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11 Articles in Volume 13, Issue #6
Ask the Expert: Cash Patient on High-Dose Oxycodone With Negative Urine Screens
Cluster Headache: Providing Relief for a Debilitating Disorder
Editor's Memo: Keeping the Trust in Difficult Times
Gout: New Guidelines for Managing An Ancient Disease
History of Pain: A Brief Overview of the 17th and 18th Centuries
Letters to The Editor: Guidelines for Opioid Prescribing, Drug Legislation
Long-term Opioids, Sickle Cell Disease, and Pain Patches
Lumbar Spinal Stenosis: A Review of the Treatment Options and Modalities
Malabsorption of Opioid Medications
Non-Opioid Pharmaceutical Treatment of Cancer Pain
Treatment of Postherpetic Neuralgia With Low Level Laser Therapy

Gout: New Guidelines for Managing An Ancient Disease

With improved understanding of the disease, more diverse therapies, and guidelines to lead the way, doctors are now positioned to help gout patients with this painful and debilitating disease.

Gout has inflicted pain on humanity for thousands of years. From Egyptian royal mummies—whose skeletons show gout-associated arthropathy—to the highly descriptive depictions of suffering by Greek and Roman playwrights, into generations of England’s aristocracy (most notably Henry VIII); gout has taken a toll on many notable historical figures.

In contrast, gout in the 21st century has not been so discriminating. Gout’s worldwide prevalence has been dramatically increasing in men and women irrespective of class, nationality, or ethnicity.1 Gout is now the most common inflammatory arthropathy in the United States,2 where it is estimated to affect more than 8 million people, or 3.9% of adults.

Gout presents as an acute mono- to poly-articular joint inflammation. Exquisite pain, redness, and swelling occur along with the potential for serum leukocytosis, low-grade fever, and elevated blood inflammatory markers.3 Gout has a predilection for the big toe, called podagra (up to 50% of first-time attacks); although ankles, knees, elbows, wrists, and hands also may be affected. An early gout attack mimics how the innate immune system treats infection, with the body going into overdrive to fight off this “foreign” invader.4

That foreign material in gout is uric acid (UA) crystals, which are deposited into the joint and soft tissue. This occurs when soluble serum urate precipitates out of solution and forms monosodium urate crystals, usually when the bloodstream concentration is >6.8 mg/dL (the point of physiologic saturation).5,6 By lowering and maintaining UA levels <6 mg/dL, the UA crystal burden will eventually resolve, eliminating acute attacks.

Since the symptoms of infection may mimic acute gout, or even co-exist, it is ideal to make a diagnosis by joint fluid analysis, looking for negatively birefringent monosodium urate crystals. In between acute gout flares, while the serum urate remains greater than the point of solubility, the deposition of UA crystals—forming a tophus—continues when the patient is asymptomatic (Figure 1). This process, called the intercritical period, is associated with low-grade joint inflammation and continued joint destruction. Visible and even deforming tophi can develop within 5 years of onset of gout in 30% of untreated patients.7

New Treatment Recommendations

It is not coincidental that the rising prevalence of gout has paralleled the rise in metabolic syndrome, renal impairment, transplant medicine, and cardiovascular disease. Gout is associated with multiple disease states and risk factors (Table 1), and gout patients often require complex medical management. They may have contraindications to common treatments, and require medications that may alter uric acid levels, making overall management challenging.8 Concomitant with a better understanding of pathophysiology and the increased prevalence of gout, a greater pharmacologic armamentarium has come to fruition over the last decade.

Responding to this increasing prevalence as well as to new therapies based on our improved understanding of gout pathophysiology, the American College of Rheumatology (ACR) recently developed non-pharmacologic and pharmacologic treatment recommendations for both acute and chronic gout.

