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Therapeutic failure of high-dose intravenous immunoglobulin in pemphigus vulgaris
Journal of the American Academy of Dennatology Volume 40, Number 3
Letters 499
REFERENCES
Michael Binder, MD Harald Kittler, MD Hubert Pehamberger, MD Klaus Wolff, MD, FRCP Department of Dermatology University of Vienna Medical School Wahringergeurtel18-20 A-1090 Vienna, Austria
1. Richert SM, D'Amico F, Rhodes AR. Cutaneous
melanoma: patient surveillance and tumor progression. J Am Acad Dennatol 1998;39:571-7. 2. Flesch R. The ABC of style. New York: Harper and Row; 1964. 3. Bergman R, Faclieru D, Sahar D, Sander CA, Kerner H, Ben-Aryeh Y, et alia. Immunophenotyping and T-cell receptor y gene rearrangement analysis as an adjunct to the histopathologic diagnosis of mycosis fungoides. J Am Acad Dennatol 1998;39:554-9.
Reply I agree. We will ask authors to provide a boxed glossary of abbreviations and begin to print them on the first page of each article asap. We will favor cOIl)prehensibility over brevity whenever we can. And we will encourage authors to report their data in graphic or tabular form without a prose rendition in the Results section whenever it works best that way. Jeffrey D. Bernhard, MD, Editor
Possible hazard to patients from immersion oil used for epiluminescence microscopy To the Editor: Epiluminescence microscopy (syn. dermoscopy or dermatoscopy) is a noninvasive technique that is designed for in vivo microscopic examination of pigmented skin lesions, particularly for the early recognition of malignant melanoma. 1 Technical prerequisites are simple hand-held microscopes with a magnifying lens, which is pressed on the lesion. The selective penetration of optical wavelengths into skin is maximized by application of clear lipophilic liquids, which decrease optical reflectance of the stratum corneum and therefore allow a view beyond the surface of the skin. This technique of oil immersion has been shown by several groups in Europe,2,3 the United States,4 and Australia5 to increase the diagnostic accuracy of pigmented skin lesions. In addition, it has been published that immersion oil serves the purpose as contact medium. 5.6 However, immersion oil is not approved for use in vivo on human skin because it may contain chlorinated paraffin and dibutyl phtalate. Both substances may have teratogenic, fetotoxic, and carcinogenic effects'? Chlorinated paraffins are known to be hepatotoxic and thyrotoxic. B Although it is highly improbable that the minimal amount of oil applied to the skin for epiluminescence microscopy could cause any harmful effects, immersion oil can easily be substituted by olive oil, glycerin, or ultrasonic conduction ge1. 9 Immersion oil should therefore be considered inappropriate for in vivo epiluminescence microscopy.
REFERENCES 1. Rigel DS. Epiluminescence microscopy in clinical diagnosis of pigmented skin lesions? Lancet 1997;349:15667. 2. Stolz W, Bilek P, Landthaler M, Merkle T, Braun FO. Skin surface microscopy. Lancet 1989;2:864-5. 3. Pehamberger H, Steiner A, Wolff K. In vivo epiluminescence microscopy of pigmented skin lesions. I. Pattern analysis of pigmented skin lesions. JAm Acad Dennatol 1987;17:571-83. 4. Kopf AW, Salopek TG, Slade J, Marghoob AA, Bart RS. Techniques of cutaneous examination for the detection of skin cancer. Cancer 1995;75:684-90. 5. Menzies SW, Crotty KA, McCarthy WHo The morphologic criteria of the pseudopod in surface microscopy. Arch DennatoI1995;131:436-40. 6. Soyer HP, Smolle J, Kerl H, Stettner H. Early diagnosis of malignant melanoma by surface microscopy. Lancet 1987;2:803. 7. European Union Safety Data Sheet 0102 132 for Immersion Oil 518C. 1995. 8. Wyatt I, Coutts CT, Elcombe CR. The effect of chlorinated paraffins on hepatic enzymes and thyroid hormones. Toxicology 1993;77:81-90. 9. Stolz W. Is the use of oil in epiluminescence microscopy necessary? Hautarzt 1993;44:742-3.
