Pemphigus



Pemphigus


Daniel Mimouni and Grant J. Anhalt


Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports


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Pemphigus is an autoimmune blistering disease of the skin with an established immunological basis but unknown etiology. Its histological hallmark is the loss of cell-to-cell adhesion (acantholysis) mediated by autoantibodies to epidermal cell-surface proteins. Pemphigus has three major variants, pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus, which are differentiated by the presence/absence of intraepithelial blisters and erosions of the skin and variable involvement of the mucous membranes. Their associated risks of morbidity and mortality vary greatly.



Management strategy


If pemphigus vulgaris is not treated definitively and promptly, the process ‘hardens’, leading to epitope spreading which makes the disease more difficult to control. Even if the initial presentation is limited, without systemic treatment it will generalize. Animal studies have clearly shown that once enough autoantibody reaches the skin, blistering will occur, and this damage cannot be prevented by anti-inflammatory agents or even pretreatment with high doses of systemic corticosteroids. Topical treatment of the mucous membranes or skin has no significant effect on the course of the disease, though topical corticosteroids or intralesional injections or corticosteroids may temporarily relieve pain and inflammation.


Other factors complicate the management, and include the following:



1. Circulating autoantibodies have a degradative half-life of about 3 weeks. Lasting improvement can only occur with reduction of both existing and newly produced antibody, so improvement occurs very slowly unless the antibodies are physically removed by plasmapheresis, or their catabolism is increased by administration of high doses of exogenous normal human immunoglobulins (IVIG).


2. Pemphigus is notorious in its persistence. Spontaneous remissions typically do not occur, and remissions and relapses are common. Most people require some form of treatment for life.


3. There is only a small repertoire of drugs that are effective at reducing autoantibody synthesis, and the most effective of those are rituximab and cyclophosphamide. The high cost of rituximab can be a barrier to treatment and cyclophosphamide has potential toxicities that cause concern to many treating physicians and can restrict the appropriate use of this drug.


4. All forms of pemphigus are rare, and this prohibits the execution of large, controlled trials. The literature discussing therapeutic regimens is dominated by small series and case reports, which is a weak evidence base for the design of rational treatment. However, we do have excellent animal models of this disease, and understand well the pathophysiology from these studies, which are instrumental in designing our approach to treatment.


Thus, the primary goal of treatment in all forms of pemphigus is to reduce the synthesis of autoantibodies by the immune system. It currently consists of three basic steps:



The commitment to the use of cyclophosphamide is a serious one. This drug is extremely effective, but use of this alkylating agent is accompanied by short-term leukopenia and a long-term increased risk of leukemia, lymphoma, and bladder cancer, as well as the risk of sterility in younger patients. The increasing use of rituximab is being explored as a way to avert having to use cyclophosphamide.


As mentioned, all types of pemphigus are rare, making large controlled trials difficult to perform. The medical literature on therapeutic regimens is dominated by small series and case reports, which provide a weak evidence base for the design of rational treatment. Some studies have suggested other potential drugs, but they cannot yet be applied because the mechanism whereby they might effectively inhibit new antibody synthesis is unknown. This list includes tetracycline and niacin (nicotinamide), methotrexate, dapsone, and gold. A recent well-performed randomized trial showed no corticosteroid-sparing benefit of cyclosporine. It is therefore not recommended for the treatment of pemphigus vulgaris, although it may still play a role in the treatment of paraneoplastic pemphigus.



Specific investigations











Accuracy of indirect immunofluorescence testing in the diagnosis of paraneoplastic pemphigus.

Helou J, Allbritton J, Anhalt GJ. J Am Acad Dermatol 1995; 32: 441–7.


The diagnosis of pemphigus is established by the fulfillment of three criteria; if one is missing, the diagnosis is uncertain:



Demonstration of IgG autoantibodies on the cell surface of affected epithelium or detection of antigen-specific autoantibodies in the blood. Pemphigus vulgaris is characterized by progressively evolving fragile blisters and erosions. Oral involvement essentially ‘always’ occurs and is the major point to differentiate pemphigus vulgaris from pemphigus foliaceus. Histologic changes include suprabasilar acantholysis and cell surface-bound IgG. Circulating autoantibodies are specific for desmoglein 3 alone when lesions are restricted to the mouth and for both desmogleins 3 and 1 when cutaneous lesions are present in addition to oral lesions. Definition of the specificity of desmoglein autoantibodies can be reliably gained by enzyme-linked immunosorbent assay (ELISA).


