Dietary supplements for chronic gout.

Dietary supplements for chronic gout (Review) Andrés M, Sivera F, Falzon L, Buchbinder R, Carmona L

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 10 http://www.thecochranelibrary.com

Dietary supplements for chronic gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . INDEX TERMS . . . . . . . . . . . . . . . . .

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[Intervention Review]

Dietary supplements for chronic gout Mariano Andrés1 , Francisca Sivera2 , Louise Falzon3 , Rachelle Buchbinder4 , Loreto Carmona5 1 Sección

de Reumatología, Hospital General Universitario de Alicante, Alicante, Spain. 2 Servicio de Reumatologia, Hospital de Elda, Elda (Alicante), Spain. 3 Center for Behavioral Cardiovascular Health, Columbia University Medical Center, New York, NY, USA. 4 Monash Department of Clinical Epidemiology, Cabrini Hospital, Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Malvern, Australia. 5 Instituto de Salud Musculoesquelética, Madrid, Spain Contact address: Mariano Andrés, Sección de Reumatología, Hospital General Universitario de Alicante, C/ Pintor Baeza, 12, Alicante, 03010, Spain. [email protected]. [email protected].

Editorial group: Cochrane Musculoskeletal Group. Publication status and date: New, published in Issue 10, 2014. Review content assessed as up-to-date: 30 June 2014. Citation: Andrés M, Sivera F, Falzon L, Buchbinder R, Carmona L. Dietary supplements for chronic gout. Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD010156. DOI: 10.1002/14651858.CD010156.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Dietary supplements are frequently used for the treatment of several medical conditions, both prescribed by physicians or self administered. However, evidence of benefit and safety of these supplements is usually limited or absent. Objectives To assess the efficacy and safety of dietary supplementation for people with chronic gout. Search methods We performed a search in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL on 6 June 2013. We applied no date or language restrictions. In addition, we performed a handsearch of the abstracts from the 2010 to 2013 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conferences, checked the references of all included studies and trial registries. Selection criteria We considered all published randomised controlled trials (RCTs) or quasi-RCTs that compared dietary supplements with no supplements, placebo, another supplement or pharmacological agents for adults with chronic gout for inclusion. Dietary supplements included, but were not limited to, amino acids, antioxidants, essential minerals, polyunsaturated fatty acids, prebiotic agents, probiotic agents and vitamins. The main outcomes were reduction in frequency of gouty attacks and trial participant withdrawal due to adverse events. We also considered pain reduction, health-related quality of life, serum uric acid (sUA) normalisation, function (i.e. activity limitation), tophus regression and the rate of serious adverse events. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. Dietary supplements for chronic gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results We identified two RCTs (160 participants) that fulfilled our inclusion criteria. As these two trials evaluated different diet supplements (enriched skim milk powder (SMP) and vitamin C) with different outcomes (gout flare prevention for enriched SMP and sUA reduction for vitamin C), we reported the results separately. One trial including 120 participants, at moderate risk of bias, compared SMP enriched with glycomacropeptides (GMP) with unenriched SMP and with lactose over three months. Participants were predominantly men aged in their 50’s who had severe gout. The frequency of acute gout attacks, measured as the number of flares per month, decreased in all three groups over the study period. The effects of enriched SMP (SMP/GMP/G600) compared with the combined control groups (SMP and lactose powder) at three months in terms of mean number of gout flares per month were uncertain (mean ± standard deviation (SD) flares per month: 0.49 ± 1.52 in SMP/GMP/G60 group versus 0.70 ± 1.28 in control groups; mean difference (MD) -0.21, 95% confidence interval (CI) -0.76 to 0.34; low-quality evidence). The number of withdrawals due to adverse effects was similar in both groups although again the results were imprecise (7/40 in SMP/GMP/G600 group versus 11/80 in control groups; risk ratio (RR) 1.27, 95% CI 0.53 to 3.03; lowquality evidence). The findings for adverse events were also uncertain (2/40 in SMP/GMP/G600 group versus 3/80 in control groups; RR 1.33, 95% CI 0.23 to 7.66; low-quality evidence). Gastrointestinal events were the most commonly reported adverse effects. Pain from self reported gout flares (measured on a 10-point Likert scale) improved slightly more in the SMP/GMP/G600 group compared with controls (mean ± SD reduction -1.97 ± 2.28 points in SMP/GMP/G600 group versus -0.94 ± 2.25 in control groups; MD -1.03, 95% CI -1.96 to -0.10; low-quality evidence). This was an absolute reduction of 10% (95% CI 20% to 1% reduction), which may not be of clinical relevance. Results were imprecise for the outcome improvement in physical function (mean ± SD Health Assessment Questionnaire (HAQ)-II (scale 0 to 3, 0 = no disability): 0.08 ± 0.23 in SMP/GMP/G60 group versus 0.11 ± 0.31 in control groups; MD -0.03, 95% CI -0.14 to 0.08; low-quality evidence). Similarly, results for sUA reduction were imprecise (mean ± SD reduction: -0.025 ± 0.067 mmol/L in SMP/GMP/G60 group versus -0.010 ± 0.069 in control groups; MD -0.01, 95% CI -0.04 to 0.01; lowquality evidence). The study did not report tophus regression and health-related quality of life impact. One trial including 40 participants, at moderate to high risk of bias, compared vitamin C alone with allopurinol and with allopurinol plus vitamin C in a three-arm trial. We only compared vitamin C with allopurinol in this review. Participants were predominantly middle-aged men, and their severity of gout was representative of gout in general. The effect of vitamin C on the rate of gout attacks was not assessed. Vitamin C did not lower sUA as much as allopurinol (-0.014 mmol/L in vitamin C group versus -0.118 mmol/L in allopurinol group; MD 0.10, 95% CI 0.06 to 0.15; low-quality evidence). The study did not assess tophus regression, pain reduction or disability or health-related quality of life impact. The study reported no adverse events and no participant withdrawal due to adverse events. Authors’ conclusions While dietary supplements may be widely used for gout, this review has shown a paucity of high-quality evidence assessing dietary supplementation.

PLAIN LANGUAGE SUMMARY Dietary supplements for chronic gout What is gout, and what are dietary supplements? Gout caused by crystal formation in the joints due to high uric acid levels in the blood. People have attacks of painful, warm and swollen joints, often at the big toe. Some people develop large accumulations of crystal just beneath the skin known as tophi. Cure can be achieved if uric acid levels in blood return to normal for a prolonged time, making the crystal deposits dissolve. Dietary supplements are preparations such as vitamins, essential minerals, prebiotics, etc. Few studies evaluate their benefits and some might not be free of harm. Study characteristics After searching the medical literature up to 6 June 2013 we found two studies The first study (120 participants) compared enriched skim milk powder (with peptides with probable anti-inflammatory effect) to standard skim milk and to lactose powder, and the second study (40 participants) compared vitamin C with allopurinol - a drug commonly used in gout. In the first study, the enriched milk aimed to Dietary supplements for chronic gout (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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reduce the frequency of gout attacks, while in the second study the vitamin C aimed to reduce the uric acid levels in blood. People with gout enrolled in both studies were predominantly middle-aged men; in the skim milk study, participants with gout appeared severe as they had very frequent attacks and 20% to 43% presented with tophi, while in the vitamin C study, participants appeared similar to ordinary participants with gout. Key results - what happens to people with gout who consume enriched skim milk powder Gout attacks People who consumed enriched skim milk powder had 0.21 fewer gout attacks per month at three months (from 0.76 fewer to 0.34 more), or 2.5 fewer gout attacks per year: - People who consumed enriched skim milk powder had 0.49 gout attacks per month (or six gout attacks per year). - People who consumed standard skim milk powder or lactose had 0.70 gout attacks per month (or eight gout attacks per year). Withdrawals due to adverse events 4 more people out of 100 who consumed enriched skim milk powder discontinued the supplement at three months (4% more withdrawals). - 18 out of 100 stopped consuming enriched skim milk powder. - 14 out of 100 stopped consuming standard skim milk powder or lactose. Pain reduction, serum uric acid (sUA) levels and physical function were uncertain. Effect on tophus regression was not measured. What happens to people with gout who consume vitamin C Serum uric acid levels - People who consumed vitamin C showed an sUA level reduction of 0.014 mmol/L after eight weeks (or 2.8% sUA reduction) - People who were administered allopurinol showed an sUA level reduction of 0.118 mmol/L after eight weeks (or 23.6% sUA reduction). There were no reports of side effects or withdrawals due to side effects in the vitamin C or allopurinol treatment groups. Effects of vitamin C on gout attacks, pain reduction, physical function and tophus regression were not measured. Quality of the evidence Low-quality evidence from one study indicated enriched skim milk, compared with standard skim milk or lactose powder, may not reduce the frequency of gout attacks or improve physical function or uric acid levels, but may reduce pain. Further research is likely to change these estimates. We do not have precise information about side effects and complications, but possible side effects may include nausea or diarrhoea. Compared with the commonly used medicine allopurinol, low-quality evidence from one study indicated the effect of vitamin C in reducing sUA levels is smaller and probably clinically unimportant. Other possible benefits of vitamin C are uncertain, as they were not evaluated in the study. No side effects were reported. Further research is likely to change these estimates.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Skim milk enriched with GMP/G600 compared with skim milk plus lactose powder for chronic gout Patient or population: people with chronic gout Settings: outpatients, community Intervention: skim milk enriched with GMP/G600 Comparison: skim milk and lactose powder Outcomes

Illustrative comparative risks* (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Comments

