Tristan Pascart

Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment

OBJECTIVE To investigate the cutaneous tolerance of febuxostat in gouty patients with skin intolerance to allopurinol. METHODS We identified all gouty patients who had sequentially received allopurinol and febuxostat in the rheumatology departments of 4 university hospitals in France and collected data from hospital files using a predefined protocol. Patients who had not visited the prescribing physician during at least 2 months after febuxostat prescription were excluded. The odds ratio (OR) for skin reaction to febuxostat in patients with a cutaneous reaction to allopurinol versus no reaction was calculated. For estimating the 95% confidence interval (95% CI), we used the usual Wald method and a bootstrap method. RESULTS In total, 113 gouty patients had sequentially received allopurinol and febuxostat; 12 did not visit the prescribing physician after febuxostat prescription and were excluded. Among 101 patients (86 males, mean age 61±13.9 years), 2/22 (9.1%) with a history of cutaneous reactions to allopurinol showed skin reactions to febuxostat. Two of 79 patients (2.5%) without a skin reaction to allopurinol showed skin intolerance to febuxostat. The ORs were not statistically significant with the usual Wald method (3.85 [95% CI 0.51-29.04]) or bootstrap method (3.86 [95% CI 0.80-18.74]). CONCLUSION The risk of skin reaction with febuxostat seems moderately increased in patients with a history of cutaneous adverse events with allopurinol. This moderate increase does not support the cross-reactivity of the two drugs.

GOSPEL 2 – Colchicine for the treatment of gout flares in France – a GOSPEL survey subgroup analysis. Doses used in common practices regardless of renal impairment and age

OBJECTIVES The objective of this sub-study was to assess the use of colchicine for the treatment of gout flares in real life conditions in the GOSPEL cohort following the 2006 EULAR recommendations for gout management. METHODS This national cross-sectional epidemiologic survey included outpatients with gout suffering from acute flare followed by randomly selected primary care physicians (n=398) and private practice rheumatologists (n=109) between October 2008 and September 2009 in France. Data regarding patient characteristics and treatment prescription was collected by each physician. Glomerular filtration rate (eGFR) was estimated using the Cockroft-Gault formula. Patients included in the survey for a gout flare filled in a specific self-questionnaire including colchicine effective intake and pain relief (numeric scale). RESULTS This analysis focused on the 349 patients presenting with gout flare and treated with colchicine. Mean (±SD) prescribed dose of colchicine was 2.8 (±0.7) mg within the first 24hours and the cumulative dose over the first three days of treatment was 6.9 (±1.8) mg. Patients with mild decline in eGFR (eDFG 60-80mL/min) were prescribed an average initial dose of 2.8mg (±0.8) mg (n=58), 2.7 (±0.8) mg in chronic kidney disease (CKD) stage 3 (n=43) and 2.5 (±0.7) mg in CKD stage 4 (n=2). Cumulative doses of colchicine did not take into account either renal impairment or age. CONCLUSIONS This study draws attention to some misuse of colchicine in daily practice and the prescription of excessive doses especially in case of renal impairment. eGFR should be enforced in daily practice.

Intraosseous pneumatocysts: a case based review

Intraosseous pneumatocysts are benign gaseous bone lesions, generally asymptomatic and incidentally discovered on X-ray. These characteristics explain why these lesions are unknown to most practitioners and their low representation in medical literature. The description of an incidentally discovered iliac pneumatocyst gives us the opportunity to provide a review of available medical literature on these frequent, but poorly known lesions.

Region specific Raman spectroscopy analysis of the femoral head reveals that trabecular bone is unlikely to contribute to non-traumatic osteonecrosis

Non-traumatic osteonecrosis (ON) of the femoral head is a common disease affecting a young population as the peak age of diagnosis is in the 40 s. The natural history of non-traumatic ON leads to a collapse of the femoral head requiring prosthetic replacement in a 60% of cases. Although trabecular bone involvement in the collapse is suspected, the underlying modifications induced at a molecular level have not been explored in humans. Here, we examine changes in the molecular composition and structure of bone as evaluated by Raman spectroscopy in human end-stage ON. Comparing samples from femoral heads harvested from 11 patients and 11 cadaveric controls, we show that the mineral and organic chemical composition of trabecular bone in ON is not modified apart from age-related differences. We also show that the molecular composition in the necrotic part of the femoral head is not different from the composition of the remaining ‘healthy’ trabecular bone of the femoral head. These findings support that quality of trabecular bone is not modified during ON despite extensive bone marrow necrosis and osteocyte death observed even in the ‘healthy’ zones on histological examination.

