`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1065
`
`
`
`Index ksue
`é
`V
`VOLUME 28 NUMBER 6
`
`yune I993
`
`’
`
`A Androgen biology as a basis for the diagnosis and
`
` CME article
`treatment of androgenic .
`disorders in women. II._
`
`LTC LEONARD C. SPERLING, MC, USA, and CPT(P) WILLIA
`
`M L. HEIMER II, MC, USA Washington, D.C.
`
`CMEiex‘amination for volume 274
`
`PUBLISHED BY Mosnv
`ST. L0-UIS,4MISS0URl 53:45
`
`ISSN 0190-9622
`
`Exh. 1065
`
`Exh. 1065
`
`
`
`JOURN/\L Of the
`AmeRICaN ACaDemY OF
`DerMaTOLOGY
`
`Copyright © 1993 by the A merican Academy of Dermatology, Inc.
`
`Editor
`Richard L. Dobson, MD
`Associate Editor
`Bruce H . Thiers, MD
`Editorial Office
`~epartment of Dermatology
`edtcal University of South Carolina
`17
`I Ashley Ave
`Ch
`.
`arleston, SC 29425-2215
`803-792-9! 55
`A .
`Phsf•stant Editors
`1 tp C. Anderson, MD
`Columb·
`W
`Ia, M issouri
`alter H. C. Burgdorf MD
`Alb
`'
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`11P M. Catalano, MD
`Bradenton, Florida
`P. Haines Ely, MD
`Grass v. 11
`p
`a ey, California
`earl E. Grimes, MD
`W Culver City, California
`NC!ark Lambert, MD
`Alf ewark, New Jersey
`red T. Lane, MD
`W Sta'!ford, California
`. ~Itchell Sams, Jr., MD
`D Bz.rmingham, A labama
`amel N. Sauder, MD
`Ham·/
`M: . 1 ton, Ontario
`ana L. Chanco Turner MD
`R Washington, D.C.
`'
`onald G. Wheeland, MD
`S acrame t C /'
`.
`n o, a iforma
`founding Editor
`· Graham Smith, Jr., MD
`Mobile, A labama
`
`VoL 28 N
`Am
`. '
`0 · 6, June 1993, the Journal of the
`encan Acad
`962
`).
`emy of Dermatology (ISSN 01 90-
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`volum IS published monthly (six issues per volume, two
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`
`June 1993
`
`CONTENTS
`
`June 1993
`
`CONTINUING MEDICAL EDUCATION
`
`Androgen biology as a basis for the diagnosis
`and treatment of androgenic disorders in
`women. II.
`LTC Leonard C. Sperling, MC, USA, and
`CPT(P) William L. Heimer II, MC, USA
`Washington, D.C.
`
`Answers to CME examination (Identification
`No. 893-105), May 1993 issue of the JouRNAL
`OF THE AMERICAN ACADEMY OF DERMATOLOGY
`
`CME examination
`
`CLINICAL AND LABORATORY STUDIES
`
`Nodular lesions of erythema elevatum diutinum
`in patients infected with the human
`immunodeficiency virus
`Philip E. LeBoit, MD, and
`Clay J. Cockerell, MD
`San Francisco, California,
`and Dallas, Texas
`
`Amplified surface microscopy
`Douglas Puppin, Jr., MD,
`Denis Salomon, MD, and
`Jean-Hilaire Saurat, MD
`Geneva, Switzerland
`
`Mucocutaneous leishmaniasis: A
`clinicopathologic classification
`Omar P. Sangueza, MD, Julio M . Sangueza,
`MD, Mathew J. Stiller, MD, and Pastor
`Sangueza, MD New York, New York, and
`La Paz, Bolivia
`
`901
`
`916
`
`917
`
`919
`
`923
`
`927
`
`Continued on page 7 A
`SA
`
`Exh. 1065
`
`
`
`Brief communications
`
`Treatment of pemphigus and linear lgA dermatosis with nicotinamide and
`tetracycline: A review of 13 cases
`
`MarshaL. Chaffins, MD,a Daniel Collison, MD,b and David P. Fivenson, MDa
`Detroit, Michigan, and Hanover, New Hampshire
`Pemphigus usually requires long-term therapy
`with oral corticosteroids, which can cause significant
`morbidity. 1' 2 Several immunomodulating drugs,
`such as cyclophosphamide, azathioprine, and gold
`have proved beneficial as steroid-sparing agents. 3, 4
`However, these agents also have limited long-term
`utility because of their potential to induce renal and
`hepatic dysfunction and bone marrow suppression.