The mean acute gout attack frequency in the intervention groups was 0. 21 lower (0.76 lower to 0.34 higher)

120 (1 study)

⊕⊕

low1

NNT not applicable, not statistically significant2

Participant withdrawals 138 per 1000 due to adverse events Participant and study investigator-reported Follow-up: 3 months

175 per 1000 (73 to 417)

120 (1 study)

⊕⊕

low1

Absolute risk difference: 4% more withdrawals (10% fewer to 18% more) Not statistically significant3

Joint pain reduction 10-point Likert scale Follow-up: 3 months

The mean joint pain reduction in the intervention groups was 1.03 points lower (1.9 to 0.1 lower)

120 (1 study)

⊕⊕

low1

Absolute risk difference: 10% (-20% to -1%). Relative percentage change: -39% (-74% to -4%). NNTB = 10 (5 to 100)2

Assumed risk

Relative effect (95% CI)

Corresponding risk

Skim milk and lactose Skim milk enriched with powder GMP/G600 Acute gout attack frequency Participant self report using gout flare diary Follow-up: 3 months

The mean acute gout attack frequency in the control groups was 0.70 gout flares per month

The mean joint pain reduction in the control groups was -0.94 points

RR 1.27 (0.53 to 3.03)

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Physical function HAQ-II questionnaire. Scale 0-3; 0 = no disability. Follow-up: 3 months

The mean physical function in the control groups was 0.11

The mean physical function in the intervention groups was 0.03 lower (0.14 lower to 0.08 higher)

120 (1 study)

⊕⊕

low1

Not statistically significant2

Tophus regression - not See comment measured

See comment

-

See comment

Not measured

sUA acid reduction4 - The mean sUA level remmol/L at follow-up: 3 duction in the control months group was -0.010 mmol/ L

The mean sUA level reduction in the intervention group was 0.01 mmol/L lower (0.04 lower to 0.01 higher)

120 (1 study)

⊕⊕

low1

Not statistically significant2

Adverse events 38 per 1000 Participant and study investigator-reported5 Follow-up: 3 months

50 per 1000 (9 to 287)

120 (1 study)

⊕⊕

low1

Absolute risk difference: 1% more adverse events (7% fewer to 9% more) Not statistically significant3

Not estimable

RR 1.33 (0.23 to 7.66)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HAQ: Health Assessment Questionnaire; RR: risk ratio; sUA: serum uric acid. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 There

was a possible influence of selection and detection bias. In addition, the imprecision of the results (in relation to the small size study) contributed to downgrade the quality of the results. Selective reporting of post hoc comparisons between skim milk powder enriched with GMP/G600 and one of the two study controls (lactose) in relation to change in gout attack frequency from baseline were noted, but it has been controlled after raw data was provided by the authors.

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2 Number

needed to treat for an additional beneficial outcome (NNTB) = not applicable when result was not statistically significant. NNT for continuous outcomes calculated using the Wells calculator software available from the Cochrane Musculoskeletal Group editorial office. 3 Number needed to treat for an additional harmful outcome (NNTH) = N/A when result was not statistically significant. NNT for dichotomous outcomes calculated using Cates NNT calculator (nntonline.net/ebm/visualrx/try.asp). 4 Data regarding sUA normalisation not reported. 5 Gastrointestinal adverse events (diarrhoea, nausea and flatulence) reported most commonly. Serious adverse events resulting in hospital admissions - none were due to the study products.

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Description of the intervention BACKGROUND

Description of the condition Gout is a musculoskeletal disease characterised by recurrent episodes of acute arthritis, due to deposition of monosodium urate (MSU) crystals in joints. It affects up to 1% to 2% of adults and is the most common inflammatory arthritis in men (Smith 2010). Persistent hyperuricaemia leads to the deposition of MSU crystals in the synovial lining, tendons, ligaments and other body sites. Most people with gout have recurrent bouts of acute arthritis, with the first metatarsophalangeal joint of the foot being the most frequently affected joint. Attacks usually resolve spontaneously within one week and the condition is asymptomatic in between episodes, although persistent subclinical inflammation has been noted in the synovial fluid from asymptomatic joints (Pascual 1999). People with longstanding disease may develop persistent arthritis, leading to joint damage and disability. Other clinical consequences of crystal deposition are the development of focal crystal nodes, known as tophi (Richette 2010). Tophi are usually found in limb extension surfaces and pressure areas, but they can appear anywhere. In addition, people with gout are at high risk of developing urate renal stones, and a form of kidney damage (urate nephropathy) has been related to the deposit of crystals in the interstitium and medulla, but the significance of this condition is unclear (Nickeleit 1997). On top of these consequences of the crystal deposits, gout is strongly associated with an increased cardiovascular risk (Krishnan 2008; Kuo 2010). To prevent further acute attacks of gout and ongoing subclinical inflammation, the aim of treatment in gout is to reduce serum uric acid (sUA) levels, which ultimately leads to dissolution of crystals from the joints and reduction in size and eventual disappearance of tophi (Perez-Ruiz 2002; Pascual 2007). When MSU crystals are absent from joints and tissues, gout can be considered to be cured (Pascual 2009a). Several drugs have been used since the mid-1980s to lower sUA levels by two mechanisms of action: 1. reduction of uric acid synthesis by the blockade of xanthine oxidase (Klinenberg 1965; Pascual 2009b), as is the case for allopurinol and febuxostat, and 2. increase of renal uric acid excretion through the inhibition of its re-absorption at the proximal convoluted tubules of the kidney (Richette 2010), as is the case for benzbromarone, sulphinpyrazone and probenecid. Recombinant uricases, such as pegloticase that convert uric acid into allantoin, have also been approved for refractory cases (Lyseng-Williamson 2011). Besides pharmacological therapy to reduce sUA, lifestyle changes (e.g. weight loss, exercise and diet modifications) might also have a role in the management of people with gout, though enough evidence is lacking to establish the exact impact of this approach in people with gout.

Dietary supplements are widely used by the general population for the purpose of preventing and treating many diseases and conditions (Wu 2011). These are usually obtained over the counter, rather than being prescribed by doctors. There are different types of dietary supplements including amino acids (e.g. carnitine, glutamine), antioxidant agents (e.g. melatonin, acetylcysteine), essential minerals (e.g. selenium, calcium, phosphorus), polyunsaturated fatty acids (PUFA), probiotics (e.g. Lactobacillus, Bifidobacterium), vitamins (e.g. vitamin C, vitamin E, folic acid) and many more. People with rheumatic diseases, such as osteoarthritis or inflammatory arthritis, often use dietary supplements (Buchbinder 2002; Vista 2011); people with other chronic musculoskeletal conditions are also reported to be frequent users of homeopathic and complementary medicines (Rossignol 2011). Despite the uncertainty from published studies, it is likely that people with gout are also taking supplements among other remedies, as a quick search on Google with “uric acid how to reduce” shows more than four million hits, most of which come from non-medical resources. However, dietary supplements might be associated with potential adverse effects. Cases of increased bleeding risk related to different herbs and herbal formulae (Wong 2012), liver injury due to Camellia sinensis tea extracts or usnic acid (Stickel 2011), or cardiac dysrhythmias due to enzyte (Philips 2010), have been reported. Taking into account the increasing use of dietary supplements, mostly with no medical prescription, these should be considered as potentially harmful.

How the intervention might work There is minimal evidence of how these supplements might work in gout; some might reduce sUA levels or have an anti-inflammatory effect, but other unidentified mechanisms are possible. Evidence suggests that diet supplements, such as vitamin C (Juraschek 2011), depurinised milk (Kocic 2012), and casein or soy proteins (Lo 2010), have sUA-lowering effects. However, most of these studies have been conducted in animals or in humans without gout. Diet supplements may also have beneficial effects on inflammation or pain, such as vitamin D (Zhang 2012), omega-3 fatty acid supplements (Mori 2006), or avocado-soybean unsaponifiables (Christensen 2008).

Why it is important to do this review Due to the significant population belief in dietary supplements for the treatment of arthritis, including gout, it is important to assess current evidence supporting these interventions. This would provide clinicians with useful information in order to optimise patient advice.


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OBJECTIVES To assess the benefits and safety of dietary supplements for the treatment of chronic gout.

METHODS

Criteria for considering studies for this review Types of studies We considered all published randomised controlled trials (RCTs) or quasi-RCTs (clinical controlled trials, CCTs) that compare dietary supplements with no supplements, placebo, another supplement or pharmacological agents for chronic gout for inclusion. As we were primarily interested in the use of dietary supplements to prevent further acute attacks of gout and to reduce sUA, we excluded trials in acute gout where the aims of treatment were different, namely to reduce acute inflammation. We included only trials that were published as full articles or available as a full trial report.

core domains included pain, joint swelling, joint tenderness, participant global assessment and activity limitations. For chronic gout, core domains included sUA, acute gout attacks, tophus burden, health-related quality of life, activity limitation, pain and participant global assessment. We included only outcome core domains for chronic gout, plus safety in this review. For the purpose of this review, if feasible, we grouped trials into those of short-term (less than three months), medium term (three to 12 months) and long-term (greater than 12 months) duration. Major outcomes

1. 2. 3. 4. 5. 6. 7.

Acute gout flares. Study withdrawals due to adverse events (AE). sUA reduction. Joint pain reduction. Participant global assessment; Total number of AEs. Tophus regression.

Minor outcomes

1. Physical function (or disability). 2. Serious AEs.

Types of participants We included adults (aged 18 years or older) with a diagnosis of chronic gout. We excluded studies that incorporated a mix of people with gout and other musculoskeletal diseases unless we could separate out results for the gout population for analysis.

