Given the increasing prevalence of gout, this author examines key risk factors, offers salient diagnostic tips and provides insights on current and emerging treatments.

Gout is the most common inflammatory joint disease in men over 40 years of age. It affects nearly 5 million Americans, according to estimates from the most recent National Health and Nutrition Examination Survey (NHANES 111). Compounding the problem is the fact that many people with gout are under-diagnosed and many are poorly or under-treated.

It is difficult to accurately measure data on a chronic disease such as gout because it is often diagnosed on the basis of an acute episode. Nevertheless, recent data from the Rochester Epidemiology Project reveals an increasing incidence of the condition. When these investigators looked at gout incidence in the late 1990s versus the incidence in the late 1970s, they noted a greater than twofold increase in the rate of primary gout.

In regard to the etiology of the condition, hyperurecemia is the underlying metabolic cause of gout. Urate (the ionized form of uric acid) is the end product of purine metabolism. Purines come from dietary sources such as proteins, endogenous purine nucleotide syntheses and purine salvage from the nucleic acids of our dead and dying cells. Purines are eliminated via the kidneys and the gastrointestinal tract. When purines are either overproduced or under-excreted, the stage is set for hyperurecemia and gout.

Gout is an inflammatory response to urate crystals that precipitate in joints or soft tissue. It is largely a disease of middle age or older men and post-menopausal women. Gout is frequently associated with the metabolic syndrome of obesity, dyslipidemia and hypertension with the well-known sequela of cardiovascular disease.

Reviewing The Stages Of Gout
Gout is a progressive and chronic disease. There are three phases of gout. These phases are preceded by asymptomatic hyperuricemia, a long period marked by the slow, gradual formation of urate crystals. Microtophi deposit in these structures slowly and quietly accumulate in joints and soft tissue. The Normative Aging Study, a 15-year prospective trial, found that the higher the initial serum urate level in men that had asymptomatic hyperuricemia, the greater the chance of a first acute flare of gout.

In the first phase of gout, clinicians generally see an acute presentation of an inflammatory monoarthritis that favors the lower extremities. The great toe, ankle or knee suddenly develops moderate to severe pain, warmth and swelling. The great toe is affected in over half of the initial attacks of gout. The pain of gout is such that the great toe must certainly feel as if it was caught in a cruel mechanical device. However, gout does not have to be articular. The olecranon bursa and Achilles tendon are well recognized non-articular sites.

Several factors set the stage for a gout attack. Hyperuricemia is often unrecognized or the patient may have had a recent onset of this condition. Rheumatology professionals are often called to ICUs to evaluate the rapid onset of a painful, warm, swollen joint. Other factors include acute illness or surgery. Trauma is another factor. One may see a patient who danced all evening in tight shoes. Alcohol, particularly beer excess, is another factor. New medication can also have an effect on serum urate concentrations. Thiazide diuretics are often the culprit.

A typical gout attack lasts less then a week if untreated. The pain is usually so intense that people present to the emergency room rather than waiting and trying to schedule an office visit. The acute presentation of gout usually involves the rapid onset of a severe hot joint.

However, some very elderly people may have a less severe presentation. It is important to work through the differential diagnosis of acute monoarthritis. Busy ER clinicians often do not have the time to perform arthrocentesis. However, clinicians should tap hot joints. After obtaining this fluid, one should obtain a culture and examine for crystals. Indeed, examining the synovial fluid and seeing urate crystals is the gold standard for making the diagnosis of gout.

There is usually no sequela from an acute gout attack. An affected individual subsequently moves into what is termed “inter-critical gout.” The initial flare is over and the patient is without symptoms. For a fortunate 5 to 10 percent of people who have had one episode of acute gout, that is the end of the matter. For the remaining 90 to 95 percent, they are subsequently subject to a pattern of recurrent acute episodes. Although the disease is quiet in this phase, hyperurecemia is still present and the disease continues to advance unless clinicians correct that perturbance. It is interesting that even in times of quiescence, clinicians can find urate crystals in joints, which set the stage for a gout flare.

It may take as long as a year to return but once there is a pattern of recurrence, the patient now has recurrent gouty arthritis, which is the second phase of gout. There are shorter intervals between flares and an increasing duration of active symptoms. These patients often become “frequent fliers” to the emergency room.

