Page 889 - Clinical Immunology_ Principles and Practice ( PDFDrive )

860 Part SEVEN Organ-Specific Inflammatory Disease

and HLA-DR14 is found in patients with PV, although the in many patients, in others, PV may flare up during corticosteroid
individual susceptibility gene differs with ethnic origin: PV therapy taper and require additional immunosuppression.
is associated with PV HLA-DRB1*04:02 in Ashkenazi Jews; Azathioprine, mycophenolate mofetil, cyclophosphamide,
DRB1*14:01/04 and DQB1*05:03 in non-Jewish patients of methotrexate, and cyclosporine are the additional immunosup-
European or Asian descent. T cells from patients with PV have pressive agents most often utilized. Azathioprine and cyclosporine
been observed to secrete high levels of interleukin-4 (IL-4) and have steroid-sparing effects in long-term treatment, but adding
IL-10 in response to specific Dsg3 peptides presented by these agents to steroids does not induce long-term remission
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DRB1*04:02. T cells reactive against Dsg3 are found in patients any better than steroids alone. In small trials, mycophenolate
with PV and also in some normal healthy subjects with HLA mofetil, used alongside prednisone, induced disease control more
DRB1*04:02. Which additional factors are required for HLA- quickly compared with prednisone alone. However, a recent larger
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susceptible individuals to develop clinical disease remains study of this failed to show statistical significance. Because of
unknown. its relatively low toxicity, azathioprine (1–3 mg/kg/day) is fre-
Both the sporadic and endemic (FS) forms of PF are associated quently chosen for adjuvant immunosuppression. Other possible
with HLA class II alleles. Susceptibility has been correlated with adjunctive therapies include parenteral gold, plasmapheresis, and
the presence of DR4, DR14, and DR1 alleles, but no single DR4 extracorporeal photochemotherapy. Treatment for PF is similar
or DR14 allele has been associated with the disease. The to that for PV, but therapy can be less aggressive, as PF is usually
HLA-DRB1 alleles DRB1*04:04, *14:02, *14:06, or *01:02 have less severe than PV and rarely fatal. Dapsone is used for intraepi-
12
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been identified as risk factors for FS (relative risk >14). These dermal IgA neutrophilic dermatosis. Occasionally, systemic
alleles all share a common sequence in the third hypervariable glucocorticoid therapy is needed, either alone or with dapsone.
domain of the DRB1 gene. Therapy for paraneoplastic pemphigus has been disappointing
Environmental factors have been implicated in FS, the endemic and usually unsuccessful.
form of PF. Healthy people living in endemic areas in South Various biological agents, including etanercept, infliximab,
America have anti-Dsg1 IgG antibodies. The proportion of normal high-dose intravenous immunoglobulin (IVIG), and rituximab,
individuals with anti-Dsg1 IgG decreases with distance from the have been tried in pemphigus, with some success. Trials with
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endemic focus of FS. In addition, normal controls and patients etanercept showed mixed results with heterogeneous responses. In
with FS from endemic areas have IgM against the nonpathogenic a trial comparing infliximab plus prednisone versus prednisone
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extracellular domain of Dsg1. This is uncommon in other alone, neither group achieved their primary endpoints, but at
pemphigus phenotypes or in patients with FS who have migrated 26 weeks, three of 10 patients given infliximab showed positive
to urban centers, suggesting exposure to an environmental antigen responses, compared with none who received prednisone alone.
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that may share epitopes with Dsg1. An IgG4 response seems Median anti-Dsg1 and anti-Dsg3 levels were lower in the infliximab
important: In endemic areas, both normal subjects and those group at 18 and 26 weeks. A single course of IVIG was effective
with preclinical disease or in remission had anti-Dsg1 antibodies in a double-blind study of patients with steroid-refractory PV. 22
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that were predominantly IgG1 ; in those with active disease, There are numerous case reports of successful use of rituximab
anti-Dsg1antibodies were predominantly IgG4. 15 in severe or recalcitrant pemphigus. In most cases, rituximab
FS has been linked to bites from bloodsucking black flies was added to systemic corticosteroid therapy. Three prospective
found in the endemic areas of Brazil. Pathogenic IgG4 antiDsg1 studies of rituximab in pemphigus, alongside corticosteroids or
antibodies from patients with FS cross-react with the LJM11 other immunomodulatory agents, have reported dramatic
sand fly salivary gland antigen. 12,16 This suggests that FS may be improvement or total clearance in most patients. 23,24 The mean
triggered in HLA-susceptible individuals by an immune response time to achieve disease control, with re-epithelialization of
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that is cross-reactive with Dsg1. mucosal and cutaneous erosions, was 3 months. The response
Although autoantibodies are clearly important in pathogenesis, to rituximab appears durable, with 58% of patients remaining
the mechanism by which they cause acantholysis is unknown. in complete remission 6 years after therapy. 24
Complement components (C3, C1q) are often present in lesional
skin, but autoantibodies can induce acantholysis in vitro and in
neonatal mice without complement activation. Overall, it seems KEY CONCEPtS
that complement may augment acantholysis, but pemphigus Pemphigus
IgG on its own can bind keratinocytes and induce loss of cell–cell
adhesion. It has been suggested that urokinase plasminogen Clinical presentations correlate with the antigenic target of the
activator is necessary for skin lesions to develop, but pemphigus autoantibodies.
antibodies remain pathogenic in plasminogen-activator knock-out Pemphigus foliaceus presents with superficial intraepidermal blisters
and antibodies directed against Dsg1 alone.
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mice. Acantholysis may be triggered by intracellular signaling Pemphigus vulgaris with only oral mucosal lesions most often has anti-
after antibodies bind to cell-surface desmogleins: p38MAPK bodies against Dsg3.
inhibition prevents disease in the mouse model. 18 Pemphigus vulgaris with skin and mucosal lesions most often has anti-
bodies against both Dsg1 and Dsg3
Therapy
Before the introduction of glucocorticoid therapy, pemphigus
was uniformly fatal. The introduction of high-dose systemic BULLOUS PEMPHIGOID
glucocorticoids and improvements in wound care have markedly
reduced mortality caused by PV, but it remains a serious condition. Clinical Features
Most blistering can be controlled with prednisone (1–2 mg/kg/ Bullous pemphigoid (BP) is characterized clinically by extremely
day, usually in divided doses). The dose can be slowly tapered pruritic, tense blisters on inflamed or noninflamed skin. These
toward alternate-day therapy. Although this will control disease lesions range from small (1–5 mm) vesicles to large bullae several