Approach
Diagnosis is often delayed by many years, as patients may not feel the need to present to their doctor with sicca symptoms, and/or the treating physician may not recognize that the patient has this systemic disease. Diagnosis is often made retrospectively when the patient comes to medical attention as a result of recurrent parotitis, or extraglandular manifestations. If criteria for diagnosis are not satisfied using less invasive testing, pathologic diagnosis, usually by minor salivary gland biopsy, or occasionally following excision of an enlarged major salivary gland suspected to be malignant, gives a definitive answer.[32][33]
Initial testing
A diagnosis of Sjogren syndrome should be suspected if the patient meets the following 5 criteria:[34][35]
Labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm²
Anti-Ro/SSA positive
Ocular staining score ≥5 (or van Bijsterveld score ≥4) in at least one eye
Schirmer test ≤5 mm/5 minutes in at least one eye
Unstimulated whole saliva flow rate ≤0.1 mL/minute.
See Criteria.
These criteria are applicable to any patient with at least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following questions:[35][36]
Have you had daily, persistent, troublesome dry eyes for more than 3 months?
Do you have a recurrent sensation of sand or gravel in the eyes?
Do you use tear substitutes more than three times a day?
Have you had a daily feeling of dry mouth for more than 3 months?
Do you frequently drink liquids to aid in swallowing dry food?
If these criteria are not met by initial testing, but alternative diagnoses have been ruled out and clinical suspicion remains, the next step in testing is sialometry for quantitation of unstimulated salivary flow. If diagnosis is not established with this procedure, the test that follows is salivary gland biopsy.
Referral to ophthalmology for specialized testing (such as lissamine green and fluorescein testing) is an option if eye symptoms are prominent.
Glandular presentation
Eye symptoms are present in nearly all patients:
Related to decreased function of lacrimal glands
Dry, itchy, burning, or gritty eyes
Commonly redness of the eyes and sensitivity to light and wind.
Mouth symptoms are present in nearly all patients:[2][37]
Related to decreased function of salivary glands
Dry mouth, burning, difficulty in chewing and swallowing certain dry foods, altered or decreased taste acuities, difficulty with speaking for long periods, and an overall markedly diminished quality of life
Many carry liquids with them at all times and awake at night in order to drink
Severe dental caries leading to loss of all teeth in many patients
Increased fungal and bacterial infections
Thicker and opaque saliva
Major salivary glands may episodically become enlarged and painful.
Dentists are often the first to detect these symptoms; their diagnosis and treatment is of critical importance.[38]
Extraglandular presentation
Patients often present with extraglandular manifestations such as fatigue, musculoskeletal disease, cutaneous involvement/vasculitis, thyroid disease, pulmonary disease, gastrointestinal disease, urogenital issues, or neurologic manifestations.
Fatigue
Fatigue is often the most reported complaint in people with Sjogren syndrome, but the underlying cause is unclear.[39][40] One study demonstrated that patients with primary Sjogren syndrome (pSS) report more fatigue than healthy controls across all dimensions of the Multidimensional Fatigue Inventory (general, physical, and mental fatigue; reduced motivation; and reduced anxiety).[39]
Musculoskeletal manifestations
Both joint and muscle manifestations are associated with Sjogren syndrome. Arthralgia impacts the peripheral joints in the majority of people with pSS, but under 2% of patients are diagnosed with arthritis.[41] The joints in the hands and wrists are predominantly involved, but patients may also experience pain in their knees, ankles, shoulders, and metatarsophalangeal joints.[41] The presence of arthritis may be underdiagnosed by physical exam; ultrasound studies may detect subclinical synovitis and erosions.[42] See Osteoarthritis, Rheumatoid arthritis, Psoriatic arthritis, and Reactive arthritis.
Evidence suggests that the prevalence of inflammatory myositis in people with Sjogren syndrome is lower than previously reported, and may be present as an overlap syndrome.[43] See Dermatomyositis and Idiopathic inflammatory myopathies.
Cutaneous manifestations/vasculitis
Common cutaneous manifestations may include dry skin (xeroderma), palpable and nonpalpable purpura, and/or urticaria-like lesions in around 50% of patients with Sjogren syndrome.[44] These symptoms may be seen as secondary to more prominent sicca symptoms; however, they can be prognostic for the risk of life-threatening conditions such as multisystem vasculitis and non-Hodgkin lymphoma.[45] See Rosacea, Atopic dermatitis, Evaluation of urticaria, and Urticaria and angioedema.
A more unusual manifestation is vasculitis of medium-sized vessels that results in a clinical picture similar to polyarteritis nodosa with visceral involvement.[46] Vasculitis is associated with the presence of anti-Ro and anti-La antibodies as well as cryoglobulins in the sera of patients.[47] See Polyarteritis nodosa.
Skin biopsy enables diagnosis in patients with rash, while an angiography is useful in those with large vessel involvement.
Thyroid disease
Evidence on the association of thyroid disease with Sjogren syndrome is variable. One longitudinal population-based study reported that the risk of Sjogren syndrome was significantly higher in women with thyroid disorders, especially women aged in their mid 40s to mid 60s.[48] However, an age- and sex-matched controlled study of 160 patients in primary care found no significant difference in the overall prevalence of any type of thyroid disease in women with Sjogren syndrome compared with matched controls without Sjogren syndrome.[49] See Central hypothyroidism and Primary hypothyroidism.
