Are You Confident of the Diagnosis?

What you should be alert for in the history

The classical presentation of gout (also called podagra) is monoarthritis affecting the first metatarsophalangeal (MTP) joint that , often awakens the patient in the middle of the night.

Gout can occur as a monoarthritis, oligoarthritis, or a polyarthritis. The areas most commonly affected are the first MTP, midtarsal joints, ankle, and knee. In the upper extremities, areas commonly affected include the proximal interphalangeal (PIP) joints, distal interphalangeal (DIP) joints, wrists, and the elbows.

In those with longstanding gout, olecranon bursitis may be seen; sometimes nodules on the ulnar forearms (tophi) are observed, mimicking rheumatoid nodules. Also possible is a polyarthritis resembling rheumatoid arthritis, occasionally occurring suddenly, even in persons who have never had podagra.

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Less commonly, dactylitis (swelling or induration of an entire digit) is seen . This may mimic osteomyelitis of a digit.

Dermatologists are likely to see patients who present with cutaneous manifestations of gout (see physical examination section below).

Predisposing factors that raise the suspicion of gout include: metabolic syndrome (insulin resistance, obesity, hypertension, hypertriglyceridemia), family history of gout, renal insufficiency, psoriasis, excessive alcohol use, excessive protein consumption, excessive fructose consumption, history of a solid organ transplantation, presentation on the day after a major holiday (the patient may have ingested large amounts of purines, ethanol, or fructose), mild trauma (the patient played tennis, stubbed toe, etc.), and dehydration.

Less common predisposing factors, but still significant include: sickle cell disease, sarcoidosis; post-operative state, fever or acute illness of almost any cause, critical illness, the fasting state or use of a severely calorie-restricted diet, myeloproliferative disorders, lymphoproliferative disorders, hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) deficiency (Lesch-Nyhan disease when homozygous), phosphoribosylpyrophosphate synthetase (PRPPase) overactivity, glucose-6-phosphatase deficiency (G6PD, von Gierke’s disease), and fructose-1-phosphate aldolase deficiency.

Use of certain medications also predisposes to hyperuricemia and gout. These medications include: diuretics (both loop diuretics and thiazide diuretics), low-dose aspirin (<1g/d) but not high-dose aspirin, cyclosporine, tacrolimus, ethambutol, pyrazinamide, ritonavir, levodopa, and nicotinic acid.

Initiating use of a hypouricemic drug (such as allopurinol, febuxostat, or probenecid) without adequate prophylaxis (such as prophylactic colchicine or a nonsteroidal anti-inflammatory drug [NSAID]) is very likely to provoke a gout attack.

Occasional symptoms include fever and chills, usually with polyarticular attacks. Fever should raise the suspicion of infection first.

Rare presentations include acute severe lumbar or thoracic pain (gout should be low on the list if a patient presents with these; we see approximately one gouty back per year, and the patient almost always has a prior history of severe gout elsewhere).

Pain is the last symptom of acute inflammation to appear, and the first to disappear; some gout sufferers will present with very early attacks (no pain yet) or partially treated attacks. It is common for swelling to persist for several weeks after pain subsides.

Presentations that are probably not gout include: involvement of MTP joints other than the first (especially if the first MTP is not involved); involvement of the hands without involvement of the knees, ankles, midtarsals, or first MTP. (Think of psoriatic arthritis or reactive arthritis if the main involvement is toes or MTPs other than the first MTP.)

Characteristic findings on physical examination


The classic sign of gout is first MTP inflammation (warmth, tenderness, swelling, redness; usually all are present). Usually, if the ankle or midtarsal joints are inflamed, the first MTP will also be inflamed (clue to the diagnosis!).

Sometimes, gout will produce a fever, especially if multiple joints are involved. Blood pressure may be elevated (hypertension is very common in gouty patients).

Rarely, gout produces obtundation (if multiple joints are involved and there is fever).

Look for (because the patient probably won’t mention) tophi (on elbows especially). Tophi also occur on ears, areas of trauma (shins), first MTP, distal interphalangeal joints (DIPs) of hands, and metacarpophalangeal joints (MCPs) (Figure 1, Figure 2, Figure 3). Tophi can occur almost anywhere on or in the body.

Also look for olecranon bursitis (“bag of water” overlying posterior elbow, but not in the elbow joint itself); however, gout is not the most common cause of olecranon bursitis (minor trauma is, but usually there is no inflammation in that case). Infection of the bursa is less common than gout, but is almost impossible to differentiate from gouty bursitis clinically; one needs to tap and culture to be sure. Early tophaceous deposition will present simply as thickening of the olecranon bursa tissues without palpable bursal fluid.

