566 45 Clinical Aspects of Sjögren’s Nancy L. Carteron, Hendrika Bootsma, Frans G.M. Kroese, Arjan Vissink, Alexandre Dumusc, and Simon J. Bowman INTRODUCTION AND EPIDEMIOLOGY Sjögren’s is an autoimmune inflammatory disorder of the exocrine glands, particularly affecting lacrimal and salivary glands, which can adversely affect quality of life (QOL) and carry a high illness and financial burden. 1-3 Hallmark symptoms are dry mouth and dry eye, often in conjunction with symptoms, such as malaise, profound fatigue, and neurocognitive dysfunction, which patients term “brain fog.” However, dry mouth and/or dry eye may not be present at disease initiation, which contributes to the diagnostic challenge and underrecognition despite high prevalence of the disease. Various extraglandular manifesta- tions (EGMs), such as neuropathy, gastrointestinal (GI) dysmotility, arthralgia, and photosensitive skin rashes can be presenting signs of the disease (Table 45.1). The sentinel feature of the disease is lymphocytic infiltration of target organs. In addition to focal lymphocytic infiltration of salivary glands, normal predominantly CD4 + T cells can be found in skin, lung, GI mucosa, and nervous system ganglia. A recent systematic review estimated the prevalence of Sjögren’s in the general population to be 7 per 100,000 person-years, 8 which makes it the most common systemic autoimmune disease after rheumatoid arthritis (RA). The disease is likely more prevalent than appreciated with 3.1 million affected persons in the United States reported in 2008 by the National Arthritis Data Workgroup. 9 The prevalence doubles when including those with additional connective tissue diseases. 10 The annual incidence of new cases is 5.8 to 5.9 per 100,000 as reported from the Mayo Clinic Olmstead Country Minnesota USA Cohorts. 11 Medical records of primary Sjögren’s cases from 1975 to 2005 and 2006 to 2015 were examined. The incidence is equivalent to the Taiwan National Health Insurance Bureau claims data, which examined new cases of primary Sjögren’s using American European Classification Criteria from 2005 to 2007, and subsequent review by the expert committee resulting in 3352 incident cases. 12 An incidence of 6.0 per 100,000 was observed. Of note in the Taiwan health insurance system, Sjögren’s is classified as a “financially catastrophic illness,” further underscoring the significant disease burden. Sjögren’s is more frequent in women than in men, with a female-to-male ratio of 9 : 1, but may be underrecognized in men and children. It can be the primary condition (primary Sjögren’s) or co-occur with another autoimmune disease, such as primary biliary cholangitis (PBC), celiac, RA, lupus, or scleroderma (secondary Sjögren’s). In PBC, the prevalence of secondary Sjögren’s is approximately 60%, in RA 30%, and in lupus 20%. The severity of the Sjögren’s manifestations may be similar in both primary and secondary Sjögren’s. The Sjögren’s component may be minimized when the focus is on another autoimmune disease of perceived greater importance. The overlapping of clinical and serologic features, in particular rheumatoid factor (RF) and antinuclear antibodies (ANAs), may also lead to an inaccurate diagnosis. 13 Sjögren’s is also associated with other organ-specific autoimmune diseases; in particular, autoimmune thyroid disease, which further underscores the autoimmune nature of the disease. 14-16 Patients with Sjögren’s may be restricted in their activities and participation in society, resulting in a reduced health-related QOL, 1,3,17-19 impaired socioeconomic status, 3 and increased health care costs. 20-22 HISTORY The first descriptions of Sjögren’s were reported by European clini- cians between 1882 and 1925. 23 In 1888, Hadden described a woman OUTLINE Introduction and Epidemiology, 566 History, 566 Clinical Presentation, 567 Glandular Manifestations, 567 Extraglandular Manifestations, 568 Lymphoma Development, 568 Dermatologic Manifestations, 569 Ear, Nose, and Throat Manifestations, 569 Pulmonary Manifestations, 569 Joint and Muscle Manifestations, 570 Gastrointestinal Manifestations, 570 Gynecologic and Urologic Manifestations and Pregnancy, 570 Kidney Manifestations, 571 Neurologic Manifestations, 571 Vasculitis, 571 Cardiovascular, 571 Hematologic Manifestations, 571 Men With Sjögren’s, 571 Childhood Sjögren’s, 571 Serologic Findings, 572 Ultrasound of Glands, 572 Classification and Diagnosis of Sjögren’s, 572 Hormonal Factors, 573 Sjögren’s in Patients With Lupus, 573 Outcome Measures, 575 Prognosis, 576