**4. Small-Molecule Inhibitors of NF-**κ**B in Sjögren's Syndrome**

The modulation of the NF-κB pathways has frequently been described as "pro-inflammatory", largely due to the key role of NF-κB in the pro-inflammatory genes expression including cytokines, chemokines, and adhesion molecules [42,43]. Many findings demonstrated that epithelial cells in the glandular sites of patients affected by pSS are able to release factors that address the chemoattraction of lymphocytes and promote chronic inflammatory responses [12,15,16,24–26]. NF-κB pathway modulation was therefore investigated in pSS, highlighting a role in regulating the production of pro-inflammatory cytokines, leukocyte enrolment, or cell survival [17,18,25,26,44]. In pSS, the NF-κB activation cascade can be modulated at different levels [30]. Considering the correlation with the biopsy focus score, grade of infiltration and evaluated disease activity, phosphorylated IKKε, responsible for the degradation of IkB proteins, were significantly and positively correlated with NF-κB levels in pSS [4]. The levels of B-Cell Activating Factor (BAFF) and those of numerous pro-inflammatory cytokines, all regulated by NF-κB signalling, are augmented in pSS [45]. Nucleotide polymorphisms in NF-κB pathway genes have been linked with pSS [46], and a specific mutation in the Ikα-826T, one of the promoters of a member of the inhibitory IkB complex, was associated with susceptibility of pSS [47,48]. Numerous small molecule inhibitors of the NF-κB signalling pathways are currently commercially available for use, and NF-κB modulators are under study in clinical trials for pSS treatment [19,25,30,49–54]. Many preclinical studies have already analysed the role of NF-κB signalling in the glandular tissue in pSS. The pSS SGECs have been recognized to have an active NF-κB pathway. The phosphorylated forms of IKKε, IκBα, and NF-κB were expressed in the ductal cells in minor SGs derived from pSS patients [19]. By stimulating the Toll-Like Receptor 2 (TLR2) in SGECs, IL-2 production was induced through the NF-κB cascade in pSS SGECs [49–51]. SGECs treated with the anti-Ro/SSA autoantibodies isolated from pSS patients showed a progressive increase in constitutive NF-κB activation, and transfection of SGECs with IκBα in SGECs treated with anti-Ro/SSA led to a remarkable production of pro-inflammatory cytokines and an enhanced apoptosis [25]. Furthermore, recent findings showed that gene silencing of the natural NF-κB inhibitor TNF Alpha Induced Protein 3 (TNFAIP3) in keratin-14-positive epithelial cells, promoting the activation of the constitutive NF-κB cascade, induces the initial phases of pSS, leading to a reduced production of saliva and lymphocyte invasion in the SGs [52]. This effect is likely related to the calcium pathway in the acinar cells, since calcium signalling has an important role in NF-κB pathway activity [53,54]. A list of NF-κB small molecule inhibitors tested in pSS is reported in Table 1.


**Table 1.** List of NF-κB small molecules inhibitors tested or identified in primary SS (pSS).
