`
`JUNE 1994
`
`Univ~;-ot Minn:
`Bio-Medical
`· Library
`06 _15 94
`
`Perifollicular lymphocytic reaction. See page 770.
`
`DERMATOLOGY IN THE OREGON PLAN
`WITH IMPLICATIONS FOR HEALTH CARE
`PLANS IN OTHER STATES
`P. S. Russell
`
`NICOTINAMIDE AND TETRACYCLINE
`THERAPY OF BULLOpS PEMPHIGOID
`D. P. Fivenson, D. L. Breneman, G. B. Rosen,
`C. S. Hersh, S. Cardone, D. Mutasim
`
`TOPICAL RETINOIC ACID (TRETINOIN)
`FOR MELASMA IN BLACK PATIENTS: A
`VEHICLE-CONTROLLED CLINICAL TRIAL
`C. K. Kimbrough-Green, C. E. M. Griffiths,
`L. J. Finkel, T. A. Hamilton, S. M. Bulengo-Ransby,
`C. N. Ellis, J. ]. Voorhees
`
`SPECIFIC PRURITIC DISEASES OF
`PREGNANCY: A PROSPECTIVE STUDY
`OF 3192 PREGNANT WOMEN
`D. Roger, L. Vaillant, A. Fignon, F. Pierre, Y. Bacq,
`].-F. Brechot, M.-C. Grangeponte, G.Lorette
`
`American Medical Association
`Physicians dedicated to the health of America
`
`FOLLICULAR DEGENERATION
`SYNDROME IN MEN
`LTC L. C. Sperling, CAPT H. G. Skelton III,
`COL K. ]. Smith, COL P. Sau, K. Friedman
`
`INHIBITION OF A MODEL OF IN VITRO
`GRANULOMA FORMATION BY
`TETRACYCLINES AND CIPROFLOXACIN:
`INVOLVEMENT OF PROTEIN KINASE C
`,...,,... ..... - .
`:P
`--·-
`~BXNBdLL****~~ ~-QIG . ~~ 4 -
`9~1 2
`#0l046085805l D l30DQ~
`UNIVERSITY OF MINNESOTA
`-·
`· - : ~u· rcAL LIBRARY
`...
`BIO ~~~ , .. ·
`,.-- ~ -~ zs· A Ul EHL
`1·
`505 E~~cX S
`~t ~ -
`-
`~
`MINNEAPOLIS MN
`5~455-U3~0
`.-------------~-----.
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__ __
`Exhibit 1063
`
`
`
`DERMATOLO
`
`JUNE 1994
`
`Univ .,:-of-Minn:
`Bio .. Medical
`, -~ibrary
`06 _1
`
`Perifollicular lymphocytic reaction. See page 770.
`
`DERMATOLOGY IN THE OREGON PLAN
`WITH IMPLICATIONS FOR HEALTH CARE
`PLANS IN OTHER STATES
`P. S. Russell
`
`NICOTINAMIDE AND TETRACYCLINE
`THERAPY OF BULLOUS PEMPHIGOID
`D.P. Fivenson, D. L. Breneman, G. B. Rosen,
`C. S. Hersh, S. Cardone, D. Mutasim
`
`TOPICAL RETINOIC ACID (TRETINOIN)
`FOR MELASMA IN BLACK PATIENTS: A
`VEHICLE~CONTROLLED CLINICAL TRIAL
`C. K. Kimbrough,Green, C. E. M. Griffiths,
`L. J. Finkel, T. A. Hamilton, S.M. Bulengo,Ransby,
`C. N. Ellis, J. J. Voorhees
`
`SPECIFIC PRURITIC DISEASES OF
`PREGNANCY: A PROSPECTIVE STUDY
`OF 3192 PREGNANT WOMEN
`D. Roger, L. Vaillant, A. Fignon, F. Pierre, Y. Bacq,
`J.'F. Brechot, M.'C. Grangeponte, G. Lorette
`
`FOLLICULAR DEGENERATION
`SYNDROME IN MEN
`LTC L. C. Sperling, CAPT H. G. Skelton III,
`COL K. J. Smith, COL P. Sau, K. Friedman
`
`INHIBITION OF A MODEL OF IN VITRO
`GRANULOMA FORMATION BY
`TETRACYCLINES AND CIPROFLOXACIN:
`INVOLVEMENT OF PROTEIN KINASE C
`
`American Medical Association
`Physicians dedicated to the health of America
`
`Exh. 1063
`
`
`
`Nicotinamide and Tetracycline Therapy
`of Bullous Pemphigoid
`
`David P. Fivenson, MD; Debra L. Breneman, MD; Gary B. Rosen, MD; Craig S. Hersh, MD;
`Scott Cardone, MD; Diya Mutasim, MD
`
`Background and Design: Th~ combination of nicotin-
`amide and tetracycline has been anecdotally reported to
`be effective in the treatment of bullous pemphigoid. We
`conducted a randomized, open-labeled trial comparing the
`combination of 500 mg of nicotinamide, three times daily,
`and 500 mg of tetracycline four times daily, with predni-
`sone therapy in 20 patients with bullous pemphigoid. The
`study was divided between an 8-week acute phase with
`fixed drug dosages and a 10-monthfollow-up phase in which
`study medications were tapered based on patient response.
