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25.

26. 27. 28.

Connective tissue disease associated with sclerodermoid features

tection of immunoglobulin interfering with prostacyclin formation. Lancet 1981;1:244-6. Moncada S, Higgs EA, Vane JR. Human arterial and venous tissues generate prostacyclin (prostaglandin X), a potent inhibitor of platelet aggregation. Lancet 1977; 2:18-20. Remuzzi G, Misiani R, Muratore D, et al. Prostaeyclin and human fetal circulation. Prostaglandins 1979;18: 341-8. Remuzzi G, Marchesi D, Zoja C, et al. Reduced umbilical and placental vascular prostacyclin in severe preeclampsia. Prostaglandins 1980;20:105-10. Omini C, Folco GC, Pasargiklian R, et al. Prostaeyclin (PGI2) in pregnant human uterus. Prostaglandins 1979;

29. Lockshin MD, Druzin ML, Goei S, et al. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl Med 1985;313:152-6. 30. Hughes GRV. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J 1983;287:10889. 31. Grob J, Bonerandi J. Cutaneous manifestations associated with the presence of the lupus anticoagulant. J AM ACAD DERMATOL1986;15:211-9. 32. Alegre VA, Winkelmann RK. Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant. J AM AcAD DERMAVOL 1988;19:117-24.

17:113-20.

Clearing of epidermolysis bullosa acquisita with cyclosporine Laura L. Crow, M.D., Jeremy P. Finkle, M.D., W. Ray Gammon, M.D., and David T. Woodley, M.D. Chapel Hill, NC Epidermolysis bullosa acquisita is a chronic, severe, subepidermal, blistering disease of the skin, characterized by marked resistance to topical and systemic therapy. This report concerns a well-documented case of a woman who had had epidermolysis bullosa acquisita for 6 years and had remained hospitalized continuously for 7 months in 1987. Her case ultimately was controlled with cyclosporine after the failure of a variety of therapeutic modalities in the hospital, including prednisone, methotrexate, azathioprine, phenytoin, vitamin E, gold sodium thiomalate (Myochrysine), isotretinoin, and plasmapheresis. In contrast to patients with pemphigus and pemphigoid treated with cyclosporine, our patient's autoantibodies did not disappear on therapy. Although its mechanism of action in epidermolysis bullosa acquisita is unknown, we propose that cyclosporine may be a helpful drug for patients whose disease is refractory to more traditional forms of therapy. (J AM ACAD DERMATOL 1988;19:937-42.)

Epidermolysis bullosa acquisita is a rare, acquired subepidermal blistering disease that characteristically is associated with skin fragility and

From the Department of Dermatology, Universityof North Carolina School of Medicine. Supported by grants AM33625 and AR30475 from the National Institutes of Health. Reprint requests to: Dr. David T. Woodley, Department of Dermatology, UNC School of Medicine, Chapel Hill, NC 27514.

that heals with scarring and milia. Initially it was classified as an epidermolysis bullosa disease by virtue of its clinical characteri.stics, which are reminiscent of hereditary dystrophic epidermolysis bullosa. ~However, more recent studies emphasizing the immunologic and ultrastructural features of the disease have shown it to be a distinct entity that most likely has an autoimmune pathogenesis. 2tt Moreover, Gammon et a112'13and others t4q6 have demonstrated that epidermolysis bullosa ac-

