IgA Vasculitis (Henoch-Schönlein Purpura)

• Primary mechanism—Aberrant IgA1 glycosylation and immune complex formation: The fundamental defect in IgAV involves dysregulation of B cell and T cell responses, resulting in production of Gd-IgA1 (galactose-deficient IgA1), a hypogalactosylated form of IgA1 that is poorly cleared by the asialoglycoprotein receptor on hepatocytes. This abnormal IgA1 escapes normal hepatic clearance and circulates at elevated levels in serum. Gd-IgA1 possesses exposed N-acetylgalactosamine residues that act as neoantigens, prompting formation of anti-glycan IgG antibodies (particularly anti-Gd-IgA1 IgG) that bind to circulating Gd-IgA1 to form large, pathogenic IgA1-IgG immune complexes. These complexes preferentially deposit in the glomeruli due to the relatively high local concentration of IgA and the structural features of the glomerular mesangium, which is rich in J chain-containing polymeric IgA receptors. The presence of circulating Gd-IgA1-IgG complexes can be measured and represents a biomarker of active disease.

• Tissue deposition and complement activation: Once IgA-IgG immune complexes deposit in the glomerular mesangium, dermal blood vessels, and other small vessels, they engage the IgA receptor (FcαRI) on mesangial cells, endothelial cells, and neutrophils, triggering activation through the alternative complement pathway (notably without C4 deposition, distinguishing this from C3-dominant vasculitides). Deposition of complement components (particularly C3) alongside IgA in glomeruli and skin vessels is characteristic of IgAV. This complement activation generates C5a, a potent chemotactic factor that recruits neutrophils and other inflammatory cells to the site of immune complex deposition. The absence of classical complement pathway activation (no C1q or C4 deposition) is a pathognomonic feature that helps distinguish IgAV from other immune complex vasculitides like systemic lupus erythematosus.

• Inflammatory cascade and tissue damage: Activation of FcαRI by deposited IgA complexes stimulates production of inflammatory cytokines (IL-6, TNF-α, IL-8, MCP-1) and reactive oxygen species (ROS) by mesangial cells and infiltrating neutrophils. Neutrophils undergo NETosis (neutrophil extracellular trap formation), releasing proteolytic enzymes and antimicrobial peptides that cause direct tissue damage and perpetuate inflammation. In the glomerulus, this leads to mesangial proliferation, matrix expansion, crescent formation (in severe cases), and capillary loop involvement, resulting in hematuria, proteinuria, and progressive renal dysfunction. In the skin, immune complex deposition in postcapillary venules causes leukocytoclastic vasculitis characterized by fibrinoid necrosis of the vessel wall, extravasation of red blood cells, and infiltration by neutrophils. In the gastrointestinal tract, immune complex deposition in the lamina propria triggers mucosal inflammation, edema, and hemorrhage, potentially leading to ischemic complications. In the joints, immune complex deposition in synovial membranes causes synovitis without permanent damage.

• Trigger mechanisms and disease initiation: IgAV is often preceded by upper respiratory tract infections (URIs) or other infections (bacterial, viral, or post-vaccination), suggesting that molecular mimicry or bystander activation plays a role in disease initiation. Pathogens such as Group A Streptococcus, Staphylococcus aureus, and Streptococcus pneumoniae have been implicated as potential triggers. The mucosal immune system responds to these pathogens with enhanced IgA production in Peyer's patches and mesenteric lymph nodes; however, in genetically predisposed individuals, this response goes awry, producing pathogenic Gd-IgA1 rather than protective, normally glycosylated IgA. The GWAS (genome-wide association studies) have identified genetic loci associated with IgAV susceptibility, including IGAN1 (on chromosome 6) and variants in immunoregulatory genes, explaining the familial clustering observed in approximately 5% of cases and the higher prevalence in certain ethnic groups (Asian and Hispanic populations have higher incidence).

