Prophylaxis of acute flares when initiating febuxostat for chronic gouty arthritis in a real-world clinical setting

Objective: Flare prophylaxis is recommended during urate-lowering therapy (ULT) despite lack of proven benefit especially when initiating febuxostat. We investigated if colchicine or steroids administration during initiation of febuxostat for chronic gouty arthritis reduces the frequency and/or severity of acute gout flares.

Methods: Patients with confirmed diagnosis of gout starting febuxostat were retrospectively studied. Frequency, severity, and length of flares were analyzed. Assessment of severity based on a visual analog scale (VAS).

Results: Two hundred and seventy-three patients were studied. The mean dose of colchicine and steroids was 0.53?±?0.15?mg PO QD and 7.55?±?1.30?mg prednisone equivalent PO QD; while the duration was 6.13?±?1.14 and 6.20?±?1.36 months, respectively. Subjects treated with colchicine and steroids suffered fewer total flares (0.30, 0.96 vs 2.47, p?=?.000), fewer flares from 0 to 3 months (0.26, 0.71 vs 1.72, p?=?.000), less severe flares assessed by VAS than those without prophylactic therapy (3.65, 3.49 vs 5.54, p?=?.000). Both total flares (p?=?.003) and flares from 0 to 3 months (p?=?.008) of the colchicine group were fewer than the steroids group. There were no significant differences in length of flares among groups (p?=?.815). Both colchicine and steroids were well tolerated.

Conclusion: The use of colchicine or steroids prophylaxis reduces the frequency and severity of acute gout flares during initiation of febuxostat for chronic gouty arthritis. Colchicine is superior to steroids in flares prophylaxis. Prophylactic therapy with colchicine 0.5?mg PO QD or steroids 7.5?mg prednisone equivalent PO QD for 6 months is suggested.     

Quality of life and quality of care for patients with gout

Significant pain, activity limitation, and disability in patients with acute and chronic gouty arthritis lower health-related quality of life. Although many effective therapies are available for gouty arthritis, medication errors are common. One goal of therapy is to reduce the frequency of gout flares by lowering serum uric acid. Further, evidence suggests that the quality of care provided to patients with gout may also impact health-related quality of life. This article reviews evidence concerning quality of care and quality of life for patients with gout.     

Secondary gout associated with chronic myeloproliferative disorders.

The early recognition of acute gouty arthritis, prompt institution of colchicine and/or other antigouty inflammatory drugs, and the use of colchicine prophylactically during the interval periods are necessary measures for the control of secondary gout. The importance of administering allopurinol to prevent the extreme hyperuricemia and excessive hyperuricosuria in blood dyscrasias even before the onset of gouty arthritis should not be overlooked. However, the dosage of allopurinol must be titrated according to the degree of the hyperuricemia and of hyperuricosuria. The control of excessive hyperuricemia in patients receiving chemotherapy is particularly important. The side effects including its impact on the liver and the hemopoietic system should be kept in mind. It must also be remembered that the therapy may change the clinical course of secondary gout, but the course of the underlying blood dyscrasias may not be altered.     

Initiation of Allopurinol at First Medical Contact for Acute Attacks of Gout: A Randomized Clinical Trial

ObjectiveStreamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack.MethodsA total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30.ResultsOn the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P = .37), declining to 0.18 versus 0.27 (P = .54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P = .60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point.ConclusionsAllopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers.     

Gout in the heart transplant recipient: physiologic puzzle and therapeutic challenge