Therapeutic failure of high-dose intravenous immunoglobulin in pemphigus vulgaris To the Editor: High-dose intravenous immunoglobulin (hdIVlg) has been used to treat an increasing number of dermatologic conditions.! In pemphigus vulgaris (PV), hdlVlg has been used successfully in a small number of open uncontrolled trials and individual cases. 2-B The advantages of this adjunctive therapy are efficacy and the lack of side effects usually associated with steroids, currently the mainstay of treatment. The disadvantages are the inconvenience to patients; exposure to a blood product derived from 10,000 to 20,000 donors; side effects, including aseptic meningitis 9 (which are largely controllable); and considerable expense. The annual cost of treatment with hdlVlg in a man weighing 70 kg who is using immunoglobulin at $25/g at a dose of 2 g/kg per month is $42,000. There has been only one report of therapeutic failure with hdlVlg in PV5; however, hdlVlg was used as monotherapy and only a single cycle of treatment was given. We report a case of severe PV in which hdlVlg
Journal of the American Academy of Dermatology March 1999
500 Letters was used as adjunctive second-line therapy for multiple cycles without success. A 52-year-old woman presented with a 9-year history of severe oral, esophageal, and widespread skin blisters and erosions, thalassemia trait, and osteoporosis. The diagnosis of PV was confirmed by characteristic histopathologic findings and direct immunofluorescence. PV antibodies of the IgG class were detected at a peak titer of 1:3200, and there was no evidence of an underlying malignancy. The patient had been treated with several second-line agents in addition to a maintenance dose of oral prednisolone (between 20 and 50 mg daily). These included azathioprine (100 mg daily), dapsone (l00 to 150 mg daily), cyclophosphamide (l00 mg daily), cyclosporine (5 mg/kg daily), and a trial of plasma exchange. Each therapy was given for at least 3 months. In view of the severity of her disease and the lack of success with other second-line treatment, a trial of hdIVIg (Sandoglobulin) was begun at 2 g/kg per month for 10 months. The trough level of IgG was maintained at more than 20 gIL to ensure that therapeutic intravascular levels were achieved. After the first cycle, which was given in combination with cyclosporine, transient improvement was noted. Further relapse occurred after 2 weeks, and she was treated sequentially with mycophenolate (1 g twice daily), gold (50 mg intramuscularly weekly), methotrexate (15 mg weekly), tacrolimus (2.4 mg twice daily), and intravenous cyclophosphamide at 750 mg pulses while the patient remained on a regimen of steroids and hdIVIg. She continued to require multiple regular hospital admissions for treatment of infection and skin care. Her condition continued to worsen, and multiple painful areas of skin loss required continuous nursing care and opiate pain relief. The patient and her family requested withdrawal of active treatment, and she died shortly afterward of sepsis. This is the first report of therapeutic failure of an adequate trial of hdIVIg used as an adjunctive treatment, which may reflect a reporting bias for successful therapy. Caution is needed in the interpretation of the published uncontrolled data, and the urgent need for a double-blind, placebo-controlled trial in this area is emphasized. If all the case reports and trials of hdIVIg in dermatological disease are amalgamated, a success
rate of approximately 40% was observed when hdIVIg was used as monotherapy, which increased to 80% when given an adjunctive treatment. 1 A controlled trial using hdIVIg as adjunctive therapy to a second-line agent with significant effects on antibody production in refractory cases of PV would help in defining the place of hdIVIg. Given a sufficient number of patients, the crucial questions of dose and interval between cycles may also be addressed. Stephen lolles, MSc, MRCp, DipRCPath lenny Hughes, MRCP Malcolm Rustin, MD, FRCP National Institute for Medical Research Division of Cellular Immunology The Ridgeway Mill Hill London, NW7 IAA, England
REFERENCES 1. Jolles S, Hughes J, Whittaker S. Dermatological uses of
2. 3. 4.
5.
6.
7. 8. 9.
high-dose intravenous immunoglobulin. Arch Dermatol 1998;134:80-6. Colonna L, Cianchini G, Frezzolini A, et al. Intravenous immunoglobulins for pemphigus vulgaris: adjuvant or first choice therapy. Br J DermatoI1998;138:1102-3. Wever S, Zillikenz D, Broker EB. Successful treatment of pemphigus vulgaris by pulsed intravenous immunoglobulin therapy. Br J DermatoI1996;135:862-3. Beckers RC, Brand A, Vermeer BJ, Boom BW. Adjuvant high-dose intravenous gammaglobulin in the treatment of pemphigus and bullous pemphigoid: experience in six patients. Br J Dermatol 1995;133:289-93. Tappeiner G, Steiner A. High-dosage intravenous gamma globulin: therapeutic failure in pemphigus and pemphigoid [see comments]. JAm Acad Dermatol 1989;20: 684-5. Messer G, Sizmann N, Feucht H, Meurer M. High-dose intravenous immunoglobulins for immediate control of severe pemphigus vulgaris. Br J Dermatol 1995;133: 1014-6. / Humbert P, Derancourt C, Aubin F, Agache P. Effects of intravenous 'Y-globulin in pemphigus [letter]. JAm Acad Dermatol 1990;22:326. Bewley AP, Keefe M. Successful treatment of pemphigus vulgaris by pulsed intravenous immunoglobulin therapy. Br J DermatoI1996;135:128-9. Jolles S, Hill H. Management of aseptic meningitis secondary to intravenous immunoglobulin. BMJ 1998;316: 936.
