Page 826 - Clinical Immunology_ Principles and Practice ( PDFDrive )

798 Part SIX Systemic Immune Diseases

PATHOGENESIS OF EGPA define disease entities. They are not true classification or diagnostic
criteria because they are not evidence based (they are consensus
Despite the established role of ANCA in GPA and MPA, the of opinion from several experts); but they have advantages over
pathogenic role of ANCA in EGPA is less clear. In EGPA, only the 1990 ACR criteria. They were developed after recognition
30–40% of patients are ANCA positive; the presence or absence of ANCAs, which are an important part of the 2013 definitions.
of ANCA in EGPA defines distinct clinical phenotypes. The One of the major flaws of the ACR criteria is the failure to
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pathological hallmark of EGPA is prominent tissue and peripheral recognize MPA as an entity separate from PAN. This failure to
blood eosinophilia, suggesting a central pathogenic role for the separate PAN and MPA has probably prevented proper diagnosis,
eosinophil. EGPA is considered to be Th2 mediated, given the and it is a historical legacy from an assumption that almost all
striking early allergic manifestations, together with the marked forms of vasculitis are, in fact, variations of PAN.
increase in circulating Th2 cytokines, including IL-5, which plays
a crucial role in eosinophil differentiation in bone marrow as DIAGNOSIS
well as recruitment and activation of eosinophils at sites of
inflammation. IL-5 could delay apoptosis of eosinophils and Individual Diseases
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modulate the function of mast cells and basophils. Elevated AAV are a group of three main entities: GPA, MPA, and EGPA.
levels of IFN-γ (a potent Th1 cytokine involved in granuloma These three conditions overlap with many shared clinical features.
formation) provide evidence for the involvement of other Th Figs. 58.2 and 58.3 describe clinical patterns in patients with
responses. Th17 responses are upregulated, and B lymphocytes MPA and GPA and show that there are many similarities, with
and humoral responses are likely to be important, given that a dominance of kidney and lung involvement in both conditions.
B-cell depletion can induce remission and reduce circulating EGPA is characterized by eosinophilia, late-onset asthma, and
IL-5 and eosinophils. neuropathic involvement, but cardiac involvement may develop
The precise mechanisms of eosinophil-mediated inflammation in a subset of patients with EGPA, particularly in association
in EPGA remains unclear. Eosinophils are granulocytic cells with hypereosinophilia. Systemic features, such as malaise, fever,
capable of releasing multiple proinflammatory cytokines, che- weight loss, or myalgia, could be mistaken for a variety of other
mokines, and reactive oxygen species, which have direct effects conditions, and it may delay recognition of disease. Patients with
on the vessel and perivascular tissues, including tissue fibrosis, MPA can present just with isolated microscopic hematuria and
thrombosis, and allergic inflammation; indirect effects include hypertension, with nonspecific systemic features. In contrast,
recruitment and activation of other inflammatory cells to perpetu- patients with GPA typically suffer from upper airway problems,
ate the inflammatory response. with nasal crusting, blood-stained discharge, sinusitis, or hearing
loss. In anti–glomerular basement membrane (anti-GBM)
CLASSIFICATION antibody disease, clinical features sometimes overlap with those
of AAV, but the dominant features are pulmonary hemorrhage
Several sets of classification criteria have been published, the most leading to hemoptysis and rapid deterioration in renal function.
recent being one by the American College of Rheumatology (ACR) It is not entirely clear whether the anti-GBM disease should be
in 1990. These are primarily for the purposes of epidemiological regarded vasculitis or vasculopathy, but it has been included in
studies or for defining patients for inclusion in clinical studies, the current Chapel Hill Consensus definitions of a small-vessel
rather than being used in clinical practice. However, as is often the vasculitis. Confusingly, some patients with anti-GBM antibodies
case with classification criteria, they are misapplied as diagnostic also have ANCA.
criteria in daily practice and may fail to provide a clear-cut distinc- The clinical course in MPA is typically acute, whereas GPA
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tion between vasculitis and other conditions. An international may remain undiagnosed for several months or even years before
effort is currently underway to develop improved classification the upper airway and or lower airway symptoms are recognized
criteria as well as diagnostic criteria for patients with vasculitis as being related to vasculitis. For almost all forms of acute AAV,
or suspected vasculitis, and it is likely to lead to a new set of the differential diagnosis is infection, cancer, or drug toxicity.
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evidence-based criteria to improve diagnosis and classification of One of the drugs recently recognized to mimic AAV is cocaine,
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vasculitis in the future. There is considerable overlap between which can cause local tissue necrosis, especially in the palate,
different forms of vasculitis. The group of patients with diseases leading to palatal and nasal septal perforation. Interestingly
clustered around the presence of ANCA share many features cocaine can induce ANCA production and therefore can be a
in common, particularly the presence of glomerulonephritis true mimic of AAV. Typically the ANCA is directed against elastase
and pulmonary infiltrates. In the case of EGPA, patients also or is nonspecific. Careful history taking, sometimes with sensitive,
experience rhinitis, nasal polyps, asthma, and rashes and may confidential, repeated questioning, may be required to eventually
develop mononeuritis multiplex or sensory peripheral neuropathy. identify this as a cause of a patient’s condition. Contamination
In addition to renal and lung inflammation, patients with GPA of cocaine with levamisole is becoming a growing problem.
typically suffer from upper respiratory problems, such as nasal Presumably, levamisole (a veterinary anthelmintic agent) is a
crusting or discharge; subglottic stenosis; or hearing loss. Patients cheap white powder that can be mixed readily with cocaine but
with MPA do not usually develop significant upper airway disease; can cause an acute necrotizing vasculitis of skin and the extremi-
their disease tends to be more limited to the kidneys and/or lungs. ties. Discontinuation of levamisole and cocaine usually stops
All of these conditions can also affect any other organs, such as further progression of disease, but once palatal or nasal perforation
skin. Skin is the most commonly affected site in most forms of has developed, patients may require local surgical repair.
vasculitis. This can vary from small infarcts around nail edges Cryoglobulinemic vasculitis typically presents with purpuric
to purpura, ulcers, nodules, and even gangrene. lesions on the legs, and the lesions may ulcerate. Patients often
The development of consensus criteria for diagnosis by the complain of joint pains and malaise. Neuropathies can occur
Chapel Hill group has provided a more rational approach to with either mononeuritis multiplex or sensory neuropathy;