SLE

Prof. (Dr.) Siba Prasad Dalai

INTRODUCTION
Systemic Lupus Erythematosus (SLE) is a chronic, multisystem
autoimmune disease characterized by:
• Loss of self-tolerance
• Production of autoantibodies (especially ANA, anti-dsDNA)
• Immune complex deposition
• Complement activation
• Multiorgan inflammation
It has a relapsing–remitting course and heterogeneous presentation.
EPIDEMIOLOGY
•Prevalence: 20–150 per 100,000
•Female:Male ratio = 9:1
•Peak age: 15–45 years
•Higher severity in:
Asian populations
African descent

•In India: rising recognition, lupus nephritis relatively common

at presentation.
PATHOGENESIS
A. Genetic Factors
• HLA-DR2, HLA-DR3
• Complement deficiencies (C1q, C2, C4)
• IRF5, STAT4 polymorphisms
B. Environmental Triggers
• UV radiation
• EBV infection
• Smoking
• Drugs (hydralazine, procainamide, isoniazid)
C. Hormonal
• Estrogen promotes B-cell survival
IMMUNOPATHOGENESIS
Central Events:
• Defective clearance of apoptotic cells
• Nuclear antigen exposure
• Autoantibody formation
• Immune complex deposition
• Complement activation
• Organ damage
Key Mechanisms:
• Type I interferon pathway activation
• B-cell hyperactivity
• T-regulatory cell dysfunction
• NETosis (neutrophil extracellular traps)
CLINICAL FEATURES
A. Constitutional C. Musculoskeletal
• Fever • Non-erosive arthritis
• Fatigue • Arthralgia
• Weight loss D. Renal
B. Mucocutaneous • Proteinuria
• Malar rash • Hematuria
• Discoid rash • Hypertension
• Photosensitivity • Nephrotic/nephritic syndrome
• Oral ulcers
• Alopecia
CLINICAL FEATURES
E. Neuropsychiatric G. Cardiopulmonary
• Seizures • Pericarditis
• Psychosis • Pleural effusion
• Cognitive dysfunction • Libman–Sacks endocarditis
• Stroke H. Vascular
F. Hematologic • Raynaud’s phenomenon
• Hemolytic anemia • Antiphospholipid syndrome
• Leukopenia
• Thrombocytopenia
MALAR RASH

DISCOID RASH
Key Characteristics of SLE Rash:
•Appearance: A characteristic butterfly shape across the bridge of the nose and both
cheeks. It may also appear on the face, neck, upper chest, and elbows.
•Triggers: Sun exposure (UV rays) frequently causes or worsens the rash.
•Duration: The rash may come and go, often described as flaring up

.Types of Lupus Rashes:

•Acute Cutaneous Lupus: The classic butterfly (malar) rash.
•Subacute Cutaneous Lupus (SCLE): Red, raised patches or rings, often in sun-exposed
areas.
•Chronic Cutaneous Lupus (Discoid Lupus): Thick, scaly, red patches that may cause
scarring.

Management and Treatment:

•Sun Protection: Daily use of high-SPF (at least 50) sunscreen is crucial.
•Avoid Triggers: Stay out of direct sun between 10 a.m. and 4 p.m.
•Medication: Topical steroids, Hydroxychloroquine), or immunosuppressants to manage
flares
usually painless, pale yellow, or greyish-
white with red borders, typically
appearing on the palate, buccal mucosa,
or lips
SLE ARTHRITIS
JACCOUDS ARTHRITIS
typically non-erosive, inflammatory
condition affecting joints, characterized
by pain, swelling, and morning stiffness,
particularly in the hands, wrists, and
knees. Unlike rheumatoid arthritis, it
rarely causes permanent joint damage,
though it can cause significant,
fluctuating pain.
DIAGNOSIS
2019 EULAR/ACR Criteria
• Entry criterion: ANA ≥1:80
• Then weighted scoring system.
❑ Major domains:
• Constitutional
• Hematologic
• Neuropsychiatric
• Mucocutaneous
• Serosal
• Musculoskeletal
• Renal
• Immunologic (anti-dsDNA, anti-Sm, low complement, antiphospholipid)
• Score ≥10 → SLE
AUTO ANTIBODIES IN SLE
Antibody Significance

