IgA vasculitis (Henoch-Schönlein purpura):

A literature review
Tamás Rácz
Student, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca

Abstract. Immunoglobulin A vasculitis (IgAV, formerly called Henoch-Schönlein purpura) is one

of the most common vasculitides of pediatric patients. The disease is characterized by leukocytoclastic
vasculitis with deposition of IgA immune complexes in the vessel walls of the affected organs. IgAV is
considered a self-limited disease with an excellent outcome and spontaneous resolution of the symptoms.
However, a small percentage of patients, who are most frequently adults, can develop end-stage renal
disease. The main causes of morbidity and mortality are the renal and gastrointestinal complications of
IgAV. Adult patients with IgAV need to be carefully monitored because there is no correlation between
the initial presentation of adult patients and long-term renal outcome. There is a possibility that initial
mild symptomatology develops into a serious renal disease. The management of patients with gastroin-
testinal and renal complications is controversial. Currently, there are many treatment possibilities, but no
evidence-based algorithm has been developed.
This review article gives a general overview of IgA vasculitis, focusing on the pathogenesis, symptom-
atology, diagnosis, treatment and prognosis of the disease.
Keywords: immunoglobulin A vasculitis, Henoch-Schönlein purpura, symptomatology, immuno-
globulin A nephritis, prognosis

Introduction ence for Nomenclature of Vasculitides, experts

Immunoglobulin A vasculitis (IgAV, Henoch- decided to replace the eponym with IgA vascu-
Schönlein purpura) was first described in 1802 litis, which indicates the pathogenetic feature
by William Heberden, who presented in his of the disease, the deposition of IgA immune
work the case of two boys who had the typical complexes into the walls of small vessels [3].
symptomatology of IgAV [1]. The disease was
named after two German physicians, Johann Epidemiology
Lukas Schönlein (1793-1864) and Eduard The annual incidence of IgAV is 20 per
Henoch (1820-1910). In 1837, Schönlein de- 100,000 children younger than 17 years [4].
scribed the association between purpura and The annual incidence of the disease in the adult
arthralgia. A few years later, Henoch added population is much lower, 0.1 to 1.8 cases per
gastrointestinal and renal involvement [2,3]. 100,000 adults [3]. The peak incidence of the
Up until 2012, the disease was called Henoch- disease is between 4 and 7 years [4].
Schönlein purpura. In 2012, at the revised IgAV predominantly occurs in the cold
Chapel Hill International Consensus Confer- months of the year (autumn, winter, spring) and

13
is associated with upper respiratory tract infec-
tions, especially those caused by Streptococcus
[2,5]. The disease rather affects boys than girls;
male-to-female ratios of 1.2-1.8:1 have been de-
scribed. IgAV is less frequent in African Ameri-
can compared to Caucasian or Asian children [5].
Etiology and pathogenesis
The majority of IgAV cases are associated
with previous upper respiratory tract or gastro-
intestinal tract infections. The most commonly
found pathogens of these infections are Strep-
tococcus, Staphylococcus and human parainfluenza
virus. Other infectious agents, drugs, insect
bites and vaccination can also be a possible trig-
ger of IgAV. In the literature there are a few re-
ported cases of IgAV triggered by influenza vac-
cination, during the pandemic influenza A virus
(H1N1) outbreak in 2009 [6]. Even though
there were a number of post-vaccination vascu-
litis cases described in the literature, systematic
reviews do not allow to establish a significant
connection between vasculitides such as IgAV
and patient vaccination history [7].
Infection with Helicobacter pylori (H. pylori)
has been shown to play a potential pathoge-
netic role in the case of IgAV [8]. There are
many mechanisms that could explain the role
of H. pylori in the pathogenesis of IgAV. Firstly,
mucosal infection causes upregulation of inter-
leukin 6 (IL-6) production which could alter
the normal glycosylation process of IgA1 and
lead to IgAV [9]. Secondly, a major virulence
factor of H. pylori, the cytotoxin associated gene
A protein (CagA), promotes the underglyco-
sylation of IgA1 by downregulating galactos-
yltransferase and its chaperone involved in the
glycosylation process [10]. A meta-analysis from
China showed that H. pylori-positive children
are 3.8 times more predisposed to develop
IgAV compared to uninfected children and
eradication therapy is capable of reducing the
recurrence rate of IgAV in infected children
[8,11,12]. Although the meta-analysis showed
some positive associations, it cannot be consid-
ered as a high level of evidence. The reason for
this is that the meta-analysis comprised stud-
14 15
ies in which different diagnostic tests for the
detection of H. pylori infections were used and
the clinical studies included only the Chinese
population, where high-toxicity CagA positive
strains are dominant compared to other parts
of the world [11,12].
