Henoch-Schönlein purpura, as defined by the International Consensus Conference on Nomenclature of Systemic Vasculitides, is “a vasculitis with IgA dominant immune deposits affecting small vessels and typically involving the skin, gut and glomeruli and associated with arthralgias or arthritis.” There is much evidence to suggest that HSP and IgAN represent a spectrum of clinical presentations of similar disorders with HSP being the systemic form of IgAN. Both HSP and IgAN can occur consecutively in the same patient and each has been described in identical twins. Both diseases bear similar immunologic abnormalities and renal histologic findings. Furthermore, a history of recent or simultaneous infection (upper respiratory, gastrointestinal, or urinary tract) is common in children with both HSP and IgAN.
HSP can occur at any age, but preferentially affects children between the ages of 5 and 15 years. It is the most common cause of acute systemic vasculitis in children, with an incidence estimated at 10–20 cases per 100,000 children per year. In adults, the annual incidence is much lower (1.3–1.4/100,000), with a mean age of presentation of about 50 years.
Renal involvement varies depending on the diagnostic criteria used and method of detection of renal disease. In children, nephritis (HSPN) is manifested in 20–40% of cases but occurs more frequently in adults (50–85%).
There are significant gaps in our understanding of the pathogenesis of HSP, although abnormalities in IgA play a central role. Increases in both serum polymeric IgA1 and IgA1-containing immune complexes are present. Deposition of IgA1-containing immune complexes is associated with a systemic small vessel vasculitis and capillary damage. Complement activation, platelet activation, and release of cytokines and growth factors may all contribute to the pathogenesis. Why this leads to systemic vasculitis and extrarenal manifestations in HSP and not in isolated IgAN is unknown. Diminished galactosylation of IgA1 appears to correlate with the presence of nephritis as patients with HSP, but without nephritis, have normal IgA1 glycosylation.
Numerous infectious agents (ie, varicella, HIV, parvovirus B19, hepatitis A and B, mycoplasma, group A streptococci, Epstein-Barr virus, and Campylobacter enteritis) as well as other factors (medications, vaccinations, insect bites) have been linked to the development of HSP, but a causative relationship is unproven. IgA ANCA has also been found in some patients with HSP, but its pathogenetic role and clinical significance are unclear.
The classical clinical presentation includes palpable purpura (present in most cases), polyarthralgias (75–80% of cases), and abdominal pain (50–75% of cases). Symptoms and signs can occur in any order and at any time over a course of several days to weeks, and reflect the systemic leukocytoclastic vasculitis. The skin lesions usually appear as crops of palpable purpura on the lower limbs and buttocks. Gastrointestinal involvement is characterized by colicky abdominal pain sometimes associated with gastrointestinal bleeding (melena, hematochezia, or occult). Joint involvement, consisting of arthralgias or frank arthritis, is typically limited to the knees and ankles, and does not lead to permanent deformity. Pulmonary, neurologic, genitourinary, and cardiac manifestations may also occur.
Renal manifestations may occur within days or up to several weeks after onset of the clinical presentation of HSP, but rarely precedes the other major components of the disease. Renal findings include hematuria (microscopic or gross), proteinuria, and abnormal renal function tests.
Laboratory tests are nonspecific. Coagulation tests and platelet counts are normal despite the presence of dramatic purpuric lesions. Plasma creatinine may be normal or elevated. Serum complement levels are normal and cryoglobulins are absent. Serum IgA levels may be elevated, but measurement of IgA levels is not diagnostic and they do not correlate with disease severity. Urinalysis in affected individuals reveals blood and protein, which is often mild (<500 mg/day), but can be in the nephrotic range. The urine sediment typically has red cells and cellular casts consistent with nephritis.
