infection and rosacea, we found a more
`between HP
`favourable clinical response to anti-HP treatment in the
`CLO-positive than in the CLO-negative group of rosacea
`patients. Our results support the theory that HP is not the
`direct cause of rosacea but that it may be an aggravating
`factor, probably more in the erythematous type than in the
`papular and glandular types. However, to establish the exact
`causative role of HP in rosacea, studies with a larger group
`of patients must be carried out.
`
`Departments of Dermatology
`and *Internal Medicine,
`Korea University College of Medicine,
`Guro 152-703,
`Seoul,
`Korea
`
`S.W.SoN
`I. H. KIM
`C.H.OH
`J.G.KIM*
`
`References
`1 Parish LC, Witkowski JA. Acne rosacea and Helicobacter pylori
`betrothed. Int J Dermatol1995; 34: 236-7.
`2 Rebora A. Drago F. Parodi A. May Helicobacter pylori be important
`for dermatologists? Dermatology 1995; 191: 6-8.
`3 Rebora A, Drago F, Picciotto A. Helicobacter pylori in patients with
`rosacea. Am J Gastroenterol1994; 89: 1603-4.
`4 Kolibasova K, T6thova I, Baumgartner J, Fila V. Eradication of
`Helicobacter pylori as the only successful treatment in rosacea.
`(Letter.) Arch Dermatol 1996; 132: 1393.
`5 Powell PC, Dawa MA, Duguid C. Positive Helicobacter pylori serology
`in rosacea patients. Ir J Med Sci 1992; 161: S75 (Abstr.).
`6 Schneider MA, Skinner RBJ, Rosenberg EW et al. Serological
`determination of Helicobacter pylori in rosacea patients and controls.
`Clin Res 1992; 40: 831A (Abstr.).
`7 Malaty HM, Kim JG, Kim SD et al. Prevalence of Helicobacter pylori
`infection in Korean children: inverse relation to socioeconomic
`status despite a uniformly high prevalence in adults. Am J Epidemiol
`1996; 143: 257-62.
`8 Sharma VK, Lynn A, Kaminski M et al. A study of the
`prevalence of Helicobacter pylori infection and other markers of
`upper gastrointestinal tract disease in patients with rosacea. Am
`J Gastroenterol 1998; 93: 220-2.
`
`Minocycline for the treatment of cutaneous silicone
`granulomas
`SIR, Granulomatous reactions named siliconomas have been
`reported after silicone injections in face or breast soft tissues
`and after silicone implants. 1 Treatment of siliconoma is
`difficult and often requires surgical excision. We report two
`patients with exuberant siliconoma who were successfully
`treated with minocycline.
`The first patient, a 49-year-old woman, presented with a
`diffuse, erythematous and indurated facial oedema (Fig. 1a).
`Cervical lymphadenopathy was also noted. Histopathological
`examination of a skin biopsy showed vacuoles in the dermis
`surrounded by a dense mononuclear infiltrate (Fig. 2). A clear,
`greasy material extracted from a fresh biopsy was identified as
`dimethylsiloxane oil by Fourier transformed infrared spectro-
`scopy. The likely cause was treatment of facial wrinkles by
`
`CORRESPONDENCE
`
`985
`
`local injections over a 3-year period, 8 years ago. Prednisone
`1 mg/kg per day was first given, but 4 days later the patient
`developed glucose intolerance for which she required insulin
`therapy. Because of the glucose intolerance and the lack of
`efficacy of high doses of prednisone, minocycline 100 mg twice
`daily was added as adjuvant therapy to
`the previous
`corticosteroid regimen.
`The clinical response of cutaneous symptoms was notice-
`able 3 weeks after the introduction of the minocycline and
`allowed a rapid reduction of the prednisone dosage. The
`erythematous indurated oedema of the face progressively
`decreased, leading to a complete resolution in 8 weeks (Fig.
`1b). Prednisone was stopped 4 months after the onset of
`minocycline therapy. Two months later the dose of mino-
`cycline was reduced to 100 mg once daily. The oedema
`reappeared clearly on the lower eyelids. Complete resolution
`was again rapidly obtained when the dosage of minocycline
`was increased once more to 100 mg twice daily.
