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OBJECTIVE: Classification criteria for calcium pyrophosphate deposition disease (CPPD) will facilitate clinical research on this common crystalline arthritis. We report on the first two phases of a four-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 five literature databases and contributions from a 35-member Combined Expert Committee and two 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 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, wrist, and one 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.

Duloxetine is a treatment approved by the US Food and Drug Administration for both osteoarthritis (OA) pain and depression, though uptake of duloxetine in knee OA management varies. We examined the cost-effectiveness of adding duloxetine to knee OA care in the absence or presence of depression screening.We used the Osteoarthritis Policy Model, a validated computer microsimulation of knee OA, to examine the value of duloxetine for patients with knee OA who have moderate pain by comparing 3 strategies: 1) usual care, 2) usual care plus duloxetine for patients who screen positive for depression on the Patient Health Questionnaire 9 (PHQ-9), and 3) usual care plus universal duloxetine. Outcome measures included quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. Model inputs, drawn from the published literature and national databases, included annual cost of duloxetine ($721-937); average pain reduction for duloxetine (17.5 points on the Western Ontario and McMaster Universities Osteoarthritis Index pain scale [0-100]), and likelihood of depression remission with duloxetine (27.4%). We considered 2 willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY. We varied parameters related to the PHQ-9 and the cost of duloxetine, efficacy, and toxicities to address uncertainty in model inputs.The screening strategy led to an additional 17 QALYs per 1,000 subjects and increased costs by $289/subject (ICER = $17,000/QALY). Universal duloxetine led to an additional 31 QALYs per 1,000 subjects and $1,205 per subject (ICER = $39,300/QALY). Under the majority of sensitivity analyses, universal duloxetine was cost-effective at the $100,000/QALY threshold.The addition of duloxetine to usual care for knee OA patients with moderate pain, regardless of depressive symptoms, is cost-effective at frequently used WTP thresholds.

Objectives To examine the cross-sectional association of ascending pain mechanisms (APM), implicated in pain sensitization (PS), and descending pain modulation with pain patterns and unpredictability of pain. Methods The Multicenter Osteoarthritis (OA) Study is a longitudinal cohort of older adults with or at risk of knee OA. Peripheral and central APM were assessed using quantitative sensory tests (QST); pressure pain thresholds (PPTs) using a handheld pressure algometer (knee/peripheral and wrist/central), temporal summation (TS) using weighted probes (wrist/central). Descending modulation was assessed by conditioned pain modulation (CPM) using PPTs and a forearm ischemia test. Pain patterns were characterized based on responses to the Intermittent and Constant OA Pain (ICOAP) 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 QST measures to pain patterns using regression models with generalized estimating equations. Results There were 2794 participants (mean age 63.9, BMI 29.5 kg/m2 , 57% female). Lower PS (by wrist PPT) OR = 0.80 (95% CI 0.68, 0.93) and adequate CPM, OR = 1.45 (1.10, 1.92) were associated with having constant +/- intermittent pain compared with intermittent pain only. Higher PS (by PPT and TS) was associated with higher likelihood of unpredictable pain. Conclusions Knee pain patterns appear to be related to peripheral +/- central facilitated APM, and descending modulatory mechanisms. These findings highlight the need for a broader approach to understanding pain mechanisms by symptomatic disease progression.

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.

Summary Objective To compare ground reaction force patterns (GRF) during walking among legs defined by presence or absence of knee pain and/or radiographic knee osteoarthritis (ROA). Method Principal component analysis extracted major modes of variation (PCs) in GRF data from the Multicenter Osteoarthritis Study during self-paced walking. Legs were categorized as pain + ROA (n = 168), ROA only (n = 303), pain only (n = 476), or control (n = 1877). Relationships between group and GRF PCs were examined using Generalized Estimating Equations, adjusted for age, sex, body mass index, race, and clinic site with and without additional adjustment for gait speed. Results With or without speed adjustment, pain + ROA had flatter vertical GRF waveforms than control (speed adjusted PC2 difference [95%CI]: −66 [-113,-20]), pain + ROA and ROA only had higher lateral GRF at impact and greater mid-stance medial GRF than control (speed adjusted PC3 difference: 9 [3,16] and 6 [2,10], respectively), and ROA only had higher early vs late medial GRF than control (speed adjusted PC2 difference: 7 [2,13]). Pain only had flatter vertical GRF waveforms and a smaller difference between anterior and posterior GRF than control only without speed adjustment. Conclusion In this large sample, sustained mid-stance loading and higher impact loads were identified in legs with ROA or ROA and pain, even when adjusting for differences in gait speed and other confounders. While it remains to be seen whether these features precede or result from ROA and pain, the presence of these patterns in the speed-adjusted models could have implications on gait interventions aimed to change joint loading.

Objectives Over one-third of patients with RA exhibit evidence of fibromyalgianess, which is associated with higher rates of disability and inadequate responsiveness to RA treatment. Patients with RA often remain on glucocorticoids long-term, despite the known risk of dose-dependent morbidity. We undertook this study to examine the relationship between fibromyalgianess and glucocorticoid persistence among RA patients. Methods We followed participants with active RA on oral prednisone for ∼3 months after initiating a new DMARD. Fibromyalgianess was measured using the Fibromyalgia Survey Questionnaire (FSQ), previously shown to correlate with key FM features often superimposed upon RA. Severity of fibromyalgianess was stratified as follows: FSQ 10 high/very high. The association between baseline fibromyalgianess and glucocorticoid persistence, defined as prednisone use at 3-month follow-up visit after DMARD initiation, was assessed using multiple logistic regression adjusted for baseline demographics, RA duration, serostatus and inflammatory activity assessed using swollen joint count and CRP. Results Of the 97 participants on prednisone at baseline, 65% were still taking prednisone at follow-up. Fifty-seven percent of participants with low baseline fibromyalgianess had persistent glucocorticoid use, compared with 84% of participants with high or very high fibromyalgianess. After adjustment for non-inflammatory factors and inflammatory activity, participants with high/very high baseline fibromyalgianess were more likely to be taking prednisone at follow-up relative to those with low fibromyalgianess [odds ratio 4.99 (95% CI 1.20, 20.73)]. Conclusion High fibromyalgianess is associated with persistent glucocorticoid use, independent of inflammatory activity.

