Clinical manifestations of Sjögren’s disease: Extraglandular disease

INTRODUCTION — Sjögren’s disease (SjD) is a chronic systemic autoimmune disorder characterized by autoimmune-induced inflammation of exocrine glands, particularly the lacrimal and salivary glands, with resultant dry eyes and dry mouth. However, the clinical manifestations of SjD include both exocrine gland involvement and extraglandular disease features [1]. SjD occurs in a primary form not associated with other diseases and a secondary form that complicates or overlaps other rheumatic conditions, most commonly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

In both primary and secondary SjD, decreased exocrine gland function leads to a combination of dry eye (keratoconjunctivitis sicca) and dry mouth (xerostomia) symptoms [2,3]. In addition, a variety of other disease manifestations can occur that may affect a range of tissues involving most organ systems.

The extraglandular disease manifestations of SjD will be reviewed here. The exocrine manifestations, diagnosis, treatment, and prognosis of both sicca and extraglandular manifestations are discussed separately. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Diagnosis and classification of Sjögren’s disease" and "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease" and "Overview of the management and prognosis of Sjögren's disease".)

PATHOGENESIS — The extraglandular manifestations of Sjögren’s disease (SjD) arise from diverse pathogenetic mechanisms [4]. Some represent autoimmune-induced inflammation centered on ductal epithelial structures in various organs, such as the liver (eg, primary biliary cholangitis [PBC; previously referred to as primary biliary cirrhosis]) and kidney (eg, interstitial nephritis). These are akin to the inflammation occurring in the salivary and lacrimal glands (termed "autoimmune epithelitis" by some authors) and tend to be relatively stable and chronic.

Other extraglandular manifestations, such as glomerulonephritis and vasculitis, arise from immune-complex deposition. These develop most often in the context of cryoglobulinemia and may have a higher degree of morbidity and mortality compared with the immune response in ductal epithelial structures. Additionally, some manifestations relate to lymphoproliferation, such as lymphocytic interstitial pneumonitis (LIP) and lymphoma. The pathogenesis of other extraglandular manifestations is not well-understood; a prime example is the fatigue that occurs in many patients. The pathogenesis of SjD is discussed in more detail separately. (See "Pathogenesis of Sjögren’s disease".)

EXTRAGLANDULAR ORGAN INVOLVEMENT

Disease spectrum — Many organs other than the exocrine glands may be affected in patients with Sjögren’s disease (SjD); these include the skin and joints; the lungs, heart, and gastrointestinal tract, including the pancreas and liver; the kidneys, bladder, and gynecologic system; and both the peripheral nervous system (PNS) and central nervous system (CNS) [1]. Additionally, hematologic abnormalities are often present and there is an increased risk of lymphoproliferative disorders. Vascular disease, including cutaneous vasculitis and Raynaud phenomenon, may occur. Some extraglandular manifestations result from SjD itself, while others result from comorbid rheumatic or other autoimmune disease. Examples of the latter include autoimmune thyroid disorders, neuromyelitis optica, and celiac disease. The presence of SjD in a pregnant woman also has potential implications for the fetus and newborn during gestation and after delivery. (See 'Pregnancy' below.)

The relatively common overlap of SjD with other autoimmune diseases may confound the interpretation of its extraglandular manifestations, since some organ involvement may not be unique to SjD but instead reflects overlap with another autoimmune disorder that may be fully or only partially expressed [5]. In addition, the presence of an associated rheumatic disease may increase the risk of lymphoma development in SjD [6]. In some cases (eg, interstitial cystitis, psychiatric symptoms), it is unclear whether abnormalities are related to the SjD itself or an associated but separate condition. However, the presence of relatively disease-specific autoantibodies in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), myositis, and systemic sclerosis (SSc, scleroderma) may help in making these distinctions, particularly when these antibodies are found in SjD patients with overlap features of another systemic rheumatic disease.

A series of different classification criteria has been used to define and characterize SjD; thus, different classification criteria have been used in the various studies that describe the frequency with which an area or organ may be affected in SjD patients. This has resulted in varying estimates of the frequency and severity of particular clinical manifestations [7,8]. Most information cited in this topic review relied upon the 2002 American European Consensus Group (AECG) classification criteria [9,10]. These differed from earlier criteria for SjD in their requirement for either anti-SSA and/or anti-SSB antibodies or the finding of focal lymphocytic sialadenitis with a focus score of 1 or higher on a minor salivary gland biopsy (ie, a positive lip biopsy). Thus, publications using the AECG criteria excluded patients who might have dry eyes and dry mouth but lacked both of these other features (serology and histopathology).

In 2016, a different set of criteria was jointly approved by the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) that differed from the AECG criteria in several respects, including the exclusion of subjective ocular or oral dryness, anti-La/SSB antibodies (when present without anti-Ro/SSA antibodies), parotid scintigraphy, and sialography as criteria. The criteria are only applicable to any patient with at least one symptom of ocular or oral dryness, salivary glandular enlargement, or a systemic manifestation typical of SjD. The criteria were specifically validated for primary SjD but can be applied to SjD in association with other autoimmune diseases pending additional study. The ACR/EULAR criteria mirror the earlier 2002 criteria with their requirement for either positive anti-Ro/SSA serology or a positive lip biopsy [11,12]. (See "Diagnosis and classification of Sjögren’s disease", section on 'Classification criteria'.)

Skin — The major skin findings in SjD include [13]:

●Xerosis (ie, abnormal dryness) (see 'Xerosis' below)

●Purpura, associated with vascular or hematologic abnormalities (see 'Cutaneous vasculitis' below and 'Hypergammaglobulinemia and hypogammaglobulinemia' below and 'Cryoglobulins' below)

●Raynaud phenomenon (see 'Raynaud phenomenon' below)

●Cutaneous vasculitis (see 'Cutaneous vasculitis' below)

●Annular erythema (see 'Annular erythema' below)

●Other manifestations, including eyelid dermatitis and angular cheilitis (see 'Other skin lesions' below)

Xerosis — The most common cutaneous features of SjD are dryness and its sequela, pruritus [14-19]. Xerosis is estimated to occur in 31 to 72 percent of patients with SjD and is characterized by dry, scaly skin, most often affecting the lower extremities and axillary creases [14,19]. In a clinical trial of 120 patients with primary SjD with recent-onset or systemic disease, 48 percent rated their cutaneous dryness as 50 mm or more on a 100 mm visual analog scale of severity at baseline [20]. The xerosis has been variably attributed to a specific alteration in the protective function of the skin's outer layer, the stratum corneum, and to decreased sebaceous or sweat gland secretion [16,17,21]. Quantitative analyses of sweating and skin barrier function in patients with SjD compared with controls have yielded inconsistent results [17,21-23]. In addition, inflammation of the eccrine glands has not been a consistent finding [24]. Factors associated with xerosis include older age, frequent bathing, and low humidity. Symptoms tend to be worse in the winter in cold climates.