While the number of people who proceed to chronic gout, the third phase of gout, is uncertain, it is likely related to how well the underlying hyperurecemia is controlled or, more commonly, uncontrolled. In this stage, chronic arthritis (often polyarticular) is the major manifestation. Flares continue but are superimposed on a background of daily arthritis discomfort. At this stage, clinicians can see tophi, which are masses of urate crystals in soft tissue. They favor the periarticular regions, particularly of the elbow and small joints of the hand. The Achilles tendons and, at times, the helix of the ears are other common sites for the sprouting of tophi.

Microtophi form in the early stages of gout and clinically apparent tophi mark the later stages. However, using sensitive imaging such as MRI between these stages can help reveal hidden damage to joints. Bone and joint abnormalities are apparent on plain x-rays. Once tophi develop, they are often painful and destructive, causing deformities to the joints over time. In association with a higher serum urate, clinicians will see an earlier and more extensive appearance of tophi.

Who Has Increased Risk Factors For Gout?
Historically, gout was considered a disease of wealthy men. Hippocrates stated gout was “the arthritis of the rich” since he observed it in educated men who could afford rich foods and plentiful alcohol. While the historical archetype is true, the risk factors that predisposed to gout in the past are present for most American, middle-aged men and post-menopausal women. Obesity and weight gain are strong risk factors for gout and there is current epidemic of this in the United States as well as the aforementioned metabolic syndrome.

Elevated serum urate is the underlying metabolic background in which gout develops. Several large population studies conducted in the U.S. and Taiwan indicate that as the decades progress, uric acid levels are increasing in the general population. This epidemiologic evidence points to an important upward trend in average serum urate levels in advanced industrial societies. This has implications not only for the disease of gout but perhaps for serum urate elevation as an independent risk factor for cardiovascular disease. Currently, there is avid investigation into the relationships between hyperurecemia and a number of other significant comorbidities.

Men tend to have higher serum urate levels then pre-menopausal women. However, women catch up with men after menopause. Decreased estrogen may diminish the renal excretion of uric acid. Regardless of gender, urate crystallizes at a level of 6.8mg/dL. Therefore, men or women whose serum urate measures much more then 6.0mgs/dL are at risk for developing gout. Differences in serum urate for men and pre-menopausal women have resulted in many clinical labs assigning different normative ranges of serum urate for men and women. Astute clinicians should ignore these disparate normative ranges. Keep in mind that serum urate crystallizes at the same concentration — 6.8ml/dL — for all people. Clinicians should also remember that women comprise half of patients with gout that are over the age of 60. The declining use of estrogen replacement therapy may lead us to begin seeing gout at an earlier age in older women than we are presently observing.

Years of bathing tissue in high levels of serum urate takes a toll. Serum urate deposits in joints, soft tissue and the kidneys. Urate deposits cause the symptoms of gout. Clinical manifestations increase as the duration of hyperurecemia increases. Wallace et. al., looked at ten years of managed care data for gout incidence. They saw there was a significantly higher prevalence of gout and clinically significant hyperuricemia in the older age groups.

When it comes to hyperuricemia and gout, commonly associated comorbidities such as obesity, hypertension, renal insufficiency and cardiovascular disease are common in older people. The improved survival rate from these diseases may result in more frequent gout diagnoses.

Photo courtesy of The American College of Rheumatology

As clinicians more aggressively treat the comorbidities above, those very treatments often drive up serum urate. Diuretics are still considered first line treatment for hypertension and heart failure. However, they do lead to increased uric acid reabsorption. The thiazides in particular are notorious for this effect. This class of anti-hypertensive medications is associated with increased acute flares of gout. When we suspect that a patient has gout, the first question we ask is whether the patient has just begun treatment with hydrochlorothiazide (HCTZ) or Lasix.

High dose aspirin (not the cardiac prevention dosages) drives up serum urate and decreases uric acid clearance. The literature has revealed a higher incidence of gout in people taking niacin as well but the benefit of safe niacin therapy tips the risk/benefit ratio in its favor.

