classification criteria. METHODS: CPPD classification criteria development is overseen by a 12-member steering committee. Item generation (phase I) included a scoping literature review of 5 literature databases and contributions from a 35-member combined expert committee and 2 patient research partners. Item reduction and refinement (phase II) involved a combined expert committee meeting, discussions among clinical, imaging, and laboratory advisory groups, and an item-rating exercise to assess the influence of individual items toward classification. The steering committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development. RESULTS: Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The advisory groups eliminated items that they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item-rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the steering committee recommended focusing on imaging of the knee and wrist and 1 additional affected joint for calcification suggestive of CPP crystal deposition. CONCLUSION: A data- and expert-driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.

ObjectiveTo summarize proceedings of a workshop convened to discuss the current state of science in the disease of osteoarthritis (OA), identify the knowledge gaps, and examine the developmental and regulatory challenges in bringing these products to market.DesignSummary of the one-day workshop held virtually on June 22nd, 2021.ResultsSpeakers selected by the Planning Committee presented data on the current approach to assessment of OA therapies, biomarkers in OA drug development, and the assessment of disease progression and long-term benefit.ConclusionsDemonstrated by numerous failed clinical trials, OA is a challenging disease for which to develop therapeutics. The challenge is magnified by the slow time of onset of disease and the need for clinical trials of long duration and/or large sample size to demonstrate the effect of an intervention. The OA science community, including academia, pharmaceutical companies, regulatory agencies, and patient communities, must continue to develop and test better clinical endpoints that meaningfully reflect disease modification related to long-term patient benefit.

ObjectiveThe lack of strong association between knee osteoarthritis (OA) structural features and pain continues to perplex researchers and clinicians. Evaluating the patellofemoral joint in addition to the tibiofemoral joint alone has contributed to explaining this structure-pain discordance, hence justifying a more comprehensive evaluation of whole-knee OA and pain. The present study, therefore, was undertaken to evaluate the association between patellofemoral and tibiofemoral OA features with localized anterior knee pain (AKP) using 2 study designs.MethodsUsing cross-sectional data from the Multicenter Osteoarthritis Study, our first approach was a within-person, knee-matched design in which we identified participants with unilateral AKP. We then assessed magnetic resonance imaging (MRI)-derived OA features (cartilage damage, bone marrow lesions [BMLs], osteophytes, and inflammation) in both knees and evaluated the association of patellofemoral and tibiofemoral OA features to unilateral AKP. In our second approach, MRIs from 1 knee per person were scored, and we evaluated the association of OA features to AKP in participants with AKP and participants with no frequent knee pain.ResultsUsing the first approach (n = 71, 66% women, mean ± SD age 69 ± 8 years), lateral patellofemoral osteophytes (odds ratio [OR] 5.0 [95% confidence interval (95% CI) 1.7-14.6]), whole-knee joint effusion-synovitis (OR 4.7 [95% CI 1.3-16.2]), and infrapatellar synovitis (OR 2.8 [95% CI 1.0-7.8]) were associated with AKP. Using the second approach (n = 882, 59% women, mean ± SD age 69 ± 7 years), lateral and medial patellofemoral cartilage damage (prevalence ratio [PR] 2.3 [95% CI 1.3-4.0] and PR 1.9 [95% CI 1.1-3.3], respectively) and lateral patellofemoral BMLs (PR 2.6 [95% CI 1.5-4.7]) were associated with AKP.ConclusionPatellofemoral but not tibiofemoral joint OA features and inflammation were associated with AKP.