Raynaud phenomenon — Raynaud phenomenon has been reported in 13 to 30 percent of patients with SjD [25,26]. It is more prevalent and severe in those patients with anticentromere antibodies [27]. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

Cutaneous vasculitis — Cutaneous vasculitis occurs in approximately 4 to 10 percent of patients with primary SjD [20,28-30]. It typically involves capillaries, arterioles, and venules, which leads to clinical manifestations typical of small-vessel vasculitis. Palpable purpura is the most common sign, but urticarial lesions, macules, papules, and small ulcerated areas may also occur. The lesions are commonly distributed over the lower extremities, but urticarial lesions are occasionally seen over the arms, the trunk, or even the face [31,32]. Two forms of histopathology have been described [33]. One form is typical of leukocytoclastic vasculitis; there is infiltration of the vessel walls by neutrophils with fibrinoid necrosis, lumen occlusion, leukocytoclasis, or erythrocyte extravasation. The second is characterized by invasion and disruption of the vessel wall by mononuclear cells. (See "Overview of cutaneous small vessel vasculitis", section on 'Clinical presentation'.)

The minority of patients who have medium-sized vessel disease can develop large cutaneous ulcers and internal organ involvement that mimics polyarteritis nodosa or rheumatoid vasculitis. SjD patients with this type of vasculitis usually have cryoglobulins [34]. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Skin disease' and "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Cutaneous vasculitis'.)

Because of the frequency with which cutaneous vasculitis in SjD is associated with antibodies to the Ro/SSA antigen [35], this complication of SjD may be difficult to distinguish from the benign hyperglobulinemic purpura of Waldenström [31,36,37]. This latter entity is characterized by recurrent purpuric lesions (usually on the lower extremities), an elevated erythrocyte sedimentation rate (ESR), anemia, leukopenia, normal platelet counts, polyclonal hypergammaglobulinemia, and antibodies to the Ro/SSA antigen (see "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems"). It can be primary, especially in young women, and secondary, most frequently in SjD, RA, and SLE, and rarely in patients with lymphoma and multiple myeloma. In a study of a large Italian multicenter cohort, stratification of SjD patients with hypergammaglobulinemic purpura by the presence or absence of cryoglobulins revealed important clinical and biologic differences; those with cryoglobulins were at increased risk of lymphoma and peripheral nerve and renal involvement [38].

The development of cutaneous vasculitis may have important prognostic implications, as such patients are more likely than those lacking vasculitis to develop other extraglandular manifestations, including lymphoma, and to die of disease-related complications [32,39,40].

Annular erythema — A cutaneous eruption characterized as annular erythema, has been described in a minority of patients with SjD [41,42]. It was described as a manifestation of primary SjD in Japanese patients in a number of case reports in the 1980s and 1990s. Reports of this skin lesion in SjD were initially rare in Western populations. However, in a 2014 analysis of a Spanish cohort of primary SjD, the prevalence of annular erythema was 9 percent [41]. The annular erythema resembles but may be distinct from subacute cutaneous lupus (SCLE), which may also develop in patients with SjD. Annular erythema occurs more commonly in women and in patients with antibodies to Ro/SSA and/or La/SSB antigens [41,42]. Infrequently, other immunological markers are present.

Annular erythema has three clinical patterns: an erythematous elevated indurated ring-like lesion resembling Sweet disease, a marginally scaling polycyclic erythema clinically very similar to SCLE, and an erythematous papular eruption resembling an insect bite reaction. None of these lesions result in scarring or atrophy. The eruption favors the face and neck but can involve the extremities and trunk. Photosensitivity is seen more frequently in White and Black than in Asian individuals. Histopathologic findings of annular erythema in SjD include a deep perivascular and or periappendageal lymphocytic infiltrate; the patients lack the specific epidermal changes of SCLE [42]. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems" and "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.)

Other skin lesions — Other cutaneous manifestations associated with SjD include [1,19]:

●Erythema multiforme-like lesions. Such lesions can occur in association with anti-SSA/Ro and/or anti-SSB/La antibodies and rheumatoid factor (RF), usually in patients with SLE or SLE/SS overlap [43]. This is known as Rowell syndrome and may be associated with chilblains or pernio.

●Erythema nodosum. (See "Erythema nodosum".)

●Livedo reticularis. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'When to suspect cutaneous vasculitis'.)

●Lichen planus. (See "Lichen planus".)

●Vitiligo. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)

●Frontal fibrosing alopecia [44].

●Cutaneous amyloidosis [45].

●Granuloma annulare. (See "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis".)

●Angular cheilitis. (See "Cheilitis", section on 'Angular cheilitis'.)

●Eyelid dermatitis. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Dry eye'.)

Musculoskeletal — SjD may be associated with both joint and muscle manifestations, including arthralgia and (less often) arthritis, as well as myopathy, which is often asymptomatic. (See 'Joints' below and 'Muscles' below.)

Joints — Approximately 50 percent of patients with primary SjD report arthralgia, with or without evidence of arthritis [46]. The arthropathy is usually symmetric, intermittent, nonerosive on plain radiographs, and nondeforming. The hands, wrists, and knees are preferentially affected [47]. Ultrasonography of the hand and wrist joints may detect subclinical synovitis and erosions in patients with hand pain but equivocal clinical joint examinations [48,49]. In one study, the prevalence of synovitis was 21.7 percent and that of erosions was 34.8 percent, when assessed with ultrasonography. The erosions were predominantly in the wrist joints [49].

RF was found in approximately 40 percent of patients with SjD in one large series, and was more common in patients with than without articular symptoms (45 versus 33 percent) [35]. Anti-citrullinated peptide antibodies (ACPA) are detected in 5 to 10 percent of patients with primary SjD [50]. Patients with RF or ACPA defined a subset of SjD patients with more severe inflammatory arthritis, which was often erosive, and with a higher risk of progression to RA [50-54]. (See 'Autoantibodies' below.)

Muscles — A mild inflammatory myopathy that is either subclinical or characterized by the insidious onset of proximal muscle weakness may occur in SjD. The frequency with which myopathy is found depends upon the extent to which it is sought; the reported incidence ranges from 1 to 14 percent [55]. In the French Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort of 395 primary SjD patients with 5 or more years of follow-up, myositis was suspected in 38 patients but confirmed in only 4 patients (1 percent) after careful evaluation [55].

Inclusion body myositis has also been linked to SjD and should be sought in patients with more insidious onset of weakness with relatively low muscle enzyme elevations [56,57] (see "Clinical manifestations and diagnosis of inclusion body myositis"). It had a prevalence of 0.5 percent in the French ASSESS cohort of primary SjD patients, much higher than in the general population [55]. Antibodies to cytosolic 5'-nucleotidase 1A are a marker of inclusion body myositis but can be detected in up to 36 percent of SjD patients without overt muscle disease [58].

