Correspondence
Oral and Topical Corticosteroids in Bullous Pemphigoid
N Engl J Med 2002; 347:143-145July 11, 2002
- Article
To the Editor:
Joly et al. (Jan. 31 issue)1 report mortality rates among patients with bullous pemphigoid that are substantially higher than those in four previous British and American studies (a one-year mortality rate of 19 percent, a two-year mortality rate of 6 percent, and three-year mortality rates of 28 percent and 30 percent2) but similar to that in another French study (a one-year mortality rate of 41 percent3), suggesting that survival of patients with bullous pemphigoid may vary according to the ethnic background. Thus, the findings reported by Joly et al. cannot be extrapolated to all patients with bullous pemphigoid, and additional randomized trials are necessary for validation.
With regard to the editorial by Stern,4 since linear deposition of IgG and C3 are found in the epidermal basement membrane in patients with diseases other than bullous pemphigoid, indirect immunofluorescence studies of salt-split skin, not positive histopathological studies demonstrating such deposition, are considered to be the diagnostic standard.2 One study found that 15 percent of patients with linear IgG or C3 deposits in the basement membrane had epidermolysis bullosa acquisita or bullous systemic lupus erythematosus.5 Although patients with cicatricial pemphigoid, linear IgA disease, or chronic bullous disease of childhood may uncommonly have autoantibodies against type VII collagen, most would classify these patients as having epidermolysis bullosa acquisita. LAD-1 is part of bullous pemphigoid antigen 2,6 not a 97-kD protein distinct from bullous pemphigoid antigen 2. Bullous pemphigoid and herpes gestationis are not immunologically identical, since patients with herpes gestationis have specific HLA associations, avid complement-fixing IgG antibodies, and linear C3 deposits, whereas patients with bullous pemphigoid have no HLA associations, less avid complement-fixing IgG antibodies, and linear deposits of C3 and IgG.
6 ReferencesNeil J. Korman, M.D., Ph.D.
Case Western Reserve University, Cleveland, OH 44106
njk2@po.cwru. edu 1
Joly P ,Roujeau J-C ,Benichou J , et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002;346:321-327
Full Text | Web of Science | Medline2
Korman NJ . Bullous pemphigoid: the latest in diagnosis, prognosis, and therapy. Arch Dermatol 1998;134:1137-1141
CrossRef | Web of Science | Medline3
Roujeau J-C ,Lok C ,Bastuji-Garin S ,Mhalla S ,Enginger V ,Bernard P . High risk of death in elderly patients with extensive bullous pemphigoid. Arch Dermatol 1998;134:465-469
CrossRef | Web of Science | Medline4
Stern RS . Bullous pemphigoid therapy -- think globally, act locally. N Engl J Med 2002;346:364-367
Full Text | Web of Science | Medline5
Vaillant L ,Bernard P ,Joly P , et al. Evaluation of clinical criteria for diagnosis of bullous pemphigoid. Arch Dermatol 1998;134:1075-1080
CrossRef | Web of Science | Medline6
Zone JJ ,Taylor TB ,Meyer LJ ,Petersen MJ . The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAg2. J Invest Dermatol 1998;110:207-210
CrossRef | Web of Science | Medline
To the Editor:
A recent systematic review of treatments for bullous pemphigoid1 highlights the increased mortality associated with higher doses of oral prednisolone. There is good evidence to support the use of 20 to 40 mg of prednisolone (0.5 mg per kilogram of body weight) in combination with topical therapy and other nontoxic antiinflammatory drugs, such as minocycline and nicotinamide.1,2 Given that Joly et al. did not compare prednisone at a dose of 1 mg per kilogram per day with prednisone at a dose of 0.5 mg per kilogram per day for the treatment of extensive bullous pemphigoid, one cannot conclude that the lower dose would not be appropriate. Further evaluation is required to determine the optimal dose and the optimal proportions of corticosteroids to be delivered by the oral and topical routes.
