Increase in thyroid stimulating hormone levels in patients with gout treated with inhibitors of xanthine oxidoreductase.

Increase in thyroid stimulating hormone (TSH) levels over the upper normal limit has been reported in a small percentage of patients treated with febuxostat in clinical trials, but a mechanistic explanation is not yet available. In an observational parallel longitudinal cohort study, we evaluated changes in TSH levels in patients with gout at baseline and during urate-lowering treatment with febuxostat. Patients to be started on allopurinol who had a measurement of TSH in the 6-month period prior to baseline evaluation were used for comparison. TSH levels and change in TSH levels at 12-month follow-up were compared between groups. Patients with abnormal TSH levels or previous thyroid disease or on amiodarone were not included for analysis. Eighty-eight patients treated with febuxostat and 87 with allopurinol were available for comparisons. Patients to be treated with febuxostat had higher urate levels and TSH levels, more severe gout, and poorer renal function, but were similar regarding other characteristics. A similar rise in TSH levels was observed in both groups (0.4 and 0.5 µUI/mL for febuxostat and allopurinol, respectively); at 12-mo, 7/88 (7.9 %) of patients on febuxostat and 4/87 (3.4 %) of patients on allopurinol showed TSH levels over 0.5 µUI/mL. Doses prescribed (corrected for estimated glomerular filtration rate in the case if patients on allopurinol) and baseline TSH levels were determinants of TSH levels at 12-month follow-up. No impact on free T4 (fT4) levels was observed. Febuxostat, but also allopurinol, increased TSH levels in a dose-dependent way, thus suggesting rather a class effect than a drug effect, but with no apparent impact on either clinical or fT4 levels.

Renal clearance of uric acid is linked to insulin resistance and lower excretion of sodium in gout patients.

Inefficient renal excretion of uric acid is the main pathophysiological mechanism for hyperuricemia in gout patients. Polymorphisms of renal tubular transporters linked with sodium and monosaccharide transport have yet to be demonstrated. We intended to evaluate the impact of insulin resistance, evaluated with the homeostasis model assessment (HOMA), through a transversal study of non-diabetic patients with gout, with normal renal function, not treated with any medication but colchicine as prophylaxis. One hundred and thirty-three patients were evaluated. Clearance of uric acid was inversely correlated with insulin resistance and directly correlated with fractional excretion of sodium. In multivariate analysis, hypertension and hyperlipidemia, in addition to insulin resistance and fractional excretion of sodium, were associated with renal clearance of uric acid. HOMA cutoff for efficient versus inefficient renal handling of uric acid was 2.72, close to that observed in studies of reference population. The impact of insulin resistance and renal handling of sodium on renal clearance of uric acid may help to explain why hyperuricemia is more commonly associated with diabetes and hypertension.

Canakinumab for gout: a specific, patient-profiled indication.

The role of interleukin-1 (IL-1) in inflammation induced by crystals, and especially by monosodium urate crystals (MSUCs), has raised much interest in both basic and clinical investigation. Several drugs have been developed, and more are still in development, to block IL-1 driven inflammation, though to date only canakinumab (blocking IL-1ß) has been labelled, yet limited to the European Union, with a restricted indication to treat episodes of acute inflammation (EAIs) in patients with gout in whom other therapeutic choices are unacceptable. Other medications developed for IL-1 blocking, such as anakinra and rilonacept, have been tested in gout patients in clinical trials, but lack label approval and may be further restricted to orphan indication in gout. Notwithstanding, the use of IL-1 blockade to prevent EAIs in gout looks promising, but no drug has yet obtained approval for such an indication.

Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout.

