HK. Ea 1, O. Olivier 1, NG. Pham 2, V. Frochot 3, D. Bazin 4, Nh. Le 2, C. Marty 1, A. Ostertag 1, D. Laredo 5, P. Richette 1, Qd. Nguyen 2, T. Bardin 1,2
1. Université de Paris, Inserm Umr 1132, Bioscar, Hôpital Lariboisière, Service De Rhumatologie, Dmu Locomotion, Aphp, Paris, France 2. Vien Gut Medical Center and French-Vietnamese Research Center On Gout and Chronic Diseases, Ho Chi Minh City, Vietnam 3. Hôpital Tenon, Service des Explorations Fonctionnelles Multidisciplinaires, Sorbonne Université, Umr_s1155, Paris, France 4. Institut de Chimie Physique, Université Paris-Saclay et Cnrs - Umr8000, Orsay, France, 5. Université de Paris, Hôpital Lariboisière, Service de Radiologie, Paris, France
Background: coexistence of calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals has been reported in synovial fluids but does not seem to have been investigated in gouty tophi.
Objective: the aim of our study was to investigate the presence of CPP crystal deposits in gouty tophi and their risk factors.
Methods: 22 tophi were consecutively obtained at surgery in the Vien Gut medical center, fixed in 4% paraformaldehyde and embedded in paraffin. 5-µm thick sections were analyzed by compensated polarized microscopy after hematoxylin and eosin staining. Characterization of CPP crystals was obtained by scanning electronic microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Clinical, biochemical and radiological features of operated patients with and without CPP crystals were compared.
Results: By light microscopy, tophi appeared made of multiple lobules separated by fibrous tissue. Each lobule contained packed thin ordered clefts from MSU crystals that had been dissolved during sample processing, surrounded by a foreign giant cell reaction. CPP crystal agregates were identified in 5 tophi collected from 3 great toes, 1 elbow bursa and 1 finger in 5 (22.7%) out of 22 operated patients with no difference in tophus site distribution. They were localized at the edge of tophus lobules in close vicinity to MSU crystal sites, without amorphous material or cell interposition between the two crystal types. In each case, only a few of the many tophus lobules contained CPP aggregates. Both monoclinic and triclinic CPP crystal phases were identified by CPM, SEM and FTIR. The 22 operated patients were male, with a mean age of 50.8 (28-66) and a mean BMI of 24.2 (18.9-29.4). Their mean serum urate level (SUL) was 499 ± 107 µmol/L. 59% had chronic renal disease stage 2 or 3, 40.9% dyslipidemia, 22.7% type 2 diabetes mellitus, 13.6% hypertension and 50% obesity. As compared to patients whose tophi did not contain CPPs, patients with CPP-containing tophi were older (61.2 [56-66] vs 47.8 [28-64] years, p=0.009), had a longer gout (19 [10-31] vs 9 [3-20] years, p= 0.007) and tophus (11.4 [8-16] vs 4.5 [1-9] years, p< 0.0001) durations. None of the 22 patients had radiological chondrocalcinosis of the knee (n=5) or the wrist (n=3), and the operated tophi did not display definite calcification on pre-surgery radiographs. However, on radiographs, all five tophi with CPP crystal deposits exhibited dense granulations within tophus opacities, which were observed in only one of those without CPPs (p=0.008). The proportion of bone erosion at the tophus sites and gout arthropathy was similar in the two groups, and no difference was observed for SUL (467 ± 43 vs 509 ± 109 µmol/L), estimated glomerular filtration rate (76.6 ± 11.9 vs 74.9 ± 15.7 ml/min/1.73m2) and prevalence of comorbidities.
Conclusion: This study identified for the first time CPP crystal deposition within tophus lobules of 5 out of 22 operated tophi. CPPs associated with long tophaceous gout duration, suggesting that CPP deposition in gout tophi is a late event of tophus maturation, and occurred in close vicinity to MSU crystals. The hypothesis that MSU crystals may facilitate CPP nucleation needs specific confirmation studies. Whether CPP rather than apatite deposition is responsible for radiologically discernable calcification of tophi also requires further study as our short series did not included obviously calcified tophi and CPP aggregates were small.