Objectives,To examine the association of antecedent infection and acute healthcare utilization as risk factors for frailty in Systemic Lupus Erythematosus (SLE).,Methods,Participants from a longitudinal, single-center SLE cohort were surveyed cross-sectionally for presence of frailty, utilizing two different tools: 1) SLICC-FI; and 2) FRAIL scale. We examined association of frailty with two risk factors: 1) Infection within prior 3 months (Yes/No) and 2) Acute level care utilization (hospitalization, emergency department or urgent care visits) over prior 3 months (Yes/No), using logistic regression models adjusted for relevant covariates. In sensitivity analyses, we examined medications use in relation to frailty.,Results,87 respondents (93.1% female, 36.8% Black, mean age 42.3 years, mean SLE duration 14.2 years, 9.2% antecedent infection and 19.5% acute level care utilization) were included. Prevalence of frailty was 26.4% by SLICC-FI and 14.9% by FRAIL scale. After covariate adjustment, infection was associated with greater odds of frailty by SLICC-FI (OR 7.19, 95% CI 1.15-44.65). Sensitivity analyses demonstrated increased odds of frailty with prednisone use by SLICC-FI (OR 2.34, 95% CI 0.88-6.26) and by FRAIL scale (OR 9.64, 95% CI 2.39-38.80).,Conclusions,In this study, frailty was prevalent in SLE by SLICC-FI and FRAIL scale. Antecedent infection and prednisone use were associated with greater odds of frailty in SLE in this cross-sectional study. Large prospective studies are needed to corroborate our findings and elucidate mechanistic underpinnings into infection and prednisone use with development of frailty in SLE.

Knee and hip osteoarthritis (OA) are highly prevalent joint diseases that lead to chronic pain, disability, and increased mortality. In this review, we provide a summary of nonsurgical treatments available for knee and hip OA that have evidence to support their use. We also provide a summary of the treatments available for knee and hip OA that do not have sufficient evidence to support their use. Treatments covered in this review include pharmacologic and nonpharmacologic modalities. Cite this article as: Misra D, Felson DT. Evidence-based review of nonsurgical treatments for knee and hip osteoarthritis. Eur J Rheumatol. Published online March 25, 2024. doi: 10.5152/ eurjrheum.2024.22096.

Objective Inflammation worsens joint destruction in osteoarthritis (OA) and aggravates pain. Although n‐3 fatty acids reduce inflammation, different n‐3 fatty acids have different effects on inflammation and clinical outcomes, with eicosapentaenoic acid (EPA) having the strongest effect. We examined whether specific essential fatty acid levels affected the development of OA. Methods We studied participants from the Multicenter Osteoarthritis Study (MOST) at risk of developing knee OA. As part of MOST, participants were asked repeatedly about knee pain, and knee radiographs and magnetic resonance images (MRIs) were obtained. Using baseline fasting samples, we analyzed serum fatty acids with standard assays. After excluding participants with baseline OA, we defined two sets of cases based on their status through 60 months’ follow‐up: those developing incident radiographic OA and those developing incident symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of MRI cartilage damage and synovitis and worsening knee pain and evaluated the number of hand joints affected by nodules. In regression models, we tested the association of each OA outcome with levels of specific n‐3 and n‐6 fatty acids, adjusting for age, sex, body mass index, education, physical activity, race, baseline pain, smoking, statin use, and depressive symptoms. Results We studied 363 cases with incident symptomatic knee OA and 295 with incident radiographic knee OA. The mean age was 62 years (59% women). We found no associations of specific n‐3 fatty acid levels, including EPA, or of n‐6 fatty acid levels with incident OA (eg, for incident symptomatic knee OA, the odds ratio per SD increase in EPA was 1.0 [95% confidence interval 0.87–1.17]). Results for other OA outcomes also failed to suggest a protective effect of specific n‐3 fatty acids with OA outcomes. Conclusion We found no association of serum levels of EPA or of other specific n‐3 fatty acids or n‐6 fatty acids with risk of incident knee OA or other OA outcomes.

Cite this article as: Misra D. Special issue on osteoarthritis: Risk factors and treatment strategies. Eur J Rheumatol. 2024;11(suppl 1):S1-S2.

