IgA Vasculitis — Henoch-Schonlein Purpura

IgA-Dominant Immune Complex Deposition

• Aberrant mucosal immune response leads to increased IgA1 production with galactose-deficient O-glycosylation of the hinge region
• Circulating IgA1-containing immune complexes deposit in small vessels throughout affected organs
• Complement activation via the alternative pathway (not classical pathway) generates C3a and C5a, perpetuating inflammation
• Galactose-deficient IgA1 is poorly cleared by the hepatic asialoglycoprotein receptor, promoting systemic accumulation

Endothelial Injury and Leukocyte Infiltration

• Immune complex deposition in vessel walls triggers endothelial activation and increased vascular permeability
• ANCA-negative neutrophilic infiltration predominates; neutrophil extracellular traps (NETs) contribute to tissue damage
• Upregulation of adhesion molecules (ICAM-1, VCAM-1) facilitates leukocyte recruitment into vessel walls
• Cytokine release (TNF-α, IL-6, IL-8) amplifies inflammation and vascular injury

Organ-Specific Manifestations

• Skin: Leukocytoclastic vasculitis of postcapillary venules in dermis; IgA deposition on direct immunofluorescence (DIF)
• Kidneys: Proliferative glomerulonephritis with IgA-dominant deposits on immunofluorescence; mesangial proliferation progresses to crescent formation in severe disease
• GI tract: Ischemic injury from vasculitis affecting mucosa and submucosa; may progress to perforation
• Heart: Myocarditis from immune complex deposition; coronary artery involvement rare but documented; valvulitis with aortic/mitral regurgitation possible

Infectious Triggers

• Upper respiratory tract infection (most common; typically Group A Streptococcus) precedes disease in 30-50% of cases
• Post-infectious phenomena: Disease typically develops 1-3 weeks after infection
• Other implicated organisms: Adenovirus, parvovirus B19, hepatitis B and C, HIV

Medication and Environmental Exposures

• Antibiotics (particularly amoxicillin, cephalosporins)
• NSAIDs (may precipitate relapse or worsen renal disease)
• Vaccinations (rare temporal association)
• Food additives and environmental allergens (postulated but unproven)

Genetic and Demographic Factors

• Asian and Mediterranean ancestry: Higher incidence compared to Caucasians
• Male predominance (1.5-2:1 ratio)
• HLA associations: HLA-A2, HLA-B35 increase susceptibility
• Family clustering: Rare but documented familial cases
• Secondary associations: Malignancy (especially bronchial and gastric), chronic liver disease, systemic lupus erythematosus

Cardinal Features (Tetrad)

Cutaneous Manifestations

• Palpable purpura: Non-blanching, symmetric involvement of lower extremities and buttocks; typically 2-10 mm diameter; evolves over days
• Urticarial lesions: May precede purpura development
• Distribution pattern: Gravity-dependent; predominantly below waist (unlike thrombocytopenic purpura)
• Palatal involvement: Uncommon but characteristic when present

Articular Involvement

• Arthralgia (75% of patients): Knee and ankle joints most frequently; typically non-erosive
• Arthritis: Swelling and effusions in 25-50%; self-limited, resolving within weeks
• Morning stiffness: Distinguishes inflammatory arthropathy presentation

Gastrointestinal Manifestations

• Colicky abdominal pain: 50-75% of patients; periumbilical or diffuse distribution
• GI bleeding: Melena or hematochezia (15-20%); occasionally massive
• Nausea/vomiting: Common
• Abdominal examination: May reveal tenderness; rebound tenderness suggests ischemia
• Severe complications: Intussusception (children), bowel perforation, pancreatitis

Renal Involvement

• Hematuria: Microscopic or macroscopic; present in 40-50% at onset
• Proteinuria: Variable degree; nephrotic range in 5-10%
• Hypertension: May develop secondary to glomerulonephritis
• Acute kidney injury: In severe proliferative disease

Cardiopulmonary Involvement (Board-Critical)

• Myocarditis: Chest pain, dyspnea, arrhythmias; rare but carries poor prognosis
• Pericarditis: Chest pain relieved by sitting forward; pericardial effusion on echocardiography
• Valvular disease: Aortic or mitral regurgitation from vasculitis; distinguished from acute rheumatic fever by absence of migratory polyarthritis
• Pulmonary hemorrhage: Rare; hemoptysis, dyspnea; associated with severe disease
• Coronary artery vasculitis: Documented angiographically; myocardial infarction possible

Systemic Findings

• Low-grade fever: Variable; typically mild
• Lymphadenopathy: Uncommon; suggests alternative diagnosis
• Hepatosplenomegaly: Rare
• Testicular involvement: Acute scrotal pain from vasculitis of spermatic cord; mimics torsion (requires ultrasound for differentiation)

Clinical Diagnosis Criteria

• Entry criterion: Palpable purpura (mandatory for inclusion)
• Additional criteria:
• Age of onset >4 years: 1 point
• Abdominal pain: 1 point
• IgA deposition on immunofluorescence: 1 point
• Arthritis/arthralgia: 1 point