`Nicotinamide in combination with tetracycline
`has been reported to be effective for bullous pem-
`phigoid (BP) and linear lgA bullous dermatosis
`(LABD ). s, 6 This regimen has the advantage of
`lower toxicity compared with corticosteroids and
`immunosuppressant regimens. We have treated 11
`cases of pemphigus and two cases of LABD with
`nicotinamide and tetracycline and report our expe-
`rience.
`
`A complete blood cell count as well as levels of
`serum electrolytes, glucose, serum glutamic oxalo-
`acetic transferase, serum glutamic pyruvate trans-
`ferase, )'-glutamyl transferase, and bilirubin were
`determined on all patients before beginning therapy,
`after 4 to 8 weeks of treatment, and periodically
`thereafter. In four patients pemphigus autoanti-
`bodies were determined by indirect immunofluores-
`cence on monkey esophagus at the time of diagnosis
`and after at least 8 weeks of treatment.
`RESULTS
`The therapeutic responses of the patients are
`summarized in Table I. When evaluated as a group,
`7 of 13 patients experienced CR. Four patients had
`PR, and two patients failed to respond. Of the six
`patients with PV, three had CR, two had PR, and
`one had NR. Only two patients with PV were able
`to be treated with nicotinamide and tetracycline
`alone; the four other patients required a mean daily
`dose of 8 mg of prednisone to control disease activ-
`ity. Patient 3 was also treated with 150 mg of aza-
`thioprine per day. The follow-up period for these
`patients ranged from 6 to 13 months (mean 9
`months).
`Of the five patients with superficial pemphigus,
`two had CR, two had PR, and one patient did not
`respond. Only one patient (patient 1 0) required a
`mean daily dose of 7.5 mg of prednisone for 10
`months. For the last 5 months his disease has been
`controlled with tetracycline and nicotinamide alone.
`The follow-up period for these patients ranges from
`11 to 41 months (mean 22 months).
`Three of four patients had a significant reduction
`in pemphigus antibody titers during treatment. Pa-
`tients 1 and 2 had a twofold decrease. Patient l 0 had
`an initial titer of 1:2560 that became negative dur-
`ing treatment.
`Both patients with LABD achieved rapid and
`complete clearing. However, patient 12 discontin-
`ued therapy after 2 months because of persistent
`headaches. He has subsequently remained clear
`
`MATERIAL AND METHODS
`Eleven patients with pemphigus (six with pem-
`phigus vulgaris [PV], three with pemphigus folia-
`ceus [PF], two with pemphigus erythematosus [PE])
`and two patients with LABD were treated with nic-
`otinamide, 1.5 gmjday, and tetracycline, 2 gmjday,
`with or without oral corticosteroids as summarized
`in Table I. The clinical diagnosis was confirmed in
`all cases by routine histopathology and immunoflu-
`orescence studies.
`Therapeutic responses were graded by the degree
`of clinical improvement after 8 weeks of treatment.
`Responses were recorded as follows: complete re-
`sponse ( CR) = total clearing of lesions; partial re-
`sponse (PR) = clearing of more than 50% of lesions;
`and no response (NR) = clearing less than 50% of
`lesions or worsening of the disease.
`
`From the Departments of Dermatology, Henry Ford Hospital, Detroit";
`a nd Da rtmouth University, Hanoverb
`Reprint requests: Marsha L. C haffins, MD, Henry Ford Hospital, 2799
`W. Grand Blvd., Detroit, MI 48202.
`J AM A CAD D ERMATOL 1993;28:998-1 000.
`Copyright © 1993 by the American Academy of Dermatology, Inc.
`0190-9622/93$1.00 + .10 16/ 54/ 43729
`
`998
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`Exh. 1065
`
`
`
`Journal of the American Academy of Dermatology
`Volume 28, Number 6
`
`Brief communications 999
`
`Table I. History and therapeutic response of patients treated with nicotinamide and tetracycline for
`autoimmune bullous diseases
`
`Diagnosis
`
`Concurrent trea trnent
`
`Response*
`
`Follow-up
`period (mo)
`
`Patient
`
`I
`2
`3
`
`4
`5
`6
`7
`8
`9
`lO
`I I
`12
`
`Age (yr)/
`Sex
`
`34/M
`47/F
`71/F
`
`81/M
`57/F
`41/F
`60/F
`51/M
`50/M
`28/F
`73/M
`70/M
`
`PV
`PV
`PV
`
`PV
`PV, oral
`PV, oral
`PF
`PF
`PF
`PE
`PE
`LABD
`
`Topical steroids
`Prednisone, 5 mg q.o.d.-30 mg q.d.