Letters 499
REFERENCES
Michael Binder, MD Harald Kittler, MD Hubert Pehamberger, MD Klaus Wolff, MD, FRCP Department of Dermatology University of Vienna Medical School Wahringergeurtel18-20 A-1090 Vienna, Austria
1. Richert SM, D'Amico F, Rhodes AR. Cutaneous
melanoma: patient surveillance and tumor progression. J Am Acad Dennatol 1998;39:571-7. 2. Flesch R. The ABC of style. New York: Harper and Row; 1964. 3. Bergman R, Faclieru D, Sahar D, Sander CA, Kerner H, Ben-Aryeh Y, et alia. Immunophenotyping and T-cell receptor y gene rearrangement analysis as an adjunct to the histopathologic diagnosis of mycosis fungoides. J Am Acad Dennatol 1998;39:554-9.
Reply I agree. We will ask authors to provide a boxed glossary of abbreviations and begin to print them on the first page of each article asap. We will favor cOIl)prehensibility over brevity whenever we can. And we will encourage authors to report their data in graphic or tabular form without a prose rendition in the Results section whenever it works best that way. Jeffrey D. Bernhard, MD, Editor
Possible hazard to patients from immersion oil used for epiluminescence microscopy To the Editor: Epiluminescence microscopy (syn. dermoscopy or dermatoscopy) is a noninvasive technique that is designed for in vivo microscopic examination of pigmented skin lesions, particularly for the early recognition of malignant melanoma. 1 Technical prerequisites are simple hand-held microscopes with a magnifying lens, which is pressed on the lesion. The selective penetration of optical wavelengths into skin is maximized by application of clear lipophilic liquids, which decrease optical reflectance of the stratum corneum and therefore allow a view beyond the surface of the skin. This technique of oil immersion has been shown by several groups in Europe,2,3 the United States,4 and Australia5 to increase the diagnostic accuracy of pigmented skin lesions. In addition, it has been published that immersion oil serves the purpose as contact medium. 5.6 However, immersion oil is not approved for use in vivo on human skin because it may contain chlorinated paraffin and dibutyl phtalate. Both substances may have teratogenic, fetotoxic, and carcinogenic effects'? Chlorinated paraffins are known to be hepatotoxic and thyrotoxic. B Although it is highly improbable that the minimal amount of oil applied to the skin for epiluminescence microscopy could cause any harmful effects, immersion oil can easily be substituted by olive oil, glycerin, or ultrasonic conduction ge1. 9 Immersion oil should therefore be considered inappropriate for in vivo epiluminescence microscopy.
REFERENCES 1. Rigel DS. Epiluminescence microscopy in clinical diagnosis of pigmented skin lesions? Lancet 1997;349:15667. 2. Stolz W, Bilek P, Landthaler M, Merkle T, Braun FO. Skin surface microscopy. Lancet 1989;2:864-5. 3. Pehamberger H, Steiner A, Wolff K. In vivo epiluminescence microscopy of pigmented skin lesions. I. Pattern analysis of pigmented skin lesions. JAm Acad Dennatol 1987;17:571-83. 4. Kopf AW, Salopek TG, Slade J, Marghoob AA, Bart RS. Techniques of cutaneous examination for the detection of skin cancer. Cancer 1995;75:684-90. 5. Menzies SW, Crotty KA, McCarthy WHo The morphologic criteria of the pseudopod in surface microscopy. Arch DennatoI1995;131:436-40. 6. Soyer HP, Smolle J, Kerl H, Stettner H. Early diagnosis of malignant melanoma by surface microscopy. Lancet 1987;2:803. 7. European Union Safety Data Sheet 0102 132 for Immersion Oil 518C. 1995. 8. Wyatt I, Coutts CT, Elcombe CR. The effect of chlorinated paraffins on hepatic enzymes and thyroid hormones. Toxicology 1993;77:81-90. 9. Stolz W. Is the use of oil in epiluminescence microscopy necessary? Hautarzt 1993;44:742-3.