Blood Work

• Complete blood count: Normal platelet count (distinguishes from thrombocytopenic causes); mild anemia possible
• Renal function: Baseline creatinine, BUN; assess for acute kidney injury
• Urinalysis: Hematuria and/or proteinuria present in 40-50%; RBC casts indicate glomerulonephritis
• 24-hour urine protein: Quantify proteinuria; assess for nephrotic range (>3.5 g/day)
• Complement levels: C3 and C4 typically normal (unlike post-infectious GN); helpful for differential diagnosis
• Immunoglobulins: IgA levels elevated in some patients but not specific
• Coagulation studies: PT/INR, PTT normal; excludes DIC
• Liver function tests: Obtain baseline; pancreatitis causes elevated amylase and lipase

Imaging and Tissue Diagnosis

• Renal ultrasound: Assess parenchymal echogenicity, size, rule out obstructing pathology; identify cysts in hereditary disease
• Skin biopsy: Gold standard for diagnosis; shows leukocytoclastic vasculitis on H&E with IgA-dominant deposits on direct immunofluorescence (DIF) — pathognomonic finding
• Kidney biopsy: Indicated if proteinuria >1 g/day, hematuria with proteinuria, elevated creatinine, or hypertension
• Light microscopy: Mesangial IgA proliferative glomerulonephritis (MPGN); crescents in severe disease
• Immunofluorescence: IgA, C3 co-deposition in mesangium and capillary walls
• Electron microscopy: Electron-dense deposits in mesangium (IgA)
• MEST-C scoring: Stratifies prognosis (Mesangial proliferation, Endocapillary proliferation, Segmental sclerosis, Tubular atrophy/interstitial fibrosis, Crescents)

Echocardiography

• Baseline transthoracic echo: Assess for myocarditis (wall motion abnormalities, reduced ejection fraction), pericardial effusion, valvular regurgitation
• Consider if chest pain, dyspnea, or cardiac exam abnormalities present
• Repeat echo if clinical deterioration or persistent cardiac symptoms

Electrocardiography

• ECG abnormalities: Nonspecific ST-T wave changes in myocarditis; arrhythmias (may indicate myocardial inflammation)
• Baseline ECG helpful if cardiac symptoms develop

Differential Diagnosis Considerations

• Post-infectious glomerulonephritis: C3 dominant (not IgA), history of streptococcal infection
• ANCA-associated vasculitis: ANCA positive, absence of IgA deposition, older age
• Drug-induced vasculitis: Timeline correlates with medication exposure
• Thrombocytopenic purpura (ITP, TTP): Low platelets; absence of systemic features
• Acute rheumatic fever: Migratory polyarthritis, lacks palpable purpura, positive streptococcal serology
• Systemic lupus erythematosus: ANA positive, complement deficiency, different renal pattern

Mild Disease (Limited Skin and Joint Involvement)

• Supportive care: NSAIDs for joint pain and fever; avoid excessive NSAID exposure due to risk of renal exacerbation
• Patient education: Rest, elevation of affected limbs
• Observation: Most children with limited disease remit spontaneously over weeks to months

Moderate Disease (GI Involvement or Progressive Renal Disease)

First-Line: Corticosteroids

• Mechanism: Suppress inflammatory cascade, reduce immune complex deposition, prevent progression
• Dosing regimens:
• Oral: Prednisone 0.5-1 mg/kg/day (max 60 mg/day), tapering over 4-6 weeks based on response
• Intravenous: Methylprednisolone 10-30 mg/kg (max 1 g) daily for 3 days, then transition to oral therapy for moderate-severe GI disease or rapidly progressive renal disease
• Consider pulse therapy for severe presentations
• Timing: Initiate early; GI bleeding typically responsive within 24-48 hours
• Monitoring: Watch for infection, glucose elevation, behavioral changes in children

Gastrointestinal Management

• H2-receptor antagonist or proton pump inhibitor: Omeprazole 20-40 mg daily for mucosal protection
• Antispasmodics (if appropriate): Dicyclomine for pain control without masking serious complications
• Nutritional support: NPO status if severe; IV hydration if unable to maintain oral intake
• Surgical consultation: If clinical signs of perforation (fever, severe focal peritonitis, imaging evidence)

Severe Disease (Rapidly Progressive Glomerulonephritis, Cardiopulmonary Involvement)

First-Line Immunosuppression

• IV methylprednisolone pulse: 1000 mg daily for 3 days, followed by oral prednisone 1 mg/kg/day, then taper
• Accelerates renal recovery; reduces progression to chronic kidney disease
• Particularly effective when combined with IVIG or cyclophosphamide in RPGN

• Cyclophosphamide (Cytoxan): Reserved for crescentic glomerulonephritis (>50% crescents) or rapidly rising creatinine
• Dosing: IV 500-1000 mg/m² monthly for 6 months, or oral daily dosing
• Mechanism: Alkylating agent; depletes B and T lymphocytes, suppresses immune complex formation
• Monitoring: CBC, urinalysis for hemorrhagic cystitis; ensure adequate hydration and Mesna uroprotection
• Contraindications: Active infection, severe cytopenias; pregnancy

