gout: ?colchicine needed when starting allopurinol

 I am very sorry but there was an error in my reading of the article for this blog (which was sent out as below): I misread their conclusion “placebo is not non-inferior to colchicine in prevention of gout flares in the first 6 months of starting allopurinol using the ‘start-low go-slow’ strategy” with the double negative.  Sorry about that. I would restate my conclusions as follows:

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-- placebo was not non-inferior to colchicine in the primary outcome of 6 month followup. Colchicine did in fact help

-- this was not true at the secondary outcome of analysis at 12 months, largely because of an increased risk of gout for 3 months after cessation of the colchicine (ie, it all evened out at 12 months)

-- the reason why this skewed effect happened might well be from the fact that it took 3 months for the allopurinol plus colchicine to get the serum urate levels below their target of 6 mg/dL, which might suggest a 9-month colchicine course (as I mentioned in the first email)

    -- and we know from several older studies with higher dosing of allopurinol that it takes 6 months before there is any lowering of gout attacks

-- but there are also some very important holes that remain in the current study:

    -- 25% of the patients had tophi. This is a large percent of the participants who are at much higher risk of recurrent gout (presumably because of their large uric acid burden that takes longer to decrease sufficiently). Perhaps the 75% without tophi actually did not have an increase in gout after stopping the colchicine after 6 months?? And those with tophi were randomized to a serum urate level <6 mg/dL, which might well be insufficient (the 2012 rheum guidelines suggested <5 mg/dL, which is what is done in other countries

    -- we have no information on the intensity of the gout flares. Were they less intense in those on colchicine? If milder, maybe no need to give colchicine prophylactically. Perhaps as needed, as I suggested

-- that all being said, my personal approach has been largely to have people with gout take colchicine long-term, as I mentioned, because of the cardiovascular benefit. And all of them I have treated are at high cardiovascular risk, and the studies are impressive to me that colchicine is associated with lower cardiovascular risk, per the comments in the blog

-- those patients who may be at lower cardiovascular risk or do not want longterm meds might well benefit from colchicine, perhaps for 9 months, or by having colchicine at home to use for gout attacks if they occur

    -- and, given the low rate of gout attacks in both colchicine and placebo groups (around 1-2%), that may well be a reasonable strategy….

 

So, sorry about that.  geoff

 

Best, geoff

 

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A recent study found that it does not seem to be necessary to give colchicine to patients who have gout and are put on low-dose allopurinol with a slow titration up (see gout colchicine may not dec with allopurinol AnnRheumDis2023 in dropbox, or https://doi.org/10.1136/ard-2023-224731)

 

Details:

-- 200 participants with gout flare in the past 6 months were randomized to colchicine 0.5 mg/d vs placebo when starting allopurinol 100mg (50mg if patient had chronic kidney disease at least stage 3), with titration monthly to achieve a serum urate (SU) level <6mg/dL (0.36 mmol/L). This up-titration of allopurinol was not continued if there were 3 consecutive serum SU levels below the 6 mg/dL target

-- mean age 56, 93% men

-- duration of gout 11 years, serum urate (SU) level 8.41 mg/dL m (0.50 mmol/L) [though 8.74 mg/dL in the group randomized to colchicine, 8.07 mg/dL in those on placebo]

-- creatinine 1.06 mg/dL, eGFR 77, CK 131

-- gout flares in past 6 months: 2; in last month: 1

-- tophi present in 25%

-- comorbidities: obesity 55%, hypertension 45%, hyperlipidemia 34%, cardiovascular disease 20%, eGFR<60 15%, kidney stones 9%, diabetes 7%

-- meds: diuretic 13%, aspirin 16%

 

-- primary efficacy outcome: mean number of self-reported gout flares/month, from 0-6 months

    -- there was a prespecified non-inferiority margin of 0.12 gout flares/month

-- primary safety outcome: self-reported adverse effects over the 6-month period

-- secondary outcomes:

    -- numbers of gout flares between 0-3 months, 6-12 months, 0-12 months; % of participants with gout flares over the entire study period; time to first gout flare; change in SU from baseline; change in baseline subcutaneous tophus count; change in baseline pain VAS (visual-analogue scale), activity limitation (HAQ, Health Assessment Questionnaire) and health-related quality of life (EQ-5D-3L)

 

Results:

-- number of gouty attacks:

    -- colchicine group: 0.35 (0.22-0.49)

