Gout: The King of Diseases

Max Hamburger, MD, Bonny P. McClain, MS, DC, and N. Lawrence Edwards, MD

What is Gout?

The history of gout reaches back many millennia, making it one of the oldest and most recorded forms of arthritis. Egyptians first identified gout in 2640 BC. Hippocrates, weighing in during the 5th century BC, had many original observations still relevant in modern times. Often associated with overindulgence of rich food and drink reaching back to the 15th and 16th centuries, gout is often referred to as the disease of kings. More recently, the epidemic rise in the occurrence of gout has lead to it being called the king of diseases.

Above: Famous Figures in History with Gout. Left; Henry VIII, Sir Isaac Newton, Thomas Jefferson, and Benjamin Franklin.

The prevalence of gout in the United States has risen over the last 20 years and now affects 8.3 million Americans. High levels of fructose and the obesity epidemic in American diets appear to be the causative factors in the continued increase in instances of gout. Caused by high levels of uric acid or hyperuricemia, it is a type of inflammatory arthritis characterized by the sudden onset of red, swollen, hot, and exquisitely painful joints.

Uric acid is produced from the breakdown of purines, which are chemicals that occur naturally in the body, but are also found in certain foods, such as red and organ meats, beer, and shellfish. Although most uric acid dissolves in the blood and travels to the kidneys, where it is excreted in the urine, gout can result when too much uric acid is produced or isn’t removed adequately creating an increase in the levels of uric acid. The pain associated with gout occurs when urate crystals or tophi accumulate in and around a joint, causing the inflammation and intense pain of a gout attack. Urate crystals form on the surfaces of cartilage in joints, while tophi are large accumulations of uric acid that are often visible and easily felt by patient and physician alike.

How is Gout Diagnosed?

Experiencing certain signs and symptoms should raise the suspicion of gout. These include swelling, redness, heat, and severely painful attacks that occur suddenly and most commonly overnight. However, an absolute diagnosis is only available through the identification of monosodium urate (MSU) crystals in the fluid that lubricates the joint (synovial fluid)—done by inserting a needle into an involved joint or tophus and analyzing fluid for the presence of crystals. However, since gout is often diagnosed and treated in primary care offices, individuals that present characteristic symptoms are many times assigned a presumptive diagnosis without the confirmatory procedure. Because patients with gout tend to present with a number of additional or Comorbid conditions, thorough evaluation from a physician is an important aspect in the diagnosis. It is also crucial to note that women often have different signs and symptoms of gout that may go unnoticed. Women are typically older by almost a decade than men when diagnosed with their first gout attack and often have multiple joints affected as compared to men.

What’s the Risk?

Many factors may increase the risk of initial or repeat attacks of gout, among them family history and excessive alcohol use or anything that leads to increased levels of uric acid. Men also have an increased risk of gout attacks. By contrast, premenopausal women typically have naturally occurring lower levels of uric acid. Other risk factors include high blood pressure (hypertension), diabetes, increased levels of fat and cholesterol in the blood (hyperlipidemia), obesity, chronic kidney disease, and narrowing of the arteries (arteriosclerosis). Ironically, some of the medications available to treat these conditions can also increase uric acid levels, making it challenging to manage the symptoms of gout—including thiazide diuretics for hypertension and low dose aspirin. Patients should not stop taking aspirin or diuretics without consulting with their physician. It is also important to fully inform health care providers about all the medicines you are taking, especially when new ones are prescribed. Certain risk factors can also be minimized by adhering to lifestyle changes such as weight-control and avoiding excessive amounts of foods with high levels of purines.

A few people may never experience another gout attack after an initial episode, but it may occur several times each year in others. Untreated gout may lead to a destructive and crippling arthritis as well as tophi development in fingers, hands, feet, elbows, knees, the outer rim (helix) of the ear, or Achilles tendons. Urate crystals may also collect in the urinary tract, causing kidney stones. However, certain medications can minimize this risk.

Although the quality of evidence for nondrug related recommendations is low, findings support the need for weight reduction and modification of dietary habits. Limiting the consumption of sugary beverages and beer as well as replacing the protein contribution from beef, lamb, and shellfish with nuts, legumes, and whole grains have demonstrated effectiveness at both controlling cardiovascular risk factors and preventing gout attacks. Moderate consumption of wine may even be acceptable for individuals while coffee and non-fat dairy products could actually help to lower uric acid levels.