Dermatologic manifestations include nodular tophi (Figure 4), intradermal plaque-like tophi (Figure 5), sinuses draining white pasty chalky material (Figure 6) ), bullous lesions (Figure 7), and even rather large areas of noninfectious cellulitis. Redness can occasionally extend several inches from inflamed joints. Concerning the often talked about but rarely seen tophi on the helices of the ears, our experience over the past 25 years suggests that the prevalence of such tophi parallels the popularity of hats.

Bullous lesions are unusual, and are perhaps somewhat unexpected in the setting of gout. They seem to occur at sites where sinus tracts are developing. The overlying skin separates from the subcutaneous tissues and noninflammatory fluid collects, usually with some crystals, but with a more clear than milky appearance.

Bullous lesions may be 1-3cm in diameter. When unroofed, white tophaceous deposits are visible in the subcutaneous tissues and often the developing sinus tract is apparent. Untreated, gouty sinus tracts may persist for years. For reasons that are unclear, infection is unusual. Healing occurs only with hypouricemic therapy or with surgery to remove tophaceous deposits.

There are only a few reports of patients with gouty panniculitis. Panniculitis requires demonstration of typical crystals within the subcutaneous fat layer, with the presence of inflammatory cells. Panniculitis has been described as nodular lesions of the anterior or posterior legs that quickly ulcerate, draining serous or opaque fluid that contains crystals. Rather widespread postinflammatory hyperpigmentation may develop.

Expected results of diagnostic studies


In serum, uric acid is usually (but not always) elevated. The higher the uric acid level, the more likely it is that the patient has gout. Levels greater than 10mg/dl are very suggestive. It is also important to realize that most persons with a mildly elevated uric acid level will never develop gout. Thus, an elevated uric acid level (particularly if it is less than 9mg/dl) can be a red herring. Very often, there is renal insufficiency in persons with gout. The white blood count (WBC) may be elevated due to inflammation, particularly in polyarticular attacks.

The synovial fluid is usually cloudy, but not always. Hold it up to the light; sometimes chalk-white flecks (tophi) will be visible in the fluid. Occasionally, the fluid will contain so much monosodium urate (MSU) that it appears milky (Figure 8).

The synovial fluid WBC is usually in the range of 1000-50,000, but can be even higher. (When higher, this must raise the question of septic arthritis). MSU crystals will usually be reported by the lab, but not always. A negative tap does not rule out gout. MSU crystals can be visualized as intracellular and/or extracellular needles under ordinary unpolarized light, but a positive identification requires compensated polarized light (Figure 9).

Under compensated polarized light, MSU crystals appear as bright yellow needle-shaped crystals when aligned with the long axis of the compensating filter, and bright blue when they are perpendicular to the long axis of the compensating filter.

Without compensated polarized light, MSU crystals can be confused with calcium pyrophosphate dihydrate (CPPD) crystals. CPPD crystals tend to be shorter and more rhomboid or rectangular in appearance. CPPD crystals have birefringence that is opposite that of MSU crystals. They are blue when aligned with the long axis of the compensating filter and yellow when perpendicular, and their colors are not as bright.


Radiographs will usually be normal. If gout has been long-standing, the characteristic “overhanging edge” may be visible (Figure 10). There may be erosions, usually with sclerotic margins (in contrast to the erosions of rheumatoid arthritis). There is usually no joint space narrowing, again in contrast to rheumatoid arthritis. There is usually no periarticular demineralization (again in contrast to rheumatoid arthritis).

Ultrasound is very helpful, but requires substantial training. It will usually show an effusion in affected joints. Tophaceous material is often visualized around the affected joints. Tophaceous material may also be visible around some noninflamed joints . Look for the characteristic “double contour” sign of the gouty joint (Figure 11).

Magnetic resonance imaging (MRI) is not the imaging modality of first choice. If an MRI has been obtained, it is probably by accident. MRI often erroneously suggests the diagnosis of osteomyelitis, particularly in spinal gout, and particularly if there are erosions and/or bone marrow edema. MRI will typically show joint effusions and sometimes tophaceous material around joints.