    – placebo group: 0.61 (0.47-0.74)

        – mean difference: 0.25 (0.07-0.44); ie, placebo was non-inferior (p=0.92), given the confidence intervals

    -- these results were essentially identical in the intention-to-treat and the per-protocol analyses

-- first 3 months: the mean number of gout flares was lower in those on colchicine, 0.45 vs 0.74/month, p=0.02

-- over the 12 months: no difference total number of gout flares, p=0.68

   -- but, this average does undercut some not so subtle differences: those on colchicine had fewer gout flares in the first 6 months (0.45 vs 0.74 flares/month, p=0.02), and more from months 6-12 on stopping the colchicine (0.46 vs 0.32/month, p=0.15, not statistically significant; but from the graphs below, those stopping the colchicine seemed to do much worse months 7-9)

   -- and, for the group as a whole, it took 3 months to get to the target SU of <6 mg/dL (0.36 mmol/L)

 

 

-- No difference in pain VAS, Health Assessment Questionnaire, or health-related quality of life at 6 months or 12 months

-- No difference in the tophus count between the groups

 

-- adverse events (AEs):

    --serious adverse events: 11 in colchicine group in 7 participants vs 3 in placebo group in 2 participants

        -- only one serious adverse event was felt to be possibly related to allopurinol: skin rash (not further described) in a patient on placebo

    -- non-serious adverse events: 84 in each group

        -- more significant major differences between groups: GI disorders (40 colchicine vs 45 placebo), musculoskeletal (31 colchicine, 34 placebo), skin (23 colchicine, 18 placebo)

            -- AEs that were expected to be found more with colchicine: diarrhea (29 colchicine, 36 placebo), abdominal pain (7 colchicine, 10 placebo), nausea (9 colchicine, 7 placebo), vomiting (3 colchicine, 6 placebo), muscle weakness (12 colchicine, 8 placebo)

    -- Ie: not much difference between the groups

 

Commentary:

-- this study provided evidence that placebo was not inferior to a 6-month course of colchicine in preventing gout recurrence, at both the 6-month and 12-month times

-- there was no difference in pain scores or several measures of quality of life in the 2 groups

 

--the standard of care for patients put on allopurinol for uric acid lowering has typically been to prescribe colchicine or another anti-inflammatory agent to diminish the likelihood of instigating a gout attack, and that this anti-inflammatory med should last at least 3 months (though gout attacks have been reported in several studies to occur for the first 6 months after allopurinol initiation)

    -- codifying this approach, the most recent (2020) gout management guidelines from the American College of Rheumatology state: “administering concomitant anti-inflammatory prophylaxis therapy (eg colchicine, NSAIDs, prednisone/prednisolone) over no anti-inflammatory prophylaxis therapy is strongly recommended”, and “continuing concomitant anti-inflammatory prophylaxis therapy for 3-6 months over 3 months…is strongly recommended”): see gout management guidelines AmColRheum2020 in dropbox, or https://pubmed.ncbi.nlm.nih.gov/32390306/ )

    -- but this colchicine timeframe was based on older studies when it was recommended to start with higher doses of allopurinol (300mg) vs the current approach of lower doses (100mg, or 50mg if CKD of at least stage 3) and titrating up slowly. This start-low-go-slow approach was initiated largely to decrease the risk of the allopurinol hypersensitivity syndrome, a potentially fatal condition (though this conclusion has only suggestive data, no clear comparisons by RCTs)

        -- ie, this 6-month mark of continuing the colchicine is based on the older studies where there was this much higher initial dose of allopurinol (300mg), and presumably more rapid achievement of SU levels in the target range than with the slow titration now being used. With the start-low-go-slow strategy that took 3 months to achieve the SU level <6 mg/dL, perhaps a 9-month course of colchicine would have been more appropriate than a 6-month one??

 

-- this all brings up the issue of tophaceous gout (25% of the individuals in this study), patients who may be very different from those without tophi (very unfortunately, there was no outcome breakdown in this study separating those with vs without tophi):

    -- did it take less time for those with nontophaceous gout to achieve the SU target, so a shorter course of colchicine would be more reasonable?

    -- those with tophi are typically treated as severe gout patients, with a lower SU target of 5mg/dL. How many of these patients actually achieved this lower SU level (this target was not included in the study)? Were these individuals the ones who had breakthrough gout flares after 6 months? If they had more aggressive allopurinol therapy as a group, how would they have responded? How long was colchicine taken by the non-tophaceous group until their numbers of gout flares decreased?