`Prednisone, 5 mgj day
`Azathioprine, !50 mgjday
`Topical steroids
`Prednisone, 2.5 mgjday
`Prednisone, 10 mgjday
`None
`Topical steroids
`Topical steroids
`Prednisone, 7.5-0 mgj day
`None
`Antihistamines, topical steroids
`
`CR
`PR
`PR
`
`CR
`CR
`NR
`CR
`CR
`PR
`PR
`NR
`CR
`
`8
`6
`10
`
`9
`14
`
`24
`41
`11
`13
`
`2 mowj
`medication,
`I I mo clear
`19
`
`13
`
`69/F
`
`LABD
`
`Topical steroids
`
`CR
`LABD, Linear IgA bullous dermatosis; PE, pemphigus erythematosus; PF, pemphigus foliaceus; PV, pemphigus vulgaris.
`*Responses graded as: CR =complete response (all lesions resolved) after 8 weeks of nicotinamide/tetracycline; PR =partial response (>50% of le-
`sions resolved) after 8 weeks of nicotinamide/tetracycline; NR =no response (<50% of lesions resolved) or worsening of disease after 8 weeks of nic-
`otinamide/tetracycline.
`
`with topical steroid therapy for approximately I
`year. Patient 13 (previously reported in Peoples and
`Fivenson5) has remained clear for more than 2 years
`with nicotinamide and tetracycline therapy.
`Eight of the 13 patients reported no adverse
`effects. There were no abnormalities in any patient's
`serum chemical or hematologic findings. Four pa-
`tients experienced nausea, abdominal discomfort,
`and mild diarrhea. Gastrointestinal symptoms were
`relieved in three patients when minocycline, 100 mg
`twice a day, was substituted for tetracycline and in
`the fourth patient when the dose of tetracycline was
`reduced to 1.5 gmjday. Patient 10 developed a gen-
`eralized morbilliform eruption that was believed to
`be caused by tetracycline but was able to tolerate
`minocycline, 100 mg twice a day. Patient 12 expe-
`rienced headaches with nicotinamide and tetracy-
`cline, as well as with nicotinamide and minocycline.
`
`DISCUSSION
`Although this is an uncontrolled study with a
`limited follow-up period, the preliminary results ap-
`pear promising. Six of 11 patients with pemphigus
`and two patients with LABD were able to be
`controlled with nicotinamide and tetracycline as
`their only oral agents. We should emphasize that
`this combination was adequate therapy in only two
`
`of six patients with PV. The role of these agents in
`PV appears to be that of a steroid-sparing adjuvant,
`rather than a steroid alternative. The combination of
`nicotinamide and tetracycline was found to be an
`effective alternative to steroids in superficial pem-
`phigus (PE and PF) and LABD in six of seven pa-
`tients.
`The primary advantage nicotinamide and tetra-
`cycline offer over corticosteroids and immunosup-
`pressive agents is a broader safety profile. The most
`common side effect in our patients was gastrointes-
`tinal upset. In higher doses, nicotinamide has been
`reported to produce flushing, pruritus, headache,
`vomiting, and a flu-like syndrome. 7·9 Acanthosis ni-
`gricans, ichthyosiform skin changes, and hepatotox-
`icity have also been reported. 8• 10• 11 The side effects
`of tetracycline are well known and have been
`reviewed elsewhere. 12• 13
`Because this study is uncontrolled, it is possible
`that a selection bias towards patients with a ten-
`dency toward milder disease or spontaneous remis-
`sion may have occurred. However, the fact that sev-
`eral of our patients (7, 8, 10, and 13) had recurrences
`when nicotinamide and tetracycline were discontin-
`ued argues against this explanation for the thera-
`peutic results.