Search methods for identification of studies A librarian devised a strategy search in MEDLINE (Ovid); the review authors reviewed the strategy and refined it until a final version was agreed upon. We modified this for the other databases.

Types of interventions We included all trials evaluating any dietary supplement including, but not limited to, amino acids, antioxidants, PUFAs, prebiotic agents, probiotic agents, vitamins, alone or in combination. We examined all doses and administration routes. Comparators could have been: 1. placebo; 2. no treatment; 3. a different dietary supplement; 4. pharmacological therapy (e.g. allopurinol); 5. non-pharmacological therapy (e.g. diet modification); 6. combination therapy (any of the above combinations). Types of outcome measures OMERACT (Outcome Measures in Rheumatology) is an international network interested in outcome measurement across the spectrum of rheumatology intervention studies (Tugwell 1993). At the OMERACT-9 conference, the core and discretionary domains for outcome measurement in clinical studies of acute and chronic gout were defined (Schumacher 2009). For acute gout,

Electronic searches We searched the following databases for RCTs or CCTs using the search strategies detailed in the appendices: 1. the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 5, 2013 (Appendix 1); 2. MEDLINE (Ovid) 1950 to 6 June 2013 (Appendix 2); 3. EMBASE 1980 to 6 June 2013 (Appendix 3); 4. Cumulative Index to Nursing and Allied Health Literature (CINAHL) 1937 to 6 June 2013 (Appendix 4). We searched the CINAHL database because data regarding dietary supplements might be published in non-medical journals that were not covered by the other databases. We applied no language restrictions. Searching other resources We handsearched the abstracts from the two major international rheumatology scientific meetings, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), for 2010 to 2013. We inspected the


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reference lists of included articles to identify additional trials. We searched ClinicalTrials.gov (www.clinicaltrials.gov, accessed 1 July 2013); the Australian & New Zealand Clinical Trial Registry (www.anzctr.org.au, accessed 1 July 2013) and the World Health Organization (WHO) Clinical Trials Registry Platform ( www.who.int/ictrp/en/, accessed 1 July 2013) to identify potential ongoing studies.

Data collection and analysis We downloaded the full search to a reference management library (Endnote® X5.0.1, PDFTron, 2010) and eliminated duplicates. Two review authors (MA, FS) selected the studies for detailed review and collected the data, including items to assess risk of bias, of the finally included studies. We resolved any disagreements by discussion with a third review author (LC). Selection of studies Two review authors independently assessed the titles and abstracts of all identified registers to identify the trials that fulfilled selection criteria. We retrieved all possibly relevant articles, including those with a related title and without an abstract, in full text. We resolved any disagreements in study selection by consensus or by discussion with a third review author if needed. We translated studies into English where necessary. Data extraction and management We prepared pre-piloted forms in advance to help collecting the relevant data. Two review authors independently extracted relevant information from the included trials extracting study design, characteristics of study population, treatment regimen and duration, outcomes and timing of outcome assessment. We extracted the raw data (means and standard deviations (SD) for continuous outcomes and number of events or participants for dichotomous outcomes) for outcomes of interest. We resolved differences in data extraction by referring back to the original articles and establishing consensus. We consulted a third review author to resolve differences if necessary. Assessment of risk of bias in included studies Two review authors independently assessed the potential for bias using The Cochrane Collaboration’s tool for assessing risk of bias (Higgins 2011a). This included assessing the potential for bias in the following domains: random sequence generation; allocation concealment; blinding of participants, personnel and outcome assessors; completeness of outcome data; selective reporting and other sources of bias (i.e. conflicts of interest with the study sponsor). We graded each of these domains as ’low risk’ of bias, ’high risk’ of bias or ’unclear risk’ of bias (either lack of adequate

information or uncertainty over the potential for bias). We resolved disagreements by consensus; a third review author acted as arbiter. Measures of treatment effect We used The Cochrane Collaboration’s statistical software, Review Manager (RevMan 2012), to analysed data. We planned to perform meta-analyses only if the data of the included studies were sufficiently clinically homogeneous. We presented the results of dichotomous data as risk ratios (RRs) with the corresponding 95% confidence intervals (CIs). We presented the results of continuous variables as mean differences (MDs) between the intervention and comparator groups with the corresponding 95% CIs. When different scales were used to measure the same conceptual domain, we calculated standardised mean differences (SMDs) with the corresponding 95% CIs instead. For the calculation of SMD, we divided the MD by the SD, resulting in a measure without units of treatment effect. SMDs larger than zero indicated a beneficial effect of the dietary supplementation. As described in Cohen 1988, an SMD of 0.2 indicated a small beneficial effect, 0.5 a medium effect and 0.8 a large effect in favour of dietary supplementation. We considered SMD as clinically relevant if it was greater than 0.5. SMD was translated back into the original units of the particular instrument, in order to facilitate appraisal by clinicians (Schünemann 2011b). We considered the results of count data (such as the number of gout flares) as continuous outcome data if events were common and as RRs if they were rare events (Deeks 2011). Unit of analysis issues For studies containing more than two intervention groups, making multiple pair-wise comparisons between all possible pairs of intervention groups possible, we planned to include the same group of participants only once in the meta-analysis. In the event that we had identified cross-over trials in which the reporting of continuous outcome data precluded paired analysis, we planned to include these data in a meta-analysis, in order to avoid unit of analysis error. Where we thought carry-over effects existed, and where sufficient data existed, we intended to include data from the first period only in the analysis (Higgins 2011a). Where outcomes were collected at multiple follow-up times (within the short-term, medium-term and long-term time frames), we extracted the last outcome. Dealing with missing data When data were missing or incomplete, we contacted study authors for further information. In cases where individual data were missing from the reported results, and no further information was forthcoming from the study authors, we assumed the missing values to have a poor outcome.


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For dichotomous variables that measured AEs, we calculated the withdrawal rate using the number of participants that received treatment as the denominator (worst-case analysis). For dichotomous outcomes that measured benefits, we calculated the worstcase analysis using the number of randomised individuals as the denominator. For continuous variables, we calculated the MD or the SMD based on the number of participants analysed at the time point. If the number of participants analysed was not available, we would have used the number of randomised participants in each group at baseline. Where possible, we planned to calculate missing SDs from other statistics such as standard errors, CI or P values, according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). If we could not calculate missing SDs, and there were very few missing, we planned to impute them from other studies in the meta-analysis (Higgins 2011c).

Assessment of heterogeneity We planned to assess both clinical and statistical heterogeneity between studies. First, we planned to assess studies for clinical homogeneity with respect to study participants, intervention groups, outcome measures and timing of outcome. For studies judged as clinically similar, we assessed statistical heterogeneity using the I2 statistic (Deeks 2011). We used the following approximate thresholds for the interpretation of I2 : 0% to 40% heterogeneity might not be important, 30% to 60% represented moderate heterogeneity, 50% to 90% represented substantial heterogeneity and greater than 75% represented considerable heterogeneity. In cases of substantial heterogeneity, we planned to explore the data further, including subgroup analyses, to explain the heterogeneity.

Assessment of reporting biases To assess whether reporting bias was present, we determined whether the protocols of included trials were published before recruitment of participants began. For trials published after 1 July 2005, we searched the WHO International Clinical Trials Registry Platform (apps.who.int/trialsearch/). We planned to evaluate whether or not selective reporting of outcomes was present. We planned to compare the fixed-effect estimate against the random-effects model to assess the possible presence of small sample bias in the published literature (i.e. in which the intervention effect was more beneficial in smaller studies). In the presence of small sample bias, the random-effects estimate of the intervention is more beneficial than the fixed-effect estimate (Sterne 2011). We planned to explore the potential for reporting bias using funnel plots if at least 10 studies were available for meta-analysis.

Data synthesis We presented the characteristics of included studies in an evidence table (see Characteristics of included studies table), results from the search and selection of studies in a flowchart, risk of bias in a figure and specific results by type of study, and by outcome. If we considered studies sufficiently homogeneous, we planned to pool data in a meta-analysis using a random-effects model irrespective of the I2 statistic results. We planned to perform analyses were using Review Manager 5 and produce forest plots for all analyses (RevMan 2012).

’Summary of findings’ tables We presented key findings using ’Summary of findings’ tables. These tables provide key information concerning the quality of evidence, the effect size of the interventions examined and the available data on the outcomes, as recommended by The Cochrane Collaboration (Schünemann 2011a). It includes an overall grading of the evidence related to each of the main outcomes using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach (Schünemann 2011b). We reported the absolute and relative magnitude of effect and the number needed to treat (NNT; only for outcomes with a statistically significant difference between groups) in the ’Summary of findings’ tables. For dichotomous outcomes, we calculated the absolute risk difference using the risk difference statistic in Review Manager 5 (RevMan 2012), and expressed the result as a percentage. For continuous outcomes, we calculated the absolute benefit as the improvement in the intervention group minus the improvement in the control group (MD), expressed in the original units, and as a percentage. We calculated the relative per cent change for dichotomous data as the RR - 1 and expressed it as a percentage. For continuous outcomes, we calculated the relative difference in the change from baseline as the absolute benefit divided by the baseline mean of the control group. We calculated the number needed to treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH) from the control group event rate (unless the population event rate was known) and the RR using the Visual Rx NNT calculator (Cates 2008). For continuous outcomes, we calculated the NNT using the Wells calculator software available at the Cochrane Musculoskeletal Group editorial office. The minimal clinically important difference (MCID) - defined as the smallest difference in score in the domain of interest that participants perceived as beneficial (or worse) and that may lead to, in the absence of troublesome adverse effects and excessive costs, a change in the participant’s management (Khanna 2007) - for each outcome was determined for input into the calculator. For pain, we used a reduction of 1.5 points on


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a 10-point scale as the MCID. For sUA reduction, the MCID has not yet been established although determination of an MCID may be unnecessary for sUA reduction, as the aim of the treatment is to normalise levels in order to dissolve the MSU crystals. For other outcomes included in this review, no MCID has been established for people with chronic gout. For the ’Summary of findings’ table, we included the following outcomes: 1. acute gout flares; 2. study withdrawals due to serious AEs; 3. sUA reduction; 4. pain reduction; 5. participant global assessment; 6. total number of AEs; 7. tophus regression.

participants were allopurinol naive and we have reported this subgroup analysis. Sensitivity analysis Where sufficient studies existed, we planned sensitivity analyses to assess the impact of including trials in meta-analysis that were susceptible to selection bias (i.e. with inadequate or unclear allocation concealment), and including trials susceptible to detection bias (i.e. with inadequate or unclear outcome assessment blinding). However, as there were only two included studies and pooling was not possible, we performed no sensitivity analyses.

