DÄ internationalArchive13/2017Treatment Options for Gout

Review article

Treatment Options for Gout

Dtsch Arztebl Int 2017; 114: 215-22. DOI: 10.3238/arztebl.2017.0215

Engel, B; Just, J; Bleckwenn, M; Weckbecker, K

Background: 1–2% of adults in Germany suffer from gout. Gout is one of the few rheumatological diseases that can be cured. It arises through the deposition of uric acid crystals in joints as a result of hyperuricemia. Painful redness and swelling of the affected joints are typical findings. Multiple pertinent guidelines and treatment recommendations have been published, but there is reason to believe that patients with gout are not always treated accordingly.

Methods: This review is based on relevant publications from the years 2000–2016 that were retrieved by a selective search in the Cochrane and PubMed databases.

Results: In a person with normal renal function, asymptomatic hyperuricemia is not an indication for treatment to lower the serum uric acid level. The drugs of first choice for acute gouty arthritis are nonsteroidal anti-inflammatory drugs (NSAID), corticosteroids, and colchicine. Treatment with xanthine oxidase inhibitors (XOI) or uricosuric drugs is indicated for patients with a recurrent or severe course; the target uric acid value is <6 mg/dL. Long-term treatment should be initiated only after resolution of the acute attack. For patients with refractory gout, lesinurad (approved in February 2016) in combination with XOI is a new treatment option that can be considered. Comprehensive patient education and counseling is an important component of the treatment of patients with gout. Regular laboratory follow-up is necessary as well.

Conclusion: The prevalence of gout is rising around the world. Patients with gout could benefit greatly from consistent implementation of the existing treatment guidelines and recommendations. In the future, controlled trials should be conducted to determine the best time to start treatment and the optimal target level for the serum uric acid concentration in terms of a risk/benefit analysis.

LNSLNS

Approximately 1 to 2% of adults in Germany suffer from gout and around 20% from hyperuricemia. This makes gout the most widespread form of arthritis nationwide (1). It is one of the few rheumatic diseases that can be cured. Gout is caused by the deposition of uric acid crystals in joints or in tissues around joints as a result of hyperuricemia. Typically, painful swelling and reddening occur in the affected joint. An increase in the prevalence and incidence of gout has been observed worldwide (e1). There is no data on Germany specifically. However, because current incidence levels are similar to the incidence found in Annemans’ study (1), it can be inferred that the situation in Germany is the same. Attention has shifted back to gout for both health-related and economic reasons (1, 2, e1). In the past, multiple guidelines and treatment recommendations were published in order to improve care for gout patients. However, care currently fails to comply with these guidelines in a number of ways. These include overuse of allopurinol for asymptomatic patients with hyperuricemia and a failure to monitor uric acid-lowering drug therapy. Multiple studies have shown this discrepancy between treatment recommendations and clinical practice (3, 4, e1e3).

Methods

The authors performed a selective search of the literature for the years 2000 to 2016 in the Cochrane Database and in PubMed. In PubMed the following search terms were used: “gout” OR “hyperuricemia”; filters activated: “meta-analysis,” “systematic reviews,” “randomized controlled trial,” “guideline,” “clinical trial,” “abstract,” “publication date from 2000/01/01,” “humans,” “English,” “German.” The initial search yielded 628 hits. Following the analysis of titles and abstracts, 159 sources remained; these were used as the basis for a qualitative synthesis. Some older, basic publications were added individually. A detailed description of the procedure, which complied with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) Statement, is available from the authors.

Results

Our search yielded little literature of high quality in terms of level of evidence and study design. This article states the grade of each recommendation according to the most recent guidelines (5, 6) in parentheses.

Definitions

Gout is divided into 4 stages (e4):

  • Asymptomatic deposits in tissues
  • Acute gout: This is defined as rapidly-developing inflammation, usually of only one joint, with painful overheating and swelling. Uric acid crystals trigger the inflammation reaction in joints or tissues around joints.
  • Intercritical periods: These are clinically inactive disease phases between 2 flares. During these periods, gout patients also have hyperuricemia, which can lead to increased deposition of urate crystals in tissues. Intercritical periods become shorter as the disease progresses.
  • Chronic gout: This is characterized by long-term joint inflammation, which leads to joint pain at rest and/or on movement.

Prevalence

According to the European League Against Rheumatism (EULAR), the prevalence of symptomatic gout among the adult Western population is 1 to 2% (7), rising to 7% in those aged over 65 years (1). Publications to date do not give prevalence figures for individual stages of gout.

