Journal of Dermalologica/ Trtalmenl (1989), 1, 23-25
`
`(b) Journal of Dermatological Treatment, 1989
`
`The successful use of minocycline in pyoderma gangrenosum - a report of
`seven cases and review of the literature
`
`John Berth-Jones MRCP1, Stella Veronica Tan BSc, MB BS1, Robin Alan Charles Graham-Brown
`BSc, MRCP1 & Andrew Charles Pembroke MA, FRCP2
`r Department of Dermatology, Leicester Royal Infirmary, Leicester LEI 5 WW: 1 Kings College Hospital, London
`
`We report seven cases in which minocycline was success-
`fully used to treat pyoderma gangrenosum. This more than
`doubles the six previously reported cases. MinocycHne is
`considerably safer than systemic steroids and may,
`therefore, represent a useful advance in the treatment of
`this disease.
`
`Introduction
`
`It is often stated that a disease with many remedies has no
`cure. Pyoderma gangrenosum (PG) might appear to be a
`prime example of such a disease. The established treat-
`ment consists of high doses of oral steroids - with or
`without 'steroid sparing agents'. 1 Among alternative
`treatments advocated are: topical steroids, clofazimine,Z
`
`intra-lesional triamcinolone,3 cyclosporin A: topical
`
`disodium cromoglycate, s cyclophosphamide, 6 azathiop-
`rine,' sulphasalazine,• dapsone,' plasma exchange10 and
`minocycline. 11 - 13
`Of all these agents minocycline is, in our experience, the
`safest, and appears currently to be the most widely used.
`We were therefore surprised to discover that the entire
`literature on the use ofminocycline in PG consists of three
`reports of successful use of the drug in a total of six
`cases. 11- 13
`·
`This is presumably due to the relative rarity ofPG and
`other inherent difficulties in performing a trial of any new
`treatment. Not least of these are the heterogeneity in the
`severity of PG and in the diseases associated with it.
`We therefore wish to report our experience of the use of
`minocycline in a further seven cases of PG.
`
`cinolone effected complete resolution. Minocycline was
`discontinued in July 1983.
`A further recurrence developed in Novem~?er 1983,
`involving the right scapular region. This responded
`completely within 3 months to minocycline 100 mg bd
`and two intralesional injections of triamcinolone. The
`minocycline was then continued at the dose of 100 mg bd
`until April 1985 when the dose was halved.
`Two additional recurrences ofPG developed following
`attempts to reduce the dose of minocycline, and resolved
`after the dose was restored. Two doses of intralesional
`steroid were injeeted on one occasion, and a single dose
`on the other. The dose of minocycline was then main-
`tained at 1 00 mg tds and he remained free from pyoderma
`for 2 years.
`Two subsequent minor recurrences have responded
`promptly to an increase in the dose of minocycline to
`200 mg daily and intralesional steroid injections.
`
`Case2
`Mr JB presented in July 1981 at the age of 69, with a 5
`month history of weeping ulcers over the back, chest, and
`arms. The clinical appearances were considered diagnos·
`tic of PG, and histology was compatible. Investigations
`revealed no evidence of additional pathology.
`He was treated with minocycline I 00 mg bd and the
`lesions gradually improved. Three months later only two
`remained, although complete healing took 6 months.
`Minocycline was continued in the same dose for a further
`6 months and then stopped. There was no evidence of
`recurrence after a further 9 months of follow-up.
`
`Case reports
`
`Case 1
`Mr AC first developed PG in June 1977, aged 24, as a
`complication of facial acne vulgaris. This remained active
`in spite of treatment with oral prednisolone in high doses
`(55-80 mg alt die) for 18 months, before resolving on
`prednisolone 80 mg every other day. Extensive investiga-
`tion revealed no evidence of any associated disease.
`Lesions of pyoderma recurred in May 1983 involving
`the right temple. Treatment was commenced with in-
`tralesional triamcinolone, but no response was obtained.
