Henoch-Schönlein purpura

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Overview
In medicine (rheumatology and pediatrics) Henoch-Schönlein purpura (HSP, also known as allergic purpura) is a systemic vasculitis (inflammation of blood vessels) characterized by deposition of immune complexes containing the antibody IgA, especially in the skin and kidney. It occurs mainly in children. Typical symptoms include palpable purpura (small hemorrhages in the skin), joint pains and abdominal pain. Most cases are self-limiting and require no treatment apart from symptom control, but the disease may relapse (in 33% of cases) and cause irreversible kidney damage (in 1%).

Epidemiology
HSP occurs more often in children than in adults, and usually follows an upper respiratory tract infection. Half of affected patients are below the age of six, and 90% under ten. It occurs more often in boys than in girls (about twice as often).

The incidence of HSP in children is about 20 per 100,000 children per year; this makes it the most common vasculitis in childhood.

Pathophysiology & Etiology
HSP can develop after infections with streptococci (β-haemolytic, Lancefield group A), hepatitis B, herpes simplex virus, parvovirus B19, Coxsackievirus, adenovirus, Helicobacter pylori, measles, mumps, rubella, mycoplasma and numerous others. Drugs linked to HSP, usually as an ideosyncratic reaction, include vancomycin, ranitidine, streptokinase, cefuroxime, diclofenac, enalapril and captopril. Several diseases have been reported to be associated with HSP, often without a causative link. Only in about 35% of cases can HSP be traced to any of these causes.

The exact cause of HSP is unknown, but most of its features are due to the deposition of abnormal antibodies in the wall of blood vessels, leading to vasculitis. These antibodies are of the subclass IgA1 in polymers; it is uncertain whether the main cause is overproduction (in the digestive tract or the bone marrow) or decreased removal of abnormal IgA from the circulation. It is suspected that abnormalities in the IgA1 molecule may provide an explanation for its abnormal behaviour in both HSP and the related condition IgA nephropathy. One of the characteristics of IgA1 (and IgD) is the presence of an 18 amino acid-long hinge region between complement-fixating region 1 and 2. Of the amino acids, half is proline, while the other ones are mainly serine and threonine. The majority of the serines and the threonines have elaborate sugar chains, connected through oxygen atoms (O-glycosylation). This process is thought to stabilise the IgA molecule and make it less prone to proteolysis. The first sugar is always N-acetyl-galactosamine (GalNAc), followed by other galactoses and sialic acid. In HSP and IgAN, it appears that these sugar chains are deficient. The exact reason for these abnormalities are not known.

Diagnosis
The diagnosis is based on the combination of the symptoms, as very few other diseases cause the same symptoms together. Blood tests may show elevated creatinine and urea levels (in kidney involvement), raised IgA levels (in about 50% ), and raised C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) results; none are specific for Henoch-Schönlein purpura. The platelet count may be raised, and distinguishes the purpura from diseases in which the low platelets are the cause of the purpura (idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura).

If there is doubt about the cause of the skin lesions, a biopsy of the skin may be performed to distinguish the purpura from other diseases that cause purpura (such as vasculitis due to cryoglobulinemia); on microscopy the appearances are of a hypersensitivity vasculitis and immunofluorescence demonstrates IgA and C3 (a protein of the complement system) in the blood vessel wall.

On the basis of symptoms, it is possible to distinguish HSP from hypersensitivity vasculitis (HV). In a series comparing 85 HSP patients with 93 HV patients, five symptoms were found to be indicative of HSP: palpable purpura, abdominal angina, digestive tract hemorrhage (not due to intussussception), hematuria and age less than 20. The presence of three or more of these indicators has an 87% sensitivity for predicting HSP.

Biopsy of the kidney may be performed both to establish the diagnosis or to assess the severity of already suspected kidney disease. The main findings on kidney biopsy are increased cells in the mesangium (part of the glomerulus, where blood is filtered), white blood cells, and the development of crescents. The changes are indistinguishable from those observed IgA nephropathy.