The presence of significant muscle weakness and marked muscle enzyme elevations together with sicca symptoms may suggest SjD overlapping with another systemic rheumatic disease, such as antisynthetase syndrome. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes" and "Mixed connective tissue disease".)

Fatigue and fibromyalgia — Fatigue is one of the most common symptoms in SjD, but its pathogenesis remains incompletely understood [59]. Despite the association of fatigue with systemic disease activity, the levels of proinflammatory cytokines were inversely related to patient-reported levels of fatigue in a study of 159 participants of the United Kingdom Primary Sjögren's Syndrome Registry, arguing against a role for these cytokines in the genesis of fatigue in many SjD patients [60]. By contrast, four independent patient-reported measures of fatigue improved in SjD patients treated with an RNase Fc fusion protein in a phase II randomized placebo-controlled clinical trial [61]. Reduction of fatigue was the primary outcome measure in a randomized trial of rituximab in 17 patients with primary SjD [62]; significant improvement from baseline in patient-reported fatigue was observed in the rituximab group compared with the placebo group. However, this finding was not confirmed in a subsequent randomized trial of rituximab involving 133 subjects [63].

Patients with SjD suffer from sleep disorders, usually due to disruption of sleep patterns by a cycle of xerostomia-stimulating polydipsia with resultant polyuria [64]. Other causes of fatigue affecting some patients with SjD is hypothyroidism (see 'Thyroid disease' below) and depression [60].

Fibromyalgia may also engender fatigue in SjD; it had a prevalence of 15 to 31 percent in two large SjD cohorts [65,66]. The high prevalence of fibromyalgia in SjD and other autoimmune rheumatic diseases has prompted a search for an autoimmune pathogenesis of fibromyalgia. Support for this has come from the demonstration that fibromyalgia symptoms can be induced in mice after the passive transfer of purified serum immunoglobulin (Ig) G from fibromyalgia patients [67]. Binding of the transferred IgG to satellite glial cells and neurons in the murine dorsal root ganglia was demonstrated and postulated to explain an observed decrease in epidermal nerve fiber density in the mouse paw and increased sensitivity of their peripheral nociceptors. Dorsal root ganglionitis underlies some forms of peripheral nerve involvement in SjD (see "Neurologic manifestations of Sjögren's disease") and might constitute a pathogenetic link with fibromyalgia.

In some SjD patients, fatigue undoubtedly relates to disease activity, such as inflammatory arthritis, ocular pain and visual impairment, and more serious internal organ involvement (eg, interstitial pneumonitis). (See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Rituximab'.)

Thyroid disease — Evidence of thyroid disease, including some form of structural, hormonal, or thyroid autoantibody abnormalities, has been found in 10 to 70 percent of patients with primary SjD in a number of geographically diverse studies, with autoimmune thyroiditis being most common [68-73]. Polyautoimmunity denotes the clustering of different autoimmune diseases in the same individual and may underlie this association [74]. However, whether thyroid disease has a specific association with SjD remains uncertain, with some data suggesting there is no significant association.

Support for a relationship comes from reports that the risk of developing SjD was significantly increased in women with thyroid disorders in a longitudinal population-based study in Taiwan [75]. Moreover, autoimmune diseases, particularly autoimmune thyroid disease, tend to aggregate in the first-degree relatives of patients with primary SjD [76].

Other observations do not support a link between SjD and thyroid disease. As an example, patients with SjD, being older and predominantly female, would be expected to have a higher incidence of thyroid disease than the general population. Consistent with this, in a well-designed study that compared 160 patients with primary SjD with 75 age- and sex-matched controls from a primary care center, there was no statistically significant difference between the groups in the overall prevalence of thyroid disease or any particular type of thyroid disease [77]. Similarly, in a case-control study from Turkey, the frequency of thyroid antibodies was not increased in patients with primary SjD compared with those with either RA, secondary SjD, or healthy controls [78].

Lungs — The airways and interstitium are the primary targets of lung disease in SjD [79-81]. Approximately 10 to 20 percent of SjD patients have clinically significant lung disease defined classically by symptoms and an abnormal pulmonary function test or chest radiograph [82]. However, a far greater number of patients have lung abnormalities detectable with pulmonary function tests, bronchoalveolar lavage, and computed tomography (CT), and some may report cough or dyspnea [81,82]. Consensus guidelines for the evaluation and management of pulmonary disease in SjD, developed by the Sjögren's Foundation, were published in 2020 [83]. Interstitial lung disease will be reviewed very briefly here and is discussed in detail separately. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis".)

●Upper respiratory tract and airways – SjD may affect the upper respiratory tract as well as large and small airways. Involvement of exocrine glands in the upper airways leads to symptoms related to the nose, sinuses, and posterior pharynx in 50 to 70 percent of patients with SjD [84]. Such patients can have recurrent nonallergic rhinitis and sinusitis. The most common symptom of laryngeal, tracheal, and bronchial involvement is a dry cough, which may be persistent and irritating. If the patient does not have other features of SjD, the diagnosis may be missed, and the patient may be treated incorrectly for asthma or bronchitis. Only 20 percent of affected patients have abnormalities that can be identified by rhinoscopy or indirect laryngoscopy [84].

Bronchial dryness becomes especially important in two situations. First, in the presence of upper airway infections, there is a tendency to develop mucus plug inspissation. This may be exacerbated by over-the-counter cold preparations that contain anticholinergic drugs. Second, mucus plugs can occur postoperatively, as a result of anticholinergic drugs given by the anesthetist and of the dehydrating effects of the operating room.

Saliva acts as a buffer for refluxed gastric acid and its deficiency can thus lead to laryngeal damage and symptoms of globus, excessive throat clearing, cough, and hoarseness. Lymphocytic infiltration of the submucosal glands in the nasopharynx, larynx, trachea, and bronchi leads to desiccation of the mucosa of the respiratory tree, alteration in the viscosity of the mucus, and impaired mucociliary clearance, resulting in a persistent dry cough, hoarseness, and nasal dryness and crusting [85]. In cross-sectional studies of SjD patients, there is a high frequency of large airway disease, as evidenced by CT scanning and pulmonary function tests [81]. Patients may report dry cough, recurrent bronchitis, and dyspnea. High-resolution CT imaging may show bronchial airway thickening, bronchiectasis, centrilobular nodules, reticular or reticulonodular infiltrates, and air trapping. Pulmonary function studies show varied and usually mild abnormalities, including reductions in maximal expiratory flows at 25 percent of vital capacity (MEF₂₅) and a reduced diffusing capacity for carbon monoxide [82].

