Robert T. Keenan

Prevalence of Contraindications and Prescription of Pharmacologic Therapies for Gout

BACKGROUND Patients with gout have comorbidities, but the impact of these comorbidities on treatment has not been studied. METHODS A total of 575 patients with gout were stratified according to certainty of diagnosis according to International Classification of Diseases, 9th Revision, Clinical Modification code alone (cohort I), American College of Radiology criteria (cohort II), and crystal diagnosis (cohort III). Comorbid conditions were defined according to International Classification of Diseases, 9th Revision, Clinical Modification codes, and stratified as either moderate or severe. Drug contraindications were defined as moderate or strong, based on Food and Drug Administration criteria and severity of disease. RESULTS The most common comorbidity was hypertension (prevalence 0.89). The presence of comorbidities resulted in a high frequency of contraindications to approved gout medications. More than 90% of patients had at least 1 contraindication to nonsteroidal anti-inflammatory drugs. Many patients demonstrated multiple contraindications to 1 or more gout medications. Frequently, patients were prescribed medications to which they harbored contraindications. The prevalence of patients prescribed colchicine despite having at least 1 strong contraindication was 30% (cohort I), 37% (cohort II), and 39.6% (cohort III). CONCLUSION Patients with gout typically harbor multiple comorbidities that result in contraindications to many of the medications available to treat gout. Frequently, despite contraindications to gout therapies, patients are frequently prescribed these medications.

Colchicine use is associated with decreased prevalence of myocardial infarction in patients with gout.

Objective. The ability of antiinflammatory strategies to alter cardiovascular risk has not been rigorously examined. Colchicine is an antiinflammatory agent that affects macrophages, neutrophils, and endothelial cells, all of which are implicated in the pathogenesis of cardiovascular disease. We examined whether colchicine use was associated with a reduced risk of myocardial infarction (MI) in patients with gout. Methods. We conducted a retrospective, cross-sectional study of all patients with an International Classification of Diseases, 9th ed, code for gout in the electronic medical record (EMR) of the New York Harbor Healthcare System Veterans Affairs network and ≥ 1 hospital visit between August 2007 and August 2008. Hospital pharmacy data were used to identify patients who had filled at least 1 colchicine prescription versus those who had not. Demographics and CV comorbidities were collected by EMR review. The primary outcome was diagnosis of MI. Secondary outcomes included all-cause mortality and C-reactive protein (CRP) level. Results. In total, 1288 gout patients were identified. Colchicine (n = 576) and no colchicine (n = 712) groups had similar baseline demographics and serum urate levels. Prevalence of MI was 1.2% in the colchicine versus 2.6% in the no-colchicine group (p = 0.03). Colchicine users also had fewer deaths and lower CRP levels, although these did not achieve statistical significance. Colchicine effects persisted when allopurinol users were excluded from the analysis. Conclusion. In this hypothesis-generating study, gout patients who took colchicine had a significantly lower prevalence of MI and exhibited trends toward reduced all-cause mortality and lower CRP level versus those who did not take colchicine.

Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study)

Objectives Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. Methods Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data. Results Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively. Conclusion Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. Trial registration number NCT01493531.

Gout, Hyperuricemia, and the Risk of Cardiovascular Disease: Cause and Effect?

Gout and hyperuricemia have long been suspected to be risk factors for cardiovascular disease. However, studies have frequently failed to distinguish whether these entities have an independent effect on cardiovascular risk or serve as markers for other risk factors. In vitro and animal studies suggest that uric acid is a biologically active compound that can increase inflammatory mediators known to lead to vascular damage. In contrast, uric acid also has potentially protective effects as a strong antioxidant, approaching the potency of vitamin C. Large clinical trials demonstrate a consistent relationship between elevated serum uric acid and a variety of cardiovascular diseases, although the strength of association varies greatly. We review the evidence for and against an independent role for hyperuricemia and/or gout in cardiovascular pathology.

Unusual clinical presentations of gout.

Purpose of reviewThe dogmatic description of gout is described as an inflammatory crystal-induced arthropathy that afflicts peripheral joints. This manuscript describes many recent cases and unusual clinical presentations of gout. Emphasis is placed on the ability of gout to cause diagnostic dilemmas that can impact patient treatment and care. Recent findingsVarious genetic mutations can predispose patients in developing early onset gout. Environmental exposures, medications, and certain patient populations can affect pathophysiology of uric acid, predisposing patients both typical and atypical manifestations of gout. Numerous reports have described gout deposition in unusual parts of the body, which can mimic unrelated disease processes. SummaryAlthough classic gout is still most commonly seen, the disease can manifest as with a wide array of presentations. It is likely that such atypical presentations are a result of a complexity of reasons. When presented with a diagnostic challenge in a patient with gout, the clinician should be aware of unusual manifestations of gout and consider it in the differential.

RS3PE presenting in a unilateral pattern: case report and review of the literature.