RESULTS Subgroup analysis and investigation of heterogeneity In order to explore the heterogeneity of the included studies, we planned a subgroup analysis (if sufficient data were available) for the effect of gender, as different levels of sUA have been reported in men and women (Stamp 2011). Ideally, we would extract the main outcomes separately for men and women from within each trial. We planned to compare the effect sizes in the subgroup analyses informally to assess possible differences in response to treatment by considering the overlap of the CIs of the summary estimates in the two subgroups - non-overlap of the CIs indicated statistical significance. However, as we had anticipated, the outcomes were not reported by gender within the trials, precluding this planned analysis. However, one trial did report data by whether or not

Description of studies We screened the results of the search and only two studies met the selection criteria. Results of the search The search retrieved 2848 references, of which 645 were duplicates, we rejected 2105 studies because of a different study population, 34 because of wrong study design and 62 because the intervention was other than dietary (Figure 1). We selected the remaining two articles for detailed review. We identified no additional studies from ACR and EULAR abstracts (2010 to 2013) or from a handsearch of the reference lists of included studies.


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Figure 1. Study flow diagram.


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Included studies Two studies met our inclusion criteria and were included in the review. Both studies were RCTs, and both were performed in New Zealand. See Characteristics of included studies for detailed information. Dalbeth 2012 was a randomised double-blind trial that tested enriched skim milk powder (SMP) for the prevention of gouty flares during a three-month period. The study enrolled 120 participants with recurrent gout flares, from primary- and secondary-care clinics, and from public advertisement. Participants were required to be at least 18 years old, fulfil the ACR criteria for gout and have had at least two gout flares in the preceding four months. People with lactose intolerance or severe renal failure (estimated glomerular filtration rate less than 30 mL/minute) were excluded. Enrolled participants were predominantly middle-aged white men, with a long duration of gout (about 15 years). Gout was poorly controlled, as participants reported frequent gout flares, and onethird of participants had tophaceous disease. Mean sUA was 0.42 mmol/L (slightly over normal). Mean serum creatinine was 91 µmol/L (normal). Half of the participants were taking allopurinol; this was not modified throughout the study. The proportion of participants receiving background non-steroidal anti-inflammatory drugs (NSAIDs) was 27%, colchicine 27% and prednisolone 13%. Participants were randomised to receive 1. lactose powder, 2. SMP or 3. SMP enriched with glycomacropeptides (GMP) 1.5 g and G600 milk fat extract 0.525 g. The primary end point was the change in frequency of gout flares, both defined as pain at rest greater than 3 on a 10-point Likert scale and as participant self reported flare, registered by the participant in a daily flare diary, measured monthly for three months. Other outcomes measured were AEs rate, reduction in pain during the acute gout flares, physical function evaluated through the Health Assessment Questionnaire (HAQ)-II and the reduction of sUA. Other outcomes specified as being of interest in our review were not measured in this trial. Outcomes were reported at one, two and three months after

exposure to the dairy interventions. Stamp 2013 was a randomised open trial assessing the effects of vitamin C compared with allopurinol in sUA reduction during an eight-week period. Forty participants with gout fulfilling the ACR classification criteria with an sUA over 0.36 mmol/L at baseline were included. Enrolled participants were predominantly middleaged white men (mean 58 years of age, 90% men), who were overweight (mean body mass index: 31.2 kg/m2 ). Mean sUA at enrolment was 0.50 mmol/L, with normal renal function (estimated glomerular filtration rate over 66.7 mL/minute). Background use of diuretics was 27.5% and aspirin 30%. No data regarding disease duration or acute attacks rate were provided. Participants were stratified by allopurinol use at enrolment. Twenty participants were already on allopurinol (50%, mean dose at trial entry 345 mg daily) and were randomised to receive either an increase in allopurinol dose (10 participants) 50 to 100 mg daily or to receive vitamin C 500 mg/day (10 participants). Twenty participants were not taking allopurinol (50%) and were randomised to receive either allopurinol starting at 50 to 100 mg daily, with further dose adjustment at four weeks based on sUA level (10 participants) or vitamin C 500 mg daily (10 participants). Mean reduction of sUA at eight weeks was the primary end point of the trial. AE rate was also reported although it was not a pre-specified end point. None of the other outcomes specified as being of interest in our review were measured in this trial.

Excluded studies We excluded no studies after detailed review.

Risk of bias in included studies We assessed Dalbeth 2012 as being of unclear risk of bias and Stamp 2013 to be at moderate to high risk of bias (Figure 2). See Characteristics of included studies for detailed information about the risk of bias.


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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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Allocation Both trials were at low risk of bias with respect to random sequence generation. Dalbeth 2012 used a random block randomisation algorithm to generate the randomisation schedule. In Stamp 2013, the randomisation list was computer generated by an independent statistician. Randomisation was stratified by allopurinol use in permuted blocks of size four. Dalbeth 2012 was at unclear risk of bias for allocation concealment, as it is stated that participants and study staff were blinded to treatment allocation, but no details of the actual method of allocation concealment was provided. Stamp 2013 was at high risk of bias; despite no information regarding intervention concealment being given by the authors, it is an open trial.

study authors’ discussion of GMP/G600 SMP effect on lowering diastolic blood pressure, only reporting the results of its post hoc comparison with the lactose control group. In the study by Stamp 2013, all pre-defined outcomes in the protocol registered at the Australian & New Zealand Clinical Trial Registry (ACTRN12610000545066) were reported in the results. Other potential sources of bias

In Dalbeth 2012, all study agents were a cream-coloured powder. This was administered daily as 250 mL vanilla flavoured shake, so participants were unable to distinguish the type of milk they were taking. Study staff were also blinded to treatment allocation throughout the study. All study participants were treated in the same way and examined according to the same protocol. The study by Stamp 2013 was open, so both participants and physicians were aware of treatment allocation. This may have resulted in performance and detection bias for participant-reported and outcome assessor measured outcomes, but its influence on measurement of laboratory outcomes (sUA levels) was probably unimportant.

In the study by Dalbeth 2012, groups were well matched at baseline except for higher diuretic use in the GMP/G600 SMP group. The commencement or discontinuation rates of diuretics, allopurinol, colchicine, prednisone or NSAIDs did not differ between groups throughout the follow-up period. Compliance was acceptable in all groups (rate of participants who dropped the study or discontinued the dairy product ranged between 13% and 18%). It is noteworthy that study funding was provided by LactoPharma (a joint venture between Fonterra Ltd, Fonterra R&D Ltd and Auckland UniServices Ltd) and the New Zealand Government Foundation for Research Science and Technology. The role of the company in the study was not clearly addressed. The review authors BK-S, AM and KP are employees of Fonterra Co-operative Group Ltd. The review authors AM, ND and KP are named inventors on a patent application related to milk products and gout. Participant adherence to medications was not clearly described in the study by Stamp 2013, but oxypurinol and ascorbic acid levels were measured in all study participants, so that could be considered an indirect measure of adherence.

Incomplete outcome data

Effects of interventions

In the study by Dalbeth 2012, of the 120 participants who started, 102 (85%) completed the three-month study per protocol (two discontinued for AEs, eight were lost to follow-up and eight continued the study without taking the study medication after an AE). No significant differences were noted between groups in the dropout rate. All 40 randomised participants completed the eight-week study period in the trial by Stamp 2013.

See: Summary of findings for the main comparison Skim milk enriched with GMP/G600 compared with skim milk plus lactose powder for chronic gout; Summary of findings 2 Vitamin C compared with allopurinol for chronic gout We performed no meta-analysis as the two included studies evaluated different supplements. Therefore, we have presented results for each trial separately. See Summary of findings for the main comparison and Summary of findings 2 for detailed information.