Etiology

Gout can be caused by overproduction of uric acid (10% of cases) or lowered renal uric acid excretion (90%) (e5). Rarer causes of gout are genetic purine metabolism disorders such as the Lesch–Nyhan syndrome (e6).

Uric acid is the end product of purine metabolism in humans. The solubility product of uric acid at 37 °C is 6.8 mg/dL (8). Hyperuricemia can favor the precipitation of urate crystals in tissues, leading to gout. Incidence of gout rises with uric acid level (9) (Table 1). Uric acid crystals precipitate faster at lower temperatures, so toes, fingers, hands, feet, elbows, and ears are the principal sites of gout flares and deposition of uric acid crystals in soft tissues (gout tophi). Uric acid crystals may also be deposited in the urinary tract (urolithiasis).

Gout incidence by serum uric acid level*
Gout incidence by serum uric acid level*
Table 1
Gout incidence by serum uric acid level*

The uric acid crystals that have precipitated lead to inflammasome activation in monocytes and the subsequent release of various inflammatory mediators such as interleukin-1 (10). If left untreated, an acute gout flare lasts between 3 days and 2 weeks. A patient’s first gout flare is monoarthritis in up to 90% of cases, most commonly inflammation of the joint at the base of the big toe (podagra) (11). Polyarthritis is more common in older patients (4).

Diagnosis

In primary care practice, a gout flare is diagnosed on the basis of examination (typical pattern of involvement) and medial history (after ruling out red flags: trauma, condition following intra-articular injection, surgery, fever, poor general health) (e7). In 2015 the US and European rheumatology societies (the American College of Rheumatology [ACR] and EULAR respectively) developed a clinical diagnosis score (12) (Table 2). These diagnosis criteria state that evidence of uric acid crystals on joint puncture is sufficient to confirm a diagnosis of gout. Due to risk/benefit considerations, these authors advise against diagnostic puncture where clinical findings unambiguously indicate a gout flare (C).

Diagnosis criteria for gout*
Diagnosis criteria for gout*
Table 2
Diagnosis criteria for gout*

Laboratory and X-ray analysis

One-third of patients with an acute gout flare have normal uric acid levels (e8). A normal serum uric acid level in cases of acute arthritis does not rule out gouty arthritis. A high uric acid level increases the probability of gouty arthritis but does not confirm the diagnosis (12) (C). In an acute gout flare, uric acid precipitates and, as uric acid crystals, causes the patient’s complaints; this may lead to a reduction in the measurable blood uric acid level. Uric acid level measurement a few weeks after a flare in order to monitor disease progression is recommended (13) (B).

Laboratory tests may be necessary for further clarification in cases of atypical progression or for differential diagnosis. The following diseases must be considered in differential diagnosis of acute gout:

  • Septic arthritis
  • Trauma
  • Active arthritis
  • Pseudogout
  • Rheumatoid arthritis

Annual laboratory tests, particularly of retention levels and uric acid level, should be performed to monitor the progression of chronic gout (14) (B).

To date, conventional imaging has not played a major role in primary diagnosis, as gout does not cause radiologically visible bone changes until it has progressed to a late stage (e9). Earlier detection of tophi in soft tissues may be used to monitor treatment in the future. Ultrasound examination can be used as a noninvasive option. Sonography shows synovialitis with markedly increased vascularization and a double contour sign. (e10, 15). Dual-energy CT (DECT) can reveal small deposits of uric acid crystals but should only be considered if findings for differential diagnoses are unclear, as it involves radiation exposure, is expensive, and has low overall sensitivity (15) (C).

Treatment

Gout treatment rests on 2 pillars: nonpharmacological and pharmacological therapy. How much of each should be used depends on the individual patient’s needs. Stage (acute gout, intercritical phase, or chronic gout), individual factors (number of flares, radiological findings), and general risk factors play a crucial role in this.

Nonpharmacological therapy

This includes patient education, dietary recommendations, and resting the joint.

Patient education (C): One approach to gout treatment is patient education. Hyperuricemia is more common with current lifestyle trends (increasing lack of exercise, excess weight). A cohort study conducted in England showed that detailed education led to successful gout management by patients (e11).

Dietary recommendations: Diet affects uric acid levels. Changes to diet and lifestyle can reduce uric acid levels by up to 18% (16). Several studies have shown that less than 50% of gout patients surveyed were informed of the association between particular foods and gout (e12).