The serious drawback to topical therapy alone in the study by Joly et al. was that some patients required nursing assistance. The authors do not report the number of patients who required such care or the cost of delivery. We do not believe that the main conclusion, that oral corticosteroids are no longer justified for treatment of severe bullous pemphigoid, is correct.
2 ReferencesMichael R. Ardern-Jones, M.R.C.P.
Vanessa A. Venning, D.M.
Fenella Wojnarowska, D.M.
Churchill Hospital, Oxford OX3 7LJ, United Kingdom
mikeaj@talk21.com 1
Khumalo NP ,Murrell DF ,Wojnarowska F ,Kirtschig G . A systematic review of treatments for bullous pemphigoid. Arch Dermatol 2002;138:385-389
CrossRef | Web of Science | Medline2
Fivenson DP ,Breneman DL ,Rosen GB ,Hersh CS ,Cardone S ,Mutasim D . Nicotinamide and tetracycline therapy of bullous pemphigoid. Arch Dermatol 1994;130:753-758
CrossRef | Web of Science | Medline
To the Editor:
An overlooked explanation for the finding that clobetasol, a highly potent topical corticosteroid, is as effective as prednisone for the treatment of bullous pemphigoid is that the medication is absorbed through the skin, resulting in blood corticosteroid levels similar to those achieved by systemic therapy.
Topically applied clobetasol is absorbed rapidly; 12.5 mg applied to normal skin results in peak plasma levels one fourth as high as those attained with 10 mg of prednisone (i.e., 6 to 7 ng per milliliter vs. 24.5 ng per milliliter).1,2 Blood levels in patients with bullous pemphigoid are probably higher than that, since corticosteroid absorption is increased by a factor of 16 when skin is blistered,3 as it is in this disease. Furthermore, the potency of clobetasol is much greater than that of prednisone — 360 times as high, according to assays of vasoconstriction. Thus, the daily topical application of 20 mg of clobetasol (40 g of 0.05 percent clobetasol cream per day) might well have a systemic effect similar to, or perhaps greater than, that achieved in the patients in the control group treated with 60 mg of prednisone per day.
If the therapeutic effect of clobetasol results from its systemic absorption, the safety of this approach may be no greater than that of conventional therapy with systemic corticosteroids and may be outweighed by its disadvantages — cost (a wholesale price 110 times that of prednisone4) and the difficulty involved, particularly for the elderly, in applying cream twice daily to the entire body.
4 ReferencesJean-Claude Bystryn, M.D.
Brent D. Wainwright, M.D.
Jerome L. Shupack, M.D.
New York University Medical Center, New York, NY 10016
bystryn@nyu.edu 1
Olsen EA ,Cornell RC . Topical clobetasol-17-propionate: review of its clinical efficacy and safety. J Am Acad Dermatol 1986;15:246-255
CrossRef | Web of Science | Medline2
Ferry JJ ,Horvath AM ,Bekersky I ,Heath EC ,Ryan CF ,Colburn WA . Relative and absolute bioavailability of prednisone and prednisolone after separate oral and intravenous doses. J Clin Pharmacol 1988;28:81-87
Web of Science | Medline3
Korting HC, Maibach HI. Topical glucocorticoids with increased benefit/risk ratio. Vol. 21 of Current problems in dermatology. New York: S. Karger Publishing, 1993:51, 54.