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Fig. 1. Patient's skin before cyclosporine. A, A large, tense blister on a field of scarring. B, Marked milia formation around a healed lesion. quisita may present as an inflammatory bullous dermatosis, reminiscent o f bullous or cicatricial pemphigoid, in addition to its more classic presentation as a noninflammatory mechanobullousappearing disease. In such inflammatory cases, clinicians m a y suspect the diagnosis of epidermolysis bullosa acquisita when the patient responds poorly to systemic corticosteroids and other immunosuppressives, agents to which bullous pemphigoid usually responds. Regardless of the clinical presentation, epidermolysis bullosa acquisita is a notoriously difficult disease to treat. Recently, Connolly and Sander j7 reported the first case of epidermolysis bullosa acquisita responding to cyclosporine, a potent T cell suppressor. We report here a case of long-standing epidermolysis bullosa acquisita that was refractory to a variety of immunosuppressive and antiinflammatory drugs but that responded to oral cyelosporine. CASE R E P O R T A 67-year-old black woman with a history of adultonset diabetes mellitus, mild hypertension, and gout was seen in April 1981 at the UNC department of dermatology with a 3-week history of pruritus and bullae, which began on the wrists and spread to the scalp, face, axillae, inframammary skin, and back. A biopsy specimen stained with hematoxylin and eosin showed a subepidermal blister; direct immunofluorescence of perilesional skin showed 4 + linear IgG and C3, and 2 + IgM at the basement membrane zone. Indirect immunofluorescence staining of nomaal human skin substrate with the patient's serum demonstrated a circtdating anti-basement tnembrane zone autoantibody with a ti-

ter of 1:320. The diagnosis was bullous pemphigoid, and the patient's condition was treated with oral prednisone, 40 mg daily. Despite various dosages of prednisone, she continued to have frequent flares of new blisters and concurrent bacterial skin infections. This exacerbation prompted a short trial of methotrexate in July 198 l, which was without effect. In December 1982, direct immunoelectron microscopy of perilesional skin demonstrated IgG deposits beneath the lamina densa. No deposits were noted in the lamina lucida or associated with hemidesmosomes. Moreover, antibody in the.patient's serum and antibody eluted from the basement membrane zone of her skin was shown to be specifically directed to the epidermolysis bullosa acquisita antigen (molecular weight = 290,000 daltons) by Western immunoblot test. 8 The diagnosis was changed to epidermolysis bullosa acquisita. Over the next 4V2 years the patient continued to have severe disease with frequent flares of new blisters, erosions, scar formation, and milia. Multiple therapeutic modalities were tried, but they failed, including a combination of varying doses of prednisone with azathioprine, methotrexate, phenytoin, vitamin E, gold sodium thiomalate, and isotretinoin, as well as a trial of plasmapheresis. Additional complications included frequent Staphylococcus attreus skin infections, iatrogenic S. aureus septicemia resulting from plasmapheresis, diabetes mellitus, hypothermia, and an episode of second-degree heart block that required a permanent pacemaker. The patient's diabetes mellitus was persistently difficult to manage, in part because of systemic prednisone. The patient was hospitalized from November 1986 through May 1987, and the epidermolysis bullosa acquisita continued to be severely active, with flares of new lesions, despite 60 nag prednisone every other day, 100 mg azathioprine every day, and trials of vitamin E

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Clearing of epidermolysis with cyclosporine

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T,

2o

,z, 15

OI

PREDNIfiONE {mq POqod ) 13-CiS-RETINO~CACID (mg POqd)

i

2

i

1

1

4

i

6

i

i

i

8

60

i

IO

i

i

I

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!

i

i

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20 40

22

3", 30

24

26

25 20 15

40 AZATHIOPRINE (rag POqd)

I00

CYA I (mg/kg) 2

I 4

TIME (Weeks)

Fig. 2. A time-course graph of the number of new blisters formed each week while the

patient was taking various medications. Note that when eyelosporine (CYA), 6 mg/kg, was instituted at week 18, a marked and consistent decrease in new blister tormation occurred.

and 40 mg isotretinoin every day. Physical examination revealed large erosions on both shins, multiple erosions in both axillae and on the shoulders, extensive milia, and two to fifteen new blisters per day (Fig. 1). . In early May 1987 isotretinoin and azathioprine were discontinued. The patient remained on a regimen of 50 mg oral prednisone every other day, and oral cyclosporine, 2 mg/kg/day, was begun and gradually increased over 2 weeks to a dosage of 6 mg/kg/day while clinical response, plasma levels of cyclosporine, serum creatinine levels, and hepatic enzymes were being monitored. The patient improved dramatically on a regimen of cyclosporine, 6 rag/kg/day. Within 2 weeks she was clear of all blisters, and at 5 weeks all erosions had healed. The number of blisters dropped from 2 to 15 per day during the month before treatment to fewer than 2 per week in the 37 days after treatment (Fig. 2). The few new blisters that developed while the patient was taking cyclosporine were confined to dependent areas, predominantly the toes. Furthermore, the patient is taking no azathioprine, and the prednisone has been decreased from 60 mg to 7.5 mg every other day. At this writing the patient has been taking cyclosporine for more than 90 days and her skin is clear of all blisters and erosions for the first time since the onset of disease 6 years ago. To date we have noted no adverse effects. The patient's serum creatinine level has remained stable at 0.9 mg/dl, liver function tests are unchanged, and her

