Treating hyperuricemia of gout: safety and efficacy of febuxostat and allopurinol in older versus younger subjects

Despite an increasing incidence of gout in older age patients with multiple metabolic and cardiovascular comorbidities, there are limited data addressing whether currently available urate-lowering therapy is comparably effective and safe in older (≥65 years of age) versus younger (<65 years of age) patients. In this secondary analysis of data from the CONFIRMS trial, we found that among 374 older subjects, urate-lowering therapy with approved doses of febuxostat or commonly prescribed doses of allopurinol was at least comparable to that in 1894 younger subjects and was well tolerated despite high rates of renal impairment and cardiovascular comorbidities in the older subjects.     

Adherence with urate-lowering therapies for the treatment of gout

Introduction  

Adherence to urate-lowering drugs (ULDs) has not been well evaluated among those with gout. Our aim was to assess the level and determinants of non-adherence with ULDs prescribed for gout.     

A concise history of gout and hyperuricemia and their treatment

First identified by the Egyptians in 2640 BC, podagra (acute gout occurring in the first metatarsophalangeal joint) was later recognized by Hippocrates in the fifth century BC, who referred to it as 'the unwalkable disease'. The term is derived from the Latin word gutta (or 'drop'), and referred to the prevailing medieval belief that an excess of one of the four 'humors'--which in equilibrium were thought to maintain health--would, under certain circumstances, 'drop' or flow into a joint, causing pain and inflammation. Throughout history, gout has been associated with rich foods and excessive alcohol consumption. Because it is clearly associated with a lifestyle that, at least in the past, could only be afforded by the affluent, gout has been referred to as the 'disease of kings'. Although there is evidence that colchicine, an alkaloid derived from the autumn crocus (Colchicum autumnale), was used as a powerful purgative in ancient Greece more than 2000 years ago, its first use as a selective and specific treatment for gout is attributed to the Byzantine Christian physician Alexander of Tralles in the sixth century AD. Uricosuric agents were first used at the end of the 19th century. In the modern era, nonsteroidal anti-inflammatory drugs are usually the drugs of choice for treating acute gout. Perhaps the most important historical advance in the treatment of hyperuricemia was the development of xanthine oxidase inhibitors, which are effective in reducing plasma and urinary urate levels and have been shown to reverse the development of tophaceous deposits.     

Gout. Novel therapies for treatment of gout and hyperuricemia

In the past few decades, gout has increased not only in prevalence, but also in clinical complexity, the latter accentuated in part by a dearth of novel advances in treatments for hyperuricemia and gouty arthritis. Fortunately, recent research reviewed here, much of it founded on elegant translational studies of the past decade, highlights how gout can be better managed with cost-effective, well-established therapies. In addition, the advent of both new urate-lowering and anti-inflammatory drugs, also reviewed here, promises for improved management of refractory gout, including in subjects with co-morbidities such as chronic kidney disease. Effectively delivering improved management of hyperuricemia and gout will require a frame shift in practice patterns, including increased recognition of the implications of refractory disease and frequent noncompliance of patients with gout, and understanding the evidence basis for therapeutic targets in serum urate-lowering and gouty inflammation.     

Ultrasonography in the diagnosis of asymptomatic hyperuricemia and gout

ABSTRACT

Sonography has detected urate deposits in 34%–42% of the patients with asymptomatic hyperuricemia. This may prompt reclassification of asymptomatic hyperuricemia into “asymptomatic gout” and consideration of urate lowering therapy (ULT) to resolve urate deposits. In patients with gout and no visible tophi, sonography has detected urate deposits in half of the patients. This may allow diagnosing “tophaceous gout” and influencing the serum urate target level, prophylaxis to avoid acute gout flares during ULT, and clinical follow-up. Current accessibility to sonography may better classify patients with hyperuricemia and gout and contribute to delineate therapeutic objectives and clinical guidance.     

