Phases and Natural History of Sjögren's Disease: A New Model for an Old Disease?

Abstract

Sjögren's disease (SjD) is an archetypal and heterogenous autoimmune disorder that is characterized by exocrine glandular dysfunction. A proportion of patients develop severe extraglandular manifestations, such as cryoglobulinemia, and have an increased risk of lymphoma, both of which can adversely affect quality of life and occasionally mortality. As with most autoimmune disorders, the pathogenesis is poorly understood and difficult to predict, and, frustratingly, there is a lack of targeted therapies to cure this disease. We review the disease manifestations of SjD and propose a staged model for understanding the evolution of pathology. In longitudinal studies, most patients remain relatively stable in terms of their laboratory and clinical parameters. However, in the setting of various risk factors, a proportion of patients develop severe symptoms and/or lymphoma. We discuss potential underlying mechanisms for disease progression and the strengths and limitations of using a staged model to correlate the pathogenesis and spectrum of manifestations in SjD. Ultimately, understanding how and why some patients remain relatively stable, whereas others progress and develop florid systemic disease and a fraction develop lymphoma, is key to developing preventative and therapeutic treatments.

Serological intermolecular epitope spreading in a patient with primary Sjögren’s syndrome

“…Given that serological manifestations including autoantibodies may precede the onset of clinical features and SS diagnosis by many years and appear in otherwise healthy individuals,15 31 it is reasonable for us to continue periodically monitoring the patient to check for the development of severe extraglandular manifestations. However, SS is a disease that generally sees clinical stability in longitudinal studies,1 providing some reassurance. Autoantibody profiles tend to also remain very stable and to our knowledge, we provide the first described instance of an SS patient longitudinally developing new autoantibodies to the Ro/La RNP complex.…”

“…Sjögren’s syndrome (SS) is one of the prototypic systemic autoimmune diseases characterised by autoreactive T and B cells, sicca symptoms and in a good percentage of patients, various extraglandular manifestations. 1 While most patients experience stable disease, around 5%–10% of SS patients develop lymphoma and related complications. 1 Autoantibodies to the Ro/La ribonucleoprotein (RNP) complex (anti-Ro52, anti-Ro60 and anti-La) are highly characteristic and are the by-products of failed immunological tolerance.…”

“… 1 While most patients experience stable disease, around 5%–10% of SS patients develop lymphoma and related complications. 1 Autoantibodies to the Ro/La ribonucleoprotein (RNP) complex (anti-Ro52, anti-Ro60 and anti-La) are highly characteristic and are the by-products of failed immunological tolerance. They are best known as being diagnostic biomarkers, 2 yet little is known about the origins and mechanisms of sustained autoantibody production.…”

“…Sjögren’s syndrome (SS) is one of the prototypic systemic autoimmune diseases characterised by autoreactive T and B cells, sicca symptoms and in a good percentage of patients, various extraglandular manifestations 1. While most patients experience stable disease, around 5%–10% of SS patients develop lymphoma and related complications 1.…”

Isolated anti-Ro52 identifies a severe subset of Sjögren’s syndrome patients

“…Sjögren’s syndrome (SS) is a systemic autoimmune disease characterised by sicca symptoms, fatigue, autoantibodies, B cell hyper-reactivity and variable presentations of extra-glandular manifestations including neuropathy, cryoglobulinaemic vasculitis and lymphoma. Despite being described for many decades, no effective and specific treatments exist and management is focused on alleviating troubling symptoms and addressing organ-threatening complications ( 1 ). IgG autoantibodies against the Ro/La ribonucleoprotein nuclear complex are highly characteristic in SS and forms part of the diagnostic criteria for this disorder ( 2 ).…”