Page 893 - Clinical Immunology_ Principles and Practice ( PDFDrive )

864 Part SEVEN Organ-Specific Inflammatory Disease

have provided additional support for the critical role of anti-type relationship to herpes virus infections. The term pemphigoid
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VII collagen antibodies in the pathogenesis of EBA. In experi- gestationis eliminates this confusion and emphasizes the patho-
mental mouse-model EBA, induction of specific types of antibod- physiological similarity of PG to BP.
ies is linked to the MHC haplotype suggesting future work may PG is rare, occurring in <1 in 50 000 pregnancies in North
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identify non-MHC EBA susceptibility genes. Utilizing a four-way, America. It usually presents in the third trimester or in the
autoimmune-prone, advanced mouse intercross line immunized immediate postpartum period. Disease flare-ups beyond the
with a COL7 fragment to induce EBA, investigators identified immediate postpartum period do occur, and patients have been
quantitative trait loci (QTLs) on chromosomes 9, 12, 14, and reported to develop blisters when menses return or when oral
19 associated with disease development and QTLs on chromo- contraceptives are used. Although PG may recur in subsequent
4
somes 1, 15, and 19 associated with maximum disease severity. pregnancies, this is not absolute.
In this model, gene–microbiota interactions appear to promote PG presents as tense blisters, often on an urticarial base,
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disease development. Finally, identification of other mediators ranging in size from small (3–5 mm) vesicles to large (1–2 cm)
in inflammatory EBA, such as heat shock protein-90 (HSP-90), bullae. The blisters often begin on the abdomen, although the
granulocyte macrophage–colony-stimulating factor (GM-CSF), entire body can be involved. Pruritus is common and can be
chemokine ligand-1 (CXCL1), CXCL2, or IL-1, suggests other severe.
possible candidates for therapeutic targeting. 38 PG is associated with maternal and fetal morbidity. In the
mother, morbidity mainly relates to skin disease, with extensive
Treatment itching and blister formation. Recent data indicate a better
Spontaneous resolution is infrequent in EBA, and management prognosis for the fetus than previously reported, with a 20%
is difficult. The main goals of therapy are to minimize blistering risk for premature delivery. Small-for-gestational-age birth weight
and scar formation, with particular attention to ocular and oral and spontaneous abortion are only marginally increased in
mucosal lesions. Systemic glucocorticoids are the mainstay of frequency. Similar effects have been found in pregnant women
therapy, especially for patients with inflammatory EBA. Unfor- receiving systemic corticosteroid treatment for allergy, asthma,
tunately, even high-dose systemic steroids do not usually improve inflammatory bowel disease, and so on. Low birth weights and
skin fragility and trauma-induced blister formation. Mucosal prematurity are significantly associated with early onset of PG
lesions often respond to systemic steroids (prednisone 0.5–1.5 mg/ (in first or second trimester), rather than exposure to corticoster-
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kg/day) but may recur with tapering and/or discontinuation oids during pregnancy. Up to 10% of children born to mothers
of steroids. Several adjunctive agents, including azathioprine, with PG develop skin lesions similar to those in the mother,
cyclophosphamide, colchicine, dapsone, hydroxychloroquine, likely as a result of transplacental crossing of maternal autoan-
and plasmapheresis, have been proposed, but none has been tibodies. The typical presentation is an erythematous urticarial
consistently effective. Cyclosporine has been used to treat patients or vesicular rash; yellowish plaques on erythematous base and
with EBA with some success, although toxicity can limit therapy. frank bullae have also been reported. The disease is generally
Photopheresis, IVIG, and rituximab have also been reported mild and resolves spontaneously over days to weeks as maternal
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to be effective in some patients with refractory EBA. Mucous antibodies are cleared.
membrane lesions can prove particularly difficult to manage The histopathology of PG lesions is not diagnostic. Subepi-
and may require systemic therapy. Patients with ocular lesions dermal blisters are seen with necrotic basal keratinocytes and a
need ophthalmologist review and may require systemic gluco- perivascular infiltrate containing eosinophils, neutrophils,
corticoids to prevent conjunctival scarring. Oral mucous lymphocytes, and monocytes.
membrane lesions can sometimes be managed with frequent Direct immunofluorescence studies of the skin of patients
application of potent topical steroid ointments or gels (0.05% with PG shows linear deposition of C3 at the DEJ. In addition,
clobetasol propionate, 0.05% fluocinonide). If this fails and the 30–50% of patients have linear IgG deposits in a similar pattern.
degree of oral erosions inhibits appropriate nutrition, systemic Occasionally IgA, IgM, C1q, C4, properdin, factor B, and C5
glucocorticoid therapy may be required. Clinicians should also may be present in the lamina lucida. Indirect immunofluorescence
be aware of possible involvement of esophageal mucosa and/or reveals circulating IgG antibodies directed against the epidermal
tracheal mucosa and involve appropriate specialists to monitor basement membrane in only ~30% of patients. In contrast,
and treat these potentially severe complications. 50–75% of patients have IgG antibody directed against epithelial
As well as therapies targeting B cells, novel therapeutic targets basement membrane as shown by complement fixation techniques.
addressing autoreactive T cells are being studied in the treatment This IgG anti–basement membrane antibody fixes complement
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of EBA. These include inhibitors of the stress-inducible HSP-90. in vitro but is not detected by routine indirect immunofluores-
Strategies targeting other features of EBA, such as neutrophil cence because of its low concentration. These autoantibodies
recruitment and complement activation, are also being explored. can cross the placenta: Infants born to mothers with PG often
The management of chronic skin wounds is vital in EBA. have C3 deposits at the DEJ, but without any clinical skin disease.
Protection of skin from trauma and early use of topical and These IgG antibodies bind the epithelial side of saline-split skin,
systemic antibiotics are critical to improving the rate of healing. as seen in BP.
The development of new biological dressings for chronic ulcers
has also proven helpful in the management of these wounds. Pathogenesis
Sera from most patients with PG bind to BPAG2 but do not
PEMPHIGOID GESTATIONIS react with BPAG1. The role of pregnancy and other hormonal
factors in the development of PG is not understood.
PG is a rare, itchy, blistering disease of pregnancy and the Patients with PG have an increased frequency of HLA-DR3;
puerperium characterized by linear deposits of IgG and C3 at the greatest relative risk is when HLA-DR3 and HLA-DR4 are
the DEJ. Formerly known as “herpes gestationis,” PG has no both present. Patients with PG have an increased frequency of