Pain Reduction With Oral Methotrexate in Knee Osteoarthritis : A Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain. OBJECTIVE: To assess symptomatic benefits of methotrexate in knee OA (KOA). DESIGN: A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41). SETTING: 15 secondary care musculoskeletal clinics in the United Kingdom. PARTICIPANTS: A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion. INTERVENTION: Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia. MEASUREMENTS: The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs). RESULTS: A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate (n = 77) or placebo (n = 78). Follow-up was 86% (n = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2). LIMITATION: Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance. CONCLUSION: Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months. PRIMARY FUNDING SOURCE: Versus Arthritis.

Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial.

Background: Synovitis is believed to play a role in producing symptoms in persons with hand osteoarthritis, but data on slow-acting anti-inflammatory treatments are sparse. Objective: To determine the effectiveness of hydroxychloroquine versus placebo as an analgesic treatment of hand osteoarthritis. Design: Randomized, double-blind, placebo-controlled clinical trial with 12-month follow-up. (ISRCTN registry number: ISRCTN91859104). Setting: 13 primary and secondary care centers in England. Participants: Of 316 patients screened, 248 participants (82% women; mean age, 62.7 years) with symptomatic (pain ≥4 on a 0- to 10-point visual analogue scale) and radiographic hand osteoarthritis were randomly assigned and 210 (84.7%) completed the 6-month primary end point. Intervention: Hydroxychloroquine (200 to 400 mg) or placebo (1:1) for 12 months with ongoing usual care. Measurements: The primary end point was average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]) at 6 months. Secondary end points included self-reported pain and function, grip strength, quality of life, radiographic structural change, and adverse events. Baseline ultrasonography was done. Results: At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group, with a treatment difference of -0.16 point (95% CI, -0.73 to 0.40 point) (P = 0.57). Results were robust to adjustments for adherence, missing data, and use of rescue medication. No significant treatment differences existed at 3, 6, or 12 months for any secondary outcomes. The percentage of participants with at least 1 joint with synovitis was 94% (134 of 143) on grayscale ultrasonography and 59% on power Doppler. Baseline structural damage or synovitis did not affect treatment response. Fifteen serious adverse events were reported (7 in the hydroxychloroquine group [3 defined as possibly related] and 8 in the placebo group). Limitation: Hydroxychloroquine dosage restrictions may have reduced efficacy. Conclusion: Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis. Primary Funding Source: Arthritis Research UK.

Developing a toolkit for the assessment and monitoring of musculoskeletal ageing.

The complexities and heterogeneity of the ageing process have slowed the development of consensus on appropriate biomarkers of healthy ageing. The Medical Research Council-Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA) is a collaboration between researchers and clinicians at the Universities of Liverpool, Sheffield and Newcastle. One of CIMA's objectives is to 'Identify and share optimal techniques and approaches to monitor age-related changes in all musculoskeletal tissues, and to provide an integrated assessment of musculoskeletal function'-in other words to develop a toolkit for assessing musculoskeletal ageing. This toolkit is envisaged as an instrument that can be used to characterise and quantify musculoskeletal function during 'normal' ageing, lend itself to use in large-scale, internationally important cohorts, and provide a set of biomarker outcome measures for epidemiological and intervention studies designed to enhance healthy musculoskeletal ageing. Such potential biomarkers include: biochemical measurements in biofluids or tissue samples, in vivo measurements of body composition, imaging of structural and physical properties, and functional tests. This review assesses candidate biomarkers of musculoskeletal ageing under these four headings, details their biological bases, strengths and limitations, and makes practical recommendations for their use. In addition, we identify gaps in the evidence base and priorities for further research on biomarkers of musculoskeletal ageing.

Paracetamol: not as safe as we thought? A systematic literature review of observational studies.

