IgA Vasculitis in Adults

 

IgA Vasculitis in Adults: Current Perspectives on Diagnosis and Management

Dr Neeraj Manikath ,claude.ai

Abstract

IgA vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is a small-vessel vasculitis characterized by IgA1-dominant immune deposits. While primarily considered a pediatric condition, adult-onset IgAV presents unique diagnostic and therapeutic challenges due to its lower incidence, more severe manifestations, and poorer outcomes compared to childhood cases. This review summarizes current evidence on adult IgAV, with particular focus on epidemiology, pathophysiology, clinical manifestations, diagnostic criteria, and management strategies. Recent advances in biomarkers, imaging modalities, and novel therapeutic approaches are also discussed, providing rheumatologists with a comprehensive and updated framework for managing this complex vasculitis in adult patients.

Introduction

IgA vasculitis (IgAV) is a small-vessel leukocytoclastic vasculitis characterized by deposition of IgA1-dominant immune complexes in vessel walls[1]. It predominantly affects children, with an incidence of 10-20 cases per 100,000 population annually[2]. In contrast, adult-onset IgAV is relatively rare, with approximately 0.8-1.8 cases per 100,000 adults per year[3].

While historically known as Henoch-Schönlein purpura (HSP), the nomenclature was revised by the 2012 Chapel Hill Consensus Conference (CHCC) to reflect the pathophysiological mechanism of the disease[4]. Despite its lower incidence in adults, IgAV in this population presents with more severe clinical manifestations and poorer outcomes, particularly regarding renal involvement, making it a significant concern for practicing rheumatologists[5,6].

This review aims to provide an updated perspective on the diagnosis and management of adult IgAV, integrating recent advances in understanding disease mechanisms, biomarkers, and therapeutic strategies to guide evidence-based clinical practice.

Epidemiology and Risk Factors

The incidence of adult IgAV varies geographically, with higher rates reported in Asian populations compared to Western countries[7]. Unlike the pediatric population, where males are predominantly affected with a male-to-female ratio of 1.5:1, adult IgAV shows a more balanced gender distribution[8]. The peak incidence occurs in adults aged 20-40 years, though cases have been reported across all age groups[9].

Several triggers have been identified in adult IgAV:

1. Infections: Upper respiratory tract infections precede approximately 30-50% of adult cases, with Streptococcus species being the most commonly implicated pathogen[10].

2. Medications: Various drugs have been associated with IgAV, including antibiotics (particularly beta-lactams), non-steroidal anti-inflammatory drugs (NSAIDs), and angiotensin-converting enzyme inhibitors (ACEIs)[11].

3. Malignancies: Adult IgAV has a stronger association with malignancy compared to pediatric cases. Solid tumors, particularly of the lung, prostate, and gastrointestinal tract, as well as hematological malignancies, have been reported in 5-10% of adult patients[12,13].

4. Genetic factors: HLA-DRB101 and HLA-B41 alleles have been associated with increased susceptibility to IgAV in adults, though these associations are less well-established than in pediatric populations[14].

Pathophysiology

The pathogenesis of IgAV involves aberrant production and glycosylation of IgA1, formation of immune complexes, and subsequent vascular inflammation. Recent advances have expanded our understanding of these mechanisms:

Aberrant IgA1 Production and Glycosylation

IgAV is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1). This abnormally glycosylated IgA1 contains reduced O-linked galactose in the hinge region, exposing N-acetylgalactosamine (GalNAc) residues[15]. Recent research has identified dysregulation of several glycosyltransferases, particularly C1GALT1 (core 1 β1,3-galactosyltransferase) and its chaperone Cosmc, in patients with IgAV[16].

Immune Complex Formation

The exposed GalNAc residues on Gd-IgA1 are recognized by naturally occurring anti-glycan IgG and IgA autoantibodies, leading to the formation of circulating immune complexes[17]. These complexes have reduced clearance by the hepatic asialoglycoprotein receptor and increased affinity for mesangial cells and endothelial surfaces[18].

Vascular Inflammation

Deposition of immune complexes in vessel walls activates the complement system, particularly the alternative and lectin pathways, resulting in the recruitment of inflammatory cells and release of pro-inflammatory cytokines[19]. Recent studies have highlighted the role of neutrophil extracellular traps (NETs) in amplifying vascular damage in IgAV[20].