ObjectiveTo determine the relationship of patellofemoral osteoarthritis (PFOA) to changes in performance-based function over 7 years.MethodsThere were 2666 participants (62.2 ± 8.0 yrs, BMI 30.6 ± 5.9 kg/m2, 60% female) from the Multicenter Osteoarthritis Study with knee radiographs at baseline who completed repeated chair stands and a 20-meter walk test (20MWT) at baseline, 2.5, 5, and 7 years. Generalized linear models assessed the relation of radiographic PFOA and radiographic PFOA with frequent knee pain to longitudinal changes in performance-based function. Analyses were adjusted for age, sex, BMI, tibiofemoral OA, and injury/surgery.ResultsLinear models demonstrated a significant group-by-time interaction for the repeated chair stands (P = 0.04) and the 20MWT (P < 0.0001). Those with radiographic PFOA took 1.01 seconds longer on the repeated chair stands (P = 0.02) and 1.69 seconds longer on the 20MWT (P < 0.0001) at 7 years compared with baseline. When examining the relation of radiographic PFOA with frequent knee pain to performance-based function, there was a significant group-by-time interaction for repeated chair stands (P = 0.05) and the 20MWT (P < 0.0001). Those with radiographic PFOA with frequent knee pain increased their time on the repeated chair stands by 1.12 seconds (P = 0.04) and on the 20MWT by 1.91 seconds (P < 0.0001) over 7 years.ConclusionIndividuals with radiographic PFOA and those with radiographic PFOA with frequent knee pain have worsening of performance-based function over time. This knowledge may present opportunities to plan for early treatment strategies for PFOA to limit functional decline over time.

ObjectiveTo examine the cross-sectional association of ascending pain mechanisms, implicated in pain sensitization, and descending pain modulation with pain patterns and unpredictability of pain.MethodsThe Multicenter Osteoarthritis Study is a longitudinal cohort of older adults with or at risk of knee osteoarthritis. Peripheral and central ascending pain mechanisms were assessed using quantitative sensory tests, pressure pain thresholds using a handheld pressure algometer (knee/peripheral and wrist/central), and temporal summation using weighted probes (wrist/central). Descending modulation was assessed by conditioned pain modulation using pressure pain thresholds and a forearm ischemia test. Pain patterns were characterized based on responses to the Intermittent and Constant Osteoarthritis Pain questionnaire: 1) no intermittent or constant pain, 2) intermittent pain only, 3) constant pain only, and 4) combined constant and intermittent pain. A question regarding frequency assessed unpredictable pain. We assessed the association of quantitative sensory test measures to pain patterns using regression models with generalized estimating equations.ResultsThere were 2,794 participants (mean age 63.9 years, body mass index 29.5 kg/m2 , and 57% female). Lower pain sensitization by wrist pressure pain threshold (odds ratio [OR] 0.80 [95% confidence interval (95% CI) 0.68, 0.93]) and adequate conditioned pain modulation (OR 1.45 [95% CI 1.10, 1.92]) were associated with having constant ± intermittent pain compared with intermittent pain only. Higher pain sensitization (by pressure pain thresholds and temporal summation) was associated with a higher likelihood of unpredictable pain.ConclusionKnee pain patterns appear to be related to peripheral ± central facilitated ascending pain mechanisms and descending modulatory mechanisms. These findings highlight the need for a broader approach to understanding pain mechanisms by symptomatic disease progression.

ObjectiveAnkylosing spondylitis (AS) and psoriatic arthritis (PsA) often affect the hip and/or knee. If effective, treatments might reduce risk of total hip or total knee arthroplasty (THA/TKA). We evaluated risk of THA/TKA related to use of medical therapies in AS/PsA.MethodsWe conducted a nested case-control study using 1994-2018 data from the OptumLabs Data Warehouse, which includes deidentified medical and pharmacy claims, laboratory results, and enrollment records for commercial and Medicare Advantage enrollees. Among those with AS/PsA, THA/TKA cases were matched up to 4 controls by sex, age, AS/PsA diagnosis, diagnosis year, insurance type, obesity, and prior THA/TKA. We assessed AS/PsA treatment 6 months prior to THA/TKA, including disease-modifying antirheumatic drugs (DMARDs) and tumor necrosis factor inhibitors (TNFi), alone or in combination, stratified by nonsteroidal antiinflammatory drug (NSAID) use. We evaluated the relation of treatment to risk of THA/TKA using conditional logistical regression with adjustment for confounders.ResultsAmong 16,748 adults with AS, there were 444 THA/TKA cases and 1613 matched controls. Among 34,512 adults with PsA, there were 1003 cases and 3793 controls. Adjusted ORs for treatment category and THA/TKA ranged from 0.60 to 1.92; however, none were statistically significant. Results were similarly null in several sensitivity analyses.ConclusionOdds of THA/TKA were not reduced with any combinations of NSAIDs, DMARDs, or TNFi among persons with AS or PsA. Given current utilization patterns in this population of US adults with AS and PsA, these medical therapies did not appear to be associated with less end-stage peripheral joint damage.