There are numerous pieces of evidence which
support the claim that genetics plays a crucial
role in the pathogenesis of IgAV. One of these
is the fact that the incidence of the disease dif-
fers between ethnic groups [5,13]. A few cases
of familial aggregation of IgAV have also been
reported. Although no mutations have been de-
scribed which could directly cause IgAV, sever-
al polymorphisms of different genes have been
associated with the disease. When the genetic
code of healthy individuals was compared with
the genetic code of IgAV patients, the most im-
portant difference was found in human leuko-
cyte antigen (HLA) genes. The disease has been
associated with HLA class I and class II region,
the strongest connection being described with
HLA-DRB1*01 [13,14]. HLA-DRB1*07 was
negatively associated with IgAV [13]. A poten-
tial association between IgAV and the poly-
morphisms of the genes regulating immune
and inflammatory pathways such as cytokines,
chemokines, adhesion molecules has been sug-
gested by several studies. These polymorphisms
play a less important role in the pathogenesis of
the disease than the HLA region [13,14]. Some
studies concluded that the Mediterranean fever
(MEFV) gene, which encodes pyrin, a protein
absent or abnormally functioning in patients
with familial Mediterranean fever, can play a
role in the pathogenesis of IgAV [14,15].
The most important pathogenetic feature of
IgAV is the formation of IgA1-containing im-
mune complexes and their deposition in the
small vessels of the human body. IgA is an an-
tibody subclass which plays a crucial role in the
immune function of mucosal defense. IgA can
be found in mucosal secretions where it binds,
agglutinates pathogens (SIgA), and in serum
where it is present as a monomeric molecule
(mIgA). In diseases such as immunoglobulin A
nephropathy (IgAN) and IgAV, the hinge region
of IgA, which in normal individuals is heavily alternative complement pathway, which leads
glycosylated, presents structural abnormalities to tissue destruction, inflammation and organ-
[2,13]. In both diseases, patients have galactose specific manifestations of the disease [2,13,16].
(Gal) deficient glycosylation of the hinge region, Like in systemic lupus erythematosus and
which exposes N-acetylgalactosamine (GalNAc) other immune-mediated diseases, IgAV has
as terminal glycan. The newly produced galactose been associated with the presence of anti-endo-
deficient IgA1 antibodies (Gd-IgA1) can func- thelial cell antibodies (AECAs) [8]. It is believed
tion as a neoepitope and induce the formation that infection with microorganisms leads to pro-
of anti-Gd-IgA1 autoantibodies [13]. Another duction of IgA1 autoantibodies which cross-
theory has also been described which explains react with endothelial cells (ECs) and become
the production of autoantibodies by the pres- AECAs. A possible antigen for AECAs in IgAV
ence of previous microbial or viral infection. patients is β2-glycoprotein I (β2GPI) [5,8,17,18].
Because many microorganisms express GalNAc Anti-β2GPI antibodies are at the same time anti-
on their surface, it is possible that IgG antibod- cardiolipin (aCL) antibodies [19]. β2GPI adheres
ies against GalNAc on the microorganisms to EC membranes and reveals epitopes which
cross-react with the terminal glycans of Gd- are normally hidden and which bind AECAs.
IgA1. This leads to the formation of Gd-IgA1- After AECAs, β2GPIs and ECs interact, they
IgG immune complexes. produce endothelial cell activation and comple-
ment-dependent cytotoxicity [8,17]. It has been
described that IgA AECAs in IgAV patients in-
duce interleukin 8 (IL-8) production by the ECs
which promote neutrophil chemotaxis [8,20]. It
has been shown that increased systemic levels of
tumor necrosis factor alpha (TNF-α) might en-
hance the production of AECAs, which increas-
es inflammation by activating ECs and forms a
positive feedback loop [8,18].
IgG – immunoglobulin G; Clinical manifestations in children
anti-Gd-IgA1 – anti-galactose deficient IgAV is characterized by a tetrad of symptoms:
immunoglobulin A1. ▶▶ Palpable purpura without thrombocyto-
penia and coagulopathy
Figure 1. The formation of IgG anti-Gd- ▶▶ Arthritis, arthralgia
IgA1 immune complexes [8] ▶▶ Abdominal pain
▶▶ Renal disease [5].
