A Review of IgA Vasculitis (Henoch-Schönlein Purpura) Past, Present, and Future

Background

IgA vasculitis, or Henoch-Schönlein purpura, is now recognized as a systemic hypersensitivity vasculitis caused by the deposition of immune complexes in small blood vessels, including the renal glomeruli [1]. The presentation in the skin is often a non-thrombocytopenic purpura or urticaria [1,2]. Worldwide, IgA nephropathy is the most common cause of primary glomerulonephritis, with a major effect on public health and global healthcare resources [3,4]. Although the clinical presentation of IgA vasculitis classically includes a combination of cutaneous vasculitis, arthritis, gastrointestinal, and renal involvement, patients may experience exacerbations or flares [5]. Rare variants can involve the lungs or central nervous system (CNS) or be limited to the skin (purpura) or kidneys (IgA nephropathy) [5]. Detection of IgA deposition in small blood vessels and the renal glomeruli is diagnostic in most cases [6,7]. IgA vasculitis represents a paradigm in the medical history of an important systemic vasculitis that can be a diagnostic challenge and continues to be a topic for research into its causes and pathogenesis. This article aims to review the history, current classification, epidemiology, presentation, and diagnosis of IgA vasculitis and nephropathy, disease associations or trigger factors, including infections, vaccines, and therapeutic agents, and highlights some future approaches to improve diagnosis and clinical management.

The First Identified Systemic Vasculitis: IgA Vasculitis, or Henoch-Schönlein Purpura

In 1837, Johann Lukas Schönlein, a German physician who had a significant role in establishing medicine as a natural science, first described the clinical association of purpura, arthralgia, and arthritis [8]. In 1874, Eduard Henoch, a student of Schönlein, reported cases of children with purpura, abdominal pain, bloody diarrhea, and joint pain [9,10]. Henoch highlighted the systemic effects of the condition that initially became known as Henoch-Schönlein purpura and then IgA vasculitis [9,10].

In 1866, the physician Adolf Kussmaul and the pathologist Rudolf Maier described a 27-year-old German man with multiple arterial inflammatory nodules, including the coronary arteries [11]. Kussmaul and Maierand named this condition ‘periarteritis nodosa,’ possibly the first published case of polyarteritis nodosa (PAN) [11]. In 1982, Davies and colleagues wrote a seminal letter to the British Medical Journal (BMJ) in which they first described the use of indirect immunofluorescence to detect a factor in the cytoplasm of neutrophils in eight patients with necrotizing crescentic glomerulonephritis [12]. Still, more than 50 years ago, the classification and terminology of vasculitis lacked clarity [13].

Systemic or syndromic vasculitis has often been named after the clinician who first described the condition, resulting in non-descriptive eponyms, which continue to be confusing [14–17]. Also, the early classification systems used were based on clinical findings, such as localized, systemic, small vessel, large vessel, adult, or pediatric vasculitis, or on the histopathology findings, such as neutrophilic, eosinophilic, lymphocytic, or granulomatous vasculitis [16,17].

Current Classification Criteria and Clinical Guidelines

Since the 1980s, developments in immunology, imaging, and immune markers on tissue biopsies have clarified the nomenclature and classification of vasculitis [16]. In 1990, the American College of Rheumatology (ACR) proposed classification criteria for the major types of vasculitis [18]. In 1990, the ACR published criteria for the classification of seven types of systemic vasculitis: giant cell arteritis (GCA), Takayasu’s arteritis, eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), granulomatosis with polyangiitis, polyarteritis nodosa (PAN), IgA vasculitis (Henoch-Schönlein purpura), and hypersensitivity vasculitis [18]. These criteria were supported by the 1994 International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC) for the most common types of vasculitis known to exist at that time [19]. However, it was not until 2012 that anti-neutrophil cytoplasm antibodies (ANCA) and microscopic polyangiitis were included when the 2012 revised International Chapel Hill Consensus Conference guidelines were published [20].

In 2006, consensus criteria were proposed for childhood vasculitis by the European Alliance of Associations for Rheumatology (EULAR) and the Paediatric Rheumatology European Society (PReS), which were updated in 2010 [21,22]. In 2018, a dermatologic addendum was added to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012) on the topic of vasculitis affecting the skin (D-CHCC) to standardize the definitions and nomenclature for cutaneous components of systemic vasculitis [23]. The D-CHCC classification recommends that there should be clarity for cutaneous IgA vasculitis as a component of systemic IgA vasculitis to distinguish this condition from the variant of skin-limited IgA vasculitis [23].

