preventing gout flares when urate lowering therapy

 A recent meta-analysis confirmed that gout needs to be treated with anti-inflammatory meds for longer than three months after initiating urate-lowering meds in order to decrease the risk of a recurrent flare  (see gout flares high after stopping prophy ArthCareRes2024 in dropbox, or DOI 10.1002/acr.25486)

 

Details:

--researchers found 6 trials in the literature and one with aggregated unpublished data from the VA (the VA STOP Gout trial), with a total of 2972 participants

    -- these trials were chosen because they had at least one study arm with starting or intensifying urate-lowering therapy (ULT) in which anti-inflammatory prophylaxis was prescribed; these included trials needed to report the percentage of participants with at least one gout flare both during and after the period of anti-inflammatory prophylaxis was documented 

-- trial durations ranged from 24 to 104 weeks, and anti-inflammatory prophylaxis durations from 8 to 48 weeks

-- 93% participants were male with a mean age of 53 years (range from 47 to 63 years). No other documented demographics, comorbidities, medications, diet/exercise/social conditions were mentioned (this information varied substantially from study to study, so they could not be blended together): see their table 1 for more information about the specifics of these 7 studies

-- the researchers specifically assessed three observation periods:

    -- just before stopping anti-inflammatory prophylaxis (ie, still taking the anti-inflammatory med)

    -- within 3 months of stopping anti-inflammatory prophylaxis

    -- whatever was the last period of the trials available in the studies (which varied a lot, from 8 to 48 weeks)

 

 Results:

-- percentage of participants with at least one gout flare:

    -- while on anti-inflammatory prophylaxis: 14.7% (11.3%-18.5%)

    -- during the 3 months after ceasing anti-inflammatory prophylaxis: 29.7% (22.9%-37.0%)

        -- mean difference, as compared to while taking anti-inflammatory prophylaxis: -14.8% (-21.2% to -8.5%), p<0.0001

    -- during last period of the study: 12.2% (6.8%-19.0%)

        -- mean difference as compared to after ceasing anti-inflammatory prophylaxis: 16.0% (-9.2% to 22.9%), p<0.001

        -- no significant mean difference in the percentage of participants having gout flare while on anti-inflammatory prophylaxis vs during the last period of the study (see graph)

 -- sensitivity analyses did not show any significant difference from the above results (despite considerable heterogeneity in the results), considering those on prophylaxis less than three months, those on prophylaxis greater than three months, or studies with all three time points available

 

 Commentary:

-- as has been known for a long time, starting or intensifying urate lowering therapy (ULT) often leads to gout flares, resulting in the recommendation that anti-inflammatory prophylaxis should be co-prescribed when ULT therapy is started or intensified

-- typically this anti-inflammatory prophylaxis is provided by low-dose colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs). I am personally against using long-term NSAIDs for a few reasons:

    -- NSAIDs are associated with many adverse effects (as noted in many of my prior blogs), including several gastrointestinal issues (gastritis, ulcers, bleeding, diarrhea), acute and chronic kidney disease, increased risk of heart failure and atherothrombotic events, high blood pressure, fluid retention, hepatitis, cognitive dysfunction, transverse myelitis, as well as well as leading to dysbiosis of the gut microbiome with, no doubt, potentially profound effects on the body and brain: https://pmc.ncbi.nlm.nih.gov/articles/PMC7426480/ ...  Of course, some adverse effects are more common than others 

    -- a few older studies over the past several decades have noted increased cardiovascular events in those taking NSAIDs (one meta-analysis finding that ibuprofen is worse than naproxen, though the latter was found to have more GI bleeding):

    -- of note, the risk of major GI bleeding is 3-fold higher in those who have untreated H. pylori infection: eg, a study of 100 H pylori positive patients about to begin long-term NSAIDs found that those who had their H pylori eradicated had a 12% chance of ulcer on endoscopy at 6 months vs 34% in those who did not have their H pylori treated, with the incidence of complicated ulcers (symptomatic/bleeding) being 4% vs 27% (see  hpylori and nsaid lancet 2002 in dropbox or Lancet 2002; 359: 9–13: see https://gmodestmedblogs.blogspot.com/2015/05/h-pylori-and-nsaids-increased-gi.html; also patients on low-dose aspirin who have H pylori infections have more bleeding: https://gmodestmedblogs.blogspot.com/2013/04/h-pylori-erdication-if-on-aspirin.html

