By Dr. Geoffrey Modest
A comparative effectiveness review from the Agency for Healthcare Research and Quality (AHRQ) was just published on the management of gout (see https://www.effectivehealthcare.ahrq.gov/ehc/products/564/2196/gout-management-executive-160314.pdf for the executive summary; or for full report, see https://www.effectivehealthcare.ahrq.gov/ehc/products/564/2195/gout-management-report-160314.pdf (138 pages, not including references, etc, but including the executive summary).
- 8 million patients in US have gout
- Typical attacks, especially early in the disease, last 7-14 days without meds
- Chronic gout tends to develop after years of increasing acute attacks, and may be associated with tophi (typically after 10 years of untreated gout)
- Risk factors: hyperuricemia, but also some combo of genetics, hormonal, metabolic and dietary risk factors. also family history, advancing age, male sex, and early menopause in women. thiazides may also be a risk factor
- The solubility factor of urate is 6.8 mg/dl, though there seem to be several factors that lead to urate deposition, including temperature, local pH, as well as the concentration of urate. Several studies (including the Framingham study) show that the 5-year incidence of acute gout in men increases from 10% in those with serum urate levels of 6.0-6.9, to 48% if serum levels are >8. And the risk is higher if there were a prior gout attack: the 1-year incidence is 30% if the urate level is 6.0-6.9; and >70% if urate > 8mg/dl.
- Key question 1 (acute gout treatment)
- Colchicine works to reduce pain in acute gout (strength-of-evidence SOE — high). this is typically 0.6mg tablets: 2 tablets right away, then 1 tablet every hour for 6 hours or until diarrhea)
- Low-dose colchicine is as effective with fewer adverse effects (SOE — moderate). this is typically 2 tablets initially then only 1 more tablet one hour later
- NSAIDs reduce pain (SOE — high)
- Doesn’t matter which NSAID one uses (SOE — moderate) [though digging into their supportive data, there really are no studies done looking at some of the more common NSAIDs, such as ibuprofen or naproxen, though my experience and my sense of prevailing experience is that these work just fine]
- Systemic steroids reduce pain (SOE — high)
- Not enough evidence to comment on effect of meds on joint swelling, tenderness, ADLs, patient global assessment
- Adverse effects with colchicine are mostly GI (23-77%), NSAIDs also GI (>10%, but <1% with serious GI issues like bleeds), steroid adverse effects are mostly from long-term use, except dysphoria, increased blood sugar, immune suppression, fluid retention [i would add the not-so-common but severe avascular necrosis of hip/shoulder, which can occur with short-term use]
- Key question 2 (dietary and lifestyle management of gout)
- Insufficient evidence for anything for gout management (reducing dietary purines, protein, alcohol; increasing consumption of cherries, milk products, vitamin C; losing weight)
- Insufficient evidence for anything for reducing serum urate levels (decreasing red meat, shellfish, yeast; or increasing low fat dairy, veges, cherries as compared to just weight loss and decreasing alcohol)
- Insufficient evidence for Traditional Chinese medicine (herbs, acupuncture) on symptomatic outcomes
- Key question 3: pharmacologic management of gout
- Urate lowering therapy does NOT reduce the risk of acute gout attack in first 6 months (SOE — high)
- But urate lowering therapy DOES reduce risk of acute attacks after 1 year of therapy (SOE — moderate)
- No difference between febuxostat 40mg and allopurinol 300mg in lowering serum urate levels (SOE — high) [by the way, allopurinol has been around and used for >40 years]
- Effect of feboxustat vs allopurinol on tophi — insufficient evidence
- Using low dose colchicine or NSAIDs prophylactically does reduce gout attacks when beginning urate lowering therapy (SOE — high)
- Longer courses of prophylaxis with colchicine or NSAIDs (>8 weeks) are more effective than shorter courses in preventing gout attacks when beginning urate lowering therapy (SOE — moderate)
- Including dietary advice to urate lowering therapy — insufficient evidence
- Adverse reactions for allopurinol: rash in 5%, mostly mild. can get bad reactions (TEN, Stevens Johnson, DRESS syndrome) but too rarely to be found in the studies (though risk of DRESS is higher if HLA-B*5801 allele is present). for febuxostat, abdominal pain, diarrhea, musculoskel pain (5-20%), but not statistically different from placebo; and no real difference in adverse effects from allopurinol (SOE — high)
- Key question 4: treatment monitoring of patients with gout
- Utility of monitoring uric acid levels in those on meds – insufficient evidence
- Treating to a specific target uric acid level reduces the risk of gout (SOE — low, but “logic supports some monitoring”
- Key question 5: discontinuation of meds for patients with acute or chronic gout
- Discontinuing meds after 5 years with urate levels <7 mg/dl, and where subsequent uric acid levels are <7 mg./dl off meds –insufficient evidence
- Using low dose colchicine or NSAIDs for >8 weeks when beginning urate lowering therapy does result in fewer gouty attacks (SOE — moderate)