Dual-energy computed tomography (CT) scanis a new technique that uses two beams of different energies. Various materials will have different patterns of energy absorption for each of the two beams. In this way, tophaceous material can be distinguished from other soft tissues and from calcium-containing deposits. Three-dimensional color-coded images are displayed. This technique is not yet widely available.

Diagnosis confirmation

There is only one way to confirm gout, and that is by seeing the classic needle-shaped negatively birefringent crystals in fluid or tissue. Either synovial fluid or a tophaceous deposit may be examined. A tophaceous deposit can be opened with a needle (after appropriate anesthetic administration, if necessary) and some of the white pasty material can be placed on a glass slide and examined with a microscope. Tophaceous material is almost pure MSU crystals, usually without white blood cells.


The differential diagnosis of acute monoarticular arthritis is fairly wide. It is most important to look for septic arthritis (especially before injecting corticosteroid esters into joints). The most common differential is pseudogout (chapter 1363). Occasionally, psoriatic arthritis or the arthritis of inflammatory bowel disease can mimic gout.

Psoriatic arthritis tends to affect the second and third MTP joints, usually without involvement of the first MTP. Rheumatoid arthritis is also in the differential. This is because chronic gout with tophaceous material around multiple joints can almost perfectly mimic rheumatoid arthritis. It is best not to diagnose rheumatoid arthritis in a middle-aged male without tapping a joint or otherwise ensuring that gout is not present.

Pseudogout is much more likely to affect the knee, and tends to affect older individuals more than does gout. For example, an 80-year-old female who develops her first episode of acute knee inflammation while hospitalized for pneumonia is overwhelmingly more likely to have pseudogout than gout. Pseudopseudogout (acute hydroxyapatite periarthritis) can also mimic gout. (See chapter on pseudogout).

Who is at Risk for Developing this Disease?

By far the most common type of person to present with gout will be a middle-aged or elderly male with the metabolic syndrome. In other words, he will be overweight, have non-insulin-dependent diabetes, hypertension, and very likely, mild renal insufficiency. A frequent accompaniment is a history of cardiovascular disease. In approximately 25% of cases, there will be a family history of either gout or kidney stones.

The excess calories that fuel the metabolic syndrome may come from food in general, ethanol, or fructose. Of the various forms of ethanol, beer has more hyperuricemic effect than other forms of ethanol.

Our understanding of the epidemiology of gout was increased recently with the realization that excess fructose consumption also has a hyperuricemic effect. Interestingly, excessive fructose may also have a hypertensive effect and a toxic effect on renal function. Most fructose is consumed in the form of sweetened soft drinks, sweetened fruit juice drinks, or large amounts of pure fruit juices. This is currently an area of intensive research.

An additional common predisposing factor is the use of diuretics, including low-dose hydrochlorothiazide (HCTZ) for blood pressure control. Although women traditionally have a lower risk of gout than men, the risk of gout rises progressively after menopause, eventually equaling that in men. One somewhat unusual but characteristic presentation is the elderly woman taking a diuretic who develops inflammation in her DIP joints.

If the physician has access to a previous serum uric acid level, this information may help greatly in estimating the patient’s risk of having gout. A serum uric acid level less than 5mg/dl makes gout very unlikely; a serum uric acid level greater than 10mg/dl makes gout quite likely.

Approximately 30% of persons with a uric acid level greater than 10mg/dl will have gout in the next five years. Levels between 5mg/dl and 10mg/dl are in the gray zone. It must be underscored that a normal serum uric acid level by no means rules out gout. A corollary of this is that gout cannot be diagnosed based on a serum uric acid level; only the likelihood of gout can be estimated.

Hyperuricemic patients are traditionally divided into two groups: underexcretors and overproducers. About 85% of gouty patients are underexcretors; that is, the kidney excretes a normal amount of uric acid, but at a higher-than-normal serum uric acid level. This category includes most gouty patients with the metabolic syndrome, and many forms of familial gout. The other 15% of gouty patients are overproducers; that is, their bodies make too much uric acid. Most of these patients have underlying conditions that predispose to rapid cell turnover.

Among the latter group are patients with psoriasis. The dermatologist may willingly or unwillingly be called upon to help make a distinction between psoriatic arthritis and gouty arthritis.

There are some familial overproducers as well. A few familial overproducers will have the classic enzyme defects , but most will not. As noted above, there are many medications that are associated with hyperuricemia.

