Summary

Systemic Lupus Erythematosus (SLE) is the distinct prototype of a systemic autoimmune disease. Unlike organ-specific destruction (e.g., Type 1 Diabetes), SLE is characterized by a loss of tolerance to nuclear antigens (DNA, Histones), resulting in the production of autoantibodies that form Immune Complexes. These complexes deposit in vascular beds across the body—Skin, Joints, Kidneys, Brain, and Pleura—triggering complement activation and inflammation (Type III Hypersensitivity).

It predominantly affects young women (9:1) of childbearing age, with a disproportionate burden on African-Caribbean and Asian populations. The clinical course is one of Relapsing-Remitting flares. The greatest threat to life is Lupus Nephritis (leading to ESRF) and accelerated Cardiovascular Disease. Management has evolved from high-dose steroids to steroid-sparing agents (Hydroxychloroquine for all, MMF/Cyclophosphamide for organs) and targeted Biologics (Belimumab, Anifrolumab).

Key Facts

• Demographic: Female:Male 9:1. Peak onset 15-45 years.
• Hallmark Antibody: ANA (>95% sensitive).
• Specific Antibody: Anti-dsDNA (>95% specific, tracks disease activity).
• Cornerstone Drug: Hydroxychloroquine (reduces mortality and flares).
• Major Complication: Lupus Nephritis (Class III/IV requires aggressive immunosuppression).

Clinical Pearls

"Hydroxychloroquine is Life Insurance": Every SLE patient should be on HCQ unless contraindicated. It prevents flares, reduces organ damage, reduces thrombosis, AND improves survival. Stopping it is the #1 cause of flare.

"The Renal Rule": Lupus Nephritis is often asymptomatic until it is too late. Every lupus patient needs a Urine Dipstick and BP check at EVERY clinic visit. "Frothy urine" means significant proteinuria.

"It's not just Lupus": 30-40% of SLE patients have Antiphospholipid Antibodies. They are at risk of clots (DVT/PE/Stroke) and recurrent miscarriage. Always screen for APS.

"Serositis vs Infection": A lupus patient with chest pain and fever. Is it Pleuritis (Lupus) or Pneumonia (Infection)?

• High CRP = Likely Infection (Lupus flares rarely raise CRP significantly unless there is synovitis/serositis).
• High ESR = Likely Lupus.

SLE is fundamentally a failure of the body to clear up its own mess.

1. Defective Apoptosis Clearance:

• Cells die every day (apoptosis). In healthy people, macrophages eat the debris quietly.
• In SLE, clearance is slow. Apoptotic cells persist ("secondary necrosis") and spill their contents (Nucleosomes, DNA, Ro/La antigens) into the extracellular space.

2. Loss of Tolerance:

• Dendritic cells see this "self-DNA" and mistake it for viral DNA (via Taller-Like Receptors TLR-7/9).
• They activate T-Cells, which help B-Cells make high-affinity IgG antibodies against the nucleus (ANA, Anti-dsDNA).

3. Immune Complex Deposition:

• Antibody + Antigen = Immune Complex.
• These complexes circulate and get stuck in "filters":
  • Glomerulus -> Nephritis.
  • Skin/dermo-epidermal junction -> Rash.
  • Synovium -> Arthritis.
  • Choroid Plexus -> CNS Lupus.

4. Complement Consumption:

• The complexes activate the Classical Complement Pathway (C1q, C3, C4).
• Result: Low C3/C4 in blood (consumed in tissues) and massive inflammation.

5. Interferon Signature:

• Plasmacytoid Dendritic Cells pump out Type 1 Interferon (IFN-alpha). This keeps the immune system in a distinct "viral alert" state.

"The Great Imitator" - SLE can affect any organ.

1. Constitutional (90%)

• Fatigue: Often debilitating and disproportionate to organ damage.
• Fever: Low grade during flares (Rule out infection!).
• Weight Loss.

2. Mucocutaneous (80%)

• Malar Rash: "Butterfly" erythema over cheeks/nose. Spares nasolabial folds. Photosensitive.
• Discoid Lupus: Chronic, scarring, coin-shaped lesions with central atrophy. Often on scalp (alopecia).
• Subacute Cutaneous LE (SCLE): Annular/polycyclic rash. Highly photosensitive. Anti-Ro positive.
• Alopecia: Non-scarring (hair thins during flare) or Scarring (Discoid).
• Oral Ulcers: Painless ulcers on the hard palate.