• IVIG (Intravenous Immunoglobulin): 2 g/kg over 3-5 days for fulminant vasculitis
• Mechanism: Provides IgG, suppresses pathogenic IgA; blocks Fc receptor engagement
• Efficacy: Reported benefit in case series; limited RCT data
• Consider adjunctive therapy with steroids and cyclophosphamide

Myocarditis Management

• Systemic corticosteroids: Essential; high-dose IV methylprednisolone (1 g daily × 3 days)
• ACE inhibitors or ARBs: Lisinopril 10 mg daily or losartan 50 mg daily for cardioprotection; reduce LV remodeling
• Beta-blockers: Carvedilol or metoprolol if systolic dysfunction present; start low, titrate cautiously
• Diuretics: Furosemide 20-40 mg daily if signs of heart failure; titrate to euvolemia
• Cardiology consultation: Serial echocardiography; consider advanced imaging (cardiac MRI) if ejection fraction <40%
• Arrhythmia management: Continuous monitoring; antiarrhythmic agents as needed

Renal-Protective Strategies

• ACE inhibitor or ARB: Lisinopril 10-20 mg daily or losartan 100 mg daily
• Mechanism: Reduce glomerular hypertension, decrease proteinuria, slow progression to CKD
• Initiate early, even with normal baseline creatinine if proteinuria present
• Monitor potassium and creatinine; adjust for renal function
• Blood pressure control: Target <50th percentile for age (children) or <130/80 mm Hg (adults)
• Use ACE-I/ARB as first-line; add calcium channel blocker or diuretic as needed
• Dietary measures: Low-sodium diet (<2 g daily); protein restriction (0.8 g/kg/day) if proteinuria >1 g/day

Non-Pharmacological Interventions

• Infection prevention: Prompt treatment of upper respiratory and skin infections to prevent triggers
• Medication review: Avoid NSAIDs (exacerbate renal disease); use acetaminophen for pain
• Activity modification: Rest during acute phase; gradual return to activity
• Follow-up planning: Establish nephrology co-management for progressive renal disease

Renal Complications (Most Important)

• Hematuria/Proteinuria: Transient microscopic hematuria common and self-limited; persistent hematuria with proteinuria suggests progressive disease
• Acute glomerulonephritis: Rising creatinine, edema, hypertension; managed with steroids and supportive care
• Rapidly Progressive Glomerulonephritis (RPGN): Creatinine doubling in weeks to months; crescentic involvement >50%; requires IV methylprednisolone pulse plus cyclophosphamide for renal salvage
• Mechanism: Necrotizing lesions with fibrinoid necrosis and crescent formation
• **Progn

• The classic stem: a school-age boy, 1-3 weeks after an upper respiratory infection, with palpable purpura on the buttocks and extensor legs, colicky abdominal pain, and arthralgia of knees/ankles. This tetrad is IgA vasculitis until proven otherwise.
• Normal platelet count and normal PT/PTT are the single most tested discriminator. Purpura that is palpable is vasculitic (inflamed vessel wall + extravasation), not thrombocytopenic — do not choose ITP, TTP, or DIC when platelets and coagulation studies are normal.
• The best next step in every suspected case is a urinalysis (with blood pressure and serum creatinine). Nephritis determines prognosis, may appear weeks after the rash, and dysmorphic RBCs/RBC casts confirm glomerular origin. Serial urinalysis and BP checks continue for months after the rash resolves.
• Normal C3 and C4 separate IgA vasculitis from post-streptococcal glomerulonephritis (low C3) and lupus nephritis (low C3 and C4), even though both can follow a streptococcal infection.
• Biopsy buzzword: leukocytoclastic vasculitis with IgA-dominant deposits on direct immunofluorescence; the renal lesion is histologically indistinguishable from IgA nephropathy — both stem from galactose-deficient IgA1, so treat them as the same disease in different vascular beds. KDIGO's glomerular disease guidance manages IgA vasculitis nephritis along IgA nephropathy lines, with RAS blockade as the supportive backbone.
• The association examiners love: abdominal pain plus a currant-jelly stool or a palpable mass = intussusception, and in IgA vasculitis it is characteristically ileoileal, so ultrasound — not air/contrast enema — is the diagnostic test of choice.
• Acute scrotal pain from vasculitis of the cord mimics torsion; Doppler ultrasound is mandatory because missing torsion costs a testis.
• Common distractor: corticosteroids shorten abdominal pain and arthritis but should not be selected as prophylaxis against developing nephritis. Also avoid antibiotics reflexively — this is post-infectious immune complex disease, not active infection.
• Adults do worse than children: higher rates of persistent proteinuria and progression to CKD, so adult presentations warrant a lower threshold for renal biopsy and nephrology referral.