Definition

IgA vasculitis (formerly Henoch–Schönlein purpura) is a small-vessel immune complex vasculitis characterized by predominant IgA1 deposition within vessel walls.

It classically presents with:

• Palpable purpura

• Arthralgia/arthritis

• Gastrointestinal involvement

• Renal disease (IgA nephropathy-like)

It is the most common systemic vasculitis of childhood.

Epidemiology

• Predominantly affects children between 3–15 years

• Slight male predominance

• Often follows an upper respiratory tract infection

• More common in autumn and winter

Adults develop:

• More severe renal disease

• Higher risk of chronic kidney impairment

Etiology & Triggers

Usually preceded by antigenic stimulation causing abnormal IgA immune responses.

Common triggers:

• Upper respiratory infections

• Streptococcal infection

• Viral infections

• Mycoplasma

• Vaccination

• Drugs

• Food allergens (rare)

FOUNDATIONS (First Principles)

Normal Histology Relevant to Disease

Small Dermal Blood Vessels

Postcapillary venules in superficial dermis regulate:

• Leukocyte trafficking

• Vascular permeability

• Inflammatory responses

Normal endothelial cells maintain:

• Antithrombotic surface

• Tight barrier function

• Controlled leukocyte adhesion

Immunoglobulin A (IgA)

IgA is the major mucosal immunoglobulin.
Normally:

• Produced by plasma cells

• Protects mucosal surfaces

• Cleared efficiently by liver and reticuloendothelial system

Neutrophils

Neutrophils normally:

• Migrate to infection sites

• Destroy pathogens through enzymes and reactive oxygen species

• Undergo apoptosis after activation

INITIATING EVENT

The earliest abnormality is:

• Formation of aberrantly glycosylated IgA1 molecules

These abnormal IgA1 molecules:

• Are poorly cleared

• Become antigenic

• Form circulating immune complexes

Immune complexes deposit in:

• Small vessel walls

• Mesangium of kidneys

This activates:

• Complement pathway (mainly alternative and lectin pathways)

• Neutrophil recruitment

• Endothelial injury

PATHOGENESIS (Cause → Effect Chain)

Step 1: Triggering Antigen Exposure

Usually respiratory infection stimulates mucosal immune system.

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Step 2: Abnormal IgA1 Production

B cells produce galactose-deficient IgA1.

Why important?

• Altered glycosylation exposes neoepitopes

• Autoantibodies form against abnormal IgA1

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Step 3: Immune Complex Formation

Circulating IgA-containing immune complexes form.

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Step 4: Vascular Deposition

Complexes deposit in:

• Superficial dermal postcapillary venules

• Glomerular mesangium

• GI tract vessels

• Synovial vessels

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Step 5: Complement Activation

Complement activation generates:

• C3a

• C5a

These recruit neutrophils.

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Step 6: Leukocytoclastic Vasculitis

Activated neutrophils release:

• Proteases

• Reactive oxygen species

• Myeloperoxidase

This causes:

• Endothelial damage

• Fibrinoid necrosis

• RBC extravasation

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Step 7: Clinical Purpura

Extravasated RBCs produce:

• Non-blanching palpable purpura

Palpability occurs because:

• Vessel inflammation causes dermal edema and inflammatory infiltrate

Clinical Features

Cutaneous Manifestations

Palpable Purpura

• Symmetrical

• Lower limbs and buttocks predominant

• Non-thrombocytopenic

• May coalesce

Lesions may evolve into:

• Vesicles

• Bullae

• Necrosis

• Ulcers (more common in adults)

Other Skin Findings

• Urticarial lesions

• Edema of hands, feet, scalp

• Livedo reticularis (rare)

Joint Involvement

• Arthralgia or arthritis

• Knees and ankles commonly involved

• Transient and non-erosive

Gastrointestinal Disease

Due to bowel wall vasculitis.

Features:

• Colicky abdominal pain

• GI bleeding

• Melena

• Intussusception (children)

Renal Involvement

Most important prognostic factor.