In 2019, an international panel of 16 international experts developed a consensus guideline of seven recommendations for diagnosis and 19 for treating pediatric IgA vasculitis, the Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative [24]. The 2019 SHARE diagnostic recommendations include confirmatory skin and renal biopsy diagnosis, renal laboratory investigations, and imaging [24]. Treatment recommendations include appropriate analgesia and angiotensin-converting enzyme (ACE) inhibitors [24]. A structured approach is recommended for treating IgA nephropathy, including corticosteroids and second-line agents in mild, moderate, and severe disease, ACE inhibitors, and maintenance therapy [24]. These classification systems and guidelines, developed by immunologists, rheumatologists, and pathologists, aim to improve diagnostic accuracy and patient management and continue to drive studies in the diagnosis, causes, prevention, and management of vasculitis, including IgA vasculitis.

Epidemiology of IgA Vasculitis

Worldwide, approximately 90% of cases of IgA vasculitis occur in children between 3–15 years of age, with a mean age of 6 years, and also occurs less commonly in adults [25,26]. IgA vasculitis is the most prevalent systemic vasculitis, with an estimated global incidence in 2019 of between 3–27 per 100,000 [25,27]. In 2015, the mean age of onset for IgA vasculitis in adults was reported to be 50 years, and it was more common in men than in women [28].

Population studies have shown that IgA vasculitis varies between geographical regions and has seasonal peaks, possibly due to its association with infectious disease [29]. In the northern hemisphere, the incidence of IgA vasculitis is mainly between November and January [25]. In Asia, the annual incidence in children is 70 cases per 100,000 [30]. In 2002, in a population study in the UK, the annual incidence was approximately 20 per 100,000 in children <17 years of age, with a peak incidence of 70 cases per 100,000 in children between 4–6 years of age [30,31]. In the US, the annual incidence of IgA vasculitis is approximately 3–27 cases per 100,000 in children and infants and <2 new cases per 100,000 in adults [25].

Epidemiological studies have shown differences in the human leukocyte antigen (HLA) and immune gene polymorphisms, which support the role of genetic or ethnic disease susceptibility for IgA vasculitis [32,33]. Recently identified disease-susceptibility gene polymorphisms involve genes encoding endothelial nitric oxide synthase (eNOS), interleukin-18 (IL-18), and angiotensin-converting enzyme (ACE) [34,35].

Risk Factors for IgA Vasculitis

Approximately 50% of cases of IgA vasculitis are preceded by an upper respiratory tract infection (URTI), most commonly due to Streptococcus [36,37]. In children, there is a recognized association between vaccination and subsequent development of IgA vasculitis [38,39]. However, the risk is low and is outweighed by the risk of not being vaccinated against childhood infection [38,39]. There are also reports of a temporal relationship between the onset of IgA vasculitis and treatment with several classes of drugs, including new biologics and targeted therapies [40–43].

Recently, co-infection with Cryptosporidium and Giardia has been reported in a case of IgA vasculitis and nephropathy [42]. However, several other infectious agents, insect bites, and vaccinations have been associated with the onset of IgA vasculitis and may act as disease triggers [43]. An important disease associated with IgA vasculitis is familial Mediterranean fever, in which the presentation of IgA vasculitis is more commonly associated with gastrointestinal tract involvement [44]. IgA vasculitis and nephropathy have also been reported as rare complications of COVID-19 vaccinations (Table 1) [45,46].

Clinical Presentation in Children

In contrast to many other forms of systemic vasculitis, IgA vasculitis in children is typically self-limited [25]. In children, there are four main presenting symptoms and signs: palpable purpura without thrombocytopenia or coagulopathy; arthritis and arthralgia; abdominal pain, sometimes associated with bleeding; and renal disease (IgA nephropathy) that presents with proteinuria [25]. In global population studies, adults with IgA nephropathy had significantly worse renal impairment when compared with children [25,26]

Children with IgA vasculitis, or Henoch-Schönlein purpura, commonly present at a mean age of onset of 6–7 years with four main signs and symptoms: palpable purpura without thrombocytopenia or coagulopathy; arthritis or arthralgia; abdominal pain; renal disease, usually with proteinuria [47,48]. The clinical signs and symptoms may develop in children over days or weeks, usually including purpura and joint pain [47,48]. However, the initial diagnosis may be delayed due to the many differential diagnoses associated with the signs and symptoms alone (Table 2) [47,48]. Up to 50% of children have gastrointestinal symptoms that can be mild (abdominal pain, nausea, vomiting) to gastrointestinal hemorrhage, obstruction, or perforation due to the effects of small vessel vasculitis [49]. IgA nephropathy is reported in between 20–54% percent of children with IgA vasculitis and is more common in older children and adults [48].

