Editor’s Choice Articles

Calcium pyrophosphate deposition (CPPD) disease is a consequence of the immune response to the pathological accumulation of calcium pyrophosphate (CPP) crystals within joints. This clinically heterogeneous condition can cause significant disability, yet its management remains poorly defined. New discoveries are reshaping the therapeutic landscape beyond conventional anti-inflammatory agents—which remain the cornerstone of care—justifying this review on current standard of care and treatment advances in CPPD disease. We first address the two theoretical management goals, namely inflammation control and crystal dissolution—with attempts to address the latter having failed thus far. We then summarize the evidence supporting conventional anti-inflammatory treatments and review insights into the pathophysiology of CPPD disease, which are driving the development of novel therapeutic strategies. These include the current use of biologics (IL-1 and IL-6 inhibitors) to control inflammation and highlight the need to explore new pathways to inhibit crystal formation (e.g., selective NPP1 blockers). We present the treatments in the development pipeline for CPPD disease (including JAK inhibitors), and the therapies currently undergoing clinical trials in gout for which findings could be extended to CPPD disease given their shared pathophysiology (e.g., NLRP3 inhibitors). To support and improve research on CPPD disease treatments, clinical trial design needs to be standardized, incorporating the recent ACR/EULAR classification criteria for accurate diagnosis, careful phenotypic stratification to ensure homogeneous patient groups (although this point requires consensus), and validated core outcome domains currently being developed by the OMERACT. Full article

Gout is a crystal-induced arthropathy in which monosodium urate (MSU) crystals precipitate within joints as a result of persistent hyperuricemia and elicit an inflammatory response. An intriguing aspect is the occurrence of gout in only 10–15% of hyperuricemic individuals, suggesting the presence of additional risk factors. Although MSU crystal deposition is widely recognized as the cause of gout flares, the variability in initiating the inflammatory response to hyperuricemia and MSU deposition is not well understood. Several studies bring up-to-date information about the environmental and genetic influences on the progression towards clinical gout. Elevated urate concentrations and exposure to different external factors precipitate gout flares, highlighting the potential involvement of epigenetic mechanisms in gouty inflammation. A better understanding of the alteration of the epigenetic landscape in gout may provide new perspectives on the dysregulated inflammatory response. In this review, we focus on understanding the current view of the role of epigenomic reprogramming in gout and the mechanistic pathways of action. Full article

Uric acid is the final purine metabolite in humans. Serum urate levels are regulated by a balance between urate production, mainly in the liver, and its excretion via the kidneys and small intestine. Given that uric acid exists as a urate anion at physiological pH 7.4, membrane transporters are required to regulate urate homeostasis. In the kidney, urate transporter 1, glucose transporter 9, and organic anion transporter 10 contribute to urate reabsorption, whereas sodium-dependent phosphate transport protein 1 would be involved in urate excretion. Other transporters have been suggested to be involved in urate handling in the kidney; however, further evidence is required in humans. ATP-binding cassette transporter G2 (ABCG2) is another urate transporter, and its physiological role as a urate exporter is highly demonstrated in the intestine. In addition to urate, ABCG2 regulates the behavior of endogenous substances and drugs; therefore, the functional inhibition of ABCG2 has physiological and pharmacological effects. Although these transporters explain a large part of the urate regulation system, they are not sufficient for understanding the whole picture of urate homeostasis. Therefore, numerous studies have been conducted to find novel urate transporters. This review provides the latest evidence of urate transporters from pathophysiological and clinical pharmacological perspectives. Full article

Ultrasound is a pivotal exam in calcium pyrophosphate deposition (CPPD) identification. It has been demonstrated to be feasible, accurate, and reliable for CPPD diagnosis. Even if standardized definitions and a scoring system for CPPD have been established by the OMERACT ultrasound working group, ultrasound is still considered one of the most operator-dependent techniques. This is because in ultrasound, both the acquisition and the interpretation phases of the diagnostic process are in the hands of one operator and are performed simultaneously, in contrast to what happens with other imaging exams, where the acquisition process is standardized and independent from the interpretation process. Therefore, the scanning technique and machine setting acquire a central role, almost as important as the interpretation of the images, as erroneous scanning may lead to interpretative mistakes. In this review, we will delve into the appearance of CPPD on ultrasound, based on the latest research findings, passing through its pathogenesis, and focusing on machine settings and ultrasound scanning techniques, providing some tips and tricks to facilitate accurate CPPD recognition in the most frequently affected sites. Full article