ObjectiveTo examine the relation of knee pain patterns to pain severity and to radiographic osteoarthritis (OA) severity and duration.MethodsThe Multicenter Osteoarthritis Study is a longitudinal cohort of older adults with or at risk of knee OA. Participants' Intermittent and Constant Osteoarthritis Pain (ICOAP) scores were characterized as 1) no intermittent or constant pain, 2) intermittent pain only, 3) constant pain only, and 4) a combination of constant and intermittent pain. Knee pain severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale and a visual analog scale (VAS). Radiographic knee OA (ROA) severity was defined as Kellgren/Lawrence grade ≥2, and ROA duration was defined according to the clinic visit at which ROA was first noted. We assessed the relation of ICOAP pain patterns to knee pain severity, ROA severity, and ROA duration using regression models with generalized estimating equations.ResultsThere were 2,322 participants (mean age 68.8 years, body mass index 31.0 kg/m2 , 60% female). Higher ICOAP pain patterns, i.e., a mix of constant and intermittent pain, were associated with greater WOMAC pain severity compared with those patients without either pain pattern (odds ratio [OR] 43.2 [95% confidence interval (95% CI) 26.4-61.3]). Results were similar for the VAS (OR 71.2 [95% CI 45.7-110.9]). Those patients with more severe and longer duration of ROA were more likely to have a mix of constant and intermittent pain compared with those without either pain (OR 3.7 [95% CI 3.1-4.6] and OR 2.9 [95% CI 2.5-3.5], respectively).ConclusionKnee pain patterns are associated with radiographic disease stage and duration, as well as pain severity, highlighting the fact that pain patterns are important for understanding symptomatic disease progression.

OBJECTIVE: To compare the relative efficacy and safety of pharmacologic antiinflammatory interventions for gout flares. METHODS: We searched Ovid Medline, Embase, and Cochrane library for randomized controlled trials (RCTs) that compared pharmacologic antiinflammatory treatment of gout flares. We conducted a network meta-analysis (NMA) using a frequentist framework and assessed the certainty of evidence and made conclusions using the Grading of Recommendations Assessment, Development, and Evaluation for NMA. RESULTS: In the 30 eligible RCTs, canakinumab provided the highest pain reduction at day 2 and at longest follow-up (mean difference relative to acetic acid derivative nonsteroidal antiinflammatory drugs [NSAIDs] -41.12 [95% confidence interval (95% CI) -53.36, -29.11] on a 0-100 scale at day 2, and mean difference -12.84 [95% CI -20.76, -4.91] at longest follow-up; both moderate certainty; minimum important difference -19). Intravenous or intramuscular corticosteroids were inferior to canakinumab but may be better than the other commonly used interventions (low to very low certainty). For joint tenderness, canakinumab may be the most effective intervention at day 2. Acetic acid derivative NSAIDs improved joint swelling better than ibuprofen NSAIDs at day 2 (mean difference -0.29 [95% CI -0.56, -0.02] on a 0-4 scale; moderate certainty) and improved patient global assessment (PtGA) greater than ibuprofen NSAIDs at the longest follow-up (mean difference -0.44 [95% CI -0.86, -0.02]; moderate). CONCLUSION: Canakinumab may be superior to other alternatives and intravenous or intramuscular corticosteroids may be the second best in pain reduction. Acetic acid derivative NSAIDs may be superior to ibuprofen NSAIDs in improving joint swelling and PtGA.

