[Update on Sep 23rd 2013] The Management of Gout Part 1 (ULT and CTGA)

September 23, 2013 Pharmacotherapy, Therapeutics 2 comments , ,

In afore blog we had discussed about the management of gout. Today we update the information for the management of gout based on the latest (2012) clinical guidelines for the management of gout from American College of Rheumatology.

In this post we will discuss about the urate-lowering therapy (ULT) and chronic gouty arthritis with tophaceous disease detected on physical examination (CTGA/chronic tophaceous gouty arthropathy). Note CTGA is defined as chronic gouty arthritis with tophaceous disease detected on physical examination.

In this latest clinical guideline, patients with gout have been divided into 9 cohorts, as shown in picture below.

Figure 1. Fundamental case scenarios in ACR 2012 guideline for gout

If the diagnosis of gout is obtained and correct, a list of steps should be considered as the principles of management for all gout case scenarios.Gout Case Scenarios

Step 1. Patient education on the disease,  the diet and the life-sytle recommendations.

These recommendations belong to nonpharmacologic ULT. Generally they include:

1.weight loss for obese patients, to achieve BMI that promotes general health;

2.healthy overall diet;

3.smoking cessation;

4.exercise (achieve physical fitness); and

5.stay well hydrated.

Diet and food are categorized into three groups: diet needed to avoid, diet needed to limit, and diet encouraged.

The food must avoid consists of [1] organ meats high in purine content (e.g., sweetbreads, liver, kidney), [2] high fructose corn syrup-sweetened sodas and other beverages or foods, [3] alcohol overuse (defined as more than 2 servings per day for a male and 1 serving per day for a female), and any alcohol use in gout during periods of frequent gout attacks or advanced gout under poor control.

The food must limit consists of [1] sizes of beef, lamb, pork, seafood with high purine content (e.g., sardines, shellfish), [2] naturally sweet fruit juices, table sugar and sweetened beverages and desserts, and [3] table salt including in sauces and gravies.

The food encouraged are low-fat or non-fat dairy products, vegetables.

Step 2. The causes of hyperuricemia must be clear for all gout patients. To obtain this intention cetain medical evaluations of certain agents and comorbidities should be performed if indicated since that certain agents and comorbidities can promote hyperuricemia (either causing underexcretion or overproduction of uric acid). Note it is important to identify medications that elevate serum urate level, under which nonessential medications should be stopped.

If patients excrete more than 800 mg of uric acid in 24 hours while eating a regular diet, they are overexcretors and thus overproducers of uric acid. If the patient excretes less than 600 mg of uric acid per 24-hour period on a purine-free diet or less than 800 mg per 24-hour period on an unrestricted diet, the patient is considered a hypoexcreter (Note that this sentence has been removed from the latest Medscape reference for the management of gout).

It is controversial that whether to perform 24-hour urine uric acid evaluation in gout patients with former or present urolithiasis. The 2012 ACR guildeline recommended screening for uric acid overproduction in patient subsets with gout clinical disease onset before age 25 yrs or a history of urolithiasis. In contrast, the latest Medscape reference said a 24-hour urine test of uric acid excretion need not be performed since the patient clearly will need allopurinol (overproducer).

If [1] unclear etiology of hyperuricemia; [2] refractory signs or symptoms of gout; [3] difficulty in reaching the target serum urate level, particularly with renal impairment and a trial of XOI treatment; [4] multiple and/or serious adverse events from pharmacologic ULT, referring  the patients to a specialist is recommended.

Step 3. Evaluating for gout disease activity and burden. Evaluate gout patients and categorize them into the nine subgroup as shown in figure above. A history and thorough physical examination for symptoms of arthritis and signs needed to be assessed.

Step 4. Pharmacologic ULT should be started if indicated. Indications for pharmacologic ULT are any patient with established diagnosis of gouty arthritis and with:

  • Tophus or tophi by clinical exam or imaging study;
  • Frequent attack of acute gouty arthritis (≥2 attacks per year);
  • CKD stage 2 or worse; and/or
  • Past urolithiasis.