PURPOSE: Hyperuricemia and gouty arthritis have been associated with cyclosporine use in renal transplant recipients. Patients requiring heart or heart-lung transplantation may have additional risk factors for the development of gout, yet it has not previously been described in this population. We share herein our clinical experience with gouty arthritis in six heart transplant recipients. PATIENTS AND METHODS: During a one-year period, six hospitalized male heart transplant patients were seen in consultation for gouty arthritis. Five were subsequently followed for gout as outpatients; the sixth died within six months. Management included trials of nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, allopurinol, and intra-articular steroid injections, as well as attempts to minimize cyclosporine nephrotoxicity. RESULTS: Three patients had gout in remission at time of transplant surgery, and three others developed gout for the first time two to 45 months after transplantation. Following transplant surgery, both pre-existing and new-onset gout appeared to exhibit an accelerated course, with unusually rapid development of chronic polyarticular disease and tophi in four of the five patients followed for more than six months. Peak serum uric acid levels ranged from 11.0 mg/dL to 16.5 mg/dL. NSAIDs produced reversible renal insufficiency in four patients. Gout-related infections occurred in three patients, one of whom died. CONCLUSION: Acute gouty arthritis may occur in the heart transplant recipient despite concomitant use of immunosuppressive drugs. Cyclosporine, with its attendant hypertension and nephrotoxicity, appears to be the major risk factor for hyperuricemia in this setting, leading to the accelerated development of tophi and chronic polyarthritis. Management is complicated by the patients' renal insufficiency and propensity to infection, as well as by interaction with transplant-related medications. Prevention of hyperuricemia by minimizing cyclosporine nephrotoxicity appears to be the best management strategy, with judicious use of allopurinol for those patients in whom this preventive approach fails.     

An update on gout

Gout is the most common cause of inflammatory arthritis in men aged more than 50, affecting approximately 1–2% of adult men in the Western world. The incidence and prevalence of gout is on the rise. Increasing longevity, dietary trends, obesity, metabolic syndrome, hypertension, increased use of low-dose aspirin, major organ transplantation and increased survival from coronary artery disease and end-stage renal disease have been implicated as the possible contributory factors. By far, the commonest cause of hyperuricaemia (that accounts for 90% of patients with gout) is decreased renal clearance. Patients with gout should avoid excess of alcohol (beer and spirits, particularly), red-meat and sea-food. Vegetarian food and dairy products reduce the risk of gouty arthritis. For the treatment of acute gout, options include non-steroidal antirheumatic drugs (NSAIDs), steroids (systemic or intra-articular) and colchicine. High dose of colchicine often results in diarrhoea and should be best avoided. Most patients respond within 18 hours to a dose of 0.5 mg twice daily. Colchicine is contraindicated if creatinine clearance is lower than 30 ml/min. Optimal treatment of chronic gout requires long-term reduction of serum urate to the lower half of the normal uric acid reference range. Prevention of attacks requires modification of lifestyle factors such as weight loss, moderation in the consumption of alcohol and meat and withdrawal of drugs known to cause elevated uric acid levels. Drugs used for chronic gout can be divided in three categories: (a) Uricostatic (xanthine oxidase inhibitor), e.g. allopurinol, oxipurinol, febuxostat, (b) Uricosuric, e.g. benzbromarone, sulfinpyrazone, probenecid, losartan, fenofibrate and (c) Uricolytic, e.g. uricozyme, rasburicase. Febuxostat is a new oral xanthine oxidase inhibitor, which has been shown to be more powerful in lowering uric acid levels compared to allopurinol. The drug is mainly metabolised by the liver and can be used in renal and hepatic insufficiency with no dose adjustment. Benzbromarone is an excellent uricosuric agent. Pegylated uricase is currently under development.     

Medication errors with the use of allopurinol and colchicine: a retrospective study of a national, anonymous Internet-accessible error reporting system

OBJECTIVE: To more closely assess medication errors in gout care, we examined data from a national, Internet-accessible error reporting program over a 5-year reporting period. METHODS: We examined data from the MEDMARX database, covering the period from January 1, 1999 through December 31, 2003. For allopurinol and colchicine, we examined error severity, source, type, contributing factors, and healthcare personnel involved in errors, and we detailed errors resulting in patient harm. Causes of error and the frequency of other error characteristics were compared for gout medications versus other musculoskeletal treatments using the chi-square statistic. RESULTS: Gout medication errors occurred in 39% (n = 273) of facilities participating in the MEDMARX program. Reported errors were predominantly from the inpatient hospital setting and related to the use of allopurinol (n = 524), followed by colchicine (n = 315), probenecid (n = 50), and sulfinpyrazone (n = 2). Compared to errors involving other musculoskeletal treatments, allopurinol and colchicine errors were more often ascribed to problems with physician prescribing (7% for other therapies versus 23-39% for allopurinol and colchicine, p < 0.0001) and less often due to problems with drug administration or nursing error (50% vs 23-27%, p < 0.0001). CONCLUSION: Our results suggest that inappropriate prescribing practices are characteristic of errors occurring with the use of allopurinol and colchicine. Physician prescribing practices are a potential target for quality improvement interventions in gout care.     