The clinical manifestations of IgAV may de-
In healthy individuals, IgA1 is metabolized velop in days or weeks and their order of pre-
in the liver, after interaction with asialoglyco- sentation may vary. Palpable purpura and joint
protein receptors (ASGP-R) expressed on the pain are in general the first symptoms of the
surface of hepatocytes, which is followed by the disease. In case of absence of the classic purpu-
internalization and degradation of IgA1. After ric rash, the diagnosis of IgAV may not be that
the formation of Gd-IgA1-IgG immune com- obvious [5].
plexes, these cannot reach the space of Disse and ▷▷ Skin manifestations
be metabolized, but they cross the endothelial In three quarters of the cases, rash is the first
fenestrae and deposit in the glomerulus or in the sign of the disease. At the beginning, the rash
small vessels of other organs. This is followed by is characterized by erythematous, macular or
the activation of the mannan-binding lectin and urticarial wheals. Lesions tend to merge and
evolve into ecchymoses, petechiae and palpable
purpura, which can be itchy, but almost never
painful [5]. The rash appears in crops and is
localized in gravity-dependent areas and pres-
sure points. In toddlers, the most frequently
involved area is the buttocks, but in older chil-
dren, facial, trunk and upper extremity involve-
ment can also be observed [5]. In <2% of the
patients, blisters, either vesicles (≤0.5 in diam-
eter) or bullae (≥0.5 in diameter) can be seen.
They are distributed in the same regions of the
body and develop concomitantly with palpable
purpura [21]. After skin lesions disappear, the
previously affected skin will be discolored by
the remaining hemosiderin [22].
Figure 2. Classical skin lesions of immuno-
globulin A vasculitis (Henoch-Schönlein
purpura), with palpable purpura on the
extremities
16 17
▷▷ Joint manifestations
Up to 84% of the patients present arthritis
or arthralgia [5]. The majority of the pediatric
patients present these symptoms simultaneously
with the rashes, but joint symptomatology can
occur even 11 days after the appearance of pal-
pable purpura [24]. Joint involvement can be
the first manifestation of IgAV in about 15%
of the cases. Arthritis is typically oligoarticular,
transient or migratory, affecting the large joints
of the lower limbs, such as hips, knees, ankles
and feet. The involvement of elbows, wrists and
hands is less frequent [25]. Arthritis is charac-
terized by periarticular swelling and tenderness,
but it lacks joint effusion, erythema or warmth.
Arthritis is non-deforming, disappearing in a few
weeks time without any sequelae. Some studies
show that about one third of patients experience
the recurrence of joint symptomatology within 6
months of the appearance of the first symptoms
[5,24].
▷▷ Gastrointestinal involvement
Gastrointestinal (GI) symptomatology is a
relatively frequent manifestation of IgAV, oc-
curring in approximately two thirds of the af-
fected children. Symptoms are caused by the
deposition of immune complexes in the small
vessels of the gastrointestinal tract, which leads
to vasculitis of the splanchnic circulation (mes-
enteric vasculitis) [26]. Typically, GI symptoms
develop 8 days after the appearance of purpura,
but in about 25% of patients they occur before
the first signs of skin involvement. In a minor-
ity of patients, GI symptomatology is the first
clinical manifestation of the disease [27]. In such
patients, the diagnosis of IgAV can be difficult
for clinicians. Differential diagnosis with acute
abdomen, especially in children, has to be con-
sidered [5,22].
The most important GI symptom is diffuse,
colicky abdominal pain, which worsens after
meals. Other symptoms include nausea, vomit-
ing, hematemesis, melena, hematochezia, tran-
sient paralytic ileus, acute acalculous cholecys-
titis, intestinal perforation, hemorrhagic ascites
with serositis, acute pancreatitis, biliary cirrho-
sis [26]. More severe symptoms include gastro-
intestinal hemorrhage, bowel ischemia, bowel
necrosis, intussusception, bowel perforation [5].
Submucosal hemorrhage and edema can lead to
a positive guaiac fecal occult blood test in one
half of the patients. Massive gastrointestinal
hemorrhages are rare [2,5]. Hypoalbuminemia
without proteinuria can indicate mucosal injury
and protein loss [22].
The most common endoscopic findings are
erythema, edema, petechiae, ulcers, hematoma-
like protrusions, ecchymotic lesions, superficial
ulcers and strictures. Typically, the stomach and
the descending duodenum are involved. On co­
lo­noscopy, ileal and rectal ulcers can be observed.
The terminal region of the ileum is most fre-
quently involved, where the lesions are more se-
vere compared to other areas [5,26].
Intussusception is present in 3-4% of the cases
and is typically ileoileal, in contrast with idio-
pathic intussusception, which is usually ileocolic
[2,5,26].
Recent studies show that increased fecal cal-
protectin is associated with GI involvement [28].
