and advocated for and advised on an National Institute of Dental and Craniofacial Research (NIDCR) sponsored international registry in SS (SICCA) at the University of California, San Francisco (UCSF). The NIDCR-funded SICCA registry marks the largest SS research grant awarded by the NIH.

Over the last decade, the Þrst-ever FDAapproved drugs for SS came to market: Salagen and Evoxac for dry mouth and Restasis for dry eye. More recently, additional drugs have been approved for marketing: Numoisyn, Neutrasal, and CalphoVess for dry mouth and FreshKote for dry eye. All of these drugs, however, target speciÞc symptoms and signs of SS and do not treat the underlying immunological basis for the disease or its many systemic manifestations. The Foundation believes that the consortium will serve to accelerate the discovery and clinical development of novel agents that will treat the underlying disease process and thus systemic complications. More than two dozen candidate drugs/biologics either in development or already approved for use in other closely related autoimmune diseases have been identiÞed and targeted for review and discussions with the companies that manufacture or market them.

As we enter an era characterized by an everexpanding repertoire of effective biologic therapies for multiple autoimmune disorders, it is anticipated that a number of these therapies will also have the potential for clinical efÞcacy in SS. For example, the successful clinical development of Benlysta for the treatment of systemic lupus erythematosus (SLE) will soon result in an FDA regulatory submission for approval (NDA). Such a targeted B-cell therapy and others in development are ideal candidates for clinical trials in SS. A number of early stage clinical trials already have been or are being conducted with B-cell therapies in SS. The SSF has worked closely with the companies sponsoring these clinical trials to expand the potential clinical indications to SS. The SSF Clinical Trials Consortium will continue to interface with biotechnology/pharmaceutical companies to facilitate the development of new therapies and provide guidance in the conduct, design, and execution of clinical trials.

31.3Professional Education and Awareness

Efforts to improve education and awareness about SS among various health care professionals who treat this complex, multifaceted disorder are a major focus of the SSF. The SSF has developed a number of approaches to attain these goals. The Þrst-ever publication for professionals, the Sjögren’s Quarterly, was launched in 2006, providing a unique educational resource for clinicians and researchers. By early 2010, about 4,000 US professionals were receiving the newsletter as well as another 500 international recipients. Annual meetings organized by the SSF at the American College of Rheumatology (ACR) address the latest topics of interest to rheumatologists such as the promise of new therapeutics in SS. Additionally, SSF leaders have partnered with the ACR to increase the number of SjšgrenÕs-related workshops and symposia presented at its national and regional meetings. A Nursing Education Committee was also formed to provide updated presentations on SS as a womenÕs health issue to the nursing community. A basic guide on all aspects of SjšgrenÕs syndrome, The Sjögren’s Syndrome Handbook, is published by Oxford University Press as an ofÞcial publication of the SSF and is regularly updated.

In order to increase our knowledge about disease morbidity in SS patients and provide this information to educate physicians, the SSF in 2007 worked with Harris Interactive and a company sponsor to compile a major survey of SS patients. The study on Burden of Illness and General Health-Related Quality of Life in a US SjšgrenÕs Syndrome Population has led to numerous publications in professional journals and presentations at professional conferences.

The Foundation also provides educational materials for physicians to distribute to their patients, including brochures, booklets on selfhelp tips, and products for symptoms of SS. Medical professionals are encouraged to join the SSF and invite their patients also to become members and receive ÒThe Moisture Seekers,Ó

32.1Introduction

We are in an era of potent biological treatments for rheumatic diseases. SpeciÞc cytokines and cytokine receptors can be efÞciently blocked, interactions between T and B lymphocytes can be targeted, co-stimulatory receptors on T cells can be blocked, and B-cell or T-cell populations can be drastically reduced or eliminated through the administration of monoclonal antibodies. Primary SjšgrenÕs syndrome seems ripe for intervention with biologicals. The central abnormality is abnormal accumulation of lymphocytes in exocrine organs. Strategies to destroy these unwelcome lymphocytes, to neutralize the harmful cytokines they secrete, or to interfere with their trafÞcking are attractive solutions to the problem of ectopic lymphocyte accumulation. Somewhat less attractive approaches are to inhibit the global reactivity of T or B cells with monoclonal antibodies or to inhibit cellular interactions.

