V. Prajapati; P. R. Mydlarski MD, FRCPC
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.
- Yeh SW, Ahmed B, Sami N, et al. Blistering disorders: diagnosis 1. and treatment. Dermatol Ther 16(3):214-23 (2003 Sep).
- Dick SE, Werth VP. Pemphigus: a treatment update. 2. Autoimmunity 39(7):591-9 (2006 Nov).
- Amagai M, Klaus-Kovtun V, Stanley JR. Autoantibodies against 3. a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 67(5):869-77 (1991 Nov).
- Mydlarski PR, Ho V, Shear NH. Canadian consensus statement on 4. the use of intravenous immunoglobulin therapy in dermatology. J Cutan Med Surg 10(5):205-21 (2006 Sep-Oct).
- Jablonska S, Chorzelski T, Blaszczyk M. Immunosuppressants in 5. the treatment of pemphigus. Br J Dermatol 83(2):315-23 (1970 Aug).
- Bystryn JC. Adjuvant therapy of pemphigus. 6. Arch Dermatol 120(7):941-51 (1984 Jul).
- Bystryn JC, Steinman NM. The adjuvant therapy of pemphigus. 7. An update. Arch Dermatol 132(2):203-12 (1996 Feb).
- Bystryn JC, Rudolph JL. Pemphigus. 8. Lancet 366(9479):61-73 (2005 Jul).
- Buchman AL. Side effects of corticosteroid therapy. 9. J Clin Gastroenterol 33(4):289-94 (2001 Oct).
- Yeh SW, Sami N, Ahmed AR. Treatment of pemphigus vulgaris: 10. current and emerging options. Am J Clin Dermatol 6(5):327-42 (2005).
- Jolles S, Sewell WA, Misbah SA. Clinical uses of intravenous 11. immunoglobulin. Clin Exp Immunol 142(1):1-11 (2005 Oct).
- Bystryn JC, Jiao D. IVIg selectively and rapidly decreases 12. circulating pathogenic autoantibodies in pemphigus vulgaris. Autoimmunity 39(7):601-7 (2006 Nov).
- Ahmed AR. Intravenous immunoglobulin therapy in the treatment 13. of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment. J Am Acad Dermatol 45(5):679-90 (2001 Nov).
- Bystryn JC, Jiao D, Natow S. Treatment of pemphigus with 14. intravenous immunoglobulin. J Am Acad Dermatol 47(3):358-63 (2002 Sep).
- Sami N, Qureshi A, Ruocco E, et al. Corticosteroid-sparing 15. effect of intravenous immunoglobulin therapy in patients with pemphigus vulgaris. Arch Dermatol 138(9):1158-62 (2002 Sep).
- Baum S, Scope A, Barzilai A, et al. The role of IVIg treatment 16. in severe pemphigus vulgaris. J Eur Acad Dermatol Venereol 20(5):548-52 (2006 May).
- Wetter DA, Davis MD, Yiannias JA, et al. Effectiveness of 17. intravenous immunoglobulin therapy for skin disease other than toxic epidermal necrolysis: a retrospective review of Mayo Clinic experience. Mayo Clin Proc 80(1):41-7 (2005 Jan).
- Segura S, Iranzo P, Martínez-de Pablo I, et al. High-dose 18. intravenous immunoglobulins for the treatment of autoimmune mucocutaneous blistering diseases: evaluation of its use in 19 cases. J Am Acad Dermatol 56(6):960-7 (2007 Jun).
- Guillaume JC, Roujeau JC, Morel P, et al. Controlled study of 19. plasma exchange in pemphigus. Arch Dermatol 124(11):1659-63 (1988 Nov).
- Blaszczyk M, Chorzelski TP, Jablonska S, et al. Indications for 20. future studies on the treatment of pemphigus with plasmapheresis. Arch Dermatol 125(6):843-4 (1989 Jun).
- Roujeau JC, Andre C, Joneau Fabre M, et al. Plasma exchange 21. in pemphigus. Uncontrolled study of ten patients. Arch Dermatol 119(3):215-21 (1993 Mar).
- Sondergaard K, Carstens J, Zachariae H. The steroid-sparing 22. effect of long-term plasmapheresis in pemphigus: an update. Ther Apher 1(2):155-8 (1997 May).
- Turner MS, Sutton D, Sauder DN. The use of plasmapheresis and 23. immunosuppression in the treatment of pemphigus vulgaris. J Am Acad Dermatol 43(6):1058-64 (2000 Dec).
- Tan-Lim R, Bystryn JC. Effect of plasmapheresis therapy on 24. circulating levels of pemphigus antibodies. J Am Acad Dermatol 22(1):35-40 (1990 Jan).
- Eming R, Hertl M. Immunoadsorption in pemphigus. 25. Autoimmunity 39(7):609-16 (2006 Nov).
- Ogata K, Yasuda K, Matsushita M, et al. Successful treatment of 26. adolescent pemphigus vulgaris by immunoadsorption method. J Dermatol 26(4):236-9 (1999 Apr).
