Henoch-Schonlein Purpura (IgA Vasculitis)

IgA vasculitis (IgAV) was first described in 1802 by the English physician William Heberden, in two boys who presented with abdominal pain, purpuric rash, and arthralgia.[9]  The historical term for the condition honors the German pediatrician Eduard Heinrich Henoch and his teacher Johann Lukas Schönlein, who described the association of non-thrombocytopenic purpura with joint pain in 1837 and called the condition purpura rheumatica.[10] Henoch added GI and kidney involvement in 1874.[11]  In addition to Henoch-Schönlein purpura, IgAV has also been referred to as Schönlein-Henoch purpura, anaphylactoid purpura.

IgAV is an acute IgA–mediated disorder characterized by a generalized vasculitis involving the small vessels of the skin, the gastrointestinal (GI) tract, the kidneys, the joints, and, rarely, the lungs and the central nervous system (CNS).[2, 12] It is a subset of necrotizing vasculitis characterized by fibrinoid destruction of blood vessels and leukocytoclasis.

The prevalence of IgAV peaks in children aged 3-10 years, with the mean age at presentation being 6 years, but the condition is also seen in adults.[13]  It has been reported that IgAV will occur in 10-30 per 100,000 children younger than 17 years will develop IgAV. There is a strong ethnic influence on the incidence of the disease, with approximately 70 cases per 100,000 children annually in Asia.[14]  In the Northern Hemisphere, the disease occurs mostly between November and January. IgAV has typically been reported to be more common in males, with a male-to-female ratio ranging from 1.5-2:1, but some studies have found a more equal distribution between the sexes.[15, 16]

The dominant clinical features of IgAV include cutaneous purpura, arthritis, abdominal pain, and nephritis. These manifestations may develop over the course of days to weeks and may vary in their order of presentation. The classic rash of IgAV is not the initial presenting sign in approximately one-quarter of patients. In one half to two thirds of children, an upper respiratory tract infection (URTI) precedes the clinical onset of IgAV by 1-3 weeks. In general, patients with IgAV appear mildly ill. They often have a low-grade fever, with a temperature that usually does not exceed 38°C (100.4°F).

IgAV is typically an acute, self-limited illness, and treatment is primarily supportive. In the majority of children, symptoms and signs of IgAV resolve within several days or months and the outcome is excellent. However, one third of patients have 1 or more recurrences.

Kidney involvement is the most important determinant of long-term morbidity. Up to 30-50% of children present with hematuria and/or proteinuria, or develop it within 4-6 weeks of the initial presentation. This is usually mild and self-limiting.  However, approximately 20% of IgAV children with nephritis (7% of all IgAV cases) will develop either a nephritis or nephrotic syndrome.[17, 18, 19, 20, 21, 22]

Keratitis and uveitis are rare sequelae of eye involvement.

IgA clearly plays a critical role in the immunopathogenesis of IgAV, as evidenced by increased serum IgA concentrations, IgA-containing circulating immune complexes, and IgA deposition in vessel walls of affected organs and in the kidney mesangium. Deposition of IgA aggregates or IgA complexes in target organs occurs with activation of the alternative complement pathway (with deposition of C3). This results in an elaboration of inflammatory mediators, including vascular prostaglandins such as prostacyclin, that may play a central role in the pathogenesis of IgAV and its organ-specific clinical manifestations.ref130}

IgA is found in the serum and mucosal secretions and is a major class of immunoglobulins that plays an important role in mucosal immunity. IgAV is almost exclusively associated with abnormalities involving IgA1, rather than IgA2. IgA1 is phylogenetically younger and differs from IgA2 by insertion of a 13-17 amino acid sequence in the hinge region of the IgA1 molecule.[23] The predominance of IgA1 in IgAV may be a consequence of abnormal glycosylation of O-linked oligosaccharides unique to the IgA1 hinge region. Patients with IgAV and IgA nephritis express inherited galactose-deficient glycosylation of IgA1 molecules.[24]

IgAV-associated nephritis is characterized by an abnormal IgA1 glycosylation pattern with reduced galactosylation.[25] The hinge region of IgA1 contains up to six major glycosylation sites at serine and threonine residues. The O-glycans include a core N-acetylgalactosamine (GalNAc), which is usually extended with galactose to form Galβ1,3GalNAc, which can bind to N-acetylneuraminic acid (Neu5Ac). Thus, each IgA1 O-glycan can have one of four short carbohydrate structures (types III, IV, V, and VI), leading to a mixture of IgA1 forms with varying degrees of galactosylation.

Patients with IgAV-associated nephritis have a high prevalence of galactose-deficient (types I and II) IgA1.[25]  The lack of terminal β1,3-galactosyl residues in the hinge region of IgA might be due to reduced activity of β1,3-galactosyltransferase in IgA1-producing peripheral B cells. This reduction of galactosylation results in exposure of GalNAc residues in the IgA1 surface, forming a novel antigen and inducing a humoral IgG autoimmune response.[26]  

Circulating complexes of mixed IgG and galactose-deficient IgA1 are not only detected in patients with IgAV but also in the serum of patients with mucosal infections.[27]  The finding that galactose-deficient IgA1 molecules are only found in IgAV during an episodes of nephritis lends support to the pathophysiological role of galactose-deficient IgA1 molecules in IgAV nephritis.[28]

A subpopulation of human lymphocytes bears surface Fc and/or C3 receptors (complement receptor lymphocytes), which can bind circulating immune complexes or C3 generated by activation of the alternative complement pathway. Such immune complexes appear in IgAV and may be part of the pathogenetic mechanism.

Some have speculated that an antigen stimulates the production of IgA, which, in turn, causes the vasculitis. Allergens, such as foods, horse serum, insect bites, exposure to cold, and drugs (eg, ampicillin, erythromycin, penicillin, quinidine, and quinine), may precipitate the illness. Infectious causes include bacteria (eg, Haemophilus parainfluenzae, Mycoplasma, Legionella, Yersinia, Shigella, or Salmonella) and viruses (eg, adenoviruses, Epstein-Barr virus [EBV], parvoviruses, or varicella-zoster virus [VZV]). Vaccines such as those against cholera, measles, paratyphoid A and B, typhoid, and yellow fever have also been implicated. However, there is no evidence supporting a direct role of herpesvirus, retrovirus, or parvovirus infection in the pathogenesis of IgAV.

Alterations in the production of interleukins (ILs) and growth factors may also play a pathogenetic role. Tumor necrosis factor (TNF), IL-1, and IL-6 may mediate the inflammatory process present in IgAV. Transforming growth factor (TGF)–β is a recognized stimulant of IgA production. The elevated levels of hepatocyte growth factor present during the acute phase of IgAV may reflect endothelial-cell damage or dysfunction. Increased levels of vascular endothelial growth factor (VEGF) may at least partly induce these changes.

Cytokines have been implicated in the pathogenesis of IgAV, and endothelins (ETs), which are vasoconstrictor hormones produced by endothelial cells, may also have a role. levels of ET-1 are substantially higher during the acute phase of the disease than during remission or in a control group of children. However, ET-1 levels do not appear to be correlated with morbidity, severity of disease, or acute-phase reactant response.

Although several lines of evidence suggest a genetic susceptibility to IgAV, the fundamental basis for this abnormality remains unclear. A functional correlation of the IL1RN-2 allele and IL-1ra production in patients with IgA nephropathy and IgAV nephritis has been described. Therefore, gene polymorphism may contribute to the diversity of clinical responses to inflammatory stimulation. The prevalence of the human parvovirus B19 component NS1 gene in patients with IgAV and hypersensitivity vasculitis is increased.