Background Total knee replacement (TKR) is an effective and cost-effective strategy for treating end-stage knee osteoarthritis. Greater risk for complications among TKR recipients with a body mass index (BMI) of 40 kg/m2 or greater has raised concerns about the value of TKR in this population. Objective To assess the value of TKR in recipients with a BMI of 40 kg/m2 or greater using a cost-effectiveness analysis. Design Osteoarthritis Policy Model to assess long-term clinical benefits, costs, and cost-effectiveness of TKR in patients with a BMI of 40 kg/m2 or greater. Data sources Total knee replacement parameters from longitudinal studies and published literature, and costs from Medicare Physician Fee Schedules, the Healthcare Cost and Utilization Project, and published data. Target population Recipients of TKR with a BMI of 40 kg/m2 or greater in the United States. Time horizon Lifetime. Perspective Health care sector. Intervention Total knee replacement. Outcome measures Cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. Results of base-case analysis Total knee replacement increased QALYs by 0.71 year and lifetime medical costs by $25 200 among patients aged 50 to 65 years with a BMI of 40 kg/m2 or greater, resulting in an ICER of $35 200. Total knee replacement in patients older than 65 years with a BMI of 40 kg/m2 or greater increased QALYs by 0.39 year and costs by $21 100, resulting in an ICER of $54 100. Results of sensitivity analysis In TKR recipients with a BMI of 40 kg/m2 or greater and diabetes and cardiovascular disease, ICERs were below $75 000 per QALY. Results were most sensitive to complication rates and preoperative pain levels. In the probabilistic sensitivity analysis, at a $55 000-per-QALY willingness-to-pay threshold, TKR had a 100% and 90% likelihood of being a cost-effective strategy for patients aged 50 to 65 years and patients older than 65 years, respectively. Limitation Data are derived from several sources. Conclusion From a cost-effectiveness perspective, TKR offers good value in patients with a BMI of 40 kg/m2 or greater, including those with multiple comorbidities. Primary funding source National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.

OBJECTIVE To examine the relation of knee pain patterns to pain severity and to radiographic osteoarthritis (OA) severity and duration. METHODS The 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. RESULTS There 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). CONCLUSION Knee 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.

The US FDA-mandated CARES trial, published in 2018, reported increased all-cause and cardiovascular (CV) death in participants randomized to febuxostat compared with allopurinol. The subsequent FDA Drug Safety Communication and Boxed Warning resulted in substantial reductions in febuxostat use in the US. The EMA-mandated Febuxostat versus Allopurinol Streamlined Trial (FAST), published in 2020, found no increased risk of composite CV events, CV mortality or all-cause mortality for febuxostat, compared with allopurinol. This commentary discusses implications of these new findings for gout management.

ObjectivesVitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP.MethodsWe investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association.ResultsAcenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94–3.20), both for knee (OR=2.34, 95% CI=1.67–3.22) and hip OA (OR=2.74, 95% CI=1.82–4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69–6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78–1.33).ConclusionsThese findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.

Objective.Ankylosing 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.Methods.We 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.Results.Among 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.Conclusion.Odds 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.

Summary Objective To identify proximate causes (‘triggers’) of flares in adults with, or at risk of, knee osteoarthritis (OA), estimate their course and consequences, and determine higher risk individuals. Methods In this 13-week web-based case-crossover study adults aged ≥40 years, with or without a recorded diagnosis of knee OA, and no inflammatory arthropathy who self-reported a knee flare completed a questionnaire capturing information on exposure to 21 putative activity-related, psychosocial and environmental triggers (hazard period, ≤72 hours prior). Comparisons were made with identical exposure measurements at four 4-weekly scheduled time points (non-flare control period) using conditional logistic regression. Flare was defined as a sudden onset of worsening signs and symptoms, sustained for ≥24 hours. Flare characteristics, course and consequence were analysed descriptively. Associations between flare frequency and baseline characteristics were estimated using Poisson regression. Results Of 744 recruited participants (mean age (SD) 62.1 (10.2) years; 61% female), 376 reported 568 flares (hazards) and provided 867 valid control period measurements. Thirteen exposures (8 activity-related, 5 psychosocial/environmental) were positively associated with flare onset within 24 hours (strongest odds ratio estimate, knee buckling: 9.06: 95% confidence interval [CI] 5.86, 13.99; weakest, cold/damp weather: 1.45: 95%CI 1.12, 1.87). Median flare duration was 5 days (IQR 3, 8), less common if older (incident rate ratio [IRR] 0.98: 95%CI 0.97, 0.99), more common if female (IRR 1.85: 95%CI 1.43, 2.39). Conclusions Multiple activity-related, psychosocial and environmental exposures are implicated in triggering flares. This evidence can help inform prevention and acute symptom management for patients and clinicians.

Summary Objective Knee osteoarthritis (OA) is predominantly characterized by pain with weight-bearing activities. Pain at rest also occurs but the mechanisms for this are not clear. We evaluated the relations of nociceptive signal alterations to weight-bearing and non-weight-bearing pain in knee OA. Design We used data from a NIH–funded longitudinal cohort of older adults with or at risk of knee OA. We evaluated quantitative sensory testing (QST) measures (pressure pain threshold (PPT) at patellae and the wrist; mechanical temporal summation (TS); conditioned pain modulation (CPM)). Each WOMAC pain question was dichotomized as having at least moderate pain, and we further categorized them as weight-bearing pain and non-weight-bearing pain. We evaluated the relation of QST measures to each pain outcome using logistic regression, adjusting for potential confounders. Results 2749 participants (5479 knees) were included (mean age 64±11, 57% female). Each SD unit decrease in patellar PPT was associated with greater odds of both weight-bearing pain (OR 1.51 (95% CI 1.27, 1.79)) and non-weight-bearing pain (OR 1.46 (1.20-1.77)), while wrist PPT was associated with greater odds of weight-bearing pain (OR 1.27 (1.15, 1.39)) but only with pain during sitting/lying (OR 1.20 (1.01, 1.43)). TS was significantly associated with greater odds of pain with walking and stairs (OR 1.11 (1.01, 1.23), 1.11 (1.03, 1.20), respectively). CPM was not associated with any pain outcomes. Conclusions Our findings challenge the hypothesis that non-weight-bearing pain may reflect greater pain sensitization and/or inefficient CPM than weight-bearing pain in knee OA, suggesting other mechanisms are likely responsible.

Current management of osteoarthritis (OA) is primarily focused on symptom control. Intra-articular corticosteroid (IACS) injections are often used for pain management of hip and knee OA in patients who have not responded to oral or topical analgesics. Recent case series suggested that negative structural outcomes including accelerated OA progression, subchondral insufficiency fracture, complications of pre-existing osteonecrosis, and rapid joint destruction (including bone loss) may be observed in patients who received IACS injections. This expert panel report reviews the current understanding of pain in OA, summarizes current international guidelines regarding indications for IACS injection, and considers preinterventional safety measures, including imaging. Potential profiles of those who would likely benefit from IACS injection and a suggestion for an updated patient consent form are presented. As of today, there is no established recommendation or consensus regarding imaging, clinical, or laboratory markers before an IACS injection to screen for OA-related imaging abnormalities. Repeating radiographs before each subsequent IACS injection remains controversial. The true cause and natural history of these complications are unclear and require further study. To determine the cause and natural history, large prospective studies evaluating the risk of accelerated OA or joint destruction after IACS injections are needed. However, given the relatively rare incidence of these adverse outcomes, any clinical trial would be challenging in design and a large number of patients would need to be included.