Confirmation of the diagnosis requires the identification of tissue deposition of IgA in the skin or kidney. Renal biopsy, the more invasive of the two options, is generally reserved for those with an unclear diagnosis or with evidence of more severe renal involvement. Biopsy of skin lesions reveals leukocytoclastic vasculitis with vessel wall necrosis and perivascular accumulation of inflammatory cells, mostly polymorphonuclear leukocytes and mononuclear cells, surrounding the capillaries and postcapillary venules of the dermis. Immunofluorescence reveals the presence of IgA. In some cases, these findings can be seen in areas of skin that appear uninvolved.
In renal biopsies, histologic findings resemble those of IgAN. A mesangioproliferative glomerulonephritis is typical, although some will have a membranoproliferative pattern. Necrotizing glomerular lesions, diffuse endocapillary proliferation, crescents, and fibrin deposits are more frequent in HSPN than in IgAN. Immunofluorescence microscopy demonstrates the characteristic granular deposition of IgA in the mesangium indistinguishable from that seen in IgAN. On electron microscopy, electron-dense deposits are scattered throughout the mesangium. In some patients, prominent capillary wall deposits of IgA and occasionally subepithelial deposits are present.
In children, the characteristic tetrad of rash, joint, gastrointestinal, and renal involvement usually makes the syndrome of HSP clearly identifiable. Clotting disorders, septic emboli, and infections (ie, meningococcemia, gonococcemia, rickettsial) may mimic the findings of HSP. Any of the four major symptoms or signs may be present before the other, which may lead to misdirected evaluations (ie, abdominal pains alone may be mistaken for cholecystitis, appendicitis, and bowel infarction).
The differential diagnosis is much broader in adults and it must be distinguished from other forms of vasculitis including pauci-immune small vessel vasculitis, polyarteritis nodosa, systemic lupus erythematosis (SLE), cryoglobulinemia, and hypersensitivity vasculitis. Clinical and histologic characteristics in combination with serologic testing for ANCA, anti-GBM, cryoglobulins, hepatitis B and C, antinuclear antibody (ANA), and complement levels narrow the diagnosis.
In patients with normal kidney function, treatment is generally supportive. There are limited data available that define the optimal treatment for patients with renal involvement. Most patients require no specific therapy, as spontaneous remission is common. However, in patients with rapidly progressive renal failure caused by crescentic nephritis, aggressive therapy using high-dose pulse methylprednisolone in combination with cyclophosphamide followed by oral prednisone to decrease the inflammatory process may be beneficial. Uncertainty remains as to the optimal duration of therapy. Other regimens used with variable results include azathioprine, dipyridamole, urokinase, immune globulin, and plasma exchange. There are anecdotal reports of abatement of persistent HSP (purpuric rash, hematuria, and proteinuria) with fish oil in combination with ACEI, as well as cyclosporine A/steroid combinations. Prospective randomized clinical trials are needed to truly evaluate the efficacy of any of these agents.
In the majority of patients, HSP is a self-limiting illness characterized by spontaneous resolution of manifestations and a good prognosis. One-third to one-half of patients will have one or more recurrences of symptoms, usually within 6 weeks, but they may recur as late as 3–7 years later.
Transient hematuria and proteinuria typically resolve within several months. Spontaneous recovery may also occur in patients with severe renal involvement including acute renal failure and nephrotic-range proteinuria. The incidence of long-term renal impairment varies among the different series in the literature. In children, renal survival is generally over 95% at 15 years. The prognosis of HSPN in adults may be worse than that of children with up to 30% of adults showing chronic decline in glomerular filtration rate with progression to ESRD. Nephrotic syndrome, persistent proteinuria, elevated serum creatinine at onset, extensive crescents (>50%), and advanced tubulointerstitial disease on renal biopsy are associated with a worse renal prognosis.
Recurrent renal disease can occur in renal transplants. Histologic recurrences of HSPN may occur in up to 50% of renal transplants and are associated with clinical disease in 20% and graft loss in 9% of cases. Graft loss may be more likely in patients who had aggressive initial disease with rapid progression to ESRD, or who undergo transplant either with living related donors or while still clinically active.
Dixit M et al: Managing Henoch–Schönlein purpura in children with fish oil and ACE inhibitor therapy. Nephrology 2004;9;381.