OBJECTIVES To review the clinical features and pathophysiologic implications of remitting seronegative symmetrical synovitis with pitting edema (RS(3)PE) presenting in a unilateral manner. METHODS We identified and characterized an index case of RS(3)PE presenting in a unilateral pattern. We subsequently performed a systematic literature search to identify other reports of patients with unilateral RS(3)PE. RESULTS The index case was a 76-year-old male with a prior history of right hemiparesis owing to a cerebrovascular accident 25 years prior, who developed a classic picture of RS(3)PE involving hand (metacarpophalageal and wrist joint) arthritis and dorsal pitting edema, accompanied by an elevated erythrocyte sedimentation rate, but only in the nonhemiparetic hand. The condition responded rapidly to low-dose prednisone. Our literature search identified 5 other cases of unilateral RS(3)PE, including 2 presented only in the Italian or German literature. Of the 5 cases, 2 were in patients with preexisting neurologic disease, in which the neurologically affected side was spared. One additional case initially presented as unilateral disease but rapidly progressed to bilaterality. Two cases presented in a fully unilateral manner despite no reported neurologic abnormalities on the unaffected sides. CONCLUSIONS While RS(3)PE is almost always a symmetric disease of the upper extremities, it may rarely present in a unilateral fashion. The apparent ability of neuropathic changes to protect against the expression of RS(3)PE in an extremity suggests a role for neural and possibly other local factors in the genesis/modulation of the onset or maintenance of RS(3)PE.

Genetics of Hyperuricemia and Gout: Implications for the Present and Future

Gout is the most common inflammatory arthropathy and occurs in the setting of elevated serum urate levels. Gout is also known to be associated with multiple comorbidities including cardiovascular disease and the metabolic syndrome. Recent advances in research have increased our understanding and improved our knowledge of the pathophysiology of gout. Genome-wide association studies have permitted the identification of several new and common genetic factors that contribute to hyperuricemia and gout. Most of these are involved with the renal urate transport system (the uric acid transportasome), generally considered the most influential regulator of serum urate homeostasis. Thus far, SCL22A12, SCL2A9, and GLUT9 have been found to have the greatest variation and most influence on serum urate levels. However, genetics are only a part of the explanation in the development of hyperuricemia and gout. As results have been mixed, the role of known urate influential genes in gout’s associated comorbidities remains unclear. Regardless, GWAS findings have expanded our understanding of the pathophysiology of hyperuricemia and gout, and will likely play a role in the development of future therapies and treatment of this ancient disease.

Safety of urate-lowering therapies: managing the risks to gain the benefits.

Gout is a metabolic disorder of purine metabolism and uric acid elimination. Over time, acute gout can develop into a chronic, disabling arthropathy, often associated with multiple comorbidities. Gout patients have often been undertreated, partly because of the clinicians perceived risks of a therapy outweighing its potential benefits. The approval of new therapies to treat hyperuricemia in gout has led to a new understanding of gout management and medication safety regarding new and old therapies. This review focuses on potential safety issues of currently available urate-lowering therapies and outlines strategies to minimize risks so their benefits can be reached.

New and Pipeline Drugs for Gout

Gout is the most common inflammatory arthropathy in the western world. Affecting millions and accounting for lost wages, increased health care costs, and significant disability, it remains a burden for those afflicted, their families, and the health care system. Despite the availability of a number of effective therapies, gout is often inadequately treated, and its impact on the patients overall health and well-being is underestimated by physicians and patients alike. For many decades, controlling acute flares was the priority in the management of gout. More recently, however, a deeper understanding of gout pathophysiology has resulted in a new appreciation that gout impacts the patient with consequences well beyond the episodes of acute inflammatory arthritis. Reflecting the chronic nature of the disease, gout treatment needs to be chronic as well, and aimed at reducing the underlying cause of gout—hyperuricemia—as well as the symptom of acute attacks. Therapy therefore requires both urate lowering and anti-inflammatory strategies. Unfortunately, the most commonly used urate lowering and anti-inflammatory treatments may be problematic in some gout patients, who often have multiple comorbidities that establish relative contraindications. Novel urate lowering therapies, and new medications to treat and prevent acute gouty flares, can not only improve care of the individual; they can also lead to a better discourse for the edification of those who manage and are managed for this underestimated disease. In this paper, we discuss new and pipeline drugs for acute gout, prophylactic anti-inflammatory therapies as well as urate lowering therapies.

Febuxostat: a new agent for lowering serum urate.

The prevalence of gout has been increasing in epidemic proportions over the last several decades. Hyperuricemia has been shown to be associated with metabolic syndrome and to be an independent risk factor for cardiovascular disease. Associations between hyperuricemia, obesity and aging have provided an impetus in recent years to develop alternative methods of treating hyperuricemia and gout. Febuxostat is a new non-purine xanthine oxidase inhibitor indicated for chronic gout. Febuxostat has been shown to quickly and effectively lower serum urate levels in patients with chronic gout. This manuscript will review febuxostat, its pharmacokinetics and pharmacodynamics, efficacy and adverse events and use in patients with comorbid conditions. The review will also summarize the phase III trials leading up to the drugs approval by both the European Commission in 2008 and the U.S. FDA in 2009. Possible implications the medication may have in the future on gout and hyperuricemia will also be discussed.