ANA Screening

Anti-dsDNA Renal activity

Anti-Sm Specific

Anti-Ro (SSA) Neonatal lupus

Anti-La (SSB) Sjogren overlap

Anti-phospholipid Thrombosis

Anti-histone Drug-induced lupus

LAB EVALUATION
1. CBC (cytopenias)
2. ESR ↑ (CRP often normal unless infection)
3. Urine R/M
4. 24 hr protein
5. Complement levels (C3, C4)
6. Anti-dsDNA titers (disease activity marker)
7. Renal biopsy if:
8. Proteinuria >500 mg/day
9. Active urine sediment
DISEASE ACTIVITY SCORES
• SLEDAI
• BILAG
• Physician Global Assessment
Used in clinical trials and follow-up.
• The SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score is a weighted index ranging from
0 to 105 used to assess disease activity in lupus patients, with higher scores indicating greater activity.
• It measures 24 clinical and laboratory items across 9 organ systems, specifically evaluating manifestations
present within the last 10 days.
Key SLEDAI Score Interpretations:
• No activity: 0
• Mild activity: 1-5
• Moderate activity: 6-10
• High activity: 11-19
• Very high activity: > 20
Clinical Implications:
• Treatment Changes: Scores > 5 are generally associated with a > 50% probability of initiating new therapy.
• Flare: An increase of > 3 points indicates a SLE flare-up.
• Improvement: A reduction of > 3 points indicates improvement.
• Remission: A score of 0 is considered remission.

The most common version, SLEDAI-2K, is a widely accepted, standardized tool used by rheumatologists to
quantify disease activity.
DIFFERENTIAL DIAGNOSIS

[Link] arthritis
[Link] connective tissue disease
[Link] syndrome
[Link]
[Link]
[Link]-induced lupus
[Link] (TB, HIV)
MANAGEMENT
GENERAL PRINCIPLES B. MILD DISEASE
• Lifelong disease • NSAIDs
• Organ-specific therapy • Low dose steroids
• Prevent flares • HCQ
• Minimize steroid toxicity

C. MODERATE DISEASE
A. ALL PATIENTS
• Prednisolone 0.5 mg/kg
• Hydroxychloroquine
• Add:
• Dose: 5 mg/kg/day (max 400 mg)
• Azathioprine
• Reduces flares • Methotrexate
• Improves survival • Mycophenolate mofetil

• Retinal screening annually after 5 years

MANAGEMENT
D. SEVERE DISEASE E. BIOLOGICS
• Lupus Nephritis (Class III/IV) • Belimumab
• Induction: • Anti-BAFF (beta cell activating
• IV Methylprednisolone pulses factor)
• Mycophenolate mofetil • For refractory SLE
OR • Rituximab
• Cyclophosphamide (NIH / Euro- • Off-label in refractory cases
Lupus protocol) • Anifrolumab
• Maintenance: • Targets type I interferon pathway
• MMF or Azathioprine
RECENT ADVANCES

•Interferon pathway inhibitors

•B-cell targeted therapy
•Treat-to-target approach
•Biomarkers (anti-C1q)
•Low-dose IL-2 trials
Pregnancy in SLE
Safe drugs: Monitor:
• Hydroxychloroquine • Anti-Ro/La (risk of neonatal
• Azathioprine lupus)
• Low dose steroids • Antiphospholipid antibodies
Avoid:
• Mycophenolate
• Methotrexate
• Cyclophosphamide
PROGNOSIS
• Improved survival (10-year survival >90%)

Poor prognostic factors:

