achieved complete remission were numerically but not statistically higher in the groups receiving higher IFN doses (150 IU t.i.d., 450 IU o.d., and 450 IU t.i.d.) compared to the low-dose (150 IU o.d.) or placebo groups. Increases in stimulated salivary flow did reach significance for the 150 IU t.i.d. group by week 12.

A phase III trial examined the efficacy of the 150 IU t.i.d.dose of IFN in 497 patients with pSS [12]. Treated patients had a significant increase in unstimulated whole salivary flow. Improvement in unstimulated whole salivary flow correlated with improvement in symptom scores for ocular and oral dryness. The primary endpoint of this study (increases in salivary flow and VAS for oral dryness) was not met. To date, oral low-dose IFN has not received approval for the treatment of SS. Yamada et al. [13] treated three patients with pSS and progressive, relapsing demyelinating polyneuropathy with interferon-a three million units three times weekly. The patients had previously failed therapy with glucocorticoids, multiple immunosuppressive agents, and IVIg. All three patients experienced significant improvement in their neurological symptoms and electrophysiologic parameters. In addition, improvement was noted in mononuclear infiltration upon repeat minor salivary gland biopsy and in SS-A and SS-B titers. Because the development of SS and SLE was described in an HCV patient treated with interferon-a 2b [14], a degree of caution should be used in considering IFN-a for therapy of SS.

39.3Mycophenolic Acid

Mycophenolic acid (MPA) is an oral immunosuppressive agent established for suppression of transplant rejection. More recently, MPA has been shown to be efficacious in the treatment of lupus nephritis. MPA selectively inhibits inosine monophosphate (IMP) dehydrogenase. Inosinic acid is the ribonucleotide of hypoxanthine and is the initial nucleotide formed in purine synthesis. Since proliferation of activated T and B lymphocytes is dependent on de novo purine synthesis, IMP dehydrogenase inhibition by MPA has proven useful for the treatment of autoimmune disease.

Willeke et al. [15] conducted a prospective open-label pilot study of MPA in 11 patients fulfilling American-European Consensus Criteria for pSS. MPA was administered in the form of mycophenolate sodium (MPS) starting with 360 mg daily and increasing to a maximum of 1,440 mg daily; a dose equivalent to 2 g of mycophenolate mofetil (MMF). Eight patients completed the study. Two patients withdrew due to adverse affects (GI intolerance and vertigo). One patient was withdrawn following hospitalization for pneumonia. Significant improvement was noted in VAS for sicca complaints and requirement for artificial tears. Although there was some improvement in the Schirmer test, this was not significant. It was noted, however, that a major improvement in glandular function was noted in two patients with relatively short disease duration. Significant reduction was seen in levels of gamma globulins, total IgM, and rheumatoid factor. Further study of mycophenolate in early SS patients appears warranted.

39.4Mizoribine

Another IMP dehydrogenase inhibitor, mizoribine, was originally developed as an antifungal agent in Japan. Initially approved in that country for the suppression of renal transplant rejection, mizoribine has subsequently been used to treat RA, SLE nephritis, and idiopathic nephrotic syndrome [16]. Nakayamada et al. conducted a multicenter open-label clinical trial in 59 patients who fulfilled the Japanese Ministry of Health and Welfare’s diagnostic criteria for SS. The patients were treated with mizoribine 50 mg t.i.d. for 16 weeks [17]. The authors noted a significant improvement in salivary secretion volume (measured at 2 min), patients’ assessments of dry mouth and dry eye symptoms, and physician global assessment. Differences in immunological parameters, including total immunoglobulins and levels of Ro and La antibodies, were not noted. Approximately 30% of patients experienced adverse events, the most common of which were liver function test abnormalities, cytopenias, and gastrointestinal symptoms. These authors also examined response to mizoribine in relation to the degree of histologic change on minor salivary gland biopsy [18]. Patients with moderate degrees of lymphocytic infiltration, fibrosis, and acinar atrophy demonstrated superior responses to mizoribine as compared to those with mild or severe degrees of these histologic categories. As shown for the other IMPDH inhibitor, mycophenolate (above) in preliminary studies, patients with earlier stages of disease may be responsive to these agents.

39.5Rebamipide

Rebamipide is a cytoprotective agent used in Japan primarily to treat peptic ulcer disease [19]. Rebamipide inhibits NSAID-induced gastric mucosal damage in animals. Its major mechanism of action was believed initially to be enhancement of local prostaglandin synthesis accomplished by induction of COX-2 and upregulation of EP4 receptor gene expression, ultimately resulting in the stimulation of mucus secretion. More recently, rebamipide has been shown to enhance the local production of growth factors such as epidermal growth factor (EGF), hepatocyte growth factor (HSF), and vascular endothelial growth factor (VEGF). Rebamipide also induces heat shock proteins and anti-oxidant mechanisms, such as the inhibition of lipid peroxidation.