Manifestations:

• Hematuria

• Proteinuria

• Nephritic syndrome

• Nephrotic syndrome

• Rapidly progressive GN (rare)

Histologically resembles IgA nephropathy.

HISTOPATHOLOGY EXPLAINED

Core Histological Pattern

Leukocytoclastic Vasculitis

Immune complexes→Complement activation→Neutrophilic vascular injuryImmune complexes→Complement activation→Neutrophilic vascular injury

Main site:

• Superficial dermal postcapillary venules

Microscopic Findings

1. Neutrophilic Infiltration Around Vessels

Neutrophils accumulate around vessel walls.

Why?

• Immune complexes activate complement

• C5a strongly attracts neutrophils

Normally vessels contain no inflammatory infiltrate.

2. Leukocytoclasia

“Leukocytoclasia” means nuclear dust from fragmented neutrophils.

Why does it occur?

• Activated neutrophils undergo destruction after degranulation

• Nuclear fragmentation leaves basophilic debris

Under H&E:

• Small dark blue nuclear fragments around vessels

This is the hallmark of small-vessel leukocytoclastic vasculitis.

3. Fibrinoid Necrosis

Vessel wall becomes eosinophilic and smudgy.

Why?

• Plasma proteins and fibrin leak into damaged vessel wall

• Endothelial destruction occurs

“Hyalinized pink vessel wall” on H&E corresponds to fibrin deposition and necrosis.

4. Extravasated Red Blood Cells

RBCs leak through damaged vessels into dermis.

This produces:

• Purpura clinically

Over time:

• Hemosiderin deposition develops

5. Endothelial Swelling

Represents endothelial activation and injury.

Direct Immunofluorescence (DIF)

Most important diagnostic test.

Shows:

• Granular IgA deposition in vessel walls

Often accompanied by:

• C3

• Fibrin

Why granular?

• Immune complexes deposit irregularly along vessel wall

DIF is best performed on:

• Fresh lesion (<24–48 hours old)

TEMPORAL EVOLUTION

Early Lesions

• Neutrophilic vasculitis

• Minimal leukocytoclasia

Fully Developed Lesions

• Prominent leukocytoclasia

• Fibrinoid necrosis

• RBC extravasation

Late Lesions

• Lymphocytic infiltrate replaces neutrophils

• Hemosiderin deposition

• Less obvious vasculitis

NAMING LOGIC & TERMINOLOGY

“Leukocytoclastic”

• “Leukocyto” = leukocytes

• “Clastic” = broken

Refers to fragmented neutrophil nuclei.

“Palpable Purpura”

Purpura becomes palpable because inflammation and edema elevate the lesion above skin surface.

Simple petechiae are flat because they lack vessel wall inflammation.

“Fibrinoid Necrosis”

“Fibrinoid” refers to fibrin-like eosinophilic appearance of damaged vessel wall.

STAINING & MARKERS

H&E

Demonstrates:

• Neutrophils

• Nuclear dust

• Fibrinoid necrosis

• RBC extravasation

Direct Immunofluorescence

Key finding:

• IgA deposition in vessel walls

Useful because:

• Distinguishes IgA vasculitis from other leukocytoclastic vasculitides

PATTERN RECOGNITION & DIAGNOSTIC LOGIC

Diagnostic Pattern

If:

• Palpable purpura

• Lower limb predominance

• Child with abdominal pain/arthritis

→ Think IgA vasculitis

Histological Diagnostic Logic

Leukocytoclastic vasculitis + IgA deposition

→ IgA vasculitis

Leukocytoclastic vasculitis without IgA

→ Consider:

• Hypersensitivity vasculitis

• ANCA-associated vasculitis

• Cryoglobulinemic vasculitis

Differential Diagnosis

Other Small Vessel Vasculitides

Hypersensitivity Vasculitis

• Similar histology

• No dominant IgA deposition

ANCA-associated Vasculitis

• Often systemic severe disease

• Pauci-immune DIF

Cryoglobulinemic Vasculitis

• Associated with hepatitis C

• Purpura with arthralgia and neuropathy

Meningococcemia

Purpura with fever and toxicity.

