CME #123 Managing
Pemphigus Vulgaris
July 2005
CME #123— July 2005
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
Though there have been significant improvements in the management of pemphigus vulgaris, there is still a great deal of variation among the experts regarding disease management. In this article, Jennifer C. Haley, M.D., and Janiene Luke, B.S., review current management of pemphigus vulgaris and provide an overview of all available treatments and potential side effects of these agents.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, and fax to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Managing Pemphigus Vulgaris
T hough rare, pemphigus vulgaris (PV) is a potentially life-threatening autoimmune bullous disorder affecting 0.1 to 0.42 people per 100,000. The disease, which typically develops in mid-life with a peak incidence of onset between the fourth and sixth decades,1 has an increased incidence in people of Mediterranean descent.
Phemphigus vulgaris is a disease that often follows a stormy course, waxing and waning in severity. Characterized by flaccid bullae, PV often originates in the scalp or mucous membranes, and may later evolve into a generalized distribution.
Although the pathophysiology of pemphigus is not completely understood, it is known that the disease develops as a result of B cell production of autoantibodies binding to desmosomal cadherins. Desmoglein 1 and 3 are the targets of the autoantibodies. These proteins are responsible for cohesion of the epithelial cells. Evidence suggests that antibodies in PV cause acantholysis and blister formation. The mechanism initiating autoantibody formation is
not known.2,3
Historically, pemphigus vulgaris had a very high mortality, approaching 100%. Blister formation can result in extensive erosions, which can cause weight loss and nutritional deficiency when oral mucosal involvement is extensive. Additionally, loss of skin integrity can result in fluid and electrolyte imbalance, susceptibility to infection and sepsis, temperature dysregulation and death.2
With the development of corticosteroids and adjuvant therapy, the current mortality rate approaches 10%. The majority of deaths are now related to complications secondary to the medications used to manage the disease.
Although there has been significant improvement in the management of pemphigus vulgaris, few controlled studies have evaluated these modalities.
To complicate things further, variation of disease management strategies exists among the experts. A telephone-based survey of 24 experts in pemphigus revealed that only 75% chose prednisone as first-line therapy. The dosage varied with about half of clinicians starting at
1 mg/kg/d with the remainder using higher doses.
Approximately one-third of clinicians surveyed had the expectation that patients would completely stop corticosteroids at some point. Others looked toward achieving a dose between
2.5 mg/d to 10 mg/d of prednisone.
This survey found that:
• 44% of clinicians initiated azathioprine (Azasan) as the first choice
for adjuvant therapy
• 20% used mycophenolate mofetil (CellCept)
• 16% prescribed cyclophosphamide
• 8% prescribed methotrexate as the first choice for adjuvent therapy.4
The purpose of this article is to review current management of pemphigus vulgaris and potential side effects of these agents.
Clinical Presentation and Diagnosis
The clinical presentation of pemphigus vulgaris varies, with between 25% to 50% of patients suffering from mucous membrane involvement. There is an increased incidence of systemic lupus erythematosus in patients with pemphigus. Additionally, pemphigus vulgaris may be associated with underlying malignancy or certain medications.
To make the diagnosis of PV, the clinician must obtain a skin or mucosal biopsy for histologic analysis, and complete a direct immunofluorescence of perilesional, intact skin or uninvolved skin. Histologically, biopsies reveal suprabasilar acantholysis, which is highly suggestive of PV. Deposition of IgG in the intercellular spaces of the epidermis confirms the diagnosis.5 Indirect immunofluorescence may be used to detect circulating autoantibodies in serum and recently ELISA has been used for direct measurement of Dsg 1 and Dsg 3 antibodies in serum.2,6
Treatment
As mentioned above, corticosteroids have been a mainstay in the treatment of pemphigus vulgaris. Although extremely effective in initial control of the disease, the many adverse effects associated with long-term use requires the clinician to seek adjuvant therapy. Corticosteroids can be effectively administered orally or intravenously. The starting dose is typically 1 mg/kg/d. Mutasim reports that most patients obtain remission in 4 to 12 weeks.2 Adjuvant therapy is often needed to maintain control of the disease on lower doses of corticosteroids.
Azathioprine
Azathioprine, often the first-line choice in adjuvant therapy of PV, has shown a steroid-sparing effect.6 A derivative of 6-mercaptopurine, this drug blocks DNA in lymphoid cells and inhibits neutrophil trafficking and cellular cytotoxicity. The recommended dosage is between 2 mg/kg/d to 4 mg/kg/d. The medication is typically tolerated better than some other adjuvant agents such as cyclophosphamide, although it seems to be less effective.2
In a publication looking at seven studies involving 105 patients, Bystryn and Steinman reported that remissions were induced in 28% of patients.7 The more serious of the many side effects of azathioprine is hepatotoxicity and myelosuppression, requiring monitoring of liver function tests and blood counts.