Gershoni-Baruch et al showed that in the Israeli population, 10% of patients with IgAV were homozygous for mutations in MEFV (the gene defective in familial Mediterranean fever that encodes the protein pyrin/marenostrin, which regulates caspase-1 activation and IL-1b production).  An additional 17% of patients with IgAV had heterozygous defects of this gene.[29]  Peru et al reported an increased risk of IgAV in children carrying HLA A2, A11, and B35 antigens and a reduced risk in those carrying HLA A1, B49, and B50 antigens.[30]

Researchers are currently investigating the importance of nitric oxide (NO) production in disease activity. Inducible NO synthase polymorphism has been associated with susceptibility to IgAV in northwestern Spain. Aliyazicioglu et al have suggested that leptin and NO may play a role in the immunoinflammatory process of IgAV, especially in the acute phase.[31]

IgAV that is likely due to montelukast has been noted in patients who present with subacute intestinal obstruction.

Yilmaz et al examined markers of hypercoagulability in 28 children with IgAV and 79 healthy children, and found that levels of fibrinogen, D-dimer, thrombin-antithrombin (TAT) complex, prothrombin fragment (PF)-1, PF-2, and von Willebrand factor antigen (vWAg) and its activity (RiCof) were significantly higher during the acute phase than during the recovery phase and were significantly higher in patients with IgAV than in control subjects.[32] The severity of disease correlated significantly with TAT, PF-1, PF-2, vWAg, and D-dimer levels. Higher levels of matrix metalloproteinase–9 (MMP-9) in urine and serum appear to correlate with increased nephrologic severity in children with IgAV. Use of TNF-α blockers such as adalimumab may increase the risk of developing IgAV.

IgA vasculitis versus IgA nephropathy

IgAV and IgA nephropathy appear to be related disorders. However, the precise relation between them requires further definition. The question has been raised as to whether IgAV and IgA nephropathy are two aspects of a single disease entity or two distinct entities. The following commonalities and differences have been noted:

• IgA nephropathy almost exclusively involves young adults and typically affects only the kidneys, whereas IgAV affects mostly children and involves the skin and connective tissues, GI tract, joints, and scrotum, as well as the kidneys.[33, 34]

• IgAV-associated nephritis is more benign in children than in adults, with the latter tending to show a chronic and relentless course similar to that of primary IgA nephropathy.[35, 36, 34]

• ​In IgAV-associated nephritis, repeated and prolonged episodes of acute glomerular inflammation lead to fibrous scars and hyperfiltration in the remaining areas, resulting in chronic kidney disease that may progress to chronic kidney failure. Thus the number and severity of acute episodes of IgAV-associated nephritis have a crucial role in the subsequent progression and loss of kidney function. In IgA nephropathy, initiation and progression to chronic kidney failure occurs slowly and often is asymptomatic, with development of glomerulosclerosis and tubulointerstitial fibrosis. ^[37]

• The occurrence of extrarenal manifestations in IgA nephropathy is similar to that in IgAV.

• IgA nephropathy has developed in patients with a history of IgAV, and IgAV and IgA nephropathy have occurred in the same families; in a survey of 40 families in which 2 or more members had IgA nephropathy, 5 presented with IgAV.[38]

• Patients with IgAV who undergo kidney transplantation develop IgA deposits in the graft.

• The prevalence of both conditions is high in certain geographic areas.

• Similar changes in the IgA system (ie, high IgA, IgA-1C, IgA1-IC, IgA-fibronectin aggregates, aberrantly glycosylated IgA in the circulation) occur in both diseases.[39, 40, 41]

• Cystic changes in the ovaries of a prepubertal girl with IgAV have been recorded.[42]

Overall, the data tend to support the view that IgAV and IgA nephropathy are distinct diseases.[43] Zhou et al examined 31 children aged 3-15 years with IgA nephropathy and 120 children aged 4-15 years with IgAV, noting their clinical manifestations, blood biochemistries, serum immunology, and follow-up data.[44] Pathologic findings on light microscopy, immunofluorescence study, and electron microscopy of kidney biopsy specimens were analyzed and compared between 31 children with IgA nephropathy and 32 children with IgAV.

The age of onset was older than 12 years in 25.8% of the children with IgA nephropathy but in only 10% of those with IgAV.[44] Clinical patterns of IgA nephropathy were similar to those of IgAV, but extrarenal manifestations were observed more often in patients with IgAV. All of the IgAV patients had skin purpura, 59% had GI symptoms, and 47% had arthralgia. Of the children with IgA nephropathy, only 3.2% had abdominal pain.[44] Kidney pathology in patients with IgA nephrology versus those with IgAV was as follows:

• Global sclerosis: 35.5% vs 3.1%
• Mesangial sclerosis: 41.9% vs 6.3%
• Endothelial proliferation: 29% vs 65.6%
• Thin basement-membrane nephropathy: 6.5% vs 0%

In the kidneys of patients with IgAV, electronically dense deposits were sparse, loose, and widely spread in the glomerular mesangium, in the subendothelial area, and even in the intra-basement membranes. In those with IgA nephropathy, the deposits were dense, lumpy, and mostly limited to mesangium and paramesangium.[44]

Immunoglobulin G (IgG) was found in glomerular immune deposits in 71.9% of patients with IgAV but in only 19.4% of patients with IgA nephropathy.[44] No IgG deposit was observed in 81.6% of those with IgA nephropathy; most had IgA and immunoglobulin M (IgM) or C3 deposits. Predominant IgG deposits were found in 12.5% of IgAV patients, with relatively weak IgA deposits. Moreover, 6.3% of IgAV patients had linear IgG deposits in the glomerular capillary wall, a finding that was not noted in patients with IgA nephropathy.

The rate of complete remission was 72.5% in patients with IgAV at an average of 20 months’ follow-up; the corresponding rate was 19.4% in those with IgA nephropathy after 34 months’ follow-up.[44] Moreover, 64.5% of patients with IgA nephropathy had consistent hematuria and proteinuria, and 16.1% had active nephritides.

The important clinicopathologic differences Zhou et al found between IgAV and IgA nephropathy argue against the single-disease hypothesis.

The etiology of IgAV remains to be clearly defined but is thought to be multifactorial, with genetic, environmental, and antigenic components. More than 75% of patients report antecedent upper respiratory tract or GI infection. Multiple bacterial and viral infectious agents have been associated with the development of IgAV, and cases also have been reported after drug ingestions and vaccinations.[45, 46]

Infections that may precede the development of IgAV include the following:

• Group A streptococcal infection (most common)
• Infectious mononucleosis
• Subacute bacterial endocarditis
• Hepatitis
• Hepatitis C–related liver cirrhosis
• Mycoplasma infection
• Campylobacter enteritis
• Helicobacter pylori infection ^{[47, 48, 49]} (specifically noted in China ^[50] )
• Yersinia infection
• Shigella infection
• Salmonella infection
• Brucellosis
• Legionella species
• Parvovirus
• Adenovirus
• Epstein-Barr virus (EBV) infection
• Varicella-zoster virus (VZV) infection
• Rotavirus
• COVID-19 ^[51]

Vaccinations that may precede the development of IgAV include the following:

• Typhoid and paratyphoid A and B
• Measles
• Yellow fever
• Cholera
• COVID-19 ^{[52, 46]}

Environmental exposure to the following may precede the development of IgAV:

• Drugs (eg, ampicillin, erythromycin, penicillin, quinidine, quinine, losartan, and cytarabine ^[53] )
• Foods
• Horse serum
• Cold temperatures
• Insect bites

Glomerulocystic kidney disease has also been noted as a risk factor.