        -- colchicine may decrease the risk of cardiovascular disease in patients with gout: https://gmodestmedblogs.blogspot.com/2016/10/colchicine-may-lower-cardiac-risk-in.html ; there are quite suggestive data that allopurinol is also associated with decreased cardiovascular disease: https://gmodestmedblogs.blogspot.com/2016/03/hyperuricemia-allopurinol-decreases.html

-- and, a recent article compared patients with gout and put on allopurinol accompanied by either NSAIDs or colchicine for prophylaxis against a gout flare, found that colchicine was associated with significantly fewer cardiovascular events (see gout prophyl colchicine safer than NSAID ArthRheum2025 in dropbox, or DOI: 10.1002/art.43259). in brief:

    --a sequential, propensity score-matched, new-user comparative effectiveness study to compare the risk of major adverse cardiovascular events (MACE: composite of MI, stroke, or cardiovascular death) in 18,120 adults with gout who were started on allopurinol along with either NSAIDs or colchicine for gout prophylaxis [though H Pylori status was not assessed, and we do know that H Pylori is the most common persistent bacterial infection in the world, with about 50% being infected and about 30-40% in the US...].

    -- rate of incident MACE  and cardiovascular deaths were higher among NSAID users versus colchicine users, with a rate difference of 38.8 (15.4- 62.2) and 10.9 (0.7-21.1) per 1000 person-years, respectively

        -- the hazard ratios found a 56% increase and 2.5-fold rate, respectively

-- bottom line: it really makes sense to prescribe low-dose colchicine for gout prophylaxis. several studies have found benefit post-MI (likely from its anti-inflammatory effect), and a recent study found decreased cardiovascular events in those with diabetes and a recent MI who took colchicine: https://gmodestmedblogs.blogspot.com/2024/03/colchicine-decreases-cardiovasc-events.html

    -- and to assess and treat H pylori status when positive

   

- so, I am significantly in favor of chronic colchicine therapy:

    -- low-dose colchicine, 0.6 mg once or twice a day seems to work quite well (there is a new 0.5mg dosage, but it can be quite expensive)

        -- in general, systemic inflammation is associated with a multitude of adverse clinical effects, including everything from heart disease, diabetes, cancer, rheumatoid arthritis, etc. And the chronic inflammation is also found with many psychosocial problems including depression and stress, as well as increased microplastic levels and pollution) and colchicine is a strong anti-inflammatory med

    -- it would be useful to know if colchicine decreased the scourge of the adverse effects of chronic inflammation and provided actual clinical benefit

        -- a 12-year cohort study did find that male patients with gout who were on colchicine had a 15% decreased cancer incidence (https://pmc.ncbi.nlm.nih.gov/articles/PMC5058879/ ). it would be great to have more information on this for cancer and the other conditions mentioned

-- the general understanding as to why initiating ULT is associated with increased gout is that there is a large uric acid load in the body of those who ultimately develop gout, and the ULT leads to a decrease in serum urate levels that shifts the equilibrium to more dissolution of the crystals in the tissues and leading to higher free uric acid that can invade the joint space. One line of evidence is that gout flares after starting ULT are directly related to the magnitude of the serum urate level reduction from the baseline 

    -- the continued increase in gout flares over many months is felt to be from the excessive amount of uric acid in the body at the time the first gout attack happens, and these large body stores dissolve relatively slowly and are excreted over many months or even years

-- the recommended duration of anti-inflammatory prophylaxis per the 2012 American College of Rheumatology guidelines was 3 months after achieving the target serum urate levels for individuals who do not have tophi. The more recent 2020 guidelines suggest anti-inflammatory prophylaxis for 3 to 6 months with ongoing evaluation and continued prophylaxis as needed if there were there were ongoing gout flares (https://gmodestmedblogs.blogspot.com/2020/06/new-gout-management-guidelines.html ). other guidelines such as the EULAR guidelines of 2016 and the British Society of Rheumatology recommended anti-inflammatory prophylaxis for up to six months