Newer tests to evaluate risk for hepatotoxicity and myelosuppression are available. Measuring the activity of thiopurine methyltransferase (TPMT) may assist in evaluating tolerance and in determining the ideal dosing for the individual. For patients taking the drug, 0.3% will have low to no enzyme activity and therefore will have a significantly high risk for toxicity. Also, 11% have a reduced activity of TPMT, requiring a reduced dose of the drug. In addition, 89% will have a normal to high activity and may tolerate higher doses. Measuring metabolites of azathioprine, such as 6-thioguanine and 6-MMPN, may assist the clinician in predicting likelihood of response, risk of leukopenia and hepatotoxicity.
In addition to liver and bone marrow toxicity, adverse effects of azathioprine include infection, malignancy, gastrointestinal disturbances and drug-induced hypersensitivity syndrome.
Mycophenolate MoFetilMycophenolate mofetil (MMF) is a precursor to the active metabolite mycophenolic acid. It is absorbed by the gastrointestinal tract and hydrolyzed to its active metabolite. The dosage is between 2 g/d to 3 g/d.
Mycophenolate mofetil inhibits de novo guanine synthesis by inhibiting an enzyme expressed in proliferating B and T cells. Other cells can use the salvage pathway for guanine, making MMF a selective inhibitor of T-cell proliferation. The drug also inhibits lymphocyte trafficking and impairs nitric oxide production. Originally used in pemphigus in 1997, MMF is often effective and well tolerated.
Several reports exist of successful management of pemphigus vulgaris with myocophenolate mofetil in patients who failed to respond to azathioprine.8 Some studies have shown MMF to be successful as monotherapy in managing PV.9,10 Potential side effects include fatigue, gastrointestinal and urinary disturbances, myelosuppression, infections, and lymphoma.
Cyclophosphamide
Cyclophosphamide is an alkylating agent that has been shown to have a steroid-sparing effect and is useful in patients with severe PV who may have failed therapy with azathioprine or MMF.
In a study of 20 patients with pemphigus vulgaris, 17 achieved complete remission when treated with cyclophosphamide.11 The drug can be effectively prescribed in a daily oral dose or administered intravenously in a single or monthly pulse regimen. Although this agent is effective in managing patients with recalcitrant disease, it has many significant side effects, such as neutropenia, gastrointestinal disturbances and secondary infertility, limiting its use.5 There is also a risk for hemorrhagic cystitis, hematologic malignancies and transitional cell carcinoma of the bladder. Given these serious potential side effects, cyclophosphamide is typically used less frequently than some other adjuvant agents, despite its efficacy.
Methotrexate
Methotrexate is a folic acid analog that inhibits purine synthesis. It acts by inhibiting humoral immunity, modulating cellular immunity and reducing cytokine secretion.
Used with corticosteroids, it has been shown to be somewhat effective as a steroid-sparing agent. However, overall, it appears to be less adequate than other agents.12
Plasmapheresis
Patients with severe or refractory PV may benefit from plasmapheresis, which has shown some efficacy in previous studies, although its role in managing the disease is controversial.
A controlled study of plasma exchange in pemphigus failed to show significant improvement among patients treated with plasmapheresis and corticosteroids as compared to patients treated with corticosteroids alone. Other studies have shown more favorable outcomes.
In a study performed by Turner et al, the use of pulse IV cyclophosphamide following plasmapheresis resulted in the best clinical outcome when compared to other adjuvant agents.14,15
Plasmapheresis should be used with caution as there is a significant risk of sepsis during treatment.
Gold Therapy
Gold therapy has been used successfully to treat PV. It is slow acting and results are typically not observed for up to 6 months following initiation of treatment. Pandya and Dyke reported on
21 patients with PV treated with Gold. The vast majority responded to therapy, however many suffered side effects from the medication that resolved upon discontinuation of the drug.16
Adverse effects include mucocutaneous reactions, renal toxicity, gastrointestinal disturbance and, rarely, aplastic anemia and pulmonary fibrosis.
The oral medication is better tolerated than the parenteral forms. Auranofin, the oral formulation, is started at a dose of 3 mg twice daily to a maximum dose of 9 mg/d. The intramuscular agents, aurothioglucose and aurothiomalate, are titrated up from an initial dose of 10 mg I.M. followed one week later by 25 mg I.M. then 50 mg I.M. bi-weekly.2
Other Treatment Options
Tetracyclines and niacinamide have been reported effective in selected case series.2,17
Intravenous immunoglobulin (IVIg) is one of the newer agents used in managing recalcitrant PV. IVIg is prepared from pooled human plasma (usually from 3,000 to 10,000 donors) The IgG portion is extracted from blood by cold ethanol fractionation then is concentrated and infused. IVIg consists of intact IgG molecules with the same distribution of IgG subclasses in normal human serum. The product contains a broad range of immune antibodies against pathogens and foreign antigens. The mechanism of action is not clear, but it is proposed to work by binding Fc receptors on macrophages inhibiting complement and complement-mediated damage and by neutralizing circulating autoantibodies.18 IVIg may also act by its effects on cytokine production, apoptosis, and neutralization of unknown toxins.
