Prophylaxis of Attacks of Acute Gouty Arthritis

Key Points

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Gout attacks (also called “flares”) are commonly precipitated by factors that induce rapid rise (e.g., diet and alcohol excess, intensive diuresis for congestive heart failure) or decline of serum urate (e.g., initiation of urate-lowering therapy [ULT]).
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Acute gout attacks that occur early in ULT are likely due to proinflammatory effects in joint tissue via remodeling and altered stability of tophi in the joint, particularly in response to rapid, extensive lowering of serum urate.
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All forms of alcohol, ingested in a concentrated time period (e.g., more than three servings in a 24-hour period), promote gout flares.
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Dehydration appears central to promotion of many gout attacks, can be promoted by “binges” of alcohol or caffeine consumption, and may help account for seasonal increases in rates of acute gout attacks in spring and summer. Conversely, consumption of five to eight 250-ml servings of water daily (unless medically contraindicated) may help suppress gout flares.
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In clinical practice, gout flare prophylaxis should be combined with the initiation of the pharmacologic ULT program in all patients. Oral ULT should start a submaximal dose, and then build up to the dose of ULT that achieves the serum urate target. Gout attacks contribute to decreased adherence in the first months after initiation of ULT, and patient education on the likelihood of gout flares is essential.
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Low-dose colchicine therapy is effective for prophylaxis of acute gout, and low-dose oral nonsteroidal antiinflammatory drug therapy (e.g., naproxen 250 mg twice daily) is an alternative. Colchicine prophylaxis should be started 1 to 2 weeks before initiation of ULT and continued for at least 6 months, and longer if visible tophi remain or ULT has not achieved the target level (typically less than 6 mg/dl).
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Even low doses of daily prophylactic colchicine treatment can be associated with toxicities. Colchicine dose should be reduced, or the drug should be avoided where drug-drug interactions are likely (e.g., clarithromycin, erythromycin, disulfiram), in chronic kidney disease, and in those over age 70.
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Use of low-dose corticosteroids for gout attack prophylaxis is not evidence based and should generally be avoided, or used as a last resort; we do not know what the minimum doses of corticosteroids are for efficacy in gout flare prophylaxis.
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Therapy with interleukin-1 antagonists is an emerging approach for prophylaxis of gout attacks that has been successful in phase II and III clinical trials, although this is not Food and Drug Administration approved at the time in 2011 that this is written.

Supported by the VA Research Service.

Introduction

A key therapeutic objective in gout is to prevent the acute, painful, and debilitating attacks (also called “flares”) that make such an impact on quality of life in the disease. Understanding therapeutic strategies to prevent gout attacks, beyond pharmacologic and nonpharmacologic measures for lowering of serum urate to ultimately dissolve tissue urate crystal deposits, requires appreciation of the most common precipitating factors of acute gout flares, which are listed in Table 15-1 .

Table 15-1

Major Factors That Precipitate Attacks of Gout

Initial phase (first 3-6 months in particular) of urate-lowering therapy

Dehydration

Joint trauma or abnormal biomechanical loading: e.g., at first metatarsophalangeal joint

Intercurrent medical or surgical illness: e.g., pneumonia, deep venous thrombosis, congestive heart failure, exacerbation, general surgery (especially in first 48 hours of postoperative state)

Excess consumption, in a period of hours to 1 to 2 days, of:

Alcohol (beer, wine, or spirits)

Caffeine (4 or more servings of caffeinated beverages in a 24-hour period)

Sudden extreme nutrient deprivation (e.g., “crash diets”, or initial post–bariatric surgery period)

Factors That Precipitate Gout Attacks

Urate-Lowering Therapy

Accelerated rises or declines of serum urate, due to altered purine intake, hydration, and urate-lowering drugs, are the most common fundamental factors driving flares of acute gout. Gout flares driven by urate-lowering therapy (ULT) are most likely mediated by inflammatory effects in joint tissue brought about by remodeling and altered stability of tophi in the joint, and release of naked urate crystals (i.e., lacking protein coat) from tophi may be responsible. The more rapid and extensive the lowering of serum urate, by any pharmacologic means, the more likely it is that attacks will develop in the first 3 to 6 months of ULT. As such, the most recent U.S. Food and Drug Administration (FDA)–approved advanced therapeutics for urate lowering (febuxostat and pegloticase) have produced substantially high rates of gout flares in the first few months of therapy in clinical trials, particularly when adequate gout flare prophylaxis is not used or prematurely discontinued. For example, the early flare rate in phase II studies of pegloticase (in which patients were not premedicated with corticosteroids) approached 80%. In the Febuxostat Versus Allopurinol Control Trial in Subjects With Gout (FACT trial), acute gout attacks were reported in about 30% to 45% of subjects between weeks 8 and 16. This time frame was in conjunction with the discontinuation, by trial design, of pharmacologic gout attack prophylaxis with low-dose colchicine (or low-dose nonsteroidal antiinflammatory drugs [NSAIDs]).