Selective reporting

Skim milk enriched with GMP/G600 versus skim milk and lactose powder

Blinding

In the study by Dalbeth 2012, all outcomes planned in the protocol registered at the Australian & New Zealand Clinical Trial Registry (ACTRN12609000479202) were reported in the paper. Dalbeth 2012 also reported the findings of a post hoc comparison between two interventions (GMP/G600 SMP and lactose control) and their effects on the study’s primary end point (change in gout flare frequency), although not the results of the third intervention (standard SMP). The same selective reporting occurred in the

Dalbeth 2012 showed a significant reduction in the rate of gout flares with all three dairy products (skim milk enriched with GMP/ G600, standard skim milk and lactose powder) over the threemonth study period; however, there were no differences in the number of gout flares between groups. After combining the two control groups (standard SMP and lactose powder) - using the raw data given by the study authors - and calculating the SD from


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the 95% CI, we found that the rate of gout flares in the GMP/ G600 SMP group was 0.49 ± 1.52 flares per month compared with 0.70 ± 1.28 flares per month in the combined control group. The MD in the change in number of gout flares at three months from baseline between GMP/G600 SMP and the control groups was -0.21 flares per month (95% CI -0.76 to 0.34) (Analysis 1.1). The rate of AE and withdrawals due to AEs were similar between the three study groups: 7/40 participants dropped out because of an AE in the GMP/G600 SMP group and 11/80 participants dropped out from the joint control groups (RR 1.27, 95% CI 0.53 to 3.03) (Analysis 1.2). The risk of any AE (14/40 in the GMP/G600 SMP group versus 28/80 in the control groups; RR 0.97, 95% CI 0.66 to 1.45) and the risk of serious AE (2/40 in the GMP/G600 SMP group versus 3/80 in the control groups; RR 1.33, 95% CI 0.23 to 7.66) were also similar between groups. Regarding secondary outcomes, GMP/G600 SMP was superior to the two control groups in terms of improvement in pain during gout flares (-1.97 ± 2.28 in GMP/G600 SMP group versus -0.94 ± 2.25 in controls, using a 0- to 10-point Likert scale; MD -1.03, 95% CI -1.89 to -0.17). (Analysis 1.3). There was no significant

differences in sUA reduction (-0.024 ± 0.066 in GMP/G600 SMP versus -0.010 ± 0.068 in control group; MD -0.01, 95% CI -0.04 to 0.01) (Analysis 1.4); data regarding sUA normalisation were not provided. In physical function, assessed using HAQ-II, no significant differences were found between groups at three months (0.08 ± 0.23 in the GMP/G600 SMP group versus 0.11 ± 0.32 in the control groups; MD -0.03, 95% CI -0.14 to 0.08) (Analysis 1.5). Vitamin C versus allopurinol Stamp 2013 found that at the end of the eight-week study period, mean reduction of sUA significantly favoured the allopurinol group compared with the vitamin C group (mean reduction: 0.118 ± 0.072 mmol/L in allopurinol group versus 0.014 ± 0.072 mmol/L in vitamin C group; MD 0.10, 95% CI 0.06 to 0.15) (Analysis 2.1). In the paper, the authors performed a subgroup analysis based upon whether or not participants were taking allopurinol at study entry and found that this did not affect treatment response (Analysis 2.2; Figure 3).

Figure 3. Forest plot of comparison: Vitamin C versus allopurinol, outcome: sUA reduction (subgroup analysis) [mmol/L].

No AEs were detected in either group. No other outcomes of interest in our review were measured in this trial.


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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Vitamin C compared with allopurinol for chronic gout Patient or population: participants with chronic gout and sUA level > 0.36mmol/L Settings: outpatients, rheumatology clinics Intervention: vitamin C Comparison: allopurinol Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Allopurinol

Vitamin C

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Comments

Acute gout attack fre- See comment quency - not reported

See comment

Not estimable

-

See comment

Not measured or reported

Participant withdrawals None due to adverse events Follow-up: 8 weeks

None

-

40 (1 study)

⊕⊕

low1

-

Joint pain reduction - not See comment reported

See comment

Not estimable

-

See comment


Physical function - not See comment reported

See comment

Not estimable

-

See comment


Tophus regression - not See comment measured

See comment

Not estimable

-

See comment


40 (1 study)

⊕⊕

low1

Absolute risk difference: 0.10 NNT = 102

sUA reduction Follow-up: 8 weeks

The mean sUA reduction The mean sUA reduction in the control group was - in the intervention group 0.118 mmol/L was 0.10 mmol/L higher (0.06 to 0.15)

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Adverse events Follow- None reported up: 8 weeks

None reported

-

40 (1 study)

⊕⊕

low1

None reported. No participant developed oxalate renal stones or oxalosis

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; sUA: serum uric acid. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Potential

selection, performance and detection bias might influence the results, as it is an open trial. needed to treat for an additional beneficial outcome (NNTB) = not applicable when result is not statistically significant. NNT for continuous outcomes calculated using the Wells calculator software available from the Cochrane Musculoskeletal Group editorial office.

2 Number

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DISCUSSION Summary of main results In our search, we only identified two RCTs that tested the benefits of two different dietary supplements in people with chronic gout, one trial assessed enriched skim milk and the other evaluated vitamin C. Skim milk enriched with GMP/G600 One trial, including 120 participants and at moderate risk of bias, compared enriched SMP with GMP/G600 versus standard SMP and versus lactose powder. There were no differences between groups in terms of frequency of gout flares, AE rate (where gastrointestinal disturbances were the most commonly reported), physical function and sUA reduction. Participants in the GMP/ G600 SMP group reported a greater improvement in pain from self reported gout flares, but this might be of doubtful clinical relevance. Withdrawal due to AEs did not differ between groups but it was deemed rather high. Tophus regression and health-related quality of life impact were not assessed in the study. Compared with standard skim milk or lactose powder, skim milk enriched with GMP and G600 was of unclear benefit in reducing flares of gout based on a single trial that was at moderate risk of bias.

Vitamin C One trial, of 40 participants and at moderate to high risk of bias, evaluated the effect of vitamin C on sUA levels compared with allopurinol over eight weeks. Participants were stratified regarding the use of allopurinol at the entry of the study. Overall, reduction of sUA with vitamin C was significantly lesser than with allopurinol. There were no significant AEs reported in either group. No other outcomes of interest for this review were measured in this study. Compared with allopurinol, vitamin C was of unclear benefit in reducing sUA levels in people with gout based on a single trial that was at moderate to high risk of bias.

Overall completeness and applicability of evidence Enriched SMP and vitamin C were the only dietary supplements tested in gout, based on our search. Participants in the study by Dalbeth 2012 do not seem very representative of the average gout population, as they reported very recurrent flares (3.9 to 5.1 flares in the four months preceding the enrolment), and 20% to 43% showed tophi. This fact might be attributable to ethnic issues, as the study was performed in New Zealand and Maori and Pacific people have been shown to have a severe form of gout (Rose 1975); however, in Dalbeth 2012, over 70% of participants were white. Other characteristics, such

as being middle aged (mean range 56 to 57 years), predominant male (88% to 93%) are typical of the disease. The low use of allopurinol (53% to 55%) or colchicine (18% to 33%) is in keeping with other studies, where many participants in the clinical setting are never prescribed or do not adhere to urate-lowering therapy, or flare prophylaxis is seldom considered (Perez-Ruiz 2011). Participants recruited in the study by Stamp 2013 appeared representative of people with gout in clinics (Yu 1984). The dietary supplements identified in this review comprised two different targets of the management of gout; enriched milk powder was tested as an anti-inflammatory agent reducing acute gout flares, while vitamin C would act as an sUA-lowering agent. However, the effect of these supplements appears clinically marginal if any in light of the revised studies. Perhaps, the dose of vitamin C tested in Stamp 2013 was insufficient, as previous reports noted a significant sUA reduction (through increasing uric acid urinary excretion) with larger doses in hyperuricaemic participants without gout (Stein 1976; Berger 1977; Mitch 1981). Other supplements have been tested in people with asymptomatic hyperuricaemia, not in gout. Reducing sUA levels to control hyperuricaemia will lead to dissolving MSU crystals from joints or tissues, but other aims should be considered in people with gout, as a reduction in the number of acute attacks, an improvement in health-related quality of life or regression of the tophi. An anti-inflammatory effect to control acute episodes or the persistent subclinical inflammation would be also suitable for people with gout. Based on this, we deem the studies in people with hyperuricaemia are not entirely applicable to people with gout, and thus we have not included them in this review. Other supplements, such as amino acids, PUFA or antioxidants, are widely used for treatment of several disorders, but our search identified no studies. In addition, some dietary interventions, such as black tea or cherries, which may not really be considered supplements, have shown some effect in reducing sUA levels or controlling acute attacks in people with hyperuricaemia or gout. However, these types of interventions were out of the scope of this review, and lifestyle interventions have been addressed by another Cochrane review (Moi 2013). In addition, population-based studies have identified a number of diet patterns that may be associated with an increased risk of developing hyperuricaemia and gout, such as alcohol or high fructose-enriched beverages. However, giving diet advice based on these results, with no confirmation through intervention studies, warrants caution (Rose 1985), as the effect of these interventions in the individual participant will probably be small or lacking, especially in people with gout, where this effect appears to us incapable of reducing sUA to a level enough to make all MSU crystal dissolve.

Quality of the evidence Our search identified only two studies enrolling 160 participants. It is likely that the small number of trials identified reflects the lack


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of high-quality research in this area rather than publication bias. We deemed the included studies of low quality; issues regarding the study design and imprecision of results reduced the quality of the results, with particular concerns in selective reporting bias and absence of blinding. Relevant outcomes for gout management, such as prevention of acute attacks or sUA reduction, were only assessed in a single study each, and tophus regression was not reported in the included studies.

and whether the addition of glycomacropeptide to SMP add any benefit to the use of standard skim milk and lactose powder in reducing acute gout flares in people with gout remains uncertain. Further research is likely to change the estimates. Findings from this review should be taken into account when considering the prescription of or the advice given regarding dietary supplements for people with chronic gout.