Many authors recommend the same diet as for cardiovascular event prevention (www.degam.de/patienten
informationen.html—in German). A large cohort study has shown that weight loss and subsequently improved metabolic status can also reduce the incidence of gout flares (e13) (B). Dietary recommendations (Box) are based on pathophysiological considerations and are compatible with other healthy dietary recommendations. No randomized controlled trials have yet investigated whether the recommendations have a positive effect on patients’ gout progression (17).

Dosing of allopurinol for patients with kidney failure
Dosing of allopurinol for patients with kidney failure
eTable
Dosing of allopurinol for patients with kidney failure
Dietary recommendations for gout
Dietary recommendations for gout
Box
Dietary recommendations for gout

Resting the joint: A systematic review showed that correct rest for the joint can also contribute to the treatment of an acute gout flare. The affected joint should be raised and cooled (18) (C).

Pharmacological therapy for acute gout

Pharmacological therapy for acute gout aims to achieve an absence of pain and resolution of joint inflammation as rapidly as possible. Without pharmacological treatment, a gout flare lasts between 3 days and 2 weeks. In general, anti-inflammatory therapy should be begun immediately, preferably within 12 to 24 hours of onset of an acute gout flare (B). First-line treatment options are nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and colchicine (5) (A). Treatment usually relieves symptoms after 24 hours (19). The decision which of the 3 substance groups to use depends on the patient’s comorbidities and the physician’s experience. Table 3 provides an overview of treatment options.

Treatment options for acute gout
Treatment options for acute gout
Table 3
Treatment options for acute gout

In addition, it is recommended that treatment with drugs that induce hyperuricemia, particularly diuretics and low-dose acetylsalicylic acid, should not be begun in patients with acute gout, and that the dose of established therapy should not be increased (5, 16) (B).

Gout patients occasionally suffer from comorbidities that are incompatible with NSAID, colchicine, or cortisone treatment. Recent studies have shown that interleukin-1 is an important mediator of inflammation in acute gout. According to a Cochrane review (24), interleukin-1 antagonists can be considered as an alternative option if all 3 standard treatment options are contraindicated or not tolerated (B).

Uric acid-lowering drugs used to treat chronic gout are contraindicated for the treatment of acute gout flares, as they can also cause acute gout flares (25) (C). Long-established uric acid-lowering therapy should continue to be administered during an acute gout flare.

Treatment of asymptomatic hyperuricemia

Studies published to date indicate that treatment for asymptomatic hyperuricemia in patients with healthy kidneys cannot be recommended (26) (C). Two meta-analyses indicate an increase in cardiovascular risk in particular for hyperuricemia patients (e15, 21). However, there are no available studies that yield an unambiguous conclusion. In in vitro studies, uric acid has shown an antioxidant and therefore protective effect (e16). Further studies on this are required.

Chronic gout treatment

Chronic gout treatment should aim to prevent gout progression and further gout flares, to eliminate any urate deposits, and to reverse tophus formation. International guidelines recommend that uric acid levels be adjusted to well below the solubility limit of 6.8 mg/dL in order to prevent deposits (14, 16, e11). There are currently no available studies that have investigated the optimum target uric acid levels. The German College of General Practitioners and Family Physicians (DEGAM, Deutsche Gesellschaft für Allgemeinmedizin) recommends that uric acid levels should be maintained below 6.5 mg (27). The EULAR advises uric acid levels of less than 6 mg/dL, and even as low as <5 mg/dL in patients with severe gout (B). Lifelong therapy is recommended. A prospective cohort study has shown that withdrawal can be attempted after uric acid levels have successfully been maintained at a low level for more than 5 years (28) (B).

Long-term therapy should begin no sooner than 2 weeks after the beginning of an acute gout flare (B).

Long-term therapy is recommended for patients with the following symptoms (16, 27) (B):

  • More than 2 gout flares per year
  • Urolithiasis and gout
  • Known overproduction of uric acid, e.g. during chemotherapy
  • Pre-existing tophi

According to EULAR recommendations, the option of beginning treatment early should be discussed with patients in order to reduce crystallization if gout does continue to progress (6). However, there is no clear evidence supporting this. Because allopurinol also has side effects and can lead to increased gout flares, particularly after the beginning of treatment, these authors recommend that patients should first try to reduce their uric acid levels through lifestyle changes.

Increased gout flares may occur in the first weeks to months after the beginning of uric acid-lowering treatment. When serum uric acid levels fall, uric acid deposits are mobilized from the tissues (e8, 29, 30). There are no randomized controlled trials on gout flare prophylaxis. Current knowledge has been obtained from febuxostat authorization studies and other sources (5). More gout flares have been described after the beginning of febuxostat treatment than of allopurinol treatment; however, there are no significant differences after longer-term administration. It is recommended that uric acid-lowering treatment be begun with a gradual dose increase (6) (C). Low-dose colchicine (0.5 mg/day) or a low-dose NSAID is recommended for 6 months to prevent flares (31, 32) (B).