So, this report reveals the soft underbelly of medical studies. Gout has been around for eons. We have really old therapies that work (e.g. colchicine). There are thousands (?probably many more) studies on gout. But very few answered the above key questions directly (which are really the biggies for primary care). Of interest, despite the plethora of “insufficient evidence” above, they comment that even though there are not definitive placebo-controlled RCTs on the meds (this comment was only for meds!!!), they decided to give reasonable SOEs about the usefulness of the meds given the understanding of pathophysiology: i.e., there’s lots of inflammation, so steroids are good (and, they state it would probably be unethical to do a steroid vs placebo study). As are NSAIDs. Though there was no comment about (in my opinion, and as expressed before) the dramatic benefit of intra-articular steroid injections. Similarly for chronic gout: it is useful to lower serum urate levels. But there is scant evidence of “treating-to-target” or how long to give meds, and they give no recommendation. Though it is clear that serum uric acid levels is a strong predictor of acute gout and that some open-label extensions of studies have shown a graded relationship between achieved serum uric acid levels and risk of acute gout (the Am Col of Rheum suggests a goal of <6 mg/dl, which makes sense given the Framingham Study showing a 30% recurrence rate with uric acid levels of 6.0-6.9). Another issue is that even the “good” studies done often reflect a skewed population (e.g. in major trials of urate lowering therapy, the presence of tophi is >20%, whereas in primary care it is about 10%). But, I think that one of the big shortcomings to this review is that though they do rate meds for gout based on pathophysiology, they do not do so for nonpharmacologic approaches which also decrease urate levels (e.g., weight loss, low purine diet, decrease alcohol, decrease fructose), which to me reeks of a bias….
- The current analysis does include newer studies, but sheds little additional light because of the lack of rigorously assessed interventions. However, there are lots of guidelines out there, and I think they mostly make sense overall, despite the lack of rock-solid data (see http://blogs.bmj.com/bmjebmspotlight/2016/03/04/primary-care-corner-with-geoffrey-modest-md-oral-steroids-for-acute-gout/ for a recent article on steroids vs NSAIDs, but it includes my blog evaluating the Am College of Rheum guidelines from 2012). At least those older guidelines promote nonpharmicologic interventions and are pretty useful in clinical practice.
- They dismiss using uricosuric agents because allopurinol works probably better and is easier to take, and requires less workup. No comment on losartan to lower uric acid levels, which is in the Am College of Rheum recommendations, and which I use preferentially in those with concommitant hypertension. (see doi: 10.1136/bmj.d8190)
- And a couple of points from my experience:
- I see an 84 yo man with heart failure, CKD stage 2-3, with a documented symptomatically severe gouty attack, who went to an ER and was given oral prednisione, with some benefit. he came to see me and had prepatellar bursitis. I injected this with steroids, and he responded dramatically. Subsequent uric acid was 10.8. I decided to treat him with febuxostat (given his kidney disease and his really high uric acid, though I suspect allopurinol would have been fine) and his uric acid within weeks plummeted to 4.9. Then he had severe gout in his other knee after finishing one month of colchicine prophylaxis, with documented urate crystals, injected again and responded right away. Of note his repeat uric acid was 4.4. so, (and this is confirmed in studies and in above review), prophylaxis should really be for 3 months, even if the uric acid level plummets as it did in this patient.
- I have seen significant improvements of serum uric acid with decreasing high-fructose corn syrup ingestion: I just saw one of my patients for a routine visit — 77yo man with crystal-proven gout in October 2013, stable CKD stage 3, uric acid level 2 months later was 8.4. He stopped drinking soft drinks completely, and his uric acid decreased over the next 6 months to 7.3, without much other change in lifestyle. He has been now doing more exercise , weight is stable, and uric acid level last week was 6.4. No urate lowering meds. No further attacks of gout. So, anecdotally and based on him and a few other patients, I will continue with pushing an aggressive nonpharmacologic management as my first approach, including the several recommendations above (decrease red meat, alcohol, etc) as well as decrease in sodas and other sources of high-fructose corn syrup (there are some studies I have seen of fructose restriction leading to lowering of uric acid levels, though I have seen nothing on the effects on clinical gout. There are some observational studies: the Nurses’ Health Study found an association between fructose consumption and gouty attacks). Of note, the complete text from AHRQ does include fructose as a risk factor, though no recommendation. and, by the way, coffee and low-fat dairy may be protective
- I will continue to inject joints, patient willing (and they all are, in my experience, given the severe pain of gout). My success rate is approx 100% and usually pretty much right away, adverse effects are zero (in my experience), and the patients typically dance their way down the hall after the injection (especially after injecting a great toe or knee). More in the blog noted above. The full AHRQ report does note that there are no randomized trials done on injections, so not mentioned (though, they do include systemic steroids, where there are also no randomized trials. Go figure….)