ObjectiveDisagreement exists between rheumatology and primary care societies regarding gout management. This paper describes a formal process for gathering input from stakeholders in the planning of a trial to compare gout management strategies.MethodsWe recruited patients, nurses, physician assistants, primary care clinicians, and rheumatologists to participate in a modified Delphi panel (mDP) to provide input on design of a trial focused on optimal management for primary care patients with gout. The 16 panelists received a plain-language briefing document that discussed the rationale for the trial, key clinical issues in gout, and aspects of trial design. The panelists also received information and considerations on nine voting questions (VQs), judged to be the key design questions. Cognitive interviews with panelists ensured that the VQs were understood by the range of panelists involved in the mDP. Panelists were asked to score all VQs from 1 (definitely no) to 9 (definitely yes). Two voting rounds were conducted-round 1 by email and round 2 by video conference.ResultsThe VQs were modified through the cognitive interviews. The round 1 voting resulted in consensus on eight items, with consensus defined as median voting score in the same tercile (1-3, 4-6 or 7-9). Re-voting at the meeting (round 2) reached consensus on the remaining item.ConclusionAn mDP with various stakeholders facilitated consensus on the design of a trial of different management strategies for chronic gout. This method may be useful for designing trials of clinical questions with substantial disagreement across stakeholders.

ObjectiveThe objective of this study was to understand patient perspectives to inform the voting process for the 2020 American College of Rheumatology (ACR) gout treatment guideline.MethodsWe conducted a panel meeting of eight patients with gout in Birmingham, Alabama. Patients were referred to the project by private and academic rheumatologists in the Birmingham area. All participants received orientation related to the guideline development process and evidence rating at the beginning of the meeting. With the help of a physician moderator, the patient panel reviewed nine key clinical scenarios and the supporting evidence and discussed their views and perspectives related to each. They also provided their preference for one of the two treatment options for each clinical scenario.ResultsThe patient panel included eight men with gout. Of these eight participants, seven received their gout care from a rheumatologist and one from a primary care physician. Patients favored more active urate-lowering therapy (ULT) management and interventional management of gout flares to achieve desired clinical outcomes, resulting in unanimous consensus on choices related to six clinical scenarios: ULT initiation in gout, treat-to-target management strategy, use of pegloticase for refractory gout, starting ULT during a gout flare, using injectable treatments (over oral) for acute gout flares, and use of febuxostat in people with cardiovascular disease.ConclusionKnowledge of patient preferences and values is valuable and was influential for the development of the 2020 ACR gout treatment guideline.

ObjectiveDetermine the relation of symptomatic and structural features of patellofemoral osteoarthritis (PFOA) to psychological characteristics and measures of pain sensitization, in older adults with or at risk of knee osteoarthritis (OA).MethodsThis study included 1112 participants from the Multicenter Osteoarthritis Study (713 females, mean age 66.8 ± SD 7.6 yrs, body mass index 29.5 ± 4.8 kg/m2). Participants were grouped based on the presence of PFOA symptoms (anterior knee pain and pain on stairs) and magnetic resonance imaging (MRI) PFOA (full-thickness cartilage lesion with bone marrow lesion): (1) patellofemoral (PF) symptoms with MRI PFOA; (2) PF symptoms without MRI PFOA; (3) MRI PFOA without PF symptoms; and (4) no PF symptoms or MRI PFOA (no PFOA). Relation of PFOA classification to depressive symptoms, catastrophizing, temporal summation (TS) and pressure pain thresholds (PPT) was evaluated using logistic (categorical variables) and linear regression (continuous variables).ResultsCompared with no PFOA, those with PF symptoms with or without MRI PFOA had significantly greater odds of depressive symptoms, catastrophizing, and patellar TS (OR range 1.5-2.01), and those with PF symptoms without MRI PFOA had significantly greater odds of wrist TS (OR 1.66). Males with PF symptoms without MRI PFOA had significantly lower pressure PPT at the patella compared with no PFOA and those with MRI PFOA only (no symptoms). There were no significant differences at the wrist for males, or the patella or wrist for females.ConclusionPersons with PFOA symptoms, regardless of MRI PFOA status, are more likely to demonstrate depressive symptoms, catastrophizing, and TS. Males with PFOA symptoms without MRI PFOA demonstrate local hyperalgesia.