International guidelines describe xanthine oxidase inhibitors as first-line treatment and uricosuric agents as second-line treatment. The leading xanthine oxidase inhibitor and uricosuric agent are allopurinol and probenecid respectively. Possible treatment options are listed in Table 4. A higher proportion of patients achieve the target uric acid level of 6 mg/dL with febuxostat—which is also a xanthine oxidase inhibitor—than with allopurinol (48% versus 22% [32]). Febuxostat is therefore a possible option for treatment-refractory hyperuricemia. Should this escalation be insufficient, combination therapy with a xanthine oxidase inhibitor and lesinurad, a selective inhibitor of the URAT1 transporter, is possible. In general, regular laboratory testing should be performed to monitor treatment success, and treatment should be adjusted if necessary (C). Urate oxidase should also be mentioned as a treatment option for treatment-refractory patients. However, this drug was taken off the market in mid-2016.

Treatment options for chronic gout
Treatment options for chronic gout
Table 4
Treatment options for chronic gout

Discussion

Despite the high prevalence of gout, there have been only a few randomized clinical trials on which conclusions can be based to aid the development of evidence-based medicine. Recommendations are often based on pathophysiological considerations. There is a clear need to fill in the gaps.

Some questions have not yet been researched conclusively, such as the effect of uric acid on the human body. For clinical practice it is of interest whether asymptomatic hyperuricemia is an independent cardiovascular risk factor or whether very low uric acid levels over long periods have an adverse effect on the central nervous system. Further research is also needed on the effect of uric acid on renal function. In summary, controlled trials on optimum uric acid level should be conducted, involving risk/benefit analysis of serum uric acid.

Further studies from which conclusions can be drawn researching the optimum time to begin treatment for chronic gout would also be of practical interest. Can uric acid-lowering therapy be started as early as during an acute gout flare? To date, only one, single-center study with a total of 57 patients has addressed this question (e22). This found no adverse effect on the frequency of gout flares as a result of beginning uric acid-lowering therapy early (less than 7 days after the beginning of a gout flare).

After a long hiatus in treatment options, there are now new options on the market. How useful they are remains to be seen.

A new drug for the treatment of acute gout is the IL-1 antagonist canakinumab. This is authorized for use when the 3 standard treatment options (NSAIDs, corticosteroids, and colchicine) are not tolerated, insufficiently effective, or contraindicated. Newly on the market for chronic gout is lesinurad, which is authorized for use in combination with a xanthine oxidase inhibitor for patients whose gout is refractory to standard treatment (a xanthine oxidase inhibitor or probenecid).

Conclusion for clinical practice

It is important to respond to gout appropriately at an early stage in order to avoid painful, chronic disease for patients. To improve compliance, particular emphasis should be placed on educating and involving patients. Regular laboratory testing should be performed during treatment to monitor progression. Withdrawal may be attempted after therapy has successfully lowered uric acid levels for several years.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 21 July 2016, revised version accepted on
29 December 2016.

Translated from the original German by Caroline Shimakawa-Devitt, M.A.

Corresponding author:
Dr. med. Bettina Engel
Institut für Hausarztmedizin
Universitätsklinikum Bonn/Medizinische Fakultät
53127 Bonn, Germany
bettina.engel@ukb.uni-bonn.de

Supplementary material
For eReferences please refer to:
www.aerzteblatt-internatioanl.de/ref1317

eTable:
www.aerzteblatt-international.de/17m0215

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Institute of General Practice and Family Medicine, University Hospital Bonn: Dr. med. Engel, Dr. med. Just, Dr. med. Bleckwenn, Prof. Dr. med. Weckbecker
Dietary recommendations for gout
Dietary recommendations for gout
Box
Dietary recommendations for gout
Gout incidence by serum uric acid level*
Gout incidence by serum uric acid level*
Table 1
Gout incidence by serum uric acid level*
Diagnosis criteria for gout*
Diagnosis criteria for gout*
Table 2
Diagnosis criteria for gout*
Treatment options for acute gout
Treatment options for acute gout
Table 3
Treatment options for acute gout
Treatment options for chronic gout
Treatment options for chronic gout
Table 4
Treatment options for chronic gout
Dosing of allopurinol for patients with kidney failure
Dosing of allopurinol for patients with kidney failure
eTable
Dosing of allopurinol for patients with kidney failure
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