Efficacy and safety of febuxostat in 73 gouty patients with stage 4/5 chronic kidney disease: A retrospective study of 10 centers

OBJECTIVES The allopurinol dose is limited in chronic kidney disease, particularly stage 4/5 chronic kidney disease. Febuxostat has a hepatic metabolism and has been approved without dose adaptation in gouty patients with stage 1-3 chronic kidney disease. We aimed to study the safety and efficacy of febuxostat for stage 4/5 chronic kidney disease. METHODS In this retrospective study, we included patients with (1) a diagnosis of gout, (2) febuxostat treatment, (3) estimated glomerular filtration rate≤30mL/min/1.73m2 (Modification of Diet in Renal Disease formula) at febuxostat initiation and (4) follow-up for at least 3 months after febuxostat initiation. Efficacy, safety and variation in estimated glomerular filtration rate were analyzed. RESULTS We included 73 patients (mean age 70.2±11.8, 61 men, 31 with vascular chronic kidney disease and 18 renal transplantation) with gout (baseline serum uric acid level=9.86±2.85mg/dL, mean gout duration 6.2±7.0 years) from 10 academic centers. Comorbidities included cardiac failure (17.8%), hypertension (98.6%), diabetes mellitus (30.1%), dyslipidemia (64.8%) and history of cardiovascular events (38.4%). At the last visit (mean follow-up 68.5±64.8 weeks), the daily dose of febuxostat was 40mg for 7 patients (10.5%), 80mg for 50 (74.6%) and 120mg for 10 (14.9%). Serum uric acid level was<6mg/dL for 49 patients (67%). Renal function improved for 18 patients, was unchanged for 24 and worsened for 31; 19 patients experienced flares and 1 patient, limb edema. CONCLUSION Febuxostat seemed efficient in gouty patients with stage 4/5 chronic kidney disease. However, safety data were not clear regarding renal function. Larger studies are needed to assess safety.

Current and future therapies for gout

ABSTRACT Introduction: Gout is a common disease responsible for recurrent flares triggered by the deposition of monosodium urate crystals secondary to longstanding hyperuricaemia. The management of gout implies both the treatment of flares and the treatment of hyperuricaemia itself. Recent improvement in the understanding of the disease led to the development of new drugs. Areas covered: This review covers data related to ‘old’ treatments of flares and hyperuricaemia, evidence on the recently approved drugs and emerging therapies in development. Expert opinion: Recent data provide a good grasp of the optimal use of colchicine, corticosteroids and NSAIDs for the treatment of flares. Interleukin-1 blocking therapies have an increasing role in the management of difficult-to-treat gout. Sub-optimal use of allopurinol is common and its potency to reduce serum uric acid (SUA) levels is underestimated. Febuxostat effectively reduces SUA levels. New uricosurics, notably lesinurad and arhalofenate, in combination with xanthine oxidase inhibitors, offer promising perspectives to help a greater number of patients achieve sufficient SUA reduction.

Gout: state of the art after a decade of developments

This review article summarizes the relevant English literature on gout from 2010 through April 2017. It emphasizes that the current epidemiology of gout indicates a rising prevalence worldwide, not only in Western countries but also in Southeast Asia, in close relationship with the obesity and metabolic syndrome epidemics. New pathogenic mechanisms of chronic hyperuricaemia focus on the gut (microbiota, ABCG2 expression) after the kidney. Cardiovascular and renal comorbidities are the key points to consider in terms of management. New imaging tools are available, including US with key features and dual-energy CT rendering it able to reveal deposits of urate crystals. These deposits are now included in new diagnostic and classification criteria. Overall, half of the patients with gout are readily treated with allopurinol, the recommended xanthine oxidase inhibitor (XOI), with prophylaxis for flares with low-dose daily colchicine. The main management issues are related to patient adherence, because gout patients have the lowest rate of medication possession ratio at 1 year, but they also include clinical inertia by physicians, meaning XOI dosage is not titrated according to regular serum uric acid level measurements for targeting serum uric acid levels for uncomplicated (6.0 mg/dl) and complicated gout, or the British Society for Rheumatology recommended target (5.0 mg/dl). Difficult-to-treat gout encompasses polyarticular flares, and mostly patients with comorbidities, renal or heart failure, leading to contraindications or side effects of standard-of-care drugs (colchicine, NSAIDs, oral steroids) for flares; and tophaceous and/or destructive arthropathies, leading to switching between XOIs (febuxostat) or to combining XOI and uricosurics.

Ultrasonography and dual-energy computed tomography provide different quantification of urate burden in gout: results from a cross-sectional study

BackgroundUltrasonography (US) and dual-energy computed tomography (DECT) can assess urate burden in gout. The objective of this study was to compare the quantification of urate deposition provided by US to the one provided by DECT.MethodsPatients with a diagnosis of gout were prospectively recruited to undergo quantification of urate deposition using US and DECT. US examination for tophi and the double contour (DC) sign was performed on the knees and feet and corresponding DECT scans provided volumes of tophi and of overall urate deposition. The primary endpoint was the intra-class correlation coefficient (ICC) of the volume of the index tophus measured by US and DECT and its 95% confidence interval (CI 95%).ResultsOf the 64 patients included, 34 presented with at least one tophus on US. DECT inter-reader agreement for urate deposition was perfect with an ICC of 1 (1–1) and good for the measurement of the index tophus with an ICC of 0.69 (0.47–0.83). The ICC for the measurement of the index tophus between the two techniques was poor with a value of 0.45 (0.1–0.71). The average ratio between the index tophi volume as assessed by DECT and US was 0.65. The number of DC-positive joints did not correlate with DECT volume of overall deposits (Spearman correlation coefficient of 0.23).ConclusionsDECT measurements of tophi give smaller volumes to the same tophi measured with US, and US signs of urate deposition in joints do not correlate with overall DECT volumes of extra-articular deposition.

