recurrent gout: serum uric acid level is predictive

 A recent article evaluated serum uric acid levels in patients with known gout and their subsequent development of recurrent gout attacks (see gout uric acid levels and recurrent gout JAMA2024 in dropbox, or doi:10.1001/jama.2023.26640)

 

Details:

-- a retrospective study of 3613 patients aged 40 to 69 with a history of gout who were in the UK Biobank database and had a single serum uric acid level checked between 2006 and 2010, then followed until 2020 through the Primary Care Linked Data medical record linkage and the Hospital Episode Statistics databases

-- 86% men, mean age 60, 99% white

-- mean serum urate level 6.9 mg/dL, BMI 30, daily alcohol consumption 32%/no alcohol consumption 6%, current smokers 9%/former smokers 48%, coffee intake none in 23%/1 to 2 cups per day 40%/3 to 5 cups per day 23%

-- red meat intake 4 servings per week, poultry intake 2 servings per week

-- diuretic use at baseline 12%, uric acid lowering therapy at baseline 21%, hypertension 31%, cardiovascular disease 13%, diabetes 13%, chronic kidney disease at least stage III 6%

       -- serum uric acid levels were higher in men, those with higher BMI, greater alcohol consumption, smoking, greater red meat intake, diuretic use, and having chronic kidney disease; older age and use of urate lowering therapy (ULT) were associated with lower serum uric acid (SUA) levels

-- main outcome and measure: rate of recurrent acute gout, as ascertained by hospitalization, outpatient, and prescription/procedure records, with adjusted rate ratios

-- mean follow-up was 8.3 years

 

Results:

-- there were 1773 new episodes of gout identified

    -- 72% of the total group with gout had no recurrent gout episodes: 16% had one, 6% had two, and 5% had at least three acute gout episodes

-- in the fully adjusted model (adjusted for age, sex, race, BMI as a continuous variable, smoking status, alcohol intake, coffee intake, red meat, fish and poultry intake, current use of diuretic medications, urate lowering therapy, and prevalent diabetes, cardiovascular disease, hypertension, and chronic kidney disease):

    -- at 1 year: 63% increased risk for each 1 mg/dL of serum uric acid (SUA) increase above 6 mg/dL, RR 1.63 (1.48- 1.80)

    -- at 2 years: 65% increased risk for each 1 mg/dL of SUA  increase above 6 mg/dL, RR 1.65 (1.53-1.78)

    -- at 10 years: 58% increased risk for each 1 mg/dL of SUA increase above 6 mg/dL, RR 1.58 (1.50- 1.66)

        -- as a reference, the number of gout flares per 1000 person-years in those with SUA levels >10 mg/dL varied from 133 at 10 years to a maximum of 307 in one year

 

 

-- overall, 95% of the new gout flares occurred in people with a baseline SUA of  >6 mg/dL, and 98% occur in those with people with levels >5 mg/dL

-- in subgroup analyses, recurrent gout flares over 10 years were statistically the same for those younger versus older than 60yo, men versus women, nonwhite versus white, CKD at least stage III, diuretic use, or urate lowering therapy use (though in many of these groupings, there were very few people involved; especially for race, CKD, diuretic use, and ULT use)

 

Commentary:

-- gout affects more than 12 million adults in the US, and it is associated with severe pain with the acute attack, reduced quality of life, and a transient increase in major cardiovascular and venous thrombotic events

-- the saturation point for monosodium urate level crystallization is an SUA of 6.8 mg/dL. However, in physiologic fluids, supersaturation without crystallization can occur, since the solubility of urate in joint fluids may be influenced by local temperature, pH level, concentration of cations, level of articular dehydration, and the presence of nucleating agents

-- one important point in this study was that ULT use itself was not related to recurrent gouty attacks; those people at the same level of SUA, whether achieved by meds or not, had similar likelihood of recurrent gout. 

-- given the prior lack of studies that actually randomized individuals to differing SUA targets, guidelines have been unclear on what the appropriate SUA target should be:

    -- the 2020 American College of Rheumatology guidelines suggested an SUA target of <6mg/mL: https://gmodestmedblogs.blogspot.com/2020/06/new-gout-management-guidelines.html 

    -- their prior 2012 guidelines did allow for a target of <5 mg/dL in those with tophaceous gout (and many people still use this lower target for tophaceous gout , given that the uric acid load in the body is much higher in those with tophi and there is evidence that a lower SUA speeds the resolution of tophi)

    -- of note, the 2017 British Society of for Rheumatology guidelines for the management of gout have a much lower SUA target of 300 µmol/L (3.4 mg/dL) initially which could be increased to 360 µmol/L (4.1 mg/dL) after the patient was stable: https://academic.oup.com/rheumatology/article/56/7/e1/3855179

 

