Daily Health and Medicine News

Gout drug may help some with few treatment options

A new drug that’s injected intravenously may help some very sick gout patients who don’t get better with usual treatment, according to a new study.

The research was designed and funded by the pharmaceutical company Savient, which markets the drug, called Krystexxa, or pegloticase.

Patients taking the drug had fewer gout symptoms a few months after starting treatment than those who got a sham treatment — but they were also more likely to have a serious reaction to the injections.

The researchers say most gout patients don’t have very severe disease and should not be using the drug.

“The progression in these individuals is extreme,” study author Dr. Michael Becker, from the University of Chicago, told Reuters Health. The patients in the study had “gone on to have really severe — on average disabling — (gout), poor quality of life (and) lots of pain.”

“This is not a medication to be undertaken in a much larger group of patients,” he added.

Of 5 or 6 million people in the U.S. with gout, about three percent do not get better with typical gout drugs, such as Lopurin and Zyloprim, or they can’t take the medication for another reason, Becker and colleagues note in the Journal of the American Medical Association. Last year, the U.S. Food and Drug Administration approved Krystexxa — given by injection every other week — for use in those patients.

Gout is a form of arthritis that occurs when uric acid — generally passed out of the body in the urine — accumulates in joints and forms crystals, causing swelling and pain. Krystexxa works by breaking that uric acid down into a form that’s more easily passed through the body.

The current report combines data from two drug trials involving 212 patients with chronic gout. Study participants who got the drug injection every two weeks for six months were compared to a group that received injections once a month and a group that got only drug-free placebo injections.

The majority of patients were men — in their fifties, on average.

Krystexxa caused uric acid levels to fall quickly — but that response didn’t always last. Forty-two percent of patients in the biweekly group and 35 percent in the monthly group still had lowered uric acid six months after starting treatment.

On average, patients who received the drug had a bigger improvement in their general physical function and quality of life compared to those who only got the drug-free injections. And those who got the most frequent drug injections also reported the least pain.

However, more than nine out of ten patients reported at least one “adverse event” — including painful gout flare-ups or reactions to the injections, including a few cases of breathing problems. Those reactions were more common in patients taking Krystexxa.

Some patients also reported headaches and nausea.

Becker said doctors could test which patients had stopped responding to the drug and halt treatment to avoid unnecessary risks in people whose gout isn’t getting any better.

Krystexxa costs about $5,000 per month. Becker said patients whose symptoms improved with the injections could probably go back on cheaper medications — but it’s not clear yet how long most patients would have to get the injections first.

Most patients in the study also had heart conditions, or at least the risk factors for heart disease. Gout often occurs together with obesity and high blood pressure.

Becker said patients who don’t respond to Lopurin and Zyloprim have a couple of other medication options (including Uloric, approved by the FDA in 2009), but gout drugs can take up to several years to really kick in — and some patients with severe disease can’t wait that long. For a number of those patients, Krystexxa may be worth the risks and cost.

“When you have seriously ill people who have no options, 40 percent (of patients getting better) is pretty good,” he said. “Gout can be a really serious and disabling disease. With this and other (drugs) that are coming into line for treatment, we can do a good job in virtually all these people, including the sickest.”

Pegloticase an Option in Patients With Refractory Gout

Adults with severe chronic gout refractory to conventional urate-lowering therapy may respond to treatment with pegloticase (Krystexxa; Savient Pharmaceuticals, Inc), with reductions in uric acid levels, as well as improved physical function and quality of life.

The findings were based on 2 company-sponsored studies published in the August 17 issue of the Journal of the American Medical Association.

Long-term urate-lowering therapy is the mainstay of treatment of gout, John S. Sundy, MD, PhD, of Duke University Medical Center, Durham, North Carolina, and colleagues note in their study.

In roughly 3% of patients, conventional oral urate–lowering agents fail to achieve target uric acid levels of less than 6.0 mg/dL. Pegloticase was developed for this group of patients.