Given the lack of any speciÞc therapy for SjšgrenÕs syndrome (SS), physicians have begun to administer various biological agents in the hope of intervening in a beneÞcial way to reduce the cellular inÞltrate so characteristic of SS and, more importantly, to reverse or ameliorate functional changes wrought by SS autoimmunity. In this chapter, we will discuss the rationale for therapy, review the published experience with biological agents, and outline promising future directions in this area.

32.2For Which Patients Should Biological Therapy Be Considered?

SjšgrenÕs syndrome manifestations are highly variable, ranging from localized sicca symptoms to serious complications of central nervous system disease, vasculitis, and cytopenias. Given the cost and risk of present biological therapy, it seems reasonable that patients with severe systemic manifestations of SS, particularly those refractory to conventional therapy, are the

candidates for biological therapy. These would include patients with severe vasculitis, cryoglobulinemia, neurological manifestations (both CNS and peripheral), cytopenias, and severe and active interstitial lung disease. Patients with severe parotid enlargement and intractable ophthalmological problems related to sicca have been considered candidates in some trials. Less clear is the use of biological agents in patients with disabling fatigue. The development of validated clinical assessment tools for SS disease severity should help clarify just which patients have disease sufÞciently active or severe to merit biological treatment.

Should biological therapy be given early in the course of disease or should it be reserved for patients with advanced pathology? Late in the course of disease, much of the architecture of exocrine glands becomes obliterated due to scarring and Þbrosis. It seems sensible that candidates for therapies aimed at intervening in active immunological processes should have evidence of ongoing destruction of tissue. As biological markers of SjšgrenÕs syndrome activity are not readily available, clinical assessment is needed. In a B-cell depletion study cited below, patients with salivary ßow rates less than 0.15 mL/min were excluded in an effort to select those with the most potential to beneÞt.

32.3Scientific Rationale for Biological Treatment

Any biological intervention to ameliorate SS must consider the mechanisms of lymphocytic inÞltration in the illness; the trafÞcking and turnover of inÞltrating cells; the mechanism of epithelial injury; and the potential degree of reversibility of pathology.

Lymphocytes in SS lesions must enter glandular tissue from the circulation and then must localize in tissue through the action of adhesion molecules and chemokines. In particular, CXCL13 and CCL21 [1] seem of special importance in T-cell trafÞcking to exocrine glands. As will be discussed later, intervention at the level

of lymphocyte migration is an exciting approach that has not yet been tried.

Once lymphocytes are in glandular tissue, their activation and their generation of local immune responses provide opportunities for intervention. Both T and B lymphocytes are present in inßammatory inÞltrates, and both show evidence of activation as assessed by acquisition of co-stimulatory molecules, other activation molecules, and class II MHC molecules [2]. Whether T-cell activation precedes and causes B-cell activation, or vice versa, is still a matter of controversy and therapeutic trials of biologics may help to resolve this question. T cells may cause tissue injury through cytokine production, through cognate interactions with B cells mediated by CD40ÐCD40L, and via secretion of cytokines [3]. This injury may take the form of induction of apoptosis in glandular epithelial tissue, with consequent destruction and loss of secretory function, as well as the injury and interruption of autonomic nervous system pathways, leading to impaired glandular innervation and decreased tear or saliva production [4]. Targeting of T cells, and in particular of T-cell subsets in affected tissues, might lead to decreased glandular inÞltration and damage.

T cells may enhance activation of B cells or may act to attract them to glands. Alternatively, SS pathology may predominantly be due to glandular attraction and accumulation of B cells. Once within tissues, B cells may mediate injury by cytokine production, by presentation of antigens, and by secretion of antibodies with potential functional consequences.

32.4TNF-α(alpha) Inhibition

Tumor necrosis factor-α (TNF-α) is expressed in salivary gland duct cells in patients with SjšgrenÕs syndrome. TNF-α initiates the release of matrix metalloproteinases from glandular epithelial cells, triggers the expression of endothelial adhesion molecules, and promotes the inßux of mononuclear cells into the salivary glands and other epithelia such as lung and

kidney. The administration of pegylated recombinant methionyl human soluble TNF receptor type I in animal models of SjšgrenÕs syndrome prevented lymphocytic inÞltration into lacrimal and salivary glands and blocked the development of autoimmunity [5]. These Þndings provided the basis for investigating TNF-α inhibition. The three primary biologic agents targeting tumor necrosis factor-α are the chimeric monoclonal IgG1 antibody inßiximab, the receptor fusion protein etanercept, and the fully humanized monoclonal antibody adalimumab. The initial studies of anti-TNF-α therapy for SjšgrenÕs syndrome appeared promising, however, subsequent studies failed to demonstrate efÞcacy of TNF-α inhibitors.

