Henoch-Schonlein Purpura

Updated: Nov 10, 2016
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Craig B Langman, MD  more...
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Overview

Practice Essentials

Henoch-Schönlein purpura (HSP) is an acute immunoglobulin A (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). See the image below.

Characteristic rash of Henoch-Schönlein purpura. Characteristic rash of Henoch-Schönlein purpura.

Signs and symptoms

The typical prodrome of HSP includes the following:

  • Headache
  • Anorexia
  • Fever

Subsequently, symptoms develop, of which the following are the most common:

  • Rash (95-100% of cases), especially involving the legs; this is the hallmark of the disease
  • 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

Because HSP can affect all organ systems, a full physical examination is indicated. Physical findings in HSP may include the following:

  • Skin findings (usually the first sign of HSP) - Erythematous macular or urticarial lesions, progressing to blanching papules and later to palpable purpura; typically symmetrical and tend to be distributed in dependent body areas, such as the ankles and lower legs in older children and adults and the back, buttocks, upper extremities, and upper thighs in young children; hives, angioedema, and target lesions can also occur
  • Renal findings - Acute glomerular lesions, including mesangial hypercellularity, endocapillary proliferation, necrosis, cellular crescents, and leukocyte infiltration
  • Gastrointestinal (GI) findings - Abdominal pain, melena, bloody diarrhea, hematemesis, duodenal ulcers, and massive GI hemorrhage
  • Joint findings - Arthralgia and swelling
  • 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 HSP. 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 or lungs; stenosing ureteritis, priapism, penile edema, or orchitis; vasculitis involving the central nervous system (CNS) and intracranial hemorrhage; bilateral subperiosteal orbital hematomas; adrenal hematomas; acute pancreatitis as the sole presenting feature (rare); cystic changes of the ovaries

See Presentation for more detail.

Diagnosis

No specific diagnostic laboratory test is available to assess for markers of HSP. The following general laboratory tests may be helpful for excluding other diagnoses and evaluating renal function:

  • Antinuclear antibody (ANA) and rheumatoid factor (RF)
  • Factors VIII and XIII
  • Urinalysis
  • Complete blood count (CBC)
  • Platelet count
  • Erythrocyte sedimentation rate (ESR)
  • Stool guaiac test
  • Blood urea nitrogen (BUN) and creatinine
  • Amylase and lipase
  • Electrolytes
  • Plasma D-dimer
  • Plasma thrombin-antithrombin (TAT) complex, prothrombin fragment (PF)-1, and PF-2
  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
  • Serum IgA
  • Antistreptolysin O (ASO)
  • CH50
  • C3 and C4
  • Immunocomplexes of IgG and IgA

Imaging modalities that may be considered include the following:

  • Ultrasonography (abdominal, scrotal/testicular)
  • Radiography (chest radiography; plain radiography of the abdomen; contrast radiography of the small intestine; barium enema study)
  • Magnetic resonance imaging (MRI; for assessing neurologic findings)
  • Computed tomography (CT) of the head or abdomen

Other studies that may be warranted are as follows:

  • Endoscopy
  • Renal biopsy (particularly when nephrotic syndrome persists and when renal function deteriorates)

See Workup for more detail.

Management

Treatment remains primarily supportive in most cases, though pharmacotherapy, plasmapheresis, and surgical interventions may also be considered in select cases.

Supportive measures may include the following:

  • Ensuring adequate hydration
  • Monitoring for abdominal and renal complications
  • Treating minor symptoms of arthritis, edema, fever, or malaise
  • Eating a bland diet
  • Discontinuance of any drugs suspected of playing a causative role

Joint and soft tissue discomfort may be reduced by giving analgesics, such as the following:

  • Acetaminophen
  • Ibuprofen
  • Flurbiprofen
  • Ketoprofen
  • Naproxen

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

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)
  • Danazol
  • Fish oil

Plasmapheresis may be effective in delaying the progression of kidney disease.

Surgical interventions that may be considered in specific circumstances include the following:

  • Surgery for severe bowel ischemia
  • Kidney transplantation for severe renal disease that is resistant to medical therapy
  • Tonsillectomy together with corticosteroid pulse therapy for progressive HSP nephritis

See Treatment and Medication for more detail.

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Background

Henoch-Schönlein purpura (HSP; also referred to as Schönlein-Henoch purpura, anaphylactoid purpura, or purpura rheumatica) is an acute immunoglobulin A (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). [1, 2, 3] It is a subset of necrotizing vasculitis characterized by fibrinoid destruction of blood vessels and leukocytoclasis.

The prevalence of HSP peaks in children aged 3-10 years, but the condition is also seen in adults. [4] In the Northern hemisphere, the disease occurs mostly between November and January. The male-to-female ratio is 1.5-2:1.

The dominant clinical features of HSP include cutaneous purpura, arthritis, abdominal pain, GI bleeding, orchitis, and nephritis. In one half to two thirds of children, an upper respiratory tract infection (URTI) precedes the clinical onset of HSP by 1-3 weeks. In general, patients with HSP appear mildly ill. They often have a fever, with a temperature that usually does not exceed 38°C (100.4°F).