Clinically, the categorization as to whether a patient is an overproducer or an underexcretor is made on the basis of a 24-hour urine collection to measure uric acid excretion. Interestingly, ethanol causes both underexcretion by the kidney and also overproduction by the body. An alcoholic who suddenly discontinues ethanol may develop an acute attack related to the sudden fall in serum uric acid level that ensues.

Occasionally, the body goes into a temporary high-production state. This can happen with a fever or during the postoperative state. During such times, relative dehydration may also cause underexcretion of uric acid.

Noncompliance with medications for gout is common. Suddenly starting or stopping a hypouricemic agent (such as allopurinol, febuxostat, or probenecid) may provoke an attack. Patients frequently discontinue their prophylactic colchicine or an NSAID, leaving themselves open to acute attacks.

In summary, the epidemiology of gout is such that nearly every patient will be found to have at least one risk factor, making the physician’s job somewhat easier.

What is the Cause of the Disease?

The cause of clinical gout in all patients is the deposition of MSU in various tissues. Strictly speaking, this is the cause of only tophaceous deposits. Clinical gout occurs when the crystals trigger the inflammatory cascade. For reasons that are unclear, most clinically evident tophi (including tophaceous deposits in the skin) do not incite inflammation under normal circumstances. Thus, tophi are normally not painful. This explains how tophi near the elbows can so easily be confused with rheumatoid nodules.


It is thought that various stimuli such as minor trauma can dislodge some crystals, exposing surfaces that are not coated by protective plasma proteins, provoking rapid (within 1-4 hours) and intense inflammation.

Gout attacks are not confined to the joints. There is frequently soft-tissue deposition of MSU that is not evident on examination. For instance, involvement of the posterior tibial tendon sheath can provoke intense inflammation that perfectly mimics cellulitis of the lower extremity, including fever and leukocytosis.

If it is unclear what triggers the gout attack, it is even less clear why the attack will eventually subside spontaneously, even without treatment, often leaving in its wake even larger deposits of MSU.

Most tophi form slowly, over months or even years, but it is possible in a high cellular turnover state to form large visible tophi in a matter of a few days.

Just as MSU is deposited when the serum uric acid level is above the saturation point, so MSU will slowly dissolve when the serum uric acid level falls, hence the efficacy of hypouricemic drugs.

Systemic Implications and Complications

Gout keeps characteristic but unseemly company. Common comorbidities often limit treatment options. Comorbidities include hypertension, type 2 diabetes (usually with insulin resistance), and hypertriglyceridemia. Many such patients will also have renal insufficiency.

An additional minority of gout sufferers will exhibit ethanol overconsumption. The pathogenesis of these comorbidities is still a matter of some debate. Hyperuricemia is intimately associated with the metabolic syndrome. In persons who are genetically predisposed to the metabolic syndrome, the trigger is usually weight gain in midlife.

Centripetal obesity, in particular, causes expression of insulin resistance and hypertension for some reason, and affects renal handling of uric acid. While the development of renal insufficiency has traditionally been blamed on hypertension, there is accumulating evidence that hyperuricemia itself causes hypertension, renal damage (eventually), and is an independent risk factor for cardiovascular disease.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Acute Attack Treatment Lifestyle/Diet Attack Prophylaxis Hypouricemic Treatment
Ice, rest, elevation Weight loss Low-dose NSAID Vitamin C
NSAID Ethanol restriction, esp. beer Low-dose colchicine Probenecid
Colchicine Fructose reduction Interleukin-1 antagonist (unapproved use) Allopurinol
Intra-articular corticosteroids Red meat, purine reduction Febuxostat
Systemic corticosteroids Increase dairy, vegetable protein, cherry juice Pegloticase (uricase)
Interleukin-1 antagonists (unapproved use) Blood pressure control Losartan +/- fenofibrate (unapproved use)

Optimal Therapeutic Approach for this Disease

No matter which pharmacologic treatment is ultimately chosen, rest, ice, and elevation are important adjuncts in the treatment of gout and pseudogout. Ice and rest have been shown to reduce the WBC in the synovial fluid of gouty joints.

For the healthy middle-aged gout sufferer with one or two inflamed joints, NSAIDs are generally the treatment of choice. As a rule, NSAIDs must be started within 24 hours (preferably within one or two hours) of the attack onset to be effective.

A number of NSAIDs have been studied. None is clearly superior to another. COX-2 inhibitors also seem to be effective and are more gentle on the gastrointestinal tract than traditional NSAIDs. There is some evidence that the one currently available COX-2 inhibitor (celecoxib) is more gentle on the kidney.

