Robert I. Fox

Sjögren's syndrome

The literature published over the past year on Sjögrens syndrome is reviewed, including epidemiology, genetic, environmental, and clinical features. The criteria for the classification of Sjögrens syndrome remain controversial, potentially leading to confusion in clinical practice and in research publications. Dryness of the eyes and mouth can result from either interruption of the neurovascular innervation of the glands or from any infiltrative process that affects the ability of the glands to secrete. Recent studies have demonstrated that sicca symptoms also can result from autonomie neuropathy in patients with diabetes, multiple sclerosis, or systemic lupus erythematosus. It is suggested that the term Sjögrens syndrome be used to describe one subset of patients with sicca symptoms who exhibit particular major histocompatibility complex antigens, the presence of T cell lymphoid infiltrates on glandular biopsy, and specific autoantibodies in their sera. Even using these restrictive criteria for classification, no single environmental factor has been shown as necessary or sufficient for pathogenesis. Recent studies on Epstein-Barr virus have indicated a novel deleted virus in some Chinese Sjögrens syndrome patients. Other patients with sicca symptoms and autoimmune features may have infections with HIV or hepatitis C virus.

PATHOGENESIS AND TREATMENT OF SJOGREN'S SYNDROME

The criteria for diagnosis of primary Sjögrens syndrome continue to be controversial, leading to confusion in clinical practice and in the research literature. Among Sjögrens syndrome patients who fulfill the European criteria, only 15% of those would fulfill the San Diego criteria. This difference in disease classification leads to difficulty in evaluating clinical trials and in elucidating pathogenetic mechanisms, because different patient populations are evaluated. As a result of the ease and safety of minor salivary gland biopsy, Sjögrens syndrome serves as a prototype model to study the immunopathogenic features of a human organ-specific autoimmune disease. Critical features of pathogenesis include: 1) failure to delete autoimmune T cells at the level of thymic selection; 2) homing of autoimmune lymphocytes to salivary and lacrimal glands via high endothelial venules; 3) clonal expansion of autoimmune T cells in the glands; 4) upregulation of major histocompatibility antigens and adhesive molecules by epithelial cells in the glands; 5) secretion of proinflammatory cytokines by both lymphocytes and epithelial cells; 6) decreased neural innervation of the glands; 7) failure of residual glandular tissue express secretory functions; and 8) failure to remove autoimmune T cells by normal mechanisms of apoptosis. Each of these steps is regulated by cell-matrix interactions, cytokine and growth factor secretion, cell membrane receptor stimulation, second signals in the cytoplasm, and nuclear transcription factors. Recent studies on each of these steps in Sjögrens syndrome have suggested their role in pathogenesis and, consequently, their potential as sites for therapeutic intervention.

Evolving concepts of diagnosis, pathogenesis, and therapy of Sjögren's syndrome.

Differences in diagnostic criteria for Sjögrens Syndrome (SS) have led to confusion in the research literature and in clinical practice. A particular challenge is the clinical diagnosis of the patients with sicca symptoms, fibromyalgia, chronic fatigue, vague cognitive defects, and a low titer antinuclear antibody. Until recently, many of these patients would have been classified as primary SS using the European criteria. A suggested revision of the European criteria will require inclusion of anti SS-A antibody or characteristic minor salivary gland biopsy, leading to greater agreement between European and San Diego criteria. Recent studies have emphasized that lacrimal and salivary gland flow involves an entire functional unit that includes the mucosal surface (the site of inflammation), efferent nerve signals sent to the midbrain (lacrimatory and salvatory nucleus), efferent neural signals from the brain, and acinal/ductal structures in the gland. Thus, symptoms of dryness or pain can result from interferences with any part of this functional unit. The initiating antigens in SS remain unknown, but immune reactivity against SS-A, SS-B, fodrin, alpha- amylase, and carbonic anhydrase have been demonstrated in patients with established disease. The inflammatory process in the gland releases metalloproteinases that alter the relationship of epithelial cells to their matrix, an interaction that is necessary for glandular function and survival. Therapies for SS remain inadequate. In SS patients with immune-mediated extraglandular manifestation (ie, lung, kidney, skin, nerve), the therapeutic approach is similar to systemic lupus erythematosus, although these therapies have relatively little effect on tear or saliva flow.