Intermittent control of hyperuricemia in the treatment of gout

Fifty patients with gout were randomly allocated to one of 2 groups receiving allopurinol, either continuously or for 2 months every year. Patients with renal functional impairment or tophacous gout were excluded. Duration of treatment ranged from 2-4 years. Acute gouty arthritis occurred to a similar degree in the 2 groups during the first year, but thereafter attacks occurred with diminishing frequency in the continuous group compared with the intermittent group. We concluded that the intermittent administration of allopurinol as given here is less effective in controlling symptoms of gout than continuous therapy.     

Allopurinol treatment and its effect on renal function in gout: a controlled study.

Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys.     

Updates in the management of gout

The majority of patients with gout are cared for by primary care physicians. Although both the physician and patient may easily recognize the acute arthritis of gout, errors in selecting the most appropriate medication and proper dose are common. The clinical stages of gout include asymptomatic hyperuricemia, intermittent gouty arthritis, and chronic tophaceous gout. Treatment of gout is usually considered after the first attack of arthritis, typically podagra. The aims of treatment are to alleviate the pain and inflammation associated with acute attacks, prevent future attacks, and decrease uric acid levels. Confusion frequently arises because certain medications such as colchicine may have dual purposes: to treat an acute attack and to suppress future attacks. The purpose of this management update is to provide practical advice about prescribing the proper medication considering both treatment goals and patient comorbidities.     

The effect of control and self-medication of chronic gout in a developing country. Outcome after 10 years

OBJECTIVE: We describe a 10 year observation of the effect of control of hyperuricemia compared with self-medication alone in patients with chronic gout. METHODS: We studied 299 consecutively self-referred Malayo-Polynesian men with chronic gout, mean age 35 +/- 14.3 SD years. Subjects comprised 228 cases with chronic gout without tophi or urolithiasis (Group 1) and 71 with those complications (Group 2). Attacks of acute gouty arthritis were treated with nonsteroidal antiinflammatory drugs (NSAID) and/or corticosteroids. After acute arthritis had settled, urate-lowering drugs were instituted in both groups combined with low dose colchicine and/or low dose NSAID for at least 0.5-2 years. Urate levels were maintained longterm at a mean of < 5 mg/dl. After 10 years, the dropouts were traced and evaluated for comparison with baseline and those who remained in the study. In Group 2 the urate-lowering drugs were continued. RESULTS: Control of gout and hyperuricemia was achieved in all patients who remained under control: 91.6% of the 299 patients for at least 2 years (short-term), up to 5 years in 87.5% (medium term), and up to 10 years in 79.6% (longterm). In Group 1 (chronic gout without complication) only 36.8% had no attacks during 8 years, after they had tapered urate-lowering drug after the first 2 years of the study. In the 61 dropouts the intermittent symptomatic treatment and/or self-medication without longterm control of hyperuricemia resulted after 1 decade in chronic gout with more complications and associated conditions leading to increased morbidity, disability, and comorbidity, and 3 early mortalities. CONCLUSION: By controlling hyperuricemia, improvement of the prognosis of chronic gout, comorbidity, and early death was achieved compared with self-medication alone. Self-medication in a developing country if continued unchecked may become a public health problem in a population with a high prevalence rate of gout.     