The pathologic basis for airway disease in SjD has been largely deduced from analysis of lung biopsy material from patients with symptomatic interstitial lung disease. Bronchiolitis is the main airway lesion, including follicular, chronic, and obliterative forms [86,87]. Follicular bronchiolitis has been specifically linked to connective tissue diseases, such as SjD and RA. It is characterized by the formation of hyperplastic lymphoid follicles in the bronchiolar walls leading to obstruction of the bronchiolar lumen [88]. The ensuing submucosal and peribronchial fibrosis can also restrict the lumen. A valve phenomenon may ensue and result in lung cysts or bullae.

●Cystic lung disease – Thin-walled lung cysts are present in 12 to 46 percent of SjD patients [89,90]. They are usually multiple, bilateral, located in the middle and lower lung zones, and associated with other pulmonary lesions, including pulmonary amyloidosis, lymphocytic interstitial pneumonitis, and lymphoma (image 1). The cysts often vary in size, may have internal septations, and are often found in conjunction with other radiographic abnormalities, including bronchiectasis, micronodules, ground-glass opacity, and/or air-trapping. They are an isolated radiologic lesion of the lung in a minority of patients. Most patients are asymptomatic. Affected patients tend to be older and have anti-Ro/SSA antibodies [90]. In two prospective analyses, there was no change in the number or size of the cysts during median follow-up of four years [89,90]. This form of cystic lung disease may be the presenting manifestation of SjD, and needs to be differentiated from lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis [91]. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation" and "Pulmonary Langerhans cell histiocytosis".)

●Interstitial lung disease – Interstitial lung disease in SjD has several forms, including non-specific interstitial pneumonitis (NSIP), usual interstitial pneumonitis (UIP), lymphocytic interstitial pneumonitis (LIP), and cryptogenic organizing pneumonia (COP) [92,93]. Dyspnea and cough are the usual presenting symptoms. NSIP is the most common histopathologic lesion but is a form of lung injury common to a variety of connective tissue diseases and hypersensitivity reactions. These patients should be evaluated for possible overlap with other rheumatic diseases, including testing for antisynthetase and scleroderma-associated antibodies. LIP has a strong association with primary SjD. It is characterized by a lymphoplasmacytic infiltrates within the interstitium, often forming nodular lymphoid aggregates with or without germinal centers, and lymphocytes within alveolar spaces [94]. Follicular bronchiolitis often coexists. Affected patients usually have a polyclonal or monoclonal gammopathy. LIP can be a precursor to a bronchus-associated lymphoid tissue (BALT) lymphoma. These are discussed in more detail elsewhere. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis".)

Heart and cardiovascular system — SjD may be associated with increased risk for cardiovascular disease. Pericarditis and myocardial disease may occur, but are rarely evident clinically, and heart block is also rare but may occur in adults with SjD.

In cohort studies, SjD was an independent risk factor for arterial wall thickening (a marker of subclinical atherosclerosis) [95,96], cerebrovascular events and myocardial infarction [97-99], venous thromboembolism [98], hypertension, and hypertriglyceridemia [100]. In one study, the increased risk of cardiovascular disease was highest among those patients with both anti-Ro/SSA and anti-La/SSB antibodies [98]. By contrast, in a study of 312 patients with primary SjD, the frequency of cardiovascular disease in primary SjD patients was no different from matched controls without autoimmune disease [101]. Similarly, the risk of ischemic heart disease was modestly decreased among SjD patients, compared with controls, in a cross-sectional study of a large administrative database of inpatient encounters at United States hospitals [102].

Acute pericarditis and myocarditis are rare complications of primary SjD [103,104], but echocardiographic evidence of prior pericarditis or left ventricular diastolic dysfunction is more common [103]. In an echocardiographic study of 107 consecutive primary SjD patients without clinically apparent heart disease and 112 age- and sex-matched healthy controls, valvular regurgitation, clinically silent pericardial effusion, pulmonary hypertension, and increased left ventricular mass index were significantly more prevalent in the SjD patients [105]. Hypocomplementemia, age, and cryoglobulinemia were predictors of some of these findings.

Heart block is rare in adult SjD patients and is not consistently associated with anti-SSA/Ro antibodies [106]. Congenital heart block may develop in the fetus of a pregnant woman with SjD as a result of transplacental passage of anti-SSA/Ro antibodies. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Gastrointestinal tract — Manifestations of SjD related to the entire gastrointestinal tract, as well as the liver and pancreas, have been described. Dysphagia, nausea, dyspepsia and gastritis, celiac disease, hepatic abnormalities, and (usually subclinical) pancreatic disease have been observed. The oral manifestations of SjD are described elsewhere. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease".)

●Oropharynx, upper gastrointestinal tract, and stomach – Dysphagia is common in SjD, but its occurrence correlates poorly with salivary flow rates [107], arguing for mechanisms apart from a lack of saliva. Orofacial and pharyngeal muscle dysfunction and esophageal dysmotility have also been reported [108-111], and gastric emptying may be delayed as a result of autonomic dysfunction [112].

Nausea, epigastric pain, and dyspepsia are other frequent symptoms [113]. An atrophic chronic gastritis was evident in 5 percent of a Spanish multicenter SjD cohort of 437 patients [114]. Gastric biopsies in one study of seven patients were characterized by mononuclear cell infiltrates within the lamina propria, composed mostly of CD4-positive T cells [115]. Achlorhydria and hypopepsinogenemia can also occur. In a Spanish cohort of 335 patients with primary SjD, 27 percent had antiparietal cell antibodies, but only 2 percent with these antibodies had pernicious anemia and/or atrophic gastritis [116].

Patients who have gastritis may be infected with Helicobacter pylori, an organism associated with mucosa-associated lymphoid tissue (MALT) lymphoma of the salivary glands in rare patients [117,118]. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)

●Celiac disease – Celiac disease (gluten enteropathy) may be more prevalent in patients with SjD than in the general population. In an Italian study of 354 patients with SjD and 14.298 age- and sex-matched control subjects, the prevalence of histologically confirmed celiac disease was greater in the patients with SjD than in the controls (6.78 versus 0.64 percent) [119]. Similar results were noted in a Hungarian study of 111 patients [120]. The reported prevalence of celiac disease in SjD is similar to that of celiac disease in disorders such as type 1 diabetes and autoimmune thyroid disease. (See "Diagnosis of celiac disease in adults".)

●Liver – SjD is associated with hepatic abnormalities, including (usually mildly) abnormal biochemical tests and histologic changes of primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) or autoimmune hepatitis. The hepatic function test abnormalities may be hepatocellular or predominantly cholestatic in pattern and are persistent in 5 to 26 percent of patients [121,122]. Other causes of liver dysfunction in SjD include hepatitis C virus infection, nonalcoholic fatty liver disease, and drug toxicity [123].

Patients with PBC have an 18 to 38 percent prevalence of SjD [124]. However, clinically overt PBC is found in less than 4 percent of SjD patients in large cohorts [8,114,116,125] (see "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis"). Similarly, autoimmune hepatitis is present in less than 2 percent of primary SjD patients [114,123]. In a large SjD cohort, antimitochondrial and anti-smooth muscle antibodies were present, respectively, in 8 and 62 percent of patients, raising the possibility that subclinical autoimmune liver disease is more common in SjD [116].

