Experts attempt first treat-to-target recommendations in gout

The first treat-to-target recommendations for gout emphasize keeping serum uric acid levels below 6 mg/dL (less than 360 mmol/L), but base this and other guidance on expert opinion because no published trials have compared gout treatments head to head.

“[We] considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications, and monitoring serum urate levels were also considered to be of major importance,” wrote Uta Kiltz, MD, of Rheumazentrum Ruhrgebiet and Ruhr University Bochum in Herne, Germany, and her coauthors (Ann Rheum Dis. 2016 Sep 22. doi: 10.1136/annrheumdis-2016-20946).

Treating to a therapeutic target is becoming the norm in rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. But despite some recent progress in gout – including updated recommendations (Ann Rheum Dis. 2016 Jul 25 doi: 10.1136/annrheumdis-2016-209707) and Food and Drug Administration approval of the first selective urate transporter inhibitor – it is lagging behind, said Kenneth Saag, MD, a guideline coauthor and rheumatologist at the University of Alabama at Birmingham.

“This is partly because gout has been a dramatically understudied disease,” Dr. Saag said in an interview. Indeed, although it affects at least 8 million people in the United States, is the most common form of inflammatory arthritis in men, and is rising in prevalence with population aging and the obesity epidemic, gout has received much less research funding than rheumatoid arthritis, he noted.

Gout’s insidious nature may be one reason. “Gout affects people in an intermittent way before it becomes a chronic arthritis, and during that initial phase, it is not viewed by many as more than a nuisance,” Dr. Saag said. “The challenge is that gout really is a disease that ultimately causes a lot of morbidity. If serum urate levels are not controlled, hypertension, heart disease, and kidney disease can all accompany gout.”

Accordingly, the No. 1 goal in gout is to meet the serum urate target, and it “doesn’t really matter” what clinicians use to get there, Dr. Saag said. Both allopurinol and febuxostat can effectively lower serum uric acid levels, thereby reducing flares. If patients do not reach target on a xanthine oxidase inhibitor alone, lesinurad (Zurampic) can be added.

But treatment compliance is a problem in gout, and so the guidelines also emphasize patient education. “Just like with managing diabetes, patients need to understand that you have to get to a level,” Dr. Saag said. “Patients with diabetes are now tuned into the idea of measuring hemoglobin A_1c, but it turns out that uric acid is even easier to measure. We have a really good target in gout – if you can get serum uric acid below a certain level for enough time, you won’t have gout anymore. This is one condition in rheumatology that you can actually get rid of with aggressive therapy.”

To create the guidelines, the authors systematically searched Medline, EMBASE, and the Cochrane database for trials of gout in which clinicians used prespecified timelines and endpoints to guide therapy. Fifty-five papers met criteria for full review, but none reported on randomized trials of treat-to-target approaches, so the authors based their guidance on expert opinion. Although most recommendations reflect a “very high level of agreement,” the authors underscore the yawning research gap in gout by listing questions to guide future studies. These begin with the most fundamental – “What is the optimal target serum urate level to manage gout?” and “How often should the serum urate level be measured to optimally control disease?”

At least some answers may be forthcoming, Dr. Saag said. The U.S. Department of Veterans Affairs’ Office of Research and Development is planning a first-in-kind randomized, open-label, non-inferiority trial comparing allopurinol and febuxostat in 950 patients with gout, including those with comorbid stage 3 (moderate) chronic kidney disease. Researchers will titrate doses based on a treat-to-target approach. Recruitment will occur over 2 years, the trial will run for 4 years, and participants will be followed for 72 weeks.

Novartis, Berlin-Chemie Menarini, AstraZeneca, and Ardea Biosciences provided funding for the creation of the recommendations. Dr. Kiltz disclosed research support and consultancy fees from AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and UCB. Dr. Saag disclosed ties to Ardea/AstraZeneca, Crealta, and Takeda. Seven other guidelines authors disclosed ties to industry. The remaining six had no conflicts of interest.