A recent blog post by The New York Times columnist Frank Bruni, who served as an esteemed restaurant critic for five self-described gluttonous years, detailed his evolving relationship with gout. Bruni recalled health warnings from his twenties describing uric acid levels that “were naturally higher than the norm or the ideal.” Though not certain whether his diagnosis was directly related to his meat-focused, high-fat diet, and alcohol intake pursued during his years as a restaurant critic, he acknowledges a few benefits of his newly austere health-focused lifestyle: managing his diet and following a medication regimen that minimizes the bouts of debilitating pain.

Health care professionals face challenges to the effective management of patients such as non-adherence to necessary lifestyle changes and prescribed medications. Individuals with gout benefit from patient education that describes key issues such as the risk of acquiring more severe conditions, this knowledge being a key aspect of adhering to both lifestyle recommendations and prescribed medications.

Treatments for Gout

Since the publication of gout treatment guidelines in 2006 by the European League
Against Rheumatism (EULAR), there have been significant advances in management and treatment options. Updated recommendations were published in 2011 and specifically focused on the needs of primary care physicians who are seeing an increasing number of individuals with current gout or at risk for a reoccurrence. Later in 2012, the American College of Rheumatology will be publishing their guidelines as well.

Treatment of gout is aimed first at reducing and eliminating the symptoms of the acute attack. Three types of medications can be used to treat the acute attack: colchicine, nonsteroidal anti-inflammatory drugs known as NSAIDs, and corticosteroids (e.g. prednisone).

Colchicine (Colcrys®) has been proven to be effective in reducing gout pain especially if initiated within the first day of symptoms. Derived from the autumn crocus plant, colchicines has been used to manage gout symptoms for thousands of years. Thus it has been in use since before the establishment of the Food and Drug Administration (FDA). Recently, the FDA was mandated by Congress to bring all previously unapproved medications into compliance with guidelines and regulations that apply to all medications. Colchicine was approved as a branded drug in 2009 by the FDA to help treat acute gout and prevent recurrence of attacks.

URL Pharma conducted research that showed lower doses than traditionally prescribed are effective in treating acute gout with a dramatically reduced occurrence of adverse reactions. Thus, patients who may have been using colchicines before it became officially approved should contact their physicians to be updated on current prescribing guidelines. Research also identified many critically important drug-drug interactions and showed how to minimize the risks of these adverse reactions.

Lower, but equally effective, doses have helped to reduce the typical side effects of nausea, vomiting, and diarrhea. Colchicine, though neither a cure nor replacement for medications that lower the amount of uric acid in the body, is a valuable treatment tool because of its ability to reduce inflammation and pain.

Nonsteroidal anti-inflammatory drugs (NSAID) may also help to reduce inflammation and pain associated with gout, including ibuprofen, naproxen, and others available over-the- counter. Celecoxib (Celebrex®), meloxicam (Mobic®), and many others are options that require a prescription. All NSAIDs may be useful but carry an increased risk of gastrointestinal or stomach pain, as well as bleeding, and ulcers. The package inserts for NSAIDs should be carefully read by all patients, since these medications may also be associated with an increased risk of cardiovascular and other adverse reactions.

Certain individuals unable to take colchicines or NSAIDs may be prescribed corticosteroids to treat an acute attack, either as pills or injections—making them an option for patients who may, for whatever reason, be unable to take oral medications. Corticosteroids are powerful and may be very effective but are associated with thinning bones, poor wound healing, decreased ability to fight infection, and other possible side effects. Prescribing physicians must be knowledgeable in their use, understanding that reducing the risk of these serious side effects means employing the lowest dose that controls symptoms for the shortest possible duration.

Urate Lowering Therapy

When patients experience a second attack within a year or have tophi, after the acute attack has been successfully treated, urate lowering therapy (ULT) is next prescribed. As uric acid accumulates, it increases the risk of crystal formation in the tissues and joints. ULT’s goal is to lower the burden of uric acid on the body, leading to the resolution of the crystals that may have already formed. Though seemingly counterproductive, for up to 6 months or so the institution of ULT may increase the frequency of gout attacks in some patients—occurring because any change—up or down—in the level of uric acid in the blood may cause an attack. This problem can be prevented. Anti-inflammatory therapy started at least two weeks before beginning ULT can minimize these so called mobilization flares. If this phenomenon is not anticipated, it may be mistakenly characterized as worsening of gout or a bad reaction to treatment, rather than as the first sign of successful therapy. ULT can be very effective in the long term management of gout if handled correctly.

