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`I. Malignant involvement of the skin and,t_he genAodermat9s_e:s..{-:-=1
`'
`:* STACIA POOLE, MD, and NEIL A. VVFEKISKE, MD T,ar!1Ap5a,'Fl()ArV_i”(Vi‘$E-:'T
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`Dr. Reddy‘s Laboratories, Ltd., et al.
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`Galderma Laboratories. Inc.
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`Exhibit 1062
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`SEACIA POQVLVVVE, MD,’ and NEIL AQWFENSKE, MD
`
`‘ 1062
`
`Exh. 1062
`
`

`
`Kirsner et a/.
`
`Journal or me
`American Academy of
`Dermatology
`
`cal correlations, and a review of the literature. Am J Clin
`Pathol1972;58:524-30.
`9. MartinS. Cryofibrinogenemia, monoclonal gammopathy,
`and purpura. Arch Dermatol1979;115:208-11.
`10. Jager BV. Cryofibrinogenemia. N Engl J Med 1962;266:
`579-83.
`11. Ritzman SE, Levin WC. Cryopathies: a review. Arch In-
`tern Med 1961;107:186-204.
`12. Kalbfleisch JM, Bird RM. Cryofibrinogenemia. N Engl J
`Med 1960;263:881-6.
`13. Rachmilewitz EA, Sacks MI, Zlotnik A. Essential cryofi-
`brinogenemia: clinical pathological and immunological
`studies. Isr J Med Sci 1970;6:32-43.
`14. Copeman PWM. Cryo:fibrinogenaemia and skin ulcers:
`
`treatment with plasmapheresis [Abstract]. Br J Dermatol
`1979;101(suppl17):57.
`15. Jarrett PEM, Morland M, Clemenson G. Treatment of
`Raynaud's syndrome with stanozolol [Abstract]. Br J Surg
`"'
`1975;62:654.
`16. Ayres ML, Jarrett PEM, Browse NL. Blood viscosity,
`Raynaud's phenomenon and the effect of fibrinolytic en-
`hancement. Br J Surg 1981;68:51-4.
`17. Davidson JF, Lochhead M, McDonald GA, et al. Fibrin-
`olytic enhancement by stanozolol: a double blind trial. Br
`J Haematol1972;22:543-59.
`18. Glazer G. Atherogenic effects of anabolic steroids on serum
`lipid levels. Arch Intern Med 1991;151:1925-33.
`
`Treatment of generalized bullous pemphigoid with
`oral tetracycline
`Isabelle Thomas, MD, Sylvie Khorenian, MD, and David M. Arbesfeld, MD
`Newark, New Jersey
`
`Background: Although bullous pemphigoid (BP) is a benign self-limited disease, the main-
`stay of treatment remains systemic steroids, often in combination with immunosuppressive
`agents. This therapy has considerable potential toxicity, particularly in elderly patients with
`preexisting problems.
`Objective: The purpose of this study was to evaluate the efficacy of oral tetracycline as first-
`choice therapy in patients with BP.
`Methods: Every patient newly diagnosed with generalized BP was treated with oral tetracy-
`cline and a midpotency topical steroid.
`Results: In all five patients, blister formation was stopped and reepithelialization completed
`within 1 to 3 weeks. There was no relapse or toxicity noted; follow-up ranged from 16 to 24
`months.
`Conclusion: Oral tetracycline was found to be rapidly efficacious in all patients and devoid
`of toxicity.
`(JAM ACAD DERMATOL 1993;28:74-7.)
`
`Bullous pemphigoid (BP) is an autoimmune dis-
`order that tends to affect elderly persons who
`frequently have preexisting medical problems. Its
`course is relatively benign and, unlike pemphigus
`vulgaris, rarely life-threatening, even without treat-
`ment.1 However, the tendency has been to treat
`these patients with systemic steroids in a manner
`similar to pemphigus. As a result, the side effects re-
`sulting from therapy often tend to be more severe
`than the disease itself. In the present study, in an at-
`tempt to avoid systemic steroids, we treated every
`
`From the New Jersey Medical School and the Dermatology Service,
`East Orange Veterans Administration Medical Center.
