Chronic fatigue, pain and depression are common in patients with primary Sjögren's syndrome. These phenomena mutually affect each other and have a considerable impact on the patients' quality of life. While pain is usually regarded as a fairly somatic phenomenon, both fatigue and depression have traditionally been regarded as more-or-less of psychological origin. There is an increasing understanding that this picture is multifaceted; that there is a genetic foundation, and that biological mechanisms regulate the clinical expression through activation of evolutionary, deeply conserved neuronal pathways in the brain. This pattern is evident not only in primary Sjögren's syndrome, but also in other systemic inflammatory autoimmune diseases, in cancer and in neurodegenerative diseases like Parkinson's disease. This article will mainly focus on the biology of pain and fatigue. We describe how these factors influence each other, and act with the overarching purpose of defending the organism against harm and danger.

Primary Sjögren's syndrome (pSS) is considered to be a multifactorial disease, where underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to disease development. In the last 5 years, the first genome-wide association studies in pSS have been completed. The strongest signal of association lies within the HLA genes, whereas the non-HLA genes IRF5 and STAT4 show consistent associations in multiple ethnicities but with a smaller effect size. The majority of the genetic risk variants are found at intergenic regions and their functional impact has in most cases not been elucidated. Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNAs play a role in the pathogenesis of pSS by their modulating effects on gene expression and may constitute a dynamic link between the genome and phenotypic manifestations. This article reviews the hitherto published genetic studies and our current understanding of epigenetic mechanisms in pSS.

A histologic hallmark of primary SS (pSS) is lymphocytic infiltration of the salivary and lacrimal glands, in particular by CD4+ T and B cells. In the early stages of the disease, infiltrates are dominated by CD4+ T cells, while B cell accumulation occurs at later stages. Activated T cells contribute to pathogenesis by producing pro-inflammatory cytokines and by inducing B cell activation, which results in the establishment of a positive feedback loop. In the inflamed glandular tissues, many different CD4+ effector subsets are present, including IFN-γ-producing Th1 cells, IL-17-producing Th17 cells and IL-21-producing T follicular helper cells. In blood from pSS patients, frequently observed abnormalities of the T cell compartment are CD4+ T cell lymphopenia and enrichment of circulating follicular helper T (Tfh) cells. Tfh cells are critical mediators of T cell-dependent B cell hyperactivity and these cells can be targeted by immunotherapy. Inhibition of T cell activation, preferably early in the disease process, can mitigate B cell activity and may be a promising treatment approach in this disease.

Health-related quality of life (HRQoL) has an increasing role in medical decision-making. This review of the literature aims to provide an overview on HRQoL, costs, and work disability in SS, a disease characterized by focal lymphocytic infiltration of exocrine glands with no therapeutics of proven immunomodulatory potential. HRQoL is markedly reduced in SS in multiple studies across many countries when compared with HRQoL in healthy controls. The reduction in HRQoL is similar to that observed in other chronic diseases such as RA, SLE, FM and, interestingly, non-SS sicca syndrome. Impaired HRQoL in SS has been found to be associated with fatigue, pain/articular involvement, ocular and oral involvement, pruritus, sexual dysfunction, impaired sleep, pulmonary manifestations, psychological dysfunction and impaired physical function. Until now, no therapeutic has been shown to improve HRQoL in an adequately powered double-blind, placebo-controlled randomized controlled trial. Although primary SS does not, in general, impair life expectancy and is often inappropriately considered a benign 'nuisanvce' disease for those patients without systemic manifestations, the associated costs and work disability are striking. This, together with the significant reduction in HRQoL, strongly argues for the development of new therapeutic approaches to manage this neglected disease.

SS is a chronic, autoimmune disease of unknown aetiology for which there is no known curative treatment. Although dryness of the eyes and mouth are the classically described features, patients often experience drying of other mucosal surfaces and systemic manifestations, including fatigue and arthralgia. There is an association with other autoimmune diseases, especially thyroid disease, coeliac disease and primary biliary cholangitis. Systemic features may affect up to 70% and include inflammatory arthritis, skin involvement, haematological abnormalities, neuropathies, interstitial lung disease and a 5-10% lifetime risk of B cell lymphoma. Treatment should aim to empower patients to manage their condition; conserve, replace and stimulate secretions; prevent damage; and suppress underlying systemic disease activity.

Biological abnormalities associated with B lymphocytes are a hallmark of patients with primary Sjögren's syndrome. Those patients present abnormal distribution of B lymphocytes in peripheral blood and B cells in exocrine glands. B cells produce auto-antibodies, cytokines and present antigens but can also suppressive functions. In this review, we will summarize current knowledge on B cells in primary Sjögren's syndrome patients, demonstrate their critical role in the immunopathology of the disease and describe the past and current trials targeting B cells.

The information about comorbidities (excluding lymphoma) in primary Sjögren's syndrome (pSS) is relatively scarce. Cardiovascular disease, infections, musculoskeletal conditions or malignancy are likely the most relevant comorbid conditions in pSS. Different infections (particularly oral candidal infections) and fibromyalgia are extremely frequent in the daily clinical practice. On the other hand, the incidence of cardiovascular events and cancer in pSS is low, so information about them comes from large epidemiological studies or meta-analysis. For this reason, preclinical vascular disease is investigated by different techniques, demonstrating the presence of early atherosclerosis in pSS patients. Coronary events could be slightly more frequent in pSS than in the general population. The overall risk of malignancy in pSS patients seems to be slightly increased, likely due to excess occurrence of lymphoma. An association between pSS and thyroid cancer might exist, although it should be confirmed by further investigations.

Primary SS (pSS) is a rheumatic disease characterized by an immune-mediated exocrinopathy, resulting in severe dryness of eyes and mouth. Systemic symptoms include fatigue and joint pain and a subset of patients develop more severe disease with multi-organ involvement. Accumulating evidence points to involvement of innate immunity and aberrant activity of the type I IFN system in both the initiation and propagation of this disease. Analysis of the activity of IFN-inducible genes has evidenced that more than half of pSS patients present with a so-called 'type I IFN signature'. In this review, we examine activation of the IFN system in pSS patients and how this may drive autoimmunity through various immune cells. We further discuss the clinical value of assessing IFN activity as a biomarker in pSS patients and review novel therapies targeting IFN signalling and their potential use in pSS.