Systemic Lupus Erythematosus (SLE)

Definition

Etiology and Predisposing Factors

• Genetic: Multiple HLA and non-HLA gene associations including IRF5, STAT4, PTPN22, BLK, FCGR2A, and complement genes (C1q, C4 deficiencies strongly predispose to SLE)
• Hormonal: Estrogens promote autoimmunity; disease worsens during pregnancy and with oral contraceptive use
• Environmental triggers: UV light (photosensitivity), drugs (hydralazine, procainamide, isoniazid - drug-induced lupus), infections (EBV), smoking

Pathogenesis

1. Loss of tolerance to self-antigens - particularly nuclear antigens (DNA, histones, ribonucleoproteins)
2. Autoantibody formation - B cells produce ANA, anti-dsDNA, anti-Sm antibodies. The earliest antibodies are against RNA-binding proteins (Ro), followed by anti-dsDNA, then anti-Sm/RNP around the time of clinical diagnosis
3. Immune complex deposition - Antigen-antibody complexes deposit in kidneys (glomeruli), skin, joints, blood vessels, and choroid plexus, activating complement (C3a, C5a) and recruiting neutrophils and macrophages
4. Type I Interferon signature - Plasmacytoid dendritic cells and low-density granulocytes (LDGs) produce large amounts of type I IFN (IFN-α), which amplifies B cell activation, dendritic cell maturation, and breaks peripheral tolerance
5. NETosis - LDGs from SLE patients form NET (Neutrophil Extracellular Traps) excessively; NETs contain oxidized nucleic acids, LL37, and modified self-proteins that stimulate type I IFN via the cGAS/STING pathway and activate the NLRP3 inflammasome, releasing IL-1 and IL-18 that perpetuate tissue damage
6. Complement activation and organ damage - Immune complex deposits activate classical complement → chemotaxis of inflammatory cells → fibrinoid necrosis → end-organ damage

Clinical Features

Malar Rash

Malar rash in SLE - Goldman-Cecil Medicine

Investigations

• ANA - Sensitive but not specific (positive in >95% of SLE; required entry criterion)
• Anti-dsDNA - Highly specific; titres correlate with disease activity (especially nephritis)
• Anti-Sm - Highly specific for SLE but less sensitive
• Complement levels - Low C3, C4 (consumed in active disease)
• Antiphospholipid antibodies (anticardiolipin, anti-β2GPI, lupus anticoagulant) - in ~30%; associated with thrombosis and pregnancy loss
• CBC - Anemia, lymphopenia, thrombocytopenia
• Urinalysis - Proteinuria, red cell casts in nephritis
• Renal biopsy - For lupus nephritis classification (WHO/ISN-RPS Class I-VI)

Diagnosis - 2019 ACR/EULAR Classification Criteria

1. ANA titer ≥ 1:80 (entry criterion - must be positive)
2. Score ≥ 10 points from weighted clinical and immunologic domains

Management

• Hydroxychloroquine (HCQ) - Given to ALL SLE patients; reduces flares, thrombosis risk, and mortality. Mechanism: blocks TLR7/9 signaling
• NSAIDs / Low-dose corticosteroids - For mild disease (arthritis, serositis)
• Corticosteroids (moderate-high dose) - For major organ involvement (nephritis, CNS disease)
• Immunosuppressives:
  • Mycophenolate mofetil (MMF) or cyclophosphamide - for lupus nephritis
  • Azathioprine - maintenance therapy
  • Methotrexate - for cutaneous/articular disease
• Biologics:
  • Belimumab (anti-BAFF/BLyS) - approved for active SLE
  • Anifrolumab (anti-IFN receptor) - for moderate-severe SLE
• Antiphospholipid antibody syndrome - Long-term anticoagulation
• Lifestyle: Sun protection, avoid triggers, vaccinations, manage CVD risk

Complications and Prognosis

• Lupus nephritis progresses to end-stage renal disease in ~10-20%
• Accelerated atherosclerosis and premature cardiovascular death
• Infections (major cause of early mortality due to immunosuppression)
• Avascular necrosis (from steroids or vasculitis)
• 10-year survival >90% with modern therapy; deaths in early disease are from organ failure/infection, later from cardiovascular disease

• 8 colour-coded sections with dark blue headers: Definition, Etiology, Pathogenesis, Clinical Features, Investigations, Diagnosis (2019 ACR/EULAR criteria), Management, and Complications/Prognosis
• Formatted tables for clinical manifestations, investigations, and classification criteria with alternating row colours
• Malar rash photograph with caption
• Summary box highlighting the key exam points
• Source citations at the bottom

Dumping Syndrome

1. Definition

2. Etiology and Predisposing Causes

• Partial gastrectomy with Billroth II reconstruction - most common; loss of pyloric reservoir function
• Billroth I, Roux-en-Y reconstruction (less often)
• Vagotomy + pyloroplasty/gastroenterostomy - vagotomy abolishes receptive relaxation of proximal stomach, markedly accelerating liquid emptying
• Roux-en-Y gastric bypass (mild early dumping, usually self-limiting in 1-2 months)
• Oesophagectomy, Whipple procedure (non-pylorus sparing)

• Early type 2 diabetes (autonomic neuropathy), Zollinger-Ellison syndrome, idiopathic rapid gastric emptying

3. Pathophysiology

Early Dumping (osmotic + neurohormonal)

1. Loss of pyloric function → hyperosmolar food bolus rapidly enters duodenum/jejunum
2. Osmotic fluid shift from intravascular space into intestinal lumen → luminal distension + intravascular volume contraction
3. Loss of vagally mediated receptive relaxation raises intragastric pressure, accelerating emptying further
4. Duodenal bypass (Billroth II, Roux-en-Y) eliminates feedback receptors that normally slow emptying
5. Rapid jejunal nutrient entry triggers release of vasoactive agents: neurotensin, VIP, GLP-1, serotonin, substance P
6. Result: GI symptoms (pain, nausea, bloating, diarrhoea) + vasomotor symptoms (flushing, tachycardia, diaphoresis, syncope)

Late Dumping (reactive hypoglycaemia)

1. Rapid carbohydrate delivery → quick absorption → hyperglycaemia
2. Exaggerated GLP-1-mediated insulin release (overshoots) → reactive hypoglycaemia
3. Hypoglycaemia activates adrenal glands → catecholamine release
4. Result: diaphoresis, tremulousness, lightheadedness, tachycardia, confusion

4. Clinical Features

5. Diagnosis

• Primarily clinical - characteristic postprandial symptoms after appropriate gastric surgery
• Modified 75g OGTT:
  • Early dumping positive: haematocrit rise ≥3% OR heart rate increase ≥10 bpm at 30 min
  • Late dumping positive: blood glucose <50 mg/dL between 1-3 hours
• Radionuclide gastric emptying scintigraphy with a liquid marker (>30% emptied at 30 min = rapid); low sensitivity and specificity
• Continuous glucose monitoring (CGM): for late dumping hypoglycaemia episodes

6. Management

• Small, frequent meals (6/day); separate liquids from solids (30-45 min apart); avoid simple sugars; lie down after meals; add pectin/guar gum to retard emptying

• Billroth II → Roux-en-Y conversion (preferred)
• Pyloric reconstruction; takedown of gastrojejunostomy

7. Prognosis