`No reprints available.
`16/1/41471
`
`patient with a confirmed diagnosis of BP with oral
`tetracycline and midpotency topical steroids.
`METHODS
`The diagnosis was based on clinical examination and
`histologic and direct and indirect immunofluorescence
`studies. Patients were observed weekly until blister for-
`mation stopped, monthly until therapy was discontinued
`and then every 6 months.
`·
`
`RESULTS
`The case reports are summarized in Tables I and
`II. All patients were men, which reflects the patient
`population seen at our medical center. Three were
`black and two white. Age of the patients ranged
`from 63 to 84 years (mean 71 years). Duration of
`
`74
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`0190-9622/93 f$1.00 + .10
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`Exh. 1062
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`

`
`Volume 28
`Number 1
`January 1993
`
`Oral tetracycline for bullous pemphigoid 15
`
`Table I. Characteristics of the patients
`Patient
`No.
`
`Medical history
`
`Medications
`
`Lesions
`
`Multiple
`Face, neck
`Extremities
`Trunk
`Multiple
`Trunk
`Extremities
`
`Multiple
`Neck
`Trunk
`Extremities
`Mouth (one)
`
`Multiple
`Trunk
`Extremities
`Scattered
`Trunk
`Extremities
`
`63
`
`70
`
`Male
`
`Male
`
`75
`
`Male
`
`Hypertension
`Right CVA
`Left hemiparesis
`Seizures
`Hypertension
`Bilateral CV A
`CHF
`Dementia
`ITP
`Hypertension
`Arrhythmia
`Abdominal
`aortic aneurysm
`Diabetes mellitus
`
`Male
`
`Unremarkable
`
`HCTZ}:
`Isosorbide
`Phenytoin
`Hydroxyzine
`HCTZ
`Phenytoin
`Danazol
`Prednisone
`20 mg q.d.*
`HCTZ
`Captopril
`Nitroglycerin
`Dipyridamole
`Acetylsalicylic
`acid
`None
`
`Male
`
`Hypertension
`Left CVA
`
`HCTZ
`
`2
`
`3
`
`4
`
`5
`
`63
`
`84
`
`CHF, Congestive heart failure; CVA, cerebrovascular accident; HCTZ, hydrochlorothiazide; ITP, idiopathic thrombocytopenic purpura.
`*Administered for ITP.
`
`disease was 3 weeks to 6 months before the initiation
`of tetracycline. Four patients had hypertension
`complicated by cerebrovascular accidents in three
`patients. One had diabetes mellitus. Lesions were
`generalized in all patients, but less numerous in one.
`In all cases, the histologic findings were consistent
`with the diagnosis of BP, showing a subepidermal
`bulla with a mixed dermal inflammatory infiltrate
`made of mononuclear cells and eosinophils. Direct
`immunofluorescence was positive in all cases, with a
`linear deposition of IgG and C3. Indirect immuno-
`fluorescence was positive in three cases and negative
`in two. Except for one patient, all were treated with
`tetracycline, 2 gm daily, and a midpotency topical
`steroid cream. Bulla formation was significantly re-
`duced within 1 week and stopped within 1 to 3 weeks.
`Complete reepithelialization was noted after 1 to 3
`weeks. The 2 gm dosage was maintained for 1 to 2
`months, decreased by 500 mg decrements every
`month, and then stopped. All patients are in remis-
`sion at this time; there has been no relapse, except in
`one patient for whom tetracycline was discontinued
`too soon. Follow-up after discontinuation of tetra-
`cycline ranges from 16 to 24 months. No toxicity or
`morbidity was noted.
`
`DISCUSSION
`Until Lever's description in 1953,2 BP had been
`grouped with pemphigus vulgaris. In 1967, in con-
`firmation of Lever's hypothesis, Jordon et al.3 de-
`fined both disorders as distinct immunologic entities.