-- The main result of this current study with prospective data collection was that a single serum urate level at baseline in those who had a history of gout was highly predictive of the likelihood of a recurrent gouty attack

-- prior studies had assessed the relationship between SUA levels and developing a first gouty attack, with similar findings of the dramatic increases in clinical gout as the SUA levels increased. This was the first study with lots of granular data to assess those who had had a prior gouty attack, thereby giving us some guidance on the utility of tracking and treating SUA levels in those with a prior attack

-- one advantage of the study as it did include patients who were followed in primary care, a more general group than is followed in a specialty clinic

-- though the cardiovascular benefit of allopurinol is a bit mixed, i believe that there is a strong argument that there is a significant cardiovascular benefit: https://gmodestmedblogs.blogspot.com/2023/05/allopurinol-decreases-heart-disease.html

    -- a recent abstract based on the CARES trial assessed cardiovascular outcomes in patients with gout, finding fewer events in particular with SUA levels <5 mg/dL by utilizing either allopurinol or feboxustat: OP0151 SERUM URATE LEVEL AND CARDIOVASCULAR OUTCOMES IN GOUT PATIENTS WITH ADMINISTRATION OF FEBUXOSTAT OR ALLOPURINOL: A PATIENT-LEVEL POST-HOC ANALYSIS OF THE CARES TRIAL | Annals of the Rheumatic Diseases (bmj.com)

-- and, it is important to remember that there are important effective nonpharmacologic interventions to lower SUA levels (https://pubmed.ncbi.nlm.nih.gov/34074101/), including:

    -- stopping alcohol consumption (and the appropriate goal in general for alcohol is pretty clearly zero, see https://gmodestmedblogs.blogspot.com/2023/11/alcohol-use-disorder-meds.html for a review and discussion of meds to help)

    -- decreasing fructose consumption, especially sodas and other food products with high fructose corn syrup (fructose is the only sugar that is metabolized to form uric acid). for an interesting evolutionary perspective, see https://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html

        -- anecdotally, i have had a few patients stop their 2 bottles of soda/day and have an associated 1 mg/dL decrease in their SUAs

    -- avoiding high purine foods such as  organ meats, red meats (including lamb), and shellfish. and getting more protein from plant-based or low-fat dairy sources

    -- overall eating well: the DASH and Mediterranean diets seem to help prevent the metabolic syndrome (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9710414/); and hyperuricemia is associated with the metabolic syndrome (https://doi.org/10.1038/s41598-022-22025-2)

 

Limitations:

-- this study was based on the UK Biobank, where the participants are in general from a higher social economic status, are healthier than the general UK population, and are largely white; this all limits the generalizability to other populations

-- the patients included in the study had a recurrent gout attack that led to a hospitalization, and this presents a selection bias: those who were taken care of as outpatients in primary care may not have been included (55% of the UK Biobank cohort did not have a primary care record available and were not part of this study)

-- this study involved a single baseline SUA level, and these levels may have changed dramatically over the length of the study by changes in weight, diet, alcohol consumption, etc. And, not surprisingly, these fluctuations do seem to be important in the development of gouty flares: Fluctuation and change of serum urate levels and flares in gout: results from the NOR-Gout study - PMC (nih.gov)

-- there was no information about consumption of fructose (and especially high-fructose corn syrup) as a potential factor in increasing SUA and gout

-- there was no information presented on the severity of the gout or the presence of tophi in this study

-- though this article reinforced the importance of lowering SUA levels to decrease the likelihood of subsequent gout attacks, chronic use of low dose colchicine also seems to be effective in decreasing gout recurrences and may also decrease the likelihood of cardiovascular events: https://gmodestmedblogs.blogspot.com/2016/10/colchicine-may-lower-cardiac-risk-in.html . there is also some evidence that colchicine lowers the likelihood of adverse kidney outcomes in patients with CKD and hyperuricemia: https://pubmed.ncbi.nlm.nih.gov/35139160/ 

 

So,

-- this article reinforces the importance of lowering SUA levels in patients with gout, given that there is a significant increase in the likelihood of future gout attacks that tracks with increasing SUA levels

-- it would be interesting to know if colchicine, in a head-to-head comparison with ULT by allopurinol or febuxostat, provides similar benefits for subsequent gout attacks as well as cardiovascular and renal outcomes

-- it would also be interesting to study the combined effects of a rigorous nonpharmacologic approach to SUA lowering as part of the medical strategy (how much was it able to decrease the use of meds or lower their dosage??)

-- we also would benefit from a clear and consistent assessment of the appropriate target for SUA in those with gout, which would require RCTs on dosing regimens. is it really <6 mg/dL? or is <5mg/dL better? or does it depend on the presence of tophi? Or initial SUA levels (which may reflect the total body burden of uric acid)?

 

 

geoff

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