Molecular Analysis of the Human Autoantibody Response to α-Fodrin in Sjögren's Syndrome Reveals Novel Apoptosis-Induced Specificity

Lymphocyte infiltration of salivary and lacrimal glands leading to diminished secretion and gland destruction as a result of apoptosis is thought to be pivotal in the pathogenesis of Sjögrens syndrome (SS). The cytoskeletal protein alpha-fodrin is cleaved during this apoptotic process, and a strong antibody (Ab) response is elicited to a 120-kd fragment of cleaved alpha-fodrin in the majority of SS patients, but generally not in other diseases in which apoptosis also occurs. Little is known about the anti-alpha-fodrin autoantibody response on a molecular level. To address this issue, IgG phage display libraries were generated from the bone marrow of two SS donors and a panel of anti-alpha-fodrin IgGs was isolated by selection on alpha-fodrin immunoblots. All of the human monoclonal Abs (hmAbs) reacted with a 150-kd fragment and not with the 120-kd fragment or intact alpha-fodrin, indicating that the epitope recognized became exposed after alpha-fodrin cleavage. Analysis of a large panel of SS patients (defined by the strict San Diego diagnostic criteria) showed that 25% of SS sera exhibited this 150-kd alpha-fodrin specificity. The hmAbs stained human cultured salivary acinar cells and the staining was redistributed to surface blebs during apoptosis. They also stained inflamed acinar/ductal epithelial cells in SS salivary tissue biopsies, and only partially co-localized with monoclonal Abs recognizing the full-length alpha-fodrin. Our study shows that in SS patients, neoepitopes on the 150-kd cleaved product of alpha-fodrin become exposed to the immune system, frequently eliciting anti-150-kd alpha-fodrin Abs in addition to the previously reported anti-120-kd Abs. The anti-150-kd alpha-fodrin hmAbs may serve as valuable reagents for the study of SS pathogenesis and diagnostic analyses of SS salivary gland tissue.

Classification criteria for Sjogren's syndrome: nothing ever stands still!

Primary Sjogrens syndrome (SS) probably has the dubious distinction of having more proposed criteria than any other rheumatic condition—certainly this was the case in the 1980s and 1990s (eg, Copenhagen,1 Californian,2 Greek3 and Japanese4 criteria). In 2002, Vitali et al 5 published the revised American European Consensus Group (AECG) criteria, which have now served as the gold standard for over 10u2005years. In 2012, Shiboski et al 6 published an alternative set of criteria, provisionally adopted by the American College of Rheumatology (ACR). These latter criteria (Sjogrens International Collaborative Clinical Alliance (SICCA-ACR)) are based on objective criteria and do not necessarily require patients to have symptoms of dry eyes or dry mouth. The study by Rasmussen et al 7 examines patients with primary SS in a large cohort who fulfil either the existing AECG criteria and/or the newly proposed SICCA–ACR criteria, and discusses the similarities and differences between them with some important lessons for the field.nnThe AECG criteria were developed to screen patients with a specific set of questions regarding dryness and then validate the diagnosis with a series of objective tests that indicated immune factors in the pathogenesis. The questionnaires were developed by an expert consensus panel for sensitivity and specificity as an initial screening tool. The AECG criteria require the presence of four out of six components (one of which is symptomatic dry eyes and a second is symptomatic dry mouth), or three out of the four other objective components, although in either case one of the components has to be positive antibodies and/or a positive biopsy. The four objective components are: (1) positive anti-Ro and/or anti-La antibodies; (2) a positive labial gland biopsy defined as at least one periductal focus of 50 or more lymphocytes per 4u2005mm2 high powered field; (3) reduced …

Sjogren’s syndrome: evolving therapies

Sjogren’s syndrome (keratoconjunctivis sicca) is a relatively common disorder with incidence of ∼ 0.5% of adult women. It has both local (ocular and oral) features as well as systemic manifestations. There has been recent FDA approval of agents to stimulate salivation (pilocarpine and cevimeline) and studies are in progress to determine their role in the treatment of dry eye. New therapies are in clinical trials for ocular manifestations with the most interest focused on topical cyclosporin A and purinogenic receptor agonists. In oral therapy, topical human interferon has reported encouraging results in short-term studies. However, the high placebo response (probably reflecting the beneficial response of mechanical stimulation of the buccal mucosa by the lozenge) and the response to much cheaper therapies (such as acid maltose lozenges) may offer safer and cheaper alternatives. For systemic disease, there is interest in tumour necrosis factor inhibitors. However, the cost-effectiveness and safety of biological agents needs longer term follow up, as they appear much less dramatic in their effect on systemic lupus erythematosus or Sjogren’s syndrome than in rheumatoid arthritis.

