Alison S Kydd

Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative

We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010–2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. The level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1–10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.

Dual energy CT in gout: a prospective validation study

Objective The authors prospectively determined: (1) the specificity and sensitivity of dual energy CT (DECT) for gout; and (2) the interobserver and intraobserver reproducibility for DECT urate volume measurements. Methods Forty crystal-proven gout patients (17 tophaceous) and 40 controls with other arthritic conditions prospectively underwent DECT scans of all peripheral joints using a gout protocol that color-codes the composition of tissues. A blinded radiologist identified urate deposition to calculate specificity and sensitivity of DECT for gout. Inter-rater volumetric reproducibility was determined by two independent radiologists on 40 index tophi from the 17 tophaceous gout patients using automated software. Results The mean age of the 40 gout patients was 62 years, the mean gout duration was 13 years and 87% had a history of urate-lowering therapy (ULT). The specificity and sensitivity of DECT for gout were 0.93 (95% CI, 0.80 to 0.98) and 0.78 (0.62 to 0.89), respectively. When the authors excluded three gout cases with unreadable or incomplete scans, the sensitivity was 0.84 (95% CI, 0.68 to 0.94). The urate volumes of 40 index tophi ranged from 0.06 cm3 to 18.74 cm3 with a mean of 2.45 cm3. Interobserver and intraobserver intraclass correlation coefficients for DECT volume measurements were 1.00 (95% CI, 1.00 to 1.00) and 1.00 (95% CI, 1.00 to 1.00) with corresponding bias estimates (SD) of 0.01 (0.00) cm3 and 0.01 (0.03) cm3. Conclusions These prospective data indicate high reproducibility of DECT urate volume measures. The specificity was high, but sensitivity was more moderate, potentially due to frequent ULT use in our patients.

The Basics of Soft Tissue Healing and General Factors that Influence Such Healing

Wound healing and repair of injured tissues follows several steps in the healthy individual. Following birth, the process is initiated by the inflammatory response and subsequent steps are based on this initial response. Whereas wound healing generally leads to a repair of the injured site, it does not lead to tissue regeneration. This difference between repair and regeneration has influence on tissues such as ligaments and tendons that function in a mechanically active environment. Thus, the dynamic interface between mechanics and biology influence the effectiveness of the healing response. The biology of the host is also influenced by a variety of factors including age, gender, genetics, and tissue history, factors that impact the outcome of the healing response. This review focuses on several of the issues surrounding the healing of tissues in general and ligaments and tendons more specifically. In addition, the use of interventions such as cell and gene therapy to improve healing is discussed.

Preventing Attacks of Acute Gout When Introducing Urate-Lowering Therapy: A Systematic Literature Review

OBJECTIVE To systematically review the evidence on treatment available to prevent an acute attack of gout when initiating a urate-lowering therapy (ULT) and for how long this treatment should be continued. To also evaluate the evidence on the optimal time to start a ULT after an acute attack of gout. METHODS A systematic review as part of the 3e (Evidence, Expertise, Exchange) Initiative on Diagnosis and Management of Gout was performed using Medline, Embase, Cochrane Central Register of Controlled Trials (from 1950 to October 2011), and the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) 2010/2011 meeting abstracts. Two reviewers independently screened titles and abstracts for selection criteria. Included articles were reviewed in detail, and a risk of bias assessment (using the Cochrane tool) was performed. RESULTS The search identified 8168 articles and 197 abstracts, from which 4 randomized controlled trials were included in the review. Two of these studies compared placebo with colchicine, 1 compared differing durations of colchicine, and 1 compared colchicine with canakinumab. CONCLUSION Two randomized controlled trials have shown that colchicine prophylaxis for at least 6 months, when starting a ULT, reduces the risk of acute attacks. Canakinumab, although not currently licensed for gout, has been shown to provide prophylaxis superior to colchicine, when starting a ULT. There is no evidence on the optimum time to start a ULT after an acute gout attack.

Urate-lowering therapy for the management of gout: a summary of 2 Cochrane reviews.