Transplant patients have a uniquely high risk of gout and it does not take decades to develop. Cyclosporine appears to be the culprit. It rapidly and significantly increases serum urate by its effects on the kidney. Perhaps some of the newer anti-rejection agents will have different results. Tacrolimus may actually decrease the risk.

However, the rate of organ and stem cell transplantation has soared in recent decades. Accordingly, it is important to remember that gout develops fast and with impressively high serum urates (often over 10mg/dL). One should also be aware of the atypical manifestations. While gout favors the lower extremities in people who have not undergone transplant procedures, clinicians may often find gout in the upper extremities and axial joints of transplant patients.

Understanding The Impact Of Alcohol And Foods With High Purine
Alcohol use is an important risk factor for gout. In general, drinking alcohol raises serum urate. Several observational studies have demonstrated that people with gout consume more alcohol then those who do not have gout. Purine rich beer confers the highest risk and this is followed by hard liquor. Modest intake of wine does not increase the risk but heavy consumption likely would. People who have generally well controlled gout often have a flare of gout if they binge drink.

Food with high purine content leads to an overproduction of serum urate. The Health Professionals Follow Up Study, published earlier this year, found the highest risk for gout was associated with large amounts of red meat and seafood consumption. Dairy based foods had a negative correlation.

Investigators are speculating that the recent flush of low carbohydrate/high protein diets may increase gout but this remains to be seen. Although meat, fish and poultry are all moderately purine rich foods, protein is not a surrogate marker for purine. Nevertheless, many ER providers and practicing rheumatologists have anecdotes about patients who have had their first gout flare after starting one of the low carbohydrate/high protein diets so popular today.

When it comes to very high, purine rich foods, they are not usually eaten that often or in large quantities. These foods include anchovies, herring, sardines, mussels, clams and organ meats. While gout suffers should avoid these foods, most people with gout need more significant uric acid reductions then the 1mg/dL drop they gain by eliminating these foods.

Pertinent Diagnostic Pointers
One would make the definitive diagnosis of gout by tapping a joint effusion or suspected tophaceous deposits, and examining these under a compensated polarizing microscope. Sending the fluid for cell count as well as culture will rule out other causes of an inflamed joint such as septic arthritis, traumatic arthritis, rheumatoid arthritis or other crystal disorders such as pseudo gout (calcium pyrophosphate deposition disease).

Monosodium urate crystals have a characteristic needle shape and are strongly negatively birefringent on exam. Little else looks quite like this. Not using a compensated polarizing microscope might make one miss the very characteristic crystals of gout. Find a clinical lab that has a compensated polarizing microscope as well as a tech who can use it accurately. Then stick with that lab for crystal analysis.

Unfortunately, it is common practice to diagnose “presumed gout” based on an acute warm joint, hyperurecemia and a good response to colchicine treatment. A good clinical response to oral colchicine is in no way pathoneumonic for gout although many clinicians erroneously jump to that conclusion. Repeated “hot joints” in the right physical distribution in the background setting of hyperuricemia is another matter. This may very well be presumed gout.

In early gout, X-rays are not diagnostic. However, there are characteristic X-ray changes in late-stage gout. Overhanging edges on the margins of the bones and punched out lesions can be dramatic.

A Guide To Modalities For Treating Acute Gout
Therapies for treating gout fall into two categories: medications that treat the pain and swelling associated with the acute process, and modalities that treat the underlying metabolic disorder of hyperuricemia. Medications used for the acute process do not impact hyperuricemia. Conversely, medications and other strategies that lower serum urate have no impact on the acute process.

When patients present with acute gout, the goal is to reduce pain and inflammation early in the acutely affected joint. The sooner one initiates therapy during the patient’s flare, the faster resolution one will be able to achieve. Any of the following antiinflammatory medications constitute successful approaches as long as clinicians initiate them at the start of a flare. The longer the flare goes unattended, the harder it is to relieve. NSAIDs work rapidly but clinicians must give them in larger then usual dosages initially when treating acute gout. For example, for rapid and effective therapy, one may prescribe Indocin SR 100 mg BID until an acute flare of gout has subsided. Prescribing naproxen 1000 mg BID for the first day or two will break a flare. Once the very acute process is aborted, generally in a few days, prescribing usual dosages of NSAIDs is all that is needed to finish out the flare therapy. Some people need a PPI to ameliorate the GI effects of NSAIDs.