Presentation
Purpura, arthritis and abdominal pain are known as the "classic triad" of Henoch-Schönlein purpura. Purpura occur in all cases, joint pains and arthritis in 80%, and abdominal pain in 62%. Some include gastrointestinal hemorrhage as a fourth criterion - this occurs in 33% of cases (sometimes but not necessarily due to intussusception). The purpura typically appear on the legs and buttocks, but may also be seen on the arms, face and trunk. The abdominal pain is colicky in character. The joints involved tend to be the ankles, knees, and elbows but arthritis in the hands and feet is possible; the arthritis is non-erosive and hence causes no permanent deformity. 40% have evidence of kidney involvement, mainly in the form of hematuria (blood in the urine), but only a quarter will have this in sufficient quantities to be noticeable without laboratory tests. Problems in other organs, such as the central nervous system (brain and spinal cord) and lungs may occur, but much less commonly than the skin, bowel and kidneys.

The disease tends to last about 4 weeks, and then resolves spontaneously.

Renal disease
Of the 40% of patients who develop kidney involvement, almost all have evidence (visible or on urinalysis) of blood in the urine. More than half also have proteinuria (protein in the urine), which in one eighth is severe enough to cause nephrotic syndrome (generalised swelling due to low protein content of the blood). While abnormalities on urinalysis may continue for a long time, only 1% of all HSP patients develop chronic kidney disease. Hypertension (high blood pressure) may occur. Protein loss and high blood pressure, as well as the features on biopsy of the kidney if performed, may predict progression to advanced kidney disease. Adults are more likely than children to develop advanced kidney disease.

Criteria
Multiple standards exist for defining Henoch-Schönlein purpura. These include the 1990 American College of Rheumatology (ACR) classification and the 1994 Chapel Hill Consensus Conference (CHCC). Some have reported the ACR criteria to be more sensitive than those of the CHCC.

Treatment
Most patients do not receive therapy because of the high spontaneous recovery rate. Steroids are generally avoided. However, if they are given early in the disease episode, the duration of symptoms may be shortened, although abdominal pain does not improve significantly. Moreover, the changes of severe kidney problems are reduced.

Evidence of worsening kidney damage would normally prompt a kidney biopsy. Treatment may be indicated on the basis of the appearance of the biopsy sample; various treatments may be used, ranging from oral steroids to a combination of intravenous methylprednisolone (a potent steroid), cyclophosphamide and dipyridamole followed by prednisone. Other regimens include steroids/azathioprine, and steroids/cyclophosphamide (with or without heparin and warfarin). Intravenous immunoglobulin (IVIG) is occasionally used.

Recovery and recurrence
Overall prognosis is good in most patients, with one study showing recovery occurring in 94% and 89% of children and adults, respectively (some having needed treatment).

In children, the condition recurs in about a third of all cases and usually within the first four months after the initial attack. Recurrence is more common in older children and adults.

Kidney involvement
In adults, kidney involvement progresses to ESRD more often; in a UK series of 37 patients, 10 (27%) progressed to advanced kidney disease; proteinuria, hypertension at presentation, and pathology features (crescentic changes, interstitial fibrosis and tubular atrophy) predicted progression.

The findings on renal biopsy correlates with the severity of symptoms: asymptomatic hematuria may only have focal mesangial proliferation while those with proteinuria may have marked cellular proliferation or even crescent formation. The number of crescentic glomeruli is an important prognostic factor in determining whether the patient will develop chronic renal disease or end-stage renal disease.

In end-stage renal disease, some progress to hemodialysis or equivalent renal replacement therapy (RRT). If a kidney transplant is found for a patient on RRT, there is a risk of about 35% over 5 years that the disease will recur in the graft (transplanted kidney), and 11% that the graft will fail completely (requiring resumption of the RRT and a further transplant).

History
The disease carries the name of Eduard Heinrich Henoch (1820-1910), a German pediatrician, and his teacher Johann Lukas Schönlein (1793-1864), who described it in the 1860s. The English physician William Heberden (1710-1801) and the dermatologist Robert Willan (1757-1812) had already described the disease in 1802 and 1808, respectively, but the name Heberden-Willan disease has fallen into disuse. William Osler would be the first to see HSP as a form of allergy.