`The mechanism of action of nicotinamide and
`
`Exh. 1065
`
`
`
`1000 Brief communications
`
`Journal of the American Academy of Dermatology
`June 1993
`
`tetracycline in the treatment of autoimmune bullous
`disorders is unknown.6 Nicotinamide inhibits poly-
`morphonuclear cell (PMN) and eosinophil chemo-
`taxis and blocks IgE-mediated histamine release and
`mast cell degranulation. 14-17 The infiltrate in both
`pemphigus and BP is rich in eosinophils; thus
`eosinophil inhibition may be part of the mechanism
`of action for the observed efficacy in these disorders.
`Similarly, inhibition ofPMNs may contribute to the
`results observed in LABD.
`Another likely explanation for the therapeutic re-
`sults are the effects that nicotinamide and tetracy-
`cline have on lymphocyte function. Both agents in-
`hibit lymphocyte blast transformation in vitro. 17-19
`This effect combined with the inhibition of PMN
`and eosinophil chemotaxis could serve to downgrade
`both the afferent and efferent limbs of humoral im-
`mune responses. The decrease in intercellular sub-
`stance antibody titer observed in some patients after
`treatment with nicotinamide and tetracycline sup-
`ports this suppression of lymphocyte (B cell) activ-
`ity.
`
`REFERENCES
`1. Rosenberg FR, Sanders S, Nelson CT. Pemphigus: a 20
`year review of I 07 patients treated with corticosteroids.
`Arch Dermatol 1976;112:962-70.
`2. Ahmed AR, Moy R. Death in pemphigus. J AM ACAD
`DERMATOL 1982;7:221-8.
`3. Jablonska S, Chorzelski TP, Blaszczyk M. Immunosup-
`pressants in the treatment of pemphigus. Br J Dermatol
`1970;83:3 15-22.
`4. McDonald CJ. Use of cytotoxic drugs in dermatologic dis-
`eases. I and II. JAM ACAD DERMATOL 1985;12:753-2,
`965-75.
`5. Peoples D, Fivenson DP. Linear IgA bullous dermatosis:
`
`successful treatment with tetracycline and niacinamide. J
`AM ACAD DERMATOL 1992;26:498-9.
`.
`6. Berk MA, Lorincz AL. The treatment of bullous pemphi-
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`port. Arch Derma to! 1986; 122:670-4.
`7. Parsons WB Jr. Treatment of hypercholesterolemia by
`nicotinic acid: progress report with review of studies re-
`garding mechanism of action. Arch Intern Med 1951;
`4:736-7.
`8. Zackheim HS, Yasily DB, Westphal ML, eta!. Reactions
`to nicotinamide [Letter]. JAM ACAD DERMATOL 1981;
`4:736-7.
`9. Hoffler A. Safety, side-effects, and relative lack of toxicity
`of nicotinic acid and nicotinamide. Schizophrenia 1969;
`1:78-9.
`10. Brown J, Winkleman RK. Acanthosis nigricans: a study of
`90 cases. Medicine 1968;47:33-51.
`II . Winter SL, Boyer JL. Hepatic toxicity from large doses of
`vitamin B3 (nicotinamide). N Eng! J Med 1973;289: 1180-2.
`12. Bruce S, Wolf JE. Antibacterial agents. In: Wolverton SE,
`Wilkin JK, eds. Systemic drugs for skin disease. Philadel-
`phia: WB Saunders, 1991 .
`13. Wright AL, Colver GB. Tetracyclines: How safe are they?
`Clin Exp Dermatol1988;13:57-61.
`14. Cohen BM. A niacinamide-theophylline compound (RC-
`C-144): human and blood level studies. J Asthma Res
`1966;4:7 5-9.
`I 5. Cohen BM. A niacinamide-theophylline compound (RC-
`C-144): clinical and spirometric effects. J Asthma Res
`1966;4:81-7.
`16. Berkier E, Masinski C. Antihistaminic action of nicotina-
`.
`mide. Agents Action 1974;4: 196.
`17. Burger DR, Vanden bark AA Daves D, et a!. Nicotina-
`mide: suppression of lymph0::yte transformation with a
`component identified in human transfer factor. J Immunol
`1976;117:797-801.
`18. Thong YH, Ferrante A. Inhibition of mitogen induced hu-
`man lymphocyte proliferative responses to tetracycline an-
`alogues. Clin Exp lmmunol 1979;35:443-6.
`19. Banck G, Forsgren A. Antibiotics and suppression of lym-
`phocyte function in vitro. Antimicrob Agents Chemother
`1979;16:554-60.
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`Exh. 1065