Association of Chronic Pain with Biomarkers of Neurodegeneration, Microglial Activation, and Inflammation in Cerebrospinal Fluid and Impaired Cognitive Function.

OBJECTIVE: Debate surrounds the role of chronic pain as a risk factor for cognitive decline and dementia. This study aimed at examining the association of chronic pain with biomarkers of neurodegeneration using data from the Alzheimer's Disease Neuroimaging Initiative. METHODS: Participants were classified using the ATN (amyloid, tau, neurodegeneration) classification. Chronic pain was defined as persistent or recurrent pain reported at baseline. For each ATN group, analysis of covariance models identified differences in cerebrospinal fluid (CSF) levels of amyloid ß1-42 , phosphorylated tau 181 (ptau181 ), total tau (t-tau), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and cognitive function between chronic pain states. Differences in CSF levels of inflammatory markers between chronic pain states were further analyzed. Linear mixed effect models examined longitudinal changes. RESULTS: The study included 995 individuals, with 605 (60.81%) reporting chronic pain at baseline. At baseline, individuals with suspected non-Alzheimer pathophysiology and chronic pain showed increased CSF levels of t-tau and sTREM2. Chronic pain was associated with increased tumor necrosis factor α levels, irrespective of the ATN group. Longitudinally, an increase in ptau181 CSF levels was observed in chronic pain patients with negative amyloid and neurodegeneration markers. Amyloid-positive and neurodegeneration-negative chronic pain patients showed higher memory function cross-sectionally. No significant longitudinal decline in cognitive function was observed for any ATN group. INTERPRETATION: Our study suggests that chronic pain induces neuronal damage and microglial activation in particular subgroups of patients along the AD spectrum. Further studies are needed to confirm these findings. ANN NEUROL 2023.

[Update Gout]. / Update Gicht.

Update Gout Abstract. Gout, the most frequent arthritis worldwide, is seldomly considered a serious chronic disease. Cardiovascular morbidity and allover mortality are increased in gout patients. Prevalence of gout is very variable in different countries and is estimated to be 2.6% overall. Men are overrepresented (3:1 to 4:1). Environmental factors, such as diet and alcohol intake, are still important, but the genetic influence, e.g., in early-onset gout, gets more and more attention. Despite the broad range of therapeutic options outcomes are poor, and the disease often leads to disabling structural damages, not only in joints. Patients' education, and the involvement of trained general practitioners and nurses will hopefully improve the outcomes of this treatable disease.

The target uric acid level in multimorbid patients with gout is difficult to achieve: data from a longitudinal Swiss single-centre cohort.

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 3- and 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 follow-up 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.

[Gout management: an update]. / Therapie der Gicht.

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.

[Current epidemiology of gout]. / Gicht - Neues zur Epidemiologie.

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.

Neutrophil microvesicles resolve gout by inhibiting C5a-mediated priming of the inflammasome.

OBJECTIVES: Gout 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. METHODS: PMN-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-1ß, TGFß) and complement factors (C5a). Human PMN-Ecto were isolated from exudates of patients undergoing an acute gouty attack and functionally tested in vitro. RESULTS: C5a generated after the injection of MSU primed the inflammasome for IL-1ß 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-1ß 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 TGFß independent of MerTK. TGFß, 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. CONCLUSIONS: PMN-Ecto-mediated control of inflammasome-driven inflammation is a compelling concept of autoregulation initiated early on during PMN activation in gout.