`Minocycline I 00 mg bd was then commenced, and after
`one month of this treatment alone the lesion had almost
`healed. Three further injections of intralesional triam-
`
`Correspondence: Dr Berlh-Jones
`
`Case3
`MrsJM presented at theageof58inJanuary 1986withan
`ulcerated lesion over the lateral aspect of the right shin.
`This had been slowly enlarging since its first appearance 2
`months earlier. Her previous medical history was
`unremarkable except for recurrent episodes of posterior
`uveitis.
`Examination revealed a sloughy ulcer measuring 6 em
`in width and 7 em in length with an undetermined
`necrotic margin, the appearance being typical of PG.
`Investigations were all normal except
`for
`the
`rheumatoid factor which was positive in low titre.
`Treatment was commenced with minocycline 100 mg
`twice daily orally and 0.05 per cent fluocinonide cream
`applied daily to the ulcer under an occlusive dressing.
`The lesion began to heal within 1 week and had totally
`resolved within 2 months. Atten Dr. Reddy's Laboratories, Ltd., et al.
`minocycline were followed on
`v.
`rences of the ulcer when the do
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1057
`
`

`
`Journal of Dermorological Treatmen1 (l989), 1, 23 - 25
`
`0 Journal of Dermatological Treatment, 1989
`
`The successful use of minocycline in pyoderma gangrenosum - a report of
`seven cases and review of the literature
`
`John Berth-Jones MRCP', Stella Veronica Tan BSc, MB BS', Robin Alan Charles Graham-Brown
`BSc, MRCP' & Andrew Charles Pembroke MA, FRCP2
`'Department ojDermatology. Leicester Royal Injrmary, Leicester LEI 5 WW; 'Kings College Hospital. London
`
`We report seven cases in which minocycline was success-
`fully used to treat pyoderma gangrenosum. This more than
`doubles the six previously reported cases. Minocycline is
`considerably safer than systemic steroids and may,
`therefore, represent a useful advance in the treatment of
`this disease.
`
`Introduction
`
`It is often stated that a disease with many remedies has no
`cure. Pyoderma gangrenosum (PG) might appear to be a
`prime example of such a disease. The established treat-
`ment consists of high doses of oral steroids - with or
`without 'steroid sparing agents'.' Among alternative
`treatments advocated are: topical steroids, clofazimine;
`topical
`intra-lesional triamcinolone,' cyclosporin A,'
`disodium cromoglycate,' cyclophosphamide,6 azathiop-
`rine,' sulphasalazine,* dapsone,' plasma exchange" and
`minocycline."-"
`Of all these agents minocycline is, in our experience, the
`safest, and appears currently to be the most widely used.
`We were therefore surprised to discover that the entire
`literature on the use of minocycline in PG consists of three
`reports of successful use of the drug in a total of six
`cases. ' ' -
`This is presumably due to the relative rarity of PG and
`other inherent difficulties in performing a trial of any new
`treatment. Not least of these are the heterogeneity in the
`severity of PG and in the diseases associated with it.
`We therefore wish to report our experience of the use of
`minocycline in a further seven cases of PG.
`
`Case reports
`
`Case 1
`Mr AC first developed PG in June 1977, aged 24, as a
`complication of facial acne vulgaris. This remained active
`in spite of treatment with oral prednisolone in high doses
`(55-80mg alt die) for 18 months, before resolving on
`prednisolone 80 mg every other day. Extensive investiga-
`tion revealed no evidence of any associated disease.
`Lesions of pyoderma recurred in May 1983 involving
`the right temple. Treatment was commenced with in-
`tralesional triamcinolone, but no response was obtained.
`Minocycline 100 mg bd was then commenced, and after
`one month of this treatment alone the lesion had almost
`healed. Three further injections of intralesional triam-
`
`Correspondence: Dr Berth-Jones
`
`~~~~~~~
`
`cinolone effected complete resolution. Minocycline was
`discontinued in July 1983.
`A further recurrence developed in November 1983,
`involving the right scapular region. This responded
`completely within 3 months to minocycline 100mg bd
`and two intralesional injections of triamcinolone. The
`minocycline was then continued at the dose of 100 mg bd
`until April 1985 when the dose was halved.