The serum urate target is <6 mg/dL in all gout patients. In some patients such as patients with palpable and visible tophi, lower target of <5 mg/dL may be needed to improve gout signs and symptoms.

In the afore blog pharmacologic ULT generally is contraindicated until the acute attack is controlled (starting therapy to control hyperuricemia during an acute attack may intensify and prolong the attack), unless kidneys are at risk because of unusual uric acid load. Typically, agents lowering uric acid levels should be started a few weeks after the attack has resolved and with the protection of prophylactic colchicine or NSAIDs to prevent another attack.

Not consistent is that the 2012 ACR guideline said pharmacologic ULT could be started during an acute gout attack, provided that effective antiinflammatory management has been instituted.

Inadequate response of acute gout to pharmacologic therapy are defined as: [1].<20% improvement in pain score within 24 hours, or [2].<50% improvement in pain score >= 24 hours after initiating pharmacologic therapy. The pain score are measured by Likert scale or VAS (visual analog scales) [For more information about VAS please visit Pharmacoeconomic Evaluating Methods].

When pharmacologic ULT is initiated, serum urate should be monitored every 2-5 weeks during ULT titration. Once the serum urate target is achieved and maintaned the frequency could be prolonged to every 6 months.

Same with the former blog about gout management. Pharmacologic ULT are based on three different classes of medicatons: xanthine oxidase inhibitors, uricosuric agents, and pegloticase.

About The Strategy for Pharmacologic ULT

In this post we don’t consider detailly the contraindications, intolerance, serious adverse events, or drug-drug interactions for given agents.

XOI with either allopurinol or febuxostat is the first-line pharmacologic ULT approach. The initial allopurinol dosage should be no greater than 100 mg/day. This should be followed by gradual increase of the maintenance dose, which can safely exceed 300 mg even in patients with CKD.

Also to avoid allopurinol toxicity, the guidelines recommend considering HLA-B*5801 prescreening of patients at particularly high risk for severe adverse reaction to allopurinol (eg, Koreans with stage 3 or worse kidney disease and all patients of Han Chinese and Thai descent).

For all 9 cohorts when the serum urate target has not been met and/or with continuing disease activity, ACR recommended upward dose titration of the XOI to the respective maximum appropriate dose for the individual patient. If upward titration of the initial XOI agent was not tolerated or did not achieve the serum urate target, substitution of another XOI was an appropriate first-line option. However, if XOIs were contraindicated or not tolerated, consider uricosuric medications as alternative. Note that the unachieved target and/or continuing disease activity is with the presupposition that [1] nonpharmacologic ULT have been applied; [2] appropriate treatment and antiinflammatory prophylaxis are employed for attacks of acute gouty arthritis.

The TFP recommends single XOI therapy with either allopurinol or febuxostat as the first-line pharmacologic approach (evidence A). If XOI is contraindicated or not tolerated, probenecid is recommended as an alternative first-line pharmacologic ULT option. But FTP did not recommend probenecid as a first-line ULT monotherapy in those with a creatinine clearance below 50 ml/minute.

Pharmacologic ULT could be started during an acute gout attack, provided that effective antiinflammatory management has been instituted. Regular monitoring of serum urate (every 2-5 weeks) during ULT titration is recommended. Once the serum urate target is achieved and maintained the frequency of monitor could be prolonged to every 6 months.

If with the approach above, the serum urate target remained unachieved or continuing disease activity remained, we should titrate the dosage of the first-line single drug to the maximum tolerable dose. If issue remains despite maximum or maximum dosage is not tolerated, approach two is to add uricosuric agent to XOI. Note that the unachieved target and/or continuing disease activity is with the presupposition that [1] nonpharmacologic ULT have been applied; [2] appropriate treatment and antiinflammatory prophylaxis are employed for attacks of acute gouty arthritis.

If with approach two, the serum urate target remained unachieved or continuing disease activity remained, pegloticase might be considered as the last approach. However, pegloticase treatment shoud be limited to gout patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral ULT options.

After palpable tophi and all acute and chronic gouty arthritis gout symptoms have resolved, ULT should be continued in order to maintain serum urate <6mg/dL indefinitely.