Based on randomized controlled studies, physicians often recommended the use of low dose colchicine for the prophylaxis against mobilization flares. NSAIDs have also been recommended, but this determination was based on non-randomized controlled studies. Currently, only colchicine is FDA approved as a preventative medicine.

Allopurinol and Febuxostat

Xanthine oxidase inhibitors interfere with the formation of uric acid and lead to lower levels in the blood. Allopurinol (Zyloprim®) was the first of these to gain FDA approval in 1964 with febuxostat (Uloric®) entering the U.S. market in 2009. The target level for uric acid in the blood is 6mg/dL or less, a number patients should remember. Based on evidence from clinical trials, the EULAR committee agreed that allopurinol was a cost-effective option for long-term ULT in patients with chronic gout. Between 5-10% of people started on allopurinol prove to be intolerant of this therapy and approximately 1 in 1,000 develops a potentially serious hypersensitivity reaction. By carefully titrating or slowly adjusting doses of allopurinol to attain a therapeutic goal of lower uric acid levels, it can be used to achieve adequate clinical control in many patients that should be maintained throughout life.

Large clinical trials have shown that febuxostat is another effective therapy. In fact, at commonly used doses of both drugs, febuxostat is superior at lowering uric acid and doses do not need to be adjusted in patients with gout and mild to moderate kidney disease.

Uricosurics

Uricosuric drugs increase the amount of uric acid excreted in the urine by preventing the kidney from reabsorbing it, usually as an additional therapy when either allopurinol or febuxostat are not able to reduce the uric acid level below the target of 6.0 mg/dl.

Probenecid (Benemid®, Probalan®) is the only uricosuric agent currently approved by the FDA. Skin rashes, gastrointestinal problems, anemia, and kidney stone formation are potential side effects. Patients should also drink plenty of fluids to help reduce acidity and risk for kidney stones.

Aspirin and other salicylate drugs interfere with uricosuric drugs and may reduce effectiveness, but acetaminophen (Tylenol) is typically prescribed as a suitable alternative. Uricosurics are not recommended in patients that lack normal kidney function or who have a history of kidney stones, especially the elderly.

Pegloticase (Krystexxa®)

Inadequately treated patients or those who fail to respond to ULT can see their gout progress to a deforming disabling disease.

Refractory or treatment resistant gout may be helped by pegloticase, which recently gained FDA approved for the treatment and management of chronic gout in 2010. Pegloticase is administered intravenously at two-week intervals, potentially leading to the dissolution of tophi and a profound drop in uric acid levels. As a relatively new medication, experts are still working out the most appropriate uses for this powerful drug, limiting its use to physicians skilled in its administration. With side effects that include allergic reactions, gout flares, and congestive heart failure, it is important to carefully manage and monitor this treatment to reduce risk.

Identifying and Managing Patients with Complicated Gout

Patients that present with uncharacteristic or atypical symptoms of gout are particularly difficult to diagnose accurately. Rheumatologists and nephrologists are specialists prepared to treat patients with gout that do not respond to first line treatments or acutely ill patients with advanced renal disease or transplantation. Rheumatologists are skilled at recovering and analyzing crystals, making them the best resource for patients that do not respond to usual therapy. Good communication between primary care physicians and specialists, a multi-disciplinary approach through a well-timed referral ensure optimal care.

What Research Is Being Done on Gout?

Ongoing research is focused on optimizing available treatments more effectively, increasing the use of evidence based strategies, and introducing the research based concept of treating patients to a specific urate target. New therapies are currently in Phase III development and should become available in the next year or two.

Used singly or in combination with existing therapies, it will be possible to adequately control uric acid excess in all people with gout. Education about these therapies and lifestyle modifications will greatly lower the impact of this epidemic disease. Research is also targeting the structure of the enzymes that break down purines in the body to better understand the enzyme defects that can cause gout.

//About The Author
Dr. Hamburger is a Managing Partner at Rheumatology Associate of Long Island and Assistant Professor of Clinical Medicine at SUNY Stony Brook. He is the President of the American Society of Clinical Rheumatologists in Melville, NY.
Bonny McClain is Principal of ASSESSmint Analytics and Outcomes in Greensboro, NC.
N. Lawrence Edwards, MD is Professor, Program Director, and Vice Chairman in the Department of Medicine at the University of Florida in Gainesville.
For more patient information see www.gouteducation.org.