Henoch-Schönlein purpura (HSP) is a small vessel vasculitis that can affect the skin, joints, connective tissue, gastrointestinal tract, and kidneys. It usually affects children who are between the ages of 3 and 15, among whom the incidence is approximately 10 to 20 per 100,000/year. Less often, HSP may also affect adults, generally with more severe symptoms.
HSP occurs secondary to deposition of IgA1-dominant immune complexes in arterioles, capillaries, and venules. The pathology of the renal lesion is indistinguishable from that seen in IgA nephropathy; indeed, many consider the two conditions to be on the same pathogenetic spectrum, with HSP distinguished by the presence of extrarenal involvement.
The pathogenesis of HSP is largely unknown. Systemic deposition of IgA appears to activate the alternative complement pathway. As in IgA nephropathy (see Plate 4-16), abnormal underglycosylation of the IgA1 hinge region appears to play a role in promoting abnormal deposition, although the exact mechanisms remain poorly understood. As in IgA nephropathy, the renal disease is associated with IgA binding of mesangial cells and subsequent inﬂammation.
IgA1 antibodies are produced by peripheral B lymphocytes, but the reason for their abnormal production is unclear. Case reports have noted that HSP occurs after antecedent infections with measles, hepatitis, varicella, group A Streptococcus, and tuberculosis, as well as after vaccinations and insect bites. Although these ﬁndings suggest that abnormal immune responses to common pathogens may play a role, such an association remains speculative.
PRESENTATION AND DIAGNOSIS
The major features include palpable, nonblanching purpura (often on the lower extremities), nonerosive oligoarthritis, renal disease, and gastrointestinal disease. Most patients, however, do not exhibit all four of these components.
The renal disease can include microscopic or macroscopic hematuria, proteinuria, renal insufﬁciency, or a combination. Especially in adults, the proteinuria may be severe enough to cause signs and symptoms of the nephrotic syndrome, and acute kidney injury may also occur. The gastrointestinal disease, which occurs secondary to submucosal edema and hemorrhage, may be limited to pain and vomiting. Some patients, however, may experience more signiﬁcant complications, such as frank gastrointestinal hemorrhage or intussusception. Less common systemic manifestations include scrotal pain or swelling, as well as central nervous system disease (i.e., headache, seizures).
The major presenting symptoms tend to be palpable purpura and arthritis, with gastrointestinal and renal involvement developing in some patients over subsequent days and weeks. This sequence, however, is not universal; in 20% to 40% of patients, for example, gastrointestinal symptoms may precede the rash. Like-wise, 20% to 50% may have renal involvement at the initial presentation. Urinalysis may be remarkable for dysmorphic red blood cells, red blood cell casts, and protein. Laboratory analysis of serum is generally unremarkable, although some patients may have evidence of mild renal dysfunction. In addition, those with more severe proteinuria may be found to have hypoalbuminemia and hypercholesterolemia as parts of the nephrotic syndrome. Complement levels are generally normal. Frank gastrointestinal bleeding may cause anemia, which should be assessed using guaiac testing of stool.
Platelet counts and assays of clotting function should be normal, which can be used to exclude other causes of purpura. IgA levels are elevated in about half of patients but are neither sensitive nor speciﬁc for the diagnosis of HSP.
According to current diagnostic criteria, a patient is considered to have HSP if purpura or petechiae have a lower limb predominance, there is no evidence of thrombocytopenia or coagulopathy, and any one of following four criteria are met: (1) abdominal pain; (2) arthritis or arthralgia; (3) renal involvement (hematuria, proteinuria); and (4) histopathology showing IgA dominant or codominant deposition. The diagnosis can usually be established based on clinical indicators. When the diagnosis is uncertain but the level of suspicion is high, a skin biopsy may be performed, which classically reveals a leukocytoclastic vasculitis with IgA- dominant deposition seen on immunoﬂuorescence.
In patients with marked renal insufﬁciency, a renal biopsy may be performed to determine the extent of disease and assess for the presence of rare but serious manifestations, such as crescentic glomerulonephritis (see Plate 4-25). The renal pathologic ﬁndings are nearly identical to those seen in IgA nephropathy (see Plate 4-17). Using light microscopy, mesangial hyper- cellularity is often the major feature. In more severe cases, there may be variable amounts of endocapillary leukocyte inﬁltration and cellular crescent formation, with the latter portending a poorer prognosis. In the most severe cases, the glomerular basement membrane may appear “split,” as in membranoproliferative glomerulonephritis (see Plate 4-22).
Immunoﬂuorescence reveals dominant or codominant granular staining for IgA in the mesangium and sometimes the capillary wall. Staining for IgG and IgM may also be positive but with less intensity. The immune deposits often colocalize with C3 but only rarely with C1q. Finally, electron microscopy reveals electron dense deposits that correspond with the pattern of immune complex deposition seen on immunoﬂuorescence.
Most patients experience self-limited disease that resolves within weeks to months. During this time, treatment is mostly supportive. Nonsteroidal anti inﬂammatory drugs may be given for relief of arthritis. These do not appear to substantially increase the risk of gastrointestinal hemorrhage but may be avoided in patients with existing hemorrhage or with poor renal function (because of their effect on tubule glomerular feedback [see Plate 3-18]).
Unfortunately, there is a paucity of controlled trials regarding the treatment of severe HSP. There is some evidence that corticosteroids may improve gastrointestinal symptoms and arthritis. There is no evidence, however, that corticosteroids, cyclophosphamide, or any other agents are effective in the treatment of HSP-associated renal disease. Such agents are often given to patients with more severe disease seen on renal biopsy, such as cellular crescents, but their efﬁcacy remains anecdotal. Plasmapheresis has also been attempted, with limited data indicating a beneﬁcial effect.
After the initial episode resolves, about one third experience bouts of disease recurrence, which are usually mild and occur during the ﬁrst several months after presentation. Patients should thus receive careful follow-up during this period.
Most children have normal long-term renal function, with a small fraction experiencing persistent sediment abnormalities and even fewer experiencing renal insufﬁciency. In contrast, adults appear to have a worse renal prognosis, with a large series ﬁnding that 15% experienced ongoing moderate insufﬁciency, 13% developed advanced chronic kidney disease, and 10% progressed to ESRD. Worse prognoses are more likely in those who develop more severe renal symptoms and are found to have markers of more signiﬁcant inﬂammation, such as cellular crescents, on renal biopsy.
Renal transplantation can be performed on those who have progressed to ESRD. Disease recurrence, however, occurs in up to 25% of patients at 5 years. Although overall graft and patient survival are similar, recurrence can be associated with graft loss, especially in patients with necrotizing or crescentic lesions in their native kidneys.