blood pressure has remained stable. There have been no signs of systemic or cutaneous side effects. The patient's cyclosporine plasma levels, which notoriously vary widely, have been measured twice weekly; they have ranged from 63 to 188 ng/ml. As described by Kiistala, j8 with the use of a Dermovac apparatus (Instmmentarium Corp., Helsinki, Finland) at 300 mm Hg at room temperature, suction blisters were raised on noninvolved abdominal skin several times before cyclosporine therapy and twice during the cyclosporine regimen (Table I), when the longest blistering times occurred. However, the interpretation of this test is difficult to assess (see "Discussion"). Over the past 6 years the patient's circulating antibasement membrane zone autoantibody, as evaluated by indirect immunofluorescence extinguishing titers,* has been at its lowest level during cyclosporine therapy. Indirect immunofluorescence titers during the systemic prednisone and azathioprine regimen have varied over the past 6 years from 1:320 to 1:1280, except for a brief period in January 1985 when the patient received eight treatments of plasmapheresis twice a week in addition to prednisone, 30 mg/day, and azathioprine, 400

*E• titers are the last dilution of serum, or reagent in direct hnmunofluorescencetesting, in which basement membrane zone stainingcan be detected. Intensityof the staining wasjudged by independentviewingof the slides by three observers, who used an arbitrary scale of 0 to + 4 with + 4 as the most intense staining.

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Table I. Suction blistering times

I First IConfluentl Adjunctlvemedlcations Date I blisterl blister .I ,. withprednisone* 3/28/83 4/11 / 83 5/24/83 6/10/83 6/12/87 8 / 25 / 87

15 15 9 11 19 25

28 20 12 17 39 45

None Gold sodium thiomalate Gold sodium thiomalate Gold sodium thiomalate Cyclosporine Cyclosporine

Table II. Direct immunofluoresence extinguishing titers Date

4/81 12/85 6/87* 8/87t

I

IgG

1:320 1:640 1:1280 1:1280

1

C3

1:1280 1:320 1:2560 1:2560

*After 1 month of cyclosporine. rAfter 3 months of cycIosporine.

*Predaisone tapered to 7.5 mg every other day during cyclosporine therapy (from 7/24/87 to the date of this report).

mg/day and her indirect immunofluorescence titer dropped to 1:20. After 1 month of cyclosporine therapy, indirect immunofluorescence titers were 1:5 on intact skin and 1:40 on salt-separated skin substrate, s.~9.2~After 2 months of cyclosporine, indirect immunofluorescence titers were 1:5 on intact skin and 1:16 on salt-separated skin. All evaluations on saltseparated substrate showed fluorescent staining of the dermal side of the separation only, consistent with the diagnosis of epidermolysis bullosa acquisita. ~'2~In accordance with the immunofluorescence findings, indirect immunoelectron microscopy of the patient's serum demonstrated that her circulating autoantibody bound below the lamina densa of human skin substrate. 2.X,2~ In contrast to the indirect immunofluorescence extinguishing liters of the patient's serum on intact and salt-split normal human skin substrate, tissue-bound IgG and complement, evaluated by direct immunofluorescence extinguishing titers, did not decrease while the patient was taking cyclosporine. Biopsy specimens of perilesional skin before and after cyclosporine therapy, stained with serial dilutions of antihuman IgG and C3 (Cooper Development Co., Malvern, PA), had equivalent or higher extinguishing titers with cyclospofine therapy (Table II). DISCUSSION The treatment of epidermolysis bullosa acquisita is difficult and often has disappointing results. Resistance to steroid therapy is characteristic of the disease and should signal the possibility of epidermolysis bullosa acquisita in any patient who has a subepidermal blistering eruption with junctional IgG deposits. Clinicians may have to resort to a variety of medications for epidermolysis butlosa acquisita, either singly or in combination, to achieve even a limited response. Our patient failed to respond to the administration of prednisone, ~athioprine, phenytoin, methotrexate, gold sodium thiomalate, isotretinoin, and vitamin E. A

