ObjectivesGout is a highly inflammatory but self-limiting joint disease induced by the precipitation of monosodium urate (MSU) crystals. While it is well established that inflammasome activation by MSU mediates acute inflammation, little is known about the mechanism controlling its spontaneous resolution. The aim of this study was to analyse the role of neutrophil-derived microvesicles (PMN-Ecto) in the resolution of acute gout.MethodsPMN-Ecto were studied in a murine model of MSU-induced peritonitis using C57BL/6, MerTK−/− and C5aR−/− mice. The peritoneal compartment was assessed for the number of infiltrating neutrophils (PMN), neutrophil microvesicles (PMN-Ecto), cytokines (interleukin-1β, TGFβ) and complement factors (C5a). Human PMN-Ecto were isolated from exudates of patients undergoing an acute gouty attack and functionally tested in vitro.ResultsC5a generated after the injection of MSU primed the inflammasome for IL-1β release. Neutrophils infiltrating the peritoneum in response to C5a released phosphatidylserine (PS)-positive PMN-Ecto early on in the course of inflammation. These PMN-Ecto in turn suppressed C5a priming of the inflammasome and consequently inhibited IL-1β release and neutrophil influx. PMN-Ecto-mediated suppression required surface expression of the PS-receptor MerTK and could be reproduced using PS-expressing liposomes. In addition, ectosomes triggered the release of TGFβ independent of MerTK. TGFβ, however, was not sufficient to control acute MSU-driven inflammation in vivo. Finally, PMN-Ecto from joint aspirates of patients with gouty arthritis had similar anti-inflammatory properties.ConclusionsPMN-Ecto-mediated control of inflammasome-driven inflammation is a compelling concept of autoregulation initiated early on during PMN activation in gout.

Long-standing gout may be a risk factor for CPP deposition disease, and the frequency of CPP co-deposition may be higher than expected.

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Gout is the most common inflammatory arthritis in adults nowadays. Prevalence has risen over the last decades. Patients over 65 years are disproportionally affected. A male/female ratio of 4:1 is diminishing after menopause (still 3:1). The relative risk of developing gout increases in a linear progression with the serum uric acid level. Other risk factors beside hyperuricemia are genetic predisposition, age, male gender, adipositas, lifestyle modification, chronic kidney disease and intake of diuretics. Many gout patients suffer from comorbidities. The metabolic syndrome is associated with gout. Two fifths of patients with gout had also chronic kidney disease. Reasons for the rise in prevalence are longevity, dietary habits and the high prevalence of patients with chronic kidney disease in the general population.

Gout is the most frequent arthritis worldwide. Despite progress in therapeutic options the majority of gout patients are still insufficiently treated. International guidelines (ACR, EULAR, 3e initiative) clearly specify treatment targets: keep the patient flare-free and maintain a low urate serum level (< 360 µmol/l). The treat to target strategy includes therapy of flares, urate lowering treatment (ULT) and prophylaxis of flares. Evolution of gout guidelines over several years shows a broader indication for ULT, mandatory prophylaxis of flares during the initiation of ULT over several months and an earlier start of ULT in patients with flares as soon as symptoms have diminished. Colchicine is the preferred specific flare treatment, Caution has to be taken especially in patients with kidney disease, patients with hepatic dysfunction or in patients with interacting comedication. Low dose oral colchicine is nowadays the standard flare treatment. NSAIDs and prednisone are valuable alternatives. Interleukin-1 blockers offer a quick resolution of flares and may be an option in patients with chronic gout and severe kidney disease. Xanthinoxidase inhibitors (XOI) are the mainstay of ULT, with allopurinol still being the preferred XOI. The recently approved XOI febuxostat is eliminated mostly by the liver and can induce a faster lowering of urate. Uricosuric drugs such as probenecid are recommended in patients with sufficient renal function in whom the treatment goals cannot be reached with XOI. In Switzerland, only the two gout-lowering drugs allopurinol and probenecid are available, which reduces the therapeutic possibilities. Treatment success is often hampered by malcompliance. Recent guidelines stress the importance of patient education to ameliorate compliance. Comorbidities such as metabolic syndrome, cardiovascular and kidney disease are often found in gout patients. Patients with severe kidney disease are the most difficult to treat: the choice of antiinflammatory treatment is narrowed, ULT has to be uptitrated very carefully and patients often suffer from repeated flares. Another factor associated with treatment failure is the low physician’s adherence towards the guidelines. Therapeutic failure can lead to chronic and refractory gout (polyarticular gout, uncontrolled flare activity, chronic synovitis, destructive tophi) which makes the further management very difficult. Most gout patients are treated in primary care settings. Patients with chronic gout or at high risk for development of chronic gout (in particular patients with severe kidney disease or patients transplanted) should be additionally treated by a rheumatologist.

OBJECTIVE: To characterise adherence and treat-to-target (T2T) strategy in gout patients within a Swiss tertiary hospital.METHODS: Consecutive presenting patients with proven gout were prospectively included in this cohort. Symptoms, comorbidities, medication and laboratory values were assessed (during hospitalisation and at planned 3and 12-month follow-up assessments). RESULTS: 116 patients (98 men) with a mean age of 67 (range 23-94 years) were included, 74% of whom had active arthritis. Comorbidities were frequent: hypertension, renal impairment, and obesity were present in 72, 55 and 35% of patients, respectively. Thirty-five percent of patients received urate-lowering treatment at inclusion. Only 62 and 50% attended the 3-and 12-month follow-up. The target serum uric acid level of <360 μmol/l was achieved in 22 and 57% of patients by the 3-and 12-month followup visits, respectively. Patients followed up by rheumatologists reached the target serum uric acid at follow-up more often than those that were not (p = 0.033). Median daily allopurinol dose at 12-month follow-up was 300 mg in those achieving T2T and 100 mg in the others (p = 0.033). Flares occurred during the first 3 months in 52% and during the subsequent 9 months in 47% of patients.CONCLUSION: Only half of patients attended the planned follow-up visits, indicating low awareness for gout. Of those attending follow-up, only approximately 50% had achieved the serum urate target at 12 months. Although new treatments are available, care for gout patients remains insufficient, notably in difficult-to-treat multimorbid patient subsets as described in this cohort.

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Zusammenfassung. Gicht, die weltweit häufigste Arthritis, wird oft nicht als schwere chronische Erkrankung angesehen, obwohl die kardiovaskuläre Morbidität und die Gesamtmortalität von Gichtpatienten gegenüber der Normalbevölkerung erhöht sind. Die Prävalenz von Gicht ist in verschiedenen Ländern sehr unterschiedlich und beträgt im Mittel 2,6%. Männer sind deutlich überrepräsentiert (3:1 bis 4:1). Umweltfaktoren wie Ernährung und Alkoholkonsum sind wichtig, aber genetische Einflüsse, z.B. bei früh einsetzender Gicht, werden zunehmend beschrieben. Trotz der breiten therapeutischen Möglichkeiten sind die Ergebnisse nach wie vor unbefriedigend, und die Krankheit führt zu oft zu behindernden strukturellen Schäden. Die gezielte Information von Patienten sowie eine gute Ausbildung von Ärzten und Pflegefachpersonen können dazu beitragen die Behandlungsziele besser zu erreichen.