Pulmonary disease
Approximately 10% to 20% of patients with Sjogren syndrome have respiratory symptoms. There is evidence to suggest that the most typical pulmonary manifestations are chronic interstitial lung disease (ILD) and tracheobronchial disease. The most common presentation of ILD is nonspecific interstitial pneumonia.[50] Other types of ILD (such as organizing pneumonia, usual interstitial pneumonia, and lymphocytic interstitial pneumonitis) are rare.[50] See Idiopathic pulmonary fibrosis.
Gastrointestinal manifestations
Gastrointestinal (GI) manifestations of Sjogren syndrome may involve the whole GI tract, as well as the liver. Dysphagia, nausea, epigastric pain, and dyspepsia are common symptoms of GI manifestations.[51][52][53] See Evaluation of dysphagia and Evaluation of dyspepsia.
Some evidence suggests hepatic abnormalities in people with Sjogren syndrome, such as histologic changes of primary biliary cholangitis, or autoimmune hepatitis.[54][55] See Primary biliary cholangitis and Autoimmune hepatitis.
Urogenital manifestations
Kidney involvement in the form of renal tubular acidosis is not an uncommon manifestation of interstitial kidney disease among patients with Sjogren syndrome.[56][57] Electrolyte abnormalities consist of hypokalemia with a normal anion gap, and hyperchloremic metabolic acidosis. An occasional patient presents with severe hypokalemia that eventually leads to the diagnosis. Urinalysis and serum electrolytes show renal tubular acidosis in most patients. See Renal tubular acidosis.
Women with Sjogren syndrome may present with manifestations in the bladder such as dysuria, urinary frequency, nocturia, and urgency.[58] Gynecologic manifestations may include vulvovaginal dryness, pruritus, and dyspareunia.[59] See Evaluation of dysuria and Evaluation of dyspareunia.
Neurologic manifestations
Neurologic symptoms may precede the onset of other symptoms of Sjogren syndrome in many patients.[60] Small fiber peripheral neuropathy is the most common form of neuropathy among patients with Sjogren syndrome, and is associated with precipitating levels of anti-Ro60 (SSA) and anti-La (SSB).[61] Conversely, there is evidence that suggests a very low incidence of neuropathy; however, in this case the low incidence detected appears to be related to the fact that electrodiagnostic studies (electroencephalogram [EEG] and nerve conduction velocity) were used and these tests typically give negative results with small fiber neuropathy.[62]
Facial pain
Facial pain can occur in patients with Sjogren syndrome due to orofacial pain or burning mouth syndrome, trigeminal neuralgia, or possibly osteonecrosis of the jaw (ONJ).
Burning mouth is thought to be due to reduced salivary flow that results in secondary fungal infection and/or medication use that affects the functioning of the salivary glands.[63][64][65] See Oral candidiasis.
Trigeminal neuralgia is the most common cranial neuralgia found in patients with Sjogren syndrome. This condition typically happens bilaterally, is progressive, and may be characterized by numbness in the face, or paresthesia with or without pain.[63][66] Sensory neuropathies are more common than motor dysfunction, with the facial nerve being the most commonly involved motor nerve.[63] See Trigeminal neuralgia.
Where there is relevant clinical history, ONJ is a possible cause of facial pain. Observational data suggest a significant association between Sjogren syndrome and ONJ.[67][68]
Ruling out differential diagnoses
If the initial testing does not establish the diagnosis, other serologies may be checked to rule out alternate autoimmune conditions or overlap syndromes.
Hepatitis C should be ruled out, especially if there are any risk factors for possible exposure to contaminated blood.
In the presence of arthritic symptoms, erosions on imaging, or deformities on exam, rheumatoid factor plus anti-cyclic citrullinated peptide (CCP) may be indicated; if both are negative, rheumatoid arthritis is less likely, and primary Sjogren more likely.
ANAs are elevated in 80% of patients with Sjogren syndrome, but this test is not useful diagnostically unless lupus is being considered as an alternate diagnosis.[16] For instance, if there is malar or other photosensitive rash, nonspecific fatigue and/or fever, joint pain out of proportion to joint swelling, or weight change (usually loss). Speckled or homogeneous type pattern of ANA are found in the majority of patients with Sjogren syndrome.[21]
Biopsy
Minor salivary gland biopsy is a clinically useful final test if criteria are not met by noninvasive testing. A focus score of 1 or greater is supportive of the diagnosis of Sjogren syndrome and satisfies the American-European criteria in the presence of dry eye or dry mouth symptoms, and objective evidence of keratoconjunctivitis sicca or salivary hypofunction.[69][70]
Investigational testing, imaging modalities
Various imaging modalities are undergoing investigation for diagnosis of Sjogren syndrome, and would be most useful if performed by experienced investigators. These include: sialography, MRI, or technetium-99m pertechnetate scintigraphy.[38]
Correlations between salivary gland ultrasound (SGUS) results and focus score in the major salivary glands have been shown.[71][72][73] A subsequent study demonstrated that two four-grade semi-quantitative SGUS scoring systems (Outcome Measures in Rheumatology [OMERACT] and De Vita et al) are reliable for the evaluation of salivary glands in patients with pSS.[74]
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