Thrombocytopenic Purpura

Purpura is:

• Non-palpable

• Platelet count low

CLINICO-PATHOLOGICAL CORRELATION

Why are lesions palpable?

Because vessel inflammation produces:

• Dermal edema

• Cellular infiltrate

Why lower limb predominance?

Dependent hydrostatic pressure favors immune complex deposition.

Why purpura?

Damaged vessels leak RBCs into skin.

Why renal disease?

Mesangial IgA deposition induces glomerular inflammation.

Associated Conditions

• IgA nephropathy

• Respiratory infections

• Chronic liver disease (occasionally)

• Inflammatory bowel disease (rare association)

Investigations

Routine

• CBC

• ESR/CRP

• Urinalysis

• Renal function tests

Important

• Urine examination for hematuria/proteinuria

Skin Biopsy

• Leukocytoclastic vasculitis

DIF

• IgA deposition

Diagnostic Criteria (EULAR/PRINTO/PRES)

Mandatory:

• Purpura or petechiae with lower limb predominance

Plus one of:

• Abdominal pain

• Arthritis/arthralgia

• Renal involvement

• Histopathology showing IgA deposition

Management

General Principles

Disease is usually self-limited in children.

Treatment depends on:

• Severity

• Organ involvement

Cutaneous-Limited Disease

• Rest

• Leg elevation

• Analgesics

Mild disease may require no specific therapy.

Corticosteroids

Useful for:

• Severe abdominal pain

• Extensive edema

• Significant skin disease

Do NOT reliably prevent nephritis.

Renal Disease

Requires nephrology involvement.

May need:

• ACE inhibitors

• Corticosteroids

• Immunosuppressants

Severe crescentic GN:

• Cyclophosphamide

• Rituximab (selected cases)

Prognosis

Children

Usually excellent.

Most recover completely within weeks.

Adults

Higher risk of:

• Recurrence

• Chronic kidney disease

Important Prognostic Factors

Worst prognostic indicator:

• Renal involvement

Especially:

• Persistent proteinuria

• Crescentic GN

EXAM-FOCUSED INSIGHTS

• IgA vasculitis is the most common vasculitis of childhood.

• Palpable purpura with normal platelet count is classic.

• DIF showing vascular IgA deposition is diagnostic.

• Leukocytoclastic vasculitis is the key histological pattern.

• Lower limb predominance reflects hydrostatic pressure.

• Renal involvement determines long-term prognosis.

• Histology may become nonspecific in older lesions.

• Early biopsy is important.

• Adult disease is more severe than childhood disease.

• GI symptoms may precede rash.

MUST-KNOW BOARD EXAM QUESTIONS

1. What is the hallmark immunopathological finding in IgA vasculitis?

Granular IgA deposition in small vessel walls on DIF.

2. What is the characteristic cutaneous lesion?

Palpable purpura.

3. Which vessels are primarily involved?

Small vessels, especially postcapillary venules.

4. What is the classic histological pattern?

Leukocytoclastic vasculitis.

5. What causes palpable purpura?

Vessel wall inflammation with RBC extravasation and dermal edema.

6. Which organ determines prognosis?

Kidney.

7. What is leukocytoclasia?

Fragmentation of neutrophil nuclei producing nuclear dust.

8. Which complement pathways are mainly activated?

Alternative and lectin pathways.

9. What is the best lesion for DIF biopsy?

Fresh lesion less than 24–48 hours old.

10. What is fibrinoid necrosis?

Deposition of fibrin and plasma proteins in damaged vessel walls.

11. Which renal disease resembles IgA vasculitis nephritis?

IgA nephropathy.

12. Why are lesions usually on lower limbs?

Hydrostatic pressure promotes immune complex deposition.

13. Which age group is most commonly affected?

Children.

14. What differentiates thrombocytopenic purpura from IgA vasculitis?

Purpura in thrombocytopenia is non-palpable and platelet count is low.

15. What systemic symptoms commonly accompany the rash?

Arthralgia, abdominal pain, and renal involvement.