• Lupus nephritis
• Neuropsychiatric SLE
• Infections
• Cardiovascular disease
COMPLICATIONS
• Accelerated atherosclerosis
• Osteoporosis (steroids)
• Avascular necrosis
• Chronic kidney disease
• Secondary antiphospholipid syndrome
DRUG INDUCED LUPUS
Common drugs: Features:
• Hydralazine • Anti-histone positive
• Procainamide • Rare renal/CNS involvement
• Isoniazid • Resolves after stopping drug
• Minocycline
LUPUS NEPHRITIS
• One of the most serious manifestations of Systemic Lupus
Erythematosus (SLE) and a major determinant of morbidity and
mortality.
• Occurs in 40–60% of SLE patients
• Higher incidence in:Asians, African ancestry
• Males
• Often presents within first 5 years of SLE
• In Indian patients: frequently proliferative at diagnosis
PATHOGENESIS
Core Mechanism
[Link]-dsDNA antibodies form immune complexes
[Link] in glomerular basement membrane & mesangium
[Link] activation (classical pathway)
[Link] of inflammatory cells
[Link] injury → proteinuria, hematuria
PATHOGENESIS
Key Immunologic Players Pathologic hallmark:
• Anti-dsDNA • “Full house” immunofluorescence
• Anti-C1q • IgG
• Low C3, C4 • IgA
• Type I interferon pathway • IgM
• NETosis (neutrophil extracellular • C3
traps) • C1q
CLINICAL PRESENTATION
A. Asymptomatic C. Nephrotic syndrome
• Isolated proteinuria • Heavy proteinuria (>3.5 g/day)
B. Nephritic syndrome • Edema
• Hematuria • Hypoalbuminemia
• RBC casts D. Rapidly progressive GN (rare)
• Hypertension • Crescent formation
• Rising creatinine
INDICATIONS FOR RENAL BIOPSY
Biopsy is mandatory if:
• Proteinuria ≥500 mg/day
• Active urine sediment
• Unexplained rise in creatinine
• Nephrotic syndrome
Lupus Nephritis (ISN/RPS Classification)

Class Description
I Minimal mesangial
II Mesangial proliferative
III Focal (<50%)
IV Diffuse (>50%)
V Membranous
VI Advanced sclerosing

•Class III & IV → Proliferative → Most aggressive

•Class V → Heavy proteinuria
ACTIVITY VS CHRONICITY INDEX
Biopsy scoring includes:
Activity:
• Endocapillary proliferation
• Leukocyte infiltration
• Fibrinoid necrosis
• Crescents
Chronicity:
• Glomerulosclerosis
• Tubular atrophy
• Interstitial fibrosis
High chronicity = poor response to therapy.
LAB MONITORING
• Urine R/M
• Spot urine protein/creatinine ratio
• 24-hour protein
• Serum creatinine
• Complement levels (C3, C4)
• Anti-dsDNA titers

Rising anti-dsDNA + falling C3 → flare.