`The second patient, a 3 9-year-old woman, received illicit
`fluid silicone injections in the soft tissue of the breasts 5 years
`ago. She developed erythematous lesions which began 2
`months after the injections. There was a progressive extension
`of indurated painful subcutaneous masses on the breasts and
`painful enlarged axillary lymph nodes. Histopathological
`examination of a skin biopsy showed vacuoles in the dermis
`surrounded with a mononuclear cellular infiltrate. Surgical
`excision was not possible because of the extension of lesions,
`leading to the introduction of minocycline as first-line therapy
`at the same dosage as that in the first case. Regression of the
`inflammatory symptoms and induration began 3 weeks after
`starting minocycline, and the patient's condition was still
`improving after 2 months.
`The tolerance to the treatment was excellent in both cases.
`Many local and general adverse effects were reported after
`cosmetic usage2 of silicone oil (polydimethylsiloxane) injec-
`tions and its use was progressively abandoned. However, illicit
`silicone injections are still performed. 3 Injected silicone is
`responsible for granulomatous tissue reactions like foreign
`body granuloma occurring from a few months to 15 years3- 5
`after injection. These reactions were reported at the site of
`the injection but also in the lymph nodes and in the liver
`because of migration of silicone particles. 2•3 The treatment of
`siliconoma is difficult and, until now, surgical excision is
`warranted when possible. 5 Even though corticosteroids have
`beneficial effects in the treatment of granulomatous diseases
`lilce sarcoidosis, their usage is often associated with serious
`adverse effects, such as glucose intolerance in our first case
`and drug dependence leading to a relapse of symptoms when
`prednisone dosage is tapered.
`Minocycline is considered a major drug in the treatment of
`various dermatoses like acne, rosacea and perioral dermatitis,
`and more recently in the treatment of rheumatoid arthritis.
`The beneficial effects of minocycline are related to anti-
`inflammatory and/ or immunomodulating effects and to
`antigranulomatous properties which have been demonstrated
`in vitro. 6- 8 These data lead to the proposal of minocycline as a
`therapeutic agent for granulomatous skin reactions.
`
`© 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 963-991
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1059
`
`Exh. 1059
`
`

`
`986
`
`CORRESPONDENCE
`
`Figure 1. Patient 1. (a) Diffuse
`erythematous and indurated oedema of the
`face before treatment with minocycline. (b)
`Resolution of the oedema 2 months after
`the beginning of minocycline therapy.
`
`Figure 2. Phagocytic granuloma with
`lipidic droplets resorption (haematoxylin
`and eosin, original magnification, · 200).
`
`For both patients, our follow-up period is still short. The
`duration of the treatment may need to be long, possibly
`increasing the risk of adverse effects such as pigmentation.
`These two cases support a role for minocycline in the
`management of severe granulomas induced by silicone use
`when surgical excision is not possible.
`
`*Service d’Anatomopathologie,
`Hoˆpital Saint-Louis,
`1 Avenue Claude Vellefaux,
`75475 Paris Cedex 10,
`France
`
`Acknowledgments
`
`We thank Dr MF Grenier for helpful discussion and for
`biochemical analysis of the skin biopsy.
`
`Service de Dermatologie,
`Institut de Recherche sur la Peau,
`Pavillon Bazin,
`Paris,
`France
`
`P.SENET
`H.BACHELEZ
`L.OLLIVAUD
`D.VIGNON-PENNAMEN*
`L.DUBERTRET
`
`References
`
`1 Faure M. Complications des implants de silicone et autres mate´riaux
`dits inertes. Ann Dermatol Venereol 1995; 122: 455–9.
`2 Ellenbogen R, Ellenbogen R, Rubin L. Injectable fluid silicone
`therapy. Human morbidity and mortality.
`JAMA 1975; 234:
`308–9.
`3 Travis WD, Balogh K, Abraham JL. Silicone granulomas: Report of
`three cases and review of the literature. Hum Pathol 1985; 16:
`19–27.
`4 Achauer BM. A serious complication following medical-grade
`silicone injection of the face. Plast Reconstr Surg 1983; 71: 251–4.