3. Musculoskeletal (90%)

• Arthralgia/Arthritis: Symmetrical, polyarticular (hands/knees).
• Jaccoud's Arthropathy: Deformity (ulnar deviation) that looks like RA but is reducible (caused by tendon laxity, not bone erosion).
• Non-Erosive: X-rays are normal (unlike RA).

4. Renal (Lupus Nephritis) (50%)

• Usually asymptomatic until advanced.
• Signs: Hypertension, Peripheral Oedema.
• Urinalysis: Proteinuria, Haematuria ("Active Sediment").
• Sequelae: CKD, ESRF requiring dialysis/transplant.

5. Serositis (50%)

• Pleuritis: Pleuritic chest pain. Pleural effusion.
• Pericarditis: Pericardial effusion.

6. Neuropsychiatric (NPSLE)

• Headache: Migraine is common.
• Psychosis/Delirium: Acute confusion during flare.
• Seizures.
• Stroke: Often due to APS thrombosis.
• Mononeuritis Multiplex (Vasculitis of nerves).

7. Haematological

• Cytopenias: Autoimmune Haemolytic Anaemia (Coombs +ve), Thrombocytopenia (ITP-like), Leukopenia.

8. Cardiovascular

• Libman-Sacks Endocarditis: Sterile vegetations on mitral valve (Embolic risk).
• Accelerated Atherosclerosis: 50x risk of MI in young women.

Part 1: General Measures (For EVERYONE)

1. Sun Protection: High SPF (50+). UV avoidance.
2. Hydroxychloroquine (HCQ):
   • Dose: 5mg/kg/day (usually 200-400mg).
   • Benefit: Reduces flares by 50%. Reduces clotting. Reduces organ damage.
   • Side Effect: Retinal toxicity. Annual OCT scan after 5 years.
3. Vaccination: Flu/Pneumococcal (No live vaccines if on biologic).
4. Cardiovascular Risk: Aggressive BP/Lipid control.
5. Calcium/Vit D: If on steroids.

Part 2: Mild-Moderate (Skin/Joints)

• Topical Steroids: For rash.
• NSAIDs: Joint pain.
• Oral Steroids: Low dose Prednisolone (less than 7.5mg) for flares.
• Methotrexate / Azathioprine: Steroid-sparing agents if arthritis persists.
• Belimumab: Anti-BLyS biologic. Good for recurrent skin/joint flares despite standard therapy.

Part 3: Severe (Nephritis / CNS / Haematology)

Requires "Induction" (hit hard) and "Maintenance" (keep suppressed).

Induction (3-6 months)

• High Dose Steroids: IV Methylprednisolone pulses -> Oral taper.
• Mycophenolate Mofetil (MMF): 2-3g daily.
  • Standard of care for Nephritis (African origin especially).
  • Teratogenic.
• Cyclophosphamide (CYC): IV infusions (Euro-Lupus protocol).
  • Reserved for organ-threatening crisis or MMF failure.
  • Risk: Infertility, Bladder Cancer.

Maintenance

• MMF (lower dose) or Azathioprine.
• Wean steroids completely if possible.

Biologics in Severe Disease

• Rituximab (Anti-CD20): Used 'off-label' in UK (NHS) for refractory nephritis or haematology. Highly effective.
• Anifrolumab (Anti-IFN receptor): New drug for skin/joint disease.

"The Temporary Lupus."

• Trigger: Certain drugs act as haptens or alter DNA methylation.
• Culprits:
  • High Risk: Procainamide, Hydralazine.
  • Medium: Isoniazid, Minocycline, TNF-inhibitors (Anti-TNF induced lupus!).
• Features:
  • Arthritis, Serositis.
  • Skin/Kidney/CNS usually SPARED. (Milder than idiopathic SLE).
• Antibody: Anti-Histone (>95%). Anti-dsDNA usually negative.
• Treatment: Stop the drug. Resolves in weeks.

"High Risk, High Reward." Historically, women were told not to conceive. Now, outcomes are good IF:

1. Disease is quiescent for >6 months before conception.
2. No active nephritis.

Risks:

• Maternal: Flare (esp. Nephritis), Pre-eclampsia (increased risk).
• Fetal: Miscarriage, Prematurity, IUGR.
• Neonatal Lupus:
  • Occurs if mother is Anti-Ro/La positive.
  • Antibodies cross placenta.
  • Baby gets rash (transient) or Congenital Heart Block (Permanent - requires pacemaker).
  • Action: Serial Fetal Echo from 16-26 weeks in Anti-Ro+ mums.

Drug Safety:

• Safe: Hydroxychloroquine (MUST CONTINUE), Azathioprine, Prednisolone, Aspirin, Heparin.
• Unsafe: Mycophenolate (Miscarriage/Ear defects), Methotrexate, Cyclophosphamide.