Treatment of gout

In France, colchicine remains the standard treatment for the acute flare of gout. The lowest dose currently used decreases digestive toxicity. Doses of colchicine should be adapted to renal function and age, and possible drug interactions should be considered. Non steroidal anti-inflammatory drugs are an alternative to colchicine, but their use is frequently limited by comorbidity. When these treatments are contraindicated, corticosteroid injections can be performed after excluding septic arthritis. Systemic corticosteroids could be used in severe polyarticular flares. Anti-IL1 should provide a therapeutic alternative for severe cortico dependant gout with tophus. To prevent acute flares and reduce tophus volume, uric acid serum level should be reduced and maintained below 60 mg/L (360 μmol/L). To achieve this objective, it is often necessary to increase the daily dose of allopurinol above 300 mgs, but the need to adapt the dose to renal function is a frequent cause of therapeutic failure. In the absence of renal stone or renal colic and hyperuraturia, uricosuric drugs are the second-line treatment. Probenecid is effective when creatinine clearance is superior to 50 mL/min Benzbromarone, which was withdrawn due to hepatotoxicity, can be obtained on an individualized patient basis in the case of failure of allopurinol and probenecid. Febuxostat, which was recently approved, is a therapeutic alternative. Diuretics should be discontinued if possible. Use of fenofibrate should be discussed in the presence of dyslipidemia and losartan in patient with high blood pressure. Uricolytic drugs (pegloticase), which are currently being investigated, may be useful for the treatment of serious gout with tophus, especially in the presence of renal failure. Education of patient, identification and correction of cardiovascular risk factors should not be forgotten.     

Colchicine

The clinical pharmacology of colchicine has been reviewed and its therapeutic use described. There is still some disagreement about its diagnostic utility; it is clearly most effective in acute gout, but benefit has been reported from its use in sarcoid arthritis and in the inflammation associated with hydroxyapatite deposition.Colchicine toxicity is largely gastrointestinal in customary doses, with a choleriform syndrome of varying severity produced in 80% of patients. Larger doses in addition produce disseminated intravascular coagulation, marrow failure, hepatocellular failure, and late central-nervous-system dysfunction, among other effects. Treatment of colchicine toxicity is supportive.Colchicine metabolic studies demonstrate that the drug leaves the blood rapidly and remains in cells for protracted periods of time. Measurable amounts were still found in leukocytes as late as 10 days after a single administration, and urinary excretion persisted for a similar length of time.A comparison of the relation between function and the structure of colchicine and its analogues in the human and in two species of rodent revealed significant variability in results. It was concluded that urate crystal-induced inflammation in the rodent was not necessarily a suitable model for human acute gout.Studies of colchicine's mechanism of action in acute gout have previously suggested that it depended on interference with microtubular subunit protein aggregation. Evidence is here summarized that colchicine may have other effects on the cell and that the benefit in gout may possibly be unrelated to the microtubular action.     

La maladie goutteuse

Gout is a chronic disease due to the deposition of monosodium urate microcrystals in joints and tissues. Its incidence and prevalence are increasing worldwide in close relation with the epidemic of obesity and metabolic syndrome. Gout is related to chronic hyperuricemia that should be treated to ensure the reduction or even the disappearance of acute attacks (“gout flares”) and to reduce the size and number of tophi. If arthritis of the first metatarsophalangeal joint is the most typical form, other joints may be affected, including the spine. Demonstration of urate microcrystals arthritis allows diagnosis of gout but, in the absence of possibility of performing joint puncture, imaging may be useful for providing complementary diagnostic elements. Appropriate care is essential to reduce the number of flares and the evolution towards gouty arthropathy but also in terms of public health in order to reduce costs related to this pathology.     

P2X7R: A potential key regulator of acute gouty arthritis

Objectives

Acute gouty arthritis is an inflammatory disease resulting from the precipitation of long-term hyperuricemia-induced monosodium urate (MSU) crystals in joints, which stimulates the production of interleukin-1beta (IL-1β) and initiates an inflammatory reaction. However, some patients having MSU crystals in the joints never develop acute gouty arthritis, indicating that other predisposing factors are required for the disease onset. This review described the mechanism of production of IL-1β by MSU crystals and other possible factors during a gout attack.

Methods

The relevant English literature on IL-1β secretion stimulated by MSU crystals and other possible factors during acute gouty arthritis flares was searched and carefully reviewed.

Results

MSU crystals lead to the onset of acute gouty arthritis mainly through the activation of Toll-like receptors (TLRs) and NACHT-LRR-PYD-containing protein 3 (NALP3) inflammasome signaling and downstream IL-1β production. The predisposing factors of acute gouty arthritis, such as strenuous exercise, cold, alcolholism, and overeating have a common characteristic inducing dramatic changes of adenosine triphosphate (ATP) in the body. The ATP changes can activate the purinergic receptor P2X ligand-gated ion channel 7 (P2X7R) signaling system to regulate IL-1β secretion.