short course of plasmapheresis had no clinical effect, despite the fact that the titer of circulating antibody fell from I : 1280 to 1 : 20. The initiation of cyclosporine, 6 mg/kg/day, resulted in a dramatic cessation of blister formation. While the patient was taking cyclosporine, her anti-basement membrane zone autoantibody titer fell to its lowest level since the inception of the disease. In recent years there has been an explosion o f case reports and a few studies regarding the use of cyclosporine in a variety of different dermatologic diseases, which have been addressed in t w o recent review articles. 2~'22 Reports of the use of cyclosporine in bullous diseases have been limited. In 1985, Thivolet et a123 reported two cases of bullous pemphigoid and two with pemphigus. T h e patients were treated with oral cyclosporine, 6 mg/kg/day. The cutaneous lesions of all four cases were resolved within 1 month. In addition, the patients' circulating and tissue-bound auto antibodies, as detected by direct and indirect immunofluorescence, disappeared on therapy. Rosenkrantz et a124 reported preliminary results o f an ongoing study of dogs and cats with pemphigus foliaceus and pemphigus that were treated with oral cyclosporine, 15 to 27 mg/kg / day. There was at least mild improvement in all but one of the animals and marked improvement in two of the five animals. Connolly and Sander ~7 recently reported improvement in a 54-year-old woman with epidermolysis bullosa acquisita, who was treated with oral cyclosporine, 9 mg/kg/day. Like o u r patient, this patient's disease had been refractory to numerous medications. Common side effects of cyclosporine include nephrotoxicity, hypertension, hepatotoxicity (more common at high doses), hypertrichosis, gingival hyperplasia, fatigue, and paresthesias. 2~,~-27 To

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date our patient has had no adverse effects from cyclosporine. The dosage of 6 m g / k g / d a y is smaller than the 9 m g / k g / d a y used by Connolly and Sander ~7and is more in line with dosages that have been used for bullous pemphigoid, pemphigus, and psoriasis.JT.2~ The mechanism by which cyclosporine may work in epidermolysis bullosa acquisita is as yet unknown. Although indirect immunofluorescence titers improved, there was no demonstrable decrease in the amount of tissue-bound immuneglobulin or complement under the influence of cyclosporine in our patient (Table II). In fact, it appears that the direct immunofluorescence titers for IgG actually are increased under treatment, which contrasts with the pemphigus and pemphigoid cases reported by Thivolet et al, 23 whose patient's circulating and tissue-bound autoantibodies disappeared during cyclosporine therapy. This might suggest that the mechanism of action of cyclosporine in epidermolysis bullosa acquisita is different from that in bullous pemphigoid or pemphigus. However, additional cases of the influence of cyclosporine on these three blistering diseases will require evaluation to verify these immunologic responses. The contribution of cell-mediated immunity to the pathogenesis of epidermolysis bullosa acquisita has not been studied. It is known that cyclosporine has a selective inhibitory effect on T helper and T cytotoxic cells and works by inhibiting the synthesis and release of interleukin 1 and interleukin 2. 27,2s3~ It may be postulated that the autoantibody response to type VII procollagen might be a T helper-dependent antibody response, which could explain the efficacy of cyclosporine in epidermolysis bullosa acquisita. This hypothesis has not yet been investigated. Clearly, further studies are required to determine the efficacy and the mechanism of action of cyclosporine in epidermolysis bullosa acquisita. At this point, however, we suggest it may be a worthwhile form of therapy in patients whose disease is refractory to standard treatments. REFERENCES 1. Roenigk HH Jr, Ryan IG, Bergfeld WF. Epidcrmolysis bullosa acquisita: report of three cases and review of all published cases. Arch Dermatol 1971; 103:1-10. 2. Yaiota H, Briggaman RA, Lawley T.I, Provost "IT, Katz

Clearing of epidermolysis with cyclosporine 941

3.