`Two additional recurrences of PG developed following
`attempts to reduce the dose of minocycline, and resolved
`after the dose was restored. Two doses of intralesional
`steroid were injected on one occasion, and a single dose
`on the other. The dose of minocycline was then main-
`tained at 100 mg tds and he remained free from pyoderma
`for 2 years.
`Two subsequent minor recurrences have responded
`promptly to an increase in the dose of minocycline to
`200 mg daily and intralesional steroid injections.
`
`Case 2
`Mr JB presented in July 1981 at the age of 69, with a 5
`month history of weeping ulcers over the back, chest, and
`arms. The clinical appearances were considered diagnos-
`tic of PG, and histology was compatible. Investigations
`revealed no evidence of additional pathology.
`He was treated with minocycline 100mg bd and the
`lesions gradually improved. Three months later only two
`remained, although complete healing took 6 months.
`Minocycline was continued in the same dose for a further
`6 months and then stopped. There was no evidence of
`recurrence after a further 9 months of follow-up.
`
`Case 3
`Mrs JM presented at the age of 58 in January 1986 with an
`ulcerated lesion over the lateral aspect of the right shin.
`This had been slowly enlarging since its first appearance 2
`months earlier. Her previous medical history was
`unremarkable except for recurrent episodes of posterior
`uveitis.
`Examination revealed a sloughy ulcer measuring 6 cm
`in width and 7m in length with an undetermined
`necrotic margin, the appearance being typical of PG.
`Investigations were all normal except
`for
`the
`rheumatoid factor which was positive in low titre.
`Treatment was commenced with minocycline 100 mg
`twice daily orally and 0.05 per cent fluocinonide cream
`applied daily to the ulcer under an occlusive dressing.
`The lesion began to heal within 1 week and had totally
`resolved within 2 months. Attempts to reduce the dose of
`minocycline were followed on two occasions by recur-
`rences of the ulcer when the dose was reduced to below
`
`J Dermatolog Treat Downloaded from informahealthcare.com by National Library of Medicine on 05/28/15
`
`For personal use only.
`
`Exh. 1057
`
`

`
`24
`
`JOHN BERTH-JONES er al
`
`50 mg daily. She therefore remains on this dose at present
`as maintenance therapy. She requires no topical steroids.
`
`Case 4
`Mrs MC presented in January 1987 at the age of 63 with a
`3 month history of a persistent ulcer on the abdomen and
`a similar lesion which had developed on the right shin 3
`days earlier. The appearances were typical of PG. Inves-
`tigations revealed mild ulcerative colitis for which no
`treatment was initially required. Treatment was com-
`menced with minocycline 100mg bd and definite im-
`provement was noted in both lesions 2 weeks later.
`Triamcinolone was then injected into the lesions. Com-
`plete healing of the pyoderma had occurred by April. The
`dose of minocycline was maintained until June, then
`gradually tailed off.
`In December 1987 the dose of minocycline was cut to
`50 mg daily. After 1 month on this dose and during an
`episode of more active colitis, a recurrence of pyoderma
`developed on the abdomen. The dose of minocycline was
`doubled, and treatment with sulphasalazine 4 gm daily
`was commenced for her colitis. The abdominal lesion
`healed completely in approximately 6 weeks. Treatment
`was maintained with minocycline 100mg daily and
`sulphasalazine 3 gm daily, and no further recurrence
`developed.
`
`Case 5
`Mr PR presented with PG in September 1987 at the age of
`56. Typical PG lesions had developed on the left temple
`and perineum over the previous 2 months. Investigations
`revealed no evidence of any associated illness. Treatment
`was commenced with minocycline 100 mg bd and within 1
`week a marked improvement had been noted.
`The lesions subsequently continued to heal, but rather
`slowly, and the dose of minocycline was therefore in-
`creased to 100 mg tds 1 month later. During December
`1987 the perineal lesion resolved. The lesion over the
`temple improved but did not completely heal, and a single
`intralesional injection of triamcinolone was performed in
`February 1988. Three weeks later this lesion had also
`healed, leaving a fragile scar over the temple, which broke
`down occasionally when traumatized. The dose of
`minocycline was gradually reduced, and the drug was
`finally stopped in October 1988.