`
`Results: Eighteen of 20 patients enrolled in the study
`were treated, two patients were unavailable for follow-
`up. Twelve patients were treated with the combination
`of nicotinamide and tetracycline and six patients were
`treated with prednisone. There were five complete re-
`sponses, five partial responses, one nonresponder, and
`one patient with disease progression in the nicotin-
`amide and tetracycline group compared with one com-
`plete response and five partial responses in the predni-
`
`sone group. There were no statistically significant.
`differences in response parameters between the two
`groups. All five patients in the nicotinamide and tetra-
`cycline group receiving long-term follow-up remained
`disease free during medication tapering, while three pa-
`tients in the prednisone group had repeated disease flare-
`ups with steroid tapering. Adverse effects in the nicotin-
`amide and tetracycline group included gastrointestinal
`upset (two patients) and transient renal failure (one pa-
`tient). In the prednisone group, there was one occur-
`rence each of hypertension, erosive gastritis, multiple de-
`cubitus ulcers, osteomyelitis, deep venous thrombosis,
`and death related to sepsis. Two patients required insu-
`lin therapy for hyperglycemia.
`
`Conclusions: The combination of nicotinamide and tet-
`racycline appears to be a useful alternative to systemic
`steroids in the treatment of bullous pemphigoid.
`
`(Arch Dennatol. 1994;130:753-758)
`
`ULLOUS PEMPHIGOID (BP) is
`a chronic autoimmune blis-
`tering disease that is char-
`acterized by erythematous
`plaques, vesicles, and tense
`bullae that typically begin in the sixth or
`seventh decade. Traditional therapies used
`in BP include systemic corticosteroids and
`cytotoxic agents. 1 Other agents reported
`as efficacious include dapsone, cyclospo-
`rine, erythromycin, and tetracycline. 1-5 An
`effective steroid-sparing regimen could po-
`tentially benefit elderly patients with BP
`by helping to reduce the steroid-related side
`effects to which this population is prone.
`Recently, Berk and Lorincz6 presented four
`patients with BP treated effectively with-
`out steroids with a combination of nico-
`tinamide and tetracycline. 6
`We have treated a series of 20 pa-
`
`ARCH DERMATOUVOL 130, JUNE 1994
`753
`
`tients with BP in a nonrandomized fash-
`ion with the combination of nicotin-
`amide and tetracycline and found it to be
`effective. We, therefore, initiated a ran-
`domized, open-label trial to compare the
`efficacy of the combination of nicotin-
`amide and tetracycline with prednisone in
`the treatment ofBP. In this article, were-
`view our experience with the combina-
`tion of nicotinamide and tetracycline in 20
`patients enrolled in this randomized trial.
`The short-term and long-term effective-
`ness and safety of this combination therapy
`
`See Patients and Methods
`on next page
`
`From the Department of
`Dennatology, Hemy Ford
`Hospital, Detroit, Mich
`(Drs Fivenson, Rosen, and
`Hersh), and the Department
`of Dennatology, University
`of Cincinnati (Ohio)
`(Drs Breneman, Cardone, and
`Mutasim).
`
`Exh. 1063
`
`
`
`PATIENTS AND METHODS
`
`PATIENTS
`
`The study design was that of an open-label randomized trial
`comparing the combination of nicotinamide and tetracy-
`cline with prednisone in the treatment ofBP. The study pro-
`tocol was approved by the institutional review boards at
`Henry Ford Hospital, Detroit, Mich, and the University of
`Cincinnati (Ohio) Medical Center. Treatment was divided
`into two phases: an 8-week acute phase with fixed drug dos-
`ages and a 10-month follow-up period. The inclusion cri-
`teria included diagnosis of BP by clinical, histologic, and
`immunofluorescence findings, a minimum of eight le-
`sions (bullae, urticaria, or erosions/crusts), and no sys-
`temic therapy within 2 weeks of enrollment. The exclu-
`sion criteria included a history of positive tuberculin skin
`test without treatment, cicatricial pemphigoid, or poorly
`controlled systemic diseases in which therapy with pred-
`nisone, nicotinamide, or tetracycline therapy was contra-
`indicated.