●Pancreas – Since SjD is a disease of exocrine glands, involvement of the pancreas would be expected, but is rarely evident clinically. However, subclinical involvement has been documented in several studies [107]. Among 12 SjD patients without known pancreatic disease, six had abnormal pancreatic tests, including three with morphologic changes of the pancreatic ductal system evident by secretin-stimulated MRCP and four with slightly reduced pancreatic function as judged by the Lundh test [126].

SjD has been reported in association with autoimmune sclerosing pancreatitis, a disorder associated with diffuse or localized swelling of the pancreas and narrowing of the pancreatic duct [127,128]. However, some patients thought to have SjD and autoimmune pancreatitis may instead have IgG4-related systemic disease. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis" and "Diagnosis and classification of Sjögren’s disease", section on 'Nomenclature' and "Clinical manifestations and diagnosis of IgG4-related disease".)

Urogenital disease — Immune-mediated renal disease, including interstitial nephritis, can occur in patients with SjD; as may bladder dysfunction with symptoms of interstitial nephritis and gynecologic symptoms including vulvovaginal dryness, pruritus, and dyspareunia.

●Kidneys – Interstitial nephritis, renal tubular dysfunction leading to renal tubular acidosis and/or to decreased concentrating ability, and glomerular disease can occur in SjD. Renal involvement is discussed in more detail elsewhere. (See "Kidney disease in primary Sjögren's disease".)

●Bladder – Women with SjD may develop dysuria, urinary frequency, nocturia, and urgency. In the absence of a urinary tract infection, these symptoms in a patient with SjD may be secondary to interstitial cystitis. The frequency of this symptom complex was evaluated in a study of 870 Finnish women with SjD and of 1304 population controls [129]. The presence of such urinary symptoms was 20-fold higher in those with SjD (4 versus 0.2 percent in controls). In a 2015 literature review, only 13 SjD patients with biopsy-confirmed interstitial cystitis were identified, suggesting that the association of these two diseases is rare [130]. (See "Interstitial cystitis/bladder pain syndrome: Clinical features and diagnosis".)

●Gynecologic manifestations – Gynecologic symptoms, including vulvovaginal dryness, pruritus, and dyspareunia, are common in SjD and can be a significant source of morbidity [131]. Urogenital involvement may also be complicated by bacterial and candidal infections.

Dryness, pruritus, and dyspareunia may relate in part to the predilection of SjD for postmenopausal women. In one study, dyspareunia was noted to affect 40 percent of premenopausal SjD patients versus 3 percent in the healthy control population; however, half of the patients had an obvious etiology for dyspareunia [132].

The vaginal mucosa does not have secretory glands, and its basal humidification and lubrication during sexual arousal is thus dependent on fluid transudation across the vaginal epithelium. Substantial increases in T-lymphocytic infiltrates have been observed in vaginal biopsies from patients with SjD compared with healthy controls, primarily in the lamina propria just below the epithelium [133]. An effect of these infiltrates on fluid transudation has been postulated.

The Bartholin and Skene glands at the vaginal vestibule have a minor role in lubrication of the vulva; their involvement in SjD has long been cited but never proven [68].

Vasculitis — Cutaneous vasculitis occurs in a significant minority of patients, but systemic necrotizing vasculitis is rare. A rash is the most common manifestation of vasculitis in SjD patients (see 'Cutaneous vasculitis' above). Rarely, patients may develop a necrotizing vasculitis of medium-sized arteries resembling polyarteritis nodosa [134] (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults"). Similarly, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis has been reported in several case series of patients with primary SjD [135]. Manifestations of cryoglobulinemia may account for the development of membranoproliferative glomerulonephritis, sensorimotor polyneuropathies, and cutaneous vasculitis in some patients. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

Neurologic disease — A variety of neurologic manifestations may occur in SjD, including a complex array of peripheral and CNS abnormalities. Peripheral neuropathy affects approximately 10 percent of patients. Estimates of CNS involvement vary quite widely, and the nature and frequency of CNS manifestations remain controversial. Neuropathic symptoms frequently precede the diagnosis of SjD, although other symptoms of SjD may be present. The neurologic manifestations of SjD are discussed in detail separately. (See "Neurologic manifestations of Sjögren's disease".)

Psychiatric disorders — Affective disorders are the most common psychiatric disturbance in SjD patients [136,137]. Depression had a prevalence of 33 to 49 percent in small cohorts of primary SjD patients [137-139]. The pathophysiologic basis of depression in SjD is not known; a response to the stress of chronic illness and an effect of proinflammatory cytokines on neural pathways have each been postulated [139].

Hematologic manifestations — The hematologic manifestations of SjD include cytopenias, especially mild anemia and leukopenia (see 'Cytopenias' below); hypergammaglobulinemia (see 'Hypergammaglobulinemia and hypogammaglobulinemia' below); and monoclonal gammopathies, cryoglobulinemia, and lymphoma, and are primarily seen in patients with autoantibodies (particularly anti-SSA or anti-SSB antibodies).

Cytopenias — Patients with SjD may exhibit abnormal counts in any cell line, and patients with cytopenia often have involvement of more than one cell line. However, anemia is usually mild when present, and differential white blood cell counts are most often normal, even though neutropenia, eosinophilia, lymphopenia, lymphocytosis, and monocytosis may all occur. The new development of a cytopenia in a patient with established SjD can be an early sign of underlying lymphoma. Findings include:

●Anemia – A normochromic, normocytic anemia, which occurs in approximately 20 percent [8,28,39]. It is usually mild and correlates with the presence of other forms of extraglandular disease, such as cutaneous vasculitis, renal involvement, peripheral neuropathy, and cryoglobulinemia [39]. Autoimmune hemolytic anemia had a prevalence of 2.8 percent in a cohort of 565 SjD patients hospitalized in China [140].

●Leukopenia – Leukopenia, which has been reported in 12 to 22 percent of SjD cohorts [8,39,141,142]. The differential blood counts are most often normal. The white blood count may fluctuate between normal and low values during the course of disease. In most patients, the leukopenia is mild and is not associated with an increased rate of infections. However, in one study neutropenia was identified in 33 percent of a cohort of SjD patients during longitudinal follow-up, and these patients had a higher incidence of hospital admission caused by infection [142]. The rate of hospitalization was increased especially in patients with neutrophil counts of less than 1000 cells/microL.

●Mild thrombocytopenia (eg, >50,000 and <150,000 cells/microL) is present in 5 to 13 percent of patients [8,39]; severe thrombocytopenia is rare, in contrast to SLE.

