SLE and ANA patterns - Robbins-style exam answer

Systemic lupus erythematosus (SLE)

1. Immune-complex deposition - type III hypersensitivity
2. Autoantibody-mediated injury to cells and tissues - type II hypersensitivity

Loss of self-tolerance leads to ANA formation, immune-complex deposition, complement activation, and inflammation in multiple organs.

ANA in SLE

What are ANAs?

1. Antibodies to DNA
2. Antibodies to histones
3. Antibodies to non-histone proteins bound to RNA
4. Antibodies to nucleolar antigens

Important: ANA pattern is a clue, not a final diagnosis. Mixed patterns can occur because several autoantibodies may coexist.

ANA patterns and interpretation

Important antibodies in SLE

How to interpret ANA in an exam

1. ANA positive

• Supports autoimmune connective-tissue disease only if clinical features are compatible.
• It is sensitive but not specific.
• It may be positive in other autoimmune diseases and sometimes in healthy persons.

2. Homogeneous pattern

• Think: SLE / drug-induced lupus
• Then check:
  • Anti-dsDNA
  • Anti-Sm
  • Anti-histone

3. Peripheral or rim pattern

• Think: anti-dsDNA
• Strongly consider SLE with renal involvement.

4. Speckled pattern

• Think: antibodies to Sm, RNP, Ro, La
• Seen in SLE but also in Sjögren syndrome and MCTD.
• Do specific antibody testing for confirmation.

5. Nucleolar or centromere pattern

• Think mainly systemic sclerosis, not typical SLE.

Ready-to-write 5-mark answer

Memory trick

• D - anti-DsDNA: lupus nephritis, activity
• S - anti-Sm: most specific for SLE
• H - anti-Histone: drug-induced lupus
• R - anti-Ro: subacute cutaneous/neonatal lupus

Systemic Lupus Erythematosus (SLE): Pathogenesis, Morphology, Clinical Features, ANA and Diagnosis

Definition

1. Pathogenesis

Basic defect

Loss of self-tolerance to nuclear antigens leads to formation of autoantibodies and immune complexes.

Sequence

1. Genetic susceptibility
   • Association with HLA genes and other immune-regulatory genes.
   • Deficiency of early complement components, especially C1q, C2, and C4, predisposes to SLE.
   • Defective complement function causes poor clearance of apoptotic cells and immune complexes.
2. Environmental triggers
   • UV light increases apoptosis and exposes nuclear antigens.
   • Infections, certain drugs, and hormonal influences may contribute.
3. Defective clearance of apoptotic nuclear material
   • Nuclear antigens such as DNA, histones, and ribonucleoproteins persist in tissues.
4. Activation of autoreactive B and T lymphocytes
   • Autoreactive CD4+ T cells help B cells form pathogenic autoantibodies.
   • Nuclear DNA/RNA activates Toll-like receptors, enhancing ANA production.
   • Type I interferons promote B-cell, T-cell, and dendritic-cell activation.
5. Tissue injury
   • Type III hypersensitivity: DNA-anti-DNA immune complexes deposit in glomeruli, vessels, skin, joints, and serosa.
   • Complement activation causes inflammation and tissue damage.
   • Type II hypersensitivity: antibodies against RBCs, platelets, and leukocytes cause cytopenias.

Flowchart for exam

2. Autoantibodies and ANA patterns

Important antibodies

Remember: ANA positive does not itself diagnose SLE. Interpret it with symptoms, specific antibodies, complement level, urine findings, and biopsy where indicated.

3. Morphology

A. Blood vessels

• Immune-complex deposition causes acute necrotizing vasculitis.
• Vessel walls may show fibrinoid necrosis.
• Chronic vascular lesions may show intimal thickening.

B. Kidneys: lupus nephritis

• Immune complexes deposit in glomeruli.
• Findings include proliferative glomerulonephritis, capillary-wall thickening, and sclerosis.
• Wire-loop lesions: marked capillary-wall thickening due to subendothelial immune-complex deposits.
• Immunofluorescence often shows a full-house pattern: IgG, IgA, IgM, C3, and C1q.

C. Skin

• Erythematous rash with interface dermatitis.
• Degeneration of basal cells and deposition of immunoglobulin/complement at dermoepidermal junction may produce a positive lupus band test.

D. Joints

• Synovitis may occur, but joint disease is classically nonerosive.

E. Heart

• Libman-Sacks endocarditis: sterile verrucous vegetations on either surface of valve leaflets, often mitral valve.
• Pericarditis is common.

F. Hematoxylin bodies and LE cells

• Hematoxylin bodies (LE bodies): homogeneous, basophilic nuclear remnants of damaged cells coated by ANA.
• LE cell: a neutrophil or macrophage that has phagocytosed a denatured nucleus. It is of historical interest and is no longer used routinely for diagnosis.

4. Clinical features

Constitutional

• Fever, fatigue, weight loss, malaise.

Skin and mucosa

• Malar or butterfly rash
• Photosensitivity
• Discoid rash
• Oral or nasal ulcers
• Alopecia
• Raynaud phenomenon may occur.

Musculoskeletal

• Arthralgia and arthritis.
• Typically nonerosive arthritis involving small joints.

Renal

• Proteinuria, hematuria, RBC casts.
• Nephritic or nephrotic syndrome.
• Hypertension and renal failure in severe lupus nephritis.

Serosal

• Pleuritis and pleural effusion.
• Pericarditis and pericardial effusion.

Hematologic

• Autoimmune hemolytic anemia.
• Leukopenia/lymphopenia.
• Thrombocytopenia.

Neurologic

• Seizures, psychosis, cognitive dysfunction, neuropathy, stroke.

Antiphospholipid syndrome manifestations

• Recurrent arterial or venous thrombosis.
• Recurrent fetal loss.
• Thrombocytopenia.
• Prolonged PTT in vitro despite thrombotic tendency in vivo.

5. Diagnosis

Diagnosis is clinical plus immunological

• Malar/photosensitive rash
• Oral ulcers
• Nonerosive arthritis
• Serositis
• Nephritis
• Cytopenias
• Neurological manifestations

Investigations

Classification point

Short combined exam answer