Sjgren's Disease¶
Chapter 373 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 373
Key Clinical Points¶
- Sjögren's disease is a prototype autoimmune disease characterized by lymphocytic infiltration of exocrine glands (salivary/lacrimal) resulting in xerostomia, keratoconjunctivitis sicca, and profound B-cell hyperactivity.
- Prevalence is ~0.5–1%; 5–20% of patients with other autoimmune diseases exhibit sicca manifestations.
- Extraglandular manifestations occur in one-third of patients, including nonspecific (fatigue, arthralgias), periepithelial (lung, kidney, liver), immune complex-mediated (vasculitis, neuropathy, glomerulonephritis), and lymphoma.
- Sjögren's disease carries the highest risk for lymphoma development among all autoimmune diseases; most are extranodal, low-grade, marginal zone B-cell lymphomas (MALT).
- Diagnosis involves clinical assessment, ocular tests (Schirmer's I, tear breakup time), salivary studies, labial minor salivary gland biopsy, and specific serology (Ro52/60, La, etc.).
- Management focuses on symptomatic relief via artificial tears and secretion stimulants (Pilocarpine 5 mg TID, Cevimeline 30 mg).
- Critical clinical pearl: Avoid medications that decrease secretions, such as anticholinergics, diuretics, antihypertensives, and antidepressants.
- Early disease onset is associated with a more aggressive phenotype and higher frequency of systemic manifestations and serum autoantibodies.
- Specific risk factors for lymphoma include B symptoms, large lymph nodes (>7 cm), and histopathologic findings like germinal center formation.
DEFINITION & OVERVIEW¶
• Definition (Harrison's 22e): Sjögren’s disease is a prototype autoimmune disease characterized by lymphocytic infiltration of the exocrine glands resulting in xerostomia, dry eyes (keratoconjunctivitis sicca), and profound B-cell hyperactivity. • Clinical Spectrum: ◦ Organ-specific: Limited to salivary and lacrimal glands. ◦ Systemic: Involvement of extraglandular organs (lung, kidney, liver, vasculitis, neuropathy). ◦ Autoimmune epithelitis: Term for periepithelial pathology due to periepithelial accumulation of lymphocytes resulting from involvement of parenchymal organs such as the lungs, kidneys, and liver. • Classification: ◦ Primary Sjögren's disease: Occurs without other systemic rheumatic diseases. ◦ Secondary Sjögren's disease: Occurs in association with other systemic rheumatic diseases (e.g., rheumatoid arthritis, limited scleroderma, systemic lupus erythematosus). ◦ Sicca manifestations: 5–20% of patients with other autoimmune diseases can express sicca manifestations.
EPIDEMIOLOGY¶
• Prevalence: ~0.5–1%. • Demographics: Predominantly middle-aged women (female-to-male ratio 10–20:1). • Age of Onset: Can occur at any age, including childhood. • Severity Correlation: Earlier disease onset → more aggressive disease phenotype → higher occurrence of systemic manifestations and serum autoantibodies.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Immune Mechanisms: ◦ Lymphocytic infiltration of exocrine glands (primarily salivary and lacrimal). ◦ B-lymphocyte hyperreactivity → hypergammaglobulinemia and serum autoantibodies toward non-organ-specific antigens (Ro52, Ro60, and La). ◦ Primary infiltrating cells: Activated T lymphocytes; B-cell populations predominate in labial minor salivary gland tissues. ◦ Macrophages & inflammasome activation → increased risk for lymphoma development. • Glandular Epithelial Cell Role: ◦ Express costimulatory molecules and autoantigens (Ro, La) on cell surfaces. ◦ Produce proinflammatory cytokines and chemokines → formation of ectopic germinal centers. ◦ Express innate immunity receptors: Toll-like receptors (TLRs) 3, 7, and 9. ◦ Express immunoregulatory molecules: ICAM and CD40. ◦ Production of B cell–activating factor (BAFF), induced by type I and II interferons → antiapoptotic effect on B lymphocytes. • Triggers: Interaction of endogenous (e.g., intracellular stress, overexpressed nucleic acids) and exogenous triggers (e.g., viruses, hormonal triggers, stressful life events) in a genetically determined hyperactive immune response. • Genetic Factors: ◦ HLA-DQA1*0501 allele. ◦ Variations in interferon/BAFF axis (IRF5, STAT4, BAFF). ◦ B-cell function genes (EBF1, BLK). ◦ Combined genetic deficiencies in the classical complement pathway.
