Page 894 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 63 Bullous Diseases of the Skin and Mucous Membranes 865

anti-HLA antibodies compared with multiparous control subjects. normal human skin. A BP180 C-terminal domain enzyme-linked
Some studies have suggested that paternal haplotype is important immunosorbent assay (ELISA) has been evaluated as a method
in PG pathogenesis, but further prospective studies are needed. of characterizing MMP, although direct immunofluorescence
Patients with PG also have increased frequency of the C4 null remains the most sensitive test for diagnosing BP-180 MMP. 43
allele, although this may just secondary to the increased frequency
of HLA-DR3. 41 Pathogenesis
Understanding the pathogenesis of MMP has been hampered
Treatment by the heterogeneous clinical presentation and the relative lack
Therapy of PG is directed at relieving pruritus and preventing of antibodies in serum. The presence of different immunoglobulin
the development of new blisters. If the extent of disease is limited, classes at the basement membrane on immunofluorescence and
patients can be managed with topical glucocorticoids and the variable localization of these immunoglobulins on immu-
antihistamines. However, most patients with PG have extensive noelectron microscopy support the hypothesis that MMP is a
disease and need systemic glucocorticoids. Prednisone 20–60 mg/ heterogeneous disease, in which a variety of basement membrane
day is usually sufficient to control both pruritus and new blister zone proteins are targeted. In a group of patients with immune-
formation; once control has been achieved, the dosage should mediated subepithelial blistering disorders of the mucous
be reduced to the lowest possible effective dose. Occasionally, it membranes, immunoreactants were found on direct immuno-
may be possible to stop prednisone before delivery. However, fluorescence in about 90% with both skin and mucous membrane
44
PG often flares up in the immediate postpartum period. Only lesions or with mucous membrane lesions alone. In contrast,
rarely do patients require therapy beyond the initial postpartum only 40% of patients with isolated ocular disease had C3 and/
period. In patients who do require prolonged therapy after or IgG deposits. This may reflect the difficulty encountered in
delivery, immunosuppressive agents should be considered, as in biopsy of inflamed conjunctiva. On indirect immunofluorescence,
the case of the other blistering diseases. Patients being treated 11 of 14 (81%) patients with skin and mucous membrane disease
with systemic steroids or immunosuppressive drugs should be had circulating IgG anti–basement membrane zone antibodies,
counseled regarding breastfeeding restrictions. of which nine were identified as having BPAG1 and BPAG2 by
immunoblot and/or immunoprecipitation. In contrast, only 3
MUCOUS MEMBRANE PEMPHIGOID of 24 patients with only oral mucosal lesions or ocular lesions
had positive results on indirect immunofluorescence, and one
MMP, formerly termed cicatricial pemphigoid, is a rare, chronic, of the sera reacted with the BP antigens.
scarring blistering disease that predominantly affects the oral Sera from some patients with MMP react with BPAG2, whereas
and conjunctival mucosae. Conjunctival involvement ranges from others have antibodies against type VII collagen. Sera from patients
mild conjunctivitis to severe inflammation leading to symblepha- with ocular MMP react with a 205-kDa protein that has homology
ron formation, entropion, trichiasis, corneal scarring, and, in with the cytoplasmic domain of β 4 integrin and a 45-kDa protein.
some cases, to blindness. Oral lesions include gingivitis, often Some patients have antibodies against epiligrin (laminin 5), a
with erosions and desquamation, as well as erosions and ulcer- ligand for major keratinocyte integrins (α 3 β 1 and α 6 β 4 ). Patients
ations on the buccal and palatal mucosa. Esophageal and laryngeal with MMP who have anti-epiligrin antibodies need a careful
45
involvement is rare but can cause scarring and stenosis. MMP workup, as they have an increased risk of malignancy. Addition-
can also affect the genitalia, rectum, and nasopharynx. Cutaneous ally, >80% of patients with anti-epiligrin antibodies show laryngeal
46
involvement occurs in 10–25% of patients, although it is often involvement, something seen in <10% of all patients with MMP.
limited in extent and predominantly on the scalp, back, or face. 42 These data suggest that the clinical presentation of MMP is
Mucosal biopsy reveals subepidermal blisters with a cellular associated with diverse autoantibodies that react with multiple
infiltrate, usually consisting of lymphocytes and plasma cells. antigens of the skin basement membrane zone. The different
Increased numbers of neutrophils and/or eosinophils have also clinical presentations may therefore result not only from different
been reported. Skin biopsy specimens of lesions in patients with target antigens but also perhaps from different antibody-binding
MMP are indistinguishable from those of BP. sites on these antigens.
Direct immunofluorescence of perilesional skin or mucosal MMP has been linked to many different HLA class II alleles.
samples reveals linear deposition of immunoreactants at the It has been suggested that HLA-DR4 substantially increases the
basement membrane zone. In most patients with MMP, these risk of ocular disease. An increased prevalence of HLA-DQB1*03:01
46a
are IgG and C3, although IgA, IgM, and fibrin deposits have also was described in patients with isolated ocular MMP, but this
been reported. In patients who have ocular or oral mucosal MMP allele was later found to be associated with all clinical sites of
but no skin lesions, undirected skin biopsy for immunofluores- involvement and possibly to anti–basement membrane IgG
cence is unhelpful. Similarly, conjunctival biopsy can yield negative production as well as overall disease severity.
immunofluorescence in patients with otherwise typical MMP.
This may be attributed to conjunctival inflammation. Careful Therapy
evaluation for mucosal lesions and biopsy of perilesional mucosae Treatment of MMP is difficult and directed at minimizing
is often diagnostic. On immunoelectron microscopy, immuno- the scarring and resultant ocular complications. Dapsone
reactants have been found in the lamina lucida and the lamina (100–200 mg/day) is effective at controlling the early inflammatory
densa. response. Tetracyclines can also control MMP and are often
Circulating anti–basement membrane zone antibodies may combined with nicotinamide. If these are unsuccessful, treatment
be present in low titers but are usually absent in patients with with systemic glucocorticoids (1–2 mg/kg/day) may be needed,
MMP. The diagnostic yield of indirect immunofluorescence is often with adjunctive immunosuppressive therapy, such as with
not improved by using different tissue substrates, including oral azathioprine, mycophenolate mofetil, or cyclophosphamide. IVIG
and conjunctival mucosae, normal human skin, and saline-split may be useful: It starts to work rapidly and is especially helpful