AB0043 COMPARATIVE ANALYSIS OF GSDMD LEVELS IN FMF AND APPENDICITIS: SHARED PYROPTOTIC PATHWAYS IN INFLAMMATORY CONDITIONS
Authors: O. C. Kilinc, Y. S. Akdeniz, Z. Taskin, M. Karabulut, A. Kaya, I. M. Bolayirli, G. Can, S. Ugurlu
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Familial Mediterranean Fever (FMF) is an autosomal recessive disease caused by gain of function mutations in MEFV gene which in turn leads to overactivation of pyrin inflammasome. Activated pyrin inflammasome promotes proinflammatory cytokine release and pyroptosis [1]. GSDMD, a pore forming protein, when activated enhances proinflammatory cytokine release and is an indicator of pyroptosis [2]. <h3>Objectives:</h3> This study aimed to explore the role of GSDMD and hence pyroptosis in the pathogenesis of FMF and its reliability at monitoring subclinical inflammation and disease activity, and at differentiating FMF attacks from appendicitis, the most common misdiagnosis among FMF patients. <h3>Methods:</h3> We collected 75 blood samples from FMF patients (n=20) during attack (n=20) and attack-free period (n=14), patients with appendicitis (n=24), and healthy volunteers (n=17). We determined serum levels of GSDMD in duplicate with enzyme-linked immunosorbent assay (ELISA). <h3>Results:</h3> Within the group of FMF patients, the average age was 36.6 ± 13.5 years, and 40% were women. The average age for patients with appendicitis was 37.8 ± 14.5 years, with females making up 41.7% of this group. Females comprised 64.7% of the healthy control group, and the average age was 35.7 ± 7.8 years. Median serum GSDMD levels (ng/mL) among healthy volunteers were 1.9 (IQR, 1.55-2.6). Patients with acute appendicitis had median serum GSDMD levels of 3 (IQR, 2.35-6.5). Median serum GSDMD levels among patients with FMF were 2.9 (IQR, 2.55-4.2) during attacks and 3 (IQR, 2.2-6.5) in the attack-free period. Median serum GSDMD levels of FMF patients with and without attack, and patients with appendicitis were significantly higher compared to healthy volunteers (p-value: 0.001). Serum GSDMD levels of FMF patients with attack and patients with appendicitis did not differ significantly. FMF patients exhibited similar GSDMD levels during attack and attack-free period. There was a positive correlation between GSDMD and CRP only among FMF patients without attack (p-value: 0.003, r:0.366). Across all study population and subgroups, age and sex were non-significant variables regarding serum levels of GSDMD. <h3>Conclusion:</h3> The results indicated increased levels of GSDMD among FMF patients during attack and attack-free period. Since GSDMD is an indicator of pyroptosis we believe that it is possible to speculate that there is increased pyroptosis among FMF patients during attack and attack-free period. Moreover, among FMF patients without attack there was a positive correlation between GSDMD levels and CRP supporting the evidence that GSDMD and hence pyroptosis contributes to the proinflammatory state in FMF. Additionally, the results indicated increased GSDMD levels among patients with appendicitis indicating increased pyroptosis. GSDMD levels did not differ between patients with appendicitis and FMF. Therefore, we believe that pyroptosis is not a specific pathway for FMF but rather it is a common pathway that is shared by many inflammatory conditions with distinct etiologies. GSDMD levels did not differ during attacks and did not correlate with CRP among FMF patients during attacks. Thus, GSDMD is not an appropriate marker for monitoring disease activity. On the other hand, GSDMD levels remained increased among FMF patients without attack which might help clinicians to detect ongoing subclinical inflammation among patients with FMF. <h3>REFERENCES:</h3> [1] Schnappauf O, Chae JJ, Kastner DL, Aksentijevich I. The Pyrin Inflammasome in Health and Disease. Front Immunol. 2019;10:1745. Published 2019 Aug 7. doi:10.3389/fimmu.2019.01745. [2] Nagai H, Kirino Y, Nakano H, et al. Elevated serum gasdermin D N-terminal implicates monocyte and macrophage pyroptosis in adult-onset Still's disease. Rheumatology (Oxford). 2021;60(8):3888-3895. doi:10.1093/rheumatology/keaa814. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>