Sjogren's syndrome (disease)

Diagnosis

Diagnosing Sjögren's Syndrome requires a combination of characteristic symptoms, objective evidence of dryness, specific autoantibody detection, and sometimes histopathology (1, 6). Ruling out other causes of sicca symptoms is also crucial.

Clinical Evaluation & Objective Tests

• Symptom Assessment: Detailed questioning about the severity, frequency, and impact of eye and mouth dryness, as well as screening for extraglandular symptoms.
• Objective Eye Tests: Performed by an ophthalmologist.
  • Schirmer's Test: Measures tear production using filter paper strips placed in the lower eyelids. Reduced wetting (<5 mm in 5 minutes) indicates deficient tear production (1, 6).
  • Ocular Surface Staining: Using dyes like Lissamine Green or Rose Bengal to visualize damaged cells on the cornea and conjunctiva due to dryness (1, 6). Tear break-up time (TBUT) may also be assessed.
• Objective Mouth Tests:
  • Unstimulated Whole Salivary Flow Rate: Measuring the amount of saliva produced over a set time (e.g., 15 minutes) without stimulation. Low flow rates (<0.1 mL/min) suggest salivary gland hypofunction (1, 6).
  • Salivary Gland Scintigraphy or Sialography: Imaging techniques to assess salivary gland function and structure (less commonly used now) (1).

Autoantibodies (ANA, RF, SS-A/Ro, SS-B/La)

Serological testing plays a vital role:

• Antinuclear Antibody (ANA): Positive in a high percentage (80-95%) of Sjögren's patients, often with speckled or homogenous patterns (1).
• Rheumatoid Factor (RF): Frequently positive (60-70%), even in primary Sjögren's without concurrent RA (1).
• Anti-SS-A (Ro) Antibodies: Found in approximately 60-70% of primary Sjögren's patients. Associated with earlier disease onset, longer duration, more severe glandular dysfunction, and increased risk of extraglandular manifestations (like vasculitis, neuropathy, cytopenias) and lymphoma (1, 2, 7). Crucially, maternal anti-SS-A/Ro antibodies are associated with a risk of neonatal lupus, including congenital heart block in the fetus (1, 7).
• Anti-SS-B (La) Antibodies: Found in about 40-50% of primary Sjögren's patients, almost always in conjunction with anti-SS-A/Ro. Their presence may be associated with a lower risk of some severe extraglandular features compared to SS-A positivity alone, but still indicates significant autoimmune activity (1, 7).

Presence of anti-SS-A/Ro and/or anti-SS-B/La antibodies strongly supports the diagnosis of primary Sjögren's Syndrome (6).

Other Antibodies (Alpha-fodrin, Cathepsin G)

• Anti-Alpha-Fodrin Antibodies: Alpha-fodrin is a cytoskeleton protein. Antibodies against it have been reported in a high percentage of both primary and secondary Sjögren's patients, sometimes appearing early (8). However, their diagnostic utility compared to anti-SS-A/Ro and anti-SS-B/La is less established, and they are not included in current major classification criteria (6). Testing is not routinely performed in most centers.
• Anti-Cathepsin G Antibodies: Cathepsin G is a protease found in neutrophils. While antibodies against it can be found in various inflammatory rheumatic diseases including Sjögren's, SLE, and Felty's syndrome (RA + splenomegaly + neutropenia), they lack specificity for Sjögren's Syndrome and are generally not used for its diagnosis (9 - general reference on cathepsins).

Salivary Gland Biopsy

• Minor Salivary Gland Biopsy (Lip Biopsy): Considered a highly specific test. A small sample of minor salivary glands is taken from the inner lip and examined microscopically. The presence of focal lymphocytic sialadenitis (FLS), defined as aggregates of 50 or more lymphocytes (a "focus") adjacent to normal-appearing acini, is characteristic. A focus score (number of foci per 4 mm² of tissue) ≥ 1 is considered positive and strongly supports the diagnosis (1, 6).

Classification Criteria

• The 2016 ACR/EULAR classification criteria for primary Sjögren's Syndrome integrate objective findings: a positive lip biopsy (FLS ≥ 1), presence of anti-SS-A/Ro antibodies, and evidence of ocular surface damage (ocular staining score ≥ 5 or van Bijsterveld score ≥ 4). Meeting the required point threshold based on these criteria helps classify patients for clinical studies and aids clinical diagnosis (6).

Treatment

Management is tailored to the individual patient's symptoms and organ involvement, aiming to relieve dryness, manage pain and fatigue, and treat systemic complications (1, 10).

