The European League Against Rheumatism’s updated recommendations on gout generally resemble those from the American College of Rheumatology, but with several important caveats, two prominent U.S. rheumatologists said in interviews.
First came the praise. “Both ACR and EULAR are sending a consistent message that gout needs more attention and improvement in the quality of care that’s being provided,” said John FitzGerald, MD, PhD, who coauthored the 2012 ACR guidelines and is a professor of medicine and rheumatology at the University of California, Los Angeles.
Dr. John FitzGerald
EULAR also strengthened its advice to start urate-lowering therapy (ULT) early (Ann Rheum Dis. 2016 Jul 25. doi: 10.1136/annrheumdis-2016-209707). This choice reflects “the opinion of many gout experts, that delaying treatment only allows for further accumulation of monosodium urate deposition around the body, which promotes inflammation and tissue destruction and makes it harder to achieve clinical and biologic remission,” said N. Lawrence Edwards, MD, who also helped write the ACR guidelines and is a vice chairman of the department of medicine at the University of Florida, Gainesville.
Finally, EULAR again emphasized treating to a target serum urate level of less than 6.0 mg/dL. “That is definitely consistent with the current recommendations from ACR, and with the way most rheumatologists think,” Dr. FitzGerald said. “The recommendations for future research are also very good and should be commended.”
But several other points depart from the ACR guidance and have prompted critiques.
Allopurinol
Perhaps most strikingly, EULAR now recommends adjusting maximum allopurinol dose based on creatinine clearance if patients have renal impairment. “This modification is very surprising, since [it has] never been shown to affect the incidence of severe allopurinol hypersensitivity reactions,” Dr. Edwards said. “Instead, these antiquated treatment schedules have only added to the epidemic of underdosing of allopurinol by both general practitioners and rheumatologists alike.”
Dr. N. Lawrence Edwards
Indeed, requiring clinicians to consider creatinine clearance when using allopurinol in many of their gout patients might push them toward other drugs and their accompanying side effects, “without first trying a slow, safe titration” of allopurinol, Dr. FitzGerald said.
Instead, both he and Dr. Edwards recommended following the gradual allopurinol dose escalation detailed in the 2012 ACR recommendations. “The biggest risk of adverse effects with allopurinol is during the initial treatment period, whereas there is little data about maximum dose,” Dr. FitzGerald emphasized. “I think the starting dose should be 50 mg every day, or even 50 mg every other day – the latter if patients have stage 4 chronic kidney disease.”
Serum urate
EULAR also advises against letting serum urate fall below 3.0 mg/dL “in the long term” – that is, over several years. This guidance stems from reports that hyperuricemia could help prevent neurodegenerative diseases, Dr. Edwards said. But studies have never clearly linked serum urate to neurologic processes, nor have they shown that low serum urate triggers or worsens disease, he added. “The harm of this EULAR recommendation comes from the chilling effect it might have on getting internists and general practitioners to more fully engage in urate lowering in subjects with gout. They could view a therapeutic serum urate window of 3.0 mg/dL to 6.0 mg/dL as too narrow and requiring too much oversight – leading once again to undertreatment.”
Comorbidities
ACR already had recommended ULT for gout patients with chronic kidney disease or urate renoliths, but EULAR expanded this list to include not only renal impairment, but also hypertension, ischemic heart disease, and heart failure, Dr. FitzGerald pointed out. “The recommendation for hypertension was based on a systematic literature review, but hypertension is so prevalent that this additional recommendation really expands the number of patients that would be treated with ULT,” he added. “If it is a patient’s first attack of gout, I think a lot of primary care providers would be uncomfortable starting patients on ULT.”
EULAR and ACR have always diverged in their recommendations about who should receive ULT, and widening these criteria further without direct supporting evidence from a clinical trial will provoke concerns, according to Dr. FitzGerald. “The EULAR authors lay out the logic for it, but without direct evidence it will be controversial, and the risk-benefit ratio of treating this expanded list of patients is unclear.”
Febuxostat
Dr. FitzGerald also recommended starting the xanthine oxidase inhibitor febuxostat (Uloric) at 40 mg, rather than 80 mg as recommended by EULAR. “This is based on a similar logic, that starting lower and titrating up has less risks than starting at a higher dose.”
Dr. Pascal Richette, first author of the updated EULAR recommendations, disclosed fees from Ipsen Pharma/Menarini, AstraZeneca, and Savient. Dr. FitzGerald and Dr. Edwards were coauthors of the 2012 ACR guidelines on gout, part 1 and part 2.