Hypergammaglobulinemia and hypogammaglobulinemia — Hypergammaglobulinemia is common in patients with SjD, with a prevalence estimated at 36 to 62 percent [39,68,143]. It may be either polyclonal or monoclonal (see 'Monoclonal gammopathy' below). Patients with polyclonal hypergammaglobulinemia have been reported with total globulin levels as high as 14 g/dL [144].

The presence of hypergammaglobulinemia is closely linked to that of anti-Ro/SSA and anti-La/SSB antibodies and RF [39,145]. Elevated levels of IgG in SjD strongly predict the presence of abnormalities consistent with a positive minor salivary gland lip biopsy [146]. Hypergammaglobulinemia may account for some cases of elevated ESR in SjD that occur in the absence of infection, systemic vasculitis, or other apparent causes such as benign hypergammaglobulinemia purpura of Waldenström.

Hypogammaglobulinemia is less common than hypergammaglobulinemia and may reflect underlying common variable immunodeficiency [39]; it may also develop in patients with established SjD as a sign of underlying lymphoma [147].

Monoclonal gammopathy — Monoclonal gammopathies occur in patients with SjD, being detected in one study in approximately 20 percent of those patients in whom immunoelectrophoresis was performed [39]. Monoclonal IgG proteins were the most common class detected, followed by IgM. The presence of a monoclonal gammopathy was usually associated with the presence of hypergammaglobulinemia, cryoglobulinemia, or hematologic neoplasia, especially lymphoma and myeloma [148]. The incidence of lymphoma is increased among SjD patients with a monoclonal IgM-kappa protein and/or mixed monoclonal cryoglobulinemia [149,150].

The risk of multiple myeloma is increased in SjD patients relative to the general population. In a study utilizing a nationwide Taiwan health insurance database, the standardized incidence ratio (SIR) was 6.1 (95% CI 2.0-14.2) [151]. An increased risk was also observed in three cohort studies, one from Sweden (hazard ratio [HR] 2.9; 95% CI 0.9-8.7), one from a single tertiary care center in China (SIR 37.9; 95% CI 4.6-136.7), and one from a Spanish registry of SjD patients (SIR 36.17; 95% CI 25.44-51.43) [152-154]. Similarly, a personal history of SjD was increased among patients with Waldenström macroglobulinemia (odds ratio [OR] 12.1; 95% CI 3.3-45.0) in an analysis of Swedish population-based registries [155].

Cryoglobulins — Cryoglobulins are present in 9 to 16 percent of patients with primary SjD [156,157]; these patients usually had type II (monoclonal/polyclonal) mixed cryoglobulinemia [156]. The monoclonal component is usually an IgM kappa with RF activity [149,156]. Cryoglobulins in SjD are associated with the presence of cutaneous leukocytoclastic vasculitis, hypocomplementemia, and hepatitis C infection [156]. The triad of cryoglobulinemia, hypocomplementemia, and purpura correlates strongly with severe disease complications and death [35]. In one series, patients with type II mixed cryoglobulinemia exhibited an increased risk for the development of a B-cell lymphoma (6 of 18 patients) [149]. (See "Overview of cryoglobulins and cryoglobulinemia".)

Lymphoma

Prevalence and risk — Patients with SjD have an increased risk of non-Hodgkin lymphoma compared with the general population, a finding shared by diverse autoimmune disorders such as RA, SLE, and celiac disease, but which is highest for SjD [6,158]. This increased risk is evident for both primary and secondary forms of SjD. In a pooled analysis of 29,423 participants in 12 case-control studies on risk factors, the relative risk of non-Hodgkin lymphoma was 4.8 for primary and 9.6 for secondary SjD (overall risk 6.6) [6]. Estimates of the lifetime risk of non-Hodgkin lymphoma range from approximately 5 to 10 percent [39,40,159-161], which is 5 to 44 times higher than that of the normal population [29,162-164]. In a systematic review of 7 studies, the prevalence of lymphoma following diagnosis was 4 percent during the first 5 years, 10 percent at 15 years, and 18 percent at 20 years [165].

Clinical, histopathologic, and laboratory features identify patients with SjD who are at increased risk for developing lymphoma [166]. Persistent salivary gland enlargement is the most important clinical risk factor [167]. Others include cutaneous vasculitis, lymphadenopathy, splenomegaly, cryoglobulinemia, and the development of glomerulonephritis [168]. The presence of a high focus score and possibly germinal center-like structures on labial salivary gland biopsies, performed at the time of initial patient evaluation, are both predictive of lymphoma [169-171] and provide an additional rationale, other than diagnostic, for the labial gland biopsy [172]. Laboratory markers include mixed monoclonal cryoglobulinemia, low serum complement C3 or C4, an IgM kappa monoclonal protein, and neutropenia.

A multicenter case-control study involving 101 patients with primary SjD who developed lymphoma confirmed the association of salivary gland enlargement, low complement C4, cryoglobulinemia, and lymphopenia with lymphoma development in SjD, and also identified RF and disease activity as risk factors [173].

Histopathology and transition to lymphoma — SjD is characterized by polyclonal B-cell activation and by chronic inflammation of the exocrine glands. In most patients, lymphoproliferation remains confined to the glandular tissue and does not undergo malignant transformation. The transition from SjD to lymphoma is a process that requires many years. In two series, the diagnosis of lymphoma occurred at a mean of 6.5 to 7.5 years after the diagnosis of SjD [40,160].

The mechanisms by which SjD predisposes some patients to develop lymphoma are matters of ongoing study [164]. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (also called MALT lymphoma) can arise in the salivary glands from a reactive lymphoid infiltrate called lymphoepithelial sialadenitis or benign lymphoepithelial lesion [174]. Clinically, patients with lymphoepithelial sialadenitis have persistent salivary gland enlargement. The distinction between this benign lymphoid proliferation and malignant MALT lymphoma can be difficult and requires integration of findings from histopathologic, immunohistochemical, and flow cytometric analyses of appropriate biopsy material [175-177]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

In the benign lesion, there is progressive polyclonal B- and T-cell lymphoid infiltration of the salivary gland parenchyma, leading to atrophy and destruction of acini. The lymphoid infiltrate is initially periductal but then extends peripherally and contains lymphoid follicles with germinal centers. Centrocyte-like B lymphocytes present in a zone beyond the mantle of these follicles focally invade the ductal epithelium. Lymphoepithelial lesions are a characteristic finding within the lymphoid infiltrate and likely represent a later stage of this process. They are comprised of "islands" of hyperplastic ductal epithelium, both invaded and surrounded by centrocyte-like B cells, the latter process leading to a perilesional halo.

The progression of this pathologic lesion to MALT lymphoma is characterized by the expansion of the population of centrocyte-like B cells to form broad confluent zones around the lymphoepithelial lesions. In more advanced cases, the infiltrating centrocyte-like cells have a monotonous blast-like morphology [178]. There may be soft tissue or perineural invasion and sheets of plasma cells. Monoclonal B-cell populations can be found in both benign and malignant lymphoid proliferation. Aberrant expression of CD5 and CD43 by the infiltrating B-cell population is a manifestation of lymphoma.

