IgA Vasculitis (HSP) - Basics to Advanced Clinical

1. Nomenclature and Definition

IgA vasculitis is a small-vessel vasculitis characterized by palpable purpura (most commonly distributed over the buttocks and lower extremities), arthralgias, gastrointestinal signs and symptoms, and glomerulonephritis.

• Harrison's Principles of Internal Medicine 22E

2. Epidemiology

• ROSEN's Emergency Medicine; Andrews' Diseases of the Skin

3. Pathogenesis - From Molecular to Clinical

Step 1: Aberrant IgA1 Glycosylation (The Core Defect)

Step 2: Anti-glycan Autoantibodies (Second Hit)

Step 3: Immune Complex Deposition

• Skin (dermal capillaries and venules)
• Glomerular mesangium (kidneys)
• Synovium (joints)
• Intestinal submucosa (gut)

Step 4: Complement Activation and Inflammation

Additional Mediators

• Elevated TNF-alpha and IL-1beta
• Elevated vascular endothelial growth factor (VEGF) and endothelin
• Decreased factor XIII levels (associated with worse prognosis)
• High-titer IgA anti-endothelial cell antibodies (correlate with severe renal disease)

A high serum Ga-IgA1 level is not sufficient for the development of clinical symptoms. A "second hit" in the form of another environmental or inherited risk factor is required to produce IgA vasculitis.

• Firestein & Kelley's Textbook of Rheumatology

4. Triggers and Precipitants

• Upper respiratory tract infections (most common - streptococcal pharyngitis, viral URIs) - precede disease in up to 50% of cases
• Helicobacter pylori infection (implicated in childhood and adult cases)
• Drugs (antibiotics and others)
• Insect bites, foods, immunizations
• Underlying malignancy (important in adults - see below)

5. Clinical Features - The Classic Tetrad

A. Skin (100% of patients once fully established)

• Starts as mottled purpura on extensor extremities
• Becomes hemorrhagic within ~1 day
• Begins to fade in ~5 days
• New crops appear over weeks
• Distributed on lower extremities, buttocks, and posterior legs (dependent areas)
• May include urticarial lesions, vesicles, necrotic purpura, or hemangioma-like lesions
• Koebnerization: streaky/linear purpura from pressure on inflamed vessels (see image below)
• Purpura above the waist may be a marker of renal involvement

Palpable purpura in an adult with IgA vasculitis showing the Koebnerization phenomenon - Firestein & Kelley's Rheumatology

HSP rash on the buttocks and posterior thigh - Andrews' Diseases of the Skin

IgA vasculitis rash on extensor surfaces and lower torso - Comprehensive Clinical Nephrology

B. Joints (~63-82% of patients)

• Polyarthralgias progressing to arthritis
• Periarticular swelling around knees and ankles (most common joints)
• Usually without frank synovial effusion
• Non-destructive; resolves with the disease

C. Gastrointestinal Tract (~65-70% of patients)

• Colicky abdominal pain caused by gut vasculitis - typically occurs within 1 week after rash onset
• Nausea, vomiting, diarrhea, constipation
• Passage of blood and mucus per rectum (melena, hematochezia)
• Intussusception (classic risk - ultrasound required)
• Paralytic ileus, rebound tenderness, distension
• Endoscopy: purpura in upper or lower intestinal tract
• GI radiograph: "spiking" or "cobblestone" marbled appearance
• Important: GI symptoms may PRECEDE the rash in some cases, creating diagnostic difficulty and potentially leading to unnecessary exploratory surgery

D. Kidneys (10-50% in children; up to 70%+ in adults)

• Ranges from microscopic hematuria (+/- proteinuria) to nephrotic syndrome
• Red blood cell casts confirm glomerulonephritis
• Most cases are mild and self-limited in children
• Progressive glomerulonephritis and CKD/ESRD are uncommon in children but more prevalent in adults
• Nephrotic syndrome occurs in 20-30% of those biopsied
• AKI may develop from crescentic GN

6. Histopathology

Skin Biopsy (Light Microscopy)

• Neutrophilic infiltration of vessel walls
• Nuclear dust (leukocytoclasis - fragmented neutrophil nuclei)
• Fibrinoid necrosis of vessel walls
• Extravasation of red blood cells

Skin Biopsy (Direct Immunofluorescence - DIF) - DIAGNOSTIC

Renal Biopsy (Light Microscopy)

• Mesangial proliferative GN (most common)
• Diffuse endocapillary proliferation
• Crescentic GN (severe, rapidly progressive cases)

Renal Biopsy (Immunofluorescence)

• Diffuse mesangial IgA deposits (identical to IgA nephropathy)
• C3 and IgG co-deposition
• The MEST scoring system for IgAN may apply but its predictive value for IgAV nephritis has not been validated

7. Diagnosis

Clinical Diagnosis (especially in children)

1. Diffuse abdominal pain
2. Any biopsy showing predominant IgA deposition
3. Arthritis or arthralgia
4. Renal involvement (hematuria and/or proteinuria)

1990 ACR Classification Criteria (for epidemiologic use)

1. Age ≤20 years at disease onset
2. Palpable purpura
3. Acute abdominal pain
4. Granulocytes on biopsy

Laboratory Findings

Differential Diagnosis

• Septic purpura (meningococcemia) - thrombocytopenia present
• ITP / TTP - platelet count differentiates
• Streptococcal infection with rash + arthralgia
• Other systemic vasculitides (ANCA vasculitis, SLE vasculitis)
• Septic arthritis / reactive arthritis
• Acute surgical abdomen (when GI symptoms precede rash)