OBJECTIVE: Adults with radiographic knee OA (rKOA) are at increased risk of mortality and walking difficulty may modify this relation. Little is known about specific aspects of walking difficulty that increase mortality risk. We investigated the association of walking speed (objective measure of walking difficulty) with mortality and examined the threshold that best discriminated this risk in adults with rKOA. METHODS: Participants with rKOA from the Johnston County Osteoarthritis Project (JoCoOA, longitudinal population-based cohort), Osteoarthritis Initiative and Multicenter Osteoarthritis Study (OAI and MOST, cohorts of individuals with or at high risk of knee OA) were included. Baseline speed was measured via 2.4-meter (m) walk test (short-distance) in JoCoOA and 20-m walk test (standard-distance) in OAI and MOST. To examine the association of walking speed with mortality risk over nine years, hazard ratios (aHR) and 95% confidence intervals (CI) were calculated from Cox regression models adjusted for potential confounders., A Maximal Likelihood Ratio Chi-square Approach was utilized to identify an optimal threshold of walking speed predictive of mortality. RESULTS: Deaths after 9 years of follow-up occurred in 23.3% (290/1244) of JoCoOA and 5.9% (249/4215) of OAI+MOST. Walking 0.2 meters/second slower during short- and standard-distance walk tests was associated with 23% (aHR[95%CI]; 1.23[1.10, 1.39]) and 25% (1.25[1.09, 1.43]) higher mortality risk, respectively. Walking

Objective The 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. Methods We 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. Results The 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. Conclusion Knowledge of patient preferences and values is valuable and was influential for the development of the 2020 ACR gout treatment guideline.

Objective To determine the association between dysregulated central pain processing and treatment response in rheumatoid arthritis (RA). Methods One hundred eighty-two participants with active RA were followed up for 12 weeks after starting a disease-modifying antirheumatic drug (DMARD). To assess central pain processing, participants underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at the trapezius muscles, temporal summation, and conditioned pain modulation (CPM). QST measures were categorized as high central dysregulation versus low central dysregulation. The association between baseline central dysregulation and treatment response, as defined by the European League Against Rheumatism (EULAR) response criteria, was assessed using multiple logistic regression adjusted for demographic characteristics, RA-related variables, and psychosocial variables. Results A good EULAR response was achieved in fewer participants with high CPM dysregulation than participants with low CPM dysregulation (22.5% versus 40.3%; P = 0.01). A similar trend, though not significant, was noted when central dysregulation was assessed with PPT and temporal summation. The adjusted odds ratios (ORs) for the association between high central dysregulation and good EULAR response were 0.59 for PPTs (95% confidence interval [95% CI] 0.28-1.23), 0.60 for temporal summation (95% CI 0.27-1.34), and 0.40 for CPM (95% CI 0.19-0.83). In a model examining the combined effects of dysregulated temporal summation and CPM, dysregulation of both measures was associated with lower odds of achieving a good EULAR response (OR 0.23 [95% CI 0.07-0.73]). Conclusion Low CPM was significantly associated with lower odds of achieving a good EULAR response, suggesting that inefficient descending inhibitory mechanisms may be a potential treatment target for further study.

Summary Objective Bone marrow lesions (BMLs) contribute to pain and progression of knee OA. Bisphosphonates may be a potential disease-modifier through amelioration of BMLs. We sought to determine the effect of oral bisphosphonates on BML volume over 12 months. Design Women in the Osteoarthritis Initiative who newly initiated an oral bisphosphonate were propensity-score matched to non-initiators. BML volume was assessed using sagittal turbo spin echo fat-suppressed intermediate-weighted MR images at the index date and 12 months later. A validated semi-automated process was used to segment subchondral OA-related BMLs to determine total volume of BMLs based on number of voxels within the outlined area of interest. Mean change in BML volume over 12 months among bisphosphonate initiators was compared with non-initiators using multiple linear regression. Results 145 bisphosphonate initiators were identified, who were well-matched to their comparators. The difference in mean change in total BML volume between the two groups, regardless of presence of baseline BMLs, was not significant (P = 0.4, 95% CI -156.6 to +354.2). The proportion of participants with decreased, increased, or unchanged BML volumes over the 12 months were similar in both groups. Among those with baseline BMLs, bisphosphonate initiators had a greater proportion with a decrease in BML volume compared with stable or increased BML volume than non-initiators (P = 0.03). Conclusions In this ‘real-world’ setting of women starting bisphosphonates, we found no clear evidence of benefit on BML volume over a 12-month period, though a trend towards a decrease in BML volume was noted.

Objective To investigate the factors associated with discordance between patient and physician on the presence of a gout flare. Methods Patients’ self-reports of current gout flares were assessed with the question, ‘Are you having a gout flare today?’ which was then compared with a concurrent, blinded, physician’s assessment. Based on agreement or disagreement with physicians on the presence of a gout flare, flares were divided into concordant and discordant groups, respectively. Within the discordant group, two subgroups—patient-reported flare but the physician disagreed and physician-reported flare but the patient disagreed—were identified. The factors associated with discordance were analysed with multivariable logistic regression analysis. Results Of 268 gout flares, 81 (30.2%) flares were discordant, with either patient or physician disagreeing on the presence of a flare. Of the discordant flares, in 57 (70.4%) the patient reported a flare but the physician disagreed. In multivariable logistic regression analysis adjusted for demographics, disagreement among patients and physicians on the presence of a gout flare was associated with lower pain scores at rest [odds ratio (OR) for each point increase on 0–10 point pain scale 0.81 (95% Wald CI 0.73, 0.90), P < 0.0001] and less presence of joint swelling [OR 0.24 (95% CI 0.10, 0.61), P = 0.003] or joint warmth [OR 0.39 (95% CI 0.20, 0.75), P = 0.005]. Conclusion Although patients and physicians generally agree about the presence of gout flare, discordance may occur in the setting of low pain scores and in the absence of swollen or warm joints.