A pilot study and a 1-year follow-up trial with inßiximab showed improvement in objective and subjective parameters of SjšgrenÕs syndrome tested. In the pilot study, 16 patients with primary SjšgrenÕs syndrome received 3 infusions (3 mg/kg) at weeks 0, 2, and 6, which yielded signiÞcant improvement in global assessments, erythrocyte sedimentation rate, whole salivary ßow rate, tear secretion, tender joint count, fatigue score, and sensation of dry eyes and dry mouth [5]. In the follow-up study, a maintenance regimen of 1 infusion every 12 weeks was evaluated in 10 of the original 16 patients. Retreatment led to sustained improvement of primary SjšgrenÕs syndrome that was comparable with the effects from the initial three loading infusions [6]. However, a subsequent large randomized, double-blind, placebo-controlled study, the Trial of Remicade In Primary SjšgrenÕs Syndrome (TRIPSS) failed to conÞrm any beneÞt of inßiximab monotherapy. In this multicenter trial, 103 patients with active primary SjšgrenÕs syndrome were randomly assigned to either receive treatment with inßiximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and had follow-up over a 22-week period. There were no signiÞcant differences found in

erythrocyte sedimentation rate, or C-reactive protein [7].

Etanercept has also been evaluated in a small prospective uncontrolled study and a randomized placebo controlled pilot study. The Þrst study evaluated 15 patients with primary SjšgrenÕs syndrome treated with 25 mg of etanercept given subcutaneously twice a week for 12 weeks along with repeated treatments for up to 26 weeks. There was no reduction in sicca symptoms or signs; however, there was a decrease in fatigue in a subset of four patients as well as a reduction in erythrocyte sedimentation rate [8]. The second study evaluated subcutaneous administration of etanercept versus placebo in 28 patients for 12 weeks and also showed no signiÞcant clinical efÞcacy [9]. No trials of adalimumab treatment in primary SjšgrenÕs syndrome have been reported.

TNF-α may not have the critical role in SjšgrenÕs syndrome as previously thought given the results of the above studies. The failure of TNF-α blockade to protect BAFF-transgenic mice against autoimmunity may also provide insight for the observed lack of efÞcacy of TNF-α blockers in humans. BAFF-transgenic mice developed SjšgrenÕs syndrome-like features and inhibition of TNF-α in these mice did not alter secretion of autoantibodies and salivary lesions [10]. Additionally, in human SS, TNF- α inhibition with etanercept was associated with increased levels of interferon-α and BAFF [11]. Another potential explanation for the inefÞcacy of TNF-α blockers may be that TNF-α blockers administered systemically did not achieve therapeutic levels in the target glands [12]. None of the above studies evaluated tissue levels of the drugs or local TNF-α activity before or after treatment. Local gene transfer of a TNF-α blocker to salivary and lacrimal glands was successful in preventing and in some cases reversing the damage in animal studies [13].

32.5B-cell Depletion

The presence of hypergammaglobulinemia and various autoantibodies such as rheumatoid factor and anti-SSA/SSB antibodies in SjšgrenÕs syndrome provide evidence of B-cell hyperactivity.

B-cell inÞltrates, largely consisting of memory B cells, have been found in salivary gland biopsy specimens [14]. Five percent of patients with SjšgrenÕs syndrome develop malignant B- cell lymphoma, usually the mucosa-associated lymphoid tissue (MALT) type [15]. Rituximab is a chimeric humanized monoclonal antibody directed against the B-cell surface molecule CD20, which is expressed on the surface of normal and malignant pre-B and mature B lymphocytes. Rituximab leads to peripheral blood B-cell depletion for a period of 6Ð12 months. Rituximab was Þrst developed for the treatment of B-cell lymphoma and subsequently has been applied to various autoimmune disorders [16].

Several case series demonstrate the potential of rituximab as a therapeutic agent in SjšgrenÕs syndrome. One phase II study evaluated 15 patients with primary SjšgrenÕs syndrome treated with 4 infusions of rituximab (375 mg/m2) once weekly and observed over a 3-month period. Eight of the patients had primary SjšgrenÕs syndrome for less than 4 years and seven patients had MALT-type lymphomas. There was favorable 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. Three of the seven patients with MALT-type lymphoma had a complete remission, three remained stable, and one progressed. Additionally, a high incidence of human antichimeric antibodies (HACA) and associated side effects such as serum sickness were observed [17]. In one patient who underwent biopsy before and after treatment, there was improvement in salivary gland histological appearance with apparent regeneration of ductal tissue, along with an increased salivary ßow [18].

