IgA Vasculitis (Henoch-Schönlein Purpura)

Etiology

Environmental, genetic, and antigenic factors appear to contribute to the etiology of IgA vasculitis. Many patients report a preceding infection. Upper respiratory tract infections are the most common; however, patients may also present with an antecedent gastrointestinal tract or pharyngeal infection. Group A streptococcal infections have been detected in cultures from more than 30% of patients with IgAV and nephritis.[4][5] Other causative agents include:

• Coxsackie virus
• Hepatitis A and hepatitis B vaccines (and hepatitis vaccines)
• Mycoplasma spp
• Parvovirus B19
• Infectious mononucleosis
• Subacute bacterial endocarditis
• Helicobacter pylori infection
• Yersinia and Shigella spp
• Salmonella spp
• Brucellosis spp
• Legionella spp
• Campylobacter spp
• Varicella
• Parainfluenza virus
• Influenza virus (and vaccine)
• Respiratory syncytial virus
• Rotavirus
• Cytomegalovirus (CMV) reactivation
• Adenoviruses [4]

More recently, IgAV has also been found to be associated with COVID-19 infections.[5][6][7] The virus directly damages blood vessels, leading to inflammation and immune complex formation. IgAV has also been associated with COVID-19 immunizations.[8][9] Furthermore, several genetic associations have been linked to Henoch-Schönlein purpura.[10][11] Human leukocyte antigen (HLA) class 2 associations include HLA-DQA1*01:01, HLA-DQB1*05:01, and HLA-DRB1*01:01; 3 alleles, HLA-DRB1*04, HLA-DRB1*16, and HLA-DRB1*16:02, were highly related. Mediterranean fever gene (MEFV) variants are also related, especially E148Q and M694V, with E148Q being the most common subtype. Exon 10 mutations are associated with particularly severe symptoms. The AG genotype of the interleukin 1β (IL1B) gene is associated with arthritis. The rs10818488 locus in the tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) gene may reflect the severity of kidney involvement. Glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase pi 1 (GSTP1) gene polymorphisms may be associated with gastrointestinal and urinary complications. Urinary protein analysis carries an association; these proteins are P09417, Q725L0, P60900, P14550, and P09668. Finally, skin involvement in IgA vasculitis can show expression of miRNA-155-5p, miRNA-223-3p, and let-7b.   

Epidemiology

IgAV is a rare disorder that typically affects children; however, the condition can also be seen in adults and adolescents. Most affected children are younger than 10 years. IgAV is often more severe and more likely to cause long-term renal disease in adults.[4] IgAV is the most common vasculitis among children, affecting 10 to 20 per 100,000 children per year.[12] IgAV is slightly more common among boys than girls but has an approximately equal sex distribution in adults.[13]

Pathophysiology

The pathophysiology of IgA vasculitis is not fully understood; however, IgA plays a significant role. The mucous membranes of the salivary glands, lungs, and gastrointestinal tract produce IgA. Plasma B cells produce other classes of immunoglobulins (IgG, IgE, and IgM).[14] IgA1 is implicated in IgAV rather than the IgA2 subtype and is associated with abnormally low galactose levels.[8]

IgA-antibody immune complexes are formed in response to antigenic exposure from an infection or medication. These immune complexes are then deposited in the small vessels, usually capillaries, of the skin, joints, kidneys, and gastrointestinal tract. IgA-antibody immune complex deposition results in an influx of inflammatory mediators, such as prostaglandins. The complement system can also be activated when C3-receptor lymphocytes bind to immune complexes that deposit on vessel walls, contributing to the hyperinflammatory response. Immune complex deposition in the intestinal wall may cause gastrointestinal tract hemorrhage.[4] Immune complexes deposited in the skin cause palpable purpura and petechiae.[8]

Histopathology

Renal biopsy is the most definitive tool for diagnosing both IgAV with nephritis and IgA nephropathy. Both are likely to show mesangial IgA deposits. IgAV with nephritis is more likely to show capillary and subendothelial IgA deposits, as well as neutrophilic infiltration. Renal deposits of IgA-mediated immune complexes may result in mild proliferative or severe crescentic glomerulonephritis.[2][4] IgAV with nephritis is also more likely to show mixed immune complexes with IgA and IgG components, while biopsies from patients diagnosed with IgA nephropathy tend to show only IgA complexes.