Objective Pain is a significant burden for patients with rheumatoid arthritis (RA) despite advancements in treatment. We undertook this study to examine the independent contribution of pain centralization to the pain experience of patients with active RA. Methods A total of 263 RA patients with active disease underwent quantitative sensory testing (QST), including assessment of extraarticular pressure pain thresholds (PPTs), temporal summation (TS), and conditioned pain modulation (CPM). The pain experience was assessed by a pain intensity numeric rating scale and the Patient-Reported Outcomes Measurement Information System pain interference computerized adaptive test. We examined associations between QST measures and pain intensity and pain interference. Multiple linear regression models were adjusted for demographic and clinical variables, including swollen joint count and C-reactive protein level. Results Patients with the lowest PPTs (most central dysregulation) reported higher pain intensity than patients with the highest PPTs (adjusted mean difference 1.02 [95% confidence interval (95% CI) 0.37, 1.67]). Patients with the highest TS (most central dysregulation) had higher pain intensity than those with the lowest TS (adjusted mean difference 1.19 [95% CI 0.54, 1.84]). CPM was not associated with differences in pain intensity. PPT and TS were not associated with pain interference. Patients with the lowest CPM (most centrally dysregulated) had lower pain interference than patients with the highest CPM (adjusted mean difference -2.35 [95% CI -4.25, -0.44]). Conclusion Pain centralization, manifested by low PPTs and high TS, was associated with more intense pain. Clinicians should consider pain centralization as a contributor to pain intensity, independent of inflammation.

Objective Osteoarthritis (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. Methods Subjects 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. Results Of 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). Conclusion Our findings indicate that visceral fat is associated with an increased risk of musculoskeletal and widespread pain.

Objective.To determine the relationship between gout flare rate and self-categorization into remission, low disease activity (LDA), and patient acceptable symptom state (PASS).Methods.Patients with gout self-categorized as remission, LDA, and PASS, and reported number of flares over the preceding 6 and 12 months. Multinomial logistic regression was used to determine the association between being in each disease state (LDA and PASS were combined) and flare count, and self-reported current flare. A distribution-based approach and extended Youden index identified possible flare count thresholds for each state.Results.Investigators from 17 countries recruited 512 participants. Remission was associated with a median recalled flare count of zero over both 6 and 12 months. Each recalled flare reduced the likelihood of self-perceived remission compared with being in higher disease activity than LDA/PASS, by 52% for 6 months and 23% for 12 months, and the likelihood of self-perceived LDA/PASS by 15% and 5% for 6 and 12 months, respectively. A threshold of 0 flares in preceding 6 and 12 months was associated with correct classification of self-perceived remission in 58% and 56% of cases, respectively.Conclusion.Flares are significantly associated with perceptions of disease activity in gout, and no flares over the prior 6 or 12 months is necessary for most people to self-categorize as being in remission. However, recalled flare counts alone do not correctly classify all patients into self-categorized disease activity states, suggesting that other factors may also contribute to self-perceived gout disease activity.

This narrative review highlights recent literature pertaining to pain phenotyping in osteoarthritis (OA) by summarizing recent novel approaches and promising future directions. We report on four studies in knee OA that have added knowledge regarding longitudinal validation of pain phenotypes constructed with phenotypic domains other than pain that are highly stable over time; the existence of a pain susceptibility phenotype, defined by the presence of sensitivity to pressure pain thresholds and a lack of presence of psychosocial factors; the novelty and importance of movement-evoked pain supporting the association of positive quantitative sensory testing (QST) findings with greater intensity and frequency of spontaneous pain; and the external validation of a chronic pain phenotype in an independent data set that was previously identified by a systematic review. One study of people with hip OA subgrouped participants using daily pain ratings over 6 weeks demonstrating that both intermittent and constant pain are highly present in early stages of the disease, and those with higher pain intensity experience greater variability of pain. Collectively these studies have contributed new and important knowledge to our understanding of OA pain phenotypes through longitudinal or external validation, which has been a missing element in the literature. The novel examination of a movement-evoked pain phenotype may provide an avenue to greater understanding of pain variability and its correlates, and with their definitive associations with QST, further supports the importance of a mechanism-based approach to pain assessment.

OBJECTIVE Massive weight loss leads to marked knee pain reduction in individuals with knee pain, but the reason for the reduction in pain is unknown. This study was undertaken to quantify the contribution of magnetic resonance imaging (MRI)-evidenced changes in pain-sensitive structures, bone marrow lesions (BMLs), and synovitis, and changes in pain sensitization or depressive symptoms, to knee pain improvement after substantial weight loss. METHODS Morbidly obese patients with knee pain on most days were evaluated before bariatric surgery or medical weight management and at 1-year follow-up for BMLs and synovitis seen on MRI, the pressure pain threshold (PPT) at the patella and the right wrist, depressive symptoms (using the Center for Epidemiologic Studies Depression scale [CES-D]), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain survey. Natural-effects models were used to quantify the extent that achieving a minimum clinically important difference (MCID) of ≥18% on the WOMAC pain scale could be mediated by weight loss-induced changes in BMLs, synovitis, PPT, and depressive symptoms. RESULTS Of 75 participants, 53.3% lost ≥20% of weight by 1 year. Of these, 75% attained the MCID for pain improvement, compared with 34.3% in those who had

Objective: To identify distinct recovery trajectories of acute flares of knee pain and associated participant characteristics. Methods: Data were from the FLARE randomized controlled trial, a multicenter trial in 27 primary care centers in the UK and Netherlands of 3 regimes of oral nonsteroidal antiinflammatory therapy for acute flares of knee pain. Individuals with a history of inflammatory/crystal arthritis, fibromyalgia, and chronic pain syndrome were excluded. Latent class growth analysis was applied to measures of pain intensity repeated over 5 days to identify distinct recovery trajectories. The concurrent courses of interference with activity, stiffness, and swelling for each trajectory group were modelled using generalized estimating equations. Participant age, sex, obesity, and osteoarthritis diagnosis were described for each trajectory group. Results: A total of 449 participants were included (median age 55 years, 41% female, 35% obese, and 42% diagnosed with osteoarthritis). A 6-group cubic model was deemed optimal, with trajectories distinguished by rate of pain reduction and absolute level at final measurement. At the extremes were rapid and near-complete resolution (n = 41, 9%) and persistent, high pain (n = 25, 6%), but most participants showed a reduction and plateau in pain severity within 3–5 days. Within each pain trajectory group, interference with activity, stiffness, and swelling followed the same course as pain. Baseline characteristics did not differ substantially between trajectory groups. Conclusion: Even under a well-adhered to regime of oral nonsteroidal antiinflammatory medication, recovery following acute flares of knee pain is heterogeneous. Our observations that favorable trajectories are apparent within 3–5 days can help to inform treatment decision-making in the patient–health care professional consultation.

