Faculty Bibliography

Gout is a disease of hyperuricemia (HU) leading to monosodium urate crystal deposition in the joint, resulting in inflammation and joint damage. Recently, efforts have been made to characterize the intestinal microbiome of patients who suffer from HU and gout, and pre-clinical studies have evaluated the utility of prebiotics and probiotics in alleviating gout. Herein we review recent notable studies addressing these topics. In brief, the "gouty" microbiome is characterized by reduced diversity, an elevated Bacteroides: Firmicutes ratio, and reduced presence of Akkermansia and Bifidobacterium. In anserine models, supplementation with Lactobacillus probiotic strains appears to reduce serum urate (SU) and HU-induced inflammation. Murine models suggest that the chicory-derived prebiotic inulin may reduce SU, and oral supplementation with the anti-inflammatory short-chain fatty acid butyrate may lower SU by enhancing urate excretion and alleviate HU-induced tissue inflammation. Many of these studies are limited by modest numbers of participants and/or incompletely documented experimental controls, and, in the case of animal models, questionable reproducibility in humans. Many studies have been geographically limited. There remains a need for more information regarding the features of the "gouty" microbiome in wider populations, as well as for additional well-controlled probiotic and prebiotic studies in more physiologically relevant animal models prior to clinical trials.

OBJECTIVE:Controversy persists regarding the optimal management of gout in routine primary care. There is a lack of clarity on whether treating to a target serum urate (TTT-SU) versus treating to avoid symptoms (TTASx) is more effective. METHODS:We designed a randomized controlled comparative effectiveness trial aimed at patients in primary care who have known gout, have elevated SU levels, and had at least one flare in the previous 12 months. The trial was designed to be pragmatic and incorporated structured input from primary care physicians, rheumatologists, and patients. The TTASx strategy group will receive weeklong courses of typical therapies for gout flares, such as colchicine, naproxen, or an oral glucocorticoid. The TTT-SU strategy group will receive urate-lowering therapy (primarily allopurinol) with dose titration to maintain an SU level <6 mg/dL, colchicine (or naproxen) prophylaxis for the first six months of urate-lowering therapy, and access to the same flare therapies as the TTASx group. Two clinicians (nurses or physicians) per site will be trained in each strategy to manage the patients in each arm without contamination. Gout flares are the primary outcome and are assessed every two weeks by trained study staff masked to treatment assignment using a validated questionnaire. The secondary outcome is quality of life. Blood pressure control, kidney function, glycemic control, and coronary atherosclerosis are exploratory secondary outcomes. RESULTS:Several sites have started prescreening using automated search strategies in their patients' electronic health records. Of the first 1,381 patients found in primary care practices with a history of gout, 691 patients (50%) passed prescreening checks. These potentially eligible participants have a median age of 67 years, 85% are men, median SU levels are 7.2 mg/dL, and 18% are taking low dosages of allopurinol. These patients have been targeted for recruitment efforts that are underway now. CONCLUSION/CONCLUSIONS:This randomized controlled active comparator strategy trial will answer a key question in the treatment of patients with gout in primary care: the comparative effectiveness of TTT-SU versus TTASx in gout. Secondary and exploratory outcomes will add important information regarding the broader extra-articular and quality-of-life effects of lowering SU levels.

Gout, the most common inflammatory arthritis, affects as many as 5.1% of the adult population. Classically, gout is conceived as four sequential phenotypic states: 1) asymptomatic hyperuricemia 2) acute gout flare 3) inter-critical gout (gout between flares); and 4) tophaceous gout. However, these four states are paralleled by a fifth state, consisting of vascular involvement. The mechanisms and consequences of vascular gout are incompletely elucidated. In vitro and animal models indicate that soluble urate adversely affects vascular endothelium and smooth muscle. The recent discovery that soluble urate can be transported intracellularly to alter cell metabolism and epigenetics (trained innate immunity) suggests additional impacts of urate on leukocytes and endothelium. Once gout has progressed to flares, the vasculature is exposed to inflammatory mediators, both during flares and to a lesser but persistent extent inter-critically, suggesting additional mechanisms of gout's effect. We have reported that patients with gout have diminished endothelial function measured by brachial artery flow-mediated dilation. ACR gout guideline-concordant treatment improves endothelial function but is less effective in patients with cardiometabolic comorbidities. Moreover, treatment of gout patients with the anti-inflammatory colchicine and urate lowering therapy improves endothelial function and reduces the risk of both incident coronary artery disease (CAD), and MACE in patients with established CAD.