`Patients were randomized into one of two treatment
`groups: nicotinamide, 500 mg, three times daily, plus tet-
`racycline, 500 mg, four times daily, or prednisone 40 to 80
`mg/d. Minocycline, 100 mg, twice daily was substituted if
`excessive gastrointestinal upset was noted with tetracy-
`cline.
`Patients were seen weekly for 2 weeks, then biweekly
`for 2 months, then monthly for the remainder of 1 year.
`On each visit, the number of bullous, crusted, and urti-
`carial lesions on each patient were counted and plotted on
`cutaneous maps, one for lesions less than 1 em in diameter
`and one for lesions more than 1 em in diameter. The fol-
`lowing scale was used: 0, no lesions; 1 +, one to five le-
`sions; 2 +, six to 10 lesions; 3 +, 11 to 20 lesions; 4 +, 21 to
`40 lesions; and 5 +, more than 40 lesions.
`Pruritus and the physician's global assessment were
`
`also recorded at each visit. Pruritus was assessed as fol-
`lows: 0, no pruritus or burning; 1, mild pruritus or burn-
`ing (occasionally noticeable); 2, moderate pruritus or burn-
`ing (present but did not interfere with daily activity or sleep);
`and 3, severe pruritus or burning (interference with daily
`activities and/or sleep). The physician's global assessment
`was rated with respect to baseline presentation as follows:
`-3, markedly worse; -2, somewhat worse; -1, slightly
`worse; 0, no change; 1 +,slightly better; 2 +,somewhat bet-
`ter; 3 +, markedly better; and 4+, clinical remission.
`The patient's blood pressure, complete blood cell count,
`and alanine aminotransferase, aspartate aminotransferase,
`serum electrolytes, serum urea nitrogen, and creatinine con-
`centrations were obtained-at weeks 0, 1, 2, 4, 8, and 12,
`and then at 3-month intervals. A chest roentgenogram and
`a skin anergy panel (including a tuberculin skin test anti-
`gen) were obtained prior to treatment.
`Response categories were defined after 8 weeks of treat-
`ment as complete response, complete clearing of all le-
`sions; partial response, at least 50% clearing of lesions; no
`response, less than 25% clearing; and worsening, progres-
`sion of disease. During the follow-up period, disease re-
`currence was recorded if any new bullae, urticaria, or ero-
`sions and/or crusts were noted.
`
`STATISTICAL ANALYSIS
`
`The differences in numbers of bullous, crusted, and urti-
`carial skin lesions ofless than 1 em or more than 1 em were
`calculated between 1 week and baseline, 2 weeks and base-
`line, and 4 weeks and baseline, to adjust for the baseline
`conditions of the patients. The groups were then com-
`pared using Wilcoxon rank sum tests on the differences.
`Wilcoxon rank sum tests were also used to compare pru-
`ritus and global assessment between the two treatment
`groups. P values less than or equal to .01 were considered
`to be statistically significant. P values between .01 and .05
`were considered to be "borderline" significant.
`
`in the treatment of both localized and generalized BP are
`demonstrated.
`
`~
`
`"
`
`~
`
`RES"U.H1l'ill?v~,:"' ~, v '
`
`Twenty patients were enrolled between the two study cen-
`ters. This included six men between the ages of 69 and
`89 years and 14 women between the ages of 52 and 91
`years. There were 14 whites and six blacks in the study
`population. Fourteen patients were randomized to treat-
`ment with nicotinamide and tetracycline and six to pred-
`nisone treatment. The study was originally designed to
`randomize a total of 96 patients, with approximately 24
`in each treatment arm at each center. The study was ter-
`minated after the 20 patients presented were enrolled; a
`randomized, double-blind, multicenter trial has since been
`initiated. During the acute phase of the trial, there were
`
`five complete responses, five partial responses, one no
`response, and one worsening in the nicotinamide and tet-
`racycline group and one complete response and five par-
`tial responses in the prednisone group. Two patients in
`the nicotinamide/tetracycline group were unavailable for
`follow-up (Table 1 ).