▷▷ Renal involvement
Renal manifestations of IgAV are reported in
20-55% of children and consist of an inflamma-
tory reaction, called IgA nephritis (HSP nephri-
tis, HSPN), which is the most important factor
determining the morbidity and mortality of the
disease [2,26,29]. The first renal symptoms de-
velop within the first month after the appear-
ance of initial symptomatology. The most com-
mon finding on the urinalysis of IgAV patients
is isolated microscopic hematuria, but in some
patients macroscopic hematuria with or without
red cell casts can be observed. In the majority
of the patients, proteinuria occurs along with
hematuria, but less frequently it can also be iso-
lated. Exceptionally, in 2% of the cases, patients
can present with nephrotic syndrome [30,31].
Arterial hypertension may develop either at the
onset or during the recovery phase of IgA ne-
phritis [22]. Most IgA nephritis cases are mild;
only a small percentage of children develop end-
stage renal disease (ESRD). Although the time
course of the renal disease is unpredictable, pa-
tients with persistent hematuria, proteinuria and
patients older than 8 years are at a higher risk of
developing ESRD. Because renal involvement
occurs in 97% of the cases in the first 6 months,
patients should be followed up for one year after
the beginning of the first symptoms in order to
diagnose and treat efficiently the renal manifes-
tations of the disease [26,32].
▷▷ Other organ involvement
Scrotal and testicular involvement can be ob-
served in 2-38% of boys with IgAV. Common
symptoms are scrotal pain, tenderness, swelling
of the scrotum or of the involved testicle. Be-
cause in some patients unilateral presentation of
scrotal symptoms can occur, it is important to
make the differential diagnosis with testicular
torsion. In rare cases, epididymitis and orchitis
as a consequence of IgAV have also been de-
scribed [5,33].
Rarely, IgAV patients can present with signs
of either central or peripheral nervous system
involvement. The deposition of IgA can extend
to cerebral vessels and cause edema, ischemia,
infarction and hemorrhage. In the peripheral
nervous system, nerve damage can occur as a
result of ischemia produced by inflammation in
the walls of the vasa nervorum. The most sig-
nificant neurological symptoms that may oc-
cur in the case of IgAV are headaches, seizures,
ataxia, intracerebral hemorrhage, hypertensive
and posterior reversible encephalopathy syn-
drome (PRES), peripheral neuropathy [5,34,35].
Another rare, but extremely dangerous compli-
cation of IgAV is pulmonary hemorrhage [5].
Ophthalmologic manifestations include keratitis,
uveitis, scleritis, but anterior ischemic optic neu-
ropathy and central retinal artery occlusion have
also been described [5,34].
Clinical manifestations in adults
Adult IgAV symptomatology is very similar
to manifestations seen in children. The most
important difference between these two groups
is that adults develop ESRD more often and
intussusception rarely [5,36].
 Table I. Diagnostic criteria for immunoglobulin A vasculitis (IgAV, HSP), developed by complications such as ESRD, a tendency has
EULAR/PRINTO/PRES [37] been observed to study non-invasive biomark-
ers of HSPN in order to avoid kidney biopsies.
Sensitivity Specificity A recent study concluded that serum Gd-IgA1
Criterion Description (%) (%)
and urinary IgA, IgM, IgG, IL-6, IL-8, IL-10,
IgA-sCD89 (immunoglobulin A-soluble cluster
Palpable purpura or petechiae (without
Mandatory criterion: of differentiation 89), IgG-IgA could differen-
thrombocytopenia), with lower limb predo- 89 86
purpura tiate IgAV patients with nephritis from IgAV
minance
patients without nephritis at the time of diag-
nosis (38). Further clinical research is required
Diffuse colicky abdominal pain with acute
1. Abdominal pain 61 64 in order to introduce in clinical practice such
onset
non-invasive biomarkers for diagnosing HSPN.
Leukocytoclastic vasculitis with predominant
2. Histopathology deposition of IgA or proliferative glomerulo- 93 89 Treatment
nephritis with predominant deposition of IgA The management strategies of IgAV are con-
troversial. There is a general agreement that treat-
Arthritis is defined as acute onset joint swel- ment is mainly decided depending on the pres-
ling or joint pain with limitation of motion ence or absence of renal involvement [22]. Because
3. Arthritis or arthralgia 78 42 the majority of the patients recover spontaneously,
Arthralgia is defined as acute onset joint pain the management of patients without renal in-
without joint swelling or limitation of motion volvement is primarily supportive. In these cases,
treatment includes adequate hydration, rest, pain
Proteinuria >0.3 g/24 h or urine albumin/cre- relief and patient monitoring for the development
atinine ratio >30 mmol/mg in a spot morning of severe complications, such as intussusception
sample
or intracranial hemorrhage [2,22,39].
