Answers

Short answers

1 Additional studies should include a faecal occult blood test, serology for hepatitis B and C, serum protein electrophoresis, anti-streptolysin O titre, and measurement of antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, serum immunoglobulins, and cryoglobulins. Abdominal ultrasound and renal biopsy may also be indicated.

2 The most likely diagnosis is Henoch-Schönlein purpura or anaphylactoid purpura, a leucocytoclastic vasculitis of small vessels.

3 Complications of Henoch-Schönlein purpura include nephritis or nephrotic syndrome, acute and chronic renal failure, gastrointestinal bleeding, intussusception, bowel obstruction, and bowel perforation.

Long answers
1 Investigations
Cutaneous palpable purpura may signify small vessel vasculitis, which has many possible causes (box 1).^{1 2} Histological findings of leucocytoclastic vasculitis include fibrin deposition in the vessel walls, red blood cell extravasation, and neutrophilic leucocytoclasis.

Box 1 Causes of leucocytoclastic vasculitis1 2 Infections: β haemolytic streptococcal infection, Clostridium difficile, Helicobacter pylori, Mycobacterium tuberculosis, bacterial endocarditis, hepatitis B, hepatitis C, HIV, measles, mumps, varicella, parvovirus B19, coxsackie virus, adenovirus Drugs: non-steroidal anti-inflammatory drugs, β lactam antibiotics, diuretics, vancomycin, ranitidine, cefuroxime, diclofenac, streptokinase, and angiotensin converting enzyme inhibitors Collagen vascular diseases: rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, mixed cryoglobulinaemia (type II and type III) Inflammatory bowel disease: ulcerative colitis, Crohn’s disease Primary systemic vasculitides: Henoch-Schönlein purpura, antineutrophil cytoplasmic antibody associated vasculitis, urticarial vasculitis, polyarteritis nodosa Other: acute haemorraghic oedema of infancy, hairy cell leukaemia, multiple myeloma, non-Hodgkin’s lymphoma, prostate cancer, non-small cell lung cancer, food additives, exposure to cold

Patients who present with leucocytoclastic vasculitis should have a detailed history taken, and a thorough physical examination and laboratory work-up should be performed.² A complete blood count, platelet count, peripheral blood smear, and coagulation studies help rule out haematological causes. Urinalysis, estimation of glomerular filtration rate, a liver function test, urine protein to creatinine ratio, analysis of urine sediment, and measurement of blood urea nitrogen, serum creatinine, and proteinuria should be undertaken to look for renal or hepatic involvement. Serum protein electrophoresis may also be helpful. A raised erythrocyte sedimentation rate and C reactive protein concentration indicate ongoing inflammation.

Serum complement, rheumatoid factor, antinuclear antibody, anti-double stranded DNA, extractable nuclear antigen, and antineutrophil cytoplasmic antibodies should be measured to search for immunological causes of leucocytoclastic vasculitis. Immunoglobulins should be measured because hypergammaglobulinaemia can cause purpura.

Serology for hepatitis B and C, serum cryoglobulins, and cryofibrinogens may also help pinpoint the cause of vasculitis. Chest radiography and blood and urine cultures can detect occult infection. A positive pharyngeal culture and raised anti-streptolysin O and anti-DNAse B titres may indicate streptococcal infection.

Echocardiography should be performed to look for endocarditis, and stools should be examined for occult blood to look for gastrointestinal involvement, especially if Henoch-Schönlein purpura is suspected.

2 Likely diagnosis
According to the new classification of vasculitides from the European League against Rheumatism (EULAR) and the Paediatric Rheumatology European Society (PRES), Henoch-Schönlein purpura is a type of non-granulomatous, predominantly small vessel vasculitis.³ Classic clinical features include palpable purpura, arthritis or arthralgias, and abdominal pain. Although diagnosis is typically made on a clinical basis only, skin biopsy is recommended in patients with atypical presentations. Henoch-Schönlein purpura is a small vessel vasculitis characterised by leucocytoclastic vasculitis with deposition of IgA and C3. Palpable purpura are mandatory for the diagnosis of Henoch-Schönlein purpura, according to the EULAR/PRES consensus (box 2).³

Box 2 Criteria for classification of Henoch-Schönlein purpura (2006)3 Palpable purpura (mandatory criterion) in the presence of at least one of the following features: Diffuse abdominal pain Any biopsy showing predominant IgA deposition Arthritis (acute, any joint) or arthralgia Renal involvement (haematuria or proteinuria)