As it is costly, IVIg should be used in patients with severe PV where conventional therapy is contraindicated or has been refractory to conventional forms of treatment. Treatment with IVIg results in a gradual decline in pemphigus autoantibodies. One advantage of IVIg over other adjuvant agents is its rapidity of action. High-dose IVIg has been reported to clear 21 patients with severe recalcitrant PV within 4 to 5 months.19
A second author reports IVIg used in combination with cyclophosphamide resulted in cessation of new lesions within 1 week of starting IVIg and an 80% reduction of existing lesions in five of six patients.21
Ahmed reports a higher quality of life score in PV patients after treatment, fewer recurrences and fewer hospitalizations when compared with patients using glucocorticoid and immunosuppressive therapy.22
When prescribing IVIg, one must be aware that there are numerous IVIg products available in the United States with such variables as IgA content, sugar, and sodium content, half-life, plasma source and method of viral inactivation. It is important to take into account other underlying medical conditions such as diabetes mellitus or cardiovascular disease. The dosing of IVIg is 2 g/kg body weight divided over 3 days for a maximum of 144 g.2
Potential adverse effects include volume overload, allergic reactions and anaphylaxis, flu-like symptoms, cardiac events and aseptic meningitis. The literature mentions one report of up to 50 thrombotic events including pulmonary embolism, stroke and retinal vein occlusion. The proposed mechanisms of these thrombotic events include IVIg mediated increase in platelet aggregation and IgG dose-dependent increase in serum viscosity that has been shown to peak immediately following IVIg infusion.23 Although the donors and product are screened for infectious diseases, there is the theoretical risk of acquiring an infection from a contaminated source.
Rituximab is a genetically engineered chimeric murine anti-CD20 monoclonal antibody that targets malignant and non-malignant mature B cells and induces depletion of B cells in vivo.23 Pre-B cells, mature B cells and malignant B cells specifically express the CD20 antigen, but progenitor cells are spared because they lack the surface CD20. The mechanism of action in managing pemphigus is not clear, but may include killing CD20 cells via complement or antibody-dependent cytotoxicity, structural changes and apoptosis. Perhaps the drug may selectively destroy B-cell specific clones producing antibodies. Depletion of peripheral B cells occurs rapidly. Recovery begins at 6 to 9 months and counts return to normal in 9 to 12 months.
Rituximab has been shown to be effective in the treatment of B-cell lymphoma as well as other autoimmune diseases such as idiopathic thrombocytopenia, autoimmune hemolytic anemia and systemic lupus erythematosus. Case reports and case series have suggested it is effective in treating PV..24-29 The dose is 375/m2 I.V. q week for four treatments.
One study of patients treated with Rituximab showed that pemphigus lesions were healed within 6 weeks of starting therapy and remission was maintained 40 weeks after the last infusion.30
Rituximab is generally well tolerated; however, potential side effects include: neutropenia, interstitial pneumonitis, bronchospasm, angina and particularly when used in conjunction with plasmapheresis and cyclophosphamide, there is the major concern for infection
and sepsis.
More Hope for the Future
The management of pemphigus vulgaris has seen numerous advances and new developments. Perhaps these new medications will provide insight into the pathophysiology of PV and lead to the development of safer more effective treatments.
CME #123— July 2005
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
Though there have been significant improvements in the management of pemphigus vulgaris, there is still a great deal of variation among the experts regarding disease management. In this article, Jennifer C. Haley, M.D., and Janiene Luke, B.S., review current management of pemphigus vulgaris and provide an overview of all available treatments and potential side effects of these agents.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, and fax to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Managing Pemphigus Vulgaris
T hough rare, pemphigus vulgaris (PV) is a potentially life-threatening autoimmune bullous disorder affecting 0.1 to 0.42 people per 100,000. The disease, which typically develops in mid-life with a peak incidence of onset between the fourth and sixth decades,1 has an increased incidence in people of Mediterranean descent.
Phemphigus vulgaris is a disease that often follows a stormy course, waxing and waning in severity. Characterized by flaccid bullae, PV often originates in the scalp or mucous membranes, and may later evolve into a generalized distribution.
Although the pathophysiology of pemphigus is not completely understood, it is known that the disease develops as a result of B cell production of autoantibodies binding to desmosomal cadherins. Desmoglein 1 and 3 are the targets of the autoantibodies. These proteins are responsible for cohesion of the epithelial cells. Evidence suggests that antibodies in PV cause acantholysis and blister formation. The mechanism initiating autoantibody formation is
not known.2,3
Historically, pemphigus vulgaris had a very high mortality, approaching 100%. Blister formation can result in extensive erosions, which can cause weight loss and nutritional deficiency when oral mucosal involvement is extensive. Additionally, loss of skin integrity can result in fluid and electrolyte imbalance, susceptibility to infection and sepsis, temperature dysregulation and death.2
With the development of corticosteroids and adjuvant therapy, the current mortality rate approaches 10%. The majority of deaths are now related to complications secondary to the medications used to manage the disease.