`
`q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 963–991
`
`Exh. 1059
`
`

`
`CORRESPONDENCE
`
`987
`
`to
`the lower leg may be difficult
`Bowen’s disease of
`treat, particularly in the elderly, who may have thin skin and
`venous disease. Excision with direct closure may be impossible,
`and skin grafts or flaps heal poorly on the lower leg.7 With
`cryotherapy, morbidity can be high and healing slow.8
`Radiotherapy is seldom used on the lower leg because of
`radiation necrosis and prolonged ulceration.9 There is a
`recurrence rate of 25%10 for all treatments in Bowen’s disease,
`possibly related to ill-defined margins and follicular involve-
`ment.10 A recurrence rate of 72% after curettage/cautery and
`87% after radiotherapy has been reported.11
`Actinic keratoses and Bowen’s disease are frequently treated
`with topical 5-fluorouracil (5-FU), twice daily for several
`weeks, until the lesions become inflamed.11,12 Aggressive
`treatment may cause ulceration, and there is a recurrence rate
`of 8%.10 We have examined the efficacy of weekly ‘pulse’ 5-FU
`cream (Efudix, Roche) for managing Bowen’s disease of the
`lower leg.
`Twenty-six women (mean age 76 years; range 55–95
`years) presented with Bowen’s disease of the lower leg, present
`for up to 12 years. The diagnosis was confirmed histologically.
`The sites of the lesions were recorded and photographed.
`Patients were instructed to apply 5-FU cream to the lesions
`in the morning and evening on 1 day each week and given
`an information sheet
`that explained the treatment. We
`emphasized the importance of applying cream to a rim of
`normal-looking skin around the whole plaque. Treatment
`
`5 Rees TD, Ballantyne DL, Seidman I. Eyelid deformities caused by
`injection of silicone fluid. Br J Plast Surg 1971; 24: 125–8.
`6 Celerier P, Litoux P, Dreno B. In vitro modulation of epidermal
`inflammatory cytokines (IL-1a, IL-6, TNFa) by minocycline. Arch
`Dermatol Res 1996; 288: 411–14.
`7 Webster GF, Toso Sm, Hegemann L. Inhibition of a model of in vitro
`granuloma formation by tetracyclines and ciprofloxacin. Involve-
`ment of protein kinase C. Arch Dermatol 1994; 130: 748–52.
`8 Tilley BC, Alarcon GS, Heyse SP et al. Minocycline in rheumatoid
`arthritis. A 48-week, double-blind, placebo-controlled trial. Ann
`Intern Med 1995; 122: 81–9.
`
`Bowen’s disease of the leg treated with weekly pulses of 5%
`fluorouracil cream
`
`SIR, Bowen’s disease is a premalignant dermatosis charac-
`terized histologically as carcinoma in situ with full-thickness
`dysplasia of the epidermis. It mainly affects the elderly1 and
`occurs particularly on sun-exposed sites, predominantly the
`lower legs in women and the scalp and ears in men.1,2 Left
`untreated, 3–5% of patients may develop invasive carci-
`noma.3,4 Among 74 patients with Bowen’s disease, invasive
`carcinoma developed in eight over a 10-year period.5 Bowen’s
`disease has a low malignant potential, and metastases develop
`in less than 1% of cases.6
`
`Table 1. Patient details (all are women) and the results of treatment
`
`Age (years)
`
`Duration of
`treatment
`(months)
`
`Outcome
`(? clear)
`
`Rim active?
`
`69
`82
`81
`84
`80
`79
`92
`80
`86
`65
`61
`85
`55
`68
`71
`59
`63
`80
`61
`77
`85
`79
`76
`95
`80
`75
`
`6
`6
`3
`3
`3
`4
`6
`4
`2
`3
`6
`4
`3
`4
`4
`2
`6
`4
`5
`6
`6
`4
`4
`4
`3
`6
`
`no
`no
`yes
`no
`yes
`no
`yes
`no
`yes
`no
`nob
`yes
`no
`yes
`yes
`yesa
`no
`yes
`nob
`no
`no
`no
`yes
`yes
`yes
`no
`
`yes
`yes
`no
`yes
`no
`yes
`no
`yes
`no
`yes
`all active
`no
`yes
`no
`no
`no
`yes
`no
`all active
`yes
`yes
`yes
`no
`no
`no
`yes
`
`a Ulcer developed.
`b No benefit gained.
`
`Figure 1. (a) Two areas of Bowen’s disease are evident on the lower left
`leg. (b) The lesions cleared after 3 months of treatment with pulsed
`5-fluorouracil cream.
`
`q 1999 British Association of Dermatologists, British Journal of Dermatology, 140, 963–991
`
`Exh. 1059