**5. Therapeutic approaches**

Conventional therapy of SS is symptomatic and consists in alleviating of sicca features. As such, treatment consists in the use of artificial saliva and tears, surgical removal of plugs in the lachrymal ducts, the use of topical cyclosporine for ocular symptoms. Cholinergic drugs such as pilocarpine and civemeline are available to increase glandular secretion. Hydroxychloroquine is prescribed for arthralgia and myalgia, but recent studies have shown that it also has slight anticholinesterase properties in improving glandular function (Rihl et al., 2009). The efficacy of steroids is limited and restricted to patients with arthritis and severe extraglandular manifestations. Immunosuppressive treatments such as cyclophosphamide and azathioprine are used for systemic features of SS. More recently, newer immunosuppressive drugs, such as mizoribine and mycophenolate mofetil, have shown promising results. These drugs inhibit inosine monophosphate dehydrogenase, the rate-limiting enzyme for purine synthesis, and have an antiproliferative effect on activated lymphocytes (Becker et al., 2010). An intraoral electrostimulation device showed promising results in alleviating xerostomia and increasing salivary output (Strietzel et al., 2011).

#### **5.1 B-cell targeted therapies**

Rituximab, a chimeric monoclonal mouse antibody that targets CD20 at the surface of Bcells, is the most studied biologic therapy in SS. Several pilot studies have shown efficacy of rituximab in terms of improvement of fatigue, quality of life and glandular function. A randomized-controlled trial has confirmed these results (Meijer et al., 2010). Epratuzumab is a humanized antibody directed against the B cell antigen CD22. An open labeled trial has shown improvement of sicca symptoms and fatigue scores (Steinfeld et al., 2006).

#### **5.2 Inhibition of IFN release**

Interferon- (IFN) plays a pivotal role in the pathogenesis of several autoimmune diseases including SS. Besides antiviral effects, IFN- has immunomodulating properties. Four pilot studies have shown beneficial effects of oromucosal IFN-, whereby salivary flow was increased and salivary gland histology after treatment demonstrated reduced lymphocytic infiltrâtes (Cummins et al., 2003; Tobon et al., 2010). A phase III trial performed later, showed an increase in unstimulated salivary flow but the main clinical endpoint, which was improvement of stimulated salivary flow, was not met.

#### **5.3 Transplantation of bone-marrow-derived stem cells**

Stem cells from the spleen, when harvested and transplanted in NOD mice, an animal model for SS, have been shown to regenerate salivary epithelial cells (Faustman et al., 2010). Current undergoing trials are investigating whether the transplanted adult hematopoietic cells can restore glandular function in patients suffering from SS.

#### **5.4 Gene therapy**

52 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

involved, such as stomach or kidneys.The clinical and biological factors heralding imminent are low C4 levels, palpable purpura, high 2-microglobulin levels, CD4 lymphocytopenia, parotid gland swelling and persistent enlargement and hypocaptation on salivary scintigraphy, mixed monoclonal cryoglobulinemia, leg ulcers, splenomegaly and the

Conventional therapy of SS is symptomatic and consists in alleviating of sicca features. As such, treatment consists in the use of artificial saliva and tears, surgical removal of plugs in the lachrymal ducts, the use of topical cyclosporine for ocular symptoms. Cholinergic drugs such as pilocarpine and civemeline are available to increase glandular secretion. Hydroxychloroquine is prescribed for arthralgia and myalgia, but recent studies have shown that it also has slight anticholinesterase properties in improving glandular function (Rihl et al., 2009). The efficacy of steroids is limited and restricted to patients with arthritis and severe extraglandular manifestations. Immunosuppressive treatments such as cyclophosphamide and azathioprine are used for systemic features of SS. More recently, newer immunosuppressive drugs, such as mizoribine and mycophenolate mofetil, have shown promising results. These drugs inhibit inosine monophosphate dehydrogenase, the rate-limiting enzyme for purine synthesis, and have an antiproliferative effect on activated lymphocytes (Becker et al., 2010). An intraoral electrostimulation device showed promising results in alleviating xerostomia and increasing salivary output (Strietzel et al.,

Rituximab, a chimeric monoclonal mouse antibody that targets CD20 at the surface of Bcells, is the most studied biologic therapy in SS. Several pilot studies have shown efficacy of rituximab in terms of improvement of fatigue, quality of life and glandular function. A randomized-controlled trial has confirmed these results (Meijer et al., 2010). Epratuzumab is a humanized antibody directed against the B cell antigen CD22. An open labeled trial has