Lymphoma type and features — Marginal zone lymphomas are generally viewed as the most common histologic type in SjD. They are most often extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (also called MALT lymphoma), particularly involving the parotid gland [179]. SjD patients have a 1000-fold increased risk of MALT lymphoma of the parotid gland [6], and most patients with this lymphoma have either underlying SjD or hepatitis C infection [180]. Other sites of MALT lymphoma involvement in SjD include the orbital adnexa, nasopharynx, thyroid, stomach, and lung. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Diffuse large B-cell lymphoma is also associated with SjD; in some cohorts it is more prevalent than MALT lymphomas [29], likely reflecting that they are the most common form of lymphoma in the general population. Among 77 patients with SjD and lymphoma (from a Greek cohort of 712 followed for up to 20 years), MALT lymphoma was the most common non-Hodgkin lymphoma subtype (66 percent), followed by diffuse large B-cell lymphoma (16 percent), and nodal marginal zone lymphoma (10 percent) [161]. In several case studies, transformation of a MALT lymphoma to diffuse large B-cell lymphoma has been documented by molecular analyses. This is estimated to occur in 10 percent of MALT lymphomas. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

MALT lymphomas in SjD usually involve the parotid gland and typically present as a unilateral, firm to hard mass [181]. Regional lymph node involvement is uncommon at presentation. The parotid MALT lymphomas are low-grade indolent neoplasms with 15-year relative survival of close to 80 percent [181]. SjD patients with persistent salivary gland enlargement, particularly when unilateral or asymmetric, should be investigated for lymphoma. This requires either an excisional or a core needle biopsy [182]; fine needle aspiration of lymphoma is subject to a high error rate in the head and neck [183], particularly since monoclonal B-cell populations can be seen in benign lymphoproliferation.

Pregnancy — Pregnancy outcomes among patients with SjD are generally similar to those of healthy women. However, women with SjD who have anti-Ro/SSA antibodies are at risk for giving birth to babies with neonatal lupus [184,185]. Among the manifestations of neonatal lupus, the greatest concern is congenital heart block [184,185]. The risk of congenital heart block among the offspring of pregnant SjD women who are anti-Ro/SSA antibody positive has been estimated at approximately 2 to 4 percent. Other features of neonatal lupus include cutaneous manifestations, transient hepatitis, thrombocytopenia, and anemia. The clinical manifestations, prevention, and management of neonatal lupus are described in detail separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

LABORATORY FINDINGS

General laboratory testing — The laboratory findings in patients with extraglandular manifestations of Sjögren’s disease (SjD) depend in large part on the degree of systemic inflammation and specific organ involvement. Findings may include:

●Acute phase reactants – Erythrocyte sedimentation rates (ESR) over 50 mm/hour were observed in 30 percent of 286 primary SjD patients defined by the 2002 American-European Consensus Group (AECG) criteria [30]. These elevated rates were closely correlated with higher levels of serum gammaglobulins [39]. C-reactive protein (CRP) levels may be normal or mildly elevated [186]; higher mean levels are seen in those patients with more cardiovascular risk factors [101].

●Hematologic findings – Mild anemia, cytopenias, hypergammaglobulinemia, and other abnormalities may occur. (See 'Hematologic manifestations' above.)

●Blood chemistries – Persistent liver function test abnormalities may be observed in up to 26 percent of patients (see 'Gastrointestinal tract' above). A low serum bicarbonate and elevated serum creatinine may reflect renal disease.

Autoantibodies — Serum autoantibodies are present in the majority of patients with SjD, and certain autoantibodies are strongly associated with specific clinical features, possibly contributing directly in some cases to the phenotype of individual patients. Antibodies present in patients with SjD and their clinical associations include:

●Antinuclear antibodies – An antinuclear antibody (ANA) titer of ≥1:320 was present in 64 percent of primary SjD patients in the International Sjögren's Syndrome Registry; the most common patterns of immunofluorescent staining were speckled (59 percent), SSA (21 percent), and centromere (10 percent) [8]. A negative ANA test is found in approximately 15 to 40 percent of primary SjD patients; these patients are typically older, with less severe glandular and extraglandular disease [116,187-191]. Patients with a negative fluorescent ANA test may have positive testing for anti-Ro/SSA and anti-La/SSB antibodies on solid phase immunoassays.

●Anti-Ro/SSA and anti-La/SSB antibodies – These antibodies are found in the majority of SjD patients and generally identify patients who are younger and have more severe glandular inflammation and extraglandular disease [187-189] (see "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Sjögren's disease'). Of interest, patients lacking these antibodies reported more severe chronic pain and reduced physical function in one study [192]. In addition, patients with pure sensory neuropathy tend to have a lower frequency of these antibodies (and other markers of B-activation) than patients without this form of neuropathy [193,194].

The anti-Ro/SSA reactivity is comprised of antibodies to two distinct non-homologous proteins, Ro52 and Ro60. Antibodies to both Ro52 and Ro60 coexist in the majority of SSA-positive SjD patients, often in association with anti-La/SSB antibodies [195,196] and define a subgroup with more robust disease [197]. Anti-Ro/SSA and/or anti-La/SSB antibodies may be found in healthy individuals. The prevalence of anti-SSA antibodies was 0.54 percent in the National Health and Nutrition Examination Survey of the United States population [198]. However, it is rare for the reactivity to be directed against more than one of the three SSA/SSB specificities in healthy individuals [195]. Transplacental passage of these antibodies, particularly anti-Ro52, from mother to fetus may result in congenital heart block. (See 'Pregnancy' above and "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

●Rheumatoid factor – Approximately 40 to 70 percent of SjD patients have rheumatoid factor (RF) [199], usually of the IgM or IgA isotype (see "Rheumatoid factor: Biology and utility of measurement"). In SjD, RF is associated with younger age, other serologic abnormalities (such as hypergammaglobulinemia, cryoglobulinemia, hypocomplementemia, and anti-SSA/SSB antibodies), and more frequent occurrence of extraglandular manifestations. The presence of RF is not a marker of concomitant rheumatoid arthritis (RA) in SjD; the vast majority of primary SjD patients with RF lack anti-cyclic citrullinated peptide antibodies (ACPA), a more specific marker of RA. (See "Biologic markers in the assessment of rheumatoid arthritis".)

●Centromere antibodies – Antibodies to centromere proteins (usually centromere protein B) are found in approximately 5 to 10 percent of SjD patients and are identified by a centromere staining pattern on the immunofluorescence assay for ANA or by a specific solid-phase assay. They define a subset of patients who are often older and have more frequent Raynaud phenomenon, and less frequent anti-Ro/SSA and anti-La/SSB antibodies, RF, and hyperglobulinemia [27]. The sicca manifestations of these patients may be profound. Some may have features of limited scleroderma and may meet the 2013 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria for systemic sclerosis [200]. In addition to Raynaud phenomenon, these include macular telangiectasia of the palms and face, nailfold capillary telangiectasia, and sclerodactyly.