4. Renal involvement 33 70 For children with HSPN, both nonsteroidal
Hematuria or red blood cell casts: >5 red
blood cells/high power field or red blood anti-inflammatory drug (NSAID) treatment
cell casts in the urinary sediment or ≥2+ on and glucocorticoid treatment are weak, grade
dipstick 2C recommendations, coming from small stud-
ies or case reports. Randomized controlled trials
Purpura or petechiae (mandatory criterion) for pain management in IgAV are needed [2,39].
EULAR/PRINTO/PRES
and at least one of the other four criteria for Glucocorticoid treatment should not be
HSP criteria for the
diagnosing IgAV (abdominal pain, histopa- 100 87
diagnosis of IgAV used for the prevention of renal complications
thology, arthritis or arthralgia, renal involve-
(HSP) (grade 1B recommendation). An updated Co-
ment)
chrane review from 2015 concluded that glu-
EULAR - European League Against Rheumatism; cocorticoid treatment does not reduce the risk
PRES - Paediatric Rheumatology European Society; of developing renal complications [40]. The
IgAV - immunoglobulin A vasculitis; HSP - Henoch-Schönlein purpura. Kidney Disease: Improving Global Outcomes
(KDIGO) guideline concluded that HSPN
patients with persistent proteinuria should be
Diagnosis treated with angiotensin-converting enzyme
The diagnosis of IgAV is based on clinical cri- ing IgAV. When applied to children, the criteria inhibitors (ACEIs) or angiotensin II receptor
teria. In 2010, the revised EULAR/PRINTO/ have a sensitivity of 100% and a specificity of blockers (ARBs) [41].
PRES criteria for the diagnosis of Henoch- 87%, but in the case of adult patients, both per- In case of ESRD, renal transplantation can
Schönlein purpura (IgAV) replaced the older centages are lower [22,37]. (Table I.) be performed. Even though graft loss due to
American College of Rheumatology (ACR) cri- Because HSPN occurs in 20 to 54% of chil- recurrent disease is more frequent in IgAV
teria and became the gold standard in diagnos- dren with IgAV and it can lead to serious renal than in non-IgAV patients, it has been shown
18 19
that the diagnosis of IgAV has little effect on
overall renal allograft survival [31,42].
Prognosis
Patients with IgAV have an excellent prog-
nosis. It has been generally observed that chil-
dren have a much better prognosis than adults
due to the less frequent development of ESRD.
Patients without significant renal manifesta-
tions have spontaneous resolution of symptoms
within one month [39]. Two-thirds of children
do not have recurrent disease, but in one-third
of the cases recurrence occurs within four
months after the development of initial symp-
toms [2]. Children with nephritic, nephrotic
syndrome or renal failure on diagnosis have a
higher risk of developing long-term renal im-
pairment [43]. The best predictors for relapses
are joint, gastrointestinal manifestations at di-
agnosis and a longer duration of the first epi-
sode of palpable purpura. During the relapse
episode, patients most frequently present cu-
taneous, gastrointestinal and renal symptoms
[44]. In general, relapse episodes have the same
clinical manifestation, but a milder symptom-
atology and a shorter duration [39]. In patients
with relapses, an infectious trigger of IgAV has
been less frequently described [44].
Several studies report that nephrotic syn-
drome, renal insufficiency, hypertension, cres-
centic glomerulonephritis with crescents in-
volving more than 50% of the glomeruli are
associated with poor renal outcome [31,45].
Morbidity in the initial phase of the disease is
due to GI complications such as intussuscep-
tion, bowel ischemia, bowel perforation and
acute pancreatitis. The main causes of later
morbidity are renal complications [39].
Conclusions
IgA vasculitis (Henoch-Schönlein purpura)
is the most common small vessel vasculitis of
childhood, with very good outcome for the
majority of pediatric patients. The disease is
characterized by a tetrad of symptoms: pur-
pura, arthralgia/arthritis, GI and renal mani-
festations. In the last years, there has been
progress in understanding the pathogenesis of
the disease, but the underlying cause is still un-
known. The pathogenesis of IgAV is similar to
that of IgA nephropathy; in both cases the de-
position of IgA-containing immune complexes
in small vessels has been observed. IgAV is less
frequent in adults, but adult symptomatology is
more severe than the symptomatology of chil-
dren with IgAV, older patients having a higher
risk of developing ESRD. The management of
IgAV is controversial, and an evidence-based
algorithm is needed.
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