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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).

Background The potential effect of cigarette smoking on levels of serum urate and risk of gout has been considered by a large number of studies, either as the primary variable of interest or as a covariate. Methods Here we systematically review the published evidence relating to the relationship of smoking with serum urate, hyperuricaemia, and gout. Results Many studies have reported that smoking reduces serum urate, however, the evidence has not been conclusive with other studies pointing to the opposite or no effect. It has also been suggested that smoking reduces the risk of gout, although there is some evidence to contradict this finding. Conclusion A consensus has yet to be reached as to the effect of smoking on serum urate levels and the risk of gout.

OBJECTIVES: The primary efficacy outcome in trials of urate lowering therapy (ULT) for gout is serum urate (SU). The aim of this study was to examine the strength of the relationship between SU and patient-important outcomes to determine whether SU is an adequate surrogate endpoint for clinical trials.METHODS: Multiple databases through October 2017 were searched. Randomized controlled trials comparing any ULT in people with gout with any control or placebo, ≥three months duration were included. Open label extension (OLE) trial data were included in secondary analyses. Standardized data elements were extracted independently by two reviewers.RESULTS: Ten RCTs and 3 OLE studies were identified. From the RCTs (maximum duration 24 months) meta-regression did not reveal an association between the relative risk of a gout flare and the difference in proportions of individuals with SU < 6mg/dL (P = 0.47; R 2 = 8%). In a post hoc analysis, the ratio of the time in months at which the proportion of individuals having a flare was reported/time in months at which the proportion of individuals with SU < 6mg/dL was reported was calculated and studies where the ratio was CONCLUSIONS: Based on aggregate clinical trial-level data an association between SU and gout flare could not be confirmed. However, based on observational ecological study design data-including longer duration extension studies-SU < 6mg/dL was associated with reduced gout flares.

Background Higher fructose intake has been associated with hyperuricaemia and gout. Some individuals malabsorb fructose in the small intestine. The aims of this study were to determine the rate of fructose malabsorption and the effects of gout and fructose malabsorption on serum urate in people with and without gout. Methods A total of 100 people with gout (cases) were age and gender matched with one control without gout. After a low fructose diet, fructose malabsorption was measured using a hydrogen and methane breath test with a 35g fructose load. In a subgroup of 35 cases and 35 controls, serum urate response to the fructose load over 240 minutes was measured. Results There was no significant difference in the rate of fructose malabsorption between cases and controls (48% vs. 52%; p = 0.67). Cases had a significantly lower mean (SEM) serum urate cumulative incremental concentration from baseline-240 minutes (iAUC 0-240 ) compared to controls 0.97 (0.56) vs. 4.78 (0.55); p C max was significantly lower in cases compared to controls [0.38 (0.003) vs. 0.40 (0.003); p 0-240 or C max for malabsorbers compared to normal absorbers irrespective of case–control status. The mean (SEM) increase in serum urate between baseline and 30 minutes was 0.04 (0.004)mmol/l in the controls compared to 0.009 (0.002) in the cases ( p Conclusion The rates of fructose malabsorption are similar in people with and without gout. Allopurinol inhibits the increase in serum urate induced by a fructose load suggesting that people with gout receiving allopurinol may not need to restrict dietary intake of fructose.

Objective The observed associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease are receiving increasing interest. The potential role of urate-lowering therapy in the management of these "non-gout diseases" has been raised, and in some countries it is already recommended. However, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia, much remains unknown about the causal role of urate in these "non-gout diseases" and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is potential for serious adverse effects associated with urate-lowering therapies with recent evidence suggesting that asymptomatic hyperuricaemia may be an independent risk factor for the potentially fatal allopurinol hypersensitivity syndrome. Methods Pubmed was searched in January 2016 using the search term "asymptomatic hyperuricaemia". Results and Conclusions Herein, we discuss the issues related to treating asymptomatic hyperuricaemia, which at present seems premature.

Objectives Gout is one of the most common forms of arthritis. It is well established that urate-lowering therapy that aims for a serum urate less than at least 0.36 mmol/l (6 mg/dl) is required for the successful management of gout. Allopurinol, a xanthine oxidase (XO) inhibitor, is the most commonly used urate-lowering therapy. However, many patients fail to achieve the target serum urate on allopurinol; these patients can be considered to have “inadequate response” to allopurinol. Herein, we examine the potential mechanisms and implications of inadequate response to allopurinol. Methods The literature was reviewed for potential causes for failure to reach target serum urate in patients receiving allopurinol. Results The two most common causes of inadequate response to allopurinol are poor adherence and under-dosing of allopurinol. Adherent patients who fail to achieve target serum urate on standard doses of allopurinol form a group that could be considered to be “partially resistant” to allopurinol. There are four potential mechanisms for partial allopurinol resistance: decreased conversion of allopurinol to oxypurinol; increased renal excretion of oxypurinol; abnormality in XO structure and/or function such that oxypurinol is rendered less effective and/or drug interactions. Conclusions It is important to determine the reasons for failure to achieve treatment targets with allopurinol, particularly as newer agents become available. The knowledge of the mechanisms for inadequate response may help guide the clinician towards making a therapeutic choice that is more likely to result in achieving the serum urate target.

Objectives To determine whether serum urate (SU) fulfills the Outcome measures in Rheumatology (OMERACT) soluble biomarker criteria. Methods The OMERACT soluble biomarker criteria were adapted for use in chronic gout. Potential outcome measures for use in chronic gout were identified. The literature was reviewed to determine which of the potential outcome measures were appropriate and whether there was evidence within the current literature to fulfill the OMERACT biomarker criteria. Results The assay for measurement of SU is reliable, internationally standardized, and readily accessible for use in clinical practice. The effects of sources of variability, including age, sex, ethnicity, circadian rhythms, body mass index, renal/hepatic function, and fasting, are well documented. Tophus regression was identified as appropriate structural outcome measure; however, given that not all patients have clinically apparent tophi, the number of gout flares is also identified as a key outcome measure. Conclusions Serum urate fulfills all the OMERACT biomarker criteria with the exception of its effects on outcome measures. Further analysis of existing and new data sets to determine whether a reduction in SU predicts a reduction in gout flares, the number/size of tophi, and patient reported outcomes using validated measures for these outcomes are required.

Objectives To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. Methods Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. Results At baseline, subjects had at least moderately active disease (mean ± SD DAS28 was 5.3 ± 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 ± 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). Conclusion This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.

INTRODUCTION Rheumatoid arthritis is a common inflammatory condition. A large number of patients seek alternative or complementary therapies of which diet is an important component. This article reviews the evidence for diet in rheumatoid arthritis along with the associated concept of oral tolerization. METHODS References were taken from Medline from 1966 to September 2004. The keywords, rheumatoid arthritis, diet, n-3 fatty acids, vitamins, and oral tolerization, were used. RESULTS Randomized controlled trials (RCTs) indicate that dietary supplementation with n-3 fatty acids provides modest symptomatic benefit in groups of patients with rheumatoid arthritis. Epidemiological studies and RCTs show cardiovascular benefits in the broader population and patients with ischemic heart disease. A number of mechanisms through which n-3 fats may reduce inflammation have been identified. In a small number of patients with rheumatoid arthritis, other dietary manipulation such as fasting, vegan, and elimination diets may have some benefit. However, many of these diets are impractical or difficult to sustain long term. CONCLUSIONS Dietary manipulation provides a means by which patients can a regain a sense of control over their disease. Dietary n-3 supplementation is practical and can be easily achieved with encapsulated or, less expensively, bottled fish oil.