United States statistics

In the United States, the incidence of IgAV is approximately 14-15 cases per 100,000 population in children, compared with 1-3 cases per 100,000 per year in adults.[54, 55, 56, 57]

International statistics

Worldwide, the incidence rates of IgAV in children and adolescents aged < 15 years vary widely, ranging from 3.5 per 100,000 persons in Japan to 26.7 per 100,000 persons in Scotland.[58] In the United Kingdom overall, the estimated annual incidence of IgAV is 20.4 cases per 100,000 population.[14] Incidence rates reported elsewhere in Europe are 17.5 per 100,000 in Sweden and 18.6 per 100,000 persons in France.[58]

In a study that examined the kidney biopsy results of 65 children younger than 18 years obtained by the Clinical Hospital in the Croatian region of Dalmatia over a 10-year period (1995-2005), 10.8% of glomerulonephritis cases were due to IgAV.[59]

From January 1983 to June 2004, Suehiro et al followed 4502 patients at the Pediatric Rheumatology clinic in Brazil.[60] A diagnosis of IgAV was made in 203 cases (4.5%); 5 patients (0.1%) had acute hemorrhagic edema of infancy (AHEI). All patients with AHEI were male, and the mean age at onset was 18 months (range, 8-21 months).

Age-related demographics

IgAV primarily affects children; it may be seen in adults, but much less frequently.[12, 34] In the United States, the prevalence peaks in children aged 5 years. Approximately 75% of cases occur in children aged 2-11 years; IgAV is rare in infants and young children. Acute hemorrhagic edema of infancy (AHEI), a related but milder condition, occurs in infants younger than 2 years.[61] In adults, the mean age of onset of IgAV is 50 years.[62]

In a study of patients age 14 years and older seen at a hospital in southern Spain, the incidence of IgAV was 1.5 per million population.[63] In a study of patients age 17 years and older seen in a Norwegian community hospital, the prevalence of IgAV was 3.3 cases per 100,000 inhabitants.[64]

Older age at the onset of IgAV is associated with the development of chronic kidney disease.[65]

A retrospective study of children with IgAV treated at a hospital in Indonesia found that gastrointestinal manifestations tended to occur in patients younger than 5 years old, while kidney involvement tended to occur in those 11-15 years old. The study comprised 128 patients, ranging from 6 month to 15 years of age, from 2006 to 2011. Peak morbidity was between 5-10 years of age. In most patients (71%) purpura was the first symptom; 71 patients (44.5%) had arthritis and 89 patients (69.5%) had abdominal pain, while 28 patients (21.8%) had kidney involvement.[66]

A multiinstitutional German study that included data from 202 pediatric patients with IgAV nephritis reported that children older than 10 years of age had more insidious onset of non-nephrotic proteinuria, impaired kidney function, longer delay to biopsy, and more chronic histopathologic lesions than younger children.[67]  

Sex-related demographics

In children, IgAV has typically been reported to be more common in boys, with a male-to-female ratio ranging from 1.5-2:1, but some studies have found a more equal distribution between the sexes.[15, 16] In adults, the male-to-female ratio is approximately 1:1.

Race-related demographics

Whites are affected more often than Blacks.

In a study from Thailand, patients most commonly presented between the ages of 3 and 5 years.[68] Frequency peaked from December to February. Organs involved included the skin (100%), GI tract (74.5%), and kidneys (46.8%). Joints were also affected (42.6%). Kidney involvement was detected within the first 2 months in 16 patients (72.7%); however, it was delayed until 6 months after diagnosis in 6 patients. No risk factors for kidney involvement could be identified. On mean follow-up of 2.6 years (range, 1-5 years), residual kidney disease occurred in 6 (38%) of 16 patients, but none had end-stage kidney disease.

In a study from China, a male predominance was observed in children but not in adults.[69] Preceding infection was noted in 40.5% of children and 31.6% of adults; 8.3% of children and 13.2% of adults were receiving medication at the onset of the disease. Abdominal pain was more common in children than adults (70.2% vs 28.9%), but kidney involvement was more common and severe in adults than in children; this involvement manifested as frequent hypertension and heavy proteinuria.[69] During acute attacks, leukocytosis, thrombocytosis, and elevated serum C-reactive protein (CRP) levels were most frequently observed in children, whereas elevated serum IgA and cryoglobulin levels were most common in adults.

A study of 450 cases from Turkey showed that girls, patients with atypical presentations, and patients undergoing early corticosteroid treatment had an increased risk of developing kidney disease; relapses occurred more often in children treated with corticosteroids.[70]

Familial kindreds with IgAV have been noted in Taiwanese aboriginal people.[71]

IgAV is generally a benign disease with an excellent prognosis. Spontaneous resolution is usual: Most patients experience complete resolution of symptoms within 8 weeks, and probably fewer than 5% experience chronic symptoms. However, initial attacks of IgAV can last several months, and relapses are possible. IgAV is fatal only in the rarest of cases.

A clinical course with complete resolution of the disease usually occurs in patients with the following:

• Mild kidney involvement
• No neurologic complications
• Disease that lasts less than 4-6 weeks initially

Children younger than 3 years usually have a shorter, milder course than older patients do, as well as fewer recurrences.

Recurrences occur in as many as 50% of patients within 6 weeks but can happen as late as 7 years after the initial disease. A study by Calvo-Río et al indicated that in patients with IgAV, the chance of relapse is greater in those with GI and joint manifestations: the relapse rate in patients with abdominal pain was 72.3%, compared with 62.3% in those without abdominal pain; the relapse rate in patients with joint manifestations was 27.8%, compared with 15.5% in those without joint manifestations.[72]

Although IgAV generally resolves without permanent consequences, serious GI and renal complications may occur, and the higher the number of recurrences, the higher the likelihood of permanent kidney damage. Potential GI complications include the following:

• Intussusception (usually ileoileal)
• Bowel infarction
• Bowel perforation
• Hydrops of the gallbladder
• Pancreatitis
• Massive GI bleeding

Kidney damage related to IgAV is the primary cause of morbidity and mortality. As many as 15% of patients may have long-term kidney insufficiency, but no more than 1-2% will have ESKD. As many as 20% of children who have IgAV and are treated in specialized centers require hemodialysis. The kidney prognosis appears to be worse in adults than in children (in particular, those aged ≤6 years).

Predictors of serious nephropathy or ESKD include bloody stools and persistent rash. Initial kidney manifestations and outcomes are as follows[25] :

• ​Nephrotic and nephritic syndrome - Progression to chronic kidney disease (CKD) in > 50% of cases
• Nephrotic syndrome - Progression to CKD in ±40% of cases
• Nephritic syndrome - Progression to CKD in ±15% of cases
• Heavy non-nephrotic proteinuria - Progression to CKD in ±15% of cases
• Hematuria and/minimal proteinuria - Progression to CKD in < 5% of cases
• Nephrotic syndrome persisting for < 3 months - Almost no progression to ESRD
• Nephrotic syndrome persisting for > 3 months - Progression to ESRD in ±40% of cases.