BACKGROUND: While several studies have reported a link between the presence of gout and adverse cardiovascular (CV) events in the general population, none has addressed the question of whether the mortality risk of patients with gout is influenced by disease severity. METHODS: We applied survival analysis methodology to prospectively collected data on clinical and radiographic measures of disease severity and mortality in a specialty clinic based cohort of 706 patients with gout (1992-2008). Standardised mortality ratios (SMR) were calculated to assess the magnitude of excess mortality among patients with gout compared with the underlying general population. RESULTS: Mean follow-up was 47 months. Tophaceous deposition was present in 30.5% of patients; >4 joints were involved in 34.6% of cases. Mean annual flare rate was 3.4. Arterial hypertension (41.2%), hyperlipidaemia (42.2%), diabetes mellitus (20.1%), renal function impairment (26.6%) and a previous CV event (25.3%) were recorded. 64 (9.1%) patients died, death being attributed to vascular causes in 38 (59%) patients. SMR for gout patients was 2.37 (95% CI 1.82 to 3.03), 1.57 (1.18 to 2.05) and 4.50 (2.06 to 8.54) overall, and in men and women, respectively. The presence of tophi and the highest baseline serum urate (SU) levels were independently associated with a higher risk of mortality, in addition to age, loop diuretic use and a history of a previous vascular event. In the multivariable survival regression models, with time varying covariates, the presence of tophi remained a significant mortality risk after adjustment for baseline SU levels (1.98; 1.24 to 3.20). CONCLUSIONS: High baseline SU level and the presence of subcutaneous tophi were both associated with an increased risk of mortality in patients with gout, in most cases attributed to a CV cause. This suggests a plausible pathophysiological link between greater total body urate load and CV disease.

Evaluation and treatment of gout as a chronic disease.

Gout is a disease caused by deposition of monosodium urate crystals in tissues. One of the limitations for successful treatment of gout is to consider it as an intermittent disease rather than a chronic inflammatory disease which, if improperly treated, leads to chronic clinical manifestations. In addition, gout is linked to increased cardiovascular morbidity and mortality.Urate-lowering therapy comprises both nonpharmacologic and pharmacologic interventions, but most patients will need urate-lowering drugs to achieve target therapeutic serum urate levels. Reaching target serum urate levels is associated with improvement in clinical outcomes, including a reduction of acute inflammation episodes, resolution of tophi, and improvement in health-related quality of life perception.A number of urate-lowering drugs are available but a number of patients fail to achieve or maintain therapeutic serum urate levels and go on to develop refractory chronic gout. For such patients, efforts have been made to develop new treatments (e.g., febuxostat or pegloticase).This review intends to increase the awareness of gout as a chronic deposition disease, and show that efforts should be made to properly control serum urate levels in order to achieve complete disappearance of urate crystal deposition.

A two-stage approach to the treatment of hyperuricemia in gout: the "dirty dish" hypothesis.

OBJECTIVE: It is commonly accepted that the target serum urate level in patients receiving urate-lowering therapy for dissolution of urate crystals in hyperuricemia of gout is <6 mg/dl, and that patients with gout should continue urate-lowering therapy for the rest of their lives. This study was undertaken to reevaluate whether this stringent therapeutic target to dissolve crystals must be maintained lifelong to prevent new crystal formation. METHODS: In a prospective cohort of 211 patients with gout, urate-lowering therapy was withdrawn after 5 years if no tophus was present at baseline, or 5 years after resolution of the last tophus. Data on recurrence of gout and on serum urate levels and other potentially associated variables were analyzed. RESULTS: Multivariate regression analysis of time to crystal-proven recurrence of gout showed that serum urate levels during urate-lowering treatment and after its withdrawal were independently related to gout recurrence. None of the patients who had average serum urate levels of <7 mg/dl after urate-lowering therapy withdrawal developed a crystal-proven recurrence of gout. Post hoc analysis showed that weight loss and use of drugs that lower serum urate, such as losartan or fenofibrate, were associated with serum urate levels of <7 mg/dl during followup after urate-lowering therapy withdrawal; use of diuretics was associated with failure to achieve serum urate levels of <7 mg/dl during followup. CONCLUSION: Our data support the hypothesis that after appropriate long-term treatment of hyperuricemia in gout with urate crystal dissolution being the therapeutic target, lifelong treatment can be targeted to achieve serum urate levels just below the threshold for saturation to avoid new crystal formation, similar to cleaning a dirty dish: more is required to get it clean than to keep it clean.

Influencia de la historia natural de la enfermedad en el diagnóstico previo en pacientes con gota / Influence of the natural history of disease on a previous diagnosis in patients with gout

El diagnóstico clínico de la gota puede ser preciso en formas clínicamente típicas. Sin embargo, en las formas clínicas crónicas o atípicas dicha fiabilidad parece no darse en la práctica. Se ha estudiado una cohorte de 348 pacientes con diagnóstico de gota por cristales de urato, remitidos con una valoración diagnóstica definida, de los que se recogieron datos sobre la severidad de la enfermedad en cuanto a la distribución articular y la presencia de tofos. Se analizaron los datos de precisión respecto al diagnóstico de derivación según los parámetros de severidad clínica y los facultativos que remitían a los pacientes. La mayor precisión diagnóstica se observó en las formas monoarticulares precedentes tanto en áreas de urgencias como en medicina familiar, pero no así en los remitidos por otras especialidades. La presencia de formas oligopoliarticulares redujo significativamente la precisión del diagnóstico de referencia en todos los grupos de facultativos. La presencia de tofos no favoreció la precisión diagnóstica. Las formas crónicas y severas de la gota son frecuentemente mal evaluadas desde el punto de vista clínico (AU)