For this directive the ACR brought together two groups of experts: a core expert panel that provided input into case scenario development, and a task force that voted on the scenarios. Using the RAND/UCLA consensus guidelines, this committee of “goutologists,” general rheumatologists, primary care providers, a nephrologist, and a patient representative went to work to develop guidelines that improve the quality and care of gout patients.9,10

After an approximately 2-year endeavor, the ACR task force (TF) published guidelines and recommendations in the October 2012 issue of Arthritis Care & Research. Four aspects of gout management were highlighted between two publications (Part 1 and Part 2). The first of these addressed urate-lowering therapy (ULT) options and their indications in managing gout and tophaceous gouty arthropathy. The second manuscript outlined recommendations regarding prophylaxis and treatment of acute gouty attacks. The TF did not focus on diagnosis and imaging but rather presumed the diagnosis of gout in all scenarios was correctly made. Importantly, the level of opinion designated referred to the efficacy, safety, and quality of treatments, and made no comparisons for cost or cost effectiveness.9,10 This review will highlight some of those TF recommendations.

Part 1: Recommendations for Treating the Hyperuricemia Of Gouty Arthritis

Like all medical interventions, ULTs have unique mechanisms of action, side-effect profiles, and patient risk profiles that must be considered and discussed with the patient to arrive at the best therapeutic option. The new recommendations outline those who definitely need intervention and medical management of their gout and symptoms while prioritizing the prevention of adverse effects. As not all gout patients are alike, the TF distinguished those who have only one attack (or no more than one every 12 months) and those with gout causing greater disability. Indications for ULT include patients with any gouty tophus or tophi; patients who experience at least one attack along with continued renal impairment (chronic kidney disease II or higher); or if a patient has two or more attacks in a 12-month period. Additionally, uric acid urolithiasis at any time was also a consensus indication for treatment with ULT.

Part 1 of the guidelines emphasizes the necessity of lowering serum urate to reduce a gout patient’s crystal burden even in the absence of clinically evident tophi; and regarded reducing and maintaining serum urate concentrations below a specific target, or “treating to target,” as paramount. The recommended target, based upon the physiological saturation of serum urate, is below 6 mg/dL, and less than 5 mg/dL in some cases when the crystal burden and associated morbidity is high.

Recommendations for Non-pharmacological and Pharmacological ULT

Once gout has been established, regardless of the severity, the TF agreed that the first step in lowering a patient’s serum urate levels was through prevention; including education, dietary changes, lifestyle modification, and control of co-morbid, predisposing conditions (Figure 2). For patients with a first attack, this represents an opportunity to lower serum urate levels with lifestyle changes such as weight loss, therefore potentially preventing further crystal deposition. Although there are no randomized controlled trials evaluating the efficacy of lifestyle changes, epidemiologically, studies have shown lower serum urate levels can be achieved with weight loss in the obese, eating a healthy diet, exercise, staying well hydrated, reduction in alcohol consumption, and smoking cessation.9,11,12 Providers encouraging such lifestyle changes will benefit their patients’ overall health and address co-morbidities in addition to gout.

Currently, there are five FDA-approved medications in the United States to lower UA levels (Table 2: Note does not include Zurampic). Allopurinol and febuxostat (Uloric) both prevent the body from making urate by inhibiting xanthine oxidase, while probenecid (Probalan) and pegloticase (Krystexxa) help the body eliminate urate via the kidneys and metabolizing urate, respectively. Most recently, the FDA approved lesinurad (Zurampic) for the treatment of gout . Allopurinol, the older of the xanthine oxidase inhibitors, or febuxostat are both recommended as first-line treatment, while probenecid is recommended as an alternative if at least one of the agents are not tolerated or is contraindicated (Figure 2).9 The maximum approved dose of allopurinol is 800 mg daily (given in divided doses) and febuxostat is 80 mg daily. Probenecid is not recommended for patients with a creatinine clearance less than 50 mL/min and in those with a history of nephrolithiasis. Pegloticase, typically administered by rheumatologists, is an intravenous medication reserved for patients who have failed to be controlled by, or who have contraindications to, allopurinol, febuxostat, or probenecid. A PEGylated mammalian recombinant uricase, pegloticase is reserved for individuals with a high burden of crystal disease (tophi) and arthropathy and who have failed less aggressive therapy.13

An additional option for patients who fail monotherapy with maximum dosages of xanthine oxidase inhibitors is to combine the agent with probenecid. All treatments are effective in lowering uric acid levels in most patients, but as with any medications used to treat acute gout, individual side-effect profiles and tolerance may vary.