However, patients with a normal urinalysis at 6 months and without previous renal involvement have not gone on to develop kidney problems.[73]

Pregnant women who had IgAV during childhood appear to be at increased risk for developing hypertension and proteinuria during pregnancy.[74]

Long-term prognosis of IgAV nephritis is determined by the development of CKD which sometimes is difficult to predict from the initial clinical and histological presentation. CKD can develop long-term even after apparent complete recovery from IgAV nephritis.[25]

Patients should be informed that the disease is most likely to resolve with few residual adverse effects but that relapses are possible. The clinician should explain that severe kidney involvement is rare but that if it does occur, aggressive treatment may be required.

For patient education information, see Henoch-Schonlein Purpura.

IgA vasculitis (IgAV; Henoch-Schönlein purpura) typically has a prodrome, which includes the following:

• Headache
• Anorexia
• Fever

After the prodrome, a number of symptoms develop, of which the following are the most common:

• Rash (95-100% of cases), especially involving the legs
• Abdominal pain and vomiting (35-85%)
• Joint pain (60-84%), especially involving the knees and ankles
• Subcutaneous edema (20-50%)
• Scrotal edema (2-35%)
• Bloody stools

The hallmark of the disease is the characteristic rash (see the image below), which appears in nearly all patients (though in as many as 50% of children, it may not be the presenting feature). The rash typically appears in crops, with new crops appearing in waves. Eruptions usually last an average of 3 weeks.

Characteristic rash of IgA vasculitis (Henoch-Schönlein purpura).

Lesions tend to occur on the buttocks and upper thighs in younger children and on the feet, ankles, and lower legs in older children and adults. The primary differences between children and adults appear to be the chronicity and severity of the eruption in the latter population; bullae and ulcers are more common in adults, and cutaneous exacerbations may be seen for 6 months or longer.[75] Chan et al noted a case of IgAV presenting as painful bullae on both legs.[76]

Gastrointestinal (GI) symptoms typically develop about a week after the appearance of the characteristic rash, but may precede or accompany the onset of skin lesions in IgAV or occur weeks or months later.[77] The most common such symptom is colicky abdominal pain. In addition to abdominal pain, GI findings may include the following:

• Nausea
• Vomiting
• Diarrhea with gross or occult blood
• Hematemesis
• Intussusception - This occurs in 2-3% of patients, and the lead point can be a submucosal hematoma
• Bowel infarction, with or without perforation
• Ileal stricture
• Ileus with massive GI hemorrhage
• Acute appendicitis ^{[78, 79]}

Arthralgias occur in 60-84% of patients with IgAV and are the presenting complaint in approximately 25% of children. The large joints (eg, the knees and ankles) are the ones most commonly involved, with pain and edema being the only symptoms; the wrists and fingers are less commonly involved. True arthritis does not occur, and joint effusions are rare. Generally, the arthritis resolves completely over several days without permanent articular damage.

Acute hemorrhagic edema of infancy (AHEI) usually occurs in infants aged 4-24 months, often after drug ingestion or infection. Onset is dramatic, with acute palpable purpura, ecchymoses, and tender edema of the limbs and face. Fever, if present, remains mild. Infants remain hemodynamically stable. Dermatologic findings are notable for a cockadelike rosette-shaped pattern of macular-papular-hemorrhagic lesions on the face, auricles, and extremities, which usually appear in successive crops and display varying stages of evolution at any given time.

Subcutaneous edema is most common in infants. Urticaria, petechiae, and ear lobe necrosis are additional rare skin manifestations of AHEI. Visceral involvement is rare.

Scrotal involvement is not uncommon in IgAV and may mimic testicular torsion, which must be excluded. Male patients may have associated inflammation and hemorrhage of the testes, appendix testes, spermatic cord, epididymis, or scrotal wall. True torsion is rare. Ha and Lee reported that neurologic symptoms, localized edema, and high serum C3 levels were significantly related to scrotal involvement in male patients with IgAV.[80]

In women with IgAV, gynecologic symptoms can include painful menstruation.

IgAV  can be accompanied by neurologic manifestations, particularly headaches. Ozkaya et al reported cerebral vasculitis in a child with IgAV and familial Mediterranean fever.[81] In rare cases, IgAV  can be associated with seizures, paresis, or coma.

Other neurologic manifestations of IgAV include the following:

• Altered mental status
• Apathy
• Hyperactivity
• Irritability
• Mood lability
• Somnolence
• Seizures (partial, complex partial, generalized, or status epilepticus)
• Focal deficits (eg, aphasia, ataxia, chorea, cortical blindness, hemiparesis, paraparesis, or quadriparesis)
• Polyradiculoneuropathies (eg, brachial plexus neuropathy or Guillain-Barré syndrome)
• Mononeuropathies (eg, of the facial nerve, femoral nerve, peroneal nerve, sciatic nerve, or ulnar nerve)

The liver and gallbladder can be involved in IgAV.[82] Hepatomegaly, hydrops of the gallbladder, and cholecystitis may ensue. These may contribute to a patient’s abdominal pain. Acute appendicitis has been noted in patients with IgAV.

Kidney pathology is the most important cause of morbidity and mortality in patients with IgAV. Kidney involvement may precede skin manifestations (1-4% of patients) but is usually evident during the acute phase of the disease, sometimes developing as long as 3 months after the initial presentation.[83] It may persist for as long as 6 months after the onset of the rash. In most cases, the severity of nephritis is not related to the extent of other IgAV manifestations.

Hemoptysis and hemarthroses can develop in patients who have bleeding abnormalities such as coagulopathy, factor VIII deficiency, vitamin K deficiency, or hypoprothrombinemia. Inherited thrombophilias (eg, factor V Leiden, protein C deficiency, and protein S deficiency) may contribute to necrotic cutaneous lesions in IgAV.[84]

Recurrence

Disease recurrence occurs throughout weeks to months in adults and children. In a large pediatric study by Allen et al, children older than 2 years had a recurrence rate of 50%, whereas those younger than 2 years had a recurrence rate of less than 25%.[85]

Prais et al studied 267 children (56.7% males) who were hospitalized secondary to IgAV  of whom 7 (2.7%) had IgAV that resulted in hospitalization at least twice.[86] No specific risk factor for recurrence was determined. The mean age for the first recurrence in that subgroup was 3.67 years (range, 10 months to 7.4 years), and that for the second was 5.03 years (range, 2.2-10 years), with a mean lag time of 13.5 ± 2.8 months (range, 2-26 months). The duration of the recurrence was 9-30 days. Resolution took more than 2 weeks in 72% of patients.

Because IgAV can affect all organ systems, a full physical examination is indicated. Purpura of the skin is the most prominent physical finding in IgAV, but kidney, GI, and joint manifestations are commonly present. Other manifestations have also been reported.

Skin findings

In most patients, skin lesions are the first sign of IgAV. The eruption commonly begins as erythematous macular or urticarial lesions, progressing to blanching papules and later to palpable purpura, usually 2-10 mm in diameter (see the image below). Various stages of eruption may be present simultaneously. Lesions usually occur in crops and may fade over several days.

Purpuric papules and plaques of the lower extremity characteristic of IgA vasculitis (Henoch-Schönlein purpura).

Lesions typically are symmetrical and tend to be distributed in dependent body areas, such as the ankles and lower legs in older children and adults (see the images below), and the back, buttocks, upper extremities, and upper thighs in young children (because these regions tend to be dependent in young children). The face, palms, soles, and mucous membranes usually are spared, except in infants, in whom facial involvement may not be uncommon.

Typical rash distribution of IgA vasculitis (Henoch-Schönlein purpura).