• Organ-specific manifestations driven by immune complex burden: The degree and location of immune complex deposition determine clinical manifestations. Cutaneous involvement (essentially universal) reflects systemic IgA-IgG deposition in skin microvasculature. Renal involvement (seen in 40–50% of children and up to 80% of adults) correlates with heavier glomerular immune complex deposition and predicts long-term prognosis; the ISKDC (International Study of Kidney Disease in Children) grading system (Grades I–V based on histology) and Oxford Classification provide prognostic information. Gastrointestinal involvement reflects mucosal immune complex deposition and is more common in adults. The relative absence of pulmonary and CNS involvement (despite systemic vasculitis) is notable and reflects tissue-specific patterns of IgA receptor expression and local hemodynamic factors that favor immune complex deposition in organs with unique vascular architecture.

• Infectious triggers (most significant modifiable risk factor): Upper respiratory tract infections, particularly those caused by Group A Streptococcus (GAS), Staphylococcus aureus, and other bacteria, precede IgAV onset in 30–50% of cases by 1–4 weeks, supporting a molecular mimicry hypothesis. Viral infections (cytomegalovirus, parvovirus B19, hepatitis A and B, HIV, influenza) have also been documented as triggers. The temporal relationship between infection and rash onset is a critical clinical clue for diagnosis. Post-vaccination IgAV has been reported, particularly following hepatitis B and influenza vaccines, though the true causative relationship remains debated. Understanding this temporal association is important because antibiotic treatment of the preceding infection does not prevent IgAV development, indicating that the inflammatory response to the pathogen (rather than persistent infection) drives disease pathogenesis.

• Genetic predisposition: Twin studies and familial clustering (5% of cases have positive family history) demonstrate that genetic factors confer approximately 40–50% of disease susceptibility. GWAS studies have identified multiple susceptibility loci, including the IGAN1 locus on chromosome 6q22-23 (shared with IgA nephropathy), which encodes regulatory T cell differentiation factors. Additional loci include variants affecting FCGR3B (Fc gamma receptor), ITGAM (integrin alpha-M), and immune checkpoint molecules. These genetic variants primarily affect innate immune regulation and mucosal immunity. Ethnic and geographic variations are substantial: East Asian, Hispanic, and Middle Eastern populations have 1.5–2 times higher incidence than Caucasian populations, reflecting underlying genetic differences in immune regulation. The prevalence increases with distance from the equator in temperate climates, suggesting environmental factors (seasonal infections, UV exposure) interact with genetic background.

• Other risk factors and associations: NSAIDs and certain medications (hydralazine, allopurinol, sulfonamides) may precipitate or exacerbate IgAV, though causality is difficult to establish. Malignancy can rarely trigger secondary IgA vasculitis in adults, with solid tumors (lung, gastric, prostate) and hematologic malignancies being most common; this is sometimes termed "paraneoplastic vasculitis." Inflammatory bowel disease (IBD) carries a 40–60 fold increased risk of IgAV, likely through dysregulated mucosal immunity. Notably, no clear age-related, gender-related, or socioeconomic risk factors exist, though seasonality (higher incidence in winter/spring in temperate zones) suggests respiratory triggers are seasonal.

• Palpable purpura (nearly universal, ~95% of patients): The hallmark cutaneous manifestation is a palpable, non-blanching purpura (not macular erythema) representing IgA-mediated leukocytoclastic vasculitis affecting post-capillary venules. The rash classically appears in dependent areas and sites of pressure—the lower extremities (legs and buttocks), knees, and elbows—reflecting hydrostatic pressure effects on immune complex deposition; it is symmetrical and typically crops in successive waves over days to weeks. Individual lesions evolve from red macules to raised purpura (reflecting infiltration by inflammatory cells) to scaling and crusting over 7–14 days, and residual hyperpigmentation may persist. The rash can occasionally involve the face, trunk, and genitals (including scrotum, which is pathognomonic when involved); urticaria or hemorrhagic vesicles may precede typical purpura. Notably, the rash does not respond to corticosteroids in a way that would make it blanch, though corticosteroids may reduce associated pruritus. Reexamination of the rash may reveal mucosal involvement (oral, pharyngeal, or perianal purpura), a sign of more extensive vasculitis.