Although there has been significant improvement in the management of pemphigus vulgaris, few controlled studies have evaluated these modalities.
To complicate things further, variation of disease management strategies exists among the experts. A telephone-based survey of 24 experts in pemphigus revealed that only 75% chose prednisone as first-line therapy. The dosage varied with about half of clinicians starting at
1 mg/kg/d with the remainder using higher doses.
Approximately one-third of clinicians surveyed had the expectation that patients would completely stop corticosteroids at some point. Others looked toward achieving a dose between
2.5 mg/d to 10 mg/d of prednisone.
This survey found that:
• 44% of clinicians initiated azathioprine (Azasan) as the first choice
for adjuvant therapy
• 20% used mycophenolate mofetil (CellCept)
• 16% prescribed cyclophosphamide
• 8% prescribed methotrexate as the first choice for adjuvent therapy.4
The purpose of this article is to review current management of pemphigus vulgaris and potential side effects of these agents.
Clinical Presentation and Diagnosis
The clinical presentation of pemphigus vulgaris varies, with between 25% to 50% of patients suffering from mucous membrane involvement. There is an increased incidence of systemic lupus erythematosus in patients with pemphigus. Additionally, pemphigus vulgaris may be associated with underlying malignancy or certain medications.
To make the diagnosis of PV, the clinician must obtain a skin or mucosal biopsy for histologic analysis, and complete a direct immunofluorescence of perilesional, intact skin or uninvolved skin. Histologically, biopsies reveal suprabasilar acantholysis, which is highly suggestive of PV. Deposition of IgG in the intercellular spaces of the epidermis confirms the diagnosis.5 Indirect immunofluorescence may be used to detect circulating autoantibodies in serum and recently ELISA has been used for direct measurement of Dsg 1 and Dsg 3 antibodies in serum.2,6
Treatment
As mentioned above, corticosteroids have been a mainstay in the treatment of pemphigus vulgaris. Although extremely effective in initial control of the disease, the many adverse effects associated with long-term use requires the clinician to seek adjuvant therapy. Corticosteroids can be effectively administered orally or intravenously. The starting dose is typically 1 mg/kg/d. Mutasim reports that most patients obtain remission in 4 to 12 weeks.2 Adjuvant therapy is often needed to maintain control of the disease on lower doses of corticosteroids.
Azathioprine
Azathioprine, often the first-line choice in adjuvant therapy of PV, has shown a steroid-sparing effect.6 A derivative of 6-mercaptopurine, this drug blocks DNA in lymphoid cells and inhibits neutrophil trafficking and cellular cytotoxicity. The recommended dosage is between 2 mg/kg/d to 4 mg/kg/d. The medication is typically tolerated better than some other adjuvant agents such as cyclophosphamide, although it seems to be less effective.2
In a publication looking at seven studies involving 105 patients, Bystryn and Steinman reported that remissions were induced in 28% of patients.7 The more serious of the many side effects of azathioprine is hepatotoxicity and myelosuppression, requiring monitoring of liver function tests and blood counts.
Newer tests to evaluate risk for hepatotoxicity and myelosuppression are available. Measuring the activity of thiopurine methyltransferase (TPMT) may assist in evaluating tolerance and in determining the ideal dosing for the individual. For patients taking the drug, 0.3% will have low to no enzyme activity and therefore will have a significantly high risk for toxicity. Also, 11% have a reduced activity of TPMT, requiring a reduced dose of the drug. In addition, 89% will have a normal to high activity and may tolerate higher doses. Measuring metabolites of azathioprine, such as 6-thioguanine and 6-MMPN, may assist the clinician in predicting likelihood of response, risk of leukopenia and hepatotoxicity.
In addition to liver and bone marrow toxicity, adverse effects of azathioprine include infection, malignancy, gastrointestinal disturbances and drug-induced hypersensitivity syndrome.
Mycophenolate MoFetilMycophenolate mofetil (MMF) is a precursor to the active metabolite mycophenolic acid. It is absorbed by the gastrointestinal tract and hydrolyzed to its active metabolite. The dosage is between 2 g/d to 3 g/d.
Mycophenolate mofetil inhibits de novo guanine synthesis by inhibiting an enzyme expressed in proliferating B and T cells. Other cells can use the salvage pathway for guanine, making MMF a selective inhibitor of T-cell proliferation. The drug also inhibits lymphocyte trafficking and impairs nitric oxide production. Originally used in pemphigus in 1997, MMF is often effective and well tolerated.
Several reports exist of successful management of pemphigus vulgaris with myocophenolate mofetil in patients who failed to respond to azathioprine.8 Some studies have shown MMF to be successful as monotherapy in managing PV.9,10 Potential side effects include fatigue, gastrointestinal and urinary disturbances, myelosuppression, infections, and lymphoma.