Interferon- (IFN) plays a pivotal role in the pathogenesis of several autoimmune diseases including SS. Besides antiviral effects, IFN- has immunomodulating properties. Four pilot studies have shown beneficial effects of oromucosal IFN-, whereby salivary flow was increased and salivary gland histology after treatment demonstrated reduced lymphocytic infiltrâtes (Cummins et al., 2003; Tobon et al., 2010). A phase III trial performed later, showed an increase in unstimulated salivary flow but the main clinical endpoint, which was

Stem cells from the spleen, when harvested and transplanted in NOD mice, an animal model for SS, have been shown to regenerate salivary epithelial cells (Faustman et al., 2010). Current undergoing trials are investigating whether the transplanted adult hematopoietic

shown improvement of sicca symptoms and fatigue scores (Steinfeld et al., 2006).

presence of serum or urine monoclonal bands (Voulgarelis and Moutsopoulos, 2008).

**5. Therapeutic approaches** 

**5.1 B-cell targeted therapies** 

**5.2 Inhibition of IFN release** 

improvement of stimulated salivary flow, was not met.

**5.3 Transplantation of bone-marrow-derived stem cells** 

cells can restore glandular function in patients suffering from SS.

2011).

Gene therapy consists in the introduction of new genetic material in an individual for therapeutic purposes. Several targets for gene therapy include aquaporins, inflammatory mediators, apoptotic molecules and intracellular molecules.

Initial gene therapy studies, using serotype 5 adenoviral vector (Ad5), showed extremely efficient *in vivo* gene transfer to rodent salivary glands (Mastrangeli et al., 1994). Further studies using Ad5 encoding human aquaporin 1 (Ad5hAQP1), a water channel, showed the function and potential utility of this vector to restore impaired saliva flow in rats with irradiated-induced salivary hypofunction (Delporte et al., 1997). The efficacy and scaling studies of this particular gene therapy were then performed in large animal models: rhesus macaques (O'Connell et al., 1999) and miniature pigs (Li et al., 2004). A NIH clinical trial using Ad5hAQP5 has been undertaken to test the safety and efficacy in individuals with irradiation-induced parotid salivary hypofunction.

Gene transfer therapies based on the anti-inflammatory properties of IL-10 and vasoactive intestinal peptide (VIP) have also been proposed as future treatment of SS. Indeed, administration of adenovirus vectors encoding either human IL-10 or VIP to salivary glands from NOD mice, a mouse model for SS, led to significant salivary flow improvement (Kok et al., 2003; Lodde et al., 2006).

Gene transfer has also been used to treat chronic sialadenitis and modulate apoptosis in a murine model of SS: B6-gld/gld mice deficient in Fas ligand. When infected with murine cytomegalovirus, these mice presented chronic sialadenitis similar to SS. Delivery of a recombinant adenovirus vector coding for Fas ligand to the salivary glands of these mice, induced a significant reduction in infiltrating lymphocytes (Fleck et al., 2001).

As IL17A administration to mice salivary glands, using recombinant adenoviral vector, leads to SS-like disease (Nguyen et al., 2011), localized anti-IL-17 might be effective in preventing glandular dysfunction.

#### **5.5 Other therapeutic perspectives**

BAFF is a cytokine that prevents apoptosis of B-cells and thereby contributes to the hyperreactivity of B cells and their survival. Increased BAFF secretion might explain in part the partial response of rituximab in SS patients. Targeting BAFF might therefore prove to be a future therapeutical approach (Mariette, 2008). In systemic lupus erythematous, an autoimmune disease that shares similar pathogenetic features with SS, in that both diseases are characterized by an interferon signature, Belimumab, an anti-BAFF monoclonal agent, has shown beneficial effects in a randomized controlled trial (Navarra et al., 2011). Atacicept, a fusion protein inhibiting B cell stimulation, could be a promising therapeutic drug in SS (Dorner et al., 2009).

Other therapeutic perspectives for SS also include the restoration of salivary glands function using bone marrow-derived cells (BMDCs) (Tran et al., 2011) and tissue engineering of salivary glands (Kagami et al., 2011). BMDCs transplantation by intravenous injection rescues salivary gland function in mice with head and neck irradiation by preventing apoptosis, increasing tissue vascularization, increasing the number of proliferating cells, and maintaining the putative salivary stem cells (Sumita et al., 2011; Lombaert et al., 2008). Furthermore, BMDCs transplantation into NOD mice treated as well with complete Freund's adjuvant (CFA), led to both qualitative and quantitative saliva restoration, and normoglycemia (Khalili et al., 2010). Tissue engineering of salivary glands utilizes cells, biodegradable scaffold, and signals to regenerate tissues. Since the pioneer work reporting

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