In a retrospective study, six patients with primary SjšgrenÕs syndrome treated with four infusions of rituximab (375 mg/m2) once weekly were evaluated. Five of the six patients had regression of parotid gland swelling and improvement of arthralgias. Two of the six patients had major improvement in cryoglobulinemiarelated vasculitis [19]. A third study examined 16 patients with primary SjšgrenÕs syndrome who

received rituximab for lymphoma and systemic manifestations. Four of 5 patients with lymphoma obtained complete remission and efÞcacy was observed in 9 out of 11 patients with systemic involvement. Rituximab use also allowed a signiÞcant reduction in corticosteroid use and decreased serum B-cell biomarker levels [20]. In another study, 16 patients with primary SjšgrenÕs syndrome received 2 infusions of rituximab (375 mg/m2) at weeks 0 and 2 without corticosteroids and had follow-up over 36 weeks. Visual analog scale (VAS) scores for fatigue and dryness, tender point count, and quality of life evaluated by the Short Form 36 questionnaire (SF-36) at week 12 were signiÞcantly improved. At week 36, signiÞcant improvement continued with both tender point count and tender joint count [21].

One double-blind randomized pilot study investigated 2 infusions of rituximab (1 g) versus placebo in 17 patients with primary SjšgrenÕs syndrome with follow-up over 6 months. SigniÞcant improvement from baseline in VAS scores for fatigue in the rituximab group as compared to the placebo group was noted. There was also a signiÞcant difference between the groups at 6 months in the social functioning score of SF-36 and the mental health score of SF-36 [13]. This study was the Þrst double-blind study of rituximab in primary SjšgrenÕs syndrome to demonstrate beneÞt but outcome measures were somewhat limited.

Another double-blind placebo study of rituximab in primary SjšgrenÕs syndrome was recently presented. Thirty patientsÑselected to have salivary ßow rates above 0.15 mL/minÑwere randomized to rituximab treatment (20 patients) or placebo. All patients received IV methylprednisolone before infusion and a tapering course of oral prednisolone afterward. There was signiÞcant improvement in salivary secretion rates in the rituximab-treated group, with a decrease observed in the placebo group. Rheumatoid factor levels fell substantially in the B-cell depleted patients and were slightly increased in the placebo group. There was a signiÞcant improvement in the visual analog scale score for oral

dryness in the rituximab group. Interestingly, both placebo and actively treated groups reported an improvement in generalized fatigue, but those rituximab-treated patients whose disease duration was less than 4 years showed the greatest degree of improvement. Only one patient developed serum sickness, which was judged to be mild. This study is encouraging and suggests that patients with earlier and more active disease are more likely to beneÞt from B-cell depletion therapy than are patients with long-standing illness [22].

An open trial of rituximab in 12 patients with primary SS showed signiÞcant improvement in physiciansÕ and patients VAS, yet no signiÞcant change in saliva production [23]. All patients underwent nearly complete B-cell depletion, and at the time of reconstitution peripheral B cells showed a transitional phenotype (CD19+, CD38hi, IgM+, IgD+, CD5+, CD10+, CD23+, CD27+). There was also an increase in the percentage and absolute numbers of peripheral blood B cells with a plasmablast phenotype (CD19+, CD20−, CD38hi, IgD−, CD27++) prior to the increase in transitional B cells [24]. Patients showed low levels of peripheral blood CD27+ memory cells after reconstitution, suggesting that this feature of the SjšgrenÕs phenotype may have been corrected, at least temporarily. There were no changes in CD4, CD8, NK, or T regulatory cells. Levels of IgG autoantibodies were unchanged, but there was a decrease in IgA autoantibodies against Ro and M3 muscarinic receptors [25].

32.6Monoclonal Antibody Modulation of B-cell Function

An alternative target for B-cell depletion is the B-cell-speciÞc transmembrane protein CD22, co-receptor of the B-cell receptor (BCR) that functions as a negative regulator of BCR signaling. Epratuzumab is a fully humanized monoclonal antibody to CD22 that has been investigated in primary SjšgrenÕs syndrome. Compared with rituximab, epratuzumab provokes