4. 5. 6. 7. 8.

9.

SI. Epidermolysis bullosa acquisita: ultrastructural and immunological studies. J" Invest Dermatol 1981;76: 288-92. Nieboer C, Boorsma DM, Woerdman MJ, Kalsbeek GL. Epidermolysis bullosa acquisita: immunofluorescence, electron microscopic and tmmuno~lectron microscopic studies in four patients. Br J Dermatol 1980;102:383-92. Gibbs RB, Minus HR. Epidermolysis bullosa aequisita with electron microscopicaJ studies. Arch Dermatol 1975;111:215-20. Kushniruk W. The immunopathology of epidermolysis bullosa acquisita. Can Med Assoc J 1973;108:1143-6. Wilson BD, Birnkrant AF, Beutner EH, Maize JC. Epidermolysis bullosa acquisita: a clinical disorder of varied etiologies. J AM ACADDERM^TOt-1980;3:280-91. Benedetto AV, Bergfeld WF, Taylor IS, Osborne DG. Epidermolysis bullosa acquisita: diagnosis by electron microscopy. Cleveland Clinic Q 1976;43:283-91. WoodleyDT, Briggaman RA, O'Keefe EJ, lnman AO, Queen LL, Gammon WR. Identification of the skin basement membrane autoantigen in epidermolysis bullosa acquisita. N Engl J Med 1984;310:1007-13. Ray TL, Levine JB, Weiss W, Ward PA. Epidermolysis bullosa acquisita and inflammatory bowel disease. J AM ACADDERMATOL1982;6:242-52.

10. GammonWR, Briggaman RA, 1nman AO III, Merritt C, Wheeler CE Jr. Evidence supporting a role for immunc complex-mediated inflammation in the pathogenesis of bullous lesions of systemic lupus erythematosus. J Invest Dermatol 1983;81:320-5. 11. GammonWR, Inman AO III, Wheeler CE Jr. Differences in complement-dependentchemotactic activity generated by bullous pemphigoid and epidermolysis bullosa acquisita immune complexes: demonstration by leukc~cytic attachment and organ culture methods. J Invest Dermatol 1984;83:57-61. 12. Gammon WR, Briggaman RA, Wheeler CE Jr. Epidermolysis bullosa acquisita presenting as an inflammatory bullous disease. J AM ACADDERMATOL1982;7:382-7. 13. GammonWR, Briggaman RA, Woodley DT, Heald PW, Wheeler CE. Epidermolysis bullosn acquisita--a pemphigoid-like disease. J AM ACAD DERMATOL 1984; 11:820-32. 14. Provost "lff, Maize JC, Amed AR, et al. Unusual subepidermal bullous diseases presenting as an inflammatory bullous disease. Arch Dermatol 1979;115:156-60. 15. Dahl MGC. Epidermolysis bullosa acquisita--a sign of cicatricial pemphigoid? Br J Dermato1 1979;101:475-83. 16. Richter BJ, McNutt NS. The spectrum of epidermolysis bullosa acquisita. Arch Dermatol 1979;115:1325-8. 17. Connolly SM, Sander HM. Treatment of epidermolysis bullosa acquisita with cyclosporlne [letter]. J AM ACAD DERMATOL1987;16:890. 18. Kiistala U. Dermal-epidermal separation. Ann Clin Res 1982;4-:236-46. 19. Woodley DT, Sauder D, Talley MJ, Silver M, Grotendorst G, Qwarnstrom E. Localization of basement membrane components after dermal-epidermal junction separation. J Invest Dermatol 1983;8t: 149-53. 20. Gammon WR, Briggaman RA, Inman AO 1II, Queen LL, Wheeler CE Jr. Differentiating anti-lamina lucida and anti-sublamina densa anti-BMZ antibodies by indirect immunofluorescenceon 1.0 M sodium chlorideseparated skin. J Invest Dermato! t984;82:139-4-4.