CLINICAL FEATURES¶
• Oral Manifestations: ◦ Primary symptom: Xerostomia. ◦ Symptoms: Difficulty swallowing dry food, burning mouth sensation, increased dental caries, problems with dentures. ◦ Physical Exam: Dry, erythematous sticky oral mucosa; atrophic filiform papillae; deeply fissured tongue (Figure 373-2). ◦ Saliva: Not expressible or cloudy. ◦ Parotid Enlargement: Occurs in two-thirds of patients. • Ocular Manifestations: ◦ Keratoconjunctivitis sicca: Destruction of corneal and bulbar conjunctival epithelium. ◦ Symptoms: Sandy/gritty feeling, burning, thick strands of secretion at inner canthi, decreased tearing, redness, itching, eye fatigue, increased photosensitivity. • Extraglandular (Systemic) Manifestations (1/3 of patients): ◦ Nonspecific: Fatigability (25%), low-grade fever, Raynaud's phenomenon (37%), myalgias, arthralgias, nonerosive arthritis (60%). ◦ Periepithelial: ◦ Lung (14%): Dry cough, peribronchial infiltrates, interstitial pneumonitis. ◦ Kidney (9%): Interstitial nephritis, hyposthenuria, renal tubular dysfunction → potential nephrocalcinosis. ◦ Liver (6%): Primary biliary cirrhosis stage I. ◦ Immune Complex–Mediated: ◦ Small vessel vasculitis (9%): Purpura, urticarial rash, skin ulcerations. ◦ Peripheral neuropathy (2%): Polyneuropathy (sensory or sensorimotor). ◦ Glomerulonephritis (2%): Membranoproliferative. ◦ Lymphoma: Glandular MALT lymphoma is most common. • Laboratory Findings: ◦ Leukopenia and infrequently lymphopenia. ◦ Elevated ESR (two-thirds of patients), hypergammaglobulinemia, ANA, RF, Ro52/60, La. ◦ Anticentromere → similar to limited scleroderma. ◦ Antimitochondrial → autoimmune cholangitis. ◦ 21-hydroxylase → blunted adrenal response. ◦ Citrullinated peptides → arthritis. ◦ Anticalponin-3 → peripheral neuropathies.
DIFFERENTIAL DIAGNOSIS¶
• Clinical Suspicion: Suspect Sjögren's if patient presents with eye/mouth dryness, parotid enlargement, Raynaud's phenomenon, palpable purpura, or renal tubular acidosis. • Table 373-2: Differential Diagnosis of Sicca Symptoms ◦ Xerostomia: Viral (HCV, HIV), Drugs, Psychotherapeutic, Parasympatholytic, Antihypertensive, Psychogenic, Irradiation, Diabetes, Trauma, Sjögren's, Amyloidosis, Autoimmune thyroid. ◦ Dry Eye: Inflammation, Stevens-Johnson syndrome, Pemphigoid, Chronic conjunctivitis, Chronic blepharitis, Sjögren's, Toxicity, Burns, Drugs, Neurologic conditions, Impaired lacrimal/eyelid function, Hypovitaminosis A, Blink abnormality, Anesthetic cornea, Lid scarring, Epithelial irregularity, Autoimmune thyroid. ◦ Bilateral Parotid Enlargement: Viral (Mumps, Influenza, EBV, Coxsackievirus A), Sarcoidosis, tuberculosis, IgG4-related disease, Sjögren's, Metabolic (Diabetes, Hyperlipoproteinemias), Chronic pancreatitis, Hepatic cirrhosis, Endocrine (Acromegaly, Gonadal hypofunction), Eosinophilic sialodochitis, Lymphoma. • Table 373-3: Differential Diagnosis of Sjögren's Disease ◦ HIV Infection: Predominant in young males; CD8+ T lymphocytes in salivary glands; Association with HLA-DR5; Positive serologic tests for HIV. ◦ Sjögren's Disease: Predominant in middle-aged women; Ro/La autoantibodies; CD4+ T lymphocytes in salivary glands; Association with HLA-DR3 and DRw52; Negative serologic tests for HIV. ◦ Sarcoidosis: No age or sex preference; Granulomas in salivary glands; Negative serologic tests for HIV.
INVESTIGATIONS & DIAGNOSIS¶
- Ocular Evaluation: • Schirmer's I test (tear flow). • Tear breakup time or tear lysozyme content. • Slit-lamp examination with lissamine green or Rose Bengal staining (detect punctate corneal and bulbar conjunctival ulcerations).
- Salivary Assessment: • Sialometry. • Imaging: Ultrasound, MRI, magnetic resonance sialography.
- Biopsy: • Labial minor salivary gland biopsy → look for focal lymphocytic infiltrates.
- Serology & Laboratory Tests: • ANA, RF, Ro52/60, La. • Check for leukopenia, hypergammaglobulinemia, and low C4 levels. • Anticentromere (limited scleroderma), Antimitochondrial (autoimmune cholangitis), 21-hydroxylase (adrenal), Citrullinated peptides (arthritis), Anticalponin-3 (neuropathy).
- Inclusionary/Exclusionary Testing: • Viral tests (HCV, HIV) to rule out other causes of sicca. • CXR to rule out sarcoidosis.
MANAGEMENT & TREATMENT¶
- Ocular Treatment: • Artificial tears: Hydroxypropyl methylcellulose, polyvinyl alcohol, 0.5% methylcellulose, Hypo Tears. • Corneal ulcerations: Eye patching, boric acid ointments, or cyclosporine eye drops.
- Oral & Vaginal Treatment: • Xerostomia: Water (best replacement). • Vaginal Dryness: Propionic acid gels.