TREATMENT OF LUPUS NEPHRITIS
GENERAL PRINCIPLES
• Early aggressive therapy improves outcome
• All patients must receive:
Hydroxychloroquine
Control BP (<130/80) - ACE inhibitors/ARBs
Statins if dyslipidemia
Vaccination
TREATMENT OF LUPUS NEPHRITIS
CLASS I & II
• Usually no immunosuppressive therapy
• Continue HCQ
• Low dose steroids if needed
TREATMENT OF LUPUS NEPHRITIS
CLASS III & IV (Proliferative LN)
INDUCTION (6 months)
Option 1:
• IV Methylprednisolone pulses (500–1000 mg × 3 days)
• Oral prednisolone 0.5–1 mg/kg
• Mycophenolate mofetil 2–3 g/day
Option 2:
• IV Cyclophosphamide
• NIH protocol (high dose) / Euro-Lupus protocol (low dose)
MAINTENANCE (3–5 years)
• MMF 1–2 g/day OR Azathioprine
TREATMENT OF LUPUS NEPHRITIS
CLASS V (Membranous)
• Nephrotic range proteinuria → treat with:
• Steroids + MMF
OR
• Calcineurin inhibitors (Tacrolimus, Cyclosporine)
ROLE OF BIOLOGICS
Belimumab MULTI-TARGET THERAPY
• Approved for active LN Combination:
• Reduces flares • MMF + Tacrolimus + Steroids
Rituximab Useful in Asian populations.
• Refractory LN
• B-cell depletion
Anifrolumab
Emerging option
TREATMENT RESPONSE DEFINITIONS
Complete Response
• Proteinuria <500 mg/day
• Stable creatinine
• Normal sediment
Partial Response
• ≥50% reduction proteinuria
• Stable renal function
REFRACTORY LUPUS NEPHRITIS
If no response after 6 months:
• Switch MMF ↔ Cyclophosphamide
• Add Rituximab
• Consider CNI
• Plasma exchange (rare situations)
SPECIAL SITUATIONS
Pregnancy ESRD
Safe: • Dialysis
• HCQ • Renal transplantation (best
• Azathioprine option)
• Low dose steroids • Disease recurrence ~10–20%
Avoid:
• MMF
• Cyclophosphamide
PROGNOSIS
Poor prognostic factors: 10-year renal survival:
• Delayed diagnosis • 90% (treated early)
• Class IV disease • <50% untreated proliferative LN
• High chronicity index
• Persistent proteinuria
• Non-compliance
COMPLICATIONS
• CKD
• ESRD
• Hypertension
• Thrombosis
• Infections (immunosuppression)
1
A 22-year-old woman with SLE has proteinuria 1.2 g/day and active urine
sediment. Serum creatinine normal. Next best step?
A. Increase steroids empirically
B. Add azathioprine
C. Renal biopsy
D. Start ACE inhibitor only
Answer: C. Renal biopsy
Explanation:
Proteinuria ≥500 mg/day with active sediment mandates biopsy to classify
lupus nephritis and guide therapy. Empirical treatment without histology is
inappropriate.
2
Which class of lupus nephritis most commonly presents with nephrotic
syndrome?
A. Class II
B. Class III
C. Class IV
D. Class V
Answer: D. Class V
Explanation:
Class V (membranous LN) causes subepithelial immune complex
deposition → heavy proteinuria.
3
The most common histologic class of lupus nephritis globally is:
A. Class I
B. Class II
C. Class III
D. Class IV
Answer: D. Class IV
Explanation:
Diffuse proliferative LN (Class IV) is most frequent and most severe,
especially in Asian populations.
4
“Full house” immunofluorescence refers to presence of:
A. IgG only
B. IgG + C3
C. IgG + IgA + IgM
D. IgG + IgA + IgM + C3 + C1q
Answer: D
Explanation:
Classic lupus nephritis finding: deposition of multiple
immunoglobulins plus complement.
5
Best induction therapy for Class IV lupus nephritis:
A. Azathioprine
B. Methotrexate
C. Mycophenolate mofetil
D. NSAIDs
Answer: C
Explanation:
MMF or cyclophosphamide + steroids is recommended induction
therapy for proliferative LN.
6
• A patient with lupus nephritis has rising anti-dsDNA titers and falling
C3 levels. This suggests:
• A. Remission
B. Chronic damage
C. Active flare
D. Drug toxicity
• Answer: C
• Explanation:
High dsDNA + low complement = immune complex activity and renal
flare.
7
• Which biopsy feature predicts poor response to immunosuppressive
therapy?
• A. Endocapillary proliferation
B. Crescents
C. High chronicity index
D. Leukocyte infiltration
• Answer: C
• Explanation:
Chronicity index reflects irreversible damage (fibrosis, sclerosis). High
chronicity = poor reversibility.
8
• A patient with SLE has nephrotic-range proteinuria and biopsy shows
subepithelial deposits without proliferation. Diagnosis?
• A. Class III
B. Class IV
C. Class V
D. Class VI
• Answer: C
• Explanation:
Subepithelial immune deposits → membranous LN (Class V).
9
A 30-year-old female with LN has proteinuria reduced from 4 g/day to
0.4 g/day after 8 months of therapy. Creatinine stable. This
represents:
A. No response
B. Partial response
C. Complete response
D. Relapse
Answer: C
Explanation:
Complete response = proteinuria <500 mg/day + stable renal
function.
10
• Best antihypertensive in lupus nephritis with proteinuria:
• A. Beta blocker
B. Calcium channel blocker
C. ACE inhibitor
D. Alpha blocker
• Answer: C
• Explanation:
ACE inhibitors reduce intraglomerular pressure and proteinuria.
11
A patient with Class IV LN fails MMF after 6 months. Best next step?
A. Stop therapy
B. Switch to cyclophosphamide
C. Add NSAIDs
D. Observe
Answer: B
Explanation:
Refractory LN → switch induction regimen (MMF ↔
Cyclophosphamide) or consider biologics.
High-Yield Revision Pearls
• Most severe LN: Class IV
• Nephrotic pattern: Class V
• Flare marker: ↑ anti-dsDNA + ↓ C3
• Poor prognosis: High chronicity index
• Induction: MMF or Cyclophosphamide
• Maintenance: MMF/Azathioprine
• All patients: Hydroxychloroquine