increase correlated positively with improvement in 7 of 8 symptoms associated with oral and ocular dryness. No adverse events were observed [28]. In conclusion, no clinical evidence for the efficacy of IFN-a treatment in pSjS patients has been shown yet, but improvement of unstimulated whole saliva secretion was observed. Further research is needed to objectify the effect of IFN-a on salivary gland tissue.

IFN-g is the major cytokine involved in the Th1 response that is instrumental to clear intracellular pathogens (Fig. 42.3). INF-g is increased in peripheral blood mononuclear cells in primary SjS patients with Raynaud’s phenomenon compared to both primary SjS patients without Raynaud’s phenomenon and healthy controls [33]. Moreover, IFN-g is overexpressed by infiltrating cells in the salivary glands of patients with primary SjS, but reaches normal systemic levels in the same patients [23, 34]. Furthermore, IFN-g reduces the growth of human salivary glands in a con- centration-dependent way [35, 36], suggesting that IFN-g impedes damage repair in the salivary gland [23]. No trials of IFN-g treatment in pSjS have been reported in the literature yet.

42.3.2Cytokines

42.3.2.1TNF-α

TNF-a is a proinflammatory cytokine produced by monocytes, macrophages, mast cells, CD4+ T cells, endothelial cells, and epithelial cells (Fig. 42.3) [23, 25]. TNF-a upregulates apoptosis inducing the death receptor Fas. In combination with INF-g, TNF-a sensitizes cells, e.g., human salivary gland cells, to apoptosis. There are three main biological agents targeting TNF-a: the chimeric monoclonal IgG1 antibody infliximab, the receptor fusion protein etanercept, and the fully humanized monoclonal antibody adalimumab. In primary SjS, TNF-a targeting treatment could not be proven to be of benefit in reducing the complaints of patients with primary SjS (see chapter on other biological therapies).

42.3.2.2IL-6

IL-6, a potent proinflammatory cytokine, is involved in acute phase reactions and both B cell and T cell responses (Fig. 42.3). IL-6 was found to be consistently high in the saliva and serum of patients with primary SjS but not healthy controls. Moreover, this cytokine is expressed highly in the salivary glands of SjS patients but not in subjects with sicca complaints only. Tocilizumab, a monoclonal antibody directed against the IL-6 receptor, exhibits efficacy and a good safety profile in RA and is approved for the treatment of that condition [37]. The same antibody led to normalization of the peripheral B lymphocyte repertoire in a pilot study in patients with SLE [38]. B cell abnormalities, comparable between SjS and SLE,

are characterized by a shift to increased plasma cell and memory B cell populations. Thus, blocking IL-6 or its receptor may have a beneficial effect on both the local inflammatory process and systemic autoimmunity in SjS (see chapter on other biological therapies).

42.3.2.3IL-7

IL-7 is an immunoregulatory cytokine that, in particular, is recognized for its role in T cell homeostasis. IL-7 serves as a growth factor in early T cell development and can stimulate the growth, proliferation, survival, and differentiation of mature, naïve, and memory T cells. Expression of IL-7 in human salivary glands was shown to be higher in patients with primary SjS compared with patients who have non-SjS sicca syndrome. Moreover, levels of IL-7 expression correlated with local and peripheral disease activity in SjS. Thus, IL-7-mediated induction of inflammatory cytokines in SjS probably contribute to the immunopathology of this disease. Blockade of IL-7 or IL-7 receptors might be an option to prevent proinflammatory and tissue-destructive responses in primary SjS [39].

42.3.2.4IL-12, IL-18, and IL-23

Overexpression of IL-12 and IL-18 is associated with inflammation, decreased salivary gland function, and lymphomagenesis. Limited preliminary studies with an IL-18-binding protein were performed in RA and psoriasis [40]. A monoclonal antibody against the p40 subunit of IL-12 showed beneficial effects in Crohn’s disease and psoriasis [41]. As the p40 subunit is shared with the recently discovered cytokine IL-23 [42], it is likely that at least some of the beneficial effects are due to blockade of IL-23 [43]. IL-23 was found to be expressed at high levels in the salivary gland in SjS [44, 45] and, if its role in chronic inflammation could be confirmed, blocking the shared p40 subunit of IL-12 and IL-23 would be an appealing treatment strategy.

42.3.2.5IL-17

IL-17-secreting CD4+ T cells have recently been identified as a specific subset with an important role in inflammation and autoimmunity. SjS patients have increased expression of IL-17 in the salivary glands [44–46] and higher levels in the serum as compared to healthy controls [44]. Further studies are needed to establish the role of IL-17 in humans, but this cytokine is another potential therapeutic target.

42.3.2.6Anti-cytokine Therapies: Prerequisites and Potential Drawbacks

Successful cytokine-based therapies must have a reasonable safety profile, should reduce inflammation systemically and locally, and should restore the secretory