Conclusions

We hypothesize that acute gouty arthritis is induced by two synergistic effects; one is the stimulation of MSU crystals and the other is the activation of P2X7R signaling pathways by extracellular ATP changes, which together lead to the production of IL-1β and the initiation of acute gouty arthritis. This hypothesis will provide a new avenue for the prevention and treatment of acute gouty arthritis.     

Outcome evaluations in gout

Methods to measure outcomes in gout still require consensus and validation. This Special Interest Group was assembled to identify domains of interest and is now evaluating a series of outcomes for features of acute gouty arthritis and chronic gout. To accomplish this, working groups have been formed and domains identified. Delphi methodology has been used to address gouty flares as an outcome of greatest interest. Studies addressing other outcome measures were reported at the OMERACT 8 meeting and validation has begun on some outcomes. There has been progress on developing a definition of a flare, and validating reproducibility of some chronic gout outcome measures in some domains, such as tophus size and patient perceptions. Use of these outcomes as well as a health-related quality of life measure are being studied in clinical trials. Pain on a Likert scale appears to be a valid outcome in acute gout. Final validation of these outcomes has not yet been achieved. In summary, the unique problems of evaluating outcomes in gout are finally being addressed. While no measures are available for use yet, an agenda has been developed.     

Colchicine Significantly Reduces Incident Cancer in Gout Male Patients: A 12-Year Cohort Study

Patients with gout are more likely to develop most cancers than subjects without gout. Colchicine has been used for the treatment and prevention of gouty arthritis and has been reported to have an anticancer effect in vitro. However, to date no study has evaluated the relationship between colchicine use and incident cancers in patients with gout. This study enrolled male patients with gout identified in Taiwan''s National Health Insurance Database for the years 1998 to 2011. Each gout patient was matched with 4 male controls by age and by month and year of first diagnosis, and was followed up until 2011. The study excluded those who were diagnosed with diabetes or any type of cancer within the year following enrollment. We calculated hazard ratio (HR), aged-adjusted standardized incidence ratio, and incidence of 1000 person-years analyses to evaluate cancer risk. A total of 24,050 male patients with gout and 76,129 male nongout controls were included. Patients with gout had a higher rate of incident all-cause cancers than controls (6.68% vs 6.43%, P = 0.006). A total of 13,679 patients with gout were defined as having been ever-users of colchicine and 10,371 patients with gout were defined as being never-users of colchicine. Ever-users of colchicine had a significantly lower HR of incident all-cause cancers than never-users of colchicine after adjustment for age (HR = 0.85, 95% CI = 0.77–0.94; P = 0.001). In conclusion, colchicine use was associated with a decreased risk of incident all-cause cancers in male Taiwanese patients with gout.     

The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis

OBJECTIVE: To clarify the mechanism of decreased serum uric acid (SUA) concentrations during acute gouty arthritis. METHODS: Data from patients with acute gouty arthritis during and after an attack were investigated retrospectively. Other investigations, including changes in urinary excretion and biochemical markers, were performed prospectively. RESULTS: SUA was significantly lower in the acute phase (7.5 +/- 1.4 mg/dl) than in the intercritical phase (8.5 +/- 0.9 mg/dl) (p < 0.0001). During the acute gout phase, a normal SUA level was found in 20 of 41 patients (49%). C-reactive protein (CRP) during acute attacks was significantly correlated with plasma interleukin 6 (IL-6) and cortisol (r = 0.645, p < 0.005; r = 0.460, p < 0.05). Percentage change in SUA at onset of attack correlated with CRP and IL-6 (r = 0.762, p < 0.0001; r = 0.630, p < 0.005), as well as with increased urinary excretion of uric acid, estimated by percentage change in fractional excretion of uric acid (FEua) during attack (r = 0.447, p < 0.05). Further, change in FEua was correlated with plasma cortisol levels during the acute attack (r = 0.534, p < 0.05). CONCLUSION: Decrease in SUA during acute gouty arthritis is associated with increased urinary excretion of uric acid; an inflammatory process may play a role in the mechanism.