`There was a general trend toward improvement in
`both groups in lesion counts, pruritus, and global as-
`sessment. Both treatment groups had rapid resolution of
`
`See also pages 7 48 and 781
`
`bullous and urticarial lesions in patients who achieved
`complete response or partial response. The mean pruri-
`tus score on enrollment was 2.0 for both the nicotinamide/
`tetracycline group and the prednisone group and de-
`
`ARCH DERMATOUVOL 130, JUNE 1994
`754
`
`Exh. 1063
`
`
`
`Table 1. Comparison of Patient Demographics and Responses to Therapy During the Acute Phase of a Randomized Trial of
`Nicotinamide/Tetracycline vs Prednisone in the Treatment of Bullous Pemphigoid*
`·
`
`Bullous
`>40
`>40
`0
`>20
`
`15
`>40
`>40
`>40
`>40
`5
`3
`15
`8
`0
`11
`0
`15
`
`lesions
`
`Crusted
`>40
`>40
`35
`>10
`
`30
`0
`>40
`>40
`>40
`30
`3
`>40
`3
`30
`>40
`>40
`>40
`
`Urticarial
`>40
`0
`0
`20
`
`0
`>40
`5
`0
`0
`>40
`18
`11
`>40
`3
`0
`8
`>40
`
`';'t·
`
`Treatment
`Regimen, mg/dt
`Prednisone 80
`Prednisone 80
`Prednisone 40
`Tetracycline/nicotinamide
`
`Tetracycline/nicotjnamidet
`Tetracycline/nicotinamide
`Tetracycline/nicotinamide
`Tetracycline/nicotinamide
`Tetracycline/nicotinamide
`Tetracycline/nicotinamide
`Tetracycline/nicotinamide§
`Prednisone 60
`Tetracycline/nicotinamide§
`Prednisone 40
`Tetracycline/nicotinamide
`Prednisone 60
`Tetracycline/nicotinamide
`
`Patient
`
`2
`3
`4
`
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`
`Age, y/
`Sex/Race
`77/M/W
`82/F/B
`88/F/W
`70/F/8
`
`69/M/B
`76/M/W
`89/M/W
`90/F/W
`85/F/W
`74/M/W
`73/F/W
`61/F/8
`90/F/W
`75/F/W
`81/M/W
`78/F/8
`78/F/8
`
`Response
`PR
`PR
`PR
`Unavailable for
`follow-up
`PR
`PR
`NR
`CR
`PR
`CR
`PR
`CR
`CR
`PR
`w
`PR
`Unavailable for
`follow-up
`Tetracycline/nicotinamide
`>40
`>40
`>40
`52/F/W
`CR
`18
`3
`6
`18
`Tetracycline/nicotinamide
`78/F/W
`PR
`19
`25
`>40
`>40
`Tetracycline/nicotinamide
`91/F/W
`CR
`20
`* CR indicates complete response, complete clearing after 8 weeks or less; PR, partial response, at least 50% clearing after 8 weeks; NR, no response, less
`than 25% clearing or worse after 8 weeks; and W, worsening or disease progression after 8 weeks.
`t Tetracycline, 500 mg tour times daily plus nicotinamide, 500 mg three times daily, or prednisone, 40 to 80 mg/d.
`tStopped after 4 weeks due to renal failure.
`§Minocycline substituted tor tetracycline due to gastrointestinal upset.
`
`creased to 1.5 and 1.0, respectively, at 2 weeks and 1.2
`and 0.2, respectively, at 4 weeks. The physician's global
`assessment followed a similar trend in both patient groups
`as well. Statistical comparison revealed no significant dif-
`ferences between the two treatment groups in the reduc-
`tion in numbers of skin lesions (P values ranged from
`.13 to .96 at 1, 2, and 4 weeks of therapy). Prednisone
`showed borderline significance in reducing the number
`of bullous lesions of more than 1 em after 1 week of treat-
`ment compared with the nicotinamide/tetracycline com-
`bination (P=.017). There were also no significant differ-
`ences between treatment group responses for pruritus
`(P=.32, P=.81) or the physician's global assessment (P=.40,
`P=.83) at any time point in the acute phase of the trial.
`The Fiigurre graphically demonstrates the similarity in
`responses to nicotinamide/tetracycline vs prednisone over
`time for the evaluation of skin lesions, pruritus, and the
`physician's global assessment.
`Table 1 demonstrates that not only was the combi-
`nation of tetracycline and nicotinamide efficacious in treat-
`ing localized or limited BP (patients 5, 11, 13, and 19),
`but it was also effective in patients with extensive dis-
`ease (patients 6, 8, 9, 18, and 20). Several patients with
`an excess of 100 bullae and/or erosions had their disease
`
`successfully controlled within 2 to 4 weeks of initiating
`tetracycline and nicotinamide therapy.