8. Special Population: Adults vs. Children

9. Prognostic Factors (Poor Prognosis)

• Nephrotic-range proteinuria (>1 g/day)
• Hypertension at presentation
• Crescents on renal biopsy
• Mesangial macrophages
• Tubulointerstitial fibrosis
• Decreased factor XIII levels
• Purpura above the waist
• Renal insufficiency at onset
• High-titer IgA anti-endothelial cell antibodies

10. Treatment

Supportive (all patients)

• Rest, hydration, pain management
• Acetaminophen for arthralgias
• NSAIDs for joint pain (use cautiously - avoid with severe renal involvement or active GI bleeding)
• Close follow-up: urinalysis + blood pressure monitoring for at least 6 months

Skin-Limited Disease

• Dapsone 50-200 mg/day
• Colchicine 0.6-1.2 mg twice daily

Gastrointestinal Disease

• H2 blockers for GI symptoms
• Prednisone 1 mg/kg/day (more effective for abdominal pain than analgesics; does NOT reduce renal complication risk)
• IVIG for persistent abdominal pain refractory to steroids

Renal Disease - A Spectrum of Interventions

Despite this, it is prudent to treat aggressive renal involvement with an immunosuppressive regimen that includes high-dose glucocorticoids. Mycophenolate mofetil is an excellent option for severe renal disease.

• Firestein & Kelley's Textbook of Rheumatology

Malignancy-Associated IgAV

H. pylori-Associated IgAV (Adults with GI symptoms)

11. Emergency Department Approach (Rosen's Framework)

• Cannot bear weight due to arthralgias
• Pain not controlled with oral medications
• Ongoing GI bleeding
• Renal involvement with fluid overload/AKI
• Severely elevated blood pressure

• Urinalysis (mandatory)
• BMP if hematuria or hypertension
• Abdominal ultrasound if GI bleeding/abdominal pain (rule out intussusception)
• CBC (normal platelets excludes ITP)

12. Prognosis

• Overall prognosis is excellent, especially in children
• Mortality is exceedingly rare
• Most patients recover completely, often without therapy
• Illness duration: typically 6-16 weeks
• Children with gross hematuria usually do well
• Recurrent skin disease (multiple episodes over months) is not unusual but typically resolves over months to 1 year
• 1-5% of children progress to ESRD; in adults, up to 40% may develop CKD/ESRD at 15-year follow-up
• Persistent nephropathy (usually mild) in only ~8% of overall patients

13. Transplantation

• ~50% of transplants: isolated IgA deposits in the graft
• Full-blown IgAN in the graft (clinically)
• Rarely: full systemic recurrence including rash
• Cadaveric donor may be preferable to living-related donor in children (controversial)
• Delaying transplantation after dialysis does not reduce recurrence risk

14. Recent Evidence (2024-2026)

1. Rituximab in IgAV nephritis (Xiong et al., 2024 - PMID 39249581): Evaluates the role of B-cell depletion for refractory nephritis - emerging option for severe/refractory IgAV nephritis.
2. Tacrolimus vs cyclophosphamide in HSP nephritis in children (Jiang et al., 2025 - PMID 40696685): Compares calcineurin inhibitor vs alkylating agent approaches in pediatric nephritis.
3. IgAV with necrotizing arteritis (Ribereau-Gayon et al., 2026 - PMID 42192510): A French multicenter study describing the severe subtype with medium-vessel necrotizing involvement - distinct clinical phenotype with worse prognosis.

Quick Reference Summary

HSP / IgA Vasculitis
├── Mechanism: Gd-IgA1 → anti-glycan IgG → ICs → vessel wall deposition
├── Trigger: URI, H. pylori, drugs, malignancy (adults)
├── Tetrad: Purpura + Arthralgias + Abdominal pain + Nephritis
├── DIF skin biopsy: Florid IgA deposition (DIAGNOSTIC)
├── Labs: Normal platelets, normal complement, elevated IgA (50%)
├── Kidney: Identical to IgAN on biopsy (MEST score)
├── Treatment:
│   ├── Mild: Supportive
│   ├── GI pain: Prednisone 1 mg/kg
│   ├── Renal: ACEi/ARB ± steroids ± MMF/CYC
│   └── Refractory: IVIG, rituximab (emerging)
└── Prognosis: Excellent in children; worse in adults (40% CKD at 15y)

• Repeated topics (PE appears 6 times, AF twice, AV blocks 4 times, Cardiomyopathies 3 times) - memorize those answers cold; the examiner will ask follow-up questions on them.
• Overlapping answers - several questions share content (Q3 & Q5 = DCM; Q24 & Q26 & Q27 = Pericarditis; Q6 & Q37 & Q41 & Q54 = OSA; Q1 & Q8 & Q31 & Q34 = Scleroderma). Learn the full version once, then adapt.
• Don't-miss points examiners love:
  • Beck's triad + electrical alternans = tamponade
  • PR depression on ECG = pericarditis (before even asking about ST elevation)
  • Mobitz II → permanent pacemaker (unlike Mobitz I)
  • Complete heart block → Stokes-Adams attacks + cannon a-waves
  • SAAG ≥1.1 = portal hypertension ascites
  • Anti-centromere = lcSSc/CREST; Anti-Scl-70 = dcSSc + ILD risk
  • ACE inhibitors for scleroderma renal crisis = life-saving
  • Lactulose + rifaximin for hepatic encephalopathy