`
`Case 6
`Mr JB first developed PG in November 1987, aged 62, in
`association with an IgA monoclonal band, which has so
`far behaved in a benign manner. The initial episode
`responded to systemic steroids, but the disease recurred at
`the same site on the left leg 8 months later. On this
`occasion the patient was treated with minocycline 200 mg
`bd. One week after commencing treatment the lesion had
`noticeably reduced in size. It subsequently resolved
`completely over the following 4 weeks, and the dose was
`reduced to 100 mg daily. The patient has remained in
`remission to date.
`
`Case 7
`Mr DG had suffered from rheumatoid disease for 26
`years. He presented in December 1988 at the age of 60,
`with a 1 month history of multiple ulcers over the trunk.
`
`The appearances were typical of PG. The largest lesion, in
`the right inguinal region, measured 18 cm in length by
`8 cm in width at presentation.
`Treatment commenced in hospital with minocycline
`200 mg bd. Healing was clearly evident within 4 days of
`starting treatment, and progressed rapidly, so that at the
`time of discharge, 3 weeks later, all of the ulcers on his
`trunk had healed and the lesion in the right groin had
`reduced in size to 8 cm x 4 cm. On review in outpatients 1
`month later healing had progressed further.
`
`Discussion
`
`The term pyoderma gangrenosum was first used by
`Brunsting, Goeckerman and O’Leary in 1930.14 Under
`this title these authors reported a series of five patients
`suffering from cutaneous ulcers of an unusual and
`distinctive appearance. These were surrounded by a blue
`zone, consisting of an oedematous boggy strip from 5 to
`8 mm wide, in which there developed extensive undermin-
`ing and necrosis of the subcutaneous tissue. Four of these
`patients suffered from ulcerative colitis. In early reports
`the disease was considered to be caused by a variety of
`infections with bacteria or amoebae.” Treatment was
`therefore directed towards eradication of these organisms
`using a variety of measures including antiseptics, vac-
`cines, X-rays, carbon dioxide snow, cautery,14 hyperim-
`mune steptococcic serum,I6 and, when they became
`
`available, ~ulphonamides.’~~l~*‘ However, further inves-
`tigation failed to implicate any consistent association
`with a specific organism,I9 and it was noted that if early
`pustular lesions were sampled, cultures always proved to
`be sterile.’-U
`More significantly, associations were increasingly
`recognized with a number of diseases considered to be
`linked with
`immune dysfunction. These
`included
`rheumatoid
`disease,
`chronic
`active
`hepatitis,
`inflammatory bowel disease, leukaemias, and dys-
`proteinaemias.’ Paradoxically, therefore, the treatment
`approach in general use changed from methods directed
`towards eradicating infection, to the use of systemic
`steroids and immunosuppressants. These proved highly
`effective. I
`The use of systemic steroids and immunosuppressants
`is, of course, associated with significant morbidity and
`mortality,a and the ensuing years have seen a search for
`effective safer alternatives. There has been a return to the
`use of antibiotics and, in particular, minocycline.
`The mechanism of action of these agents in PG remains
`obscure, but it has been suggested that it may be related to
`alterations in neutrophil polyrnorph function. Infiltration
`by neutrophils is a consistent histological feature of PG:‘
`and tetracyclines inhibit the chemotactic responsiveness
`of neutrophils.2J
`Side-effects of minocycline are rarely serious. They
`the face or extremities,
`include pigmentation of
`(especially at high dose),26 exanthematous, urticaria],
`bullous and fixed drug eruptions.” Photosensitive erup-
`tions also occur.” Nausea, vertigo and infections with
`candida albicans may occur.” All tetracyclines are con-
`traindicated in children under the age of 12 as they cause
`staining of the teeth. More seriously, episodes of
`headache and visual disturbance associated with raised
`intracranial pressure have been rep~rted.”.’~ This can also
`occur with tetracycline but appears to be a rare
`
`J Dermatolog Treat Downloaded from informahealthcare.com by National Library of Medicine on 05/28/15
`
`For personal use only.