In Henoch-Schönlein purpura, palpable purpura are typically located on the lower extremities, often extending to the extensor aspects of the arms and buttocks, and they are the presenting symptom in 75% of cases.⁴ The condition usually resolves without treatment but may recur and last up to four months, particularly in adults. Arthralgias and arthritis, although usually transient, may be the presenting symptom in only 15-25% of cases. They are caused by periarticular oedema and inflammation.^{4 5 6} Abdominal pain may occur as a result of petechial eruptions of the gastrointestinal tract that causes submucosal haemorrhage and oedema.⁷ Melaena, bright red blood in the stool, and haematemesis are possible manifestations of gastrointestinal involvement. A faecal occult blood test is an important diagnostic test which should be done in all patients with suspected Henoch-Schönlein purpura. Other rare systemic manifestations include subtle encephalopathy, seizures, cerebral haemorrhages, and diffuse alveolar haemorrhage.⁸ Swelling and tenderness of the scrotum and penis has been reported in boys, as a result of generalised oedema secondary to hypoalbuminaemia from renal and gastrointestinal involvement.⁸ Although the condition occurs mainly in children, it is also seen in adults. The table highlights the differences between paediatric and adult presentations.

View this table: [in this window] [in a new window]   Differences between childhood and adult Henoch-Schönlein purpura9 10

 
Although the exact cause of Henoch-Schönlein purpura is unknown, it is thought to be an autoimmune reaction triggered by infection, particularly with group A streptococci, Clostridium difficile, Helicobacter pylori, Mycobacterium tuberculosis, measles, mumps, varicella, parvovirus B19, coxsackie virus, and adenovirus.^{11 12} Certain drugs are also implicated in the onset of the disease, including vancomycin, ranitidine, cefuroxime, diclofenac, streptokinase, and angiotensin converting enzyme inhibitors. Other reported associations are leukaemia, multiple myeloma, non-Hodgkin’s lymphoma, prostate cancer, non-small cell lung cancer, food allergies, and exposure to cold.^{12 13}

The pathogenesis of Henoch-Schönlein purpura is not known, but deposits of an abnormal IgA1 isotype have been found in the skin, glomerular membrane, and gastrointestinal blood vessels. The abnormal glycosylation of the IgA1 isotype has been found to cause molecular instability, which increases the risk of proteolysis.¹⁴ Serum concentrations of tumour necrosis factor , a proinflammatory cytokine, have been found to correlate with the degree of renal impairment in Henoch-Schönlein purpura.¹⁵ Polymorphism of the gene encoding interleukin 1β may also correlate with the severity of nephropathy. Polymorphisms of the angiotensinogen and angiotensin converting enzyme genes may play a role in the development and the severity of Henoch-Schönlein purpura and associated nephropathy, but the data are conflicting.¹⁴

3 Complications
Although Henoch-Schönlein purpura is generally a self limiting disease that lasts about a month, rare but serious gastrointestinal and renal complications may occur. As stated earlier, genetic polymorphisms may be the predisposing or protective factors in developing these complications.

One potentially serious gastrointestinal complication of Henoch-Schönlein purpura is intussusception, which occurs more commonly in children (1-5% of children with Henoch-Schönlein purpura).¹⁶ An abdominal ultrasound may be indicated in children with abdominal pain. Other less common complications include bowel perforation (with or without intussusception), pancreatitis, and massive gastrointestinal haemorrhage.¹⁷

Renal complications carry a high morbidity in patients with Henoch-Schönlein purpura. Although otherwise indistinguishable from IgA nephropathy, Henoch-Schönlein purpura associated nephritis may manifest with focal and segmental proliferative glomerulonephritis and crescent formation.¹⁴ IgA and C3 are deposited around the capillaries, venules, and in the glomeruli. In addition, IgG, IgM, and fibrin may be deposited in the renal mesangium. In one retrospective study with mean follow-up of just under five years, chronic renal insufficiency occurred in up to 15% of adults and 7% of children with kidney disease severe enough to warrant biopsy.¹⁸ In addition, proteinuria greater than 1 g in 24 hours may be associated with the development of end stage renal disease.¹⁹ Urine analysis will indicate the degree of haematuria and proteinuria, if any, and if these analyses are abnormal, kidney biopsy may be indicated.

Treatment of Henoch-Schönlein purpura is mainly supportive care and removal of possible precipitating causes. Analgesics are indicated for joint and abdominal pain.²⁰ Systemic steroids have been used in patients with arthralgia or arthritis, gastrointestinal haemorrhages, and kidney involvement. These drugs do not stop or alter the courses of the disease process, particularly in the case of associated acute renal disease with haematuria and proteinuria.²¹ Cyclophosphamide, azathioprine, plasmapheresis, and intravenous immunoglobulin have shown limited success.⁸

Our patient had a kidney biopsy because of persistent haematuria and proteinuria. She was found to have IgA nephropathy with focal segmental necrosis and crescent formation.

She was treated with prednisolone 60 mg daily and her skin lesions rapidly improved. However, she developed hypertension and hyperglycaemia, probably as a result of the drug treatment. Prednisolone was lowered to 40 mg daily and subcutaneous insulin was started. Her hypertension and blood glucose subsequently improved. At follow-up her haematuria and proteinuria had resolved, and systemic steroids were gradually reduced.

Cite this as: BMJ 2009;338:b1284