4
2001 Drug topics red book. Montvale, N.J.: Medical Economics, 2001:253-4, 474.
To the Editor:
The protocol used by Joly and colleagues required the initial application of 20 g of clobetasol cream twice a day until 15 days after control of the disease had been established, followed by a gradual decrease in the dose and frequency to 10 g twice a week until the end of 12 months of therapy. As a rule of thumb, 30 g is enough to cover the average person's body once. How did subjects manage to apply considerably less than that and cover the entire body? Does the “entire surface of the body” include the palms, soles, face, scalp, and intertriginous areas? If patients have just a few blisters or localized disease, I often treat them locally with a topical corticosteroid. How do the authors treat localized disease? Finally, the cost of a 45-g tube of generic clobetasol cream at our local pharmacy is about $45. The cost of 60 mg of prednisone (an average dose) in the form of 20-mg tablets is about 70 cents a day. At these rates, treatment for 30 days with topical clobetasol cream would cost $1,350, as compared with about $21 for the oral prednisone. I wonder whether the cost differential justifies the use of topical corticosteroid, particularly in the case of moderate disease, for which the outcomes are similar.
G. Thomas Spigel, M.D.
Olean Medical Group, Olean, NY 14760Author/Editor Response
The authors reply:
To the Editor: Korman comments that the mortality rate among our patients treated with high doses of oral corticosteroids seems higher than the rates reported in British and American studies. Unfortunately, the studies cited by Korman are either retrospective studies with a substantial number of patients lost to follow-up or therapeutic studies testing immunosuppressive drugs in very limited numbers of selected patients (one study included only 26 patients).1 We suggest that these studies underestimated the actual mortality rate associated with bullous pemphigoid. Other large prospective studies of nonselected patients would be needed in order to permit meaningful comparisons of the mortality rates in various countries.
Ardern-Jones et al. suggest that patients with severe bullous pemphigoid could be adequately treated with the use of 20 to 40 mg of prednisolone per day. We agree that in a few patients, extensive bullous pemphigoid may occasionally be controlled with these low doses of oral corticosteroids. However, to date, these doses cannot be considered or proposed as standard, since the only randomized study reported in the literature that tested such low doses of corticosteroids showed that severe bullous pemphigoid was not controlled by 0.3 mg of prednisolone per kilogram per day in any of the 15 patients who received this regimen.2
It is likely that the extremely high efficacy of clobetasol propionate cream is due to the combination of local and systemic effects, as suggested by Bystryn et al. Indeed, basal cortisol levels were reduced in 19 of the 20 patients who were treated topically in our study. Treatment with topical corticosteroids has the advantage of achieving high skin levels that influence local factors of inflammation, whereas systemic absorption may suppress the synthesis of antibodies to the basement-membrane zone.
Spigel notes the high cost of topical treatment. However, the decrease of, on average, seven days in the hospital stay for patients who receive topical treatment (as compared with those who receive oral treatment), observed in patients with moderate or extensive bullous pemphigoid, should more than outweigh the higher cost of topical treatment. Moreover, this added cost pales in comparison with the overall cost of treatments such as intravenous immune globulin and mycophenolate mofetil, which have been proposed despite the lack of data from randomized trials.3
Finally, we agree that most patients with bullous pemphigoid can probably be adequately treated with lower doses — from 10 to 30 g of clobetasol propionate cream daily — depending on the extent of disease. We are currently testing the efficacy and safety of these reduced doses in a randomized, controlled trial. Our findings, based on results in more than 300 patients, indicate that a dose of 10 to 15 g is sufficient to cover the entire surface of the body, excluding the face, which is usually not involved in bullous pemphigoid.4
4 ReferencesPascal Joly, M.D., Ph.D.
Rouen University Hospital, 76031 Rouen CEDEX, France
pascal.joly@chu-rouen. fr Jean-Claude Roujeau, M.D.
Henri Mondor University Hospital, 94010 Creteil CEDEX, FranceJacques Benichou, M.D., Ph.D.