Cyclophosphamide
Cyclophosphamide is an alkylating agent that has been shown to have a steroid-sparing effect and is useful in patients with severe PV who may have failed therapy with azathioprine or MMF.
In a study of 20 patients with pemphigus vulgaris, 17 achieved complete remission when treated with cyclophosphamide.11 The drug can be effectively prescribed in a daily oral dose or administered intravenously in a single or monthly pulse regimen. Although this agent is effective in managing patients with recalcitrant disease, it has many significant side effects, such as neutropenia, gastrointestinal disturbances and secondary infertility, limiting its use.5 There is also a risk for hemorrhagic cystitis, hematologic malignancies and transitional cell carcinoma of the bladder. Given these serious potential side effects, cyclophosphamide is typically used less frequently than some other adjuvant agents, despite its efficacy.
Methotrexate
Methotrexate is a folic acid analog that inhibits purine synthesis. It acts by inhibiting humoral immunity, modulating cellular immunity and reducing cytokine secretion.
Used with corticosteroids, it has been shown to be somewhat effective as a steroid-sparing agent. However, overall, it appears to be less adequate than other agents.12
Plasmapheresis
Patients with severe or refractory PV may benefit from plasmapheresis, which has shown some efficacy in previous studies, although its role in managing the disease is controversial.
A controlled study of plasma exchange in pemphigus failed to show significant improvement among patients treated with plasmapheresis and corticosteroids as compared to patients treated with corticosteroids alone. Other studies have shown more favorable outcomes.
In a study performed by Turner et al, the use of pulse IV cyclophosphamide following plasmapheresis resulted in the best clinical outcome when compared to other adjuvant agents.14,15
Plasmapheresis should be used with caution as there is a significant risk of sepsis during treatment.
Gold Therapy
Gold therapy has been used successfully to treat PV. It is slow acting and results are typically not observed for up to 6 months following initiation of treatment. Pandya and Dyke reported on
21 patients with PV treated with Gold. The vast majority responded to therapy, however many suffered side effects from the medication that resolved upon discontinuation of the drug.16
Adverse effects include mucocutaneous reactions, renal toxicity, gastrointestinal disturbance and, rarely, aplastic anemia and pulmonary fibrosis.
The oral medication is better tolerated than the parenteral forms. Auranofin, the oral formulation, is started at a dose of 3 mg twice daily to a maximum dose of 9 mg/d. The intramuscular agents, aurothioglucose and aurothiomalate, are titrated up from an initial dose of 10 mg I.M. followed one week later by 25 mg I.M. then 50 mg I.M. bi-weekly.2
Other Treatment Options
Tetracyclines and niacinamide have been reported effective in selected case series.2,17
Intravenous immunoglobulin (IVIg) is one of the newer agents used in managing recalcitrant PV. IVIg is prepared from pooled human plasma (usually from 3,000 to 10,000 donors) The IgG portion is extracted from blood by cold ethanol fractionation then is concentrated and infused. IVIg consists of intact IgG molecules with the same distribution of IgG subclasses in normal human serum. The product contains a broad range of immune antibodies against pathogens and foreign antigens. The mechanism of action is not clear, but it is proposed to work by binding Fc receptors on macrophages inhibiting complement and complement-mediated damage and by neutralizing circulating autoantibodies.18 IVIg may also act by its effects on cytokine production, apoptosis, and neutralization of unknown toxins.
As it is costly, IVIg should be used in patients with severe PV where conventional therapy is contraindicated or has been refractory to conventional forms of treatment. Treatment with IVIg results in a gradual decline in pemphigus autoantibodies. One advantage of IVIg over other adjuvant agents is its rapidity of action. High-dose IVIg has been reported to clear 21 patients with severe recalcitrant PV within 4 to 5 months.19
A second author reports IVIg used in combination with cyclophosphamide resulted in cessation of new lesions within 1 week of starting IVIg and an 80% reduction of existing lesions in five of six patients.21
Ahmed reports a higher quality of life score in PV patients after treatment, fewer recurrences and fewer hospitalizations when compared with patients using glucocorticoid and immunosuppressive therapy.22
When prescribing IVIg, one must be aware that there are numerous IVIg products available in the United States with such variables as IgA content, sugar, and sodium content, half-life, plasma source and method of viral inactivation. It is important to take into account other underlying medical conditions such as diabetes mellitus or cardiovascular disease. The dosing of IVIg is 2 g/kg body weight divided over 3 days for a maximum of 144 g.2
Potential adverse effects include volume overload, allergic reactions and anaphylaxis, flu-like symptoms, cardiac events and aseptic meningitis. The literature mentions one report of up to 50 thrombotic events including pulmonary embolism, stroke and retinal vein occlusion. The proposed mechanisms of these thrombotic events include IVIg mediated increase in platelet aggregation and IgG dose-dependent increase in serum viscosity that has been shown to peak immediately following IVIg infusion.23 Although the donors and product are screened for infectious diseases, there is the theoretical risk of acquiring an infection from a contaminated source.