Colchicine is extremely useful when one starts this at the onset of an attack. However, it is no longer considered safe to use intravenously. In fact, the FDA is close to withdrawing the IV form of the medication from the market. Oral use is safe and 0.6mgs three to four times a day will rapidly resolve a gout flare. This only takes one to three days and then one may resume normal dosing.

Using oral colchicine every hour until the flare eases off or until diarrhea occurs is old-fashioned, cruel and unnecessary punishment.

Kenalog 60 mg IM works very well. Using a Medrol dose pack also works well but not as quickly. Performing an intraarticular steroid injection works best. We like to inject 40 mg of Depo Medrol mixed with 5 cc of bupivicaine once we have tapped off the joint effusion. We always use 5 cc of 2% lidocaine into the joint before we attempt arthrocentesis.

Here is a classic photo of gouty synovial fluid. One can see a large needle-shaped crystal of monosodium urate that has been engulfed by a neutrophil. In order to assess these characteristic crystals of gout, the author recommends using a clinical lab that has a compensated polarizing microscope.

Performing an injection of ACTH 80 units SC is our favored method when we see a patient with acute gout in the office or ER. One injection usually does the trick but it may be necessary to perform a second injection 12 hours later.

The most common mistake clinicians make in treating acute gout revolves around the urate lowering agent allopurinol. Clinicians should not start nor stop allopurinol during a gout flare. If a patient is on allopurinol, do not increase it during the acute period. If he is not on allopurinol, do not begin it during the acute flare even if the patient has very elevated serum urate. Sudden shifts either up or down in the total body urate pool will precipitate gout.

Getting a person through a gout flare can be very gratifying because response to any of the aforementioned antiinflammatory therapies is fast and effective. However, it is important to keep in mind that none of the medications have an impact on hyperuricemia, the underlying cause of gout.

What You Should Know About Addressing Hyperuricemia
When it comes to gout, the best preventive strategy is correcting hyperuricemia. However, regardless of the patient’s serum urate level, clinicians must keep those with active or resolving gout on one to two daily tablets of colchicine 0.6 mg while attempting to address the hyperuricemia. (Prescribing colchicine at these dosages and for these periods is quite safe with rare side effects. Long-term (meaning decades) use, especially in renal compromised patients, may lead to myopathy or neuropathy, which reverses when one withdraws the drug.)

Once patients achieve a serum urate of 5-6mg/dl and have maintained this for several months, clinicians can remove colchicine from the therapeutic regimen. Failure to do this will thwart a successful urate lowering treatment and the patient will have flare backs of gout.

One may employ medication to correct hyperuricemia either by promoting the excretion of urate (uricosuric agents) or by decreasing urate production. When it comes to decreasing urate production, allopurinol is the only medication approved for this indication. However, there are new exciting therapies in the pipeline. The uricosurics, such as benemid, are rarely used anymore. Both types of gout patients — those who over excrete uric acid and those who overproduce uric acid — will respond to allopurinol as long as there is no intolerance or toxicity, and clinicians have prescribed the right dosages and emphasized lifelong compliance.

Essential Principles In Achieving An Optimal Serum Urate Level
There is emerging evidence that elevated uric acid alone may be an independent risk factor in renal disease as well as cardiovascular disease. For example, people with the widespread metabolic syndrome have a positive correlation with elevated serum urate. Several ongoing studies are currently seeking to clarify the significance of this development.

When it comes to initiating a serum urate lowering medication for gout, clinicians would largely base this decision on a repeat pattern of gout flares and persistent hyperurecemia. Regardless of gender, race or age, serum urate crystallizes at 6.8 mg/dl. The target serum urate for people with gout is less then 6.0 mg/dl. In order for established tophi to reabsorb, the target level is lower, more in the 2-4 mg/dl range. Given that medications and renal function may change in any given patient, it is important to obtain yearly serum urate measures for those who are taking a urate lowering agent. Unfortunately, serum uric acid levels are no longer a part of most routine basic metabolic panels and clinician must order this separately.

