Official Journal of the
`StJohn's Dermatological Society
`
`Univ. of Minn.
`Bio-Medical
`Library
`
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1066
`Exh. 1066
`
`

`
`Clinical and E:cperimental Dermatology 1998; 23: 254-257.
`
`Combination therapy with nicotinamide and tetracyclines
`for cicatricial pemphigoid: further support for its efficacy
`
`·t..:
`
`L.REICHE, F.WOJNAROWSKA * AND E.MALLON* Dermatology Department, Amersham General
`Hospital, Amersham, Bucks HP7 O]D, and *Department of Dermatology, Oxford Radcliffe Hospital, Old Road,
`Headington, Oxford OX3 7LJ, UK
`
`Accepted for publication 17 July 1998
`
`Summary
`We have previously reported the reduction of cicatricial
`pemphigoid orodynia with minocycline. Tetracycline
`combined with high dose nicotinamide has also been
`beneficial in a number of cutaneous immunological dis-
`orders. We now report a series of eight cases in whom
`further subjective or clinical improvement accrued in
`five, after the addition of high dose (2· 5 or 3 g) nico-
`tinamide to minocycline; however, one of these then
`discontinued the nicotinamide because of headache and
`nausea, another was withdrawn from the study because of
`progressive upper respiratory tract mucosal involvement,
`and two were changed from minocycline to tetracycline
`because they developed minocycline-induced hyper-
`pigmentation.
`
`Cicatricial pemphigoid is an autoimmune blistering
`disease1 predominantly affecting the mucosae of elderly
`people. The oral, ocular or genital mucous membranes,
`and also the skin, are frequently involved. The condition
`may cause marked discomfort and can result in scarring
`and disabling stricture formation. Many patients have
`disease that is difficult to treat or have associated side-
`. effects from drugs; conventional treatment involves
`steroids, immunosuppressive therapy and dapsone, each
`of which requires close monitoring. z-s We have also
`previously reported a therapeutic benefit in cicatricial
`pemphigoid from minocycline therapy alone,6 whereas
`Berk and Lorinez reported success from combined
`tetracycline and niacinamide in bullous pemphigoid, 7
`and further studies have supported this. 8•9 Furthermore,
`Chaffins et al. reported success with nicotinamide and
`tetracycline together in 13 cases of pemphigus and linear
`IgA disease. 10 We now report our findings with the
`addition of nicotinamide to minocycline or tetracycline
`in eight patients with cicatricial pemphigoid in an open
`nonplacebo controlled study.
`
`Correspondence: Dr F.Wojnarowska.
`254
`
`Methods
`Cicatricial pemphigoid (CP) patients attending the out-
`patients departments of dermatology at Amersham Gen-
`eral Hospital, Buckinghamshire and the Oxford Radcliffe
`Hospital, Oxford, and who had been taking tetracycline
`for a period of at least 12 weeks without adequate
`symptomatic control, were invited to participate. One
`patient (Case 7) had been changed from minocycline to
`oxytetracycline several months prior to entry into the
`study because of minocycline-induced pigmentation of
`the lower legs, while the remainder (of whom Cases 5 and
`12
`6 have been discussed previously in case reports 11
`) had
`•
`been on minocycline 100 mg daily. Patients with signifi-
`cant liver function test abnormalities on preliminary
`testing were excluded and liver function tests were
`performed every 3 months. The study was approved by
`the research ethics committee in each hospital.
`Patients were commenced on 500 mg of nicotinamide
`daily, the dose then being increased by 500 mg incre-
`ments at 2-week intervals until symptomatic control was
`achieved or a maximum of 3 g daily had been reached,
`usually by 10-12 weeks. Each patient was reviewed at 4-
`6 week intervals. Two visual analogue scales of 0-9 were
`recorded at each visit to evaluate symptoms (where 0
`represented no symptoms and 9 the worst symptoms
`they had ever experienced), firstly at the time of the visit
`and secondly as an average over the preceding month; the
`average was then calculated from these two scores. The
`number and size of the lesions was also recorded as small
`( <0· 5 em), medium (0· 5-2·0 em) or large (>2·0 em), and a
`photographic record kept of each visible lesion. Once
`symptomatic control, or the maximum dose of 3 g, was
`reached the patient was maintained on nicotinamide for 6
`months before the dose was weaned off. Scores prior to
`treatment, after the maximum dose of nicotinamide had
`been taken for 6 months, and 4 months after discon-
`tinuation of the nicotinamide were then compared.