Frailty represents a dynamic multisystem state of reduced physiological reserve that increases vulnerability to adverse health outcomes. Frailty occurs prematurely in adults with immune-mediated rheumatic diseases and is emerging as an important risk factor for adverse outcomes in these conditions. In this Series paper, we present a conceptual overview of frailty and its prevalence among patients with immune-mediated rheumatic diseases. We discuss putative mechanisms of frailty relevant to these diseases, tools for frailty measurement, and potential implications of frailty assessment for clinical care. We also explore the complex inter-relationship between frailty, inflammation, and disease activity in immune-mediated rheumatic diseases. As insight is gained into the epidemiology and mechanisms of frailty among patients with immune-mediated inflammatory rheumatic diseases, the possibility of targeting frailty with an intervention that could complement standard disease-modifying therapies to prevent adverse outcomes and improve health-related quality of life becomes closer to reality.

The primary clinical features of myopathies include weakness and muscle wasting but may also present with fatigue, muscle pain, tenderness, myotonia, and muscle twitching. In the elderly, the most frequently encountered acquired disorders are the idiopathic inflammatory myopathies, toxic/ drug-induced myopathies, and muscle disease in association with endocrine and metabolic diseases. A fairly common pathway from the clinical evaluation to diagnosis is via biochemical studies, electrophysiological assessment, and muscle biopsy. In primary disorders of the muscle, electromyography characteristically shows a reduction in the size and duration of the motor unit potentials and an increase in the number of polyphasic units. Toxic and drug-induced myopathies are an important, and almost certainly underdiagnosed, group of disorders, not least because prompt removal of the offending agent may lead to full recovery. The term muscular dystrophy encompasses a group of progressive, inherited disorders in which the primary pathological process is degeneration of muscle fibres.

Objective: Proton pump inhibitors (PPIs) are among the most commonly used medications for patients with osteoarthritis (OA). Various types of PPIs have different impacts on lowering serum magnesium level that may affect knee OA progression. We aimed to compare the risk of clinically relevant endpoint of knee replacement (KR) among initiators of five different PPIs with that among histamine-2 receptor antagonist (H2RA) initiators. Design: Among patients with knee OA (>= 50 years) in The Health Improvement Network database in the UK we conducted five sequential propensity-score matched cohort studies to compare the risk of KR over 5-year among patients who initiated omeprazole (n =2,672), pantoprazole (n =664), lansoprazole (n =3,747), rabeprazole (n =751), or esomeprazole (n =827) with those who initiated H2RA. Results: The prevalence of PPI prescriptions among participants with knee OA increased from 12.7% in 2000-44.0% in 2017. Two-hundred-and-seventy-four KRs (30.8/1,000 person-years) occurred in omeprazole initiators and 230 KRs (25.4/1,000 person-years) in H2RA initiators. Compared with H2RA initiators, the risk of KR was 21% higher in omeprazole initiators (hazard ratio [HR] =1.21,95% confidence interval [CI]:1.01-1.44). Similar results were observed when pantoprazole use was compared with H2RA use (HR =1.38,95%CI:1.00-1.90). No such an increased risk of KR was observed among lansoprazole (HR =1.06,95%CI:0.92-1.23), rabeprazole (HR =0.97,95%CI:0.73-1.30), or esomeprazole (HR =0.83,95% CI:0.60-1.15) initiators compared with that among H2RA initiators. Conclusions: In this population-based cohort study, initiation of omeprazole or pantoprazole use was associated with a higher risk of KR than initiation of H2RA use. This study raises concern regarding an unexpected risk of omeprazole and pantoprazole on accelerating OA progression. (C) 2022 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

INTRODUCTION:Higher intake of fiber has been associated with lower risk of incident symptomatic osteoarthritis (OA). We examined whether levels of alkylresorcinol (AR), a marker of whole grain intake, were associated with OA in subjects in The Multicenter Osteoarthritis (MOST) Study. METHOD:Knee x-rays and knee pain were assessed at baseline and through 60-months. Stored baseline fasting plasma samples were analyzed for AR homologues (C17:0, C19:0, C21:0, C23:0, C25:0) and total AR levels (AR sum). Two nested case-control studies, one for incident radiographic OA and one for incident symptomatic OA were performed with participants re-assessed at 15, 30 and 60 months. Multivariable conditional logistic regression with baseline covariates including age, sex, BMI, physical activity, quadriceps strength, race, smoking, depressive symptoms, diabetes and knee injury tested the association of log transformed AR levels with OA outcomes. RESULTS:Seven hundred seventy-seven subjects were, on average, in their 60's, and most were women. For 60-month cumulative incidence, there was no significant association between quartiles of AR concentration and incident radiographic (e.g., for incident radiographic OA, highest vs lowest quartile of AR sum showed RR = 0.93 (95% CI 0.59, 1.47), and for symptomatic OA RR was 1.22 (95% CI 0.76, 1.94). In secondary analyses examining 30-month incidence, high AR levels were associated with a reduced risk of X-ray OA (RR = 0.31 (95% CI 0.15, 0.64). CONCLUSION:In primary analyses, AR levels were not associated with risk of OA, but secondary analyses left open the possibility that high AR levels may protect against OA.