Rituximab is a genetically engineered chimeric murine anti-CD20 monoclonal antibody that targets malignant and non-malignant mature B cells and induces depletion of B cells in vivo.23 Pre-B cells, mature B cells and malignant B cells specifically express the CD20 antigen, but progenitor cells are spared because they lack the surface CD20. The mechanism of action in managing pemphigus is not clear, but may include killing CD20 cells via complement or antibody-dependent cytotoxicity, structural changes and apoptosis. Perhaps the drug may selectively destroy B-cell specific clones producing antibodies. Depletion of peripheral B cells occurs rapidly. Recovery begins at 6 to 9 months and counts return to normal in 9 to 12 months.
Rituximab has been shown to be effective in the treatment of B-cell lymphoma as well as other autoimmune diseases such as idiopathic thrombocytopenia, autoimmune hemolytic anemia and systemic lupus erythematosus. Case reports and case series have suggested it is effective in treating PV..24-29 The dose is 375/m2 I.V. q week for four treatments.
One study of patients treated with Rituximab showed that pemphigus lesions were healed within 6 weeks of starting therapy and remission was maintained 40 weeks after the last infusion.30
Rituximab is generally well tolerated; however, potential side effects include: neutropenia, interstitial pneumonitis, bronchospasm, angina and particularly when used in conjunction with plasmapheresis and cyclophosphamide, there is the major concern for infection
and sepsis.
More Hope for the Future
The management of pemphigus vulgaris has seen numerous advances and new developments. Perhaps these new medications will provide insight into the pathophysiology of PV and lead to the development of safer more effective treatments.
CME #123— July 2005
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
Though there have been significant improvements in the management of pemphigus vulgaris, there is still a great deal of variation among the experts regarding disease management. In this article, Jennifer C. Haley, M.D., and Janiene Luke, B.S., review current management of pemphigus vulgaris and provide an overview of all available treatments and potential side effects of these agents.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, and fax to HMP Communications at (610) 560-0501. We’ll also post this course on our Web site — www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Managing Pemphigus Vulgaris
T hough rare, pemphigus vulgaris (PV) is a potentially life-threatening autoimmune bullous disorder affecting 0.1 to 0.42 people per 100,000. The disease, which typically develops in mid-life with a peak incidence of onset between the fourth and sixth decades,1 has an increased incidence in people of Mediterranean descent.
Phemphigus vulgaris is a disease that often follows a stormy course, waxing and waning in severity. Characterized by flaccid bullae, PV often originates in the scalp or mucous membranes, and may later evolve into a generalized distribution.
Although the pathophysiology of pemphigus is not completely understood, it is known that the disease develops as a result of B cell production of autoantibodies binding to desmosomal cadherins. Desmoglein 1 and 3 are the targets of the autoantibodies. These proteins are responsible for cohesion of the epithelial cells. Evidence suggests that antibodies in PV cause acantholysis and blister formation. The mechanism initiating autoantibody formation is
not known.2,3
Historically, pemphigus vulgaris had a very high mortality, approaching 100%. Blister formation can result in extensive erosions, which can cause weight loss and nutritional deficiency when oral mucosal involvement is extensive. Additionally, loss of skin integrity can result in fluid and electrolyte imbalance, susceptibility to infection and sepsis, temperature dysregulation and death.2
With the development of corticosteroids and adjuvant therapy, the current mortality rate approaches 10%. The majority of deaths are now related to complications secondary to the medications used to manage the disease.
Although there has been significant improvement in the management of pemphigus vulgaris, few controlled studies have evaluated these modalities.
To complicate things further, variation of disease management strategies exists among the experts. A telephone-based survey of 24 experts in pemphigus revealed that only 75% chose prednisone as first-line therapy. The dosage varied with about half of clinicians starting at
1 mg/kg/d with the remainder using higher doses.
Approximately one-third of clinicians surveyed had the expectation that patients would completely stop corticosteroids at some point. Others looked toward achieving a dose between
2.5 mg/d to 10 mg/d of prednisone.
This survey found that:
• 44% of clinicians initiated azathioprine (Azasan) as the first choice
for adjuvant therapy
• 20% used mycophenolate mofetil (CellCept)
• 16% prescribed cyclophosphamide
• 8% prescribed methotrexate as the first choice for adjuvent therapy.4
The purpose of this article is to review current management of pemphigus vulgaris and potential side effects of these agents.
Clinical Presentation and Diagnosis
The clinical presentation of pemphigus vulgaris varies, with between 25% to 50% of patients suffering from mucous membrane involvement. There is an increased incidence of systemic lupus erythematosus in patients with pemphigus. Additionally, pemphigus vulgaris may be associated with underlying malignancy or certain medications.