Characteristic dysbiosis in gout and the impact of a uric acid-lowering treatment,febuxostat on the gut microbiota

Gut dysbiosis is suggested to play a critical role in the pathogenesis of gout. The aim of our study was to identify the characteristic dysbiosis of the gut microbiota in gout patients and the impact of a commonly used uric acid-lowering treatment, febuxostat on gut microbiota in gout. 16S ribosomal RNA sequencing and metagenomic shotgun sequencing was performed on fecal DNA isolated from 38 untreated gout patients, 38 gout patients treated with febuxostat, and 26 healthy controls. A restriction of gut microbiota biodiversity was detected in the untreated gout patients, and the alteration was partly restored by febuxostat. Biochemical metabolic indexes involved in liver and kidney metabolism were significantly associated with the gut microbiota composition in gout patients. Functional analysis revealed that the gut microbiome of gout patients had an enriched function on carbohydrate metabolism but a lower potential for purine metabolism, which was comparatively enhanced in the febuxostat treated gout patients. A classification microbial model obtained a high mean area under the curve up to 0.973. Therefore, gut dysbiosis characterizings gout could potentially serve as a noninvasive diagnostic tool for gout and may be a promising target of future preventive interventions.     

Japanese guideline for the management of hyperuricemia and gout: second edition

Gout is a urate deposition disease caused by persistent hyperuricemia. Because gout patients present with a variety of clinical symptoms, it is necessary to have a guideline for the standard management and care of gout and hyperuricemia. The Japanese Society of Gout and Nucleic Acid Metabolism, a scientific society committed to study nucleic acid metabolism and related diseases, established the first edition of the "Guideline for the Management of Hyperuricemia and Gout" in 2002, and published the revised version in January 2010. This second edition is not only evidence based on a search of systemic literature, but also includes consensus levels by a Delphi exercise to determine the strength of the recommendations. A draft version of this guideline was reviewed by internal and external reviewers as well as a patient. In this guideline, key messages from each chapter are listed as statements together with the evidence level, consensus level, and strength of the recommendation. In this proceeding, several selected chapters on the clinical management of gout and hyperuricemia are described. We hope this guideline is appropriately used for the standard management and care of patients with hyperuricemia and gout in daily practice.     

Determinants of the clinical outcomes of gout during the first year of urate-lowering therapy

Clinical benefit early in urate-lowering treatment of gout is difficult to document. We examined data from 1,832 gouty subjects treated with either urate-lowering agents or placebo to identify determinants of gout flare incidence and tophus size during year 1 of treatment. Reductions from pretreatment serum urate levels influenced flare frequency and tophus size, but the effect of urate level on flare incidence was biphasic. Lower urate levels were associated with higher flare incidence early in treatment but lower incidence by one year. The complex relationship between urate-lowering and clinical outcome early in treatment has implications for both clinical and investigative approaches to urate-lowering management.     

高尿酸血症的治疗及微生态方面治疗的相关进展

近年,高尿酸血症(Hyperuricemin)发病率快速增加,发病年龄年轻化趋势愈加明显,临床表现更为严重,还有部分患者因高尿酸血症症状严重,并用药物多,以致不能耐受现有治疗,病情得不到有效控制,最终发展成为难治性痛风。因此,     

Pharmacokinetics and pharmacodynamics of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase/xanthine dehydrogenase (NPSIXO) in patients with gout and/or hyperuricemia

The diurnal change of sUA and the effect of febuxostat on this change were investigated in 10 patients with gout and/or hyperuricemia. The diurnal sUA change after the last dose during the 4-week treatment phase (20 mg, QD) was almost the same as the pre-treatment value. Considering the dose, the AUC(obs) and Cmax of unchanged drug in patients with gout and/or hyperuricemia were estimated to be similar to those of healthy male adults. The results show that a 6-week treatment with febuxostat is safe and well-tolerated in the target patient population for this drug.     