A 9-year-old boy with IgA vasculitis (Henoch-Schönlein purpura). Note confluence of purpura around the ankles. Image courtesy of Pamela L Dyne, MD.

A 7-year-old girl with IgA vasculitis (Henoch-Schönlein purpura). Image courtesy of Pamela L Dyne, MD.

Hemorrhagic macules, papules, and patches on the ankle and foot of a child with IgA vasculitis (Henoch-Schönlein purpura).

Palpable purpura can also be present on the forearms and pinnae. Scalp edema can occur. Hemorrhagic vesicles and bullae are rare.

Within 12-24 hours, the macules evolve into purpuric lesions that are dusky red and have a diameter of 0.5-2 cm. The lesions may coalesce into larger plaques that resemble ecchymoses (see the image below). Color in the areas of purpura progresses from red to purple and then becomes rust-colored or brown before fading. Recurrences tend to take place in the same sites as previous lesions.

Older lesions of IgA vasculitis (Henoch-Schönlein purpura) demonstrating increased extravasation with ecchymoses on dorsal foot and ankle.

Hives, angioedema, and target lesions can also occur. Vesicular eruptions and swelling and tenderness of an entire limb have been noted. Erythema multiforme–like lesions can be present. IgAV with hemorrhagic bullae in children has been noted.

In children younger than 2 years, the clinical picture may be dominated by edema of the scalp, periorbital area, hands, and feet (AHEI). The severity of edema is correlated with the severity of the vasculitis and not with the degree of proteinuria. However, the edema has been attributed to the enteric loss of protein. The “cockades” characteristic of AHEI display variable stages of evolution at any given time and look different from the normal purpura of IgAV.

The subcutaneous edema of AHEI is more common in infants. Urticaria, petechiae, and necrosis of the ear lobe are additional rare skin manifestations of AHEI. AHEI is rarely associated with visceral involvement.

Kidney findings

The most serious complication of IgAV is kidney involvement, which occurs in 50% of older children but is serious in only approximately 10% of patients. In 80% of patients, kidney involvement becomes apparent within the first 4 weeks of illness. Overall, 2-5% of patients progress to end-stage kidney disease (ESKD).

In one series, acute glomerular lesions, including mesangial hypercellularity, endocapillary proliferation, necrosis, cellular crescents, and leukocyte infiltration, were observed in 41%, 12%, 50%, 29%, and 32% of patients, respectively.[87] Only glomerular necrotizing lesions and cellular crescents correlated with the renal survival rate and were associated with clinically significant proteinuria and development of hypertension.

In a prospective study of 223 children with IgAV, Jauhola et al reported that 46% developed renal manifestations.[88] The authors recommended that children with kidney involvement be followed for more than 6 months. In addition, they noted that treatment with prednisone did not affect the renal manifestations.

Gastrointestinal findings

Abdominal pain and bloody diarrhea may precede the typical purpuric rash of IgAV, complicating the initial diagnosis and even resulting in unnecessary laparotomy. GI manifestations occur in about 50% of cases and usually consist of colicky abdominal pain, melena, or bloody diarrhea. Hematemesis occurs less frequently. Intussusception should be suspected in IgAV patients with abdominal pain or melena. Barium enema is frequently therapeutic.

The duodenum and small intestine are the most frequently involved segments of the GI tract. Duodenal ulcers also occur. Massive GI bleeding has been reported in IgAV.[89] Ileal vasculitis has also been reported.

Joint findings

Arthralgia is the presenting feature in as many as 25% of cases. Joints may be swollen, tender, and painful. Warmth, erythema, and effusions are not typically associated with IgAV. The knees and ankles are most commonly affected. On rare occasions, symptoms involve the fingers and wrists. Findings are transient but can occur again during active disease. The joints are not permanently deformed.

Other findings

Vasculitis involving the myocardium may occur. Vasculitis may also involve the lungs, resulting in pulmonary hemorrhage or severe bilateral pulmonary hemorrhage, and it may cause stenosing ureteritis, priapism, penile edema, or orchitis. Ha and Lee reported that neurologic symptoms, localized edema, and high serum C3 levels were significantly correlated with scrotal involvement in male patients with IgAV.[80] Vasculitis involving the CNS and intracranial hemorrhage have been reported.

Bilateral subperiosteal orbital hematomas have been noted. Adrenal hematomas have occurred. In rare patients, acute pancreatitis is the sole presenting feature of IgAV.[90, 91, 5] A case involving cystic changes of the ovaries and IgAV has been reported.[42]

IgAV can involve nearly every organ system. Reported complications include the following:

• Myocardial infarction
• Pulmonary hemorrhage
• Pleural effusion
• Intussusception
• GI bleeding
• Bowel infarction
• Protein-losing enteropathy ^[92]
• Chronic kidney failure
• Hematuria
• Proteinuria
• Seizures
• CNS bleeding
• Mononeuropathies
• Recurrence of symptoms, specifically those of kidney impairment (rare)

Hematuria, usually microscopic, can be accompanied by mild-to-moderate proteinuria (< 2 g/day). Oliguria, hypertension, and azotemia are rarely present. Nephrotic syndrome (urinary protein excretion > 40 mg/m2/hr or protein:creatinine ratio ≥200 mg/mmol in an early morning spot urine) can also occur. In most cases, histologic examination of the kidneys reveals mesangial proliferation that can be diffuse or focal and segmental. Resolution of the kidney involvement is the focus in these patients.

A study reported that even patients with mild forms of IgAV nephritis are at risk for significant long-term proteinuria. The study also added that very early introduction of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers may improve the long-term outcome independent of histological lesions.[93]

GI complications include hydrops of the gallbladder, pancreatitis, and GI bleeding. Surgical complications include intussusception, bowel infarction, and perforation.

Overall, 5% of patients develop ESKD. Urinary complications include bladder-wall hematoma, calcified ureter, hydronephrosis, and urethritis.

In a retrospective Korean study of 212 children with IgAV, Lee et al found palpable purpura spots 98.1% of subjects, GI symptoms in 75.0%, joint symptoms in 69.8%, renal involvement in 26.9%, and nephrotic syndrome in 4.7%. The study also found that patients with severe GI symptoms and children over age 7 years had a significantly greater incidence of kidney involvement and nephrotic syndrome.[94]

Diagnosis of IgA vasculitis (IgAV; Henoch-Schönlein purpura) is clinical and is not based on laboratory evaluation. Routine laboratory test results are usually within reference ranges. Some laboratory studies help in excluding other diagnoses and in evaluating renal function, including the following:

• Urinalysis
• Complete blood count (CBC) with platelet count and differential
• Blood urea nitrogen (BUN) level
• Creatinine level
• Prothrombin time (PT)
• Activated partial thromboplastin time (aPTT)
• Lipase level 

Some experts consider that imaging studies are indicated only if the diagnosis is uncertain. Kidney biopsy may be helpful in selected cases.