`
`LONG-TERM FOLLOW-UP
`
`The mean follow-up period was 21.3 weeks in the
`prednisone patients and 17.5 weeks in the
`nicotinamide/tetracycline patients. Eight patients
`maintained regular follow-up visits for 22 weeks or
`longer and their treatment courses and outcome are
`summarized in Table 2. Two of three prednisone-
`treated patients had repeated disease flare-ups with ta-
`pering of medication. Five patients in the nicotin-
`amide and tetracycline group remained in complete
`response for 22, 28, 42, 50, and 54 weeks of observa-
`tion while being tapered off treatment.
`
`ADVERSE EFFECTS
`
`Two patients in the nicotinamide and tetracycline
`group reported gastrointestinal upset and responded
`well to the substitution of minocycline at 100 mg
`twice daily for tetracycline. Both of these patients de-
`veloped minocycline-related hyperpigmentation
`
`ARCH DERMATOUVOL 130, JUNE 1994
`755
`
`Exh. 1063
`
`
`
`~ Acute Phase _,
`
`4
`
`10
`
`14
`12
`Time, wk
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`28
`
`~ Acute Phase _,
`
`12
`11
`10
`9
`8
`Q) 7 8 6
`c: 5
`0 ·u; 4 ~
`3
`2
`1
`0
`
`C/)
`
`~
`
`8 C/)
`en
`:::J
`.§
`a:
`
`4
`
`10
`
`12
`
`14
`Time, wk
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`28
`
`~ Acute Phase _,
`
`4
`
`~
`
`8 C/)
`
`c: I .;£
`
`E 0
`C!i
`
`Top, Mean lesion scores of bullous pemphigoid patients
`treated with prednisone vs the combination of
`nicotinamide and tetracycline in a randomized, open-label
`trial. Patients received a fixed dose of prednisone (solid
`circles) (40 to 80 mg/d [n=6}) or 500 mg of
`nicotinamide (open diamonds) twice daily plus 500 mg
`of tetracycline four times daily (nicotinamide/tetracycline
`[n=2}) tor 8 weeks during the acute phase of the study
`and were then tapered individually. The lesion score
`represented is the mean score for each treatment group
`of the sum total score of bullous, urticarial, and crust
`lesions both less than 1 em and more than 1 em in
`diameter. Skin lesions were scored on the following
`scale: 0, no lesions; 1 +, one to five lesions; 2+, six
`lesions; 3+, 11 to 20 lesions; 4+, 21 to 40 lesions; 5+,
`more than 40 lesions, thus the maximum score was 30
`for any patient. The P values between the prednisone
`and nicotinamide/tetracycline groups at 1, 2, and 4
`weeks were .61, .96, and .78, respectively. Center, Mean
`pruritus scores of the same patients as in the top part of
`the Figure. Pruritus was scored on the following scale: 0,
`no pruritus or burning; 1, mild pruritus or burning
`(occasionally noticeable); 2, moderate pruritus or
`burning (present, but not interfering with daily activities
`or sleep); and 3, severe pruritus or burning (interfering
`with daily activities and/or sleep). The P values between
`the prednisone (solid circles) and
`nicotinamide/tetracycline (open diamonds) groups at 1,
`2, and 4 weeks were .81, .45, and .32, respectively.
`Bottom, Mean physician's global assessment scores of
`the same patients as in the top and center parts of the
`Figure. Physician's global assessment was scored on the
`following score: the physician's global assessment was
`rated with respect to baseline presentation as follows:
`- 3, markedly worse; -2,. somewhat worse;
`1, slightly
`worse; 0, no change; 1+, slightly better; 2+, somewhat
`better; 3+, markedly better; and 4+, clinical remission .
`The P values between the prednisone (solid circles) and
`nicotinamide/tetracycline (open diamonds) groups at 1,
`2, and 4 weeks were .83, .40, and .40, respectively.
`
`4
`
`6
`
`10
`
`12. 14
`Time, wk
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`28
`
`within areas of old blisters and have been reported
`elsewhere. 7 One of these patients treated with minocy-
`cline also developed tinnitus, which resolved after 1
`month despite continued treatment. One patient was
`enrolled with elevated serum creatinine and serum
`urea nitrogen concentration (serum urea nitrogen,
`12.9 mmol/L [3.6 to 8.9 mmol!L] ;_creatinine, 159
`~J..mol!L [ < 133 ~J..mol!L]) and developed acute tubular
`necrosis after 4 weeks of nicotinamide and tetracycline
`therapy. His peak creatinine level was 654 ~J..mol!L and
`renal function returned to baseline within 2 weeks of
`discontinuation of nicotinamide and tetracycline
`therapy. This patient was also taking nonsteroidal
`anti-inflammatory medications (ibuprofen and aspi-
`rin) at the time renal failure was diagnosed. No other
`significant serologic or hematologic abnormalities
`were noted in the nicotinamide and tetracycline
`group.
