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Circulation Jan 2022Inflammation plays a prominent role in the development of atherosclerosis and other cardiovascular diseases, and anti-inflammatory agents may improve cardiovascular... (Review)
Review
Inflammation plays a prominent role in the development of atherosclerosis and other cardiovascular diseases, and anti-inflammatory agents may improve cardiovascular outcomes. For years, colchicine has been used as a safe and well-tolerated agent in diseases such as gout and familial Mediterranean fever. The widely available therapeutic has several anti-inflammatory effects, however, that have proven effective in a broad spectrum of cardiovascular diseases as well. It is considered standard-of-care therapy for pericarditis, and several clinical trials have evaluated its role in postoperative and postablation atrial fibrillation, postpericardiotomy syndrome, coronary artery disease, percutaneous coronary interventions, and cerebrovascular disease. We aim to summarize colchicine's pharmacodynamics and the mechanism behind its anti-inflammatory effect, outline thus far accumulated evidence on treatment with colchicine in cardiovascular disease, and present ongoing randomized clinical trials. We also emphasize real-world clinical implications that should be considered on the basis of the merits and limitations of completed trials. Altogether, colchicine's simplicity, low cost, and effectiveness may provide an important addition to other standard cardiovascular therapies. Ongoing studies will address complementary questions pertaining to the use of low-dose colchicine for the treatment of cardiovascular disease.
Topics: Cardiovascular Diseases; Colchicine; Gout Suppressants; Humans
PubMed: 34965168
DOI: 10.1161/CIRCULATIONAHA.121.056171 -
Current Opinion in Rheumatology Mar 2022The global burden of gout is rising, as are the prevalence of associated comorbidities, all-cause mortality and societal costs. In this review, we discuss recent... (Review)
Review
PURPOSE OF REVIEW
The global burden of gout is rising, as are the prevalence of associated comorbidities, all-cause mortality and societal costs. In this review, we discuss recent advances in epidemiology and treatment strategies for gout.
RECENT FINDINGS
Genetic factors and obesity are prominent contributors to hyperuricemia and gout, while dietary factors contribute to less variance in serum urate, though can still have some contribution to population attributable risk. A consensus statement by the Gout, Hyperuricemia and Crystal-Associated Disease Network outlined appropriate terminology regarding gout, which will aid in communication about various aspects of the disease. The 2020 American College of Rheumatology gout guideline offers comprehensive evidence-based recommendations for the management of hyperuricemia using urate-lowering therapy, prophylaxis when initiating urate-lowering therapy, treatment of gout flare and adjunctive management strategies. There is improved understanding of risk factors for allopurinol hypersensitivity syndrome and well tolerated use of allopurinol in chronic kidney disease. Trial data have provided new insights regarding cardiovascular risk with febuxostat. Several new drug therapies are being tested for both urate-lowering efficacy and gout flare management.
SUMMARY
Although there have been significant advances in understanding of risk factors and treatment approaches, gout remains suboptimally managed. There is substantial need for improving gout management efforts and gout education among patients and clinicians.
Topics: Allopurinol; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Symptom Flare Up
PubMed: 34907116
DOI: 10.1097/BOR.0000000000000861 -
Rheumatic Diseases Clinics of North... Nov 2022Gout is the most prevalent type of inflammatory arthritis worldwide and environmental factors contribute to hyperuricemia and risk for gout flare. Causes of... (Review)
Review
Gout is the most prevalent type of inflammatory arthritis worldwide and environmental factors contribute to hyperuricemia and risk for gout flare. Causes of hyperuricemia include increased purine consumption from meat, alcohol, and high fructose corn syrup as well as medications such as cyclosporine, low-dose aspirin, or diuretics. Triggers for gout flares include increased purine consumption and medication use such as urate lowering therapy and diuretics. Environmental exposures including lead exposure, particulate matter exposure, temperature fluctuations, and physiologic stress have been found to trigger flares. In the right clinical scenario, these factors should be considered when treating gout patients.