OBJECTIVE: The study objective was to determine the relationship of magnetic resonance imaging (MRI)-detected features of patellofemoral joint osteoarthritis to pain and functional outcomes.METHODS: We sampled 1,099 participants from the 60-month visit of the Multicenter Osteoarthritis Study (mean ± SD age: 66.8 ± 7.5 years; body mass index: 29.6 ± 4.8; 65% female). We determined the prevalence of MRI-detected features of patellofemoral joint osteoarthritis (eg, cartilage damage, bone marrow lesions, and osteophytes) and assessed the relationship between these features and knee pain severity, knee pain on stairs, chair stand time, and walking less than 6,000 steps per day. We evaluated the relationship of MRI features to each outcome using logistic and linear regression, adjusting for potential covariates.RESULTS: Participants with cartilage damage in 3-4 subregions had the highest mean pain severity (22.0/100; 95% confidence interval [CI]: 17.6-26.4 mm). They also showed higher odds of having at least mild pain on stairs (odds ratio [OR]: 3.3; 95% CI: 1.7-6.5) and of walking less than 6,000 steps per day (OR: 2.3; 95% CI: 1.1-4.4) compared with those without cartilage damage. Participants with bone marrow lesions in 3-4 subregions had higher odds of at least mild pain on stairs than those without (OR: 3.3; 95% CI: 2.2-5.2). Participants with osteophytes in 3-4 subregions also had higher odds of walking less than 6,000 steps/day (OR 2.1, 95% CI: 1.3-3.5, respectively).CONCLUSION: MRI-detected features of osteoarthritis of the patellofemoral joint are related to pain and functional performance. This knowledge highlights the need to develop treatments for those with patellofemoral joint osteoarthritis to improve pain and maximize function.

Key Points Question Are physical therapy (PT) interventions before and after total knee replacement (TKR) associated with lower risk of postoperative long-term use of opioids? Findings In this cohort study that included 67 322 individuals who underwent TKR, receipt of any pre- and post-TKR PT care, receipt of more than 5 post-TKR PT sessions, and initiation of PT care within 30 days after TKR were associated with lower risk of long-term opioid use. Meaning This study suggests that receipt of PT interventions may be associated with lower risk of long-term opioid use after TKR; these data may help inform effective dose and timing of PT interventions after TKR., Importance Many individuals who undergo total knee replacement (TKR) become long-term opioid users after TKR. Associations of physical therapy (PT) interventions before or after TKR with long-term use of opioids are not known. Objectives To evaluate associations of PT interventions before and after TKR with long-term opioid use after TKR. Design, Setting, and Participants This cohort study used data from the OptumLabs Data Warehouse on 67 322 individuals aged 40 years or older who underwent TKR from January 1, 2001, to December 31, 2016, stratified by history of opioid use. The analyses for the study included data from January 1, 1999, to December 31, 2018. Exposures Any PT interventions within 90 days before or after TKR, post-TKR PT dose as number of sessions (ie, 1-5, 6-12, and ≥13 sessions), post-TKR PT timing as number of days to initiation of care (ie, This cohort study evaluates associations of physical therapy interventions before and after total knee replacement with long-term use of opioids after total knee replacement among US adults.

Serum urate (SU) is the most common primary efficacy outcome in trials of urate-lowering therapies for gout. Despite this, it is not formally considered a validated surrogate outcome. In this paper we will outline the definitions of biomarkers and surrogate outcome measures, respectively as well as the available frameworks and challenges in the assessment of the validity of serum urate as a surrogate in gout (i.e. a reasonable replacement for gout symptoms).

Summary Objective This review outlines the most commonly used quantitative sensory tests to identify pain sensitization. We examine cross–sectional associations between quantitative sensory testing (QST) measures and OA symptoms and severity, along with longitudinal associations between QST findings and response to surgical and non-surgical treatments for OA. Design We conducted a search in PubMed for English language papers including ‘osteoarthritis’ and ‘quantitative sensory testing’ as search terms. Papers that did not pertain specifically to OA or QST were excluded. Results Pressure Pain Threshold (PPT), Conditioned Pain Modulation (CPM), and Temporal Summation (TS) are the QST measures used most frequently to identify pain sensitization. Findings indicate that persons with knee OA often exhibit lower PPT thresholds, inefficient CPM, and facilitated TS as compared with controls who do not have OA, supporting the discriminant validity of QST. Pre-treatment QST has shown some success in identifying persons who experience less pain relief from surgical and non-surgical treatments for knee OA. Post-treatment QST has shown that sometimes PPT and CPM can normalize (PPT thresholds increase, and CPM becomes efficient) in patients for whom joint replacement is successful. Recent studies indicate that QST measures are more closely associated with pain severity than OA radiographic severity, suggesting that sensitization may be a trait rather than a state. Conclusions QST may have a role in identifying persons who are susceptible to chronic pain and may offer an opportunity for personalized, more effective treatment of OA.

Objective This study aims to increase the understanding of pain mechanisms in hand OA and explore potential risk factors for pain development or worsening in a biopsychosocial framework. Another important aim is to validate potential soluble and imaging OA biomarkers. Design The follow-up examination of the Nor-Hand hospital-based observational cohort study started in October 2019 and was completed in May 2021. In total, 212 of the 300 participants with hand OA who were examined at baseline attended the follow-up study. The participants underwent clinical joint examinations, medical and functional assessments, quantitative sensory testing, fluorescence optical imaging, ultrasound of the hands, acromioclavicular joints, feet, knees and hips, conventional radiographs of the hands and feet and magnetic resonance imaging of the dominant hand. Blood and urine samples were collected, and all participants answered questions about demographic factors and OA-related questionnaires. Associations between disease variables and symptoms will be examined in cross-sectional and longitudinal analyses. Longitudinal analyses will be performed to assess the predictive value of baseline variables on hand OA outcomes. Conclusion Current knowledge about predictors for disease progression in hand OA is limited, but with longitudinal data we will be able to explore the predictive value of baseline variables on hand OA outcomes, such as changes in patient-reported outcomes or changes in soluble and imaging biomarkers. This provides a unique opportunity to gain more knowledge about the natural disease course of hand OA.

OBJECTIVE Knee osteoarthritis (OA) is a heterogeneous disease, with most patients experiencing slow disease progression and some with rapid deterioration. We aimed to identify groups of patients with symptomatic knee OA experiencing rapid structural progression. METHODS We selected participants from the Osteoarthritis Initiative with baseline Kellgren/Lawrence (K/L) grades 1-3 and knee pain, and with joint space width (JSW) on fixed-flexion knee radiographs assessed at baseline and with ≥1 follow-up over 8 years. We used latent class growth analysis to identify subgroups of JSW progression, jointly modeling time to knee replacement (KR) to account for potential informative dropouts. After identifying trajectories, we used logistic regression to assess the association between baseline characteristics and the JSW trajectory group. RESULTS We used data from 1,578 participants. Baseline radiographic severity was K/L grade 1 in 17%, K/L grade 2 in 50%, and K/L grade 3 in 33%. We identified 3 distinct JSW trajectories: 86% stable, 6% with stable JSW followed by late progression, and 8% with early progression. Incorporating information about KR resulted in 47% of KRs initially classified as stable being reclassified to 1 of the progressing trajectories. Prior knee surgery was associated with being in the late-progressing versus the stable trajectory, while obesity was associated with being in the early-progressing versus stable trajectory. CONCLUSION In addition to a subgroup of individuals experiencing early structural progression, 8-year longitudinal data allowed the identification of a late-progressing trajectory. Incorporating information about KR was important to properly identify longitudinal structural trajectories in knee OA.