OBJECTIVES: We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol. METHODS: We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome. RESULTS: Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose-response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose-response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose-response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose-response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43). DISCUSSION: Given the observational nature of the data, channelling bias may have had an important impact. However, the dose-response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

Diagnosis and management of polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a common inflammatory condition of unknown aetiology with a prevalence of 1 in 133 in the over 50s, and a female to male ratio of 2:1. Symptoms develop over a matter of weeks; typically bilateral shoulder or pelvic girdle pain and stiffness, that is worse in the mornings. Associated symptoms include low-grade fever, malaise, fatigue, low mood, poor appetite, and weight loss. There is no specific diagnostic test for PMR but the usual pattern is a commensurate rise in CRP and ESR. A small proportion of PMR patients will have normal inflammatory markers. PMR is associated with giant cell arteritis (GCA). Half of patients with GCA will have some PMR symptoms and up to one fifth of patients with PMR will have evidence of GCA. Other conditions that can mimic PMR include: rheumatic disease in the elderly e.g. rheumatoid arthritis; inflammatory muscle diseases; thyroid disease; malignancy; infection; bilateral shoulder capsulitis; osteoarthritis, Parkinsonism and depressive illness. At diagnosis and each follow-up visit it is imperative to consider the potential for associated GCA. The patient should be asked about headaches, jaw claudication and visual disturbance. If there is any suspicion of GCA, urgent discussion with the rheumatologist should take place that day.

A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.

OBJECTIVES: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. METHODS: We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. RESULTS: We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis). CONCLUSIONS: Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

Population prevalence of ultrasound features of osteoarthritis in the hand, knee and hip at age 63 years: the Newcastle thousand families birth cohort.

BACKGROUND: Musculoskeletal ultrasound has been found to be more sensitive than radiographs in detecting osteophytes. Our objective was to measure the prevalence of features of osteoarthritis (OA), in the dominant hand, knees and hips using ultrasound, within the Newcastle Thousand Families birth cohort. METHODS: Participants were aged 61-63 (mean 63) years. Knee images were scored for presence of osteophytes and effusion. Hip images were scored for the presence of osteophytes and femoral head abnormality. The first carpometacarpal joint, metacarpophalangeal, proximal interphalangeal and distal interphalangeal joints of the index finger (dominant hand) were imaged for osteophytes. RESULTS: Among 311 participants, prevalence of osteophytes at the distal interphalangeal joint was 70% while it was 23%, 10% and 41% for index proximal interphalangeal and metacarpophalangeal and thumb base carpometacarpal joints respectively. Prevalence of knee osteophytes was 30%, hip OA was 41%. Prevalence of knee effusions was 24% (right) and 20% (left). Ultrasound evidence of generalised OA (48%) and isolated hand OA (31%) was common, compared to isolated hip or knee OA (5%) and both hip and knee OA (3%). CONCLUSION: This is the first study to assess prevalence of ultrasound features of OA in a population-based sample. The higher prevalence of hand/hip OA, when compared to previous radiographic studies, supports the hypothesis that ultrasound is more sensitive than radiography in detecting OA, particularly for osteophytes.

Predictors of Placebo Response to Local (Intra-Articular) Therapy In Osteoarthritis: An Individual Participant Data Meta-Analysis.

OBJECTIVE: We undertook this study to evaluate potential predictors of placebo response with intra-articular (IA) injections for knee/hip osteoarthritis (OA) using individual participant data (IPD) from existing trials. METHODS: Randomized placebo-controlled trials evaluating IA glucocorticoid or hyaluronic acid published to September 2018 were selected. IPD for disease characteristics and outcome measures were acquired. Potential predictors of placebo response included participant characteristics, pain severity, intervention, and trial design. Placebo response was defined as at least a 20% reduction in baseline pain. Logistic regression models and odds ratios were computed as effect measures to evaluate patient and pain mechanisms and then pooled using a random effects model. Generalized mixed-effect models were applied to intervention and trial characteristics. RESULTS: Of 56 eligible trials, 6 shared data, and these were combined with the existing 4 OA Trial Bank studies, yielding 10 studies with IPD of 621 placebo participants for analysis. In the total placebo population, at short-term follow-up, the use of local anesthetic and ultrasound guidance were associated with reduced odds of placebo response. At midterm follow-up, mid- to long-term trial duration was associated with increased odds of placebo response, and worse baseline function scores were associated with reduced odds of a placebo response. CONCLUSION: The administration of local anesthetics or ultrasound guidance may reduce IA placebo response at short-term follow-up. At midterm follow-up, participants with worse baseline function scores may be less likely to respond to IA placebo, and mid- to long-term trial duration may enhance the placebo response. Further studies are required to corroborate these potential predictors of IA placebo response.