OBJECTIVE:Patients with gout are at elevated risk of multiple vascular and metabolic comorbidities. Whether they are also at risk of sarcopenia, which is known to affect patients with other rheumatic diseases, has not been previously assessed. We examined whether patients with gout have decreased lumbar muscle quality and quantity, indicating an association between gout and sarcopenia. METHODS:50 gout subjects and 25 controls, ages 45-80, underwent computed tomography imaging of the lumbosacral spine. We measured muscle quantity (skeletal muscle area [SMA] and index [SMI]) and quality (skeletal muscle radiation attenuation [SMRA] and intermuscular adipose tissue [IMAT] area and index [IMATI]) of the psoas and erector spinae muscles at the L3 level. RESULTS:70 subjects (45 gout and 25 controls) were included in the analysis. Gout subjects had higher BMI, more kidney disease and hypertension, lower exercise frequency, and higher mean serum urate and creatinine vs. controls. Lumbar SMRA was significantly lower in gout subjects vs. controls, indicating reduced muscle quality. Lumbar IMAT area was significantly higher in gout subjects vs. controls, as was lumbar IMATI, indicating increased muscle adiposity. These differences persisted after adjusting for potential confounders. In contrast, there was no significant difference between gout and control groups in lumbar SMA or lumbar SMI, suggesting that muscle quantity may not be routinely affected by the diagnosis of gout. CONCLUSIONS:Gout patients exhibit decreased lumbar muscle quality compared with controls, consistent with an association between gout and sarcopenia.

PURPOSE OF REVIEW/OBJECTIVE:To discuss what is currently known about the association and potential mechanistic interactions of hyperuricemia and gout with peripheral arterial disease (PAD). RECENT FINDINGS/RESULTS:Gout patients are at increased risk for coronary artery disease, but less is known about their risk for PAD. Studies suggest that the presence of gout and hyperuricemia are associated with PAD independent of known established risk factors. Moreover, higher SU was found to be associated with greater odds of having PAD and was independently associated with decreased absolute claudication distance. Urate's role in free radical formation, platelet aggregation, vascular smooth muscle proliferation, and impaired endothelial vasodilation may promote atherosclerotic progression. Studies suggest that patients with hyperuricemia or gout are at higher risk for developing PAD. Evidence is stronger for the relationship between elevated SU and PAD than for gout and PAD, but more data is needed. Whether elevated SU serves as a marker or cause of PAD remains to be investigated.

Accessing a joint with a needle (arthrocentesis) to extract synovial fluid is a skill intrinsic to the rheumatologist's praxis. Joint aspirations are essential for diagnosing or excluding septic joints, are the gold standard for diagnosing acute crystal arthritis, and can provide valuable information about the nature of other forms of arthritis. In appropriate settings, injecting medications into joints can provide rapid, temporary, or even prolonged relief of pain and swelling and can provide a window of relief until other treatment modalities (anti-inflammatories, immunomodulators, and physical therapy) can enforce durable responses. Soft tissue aspirations (e.g., of bursae) and soft tissue injections (of bursae, tendons, trigger points, and areas of nerve compression) can provide similar relief, earning the practitioner the gratitude of the patient. Here, we provide a primary on joint and soft tissue aspiration and injection, including indications for and against procedures, preparing for procedures, and approaches to specific musculoskeletal structures.

INTRODUCTION:Psoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5-7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression. METHODS AND ANALYSIS:The PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints. ETHICS AND DISSEMINATION:Ethics approval for this study was granted by the coordinating centre's (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations. TRIAL REGISTRATION NUMBER:NCT05004727.