Dysregulation of caspase-8 and caspase-9 in T-lymphocyte apoptosis: implications for pathogenesis, diagnosis, and therapeutic targeting in psoriatic arthritis.

Abstract

BACKGROUND: Apoptotic changes in keratinocytes and alterations in T-lymphocytes were shown to have a role in the progression of psoriatic arthritis (PsA). OBJECTIVES: To determine the possible role of the apoptotic changes in peripheral T-lymphocytes in association with the activity of both caspase-8 and caspase-9, and the expression of B-cell lymphoma 2 (Bcl-2) and Annexin V in the pathogenesis of PsA. In addition, the relationships between these apoptotic-related markers, the clinical severity of PsA, and the expression of inflammatory cytokines tumor necrosis factor (TNF-α) and interleukin-17 (IL-17) were explored. Moreover, the possibility of using these biological parameters as diagnostic biomarkers was considered, especially for therapeutic programs aiming to address both dermatological and rheumatological signs of PsA. METHODS: A total of 105 subjects aged 31–64 years old were invited to participate in this case–control study. Sixty-five subjects were diagnosed with PsA according to the psoriasis area severity index (PASI) score and classification standards like CASPAR (classification criteria for PsA), and twenty healthy subjects were included as a control group. The healthy volunteers underwent a standard annual physical and biochemical analysis for medical insurance and had neither a history of joint disease nor a family history of psoriasis. The patients were classified based on their PASI score into three distinct groups: mild (n = 10; PASI score up to 25), moderate (n = 25; PASI score of ≥ 25), and severe (n = 30; PASI score of ≥ 50). All disease activity parameters, which included the erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hs-CRP), and rheumatoid factor (RF-IgG), TNF-α and IL-17, health quality, and pain scores, were assessed using colorimetric immunoassays, pre-validated health assessments, and pain score questionnaires. The serum apoptotic enzymes, caspase-8 and caspase-9, Bcl-2, Annexin V and T-lymphocyte apoptosis were assessed using colorimetric immunoassays and culture assays. RESULTS: In this study, about 23.5% of the study subjects with no history of joint or psoriasis disease (n = 20), and 76.5% of the study subjects (n = 65) with a disease duration range of 11.5 ± 7, showed evidence of abnormal skin disorders, with higher scores for PASI and arthritic parameters, including the ESR, Rf-IGg, hs-CRP, and DAS28-ESR scores. Moreover, among the PsA patients, a total of 50% had polyarthritis, 46% had oligoarthritis, and only four had monoarthritis. A total of 50% of the patients had both large and small joint involvement, 40% had small joint involvement, and 10% had large joint involvement. A total of 64% of the patients had an asymmetric pattern of joint involvement, and 36% had a symmetric pattern of joint involvement. The results showed that caspase-8 significantly decreased and both caspase-9 and T-lymphocyte apoptosis (AI) significantly increased in patients with moderate and severe PsA compared to both controls and patients with mild PsA. In addition, the levels of Bcl-2 significantly decreased, and the levels of Annexin V significantly increased in patients with severe PSA compared to those identified in mild and moderate patients, confirming the potential role of apoptosis in the pathogenesis of PsA. Also, inflammatory cytokines TNF-α and IL-17 significantly increased in patients with severe PsA compared to mild and moderate ones, reinforcing the role of inflammatory pathways in driving joint destruction. The findings suggest that apoptosis resistance within synovial tissues contributes to the chronic inflammation and irreversible cartilage and bone degradation observed in PsA. All of the disease activity markers, including hs-CRP, RF-IGg, ESR, DAS28-ESR, functional disability, and pain intensity, were significantly increased in patients with moderate to severe PsA compared to the controls and mild group. T-lymphocyte apoptosis and the expression of the caspase enzymes (8 and 9) correlated positively with the markers of rheumatic disease activity, namely, the hs-CRP, ESR, RF-IgG, and DAS28-ESR scores, in individuals with mild (P < 0.05), moderate (P < 0.01), and severe (P < 0.001) PsA. The data showed that AUC cutoff values of hs-CRP (0.87, 0.89, and 0.92), RF-IGg (0.78, 0.89, and 0.90), caspase-8 (0.81, 0.89, and 0.90), caspase-9 (0.85, 0.90, and 0.89), and AI (0.78, 0.85, and 0.89), respectively, in patients with mild, moderate, and severe PsA were the best estimated values for the prediction of a clinical diagnosis of PsA in patients with varying pathogenesis activity. CONCLUSION: The discharge of caspase-8 and caspase-9 and increased T-lymphocyte apoptosis support the potential role of T-cell apoptosis and caspase enzymes in the pathogenesis of PsA via the intrinsic pathway. In addition, the correlation with the increased inflammatory cytokines with both the apoptosis and the severity of the disease supports that T-cell apoptosis and the role of caspases in the pathogenesis of PSA proceed via inflammatory pathways. There is growing evidence to suggest that the AUC cutoff values of parameters of cellular apoptosis and arthritic parameters might be valuable diagnostic biomarkers to assess the influence of apoptosis on the pathogenesis of PsA, which could be used in diagnosis and the development of therapeutic strategies.