HSP is typically an acute, self-limited illness, and treatment is primarily supportive. However, one third of patients have 1 or more recurrences.

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Pathophysiology

IgA clearly plays a critical role in the immunopathogenesis of HSP, as evidenced by increased serum IgA concentrations, IgA-containing circulating immune complexes, and IgA deposition in vessel walls and renal mesangium. HSP is almost exclusively associated with abnormalities involving IgA1, rather than IgA2. The predominance of IgA1 in HSP may be a consequence of abnormal glycosylation of O-linked oligosaccharides unique to the hinge region of IgA1 molecules.

IgA aggregates or IgA complexes with complement deposited in target organs, resulting in elaboration of inflammatory mediators, including vascular prostaglandins such as prostacyclin, may play a central role in the pathogenesis of HSP vasculitis.

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 HSP 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. Evidence supporting a direct role of herpesvirus, retrovirus, or parvovirus infection in the pathogenesis of HSP is lacking.

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 HSP. 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 HSP 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 HSP, 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 HSP, 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 HSP nephritis (HSPN) 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 HSP and hypersensitivity vasculitis is increased.

Results support a role of human leukocyte antigen (HLA)-B35 in the susceptibility to nephritis in unselected patients with HSP.

Researchers are currently investigating the importance of nitric oxide (NO) production in disease activity. Inducible NO synthase polymorphism has been associated with susceptibility to HSP in northwestern Spain. Aliyazicioglu et al have suggested that leptin and NO may play a role in the immunoinflammatory process of HSP, especially in the acute phase. [5]

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

Yilmaz et al examined 28 children with HSP and 79 healthy children to evaluate activities of protein C, free-protein S, and antithrombin; resistance to activated protein C; and levels of fibrinogen. [6] D-dimer, thrombin-antithrombin (TAT) complex, prothrombin fragment (PF)-1, PF-2, and von Willebrand factor antigen (vWAg) and its activity (RiCof) were also investigated.

The investigators found that in patients with HSP, fibrinogen, D-dimer, TAT complex, PF-1, PF-2, vWAg, and RiCof levels were significantly higher during the acute phase than during the recovery phase and were significantly higher than those of control subjects. [6] The severity of disease was significantly correlated with TAT, PF-1, PF-2, vWAg, and D-dimer levels.

Higher levels of matrix metalloproteinase (MMP)-9 levels in urine and serum appear to increase nephrologic severity in children with HSP.

Use of TNF-α blockers such as adalimumab may increase the risk of developing HSP.

HSP versus IgA nephropathy

HSP 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 HSP and IgA nephropathy are 2 aspects of a single disease entity or 2 distinct entities. The following commonalities and differences have been noted:

  • IgA nephropathy almost exclusively involves young adults and typically affects only the kidneys, whereas HSP affects mostly children and involves the skin and connective tissues, GI tract, joints, and scrotum, as well as the kidneys [3, 7, 8]
  • The occurrence of extrarenal manifestations in IgA nephropathy is similar to that in HSP
  • IgA nephropathy has developed in patients with a history of HSP, and HSP 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 HSP [9]
  • Patients with HSP who undergo renal 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 the 2 diseases [10, 11, 12]
  • Cystic changes in the ovaries of a prepubertal girl with HSP have been recorded

Overall, the data tend to support the view that HSP and IgA nephropathy are distinct diseases. [13] Zhou et al examined 31 children aged 3-15 years with IgA nephropathy and 120 children aged 4-15 years with HSP, noting their clinical manifestations, blood biochemistries, serum immunology, and follow-up data. [14] Renal pathologic findings on light microscopy, immunofluorescence study, and electron microscopy were analyzed and compared between 31 children with IgA nephropathy and 32 children with HSP.

The age of onset was greater than 12 years in 25.8% of the children with IgA nephropathy but in only 10% of those with HSP. [14] Clinical patterns of IgA nephropathy were similar to those of HSP, but extrarenal manifestations were observed more often in patients with HSP.

All of the HSP patients had skin purpura, 59% had GI symptoms, and 47% had arthralgia. Abdominal pain occurred in only 3.2% of children with IgA nephropathy. [14] In patients with IgA nephrology and in patients with HSP, renal pathology revealed global sclerosis in 35.5% and 3.1%, mesangial sclerosis in 41.9% and 6.3%, endothelial proliferation in 29% and 65.6%, and thin basement-membrane nephropathy in 6.5% and 0%, respectively.

In HSP, electronically dense deposits in HSP were sparse, loose, and widely spread in the glomerular mesangium, in the subendothelial area, and even in the intrabasement membranes, whereas in IgA nephropathy, the deposits were dense, lumpy, and mostly limited to mesangium and paramesangium. [14]

Immunoglobulin G (IgG) was found in glomerular immune deposits in 71.9% of patients with HSP but in only 19.4% of patients with IgA nephropathy. [14] 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 HSP patients, with relatively weak IgA deposits. Moreover, 6.3% of HSP 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 HSP at an average of 20 months’ follow-up; the corresponding rate was 19.4% in those with IgA nephropathy after 34 months’ follow-up. [14] 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 HSP and IgA nephropathy argue against the single-disease hypothesis.