As implied above, NSAIDs should be used with caution, if at all, in patients with a history of peptic ulcer disease, hypertension, renal disease, dehydration, or congestive heart failure (because of the possibility of fluid retention), and in the elderly.

Because of comorbidities, many gouty patients cannot safely use NSAIDs. The risk of NSAID gastropathy increases with age, previous history of peptic ulcer disease, smoking, congestive heart failure, and ethanol use. While indomethacin is the traditional NSAID of choice for acute gout, there is some evidence that it is more ulcerogenic than most NSAIDs, and somewhat ominously, it can cause acute renal failure when used in combination with triamterene (Dyazide® and others).

All NSAIDs increase the risk of peptic ulcer disease and therefore must be used with caution in persons taking anticoagulants. Some NSAIDs also inhibit platelet function to one degree or another, putting them in a higher risk category than others for promoting bleeding.

In the past 12 years, it has become clear that long-term use of NSAIDs is also associated with an increased risk of cardiovascular events. Some NSAIDs are actually contraindicated in the immediate postoperative period for cardiac bypass grafting (CABG) patients because of increased risk of myocardial infarction and stroke.

Colchicine is an attractive treatment option for patients with the above risk factors. Some patients even prefer colchicine because they have determined by experience that it works well for them. As with NSAIDs, colchicine must be started early to be effective in suppressing an attack. While not ulcerogenic (except at high doses), the dose that relieves a gout attack is usually close to the dose that causes diarrhea, cramping, or nausea.

Colchicine is generally considered safer than NSAIDs in persons with mild to moderate renal insufficiency. In such patients, colchicine is not contraindicated, as is commonly supposed, but both the loading dose and the maintenance dose must be reduced.

The first official Food and Drug Administration (FDA)-approved branded colchicine product (Colcrys®) was recently released in the United States. Two of the benefits of bringing this product to market are that formal dosing guidelines for patients with renal insufficiency or hepatic insufficiency were published (see official prescribing information) and that the many drug interactions of colchicine were publicized better. Contrary to popular belief, colchicine (in very reduced doses) can even be given to dialysis patients.

It is most important when prescribing a loading dose of colchicine to take into account whether patients have any colchicine in their body already. Colchicine can take up to two weeks to be eliminated in dialysis patients, in contrast to about one week in healthy persons. Intravenous colchicine is rarely used in the United States because FDA approval for this formulation was withdrawn in 2008.

Perhaps the safest way to treat a gout attack rapidly and effectively is to inject the affected joint(s) with depot corticosteroids. When properly performed, arthrocentesis should not be uncomfortable, even in the presence of inflammation. Dermatologists as a group are particularly aware of the need for proper anesthesia before performing procedures, and are well acquainted with local corticosteroid injections.

The only significant contraindication to injection with corticosteroids is infection. Depending on clinical circumstances, it may be prudent to await the results of synovial fluid culture before injecting corticosteroids. The other drawback is the length of time required to inject multiple joints.

Systemic corticosteroids are the treatment modality of choice for persons with polyarticular attacks (particularly if present more than several days), and patients who cannot use the means described above.

It is most important that systemic corticosteroids be dosed at least twice daily, preferably three times per day. Once-daily dosing is usually ineffective for significant gout attacks. Prednisone 30mg twice daily normally suffices. Corticosteroids are generally tapered over 7-10 days. Patients treated with corticosteroids have a propensity to relapse toward the end of the taper, so it is important to begin a prophylactic agent (see below) as soon as possible after starting corticosteroids.

While systemic corticosteroids can be used in persons with renal disease, hepatic disease, and/or cardiovascular disease, they must be used with caution in uncontrolled diabetics, recently postoperative patients, elderly patients with osteoporosis, and those with significant infections. Some persons with gout become corticosteroid-dependent, resulting in long-term adverse effects of corticosteroids.

A novel treatment option for severe gouty attacks is the use of interleukin-1 antagonists, although these are not FDA approved for this use. There are currently three such agents available in the United States: anakinra (Kineret®), canakinumab (Ilaris®), and rilonacept (Arcalyst®).

While prohibitively expensive if used long-term for gout prophylaxis, a short course of treatment can be quite cost effective. These agents may find their best use for severe gout attacks in hospitalized patients who cannot or should not receive corticosteroids for various reasons. The main contraindication is infection, since these agents are modestly immunosuppressive, but they are considered less immunosuppressive than tumor necrosis factor (TNF) antagonists, with which dermatologists are very familiar.

