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.
To determine the effectiveness of ...hydroxychloroquine versus placebo as an analgesic treatment of hand osteoarthritis.
Randomized, double-blind, placebo-controlled clinical trial with 12-month follow-up. (ISRCTN registry number: ISRCTN91859104).
13 primary and secondary care centers in England.
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.
Hydroxychloroquine (200 to 400 mg) or placebo (1:1) for 12 months with ongoing usual care.
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.
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).
Hydroxychloroquine dosage restrictions may have reduced efficacy.
Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis.
Arthritis Research UK.
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.
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).
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.
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).
Ultrasound-guided corticosteroid injections are highly efficacious; furthermore synovitis on ultrasound is a biomarker of response to injection.
Summary Background Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is ...increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. Methods We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11 009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42 938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. Findings We identified five genome-wide significant loci (binomial test p≤5·0×10−8 ) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 95% CI 1·08–1·16; p=7·24×10−11 ), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3 . Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2 , chromosome 6 between FILIP1 and SENP6 , chromosome 12 close to KLHDC5 and PTHLH , and in another region of chromosome 12 close to CHST11 . One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight—a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Interpretation Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. Funding arcOGEN was funded by a special purpose grant from Arthritis Research UK.
Objective
Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to ...placebo for the primary prevention of CVEs in RA patients.
Methods
A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P < 0.05. RA patients age >50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety.
Results
A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range IQR 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio HR 0.66 95% confidence interval (95% CI) 0.39, 1.11; P = 0.115 and adjusted HR 0.60 95% CI 0.32, 1.15; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter IQR 0.94, 6.08 versus 3.60 mg/liter IQR 1.47, 7.49; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 19.8%) and placebo group (n = 292 19.5%) were similar.
Conclusion
Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations.
Objective To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor ...inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs.Design Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months.Setting 24 rheumatology clinics in England.Participants Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy.Interventions Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders.Main outcome measure Primary outcome: reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. Secondary outcomes: quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data.Results 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of −0.30 with the tumour necrosis factor inhibitor strategy and −0.45 with the alternative combined drug strategy. The difference between groups in unadjusted linear regression analysis favoured the alternative strategy of combined drugs. The mean difference was −0.14, and the 95% confidence interval (−0.29 to 0.01) was below the prespecified non-inferiority boundary of 0.22. Improvements at 12 months in secondary outcomes, including quality of life and erosive progression, were similar with both strategies. Initial reductions in disease activity were greater with the biologic strategy, but these differences did not persist beyond six months. Remission was seen in 72 patients (44 with biologic strategy; 36 with alternative strategy); 28 patients had serious adverse events (18 and 10, respectively); six and 10 patients, respectively, stopped treatment because of toxicity. The alternative strategy reduced health and social care costs per patient by £3615 (€4930, $5585) for months 0-6 and £1930 for months 6-12.Conclusions In patients with active rheumatoid arthritis who meet English criteria for biologics an alternative strategy with combinations of intensive synthetic disease modifying drugs gives non-inferior outcomes to treatment with tumour necrosis factor inhibitors. Costs are reduced substantially.Trial Registration ISRCTN 37438295.
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.
PDF