Implications for research Potential biases in the review process Despite a broad search retrieving more than 2800 hits, we only identified two trials that fulfilled the inclusion criteria for this review. We included several different terms for gout and for dietary supplementation (as a general intervention and for different individual ones). We acknowledge that our search is more than one year older (June 2013) than review publication, so there may be further studies to include on updating. However, it seems that the possibility of having missed relevant RCTs is low.

Agreements and disagreements with other studies or reviews To our knowledge, this is the first systematic literature review assessing the efficacy and safety of dietary supplementation in people with gout. In the case of vitamin C, several studies including one meta-analysis of RCTs (Juraschek 2011), have reported that vitamin C supplementation may lower sUA levels. However, these studies have generally been of low quality and have largely been performed in either healthy people or people with asymptomatic hyperuricaemia. In addition, the median sUA levels in the included populations were close to the upper limit of normality (Huang 2005). Therefore, we consider it doubtful that these results could be extrapolated to people with gout.

AUTHORS’ CONCLUSIONS

Taking into account the paucity of trials of dietary supplement in gout but their common use in general population, further studies are needed to establish the role of these products in the management of people with gout. Randomised controlled trials comparing dietary supplements with placebo, no treatment, other supplements and urate-lowering medications are needed before any conclusions can be made. However, we acknowledge that shortterm trials may not be the optimal method for assessing the benefits and long-term sustainability of dietary supplements, and longterm prospective longitudinal studies or registry data may also be required. The included trials in this review had unclear or moderate to high risk of bias. Further trials should consider and report their method of randomisation and treatment allocation concealment; blinding of study participants, study personnel and outcome assessment; follow-up of all participants who entered the trial and complete reporting of outcomes. Sample sizes should be reported and have adequate power to answer the research question; ideally trials should assess both the benefits and risks of dietary supplements. Our review highlights the absence of strong evidence to either support or refute the value of dietary supplementation in people with gout. Though vitamin C appeared suboptimal as urate-lowering therapy in comparison with allopurinol, this is derived from a low-quality evidence, so further trials might potentially change this conclusion. In the case of milk powder, as a potential antiinflammatory effect was noted (Dalbeth 2010), further trials comparing milk powder with non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine in the prevention of acute gout flares may be worthwhile.

Implications for practice While observational studies have reported some effects of some dietary supplements in healthy people or in people with asymptomatic hyperuricaemia (such as a lowering of serum uric acid (sUA) with vitamin C), our review showed that dietary supplementation is based on low-quality evidence to support its use in people with gout. When compared with the standard urate-lowering agent, allopurinol, the effect of vitamin C at a dose of 500 mg daily did not reduce sUA to a clinically significant degree,

ACKNOWLEDGEMENTS The review authors acknowledge the help of Maria Piedad Rosario, Librarian of the Spanish Society of Rheumatology, for her invaluable help with the access to bibliographic databases, and the generosity of the contact authors of the included studies - Drs Nicola Dalbeth and Lisa Stamp - for kindly allowing us to have access to unpublished, raw data.


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REFERENCES

References to studies included in this review Dalbeth 2012 {published and unpublished data} Dalbeth N, Ames R, Gamble GD, Horne A, Wong S, KuhnSherlock B, et al.Effects of skim milk powder enriched with glycomacropeptide and G600 milk fat extract on frequency of gout flares: a proof-of-concept randomized controlled trial. Annals of the Rheumatic Diseases 2012;71:929–34. Stamp 2013 {published and unpublished data} Stamp LK, O’Donnell JL, Frampton C, Drake JM, Zhang M, Chapman PT. Clinically insignificant effect of supplemental vitamin C on serum urate in patients with gout: a pilot randomized controlled trial. Arthritis and Rheumatism 2013;65(6):1636–42.

Additional references Berger 1977 Berger L, Gerson CD, Yü TF. The effect of ascorbic acid on uric acid excretion with a commentary on the renal handling of ascorbic acid. American Journal of Medicine 1977;62(1):71–6. Buchbinder 2002 Buchbinder R, Gingold M, Hall S, Cohen M. Nonprescription complementary treatments used by rheumatoid arthritis patients attending a community-based rheumatology practice. Internal Medicine Journal 2002;32: 208–14. Cates 2008 Cates C. Visual Rx Version 3. www.nntonline.net/visualrx/ (accessed 10 September 2014). Christensen 2008 Christensen R, Bartels EM, Astrup A, Bliddal H. Symptomatic efficacy of avocado-soybean unsaponifiables (ASU) in osteoarthritis (OA) patients: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage 2008; 16(4):399–408. Cohen 1988 Cohen J. Statistical power analysis for the behavioral sciences. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988. Dalbeth 2010 Dalbeth N, Gracey E, Pool B, Callon K, McQueen FM, Cornish J, et al.Identification of dairy fractions with antiinflammatory properties in models of acute gout. Annals of the Rheumatic Diseases 2010;69(4):766–9. Deeks 2011 Deeks JJ, Higgins JPT, Altman DG. Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Higgins 2011a Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green

S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Higgins 2011b Higgins JPT, Deeks JJ. Chapter 7: Selecting studies and collecting data. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Higgins 2011c Higgins JPT, Deeks JJ, Altman DG. Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Huang 2005 Huang HY, Appel LJ, Choi MJ, Gelber AC, Charleston J, Norkus EP, et al.The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis and Rheumatism 2005;52(6):1843–7. Juraschek 2011 Juraschek SP, Miller ER 3rd, Gelber AC. Effect of oral vitamin C supplementation on serum uric acid: a metaanalysis of randomized controlled trials. Arthritis Care and Research 2011;63(9):1295–306. Khanna 2007 Khanna D, Tsevat J. Health-related quality of life - an introduction. American Journal of Managed Care 2007;13 (Suppl 9):S218–23. Klinenberg 1965 Klinenberg JR, Goldfinger SE, Seegmiller JE. The effectiveness of the xanthine oxidase inhibitor allopurinol in the treatment of gout. Annals of Internal Medicine 1965;62: 639–47. Kocic 2012 Kocic G, Pavlovic R, Nikolic G, Stojanovic D, Jevtovic T, Sokolovic D, et al.The effect of depurinized milk draught diet on rat serum uric acid, lipid status and haematological parameters. Journal of Animal Physiology and Animal Nutrition 2012;96:648–55. Krishnan 2008 Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH, MRFIT Research Group. Long-term cardiovascular mortality among middle-aged men with gout. Archives of Internal Medicine 2008;168(10):1104–10. Kuo 2010 Kuo CF, See LC, Luo SF, Ko YS, Lin YS, Hwang JS, et al.Gout: an independent risk factor for all-cause and cardiovascular mortality. Rheumatology (Oxford) 2010;49 (1):141–6.


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Lo 2010 Lo HC, Wang YH, Chiou HY, Lai SH, Yang Y. Relative efficacy of casein or soya protein combined with palm or safflower-seed oil on hyperuricaemia in rats. British Journal of Nutrition 2010;104(1):67–75. Lyseng-Williamson 2011 Lyseng-Williamson KA. Pegloticase: in treatment-refractory chronic gout. Drugs 2011;71(16):2179–92. Mitch 1981 Mitch WE, Johnson MW, Kirshenbaum JM, Lopez RE. Effect of large oral doses of ascorbic acid on uric acid excretion by normal subjects. Clinical Pharmacology and Therapeutics 1981;29(3):318–21. Moi 2013 Moi JHY, Sriranganathan MK, Edwards CJ, Buchbinder R. Lifestyle interventions for chronic gout. Cochrane Database of Systematic Reviews 2013, Issue 5. [DOI: 10.1002/ 14651858.CD010039.pub2] Mori 2006 Mori TA, Woodman RJ. The independent effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans. Current Opinion in Clinical Nutrition and Metabolic Care 2006;9(2):95–104. Nickeleit 1997 Nickeleit V, Mihatsch MJ. Uric acid nephropathy and endstage renal disease - review of a non-disease. Nephrology Dialysis Transplantation 1997;12:1832–8. Pascual 1999 Pascual E, Batlle-Gualda E, Martínez A, Rosas J, Vela P. Synovial fluid analysis for diagnosis of intercritical gout. Annals of Internal Medicine 1999;131(10):756–9. Pascual 2007 Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Annals of the Rheumatic Diseases 2007;66(8):1056–8. Pascual 2009a Pascual E, Sivera F. Gout: new advances on diagnosis and management of an old disease. International Journal of Clinical Rheumatology 2009;4:203–20. Pascual 2009b Pascual E, Sivera F, Yasothan U, Kirkpatrick P. Febuxostat. Nature Reviews Drug Discovery 2009;8(3):191–2. Perez-Ruiz 2002 Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis and Rheumatism 2002;47(4):356–60. Perez-Ruiz 2011 Perez-Ruiz F, Carmona L, García de Yébenes MJ, Pascual E, De Miguel E, Ureña I, et al.An audit of the variability of diagnosis and management of gout in the rheumatology setting: the Gout Evaluation and Management Study. Journal of Clinical Rheumatology 2011;17:349–55.