Patient Management

Our clinical impression over the years is that the number and severity of comorbidities present in gouty patients is increasing; thus, monitoring and follow-up are considered essential.

The initial evaluation should include a blood pressure check, a comprehensive metabolic panel, a serum uric acid level, and a urinalysis. If there is evidence of renal insufficiency that has not been previously evaluated, it is prudent to obtain a renal ultrasound to look for nephrolithiasis (which is so common in gouty patients), to look for evidence of gouty nephropathy (this is not ruled out by a normal ultrasound), and to look for other kidney problems that could be causing renal insufficiency.

When available, synovial fluid should be sent for cell count, differential, crystal identification, and culture. Other synovial fluid studies are usually not helpful. If fever is present, appropriate cultures should be obtained. Occasionally, it may be so difficult to distinguish between gout and infection, that it may be prudent to give an antibiotic for 1-3 days until all the clinical evidence is available. Septic arthritis almost always requires hospital admission for definitive treatment.

The vast majority of gouty patients are treated as outpatients. It is prudent to have the patient telephone or email the office 24 hours after the office visit. If the patient is not improving, the diagnosis must be questioned and further evidence of infection should be sought. Occasionally, an initial treatment for gout will not be effective, and more intensive treatment (such as systemic corticosteroids) must be instituted.

Since gout is often a lifelong disease, and tends to worsen with time if untreated, it is most important to provide the patient with appropriate educational materials. These will initially include information on the risk factors for gout and how modification of lifestyle can have a dramatic impact on gout. These factors include: hypertension, diabetes, hyperlipidemia, cardiovascular risk, and osteoarthritis risk.

It is also important to explain the risks and proper administration of medications. It is best to use preprinted patient handouts, since patients may forget key facts (particularly if in pain). NSAIDs must be taken with food or milk. The patient should watch for melena. The patient should be instructed to taper NSAIDs or colchicine to a maintenance dose over 7-10 days.

If taking colchicine, patients should understand the need for oral rehydration and dose reduction if significant diarrhea develops. When colchicine is being used, it is essential that the dose (both loading dose and maintenance dose) be adjusted in the setting of renal insufficiency or hepatic insufficiency.

Patients taking corticosteroids who are at risk for diabetes must be instructed to monitor their serum glucose levels. Patients taking warfarin should have their prothrombin time (PT) and international normalized ratio (INR) checked after 3-5 days, because both illness and medication can affect warfarin activity. Hypertensive patients taking NSAIDs or corticosteroids may need to have their blood pressure checked in several days. If there is evidence of inadequately controlled comorbidities, the patient should be referred for appropriate medical care.

The patient should be seen back in the office one to two weeks after the attack. It is important to reassure the patient that swelling (particularly dactylitis, which is often mistaken for osteomyelitis of a digit) may take weeks to resolve, even though pain is completely gone. At this follow-up visit, determinations should be made regarding how long to prescribe prophylaxis against future attacks and whether a hypouricemic agent should be considered.

It is appropriate to give prophylaxis for at least 3-4 weeks, using either a low daily dose of an NSAID or the appropriate maintenance dose of colchicine. NSAIDs are preferred in patients with coexistent osteoarthritis because they provide some pain relief for that condition as well. Colchicine may be used in most other patients. Persons with normal hepatic and renal function can take 0.6mg of colchicine once or twice daily for prophylaxis. It is important that patients understand that colchicine does nothing to reduce serum uric acid levels, nor does it prevent deposition of MSU in tissues.

Chronic colchicine toxicity can occur in persons with mild renal insufficiency who are taking as few as two tablets per day. The toxicity will not be in the form of diarrhea or bone marrow suppression, but rather in the form of a characteristic myoneuropathy. The patient usually experiences somewhat uncomfortable distal paresthesias. The creatine kinase is usually mildly to moderately elevated as well, although muscle weakness may not be present. This situation is reversible when discovered early.

If the patient has obvious tophaceous deposits, prophylaxis should be continued until all tophaceous deposits are dissolved, which can take 2 years or more. If it is determined that the patient should begin a hypouricemic agent (see below), then prophylaxis is normally given for several months or until all tophi are dissolved.

Musculoskeletal ultrasound is an excellent tool for following dissolution of tophi around joints, where they are not detectable on physical examination. Gout attacks may occur for many months after the initiation of hypouricemic treatment because of inapparent tophaceous deposits.