1. Symptomatic Treatment for Sicca:
   • Eyes: Frequent use of preservative-free artificial tears, lubricating gels/ointments (especially at night), cyclosporine or lifitegrast ophthalmic solutions to reduce inflammation, punctal plugs (to conserve tears), protective eyewear. Referral to ophthalmology is crucial (1, 10).
   • Mouth: Meticulous oral hygiene, frequent sips of water, sugar-free chewing gum or candies to stimulate saliva, saliva substitutes/mouth sprays, fluoride treatments/varnishes to prevent caries. Prescription medications (secretagogues) like pilocarpine or cevimeline can stimulate saliva production (1, 10).
   • Other dryness: Skin moisturizers, vaginal lubricants.
2. Treatment for Musculoskeletal Symptoms:
   • NSAIDs or analgesics for mild pain.
   • Hydroxychloroquine is often used for fatigue, arthralgia, and mild arthritis (1, 10).
3. Treatment for Systemic (Extraglandular) Disease:
   • Depends on the organ involved and severity.
   • Corticosteroids may be used for flares or significant inflammation.
   • Immunosuppressants (e.g., methotrexate, azathioprine, mycophenolate mofetil) or biologic agents (e.g., rituximab, potentially belimumab) may be required for significant organ involvement (like ILD, vasculitis, severe arthritis, neurological or renal disease), typically managed by a rheumatologist (1, 10).
4. Treatment of Underlying Disease (in Secondary Sjögren's): Optimizing treatment for the associated RA, SLE, or SSc is essential.
5. Monitoring: Regular follow-up to assess symptom control, screen for complications (especially lymphoma and organ involvement), and adjust treatment.

Differential Diagnosis

Dryness symptoms (sicca) can have many causes other than Sjögren's Syndrome (1):

Condition	Key Differentiating Features
Medication Side Effects	Very common cause. Anticholinergic drugs (antihistamines, antidepressants, antipsychotics, bladder medications), diuretics, decongestants, some blood pressure medications. Dryness often improves upon stopping the drug. Autoantibodies absent.
Age-Related Dryness	Glandular function naturally declines with age. Dryness usually milder. Autoantibodies absent. Objective tests may show mild decrease but often not as severe as in Sjögren's.
Viral Infections	Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV) can cause sicca symptoms and sometimes salivary gland swelling. Specific viral testing needed.
Sarcoidosis	Granulomatous disease that can infiltrate lacrimal and salivary glands causing dryness/swelling. Often associated lung involvement (hilar lymphadenopathy), skin lesions (erythema nodosum). Elevated ACE levels, characteristic biopsy findings.
IgG4-Related Disease	Can cause Mikulicz's syndrome (symmetric swelling of lacrimal and salivary glands) and dryness. Characterized by elevated serum IgG4 levels and specific histopathology (IgG4+ plasma cell infiltrates, storiform fibrosis).
Graft-versus-Host Disease (GVHD)	Occurs after allogeneic stem cell transplant. Can cause severe sicca symptoms resembling Sjögren's. History is key.
Head/Neck Radiation	Radiation therapy for cancers can permanently damage salivary and lacrimal glands, causing severe dryness. History is diagnostic.
Anxiety/Depression	Can sometimes cause a subjective sensation of dry mouth without objective findings.

References

1. Mariette X, Criswell LA. Sjögren's Syndrome. N Engl J Med. 2018;378(10):931-939. doi:10.1056/NEJMcp1702514
2. Fox RI. Sjögren's syndrome. Lancet. 2005;366(9482):321-331. doi:10.1016/S0140-6736(05)66990-5
3. Mavragani CP, Moutsopoulos HM. Sjögren's syndrome. Annu Rev Pathol. 2014;9:273-285. doi:10.1146/annurev-pathol-012712-141838
4. Stefanski AL, Tomiak C, Pleyer U, et al. The Diagnosis and Treatment of Sjögren's Syndrome. Dtsch Arztebl Int. 2017;114(20):354-361. doi:10.3238/arztebl.2017.0354
5. Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X. Primary Sjögren syndrome. BMJ. 2012;344:e3821. doi:10.1136/bmj.e3821
6. Shiboski CH, Shiboski SC, Seror R, et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome: A consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol. 2017;69(1):35-45. doi:10.1002/art.39859
7. Baer AN, Implicit BE. Autoantibodies in Sjögren Syndrome. Rheum Dis Clin North Am. 2016;42(3):483-496. doi:10.1016/j.rdc.2016.03.008
8. Witte T, Matthias T, Arnett FC, et al. IgA and IgG autoantibodies against alpha-fodrin as markers for Sjögren's syndrome. Systemic Autoimmune Diseases. 1997;155–6. (Note: Reference relates to alpha-fodrin, older context)
9. Turk B, Turk D, Turk V. Lysosomal cysteine proteases: facts and opportunities. EMBO J. 2001;20(17):4629-4633. doi:10.1093/emboj/20.17.4629 (General reference on cathepsins)
10. Ramos-Casals M, Tzioufas AG, Stone JH, et al. Treatment of primary Sjögren syndrome: a systematic review. JAMA. 2010;304(4):452-460. doi:10.1001/jama.2010.1014