IgA vasculitis, also known as allergic purpura or Henoch-Schonlein purpura, is a systemic vasculitis caused by the deposition of IgA1 immune complexes on the vessel walls. IgA vasculitis mainly affects the skin, joints, gastrointestinal tract, and kidneys, causing skin purpura, arthritis, joint swelling, abdominal pain, gastrointestinal hemorrhage, hematuria, proteinuria, and renal insufficiency, and the heart, eyes, lungs, testis, and central nervous system can also be involved.
The etiology of IgA vasculitis is still unclear, but most occurrences in autumn and winter and the onset preceded by upper respiratory tract infections in most patients suggest that infection is an important cause of IgA vasculitis. The pathogenic bacteria include parvovirus B19, hepatitis B virus, hepatitis C virus, adenovirus, group A β-hemolytic streptococcus, Staphylococcus aureus, mycoplasma, and Helicobacter pylori. Medications, neoplastic diseases, and vaccination may lead to the occurrence of IgA vasculitis.
The pathogenesis of IgA vasculitis is not fully understood. It is currently considered to be associated with the genetic susceptibility, abnormal O-glycosylation in the hinge region of human IgA1, abnormal activation of the complement system, and the generation of inflammatory factors, proinflammatory factors, and autoantibodies.
Studies have found that HLA-DRB1 gene and its allele, HLA-B35 gene, HLA-DQA1 gene, HLA-A gene (HLA-A1101, HLA-A2601), and HLA-B gene (HLA-B1501, HLA-B3503, HLA-B52, HLA-B07, HLA-B40) are closely related to the occurrence and development of IgA vasculitis. In addition, some inflammatory factors and RAS-related target genes have been a research hotspot.
Abnormal O-glycosylation in the hinge region of human IgA1
IgA is divided into two subtypes of IgA1 and IgA2. There are 5 - 6 glycosylation sites distributed on the hinge region, which is an important marker different from IgA2 and other immunoglobulins. Abnormal O-glycosylation in the hinge region of human IgA1 leads to IgA1 not cleared by hepatocytes. Self-aggregated IgA1 forms antigen-antibody immune complex depositing in the mesangial area or endothelium, which damage the endothelial cells of small blood vessels, causing leukocytoclastic vasculitis.
The complement system participates in the IgA immune complex clearance process through the classical activation pathway, alternative activation pathway, and lectin activation pathway.
Inflammatory factors and proinflammatory factors
Inflammatory factors, such as IL-6 and IL-17, produced by Th17 cells, under the action of chemokines produced by vascular endothelial cells stimulated by some proinflammatory factors, such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), IL-2, IL-6, transforming growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF), are induced to adhere to the blood vessel walls and act on vascular endothelial cells, causing vascular inflammatory changes.
Antiphospholipid antibodies, lupus anticoagulant antibodies, antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies, IgA rheumatoid factor, and IgA antiendothelial cell antibodies play a certain role in the onset of IgA vasculitis, but the specific mechanism of action is not clear.
Signs and Symptoms
Cutaneous and mucosal purpura occurs initially, and is accompanied by fever, headache, discomfort, and anorexia. Occasionally, abdominal cramps or joint pain is the main manifestation, without skin lesions.
The earliest skin manifestation is small discrete petechiae or wheals, usually developing into palpable hemorrhagic purpura within 1 day. Individual skin lesions often resolve within 5 - 7 days, but skin lesions in groups can occur repeatedly within weeks or months. Skin lesions occur predominantly on the extensor surfaces of extremities, especially the extensor surfaces of elbows and knees, and the buttocks, as well as the torso and face. Some severe skin lesions occur in the compressed areas such as feet in shoes and socks. Purpura can fuse into large ecchymoses, and vesicles, bullae, hematoma, necrotic purpura, and ulcers can also occur. Some patients develop target skin lesions, and the punctate hemorrhagic lesions are surrounded by pale or hemorrhagic rings. Subcutaneous nodular lesions are less common.
Gastrointestinal symptoms can occur at any stage of the disease, including colic, vomiting, bleeding, intestinal paralysis, intussusception, and even intestinal perforation. 50% - 70% of patients have gastrointestinal hemorrhage. The incidence rate of intussusception in children is 1.3% - 13.6%, 90% in the ileum, 7% in the jejunum, very few in the colon. Severe abdominal pain, vomiting, rebound tenderness, and abdominal muscle tension may suggest surgical acute abdomen. Adult patients with gastrointestinal involvement are less common.
