Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
The pemphigus variants represent a group of potentially life-threatening autoimmune mucocutaneous blistering diseases. Though systemic corticosteroids have dramatically reduced the rate of disease mortality, current therapeutic options are limited by their toxicity profiles. Advancements in our understanding of the molecular mechanisms involved in the pathogenesis of pemphigus have translated into the development of novel therapies. However, few treatments have been subject to randomized controlled trials to firmly establish therapeutic efficacy. Herein, we focus on the new and emerging therapies in the management of pemphigus.
pemphigus, autoimmune skin disease
Pemphigus represents a group of rare autoimmune mucocutaneous blistering disorders. The 2 main subtypes are pemphigus vulgaris (PV) and pemphigus foliaceus (PF), each with its own clinical variants. Less common forms include paraneoplastic pemphigus, IgA pemphigus, and pemphigus herpetiformis. Since PV is the most common subtype of pemphigus worldwide, it will be the focus of this article.
PV affects both genders equally and has a mean age of onset of 50-60 years. A higher prevalence has been noted in individuals of Ashkenazi Jewish, Mediterranean, Northern Indian and Persian descents.1 Patients often present with multiple, painful erosions or flaccid bullae on the skin and/or mucous membranes. Mucosal disease precedes cutaneous involvement in the majority of the cases.2
The disease is mediated by circulating immunoglobulin G (IgG) autoantibodies against the desmosomal cadherins, desmogleins 1 and 3.3 Histopathology reveals a loss of cell-cell adhesion (acantholysis) in the suprabasilar layer of the epithelium and direct immunofluorescence (DIF) of perilesional skin reveals intercellular deposition of IgG +/– C3. As antibodies often correlate with disease activity, indirect immunofluorescence (IIF), immunoblots, and enzyme-linked immunosorbent assays (ELISA) are commonly used to quantify circulating antibody levels.4
If left untreated, PV is frequently fatal with a mortality rate ranging from 60% to 90%.5-8 While systemic corticosteroid use and other therapeutic advances have reduced this mortality rate to approximately 10%, complications from treatment are now the primary cause of morbidity and mortality in this population.6,7 The goal of managing pemphigus patients is, therefore, to induce and maintain remission with the lowest possible doses of medication, so as to minimize the risk of serious and potentially fatal adverse effects.2
Systemic corticosteroids remain the treatment of choice for pemphigus as they are both effective and capable of inducing a rapid remission. However, adverse effects of corticosteroids are both time- and dose-dependent.9 They include weight gain, diabetes, hypertension, glaucoma, cataracts, osteoporosis, avascular necrosis, peptic ulcer disease, adrenal insufficiency, electrolyte and lipid abnormalities, psychosis, immunosuppression, and increased susceptibility to infections.9 Adjuvant therapies are, therefore, used to provide a steroid-sparing effect. As these treatments typically have a slower onset of action (i.e., 4-6 weeks), they are most beneficial as maintenance therapies. Conventional adjuvants include various immunosuppressive agents such as azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide, chlorambucil and cyclopsorine, as well as anti-inflammatory agents such as gold, dapsone, colchicine and a variety of tetracycline antibiotics (Table 1).2,4,10 Unfortunately, these medications are often associated with significant toxicities and must be used with caution. Though the majority of patients will ultimately respond to conventional therapies, few patients develop recalcitrant disease.
Over the years, advances have been made to expand our therapeutic armamentarium for pemphigus. Emerging therapies include intravenous immunoglobulin (IVIg), plasmapheresis, immunoadsorption (IA), extracorporeal photochemotherapy (ECP), rituximab, tumor necrosis factor-alpha (TNF-á) antagonists (infliximab and etanercept), cholinergic agonists, and other experimental therapies such as desmoglein 3 peptides and KC706.
Intravenous Immunoglobulin (IVIg)
IVIg is a fractionated and purified blood product derived from the plasma of between 1,000 and 15,000 healthy donors per batch.4 It contains a high concentration of IgG and has a broad range of antibodies directed against pathogens, foreign antigens, and self-antigens.11 Although its exact mechanism of action remains unclear, IVIg is associated with a rapid and selective decline in the serum levels of pathogenic PV autoantibodies.12
|Drug Type||Systemic Agent||Mode of Administration||Dose|
|Dexamethasone||Oral or IV pulse||50-200mg/d for 3-5 d|
|Methylprednisolone||IV pulse||500-1,000mg/d for 3-5 d|
|IV pulse||0.5-1g/m2 monthly|
|Immunoablative high-dose (IV)||50mg/kg/d for 4 d|
|20mg/d||Oral, SC, IM or IV||5-30mg/wk|
|Biologic Agents||Etanercept||SC injection||50mg weekly|
|Rituximab||IV infusion||375mg/m2 weekly for 4 weeks;|
OR 1,000mg on days 1 and 15†
|Table 1: Therapeutic doses for immunomodulatory drugs used in the treatment of pemphigus.|
IV = intravenous, IM = intramuscular, SC = subcutaneous
† Weight-independent dosing schedule based on unpublished observations.
Three case series and 1 retrospective analysis document the efficacy of IVIg in PV.13-16 The dosage and frequency of IVIg infusions were comparable between the studies. In all 4 studies, treatment with IVIg resulted in a rapid clinical response and a corticosteroid-sparing effect.13-16 In 2 retrospective analyses, however, IVIg demonstrated a less favorable response.17,18 As the published studies are limited by their methodologies and small sample sizes, a Canadian multi-centre randomized controlled trial is underway to establish the role of IVIg in the management of PV patients.