The relationship of apolipoprotein B and very low density lipoprotein triglyceride with hyperuricemia and gout

Introduction

Gout results from an innate immune response to monosodium urate (MSU) crystals deposited in joints. Increased very low-density lipoprotein (VLDL) has been associated with gout. The apolipoprotein B (apo B), which is present on VLDL, regulates neutrophil response to MSU crystals and has been positively associated with gout. Furthermore, the gene (A1CF) encoding the complementation factor for the APOB mRNA-editing enzyme is associated with urate levels. However, the relationship of apo B and VLDL with gout and hyperuricaemia (HU) is still unclear. Therefore, we tested the association of VLDL and apo B with HU and with gout compared to HU.

Methods

New Zealand European (n = 90) and Māori and Pacific Island (Polynesian) (n = 90) male gout case and control sample sets were divided into normouricaemia (NU), asymptomatic HU and gout groups. Size exclusion chromatography and enzyme-linked immunosorbant assay was used to measure VLDL and apo B. Multivariate logistic regression was used to assess the risk of gout and HU per unit change in VLDL and apo B.

Results

Increased levels of VLDL triglycerides (Tg) were observed in the gout sample set compared to NU and HU in Europeans (P = 1.8 × 10^-6 and 1 × 10^-3, respectively), but only compared to NU in Polynesians (P = 0.023). This increase was driven by increased number of VLDL particles in the European participants and by the Tg-enrichment of existing VLDL particles in the Polynesian participants. Each mmol/L increase in VLDL Tg was significantly associated with gout in the presence of HU in Europeans, with a similar trend in Polynesians (OR = 7.61, P = 0.011 and 2.84, P = 0.069, respectively). Each μmol/L increase in total apo B trended towards decreased risk of HU (OR = 0.47; P = 0.062) and, conversely, with increased risk of gout compared to HU (OR = 5.60; P = 0.004).

Conclusions

Increased VLDL Tg is associated with the risk of gout compared to HU. A genetic approach should be taken to investigate the possibility for causality of VLDL in gout. Apolipoprotein B may have pleiotropic effects in determining HU and gout.     

特比萘芬治疗顽固性手、足癣的临床疗效及安全性评价

目的评价特比萘芬治疗顽固性手、足癣的临床疗效及安全性。方法将120例患者随机分为实验组和对照组,实验组口服特比萘芬250mg,1次/d,联合外用特比萘芬乳膏,2次/d,连续3周;对照组患者仅外用特比萘芬乳膏2次/d,连续3周。停药2周后评价最终疗效和不良反应,停药4周后观察复发率。结果停药2周后,实验组患者的临床有效率为95%,真菌学清除率为95%,不良反应发生率为5%（主要为胃肠道反应）;对照组患者的临床有效率为40%,真菌学清除率为75%。停药4周后,实验组患者未见复发,对照组患者复发率为20%。结论口服特比萘芬联合外用特比萘芬乳膏治疗顽固性手、足癣是安全、有效的。     

Choosing wisely: practical considerations on treatment efficacy and safety of asthma in the elderly

The prevalence of asthma in the most advanced ages is similar to that of younger ages. However, the concept that older individuals may suffer from allergic asthma has been largely denied in the past, and a common belief attributes to asthma the definition of “rare” disease. Indeed, asthma in the elderly is often underdiagnosed or diagnosed as COPD, thus leading to undertreatment of improper treatment. This is also due to the heterogeneity of clinical and functional presentations of geriatric asthma, including the partial loss of reversibility and the lower occurrence of the allergic component in this age range. The older asthmatic patients are also characterized the coexistence of comorbid conditions that, in conjunction with age-associated structural and functional changes of the lung, may contribute to complicate the management of asthma. The current review addresses the main issues related to the management of allergic asthma in the geriatric age. In particular, the paper aims at revising current pharmacological and non pharmacological treatments for allergic asthmatics of advanced ages, primarily focusing on their safety and efficacy, although most behaviors are an arbitrary extrapolation of what has been tested in young ages. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. Experimental studies and real life observations specifically testing the efficacy and safety of therapeutic approaches in allergic asthma in the elderly are urgently needed.     