The clinical diagnosis of gout can be quite precise in clinically typical forms. However, in chronic or atypical forms, such precision tends to be diminished in clinical practice. A cohort of 248 patients with a diagnosis of urate crystal arthropathy was studied, sent with a definite clinical evaluation, and data such as severity of the disease, joint distribution and the presence of tophi were gathered. Precision data was analyzed with respect to the referral diagnosis according to the severity parameters and the type of physician sending the patient. The best diagnostic precision was seen in the monoarticular forms that were sent both by the emergency room as well as by family physicians, but not in those sent by other specialists. The presence of oligoarticular forms reduced significantly the diagnostic precision in all of the specialties referring patients. The presence of tophi did not improve diagnostic precision.Chronic and severe forms of gout are frequently wrongly evaluated from the clinical standpoint (AU)

[Influence of the natural history of disease on a previous diagnosis in patients with gout]. / Influencia de la historia natural de la enfermedad en el diagnóstico previo en pacientes con gota.

The clinical diagnosis of gout can be quite precise in clinically typical forms. However, in chronic or atypical forms, such precision tends to be diminished in clinical practice. A cohort of 248 patients with a diagnosis of urate crystal arthropathy was studied, sent with a definite clinical evaluation, and data such as severity of the disease, joint distribution and the presence of tophi were gathered. Precision data was analyzed with respect to the referral diagnosis according to the severity parameters and the type of physician sending the patient. The best diagnostic precision was seen in the monoarticular forms that were sent both by the emergency room as well as by family physicians, but not in those sent by other specialists. The presence of oligoarticular forms reduced significantly the diagnostic precision in all of the specialties referring patients. The presence of tophi did not improve diagnostic precision. Chronic and severe forms of gout are frequently wrongly evaluated from the clinical standpoint.

Resultado del tratamiento hipouricemiante de la gota en ancianos / Results of hypouricemic treatment of gout in the elderly

Algunos autores recomiendan un abordaje conservador del tratamiento de la gota en ancianos. Sin embargo, en la bibliografía no se dispone de series publicadas al respecto.Se han revisado los datos procedentes de una cohorte de pacientes con gota. Se seleccionó a 52 de 242 pacientes (21 por ciento) con edad igual o superior a los 70 años. Evaluamos las reducciones de urato sérico, número de ataques y tofos, el porcentaje de pacientes con urato inferior a 6 mg/dl y la variación de la función renal. Se recogieron datos sobre comorbilidad y efectos adversos previos por tratamiento con antiinflamatorios no esteroides y durante el tratamiento hipouricemiante. Asimismo, se les remitió una encuesta anónima sencilla de cumplimentar.De los 49 pacientes vivos, contestaron al cuestionario 35 (71,4 por ciento), cuyos datos fueron analizados. El 87 por ciento presentaba comorbilidad. La uricemia se redujo de 8,84 ñ 1,41 a 4,70 ñ 0,91 mg/dl (p < 0,001), un 97 por ciento con cifras de urato inferiores a 6 mg/dl, y el número de ataques por paciente y año, de 3,14 ñ 1,35 a 0,17 ñ 0,3 (p < 0,001). Once de 13 (85 por ciento) de los pacientes con tofos no los tenían al final del seguimiento. El aclaramiento de creatinina pasó de 63 ñ 27 a 70 ñ 26 ml (p = 0,037). Diez pacientes habían presentado efectos adversos graves previos al tratamiento, mientras que sólo cuatro presentaron efectos adversos leves durante el tratamiento. El 66 por ciento refería encontrarse mucho mejor, el 31 por ciento mejor y sólo el 3 por ciento igual o peor. El 97 por ciento creía que su problema había sido mejor controlado desde la consulta especializada.Concluimos que la gota en ancianos, más compleja por la presencia de comorbilidad, debe ser abordada por especialistas, y los resultados, desde los puntos de vista objetivo y de los pacientes, fueron muy satisfactorios (AU)