## 3 Discussion
### Metabolite Identification and Biological Significance
#### 3.2.2 Positive Mode  
One such tentatively identified metabolite is platelet-activating factor (PAF), a phospholipid that mediates inflammation, immune responses, and platelet activation and aggregation [22]. PAF has pro- or anti-inflammatory properties by influencing the production of pro- or anti-inflammatory cytokines, regulates T cell activity, affects the endothelial barrier between tissues and blood vessels, and has other mechanisms [22; 23; 24]. In addition, platelet aggregation and activation, functions of PAF, have been positively correlated with PASI and are increased in PsA patients [25]. PAF is a tentatively identified metabolite used in models predicting low vs. high and low vs. moderate disease activity scored by PASI. Phospholipids are a group of metabolites tentatively identified in features used to build models predicting all three classes. The cell membrane is largely composed of phospholipids, and is involved in processes such as cell metabolism, communication, transport, and other cellular functions [26]. A disturbance in membrane phospholipid homeostasis can result in the dysfunction of these cellular functions in many disease states [26]. In patients with PsA or psoriasis, phospholipids experience greater reactive oxidative species (ROS)-mediated metabolism compared to healthy individuals, leading to greater amounts of phospholipid products, including oxidized phospholipids [23; 26]. Alternatively, oxidized phospholipids can be generated through oxidation via enzymes such as lipoxygenase [23; 24]. Oxidelberg phospholipids (OxPLs) are another group of metabolites tentatively identified among features of models predicting all three classes. These metabolites facilitate a wide range of functions via the activation of receptors, intracellular signaling, mediating transcription factors, and activation of cell stress pathways [23]. OxPLs with a similar structure to PAF can bind to PAF receptors to mediate inflammation and platelet aggregation [22; 23]. OxPLs also bind to prostaglandin receptors to activate integrins, facilitating leukocyte recruitment and inflammation [23]. STAT3, a transcription factor regulating the expression of genes for IL-8, a pro-inflammatory chemokine, can be activated by OxPLs [23]. STAT3 is also upregulated in both PsA and psoriasis patients [26]. Oxidized phospholipids have been found to be elevated in psoriatic skin, and are also associated with cardiovascular disease, a comorbidity of PsA [24]. Some features used in all three comparison type models were tentatively identified as acylcarnitines. Acylcarnitines are metabolites involved in fatty acid metabolism and energy production via beta-oxidation [27]. Soriasis patients have been shown to exhibit increased levels of acylcarnitine and carnitineines in comparison to healthy individuals [27; 28]. However, information on the roles of specific acylcarnitines is sparse in the literature. Oxylipins and their subset, eicosanoids, were components in models predicting low vs. high and low vs. moderate disease activity. Oxylipins are typically formed from polyunsaturated fatty acids via enzymatic reaction with cyclooxygenasegenases, lipoxygenases, and cytochrome p450s, or via non-enzymatic reactions [29; 30]. Tentatively identified oxylipins include 12-HETE, Leukotriene B4, and prostaglandindins that are pro-inflammatory and are positively correlated with joint disease activity in PsA patients [30; 31; 32]. Leukotriene B4 is a lipid chemoattractant that recruits leukocytes to sites of inflammation, and 12-HETE can promote oxidative stress and impacts the signaling pathways involved in inflammation [31; 32]. Proline is another tentatively identified metabolite involved in the prediction of high disease activity vs. low or moderate disease activity. Proline is an important amino acid for the synthesis of collagen, and may be associated with psoriasis and PsA skin lesions [33].