No evidence of an association between mitochondrial DNA variants and osteoarthritis in 7393 cases and 5122 controls.

OBJECTIVES: Osteoarthritis (OA) has a complex aetiology with a strong genetic component. Genome-wide association studies implicate several nuclear genes in the aetiology, but a major component of the heritability has yet to be defined at the molecular level. Initial studies implicate maternally inherited variants of mitochondrial DNA (mtDNA) in subgroups of patients with OA based on gender and specific joint involvement, but these findings have not been replicated. METHODS: The authors studied 138 maternally inherited mtDNA variants genotyped in a two cohort genetic association study across a total of 7393 OA cases from the arcOGEN consortium and 5122 controls genotyped in the Wellcome Trust Case Control consortium 2 study. RESULTS: Following data quality control we examined 48 mtDNA variants that were common in cohort 1 and cohort 2, and found no association with OA. None of the phenotypic subgroups previously associated with mtDNA haplogroups were associated in this study. CONCLUSIONS: We were not able to replicate previously published findings in the largest mtDNA association study to date. The evidence linking OA to mtDNA is not compelling at present.

Evaluation of the genetic overlap between osteoarthritis with body mass index and height using genome-wide association scan data.

OBJECTIVES: Obesity as measured by body mass index (BMI) is one of the major risk factors for osteoarthritis. In addition, genetic overlap has been reported between osteoarthritis and normal adult height variation. We investigated whether this relationship is due to a shared genetic aetiology on a genome-wide scale. METHODS: We compared genetic association summary statistics (effect size, p value) for BMI and height from the GIANT consortium genome-wide association study (GWAS) with genetic association summary statistics from the arcOGEN consortium osteoarthritis GWAS. Significance was evaluated by permutation. Replication of osteoarthritis association of the highlighted signals was investigated in an independent dataset. Phenotypic information of height and BMI was accounted for in a separate analysis using osteoarthritis-free controls. RESULTS: We found significant overlap between osteoarthritis and height (p=3.3×10(-5) for signals with p≤0.05) when the GIANT and arcOGEN GWAS were compared. For signals with p≤0.001 we found 17 shared signals between osteoarthritis and height and four between osteoarthritis and BMI. However, only one of the height or BMI signals that had shown evidence of association with osteoarthritis in the arcOGEN GWAS was also associated with osteoarthritis in the independent dataset: rs12149832, within the FTO gene (combined p=2.3×10(-5)). As expected, this signal was attenuated when we adjusted for BMI. CONCLUSIONS: We found a significant excess of shared signals between both osteoarthritis and height and osteoarthritis and BMI, suggestive of a common genetic aetiology. However, only one signal showed association with osteoarthritis when followed up in a new dataset.

Efficacy of a single ultrasound-guided injection for the treatment of hip osteoarthritis.