• Arthritis and arthralgia (60–80% of patients): Joint involvement occurs early in the disease course and is characteristically migratory and non-destructive. Patients describe acute onset of arthralgia or arthritis affecting the knees and ankles bilaterally and symmetrically, often accompanied by swelling, warmth, and erythema sufficient to limit weight-bearing and ambulation. The hip, wrists, and small joints of the hands can also be involved. Symptoms typically resolve within 1–2 weeks without residual damage (unlike rheumatoid arthritis or other erosive arthritides), and radiographs remain normal except for soft tissue swelling. The arthritis reflects immune complex deposition and synovial inflammation but notably spares the synovial fluid (i.e., joint fluid studies are typically non-inflammatory or only mildly inflammatory with WBC <10,000/μL). The arthralgia is often severe enough to prevent patients from walking or attending school, yet the dramatic reversibility is reassuring for prognosis.

• Abdominal pain (50–65% of patients, more common in adults): Gastrointestinal involvement manifests as acute, colicky abdominal pain that is often periumbilical or diffuse and may be accompanied by nausea, vomiting, and hematochezia or melena. The pain reflects mucosal inflammation, edema, and hemorrhage in the lamina propria caused by immune complex deposition along the entire GI tract from mouth to rectum, though the small intestine is most commonly affected. Severity ranges from mild cramping to severe pain that may mimic an acute abdomen. Occult fecal blood loss is common (positive in ~50% of cases) but overt GI bleeding (gross hematochezia or hematemesis) occurs in 10–15%. Serious GI complications include intussusception (particularly in young children, due to mucosal edema and lymphoid hyperplasia in the terminal ileum), ischemic perforation (from transmural inflammation or infarction), and protein-losing enteropathy (from mucosal erosions). GI symptoms may precede the rash or appear months later, and their presence correlates with more active systemic disease and higher risk of renal involvement. Pancreatitis and mesenteric vasculitis are rare but serious complications.

• Renal involvement (40–50% of children, 50–80% of adults): Renal manifestations represent the most serious aspect of IgAV, as they determine long-term prognosis and treatment intensity. The spectrum ranges from asymptomatic microscopic hematuria (most common) to gross hematuria, proteinuria, nephritic syndrome, or rapidly progressive glomerulonephritis (RPGN) with acute kidney injury. Typically, renal involvement appears within the first 4 weeks of systemic symptoms, but delayed presentation up to 6 months is possible. Hematuria (RBC casts in urinary sediment) indicates glomerular involvement from IgA immune complex deposition. Proteinuria ranges from mild (<1 g/day, common) to nephrotic range (>3.5 g/day, seen in 10% of children, 30% of adults). The glomerular filtration rate (GFR) is normal at onset in most cases but may decline acutely with crescentic disease; serum creatinine elevation is unusual at presentation but signals severe glomerulonephritis. The presence of elevated serum creatinine, hypertension, or nephrotic syndrome at diagnosis predicts poor renal prognosis, particularly in adults. ISKDC renal biopsy grading (Grades I–V, with Grade III–V representing proliferative and crescentic disease) and the Oxford Classification (assessing endocapillary proliferation, segmental sclerosis, cellular crescents, fibrocellular crescents, tubular atrophy, and interstitial fibrosis) provide prognostic information; approximately 10% of children develop chronic kidney disease, compared to 30–40% of adults.