The Management of Gout (Strategies)

October 16, 2012 Pharmacotherapy, Therapeutics No comments , ,

Gout is inflammation caused by monosodium urate monohydrate crystals, which is a common chronic disease. However gout can cause acute attack, which brings pain and inflammation. Also the uric acid crystals in the kidney will affect the renal function. If untreated, disorders gout causing can lead to joint destruction and renal damage.


Arthrocentesis of the affected joint is mandatory for all patients with new onset of acute monoarthritis and is very strongly recommended for those with recurrent attacks whose diagnosis has never been proven by microscopic visualization of crystals. Tophi also may be aspirated for crystal analysis under polarizing microscopy. When a patient presents with acute inflammatory monoarticular arthritis, aspiration of the involved joint is critical to rule out an infectious arthritis and to attempt to confirm a diagnosis of gout or pseudogout based on identification of crystals. Minute quantities of fluid in the shaft or hub of the needle are sufficient for synovial fluid analysis.

A prior history of gout or pseudogout dose not rule out the possibility of acute septic arthritis. In fact, the later is more common in patients with a history of crystal-induced arthritis. Septic arthritis must be diagnosed and treated promptly, because irreversible damage can occur within 4-6 hours, and the joint can be completely destroyed within 24-48 hours. Note that some patients with infectious arthritis present with a hot swollen joint and an elevated serum uric acid level, but actually not gout. So differential diagnosis between acute gout attack and septic arthritis is important. Gout is diagnosed based on the discovery of urate crystals in the synovial fluid or soft tissues.

Send joint fluid for fluid analysis, including cell count and differential, Gram stain, culture and sensitivity, and microscopic analysis for crystals. If crystals are seen, their shape and appearance under polarized light can aid in diagnosis.

In gout, crystals of monosodium urate (MSU) appear as needle-shaped intracellular and extracellular crystals. When examined with a polarizing filter, they are yellow when aligned parallel to the slow axis of the red compensator, but they turn blue when aligned across the direction of polarization (ie, they exhibit negative birefringence). Negatively birefringent urate crystals are seen on polarizing examination in 85% of specimens.

The sensitivity of a synovial fluid analysis for crystals is 84%, with a specificity of 100%. If gout remains a clinical consideration after negative analysis findings, the procedure can be repeated in another joint or with a subsequent flare. Crystals may be absent very early in a flare.

In crystal arthritis, the WBC count in the synovial fluid is usually 10,000-70,000/µL. However, it may be as low as 1000/µL or as high as 100,000/µL.

Even in the presence of crystals in the joint fluid, blood cultures are indicated if any sign of systemic toxicity is present. Septic arthritis can occur in patients with active crystalline arthropathy.

Gouty attacks are triggered by crystal formation in synovial fluid. They are not related to serum levels of uric acid. Thus, an elevated serum uric acid level does not prove the diagnosis of acute gout, although hyperuricemia is present in 95% of cases, and a normal level does not exclude the diagnosis. Renal uric acid excretion should be measured in high-risk patients, including those with renal calculi, strong family history of gout, and first attack before age 25 years.

Urinary Uric Acid

A 24-hour urinary uric acid evaluation is generally performed if uricosuric therapy is being considered. If patients excrete more than 800 mg of uric acid in 24 hours while eating a regular diet, they are overexcretors and thus overproducers of uric acid. These patients (approximately 10% of patients with gout) require allopurinol instead of probenecid to reduce uric acid levels.

Patients who excrete more than 1100 mg in 24 hours should undergo close renal function monitoring because of the risk of stones and urate nephropathy.

In patients in whom probenecid is contraindicated (eg, those with a history of renal stones or renal insufficiency), a 24-hour urine test of uric acid excretion does not need to be performed because the patient clearly will need allopurinol.

Serum Uric Acid

Measurement of serum uric acid is the most misused test in the diagnosis of gout. There is no direct relationship between serum uric acid levels and gout. As many as 10% of patients with symptoms due to gout may have normal serum uric acid levels at the time of their attack. An elevated serum uric acid level dose not indicate or predict gout. However, decreasing uric acid levels can trigger attacks of gout. And for the chronic treatment of gout serum uric acid levels is the goal.