`
`Exh. 1057
`
`

`
`phenomenon.*' This effect is not dose-related, and is
`reversible on stopping treatment.
`The use of minocycline in PG was first reported by
`Lynch and Bergfeld in 1978," following an initial chance
`observation. They 'reported four cases which responded
`to a dose of 300 mg daily. These were associated in one
`case each with rheumatoid disease, dysproteinaemia and
`ulcerative colitis. Davies and Piper'* described a further
`case, associated with rheumatoid disease, which res-
`ponded to a dose of 100 mg tds. In the French literature a
`single case showing a favourable response was reported
`by Bernard et af."
`In all our cases there was improvement of the PG
`following treatment with minocycline. Several cases also
`showed a marked tendency to relapse when the minocyc-
`line was reduced in dose or stopped. It therefore appears
`highly likely that minocycline is of real value in this
`
`References
`
`MINOCYCLINE IN PYODERMA GANGRENOSUM
`
`25
`
`condition. Furthermore, both in previous reports and in
`our cases, response to minocycline appears to occur
`regardless of disease severity or the coexistence of other
`associated conditions such as paraproteinaemias,
`rheumatoid disease, or ulcerative colitis.
`Our cases bring to a total of 13 the number of cases of
`PG reported to have been treated successfully with
`minocycline. Although the results of the use of minocyc-
`line sound very promising, further studies of the use of
`this treatment are required before it can really be
`established as a first-line modality.
`PG is a difficult disease to investigate and a double-
`blind trial of minocycline against either placebo or
`prednisolone is probably impossible. It might, however,
`be possible to perform an open study of a large group of
`patients on a multi-centre basis.
`
`1. Holt PJA, The current status of pyoderma gangrenosum.
`CIin Exp Dermatol(1979) 4 509- 16.
`2. Lovett GW, Field JP, King LE, Treatment of pyoderma
`gangrenosum with clofazimine. J Tenn Med Assoc (1 98 1 ) 74:
`567-8.
`3. Goldstein F, Krain R, Thornton JJ, Intra-lesional steroid
`therapy of pyoderma gangrenosum. J Clin Gusfroenferol
`(1985) 7: 499-501.
`4. Curley, RK, Macfarlane AW, Vickers CF, Pyoderma
`gangrenosum treated with cyclosporin A. Br J Dermafol
`(1985) 113: 601-4.
`5. Saffouri B, Hom BM, Mertesdorf JM el al, Treatment of
`pyoderma gangrenosum with disodium cromoglycate. Dig
`Dis Sci (1984) 2 9 183-5.
`6. Newell LM, Malkinson FD, Pyoderma gangrenosum.
`Response to cyclophosphamide therapy. Arch Dermafol
`(1983) 119 495-7.
`7. Shopf E, Schulz HJ, Schulz KH, Azathioprine-Behandlung
`der dermatitis ulcerosa (pyoderma gangrenosum). Haufarzf
`(1969) 20: 558-63.
`8. Perry HO, Brunsting LA, Pyoderma gangrenosum. A
`clinical study of nineteen cases. Arch Dermafol (1957) 75:
`380-6.
`9. Lorincz AL, Pearson RW, Sulphapyridine and sulphone
`type drugs in dermatology. Arch Dermafol(1962) 85: 2 - 16.
`10. Clayton R, Feiwel M, Valdimarsson H, Pyoderma gang-
`renosum with cellular immunity deficit treated with plas-
`mapheresis and leucocyte transfusions. Br J Dermatol
`(1976) 95 (SUPPI 14): 67-8.
`1 1. Lynch WS, Bergfeld WF, Pyoderma gangrenosum respon-
`sive to minocycline hydrochloride. Cuiis (1978) 21: 535-8.
`12. Davies MG, and Piper S, Pyoderma gangrenosum: success-
`ful treatment with minocycline. Clin Exp Dermafol(l98 1) 6:
`2 19-23.
`13. Bernard P, Amici JM, Catanzano G et al, Pyoderma
`gangrenosum and vasculitis. Pathogenic discussion apropos
`of three cases. Ann Dermatol Venereol(1987) 114 1229-34.