Novel Pathways

Emerging evidence suggests involvement of the interleukin-17/23 axis and dysregulation of regulatory T cells in the pathogenesis of IgAV[21]. Additionally, alterations in the gut microbiome have been implicated, with some studies reporting increased intestinal permeability and bacterial translocation preceding the onset of disease manifestations[22].

Clinical Manifestations

Adult IgAV typically presents with the classic tetrad of palpable purpura, arthralgia/arthritis, abdominal pain, and renal involvement, though the clinical spectrum varies widely. Important distinctions between adult and pediatric presentations include:

Cutaneous Manifestations

Palpable purpura occurs in nearly all (95-100%) adult patients, predominantly affecting the lower extremities and buttocks[23]. Unlike in children, adults more frequently develop severe skin lesions, including bullous, necrotic, and ulcerative changes[24]. Edema is common, particularly in the distal extremities and areas with dependent positioning.

Gastrointestinal Involvement

Gastrointestinal symptoms affect 50-85% of adult patients and range from mild abdominal discomfort to severe complications[25]. Adults exhibit higher rates of serious gastrointestinal complications compared to children, including:

• Massive gastrointestinal bleeding (10-20%)

• Intussusception (2-3%)

• Bowel perforation (1-2%)

• Pancreatitis (rare but reported)[26,27]

Endoscopic findings typically reveal erythematous, petechial, or ulcerative lesions primarily affecting the second portion of the duodenum[28].

Renal Involvement

Renal manifestations occur in 45-85% of adult patients and represent the primary determinant of long-term prognosis[29]. Compared to children, adults demonstrate:

• Higher rates of nephrotic-range proteinuria (20-35% vs. 5-15%)

• Greater frequency of nephritic syndrome (15-20% vs. 5-10%)

• Increased risk of progression to end-stage renal disease (5-15% vs. <1%)[30,31]

Microscopic hematuria is the most common urinary abnormality (80-90%), followed by proteinuria (70-80%)[32].

Articular Involvement

Arthralgia and/or arthritis affect 60-70% of adult patients, typically presenting as non-erosive, non-deforming inflammation predominantly affecting the knees and ankles[33]. Compared to children, adults more frequently experience prolonged arthritis (>2 weeks) and higher rates of persistent joint symptoms[34].

Other Manifestations

Less common but important manifestations in adults include:

1. Neurological involvement: Reported in 5-10% of adult cases, ranging from headache and behavioral changes to more severe manifestations like seizures, posterior reversible encephalopathy syndrome (PRES), and cerebral vasculitis[35].

2. Pulmonary involvement: Diffuse alveolar hemorrhage, interstitial lung disease, and pleural effusions have been reported in 0.5-5% of adult cases[36].

3. Cardiac involvement: Myocarditis, pericarditis, and coronary arteritis are rare but potentially life-threatening complications[37].

4. Orchitis: Affects approximately 2-5% of adult male patients and can lead to testicular infarction if not properly managed[38].

Diagnosis

The diagnosis of IgAV in adults remains primarily clinical, supported by laboratory findings and histopathology when necessary.

Diagnostic Criteria

Several classification criteria have been proposed for IgAV, including the American College of Rheumatology (ACR) 1990 criteria[39] and the European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society (EULAR/PRINTO/PRES) 2010 criteria[40]. However, these were primarily developed for pediatric populations.

More recently, a 2021 international consensus proposal specifically addressed diagnostic criteria for adult IgAV, including:

Major criteria:

• Palpable purpura or petechiae with lower limb predominance in the absence of thrombocytopenia

• Histopathology showing leukocytoclastic vasculitis with IgA deposits

Minor criteria:

• Arthralgia or arthritis

• Renal involvement (hematuria and/or proteinuria)

• Gastrointestinal involvement (abdominal pain or gastrointestinal bleeding)

• Recent respiratory tract infection or other identified trigger

The diagnosis of adult IgAV requires either the presence of both major criteria or one major criterion plus at least two minor criteria[41].

Laboratory Investigations

No specific laboratory test confirms the diagnosis of IgAV. Common findings include:

• Normal or elevated inflammatory markers (ESR, CRP)

• Normal platelet count (crucial to distinguish from thrombocytopenic purpura)

• Elevated serum IgA levels (40-50% of cases)

• Normal complement levels (distinguishing from other immune complex vasculitides)

• Urinalysis and kidney function tests to assess renal involvement[42]

Histopathology

Skin biopsy showing leukocytoclastic vasculitis with perivascular IgA deposition by direct immunofluorescence remains the gold standard for diagnosis when clinical presentation is atypical[43]. In adult patients with significant renal involvement, kidney biopsy may be necessary to determine the extent and class of renal damage, which influences therapeutic decisions.