The first treat-to-target recommendations for gout emphasize keeping serum uric acid levels below 6 mg/dL (less than 360 mmol/L), but base this and other guidance on expert opinion because no published trials have compared gout treatments head to head.

“[We] considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications, and monitoring serum urate levels were also considered to be of major importance,” wrote Uta Kiltz, MD, of Rheumazentrum Ruhrgebiet and Ruhr University Bochum in Herne, Germany, and her coauthors (Ann Rheum Dis. 2016 Sep 22. doi: 10.1136/annrheumdis-2016-20946).

Treating to a therapeutic target is becoming the norm in rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. But despite some recent progress in gout – including updated recommendations (Ann Rheum Dis. 2016 Jul 25 doi: 10.1136/annrheumdis-2016-209707) and Food and Drug Administration approval of the first selective urate transporter inhibitor – it is lagging behind, said Kenneth Saag, MD, a guideline coauthor and rheumatologist at the University of Alabama at Birmingham.

“This is partly because gout has been a dramatically understudied disease,” Dr. Saag said in an interview. Indeed, although it affects at least 8 million people in the United States, is the most common form of inflammatory arthritis in men, and is rising in prevalence with population aging and the obesity epidemic, gout has received much less research funding than rheumatoid arthritis, he noted.

Gout’s insidious nature may be one reason. “Gout affects people in an intermittent way before it becomes a chronic arthritis, and during that initial phase, it is not viewed by many as more than a nuisance,” Dr. Saag said. “The challenge is that gout really is a disease that ultimately causes a lot of morbidity. If serum urate levels are not controlled, hypertension, heart disease, and kidney disease can all accompany gout.”

Accordingly, the No. 1 goal in gout is to meet the serum urate target, and it “doesn’t really matter” what clinicians use to get there, Dr. Saag said. Both allopurinol and febuxostat can effectively lower serum uric acid levels, thereby reducing flares. If patients do not reach target on a xanthine oxidase inhibitor alone, lesinurad (Zurampic) can be added.

But treatment compliance is a problem in gout, and so the guidelines also emphasize patient education. “Just like with managing diabetes, patients need to understand that you have to get to a level,” Dr. Saag said. “Patients with diabetes are now tuned into the idea of measuring hemoglobin A_1c, but it turns out that uric acid is even easier to measure. We have a really good target in gout – if you can get serum uric acid below a certain level for enough time, you won’t have gout anymore. This is one condition in rheumatology that you can actually get rid of with aggressive therapy.”

To create the guidelines, the authors systematically searched Medline, EMBASE, and the Cochrane database for trials of gout in which clinicians used prespecified timelines and endpoints to guide therapy. Fifty-five papers met criteria for full review, but none reported on randomized trials of treat-to-target approaches, so the authors based their guidance on expert opinion. Although most recommendations reflect a “very high level of agreement,” the authors underscore the yawning research gap in gout by listing questions to guide future studies. These begin with the most fundamental – “What is the optimal target serum urate level to manage gout?” and “How often should the serum urate level be measured to optimally control disease?”

At least some answers may be forthcoming, Dr. Saag said. The U.S. Department of Veterans Affairs’ Office of Research and Development is planning a first-in-kind randomized, open-label, non-inferiority trial comparing allopurinol and febuxostat in 950 patients with gout, including those with comorbid stage 3 (moderate) chronic kidney disease. Researchers will titrate doses based on a treat-to-target approach. Recruitment will occur over 2 years, the trial will run for 4 years, and participants will be followed for 72 weeks.

Novartis, Berlin-Chemie Menarini, AstraZeneca, and Ardea Biosciences provided funding for the creation of the recommendations. Dr. Kiltz disclosed research support and consultancy fees from AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and UCB. Dr. Saag disclosed ties to Ardea/AstraZeneca, Crealta, and Takeda. Seven other guidelines authors disclosed ties to industry. The remaining six had no conflicts of interest.