Philips 2010 Philips M, Sullivan B, Snyder B, Allegretti PJ, McBride BF. Effect of enzyte on QT and QTc intervals. Archives of Internal Medicine 2010;170(15):1402–4. RevMan 2012 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012. Richette 2010 Richette P, Bardin T. Gout. Lancet 2010;375(9711): 318–28. Rose 1975 Rose BS. Gout in Maoris. Seminars of Arthritis and Rheumatism 1975;5(2):121–45. Rose 1985 Rose G. Sick individuals and sick populations. International Journal of Epidemiology 1985;14:32–8. Rossignol 2011 Rossignol M, Bégaud B, Avouac B, Lert F, Rouillon F, Bénichou J, et al.Who seeks primary care for musculoskeletal disorders (MSDs) with physicians prescribing homeopathic and other complementary medicine? Results from the EPI3LASER survey in France. BMC Musculoskeletal Disorders 2011;12:21. Schumacher 2009 Schumacher HR, Taylor W, Edwards L, Grainger R, Schlesinger N, Dalbeth N, et al.Outcome domains for studies of acute and chronic gout. Journal of Rheumatology 2009;36(10):2342–5. Schünemann 2011a Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and ’Summary of findings’ tables. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Schünemann 2011b Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al.Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Smith 2010 Smith EU, Diaz-Torne C, Perez-Ruiz F, March LM. Epidemiology of gout: an update. Best Practice and Research Clinical Rheumatology 2010;24(6):811–27. Stamp 2011 Stamp LK, Zhu X, Dalbeth N, Jordan S, Edwards NL, Taylor W. Serum urate as a soluble biomarker in chronic gout-evidence that serum urate fulfils the OMERACT validation criteria for soluble biomarkers. Seminars in Arthritis and Rheumatism 2011;40(6):483–500.


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Stein 1976 Stein HB, Hasan A, Fox IH. Ascorbic acid-induced uricosuria. A consequency of megavitamin therapy. Annals of Internal Medicine 1976;84:385–8. Sterne 2011 Sterne JAC, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al.Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. British Medical Journal 2011; 343:d4002. Stickel 2011 Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of liver injury associated with dietary supplements. Liver International 2011;31(5):595–605. Tugwell 1993 Tugwell P, Boers M. OMERACT conference on outcome measures in rheumatoid arthritis clinical trials: introduction. Journal of Rheumatology 1993;20(3):528–30. Vista 2011 Vista ES, Lau CS. What about supplements for osteoarthritis? A critical and evidence-based review.

International Journal of Rheumatic Diseases 2011;14(2): 152–8. Wong 2012 Wong WW, Gabriel A, Maxwell GP, Gupta SC. Bleeding risks of herbal, homeopathic, and dietary supplements: a hidden nightmare for plastic surgeons?. Aesthetic Surgery Journal 2012;32(3):332–46. Wu 2011 Wu CH, Wang CC, Kennedy J. Changes in herb and dietary supplement use in the U.S. adult population: a comparison of the 2002 and 2007 National Health Interview Surveys. Clinical Therapeutics 2011;33(11):1749–58. Yu 1984 Yu T-F. Diversity of gouty features in gouty arthritis. Seminars in Arthritis and Rheumatism 1984;13:360–68. Zhang 2012 Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW, et al.Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. Journal of Immunology 2012;188(5): 2127–35. ∗ Indicates the major publication for the study


23

CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Dalbeth 2012 Methods

3-month randomised controlled double-blind trial

Participants

n = 120 Inclusion criteria: 1. Adults aged ≥ 18 years 2. Gout diagnosed (according to the American College of Rheumatology diagnostic classification, recurrent gout flares (at least 2 flares in the preceding 4 months) 3. Participants experiencing frequent gout flares at the time of study enrolment (≥ 2 flares in the preceding 4 months) Exclusion criteria: 1. Lactose intolerance 2. Severe renal impairment (defined as estimated glomerular filtration rate < 30 mL/ minute) Lactose group (n = 40): 1. Males, n (%): 37 (93) 2. Mean age, years (SD): 57 (16) 3. White ethnicity, n (%): 28 (70) 4. Number of self reported flares in preceding 4 months, mean (SD): 3.9 (2.7) 5. Number of gout flares in baseline month, mean (SD): 1.3 (1.5) 6. Allopurinol use, n (%): 21 (53) 7. Colchicine use, n (%): 12 (30) 8. Prednisone use, n (%): 4 (10) 9. NSAID use, n (%): 11 (28) 10. Diuretic use, n (%): 2 (5) 11. sUA, mmol/L, mean (SD): 0.44 (0.11) 12. Tophaceous gout, n (%): 8 (20%) 13. Serum creatinine, µmol/L, mean (SD): 91 (18) SMP group (n = 40): 1. Males, n (%): 36 (90) 2. Mean age, years (SD): 56 (12) 3. White ethnicity, n (%): 28 (70) 4. Number of self reported flares in preceding 4 months, mean (SD): 4.5 (2.3) 5. Number of gout flares in baseline month, mean (SD): 1.1 (1.4) 6. Allopurinol use, n (%): 22 (55) 7. Colchicine use, n (%): 7 (18) 8. Prednisone use, n (%): 8 (20) 9. NSAID use, n (%): 10 (25) 10. Diuretic use, n (%): 1 (2.5) 11. sUA, mmol/L, mean (SD): 0.41 (0.09) 12. Tophaceous gout, n (%): 17 (43) 13. Serum creatinine, µmol/L, mean (SD): 91 (19) GMP/G600 SMP group (n = 40): 1. Males, n (%): 35 (88) 2. Mean age, years (SD): 56 (13)


24

Dalbeth 2012

(Continued)

3. White ethnicity, n (%): 22 (55) 4. Number of self reported flares in preceding 4 months, mean (SD): 5.1 (9.6) 5. Number of gout flares in baseline month, mean (SD): 1.8 (2.4) 6. Allopurinol use, n (%): 22 (55) 7. Colchicine use, n (%): 13 (33) 8. Prednisone use, n (%): 4 (10) 9. NSAID use, n (%): 11 (28) 10. Diuretic use, n (%): 8 (20) 11. sUA, mmol/L, mean (SD): 0.42 (0.11) 12. Tophaceous gout, n (%): 10 (25) 13. Serum creatinine, µmol/L, mean (SD): 93 (20) Interventions

Intervention 1: lactose powder, active control Intervention 2: SMP, active control Intervention 3: SMP enriched with GMP and G600 (GMP protein 1.5 g (10% total protein) and G600 0.525 g (3.5% of total protein weight))

Outcomes

Outcome assessments at 1, 2 and 3 months: Primary end point: 1. Change in frequency of gout flares Secondary end points: 1. Change in swollen joint count (/66) 2. Change in tender joint count (/68) 3. Pain (10-point Likert), (scored 0-10), where 0 = no pain and 10 = severe pain 4. Participant global assessment (0-100), where 0 = very well and 100 = very poor 5. C-reactive protein (mg/L) 6. sUA concentration (mmol/L) 7. Fractional excretion of uric acid (%) 8. Health Assessment Questionnaire (HAQ)-II, 10-item questionnaire, each item scored from 0 = without any difficulty to 3 = unable to perform. Sum of the scores of each questionnaire item divided by the number of questions answered to obtain a value between 0 (minimal loss of function) and 3 (completely disabled) 9. Open-ended enquiry to elicit adverse events

Notes

Proof-of-concept trial Study end point results not covered in this review: 1. Participants in the GMP/G600 SMP group showed a significant greater reduction in tender joint count from baseline (MD -0.49, 95% CI -0.85 to -0.12). The 95% CI suggested that there could be a benefit as it could be as much as a -1.96 difference 2. No statistical differences between groups were detected for change in the swollen joint count from baseline (MD -0.23, 95% CI -0.61 to 0.16) 3. No statistical differences in reduction of the number of self reported flares (MD -0. 49, 95% CI -1.08 to 0.09) were detected 4. The trial authors reported no statistical difference between GMP/G600 SMP and the control group in changes in serum creatinine, sUA concentrations, C-reactive protein levels, waist circumference, serum lipid profile and weight over time. Diastolic blood pressure was reported by the trial authors to decrease by a mean of 3.6 mmHg (95% CI 1.8 to 5.4) in the GMP/G600 SMP group over the study period (P value = 0.0002) , with a greater reduction in diastolic blood pressure recorded when compared with the


25

Dalbeth 2012

(Continued)

lactose control (Tukey post hoc test, P value = 0.001) Unpublished and raw data kindly supplied by Dr Nicola Dalbeth Funded by LactoPharma and the New Zealand Government Foundation for Research Science and Technology. Most of the authors declared a relevant conflict of interest Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Quote: “Patients were randomised using a random block randomisation algorithm”

Allocation concealment (selection bias)

Quote: “Participants and study staff were blinded to treatment allocation throughout the study...” Comment: no details of the actual method of allocation concealment to intervention was provided

Unclear risk

Blinding of participants and personnel Low risk (performance bias) All outcomes

Quote: “The products were dry-blended and packed into identical, custom-made aluminium foil sachets... Each intervention was a cream-coloured powder administered daily as a 250 ml vanilla flavoured shake”

Blinding of outcome assessment (detection Unclear risk bias) Laboratory assessed outcomes

1. sUA concentration 2. Fractional excretion of uric acid 3. C-reactive protein 4. Tender joint count 5. Swollen joint count 6. Adverse events Quote: “Study staff were blinded to treatment allocation throughout the study...” Comment: although not explicitly stated, it was implied from the aforementioned statement that outcome assessors were blinded

Blinding of outcome assessment (detection Low risk bias) Participant assessed outcomes

1. Gout flare frequency 2. Participant global assessment 3. Health Assessment Questionnaire (HAQ)-II

Incomplete outcome data (attrition bias) All outcomes

102 (85%) completed the study per protocol (2 discontinued for adverse events, 8 lost to follow-up and 8 continued the study without taking the study product after an adverse event) Comment: the distribution of drop-outs was even between groups as shown in sup-