No specific diagnostic laboratory test is available to assess for markers of IgAV. General laboratory tests may reveal the following:

• Antinuclear antibody (ANA) and rheumatoid factor (RF) - Absent
• Factor XIII - Reduced in about 50% of patients
• Urinalysis - Hematuria; proteinuria may also be found
• CBC - Leukocytosis with eosinophilia and a left shift; thrombocytosis is present in 67% of patients
• Platelet count - May be elevated; low platelet levels suggest thrombocytopenic purpura
• Erythrocyte sedimentation rate (ESR) - Variably elevated; may be mildly elevated in as many as 75% of patients
• Stool guaiac test - May reveal occult blood ^[95]
• Blood urea nitrogen (BUN) and creatinine - May be elevated, indicating decreased kidney function
• Amylase and lipase - May be elevated in patients with pancreatitis
• Electrolytes - Generally in the reference range, but may be affected by excessive vomiting (eg, hypokalemia, hypochloremia)
• Plasma D-dimer - May be substantially increased
• Plasma thrombin-antithrombin (TAT) complex, prothrombin fragment (PF)–1, and PF-2 - May be abnormal
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) - May be reduced (eg, hypoprothrombinemia)
• Serum immunoglobulin A (IgA) - Increased in 50-70% of patients during the acute phase of illness; higher levels are associated with kidney involvement; circulating IgA immune complexes may be present in some patients, though data supporting the presence of classic antigen-antibody complexes have been questioned
• Factor VIII - Decreased in some patients
• Antistreptolysin O (ASO) - Elevated in 30% of patients
• Complement studies - CH50 is decreased in 30% of patients; C3 and C4 are occasionally decreased
• Immunocomplexes of IgG and IgA - May be increased

Total IgA levels are not very helpful in confirming the diagnosis or providing prognostic information. Elevated serum levels of galactose-deficient IgA1 seem to distinguish IgAV patients with nephritis from those without nephritis, but this assay is not used presently in clinical practice.[96, 97]

If serial urine samples are obtained in patients with IgAV, microscopic hematuria is usually found; it is probably present in 100% of cases. However, frank nephritis appears in only 20-30% of unselected children. The entire clinical spectrum of glomerulonephritis may occur in IgAV. The most common kidney manifestations are hematuria with mild-to-moderate proteinuria.

Coppo et al reported that when severe proteinuria, hypertension, or crescents are present at onset, the risk of IgAV progression is greater in adults and females and appears linked with increasing mean proteinuria levels during follow-up, more so than in patients with decreased renal function at onset.[98] Factor XIII activity seems to correlate with severity of abdominal manifestations[99] ; thus, measuring such activity helps identify patients with severe gastrointestinal (GI) manifestations who might benefit from substitution therapy.[100, 101]

Abdominal ultrasonography may be used if GI symptoms are present. It may be better than barium enema for diagnosing intussusception, in that IgAV-related intussusception is more likely to be ileoileal than ileocolic (as is typical of idiopathic intussusception). Diagnosis of IgAV using ultrasonography and radionuclide scanning in a child presenting with bilateral acute scrotum as the main symptom has been reported. In children with GI involvement of IgAV, dedifferentiated wall thickening on ultrasonography reveals a poor clinical prognosis.[102]

Imaging of the scrotum by means of ultrasonography or a technetium radionuclide scanning may be necessary if scrotal edema is a presenting feature. Testicular ultrasonography may help in assessing the testes for hemorrhage or torsion. Doppler or radionuclide testicular scan results show normal or increased blood flow in IgAV, in contrast to the decreased blood flow seen in testicular torsion.

Bowel ultrasonographic findings include thickening of the bowel wall, free fluid, and intussusception. Hydrops of the gallbladder is rarely seen. Kidney involvement may not be evident on ultrasonography; if nephritis or nephrotic syndrome occurs, however, enlargement of the kidneys with loss of corticomedullary differentiation due to edema is observed.

If hemoptysis has been noted, a chest radiograph should be obtained. Chest radiography may help in determining the presence and extent of pulmonary hemorrhage.

Plain radiography of the abdomen may help in diagnosing intestinal obstruction. Contrast-enhanced radiography of the small intestine may demonstrate thickened mucosal folds or small barium flecks. Radiologic GI findings mainly include bowel ischemia with thumbprinting and bowel-wall edema, which is sometimes visible on abdominal radiographs.

A barium enema study may be warranted for evaluating epigastric pain, hematemesis, and melena and for confirming and treating intussusception. If barium studies are performed, typical findings of ischemic colitis may be found, including a narrow colon with thickened mucosa and thumbprinting.

Magnetic resonance imaging (MRI) is useful for assessing neurologic findings in IgAV. In particular, MRI is the most sensitive imaging technique for posterior reversible encephalopathy syndrome (PRES), a clinico-radiological syndrome that may rarely complicate IgAV. The clinical manifestations of PRES include headache, seizures, visual disturbances, lethargy, confusion, stupor, and focal neurologic findings. MRI shows bilateral gray and white matter abnormalities suggestive of edema in the posterior regions of the cerebral hemispheres.[103]

Computed tomography (CT) of the head is necessary if neurologic symptoms or severe headache persist. Abdominal CT may aid in the exclusion of other causes of abdominal pain.

Endoscopy may be needed to evaluate epigastric pain, hematemesis, and melena. Endoscopy may reveal multiple irregular ulcers, mucosal redness, and petechiae in the duodenum. The second part of the duodenum is sometimes predominantly affected. Ulcerating lesions accompanied by hematomalike protrusions can be detected in patients with histopathologically proven leukocytoclastic vasculitis.

In some cases, kidney biopsy may be useful. It should be performed when nephrotic syndrome persists (though other manifestations may have subsided) and when kidney function deteriorates. When patients present with nephrotic syndrome, hypertension, and rapidly deteriorating kidney function, biopsy often shows circumferential crescents in most of the glomeruli. The extent of the crescents is of prognostic importance. Approximately 60% of patients develop kidney failure, either in the acute phase of the disease or after several years.

The International Study of Kidney Disease in Children (ISKDC) classification is widely used for patients with IgAV nephritis.[20] Nephritis may be graded as follows:

• Grade I - Minimal glomerular abnormalities
• Grade II - Mesangial proliferation without crescents or sclerosing lesions
• Grade III (a) - Focal segmental mesangial proliferation with < 50% crescents or sclerosing lesions   
• Grade III (b) - Diffuse mesangial proliferation with < 50% crescents or sclerosing lesions
• Grade IV - Mesangial proliferation with 50% - 70% crescents or sclerosing lesions
• Grade V - > 75% crescents or sclerosing lesions
• Grade VI - Membranoproliferative-like lesions

Histopathologic features of the skin lesions in infantile IgAV can range from a typical leukocytoclastic vasculitis with or without fibrinoid necrosis to the less specific findings of a lymphohistiocytic perivascular infiltrate with extravasation of erythrocytes.

Direct immunofluorescence (DIF) testing is a useful adjunct to histopathology; the yield is substantially higher when the test is performed within 48 hours of presentation. Immunofluorescence studies reveal perivascular IgA deposition in almost all patients; this finding is rare in infantile IgAV, in which C3 and IgM are most commonly found in the affected vessel walls.

IgAV often involves the kidneys. Kidney histology in IgAV varies considerably. In some cases, most glomeruli appear unaffected on light microscopy; only a few show mesangial proliferation. In instances of moderate kidney involvement, focal and segmental intracapillary and extracapillary proliferation may be present with adhesions and small crescents. Severe cases are characterized by a diffuse proliferation with infiltration of neutrophils and circumferential crescents in most of the glomeruli. Tubular atrophy and interstitial infiltration with mononuclear cells may also be present.

In most patients, IgA deposits in the mesangium and the walls of cutaneous capillaries are detected. The IgA deposited in the mesangium is mainly of the IgA1 subclass, though IgA2 deposits are noted in rare cases. In addition to IgA, the deposits in mesangium and cutaneous capillaries frequently contain C3, IgG, and fibrin. C3 deposits are often accompanied by properdin, whereas C1Q and C4 are usually not present. This observation suggests that the complement components have been activated by means of the alternative pathway.