ULT Adverse Effects

One of the most worrisome adverse effects of ULT is allopurinol hypersensitivity syndrome (AHS). Although rare, AHS presents with a rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatocellular injury, and has a mortality rate up to 27%.14 It has been customary for clinicians to adjust or limit the maximum dose of allopurinol for fear of AHS. Dose reduction has been based on the reported relationship between renal function and “high-dose” allopurinol (>300 mg/d) in these patients and development of AHS.15,16 Hesitancy to increase allopurinol to greater than 300 mg has led to the failure of achieving serum urate levels <6 mg/dL in approximately 75% of those patients treated.17

When dosing in patients with renal impairment, the ACR guidelines support recent evidence that it is not the total dose of allopurinol that increases toxicity potential, but the larger initial dosing.18 The TF suggests allopurinol be started at 100 mg in all individuals and titrated up every 2 to 5 weeks by approximately 50 mg per week. Particularly in patients with Stage IV renal impairment, allopurinol needs to be started at 50 mg, with even slower upward titration until a sustained uric acid reduction has been achieved.9 The guidelines do not comment on whether febuxostat should be used more frequently in those with moderate to severe renal impairment since no renal adjustment is necessary in these patients. Choosing which medication is most appropriate should be made after a thoughtful discussion between the provider and the patient and may depend on a variety of factors including the patient, the patient’s insurance, and how comfortable the provider is with using allopurinol.

Epidemiological studies in the last 10 years have found that human leukocyte antigen (HLA-B)*5801 carriers have a much higher likelihood for developing allopurinol hypersensitivity. The prevalence of this HLA-B*5801 haplotype, while low in Caucasians (<1%), occurs more frequently in those of Asian descent, with highest incidence among Han Chinese, Koreans, and Thai individuals.13,19,20 The TF recommended screening these populations with a rapid polymerase chain reaction test before using xanthine oxidase inhibitors, and to consider screening individuals coming from other parts of East Asia.

Part 2: Recommendations for Therapy and Pharmacologic Prophylaxis of Acute Gouty Arthropathy

The second part of the recommendations focused on acute gout flare prophylaxis and the treatment of acute gout flares. The TF acknowledged that in clinical practice, preventing flares while lowering serum urate is an ongoing problem. Since ULT can precipitate a flare, patients often incorrectly assume that ULT is making their gout burden worse. For patient compliance with ULT, it is necessary to educate them regarding potential of flares and other adverse effects prior to starting treatment. Therefore, it is not a matter of whether or not to start prophylaxis, but rather, on a case-by-case basis, the ACR task force recommended both low-dose colchicine and non-steroidal anti-inflammatory drugs (NSAIDs) as first-line agents (Table 3). Starting 1 to 2 weeks prior to the initiation of ULT, the first option is to start colchicine dosed at 0.6 mg daily or twice daily, and if not tolerated or contraindicated, low-dose NSAIDs have utility. Either is appropriate and no data have demonstrated superiority between one NSAID over another, assuming adequate and equipotent dosing.

If both medications are not tolerated or are otherwise contraindicated, low-dose prednisone (<10 mg/d) may be beneficial. In actual practice, it may take both low-dose NSAIDs and colchicine to prevent flares in some patients, or prednisone as an alternate to one of the above. Additionally, the TF recommended prophylaxis therapy to be continued for 6 months total, or 3 months after a last attack—whichever is longer.

Treatment of Acute Gout

The ACR guidelines and numerous studies are clear that treating symptoms early, preferably within 24 hours of pain onset, leads to faster resolution and may even abate an acute attack. Importantly, stopping chronic ULT during flares is never warranted unless an adverse event to the medication is expected.

NSAIDs

NSAIDs such as indomethacin have traditionally been used to treat acute gouty attacks. The TF recommends full dosing of NSAIDs at the FDA- (or European Medical Agency-) approved anti-inflammatory doses for the treatment of acute gout. The FDA has approved indomethacin, naproxen, and sulindac for the treatment of acute gout, but other NSAIDs may be as effective. The TF acknowledged the use of cyclooxygenase-2 inhibitors in select patients with gastrointestinal contraindications or intolerance to traditional NSAIDs.

