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A man in his 20s presented with a 2-week history of a skin lesion on the left leg. He had been treated with oral beta-lactam antibiotics (amoxicillin and cefixime) and topical neomycin ointment for the past 10 days by a general practitioner. Since there was no improvement with the treatment, the patient presented to the department of dermatology at a higher centre. On examination, bulla formation along with necrosis of the central part and dusky erythema at the periphery was noted over the medial aspect of the left lower leg (figure 1). A skin biopsy was done and the findings were consistent with small vessel vasculitis (figure 2A,B).
Complete evaluation was therefore done to rule out systemic involvement. Urine examination revealed haematuria (4+) and proteinuria (3+), although there was no history of discolouration of urine or frothy urine. Anti nuclear antibody (ANA), Anti–double stranded deoxyribonucleic acid antibody (anti-dsDNA), perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) were negative. Kidney biopsy was suggestive of glomerular disease with mesangial hypercellularity, focal endocapillary proliferation, focal tubular atrophy and mesangial IgA deposits. Since biopsy of the associated skin lesion was suggestive of small vessel vasculitis, a final diagnosis of IgA vasculitis with nephritis1 was established. The patient was treated with oral prednisolone at a dose of 0.5 mg/kg per day with gradual tapering, which led to complete healing of leg ulcer in 6 weeks (figure 3). For long-term management of the kidney pathology, telmisartan was started, which resulted in a gradual resolution of haematuria and proteinuria over 3 months. At 18 months of follow-up after initial presentation, urine analysis was negative for proteinuria and haematuria and 24-hour urinary protein was within normal limits. There has been no recurrence of skin lesions so far (figure 4).
Pathogenesis of IgA vasculitis
IgA vasculitis, earlier termed as Henoch–Schönlein purpura, is a small vessel vasculitis, characterised by IgA1-dominant immune deposits in the blood vessel walls. It can be limited to a single organ or can present as multisystem vasculitis. The skin, kidney, gastrointestinal tract and joints are often involved.2
IgA vasculitis occurs as a result of a complex interplay between genetic predisposition of the host, infectious triggers and abnormal modulation of immune response. The most notable pathological feature is the deposition of IgA1-dominant IgA deposits in the vessel walls.2 It is often triggered by various infectious agents such as bacteria, viruses and vaccines. Such antigens may trigger an aberrant immune response by causing molecular mimicry leading to abnormal production of galactose-deficient IgA1, which plays a key role in the pathogenesis of IgA vasculitis.2 3 Some examples of such infectious triggers are Streptococcus, Staphylococcus aureus, Helicobacter pylori, Clostridium difficile, varicella-zoster virus, hepatitis viruses, parvovirus, HIV, cytomegalovirus and COVID-19.2 3 Vaccine triggers include both the live attenuated vaccines like measles, mumps, rubella, as well as the inactive antigen vaccines such as influenza and hepatitis B.3 Besides these microbiological triggers, the disease is also likely to affect those with a genetic predisposition, although exact estimates of its heritability are not available at present.4
IgA consists of two heavy chains and two light chains. Structurally, it has two subtypes: IgA1 and IgA2, produced in a ratio of 5:1.2 IgA1 has an O-linked glycosylation rich structure in the hinge region. This unique structure consists of 13 amino acids and it extends in the hinge region longer than IgA2. This is also the site for the binding of galactose and N-acetylgalactosamine either with or without sialic acid.2 Modifications of IgA1 in this hinge region is the key event to induce the vascular damage.3 Variation in activity or expression of enzymes which catalyse O-glycosylation of IgA1 in B-cells lead to galactose deficiency of IgA1. Production of such aberrant galactose-deficient IgA1 plays an important role in the pathogenesis of IgA vasculitis and it especially leads to renal involvement. This is explained by its better binding to the mesangial cells of the kidney.2 3
Production of IgA1 (after stimulation by mucosal antigens) is followed by formation of immune complexes. This occurs either by self-aggregation of galactose-deficient IgA1 or by binding to its autoantibodies. These circulating immune complexes are later deposited into the target organs.2
FcαRI (CD89) is a receptor for IgA, which is expressed on monocytes, macrophages, intestinal dendritic cells and Kupffer cells. It is also involved in the deposition of IgA-circulating immune complexes in the kidney.3 The interaction between CD89 and IgA-containing immune complexes leads to tissue injury by phagocytosis, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, production of reactive oxygen species and proinflammatory cytokines.2 IgA also increases leukotriene B4 production, leading to neutrophil migration in immune complex deposition sites. Platelet-activating factor is another lipid mediator that plays a role in the pathogenesis by causing increased IgA production.3
As a result of the inflammatory damage in blood vessels, transendothelial migration of neutrophils occurs.2 3 Vascular endothelial growth factor promotes vascular permeability and inflammatory cell migration from the vessels, and leads to the development of IgA vasculitis. Activation of the complement pathway further leads to tissue damage. Elevated levels of C3a, C5a and Bb fragments, and C3 and C5-9 deposits indicate the activation of the alternative pathway by the IgA immune complexes.2
This entire pathogenesis of IgA vasculitis has been recently explained with a four-hit hypothesis. These four hits are as follows4:
Hit 1—Production of galactose-deficient IgA1.
Hit 2—Generation of circulating IgG autoantibodies specific for galactose-deficient IgA1.
Hit 3—Formation of pathogenic galactose-deficient IgA1-containing immune complexes.
Hit 4—Mesangial deposition of galactose-deficient IgA1-containing immune complexes, resulting in mesangial cell activation, release of inflammatory mediators and glomerular injury.
The entire pathogenesis of IgA vasculitis has been represented in a simplified flow chart (figure 5).
As skin is a window to systemic diseases, all cases of cutaneous vasculitis must be assessed for associated systemic involvement.
In such cases, simple, inexpensive and non-invasive tests like urine routine and microscopy are extremely helpful in ruling out renal involvement.
IgA vasculitis can present with necrotic skin lesion as the initial manifestation, in contrast to common clinical presentation of palpable purpura, pain in abdomen and arthralgia.
Angiotensin receptor blockers are useful in treatment of renal pathology associated with IgA vasculitis and may reduce the need for immunosuppression.
Pathogenesis of IgA vasculitis revolves around the genetic predisposition of the host, infectious triggers and production of abnormal IgA, and it can be explained well with the four-hit hypothesis.
Production of galactose-deficient IgA1 plays an important role in causing kidney damage in cases of IgA vasculitis.
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Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: AS, SC, AC, RC. The following authors gave final approval of the manuscript: AS, SC, AC, RC.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.