    -- for a more extensive review of data on recurrent gout and the predictive levels of serum uric acid in the incidence of recurrent gout, see https://gmodestmedblogs.blogspot.com/2024/07/recurrent-gout-serum-uric-acid-level-is.html

-- there was a study, however, that compared low-dose colchicine with placebo for the first 6 months after starting allopurinol, with a further 6 months of follow-up after colchicine or placebo were discontinued, finding that the number of people experiencing a gout glare after stopping colchicine was higher than that of  those on placebo (though gout flares were lower during the first 6 months when on the colchicine vs placebo). As a result, there was no difference in the net number of gout flares per month over the entire 12 month study between these two groups (see gout colchicine prophylax needed with go slow allopurinol inc AnnRheumDis2023 in dropbox, or doi:10.1136/ard-2023-224731)

    -- the issue here is that meaningful reductions in gout flares can take many months and in some cases years, likely related to the extent of the uric acid load in the body

    -- it is also important to note that intracellular monosodium urate crystals can persist in synovial fluid after gouty attacks have been eliminated with colchicine, suggesting that stopping the colchicine might increase the inflammatory response to these crystals and increase the gout attacks after stopping the colchicine 6 months later. This raises the issue of how long to continue colchicine prophylaxis, an issue that is not clearly resolved.

    -- one suggestive finding is that those who have at least one flare in the month before stopping the colchicine and serum urate level >6.0 mg/dL have an increased risk of a gout flare after stopping the colchicine; this goes along with the above suggestion that those people with multiple gout flares while on colchicine are at higher risk of more after stopping the colchicine because of their higher urate body stores  (ie, perhaps this group should receive augmented urate lowering therapy and/or longer colchicine prophylaxis?)

 

 Limitations:

-- there are a limited number of quite disparate studies in this meta-analysis, limiting the generalizability of the results. Sensitivity analysis did not show an appreciable effect based on this, though this type of analysis lacks robust statistical assessment

-- and, as with meta-analyses in general, there are inconsistencies between the different included studies in terms of definitions and reporting of important demographic/comorbidity/medications/diet/exercise that would contribute to gout flares, limiting the statistical rigor of the results. For example, in this study most gout flares were self-reported and subject to recall bias (i.e., did the patient report a recurrent knee pain as being attributed to a gout exacerbation, underlying osteoarthritis, or gout-related joint destruction and independent of an actual gout flare?) is there "recall bias"? were patients taking the meds reliably? what was the quality of the gout flares (minimal inconvenience to disabling)? or the timing? or the number of joints?

-- this study was limited in terms of being able to assess different anti-inflammatory agents (most patients in these studies were on colchicine), vast differences in the duration of anti-inflammatory prophylaxis, the urate lowering therapies chosen, and the med for gout prophylaxis, again limiting our ability to assess these variables

-- many of the questions about gout treatment are unanswered and therefore hard to have definitive conclusions: what level of urate lowering is optimal for non-tophaceous or tophaceous gout (ie, treating patients to different target levels and assessing outcomes)? is that level different in patients with single joint vs multiple joint gout attacks? or the specific joints involved? or the number of gout flares (which may be a correlate of the total body urate load)?? how do the social/dietary components affect the recurrent gouty attacks? (eating high fructose foods? sodas? drinking alcohol? eating high urate meats/shellfish? meds that increase uric acid levels (diuretics, low dose aspirin)? different degrees of renal failure? dehydration? ...?????

so, 

-- it is quite clear from the studies done that treating gout is not a simple matter:

    -- just lowering the uric acid level with ULTs does not decrease the incidence of gout flares much for at least 6 months

    -- adding colchicine does help, though there may be rebound gout attacks on stopping it. ?does this rebound depend on how long one is on the combo of ULT and colchicine? should that length of time vary by other factors (number of gout recurrences while on colchicine, presence of tophi, etc as noted above)?

    -- does prolonging the colchicine to reap the potential non-gout benefits (eg cardiovascular) be such that we should just continue to prescribe the colchicine if well-tolerated? it is a good anti-inflammatory drug and there are studies suggesting decreased cardiovascular events, and perhaps decreased cancer incidence...

    -- we do know that chronic systemic inflammation is related to a plethora of bad long-term effects on the body

    -- and just having gout is associated with increased future cardiovascular events

geoff

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