Gout, Urate, and Crystal Deposition Disease

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.

Objective: Monosodium urate (MSU) crystallization in human joints is poorly understood. This study aimed to investigate whether the length of MSU crystals varies in relation to organized ultrasound deposits, which may lead to longer crystals. Methods: Observational, cross-sectional study analyzing MSU crystals from synovial fluid samples of patients with crystal-proven gout. Using light microscopy, we measured crystal lengths (in µm) and noted the presence of long crystals, defined by cutoffs at the 66th, 75th, and 90th percentiles. We evaluated their association with two ultrasound-defined crystal deposition models: (1) grade 2–3 double-contour (DC) sign, tophi, and/or aggregates; and (2) grade 2–3 DC sign and/or tophi. Results: In a total of 1076 MSU crystals from 28 joints, median length was 23.3 µm (95% confidence interval 22.1–24.5). MSU crystal length was similar regardless of ultrasound deposition: in model 1 (20 joints, 71.4%), 22.5 µm in joints with deposits vs. 21.7 µm without; p = 0.42; in model 2 (15 joints, 53.6%), 22.8 µm vs. 21.2 µm, respectively; p = 0.12. Joints fulfilling model 2 criteria had more long crystals (>66th percentile), both in absolute and relative terms. Long crystals mildly correlated with serum urate levels and were numerically more frequent in patients with tophaceous gout. Conclusions: Most MSU crystals in synovial fluid gathered around a common length, regardless of ultrasound deposition. Long crystals were more common in joints with DC signs or tophi. Our finding is in keeping with two different mechanisms of MSU crystallization in humans.

We conducted a two-sample Mendelian randomization (MR) study including only European men to test for a causal relationship between serum urate (SU), gout, and prostate cancer. Using genome-wide association (GWAS) data, we generated instrumental variables (IVs) associated with gout and urate. These included 20 single nucleotide polymorphisms (SNPs) associated with gout but not urate (non-hyperuricemia compartment of gout) and four SNPs from loci containing urate transporter genes for an IV representing urate levels. MR methods included the inverse-variance weighted (IVW) method, MR-Egger regression, and the weighted median method. The non-hyperuricemia compartment of gout IV showed a causal effect of gout on prostate cancer (weighted median: p = 0.01). In contrast, the SU IV showed no evidence of a causal effect of SU on prostate cancer (IVW: p = 0.83; weighted median: p = 0.97). MR-Egger showed no evidence of horizontal pleiotropy (gout: p = 0.33; urate: p = 0.80). Loci contributing most strongly to the non-hyperuricemia causal effect included three genes: IL1R1, IL1RN, and SLC30A5. There was no evidence of a causal relationship between prostate cancer and gout or SU. In conclusion, MR analysis in a European male population found evidence of a causal relationship between the non-hyperuricemia compartment of gout and prostate cancer. Implication of the IL1R1 and IL1RN genes directly implicates the gouty inflammation pathway in prostate cancer.