Low risk


26

Dalbeth 2012

(Continued)

plementary figure Selective reporting (reporting bias)

Unclear risk

Comment: all pre-specified outcomes reported. There was selective reporting of a post hoc comparison between SMP/ GMP/G600 and lactose powder control on change in gout flare frequency and lowering of diastolic blood pressure (an outcome not covered in this review)

Other bias

Unclear risk

Conflict of Interest: “This work was funded by LactoPharma (a joint venture between Fonterra Ltd, Fonterra R&D Ltd and Auckland UniServices Ltd) and the New Zealand Government Foundation for Research Science and Technology. Barbara Kuhn-Sherlock, Alastair MacGibbon and Kate Palmano are employees of Fonterra Co-operative Group Ltd. Alastair MacGibbon, Nicola Dalbeth and Kate Palmano are named inventors on a patent application related to milk products and gout.”, although it says that “Data analysis was completed by a biostatistician independent of the study sponsors”

Stamp 2013 Methods

8-week open-label, parallel, randomised controlled trial

Participants

n = 40 Inclusion criteria: 1. Gout, diagnosed by the ACR preliminary criteria 2. sUA level > 0.36 mmol/L Exclusion criteria: 1. Participants taking non-prescription vitamin supplements Stratification of participants whether taking allopurinol or not at entry Vitamin C group (n = 20): 1. Males, n (%): 18 (90) 2. Age, mean (range): 61.2 years (39-86) 3. Weight, mean (± SEM): 93.1 ± 3.3 kg 4. Body mass index, mean (± SEM): 30.4 ± 0.96 kg/m2 5. New Zealand European, n: 14 6. sUA, mean (± SEM): 0.5 ± 0.11 mmol/L 7. Estimated glomerular filtration rate, mean (± SEM): 65.5 ± 3.5 8. Taking diuretics, no (%): 6 (30) 9. Taking aspirin, no (%): 5 (25) 10. Smoker, no (%): 1 (5)


27

Stamp 2013

(Continued)

No vitamin C group (n = 20): 1. Males, n (%): 18 (90) 2. Age, mean (range): 55.0 years (27-78) 3. Weight, mean (± SEM): 100.3 ± 5.9 kg 4. Body mass index, mean (± SEM): 32.0 ± 1.5 kg/m2 5. New Zealand European, n: 11 6. sUA, mean (± SEM): 0.5 ± 0.09 mmol/L 7. Estimated glomerular filtration rate, mean (± SEM): 67.9 ± 4.6 mL/minute 8. Taking diuretics, no (%): 5 (25) 9. Taking aspirin, no (%): 7 (35) 10. Smoker, no (%): 3 (15) Interventions

Subgroup 1 (participants not taking allopurinol at entry): Intervention 1: vitamin C 500 mg daily Intervention 2: allopurinol 50-100 mg daily (dose adjustment at 4 weeks based on sUA level) Subgroup 2 (participants already taking allopurinol at entry): Intervention 1: added vitamin C 500 mg daily to the stable dose of allopurinol Intervention 2: increased the allopurinol dose (no specified dose scheme)

Outcomes

Outcome measures at 4 (only for the allopurinol group) and 8 weeks Primary end point: 1. sUA Secondary end points: 1. Plasma ascorbate levels 2. Oxypurinol levels 3. Adverse events

Notes

Allopurinol dose was adjusted at 4 weeks if sUA < 0.36 mmol/L was not achieved, while vitamin C dose was not modified Unpublished and raw data kindly supplied by Dr Lisa Stamp

Risk of bias Bias

Authors’ judgement

Random sequence generation (selection Low risk bias)


Support for judgement Quote: “Randomization of patients was stratified according to current allopurinol use, using permuted blocks of size 4...” Comment: we asked the authors, and their answer was that the randomisation list was computer generated by the independent statistician, in advance of recruitment. Randomisation was stratified on allopurinol use, separate lists for both strata and arranged in permuted blocks of size 4

28

Stamp 2013

(Continued)

Allocation concealment (selection bias)

High risk

Comment: no information regarding allocation concealment was given by the authors, but it was an open trial

Blinding of participants and personnel High risk (performance bias) All outcomes

Quote: “This was an 8-week open-label, parallel-group, randomised controlled trial. ..” Comment: neither participants nor investigators were blinded

Blinding of outcome assessment (detection Unclear risk bias) Laboratory assessed outcomes

1. sUA reduction Comment: no data regarding study staff blindness to treatment allocation was given in the study, but its influence in the urate level measurement was likely to be irrelevant

Blinding of outcome assessment (detection High risk bias) Participant assessed outcomes

1. Adverse events Comment: it was an open trial

Incomplete outcome data (attrition bias) All outcomes

Low risk

All randomised participants completed the study, with no drop-outs or loss to followup

Selective reporting (reporting bias)

Low risk

All planned outcomes were clearly reported in the results section

Other bias

Low risk

Independent research; no relation to vitamin C or allopurinol producers

CI: confidence interval; GMP: glycomacropeptide; MD: mean difference; n: number; NSAID: non-steroidal anti-inflammatory drug; SD: standard deviation; SEM: standard error of the mean; SMP: skim milk powder.


29

DATA AND ANALYSES

Comparison 1. Skim milk powder (SMP) (GMP/G600) versus control (SMP/lactose)

Outcome or subgroup title

No. of studies

1 Number of gout flares per month, after 3 months GMP/ G600 SMP versus control (SMP/lactose) 2 Participants withdrawals due to adverse events 3 Pain during gout flares (0-10 Likert Scale) 4 Serum uric acid reduction 5 Physical function

No. of participants

Statistical method

Effect size

1

Mean Difference (IV, Random, 95% CI)

Subtotals only

1

Risk Ratio (M-H, Random, 95% CI)

Subtotals only

1


Totals not selected

1 1

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

Totals not selected Totals not selected

Comparison 2. Vitamin C versus allopurinol

Outcome or subgroup title

No. of studies

1 Serum uric acid (sUA) reduction (overall) 2 sUA reduction (subgroup analysis) 2.1 Allopurinol naive 2.2 Not naive to allopurinol

No. of participants

1

Statistical method

Effect size


Totals not selected

1

40


0.10 [0.02, 0.19]

1 1

20 20

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

0.15 [0.08, 0.22] 0.06 [-0.01, 0.13]

CONTRIBUTIONS OF AUTHORS MA wrote the first draft of the review. FS, LF, RB and LC contributed to the final version of the review by providing comments and suggestions. All authors approved the final version of the review.


30

DECLARATIONS OF INTEREST The authors declare no conflicts of interests.

SOURCES OF SUPPORT Internal sources • Hospital General Universitario de Alicante, Alicante, Spain. In kind support • Hospital General Universitario de Elda, Alicante, Spain. In kind support • Columbia University Medical Center, New York, USA. In kind support • Cabrini Hospital, Malvern, Australia. In kind support • Monash University, Melbourne, Australia. In kind support • Universidad Camilo José Cela, Madrid, Spain. In kind support

External sources • No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW In addition to the pre-planned screening of 2010 to 2011 meeting abstracts of American College of Rheumatology (ACR) and European League against Rheumatism (EULAR), we also screened abstracts from the 2012 and 2013 meetings in order to increase the chance of identifying studies for our review. We added methods describing how we planned to analyse cross-over trials, if we had identified any, and described how we calculated absolute effects for dichotomous and continuous data, and the estimation of the minimal clinically important difference. We had not pre-planned a subgroup analysis to investigate whether or not response to treatment with vitamin C varies in people who were allopurinol naive or already taking allopurinol in the protocol. However, one trial did report such data. This might be relevant issue, as some authors have pointed out that the response to urate-lowering therapy in terms of sUA reduction for people who are allopurinol naive may be significantly different from people who are already taking allopurinol and have their dosage increased (Pascual 2009a). Further increases in drug doses may not result in a comparable sUA reduction; this might be related to an increase in sUA as crystalline deposits start to dissolve. Following this reasoning, we decided to include the analysis in our review.

INDEX TERMS


31

Medical Subject Headings (MeSH) ∗ Dietary

Supplements; Allopurinol [administration & dosage]; Ascorbic Acid [administration & dosage]; Chronic Disease; Gout [∗ therapy]; Lactose [administration & dosage]; Milk; Peptides [administration & dosage]; Powders; Randomized Controlled Trials as Topic

MeSH check words Adult; Animals; Humans


32

Dietary supplements for aquatic sports.

Allopurinol for chronic gout.

Dietary germanium supplements.

Hazards of dietary supplements.

Dosage recommendations for dietary fluoride supplements.

Botanicals in dietary supplements.

Supplements for Chronic Fatigue Syndrome?

[Dietary supplements and cardiovascular diseases].

Dangers of dietary germanium supplements.

Classification of Use Status for Dietary Supplements in Clinical Notes.

Determinants of dietary supplement use--healthy individuals use dietary supplements.

Clays as dietary supplements for swine: A review.

Scoping dietary supplements versus botanical medicines.

Emergency Department Visits Related to Dietary Supplements.

Interactions between dietary supplements in hospitalized patients.

Quantitative Determination of Vinpocetine in Dietary Supplements.

The use of dietary supplements in oncology.

[Liver injury from herbal and dietary supplements].

Regarding the Regulation of Dietary Supplements.

Liver injury from herbal and dietary supplements.

Adverse Effects of Nutraceuticals and Dietary Supplements.

Detection of Cyanotoxins in Algae Dietary Supplements.

Protein supplements: do they alter dietary intakes?

Hepatotoxicity induced by herbal and dietary supplements.