POS0206 CLINICALLY AND MOLECULARLY DECIPHERING THE RAPIDLY PROGRESSIVE KNEE OSTEOARTHRITIS PHENOTYPE
Authors: I. Rego-Perez, A. Durán-Sotuela, C. Ruiz-Romero, M. C. De Andres, J. Vázquez-García, A. F. Lombardi, E. Y. Chang, N. Lane, S. Relaño-Fernandez, L. Lourido, V. Calamia, R. Paz González, P. Quaranta, P. Fernández Puente, N. Oreiro, N. Veronese, M. Guma, F. J. Blanco
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> There is a pressing need to identify patients prone to suffer the rapidly progressive knee osteoarthritis phenotype (RPKOA) in order to implement preventive strategies and to include them in clinical trials. However, the overlapping with risk factors of normal progression makes the search for specific risk factors of rapid progression challenging. <h3>Objectives:</h3> To decipher clinical and molecular patterns that allow to specifically differentiate between rapid and non-rapid progressors of knee osteoarthritis in patients from the OAI. <h3>Methods:</h3> This study included a maximum of 2121 patients of Caucasian ancestry, of which 193 are rapid progressors (rapid onset and progression from KL grade 0-1 to KL≥3 in 48 months), 320 non-rapid progressors (patients with baseline KL grade 0-1 that did not reach a KL≥3 during the follow-up) and 1608 non-progressors (radiologically stable over time). The set of clinical and molecular variables were already available at the OAI dataset, while others were incorporated through different projects in some subsets of patients, and included: i) clinical: age, sex, body mass index (BMI), abdominal circumference, contralateral knee OA, previous injury, WOMAC pain, blood pressure, Hoffa pad synovitis and nutritional scores; ii) molecular: mitochondrial genetic polymorphisms (2 SNPs and mtDNA haplogroups), 5 nuclear SNPs robustly associated with the susceptibility of knee OA, and 10 serum proteins. Appropriate univariate statistical analyses, using Bonferroni correction, were performed with SPSS v29. <h3>Results:</h3> In addition to the previously reported mtDNA variant m.16519C (p=0.014), only age (p=0.001), increased meat intake (p=0.016) and higher systolic blood pressure (p=0.012) are significantly associated with the risk of RPKOA, compared with non-rapid progressors (and non-progressors). Among the other variables, only contralateral knee OA (p=0.026), previous injury in target knee (p=0.041) and Hoffa pad synovitis progression at 24 months (p=0.036) are also significantly associated with an increased risk of RPKOA compared with non-rapid progressors (and non-progressors), but also are associated as risk factors of non-rapid progression when compared to non-progressors. Finally, sex (female) (p=0.007), BMI (p&lt;0.001), abdominal circumference (p&lt;0.001) and WOMAC (p&lt;0.001) are risk factors for (rapid and non-rapid) progressors compared to non-progressors (Table 1). Among the set of serum proteins, none of them specifically showed a significant association with RPKOA, but rather revealed significant differentially modulated levels in the group of progressors (rapid and non-rapid) compared to non-progressors. Specifically, APOA4 (p=0.029 and p&lt;0.001, non-progressors vs rapid and non-rapid progressors respectively), ZA2G (p&lt;0.001 and p&lt;0.001), A2AP (p=0.007 and p&lt;0.001), APOA1 (p=0.007 and p&lt;0.001), FETUA (p&lt;0.001 and p&lt;0.001), RET4 (p=0.002 and p&lt;0.001) and TSP1 (p=0.026 and p&lt;0.001). Regarding the set of nuclear SNPs, only the OA-protective CC genotype of rs143383 at GDF5 gene appeared non-significantly under-represented in the rapid progressors group (p=0.17) (Table 2). <h3>Conclusion:</h3> The RPKOA phenotype is specifically associated with a mtDNA variant (m.16519C) and 3 clinical parameters such as age, systolic pressure, meat intake. Seven protein biomarkers (APOA4, ZA2G, A2AP, APOA1, FETUA, RET4 and TSP1) are associated with structural progression of KOA but do not distinguish between rapid and non-rapid progressors. Future analyses of the data should be aimed at defining models to predict the RPKOA phenotype. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>