Joint pain is a common symptom of joint involvement, and the incidence rate is 75%. Diffuse arm and calf pain occur initially, and most joints can be invaded, more common in the knee joint and ankle joint. It can even develop into arthritis, which is characterized by swelling around the joints, and hydrarthrosis in few patients. Arthritis can resolve without leaving deformation within few weeks. Joint involvement in adults is more common.
The incidence rate of renal involvement is 30% - 90%, with mild symptoms in most patients. Mild proteinuria and hematuria are usually present, but gross hematuria may also be visible. The long-term prognosis of gross hematuria in children is still good, few can progress to glomerulopathy, and only 1% progress to end-stage renal disease. Patients with hematuria should be followed up. Kidney involvement in adults is more common.
Pain, tenderness, and swelling of the testicles or scrotum may be present.
Headache, seizures, and encephalopathy may occur, and most of the central nervous system manifestations are transitory, except for permanent sequelae caused by occasional hemorrhagic stroke.
Respiratory tract and eyes may also be involved.
Guillain-Barre syndrome and mononeuritis are rare in this disease, but are serious symptoms associated with this disease. Hemoptysis can occur in the pulmonary vascular involvement.
Purpuric lesions are manifested by leukocytoclastic vasculitis in the upper dermal capillaries and postcapillary venules. Arteriolar vasodilatation, endothelial cell edema, luminal stenosis, thrombosis, vascular wall edema, and fibrin exudation, degeneration, and necrosis can be seen. In the early stage, neutrophil infiltration in the blood vessel wall and periphery, leukocytoclasis, nuclear dust, and extravasation of erythrocytes can be observed. In the late stage, monocyte infiltration is dominant.
IgA, C3, and cellulose depositions on the dermal vascular walls in the skin lesions can be seen in direct immunofluorescence.
If with palpable eruption and any one of the diagnostic considerations, IgA vasculitis can be diagnosed.
Diagnostic considerations include:
- Diffuse abdominal pain
- IgA deposition in biopsy at any site
- Arthritis or joint pain or both
- Renal involvement such as hematuria and proteinuria
IgA vasculitis without nephritis is a self-limited disease, and most patients can heal spontaneously within 8 week, but the recurrence rate is 30% - 40% within 1 year.
Symptomatic supportive treatment
For patients with mild skin lesions and few affected systems, symptomatic support can be given.
Immunosuppressive therapy includes glucocorticoids and immunosuppressive agents. Hormone therapy is recommended for patients with abdominal pain.
The treatment regimen includes:
- Prednisone 1 - 2mg/kg orally for 1 - 2 week, maximally 60mg, gradually reduced in dose in 1 - 2 weeks
- Hydrocortisone sodium succinate 5 - 10 mg/(kg.d) intravenously for patients with severe gastrointestinal symptoms, such as persistent abdominal pain, gastrointestinal hemorrhage, mesenteric vasculitis, and pancreatitis, and without ability to oral administration
- Methylprednisolone 5 - 10 mg/(kg.d) or a pulse treatment of 15 - 30mg(kg.d), maximally 1g/d, for 3 days with an interval of 2 weeks for severe patients with mesenteric vasculitis or massive bleeding
- Dexamethasone 0.3 mg/(kg.d), switched to oral glucocorticoids after severe symptoms controlled
Glucocorticoids do not prevent IgA vasculitis from further involving the kidneys, nor reduce the incidence of gastrointestinal complications such as intussusception, intestinal obstruction, and intestinal perforation in IgA vasculitis.
Commonly used immunosuppressive agents include cyclophosphamide, colchicine, dapsone, azathioprine, mycophenolate mofetil, cyclosporine A, and rituximab.
Blood purification treatment
For patients not ideally treated with hormones and immunosuppressive agents, blood purification treatment can be considered. Plasma exchange and blood perfusion can alleviate abnormal immune responses and improve clinical symptoms by eliminating abnormal immunoglobulins, antigen-antibody immune complexes, autoantibodies, and inflammatory factors.
For patients with intestinal obstruction, intestinal perforation, or other symptoms that cannot be treated with medications, surgical treatment should be performed.
Skin symptoms often last for 6 - 16 weeks, but 5% - 10% are chronic. Half of patients can relapse, so the entire duration can range from few months to 2 years. In addition to progressive renal failure and end-stage renal disease, the prognosis is generally good. Regardless of the signs or symptoms of nephritis, a routine urine test should be performed every month to observe the involvement of kidneys.