Page 821 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 58 Small- and Medium-Vessel Primary Vasculitis 793

prevalence of skin involvement, anemia, abnormal liver functions, with PTU-induced AAV (usually MPO-positive) are younger,
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and elevated α-fetoprotein (FP) levels ; however, the findings more commonly female compared with those with primary AAV,
were not replicated in other studies. 34 and usually have significantly higher anti-MPO ANCA titers
Lysosomal-associated membrane protein 2 (LAMP-2) is a compared with patients without vasculitis. Other ANCA subtypes
heavily glycosylated type 1 membrane protein, abundant on may be found, including HNE-ANCA and lactoferrin (LF)-ANCA;
neutrophil and endothelial cell surfaces, which shuttles between however, when PTU-induced AAV develops, MPO-ANCA is
lysosomes and the cell membrane. LAMP-2 cross-reacts with usually present, regardless of the existence of other forms of
FimH, a gram-negative adhesin, which facilitates bacterial entry ANCA. The pathogenesis of AAV related to antithyroid drugs
to host tissues. Preliminary studies have suggested a role for is unclear. PTU is predominantly metabolized in the liver, but
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LAMP-2 in small-vessel vasculitis. The LAMP-2 epitope P41–49 a proportion is modified by MPO in neutrophils. Neutrophils
has been reported to have a 100% homology with amino acids are responsible for neutrophil extracellular trap (NET) formation,
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72–80 of mature FimH. Antibodies to human LAMP-2 have and PTU can induce abnormal configured NETs in vitro; these
been shown to injure human microvascular endothelium in abnormal NETs cannot easily be released into liquid phase and
vitro and induce focal necrotizing glomerulonephritis (FNGN) are not effectively digested by DNase I, therefore remaining in
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in rats; immunization with FimH-induced pauciimmune FNGN the tissue. Immunization of rats with abnormal NETs results
associated with antibodies that bound human and rat LAMP-2; in production of MPO-ANCA. 39
furthermore, patients with pauciimmune FNGN were found to
have an increased likelihood of infections with FimH-expressing Hydralazine
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bacteria shortly before presentation of their FNGN. LAMP-2 Hydralazine is widely used to treat hypertension, acting as a
antibodies were found in patients with active disease or relapse smooth muscle relaxant and causing arterial and arteriolar
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but not in those in remission. Although this a promising vasodilation. It has been implicated in the development of drug-
new explanation for some cases of small-vessel vasculitis, induced SLE and AAV. High titers of MPO-ANCA, ANA,
the lack of replication of these findings makes them hard to anti–double-stranded DNA (dsDNA), and antihistone antibodies
substantiate. are found; hypocomplementemia is also frequent. The underlying
CpG-oligodeoxynucleotides (ODN) is a short synthetic DNA mechanism of action for hydralazine-induced AAV is not clear.
containing unmethylated CpG motifs, highly prevalent in bacterial One potential pathway by which hydralazine acts is through
DNA, and recognized by Toll-like receptor 9 (TLR9), which is reverse epigenetic silencing of tumor suppressors, but also
expressed by a variety of cells in the immune system. TLR9 potentially of MPO and PR3.
triggering results in proinflammatory IL production. It has been
reported that CpG motifs and IL-2 exposure can induce B Levamisole-Contaminated Cocaine
lymphocytes to proliferate, increase antigen presentation, produce It is commonplace for illicit drugs, such as cocaine, to be combined
a range of cytokines, and differentiate into Ig-producing cells, with adulterants, such as levamisole, in an effort to increase
ultimately leading to ANCA production. 36 profits. Levamisole is similar in physical appearance and has
possible potentiating effects on levels of dopamine in the central
DRUG INDUCED AAV nervous system. It is estimated that >75% of cocaine users in
the United States are exposed to levamisole.
The most commonly implicated drugs that can induce an Clinical manifestations of AAV induced by levamisole-
AAV-like syndrome are propylthiouracil (PTU), hydralazine, contaminated cocaine include constitutional features; arthralgia;
levamisole-adulterated cocaine, TNF-α inhibitors, sulfasalazine, retiform purpura involving the ears, face, and extremities; and,
D-penicillamine, and minocycline (Fig. 58.1). less commonly, renal and lung diseases. Laboratory abnormalities
include leukopenia, neutropenia, and high-titer p-ANCA, directed
Propylthiouracil against MPO-ANCA or against atypical p-ANCA–associated
The most commonly described drug associated with the presence antigens, such as HNE, lactoferrin, and cathepsin G. PR3-ANCA,
of ANCA is propylthiouracil (PTU). PTU is used to treat hyper- ANA, and antiphospholipid autoantibodies have also been
thyroidism and was the first drug described to induce a condition described in these patients. This multiplicity of antibodies helps
mimicking AAV in the 1990s. Even though its use has declined distinguish AAV induced by levamisole-contaminated cocaine
over time, reports of PTU-induced AAV still emerge. Clinically, from primary AAV, which usually targets just one antigen.
PTU-induced AAV may manifest as acute kidney injury caused Levamisole has an estimated mean half-life of 5.6 hours;
by pauciimmune necrotizing and crescentic glomerulonephritis therefore serum testing is likely to be negative if the most recent
in addition to respiratory tract, joint, and skin diseases. exposure occurred >24 hours prior to sample collection. Urinary
Reports of the proportion of patients who develop ANCA as detection of levamisole is highly suggestive of drug-induced
a result of exposure to antithyroid medications varies widely disease and is useful if exposure occurred <48 hours prior to
from 4% to 46%; by contrast, the prevalence of antithyroid testing.
drug-induced AAV is much lower (0–1.4%). Although PTU is The mechanism by which levamisole-contaminated cocaine
the most commonly reported antithyroid drug, methimazole induces AAV is unclear. Levamisole, like PTU, could serve as
and carbimazole have also been implicated. In a study by Noh a substrate for MPO to form reactive metabolites that might
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et al., the estimated annual incidence of antithyroid drug- induce autoimmunity. Levamisole can enhance NETosis through
induced vasculitis was 0.53–0.79 patients per 10 000 patients engagement of muscarinic (subtype 3) receptors; furthermore,
with Graves disease, especially for patients receiving propylthio- neutrophil extracellular traps (NETs) generated by levamisole
uracil; the ratio of the estimated incidence for methimazole and can induce endothelial cell death and vascular dysfunction by
propylthiouracil was 1 : 39. Most patients with PTU-induced disrupting normal endothelium-dependent vasorelaxation.
ANCA will not develop clinical features of vasculitis. Patients Abusing cocaine without levamisole can also trigger a syndrome