BackgroundPatients with rheumatoid arthritis (RA) commonly demonstrate disordered pain processing, termed pain centralization. Heightened pain sensitivity and pain pathways associated with pain centralization are often assessed using quantitative sensory testing (QST), which is not routinely available and burdensome to patients. The self-administered fibromyalgia survey questionnaire (FSQ) has been proposed as a low-burden, surrogate measure of pain centralization. We examined the correlation between FSQ and QST as measures of pain centralization in a cohort of patients with active RA. MethodsParticipants in the multicenter Central Pain in Rheumatoid Arthritis (CPIRA) cohort underwent FSQ and QST evaluation at enrollment. QST measures included pressure pain threshold (PPT) at the thumb, trapezius, wrist and knee; temporal summation (TS) at the wrist and arm; and conditioned pain modulation (CPM). Partial Spearman correlation was assessed between FSQ and each QST measure, adjusted for age, sex, race, body mass index, serologic status, swollen joint count, C-reactive protein, pain catastrophizing, and study site. We performed sensitivity analyses including a) stratified analysis by sex and b) correlations between the two sub-components of the FSQ (widespread pain index [WPI], and symptom severity scale [SSS]) and QST measures.ResultsAmong 285 participants with high RA disease activity (mean baseline Clinical Disease Activity Index score 24.56), FSQ was weakly but statistically significantly correlated with PPT ( r = -0.21 to -0.31) and TS ( r = 0.13 to 0.15) at all sites in unadjusted analyses. After adjustment, statistically significant correlations persisted for PPT at all sites except the thumb, and for TS at the wrist Sensitivity analyses did not identify differences in association based on sex or with the components of the FSQ (WPI or SSS).ConclusionsFSQ and QST were correlated among participants with active RA, but the strength of association was modest. This may be due to the high level of RA disease activity of the cohort studied. Both QST and the FSQ are likely imperfect singular measures of pain centralization.

IMPORTANCE: Effective treatments for patients with severe COVID-19 are needed. OBJECTIVE: To evaluate the efficacy of canakinumab, an anti–interleukin-1β antibody, in patients hospitalized with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020. INTERVENTION: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-80 kg; n = 227) or placebo (n = 227). MAIN OUTCOMES AND MEASURES: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19–related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. RESULTS: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, −3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19–related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of −2.3% (95% CI, −6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo. CONCLUSIONS AND RELEVANCE: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04362813

Background Risk of myocardial infarction (MI) is elevated in ankylosing spondylitis and psoriatic arthritis (AS/PsA) compared to the general population. We evaluated the risk of MI related to the use of tumor necrosis factor inhibitor (TNFi) and other therapies in AS/PsA. Methods We conducted a nested case-control study using 1994–2018 data from OptumLabs® Data Warehouse, which includes de-identified medical and pharmacy claims, laboratory results, and enrollment records for commercial and Medicare Advantage enrollees. The database contains longitudinal health information on enrollees and patients, representing a diverse mixture of ages, ethnicities and geographical regions across the United States. Assessing AS/PsA separately, MI cases were matched to 4 controls by sex, age, diagnosis year and insurance type. We evaluated treatment within 6 months prior to MI including NSAIDs (AS referent), disease-modifying anti-rheumatic drug (DMARDs; PsA referent) and TNFi alone or in combinations. We evaluated the relation of treatment categories to MI risk using conditional logistical regression adjusting for confounders. Results Among 26,648 AS subjects, there were 237 MI cases and 894 matched controls. Among 43,734 PsA subjects, there were 404 cases and 1596 controls. In AS, relative to NSAID use, the adjusted odds ratio (aOR) for MI among TNFi only users was 0.85 (95% CI 0.39–1.85) and for DMARD only users was 1.04 (95% CI 0.65–1.68). In PsA, relative to DMARD use, the aOR among TNFi only was 1.09 (95% CI 0.74–1.60). Combination therapies also had no effect. Conclusions Among AS/PsA, no combination of therapies appeared to be protective or harmful with regards to MI. Future studies should capture more AS and PsA patients and include longer term follow up to further investigate this question.

Objectives Cherry concentrate has been suggested to reduce serum urate (SU) and gout flares. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate on SU in people with gout, the most effective dose of tart cherry concentrate for lowering SU, and adverse effects. Methods Fifty people with gout and SU > 0.36 mmol/l were recruited. Half were on allopurinol and half were on no urate-lowering therapy. Participants were randomized to receive tart cherry juice concentrate: placebo, 7.5 ml, 15 ml, 22.5 ml or 30 ml twice daily for 28 days. Blood samples were taken at baseline, then at 1, 3 and 5 h post cherry and then on days 1, 3, 7, 14, 21 and 28. The area under the curve for SU was calculated over the 28-day study period. Results Cherry concentrate dose had no significant effect on reduction in SU area under the curve, urine urate excretion, change in urinary anthocyanin between day 0 and day 28, or frequency of gout flares over the 28-day study period (P = 0.76). There were 24 reported adverse events, with only one (hyperglycaemia) considered possibly to be related to cherry concentrate. Allopurinol use did not modify the effect of cherry on SU or urine urate excretion. Conclusion Tart cherry concentrate had no effect on SU or urine urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368887, ANZCTR 12615000741583).

Objective To determine the relationship between omega-3 polyunsaturated fatty acid (n-3 PUFA) consumption (dietary or supplemental) and risk of gout flares. Methods We used data from the Boston University Online Gout Study, an internet-based case-crossover study conducted from February 2003 to January 2012. At the times of gout flares (hazard period) and during gout flare-free periods (control periods), participants completed questionnaires regarding exposures, including supplements and diet, during the preceding 48 hours. We examined the relationship of self-reported n-3 PUFA-rich supplements and fish intake with the risk of recurrent gout flares using conditional logistic regression, adjusting for total purine intake, diuretic use, and other urate-lowering or flare prophylactic medications (allopurinol, nonsteroidal antiinflammatory drugs, or colchicine). Results Of the 724 participants, 85% met the 1977 American College of Rheumatology preliminary criteria for the classification of the acute arthritis of primary gout. Twenty-two percent of the participants reported some form of n-3 PUFA consumption (supplements, 4.6%; dietary fatty fish, 19%) in the 48 hours preceding a gout flare or flare-free period. The adjusted odds ratios were 1.01 (95% confidence interval [95% CI] 0.63-1.60; P = 0.98) for all 3 supplements combined and 0.74 (95% CI 0.54-0.99; P = 0.04) for consumption of ≥2 n-3 PUFA-rich fish servings. Conclusion Dietary n-3 PUFA-rich fish consumption, when adjusted for total purine intake, was associated with lower risk of recurrent gout flares, whereas n-3 PUFA supplementation alone, as taken in a self-directed manner, was not. Consumption of specific sources and adequate doses of n-3 PUFA for gout flare prevention warrants further study in an adequately powered clinical trial.