BACKGROUND: Intra-articular injection is effective for osteoarthritis, but the best single injection strategy is not known, nor are there established predictors of response. The objectives of this study were to assess and predict response to a single ultrasound-guided injection in moderate to severe hip osteoarthritis. METHODS: 77 hip osteoarthritis patients entered a prospective, randomised controlled trial, randomised to one of four groups: standard care (no injection); normal saline; non-animal stabilised hyaluronic acid (durolane) or methylprednisolone acetate (depomedrone). MAIN OUTCOME MEASURES: Numerical rating scale (NRS 0-10) 'worst pain', Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain/function. Potential predictors of response (including radiographic severity, ultrasound synovitis and baseline symptom severity) were examined using univariate logistic regression analysis and Fisher's exact test. RESULTS: NRS pain, WOMAC pain and function improved significantly for the steroid arm alone. Effect sizes at week 1 were striking: NRS pain 1.5, WOMAC pain 1.9 and WOMAC function 1.3. Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society responder criteria identified 22 responders (intention-to-treat): steroid 14 (74%; number needed to treat, two); saline, four (21%); durolane, two (11%); and no injection, two (10%; χ(2) test between groups, p<0.001). Corticosteroid arm response was maintained over 8 weeks (summary measures analysis of variance, p<0.002 for NRS pain). Synovitis was a significant predictor of response at weeks 4 and 8 (p<0.05, Fisher's exact test; week 4 OR 16.7, 95% CI 1.4 to 204). CONCLUSIONS: Ultrasound-guided corticosteroid injections are highly efficacious; furthermore synovitis on ultrasound is a biomarker of response to injection.

Reliability and validity of ultrasound imaging of features of knee osteoarthritis in the community.

BACKGROUND: Radiographs are the main outcome measure in epidemiological studies of osteoarthritis (OA). Ultrasound imaging has unique advantages in that it involves no ionising radiation, is easy to use and visualises soft tissue structures. Our objective was to measure the inter-rater reliability and validity of ultrasound imaging in the detection of features of knee OA. METHODS: Eighteen participants from a community cohort, had both knees scanned by two trained musculoskeletal sonographers, up to six weeks apart. Inter-rater reliability for osteophytes, effusion size and cartilage thickness was calculated by estimating Kappa (κ) and Intraclass correlation coefficients (ICC), as appropriate. A measure of construct validity was determined by estimating κ between the two imaging modalities in the detection of osteophytes. RESULTS: Reliability: κ for osteophyte presence was 0.77(right femur), 0.65(left femur) and 0.88 for both tibia. ICCs for effusion size were 0.70(right) and 0.85(left). Moderate to substantial agreement was found in cartilage thickness measurements. VALIDITY: For osteophytes, κ was moderate to excellent at 0.52(right) and 0.75(left). CONCLUSION: Substantial to excellent agreement was found between ultrasound observers for the presence of osteophytes and measurement of effusion size; it was moderate to substantial for femoral cartilage thickness. Moderate to substantial agreement was observed between ultrasound and radiographs for osteophyte presence.

Safety and Tolerability of Subcutaneous Methotrexate in Routine Clinical Practice.

OBJECTIVE: To show the safety and efficacy of subcutaneous (SC) methotrexate (MTX) compared to oral MTX, alternative disease-modifying antirheumatic drugs (DMARDs) monotherapy, biologic monotherapy, and combinations (conventional and biologic combination groups) in routine clinical practice. METHODS: Clinical and laboratory data were retrospectively analyzed for rheumatology clinic attendances at a large Northeast England hospital trust between January 2014 and January 2018. Rates of adverse events and stop events (transaminitis [serum alanine aminotransferase level of >80 units/liter] or neutropenia [neutrophil count of <2.0 × 109 /liter]) were calculated, with adjustment for duration of DMARD exposure. RESULTS: In the present study, 8,394 patients received DMARDs, with 2,093 patients receiving oral MTX and 949 patients receiving SC MTX. The median dose was 15 mg (interquartile range [IQR] 10-20 mg) for oral MTX, and 20 mg (IQR 15-25 mg) for SC MTX (P < 0.0001). Continuation rates were higher for SC MTX therapy when adjusted for follow-up duration, with a rate ratio (RR) of 1.54 (95% confidence interval [95% CI] 1.40-1.70) (P < 0.0001). For the time period assessed, 2,382 patients experienced 4,358 adverse events, with 1,711 incidents of transaminitis and 2,647 incidents of neutropenia recorded. Significantly fewer adverse events were observed in patients who received SC MTX monotherapy versus those who received biologic and combination DMARD therapies (P < 0.01). Compared to oral MTX, SC MTX was associated with a nonsignificant trend toward lower rates of neutropenia, but only a slightly higher rate of transaminitis (RR 1.26 [95% CI 1.07-1.48]) (P = 0.006), despite significantly higher doses of MTX. CONCLUSION: Subcutaneous MTX is safe in routine clinical practice. This is the largest study yet reported on SC MTX and provides observational data that SC MTX is continued longer and better tolerated in patients compared to other therapy groups, especially oral MTX.

