I-33. SLE, systemic sclerosis and Sjögren's syndrome

全身性エリテマトーデス・全身性硬化症・シェーグレン症候群

Systemic Lupus Erythematosus (SLE)

Systemic autoimmune disease (skin, kidney, joints, heart); relapsing-remitting, unpredictable. Wide range of autoantibodies, especially ANAs.
Epidemiology: female:male 9:1, onset 20–40 yrs.
Symptoms: glomerulonephritis, butterfly rash, pericarditis/endocarditis, arthritis.
Triggers: UV light, drugs, genetic (HLA-DR; 25–60% twin concordance), EBV.

Pathomechanism

Defective clearance of apoptotic nuclear antigens, failure of T/B tolerance, NETosis; APCs recognize nuclear antigens as foreign → autoantibodies + cellular immunity vs self.

Autoantibodies

ANAs: anti-dsDNA, anti-histone, anti-Sm, anti-nucleolar (SS-A, SS-B). Detected by indirect immunofluorescence (sensitive, not specific).
Others: anti-RBC (anemia), anti-phospholipid (→ antiphospholipid syndrome).

Tissue injury

Type II hypersensitivity: autoantibodies vs RBC/WBC/platelets → destruction.
Type III: immunocomplexes → DNA/anti-DNA in glomeruli (glomerulonephritis), skin deposition (butterfly rash, discoid), vessel walls (accelerated atherosclerosis).

Lupus nephritis

Most severe complication (usually within 5 yrs; 10-yr survival 73%). Immunocomplex deposition + autoreactive CD4/CD8 T-cells; glomerular thrombosis (antiphospholipid). Active: hypertension, ↓GFR, proteinuria, edema → cardiac decompensation.

Pregnancy

Higher risk: preeclampsia, spontaneous abortion, IUGR, preterm delivery; flares in 25%. Conceive only during sustained remission.

Sjögren’s Syndrome

Immune destruction of lacrimal + salivary glands → keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth).
Primary (60%): spontaneous, more severe sicca. Secondary (40%): with RA/SLE, milder.
Pathogenesis: CD4⁺ T-cells vs ductal epithelial antigens; autoantibodies to RNP (SS-A/SS-B).
↑Risk: pseudolymphoma (10%), Hodgkin lymphoma (1%).

Systemic Sclerosis (Scleroderma)

Intensive fibrosis of skin, GI tract, kidney, heart, lung, muscle (skin = main target).
Diffuse: widespread skin, rapid, early GI. Limited: face/fingers, late GI — CREST (Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia).
Pathomechanism: abnormal T-cell response to unknown antigen → cytokines (IL-1, TGF-β, PDGF) → ↑collagen synthesis/deposition → excessive fibrosis; B-cells → ANAs (anti-centromere, anti-topoisomerase/Scl-70); no organ autoantibody deposition. Environmental: silica exposure.
Lung disease (life-threatening): parenchymal inflammation; Th2/M2 → fibroblast proliferation; autoantibodies damage vessels → microthrombi → pulmonary arterial hypertension; interstitial fibrosis.

Shared Genetic/Environmental Factors

Genetic: HLA class II (DR/DQ) — ankylosing spondylitis (B27), RA (DR4), primary Sjögren (DR3).
Environmental: molecular mimicry, tissue necrosis breaking anergy, epitope spreading.

Biological Therapies

Monoclonal antibodies vs soluble cytokines.
Anti-TNF-α: inhibits pathological B-cell activity; opportunistic infection risk.
Anti-BAFF: blocks B-cell proliferation; belimumab (first new lupus drug in 50 yrs) — ↑remission; severe infection/anaphylaxis risk.

一問一答

▶What is systemic lupus erythematosus (SLE)?

A systemic autoimmune disease (skin, kidney, joints, heart) with a relapsing-remitting, unpredictable course and a wide range of autoantibodies, especially ANAs.

▶What is the epidemiology and typical presentation of SLE?

Female:male 9:1, onset 20–40 years; symptoms include glomerulonephritis, butterfly rash, pericarditis/endocarditis, and arthritis.

▶What is the pathomechanism of SLE?

Defective clearance of apoptotic nuclear antigens, failure of T/B tolerance, and NETosis → APCs recognize nuclear antigens as foreign → autoantibodies + cellular immunity against self.

▶What autoantibodies are found in SLE?

ANAs (anti-dsDNA, anti-histone, anti-Sm, anti-nucleolar SS-A/SS-B), plus anti-RBC (anemia) and anti-phospholipid (→ antiphospholipid syndrome).

▶What are the triggers of SLE?

UV light, drugs, genetic factors (HLA-DR; 25–60% twin concordance), and EBV.

▶What types of hypersensitivity mediate tissue injury in SLE?

Type II (autoantibodies vs RBC/WBC/platelets → destruction) and type III (immunocomplexes deposited in glomeruli, skin, and vessel walls).

▶Why is the butterfly rash and glomerulonephritis explained by type III hypersensitivity?

DNA/anti-DNA immunocomplexes deposit in glomeruli (glomerulonephritis) and skin (butterfly/discoid rash), and in vessel walls (accelerated atherosclerosis).

▶What is lupus nephritis and its prognosis?

The most severe SLE complication (usually within 5 years; 10-year survival 73%), from immunocomplex deposition + autoreactive T cells and glomerular thrombosis; active disease shows hypertension, ↓GFR, proteinuria, and edema.

▶How does SLE affect pregnancy?

Higher risk of preeclampsia, spontaneous abortion, IUGR, and preterm delivery, with flares in 25%; conception is advised only during sustained remission.

▶What is Sjögren's syndrome?

Immune destruction of the lacrimal and salivary glands → keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth).

▶How do primary and secondary Sjögren's syndrome differ?

Primary (60%): spontaneous, more severe sicca symptoms. Secondary (40%): occurs with RA/SLE and is milder.

▶What is the pathogenesis and malignancy risk of Sjögren's syndrome?

CD4⁺ T cells attack ductal epithelial antigens with autoantibodies to RNP (SS-A/SS-B); risks include pseudolymphoma (10%) and Hodgkin lymphoma (1%).

▶What is systemic sclerosis (scleroderma)?

Intensive fibrosis of skin, GI tract, kidney, heart, lung, and muscle, with skin as the main target.

▶What distinguishes diffuse from limited systemic sclerosis (CREST)?

Diffuse: widespread skin involvement, rapid, early GI disease. Limited: face/fingers, late GI — CREST (Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia).

▶What is the pathomechanism of systemic sclerosis?

An abnormal T-cell response to an unknown antigen → cytokines (IL-1, TGF-β, PDGF) → ↑collagen synthesis/deposition → excessive fibrosis; B cells make ANAs (anti-centromere, anti-Scl-70), with no organ autoantibody deposition.

▶Why is lung disease life-threatening in systemic sclerosis?

Parenchymal inflammation with Th2/M2-driven fibroblast proliferation, autoantibody vascular damage → microthrombi → pulmonary arterial hypertension, and interstitial fibrosis.

▶How are ANAs detected, and what is the test's limitation?

By indirect immunofluorescence, which is sensitive but not specific.

▶Which autoantibodies are specific to systemic sclerosis subtypes?

Anti-centromere (limited/CREST) and anti-topoisomerase (Scl-70, diffuse).

▶What environmental factor is linked to systemic sclerosis?

Silica exposure.

▶What is the role of antiphospholipid antibodies in SLE?

They cause antiphospholipid syndrome and glomerular thrombosis, contributing to lupus nephritis and pregnancy complications.