    -- since those with tophi seem to have a much higher incidence of cardiovascular disease, should they be on lifelong colchicine since it seems to be cardioprotective?? (and, is the increased cardiovascular effects in those with tophaceous gout just related to their higher urate load in their bodies, reinforcing the hyperuricemia/cardiac disease paradigm, or some other factor?)

        -- a prior study found that colchicine given to patients with gout was associated with significantly fewer cardiac events: https://gmodestmedblogs.blogspot.com/2016/10/colchicine-may-lower-cardiac-risk-in.html

        -- there are also several studies on the potential cardiovascular benefit of allopurinol, which seems to be independent of its uric acid lowering: https://gmodestmedblogs.blogspot.com/2023/05/allopurinol-decreases-heart-disease.html 

            -- of note here, uric acid itself is associated with inflammation (Uric Acid Is Associated With Inflammatory Biomarkers and Induces Inflammation Via Activating the NF-κB Signaling Pathway in HepG2 Cells | Arteriosclerosis, Thrombosis, and Vascular Biology (ahajournals.org) ); and allopurinol also has anti-inflammatory effects (Allopurinol for pain relief: more than just crystal clearance? - PMC (nih.gov))       

        -- these comments are embedded in a blog noting the potential benefits of colchicine in decreasing the progression of knee and hip osteoarthritis: https://gmodestmedblogs.blogspot.com/2023/12/colchicine-decreases-hip-and-knee.html

 

-- As a side note of interest, there was a time a few years ago when we were not allowed to prescribe colchicine because of drug company shenanigans:

    -- From a 2018 blog: http://gmodestmedblogs.blogspot.com/2018/12/generic-drug-prices-skyrocketing.html : colchicine has been around since at least the 6th century, had cost a few pennies per pill, and pre-dated the FDA rules for drug approval (ie it was never FDA-approved and was around as a generic). but URL Pharma won exclusive FDA approval to sell its brand-name drug (Colchrys) at $6/pill, based on a really inexpensive study they did of 184 patients who got placebo vs colchicine at higher or lower dose levels, finding (not-so-shockingly) that colchicine worked. and as a result URL Pharma got the FDA to outlaw generic colchicine: this really important and useful drug then required a prior approval for many years, and in many of my patients, this approval was denied (i had several patients with recurrent gout being put on allopurinol but needed colchicine both to treat their gout and prevent recurrences with allopurinol up-titration. the insurance companies mostly required me to use the much more toxic NSAIDs and prednisone prior to getting that approval.) 

 

-- another unaddressed issue (to me) for allopurinol is screening for risk of allopurinol hypersensitivity syndrome (AHS). The 2020 Am Coll of Rheum gout management guidelines (gout management guidelines AmColRheum2020 in dropbox, or https://pubmed.ncbi.nlm.nih.gov/32390306/) comments: “The HLA–B*5801 allele is associated with a markedly elevated risk for AHS. The prevalence of HLA–B*5801 is highest among persons of Han Chinese, Korean, and Thai descent (7.4%), lower among African Americans (3.8%), and even lower among whites and Hispanics (0.7% each).Testing for this allele among Asians and African American patients was reported to be cost-effective (incremental cost-effectiveness ratios <$109,000 per quality-adjusted life years). Asian and African American patients taking allopurinol both have a 3-fold increased risk of AHS compared with white patients taking allopurinol”. This brings up a few issues:

    -- allopurinol hypersensitivity syndrome is potentially lethal (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome), or at least can lead to prolonged (and expensive…) hospitalizations and disability

    -- race/ethnicity-based medicine is fraught: it has clearly been shown that many people who self-identify as a certain race/ethnicity have a wide array of genetic backgrounds

    -- we do routinely check for abacavir hypersensitivity by analysis for HLA–B*5701 (a different one from HLA–B*5801) prior to prescribing abacavir for HIV treatment, though there are similar levels of prevalence for HLA–B*5701 (https://emedicine.medscape.com/article/1969668-overview?form=fpf )  as found with HLA-B*5801. 

 

Limitations:

-- this study was done in Australia/New Zealand, with demographics/culture/diet/exercise/etc likely quite different from other areas of the globe, limiting generalizability

    -- for example, 93% of participants were male…

    -- also, the individuals in this study had a relatively low SU level of 8.4 mg/dL. Would those with much higher levels respond similarly??