Objective: Inflammation worsens joint destruction in osteoarthritis (OA) and aggravates pain. Saturated and n-6 fatty acids (FAs) increase, whereas n-3 FAs reduce inflammation. We examined whether FA levels affected the development of OA. Design: We studied participants from the Multicenter Osteoarthritis study (MOST) at risk of developing knee OA. After baseline, repeated knee x-rays and MRIs were obtained and knee symptoms queried through 60 month follow-up. Using baseline fasting samples, serum FAs were analyzed with standard assays. After excluding participants with baseline OA, we defined two sets of cases: those developing radiographic OA and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of MRI cartilage loss and synovitis and of knee pain using WOMAC and evaluated the number of hand joints affected by nodules. In regression models, we tested the association of each OA outcome with levels of saturated, n-3 and n-6 FAs adjusting for age, sex, BMI, education, race, baseline pain and depressive symptoms. Results: We studied 260 cases with incident symptomatic and 259 with incident radiographic OA. Mean age was 61 years (61% women). We found no signficant nor suggestive associations of FA levels with incident OA (e.g., for incident symptomatic OA, OR per s.d. increase in n-3 FA 1.00 (0.85, 1.18) nor with any OA outcome in knee or hand. Conclusion: Despite previously described effects on systemic inflammation, blood levels of FAs were not associated with risk of later knee OA or other OA outcomes. (c) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

ObjectiveHypomagnesemia increases the risk of chondrocalcinosis and calcium pyrophosphate disease. We examined whether the use of drugs that can cause hypomagnesemia, diuretics and proton pump inhibitors (PPIs), increases the risk of chondrocalcinosis.MethodsParticipants in the Multicenter Osteoarthritis (MOST) Study obtained weight‐bearing knee radiographs, and their medication use was recorded at baseline and 30‐, 60‐, 84‐, and 144‐month examinations. We read radiographs serially for chondrocalcinosis and characterized incident chondrocalcinosis when it first appeared. We classified diuretic use as thiazide, loop, and other. To test drug effects on incident chondrocalcinosis at each interval (eg, 30‐60 months), we excluded persons with chondrocalcinosis at the interval’s beginning. For each drug, we evaluated exposure at the beginning and end of the interval. We conducted knee‐based analyses using Bayesian mixed‐effects discrete time survival models adjusted for age, sex, body mass index, radiographic osteoarthritis, race, and clinic site.ResultsOf 5272 knees, 196 developed chondrocalcinosis. Thiazide use (21.7% of examinations) and PPI use (13.7%) were common. Neither loop nor other diuretic use was associated with incident chondrocalcinosis. Thiazide use at the beginning and end of the interval of incidence conferred a high risk (hazard ratio [HR] = 2.18; 95% confidence interval [CI] 1.23‐3.89), but use at the beginning of the interval was not associated with risk (HR = 1.04). PPI use at the interval’s beginning increased risk of chondrocalcinosis (HR = 2.29; 95% CI 1.37‐3.79).ConclusionThiazide diuretics, but not other diuretics, and PPI use probably increase the risk of chondrocalcinosis. These findings may have important clinical implications.