OBJECTIVE To systematically review the evidence on the efficacy, safety, and cost-effectiveness of urate-lowering therapy for gout: xanthine oxidase inhibitors (allopurinol and febuxostat), uricosuric medications (benzbromarone, probenecid and sulfinpyrazone), and uricases (pegloticase and rasburicase). METHODS A systematic review was performed as part of the 3e (Evidence, Expertise, Exchange) Initiative on Gout. The primary efficacy outcomes were frequency of acute gout attacks, study participant withdrawal due to adverse events, and cost-effectiveness. Serum urate-lowering was a secondary outcome and was the most commonly reported outcome in the included trials. RESULTS The search identified 17 articles for efficacy, 31 for safety, and 3 for cost-effectiveness. The main outcome described in these studies was serum urate-lowering. Allopurinol, febuxostat, and pegloticase are all effective at lowering serum urate compared to placebo and febuxostat (≥ 80 mg) was more effective at lowering serum urate than allopurinol. Compared to probenecid, benzbromarone was more effective at lowering serum urate. Regarding acute gout attacks, pegloticase and febuxostat (≥ 120 mg) resulted in more acute attacks than placebo. Regarding the primary safety outcome, more withdrawals due to adverse events were seen only when pegloticase was compared to placebo. The two trials of cost-effectiveness were inconclusive. CONCLUSION There is currently moderate quality data supporting the efficacy and safety of allopurinol, febuxostat, benzbromarone, and probenecid in gout. Pegloticase, while efficacious, is associated with more withdrawals due to adverse events and infusion reactions. There is insufficient evidence currently with respect to the cost-effectiveness or the most optimal sequencing of urate-lowering therapy.

Smoking did not modify the effects of anti-TNF treatment on health-related quality of life among Australian ankylosing spondylitis patients

OBJECTIVE The aim of this study was to examine the impact of smoking on health-related quality of life (HRQoL) among AS patients who were taking biologic DMARDS. METHODS This is a longitudinal cohort study of AS patients with anti-TNF treatment in the Australian Rheumatology Association Database (2003-11). They were assessed using the 36-item Short Form Health Survey (SF-36), Assessment of Quality of Life (AQoL) and HAQ for spondylitis (HAQ-S) on a biannual basis. Linear mixed models were used to assess the impact of smoking on HRQoL outcomes over the first 2 years of treatment. RESULTS Four hundred and twenty-two patients [73% male, mean age 44.9 years (s.d. 12.7) provided 1189 assessments for the study. Current smokers (n = 79) were slightly younger, more likely to be male, less likely to use or to have previously used prednisolone and had a slightly shorter disease duration than past smokers (n = 138) or non-smokers (n = 205). After adjusting for smoking, gender, age, education, employment, co-morbidities and medication use, including DMARDs, anti-inflammatories and analgesics, all the HRQoL measures improved significantly over the study period and the improvements were not modified by smoking status (all P-values >0.36). Current smokers tended to have a poorer HRQoL on the SF-36 physical score [-1.93 (95% CI -3.94, 0.09), P = 0.06] and the HAQ-S score [0.10 (95% CI -0.01, 0.20), P = 0.07] compared with non-smokers. CONCLUSION Among AS patients, active smoking did not diminish or modify the improvements in HRQoL from anti-TNF treatment, even though current smokers compared with non-smokers tended to have poorer scores in some HRQoL measures.

Impact of age, systemic glucocorticoids, and progressive knee arthritis on specific mRNA levels in different areas of the rabbit cornea.

Purpose: To determine the influence of factors such as age, osteoarthritis (OA), and glucocorticoid treatment on total RNA and mRNA regulation in the cornea and how these factors differ between prepupillary and peripheral areas of the cornea. Methods: Molecular analyses of corneal tissue were performed using rabbits of different age groups and skeletally mature animals that had undergone anterior cruciate ligament (ACL) transection, an established model of knee OA. Systemic glucocorticoids were administered to cohorts of the osteoarthritic and control animals to determine the influence of distal joint disease on the corneal response. Corneal tissue was analyzed for changes in mRNA levels for several relevant genes: collagen I, collagen III, collagen V, decorin core protein, cyclooxygenase-2 (COX-2), glucocorticoid receptor, and the housekeeping gene β-actin. Results: The corneal tissue was found to have diminishing total RNA with age, which is consistent with previous studies in the literature. Interestingly, in skeletally mature animals, distal joint OA was found to affect corneal mRNA levels for several important structural and inflammatory genes (collagen I, decorin core protein, and COX-2) in a manner that progressed with OA progression. Although systemic glucocorticoid treatment did not alter mRNA levels in the normal cornea, it did counteract the changes observed early after OA induction (3 weeks) while having less of an effect in later, more established arthritis (6 weeks). Conclusions: This study reveals that distal joint OA can affect mRNA levels for several structural and inflammatory genes of the cornea, changes that seem to be suppressed by systemic glucocorticoid treatment. These findings indicate that OA has associated systemic factors that influence corneal cell metabolism.