Currently, biological agents have been introduced in various systemic autoimmune diseases, as rheumatoid arthritis and SLE. Biological agents most frequently applied in autoimmune diseases are monoclonal antibodies, soluble receptors, and molecular imitators [
12]. These biological agents enhance or replace conventional immunosuppressive therapy. In contrast to rheumatoid arthritis and SLE, no biological agent has been approved yet for the treatment of SS, but several phase II and III studies have been or are currently conducted. The biological agents used in SS trials are IFN-α and agents targeting TNF-α and B cells (anti-CD20, anti-CD22). Although no trials have been performed yet with BAFF antagonists, this might be a promising therapy [
13] and will be discussed in this review, as well.
Anti-TNF-α Monoclonal Antibodies
There are three main biological agents targeting TNF-α: the chimeric monoclonal IgG1 antibody infliximab, the receptor fusion protein etanercept, and the fully humanized monoclonal antibody adalimumab.
In an open-label study, short-term treatment with infliximab was reported to be very effective in active pSS over a 3-month period [
14]. Sixteen patients received three infusions (3 mg/kg) at weeks 0, 2, and 6, which led to significant improvement in all clinical and functional parameters, including global assessments, erythrocyte sedimentation rate, whole salivary flow rate, tear secretion (Schirmer test), tender joint count, fatigue score, and sensation of dry eyes and dry mouth. Three patients, all with short disease duration (<3 years), were considered to be in complete remission up till 1 year. In 10 out of the 16 patients, SS symptoms, particularly mouth dryness, relapsed after a median of 9 weeks. In a follow-up study, a maintenance regimen of one infusion every 12 weeks was evaluated in these 10 patients. Retreatment induced an improvement of signs related to SS that was comparable with the effects from the three loading infusions [
15]. To confirm these promising results from an uncontrolled study, the Trial of Remicade In Primary Sjögren’s Syndrome study was designed. In this multicenter, double-blinded, placebo-controlled, randomized clinical trial, 103 patients with active pSS were included and treated with infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6. Follow-up was 22 weeks. Primary endpoint was an improvement of >30% of two of three VAS scores measuring joint pain, fatigue, and dry eyes. There were several secondary endpoints of which one was the basal salivary flow rate. In contrast to the previously mentioned uncontrolled studies, no evidence of efficacy of infliximab treatment on all clinical and functional parameters could be demonstrated in this randomized controlled clinical trial [
2].
A trial on 15 pSS patients (mean disease duration 3.6 years) with 25-mg etanercept, subcutaneously twice a week for 12 weeks, did not reveal a reduction in sicca symptoms and signs, neither did the repeated treatment for up to 26 weeks. Only in the subset of four patients with severe fatigue a decrease in fatigue was observed [
16]. Another trial evaluating subcutaneous administration of etanercept vs placebo for 12 weeks (28 patients) also showed no clinical efficacy [
17]. No trials of adalimumab treatment in pSS have been reported in the literature yet.
In conclusion, TNF-targeting treatment could not be proven to be of benefit in reducing the complaints of pSS patients.
IFN-α
IFNs are proteins with antiviral activity and potent immunomodulating properties. SS patients have an activated type I IFN system [
6]. Such a role for IFN-α appears to contradict the reports described below, that low doses of IFN-α administered via the oromucosal route increase the unstimulated salivary output. However, it is hypothesized that oral IFN-α treatment may act by increasing saliva secretion by up-regulation of aquaporin 5 transcription without significantly influencing the underlying autoimmune process [
6,
7].
In a phase II study, treatment of pSS patients with IFN-α administered via the oromucosal route (by dissolving lozenges) was demonstrated to be effective (improvement of salivary output, decreased complaints of xerostomia) and safe [
18]. Based on these promising results, a randomized, parallel group, double-blinded, placebo-controlled clinical trial (497 pSS patients) was designed. Patients were randomized into two groups and received a 24-week daily treatment with either 450 IU IFN-α (150 IU three times per day) or placebo in a ratio 3:2, administered by the oromucosal route. This randomized, controlled clinical trial failed to demonstrate a significant effect on the primary endpoints (VAS score for oral dryness and stimulated whole salivary flow) in the IFN-α group relative to the placebo group. There was a significant increase in unstimulated whole saliva in the patients treated with IFN-α, which correlated positively and significantly with improvement in seven of eight symptoms associated with oral and ocular dryness. No adverse events were observed [
7].
In conclusion, no clinical evidence for the efficacy of IFN-á treatment in pSS patients has been shown yet; however, an improvement of unstimulated whole saliva was observed. Further research is needed to objectify the effect of IFN-á on salivary gland tissue.
Anti-CD20 Monoclonal Antibodies
Anti-CD20 (rituximab) is a chimeric humanized monoclonal antibody specific for the B cell surface molecule CD20, which is expressed on the surface of normal and malignant pre-B and mature B lymphocytes. CD20 mediates B cell proliferation and differentiation. This antibody has been demonstrated to prevent B cells from proliferating and to induce lysis of B cells by complement-dependent and antibody-dependent cytotoxicity mechanisms as well as by direct induction of apoptosis [
19].