`
`Results
`Eight patients were entered into the trial, seven of whom
`
`© 1998 Blackwell Science Ltd
`
`Exh. 1066
`
`

`
`NICOTINAMIDE AND MINOCYCLINE FOR CICATRICAL PEl\llPHIGOID
`Table 1. Response of CP patients response to 6 months of nicotinamide (2.5-3 g) added to minocycline 100 mg or tetracycline 1 g
`
`255
`
`Visual analogue score
`
`Lesions pre-nicotinamide
`
`-\:;
`
`Size
`
`Small
`Small
`Small
`Small
`Medium
`Small
`Small
`Small
`Small
`Medium
`Small
`Small
`Large
`Small
`Small
`Medium
`Medium
`Medium
`
`Small
`Small
`Small
`Small
`Small
`
`Number
`
`Clinical progress
`
`10
`3
`3
`3 Blisters
`2
`1
`1
`4
`2
`1
`2
`2
`1
`1
`2
`7
`3
`Extensive cutaneous
`disease
`1
`3
`2
`4
`1
`Discomfort
`
`Improved
`Improved
`Improved
`Nil
`Stopped
`Nausea
`
`Varied
`Improved
`Resolved
`Resolved
`Improved
`Unchanged
`Evolved
`Resolved
`Improved
`Improved
`Improved
`
`Improved
`Improved
`Improved
`Unchanged
`Improved
`
`epiglottic
`ulcers/ stridor
`
`Age
`(years)
`
`Case
`
`Sex Before*
`
`Duringt After!
`
`Site
`
`1
`2§
`
`3
`
`4
`
`5§
`
`6
`
`7
`
`8
`
`68
`62
`
`73
`
`68
`
`71
`
`72
`
`71
`
`62
`
`M
`F
`
`M
`
`M
`
`F
`
`F
`
`F
`
`F
`
`6
`7
`
`5
`
`4
`
`6
`
`6
`
`5
`
`6
`
`6
`5
`
`4
`
`4
`
`4
`
`4
`
`4
`
`7
`
`5
`5
`
`4
`
`4
`
`4
`
`4
`
`4
`
`6
`
`Gingiva
`Palate
`Gingiva
`Conjunctiva
`Palate
`Forehead
`Chin
`Buccal mucosa
`Gingiva
`Groin
`Buccal mucosa
`Palate
`Vulva
`Leg
`Buccal mucosa
`Vulva
`Perianal
`Cutaneous
`
`Conjunctiva
`Buccal mucosa
`Vulva
`Perianal
`Buccal
`mucosa/
`pharynx
`
`*Pre-nicotinamide.
`t After 6 months' nicotinamide treatment.
`!Four months after stopping nicotinamide.
`§Changed from minocycline 100 mg to tetracycline 500 mg twice daily, mid-treatment, because of minocycline pigmentation.
`
`perianal ulceration that was resistant to therapy, while the
`oral and conjunctival disease responded to combination
`therapy. The perianal disease was however complicated
`by haemorrhoids which required surgical excision during
`the study period. Nicotinamide was discontinued in Case
`8 after 12 weeks because of the development of progres-
`sive upper respiratory tract mucosal involvement causing
`stridor: ulceration of the epiglottis was visible at
`bronchoscopy and high dose oral steroid therapy and
`tracheostomy was required to control the symptoms.
`Two of the patients (Cases 2 and 5) also developed
`unacceptable minocycline-induced hyperpigmentation
`during· the study and were therefore changed to tetra-
`cycline 1 g daily instead.
`
`tolerated nicotinamide well; however, Case 3 discontin-
`ued the drug after 2 weeks of 1 g per day because of
`dizziness and nausea; these symptoms then improved
`within 5 days. Symptoms related to his CP did not
`change during the medication period.
`Cases 1 and 5 increased their doses of nicotinamide up
`to 3 g, whereas the remainder reached a maximum dose
`of 2·5 g. None of these patients experienced any adverse
`effects and there were no liver function abnormalities
`detected in any patient during the study.