Bone Samples Extracted from Embalmed Subjects Are Not Appropriate for the Assessment of Bone Quality at the Molecular Level Using Raman Spectroscopy.

Bone samples extracted from embalmed cadavers are commonly used as controls in the study of bone. The effects of embalmment on the molecular composition of bone are unknown. The objective of this study was to determine the effect of embalmment on the molecular composition and structure of bone, as evaluated by Raman spectroscopy. Bone samples of femoral heads from five embalmed donors and five fresh-frozen donors were compared using Raman microspectroscopy with DuoScan technology. Physicochemical parameters simultaneously describing the organic and mineral phases of bone were compared using the Mann-Whitney U test. Partial least squares discriminant analysis (PLS-DA) was used to determine specific Raman spectral features of each group. Study of the mineral phase showed a 15% reduction of the mineral-to-matrix ratio (p < 0.001), an 8% decrease of type B carbonate substitution (p < 0.001), and a 2% increase in crystallinity (p < 0.001) in the embalmed donors group compared to those of the fresh donors group. Regarding the organic phase of bone, the hydroxyproline-to-proline ratio was increased by 18% in the embalmed group (p < 0.001), with no variation in both the relative proteoglycan content (GAG/CH3) (p = 0.08) and collagen maturity (p = 0.57). PLS-DA showed that the embalmed group was characterized mainly by peaks assigned to hydroxyproline, lipids, and collagen. Embalmment induces significant modifications of the molecular composition of bone. Bone samples from embalmed subjects should be avoided as controls for Raman spectroscopy studies. Preservation procedures performed prior to bone sampling should be reported in studies using human cadaver samples.

Gout: from international guidelines to current practice. Results from a physician questionnaire.

Li et al. recently addressed in this journal the issue of the knowledge of gout by patients and physicians in China, showing a rather poor awareness of its management by nonrheumatologists [1]. Similar data was also recently gathered in the USA by Harrold et al. [2]. The overall conclusion was a profound inconsistency between physicians’ habits and international guidelines, thus suggesting very common care deficiencies in gout. However, this survey was prior to the 2012 American College of Rheumatology (ACR) guidelines [3, 4] which may have contributed to such inconsistency. Roddy et al. [5] had previously provided data giving similar results of the lack of concordance between gout management in the UK and at the time, the very recent European League against Rheumatism (EULAR) recommendations [6, 7]. A survey of 977 physicians including 90 % of general practitioners and 10 % of rheumatologists in private practices was performed in France from September 2010 to May 2011. Each physician completed a questionnaire assessing their common practice on the issue of gout. This survey was prior to the 2012 ACR guidelines but came however late after the 2006 EULAR recommendations which thus had largely been spread and recognized as a reference in Europe and therefore in France. Hyperuricemia was considered useful for the diagnosis of gout for 90.2% of practitioners, far above the 47.6% that found MSU crystal identification necessary in common practice, although recommended by three diagnosis propositions of the EULAR. Rapid development of joint inflammation had been judged highly evocative of crystal arthritis by the EULAR, yet, out of eight proposed clinical features of gout, it was ranked sixth by order of importance for its diagnosis. Some consistency was reached in regard to treatment habits. Indeed, SUA target level was 5.98 (±0.75)mg/dl, which was more consistent with the 6 mg/dl recommended both by the ACR and the EULAR. Prophylaxis against acute attacks was prescribed by 94.8 % of the enquired physicians for 63 days (±57 days), thus below the 6 months recommended by the ACR but, however, above the month suggested by EULAR guidelines. Only 33.5 % of practitioners found relevant in the management of gout patients to assess renal function and search for chronic kidney disease. Although the issue of the cardiovascular risk of gout patients has largely been addressed by all international guidelines, this topic remains neglected in common practice. Indeed, during the management of gout, only 14.1 % of the enquired physicians estimated that the metabolic syndrome had to be assessed. Of note, only 7.2 % of primary care providers judged necessary to assess the patients’ alcohol consumption. Dalbeth recently underlined the disconnection between practitioners facing gout patients in their everyday practice and those that would lead guidelines [8]. Even though the data we provide here is limited, there seems to be a progressive improvement of physicians’ consistency with international guidelines in regard to treatment of gout. This could be linked to an eventual time-related spread of these guidelines. Yet, similarly to China and the USA, the knowledge of the management of gout clearly remains to be improved in France, 5 years after the last EULAR recommendations at the time of the study.