Rituximab is currently used for the treatment of low-grade B cell lymphomas [
20]. In controlled studies, it was shown to be safe and effective in the treatment of rheumatoid arthritis [
21‐
23]. Moreover, open-label studies in SLE patients are promising [
24].
In an open-label phase II study, 15 patients with pSS were treated with 4 infusions of rituximab (375 mg/m2 once weekly) and followed up for a 3-month period. Eight of the 15 patients were early pSS patients (mean disease duration 28 months, all had residual salivary gland function at baseline), and 7 patients had a concomitant mucosa-associated lymphoid tissue (MALT) lymphoma (mean disease duration 79 months).
In the early pSS patients, rituximab treatment resulted in significant improvement of subjective symptoms and an increase in salivary gland function. All patients showed a rapid depletion of peripheral B cells within a few weeks, accompanied by a decrease in IgM-RF levels [
8]. Repeated parotid gland biopsies in five of the early patients after treatment showed redifferentation of the lymphoepithelial duct lesions into normal striated ducts, possibly indicating regeneration of salivary gland tissue (unpublished data).
Five of the eight pSS patients without a MALT lymphoma received a second course of rituximab (after 9–11 months) due to recurrence of symptoms. Retreatment resulted in the same significant improvement of the salivary flow rate and subjective symptoms compared to the results of the first treatment, together with a decrease in B cells and IgM-RF levels.
Six of the seven MALT/pSS patients were initially effectively treated with rituximab. The remaining MALT/pSS patient had progressive MALT disease and severe extraglandular SS disease within 3 months after the start of rituximab treatment. Cyclophosphamide was added, which led to stable disease of both MALT and SS. One of the six patients initially responding had a recurrence of MALT lymphoma after 9 months and was successfully retreated with rituximab. The other patients are still in remission (unpublished data).
In another open-label study, 16 pSS patients received only two weekly rituximab infusions (375 mg/m
2), with a follow-up of 36 weeks. Again, treatment resulted in rapid complete depletion of peripheral B cells. At week 12, a significant improvement of VAS scores for fatigue and dryness was recorded, and at week 36, a significant improvement for VAS scores for global disease, fatigue, dry mouth, dry eyes, and dry vagina, but also in the number of tender joint and tender joint counts was seen [
25]. Both in the study of Pijpe et al. [
8] and the study of Devauchelle-Pensec et al. [
25], patients with a short disease duration showed more improvements than patients with longer disease duration.
Two trials retrospectively evaluated the effect of rituximab (four infusions of 375 mg/m
2) in 18 pSS patients (mean disease duration 10 years) with systemic features. Self-reported dryness improved in six patients (VAS scores not known for three patients, no improvement in the other nine patients). Both studies reported good efficacy of the treatment on systemic features [
26,
27].
In conclusion, in phase II trials, it has been shown that rituximab seems to be effective for at least 6–9 months in pSS patients with active disease, improving both subjective and objective complaints. Retreatment with rituximab resulted in a similar good clinical response. In pSS patients with longer disease duration, without residual salivary gland function, rituximab treatment seems to be effective for systemic features. To confirm these promising results, randomized placebo-controlled clinical trials are needed.
Anti-CD22 Monoclonal Antibodies
Epratuzumab is a fully humanized monoclonal antibody specific for the B cell surface molecule CD22. CD22 is expressed on the surface of normal mature and malignant B lymphocytes. CD22 appears to be involved in the regulation of B cell activation through B cell receptor signaling and cell adhesion [
28]. In an open-label phase I/II study, safety and efficacy of epratuzumab were investigated in 16 pSS patients. Follow-up was 6 months. These pSS patients received four doses of 360 mg/m
2 epratuzumab intravenously. Mean disease duration before therapy was 2.9 years, and none of the patients had received prior B cell-targeted therapy. Most improvements occurred in the Schirmer test, unstimulated whole salivary flow and the VAS score for fatigue. The new developed disease activity score consisted of the four domains: dryness of the eyes, dryness of the mouth, fatigue, and laboratory parameters. Based on this score, 53% achieved at least 20% improvement in at least two domains at 6 weeks. Corresponding rates for 10, 18, and 32 weeks are 53, 47, and 67%. Remarkably, the number of responders was higher 6 months after the treatment administration than earlier. Peripheral B cells decreased with a median decrease of 54 and 39% at 6 and 18 weeks, respectively.
In conclusion, epratuzumab seems to be an effective treatment. Randomized, placebo-controlled clinical trials are needed before epratuzumab can be advised for general treatment in pSS patients [
29].
Anti-BAFF
BAFF is a B cell-activating factor that acts as a positive regulator of B cell function and expansion. BAFF levels were found elevated in serum and saliva in SS patients, but no correlation could be shown between serum and saliva levels [
30]. However, circulating levels of BAFF in pSS patients were shown to be a marker for disease activity [
11].
To the best of our knowledge, no trials have been performed with anti-BAFF treatment in SS yet, but such an approach might be considered for future trials. Currently, two human BAFF antagonists have been developed, a human antibody (anti-BLyS) that binds to soluble BAFF and a fusion protein of one of the BAFF receptors [
31,
32]. Especially, SS patients with elevated BAFF levels, hypergammaglobulinemia, elevated levels of autoantibodies, and associated B cell lymphoma might be candidates for anti-BAFF treatment [
33].