    -- as above, this group may have been at lower risk of allopurinol hypersensitivity syndrome by being from a specific area of the world where perhaps (??) the HLA–B*5801 allele is less evident

-- we do not know the intensity of the gout attacks in patients on daily colchicine vs placebo. though the patients in the above study did have more attacks in those on placebo in the first 3 months, it would be useful to know if those on colchicine had very mild attacks for example vs those on placebo having severe, disabling attacks. That might justify the colchicine despite their conclusions

    -- their prespecified inferiority margin was 0.12 gout flares/month, which translates to 0.72 flares over the 6-month period, especially  in the first 3 months which was also the time period it took to achieve the target SU level. So there were relatively few attacks (<1/month) and if they were not severe, it might not really be necessary for a daily colchicine

-- it would be useful also to know if there was a difference in subsequent gout attacks if the patient had few vs many prior flares

-- was the target of 6 months of colchicine the right one, as noted above? it did take 3 months for the mean SU level to be less than the target of 6 mg/dL. Perhaps the target should have been 9 months of colchicine, given this 3-month delay

-- and, as per above, it would have been very useful to have subgroup analysis to see if those with tophi (or other issues, such as comorbidities, or high fructose meals that increase SU levels) have exaggerated gout responses when put on allopurinol.

    -- in fact, the 2020 Am Coll of Rheum guidelines cited above were reluctant to give a different cutpoint SU level for patients with tophi or more aggressive gout: they stated that the goal for all was SU<6 mg/d, but noted “This guideline is not intended to contradict or dispute prior recommendations. There is ample evidence that lower SU levels hasten the resolution of tophi and are associated with less frequent gout flares, suggesting that lower SU thresholds may be preferable for patients with more burdensome gout”

    -- and, perhaps a better study would have used the old cutpoint SU of <5mg/dL given this higher likelihood of gout flares with the <6mg/dL cutpoint

-- this study assessed allopurinol only for lowering SU levels:

    -- there are other meds that should be tested: eg febuxostat

    -- there are nonpharmacologic approaches that help lower SU levels: decreasing fructose intake (sodas are a low hanging fruit here), weight loss when appropriate, decreasing purine intake, meat/seafood consumption (the purine/meat/seafood change is likely less implementable than the fructose one, typically has an effect of <1mg/dL in SU levels, and may lead to substituting more carbohydrates including high-fructose corn syrup)

 

so, this is good news:

-- gout is really common and associated with potentially significant morbidity

--hyperuricemia is likely associated with increased adverse cardiovascular events, and allopurinol has been shown to decrease those events in several studies, as noted above

--the traditional way of treating hyperuricemia with urate-lowering therapy had involved high doses of urate-lowering meds and documented increased gout flares

--prevention of these gout flares relies on pretty toxic meds for up to 6 months: colchicine, long-term NSAIDs, corticosteroids (though colchicine may well have cardiovascular benefits and fewer adverse effects, as opposed to the potential harms with NSAIDs or corticosteroids)

--hence the welcoming possibility that treatment is easier using the start-low-go-slow approach without needing these anti-inflammatories, though the step-up therapy does require more clinical interactions and blood tests

-- but, as with most studies, this one asks more questions than it answers:

    -- should people with nontophaceous gout not be on colchicine at all?? (ie, was the group having more gouty attacks in the first 3 months those with tophi?, were these attacks clinically significant enough to require colchicine?)

    -- should those with tophi be on colchicine for 9 months given the slow allopurinol titration (which may be even slower if the person has CKD stage 3 or worse who have a slower titration?)

        -- and, perhaps those with tophi (or underlying cardiovasc  disease) should be on indefinite colchicine if tolerated to help decrease their cardiovascular risk, which seems to be higher in those with tophi?

 

So what is one to do, given the holes in the current study??? I think the following are reasonable:

-- the go-low-go-slow approach makes sense, which is also often reasonable with meds for patients with largely asymptomatic hypertension, diabetes, heart failure, etc

-- I think it does make sense to check for the HLA–B*5801 allele in general prior to starting allopurinol

-- if the patient has high cardiac risk or has tophi (which seem to place patients at higher cardiac risk), I would strongly consider adding colchicine chronically (ie not stopping after 3-6 months)

-- otherwise, I think it makes sense to give the patient colchicine to have at home and only take only if they have a gout flare on the allopurinol

 

geoff

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