Clinical Presentation in Adults

The clinical presentation of IgA vasculitis in adults is similar to that in children [50]. However, in adults, there are two main differences; abdominal symptoms are less common, but renal involvement is more significant, including end-stage kidney disease (ESKD) [50]. Importantly, adults with no known trigger for developing IgA vasculitis should be investigated for solid-organ malignancy, a recognized risk factor [50]. A rare side effect of chemotherapy is IgA vasculitis, which has been identified in recent case reports [41]. The differential diagnoses of the presentation, symptoms, and signs of IgA vasculitis can be complex and are summarized in Table 2.

The most common presentation of IgA nephropathy in adults is hematuria, with or without red blood cell (RBC) casts, and proteinuria [50,51]. The co-existence of hematuria and proteinuria is associated with an increased risk of progressive renal disease, which is more common in adults [51]. Risk factors for IgA nephropathy are also poorly understood. However, some recent studies have identified older age at the onset of IgA vasculitis, gastrointestinal symptoms, disease relapses, leucocytosis, and low C3 levels as risk factors [52]. Therefore, long-term follow-up is essential in patients with a history of IgA vasculitis.

Less commonly, other organ systems may be involved in IgA vasculitis. Urologic involvement may include the scrotum, ureter, bladder, prostate, and testis [53]. There have been few reports of central and peripheral nervous system involvement. However, pulmonary involvement, probably due to vasculitis of the alveoli capillaries, is often overlooked [54]. For example, in an early study reported in 1992, Chaussain and colleagues evaluated a cohort of patients hospitalized for IgA vasculitis and identified interstitial lung changes (69%) and impaired lung diffusion capacity (97%) despite the absence of significant respiratory symptoms [55]. However, severe lung involvement and pulmonary hemorrhage are rare in children and are primarily reported in adults and adolescents [56].

Diagnosis of IgA Vasculitis

When the clinical presentation is typical, the clinical findings of palpable purpura without thrombocytopenia or coagulopathy and two or three of the remaining clinical features: arthritis or arthralgia, abdominal pain, and renal disease should lead to further investigations for IgA vasculitis [25,34].

Currently, no specific diagnostic serological laboratory tests or biomarkers for IgA vasculitis exist. However, serum IgA levels are increased in 50–70% of patients with IgA vasculitis, and high levels are associated with IgA nephropathy [57,58]. The findings from routine blood tests may be nonspecific, which is why biopsy with histopathology, showing a leukocytoclastic vasculitis, predominantly in postcapillary venules, and immunohistochemistry or immunofluorescence for IgA is essential for the diagnosis [58]. The diagnostic histopathology of IgA vasculitis is of small vessel and capillary leukocytoclastic vasculitis in the skin, major organs, and the renal glomerular capillaries [6,7]. Immunohistochemistry and immunofluorescence can identify IgA immune complexes [6,7].

In the skin, purpuric lesions in IgA vasculitis show a leukocytoclastic neutrophilic vasculitis involving postcapillary venules in the papillary dermis [6,7]. In patients with purpura, the skin biopsy should include recent skin lesions with intact vessels [58]. Immunofluorescence for IgA requires a second skin biopsy for frozen section analysis of IgA immunofluorescence [58]. Immunohistochemistry and immunofluorescence predominantly identify IgA, fibrin, and complement component 3 (C3) and, less commonly, IgG and IgM deposits in vessel walls [6,7].

A renal biopsy can be done if the diagnosis is unclear or there is clinical evidence of renal involvement. The light microscopy of IgA nephropathy may range from mesangial proliferation to severe crescentic glomerulonephritis [6,7]. Immunofluorescence of the renal biopsy will show IgA, C3, fibrin, IgG, and, less commonly, IgM in renal glomerular capillaries and mesangial cells [6,7]. Electron microscopy may also show subepithelial and mesangial deposits extending into subendothelial areas [6,7].