To make the diagnosis of PV, the clinician must obtain a skin or mucosal biopsy for histologic analysis, and complete a direct immunofluorescence of perilesional, intact skin or uninvolved skin. Histologically, biopsies reveal suprabasilar acantholysis, which is highly suggestive of PV. Deposition of IgG in the intercellular spaces of the epidermis confirms the diagnosis.5 Indirect immunofluorescence may be used to detect circulating autoantibodies in serum and recently ELISA has been used for direct measurement of Dsg 1 and Dsg 3 antibodies in serum.2,6
Treatment
As mentioned above, corticosteroids have been a mainstay in the treatment of pemphigus vulgaris. Although extremely effective in initial control of the disease, the many adverse effects associated with long-term use requires the clinician to seek adjuvant therapy. Corticosteroids can be effectively administered orally or intravenously. The starting dose is typically 1 mg/kg/d. Mutasim reports that most patients obtain remission in 4 to 12 weeks.2 Adjuvant therapy is often needed to maintain control of the disease on lower doses of corticosteroids.
Azathioprine
Azathioprine, often the first-line choice in adjuvant therapy of PV, has shown a steroid-sparing effect.6 A derivative of 6-mercaptopurine, this drug blocks DNA in lymphoid cells and inhibits neutrophil trafficking and cellular cytotoxicity. The recommended dosage is between 2 mg/kg/d to 4 mg/kg/d. The medication is typically tolerated better than some other adjuvant agents such as cyclophosphamide, although it seems to be less effective.2
In a publication looking at seven studies involving 105 patients, Bystryn and Steinman reported that remissions were induced in 28% of patients.7 The more serious of the many side effects of azathioprine is hepatotoxicity and myelosuppression, requiring monitoring of liver function tests and blood counts.
Newer tests to evaluate risk for hepatotoxicity and myelosuppression are available. Measuring the activity of thiopurine methyltransferase (TPMT) may assist in evaluating tolerance and in determining the ideal dosing for the individual. For patients taking the drug, 0.3% will have low to no enzyme activity and therefore will have a significantly high risk for toxicity. Also, 11% have a reduced activity of TPMT, requiring a reduced dose of the drug. In addition, 89% will have a normal to high activity and may tolerate higher doses. Measuring metabolites of azathioprine, such as 6-thioguanine and 6-MMPN, may assist the clinician in predicting likelihood of response, risk of leukopenia and hepatotoxicity.
In addition to liver and bone marrow toxicity, adverse effects of azathioprine include infection, malignancy, gastrointestinal disturbances and drug-induced hypersensitivity syndrome.
Mycophenolate MoFetilMycophenolate mofetil (MMF) is a precursor to the active metabolite mycophenolic acid. It is absorbed by the gastrointestinal tract and hydrolyzed to its active metabolite. The dosage is between 2 g/d to 3 g/d.
Mycophenolate mofetil inhibits de novo guanine synthesis by inhibiting an enzyme expressed in proliferating B and T cells. Other cells can use the salvage pathway for guanine, making MMF a selective inhibitor of T-cell proliferation. The drug also inhibits lymphocyte trafficking and impairs nitric oxide production. Originally used in pemphigus in 1997, MMF is often effective and well tolerated.
Several reports exist of successful management of pemphigus vulgaris with myocophenolate mofetil in patients who failed to respond to azathioprine.8 Some studies have shown MMF to be successful as monotherapy in managing PV.9,10 Potential side effects include fatigue, gastrointestinal and urinary disturbances, myelosuppression, infections, and lymphoma.
Cyclophosphamide
Cyclophosphamide is an alkylating agent that has been shown to have a steroid-sparing effect and is useful in patients with severe PV who may have failed therapy with azathioprine or MMF.
In a study of 20 patients with pemphigus vulgaris, 17 achieved complete remission when treated with cyclophosphamide.11 The drug can be effectively prescribed in a daily oral dose or administered intravenously in a single or monthly pulse regimen. Although this agent is effective in managing patients with recalcitrant disease, it has many significant side effects, such as neutropenia, gastrointestinal disturbances and secondary infertility, limiting its use.5 There is also a risk for hemorrhagic cystitis, hematologic malignancies and transitional cell carcinoma of the bladder. Given these serious potential side effects, cyclophosphamide is typically used less frequently than some other adjuvant agents, despite its efficacy.
Methotrexate
Methotrexate is a folic acid analog that inhibits purine synthesis. It acts by inhibiting humoral immunity, modulating cellular immunity and reducing cytokine secretion.
Used with corticosteroids, it has been shown to be somewhat effective as a steroid-sparing agent. However, overall, it appears to be less adequate than other agents.12
Plasmapheresis
Patients with severe or refractory PV may benefit from plasmapheresis, which has shown some efficacy in previous studies, although its role in managing the disease is controversial.
A controlled study of plasma exchange in pemphigus failed to show significant improvement among patients treated with plasmapheresis and corticosteroids as compared to patients treated with corticosteroids alone. Other studies have shown more favorable outcomes.
In a study performed by Turner et al, the use of pulse IV cyclophosphamide following plasmapheresis resulted in the best clinical outcome when compared to other adjuvant agents.14,15
Plasmapheresis should be used with caution as there is a significant risk of sepsis during treatment.