There is no specific treatment for the dermatologic manifestations of gout. Tophi are removed by reducing serum uric acid level or by surgery. While infection is unusual, minor trauma can provoke acute inflammation that closely resembles infection. Sinus tracts that continue to drain should be treated locally and absorbent dressing should be used.

Hypouricemic therapy should be considered for gouty patients with more than two or three attacks per year, particularly those with a history of nephrolithiasis, those with tophi, and those at risk of chronic joint damage. Lifestyle changes are the first step toward reducing serum uric acid.

Currently approved pharmacologic agents include probenecid, allopurinol, and febuxostat. Occasionally, losartan, with or without fenofibrate, can be used adjunctively for their modest urate-lowering effect, although they are not FDA approved for this purpose. Any hypouricemic agent should be started at a low dose and escalated gradually over several weeks to minimize the risk of acute gout attacks. Prophylaxis with colchicine or an NSAID is strongly recommended.

Not every gouty patient requires a hypouricemic agent. Some patients will make lifestyle changes that will reduce their serum uric acid level, prevent future attacks, and hasten dissolution of tophi, if any. Some patients have only rare attacks and no tophi. They may do well simply treating each attack as it comes.

Some elderly patients may be most appropriately treated with chronic prophylaxis against attacks, without using hypouricemic treatment, depending on degree of expected joint and kidney damage in their remaining years.

Some patients are notoriously noncompliant with hypouricemic therapy. Starting and stopping treatment frequently will only provoke additional attacks due to rapid fluctuations in the serum uric acid level.

The need for hypouricemic therapy is usually lifelong, and the therapy requires a significant commitment on the part of the patient. Patients occasionally abandon hypouricemic therapy because they perceive that it initially increases the frequency of gout attacks. Most such attacks can be prevented with colchicine, an NSAID, low-dose corticosteroids, or an interleukin-1 antagonist. The latter are not FDA approved for this use.

If it is determined that a hypouricemic agent should be started, it may be helpful to know if the patient is an underexcretor or an overproducer. In either case, and with any hypouricemic agent, the goal will be to reduce serum uric acid to less than 6mg/dl in order to encourage dissolution of tophi. Some patients require a serum uric acid level that is closer to 5mg/dl to effectively dissolve tophi.

As a rule, it is still considered prudent to use probenecid in underexcretors because the drug is perceived as safer than the more popular allopurinol. It is unclear if the availability of febuxostat will further impact the already limited popularity of probenecid.

Probenecid should not be used if creatinine clearance is less than 50-60ml/min because it will not be effective. It should also not be used in patients who have had nephrolithiasis because it may increase stone formation. Probenecid affects the excretion of many drugs, so it is important to check for interactions at the time of prescribing.

At this time, allopurinol is the most commonly used hypouricemic agent because it is perceived as more effective than probenecid, and requires only once-daily dosing. It has the advantage of reducing the frequency of nephrolithiasis because as a xanthine oxidase inhibitor, it reduces the excretion of uric acid, unlike probenecid. Although approved for use in doses up to 800mg/d (doses above 400mg/d should be given in divided doses), the risk of serious idiosyncratic toxicity has been reported to increase at higher doses, in persons with renal insufficiency, and in those receiving diuretics.

In general, patients with renal insufficiency will use lower doses because of impaired excretion of allopurinol, and particularly oxypurinol, a major active metabolite. At any given dose, the serum uric acid level will generally plateau after seven days, but take somewhat longer to plateau in patients with moderate to severe renal insufficiency.

Both allopurinol and febuxostat have potentially life-threatening drug interactions with azathioprine, 6-mercaptopurine, and to a lesser extent theophylline. Metabolism of these xanthine derivatives is strongly inhibited by allopurinol. Allopurinol may prolong coagulation times in users of warfarin.

Allopurinol has a rather high rate of hypersensitivity reactions, usually in the form of generalized rash. Generally, the rash resolves upon discontinuation, but unlike some other drugs, it is not recommended that allopurinol be restarted because the second rash may be toxic epidermal necrolysis. If it is absolutely essential that allopurinol be restarted, a published desensitization protocol should be used.

Unfortunately, serious allopurinol toxicity is both completely unpredictable and common enough to be a major concern. The “allopurinol hypersensitivity syndrome” is life threatening and includes fever, rash, hepatitis, eosinophilia, and renal failure. This syndrome can masquerade as a multisystem inflammatory disease such as vasculitis. The most concerning feature of this syndrome is that it often responds neither to drug discontinuation nor to corticosteroids, but is often relentlessly progressive and fatal.

