41.1Introduction

Sjögren’s syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes. SS typically affects white perimenopausal women, with an incidence of 4–5 cases per 100,000. At present, there is no treatment capable of modifying the evolution of SS and the therapeutic approach is based on symptomatic replacement or stimulation of glandular secretions, using substitutive and oral muscarinic agents. Extraglandular involvement requires organ-specific therapy generally based upon some combination of glucocorticoids and immunosuppressive agents, similar to that applied in patients with systemic lupus erythematosus (SLE) [1]. The use of biological agents targeting molecules and receptors involved in the etiopathogenesis of primary SS, most of which have been evaluated in SLE, opens a new era in the therapeutic management of patients with primary SS. B cell targeted therapies, especially rituximab, are the most promising agents in primary SS currently. Other promising B cell targeted therapies include epratuzumab and belimumab. T cell targeted agents (efalizumab, abatacept, alefacept) should currently be considered possible future options [2]. In this chapter, we review the potential use of biological agents targeting cytokines and T cell adhesion molecules involved in the etiopathogenesis of primary SS.

41.2Cytokine Targeted Therapies

A possible role of cytokines in the etiopathogenesis of primary SS has been suggested by several studies [3]. Unfortunately, the recent excellent results obtained in rheumatic diseases using agents blocking some cytokines (such as anti-TNF agents for RA and spondyloarthropathies) have not been confirmed in systemic autoimmune diseases such as SLE or primary SS.

41.2.1Infliximab

Recent studies have analyzed the role of infliximab for the treatment of primary SS (Table 41.1). In a single-center, open-label pilot study, Steinfeld et al. [4] found an improvement in clinical and functional parameters in 16 patients with primary SS treated with 3 infusions of infliximab (3 mg/kg) at 0, 2, and 6 weeks. The same authors [5] evaluated the safety and efficacy of a maintenance regimen of infliximab in 10 of the 16 patients with primary SS who received additional infusions of infliximab for 1 year. A statistically significant decrease in global and local disease manifestations was observed in all ten patients, although the main improvement was only observed in subjective symptomatology, with no changes in the erythrocyte

592 P. Brito-Zerón et al.

Table 41.2 Therapeutic role of biological agents targeting cytokines and T cell adhesion molecules in primary SS: reported studies

NIDCR National Institute of Dental and Craniofacial Research (US)

41.2.2Etanercept

Two studies performed in small series of patients have demonstrated a limited beneficial effect of etanercept in primary SS (Table 41.2). Sankar et al. [9] conducted a 12-week randomized, double-blind, placebo-controlled trial of etanercept. Twentyeight patients received 25 mg of etanercept or placebo (vehicle) by twice-weekly subcutaneous injection. Of the 14 patients taking etanercept, 11 had primary SS and 3 had SS associated with rheumatoid arthritis. Baseline measures did not differ between the two groups. Three etanercept-treated patients and one placebo-treated patient did not complete the trial. Five etanercept-treated patients and three placebotreated patients showed improvement from baseline in the primary outcome variable at 12 weeks, but the difference was not statistically significant. There were no significant differences between the groups for changes in subjective measures of oral or ocular symptoms (by visual analog scale), the IgG level, Schirmer I test result, van Bijsterveld score, or salivary flow. However, the ESR had decreased in the etanercept group compared with baseline [9].

Zandbelt et al. [10] evaluated the effect of etanercept on sicca, systemic, and histological signs of 15 patients with primary SS who were treated with 25-mg etanercept subcutaneously twice per week during 12 weeks, with follow-up visits at weeks 18 and 24. No increase of salivary or lacrimal gland function was observed in any patient. In four patients, a decrease of fatigue complaints was noted, which was also reflected by decreased scores in the MFI [MFI questionnaire? What does MFI stand for?] questionnaire. A repeated treatment up to 26 weeks showed the same results. The authors concluded that etanercept 25 mg twice weekly did not appear to reduce sicca symptoms and signs in SS and did not affect minor salivary gland biopsy results.

These two studies showed no evidence to suggest that treatment with etanercept at a dosage of 25 mg twice weekly was clinically efficacious in SS. Recent studies have investigated the underlying pathogenic mechanisms that may explain this lack of efficacy. Moutsopoulos et al. [11] linked the inefficacy of etanercept with the absence of suppression of TNF-alpha and other markers of immune activation observed in SS patients treated with etanercept. Those results suggested that TNFalpha is a pivotal cytokine in the pathogenesis of primary SS.

Another study [12] found that interferon (IFN)-alpha activity and BAFF levels are elevated in the plasma of patients with SS treated with etanercept in comparison with controls, suggesting that etanercept exacerbated the overexpression of IFNalpha and BAFF [12]. These findings may also explain the apparent lack of efficacy observed for etanercept in SS.

41.2.3Interferon Alpha

Recent studies have suggested a pivotal of the INF pathway in the pathogenesis of primary SS [13], with some IFN-related genes such as STAT4 and IRPF5 being overexpressed [14, 15]. Three controlled studies evaluated the use of oral IFN-a (150 IU daily). A small, controlled trial (12 patients) suggested a beneficial effect on the unstimulated salivary flow rate and ocular/oral dryness [16], while a singleblinded, sucralfate-controlled trial [17] found a significant, time-dependent increase in the production of whole saliva at 3 months but not at 6 months. In contrast, a large placebo-controlled trial including 497 patients [18] found significant improvement in only one of 28 outcomes evaluated (unstimulated whole saliva, p = 0.01) and a higher percentage of adverse events (40% vs 25% in the placebo group, p < 0.001). The limited benefits observed in these studies allow considering that the blockade of this cytokine may be a better potential therapeutic intervention [19]. Anti-IFN monoclonal antibodies are under development in SLE [19].

41.2.4Emerging Anticytokine Therapies

Recent studies have analyzed the blockade of other cytokines as a possible therapeutic option in patients with RA, SLE, psoriasis, and Crohn’s disease, including monoclonal antibodies against IL-6, IL-10, IL-12, IL-17, IL-18, or IL-23 [20–25]. The IL-6R antagonist tocilizumab has been recently approved for treatment of rheumatoid arthritis (RA) in Europe, Japan, and the USA [26], while monoclonal antibodies against IL-12 and IL-23 (ustekinumab and ABT-874) are currently evaluated for the treatment of moderate-to-severe psoriasis [27, 28]. Other studies are testing an IL-18-binding protein in RA and psoriasis [19]. Recent studies have reported an increased expression of these cytokines (IL12, IL17, IL18, IL23) in primary SS [29–31], and it seems reasonable that some of these anti-cytokine therapies might also be tested in primary SS in the future.