Osteoporosis, fracture, osteoarthritis & sarcopenia: A systematic review of circulating microRNA association.

Circulating microRNAs (c-miRs) show promise as biomarkers. This systematic review explores their potential association with age-related fracture/osteoporosis (OP), osteoarthritis (OA) and sarcopenia (SP), as well as cross-disease association. Most overlap occurred between OA and OP, suggesting potentially shared microRNA activity. There was little agreement in results across studies. Few reported receiver operating characteristic analysis (ROC) and many identified significant dysregulation in disease, but direction of effect was commonly conflicting. c-miRs with most evidence for consistency in dysregulation included miR-146a, miR-155 and miR-98 for OA (upregulated). Area under the curve (AUC) for miR-146a biomarker performance was AUC 0.92, p = 0.028. miR-125b (AUC 0.76-0.89), miR-100, miR-148a and miR-24 were consistently upregulated in OP. Insufficient evidence exists for c-miRs in SP. Study quality was typically rated intermediate/high risk of bias. Wide study heterogeneity meant meta-analysis was not possible. We provide detailed critique and recommendations for future approaches in c-miR analyses based on this review.

Clinical and cost-effectiveness of bracing in symptomatic knee osteoarthritis management: protocol for a multicentre, primary care, randomised, parallel-group, superiority trial.

BACKGROUND: Brace effectiveness for knee osteoarthritis (OA) remains unclear and international guidelines offer conflicting recommendations. Our trial will determine the clinical and cost-effectiveness of adding knee bracing (matched to patients' clinical and radiographic presentation and with adherence support) to a package of advice, written information and exercise instruction delivered by physiotherapists. METHODS AND ANALYSIS: A multicentre, pragmatic, two-parallel group, single-blind, superiority, randomised controlled trial with internal pilot and nested qualitative study. 434 eligible participants with symptomatic knee OA identified from general practice, physiotherapy referrals and self-referral will be randomised 1:1 to advice, written information and exercise instruction and knee brace versus advice, written information and exercise instruction alone. The primary analysis will be intention-to-treat comparing treatment arms on the primary outcome (Knee Osteoarthritis Outcomes Score (KOOS)-5) (composite knee score) at the primary endpoint (6 months) adjusted for prespecified covariates. Secondary analysis of KOOS subscales (pain, other symptoms, activities of daily living, function in sport and recreation, knee-related quality of life), self-reported pain, instability (buckling), treatment response, physical activity, social participation, self-efficacy and treatment acceptability will occur at 3, 6, and 12 months postrandomisation. Analysis of covariance and logistic regression will model continuous and dichotomous outcomes, respectively. Treatment effect estimates will be presented as mean differences or ORs with 95% CIs. Economic evaluation will estimate cost-effectiveness. Semistructured interviews to explore acceptability and experiences of trial interventions will be conducted with participants and physiotherapists delivering interventions. ETHICS AND DISSEMINATION: North West Preston Research Ethics Committee, the Health Research Authority and Health and Care Research in Wales approved the study (REC Reference: 19/NW/0183; IRAS Reference: 247370). This protocol has been coproduced with stakeholders including patients and public. Findings will be disseminated to patients and a range of stakeholders. TRIAL REGISTRATION NUMBER: ISRCTN28555470.

The prevalence of osteoporosis in patients with severe hip and knee osteoarthritis awaiting joint arthroplasty.