Febuxostat is another xanthine oxidase inhibitor that was recently FDA approved and is an alternative to allopurinol. Because of the higher cost of febuxostat, it is generally reserved for patients who cannot take allopurinol. It offers several advantages over allopurinol, including much better retention of efficacy in the presence of renal insufficiency, and probably less risk of serious hypersensitivity reactions. Of some concern is a small increase in the number of cardiovascular events noted in clinical trials in head-to-head comparisons with allopurinol. The reason for these is unclear.

Intravenous pegylated uricase (pegloticase, Krystexxa®, Savient Pharmaceuticals) was recently FDA approved for chronic gout refractory to conventional treatment, and may offer an alternative to the above hypouricemic options, particularly in those with severe tophaceous disease. In such cases, intravenous uricase is capable of dissolving all tophi in a matter of weeks or months. At this time, hypersensitivity reactions and high cost remain as significant barriers. It is contraindicated in patients with G6PD deficiency.

Unusual Clinical Scenarios to Consider in Patient Management

Gout in solid organ transplant patients can be particularly severe. This appears to be caused not only by mild renal insufficiency but also by the use of cyclosporine, which that raises uric acid levels. Tacrolimus is related to cyclosporine but is somewhat less likely to provoke hyperuricemia.

Occasionally, severely ill patients will have polyarticular gout with fever, leukocytosis, and obtundation. In such cases, it may be difficult to exclude infection, and antibiotics are given until the diagnosis becomes clear. There is usually dramatic improvement with high-dose systemic corticosteroids.

What is the Evidence?

Shah, A, Keenan, RT. “Gout, hyperuricemia, and the risk of cardiovascular disease: cause and effect”. Curr Rheumatol Rep. vol. 12. Apr 2010. pp. 118-24. (Reviews the recent studies identifying hyperuricemia as an independent risk factor for cardiovascular disease)

Schlesinger, N. “New agents for the treatment of gout and hyperuricemia: febuxostat, puricase, and beyond”. Curr Rheumatol Rep. vol. 12. Apr 2010. pp. 130-4. (Comprehensive discussion of current and future treatments)

Richette, P, Bardin, T. “Gout”. Lancet. vol. 375. Jan 23 2010. pp. 318-28. (Thorough up-to-date discussion on risk factors, pathogenesis, and treatment)

Ochoa, CD, Valderrama, V, Mejia, J. “Panniculitis: another clinical expression of gout”. Rheumatol Int. Aug 21 2010. (Panniculitis is a rare presentation of gout; dermatologists should be aware of this clinical expression.)

Choi, HK. “A prescription for lifestyle change in patients with hyperuricemia and gout”. Curr Opin Rheumatol. vol. 22. Mar 2010. pp. 165-72. (Excellent discussion of the risk factors responsible for the current epidemic of gout. Highlights the role of excessive fructose intake.)

Thiele, RG, Schlesinger, N. “Ultrasonography shows disappearance of monosodium urate crystal deposition on hyaline cartilage after sustained normouricemia is achieved”. Rheumatol Int. Jun 20, 2009. (Ultrasound is an inexpensive noninvasive means of following the progression of hypouricemic treatment. It can sometimes help to diagnose gout without arthrocentesis.)

Terkeltaub, RA. “Colchicine update: 2008”. Semin Arthritis Rheum. vol. 38. Jun 2009. pp. 411-9. (Good discussion of mechanisms of action of colchicine, drug interactions, and dosage adjustment. Good discussion of present and future treatment options.)

Choi, HK, Gao, X, Curhan, G. “Vitamin C intake and the risk of gout in men: a prospective study”. Arch Intern Med. vol. 169. Mar 9 2009. pp. 502-7. ( A reminder to tell gout patients about vitamin C. This study provides the evidence.)

So, A, De Smedt, T, Revaz, S, Tschopp, J. “A pilot study of IL-1 inhibition by anakinra in acute gout”. Arthritis Res Ther. vol. 9. 2007. pp. R28(Anakinra [Kineret®, Amgen Inc.] is FDA-approved for rheumatoid arthritis but was surprisingly effective for treatment and prevention of gout attacks.)

Falasca, GF. “Metabolic diseases: gout”. Clin Dermatol. vol. 24. Nov-Dec 2006. pp. 498-508. (Review of the dermatologic features of gout with discussion of treatment)