Dehydration, Concomitant Illness, and Trauma

Dehydration, with associated elevation in serum urate, appears to promote gout flares in instances such as intensive diuresis with intravascular volume depletion in congestive heart failure and may, with increased activity, account for seasonal increases in gout-flare rates in spring and summer. In an Internet-based case-crossover study, water consumption was associated with decreased risk of gout flares. Ingestion in a 24-hour period of five to eight servings of water (250 ml per serving, which is the volume of the standard drinking glass) was associated with decreased odds ratio (OR) of gout flare of 0.6 (95% confidence interval [CI] 0.4 to 0.9). Moreover, drinking more than eight servings per day was associated with adjusted OR 0.54 (95% CI 0.32 to 0.9) ( p = .02) ; adjustments in this study were for diuretic use and for purine and alcohol. Extreme nutrient deprivation (e.g., via “crash diets” or in the initial postoperative period of bariatric surgery) also has the potential to induce gout flares by promoting fluctuations in serum urate.

Gout attacks commonly occur in the first 1 to 2 days postoperatively in the setting of major surgery and general anesthesia. Maintenance of adequate hydration would likely be a factor in preventing postoperative gout attacks, although gout attacks in this clinical scenario also likely are provoked by tissue trauma with consequent systemic cytokine release. In fact, gout flares can be triggered by systemic and regional medical illnesses as well, including pneumonia and deep venous thrombosis. Trauma to joints, exemplified by subtle excesses in biomechanical forces on the first metatarsophalangeal joint mediated both by ambulation and poor-fitting footwear, also can promote gout attacks, likely by effects on tophus stability, inflammation, and fluid and solute shifts in the joint space.

Excesses in Diet, Alcohol, and Caffeine

It has long been recognized by medical and lay public alike that precipitating factors for gout attacks include excesses in dietary purine and alcohol intake, which induce fluctuation (typically rapid rise and fall) of serum urate that could modify tophus structure. In addition, dietary excesses also have been suggested to have a priming effect on urate crystal–induced inflammation by increasing free fatty acid–driven TLR2-mediated activation of cells in the joint including mononuclear phagocytes.

Although middle-aged male wine drinkers without gout do not, unlike beer and spirit drinkers, have an increased risk of developing gout, all forms of alcohol, when ingested in a condensed period of time, appear to be associated with an increased risk of gout attacks. Specifically, in an Internet-based case-crossover study, five or more standard servings of alcohol (beer, wine, or spirits) in a 24- or 48-hour period at least doubled the risk of gout attack. A dose response for alcohol was more clear for consumption patterns in a 24-hour period, and three or more servings of alcohol in 1 day appears to be a critical number linked with the onset of gout attacks. One suspects that the effects of intense alcohol consumption to promote gout attacks may relate not simply to acute elevation in serum urate but also to decreased hydration. In this context, “binges” of caffeine-containing beverage consumption (four or more servings per 24-hour period prior to the gout attack) also were suggested to be associated with gout attacks in an Internet-based case-crossover study.

Therapeutic Options for Gout Attack Prophylaxis

Nonpharmacologic Strategies of Attack Prevention

Table 15-2 summarizes approaches to gout attack prophylaxis. Some patients who decline, do not adhere to, or are not prescribed pharmacologic ULT, attempt, on their own, or are advised to manage their gout indefinitely by prophylaxis of attacks by itself. “Moderation” of diet and alcohol serving sizes and frequency is the most common first step, and it clearly has benefits to overall health. Each portion size (appetizer, main course, dessert) needs to be moderated in size with such a strategy. A useful concept for the main course is to have the patient conceptualize a dinner portion for a 9-inch diameter plate size (about 800 to 900 food calories on average) rather than the current U.S. standard of 12 inches for a dinner plate (about 1800 food calories on average). Maintenance of oral hydration with repeated servings of water (five to eight per day) and avoidance of “binges” of caffeine-containing beverages (four or more servings per day) are best advised. Other dietary excesses that are advisable to avoid include “crash weight-loss diets” (due to dehydration and lactic acidosis that can raise serum urate) and “yeast-based diets” (due to their high purine content). The role of the folk remedy of cherries (or commercially available cherry juice extract), which theoretically provides urate-lowering activity of ascorbate and antiinflammatory effects of the anthocyanins particularly enriched in sour or tart cherries, has not yet been subjected to adequate study.