The inflammatory process of gout and its treatment

Gouty arthritis is a characteristically intense acute inflammatory reaction that erupts in response to articular deposits of monosodium urate (MSU) crystals. Important recent molecular biologic advances in this field have given us a clear picture of the mechanistic basis of gouty inflammation. The innate immune inflammatory response is critically involved in the pathology of gout. Specifically, MSU crystals promote inflammation directly by stimulating cells via Toll-like receptor signaling and by providing a surface for cleavage of C5 and formation of complement membrane attack complex (C5b-9), culminating in secretion of cytokines, chemokines, and other inflammatory mediators with a dramatic influx of neutrophils into the joint. Despite the detailed mechanistic picture for gouty inflammation, there are no placebo-controlled, randomized clinical studies for any of the therapies commonly used, although comparative studies have demonstrated that many nonsteroidal anti-inflammatory drugs are equivalent to indomethacin with respect to controlling acute gouty attacks. In general, the first line of anti-inflammatory therapy for acute gout is nonsteroidal anti-inflammatory drugs, and the selective cyclo-oxygenase-2 inhibitor celecoxib can be used where appropriate. The second line of treatment is glucocorticosteroids, given systemically (oral, intravenous, or intramuscular) or intra-articularly. Alternatively, synthetic adrenocorticotropic hormone is effective, partly via induction of adrenal glucocorticosteroids and partly via rapid peripheral suppression of leukocyte activation by melatonin receptor 3 signaling. The third line of treatment is oral colchicine, which is highly effective when given early in an acute gouty attack, but it is poorly tolerated because of predictable gastrointestinal side effects.     

益生菌联合美沙拉秦治疗溃疡性结肠炎的疗效和安全性观察

目的探讨益生菌联合美沙拉秦对轻、中度活动期溃疡性结肠炎患者的临床疗效和安全性以及比较患者治疗前后实验室多种指标的改变。方法 42例确诊的轻、中度溃疡性结肠炎患者,采用随机对照的研究方法分为两组。其中治疗组(养乐多1瓶/次+艾迪莎1g/次、1日3次)20例,对照组(艾迪莎1g/次、1日3次)22例,共观察6个月。治疗前、后两组患者临床表现、安全性和实验室多种指标也进行比较。结果治疗组临床治疗总有效率为90.00%,对照组为81.82%,治疗组临床完全缓解率为45.00%,对照组为31.82%,治疗组的完全缓解率和总有效率均显著高于对照组(χ2值分别为57.48、59.42,P0.05),前者总复发率显著低于后者(χ2=58.65,P0.05)。且治疗中未见不良反应和副作用。治疗组治疗6个月后血红蛋白、红细胞压积和白蛋白水平均显著升高(t值分别为2.82、2.21、2.18,P0.05),而对照组在治疗后血红蛋白、白蛋白和红细胞压积均没有发生明显改变(t值分别为0.10、0.11、0.20,P0.05);治疗组的血沉和c-反应蛋白均非常显著下降(t值分别为5.17、4.87,P0.01),而对照组血沉和c-反应蛋白均显著下降(t值分别为3.01、2.43,P0.05);治疗组的血清TNF-α、IL-17和IL-23细胞因子出现非常显著下降(t值分别为3.39、5.98、12.19,P0.01),而对照组的血清TNF-α、IL-17和IL-23细胞因子出现显著下降(t值分别为2.33、2.59、11.37,P0.05);治疗6个月后两组间上述指标差异均有统计学意义(t值分别为2.92、2.23、2.09、2.09、2.34、2.26、2.78、2.71,P0.05),治疗组血红蛋白、红细胞压积和白蛋白水平均显著高于对照组,血沉和c-反应蛋白均显著低于对照组,治疗组的血清TNF-α、IL-17和IL-23细胞因子均显著低于对照组。结论益生菌联合美沙拉秦对轻、中度活动期溃疡性结肠炎患者比单用美沙拉秦更能显著地降低促炎症性细胞因子水平,诱导活动期溃疡性结肠炎的缓解作用和维持缓解作用更强,显示出良好的安全性和有效的治疗效果,表明该益生菌对溃疡性结肠炎具有良好的辅助治疗作用。