Effects of Allopurinol on Inflammatory Markers and Morphostructural Changes Evidenced by Musculoskeletal Ultrasound in Individuals With Asymptomatic Hyperuricemia. A Proof of Concept

Gout is the most prevalent inflammatory rheumatological disease among young men, affecting about 4% of the general population. Caused by the deposit of monosodium urate (MSU) crystals which form because of high urate concentrations in serum. Currently, there is no universal definition for hyperuricemia but The Gout, Hyperuricemia, and Crystal-Associated Disease Network (G-CAN) define hyperuricemia as a blood urate concentration above the saturation threshold which is usually understood to be urate levels over 7 mg/dL. For this study, the term urate will be used as the final circulating product of the enzyme xanthine oxidase in the purine metabolism which favors the precipitation and formation of MSU crystals. Even tough, hyperuricemia is often asymptomatic, the clinical presentation can be that of gouty arthritis, uric acid nephropathy, urolithiasis and/or chronic tophaceous gout.

The relevance of asymptomatic hyperuricemia lays in the relation to other chronic degenerative diseases, including atherosclerotic disease, systemic arterial hypertension, coronary artery disease and chronic kidney disease.

A logistic regression analysis made by Zhu et al, looking specifically at the demographics of gout and asymptomatic hyperuricemia based on the data from The National Health and Nutrition Examination Survey (NHANES) showed a general hyperuricemia prevalence of 13.2%, which corresponds to about 26.6 million individuals. Additionally, it was observed that hyperuricemia increases with age, it being more common in individuals over 65 years, prevalence of 31%, corresponding to approximately 10.7 million American adults. Other epidemiological studies have evidenced the relationship between asymptomatic hyperuricemia y different comorbidities for example atherosclerotic disease, systemic arterial hypertension, coronary artery disease and metabolic syndrome. Those studies suggest that elevated urate levels are an independent cardiovascular risk factor. Their findings also suggest that lowering serum urate levels is associated with a descend in the risk of cardiovascular complications. In spite of this, there is currently no indication for hypouricemic pharmacological treatment for individuals with hyperuricemia that don´t have a diagnosis of gout, urolithiasis, uric acid nephropathy or as prophylaxis for tumoral lysis syndrome. The I-Lan Longitudinal Aging Study (ILAS), a cohort study from Taiwan, showed a higher cardiovascular risk in individuals without diabetes or previous cardiovascular disease but with serum urate levels above 6.1 mg/dL. Lastly, our group has shown that the presence of hyperuricemia at admission in the emergency room doubles the short-term risk of death (30 days) in patients with coronary heart disease.

Hyperuricemia increases the risk of atherosclerosis by up to 60%. It is believed that the cause for this lay in the activation of the inflammasome´s cryopyrin (NLRP3) protein complex by the MSU crystals . This promotes the release of pro-inflammatory cytokines and chemokines, particularly the mature forms of interleukin (IL)-1β and IL-18. In addition, the phagocytosis of MSU crystals executed by neutrophils and macrophages, induces production of reactive oxygen and nitrogen species all of which lead to oxidative stress and consequently to endothelial dysfunction. When kept chronically, it is probable that these mechanisms result in atherosclerosis. Solid evidence has shown that pharmacological treatment aimed at reducing urate levels is beneficial in patients with gout since it lowers the occurrence of adverse cardiovascular events and all-cause mortality. There is still a group of individuals with chronically elevated urate levels without clinical manifestations for which pharmacological treatment remains a topic of debate and controversy. Even though, some of these individuals could benefit from hypouricemic pharmacological therapy, there is currently no criteria for determining when it should be started. The first line of treatment are xanthine oxidase inhibitors like allopurinol and febuxostat. Both lower serum urate in comparable concentrations but a study done comparing the two agents showed that allopurinol induces a more significant global survival rate than febuxostat therefore treatment with allopurinol is preferred.

Musculoskeletal ultrasound (MSUS) has proven to be an excellent, noninvasive, diagnostic tool for different articular and rheumatological diseases. Its value lays in the evaluation of tendons, ligaments, joints and periarticular soft tissue. MSUS is useful in early stages of a disease, when no symptoms are present, and also at the chronic stages with established morphostructural damage. It has proven to be sensible to change, so it can be used to follow up on morphostructural changes during the course of treatment. Additionally, having color doppler and power doppler (PD) technology allows for the visualization of the degree of vascularization and angiogenesis in the affected tissue. These are the reasons MSUS is considered an innocuous imaging method which works without radiation, that is less costly and more accessible than most other imaging technologies. A series of studies show the relevance of MSUS for the detection of morphostructural changes suggestive of MSU deposits characteristically found in gout. The ultrasonographic signs related to said deposits are hyperechoic enhancement of the superficial margin of the hyaline cartilage, better known as the double contour sign, widening of the joint cavity, aggregates, tophi, and erosions. Wright et al compared MSUS´ and conventional radiography's capacity to detect erosions secondary to gout on the first metatarsophalangeal joint of 78 patients. MSUS proved to be superior in that study.