`All patients (except Cases 3 and 8) derived marked
`clinical improvement during and for 4 months after the
`course of nicotinamide (Table 1 ); of these, subjective
`(visual analogue score) improvement was noted in five
`patients (cases 1, 2, 5, 6, 7). Case 4 remained unchanged,
`Case 5 was the only patient to develop a new lesion (small
`Discussion
`leg erosion) during the study period and Case 6 had
`extensive cutaneous disease, including bilateral palmar
`Nicotinic acid is a vitamin (B3); it is converted to nico-
`involvement, and this, together with oral and genital
`tinamide in the body and then functions as an essential
`ulceration, was improved by nicotinamide and mino-
`coenzyme, accepting hydrogen ions in tissue respiration
`oxidation-reduction reactions. 13 Nicotinamide also inhibits
`cycline combination therapy after 2 months. Case 7 had
`© 1998 Blackwell Science Ltd, Clinical and Experimental Dermatology, 23, 254-257
`
`Exh. 1066
`
`

`
`256
`
`L.REICHE, F.WOJNAROWSKA AND E.MALLON
`
`clinical assessment is thus very difficult. For these
`reasons we measured the clinical response subjectively
`with visual analogue scales, and clinically by recording
`the number of lesions, measuring their size and keeping
`photographic records. We further chose a 6-month
`period of 1tssessment as a reasonable time frame to
`incorporate the effects of such a fluctuating disease.
`However, this was a pilot, nonplacebo controlled study,
`and should now be followed by a double blind cross-over
`investigation. The striking advantage that nicotinamide
`and tetracycline combination therapy has over treatment
`with corticosteroids and other
`immunosuppressive
`agents is their better side-effect profile in a disease
`which frequently requires prolonged therapy over many
`years. In the light of the dramatic clinical benefits shown
`in this study, therefore we felt these preliminary results
`should be reported.
`
`serum phosphodiesterase, resulting in increased cyclic
`adenosine monophosphate (cAMP) concentrations and,
`in turn, reduced protease release from leucocytes. 13 In
`addition, it inhibits antigen-induced lymphocyte prolif-
`eration and transformation, 14 neutrophil and ·eosinophil
`chemotaxis and secretion, 10 mast cell histamine release
`and is a free radical scavenger. Such properties may
`account for its apparent beneficial effects in a wide
`variety of immunological and inflammatory skin diseases;
`thus a number of these have benefited from high dose
`(300-2500 mg/ day) therapy, particularly dermatitis herpe-
`h
`1
`d'
`.
`1' d
`. c
`. 15
`t11ormts,
`eryt ema e evatum mtmum,
`genera tze
`16
`~ranuloma annulare, 17 various immunobullous diseases, 6
`-
`2 pollmorphic light eruptiol), 18 and necrobiosis lipoi-
`dica.1 Cicatricial pemphigoid is also an immunological
`mucosal and cutaneous disorder, the in vivo deposition of
`immunoglobulins and complement at the basement
`membrane zone with the presence of circulating base-
`ment membrane zone antibodies providing the evidence
`for an autoimmune aetiology.
`Nicotinic acid,
`the precursor of nicotinamide,
`however, has been associated with liver function abnorm-
`alities when used in large doses (3-10 ~/day) in the
`treatment of hypercholesterolaemia. 20- 5 Reversible
`hepatic toxicity has been reported once, following the
`use of 9 g/ day of nicotinamide. Nevertheless we detected
`no liver function abnormalities in our eight cases.
`Furthermore, unlike nicotinic acid, nicotinamide is not
`a potent vasodilator and does not cause flushing14 or
`impair glucose tolerance. It is possible that higher doses
`of the drug could produce further clinical improvement
`than we have reported in our cases, but a closer monitor-
`ing ofliver function tests would then be advised. It would
`also seem prudent to monitor the liver in all patients
`receiving long-term, high dosage therapy. We have also
`previously reported a high prevalence of minocycline-
`induced hyperpigmentation in CP patients, who are also
`often elderly, 6 and a further two cases (2 and 5) developed
`this problem during this study.
`Tetracyclines suppress leucocyte chemotaxis in vitro
`and in vivo at therapeutic concentrations and this is their
`proposed mechanism of action in inflammatory skin
`disease. 7 We have also previously discussed the immuno-
`logical effects of this drug3 and postulated that the
`combined effect of both minocycline and nicotinamide
`in blast transformation inhibition and the inhibition of
`neutrophil and eosinophil chemotaxis could serve to
`downgrade both the afferent and efferent limbs of humoral
`immune responses. 11 Such mechanisms could therefore
`explain the clear additional benefit that we have shown by
`the addition of high dose nicotinamide to minocycline (or
`tetracycline) in CP.
`CP is a rare disease which runs a variable course and
`the acute features of discomfort and ulceration are prone
`to spontaneous relapses and remissions. Objective
`© 1998 Blackwell Science Ltd, Clinical and Experime11tal Dermatology, 23, 254-257
`
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`© 1998 Blackwell Science Ltd, Clinical and E:t-perimental Dermatology, 23, 254-257
`
`Exh. 1066