- Secretion Stimulation: • Pilocarpine: 5 mg TID. • Cevimeline: 30 mg.
- Systemic Management: • Glucocorticoids for systemic manifestations. • Immunosuppressants for vasculitis, renal involvement, or lung involvement.
- Drug Avoidance (Critical): • Do not use: Anticholinergics, diuretics, antihypertensives, and antidepressants that decrease lacrimal and salivary secretions.
PROGNOSIS & COMPLICATIONS¶
• Lymphoma Risk (Highest among all autoimmune diseases): ◦ High-risk features: ◦ Clinical: Parotid gland enlargement, severe tongue atrophy, palpable purura. ◦ Serological/Lab: Ro/SSA and La/SSA autoantigens, low C4 complement level, monoclonal gammopathy, cryoglobulins. ◦ Histopathologic: Germinal center formation, heavy focal lymphocytic infiltrates. ◦ Survival Factors: Decreased in patients with B symptoms, lymph node mass >7 cm in diameter, or high/intermediate histologic grade. ◦ Monitoring: FDG-PET/CT to exclude lymphoma when suspected. • Other Complications: ◦ Cardiovascular: Increased risk of cardiovascular disease. ◦ Renal: Untreated acidosis → nephrocalcinosis. ◦ General: Disease evolution is typically slow and often follows a benign course.
KEY PEARLS & CLINICAL TRAPS¶
• Lymphoma Risk: Highest among all autoimmune diseases; most are extranodal, low-grade, marginal zone B-cell lymphomas (MALT). • Parotid Enlargement: Occurs in two-thirds of patients. • Arthritis: Characteristically nonerosive. • Drug Safety: Strictly avoid anticholinergics, diuretics, antihypertensives, and antidepressants to preserve secretions. • Clinical Correlation: Early onset → more aggressive phenotype. • Diagnostic Rule: Use FDG-PET/CT if lymphoma is suspected to rule out malignancy.
Reference Tables¶
TABLE 373-1 Prevalence of Extraglandular Manifestations in Primary Sjögren’s disease¶
Harrison's 22e, p.2877
| CLINICAL MANIFESTATION | PERCENT | REMARKS |
|---|---|---|
| Nonspecific | ||
| Fatigability/myalgias | 25 | Fibromyalgia |
| Arthralgias/arthritis | 60 | Usually nonerosive, leading to Jaccoud’s arthropathy |
| Raynaud’s phenomenon | 37 | In one-third of patients, precedes sicca manifestations |
| Periepithelial | ||
| 14 | ||
| 9 | ||
| 6 | ||
| Immune complex–mediated | ||
| Small vessel vasculitis | 9 | Purpura, urticarial lesions |
| Peripheral neuropathy | 2 | Polyneuropathy, either sensory or sensorimotor |
| Glomerulonephritis | 2 | Membranoproliferative |
| Lymphoma |
TABLE 373-2 Differential Diagnosis of Sicca Symptoms XEROSTOMIA Viral infections¶
Harrison's 22e, p.2878
| XEROSTOMIA | DRY EYE | BILATERAL PAROTID GLAND ENLARGEMENT |
|---|---|---|
| Viral infections (HCV, HIV) Drugs Psychotherapeutic Parasympatholytic Antihypertensive Psychogenic origin Irradiation Diabetes mellitus Trauma Sjögren’s disease Amyloidosis Autoimmune thyroid disease |
Inflammation Stevens-Johnson syndrome Pemphigoid Chronic conjunctivitis Chronic blepharitis Sjögren’s Disease Toxicity Burns Drugs Neurologic conditions Impaired lacrimal gland function Impaired eyelid function Miscellaneous Trauma Hypovitaminosis A Blink abnormality Anesthetic cornea Lid scarring Epithelial irregularity Autoimmune thyroid disease |
Viral infections Mumps Influenza Epstein-Barr virus Coxsackievirus A Cytomegalovirus HIV, HCV Sarcoidosis, tuberculosis IgG4-related disease Sjögren’s disease Metabolic disorders Diabetes mellitus Hyperlipoproteinemias (types IV and V) Chronic pancreatitis Hepatic cirrhosis Endocrine Acromegaly Gonadal hypofunction Eosinophilic sialodochitis Lymphoma |
TABLE 373-3 Differential Diagnosis of Sjögren’s disease¶
Harrison's 22e, p.2878
| HIV INFECTION AND SICCA SYNDROME |
SJÖGREN’S DISEASE | SARCOIDOSIS |
|---|---|---|
| Predominant in young males |
Predominant in middle- aged women |
No age or sex preference |
| Presence of autoantibodies |
||
| Lymphoid infiltrates of salivary glands by CD8+ T lymphocytes |
Lymphoid infiltrates of salivary glands by CD4+ T lymphocytes |
Granulomas in salivary glands |
| Association with HLA-DR3 and DRw52 |
||
| Positive serologic tests for HIV |
Negative serologic tests for HIV |
Negative serologic tests for HIV |