The histopathological classification of IgA nephropathy (Oxford classification) has been adapted for IgAV nephritis, evaluating:

• Mesangial hypercellularity (M)

• Endocapillary proliferation (E)

• Segmental glomerulosclerosis (S)

• Tubular atrophy/interstitial fibrosis (T)

• Crescents (C)[44]

Differential Diagnosis

The differential diagnosis of adult IgAV includes:

• Other primary vasculitides (ANCA-associated vasculitis, cryoglobulinemic vasculitis)

• Secondary vasculitides (drug-induced, infection-related)

• Thrombotic microangiopathies

• Other causes of purpura (thrombocytopenia, coagulation disorders)

• Inflammatory bowel disease (when gastrointestinal symptoms predominate)[45]

In adults, particularly those over 50 years, thorough evaluation for underlying malignancy is warranted given the established association[46].

Biomarkers

Several potential biomarkers for disease activity and prognosis have been investigated:

1. Serum Gd-IgA1 levels: Correlate with disease activity and risk of renal involvement[47].

2. Urinary biomarkers: Including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and monocyte chemoattractant protein-1 (MCP-1), which may predict severity of renal involvement[48].

3. Genetic markers: Polymorphisms in genes encoding cytokines (IL-1, IL-6, TNF-α) and adhesion molecules have been associated with disease susceptibility and severity[49].

4. Complement activation products: Particularly those of the alternative pathway (C3a, Bb fragment), which correlate with disease activity[50].

Treatment

Management of adult IgAV remains challenging due to the lack of large randomized controlled trials. Treatment approaches vary based on disease severity and organ involvement.

Mild Disease

For patients with isolated cutaneous and mild joint involvement:

• Supportive care with rest and adequate hydration

• NSAIDs for arthralgia (with caution in patients with renal involvement)

• Antihistamines for pruritus associated with cutaneous lesions

• Monitoring for development of systemic complications[51]

Moderate-to-Severe Disease Without Significant Renal Involvement

For patients with significant cutaneous, gastrointestinal, or joint manifestations:

1. Corticosteroids: Prednisone or prednisolone (0.5-1 mg/kg/day for 2-4 weeks with subsequent tapering) has been shown to alleviate symptoms and possibly reduce the risk of gastrointestinal complications, though evidence for long-term benefit is limited[52].

2. Colchicine: Some studies have reported efficacy in treating cutaneous manifestations (0.5-1.5 mg/day), particularly in cases refractory to corticosteroids[53].

3. Dapsone: May be effective for chronic or relapsing cutaneous disease (50-150 mg/day), acting through inhibition of neutrophil recruitment and function[54].

Severe Disease With Significant Renal Involvement

For patients with nephrotic-range proteinuria, rapidly progressive glomerulonephritis, or other severe manifestations:

1. High-dose corticosteroids: Initial treatment typically involves methylprednisolone pulses (0.5-1 g/day for 3 days) followed by oral prednisone (1 mg/kg/day)[55].

2. Cyclophosphamide: Used in combination with corticosteroids for severe renal involvement, particularly in the presence of crescentic glomerulonephritis (2 mg/kg/day orally or 0.5-1 g/m² IV monthly)[56].

3. Rituximab: Emerging evidence supports the use of rituximab (375 mg/m² weekly for 4 weeks or two 1-g doses two weeks apart) in refractory cases, particularly those with severe renal involvement[57,58].

4. Plasma exchange: May be considered in rapidly progressive glomerulonephritis or life-threatening gastrointestinal or pulmonary hemorrhage, though evidence is mainly derived from small case series[59].

5. Mycophenolate mofetil: Used as steroid-sparing agent (1-2 g/day) in maintenance therapy after induction with more potent immunosuppressants[60].

Novel and Emerging Therapies

Several targeted therapies have shown promise in small studies or case reports:

1. IVIG: High-dose intravenous immunoglobulin (2 g/kg divided over 2-5 days) may be effective in refractory cases, potentially through immunomodulation and inhibition of complement activation[61].