Mechanisms in the Pathogenesis of IgA Vasculitis

IgA vasculitis is an immune-mediated hypersensitivity disease caused by the deposition and immune complexes in small vessels and complement activation that recruits neutrophil polymorphs [59]. Chemical and infectious causes have been identified (Table 1) [59]. How and why these factors may act as immune triggers for IgA vasculitis remains unknown [59]. However, a combination of genetic, environmental, and immunological factors is likely to be involved [59].

There are two subtypes of IgA, galactose-deficient IgA1 (Gd-IgA1) and galactose-deficient IgA2 (Gd-IgA2) [60,61]. However, a further diagnostic finding, which remains unexplained, is that only the Gd-IgA1 subtype is found in lesions of IgA vasculitis, which initially raised hopes for a diagnostic marker [60,61]. However, in 2021, Tang and colleagues reported that although serum Gd-IgA1 might be involved in the pathogenesis of IgA vasculitis and nephropathy, they found no statistically significant correlation between serum Gd-IgA1 levels and the incidence or clinical and pathological presentation [62].

Other recently studied factors involved in the pathogenesis of IgA vasculitis include the effects of raised serum levels of both IgA and IgA immune complexes, IgA anticardiolipin antibodies, alterations in the glycosylation of IgA, and levels of circulating inflammatory cytokines, including transforming growth factor-beta (TGF-beta) [63,64]. Recent studies have shown that IgA anticardiolipin antibodies are present in cases of IgA vasculitis [63,64]. However, these serum markers do not have sufficient sensitivity or specificity for use as diagnostic biomarkers.

In 2012, Yang and colleagues identified β2-glycoprotein I (β2GPI) as a possible antigenic target for IgA vasculitis [65]. Although these initial findings generated interest in IgA anti-β2GPI antibodies in childhood IgA vasculitis and suggested that β2GPI may be an important autoantigen, these findings have not been confirmed, probably because the pathogenesis of IgA vasculitis is more complex [65]. In 2017, Pillebout and colleagues identified serum Gd-IgA1 and serum immune complexes of IgA-CD89 and urinary IgA, IgG, IgM, IL-6, IL-8, IL-10, IgA, and IgG in pediatric patients with renal involvement at the time of diagnosis [66]. However, studies continue to attempt to identify risk factors and diagnostic and prognostic biomarkers for childhood and adult IgA vasculitis and nephropathy.

Future Studies and Unmet Clinical Needs

Clinical studies continue to identify atypical presentations of IgA vasculitis that support the need for continued clinical research, possible revisions in classification systems, and the identification of unmet needs in clinical management. Recently, Marro and colleagues reported a retrospective study from a major childrens’ hospital in the UK of 13 cases of atypical IgA vasculitis [67]. Delays in diagnosis and treatment and a lack of high-quality evidence for treatment planning were identified [67]. Because of the global health burden due to IgA nephropathy, increased efforts are being made to identify and prevent risk factors and to treat this disease. Recent studies on the pathogenesis of IgA nephropathy have identified biomarkers that could be potential therapeutic targets, including a proliferation-inducing ligand (APRIL) and other members of the tumor necrosis factor (TNF) superfamily [68]. In January 2024, Mathur and colleagues reported the findings from a phase 2, double-blind, randomized, placebo-controlled trial that included adults with a biopsy diagnosis of IgA nephropathy at high risk for disease progression, to evaluate the safety and efficacy of ibeprenlimab, a humanized IgG2 monoclonal antibody that binds to APRIL (NCT04287985) [69]. At 12 months, patients treated with sibeprenlimab had significantly reduced proteinuria compared with placebo [69].

Conclusions

Since 1837, when Schönlein first described the clinical association of purpura, arthralgia, and arthritis, there have been significant developments in diagnosis and understanding of the pathogenesis of IgA vasculitis. However, the causes and risk factors remain unknown, so further studies are required to improve the prevention and management of IgA vasculitis and nephropathy. New developments in vaccines and therapeutic agents for malignancy and other chronic diseases and changing patterns of infectious disease will likely continue contributing to the incidence and global public health challenge of IgA vasculitis.