Rouen University Hospital, 76031 Rouen CEDEX, France1
Korman NJ . Bullous pemphigoid: the latest in diagnosis, prognosis, and therapy. Arch Dermatol 1998;134:1137-1141
CrossRef | Web of Science | Medline2
Roujeau JC ,Guillaume JC ,Morel P , et al. Plasma exchange in bullous pemphigoid. Lancet 1984;2:486-488
CrossRef | Web of Science | Medline3
Stern RS . Bullous pemphigoid therapy -- think globally, act locally. N Engl J Med 2002;346:364-367
Full Text | Web of Science | Medline4
Cordel N ,Hautemaniere A ,Roujeau JC , et al. Etude de “dose ranging“ dans le traitement initial de la pemphigoïde bulleuse par corticothérapie locale. Ann Dermatol Venereol 2000;127:Suppl:4S5-4S5
Author/Editor Response
The editorialist replies:
To the Editor: Dr. Korman appears to equate higher resolution with superiority. In clinical practice, the most appropriate test may not have the highest resolution or be the most expensive. Rather, if a test is required to confirm or rule out a diagnosis with greater precision than can be done on the basis of clinical criteria alone, that test should be selected according to factors such as sensitivity and specificity, the probability of the diagnosis under consideration, and the cost.
Direct immunofluorescence testing is used to confirm (or rule out) the clinical diagnosis of various autoimmune blistering skin diseases. Since such testing was first described 35 years ago, modifications, including so-called salt-split tests, have become available. These modifications may permit more precise localization of immunoreactants in the basement-membrane zone, but I judged discussion of this arcane topic to be of limited interest to the intended readers of my editorial. In addition, immunofluorescence testing of salt-split skin has not been demonstrated to have a higher predictive value than clinical criteria alone.1
Patients with bullous pemphigoid, epidermolysis bullosa acquisita, or bullous lupus typically have distinctive clinical features. When an autoimmune blistering skin disease is suspected, clinical data along with traditional direct immunofluorescence testing are usually sufficient for an accurate diagnosis. In the rare case of a patient with a clinical presentation compatible with multiple autoimmune blistering skin diseases, the more expensive salt-split skin study or even higher-resolution studies are useful and indicated.
I have always thought that elderly and pregnant patients with autoimmune, subepidermal blistering diseases differ from other patients in many clinical and some immunologic aspects. As I noted, their antibodies do share the same principal antigenic targets.
1 ReferencesRobert S. Stern, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
rstern@caregroup.harvard. edu 1
Vaillant L ,Bernard P ,Joly P , et al. Evaluation of clinical criteria for diagnosis of bullous pemphigoid. Arch Dermatol 1998;134:1075-1080
CrossRef | Web of Science | Medline
- Citing Articles (7)
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1
Donna A. Culton, Luis A. Diaz. (2012) Treatment of subepidermal immunobullous diseases. Clinics in Dermatology 30:1, 95-102
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Elena M. Varoni, Alessia Molteni, Andrea Sardella, Antonio Carrassi, Domenico Di Candia, Fausto Gigli, Franco Lodi, Giovanni Lodi. (2011) Pharmacokinetics study about topical clobetasol on oral mucosa. Journal of Oral Pathology & Medicineno-no
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Gilles Safa, Laure Darrieux. (2011) Nonbullous pemphigoid treated with doxycycline monotherapy: Report of 4 cases. Journal of the American Academy of Dermatology 64:6, e116-e118
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Timothy Patton, Neil J Korman. (2006) Bullous pemphigoid treatment review. Expert Opinion on Pharmacotherapy 7:17, 2403-2411
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Matthias Goebeler, Detlef Zillikens. (2006) Bullous pemphigoid: diagnosis and management. Expert Review of Dermatology 1:3, 401-411
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Ignacio García-Doval, Alberto Conde, Eugenia Mayo, Manuel J. Cruces. (2006) Sustitución de corticoterapia sistémica por tópica en pacientes con penfigoide ampolloso generalizado y iatrogenia esteroidea grave. Actas Dermo-Sifiliográficas 97:3, 186-188
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Philina M. Lamb, Edward Abell, Michael Tharp, Roy Frye, Jau-Shyong Deng. (2006) Prodromal bullous pemphigoid. International Journal of Dermatology 45:3, 209-214
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