Table 15-2

Nonpharmacologic and Pharmacologic Gout Attack Prophylaxis Regimens

Nonpharmacologic

Employ well-fitted footwear

Maintain hydration daily (e.g., 5-8 servings of water daily)

Avoid so-called “crash diets” built on a foundation of extreme nutrient deprivation for days to weeks

Avoid concentrated excesses of:

Purine-rich food (e.g., meat, shellfish, seafood)

Any form of alcohol

Caffeine

Yeast

Pharmacologic

For ULT initiation:

Oral colchicine 0.6 mg once or twice daily for at least 6 months; start colchicine prophylaxis 1 week before starting ULT.

Continue colchicine prophylaxis longer than 6 months in patients with visible tophi, continuing gout flares, or for at least 3 months after serum urate is normalized to <6.0 mg/dl in those with refractory hyperuricemia

Reduce colchicine dose in those:

In stage 3 or worse chronic kidney disease (i.e., CrCl <60 ml/min adjusted for ideal body weight)

With potential drug-drug interactions

Patients >70 years of age (extent of dose reduction is not yet evidence based)

Alternative Regimen

Low-dose NSAID prophylaxis for same duration as for colchicine, (e.g., naproxen 250 mg twice daily, or indomethacin 25 mg PO twice daily)

Caveat: The evidence basis for NSAID-based gout attack prophylaxis regimens is less established than for colchicine

Avoid use of low-dose corticosteroids as prophylaxis for gout flares:

The dose level of corticosteroids adequate to prevent gout attacks is not known, and it is difficult to wean gout patients from low-dose prednisone due to rebound flares

Experimental

Interleukin-1 inhibition; this strategy has given positive results compared to both placebo and the active comparator colchicine 0.5 mg daily in advanced clinical trials

Pharmacologic Strategies of Attack Prevention

Since the vast majority of gout patients with a history of at least one acute attack will have additional gout flares in future years, pharmacologic therapy with colchicine or NSAID alone (without ULT) is not recommended in clinical practice. The general principles when initiating ULT with allopurinol, febuxostat, and uricosurics include starting at a submaximal dose and gradually titrating upward, over a period of weeks to months, to achieve the target serum urate level. This strategy of upward dose adjustments is held to reduce the incidence of early acute gout attacks in ULT and is the FDA-recommended and European League Against Rheumatism (EULAR)–recommended strategy for allopurinol, for example.

For prophylaxis of acute gout attacks, low-dose colchicine therapy is the first choice and, as an alternative, low-dose NSAID therapy is commenced when colchicine is not well tolerated or is contraindicated. It should be noted that colchicine intolerance may be overstated by some patients, based on previous, non–FDA-approved regimens of acute gout in which colchicine was administered hourly over an extended period until diarrhea, pain relief, or a maximum of dose of about 5 to 7 mg was achieved.

In clinical practice, colchicine for gout attack prophylaxis is commenced 1 to 2 weeks before initiation of serum ULT and continued for at least 6 months (if successful serum urate lowering less than 6 mg/dl is achieved and no tophi are visibly detectable). It is noteworthy that in the FACT trial, prophylactic low-dose colchicine or low-dose NSAID therapy was discontinued 8 weeks into ULT with allopurinol or febuxostat, and gout attacks markedly increased between 8 and 12 weeks into ULT. In contrast, there was continual gout attack prophylaxis therapy through 6 months in the CONFIRMS trial of the same ULT drugs and, under these conditions, a flatter incidence of acute gout attacks.

Early gout flares contribute to decreased adherence with ULT, a major problem in clinical practice for gout care. Since gout patients appear to be much less adherent overall than patients with many other medical disorders, patient expectations must be adequately addressed when starting ULT.

Evidence basis for low-dose colchicine prophylaxis of acute gout flares after starting ULT becomes clear from comparison of the FACT and CONFIRMS trial data. It is buttressed by a small (N = 43), randomized, placebo-controlled study of patients starting allopurinol as ULT ( Fig. 15-1 ) . In this study by Borstad et al., colchicine was continued for at least 3 months beyond the point at which the serum urate target level was reached, and subjects who remained on colchicine for 6 months retained significant clinical benefit. Acute gout attacks developed in 33% on colchicine 0.6 mg twice daily and 77% taking placebo ( p = .008). Gout attacks were less severe with colchicine than placebo ( p = .018).