BACKGROUND: the presence of osteoporosis in patients with hip and knee osteoarthritis (OA) has important implications for understanding disease progression and providing optimal surgical and medical management. OBJECTIVE: to determine the prevalence of osteoporosis among patients with osteoarthritis awaiting total knee arthroplasty or total hip arthroplasty aged between 65 and 80 years. DESIGN: cross-sectional observational study. SETTING: tertiary referral centre in Newcastle upon Tyne, UK. SUBJECTS: patients with osteoarthritis awaiting total knee hip arthroplasty aged between 65 and 80 years. METHODS: lumbar spine, bilateral femoral and forearm bone mineral density (BMD) measurements were obtained using dual-energy X-ray absorptiometry. RESULTS: the cohort consisted of 199 patients with a mean age of 72 years (SD 4), and 113 (57%) were women. The overall rate of osteoporosis at any site was 23% (46/199) and a further 43% (85/199) of patients would have been classified as osteopaenic according to World Health Organization criteria. Osteoporosis was more commonly detected in the forearm (14%) than the lumbar spine (8.5%) and proximal femur of the index side (8.2%). CONCLUSIONS: in summary, a significant proportion of patients with end-stage OA have osteoporosis but this diagnosis may be missed unless BMD measurements are performed at sites distant from joints affected by OA.

Cost-Effectiveness of Combination Disease-Modifying Antirheumatic Drugs Versus Tumor Necrosis Factor Inhibitors in Active Rheumatoid Arthritis: A Pragmatic, Randomized, Multicenter Trial.

OBJECTIVE: To determine whether intensive combinations of conventional synthetic disease-modifying antirheumatic drugs (csDMARDS) achieve similar clinical benefits more cheaply than high-cost biologics such as tumor necrosis factor inhibitors (TNFi) in patients with active rheumatoid arthritis (RA) whose illness has failed to respond to methotrexate and another DMARD. METHODS: We used within-trial cost-effectiveness and cost-utility analyses from health and social care and 2 societal perspectives. Participants were recruited into an open-label, 12-month, pragmatic, randomized, multicenter, 2-arm, noninferiority trial in 24 rheumatology clinics in England and Wales. Costs were linked with the Health Assessment Questionnaire (HAQ; primary outcome) and quality-adjusted life years derived from 2 measures (Short-Form 36 health survey and EuroQol 5-domain 3-level instrument). RESULTS: In total, 205 participants were recruited, 104 in the csDMARD arm and 101 in the TNFi arm. Participants in the csDMARD arm with poor response at 6 months were offered TNFi; 46 participants (44%) switched. Relevant cost and outcome data were available for 93% of participants at 6-month follow-up and for 91-92% of participants at 12-month follow-up. The csDMARD arm had significantly lower total costs from all perspectives (6-month health and social care adjusted mean difference -£3,615 [95% confidence interval (95% CI) -4,104, -3,182]; 12-month health and social care adjusted mean difference -£1,930 [95% CI -2,599, -1,301]). The HAQ score showed benefit to the csDMARD arm at 12 months (-0.16 [95% CI -0.32, -0.01]); other outcomes/follow-ups showed no differences. CONCLUSION: Starting treatment with csDMARDs, rather than TNFi, achieves similar outcomes at significantly lower costs. Patients with active RA and who meet the National Institute for Health and Care Excellence criteria for expensive biologics can be treated with combinations of intensive csDMARDs in a cost-effective manner.

Mixed methods study of a new model of care for chronic disease: co-design and sustainable implementation of group consultations into clinical practice.