In pemphigus foliaceus, mucosal lesions ‘never’ occur. This is the major clinical feature differentiating pemphigus foliaceus from pemphigus vulgaris. The cutaneous lesions are superficial scaling erosions. Immunopathologic studies reveal subcorneal acantholysis and tissue-bound and circulating antidesmoglein 1 antibodies.


Paraneoplastic pemphigus occurs in the context of the several lymphoproliferative disorders: non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman disease, thymoma, and retroperitoneal sarcoma. Intractable mucositis with lichenoid erosions is the most constant clinical finding. Polymorphous cutaneous involvement with lesions that resemble erythema multiforme, pemphigus, pemphigoid, or lichenoid eruptions is observed. Histologic study shows suprabasilar acantholysis or interface/lichenoid changes. The key diagnostic finding is the presence of antibodies against desmogleins 3 and 1 and additional autoantibodies against epithelial plakin proteins, such as desmoplakin, envoplakin, and periplakin, which may be identified by immunoblotting or immunoprecipitation techniques. They may also be inferred with immunofluorescence techniques showing their reactivity with murine bladder epithelium, although the lichenoid variant of paraneoplastic pemphigus has been occasionally reported with the complete absence of the characteristic autoantibodies.



First-line therapies















Pemphigus vulgaris and foliaceus
imageSystemic corticosteroids B
imageRituximab D


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The first-line therapy for all forms of pemphigus is systemic corticosteroids. Corticosteroids work relatively quickly and are relatively safe when used at appropriate doses for limited periods of time. In the past, regimens of rapidly accelerating doses of corticosteroids were administered, but they were found to be associated with unacceptably high morbidity and mortality risks. Initial treatment should start at 1 mg/kg daily (lean body weight). A good clinical response, defined as a resolution of the majority of existing lesions and absence of newly developing lesions, should be evident within two to 3 months. The dose should then be reduced to 40 mg daily and subsequently tapered over 6 to 9 months, ideally to a maintenance dose of 5 mg every other day. Tapering can be accomplished by reduction of the prednisone by an average of 10 mg/month initially, and 5 mg/month later. There are some advantages to beginning an alternate dose regimen at 40 mg daily, so that monthly reductions would ideally be 40/20 mg alternate days, 40/0 mg, 30/0 mg, 20/0 mg, 15/0 mg, and 10/0 mg, and then 5/0 mg alternate days for maintenance.


The use of a second-line therapy is certainly indicated if significant corticosteroid side effects develop or are expected to develop during the ideal prednisone taper, if the disease does not improve sufficiently to allow continuous tapering, or the disease flares. With the introduction of better tolerated drugs such as mycophenolate mofetil, it is reasonable to use a second agent from the start of therapy in all patients with moderate to severe disease from the start of therapy, in anticipation of steroid-sparing benefits.


Monthly pulse corticosteroids have been suggested as a less toxic alternative to daily oral therapy, but pemphigus is very persistent, and more consistent daily or alternate day dosing is usually required to achieve suppression.


Patients must be monitored for corticosteroid-induced osteopenia by bone mineral density studies (DEXA scan) at institution of therapy and annually thereafter. Patients without a history of renal calculi may be given prophylactic supplemental calcium 1500 mg daily and vitamin D, 400–800 IU daily. In patients with osteopenia or osteoporosis, additional therapies may include hormone replacement in women (estrogen/progesterone, or raloxifen in those with a contraindication for estrogens, such as a history of breast carcinoma) or exogenous testosterone in men with low serum testosterone levels, or a bisphosphonate such as alendronate, or intranasal calcitonin.


In pemphigus vulgaris, therapy as outlined should commence in all patients once the diagnosis is confirmed. Even in cases with limited oral lesions, the disease will progress unless treated with systemic agents, and palliative therapy with topical agents or intralesional injections just delays definitive therapy. There is clinical evidence that early intervention with definitive treatment leads to a better long-term outcome. In pemphigus foliaceus, however, not every patient requires immediate treatment. Some patients have a very limited and smoldering disease, and can therefore benefit from some palliative treatment, such as topical corticosteroids. Paraneoplastic pemphigus is usually relentlessly progressive, justifying the immediate institution of systemic corticosteroids and a second-line treatment. If a patient has an associated benign lymphoproliferative disorder, such as thymoma, hyaline vascular Castleman disease, or sarcoma, complete surgical removal should be attempted to prolong disease remission.


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Aug 7, 2016 | Posted by in Dermatology | Comments Off on Pemphigus

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