`In the prednisone group, there was one occurrence
`each of hypertension (after week 9 of therapy), osteo-
`
`myelitis of the toe (after week 7), multiple decubitus ul-
`cers (after week 18), and deep venous thrombosis and
`erosive gastritis (after week 12). There was also one death
`in the prednisone group due to sepsis complicated by as-
`piration pneumonia. Two patients developed hypergly-
`cemia necessitating supplemental insulin therapy.
`
`Treatment of BP has historically involved systemic cor-
`ticosteroids and immunosuppressive agents. 1 Because pa-
`tients are often elderly, they are more prone to suffer from
`a number of other medical problems such as diabetes,
`hypertension, congestive heart failure, and osteoporosis
`that place them at higher risk for developing side effects
`from systemic corticosteroid therapy. Berk and Lorincz6
`initially reported successful treatment of four patients with
`BP using the combination in 1986.6 In preliminary ex-
`periences at our institutions using nicotinamide and tet-
`racycline in treating 20 patients with BP, we found this
`
`ARCH DERMATOUVOL 130, JUNE 1994
`756
`
`Exh. 1063
`
`
`
`Table 2. long-term Follow-up Results and Complications in Patients With Bullous Pemphigoid Treated With Nicotinamide
`and Tetracycline vs Prednisone*
`
`Patient
`
`Treatment Regiment
`Prednisone, taper
`
`Follow-up
`Period, wk
`42
`
`8
`10
`11
`
`12
`13
`
`16
`18
`
`Tetracycline/nicotinamide, taper
`Tetracycline/nicotinamide, taper
`Tetracycline/nicotinamide, taper
`
`Prednisone, taper
`Tetracycline/nicotinamide, taper
`
`Prednisone, taper
`Tetracycline/nicotinamide, taper
`
`50
`28
`42
`
`26
`22
`
`34
`54
`
`Outcome
`PR, repeated flares
`of diseastl, ·
`CR
`CR
`Flare week 12, add 4 week
`prednisone taper
`Flare, week 25
`CR
`
`PR
`CR
`
`Complications
`Decubitus ulcers,
`weeks 18 and 38
`None
`None
`Herpes zoster, week 18
`
`None
`Gastrointestinal upset,
`tetracycline changed to
`minocycline, week 4
`Hypertension, week 9
`None
`
`*CR indicates complete response, complete clearing after 8 weeks or more; PR, partial response, at least 50% clearing after 8 weeks; NR, no response,
`less than 25% clearing or worse after 8 weeks; and W, worsening, after 8 weeks or progression.
`t Tetracycline, 500 mg tour times daily plus nicotinamide, 500 mg three times daily, or prednisone; 40 to 80 mg/d.
`
`combination an effective alternative therapy to systemic
`steroids in the majority of patients (unpublished obser-
`vations). These uncontrolled observations led to the pre-
`sent randomized, open-label trial comparing nicotin-
`amide and tetracycline with prednisone in the treatment
`ofBP.
`The results of our uncontrolled observations and this
`randomized trial suggest that the combination of nico-
`tinamide and tetracycline may be a useful alternative for
`first-line therapy in the acute treatment ofBP. Although
`the number of patients studied was not large, these re-
`sults suggest comparable efficacy for the nicotinamide/
`tetracycline combination with prednisone in the treat-
`ment ofBP. The efficacy of nicotinamide/tetracycline was
`independent of the number of lesions, as no correlation
`was observed between the extent of disease and the abil-
`ity to respond to the nicotinamide and tetracycline
`combination.
`In this group of patients, fewer short-term and long-
`term adverse effects occurred in the patients treated with
`the nicotinamide/tetracycline combination compared with
`prednisone therapy. Five of six patients randomized to
`prednisone developed major complications while receiv-
`ing therapy including hypertension, decubitus ulcers, ero-
`sive gastritis, and serious infections, with one death due
`to sepsis. These underscore the potential toxic effects of
`corticosteroid therapy in patients with BP. In compari-
`son, fewer significant adverse effects occurred with nico-
`tinamide/tetracycline therapy. Those patients with gas-
`trointestinal upset had complete amelioration with
`minocycline substitution for tetracycline while main-
`taining comparable efficacy. Only the one patient treated
`with this combination who developed acute tubular ne-
`crosis (patient 5) was withdrawn from the study due to
`a side effect. This occurrence has lead us to recommend
`
`exclusion of patients with a serum creatinine level of more
`than 177 1-1mol/L or a serum urea nitrogen level of more
`than 14.3 mmol/L from being treated with nicotinamide/
`tetracycline as well as avoidance of other potentially neph-
`rotoxic drugs (eg, nonsteroidal anti-inflammatory medi-
`cations). The pathophysiology of renal failure due to
`tetracycline in patients with baseline mild renal insuffi-
`ciency involves decreased clearance of tetracycline with
`resulting accumulation of toxic metabolites in the renal
`tubules. 8·9 Minocycline, which is metabolized in the liver
`prior to renal excretion, is considered a safe alternative
`to tetracycline in patients with mild renal insuffi-
`ciency.8·9
`Potential adverse effects reported with nicotin-
`amide therapy include hepatotoxicity, pruritus, and flush-
`ing; these have generally been reported in patients tak-
`ing a much higher dose than those used in this study.