Several professional organizations have recommended tramadol as one of the first-line or second-line therapies for patients with chronic noncancer pain and its prescription has been increasing rapidly worldwide; however, the safety profile of tramadol, such as risk of fracture, remains unclear. This study aimed to examine the association of tramadol with risk of hip fracture. Among individuals age 50 years or older without a history of hip fracture, cancer, or opioid use disorder in The Health Improvement Network (THIN) database in the United Kingdom general practice (2000-2017), five sequential propensity score-matched cohort studies were assembled, ie, participants who initiated tramadol or those who initiated one of the following medications: codeine (n = 146,956) (another commonly used weak opioid), naproxen (n = 115,109) or ibuprofen (n = 107,438) (commonly used nonselective nonsteroidal anti-inflammatory drugs [NSAIDs]), celecoxib (n = 43,130), or etoricoxib (n = 27,689) (cyclooxygenase-2 inhibitors). The outcome was incident hip fracture over 1 year. After propensity-score matching, the included participants had a mean age of 65.7 years and 56.9% were women. During the 1-year follow-up, 518 hip fracture (3.7/1000 person-years) occurred in the tramadol cohort and 401 (2.9/1000 person-years) occurred in the codeine cohort. Compared with codeine, hazard ratio (HR) of hip fracture for tramadol was 1.28 (95% confidence interval [CI] 1.13 to 1.46). Risk of hip fracture was also higher in the tramadol cohort than in the naproxen (2.9/1000 person-years for tramadol, 1.7/1000 person-years for naproxen; HR = 1.69, 95% CI 1.41 to 2.03), ibuprofen (3.4/1000 person-years for tramadol, 2.0/1000 person-years for ibuprofen; HR = 1.65, 95% CI 1.39 to 1.96), celecoxib (3.4/1000 person-years for tramadol, 1.8/1000 person-years for celecoxib; HR = 1.85, 95% CI 1.40 to 2.44), or etoricoxib (2.9/1000 person-years for tramadol, 1.5/1000 person-years for etoricoxib; HR = 1.96, 95% CI 1.34 to 2.87) cohort. In this population-based cohort study, the initiation of tramadol was associated with a higher risk of hip fracture than initiation of codeine and commonly used NSAIDs, suggesting a need to revisit several guidelines on tramadol use in clinical practice. © 2020 American Society for Bone and Mineral Research.

Objective To 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. Methods We 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. Results Based 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. Conclusion This 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.

Currently, no biomarkers are available for structural changes in osteoarthritis structural disease in osteoarthritis (OA) (1). Increase in the permeability of the synovial/blood barrier in OA enables greater exchange between the synovial cavity and systemic circulation. Thus, it is possible to identify systemic biomarkers relevant to prognosis, diagnosis, or phenotyping that may reflect changes in the synovial cavity. We aimed to correlate the levels of potential biomarkers associated with OA in synovial fluid and serum of patients with knee OA to understand whether local changes in these mediators are reflected systemically. We focused on senescence-associated secretory factors because advanced age is a major risk factor and senescence is implicated in aging and OA. To our knowledge, no previous studies have assessed this correlation. We recruited community-dwelling, ambulatory patients with knee OA from rheumatology clinic at Boston Medical Center, Boston, MA, USA. All participants underwent knee effusion aspiration at least once on a prior visit to exclude inflammatory and crystal arthritis. The knee synovial fluid that was aspirated for usual care during clinic visit and blood were collected contemporaneously and stored at -80°C. The synovial fluid and serum were anaJose E. Rubio1 , Carla Scanzello2 , David T. Felson3 , Matt B. Au3 , Joyce Goggins3 , Anne Plunkett3 , Devyani Misra3 Letter to the Editor

Background Longitudinal evidence on change of serum urate level with mortality risk is limited as prior studies have a measurement of serum urate at a single time point. Further, the combined effect of serum urate and systemic inflammation on mortality is unknown. Methods We conducted a prospective cohort study of 152,358 participants (122,045 men and 30,313 women) with repeated measurements of serum urate in 2006, 2008, 2010, and 2012 (107,751 participants had all four measurements of serum urate). We used the Cox proportional hazard model to examine the association between cumulative average and changes in serum urate with mortality. The combined effect of serum urate and systemic inflammation was determined by testing the interaction of serum urate and high-sensitive C-reactive protein (hs-CRP) in relation to mortality risk. Results During a median follow-up of 8.7 (interquartile range 6.3–9.2) years, we identified 7564 all-cause deaths, 1763 CVD deaths, 1706 cancer deaths, and 1572 other deaths. We observed U-shaped relationships of cumulative average serum urate with all-cause mortality, cardiovascular mortality, and other mortalities. Compared with participants with stable serum urate, those with greater increases in serum urate had a 1.7-fold elevated mortality (hazard ratio (HR) = 1.66, 95% confidence interval (CI) = 1.49–1.84), and those with decreased serum urate had a 2-fold elevated mortality risk (HR = 2.14, 95% CI 1.93–2.37). Participants with both hyperuricemia and hs-CRP had 1.6 times higher mortality, compared with those with low serum urate and hs-CRP levels (HR = 1.56, 95% CI 1.37–1.76). Conclusions We observed a U-shaped relationship of long-term cumulative average serum urate with all-cause mortality, cardiovascular mortality, and other mortalities. Compared with participants with relatively stable serum urate levels, a greater increase or decrease in serum urate was associated with elevated mortality. Participants with both hyperuricemia and high systemic inflammation had the greatest mortality risk compared with those with low serum urate and low hs-CRP levels.