"Sticky Blood." Can be Primary (standalone) or Secondary (with SLE).

• Diagnosis (Sapporo Criteria):
  • Clinical: Vascular Thrombosis (Arterial/Venous) OR Pregnancy Morbidity (3+ miscarriages under 10w, or 1+ death after 10w, or severe pre-eclampsia).
  • Lab: Lupus Anticoagulant, Anti-Cardiolipin, Anti-B2GP1 (Must be positive on 2 occasions 12 weeks apart).
• Management:
  • Clot: LIFELONG Warfarin (INR 2-3 for venous, 3-4 for arterial/recurrent). DOACs generally avoided in high-risk APS (Triple positive).
  • Obstetric: Low Dose Aspirin + Prophylactic LMWH during pregnancy.

Pre-operative:

• C-Spine: Unlike RA, C-spine is stable.
• Steroids: Need stress dose (IV Hydrocortisone) if on long-term pred.
• Renal: Check electrolytes/GFR.
• Clotting: High risk of DVT (Hypercoagulable) vs Bleeding (Thrombocytopenia).
• Drugs: Hold MMF/MTX for 1 week? (Debated - usually continue if clean surgery).

Post-operative:

• Infection risk high.
• Wound healing delayed by steroids.

Case 1: The "New Rash"

Presentation: 24-year-old female presents with a rash on her face after a holiday in Spain. Also complains of joint pain in hands. Inv: ANA +, Anti-dsDNA +, C3 Low. Urinalysis specific gravity normal, no protein. Diagnosis: New presentation SLE. Skin/Joint predominant. Rx: Hydroxychloroquine + Short course Prednisolone + Sunscreen advice.

Case 2: The "Foamy Urine"

Presentation: 30-year-old female with known SLE (on HCQ) notices swollen ankles and frothy urine. BP 160/95. Inv: Urine PCR 300mg/mmol (Nephrotic range). Creatinine 120. Action: Urgent Renal Biopsy. Result: Class IV Diffuse Proliferative Nephritis. Rx: Induction with MMF 1.5g BD + IV Methylprednisolone. BP control with Ramipril.

Case 3: The "Seizure"

Presentation: 19-year-old female with SLE presents with first onset generalized tonic-clonic seizure. No history of epilepsy. DDx: Infection (Meningitis), Drug withdrawal, Electrolytes, NPSLE. Inv: MRI Brain (High signal lesions), Lumbar Puncture (exclude infection, check neuronal antibodies). Ribosomal P antibody positive. Diagnosis: Neuropsychiatric Lupus. Rx: Cyclophosphamide pulse therapy.

What is Lupus?

Think of your immune system as a security guard. It is supposed to fight intruders (viruses). In Lupus, the security guard gets confused and starts arresting the innocent staff (your own cells). This causes inflammation in different parts of the building (body).

Why do I have it?

It's a mix of your genes (susceptibility) and a trigger (like the sun, stress, or a virus). It is not an infection, and it is not contagious.

Is it curable?

Not yet, but it is treatable. Most women with Lupus live normal lives, have careers, and have babies. The key is keeping the "security guard" calm with medication.

Why Hydroxychloroquine?

This is your "background hostility dampener". It stops the security guard from over-reacting. It is the most important drug you take. It takes 3 months to build up, so don't stop it if you don't feel better immediately.

Signs to Elicit

1. Hands: Look for rash between knuckles (Lupus) vs on knuckles (Dermatomyositis). Look for nail fold infarcts.
2. Mouth: Use a torch to look at the hard palate (ulcers).
3. Scalp: Look for discoid scarring / alopecia.
4. Urine: Ask "Has a dipstick been done?"

Viva Questions

• Q: Distinguish Drug-Induced Lupus from SLE?
  • A: Anti-Histone positive. Anti-dsDNA negative. Normal Complement. Resolves on stopping drug.
• Q: Why do we measure Complement levels?
  • A: They drop during a flare because they are being consumed in immune complexes.
• Q: What is the risk of falling pregnant with active nephritis?
  • A: Very high risk of progression to renal failure and pre-eclampsia/fetal loss.

Mechanism:

• B-Cell Activating Factor (BAFF) - also known as BLyS - is a cytokine that keeps B-cells alive.
• Lupus patients have high BLyS.
• Belimumab is a monoclonal antibody that inhibits BLyS.
• Result: B-cells undergo apoptosis (commit suicide). Autoantibody levels fall.
• NICE Indication: Add-on therapy for autoantibody-positive SLE with high disease activity despite standard therapy.

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.