Topics: Humans; Gout; Hyperuricemia; Symptom Flare Up; Purines; Diuretics; Gout Suppressants
PubMed: 36333002
DOI: 10.1016/j.rdc.2022.06.009 -
JPMA. the Journal of the Pakistan... Apr 2021The current review was planned to assess updated knowledge about gout and to highlight the various areas which need to be focussed upon for better healthcare. Relevant... (Review)
Review
The current review was planned to assess updated knowledge about gout and to highlight the various areas which need to be focussed upon for better healthcare. Relevant articles published in English language were reviewed by utilising various databases including Google Scholar, Springer Link, Science Direct and MEDLINE. Data revealed a precipitating number of gout cases from the developed countries, while the developing countries on the other hand were found to be faced with an even higher threat. The risk factors and pathophysiology of gout are immaculate and clearly established. Hence, appropriate measures can be explored and worked on to pinpoint diagnosis, and economical treatment. In order to lessen the elevated global health burden along with revolutionising the patient's quality of life, an immediate action is required in certain aspects, like the adoption of a healthy modified lifestyle, a reduction in exposure to risk factors, robust prophylactic measures, bettering awareness, and an approach to early diagnosis followed by optimal treatment protocols.
Topics: Gout; Gout Suppressants; Humans; Quality of Life; Risk Factors
PubMed: 34125777
DOI: 10.47391/JPMA.313 -
Clinical Therapeutics Oct 2014The aims of this article were to systematically review the literature about the mechanism of action of colchicine in the multimodal pathology of acute inflammation... (Review)
Review
PURPOSE
The aims of this article were to systematically review the literature about the mechanism of action of colchicine in the multimodal pathology of acute inflammation associated with gout and to consider the clinical utility of colchicine in other chronic inflammatory diseases.
METHODS
The English-language literature on PubMed was searched for articles published between 1990 and October 2013, with a cross-reference to citations across all years. Relevant articles pertaining to the mechanism of action of colchicine and the clinical applications of colchicine in gout and other inflammatory conditions were identified and reviewed.
FINDINGS
The molecular pathology of acute inflammation associated with gouty arthritis involves several concurrent pathways triggered by a variety of interactions between monosodium urate crystals and the surface of cells. Colchicine modulates multiple pro- and antiinflammatory pathways associated with gouty arthritis. Colchicine prevents microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis. Many of these cellular processes can be found in other diseases involving chronic inflammation. The multimodal mechanism of action of colchicine suggests potential efficacy of colchicine in other comorbid conditions associated with gout, such as osteoarthritis and cardiovascular disease.
IMPLICATIONS
Colchicine has multiple mechanisms of action that affect inflammatory processes and result in its utility for treating and preventing acute gout flare. Other chronic inflammatory diseases that invoke these molecular pathways may represent new therapeutic applications for colchicine.
Topics: Animals; Anti-Inflammatory Agents; Chronic Disease; Colchicine; Gout; Gout Suppressants; Humans
PubMed: 25151572
DOI: 10.1016/j.clinthera.2014.07.017 -
Seminars in Arthritis and Rheumatism Jun 2020Gout is a disease in which the metabolic condition hyperuricemia leads to the formation of monosodium urate crystals, which provoke acute and chronic inflammatory... (Review)
Review
Gout is a disease in which the metabolic condition hyperuricemia leads to the formation of monosodium urate crystals, which provoke acute and chronic inflammatory responses through activation of the innate immune system. Recent advances in our knowledge of gout pathogenesis have emphasized the role of the kidneys in urate handling, the evolutionary loss of uricase as a necessary precondition for hyperuricemia, and the central role of IL-1ß in the pathogenesis of gouty inflammation. These, and other advances, have shaped our current strategies for managing gout. Here, we review the most current, evidence-based gout management approaches, including treating acute flares, addressing gout through the long-term regulation of serum urate, and prophylaxis against gouty flares during urate lowering.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Male; Symptom Flare Up; Uric Acid
PubMed: 32620199
DOI: 10.1016/j.semarthrit.2020.04.010 -
The New England Journal of Medicine Mar 2018Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease.
METHODS
We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization).
RESULTS
In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis.
CONCLUSIONS
In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).
Topics: Aged; Allopurinol; Cardiovascular Diseases; Cause of Death; Double-Blind Method; Febuxostat; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged
PubMed: 29527974
DOI: 10.1056/NEJMoa1710895 -
Seminars in Arthritis and Rheumatism Dec 2015To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. (Review)
Review
OBJECTIVES
To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions.