• Physical examination findings: Beyond the characteristic palpable, non-blanching purpura (confirmed by the inability to blanch it with pressure), the exam may reveal joint swelling and tenderness (particularly knees and ankles), abdominal tenderness (especially periumbilical), and blood pressure elevation (indicating renal involvement with hypertension). Scrotal involvement (purpura or hemorrhagic swelling), though uncommon, is virtually pathognomonic for IgAV. In severe cases, edema (from nephrotic syndrome or GI protein loss), pallor (from anemia due to GI blood loss), or signs of acute kidney injury (fluid overload, hypertension, uremia) may be evident. Absence of hepatosplenomegaly and lymphadenopathy is notable and helps exclude other systemic vasculitides and malignancies.

• Important clinical variants and atypical presentations: Some patients present with isolated cutaneous involvement (limited cutaneous IgAV, formerly cutaneous HSP), defined as purpura without systemic manifestations, though up to 25% eventually develop renal involvement despite initial cutaneous-only disease. Adult IgAV (≥

Initial laboratory evaluation (exclude the dangerous mimics)

• CBC with platelet count and coagulation studies: the platelet count is normal or elevated and PT/aPTT are normal. This is the single most important discriminator from immune thrombocytopenia, disseminated intravascular coagulation, and meningococcemia — purpura that is palpable with normal platelets implies vasculitis, not a bleeding diathesis. Mild normocytic anemia suggests occult GI loss.
• Urinalysis with microscopy plus urine protein-to-creatinine ratio and serum creatinine: dysmorphic RBCs and RBC casts localize bleeding to the glomerulus; quantified proteinuria stratifies nephritis severity. Blood pressure must be measured at every visit.
• Inflammatory markers and complement: ESR/CRP are mildly elevated and nonspecific; C3 and C4 are normal, since the alternative-pathway activation described above does not consume classical-pathway components. Low complement should redirect you toward lupus nephritis or post-streptococcal glomerulonephritis.
• Serum IgA is elevated in only about half of patients and is not diagnostic. ANA and ANCA are negative and are obtained only when the presentation is atypical or adult-onset.

Confirmatory histology

• Skin biopsy of a fresh lesion with direct immunofluorescence: leukocytoclastic vasculitis of postcapillary venules with IgA-dominant perivascular deposits — the confirmatory test when the rash is atypical, in adults, or when malignancy-associated vasculitis is a concern.
• Renal biopsy is the gold standard for nephritis and is reserved for nephrotic-range proteinuria, persistent significant proteinuria, hypertension with renal impairment, or rising creatinine. Light microscopy shows mesangial proliferation with crescents in severe disease; immunofluorescence shows mesangial IgA and C3 without C1q. Graded by the ISKDC system and the Oxford (MEST-C) classification.

Initial stabilization

• Assess for surgical abdomen and hypovolemia first: severe abdominal pain, bilious vomiting, or hematochezia mandates imaging and surgical consultation before analgesia is escalated. Significant GI bleeding requires IV fluids, transfusion as needed, and endoscopy or surgery.
• Hypertension and volume overload from nephritis are treated conventionally; RPGN requires urgent nephrology involvement.

First-line therapy

• Supportive care: hydration, rest, elevation of dependent areas, and acetaminophen for arthralgia. NSAIDs (e.g., naproxen) are effective for arthritis but should be avoided when there is renal impairment or GI bleeding.
• Systemic glucocorticoids, typically oral prednisone/prednisolone (IV methylprednisolone if oral intake is impossible), are indicated for severe abdominal pain, GI bleeding, orchitis, or disabling arthritis. Steroids shorten the duration of abdominal pain but — a heavily tested point — do not prevent the development of nephritis and are not given prophylactically for skin disease alone.

• RAAS blockade: an ACE inhibitor or ARB (e.g., lisinopril) for persistent proteinuria and blood-pressure control, exploiting reduction of intraglomerular pressure.
• Crescentic or rapidly progressive disease: high-dose glucocorticoids with a cytotoxic/immunosuppressive agent such as cyclophosphamide; azathioprine, mycophenolate, rituximab, and plasma exchange are used in refractory cases with weaker evidence.
• Dialysis and transplantation for end-stage disease; recurrent IgA deposition in the allograft can occur.