`Unlike pemphigus vulgaris in which the mortality
`rate was high (90%) before the steroid era, the nat-
`ural course of BP tends to be more benign and less
`protracted. It rarely lasts more than 5 to 6 years and
`has a low mortality rate even if untreated. BP is
`characterized by spontaneous remissions and exac-
`erbations; relapses are easily controlled.4 However,
`to date systemic steroids remain the mainstay of
`therapy for generalized disease.5 To reduce the dose
`of steroids and their side effects, immunosuppressive
`agents such as azathioprine, cyclophosphamide,
`methotrexate, or chlorambucil with their own po-
`tential toxicity are frequently used, sometimes from
`the onset.
`It seems that in many cases the toxicity resulting
`from treatment is disproportionate to the low risk
`from the disease itself. Only recently have more be-
`nign treatments been reported. Erythromycin has
`been used in a few cases since 1982, but results are
`inconclusive. 6, 7 Topical steroids have generally been
`
`Exh. 1062
`
`

`
`7 6 Thomas et a!.
`
`Table II. Therapy and results
`
`Patient
`No.
`
`Disease duration
`(mo)
`
`4mo
`
`2
`
`Unknown
`
`3
`
`1 mo
`
`4
`
`5
`
`1 mo
`
`6mo
`
`Betamethasone
`valerate 0.1%
`cream X 1 wk
`Betamethasone
`dipropionate 0.05%
`cream-TCN X 1
`n;w, 2 gm X 2 mo,
`1.5 gm X 2 mo, 1
`gm X 2 mo, 500
`mg X 2 mo, then
`stopped
`Fluocinonide 0.05%
`ointment
`TCN 2 gm X 1 mo,
`1.5 gm X 1 mo, 1
`gm X 1 mo, 500
`mg X 1 mo, then
`stopped
`Fluocinonide 0.05%
`ointment
`TCN 2 gm X 1 mo,
`then stopped
`TCN 2 gm X 1 mo,
`1.5 gm X 1 mo, 1
`gm X 1 mo, 500
`mg X 1 mo, then
`stopped
`Fluocinonide 0.05%
`ointment
`TCN 2 gm X 1 mo,
`1.5 gm X 1 mo, 1
`gm X 1 mo, 500
`mg X 1 mo, then
`stopped
`Fluocinonide 0.05%
`ointment alone
`TCNX4mo
`TCN 1 gm X 2 mo,
`500mgX 2 mo,
`then stopped
`
`Results
`
`Treatment
`
`Blisters
`
`Reepithelialization
`
`None at 3 wk
`
`3 wk
`
`Journal of the
`American Academy of
`Dermatology
`
`FoUow-up after
`discontinuation
`ofTeN
`
`16 mo, no
`relapse to date
`
`None at 1 wk
`
`2wk
`
`None at 1 wk
`
`2wk
`
`None at 1 wk
`
`1 wk
`
`16 mo, died of
`gastrointestinal
`bleeding
`
`Mild flare at
`2 wk after
`discontinuation
`ofTCN
`24mo
`
`None at 1 wk
`
`1 wk
`
`21 mo
`
`1 to 2 per wk
`
`Erosions
`
`None at 1 wk
`
`1 wk
`
`N/A
`
`N/A, Not applicable; TCN, tetracycline.
`
`reserved for localized disease although clobetasol
`propionate alone was reported to clear 10 patients,
`but the extent of the bullous eruption was not spec-
`ified.8
`Tetracycline alone has been used for localized
`disease9 or in combination with niacinamide. 1 0 How-
`ever, there is no publication on the use of tetracycline
`alone for generalized disease.