History and Physical

The classic presentation of IgA vasculitis includes palpable purpura, gastrointestinal complaints, arthralgias, and renal involvement. Patients may present with any of the following signs or symptoms:

• Rash
• Fatigue
• Headache
• Fever
• Joint pain
• Subcutaneous edema
• Diarrhea
• Hematemesis
• Abdominal pain
• Vomiting
• Rectal bleeding
• Scrotal edema

Physical Examination

Skin

Skin involvement is present in all patients with IgAV and is usually the earliest sign.[1] The rash associated with IgA vasculitis often starts as erythematous, macular, or urticarial lesions (see Image. Henoch-Schönlein Purpura). The rash then develops into palpable purpura and petechiae that most commonly affect the buttocks and lower extremities, particularly the extensor surfaces. Approximately one-third of patients experience the rash on the upper extremities and trunk, but the findings are primarily in dependent structures, which vary by age group and mobility status.[12] The lesions can become bullous or necrotic, and the bullous form has been associated with progressive, treatment-resistant renal failure.[15] The lesions change from red to purple, then rust-colored, before fading. These changes occur over approximately 10 days.[4]

Gastrointestinal Tract

Gastrointestinal tract findings may occur in 10% to 40% of patients before the rash.[12] Patients may present with nausea and vomiting, which may worsen after meals. Potentially life-threatening complications include intussusception, bowel perforation, bowel gangrene, and massive hemorrhage. Intussusception is the most common life-threatening gastrointestinal tract complication, affecting 3% to 4% of patients with IgAV.[1] Other presenting signs and symptoms include extensive skin lesions, an increased D-dimer level, atypical rashes, and joint involvement.[16]  

Renal

Renal symptoms typically occur within 1 to 3 months after the development of a rash in 20% to 55% of children with IgAV.[12] Renal manifestations include hematuria, proteinuria, nephrotic syndrome, nephritic syndrome, and renal failure. The most common renal manifestation is microscopic hematuria.[12] Severe proteinuria may present as nephrotic syndrome, and patients with persistent proteinuria are at high risk of developing progressive glomerulonephritis. Patients may also develop ureteric obstructions. Approximately 50% of patients develop renal manifestations, with less than 1% progressing to end-stage renal failure.[17] Death from IgA vasculitis is rare; however, renal disease is the most common cause of morbidity and mortality in patients with the disorder.[4]

Joints

Approximately 15% of patients with IgA vasculitis present with arthritis as the initial symptom, and overall, arthralgia or arthritis occurs in 75% of children with the disorder.[12] Patients often present with painful, swollen joints, most commonly in the knees, ankles, hands, and feet. The arthralgias are typically transient and nondestructive

Central Nervous System

Central nervous system involvement is rare; however, when it occurs, patients may present with headaches, dizziness, ataxia, seizures, irritability, mononeuropathy, intracranial hemorrhage, or acute motor sensory axonal neuropathy.[12]

Evaluation

The diagnosis of IgA vasculitis is made based on the presence of petechiae without thrombocytopenia or palpable purpura that predominantly affects the lower extremities, plus at least 1 of the following 4 characteristics:

1. Abdominal pain
2. Arthralgia or arthritis
3. Renal involvement (proteinuria, red blood cell casts, or hematuria)
4. Proliferative glomerulonephritis or leukocytoclastic vasculitis with predominant deposition of IgA on histology [1]

Clinicians should order a urinalysis with microscopy to identify hematuria, proteinuria, or red blood cell casts. If the urine dipstick results are positive for protein, a 24-hour collection should be obtained to quantify the protein excretion.[1] A positive urine protein result is considered a harbinger of IgAV recurrence.[18] Measurement of serum IgA levels is nondiagnostic because levels vary significantly, but a significant elevation is suggestive of the disease. Antistreptolysin O titers should also be obtained. Furthermore, ultrasonography is often an initial imaging test to rule out hydronephrosis. Endoscopy can show purpura in the duodenum, stomach, and colon. Elevated D-dimer levels are seen with intussusception.[19]

Treatment / Management

Unless renal involvement is present, symptomatic and supportive care are the foundations of treatment for patients with IgAV. Acetaminophen or opioids are often preferred for pain control over nonsteroidal anti-inflammatory drugs in the setting of gastrointestinal tract or renal involvement.[20] Severe abdominal pain should prompt consideration of prednisone or prednisolone with a taper.[21] Ultrasonography confirms intussusception, and air-contrast enemas or surgical correction may follow.[19][22](B2)

Supportive and Symptomatic Care

• Rehydration with intravenous fluids
• Pain control
• Wound care for ulcerative skin lesions

Management of IgA Vasculitis Nephritis

Angiotensin-converting enzyme inhibitors: Angiotensin-converting enzyme inhibition can decrease proteinuria.[23] These agents are described as renoprotective because they decrease glomerular cell proliferation and fibrosis. However, angiotensin-converting enzyme inhibitors also have the propensity to induce a rare adult form of this disease.[24][25](B3)

Inhibition of the renin-angiotensin-aldosterone system has been shown to reduce proteinuria across various pathologies. Reducing long-term renal complications, such as decreased glomerular filtration rate, chronic kidney disease, and progression to end-stage renal disease, is critical. These agents are most often used in adults, who have less spontaneous recovery than children and are more likely to have hypertension.