Treatment Strategy of Gout

Gout is managed in 3 stages: 1.treating the acute attack; 2.providing prophylaxis to prevent acute flares; 3.lowering excess stores of urate to prevent flares of gouty arthritis and to prevent tissue deposition of urate crystals. (more…)

Gout and the Antihypertensives

August 4, 2012 Adverse Drug Reactions, Cardiology, Therapeutics 1 comment , , , , , ,

The inflammatory arthritic condition of gout.

Gout, the inflammatory arthritic condition triggered by crystallization of uric acid within the joints, has risen in the United States. A research studied by Dr. Choi (Hyon K. Choi, MD, DrPH) and his colleagues shown that 74% of US gout patients also have hypertension. Dr. Choi’s group also has shown that hypertension is an important independent risk factor for gout. In patients with hypertension, the incidence of gout has been calculated as 3 times higher than in normotensive patients.

Simplistic speaking, much of this added risk is attributed to the use of diuretics, which are associated with increased serum uric acid levels. But hypertension itself is associated with increased risk of gout. Not only diuretics, but also other nondiuretic classes of antihypertensive drugs have been shown to affect serum uric acid levels.

Generally, with the use of diuretics, beta-blockers, ACEI, and non-losartan angiotensin II receptor blockers (ARBs), the risk of gout incresed.

However as antihypertensive drugs, calcium channel blockers (CCBs) and losartan (a kind of ARBs), are associated with reduced risk of gout.

In an editorial published alongside the study report, Luis M. Ruilope, MD, (Hospital 12 de Octubre and University Autonoma, Madrid, Spain) noted that a reduction in serum uric acid “as well as reducing incident gout, could also improve the cardiovascular and renal prognosis of patients with hypertension.” Thus, to control the serum uric level is important for hypertensive patients.

A number of variables affect serum uric acid levels and the risk of gout, including many life style factors such as adiposity, represented by BMI; dietary factors, particularly alcohol consumption, fructose-rich beverages such as sugary sodas, and a purine-rich diet, particularly animal sources of purine such as red meat or seafood. And in right here, finally, drugs can cause increased risk of gout.

The mechanism of increased risk of gout with hypertension is that as blood pressure elevates, serum uric acid concentration increases, which appears to be a dose-response relationship. Also urate excretion is lower in hypertensive patients than in normotensive individuals. Reduced renal blood flow with increased renal and systemic vascular resistance may also contribute to elevated serum uric acid levels. eventually leading to an increased risk of gout.

The mechanism of increased risk of gout with antihypertensive drugs are variable. Diuretics, the loop and thiazide-type diuretics, can increase serum uric acid levels and the risk of gout. The mechanism of the nondiuretic antihypertensive drugs include ACE inhibitors, non-losartan ARBs are unknown. But clinical trials has shown beta-blockers can increase serum uric acid levels slightly. the mechanism of beta-blockers is unknown neither.

Here I find some data. With beta-blockers, the risk of gout was 48% higher in people with hypertension. ACEIs also have the identical effect. But there is an exception – the diuretics.

Fortunately, specific antihypertensive drugs contribute to the reduce risk for gout. The unique ARB, losartan, lowered uric acid levels in one clinical trial. Bench studies have shown that losartan causes increased uric acid secretion (uricosuria) by inhibiting urate/anion transport in brush-border cells of the renal proximal tubules through inhibition of urate transporter 1 (URAT 1). That is losartan inhibits uric acid reabsorption, causing uricosuria, eventually driving down blood uric acid levels and the reduced risk of gout.

Also CCBs including dihydropyridines and nondihydropyridines have the ability to decrease the risk of gout. The mechanism is unkown. For people with hypertension, taking CCBs lowered their risk of gout by 13% compared with people with hypertension who were not taking a CCB.

To rudece the risk of gout in hypertensive patients, we couldn’t avoid these antihypertensive drugs such as ACEIs, ARBs, or diuretics. Because these patients benefits from these drugs. Thus when the antihypertensive regimen contains drugs increasing risk of gout, we may add another antihypertensive drug that decreases the risk of gout. With the use of the protective drugs, like CCB or losartan, the risk should become even lower.