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Etiology

The etiology of HSP remains to be clearly defined but is thought to be multifactorial, with genetic, environmental, and antigenic components. More than 75% of patients report antecedent URTI, pharyngeal infection, or GI infection. Multiple bacterial and viral infectious agents have been associated with the development of HSP, and cases also have been reported after drug ingestions and vaccinations. [15]

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

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

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

  • Drugs (eg, ampicillin, erythromycin, penicillin, quinidine, quinine, losartan, and cytarabine [20] )
  • Foods
  • Horse serum
  • Cold exposure
  • Insect bites

Glomerulocystic kidney disease has also been noted.

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Epidemiology

United States statistics

In the United States, the prevalence of HSP is approximately 14-15 cases per 100,000 population.

International statistics

In the United Kingdom, the estimated annual incidence of HSP is 20.4 cases per 100,000 population. [21] In a Norwegian community hospital, the prevalence of Henoch-Schoenlein purpura was 3.3 cases per 100,000 inhabitants. [22]

In a study that examined the renal 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 HSP. [23]

Nong et al reviewed the records of 107 Taiwanese pediatric patients diagnosed with HSP between 1991 and 2005 who had a mean age of 6.2 ± 2.5 years (range, 2-13 years); the male-to-female ratio was 1:0.7. [24] The primary symptoms included the following:

  • Rashes (95.3%)
  • GI symptoms (72.0%)
  • Joint involvement (46.7%)
  • Kidney involvement (28.0%)

The most common first manifestations were as follows:

  • Rashes (56.1%)
  • GI symptoms (35.5%)
  • Joint involvement (12.1%)

From January 1983 to June 2004, Suehiro et al followed 4502 patients at the Pediatric Rheumatology clinic in Brazil. [25] A diagnosis of HSP 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

HSP primarily affects children; it may be seen in adults, but much less frequently. [2, 8] In the United States, the prevalence peaks in children aged 5 years. Approximately 75% of cases occur in children aged 2-11 years; HSP is rare in infants and young children. Older age at the onset of HSP is associated with the development of chronic renal disease. [26] AHEI, a related but milder condition, occurs in infants younger than 2 years. [27]

Ghrahani et al conducted a retrospective study in children with HSP in Hasan Sadikin Hospital from 2006 to 2011 to evaluate renal involvement in children with HSP. The authors reported that there were 128 patients with an age range from 6 month to 15 years. Peak morbidity was between 5-10 years old. In most patients (71%) purpura was the first symptom. Seventy-one patients (44.5%) had arthritis and 89 patients (69.5%) had abdominal pain, while renal involvement was in 28 patients (21.8%). Gastrointestinal manifestations tend to manifest in patients less than 5 years old, while renal involvement tend to manifest in age group 11-15 years old. The authors concluded that renal involvement in children with HSP is more common in age group 11 to 15 years old. [28]

Sex-related demographics

HSP occurs more often in boys than in girls. In children, the male-to-female ratio is 1.5-2:1. 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. [29] 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%). Renal 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 renal involvement could be identified in this study. [29] Mean follow-up time was 2.6 years (range, 1-5 years). Residual renal disease occurred in 6 (38%) of 16 patients, but none had end-stage renal disease (ESRD).

In a study from China, a male predominance was observed in children but not in adults. [30] 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.

The investigators found that abdominal pain was more common in children than adults (70.2% vs 28.9%), but renal involvement was more common and severe in adults than in children; this involvement manifested as frequent hypertension and heavy proteinuria. [30] 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. [31]

Familial kindreds with HSP have been noted in Taiwanese aboriginal people. [32]

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Prognosis

HSP 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. Initial attacks of HSP can last several months, and relapses are possible. HSP 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 HSP, the chance of relapse is greater in those with GI and joint manifestations, with 72.3% of patients in the study with abdominal pain relapsing, compared with 62.3% of those who did not, and 27.8% of patients with joint manifestations relapsing, compared with 15.5% of those who did not. [33]

Although HSP 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 renal damage. Potential GI complications include intussusception (usually ileoileal), bowel infarction, bowel perforation, hydrops of the gallbladder, pancreatitis, and massive GI bleeding.

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

Predictors of serious nephropathy or ESRD include the following:

  • Bloody stools
  • Rash persistence
  • Hematuria and proteinuria (patients with only hematuria do not develop ESRD, but about 15% of patients with hematuria and proteinuria do develop ESRD)
  • Signs of nephritis or nephrotic syndrome (50% of patients progress to ESRD within 10 years)
  • Renal biopsy with extensive glomerular crescents

Patients with a normal urinalysis at 6 months and without previous renal involvement have not gone on to develop kidney problems. [34]

Pregnant women who had HSP during childhood appear to be at increased risk for developing hypertension and proteinuria during pregnancy. [35]

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Patient Education

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 resources, see Blood in the Urine.

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