Henoch–schönlein purpura

 

Salient features

 

·       Most commonly occurs in children <10 years of age and in association with a preceding respiratory infection, but may also be seen in adults

 

·       Intermittent palpable purpura on extensor extremities and buttocks

 

·       IgA-dominant immune deposits in walls of small blood vessels

 

·       Arthralgias and arthritis

 

·       Abdominal pain and/or melena

 

·       Renal vasculitis often mild but can be chronic

 

·       In adults, may be associated with an underlying malignancy

 

Introduction

 

IgA vasculitis, previously called Henoch–Schönlein purpura (HSP), is an immune complex vasculitis, a specific form of CSVV characterized by IgA1‐dominant immune deposits affecting small vessels (predominantly capillaries, venules or arterioles) that typically affects children following a  recent upper respiratory tract infection, especially with β-hemolytic streptococcus but may also occur in adults. Sites of involvement include the skin, synovia, gastrointestinal tract, and kidneys. The classic tetrad consists of palpable purpura (100%), arthritis (75%), abdominal pain (50%) and hematuria (50%).

 

Epidemiology

 

HSP is the most common form of vasculitis in children, with an incidence of 10 to 20 cases per 100 000 children per year. The average age of onset is 6 years and 90% of cases occur in children <10 years of age. In adults, the incidence of HSP is 8 to 18 cases per million. HSP has a slight male predominance in both children and adults.

 

Pathogenesis

 

HSP frequently presents 1 to 2 weeks following an upper respiratory tract infection, especially in children. Streptococcal infections predispose to IgA vasculitis, and antistreptolysin O titer positivity confers a 10‐fold risk of IgA vasculitis.

The pathogenesis of IgAV is still largely unknown. The disease is characterized by IgA1-immune deposits, complement factors and neutrophil infiltration, which is accompanied with vascular inflammation. Incidence of IgAV is twice as high during fall and winter, suggesting an environmental trigger associated to climate. In IgA nephropathy immune complexes containing galactose-deficient (Gd-)IgA1 are found and thought to play a role in pathogenesis. Alternatively, it has been proposed that in IgAV IgA1 antibodies are generated against endothelial cells and that such IgA complexes can activate neutrophils via the IgA Fc receptor FcαRI (CD89), thereby inducing neutrophil migration and activation, which ultimately causes tissue damage in IgAV.

Certain genetic polymorphisms may predispose to more severe disease in HSP. For example, HLA-B35 positivity may predispose to renal disease, while patients who do not have the ICAM-1 469 K/E variant have less severe gastrointestinal involvement.

 

 

 

IgA (specifically IgA1) is thought to play a significant role in the pathogenesis of HSP, as IgA deposits in the walls of postcapillary venules of the skin and in the renal mesangium, circulating  immune complexes containing IgA and increased serum levels of IgA (in 50% with active disease), have been demonstrated in patients with HSP. In IgA vasculitis, IgA1 rather than IgA2 is the main IgA subclass deposited in skin lesions. Lack of glycosylation of the hinge region of IgA1 may promote the formation of macromolecular complexes that lodge within the mesangium and activate the alternate complement pathway.

 

 

Clinical features

 

 

 

 

Most commonly, IgA vasculitis manifests at the outset with the classic findings of purpura, arthralgia and abdominal pain. Fever occurs in approximately 20% of adults and 40% of children. Rarely, gastrointestinal involvement and arthritis can occur in the absence of skin disease.

 

The cutaneous lesions begin as erythematous macules or urticarial papules, which may evolve within 24 h into palpable purpura with hemorrhage.  Hemorrhage vesicles and bullae and necrotic ulcers may develop. A retiform pattern (raised, geometric, net like presentation) within lesions is characteristic, but not always present. The presentation may be identical to CSVV. Although it typically involves the extensor aspects of the upper and lower limbs (especially the elbows and knees) and buttocks in a symmetrical fashion, IgA vasculitis may also affect the trunk and face. Individual lesions usually regress within 10 to 14 days, with resolution of skin involvement over a period of several weeks to months.

 

Extracutaneous manifestations of HSP are common. Painful arthritis occurs in up to 75% of patients, most frequently affecting the knees and ankles. Gastrointestinal involvement (65% of patients) may precede the purpura and presents with bowel angina (diffuse abdominal pain that is worse after meals), bowel ischemia, usually including bloody diarrhea and/or vomiting. Intussusception and bowel perforation are rare complications.