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21. Biren CA, Barr RJ'. Dermatologic applications of cyclo-

22. 23. 24. 25. 26.

sporine. Arch Dermatol 1986; 122:1028-32. Page EH, Wexler DM, Guenther LC. Cyclosporin A. J AM ACADDERMATOL1986;14:785-91. Thivolet J, Barthelemy H, Rigot-Muller G, Bendelac A. Effects of cyclosporin on bullous pemphigoid and pemphigus [letter]. Lancet 1985;1:334-5. Rosenkrantz WS, Griffin CE, Barr RJ, Biren CA. Cyclosporine and cutaneous immune-mediated disease [letter]. J AM ACAD DERMATOL ] 986; 14:1088-9 Palestine AG, Nussenblatt RB, Chan CC. Side effects of systemic cyclosporine in patients not undergoing transplantation. Am J Med 1984;77:652-6. Bennett WM, Norman DJ. Action and toxicity of cyclosporine. Annu Rev Med 1986;37:215-24.

27. Bencini PL, Montagnino G, Sala F, DeVecehi A, Crosti C, Tarantino A. Cutaneous lesions in 67 cyclosporin-treated renal transplant recipients. Dermatologica 1986;172:24-30. 28. Bunjes D, Hardt C, Rollinghoff M, Wagner H. Cyclosporin A mediates immunosuppression of primary eytotoxic T-cell responses by impairing the release of interleukin 1 and interleukin 2. Eur J Immunol 1981; 11:657-61. 29. Wagner H. Cyclosporin A: mechanism of action. Transplantation Proceedings 1983;15:523-6. 30. Keown PA, Essery GL, Shiler CR, Sinclair NR, Muller R, Ulan RA. Mechanisms of immunosuppression by cyclosporin. Transplantation Proceedings 1981;13: 386-9.

Probable coexisting exogenous ochronosis and mercurial pigmentation managed by dermabrasion Pearon G. L a n g , Jr., M.D. Charleston, SC A patient with blue-gray discoloration of the face is described. Her history revealed that she had used bleaching creams containing mercury and hydroquinone for many years. Biopsy specimens of the hyperpigmented areas showed deposits that were compatible with both mercury deposition and the diagnosis of exogenous ochronosis. Dermabrasion was successfully employed to remove these deposits. (J AM ACAD DERMATOL 1988;19:942-6.)

L o n g - t e r m use of bleaching c r e a m s m a y lead to a g r a y or b l u e - b l a c k discoloration o f the skin. C r e a m s containing either m e r c u r y '-3 or hydroquinone 4"0 m a y be responsible. The patient described in this report had used for m a n y years bleaching c r e a m s containing both these agents. Bio p s y s p e c i m e n s of the h y p e r p i g r n e n t e d areas revealed deposits c o m p a t i b l e with mercury deposition and the diagnosis o f exogenous ochronosis. T h e s e deposits were s u b s e q u e n t l y successfully rem o v e d by d e r m a b r a s i o n .

From tile Department of Dermatology, Medical University of South Carolina. Reprint requests to: Dr. Pearon G. Lang, Jr., Department of Dermatology, Medical University of South Carolina, 17 i Ashley Ave., Charleston, SC 29425.

942

CASE R E P O R T The patient, a 74-year-old white woman, was referred to the Medical University of South Carolina for a pigmentary disorder of the face. Years earlier hypopigmented areas had developed on the patient's face, and she began to apply mercury-containing bleaching creams to the unaffected skin to make the pigmentation uniform. There was no history of inflammation preceding the onset of the hypopigmented areas nor had the patient used any topical medication or been exposed to any chemicals that might have caused the hypopigmentation. Several years before her referral, she had noted the development of a blue-gray pigmentation on her face. Her overall health was excellent, and she was taking no systemic medications. On physical examination the patient was noted to have a mottled pigmentation of the face. There were hypopigmented areas intermingled with hyperpig-