Plasmapheresis or plasma exchange may be used concurrently with immunosuppressive therapy. Plasmapheresis decreases inflammation and inhibits glomerular crescent formation by clearing IgA complexes.[11] The addition of corticosteroids improves disease resolution.(B3)

Immunosuppressants: A significant number are applicable in this disease. Azathioprine has been used successfully in recurrent disease, particularly with skin involvement. Results from studies showed that methotrexate had efficacy in patients with severe and recurrent gastrointestinal tract involvement. Imipramine, when combined with corticosteroids, has shown good effects, including symptomatic relief and a reduction in proteinuria. Results from studies showed that tacrolimus improved renal function. Mycophenolate mofetil is particularly helpful in patients with recurrent renal and gastrointestinal tract involvement. Cyclophosphamide, often used in combination with other immunosuppressants, has demonstrated utility in children.   

Corticosteroids: Early oral prednisone treatment is helpful in treating renal, joint, and gastrointestinal tract manifestations. Prednisone does not prevent renal disease but reduces the risk of developing persistent renal complications in children.[4] Results from several randomized controlled trials suggested that prednisone minimizes the duration and severity of abdominal pain during the first 2 weeks of treatment.[20] A recent algorithm recommends that oral prednisolone be given for low-level vasculitis nephritis, oral or pulse corticosteroids for moderate disease, and oral or pulse corticosteroids with intravenous cyclophosphamide for severe forms.[10] For second-line therapy, rituximab, azathioprine, mycophenolate mofetil, corticosteroids, and cyclophosphamide are advocated.(B3)

Fish oil, when administered in a standardized pharmaceutical formulation, has been shown in several trials to be more effective than a placebo for IgA nephropathy through potential anti-inflammatory mechanisms and may also be effective in IgAV.

Intravenous immunoglobulin can also be effective in patients with rapidly progressive glomerulonephritis. Mechanisms of action include impairing autoreactive T cells by blocking binding to antigen-presenting cells, downregulating antibody production by B cells, and blocking the Fc receptor–mediated immune response.[26]  (A1)

Dapsone suppresses interleukin-8, myeloperoxidase, and leukocyte chemotactic activity, collectively producing an anti-inflammatory effect.[27] Dapsone has notable effects on cutaneous vasculitis and gastrointestinal tract involvement, but significantly fewer effects on nephritic disease.[10][11](B3)

Differential Diagnosis

The differential diagnosis of IgAV includes the following:

• IgA nephropathy
• Acute kidney injury
• Acute glomerulonephritis
• Immune thrombocytopenia
• Disseminated intravascular coagulation
• Thrombotic thrombocytopenic purpura
• Hemolytic uremic syndrome
• Meningococcal meningitis
• Hypersensitivity vasculitis
• Systemic lupus erythematosus
• Polyarteritis nodosa
• Bacterial endocarditis
• Inflammatory bowel disease
• Granulomatosis with polyangiitis
• Rocky Mountain spotted fever

Prognosis

IgA vasculitis is typically a self-limited illness that has an excellent prognosis in patients without renal involvement. Most patients fully recover in 4 weeks.[4] IgA vasculitis recurs in approximately one-third of patients within 4 to 6 months after the initial onset. The long-term morbidity of IgA vasculitis is dependent on the extent of renal involvement. Approximately 1% of patients with IgA vasculitis will develop end-stage renal disease and require a renal transplant.[20]

Complications

IgA vasculitis involves multiple organ systems, and the potential complications are relatively extensive. Potential complications include the following:

• Renal failure
• Proteinuria
• Hematuria
• Nephrotic syndrome
• Intussusception
• Gastrointestinal tract bleeding
• Bowel infarction
• Bowel perforation
• Central nervous system bleeding
• Seizures
• Neuropathy
• Pleural effusion
• Pulmonary hemorrhage
• Testicular torsion