The specific kidney pathology of IgAV includes the following:

• Diffuse hypercellularity
• Focal and segmental proliferation
• Mesangial proliferation
• Minimal change to severe crescentic glomerulonephritis
• Segmental sclerosis fibrosis
• Mononuclear cell infiltration
• Mesangial, subendothelial, and subepithelial deposits
• Diffuse glomerular deposits of IgA, C3, fibrin, immunoglobulin G (IgG), properdin, and immunoglobulin M (IgM)
• IgA deposits in the mesangium

To date, no form of therapy has been found to shorten the duration of IgA vasculitis (IgAV; Henoch-Schönlein purpura) to any significant degree. Therefore, treatment remains primarily supportive in most cases. This is consonant with the understanding that IgAV is a self-limited disease. The majority of patients recover quickly (ie, within several weeks) without treatment.[104]

Management of IgAV includes adequate hydration; immediate discontinuation of any exposure to antigenic stimulants (eg, drugs); and follow-up each week for the first month, every other week for the second month, and monthly thereafter until abnormal urinary findings subside.

Hospital admission and monitoring for complications should be considered. Hospitalization should be strongly considered for IgAV patients with severe abdominal pain, significant gastrointestinal (GI) bleeding, or marked kidney insufficiency. Complications such as acute abdomen, acute scrotum, and acute kidney injury may be severe and may occur precipitously.

IgAV may mimic an abdominal emergency and, in its most severe form, result in small-bowel infarction, perforation, or both.

In adults with IgAV, permanent kidney involvement is not uncommon. All pregnant women with even mild kidney symptoms at the onset of IgAV should be carefully observed during and after pregnancy. Hematuria at disease onset and persistence of kidney manifestations during the course of IgAV are significant predictors of possible development of kidney sequelae. Other features associated with the development of kidney sequelae include the following:

• Onset in summer
• Anemia at disease onset
• Relapse 

Nephropathy is treated supportively, with monitoring of fluid and electrolyte balance, restriction of salt intake, and administration of antihypertensives when needed. Various drugs (eg, corticosteroids, azathioprine, and cyclophosphamide) and plasmapheresis have been used to prevent progression of kidney disease, but the results have been inconsistent, and no data from controlled studies are available.

Dietary restrictions have no clear role in the management of IgAV. Activities can be performed as tolerated.

Treatment of IgAV is primarily supportive and includes ensuring adequate hydration and monitoring for abdominal and kidney complications. For minor complaints of arthritis, edema, fever or malaise, symptomatic treatment is advised, including use of acetaminophen, elevation of swollen extremities, eating a bland diet, and adequate hydration. All unnecessary drugs should be discontinued if a drug-related etiology is suspected.

Most patients with self-limited cases can be safely discharged home with close follow-up by the primary physician. The decision for or against hospital admission depends on the physician’s customary practice and individual preference. Admission to the hospital is recommended for control of abdominal pain or vomiting, monitoring of kidney function, confirmation of a doubted diagnosis, and observation and monitoring. Patients with kidney involvement require close attention to their fluid balance, electrolyte status, and use of antihypertensives (if indicated).

A study examining prevention and treatment of kidney disease in patients with IgAV revealed no significant difference in the risk of persistent kidney disease at 6 months and 12 months in children given prednisone for 14-28 days upon presentation in comparison with placebo or supportive treatment.[105] Also, no significant difference was noted in the risk of persistent kidney disease in children given cyclophosphamide compared with supportive treatment and with cyclosporine compared with methylprednisolone.

Analgesics

Pain control is essential for quality patient care. Analgesia with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen may reduce joint and soft tissue discomfort. Such agents are often effective and do not seem to worsen the purpura; however, they should be used cautiously in patients with renal insufficiency.

Corticosteroids

Clinicians often use corticosteroids to treat subcutaneous edema and nephritis in IgAV, as well as to ameliorate associated arthralgias and symptoms associated with GI dysfunction. However, high-quality, large, prospective studies regarding the treatment of IgAV are lacking,[105, 106, 107] and the evidence does not yet support the use of steroids to prevent or treat kidney disease.[36, 108] Some authors recommend steroids; others do not. Nevertheless, corticosteroids may be considered in the following situations:

• Persistent nephrotic syndrome
• Crescents in more than 50% of glomeruli
• Severe abdominal pain
• Substantial GI hemorrhage
• Severe soft tissue edema
• Severe scrotal edema
• Neurologic system involvement
• Intrapulmonary hemorrhage

Prednisone in a dosage of 1 mg/kg/day for 2 weeks and then tapered over 2 more weeks may shorten the duration of abdominal pain and joint symptoms, but this benefit must be weighed against the potential adverse effects of steroids.[109, 110]

A review of randomized clinical trials for any intervention used to improve renal disease in children with IgAV noted that data were very limited except for short-term prednisone; moreover, prednisone had no benefit in preventing serious long-term kidney disease.[108]

The long-term prognosis of IgAV directly depends on the severity of kidney involvement. Patients with IgAV-related kidney dysfunction may benefit from therapy. However, prophylaxis of kidney complications in IgAV, though interesting, is not currently recommended. Treatment of overt IgAV includes methylprednisolone pulse therapy and prednisone and other immunosuppressive medications. If prednisone is used, a regimen consisting of 1-2 mg/kg/day PO for 7 days is recommended. Antihypertensives may be indicated with kidney involvement.

Faedda reported favorable results from the following protocols in patients with severe IgAV[111] :

• Induction with 250-750 mg of intravenous (IV) methylprednisolone daily for 3-7 days plus oral (PO) cyclophosphamide 100-200 mg/d
• Maintenance with prednisone 100-200 mg PO every other day plus cyclophosphamide 100-200 mg/day PO for 30-75 days
• Tapering of prednisone by approximately 25 mg/month (with the cyclophosphamide dose remaining constant)
• Discontinuation of treatment after at least 6 months by abruptly stopping cyclophosphamide and tapering prednisone completely

Other agents

Other treatment regimens have included IV or oral steroids with or without any of the following:

• Azathioprine
• Cyclophosphamide
• Cyclosporine
• Dipyridamole
• High-dose IV immunoglobulin G (IVIg)
• Angiotensin-converting enzyme inhibitors (ACEIs)
• Angiotensin receptor blockers (ARBs)
• Danazol
• Fish oil

Of those, only cyclophosphamide has been shown to be effective in a randomized controlled trial. Although some studies have reported success, cyclosporine does not have sufficient clinical data to establish its utility in this setting.[112]

Azathioprine, mycophenolate mofetil, and urokinase must be tested before their use is consistently advocated. Guidelines for prescribing azathioprine in dermatology have been established.[113] No convincing studies have yet been conducted regarding the use of IVIg, factor XIII administration, antioxidant vitamin E, and fish oil to treat IgAV.[114]

A randomized clinical trial comparing cyclosporine with methylprednisolone pulses in IgAV with nephritis found that cyclosporine had superior efficacy and many fewer complications.[115] A study of 12 patients with severe IgAV nephritis indicated that patients did well with methylprednisolone at 30 mg/kg/day for 3 days followed by oral corticosteroids at 2 mg/kg/day for 2 months, cyclophosphamide at 2 mg/kg/day for 2 months, and dipyridamole at 5 mg/kg/day for 6 months.[116]

Some have noted that parvovirus B19–associated IgAV must be recognized in adults because the treatment of choice is IV gamma globulin combined with tumor necrosis factor (TNF)–α inhibitor therapy. Immunosuppressive therapy may lead to a persistent or worsening disease course in these patients.