ObjectiveWe examined the association between sleep and odds of developing knee pain, and whether this relationship varied by status of widespread pain (WSP).MethodsAt the 60-month visit of the Multicenter Osteoarthritis Study, sleep quality and restless sleep were each assessed by using a single item from 2 validated questionnaires. Each sleep measure was categorized into 3 levels, with poor/most restless sleep as the reference. WSP was defined as pain above and below the waist on both sides of the body and axially using a standard homunculus, based on the American College of Rheumatology criteria. Outcomes from 60-84 months included (1) knee pain worsening (KPW; defined as minimal clinically important difference in WOMAC pain), (2) prevalent, and (3) incident consistent frequent knee pain. We applied generalized estimating equations in multivariable logistic regression models.ResultsWe studied 2329 participants (4658 knees; 67.9 yrs, body mass index 30.9]. We found that WSP modified the relationship between sleep quality and KPW (p = 0.002 for interaction). Among persons with WSP, OR (95% CI) for KPW was 0.53 (0.35-0.78) for those with very good sleep quality (p trend < 0.001); additionally, we found the strongest association of sleep quality in persons with > 8 painful joint sites (p trend < 0.01), but not in those with ≤ 2 painful joint sites. Similar results were observed using restless sleep, in the presence of WSP. The cross-sectional relationship between sleep and prevalence of consistent frequent knee pain was significant.ConclusionBetter sleep was related to less KPW with coexisting widespread pain.

ObjectiveOsteoarthritis (OA) and pain are both made more severe by low-grade inflammation. This study was undertaken to examine whether visceral fat, a major source of inflammatory cytokines and adipokines, is associated with an increased risk of knee OA or musculoskeletal pain.MethodsSubjects in the Multicenter Osteoarthritis Study cohort, who were age 50-79 years and had or were at high risk of knee OA, underwent whole-body dual x-ray absorptiometry (DXA) at baseline. At baseline, 30 months, and 60 months radiographs and magnetic resonance images (MRIs) of the knees were obtained, and patients were asked to score the severity of their knee pain and to identify sites of joint pain using a body homunculus. Baseline DXA scans were used to measure total body fat and visceral and subcutaneous fat in the torso. The association of fat depot size with structural outcomes (incident radiographic OA and cartilage loss and synovitis on MRI) and with pain outcomes (worsening knee pain, number of painful joints, and widespread pain) was assessed. Regression analyses were adjusted for age, sex, race, education level, smoking status, physical activity, body mass index (BMI), and depressive symptoms.ResultsOf the 2,961 participants at baseline, 60.7% were women. The mean age was 62.5 years and mean BMI was 30.5 kg/m2 . After adjustment for covariates, no fat measures were associated with any structural outcomes. However, total and visceral, but not subcutaneous, fat were positively associated with worsening knee pain (P = 0.0005 for total fat and P = 0.007 for visceral fat) and widespread pain (P = 0.001 for total fat and P = 0.02 for visceral fat), and the amount of visceral fat was associated with the number of painful joints (P = 0.07).ConclusionOur findings indicate that visceral fat is associated with an increased risk of musculoskeletal and widespread pain.

OBJECTIVE: To provide guidance for the management of gout, including indications for and optimal use of urate-lowering therapy (ULT), treatment of gout flares, and lifestyle and other medication recommendations. METHODS: Fifty-seven population, intervention, comparator, and outcomes questions were developed, followed by a systematic literature review, including network meta-analyses with ratings of the available evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and patient input. A group consensus process was used to compose the final recommendations and grade their strength as strong or conditional. RESULTS: Forty-two recommendations (including 16 strong recommendations) were generated. Strong recommendations included initiation of ULT for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares; allopurinol as the preferred first-line ULT, including for those with moderate-to-severe chronic kidney disease (CKD; stage >3); using a low starting dose of allopurinol (≤100 mg/day, and lower in CKD) or febuxostat (