The drug was approved by the US Food and Drug Administration in September 2010 based in part on the results of the 2 randomized controlled trials reported in the Journal of the American Medical Association.

In comments to Medscape Medical News, Daniel Furst, MD, professor of rheumatology at the University of California, Los Angeles, and member of the American College of Rheumatology, said that pegloticase “clearly has a place as second- or third-line” therapy for refractory gout.

It fulfills an unmet need, but one that “is not yet fully characterized,” said Dr. Furst, who was not involved in these studies of pegloticase.

Parallel Randomized Controlled Trials With Similar Results

The 2 studies, known as C0405 and C0406, were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico. The studies lasted 6 months and involved a total of 225 patients: 109 in trial C0405 and 116 in trial C0406.

Study participants received 12 biweekly intravenous infusions of either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo.

One week before the first infusion and throughout the study, all participants received prophylaxis for gout flare with either colchicine (0.6 mg once or twice daily) or a nonsteroidal anti-inflammatory drug.

The primary endpoint was a plasma uric acid level of less than 6.0 mg/dL measured at months 3 and 6. A responder was defined as a patient with a plasma uric acid level of less than 6.0 mg/dL for 80% of the time or longer during months 3 and 6.

The investigators say plasma uric acid levels normalized within 24 hours of the first infusion in all patients receiving pegloticase. Some patients subsequently lost the urate-lowering response, whereas others maintained uric acid levels of less than 6.0 mg/dL throughout the trial.

When analyzed separately by dose, patients treated with biweekly pegloticase experienced response rates of 47% (20/43; 95% confidence interval [CI], 31% – 62%) and 38% (16/42; 95% CI, 24% – 54%) in the 2 trials.

Patients treated with monthly pegloticase had response rates of 20% (8/41; 95% CI, 9% – 35%) and 49% (21/43; 95% CI, 33% – 65%) in the 2 trials. Response rates were 0% in both placebo groups in the 2 trials.

When data from the 2 trials were pooled, response rates were 42% in the biweekly pegloticase group (36/85; 95% CI, 32% – 54%), 35% in the monthly pegloticase group (29/84; 95% CI, 24% – 46%), and 0% the placebo group.

The proportion of responders in both pegloticase treatment groups was significantly greater vs the placebo group in the pooled analysis (P < .001 for both), the investigators report.

They also note that average plasma uric acid levels were substantially below the 6.0-mg/dL target for the entire 6-month study period.

Forty percent of patients in the biweekly pegloticase group and 21% in the weekly pegloticase group had complete resolution of 1 or more tophi (a secondary endpoint) by the final visit vs 7% of patients in the placebo group (P = .002 and P = .20, respectively). Compared with placebo, both pegloticase doses were associated with significant improvements in physical function, quality of life, and pain on standard instruments.

Potential Adverse Events With Pegloticase

One or more adverse events occurred in more than 90% of participants in each treatment group. Serious adverse events were more common in patients treated with biweekly pegloticase (24%) and monthly pegloticase (23%) vs patients treated with placebo (12%).

Despite gout flare prophylaxis, roughly 80% of patients across the 3 pooled study groups experienced gout flare; it was the most common adverse event.

Infusion-related reaction was the second most common adverse event, occurring in 26% and 42% of patients receiving pegloticase biweekly and monthly, respectively, and in 5% of those receiving placebo. Ten percent of patients receiving pegloticase biweekly and 13% receiving it monthly dropped out of the study because of infusion-related reactions.

“Infusion-related reactions, including some cases fulfilling criteria for anaphylaxis, were the most common adverse events causing withdrawal from these trials,” the study authors note.

Although all of these reactions resolved “promptly and without sequelae, minimizing the risk for infusion-related reactions is important for the safe administration of pegloticase in clinical practice,” they advise.

Seven deaths occurred between randomization and the end of the study (4 in the pegloticase group and 3 in the placebo group).