ObjectivesThe recombinant zoster vaccine (RZV) containing a strong non-aluminium adjuvant is associated with increased risk of gout flares, presumably via NLRP3 inflammasome activation. We tested the possibility that other vaccines may also be associated with gout flares.MethodsWe conducted an online case-crossover study of patients with gout to examine the association between vaccination and gout flares. We collected information through the Internet on exposures to potential risk factors, including vaccinations, during 2-day hazard periods prior to gout flare and 2-day control periods without a flare. Conditional logistic regression was used to adjust for covariates.ResultsThere were 517 participants with gout (mean age 55 years, 79% male) who experienced gout flares during follow-up. There were 28 vaccinations during 990 hazard periods and 21 vaccinations during 1407 control periods. Vaccination was associated with twofold higher odds of gout flare (adjusted OR 1.99; 95% CI 1.01 to 3.89).ConclusionOur findings suggest vaccines other than RZV are associated with increased odds of gout flares, potentially through a shared pathogenetic mechanism like NLRP3 inflammasome. However, the absolute magnitude of increased odds of gout flares with vaccinations remains small and must be interpreted within the context of the overwhelming benefits of vaccinations.

In 1992, the Food and Drug Administration (FDA) instituted the accelerated approval regulations that allow drugs or biologics for serious conditions that fill an unmet medical need to be approved on the basis of a surrogate endpoint or an intermediate clinical endpoint. The current definition of a serious condition includes chronic disabling conditions, such as osteoarthritis (OA), and thereby provides expanded opportunities for the use of biomarkers for regulatory approval of drugs for OA. The use of surrogates or intermediate clinical endpoints for initial regulatory approval of a drug or biologic requires confirmation in a post-marketing study of a drug effect on a clinically relevant outcome, such as on how a patient feels, functions or survives. Current FDA guidance requires that the post-marketing approval (PMA) study be ongoing during the time of initial drug approval. This white paper arose out of the need to brainstorm trial designs that might be suitable for PMA of drugs initially approved, on the basis of a surrogate or intermediate clinical endpoint, for treatment of OA to alter disease progression, abnormal function or pathological changes in the morphology of the joint. In this white paper we define the concept and regulations regarding accelerated approval and propose two major study design scenarios for PMA trials in OA. The long-term goal is to discuss and refine these designs in consultation with regulatory agencies in order to facilitate development of drugs to fill the large unmet need in OA.

Objective The Patient-Reported Outcomes Measurement Information System (PROMIS) is a calibrated item bank used to assess patient-reported outcomes across multiple domains. The purpose of this study was to describe the performance of selected PROMIS measures in patients with rheumatoid arthritis (RA) with active disease who were initiating a disease-modifying antirheumatic drug (DMARD). Methods Participants in an ongoing prospective observational study completed 8 PROMIS measures before and after DMARD initiation. Linear regression models were performed to identify cross-sectional associations between baseline PROMIS measures and disease activity, measured using the Clinical Disease Activity Index (CDAI). Paired t-tests were performed to evaluate responsiveness after 12 weeks of DMARD treatment. Associations between changes in PROMIS measures and changes in the CDAI score were assessed using linear regression. Results Among the 156 participants who completed the first study visit, the mean ± SD baseline CDAI score was 25.5 ± 14.0. Baseline scores for PROMIS measures of physical health, pain, and sleep were associated with the baseline CDAI score (P ≤ 0.05). Among the 106 participants with 12-week data, all PROMIS scores improved after DMARD initiation (P ≤ 0.05). With the exception of depression, changes in all assessed PROMIS measures were correlated with changes in the CDAI score (standardized βs from |0.23| to |0.38|). Conclusion These data provide support for the utility of PROMIS measures for the assessment of physical and mental health in individuals with active RA. All PROMIS measures improved significantly after DMARD initiation, with the magnitudes of association between changes in PROMIS measures and changes in the CDAI score in the low-to-moderate range.

Objective Obesity, 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. Methods We 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. Results Among 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]). Conclusion In 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.

Background Anti-nerve growth factor (NGF) has shown promise for osteoarthritis (OA) pain efficacy, but an unanticipated joint safety signal occurred in trials. To what extent this was related to OA natural history, or was a consequence of anti-NGF agents is unclear. Of the adverse joint safety events identified, osteonecrosis has specific diagnostic codes available in the medical record to enable assessment of its frequency in the general community. We therefore investigated the rates of knee osteonecrosis in three real-world cohorts using two data sources to place these trial data in context. Methods We used data from UK-based IQVIA Medical Research Data (IMRD) of adults diagnosed with incident knee OA between 2000 and 2018 to examine the incidence of knee osteonecrosis using different definitions. Additionally, we evaluated the incidence of knee osteonecrosis in the year prior to knee replacement in IMRD and among US Medicare beneficiaries who received a knee replacement in 2011–2014. Results In IMRD, among 122,343 subjects with incident knee OA (mean age 68 years, 58% female), incidence estimates for knee osteonecrosis were 0.006–0.10%, with incidence rates of 0.01–0.17 per 1000 person-years. Among the 81,807 who had a knee replacement, the incidence of knee osteonecrosis in the year prior to knee replacement was 0.004–0.06%. In Medicare, among 316,593 with knee replacement (mean age 74, 68% female), the incidence of knee osteonecrosis was 0.24–0.7%. Conclusion Knee osteonecrosis is rare among people with knee OA, including in the year prior to knee replacement. These data provide context for interpreting osteonecrosis events in NGF trials.