OBJECTIVES: Group consultations are used for chronic conditions, such as inflammatory arthritis, but evidence of efficacy for treatment to target or achieving tight control is lacking. Our aim was to establish whether group consultation is a sustainable, co-designed routine care option and to explore factors supporting spread. METHODS: The study used mixed methods, observational process/outcome data, plus qualitative exploration of enabling themes. It was set in two community hospitals, in 2008-19, with a third hospital from 2016, and was triangulated with primary care qualitative data. There was a total of 3363 arthritis patient attendances at 183 clinics during 2008-19. The early arthritis cohort comprised 46 patients, followed monthly until the treatment target was achieved, during 2016-19. Focus groups included 15 arthritis and 11 osteoporosis group attendees. Intervention was a 2 h group consultation, attended monthly for early/active disease and annually for stable disease. Measurements included attendance, DAS, satisfaction and enabling themes. RESULTS: There was a mean number of 18.4 patients per clinic (n = 16, 2010-15; n = 18, 2016; n = 20, 2017; n = 23, 2018-19). Forty per cent (1161/2874) of patients with DAS data reached low disease activity (DAS < 3.2) or remission (DAS < 2.6). Forty-six early arthritis patients followed monthly until they achieved remission responded even better: 50% remission; and 89% low disease activity/remission by 6 months. Qualitative analysis derived five main enabling themes (efficiency, empathy, education, engagement and empowerment) and five promotors to translate these themes into practice (prioritization, personalization, participation, personality and pedagogy). Limitations included the prospectively collected observational data and pragmatic design susceptible to bias. CONCLUSION: Co-designed group consultations can be sustainable, clinically effective and efficient for monthly review of early active disease and annual review of stable disease. Promoting factors may support effective training for chronic disease group consultations.

Pain trajectory defines knee osteoarthritis subgroups: a prospective observational study.

Knee osteoarthritis (OA) is a heterogeneous disease, and identification of its subgroups/phenotypes can improve patient treatment and drug development. We aimed to identify homogeneous OA subgroups/phenotypes using pain development over time; to understand the interplay between pain and functional limitation in time course; and to investigate subgroups' responses to available pharmacological and surgical treatments. We used group-based trajectory modelling to identify pain trajectories in the phase-3 VIDEO trial (n = 474, 3-year follow-up) and also in the Osteoarthritis Initiative cohort study (n = 4796, 9-year follow-up). We extended trajectory models by (1) fitting dual trajectories to investigate the interplay between pain and functional limitation over time, and (2) including analgesic use as a time-varying covariate. Also, we investigated the relationship between trajectory groups and knee replacement in regression models. We identified 4 pain trajectory groups in the trial and 6 in the cohort. These overlapped and led us to define 4 OA phenotypes: low-fluctuating, mild-increasing, moderate-treatment-sensitive, and severe-treatment-insensitive pain. Over time, functional knee limitation followed the same trajectory as pain with almost complete concordance (94.3%) between pain and functional limitation trajectory groups. Notably, we identified a phenotype with severe pain that did not benefit from available treatments, and another one most likely to benefit from knee replacement. Thus, knee OA subgroups/phenotypes can be identified based on patients' pain experiences in studies with long and regular follow-up. We provided a robust approach, reproducible between different study designs, which informs clinicians about symptom development and delivery of treatment options and opens a new avenue toward personalized medicine in OA.

Virtual group consultations offer continuity of care globally during Covid-19.

Covid-19 has led to virtual care (mainly telephone consultations) becoming a default worldwide, despite well-documented shortcomings. Published evidence on virtual group consultations is limited, although interest and front-line experience have grown substantially since pandemic onset. Unpublished data are summarised showing feasibility of transitioning care to this model across different countries, care settings and conditions. An international webinar series has supported development and sharing of best practice and representative data on spread and utilisation of virtual groups. This model of care creates time and space for more questions and answers, so once engaged patients become staunch advocates. Group care supports personalised care and lifestyle medicine, which is growing very rapidly. In the current context, even healthcare providers under pressure can implement virtual group consultations. Most virtual group consultations have a facilitator, so this allows roles to be extended and support education of both students and new team members. These can confer greater access, continuity of care, peer support and timely information about Covid-19 and may result in better health outcomes. Given the rapid and widespread implementation of virtual care during this pandemic, data should be shared effectively and methodologically sound observational studies and clinical trials to test safety and effectiveness should be promoted now.