Massive GI hemorrhage in isolated intestinal IgAV that is responsive to IVIg infusion has been reported.[117] IVIg was used in a complex case of IgAV with brain hemorrhage, but more work must be done to validate the use of this treatment.[118]

Dapsone has been used to treat associated purpuras and arthralgias. Iqbal and Evans found it to be effective for IgAV.[119]

Rituximab has been noted to be a successful treatment for severe refractory chronic IgAV.[120]

Factor VIII concentrate has been used to relieve abdominal pain when corticosteroids are contraindicated. Recombinant factor VIIa has been used in patients with very pronounced factor XIII deficiency and compartment syndrome.

Treatment of complicated IgAV with mycophenolate mofetil has been reported in a series of patients.[121, 122]

Beneficial effects of methylprednisolone pulses with oral prednisone was reported in a prospective case series and also suggested in patients receiving combinations of multiple immunosuppressive drugs.[123, 124, 125, 126, 127]

Kidney Disease Improving Global Outcomes (KDIGO) 2021 guidelines note there are no data to support the use of glucocorticoids in the prevention of nephritis in children with mild IgAV or absent evidence of kidney involvement. Key recommendations for the management of IgAVN in children include the following[128] :

• Urinary monitoring for nephritis is necessary for 6-12 months from initial presentation of systemic disease.
• Children with IgAVN and persistent proteinuria for >3 months should be treated with an ACEi or ARB. A pediatric nephrologist should be consulted.
• A kidney biopsy should be performed in children with nephrotic-range proteinuria, impaired GFR, or persistent moderate (>1 g/d) proteinuria.
• Oral prednisone/prednisolone or pulsed intravenous methylprednisolone should be used in children with mild or moderate IgAVN.
• Children with IgAVN with nephrotic syndrome and/or rapidly deteriorating kidney function are treated in the same way as those with rapidly progressive IgAN

Plasmapheresis may be effective in delaying the progression of kidney disease. A case series demonstrated good outcomes in adults with severe IgAV who were treated with plasma exchange in addition to steroids.[129] In an uncontrolled study, Shenoy et al reported that children with severe IgAV and IgA nephropathy recover well if treated with plasmapheresis alone, without the need for immunosuppressive therapy.[130] Plasmapheresis has been useful in treating rapidly progressive IgAV nephritis.[131]

Surgery may be undertaken to treat severe bowel ischemia. Kidney transplantation may be indicated in patients with severe kidney disease that is resistant to medical therapy. Successful treatment of progressive IgAV nephritis with tonsillectomy and corticosteroid pulse therapy has been reported.

Because IgAV is a multisystem disease, consultations with the following specialists can be helpful in diagnosis and treatment:

• Dermatologist
• Gastroenterologist
• Nephrologist (particularly for assistance in determining if dialysis is indicated)
• Rheumatologist
• Dermatopathologist ^[132] (the utility of the consultation is limited to untypical or incomplete manifestations of IgAV to buttress positive vascular IgA immunohistochemical evidence of the deposits)

Consultation is recommended for patients with kidney involvement before discharge from the emergency department and for all patients who appear acutely ill.

In all patients, urinalysis and blood pressure monitoring to evaluate for renal involvement should be continued for up to 6 months after presentation, even if initial urinalysis results were normal. Once the initial course of prednisone is administered, additional prednisone appears to have no role.

When terminal renal failure develops, long-term hemodialysis should be instituted until a kidney is available for transplantation. Mesangial deposits of IgA are common in the graft, but they rarely lead to clinical manifestations of recurrent glomerulonephritis.

Children who have demonstrated renal manifestations in the acute phase and continue to have hematuria or proteinuria should be examined every 3-6 months because renal failure or hypertension can develop up to 10 years after disease onset.

NSAIDs may be administered to address joint problems. Because of the risk of Reye syndrome, the use of NSAIDs should be discussed with the patient’s physician.

In IgAV nephritis that has progressed to end-stage kidney disease, kidney transplantation is the treatment of choice. Recurrence of glomerular IgA deposits after kidney transplantation is very frequent in patients with IgAV nephritis, but does not significantly affect the rate of graft loss. In one study, the risk of graft loss at 10-year follow-up was 7.5%.[133]

Very limited data are available on pharmacologic treatment of IgA vasculitis (IgAV; Henoch-Schönlein purpura). Nonsteroidal anti-inflammatory drugs (NSAIDs) may help joint pain and do not seem to worsen the purpura; however, they should be used cautiously in patients with kidney insufficiency. Clinicians often use corticosteroids to treat subcutaneous edema and nephritis, but few prospective placebo-controlled studies have demonstrated their effectiveness. Other drugs are currently under investigation.

Class Summary

Immunosuppressive agents decrease inflammation by suppressing migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea. Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α-amino-butyryl-Nmethylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).

Methylprednisolone (Solu-Medrol, Medrol, A-Methapred, Depo-Medrol)

Methylprednisolone decreases inflammation by suppressing PMN migration and reversing increased capillary permeability.

Prednisone (Rayos)

Prednisone is an immunosuppressant used to treat autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. It stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Prednisolone (Millipred, Orapred, Orapred ODT, Prelone)

Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.

Cyclophosphamide

Cyclophosphamide

Cyclophosphamide is an alkylating agent that is chemically related to nitrogen mustards. It is a cyclic polypeptide that suppresses some humoral activity. Cyclophosphamide is transformed in the liver to active alkylating metabolites, which interfere with the growth of rapidly proliferating cells. When cyclophosphamide is used in autoimmune diseases, its mechanism of action is thought to involve immunosuppression through destruction of immune cells by DNA cross-linking.

Class Summary

Analgesic agents are most commonly used for the relief of mild-to-moderate pain. Although the effects of NSAIDs in the treatment of pain tend to be patient-specific, ibuprofen usually is the drug of choice for initial therapy; other options include flurbiprofen, ketoprofen, and naproxen. Some analgesics (eg, acetaminophen and ibuprofen) are also effective for treating fever.

Ibuprofen (Advil, Motrin, I-Prin, Ibu-200, Neo-Profen)

Ibuprofen is the drug of choice for treatment of mild-to-moderate pain, if not contraindicated; it is also effective for treating fever. Ibuprofen inhibits inflammatory reactions and pain, probably by decreasing the activity of cyclooxygenase, thereby inhibiting prostaglandin synthesis.

Acetaminophen (FeverAll, Q-Pap, Tylenol, APAP 500, Acephen)

Acetaminophen is effective for treating fever and relieving mild-to-moderate pain. It inhibits the action of endogenous pyrogens on heat-regulating centers; it also reduces fever by a direct action on the hypothalamic heat-regulating centers, thereby, in turn, increasing the dissipation of body heat via sweating and vasodilation.

Flurbiprofen

Flurbiprofen has analgesic, antipyretic, and anti-inflammatory effects. It may inhibit cyclooxygenase, causing inhibition of prostaglandin biosynthesis.

Ketoprofen

Ketoprofen is used for relief of mild-to-moderate pain and inflammation.

Naproxen (Anaprox, Naprelan, Naprosyn, Aleve)

Naproxen is used for relief of mild-to-moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, thereby reducing prostaglandin synthesis.