●Anti-citrullinated peptide antibodies – ACPA, detected by assays for anti-cyclic citrullinated peptide (CCP) antibodies, are present in approximately 5 to 22 percent of SjD patients and correlate with more severe articular manifestations and a higher risk of progression to RA [51,52,201-203].

●Antimitochondrial antibodies – Antimitochondrial antibodies are sometimes detected in patients with SjD. They are highly specific markers of primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis). In a meta-analysis of 24 studies, these antibodies had a pooled sensitivity of 85 percent and specificity of 98 percent for PBC [204]. Antimitochondrial antibodies are present in 1.7 to 13 percent of SjD patients, depending upon the cohort and assay method [205], and are associated with the presence of liver disease. However, not all SjD patients with antimitochondrial antibodies have clinical evidence of liver disease. In a Spanish cohort of 335 patients, 28 (8 percent) had antimitochondrial antibodies, of whom 14 had clinical or laboratory evidence of liver disease [116]. Liver biopsies in four of the patients with liver abnormalities showed PBC in only two. Antimitochondrial antibodies are also associated with Raynaud phenomenon, hypergammaglobulinemia, and peripheral neuropathy in SjD [116].

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●Basics topics (see "Patient education: Sjögren's disease (The Basics)")

●Beyond the Basics topics (see "Patient education: Sjögren's disease (Beyond the Basics)")

SUMMARY

●Patients with Sjögren’s disease (SjD) may have involvement of many types of organs beyond the exocrine glands. Some extraglandular manifestations result from SjD itself, while others result from comorbid rheumatic or other autoimmune disease. (See 'Extraglandular organ involvement' above and 'Disease spectrum' above.)

●The major skin findings in SjD include xerosis (ie, abnormal dryness); purpura, associated with vascular or hematologic abnormalities; Raynaud phenomenon; cutaneous vasculitis; annular erythema; and other manifestations, including eyelid dermatitis and angular cheilitis. Although cutaneous vasculitis occurs in a significant minority of patients, systemic necrotizing vasculitis is rare. (See 'Skin' above and 'Xerosis' above and 'Raynaud phenomenon' above and 'Cutaneous vasculitis' above and 'Annular erythema' above and 'Other skin lesions' above and 'Vasculitis' above.)

●SjD may be associated with both joint and muscle manifestations, including arthralgia and (less often) arthritis, as well as myopathy, which is often asymptomatic. Fatigue is one of the most common complaints in SjD, but its pathogenesis is incompletely understood. Patients with SjD suffer from sleep disorders, usually due to disruption of sleep patterns by a cycle of xerostomia-stimulating polydipsia with resultant polyuria. Fibromyalgia, usually accompanied by fatigue, is also very common in SjD. (See 'Musculoskeletal' above and 'Joints' above and 'Muscles' above and 'Fatigue and fibromyalgia' above.)

●Evidence of thyroid disease, including some form of structural, hormonal, or thyroid autoantibody abnormalities, has been found in 10 to 70 percent of patients with primary SjD in geographically diverse studies, with autoimmune thyroiditis being most common. However, whether thyroid disease has a direct relationship to SjD remains uncertain. (See 'Thyroid disease' above.)

●The upper respiratory tract, large and small airways, and interstitium are the primary targets of lung disease in SjD. About 10 to 20 percent of SjD patients have clinically significant lung disease defined by symptoms, typically cough and dyspnea, and an abnormal pulmonary function test or chest radiograph; a greater number of patients have lung abnormalities detectable with additional techniques. Thin-walled lung cysts are detected with CT imaging in 12 to 46 percent of SjD patients, often in association with other radiographic abnormalities. Most SjD patients with cystic lung disease are asymptomatic. Interstitial lung disease can occur in SjD in several forms, including non-specific interstitial pneumonitis (NSIP), usual interstitial pneumonitis (UIP), lymphocytic interstitial pneumonitis (LIP), and cryptogenic organizing pneumonia (COP). (See 'Lungs' above.)

●SjD can cause a complex array of peripheral nervous system (PNS) and brain abnormalities. Peripheral neuropathy affects about 10 percent of patients. Estimates of central nervous system (CNS) involvement vary quite widely, and the nature and frequency of CNS manifestations remain controversial. Neuropathic symptoms frequently precede the diagnosis of SjD. (See 'Neurologic disease' above and "Neurologic manifestations of Sjögren's disease".)

●Affective disorders, including depression, are the most common psychiatric disturbance in SjD patients. The pathophysiologic basis of depression in SjD is not known; a response to the stress of chronic illness and an effect of cytokines on neural pathways have each been postulated as having a role. (See 'Psychiatric disorders' above.)

●The hematologic manifestations of SjD include cytopenias, especially mild anemia and leukopenia; hypergammaglobulinemia; monoclonal gammopathies, cryoglobulinemia, and lymphoma, and are primarily seen in patients with autoantibodies (particularly anti-SSA/Ro or anti-SSB/La antibodies). The lifetime risk of non-Hodgkin lymphoma in SjD is approximately 5 to 10 percent. Non-Hodgkin lymphoma occurs at a mean of approximately seven years after the diagnosis of SjD. (See 'Hematologic manifestations' above.)

●Other areas may also be involved. The heart and cardiovascular system can be affected, with increased risk of cardiovascular disease. Manifestations related to the entire gastrointestinal tract, as well as the liver and pancreas, have been described, including dysphagia, nausea, dyspepsia and gastritis, celiac disease, hepatic abnormalities, and (usually subclinical) pancreatic disease, in addition to oral involvement. Immune-mediated renal disease, including interstitial nephritis, can occur in patients with SjD; as may bladder dysfunction, with symptoms of interstitial nephritis and gynecologic symptoms, including vulvovaginal dryness, pruritus, and dyspareunia. (See 'Heart and cardiovascular system' above and 'Gastrointestinal tract' above and 'Urogenital disease' above.)

●Certain serologic findings correlate highly with specific clinical features in SjD. Common serologic findings include antinuclear antibodies (ANA), anti-Ro/SSA and anti-La/SSB antibodies, rheumatoid factor (RF), cryoglobulinemia, and hypocomplementemia. The risk of congenital heart block among the offspring of pregnant SjD women who are anti-Ro/SSA antibody-positive is approximately 3 to 4 percent. Other laboratory findings in patients with extraglandular manifestations of SjD depend largely upon the degree of systemic inflammation and specific organ involvement. (See 'Autoantibodies' above and 'Pregnancy' above and 'Laboratory findings' above and 'General laboratory testing' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Paul Creamer, MD, and Samuel Moschella, MD, who contributed to earlier versions of this topic review.