New Biological Avenues for Sjögren’s Syndrome

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New Biological Treatments for Autoimmune Disease

SS is characterized by loss of function of the exocrine glands (sicca syndrome) and systemic manifestations caused by B cell hyperactivation and autoantibody production. One-third of the patients present signs of extraglandular involvement that extend from cutaneous vasculitis to peripheral neuropathy or pulmonary involvement. The remaining two-thirds experience mainly dryness-related symptoms. Systemic manifestations are most commonly observed in immunologically active patients and are characterized by high titers of anti-Ro/SSA and anti-La/SSB autoantibodies and rheumatoid factor. The major comorbidity in patients with SS is the development of non-Hodgkin lymphoma (NHL) that commonly arises in affected salivary glands (parotids) and confers a higher mortality risk to SS patients, significantly affecting disease prognosis. SS also represents a significant health and economic burden in patients who do not develop NHL. Recent data highlight the increased comorbid cardiovascular risk associated with SS, and the reduced quality of life of SS patients has also been described. To date, there is no approved, specific treatment for the disease. Patients are managed with a combination of immunosuppressive drugs and, in some cases, systemic disease is treated with steroids. A general consensus among SS experts is that biological therapies will play a key role in the management of subsets of SS patients, but it remains unclear what the most appropriate targets might be. Great efforts have been made in the United Kingdom and in the international community to better define subtypes of patients with SS and refine tools to measure disease activity and outcome in clinical trials. It appears that a better definition of biological as well as clinical measures of outcome will be required in the phase of the design of clinical trials.

SS pathogenesis is complex and as such provides a series of potential therapeutic targets that range from inflammatory cytokines to costimulatory molecules or cellular target therapies ( Fig. 20.1 ). SS treatment will mainly involve the repurposing of strategies used to tackle more complex and life-threatening autoimmune diseases. However, the possibility to define SS-specific targets should also be also considered, with the final aim to provide patients with SS with valuable therapeutic possibilities.

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The Interferon Signature

In 1994, Moutsopoulos first described SS as “autoimmune epithelitis” with the aim at highlighting the key role played by epithelium in the regulation of local inflammatory responses at salivary glands level. Twenty years later, it is well accepted that “activated” epithelial cells play a functional role in SS development, and in maintenance and progression of the local autoimmune inflammatory responses. Latent viral infections of the epithelium have been causally implicated in the epithelial activation, with Epstein-Barr virus, cytomegalovirus, retroviral elements, human herpes virus type 6, human T lymphotropic virus type I, human herpes virus type 8, and Coxsackie virus having been suggested at different stages as inducing or contributing to the activated state of the epithelial compartment. Although no convincing evidence has supported the causative role of any of those pathogens, the hypothetical role of a viral infection before the aberrant activation of the resident epithelium is widely accepted. More intriguingly, the persistence of viral genetic material within the epithelial cytoplasm has been suggested, which would be able to alter the biological properties of the cell and support the ongoing aberrant immune response. Supporting evidence for a viral involvement in SS pathogenesis is provided by the aberrant immune responses characterized by the type I interferon (IFN) signature. Type I IFNs are proteins able to trigger the induction of hundreds of genes implicated in antiviral response, including the B cell activating factor (BAFF) and the IFN-induced transmembrane protein 1. A prominent type I IFN signature in patients with SS has been shown both in the gene expression profile within the minor salivary glands (MSGs) and in peripheral blood cells. Moreover, plasmacytoid dendritic cells (DCs), which represent the main source of type I IFN, also accumulate in the MSGs. Despite playing an important antiviral role, type I INF appears to be responsible for the fatigue and malaise often observed in SS patients. Currently there are no clinical trials exploring the use of anti-IFN I agents in SS patients; however, some evidence derives from patients with systemic lupus erythematosus (SLE). Blocking the interferon pathway with rontalizumab, a humanized immunoglobulin (Ig) G1 anti-IFNα monoclonal antibody, in patients with moderate to severe SLE has been associated with improvements in disease activity, reduced flares, and decreased steroid use in patients with low IFN signature metric (ISM) scores. However, there has been a failure to meet the primary endpoint in patients with high ISM scores. Use of another anti-IFNα monoclonal antibody, sifalimumab, has also showed safety/tolerability in SLE patients and a partial improvement in clinical activity profile was shown. The use of compounds interfering with the IFN cascade might represent a potential target for SS.

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