Renal involvement with IgA vasculitis is common, occurring in approximately 40–50% of patients; 25% have gross hematuria and the remainder microscopic hematuria. Proteinuria occurs in 60% of these, but is uncommon in the absence of hematuria. Although the appearance of cutaneous lesions often precedes the development of nephritis, the latter is clinically evident within 3 months. In pediatric patients, risk factors for the development of nephritis include age >8 years at onset, abdominal pain, and recurrent disease. Less common manifestations of IgA vasculitis include orchitis (in 10–20% of boys), pancreatitis, neurological abnormalities, uveitis, and carditis. The lung is also a rare site of involvement, presenting as hemoptysis and/or pulmonary infiltrates due to diffuse alveolar hemorrhage. Poor prognostic factors include renal failure at the time of onset, nephrotic syndrome, and hypertension and decreased factor XIII activity.

IgA small vessel vasculitis in adults, termed adult HSP, should be considered separately, as the clinical presentation and prognosis differ from that in children. For example, necrotic skin lesions are present in 60% of adults while cutaneous necrosis is observed in <5% of children. Adults with IgA vasculitis are also more likely than children to develop chronic renal insufficiency (up to 30%), especially if they have purpura above the waist, fever and an elevated ESR. In addition, when CSVV is due to an underlying neoplasm, the latter is usually a hematologic malignancy rather than a solid organ malignancy.  However, 60–90% of adult patients with neoplasm-associated IgA vasculitis will have cancer of a solid organ, in particular lung. Adults are also more likely than children to have diarrhea and leukocytosis, to require more aggressive therapy, and to have a longer hospital stay.

 

Complications and co‐morbidities

 

End‐stage renal disease is uncommon but, if it occurs, may need renal transplantation. Renal transplant survival is over 80% at 5 years.

 

Disease course and prognosis

• Abdominal pain usually settles within a few days.
• About 25% of patients will relapse of the disease within 6 months and typically the relapse is mild and easily treated.
• IgA vasculitis can become chronic in 5–10% of patients, the cutaneous involvement usually lasting between 6 and 16 weeks.
• Patients without kidney involvement can expect to fully recover within 4-6 weeks.
• Only 1% of these patients will go on to develop end stage renal disease.

 

Investigations

 

IgA vasculitis is a clinical diagnosis, with confirmation by direct immunofluorescence and routine histology.

 

Leukocytoclastic vasculitis of the small dermal blood vessels is seen. Perivascular IgA deposits in DIF are characteristic of IgA vasculitis and can help to distinguish it from other vasculitides including CSVV. Of note, a small subset of patients has been described that meets clinical criteria of HSP but lacks IgA deposition on DIF.

 

 

Differential diagnosis

Because up to 80% of all adults with CSVV may demonstrate some vascular IgA deposition and IgA deposition can be seen in other diseases (e.g. drug hypersensitivity, IgA monoclonal gammopathy, inflammatory bowel disease, lupus erythematosus, cryoglobulin­emia), a diagnosis of HSP is supported by IgA predominance in the correct clinical setting. Of the several proposals for diagnostic criteria, the one developed by the European League against Rheumatism/Pediatric Rheumatology European Society (EULAR/PReS), may be the most clinically relevant to the dermatologist. In addition to palpable purpura (a required criterion), at least one of the following must be present:

	•	arthritis (acute, any joint) or arthralgia
	•	diffuse abdominal pain that is worse after meals
	•	any biopsy demonstrating predominant IgA deposition
	•	Renal involvement in the form of hematuria and/or proteinuria.

 

Treatment

 

Because HSP is generally self-limited and resolves over the course of weeks to months, treatment is mainly supportive. Dapsone and colchicine may decrease the duration of cutaneous lesions and frequency of recurrences. Systemic corticosteroids (prednisolone 1 mg/kg/day for 2 weeks, tapering over a further 2 weeks), are effective in treating the arthritis and abdominal pain associated with HSP, as well as reducing the gastrointestinal complications and duration of skin lesions, but do not prevent recurrences of purpura. Referral to a nephrologist is appropriate for patients with evidence of renal involvement. In adults, the following factors may predict relapsing disease: age >30 years, an underlying systemic disorder, persistent purpura >1 month, abdominal pain, hematuria, and absence of IgM on DIF.

Considerable controversy surrounds the use of corticosteroids and/or immunosuppressive medications for the treatment of severe renal disease and for preventing renal sequelae in individuals who have severe renal involvement. Pulsed intravenous methylprednisolone, cyclosporine A, cyclophosphamide, azathioprine and mycophenolate mofetil are used for the treatment of severe renal disease. In sum, the current consensus appears to be that corticosteroids do not prevent renal disease but could be used to treat severe nephritis.