The first treat-to-target recommendations for gout emphasize keeping serum uric acid levels below 6 mg/dL (less than 360 mmol/L), but base this and other guidance on expert opinion because no published trials have compared gout treatments head to head.

“[We] considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications, and monitoring serum urate levels were also considered to be of major importance,” wrote Uta Kiltz, MD, of Rheumazentrum Ruhrgebiet and Ruhr University Bochum in Herne, Germany, and her coauthors (Ann Rheum Dis. 2016 Sep 22. doi: 10.1136/annrheumdis-2016-20946).

Treating to a therapeutic target is becoming the norm in rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus. But despite some recent progress in gout – including updated recommendations (Ann Rheum Dis. 2016 Jul 25 doi: 10.1136/annrheumdis-2016-209707) and Food and Drug Administration approval of the first selective urate transporter inhibitor – it is lagging behind, said Kenneth Saag, MD, a guideline coauthor and rheumatologist at the University of Alabama at Birmingham.

“This is partly because gout has been a dramatically understudied disease,” Dr. Saag said in an interview. Indeed, although it affects at least 8 million people in the United States, is the most common form of inflammatory arthritis in men, and is rising in prevalence with population aging and the obesity epidemic, gout has received much less research funding than rheumatoid arthritis, he noted.

Gout’s insidious nature may be one reason. “Gout affects people in an intermittent way before it becomes a chronic arthritis, and during that initial phase, it is not viewed by many as more than a nuisance,” Dr. Saag said. “The challenge is that gout really is a disease that ultimately causes a lot of morbidity. If serum urate levels are not controlled, hypertension, heart disease, and kidney disease can all accompany gout.”

Accordingly, the No. 1 goal in gout is to meet the serum urate target, and it “doesn’t really matter” what clinicians use to get there, Dr. Saag said. Both allopurinol and febuxostat can effectively lower serum uric acid levels, thereby reducing flares. If patients do not reach target on a xanthine oxidase inhibitor alone, lesinurad (Zurampic) can be added.

But treatment compliance is a problem in gout, and so the guidelines also emphasize patient education. “Just like with managing diabetes, patients need to understand that you have to get to a level,” Dr. Saag said. “Patients with diabetes are now tuned into the idea of measuring hemoglobin A_1c, but it turns out that uric acid is even easier to measure. We have a really good target in gout – if you can get serum uric acid below a certain level for enough time, you won’t have gout anymore. This is one condition in rheumatology that you can actually get rid of with aggressive therapy.”

To create the guidelines, the authors systematically searched Medline, EMBASE, and the Cochrane database for trials of gout in which clinicians used prespecified timelines and endpoints to guide therapy. Fifty-five papers met criteria for full review, but none reported on randomized trials of treat-to-target approaches, so the authors based their guidance on expert opinion. Although most recommendations reflect a “very high level of agreement,” the authors underscore the yawning research gap in gout by listing questions to guide future studies. These begin with the most fundamental – “What is the optimal target serum urate level to manage gout?” and “How often should the serum urate level be measured to optimally control disease?”

At least some answers may be forthcoming, Dr. Saag said. The U.S. Department of Veterans Affairs’ Office of Research and Development is planning a first-in-kind randomized, open-label, non-inferiority trial comparing allopurinol and febuxostat in 950 patients with gout, including those with comorbid stage 3 (moderate) chronic kidney disease. Researchers will titrate doses based on a treat-to-target approach. Recruitment will occur over 2 years, the trial will run for 4 years, and participants will be followed for 72 weeks.

Novartis, Berlin-Chemie Menarini, AstraZeneca, and Ardea Biosciences provided funding for the creation of the recommendations. Dr. Kiltz disclosed research support and consultancy fees from AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and UCB. Dr. Saag disclosed ties to Ardea/AstraZeneca, Crealta, and Takeda. Seven other guidelines authors disclosed ties to industry. The remaining six had no conflicts of interest.