2. Biologics targeting TNF-α: Case reports suggest potential benefit of adalimumab and infliximab in refractory disease[62].

3. IL-17/IL-23 pathway inhibitors: Given emerging evidence of the role of the Th17 pathway in pathogenesis, secukinumab and ustekinumab have been explored in small case series with promising results[63].

4. Complement inhibitors: Eculizumab has been reported to be effective in cases with prominent complement activation[64].

5. JAK inhibitors: Tofacitinib and baricitinib have been reported in case series for refractory IgAV with encouraging outcomes[65].

Specific Management Considerations

Renal Involvement

The management of renal involvement depends on histopathological findings and clinical severity:

• Mild mesangial proliferation: ACE inhibitors or angiotensin receptor blockers for proteinuria >0.5 g/day

• Moderate proliferative disease: Corticosteroids with or without mycophenolate mofetil

• Severe proliferative disease or crescentic glomerulonephritis: Cyclophosphamide or rituximab plus corticosteroids[66]

A 2020 meta-analysis suggested that immunosuppressive therapy in adult IgAV nephritis may reduce proteinuria and stabilize renal function, but did not demonstrate definitive long-term benefit in preventing end-stage renal disease[67].

Gastrointestinal Involvement

Management of gastrointestinal manifestations includes:

• Corticosteroids for moderate-to-severe abdominal pain

• Proton pump inhibitors for gastric protection

• Careful monitoring for complications requiring surgical intervention (intussusception, perforation)

• Nutritional support in cases of prolonged symptoms[68]

Special Populations

Pregnancy

IgAV during pregnancy is rare but associated with increased risk of maternal and fetal complications. Management includes:

• Close monitoring of blood pressure and renal function

• Minimizing teratogenic medications (cyclophosphamide, mycophenolate)

• Preference for corticosteroids, azathioprine, or tacrolimus when immunosuppression is necessary

• Multidisciplinary approach involving rheumatology, nephrology, and obstetrics[69]

Elderly Patients

In elderly patients (>65 years), considerations include:

• Higher vigilance for underlying malignancy

• Careful monitoring for medication toxicity

• Dose adjustment of immunosuppressants according to renal function

• Prophylaxis against opportunistic infections during immunosuppressive therapy[70]

Prognosis and Follow-up

The prognosis of adult IgAV is generally less favorable compared to pediatric cases, particularly regarding renal outcomes.

Prognostic Factors

Factors associated with poor prognosis include:

1. Age >50 years

2. Severe renal involvement at presentation (creatinine >1.5 mg/dL, nephrotic syndrome)

3. Histological findings: presence of crescents in >50% of glomeruli, significant interstitial fibrosis

4. Persistent proteinuria >1 g/day after 6 months

5. Hypertension

6. Gastrointestinal bleeding[71,72]

Long-term Outcomes

Long-term outcomes in adult IgAV include:

• Renal outcomes: 5-15% of adults develop end-stage renal disease within 10 years

• Relapse rates: 20-30% experience at least one relapse within 5 years

• Mortality: 5-year survival rates of 90-95%, with most deaths attributed to renal failure, infections, or cardiovascular events[73,74]

Monitoring and Follow-up

A structured follow-up protocol is recommended:

• Initial phase (first 3 months): Weekly to bi-weekly monitoring of urinalysis, renal function, and blood pressure

• Intermediate phase (3-12 months): Monthly assessments

• Long-term phase (beyond 12 months): Quarterly to semi-annual evaluations for at least 5 years

Patients with significant renal involvement may require indefinite monitoring[75].

Conclusion and Future Directions

Adult IgAV represents a significant challenge for rheumatologists due to its complex presentation, potential for severe organ involvement, and limited evidence-based treatment guidelines. While our understanding of disease mechanisms has advanced considerably, translating these insights into targeted therapies remains a work in progress.

Future research should focus on:

1. Development of validated diagnostic criteria specific to adult IgAV

2. Identification of reliable biomarkers for disease activity and prognosis

3. Large randomized controlled trials evaluating both conventional and novel therapies

4. Better understanding of the relationship between IgAV and malignancy

5. Exploration of the gut-immune axis in disease pathogenesis

A multidisciplinary approach involving rheumatology, nephrology, gastroenterology, and dermatology remains crucial for optimal management of this complex vasculitis.

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