ObjectiveKnee cartilage damage is often linked to mechanical overloading. However, cartilage requires mechanical load to remain healthy, suggesting that underloading may be detrimental. This study was undertaken to examine knee overloading and underloading by defining cumulative load as the joint effects of body mass index (BMI) and daily walking, and examine the relationship between cumulative load and worsening cartilage damage over 2 years.MethodsWe used data from the Multicenter Osteoarthritis Study. Steps/day, measured by accelerometry, and BMI were calculated at the 60-month visit. Cartilage damage on magnetic resonance imaging was semiquantitatively scored using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) at the 60-month and 84-month visits; worsening damage was defined as increased WORMS between visits. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were calculated using binomial regression, with adjustment for potential confounders.ResultsOur study included 964 participants, 62% of whom were female, with a mean ± SD age of 66.9 ± 7.5 years. Participants had a mean ± SD BMI of 29.7 ± 4.8 kg/m2 and walked a mean ± SD of 7,153 ± 2,591 steps/day. Participants who walked a moderate number of steps/day (6,000-7,900) or a high number of steps/day (>7,900) and had a high BMI (>31 kg/m2 ) had a greater risk of worsening medial tibiofemoral (TF) damage (RR 2.83 [95% CI 1.46-5.48] and RR 2.61 [95% CI 1.50-4.54], respectively) compared with those who walked similar steps/day and had a low BMI (18-27 kg/m2 ). Participants with a low number of steps/day (

ObjectiveTo develop an evidence-based guideline for the comprehensive management of osteoarthritis (OA) as a collaboration between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA.MethodsWe identified clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available educational, behavioral, psychosocial, physical, mind-body, and pharmacologic therapies for OA. Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, including rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations.ResultsBased on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self-efficacy and self-management programs, tai chi, cane use, hand orthoses for first carpometacarpal (CMC) joint OA, tibiofemoral bracing for tibiofemoral knee OA, topical nonsteroidal antiinflammatory drugs (NSAIDs) for knee OA, oral NSAIDs, and intraarticular glucocorticoid injections for knee OA. Conditional recommendations were made for balance exercises, yoga, cognitive behavioral therapy, kinesiotaping for first CMC OA, orthoses for hand joints other than the first CMC joint, patellofemoral bracing for patellofemoral knee OA, acupuncture, thermal modalities, radiofrequency ablation for knee OA, topical NSAIDs, intraarticular steroid injections and chondroitin sulfate for hand OA, topical capsaicin for knee OA, acetaminophen, duloxetine, and tramadol.ConclusionThis guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

ObjectiveThere is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout.MethodsA content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions.ResultsThe content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus).ConclusionConsensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

ObjectiveIt is not clear why some individuals develop pain with knee osteoarthritis (OA). We undertook this study to identify pain susceptibility phenotypes (PSPs) and their relationship to incident persistent knee pain (PKP) 2 years later.MethodsWe identified individuals free of PKP from the Multicenter Osteoarthritis Study, a longitudinal cohort of older adults with or at risk of knee OA. Latent class analysis was used to determine PSPs that may contribute to development of PKP apart from structural pathology. These included widespread pain, poor sleep, and psychological factors as well as pressure pain threshold and temporal summation (TS) as determined by quantitative sensory testing (QST). We used logistic regression to evaluate the association of sociodemographic factors with PSPs and the relationship of PSPs to the development of PKP over 2 years.ResultsA total of 852 participants were included (mean age 67 years, body mass index 29.5 kg/m2 , 55% women). Four PSPs were identified, primarily characterized by varying proportions (low/absent, moderate, or high) of the presence of pressure pain sensitivity and of facilitated TS, reflecting different measures of sensitization. Subjects in the PSP with a high proportion of pressure pain sensitivity and a moderate proportion of facilitated TS were twice as likely to develop incident PKP over 2 years (odds ratio 1.98 [95% confidence interval 1.07-3.68]) compared with subjects in the PSP having a low proportion of sensitization by both measures.ConclusionFour PSPs were identified, 3 of which were predominated by QST evidence of sensitization and 1 of which was associated with developing PKP 2 years later. Prevention or amelioration of sensitization may be a novel approach to preventing onset of PKP in OA.