`Tetracycline has been associated with gastrointestinal up-
`set, hepatotoxicity, and phototoxicity.8-10 Long-term sys-
`temic corticosteroid therapy is associated with osteopo-
`rosis, weight gain, cataracts, hyperglycemia,
`gastrointestinal ulcers, myopathy, hypertension, and psy-
`chosis in addition to the septic complications and poor
`wound healing seen in this study.U Thus, both the ob-
`served and expected side-effect profiles for nicotinamide/
`tetracycline therapy appear to be more tolerable for the
`elderly patient with BP than those for prednisone.
`There are a variety of proposed mechanisms for the
`therapeutic effects of nicotinamide and tetracycline in BP.
`Nicotinamide may exert its therapeutic function via elec-
`tron scavenging, 12 inhibition of phosphodiesterase, 13
`and/or increased tryptophan conversion to seroto-
`nin.14·15 Nicotinamide also has direct antihistamine re-
`ceptor effects as well as effects inhibiting histamine re-
`lease, 16-20 and BP has been shown to have blister fluid
`
`ARCH DERMATOLIVOL 130, JUNE 1994
`757
`
`Exh. 1063
`
`
`
`characterized by increased levels of histamine. 21 Both nico-
`tinamide and tetracycline inhibit neutrophil and eosino-
`phil chemotaxis and secretion. 6•20•22-25 As BP is charac-
`terized by a subepidermal blister, often rich in eosinophils
`and neutrophils, inhibition of chemotaxis of these cells
`by nicotinamide and tetracycline is one of the more likely
`mechanisms of action. Other mechanisms of action in-
`clude the effect of nicotinamide on gene regulation and
`suppression of lymphocyte transformation. 26-28 Tetracy-
`cline has also been reported to experimentally increase
`cohesion of the epidermal basement membrane zone. 29
`We present data from a randomized, open-label trial
`showing that nicotinamide combined with tetracycline
`is a useful alternative to systemic steroids in the treat-
`ment of BP. The mechanism of action for this combina-
`tion is unknown but may involve some down-regulation
`of antigen-induced lymphocyte transformation, inhibi-
`tion of leukocyte chemotaxis, and/or inhibition of his-
`tamine release. These findings will need to be confirmed
`in a randomized, double-blind study, which is currently
`underway. This novel and inexpensive combination may
`offer advantages to older patients by avoiding some of
`the toxic effects of systemic steroids without significant
`loss of efficacy.
`
`Accepted for publication july 8, 1993.
`This study was supported in part by a grant from
`the Food and Drug Administration-Orphan Products
`Development Office, Detroit, Mich (No. FDU-000651)
`(Dr Fivenson).
`Presented in part at the American Academy of Der-
`matology Summer Session, June 13, 1991, Monterey,
`Calif, and before the annual meeting of the Ohio Derma-
`tological Association, September 15, 1991, Columbus.
`Reprint requests to the Department of Dermatology,
`Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI
`48202 (Dr Fivenson).
`
`1. Korman N. Bullous pemphigoid. JAm Acad Dermatol. 1987;16:907-924.
`2. Person JR, Rogers RS. Bullous pemphigoid responding to sulfapyridine and
`the sulfones. Arch Dermatol. 1977;113:61 0-615.
`3. Fox BJ, Odom RB, Findlay RF. Erythromycin therapy in bullous pemphigoid:
`possible anti-inflammatory effects. JAm Acad Dermato/. 1982;7:504-519.
`4. Thornfeldt CR, Menkes AW. Bullous pemphigoid controlled by tetracycline.
`JAm Acad Derma to/. 1987;16:305-31 0.
`
`5. Thomas I, Khorenian S, Arbesfeld DM. Treatment of generalized bullous pem-
`phigoid with oral tetracycline. JAm Acad Dermatol. 1993;28:74-77.