Because rebamipide is believed to exert its positive effects on ulcer healing via the promotion of tissue healing, its potential efficacy in chronic inflammatory disorders has been studied. Rebamipide administered per rectum has demonstrated efficacy in inflammatory bowel disease. Studies have shown positive results in stomatitis secondary to Behcet’s disease. Because of its protective effect on mucosa, rebamipide has been studied for xerostomia in SS. In a double-blind placebo-controlled trial, Sugai et al. [20] administered rebamipide at a dose of 100 mg t.i.d. to 104 subjects with SS. Patients with pSS but not secondary SS treated with rebamipide

demonstrated a significant increase in salivary secretion at weeks 2, 4, and 8. For all SS subjects, there was a trend toward improvement in overall dry mouth symptoms and objective dry mouth findings, but these differences were not statistically significant. Approximately two-thirds of patients in the active and placebo groups experienced adverse effects. The majority of these were gastrointestinal symptoms that did not lead to withdrawal from the study. There were no significant differences between the rebamipide and control groups in the incidence or type of adverse events experienced.

39.6Diquafosol

Diquafosol is a water-soluble dinucleotide (diuridine tetraphosphate) in development as a topical ocular surface disease-modifying agent for dry eye including that caused by SS [21]. Diquafosol is a selective purine receptor agonist targeted toward the stimulation of P2Y2 receptors. Topical diquafosol stimulates these receptors at the ocular surface, resulting in stimulation of secretion from multiple components of the ocular surface. P2Y2 receptor stimulation stimulates fluid and ion secretion at the conjunctival surface via non-glandular mechanisms. In addition, diquafosol enhances goblet cell mucin production. P2Y2 receptors have been shown to be present on the Meibomian gland and are thought to stimulate ocular lipid production. Thus, diquafosol appears to be capable of increasing tear production and restoring tear composition to a more normal state. Several phase III trials have been conducted comparing diquafosol to placebo. All trials demonstrated an improvement in corneal staining, although not all endpoints were met for all trials [22]. Diquafosol remains a potentially important treatment for dry eye in SS.

39.7Cladribine

Cladribine (2-chloro-2-deoxy adenosine; 2-Cda) is a purine nucleoside analogue with selective activity toward lymphocytes and monocytes. 2-Cda may also function by epigenetic mechanisms including inhibition of DNA methylation and is especially active in CD4+, CD8+ T lymphocytes and CD19+ B cells [23]. Initially approved for hairy cell leukemia, 2-Cda has been used to inhibit progression in CLL, both B cell neoplasms. Accordingly, 2-Cda has also been studied in autoimmune disorders including lupus nephritis. Most recently, oral 2-Cda has demonstrated efficacy in relapsing multiple sclerosis [24].

Voulgarelis et al. [25] reported on four patients who had pSS as well as some aspect of lymphoproliferative disorder including lymphoma or cryoglobulinemia with an IgM kappa monoclonal component. Three of four patients had long-term remission of the B cell–associated lymphoproliferative process. Some SS symptoms improved, including parotid swelling and oral dryness. A randomized study of

oral cladribine in SS, particularly for those with lymphoproliferative features, would be required to demonstrate clinical utility for the exocrine and lymphoproliferative features of SS.

39.8Fingolimod

Fingolimod (FTY 720) is a modulator of sphingosine-1-phosphate receptor (SIP1) signaling. Effects of fingolimod on lymphocytes are mediated in part by SIP1 antagonism and include inhibition of egress from secondary lymphoid tissue and suppression of IFN-gamma secretion from CD4+ lymphocytes. Recently, clinical trials have demonstrated efficacy of fingolimod for relapsing multiple sclerosis [26], and thus, may be useful in other autoimmune disorders including SS. An SIP1 modulator capable of inhibiting lymph node egress of activated T cells that subsequently target lacrimal and salivary glands would be a particularly useful property for a therapeutic agent in SS. While to date, there are no clinical trials of fingolimod in pSS, Sekiguchi and colleagues demonstrated the presence of SIP1 in inflammatory cells, vascular endothelium, and salivary gland epithelium in biopsies of minor salivary glands. SIP1 expression was enhanced in biopsies from patients with advanced disease. SIP1 enhanced gamma-interferon production from CD4+ cells. SIP1-mediated enhancement was greater in CD4+ cells obtained from SS patients [27]. Further investigation of the therapeutic potential of fingolimod in animal models of SS may provide data leading to performance of clinical trials.

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16. Moutsopoulos HM, Fragoulis GE. Is mizoribine a new therapeutic agent for Sjögren’s syndrome? Nat Rev Rheumatol. 2008;4:350–1.

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Chapter 40

B-Cell-Targeted Therapies in Sjögren’s

Syndrome

Xavier Mariette

Contents

X. Mariette

Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP),

Université Paris-Sud 11, Le Kremlin Bicêtre, France

Institut Pour la Santé et la Recherche Médicale (INSERM), Paris, France