ObjectiveObesity, defined by anthropometric measures, is a well-known risk factor for knee osteoarthritis (OA), but there is a relative paucity of data regarding the association of body composition (fat and muscle mass) with risk of knee OA. We undertook this study to examine the longitudinal association of body composition categories based on fat and muscle mass with risk of incident knee OA.MethodsWe included participants from the Multicenter Osteoarthritis Study, a longitudinal cohort of individuals with or at risk of knee OA. Based on body composition (i.e., fat and muscle mass) from whole-body dual x-ray absorptiometry, subjects were categorized as obese nonsarcopenic (obese), sarcopenic obese, sarcopenic nonobese (sarcopenic), or nonsarcopenic nonobese (the referent category). We examined the relationship of baseline body composition categories with the risk of incident radiographic OA at 60 months using binomial regression with robust variance estimation, adjusting for potential confounders.ResultsAmong 1,653 subjects without radiographic knee OA at baseline, significantly increased risk of incident radiographic knee OA was found among obese women (relative risk [RR] 2.29 [95% confidence interval {95% CI} 1.64-3.20]), obese men (RR 1.73 [95% CI 1.08-2.78]), and sarcopenic obese women (RR 2.09 [95% CI 1.17-3.73]), but not among sarcopenic obese men (RR 1.74 [95% CI 0.68-4.46]). Sarcopenia was not associated with risk of knee OA (for women, RR 0.96 [95% CI 0.62-1.49]; for men, RR 0.66 [95% CI 0.34-1.30]).ConclusionIn this large longitudinal cohort, we found body composition-based obesity and sarcopenic obesity, but not sarcopenia, to be associated with risk of knee OA. Weight loss strategies for knee OA should focus on obesity and sarcopenic obesity.

Objective: The study objective was to examine the disease, demographic, and imaging features associated with different inflammatory phenotypes of calcium pyrophosphate deposition (CPPD) disease, ie, recurrent acute calcium pyrophosphate (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 CPPD classification criteria from the American College of Rheumatology/EULAR) 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 adjusted odds ratio (aOR) and 95% confidence interval (CI) to examine the association between potential risk factors and the inflammatory phenotype. Results: Among the 618 people included (56% female; mean age [standard deviation] 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 2.92 [95% CI 1.81–4.73]), metacarpophalangeal joint osteoarthritis (aOR 1.87 [95% CI 1.17–2.97]), and scapho‐trapezo‐trapezoid (STT) joint osteoarthritis (aOR 1.83 [95% CI 1.15–2.91]), and it was negatively associated with either metabolic or familial risk for CPPD (aOR 0.60 [95% CI 0.37–0.96]). CDS was associated with male sex (aOR 2.35 [95% CI 1.21–4.59]), STT joint osteoarthritis (aOR 2.71 [95% CI 1.22–6.05]), and more joints affected with chondrocalcinosis (aOR 1.46 [95% CI 1.15–1.85]). Conclusion: CPPD disease encompasses acute and chronic inflammatory phenotypes, each with specific clinical and imaging features that need to be considered in the diagnostic workup. [ABSTRACT FROM AUTHOR]

Objective: Initiating urate‐lowering therapy (ULT) in gout can precipitate arthritis flares. There have been limited comparisons of flare risk during the initiation and escalation of allopurinol and febuxostat, administered as a treat‐to‐target strategy with optimal anti‐inflammatory prophylaxis. Methods: This was a post‐hoc analysis of a 72‐week randomized, double‐blind, placebo‐controlled, noninferiority trial comparing the efficacy of allopurinol and febuxostat. For this analysis, the occurrence of flares was examined during weeks 0 to 24 when ULT was initiated and titrated to a serum urate (sUA) goal of less than 6 mg/dl (<5 mg/dl if tophi). Flares were assessed at regular intervals through structured participant interviews. Predictors of flare, including treatment assignment, were examined using multivariable Cox proportional hazards regression. Results: Study participants (n = 940) were predominantly male (98.4%) and had a mean age of 62.1 years with approximately equal proportions receiving allopurinol or febuxostat. Mean baseline sUA was 8.5 mg/dl and all participants received anti‐inflammatory prophylaxis (90% colchicine). In a multivariable model, there were no significant associations of ULT treatment (hazard ratio [HR] 1.17; febuxostat vs allopurinol), ULT‐dose escalation (HR 1.18 vs no escalation), prophylaxis type, or individual comorbidity with flare and no evidence of ULT‐dose escalation interaction. Factors independently associated with flare risk during ULT initiation/escalation included younger age, higher baseline sUA, and absence of tophi. Conclusion: These results demonstrate that gout flare risk during the initiation and titration of allopurinol is similar to febuxostat when these agents are administered according to a treat‐to‐target strategy using gradual ULT‐dose titration and best practice gout flare prophylaxis. [ABSTRACT FROM AUTHOR]

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p