METHODS
We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed.
RESULTS
The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis.
CONCLUSION
Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions.
Topics: Arthritis, Gouty; Colchicine; Gout; Gout Suppressants; Humans; Tubulin
PubMed: 26228647
DOI: 10.1016/j.semarthrit.2015.06.013 -
Clinical Cardiology Jul 2021The cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout remains equivocal. Febuxostat had a better safety outcome compared with... (Meta-Analysis)
Meta-Analysis Review
The cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout remains equivocal. Febuxostat had a better safety outcome compared with allopurinol. In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2000 and April 4, 2021, without any language restrictions. We did a systematic review and meta-analysis of included clinical trials to evaluate the cardiovascular safety of febuxostat compared to allopurinol for treatment of chronic gout. Two reviewers independently selected studies, assessed study quality, and extracted data. Risk ratios were calculated with random effects and were reported with corresponding 95% confidence intervals (CI). From 240 potentially relevant citations, 224 papers were excluded; 16 studies were ultimately included in the analysis. Febuxostat had a better safety outcome compared with allopurinol,which was the composite of urgent coronary revascularization (OR: 0.84, 95% CI: 0.77-0.90, p < .0001) and stroke (OR: 0.87, 95% CI: 0.79-0.97, p = .009). However, that difference was not found in nonfatal myocardial infarction (OR: 0.99, 95% CI: 0.80-1.22, p = .91), cardiovascular related mortality (OR: 0.98, 95% CI: 0.69-1.38, p = .89) and all-cause mortality (OR: 0.93, 95% CI: 0.75-1.15, p = .52). No significant differences in cardiovascular related mortality and all-cause mortality were observed across any subgroup. This meta-analysis adds new evidence regarding the cardiovascular safety of febuxostat in patients. Initiation of febuxostat in patients was not associated with an increased risk of death or serious cardiovascular related adverse events compared with allopurinol.
Topics: Allopurinol; Febuxostat; Gout; Gout Suppressants; Humans; Hyperuricemia; Myocardial Infarction
PubMed: 34013998
DOI: 10.1002/clc.23643 -
The New England Journal of Medicine Dec 2005Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout.
METHODS
We randomly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter (480 micromol per liter) to receive either febuxostat (80 mg or 120 mg) or allopurinol (300 mg) once daily for 52 weeks; 760 received the study drug. Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8. The primary end point was a serum urate concentration of less than 6.0 mg per deciliter (360 micromol per liter) at the last three monthly measurements. The secondary end points included reduction in the incidence of gout flares and in tophus area.
RESULTS
The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat, 62 percent of those receiving 120 mg of febuxostat, and 21 percent of those receiving allopurinol (P<0.001 for the comparison of each febuxostat group with the allopurinol group). Although the incidence of gout flares diminished with continued treatment, the overall incidence during weeks 9 through 52 was similar in all groups: 64 percent of patients receiving 80 mg of febuxostat, 70 percent of those receiving 120 mg of febuxostat, and 64 percent of those receiving allopurinol (P=0.99 for 80 mg of febuxostat vs. allopurinol; P=0.23 for 120 mg of febuxostat vs. allopurinol). The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat, as compared with 50 percent in those receiving allopurinol (P=0.08 for 80 mg of febuxostat vs. allopurinol; P=0.16 for 120 mg of febuxostat vs. allopurinol). More patients in the high-dose febuxostat group than in the allopurinol group (P=0.003) or the low-dose febuxostat group discontinued the study. Four of the 507 patients in the two febuxostat groups (0.8 percent) and none of the 253 patients in the allopurinol group died; all deaths were from causes that the investigators (while still blinded to treatment) judged to be unrelated to the study drugs (P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group).
CONCLUSIONS
Febuxostat, at a daily dose of 80 mg or 120 mg, was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate. Similar reductions in gout flares and tophus area occurred in all treatment groups.
Topics: Allopurinol; Double-Blind Method; Enzyme Inhibitors; Febuxostat; Female; Gout; Gout Suppressants; Humans; Hyperuricemia; Male; Middle Aged; Thiazoles; Uric Acid; Xanthine Oxidase
PubMed: 16339094
DOI: 10.1056/NEJMoa050373