`6. Berk NA, Lorincz AL. The treatment of bullous pemphigoid with tetracycline
`and niacinamide. Arch Dermatol. 1986;122:670-674.
`7. Altman DA, Fivenson DP, Lee MW. Minocycline hyperpigmentation as a model
`for in situ phagocytosis by factor Xllla positive dermal dendrocytes. J Cutan
`Patho/. 1992;19:340-345.
`8. Dukes MNG. Meyler's Side Effects of Drugs. 9th ed. Princeton, NJ: Excerpta
`Medica; 1980.
`9. Cunha BA, Comer JB, Jonas M. The tetracyclines. Med Clin North Am. 1982;
`66:293-302.
`10. Zackheim HS, Vasily DB, Westphal MC, Hastings CW. Reactions to nicotin-
`amide. JAm Acad Dermatol. 1981 ;6:736-737.
`11. Axelrod L. Glucocorticoid therapy. Medicine. 1976;55:39-65.
`12. Wilson GL, Patton NJ, McCord JM, Mullins DW, Mossman BT. Mechanisms of
`streptozotocin- and alloxan-induced damage in rat B cells. Diabeto/ogia. 1984;
`27:587-591.
`13. Shinmoyama M, Kawai M, Hoshi Y, Veda I. Nicotinamide inhibition of 3', 5'
`cyclic AMP phosphodiesterase in vitro. Biochem Biophys Res Commun. 1972;
`49:1137-1141.
`14. Scherer B, Kromer W. Influence of niacinamide administration on brain 5-HT
`and a possible mode of action. Life Sci. 1972;11:189-195.
`15. Hoffer A. LSD-induced psychosis and vitamin B3. Am J Psychiatry. 1972;128:
`1155.
`16. Cohen BM. A niacinamide-theophylline compound (RC-C-144), human and blood
`level studies. J Asthma Res. 1966;4:75-79.
`17. Cohen BM. A niacinamide-theophylline compound (RC-C-144), clinical and spi-
`rometric effects. J Asthma Res. 1966;4:81-87.
`18. Bekier E, Maslinski C. Antihistaminic action of nicotinamide. Agents Action.
`197 4;4:196.
`19. Wyczolkowska J, Maslinski C. Inhibition by nicotinamide of an homologous
`PCA reaction and antigen-induced histamine release from rat peritoneal cells.
`tnt Arch Allergy App//mmuno/. 1975;49:285-292.
`20. Bekier E, Wyczolkowska J, Szych H, Maslinski C. The inhibitory effect of nico-
`tinamide on asthma-like symptoms and eosinophilia in guinea pigs, anaphy-
`lactic mast cell degranulation in mice, and histamine release from rat perito-
`neal mast cells by compound 48/80. tnt Arch Allergy App/lmmunol. 1974;47:
`737-748.
`21. Katayama I, Doi T, Nishioka K. High histamine level in the blister fluid of bul-
`lous pemphigoid. Arch Dermatol Res. 1984;276:126-127.
`22. Forsgren A, Schmeling D, Ouie PF. Effect of tetracycline on the phagocytic
`function of human leukocytes. J Infect Dis. 1974;130:412-415.
`23. Majeski JA, Alexander JW. Evaluation of tetracycline in the neutrophil chemo-
`tactic response. J Lab C/in Med. 1977;90:259-265.
`24. Esterly NB, Furey NL, Flanagan LE. The effect of antimicrobial agents on leu-
`kocyte chemotaxis. J Invest Dermatol. 1978;70:51-55.
`25. Esterly NB, Koransky JS, Furey NL, Trevisan M. Neutrophil chemotaxis in pa-
`tients with acne receiving oral tetracycline therapy. Arch Dermatol. 1984;120:
`1308-1313.
`26. Burger DR, Vandenbark AA, Daves D,Anderson WA, Vetto RM, Finke P. Nico-
`tinamide: suppression of lymphocytic transformation with a component iden-
`tified in human transfer factor. J lmmuno/. 1976;117:797 -801.
`27. Thong YH, Ferrante A. Inhibition of mitogen induced human lymphocyte prolif-
`erative responses to tetracycline analogues. Clin Exp lmmunol. 1979;35:443-446.
`28. Banck G, Forsgren A. Antibiotics and suppression of lymphocyte function in
`vitro. Antimicrob Agents Chemother. 1979;16:554-560.
`29. Humbert P, Renaud A, Millet J, et al. Evaluation of the effect of heparin and
`tetracycline on the cohesion of the dermal-epidermal junction. Acta Derm Ve-
`nereal. 1989;69:434-436.
`
`ARCH DERMATOUVOL 130, JUNE 1994
`758
`
`Exh. 1063