Plasmapheresis is the process by which plasma is removed from blood using a cell separator. The blood cells and an appropriate plasma substitute are then returned to the patient undergoing treatment. As antibodies are contained within plasma, plasmapheresis results in the removal of the pathogenic PV autoantibodies. In a multicenter study, PV patients (n=40) were randomized to receive prednisolone alone or prednisolone plus large-volume plasma exchange.19 While plasmapheresis failed to demonstrate a therapeutic benefit in this study, it has been suggested that an additional immunosuppressive (i.e., cyclophosphamide) or immunomodulatory (i.e., IVIg) therapy may be required to prevent the rebound production of pathogenic autoantibodies associated with disease flares. Multiple case series have evaluated the efficacy of plasmapheresis in treating PV.20-23 Of the 28 patients evaluated in these studies, 18 (64%) experienced complete remission, 6 (33%) experienced partial remission and 4 (22%) had no clinical improvement. Adverse effects encountered included systemic infections, acute hepatitis, thrombocytopenia, anemia, hypocalcemia, nausea, dizziness, urticaria, fever, and hypotension.20-24
IA consists of collecting patient plasma, passing it through an adsorber column (i.e., Protein A) to remove circulating immune complexes and IgG and then returning the filtered plasma to the patient.25 Four case series and 2 case reports document the efficacy of IA for the treatment of recalcitrant PV.26-31 Though patients were allowed to remain on concomitant immunosuppressive therapies, IA resulted in a dramatic clinical response and a rapid decline in desmoglein-specific IgG autoantibodies.26-31 In the study by Schmidt, et al., a corticosteroid-sparing effect was observed.27 More recently, a small case series demonstrated that IA, administered in combination with rituximab, may result in long-term remission.32 In all studies, IA was safe and well tolerated.
Extracorporeal Photochemotherapy (ECP)
In ECP, also known as photopheresis, a patient’s white blood cells are collected (leukapheresis), exposed to 8-methoxypsoralen, irradiated with ultraviolet-A light and reinfused into the patient. The proposed mechanism of action may involve inhibition of pathogenic autoantibody production by B lymphocytes.10 There are only 2 small case series and 2 case reports in the literature that document the use of ECP for refractory PV.33-36 Of the 9 PV patients treated with ECP in these studies, all experienced significant clinical improvement, and no adverse effects from ECP were noted.
Rituximab is a chimeric murine/human IgG1 anti-CD20 monoclonal antibody that targets pre-B and mature B lymphocytes, resulting in complement and antibody-dependent cytotoxicity and apoptosis. Rituximab reduces circulating B cells, thereby preventing their maturation into antibody-producing plasma cells. Multiple case reports suggest that rituximab is an effective treatment option for PV.37 Of the 18 patients with refractory PV reviewed, 3 (17%) experienced complete remission, 4 (22%) experienced clinical remission with further therapy required and 11 (61%) experienced partial remission. Systemic infections occurred in 4 of the 18 patients, resulting in 1 fatal outcome.
The largest clinical study evaluating the use of rituximab in PV has been a case series of 14 patients with refractory PV in which 12 (86%) experienced a complete remission at 3 months after a single cycle of rituximab.38 This agent was also shown to be effective when used in combination with IVIg. In a series of 11 patients with extensive, recalcitrant PV, 9 (82%) experienced a clinical remission lasting between 22-27 months with combination therapy.39
Tumor Necrosis Factor-alpha (TNF-á) Antagonists
TNF-á antagonists may be beneficial for the treatment of PV as experimental studies have demonstrated that TNF-á plays a role in the acantholytic process.40,41 Two case reports document the successful use of infliximab for refractory PV.42,43 Two additional case reports have shown clinical improvement of PV with the use of etanercept.44,45 Clinical trials for both infliximab and etanercept are currently underway.
Research suggests that acetylcholine and its receptors are involved in the acantholytic process of pemphigus.2 To date, only 2 clinical studies have been performed.46,47 In a case series of 6 patients with active PV, 3 (50%) experienced clinical improvement with the cholinergic agonist pyridostigmine bromide (Mestinon®, Valeant Pharmaceuticals).46 Two of the 3 responders were able to control their disease with pyridostigmine bromide alone and 1 patient was able to remain in remission without any medications. In a recent double-blind, placebo-controlled trial of 3 PV patients with a total of 64 lesions, those lesions treated with 4% pilocarpine gel were found to have a significantly higher epithelialization index compared with placebo.47
Other Experimental Therapies
Selective therapy using intravenous desmoglein 3 peptides was developed to suppress the production of anti-desmoglein 3 antibodies through inactivation and/or deletion of disease-associated CD4+ T lymphocytes.48 However, an open-label phase I clinical trial of PI-0824 failed to demonstrate significant changes in anti-desmoglein 3 antibody titres following treatment with 2 IV infusions of desmoglein 3 peptides.48
A novel therapy, KC706 (Kémia, Inc.) is an oral allosteric p38 mitogen-activated protein kinase (p38MAPK) inhibitor. In a murine model of pemphigus, p38MAPK inhibition prevented blister formation.49 A clinical trial is underway to determine the safety and efficacy of KC706 in the management of PV.
While corticosteroid therapy remains the mainstay of treatment for PV, the morbidity associated with its use is significant. Conventional immunosuppressive and anti-inflammatory therapies are further associated with serious and potentially life-threatening adverse events. With an improved understanding of PV pathogenesis, a number of novel therapies have been developed. Though many of these therapies appear promising, case reports and case series dominate the dermatologic literature. Randomized controlled trials are urgently required to establish their efficacy and safety in the management of pemphigus patients.
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