- Schmidt E, Klinker E, Optiz A,27. et al. Protein A immunoadsorption: a novel and effective adjuvant treatment of severe pemphigus. Br J Dermatol 148(6):1222-9 (2003 Jun).
- Luftl M, Stauber A, Mainka A, et al. Successful removal of 28. pathogenic autoantibodies in pemphigus by immunoadsorption with a tryptophan-linked polyvinylalcohol adsorber. Br J Dermatol 149(3):598-605 (2003 Sep).
- Frost N, Messer G, Fierlbeck G, et al. Treatment of pemphigus 29. vulgaris with protein A immunoadsorption: case report of long-term history showing favorable outcome. Ann NY Acad Sci 1051:591-6 (2005 Jun).
- Shimanovich I, Herzog S, Schmidt E, et al. Improved 30. protocol for treatment of pemphigus vulgaris with protein A immunoadsorption. Clin Exp Dermatol 31(6):768-74 (2006 Nov).
- Eming R, Rech J, Barth S, et al. Prolonged clinical remission 31. of patients with severe pemphigus upon rapid removal of desmoglein-reactive autoantibodies by immunoadsorption. Dermatology 212(2):177-87 (2006).
- Shimanovich I, Nitschke M, Rose C, et al. Treatment of severe 32. pemphigus with protein A immunoadsorption, rituximab and intravenous immunoglobulins. Br J Dermatol 158(2):382-8 (2008 Feb).
- Rook AH, Jegasothy BV, Heald P, et al. Extracorporeal 33. photochemotherapy for drug-resistant pemphigus vulgaris. Ann Intern Med 112(4):303-5 (1990 Feb).
- Liang G, Nahass G, Kerdel FA. Pemphigus vulgaris treated with 34. photopheresis. J Am Acad Dermatol 26(5 Pt I):779-80 (1992 May).
- Gollnick HP, Owsianowski M, Taube KM, et al. Unresponsive 35. severe generalized pemphigus vulgaris successfully controlled by extracorporeal photopheresis. J Am Acad Dermatol 28(1):122-4 (1993 Jan).
- Wollina U, Lange D, Looks A. Short-time extracorporeal 36. photochemotherapy in the treatment of drug-resistant autoimmune bullous diseases. Dermatology 198(2):140-4 (1999).
- Schmidt E, Hunzelmann N, Zillikens D, et al. Rituximab in 37. refractory autoimmune bullous diseases. Clin Exp Dermatol 31(4):503-8 (2006 Jul).
- Joly P, Mouquet H, Roujeau JC, et al. A single cycle of 38. rituximab for the treatment of severe pemphigus. N Eng J Med 357(6):545-52 (2007 Aug).
- Ahmed AR, Spigelman Z, Cavacini LA, et al. Treatment of 39. pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355(17):1772-9 (2006 Oct).
- Feliciani C, Toto P, Amerio P, et al. In vitro and in vivo expression 40. of interleukin-1alpha and tumor necrosis factor-alpha mRNA in pemphigus vulgaris: interleukin-1alpha and tumor necrosis factor-alpha are involved in acantholysis. J Invest Dermatol 114(1):71-7 (2000 Jan).
- Lopez-Robles E, Avalos-Diaz E, Vega-Memije E, et al. TNFalpha 41. and IL-6 are mediators in the blistering process of pemphigus. Int J Dermatol 40(3):185-8 (2001 Mar).
- Pardo J, Mercader P, Mahiques L, et al. Infliximab in the 42. management of severe pemphigus vulgaris. Br J Dermatol 153(1):222-3 (2005 Jul).
- Jacobi A, Shuler G, Hertl M. Rapid control of therapy-refractory 43. pemphigus vulgaris by treatment with the tumour necrosis factor-alpha inhibitor infliximab. Br J Dermatol 153(2):448-9 (2005 Aug).
- Berookhim B, Fischer HD, Weinberg JM. Treatment of recalcitrant 44. pemphigus vulgaris with tumor necrosis factor alpha antagonist etanercept. Cutis 74(4):245-7 (2004 Oct).
- Lin MH, Hsu CK, Lee JY. Successful treatment of the recalcitrant 45. pemphigus vulgaris and pemphigus vegetans with etanercept and carbon dioxide laser. Arch Dermatol 141(6):680-2 (2005 Jun).
- Grando SA, Dahl MV. Activation of keratinocyte muscarinic 46. acetylcholine receptors reverses pemphigus acantholysis. J Eur Acad Dermatol Venereol 2(2):72-86 (1993 May).
- Iraji F, Yoosefi A. Healing effect of pilocarpine gel 4% on skin 47. lesions of pemphigus vulgaris. Int J Dermatol 45(6):743-6 (2006 Jun).
- Anhalt G, Werth V, Strober B, et al. An open-label phase I clinical 48. study to assess the safety of PI-0824 in patients with pemphigus vulgaris. J Invest Dermatol 125(5):1088 (2005 Nov).
- Berkowitz P, Hu P, Warren S, et al. p38MAPK inhibition prevents 49. disease in pemphigus vulgaris mice. Proc Natl Acad Sci USA 103(34):12855-60 (2006 Aug).