Early diagnosis of primary Sjögren's syndrome: EULAR-SS task force clinical recommendations

ABSTRACT Sjögren’s syndrome (SjS) is a systemic autoimmune disease that mainly affects the exocrine glands, leading to generalized mucosal dryness. However, primary SjS may initially present with non-sicca (systemic) manifestations. When these features appear before the onset of an overt sicca syndrome, we may talk of an underlying ‘occult’ SjS. The European League Against Rheumatism (EULAR) has promoted and supported an international collaborative study group (EULAR-SS Task Force) aimed at developing consensual recommendations to provide a homogeneous approach to the patient with primary SjS presenting with systemic involvement. This review summarizes the key factors that should be taken into account in the diagnostic approach in a patient with suspected SjS according to the main clinical patterns of presentation, and is especially focused on organ-specific systemic disease presentations, including a consensus set of recommendations in order to reach an early diagnosis. Close collaboration with the different specialties involved through a comprehensive multidisciplinary approach is essential in SjS patients presenting with systemic involvements.

IgG4 levels and plasmablasts as a marker for IgG4-related disease (IgG4-RD)

Stone and his coworkers present two elegant papers on IgG4-related disease (IgG4-RD).1nnIn ‘The Diagnostic Utility of Serum IgG4 Concentrations in IgG4-Related Disease’, Carruthers et al 2 retrospectively analysed charts of 190 patients with elevation of IgG4. They also randomly selected 3360 charts with normal IgG4 levels and reviewed 190 cases for characteristics of IgG4-RD. They found: nnIn a closely related study by the same group, Wallace et al describe the ‘Diagnostic Utility of Plasmablasts as a Biomarker for IgG4 Related Disease (IgG4 RD) Independent of Serum IgG4 Levels’. nnSince we see patients with possible IgG4-RD in a variety of organs (table 1) that are often not easy to biopsy, serum IgG4 levels have incorrectly become a ‘surrogate’ marker for IgG4-RD in clinical practice.3 ,4 These articles will make us take a hard look at our current diagnostic approach to IgG4-RD.nnView this table:nnTablexa01 nIgG4-Related Diseases (IgG4-RD) are a Family Immuno-proliferative DisordersnnnnView this table:nnTablexa02 nDiagnostic criteriaxa0for IgG4-Related DiseasennnnThe spectrum of IgG4-RD is remarkably complex (table 1) and it would be nice to simply think of this complex multisystem pathology as a single pathogenetic disorder occurring in a variety of target organs.nnUnfortunately, it may not be that simple.nnIn a critical evaluation of the evolving …

Treatment Guidelines for Rheumatologic Manifestations of Sjögren's Syndrome: Use of Biologic Agents, Management of Fatigue, and Inflammatory Musculoskeletal Pain

The Sjögrens Syndrome Foundation clinical practice guidelines (CPGs) are designed to improve quality and consistency of care in Sjögrens syndrome by offering recommendations for management.

The Salivary Gland Epithelial Cell in Sjögren’s Syndrome: What Are the Steps Involved in Wounding or Killing Their Secretory Function?

In their article in this issue of The Journal , Ping, et al used in vitro cultures of epithelial cells from salivary gland tissues of patients with Sjogren’s syndrome (SS), and from control patients lacking inflammatory infiltrates1.nnThe basic process of salivary gland cell death (apoptosis) was similar both in SS salivary epithelial cells and in normal salivary epithelial cells. Thus, the key difference in the salivary gland dysfunction of the patient with SS in vivo appears to be the presence of focal T cell infiltrate in the SS gland that serves as a source of CD40 ligand (CD40L).nnAlthough their article is a nice exercise in molecular biology, with the expected molecular gymnastics (electrophoretic mobility shifts, Western blots, and TUNEL assays), the ultimate questions that arise are: What do these results mean for the patient with SS with dry mouth? How do these results influence the future for therapeutic selection of options?nnThe current study by Ping, et al is an extension of their report from 2005 on the role of CD40 and Fas in SS salivary gland cells2. Subtle points in the present study include the observation that inhibition of p38 and nuclear factor-κB (NF-κB) activation does not fully prevent CD95-mediated apoptosis (see their Figure 4). So there must be other pathways that CD40 is activating.nnParticularly in the regulation of p38 and NF-κB, many different factors influence their canonical and noncanonical activation. Thus, additional factors in situ determine the … nnAddress correspondence to Dr. Fox. E-mail: robertfoxmd{at}mac.com