Therapeutic failure of high-dose intravenous immunoglobulin in pemphigus vulgaris To the Editor: High-dose intravenous immunoglobulin (hdIVlg) has been used to treat an increasing number of dermatologic conditions.! In pemphigus vulgaris (PV), hdlVlg has been used successfully in a small number of open uncontrolled trials and individual cases. 2-B The advantages of this adjunctive therapy are efficacy and the lack of side effects usually associated with steroids, currently the mainstay of treatment. The disadvantages are the inconvenience to patients; exposure to a blood product derived from 10,000 to 20,000 donors; side effects, including aseptic meningitis 9 (which are largely controllable); and considerable expense. The annual cost of treatment with hdlVlg in a man weighing 70 kg who is using immunoglobulin at $25/g at a dose of 2 g/kg per month is $42,000. There has been only one report of therapeutic failure with hdlVlg in PV5; however, hdlVlg was used as monotherapy and only a single cycle of treatment was given. We report a case of severe PV in which hdlVlg
Journal of the American Academy of Dermatology March 1999
500 Letters was used as adjunctive second-line therapy for multiple cycles without success. A 52-year-old woman presented with a 9-year history of severe oral, esophageal, and widespread skin blisters and erosions, thalassemia trait, and osteoporosis. The diagnosis of PV was confirmed by characteristic histopathologic findings and direct immunofluorescence. PV antibodies of the IgG class were detected at a peak titer of 1:3200, and there was no evidence of an underlying malignancy. The patient had been treated with several second-line agents in addition to a maintenance dose of oral prednisolone (between 20 and 50 mg daily). These included azathioprine (100 mg daily), dapsone (l00 to 150 mg daily), cyclophosphamide (l00 mg daily), cyclosporine (5 mg/kg daily), and a trial of plasma exchange. Each therapy was given for at least 3 months. In view of the severity of her disease and the lack of success with other second-line treatment, a trial of hdIVIg (Sandoglobulin) was begun at 2 g/kg per month for 10 months. The trough level of IgG was maintained at more than 20 gIL to ensure that therapeutic intravascular levels were achieved. After the first cycle, which was given in combination with cyclosporine, transient improvement was noted. Further relapse occurred after 2 weeks, and she was treated sequentially with mycophenolate (1 g twice daily), gold (50 mg intramuscularly weekly), methotrexate (15 mg weekly), tacrolimus (2.4 mg twice daily), and intravenous cyclophosphamide at 750 mg pulses while the patient remained on a regimen of steroids and hdIVIg. She continued to require multiple regular hospital admissions for treatment of infection and skin care. Her condition continued to worsen, and multiple painful areas of skin loss required continuous nursing care and opiate pain relief. The patient and her family requested withdrawal of active treatment, and she died shortly afterward of sepsis. This is the first report of therapeutic failure of an adequate trial of hdIVIg used as an adjunctive treatment, which may reflect a reporting bias for successful therapy. Caution is needed in the interpretation of the published uncontrolled data, and the urgent need for a double-blind, placebo-controlled trial in this area is emphasized. If all the case reports and trials of hdIVIg in dermatological disease are amalgamated, a success
rate of approximately 40% was observed when hdIVIg was used as monotherapy, which increased to 80% when given an adjunctive treatment. 1 A controlled trial using hdIVIg as adjunctive therapy to a second-line agent with significant effects on antibody production in refractory cases of PV would help in defining the place of hdIVIg. Given a sufficient number of patients, the crucial questions of dose and interval between cycles may also be addressed. Stephen lolles, MSc, MRCp, DipRCPath lenny Hughes, MRCP Malcolm Rustin, MD, FRCP National Institute for Medical Research Division of Cellular Immunology The Ridgeway Mill Hill London, NW7 IAA, England
REFERENCES 1. Jolles S, Hughes J, Whittaker S. Dermatological uses of
2. 3. 4.
5.
6.
7. 8. 9.
high-dose intravenous immunoglobulin. Arch Dermatol 1998;134:80-6. Colonna L, Cianchini G, Frezzolini A, et al. Intravenous immunoglobulins for pemphigus vulgaris: adjuvant or first choice therapy. Br J DermatoI1998;138:1102-3. Wever S, Zillikenz D, Broker EB. Successful treatment of pemphigus vulgaris by pulsed intravenous immunoglobulin therapy. Br J DermatoI1996;135:862-3. Beckers RC, Brand A, Vermeer BJ, Boom BW. Adjuvant high-dose intravenous gammaglobulin in the treatment of pemphigus and bullous pemphigoid: experience in six patients. Br J Dermatol 1995;133:289-93. Tappeiner G, Steiner A. High-dosage intravenous gamma globulin: therapeutic failure in pemphigus and pemphigoid [see comments]. JAm Acad Dermatol 1989;20: 684-5. Messer G, Sizmann N, Feucht H, Meurer M. High-dose intravenous immunoglobulins for immediate control of severe pemphigus vulgaris. Br J Dermatol 1995;133: 1014-6. / Humbert P, Derancourt C, Aubin F, Agache P. Effects of intravenous 'Y-globulin in pemphigus [letter]. JAm Acad Dermatol 1990;22:326. Bewley AP, Keefe M. Successful treatment of pemphigus vulgaris by pulsed intravenous immunoglobulin therapy. Br J DermatoI1996;135:128-9. Jolles S, Hill H. Management of aseptic meningitis secondary to intravenous immunoglobulin. BMJ 1998;316: 936.