Gold Therapy
Gold therapy has been used successfully to treat PV. It is slow acting and results are typically not observed for up to 6 months following initiation of treatment. Pandya and Dyke reported on
21 patients with PV treated with Gold. The vast majority responded to therapy, however many suffered side effects from the medication that resolved upon discontinuation of the drug.16
Adverse effects include mucocutaneous reactions, renal toxicity, gastrointestinal disturbance and, rarely, aplastic anemia and pulmonary fibrosis.
The oral medication is better tolerated than the parenteral forms. Auranofin, the oral formulation, is started at a dose of 3 mg twice daily to a maximum dose of 9 mg/d. The intramuscular agents, aurothioglucose and aurothiomalate, are titrated up from an initial dose of 10 mg I.M. followed one week later by 25 mg I.M. then 50 mg I.M. bi-weekly.2
Other Treatment Options
Tetracyclines and niacinamide have been reported effective in selected case series.2,17
Intravenous immunoglobulin (IVIg) is one of the newer agents used in managing recalcitrant PV. IVIg is prepared from pooled human plasma (usually from 3,000 to 10,000 donors) The IgG portion is extracted from blood by cold ethanol fractionation then is concentrated and infused. IVIg consists of intact IgG molecules with the same distribution of IgG subclasses in normal human serum. The product contains a broad range of immune antibodies against pathogens and foreign antigens. The mechanism of action is not clear, but it is proposed to work by binding Fc receptors on macrophages inhibiting complement and complement-mediated damage and by neutralizing circulating autoantibodies.18 IVIg may also act by its effects on cytokine production, apoptosis, and neutralization of unknown toxins.
As it is costly, IVIg should be used in patients with severe PV where conventional therapy is contraindicated or has been refractory to conventional forms of treatment. Treatment with IVIg results in a gradual decline in pemphigus autoantibodies. One advantage of IVIg over other adjuvant agents is its rapidity of action. High-dose IVIg has been reported to clear 21 patients with severe recalcitrant PV within 4 to 5 months.19
A second author reports IVIg used in combination with cyclophosphamide resulted in cessation of new lesions within 1 week of starting IVIg and an 80% reduction of existing lesions in five of six patients.21
Ahmed reports a higher quality of life score in PV patients after treatment, fewer recurrences and fewer hospitalizations when compared with patients using glucocorticoid and immunosuppressive therapy.22
When prescribing IVIg, one must be aware that there are numerous IVIg products available in the United States with such variables as IgA content, sugar, and sodium content, half-life, plasma source and method of viral inactivation. It is important to take into account other underlying medical conditions such as diabetes mellitus or cardiovascular disease. The dosing of IVIg is 2 g/kg body weight divided over 3 days for a maximum of 144 g.2
Potential adverse effects include volume overload, allergic reactions and anaphylaxis, flu-like symptoms, cardiac events and aseptic meningitis. The literature mentions one report of up to 50 thrombotic events including pulmonary embolism, stroke and retinal vein occlusion. The proposed mechanisms of these thrombotic events include IVIg mediated increase in platelet aggregation and IgG dose-dependent increase in serum viscosity that has been shown to peak immediately following IVIg infusion.23 Although the donors and product are screened for infectious diseases, there is the theoretical risk of acquiring an infection from a contaminated source.
Rituximab is a genetically engineered chimeric murine anti-CD20 monoclonal antibody that targets malignant and non-malignant mature B cells and induces depletion of B cells in vivo.23 Pre-B cells, mature B cells and malignant B cells specifically express the CD20 antigen, but progenitor cells are spared because they lack the surface CD20. The mechanism of action in managing pemphigus is not clear, but may include killing CD20 cells via complement or antibody-dependent cytotoxicity, structural changes and apoptosis. Perhaps the drug may selectively destroy B-cell specific clones producing antibodies. Depletion of peripheral B cells occurs rapidly. Recovery begins at 6 to 9 months and counts return to normal in 9 to 12 months.
Rituximab has been shown to be effective in the treatment of B-cell lymphoma as well as other autoimmune diseases such as idiopathic thrombocytopenia, autoimmune hemolytic anemia and systemic lupus erythematosus. Case reports and case series have suggested it is effective in treating PV..24-29 The dose is 375/m2 I.V. q week for four treatments.
One study of patients treated with Rituximab showed that pemphigus lesions were healed within 6 weeks of starting therapy and remission was maintained 40 weeks after the last infusion.30
Rituximab is generally well tolerated; however, potential side effects include: neutropenia, interstitial pneumonitis, bronchospasm, angina and particularly when used in conjunction with plasmapheresis and cyclophosphamide, there is the major concern for infection
and sepsis.
More Hope for the Future
The management of pemphigus vulgaris has seen numerous advances and new developments. Perhaps these new medications will provide insight into the pathophysiology of PV and lead to the development of safer more effective treatments.
Current Issue
October 2024
Volume 32
Issue 7
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