A randomized controlled trial comparing celecoxib (Celebrex) versus indomethacin found that a high-dose celecoxib regimen (800 mg/d, followed by 400 mg on day 1, then 400 mg twice daily for 1 week) was effective in acute gout.21 The ACR recommended this celecoxib regimen as an option for acute gout in selected patients with contraindications or intolerance to traditional NSAIDs. It is necessary to keep in mind that the risk/benefit ratio of celecoxib in acute gout has not been fully established.

Colchicine

After 2,000 years of use, colchicine is now a branded product, Colcrys, and is no longer available in generic form in the United States. While the approval of Colcrys (and abrogation of the generic form) has been highly controversial, the clinical trials have provided evidence of what most rheumatologists have known for a long time. The clinical studies (involving patients with normal renal function only) found that giving 1.2 mg, followed by 0.6 mg given 1 hour later, was shown to be as efficacious as traditional hourly dosing, but safer, with a significantly lower rate of gastrointestinal intolerance.22 The hepatorenal clearance of colchicine and potential drug interactions with cytochrome P450 3A4 inhibitors (ex, protease inhibitors, statins, clarithromycin) should be respected; and usually 0.6 mg daily during flare and sometimes as low as 0.3 mg two to three times weekly in dialysis patients is appropriate dosing. However, the TF did not render recommendations for this complicated population and referral to a rheumatologist would be appropriate.

Corticosteroids

In clinical practice, oral and intra-articular corticosteroids are often used to treat acute gout attacks. When 1 or 2 joints are involved, the clinician might consider intra-articular injection. If intra-articular injection is impractical (not in the scope of the clinician’s usual practice, patient preference, or multiple joints are involved) an intra-muscular corticosteroid formulation followed by oral corticosteroids may be useful. Although dosing regimens vary from provider to provider, 0.5 mg/kg for 5 to 10 days has been shown in multiple studies to be effective. It is important to recognize that when a taper is too short or stopped abruptly, a rebound flare can occur.

ACTH

The TF recognized another historical treatment option in acute gout, the use of adrenocorticotropic hormone (ACTH) at a dose of 25-40 IU subcutaneously. In addition to stimulating the adrenal cortex to produce corticosteroids, ACTH also has anti-inflammatory properties by activating melanocortin receptor-3. Unfortunately, access to ACTH gel in the United States is currently limited and its cost far exceeds that of off-label therapies in development for acute gout such as the interleukin (IL)-1 inhibitors.

Investigational Treatments

The ACR guidelines do address investigational therapies that inhibit IL-1, which plays an important role in the inflammatory process of acute gouty arthritis. Clinical trials have shown that medications such as anakinra (Kineret, FDA approved for active rheumatoid arthritis) and canakinumab (Ilaris, FDA approved for juvenile idiopathic arthritis) have been effective in reducing the inflammation, pain, and swelling of acute gouty attacks.23,24 Although IL-1 inhibitors are not currently approved for treatment, there is an emerging body of literature supporting their use and represent a mechanistically elegant way of dealing with acute attacks. The TF did not address the future role of ULT currently in development such as ulodesine, lesinurad, and tranilast. These act as a purine nucleoside phosphorylase inhibitor and kidney urate transporter inhibitor, respectively. [Editor's Note: Lesinurad (Zurampic) was FDA approved for the treatment of gout in December 2015.]

Conclusion

Gout is potentially a disease with a “cure.” By maintaining a patient’s serum urate <6 mg/dL, and ideally <5 mg/dL, a patient’s uric acid crystal burden will eventually resolve, along with acute attacks. The new recommendations recognize the importance of a multidisciplinary approach to “hitting” and maintaining the serum urate “target” of <6 mg/dL. Educating our gout patients regarding lifestyle modifications, therapies, and the pathogenesis of this disease, while working as a medical community to manage comorbidities, are all steps necessary in eliminating current and future gout attacks.

Following this directive, the ultimate goal of the ACR guidelines is to improve safety issues around prescribing gout therapies, improve patient adherence, quality of care, and outcomes of all gout patients, regardless of severity. The antiquity of gout may have contributed to a certain complacency surrounding the perception and management of this disease, but with better mechanistic understanding, more diverse therapies, and guidelines to lead the way, providers are now positioned to better educate and definitively help those with this painful and debilitating disease.

Last updated on: December 23, 2015

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