We thank the authors for their interest in our work.1–3 Their approach and results provide yet additional support to the adverse impact of warfarin on osteoarthritis outcomes, as compared with direct oral anticoagulants. Deidentified data were used for this work. These data …

BackgroundIdentification of modifiable risk factors and treatments for osteoarthritis (OA) are needed. Warfarin, a vitamin K antagonist, causes fetal and animal model skeletal abnormalities. Vitamin K insufficiency has been associated with OA, but whether warfarin is also detrimental to OA is not known.MethodsWe conducted a nested case–control study using a UK general practitioner electronic medical records database. We identified cases of knee or hip replacement (KR or HR) from among adults with atrial fibrillation newly prescribed either warfarin or direct oral anticoagulants (DOACs). Cases were matched with four controls by age and sex. We assessed the relation of warfarin compared with DOAC use to risk of joint replacement using conditional logistic regression. We also evaluated different durations of warfarin use.ResultsWe identified 857 subjects with KR or HR (cases), of whom 64.6% were warfarin users, and 3428 matched controls, of whom 56.1% were warfarin users (mean age 75, 47% female). Warfarin users had a 1.59 times higher risk of joint replacement than DOAC users (adjusted OR 1.59, 95% CI 1.31 to 1.92). Longer duration of warfarin use was associated with higher risk of joint replacement in comparison with ConclusionWarfarin, a vitamin K antagonist, was associated with greater risk of KR and HR (an indicator for end-stage knee OA) than DOAC use, supporting the importance of adequate vitamin K functioning in limiting OA progression.

Introduction Elevated serum urate (SU) concentration is the central risk factor for the development of gout. The aim of this study was to examine the incidence of gout in people with low and normal SU levels ( Methods Longitudinal cohort data from the Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), and both the Original and Offspring cohorts of the Framingham Heart Study (FHS) were used to determine incident gout by baseline SU over 3, 5, 10, 12 and 15 year periods. A Cox proportional hazards model with covariables of age, gender, ethnicity, and cohort was calculated to report the hazard ratios (HR) for incident gout. Results The incidence of gout at 15 years for a baseline SU 7.00 mg/dL was 12.2%. In an adjusted Cox proportional hazards model, compared to the referent baseline SU 7.00 mg/dL (HR 18.62). Conclusion A baseline SU of 5.50 mg/dL or more is a risk factor for development of gout over 15 years. However, incident gout does occur over time in a small proportion of people with lower baseline SU levels.

Objective: The 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. Methods: Using 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. Results: Using 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. Conclusion: Patellofemoral but not tibiofemoral joint OA features and inflammation were associated with AKP.

Objective To examine the association of the volume and intensity of daily walking at baseline with the risk of knee replacement (KR) over 5 years in adults with advanced structural knee osteoarthritis. Design Prospective, longitudinal, and multicenter observational study. Setting Osteoarthritis Initiative study with follow-up from 2008-2015. Participants Community-dwelling adults with or at risk of knee osteoarthritis were recruited from 4 sites in the United States (N=516; mean age, 67.7±8.6y; body mass index, 29.3±4.7 kg/m2; 52% female). We included participants with advanced structural disease, without KR and had valid daily walking data (quantified using Actigraph GT1M), at baseline. Interventions Not applicable. Main outcomes KR. Walking volume was measured as steps/day and intensity as minutes/day spent not walking (0 steps/min) and walking at very light (1-49 steps/min), light (50-100 steps/min), or moderate (>100 steps/min) intensities. To examine the relationship of walking volume and intensity with the risk of KR, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for covariates. Results Of 516 adults with advanced structural disease, 88 received a KR over 5 years (17%). Walking an additional 1000 steps/d was not associated with the risk of KR (adjusted HR=0.95; 95% CI, 0.84-1.04). Statistically, replacing 10 min/d of very light and light walking with 10 min/d of moderate walking reduced the risk of KR incidence by 35% and 37%, respectively (adjusted HR=0.65, 95% CI, 0.45-0.94, for very light and adjusted HR=0.63; 95% CI, 0.40-1.00, for light). Conclusions Daily walking volume and intensity did not increase KR risk over 5 years and may be protective in some cases in adults with advanced structural knee osteoarthritis.

Objective Pain sensitization is associated with pain severity in persons with hand OA. What contributes to pain sensitization is unclear. This study explores whether hand OA pathologies and symptom duration are related to central sensitization. Method Participants with hand OA in the Nor-Hand study underwent bilateral hand radiography and US examination. Central sensitization was assessed with pressure pain thresholds (PPT) at remote sites (wrist, trapezius and tibialis anterior muscles) and temporal summation. We examined whether hand OA pathologies, independent of each other, including structural severity (Kellgren–Lawrence sum score, presence of erosive hand OA), inflammatory severity (greyscale synovitis and power Doppler activity sum scores) and symptom duration, were related to central sensitization, adjusting for age, sex, BMI, comorbidities and OA-severity of knee/hip. Results In 291 participants (88% women, median age 61 years, interquartile range 57–66 years) Kellgren–Lawrence, greyscale synovitis and power Doppler activity sum scores were not associated with lower PPTs at remote sites. Persons with erosive hand OA had lower PPTs at the wrist (adjusted beta −0.75, 95% CI −1.32, −0.19) and tibialis anterior (adjusted beta −0.82, 95% CI −1.54, −0.09) and had greater temporal summation (adjusted beta 0.56, 95% CI 0.12, 1.01) compared with persons with non-erosive disease. No associations were found for symptom duration. Conclusions A person’s overall amount of structural or inflammatory hand OA pathologies was not associated with central sensitization. Although persons with erosive hand OA showed greater signs of central sensitization, the small differences suggest that central sensitization is mainly explained by factors other than joint pathologies.

Symptomatic knee osteoarthritis (SKOA) is a chronic, disabling condition, requiring long-term pain management; over 800,000 SKOA patients in the US use opioids on a prolonged basis. We aimed to characterize the societal economic burden of opioid use in this population.We used the Osteoarthritis Policy Model, a validated computer simulation of SKOA, to estimate the opioid-related lifetime and annual cost generated by the US SKOA population. We included direct medical, lost productivity, criminal justice, and diversion costs. We modeled the SKOA cohort with a mean ± SD age of 54 ± 14 years and Western Ontario and McMaster Universities Osteoarthritis Index pain score of 29 ± 17 (0-100, 100 = worst). We estimated annual costs of strong ($1,381) and weak ($671) opioid regimens using Medicare fee schedules, Red Book, the Federal Supply Schedule, and published literature. The annual lost productivity and criminal justice costs of opioid use disorder (OUD), obtained from published literature, were $11,387 and $4,264, per-person, respectively. The 2015-2016 Medicare Current Beneficiary Survey provided OUD prevalence. We conducted sensitivity analyses to examine the robustness of our estimates to uncertainty in input parameters.Assuming 5.1% prevalence of prolonged strong opioid use, the total lifetime opioid-related cost generated by the US SKOA population was estimated at $14.0 billion, of which only $7.45 billion (53%) were direct medical costs.Lost productivity, diversion, and criminal justice costs comprise approximately half of opioid-related costs generated by the US SKOA population. Reducing prolonged opioid use may lead to a meaningful reduction in societal costs that can be used for other public health causes.