Sjögren’s Syndrome (SS) is a chronic autoimmune disorder where the immune system mistakenly attacks the body’s moisture-producing glands, primarily the lacrimal and salivary glands. This attack leads to the common symptoms of chronic dry eyes and dry mouth, known as sicca symptoms. Diagnosis is challenging because symptoms overlap with many other disorders, and laboratory tests are not always definitive. Individuals experiencing these symptoms often wonder if they can still have Sjögren’s Syndrome despite negative initial test results. The answer is yes; a negative blood test does not automatically exclude the disease because of a recognized subtype where the immune response does not produce the typical disease-identifying antibodies.
The Standard Screening Toolkit
The initial investigation for suspected Sjögren’s Syndrome typically begins with blood tests designed to detect specific autoantibodies. The most important are the anti-SSA (anti-Ro) and anti-SSB (anti-La) antibodies, which are present in 60% to 80% of individuals with the condition, indicating an autoimmune process.
Objective measurements of glandular function also quantify dryness symptoms. The Schirmer test measures tear production, while salivary function is screened using the unstimulated whole saliva flow rate; a volume less than 0.1 mL per minute is considered abnormally low. These initial methods establish a baseline of autoimmune markers and objective glandular dysfunction, serving as the starting point for diagnosis.
Understanding Seronegative Sjögren’s
A negative result for anti-SSA and anti-SSB autoantibodies places a patient into the “seronegative” Sjögren’s category, which occurs in approximately 20% to 40% of diagnosed patients. Seronegativity means the immune response does not produce the typical antibody profile, possibly due to a different underlying disease mechanism or the timing of the testing.
Seronegative Sjögren’s pathology centers on tissue inflammation rather than circulating antibodies; some patients produce anti-Ro antibodies only locally within the affected glands, making them undetectable in a standard blood draw. While systemic symptoms may be less severe than in seropositive cases, patients still report significant mucosal dryness, fatigue, and joint pain. Persistent, objective symptoms of dryness, despite negative serology, warrant deeper investigation for seronegative disease.
Advanced Diagnostic Confirmation
When initial serology is negative, definitive diagnosis relies on tests providing physical evidence of immune-mediated glandular damage. The gold standard is the minor salivary gland biopsy, or lip biopsy. This minimally invasive procedure removes a few minor salivary glands from the inside of the lower lip under local anesthesia.
A pathologist examines the tissue sample for focal lymphocytic sialadenitis, the hallmark of Sjögren’s. They look for clusters of at least 50 inflammatory cells (lymphocytes) surrounding the glandular ducts and acini. The severity is quantified using a “focus score”; a score of one or greater is a positive result. A positive lip biopsy provides crucial physical proof for diagnosis, especially in seronegative cases.
Objective measures of glandular function also establish damage. An unstimulated whole saliva flow rate of \(0.1\) milliliters per minute or less suggests salivary gland hypofunction. An abnormal ocular staining score measures damage to the eye surface, providing objective evidence of dry eye disease. These tests document functional impairment, which, combined with a positive biopsy, can confirm a diagnosis without classic antibodies.
Clinical Criteria and Next Steps
The final diagnosis requires a rheumatologist to synthesize all available data—symptoms, blood work, and objective test results—using a standardized framework, specifically the 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria. This system assigns weighted scores to specific findings, including anti-SSA antibodies, an abnormal ocular staining score, and a positive minor salivary gland biopsy.
A patient is classified as having Sjögren’s Syndrome if they accumulate a total score of four or more points; notably, a positive lip biopsy alone (focus score of one or greater) contributes enough points to allow diagnosis even when the anti-SSA/SSB blood test is negative. Therefore, a negative blood test should prompt consultation with a rheumatologist who understands seronegative disease and can determine if advanced objective testing is warranted to confirm diagnosis and begin management.