`
`Antibiotics such as tetracycline and erythromycin
`block bacterial synthesis by binding to the ribosomal
`30s subunit and competitively inhibit the binding of
`transfer RNA to messenger RNA. They suppress
`inflammation by inhibiting neutrophil chemotaxis
`and random migration in vitro and in vivo. 11 In BP
`they may inhibit the complement-mediated inflam-
`matory response to the basement membrane zone
`
`Exh. 1062
`
`

`
`Volume 28
`Number 1
`January 1993
`
`and mediators of the inflammatory response. In ad-
`dition, tetracycline has been shown to affect the co-
`hesion of the dermoepidermal junction.12 In rats, it
`significantly prolongs suction blister time, which
`suggests that cohesion of the dermoepidermal junc-
`tion is increased. 13
`Therapy with systemic steroids in elderly debili-
`tated patients has considerable potential toxicity.
`Deaths, particularly from bronchopneumonia asso-
`ciated with systemic steroids, are still reported in re-
`cent publications. 14-16 The use of immunosuppres-
`sive agents as steroid-sparing agents also carries its
`own potential morbidity. In addition, steroids do not
`seem to clear the bullous eruption more quickly or
`prevent relapses more effectively than tetracycline.
`It seems that it would be worth trying a more be-
`nign treatment first rather than using systemic ste-
`roids or immunosuppressive agents from the start. In
`our study all patients responded rapidly to tetracy-
`cline therapy, and there was no relapse or morbid-
`ity.
`
`REFERENCES
`1. Lever WF. Pemphigus and pemphigoid. JAM ACAD DER-
`MATOL 1979;1:2-31.
`2. Lever WF. Pemphigus. Medicine 1953;32:1-123.
`3. Jordon RE, Beutner EH, Witebsky E, et al. Basement
`membrane zone antibodies in bullous pemphigoid. JAMA
`1967;200:751-6.
`
`Oral tetracycline for bullous pemphigoid 77
`
`4. Person JR, Rogers RS. Bullous and cicatricial pemphigoid.
`Mayo Clin Proc 1977;52:54-66.
`5. Korman N. Bullous pemphigoid. JAM ACAD DERMATOL
`1987;16:907-24.
`6. Fox BJ, Odom RB, Findlay RF. Erythromycin therapy in
`bullous pemphigoid: possible anti-inflammatory effects. J
`AM ACAD DERMATOL 1982;7:504-10.
`7. Rigon JL. Traitement de la pemphigoide bulleuse par
`l'erythromycine. These Nancy, 1986:1-150.
`8. Westerhof W. Treatment of bullous pemphigoid with top-
`ical clobetasol propionate. JAM ACAD DERMATOL 1989;
`20:458-61.
`9. Thornfeldt CR, Menkes AW. Bullous pemphigoid con-
`trolled by tetracycline. J AM ACAD DERMATOL 1987;
`16:305-10.
`10. Berk MA, Lorincz AL. The treatment of bullous pemphi-
`goid with tetracycline and niacinamide. Arch Dermatol
`1986;122:670-4.
`11. Esterly NB, Furey NL, Flanagan LE. The effect of
`antimicrobial agents on leukocyte chemotaxis. J Invest
`Dermatol1978;70:51-5.
`12. Humbert P, Treffel P, Chapuis J-F, et al. The tetracyclines
`in dermatology. JAM ACAD DERMATOL 1991;25:691-7.
`13. Humbert P, Renaud A, Millet J, et al. Evaluation of the ef-
`fect of heparin and tetracycline on the cohesion of the der-
`mal-epidermaljunction. Acta Dermatol Venereol (Stockh)
`1989;69:434-6.
`14. Stevenson CJ. Treatment in bullous diseases with cortico-
`steroid drugs and corticotrophin. Br J Dermatol1960;72: 11-
`21.
`15. Savin JA. The events leading to the death of patients with
`pemphigus and pemphigoid. Br J Dermatol1979;101:521-
`34.
`16. Milligan A, Hutchinson PE. The use of chlorambucil in the
`treatment of bullous pemphigoid. JAM AcAD DERMATOL
`1990;22:796-80 1.
`
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`Exh. 1062