Summing up, Dr. Sundy and colleagues say that these parallel, 6-month, placebo-controlled trials of pegloticase treatment indicate sustained uric acid reductions and significant clinical improvements in “a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy.”

Dr. Furst commented that the 2 studies have several limitations, including, but not limited to, the “small numbers, short duration and no cost effectiveness analysis.” He also said that the “generalizability” of the results “needs further work.”

The 2 studies were sponsored by Savient Pharmaceuticals. Four study authors were employees of Savient at the time of conception and performance of the studies. A complete description of disclosures can be found in the original article.

Dr. Furst discloses that he is an investigator in a trial of febuxostat (Uloric) and serves on a task force panel that is developing guidelines for treatment of gout. He has been on a number of national committees concerned with rheumatic therapeutics, including being a member and fellow in the American College of Rheumatology and the American Society of Clinical Pharmacology and Therapeutics.

Eisenhower Rheumatology Clinic uses new diagnostic tools, treatments to tackle rising gout incidences

Gout, a painful form of arthritis, has become an increasingly common problem in the United States. Gout is now the most common inflammatory joint disease in men of all ages, and in older women. Gout is caused by high levels of the chemical uric acid in the body, which is deposited into the joints as microscopic crystals. The crystals cause episodes of intense joint swelling and pain as the body’s immune system attempts to attack and break them down. Large studies in the United States indicate that the prevalence of gout nearly doubled from 2.9 to 5.2 cases per 1000 people from 1990 to 1999.

This significant increase in gout is generally attributed to negative lifestyle trends in the U.S. population. Obesity, diabetes, high blood pressure, and the consumption of red meat, alcohol and foods sweetened with fructose have been identified as risk factors for gout. Certain medications, medical conditions such as chronic kidney disease, and genetic factors influence an individual’s risk of gout as well. Pre-menopausal women have a low rate of gout due to the protective effects of estrogen. However, after menopause the rate of gout rises and is influenced by the same risk factors affecting men.

Fortunately, new diagnostic tools and treatments are being deployed to fight the growing epidemic. The traditional diagnosis of gout requires identifying gout crystals by removing them from an affected joint with a needle and syringe. This approach is not only painful, but is technically difficult in certain joints. Eisenhower’s Rheumatology Clinic is employing a new diagnostic tool in the form of high-frequency ultrasound scanning to identify gout crystals within the joint. The scan is quick and painless and can be performed during a routine office visit. In addition, blood testing and X-rays are often performed to determine the severity of gout and to guide treatment.

Once diagnosed, many patients require a medication to treat their gout. Failure to treat gout typically results in progressive disease severity over time and may lead to irreversible joint damage. Some severe gout flares mimic serious infections and may result in unnecessary hospitalizations and antiobiotic treatments. Until recently, treatment options were limited due to a relative dearth of clinical and research interest in gout. Allopurinol, an oral medication that lowers blood levels of uric acid, has long been the mainstay of gout treatment. However, for patients allergic or intolerant to this medication, until recently there was no equally effective alternative.

Physicians now have two additional treatment options. Febuxostat, an oral medication similar to allopurinol, is available for patients who fail or cannot tolerate allopurinol. Pegloticase, an intravenous medication given as an outpatient infusion, is available for cases that fail oral treatment. For many, gout treatment is managed by a primary care physician such as an Internal Medicine or Family Medicine physician. Complicated cases may be referred to a Rheumatologist.

The importance of modifying lifestyle-related risk factors to reduce gout cannot be over-emphasized. Reducing consumption of red meats, alcohol, and fructose-sweetened foods such as soft-drinks is recommended. Consumption of low-fat dairy products has been found to reduce the risk of gout, and therefore is encouraged. Finally, maintaining an ideal body weight through healthy diet and regular aerobic exercise directly reduces the risk of gout, with the added indirect benefit of reducing high blood pressure and kidney disease. A strategy that encompasses nutritional education and lifestyle changes as well as medication management offers the best chance of success in treating and preventing gout.