IgA Vasculitis (Henoch-Schönlein Purpura)

Etiology

Environmental, genetic, and antigenic factors appear to contribute to the etiology of IgA vasculitis. Genomic studies have found an association with HLA-DQA1 and DQB1 intergenic zone, the HLA-DRB1*01:11/B1*13 loci, and DQA1*01:01/DQB1*05:01/DRB1*01:01 haplotype.[4] Many patients report a preceding infection. Upper respiratory tract infections are the most common; however, patients may also present with an antecedent gastrointestinal or pharyngeal infection.

Group A Streptococcus has been found in cultures of greater than 30% of patients with IgAV with nephritis.[5][6] 

Other causative agents include.[5]

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

More recently, IgAV has also been found in association with COVID-19 infections.[6][7] The virus is thought to damage blood vessels directly, leading to inflammation and immune complex formation. IgAV has also been seen with COVID-19 immunizations.[8]

Epidemiology

IgAV is a rare disorder that typically affects children; however, the condition can also be seen in adults and adolescents. The majority of children are aged younger than 10. It is often more severe and likely to cause long-term renal disease in adults.[5] It is the most common vasculitis among children, affecting 10 to 20 per 100,000 per year.[9] IgAV is slightly more common among boys than girls but with about equal predilection in adults.[10]

Pathophysiology

The pathophysiology of IgA vasculitis is not fully understood; however, IgA plays a significant role. Mucous membranes of the salivary glands, lungs, and gastrointestinal tract produce IgA. Plasma B-cells produce other classes of immunoglobulins (IgG, IgE, IgM).[11] 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. They are then deposited in the small vessels (usually capillaries) of the skin, joints, kidneys, and gastrointestinal tract. This 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 and deposit in the vessel walls, contributing to the hyper-inflammatory response. If the immune complexes are deposited in the intestinal wall, they may cause gastrointestinal hemorrhage.[5] Immune complexes deposited in the skin cause palpable purpura and petechiae.[8]

Histopathology

Renal biopsy is the most definitive tool to diagnose 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 and neutrophilic infiltration. Renal deposits of IgA-mediated immune complexes may result in mild proliferative or severe crescentic glomerulonephritis.[2][5] IgAV with nephritis is also more likely to show mixed immunocomplexes with IgA and IgG components, while biopsies from those 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. 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 in the upper extremities and trunk, but the findings are primarily in dependent structures, which vary by age group and mobility.[9] The lesions can potentially become bullous or necrotic, and the bullous form has been associated with progressive, treatment-resistant renal failure [12]. The lesions change from red to purple and become rust-colored before fading. These changes occur over approximately ten days.[5]

Gastrointestinal

GI findings may occur in 10% to 40% of patients before the rashes.[9] Patients may present with nausea and vomiting, worse after meals. Potential life-threatening complications include intussusception, bowel perforation, bowel gangrene, and massive hemorrhage. Intussusception is the most common life-threatening gastrointestinal complication, affecting 3% to 4% of patients with IgAV.[1]

Renal

Renal symptoms typically occur within 1 to 3 months after rash development in 20% to 55% of children with IgAV.[9] Renal manifestations include hematuria, proteinuria, nephrotic syndrome, nephritic syndrome, and renal failure. The most common renal manifestation is microscopic hematuria.[9] 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.[13] Death from IgA vasculitis is rare; however, renal disease is the most common cause of morbidity and mortality in patients with the disorder.[5]

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.[9] Patients often present with painful, swollen joints that most commonly involve the knees, ankles, hands, and feet. The arthralgias are typically transient and non-destructive.

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.[9]

Evaluation

The diagnosis of IgA vasculitis is made based on the presence of petechiae (without thrombocytopenia) or palpable purpura that predominantly affects the lower limbs plus at least one of the following four characteristics:[1]

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

Clinicians should order a urinalysis with microscopy to identify hematuria, proteinuria, or red blood cell casts. If the urine dipstick is positive for protein, a 24-hour collection should be obtained to quantify the protein excretion.[1] A positive urine protein is thought to be a harbinger of IgAV recurrence [14]. Measurement of serum IgA levels is non-diagnostic as levels vary significantly, but significant elevation is suggestive of the disease. Anti-streptolysin O titers should also be sent.

Ultrasonography is often an initial imaging test to rule out hydronephrosis. Endoscopy can show purpura in the duodenum, stomach, and colon. 

Treatment / Management

Unless renal involvement is present, symptomatic and supportive care are the foundations of treatment for patients with IgAV. Acetaminophen or narcotics are often preferred for pain control over NSAIDs in the setting of GI or renal involvement.[15] The presence of severe abdominal pain should support the use of prednisone or prednisolone in a tapered format.[16](B3)

Supportive and Symptomatic Care

• Rehydration with intravenous (IV) fluids
• Pain management
• Wound care for ulcerative skin lesions

Management of IgA Vasculitis Nephritis

• Angiotensin-converting enzyme inhibitors
• Corticosteroids
• Plasmapheresis or plasma exchange, with concurrent immunosuppressive therapy
• Immunosuppressants

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

Early oral prednisone treatment is helpful in managing renal, joint, and gastrointestinal manifestations. Prednisone does not prevent renal disease but reduces the risk of developing persistent renal complications in children.[5] According to several randomized control trials, evidence suggests that prednisone minimizes the duration and severity of abdominal pain during the first two weeks of treatment.[15] A recent algorithm is available where oral prednisolone is given for low-level vasculitis nephritis, oral/pulse steroids for moderate, and oral/pulse steroids along with intravenous cyclophosphamide for severe forms.[4] For second-line therapy, rituximab, azathioprine, mycophenolate mofetil, along with steroids and cyclophosphamide are advocated.(B3)

Fish oil (when given in regulated medicinal form) has been proven in several trials to be more effective than placebo for IgA nephropathy through what is thought to be anti-inflammatory mechanisms and may be effective in IgAV. Dapsone is an antibiotic that inhibits bacterial folate synthesis and has been described as effective in case reports, especially against purpura. It is also thought to have an anti-inflammatory effect.[4](B3)

Intravenous immunoglobulin can also be effective in cases 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.[17](A1)

Differential Diagnosis

The differential diagnosis of IgAV includes the following:

• IgA nephropathy
• Acute renal failure
• Acute glomerulonephritis
• Idiopathic thrombocytopenic purpura
• Disseminated intravascular coagulation
• Thrombotic thrombocytopenic purpura
• Hemolytic uremic syndrome
• Meningococcal meningitis
• Hypersensitivity vasculitis
• Systemic lupus erythematosus
• Polyarteritis nodosa
• Bacterial endocarditis
• Inflammatory bowel disease
• Wegener granulomatosis
• Rocky Mountain spotted fever

Prognosis

IgA vasculitis is typically a self-limited illness that demonstrates an excellent prognosis in patients without renal involvement. The majority of patients fully recover in four weeks.[5] IgA vasculitis recurs in approximately one-third of patients within 4 to 6 months after the initial onset.

The long-term morbidity of vasculitis is dependent on the extent of renal involvement. Approximately 1% of patients with IgA vasculitis will develop end-stage renal disease (ESRD) and require renal transplantation.[15]

Complications

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

• Renal Failure
• Proteinuria
• Hematuria
• Nephrotic syndrome
• Intussusception
• Gastrointestinal bleeding
• Bowel infarction
• Bowel perforation
• CNS bleeding
• Seizures
• Neuropathy
• Pleural effusion
• Pulmonary hemorrhage
• Testicular torsion