Gastrointestinal (early, often emergent)

• Intussusception — emergency: mucosal edema and submucosal hematoma form a lead point, characteristically ileoileal rather than ileocolic. Signaled by crescendo colicky pain, a palpable mass, or currant-jelly stool; ultrasound shows the target sign. Because it is small-bowel-to-small-bowel, contrast/air enema often neither diagnoses nor reduces it, and surgery is frequently required.
• Bowel ischemia and perforation — emergency: transmural vasculitic necrosis; heralded by peritonitis, rigidity, or free air. Glucocorticoids can mask peritoneal signs.
• Massive GI hemorrhage, protein-losing enteropathy, pancreatitis: mucosal ulceration and protein leak; suspect with hypoalbuminemia disproportionate to proteinuria.

Renal

• Rapidly progressive glomerulonephritis with crescents — emergency: rising creatinine, oliguria, hypertension, and RBC casts; requires urgent biopsy and immunosuppression.
• Nephrotic syndrome and chronic kidney disease: sustained mesangial injury and glomerulosclerosis; adults carry substantially higher risk of progression to CKD/ESRD than children. Persistent proteinuria and hypertension at 6 months are the key warning signs.

Other organ complications

• Scrotal involvement/orchitis: vasculitis of scrotal vessels mimics testicular torsion — emergency until Doppler ultrasound demonstrates preserved flow.
• Pulmonary (diffuse alveolar) hemorrhage — rare but emergent: hemoptysis, hypoxemia, dropping hemoglobin with diffuse infiltrates.
• CNS involvement: seizures, headache, or encephalopathy from cerebral vasculitis or, more commonly, hypertensive encephalopathy from nephritis.

Treatment-related

• Glucocorticoids: hyperglycemia, hypertension, adrenal suppression, growth suppression in children, avascular necrosis, and masking of perforation.
• NSAIDs: worsened GI bleeding and reduced GFR through prostaglandin-mediated loss of afferent arteriolar dilation.
• Cyclophosphamide: hemorrhagic cystitis from acrolein (mitigated with mesna and hydration), cytopenias, infection, infertility, and later bladder cancer/leukemia.
• ACE inhibitors/ARBs: hyperkalemia and functional creatinine rise; fetal toxicity in pregnancy.

• Palpable purpura + normal platelet count + normal coagulation studies = vasculitis, not thrombocytopenia. This is the highest-yield discriminator on Step 2 CK; the stem's normal CBC is the answer key, not incidental data.
• Buttocks and lower extremities in a 4–6-year-old after an upper respiratory infection is the classic vignette. Palpable, non-blanching, symmetric, dependent purpura is the buzzword string.
• The single best next step in almost every stem is a urinalysis (with blood pressure). Renal involvement determines prognosis, may be silent, and may appear weeks after the rash — hence surveillance urinalysis for at least 6 months.
• Severe abdominal pain in a child with IgAV = ultrasound for ileoileal intussusception. The distractor is air-contrast enema, which is the answer for the ileocolic intussusception of an otherwise healthy infant, not for IgAV.
• Normal C3 and C4 separate IgAV from post-streptococcal glomerulonephritis and lupus nephritis, both of which consume complement. Serum IgA is elevated in only about half of patients and is not the diagnostic test.
• The one association examiners test: IgA vasculitis and IgA nephropathy (Berger disease) share galactose-deficient IgA1 pathobiology and identical mesangial IgA on biopsy; IgAV is the systemic form with purpura, arthritis, and abdominal pain, whereas Berger disease classically presents as synpharyngitic gross hematuria without rash.
• Steroids relieve abdominal pain and arthritis but do not prevent nephritis — do not choose prophylactic prednisone for isolated skin disease.
• Scrotal pain requires Doppler ultrasound to exclude true torsion before attributing it to vasculitis.
• Adults with IgAV need a broader evaluation: higher rates of renal involvement, worse renal prognosis, and rare association with occult malignancy.