`14. Brunsting LA, Goeckerman WH, O'Leary PH, Pyodenna
`(echthyma) gangrenosum. Clinical and experimental obser-
`vations in five cases occurring in adults. Arch Dermal and
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`15. Greenbaum SS, Phagedaena geometrica (Brocq). Arch
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`Dermal and Syph (1941) 43: 775-801.
`16. Schmidt HW, Hyperimmune streptococcic serum in the
`treatment of pyoderma gangrenosum associated with
`ulcerative colitis and carcinoma of the colon. Proc Sluff
`Meet Muyo Clinic (1936) 11: 244-7.
`17. Weiner AL. Pyoderma gangrenosum treated with sul-
`phanilamide: case. Arch Dermal and Syph (1940) 41:
`711-17.
`18. Dostrovsky A. Sagher F. Phagedenic ulcer (pyoderma
`gangrenosum). Treatment with sulphapyridine powder and
`moist chamber therapy. Arch Dermal and Syph (1943) 48:
`164-72.
`19. Russell B. Phagedenic and gangrenous ulceration of the
`skin complicating ulcerative colitis. (Phagedaena geomet-
`ricum). Br J Dermaiol(1950) 62: I 14-23.
`20. Van der Sluis 1. Two cases of pyoderma (echthyma)
`gangrenosum associated with an abnormal serum protein
`(B2A paraprorein) - with a review of the literature. Der-
`mafologica ( 1966) 132: 409- 24.
`21. Dantzig PI, Pyoderma gangrenosum. New Engl J Med
`(1975) 292: 47-8.
`22. Stolman LP, Rosenthal D, Yaworskly R el ul. Pyoderma
`gangrenosum and rheumatoid arthritis. Arch Dermufol
`(1975) 3: 1020-3.
`23. Holt PJA, Davies MG, Saunders KC et al, Pyoderma
`gangrenosum - clinical and investigative findings in 15
`patients with special reference to polyarthritis. Medicine
`(1980) 59: 114-33.
`24. Percival GH, Pyoderma gangrenosum: the histology of the
`primary lesion. Br J Dermuiol(1957) 69: 130-6.
`25. Martin RR. Warr G. Yeager H et d. The effects of
`tetracycline on leukotaxis. JInfecf Dis (1974) 129 110-16.
`26. Basler RSW, Minocycline-related hyperpigmentation. Arch
`Dermofol(1985) 121: 606-8.
`27. Nater JP, de Groot AC, Liem DH, Unwanted effects of
`cosmetics and drugs. Elsevier: Oxford, 1985. p. 252-3.
`28. Walters BNJ, Gubbay SS, Tetracycline and benign intrac-
`ranial hypertension. Report of five cases. Br Med J (198 1)
`282: 19.
`29. Lubetzki C, Sansom M, Cohen D et al. Hypertension
`intracrinienne Enigne et minocycline. Rev Neurol (Paris)
`(1988) 144: 218-20.
`
`'
`
`J Dermatolog Treat Downloaded from informahealthcare.com by National Library of Medicine on 05/28/15
`
`For personal use only.
`
`Exh. 1057
`
`

`
`Volume 1
`
`Number 1
`
`June 1989
`
`The
`Journal of
`Dermatological
`Treatment
`
`' {
`
`L 25 '..,9
`. ,·
`
`.
`
`A
`
`010
`
`J !
`
`h
`#
`
`-
`
`Martin Dunitz and
`Macmillan Press
`
`Exh. 1057
`
`

`
`-
`
`The Journal of Dermatological Treatment is
`published by Martin Dunitz Limited and The
`Macmillan Press Ltd,
`Houndmills, Basingstoke,
`Hampshire RG21 2XS, UK.
`Telephone: Basingstoke (0256) 29242
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`
`The Journal of Dermatological Treatment will
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`included on both the topical and systemic
`treatment of skin disease as well as on
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`© The Journal ofDermatological Treatment
`ISSN 0954-6634
`
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`The Journal of Dermatological Treatment
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`Exh. 1057