While 24-hour uric acid measurements are almost never required in adults with gout, clinicians do use these measurements to evaluate for rare inherited enzymatic defects in children with gout. One would occasionally obtain this measurement in adults when investigating diseases of rapid cell turnover such as mylo- or lymphoproliferative diseases. However these are generally known and the end point of hyperurecemia is corrected regardless of the underlying cause.

If there is any guiding principle when it comes to lowering serum urate, it is the principle of “going low and going slow.” A gout flare must be completely resolved and the patient must be on colchicine therapy for at least a month before clinicians initiate allopurinol. Some experts suggest waiting two to three months. Their theory is based on the concern that abruptly disrupting the total body urate pool will bring on a gout flare. Additionally, it is widely appreciated by those who treat a good deal of acute gout that serum urate levels are often normal during a flare. This may lead a clinician to falsely assume gout is not in the differential diagnosis for that patient. Checking past records for elevated serum urate levels and rechecking it in several weeks after the flare will uncover many hyperuricemics.

Allopurinol rapidly lowers serum urate. Within a week, the full effect of the dosage will be established. Clinicians may initiate the drug at 50 to 100 mg a day and recheck the serum urate in two to three weeks. Titrating the medication slowly by 50 to 100 mg at each stage will allow for accurate titration and prevent flare backs.

Bear in mind that one size of allopurinol therapy does not fit all. Some people will achieve the serum urate goal at 100 mg per day. We have a handful of hard-to-control gout sufferers whose dosage of allopurinol is as high as 900 mg a day. As long as the titration is slow and one measures the serum urate prior to each increase in dosage, the potential to ward off adverse effects and achieve the goal will be successful. This is particularly true in renal compromised patients.

It is often difficult for patients to understand which medications are used to treat a gout flare, which are used to prevent one and which are used to correct the underlying disorder. Adding in the additional warnings about the damages of binge drinking and how non-compliance can lead to recurrent flares can make treating gout a bit complex. I often have our gout patients get a lab draw and call me the next day for phone consultation on the resulting serum urate level. We can then discuss how close we are to achieving our target. Making sure patients understand the serum urate goal number is important in the same way as it is important to ensuring that patients with diabetes understand their A1C goal.

Key Points On The Adverse Effects Of Allopurinol
Allopurinol is not the easiest of drugs to prescribe because clinicians need to titrate each patient’s dosage individually. However, the medication is widely used and is a highly effective way of reducing serum uric acid levels. When there is any degree of renal compromise and especially for those on thiazide diuretics, beginning allopurinol at 50 mg/day is most prudent. For the majority of other patients who need to achieve a lower serum urate level, clinicians can initiate allopurinol at 100 mg a day.

Repeating blood levels in three to four weeks, and titrating up will avoid most allergic skin reactions, GI intolerance and gout flare backs. True allergic reactions exist and extremely alarming hypersensitivity reactions occur rarely. From time to time with very low-grade skin reactions, we rechallange, beginning at 50 mgs. For more severe reactions the patient can be desensitized in a controlled environment.

There are two new medications of note in the drug development pipeline. Febuxostat is a selective xanthine oxidase inhibitor that has been submitted to the Food and Drug Administration for the treatment of hyperuricemia and gout. It will have a place in the lowering of serum acid because of its selectivity. It may compete successfully with allopurinol. It does not have to be dosed for renal compromise and is not hepatically cleared.

Humans lack a functioning gene to produce uricase. This enzyme converts the poorly soluble pruine metabolism product, uric acid, into the very soluble product of allantoin. Injectable forms of pegylated uricase are in drug development.

What About Asymptomatic Hyperuricemia?
At this point in time, we do not treat asymptomatic hyperurecemia. We try to identify and treat the cause (i.e., renal disease, alcohol abuse). The notable exceptions are patient who have undergone transplants and take cyclosporine. Contrary to the general rule that it takes decades of hyperurecemia for gout to develop, these patients develop significant hyperurecemia and gout quite rapidly. There is a distinct difference between cyclosporine induced hyperurecemia and primary hyprurecimia. As new anti-rejection medications are introduced to replace cyclosporine, we may see less dramatic hyperurecemia and gout then we currently see among patients who have undergone transplantations.