fHf DA~D. L TllDERQUIA
`•EMO~u.t.MED~ USRrun
`
`THE B R I. Tl S H
`o·F
`DERMATOLOGY
`
`The Official Organ of the Brltish Assoe/ation of Dermatology
`
`Edlted by Dr. P. J. HARE, 85, Harley Street, London W.l ·
`Under the dlrectlon of the Executlve Committee of the Asseclation
`President: Dr. RENWICK VICKERS
`Immediate Past Pres/dent: Dr. CLIFFORD EVANS
`Vlce-Pres/dent: Dr. R. M. B. MacKENNA
`. Hon. Treasurer: Professor J. T. IN GRAM
`Hon. Secretqry: Dr. S. C. GOLD
`Ordinary Members ofthe Comm/ttee:
`Dr. R. i-1. MEARA
`Dr. A. J, ROOK
`Dr:. 0. L. S. SCOTT
`Dr. J. S. PEGUM
`. Dr. E. WADDINGTON
`Dr. E. RITTER
`Hon. Asslstant Editor: Dr. J. R.. SIMPSON
`Regional Editorial Representatlves
`Dr. J. A. MILNE
`Dr. S. T. ANNING.
`Dr. J. M. BEARE .
`Dr. A. J. ROOK
`
`Dr. R. J. CAIRNS
`Dr. M. FEIWEL
`Dr. P. W. HANNAY
`
`VOLUME 78
`·JANUARY-DECEMBER 1966
`
`LONDON
`H .. K. LEWIS & Co. Ltd·.
`1966
`
`Dr. Reddy's Laboratories, Ltd., et al.
`V.
`Galderma Laboratories, lnc.
`IPR2015-__
`Exhibit 1006
`
`Exh. 1006
`
`

`
`649
`
`A·,CLINICAL TRIAL OF TETRACYCLINE IN ROSACEA. *
`I. B. SNEDDO~, M.B. C~.B., F.R.O.P.
`Rupert Hallam Department of Dermatology, Royal Infumary, Sheffield.
`
`THERE must be few diseases which ·cause more emotional. flushing in the
`supporters of the various theories of causation than rosacea. Whatever cause
`suggested, be it achlorhydria (Brown et al.; 1935), emotional guilt (Klaber
`and Wittkower, 1939), alterations in the jejunal mucosa (Watson et al., 1965),
`·or .the humple demodex (Robinson, 1965), .there seem tobe violent supporters
`diametrically opposed views. Yet treatment based on the supposed causes
`.remained, to .put it a,t its most favourable, unreliable. There is, in fact,
`exhaustive study to show the natural history of rosacea. Unheralded by
`fanfares, tetracycline as a method of treatment has come into current use
`the last few years (in fact there is virtually no published work on the subject,
`though David Williams has certainly drawn ·attention .to it). Early claims by
`·eh (Aron-Brunetiere et al., 1951) and Belgian (Thulliez and Gillis, 1954)
`for the efficacy of chloramphenicol .do not appear to have been
`up.
`Many of the spate of dermatological textbooks published in the last two years
`ID6lltil.Oll tetracycline as a significant agent in treatment, and this must reflect
`attitude of dermatologists as a whole, but there has been no statistical support
`this opinion. Perhaps statistics are unnecessary when the treatment is so
`that it obviously works.
`.
`W,e have used tetracyclinein Sheffield in the treatment ofrosacea since 1962
`felt that it was effective, but in order to determine how necessary or how
`~p.is expensive rem~dy w_as, the following trial. was. started. in
`ecember i964 and run for a ye.ar.
`
`INVESTIGATION.
`All new patients with rosacea, and old patients re-attending v;rith a recurrence at
`Infirmary, She.ffield and the Doncaster Gate Hospital, Rotherharn were
`\.mcl!Ucled in the tdal. Cases were accepted whether they were of the erythematous
`papular type, or the more usual pustular form. Since the aim of the trialwas
`evaluate the use of tetraoycline, few investigative procedures were carried out.
`,~..u<:11errto~.LObin estimations were done to exolude anaemia, and a number of the pustules
`·
`cultured to see whether there was a pathogenic organism, but these were
`universally negative.
`On the first attendance patients were given one month's supply of tetracycline
`250 mg. twice daily, or a dummy placebo indistinguishable in appearance, and these
`, were dispensed by the pharmacist according to a random table. No local application
`was presoribed, and the patient ·was instructed to continue washing and the use of
`* Based on a paper read at the Anriual Meeting of the British Association of Dermatology .in
`Oxford, July, 1966,
`·
`.
`
`Exh. 1006
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`

`
`650
`
`I. B. SNEDDON
`
`cosmetics in their accustonied way. No instructions t.o avoid hot d.rinks or
`diet or their·mode of living were given.
`Progress was assessed at 2 weeks and 4 weeks, and the assessment was made
`same physician who had exan:Pned the patient in the first instance. After 4
`all patients were given aotive tetraoycline 250 mg. b.d. and further progress
`fortnightly for another moD;th, and many of the patients followed up for
`At the end of the year there were 85 patients who had been included in
`but 7 of these were not in the final analysis because 2 failed to attend, 2
`continue with tetracycline after two weeks ( one said he was constipated, and
`other had a sore mouth) and 3 patients were found to have incorreot iliagnoses, O).lf,l:;;;5j~i~~iH
`a papular light eruption, one disooid lupus 'erythematosus, and one acne YUlgaris~
`There remained 78, 52 women of average age 47, but with two-thirds in the a .. ~ ~e:)\::~i.%!~'~
`groups 35-55, and 26 men of average age 54, of whom half were over the age of t:::ac, ... '.''1"'"'!.i
`These .figures would support other workers who have fou:nd rosacea is more oornm'on:::.:·~'J.!~g{\1
`in women than men, and tends to affect an earlier age group.
`
`RESULTS.
`At the end of the first month's treatment it was ·considered that ~i::!öö~::~:s•~;~,p1~:3.;,.:·;;;;,Kr:i:·
`improvement as shown by disappearance of pustules, flattening of papules --~·-····", ....... ".
`diminution of erythema, was detectable in 47 and no improvement in 3 ......... ",.,, .. ,,,,., ..... .
`Though the code was not broken until after the end of the trial, and in
`after all .assessments had been made, it is more convenient to consider
`relationship of active and inactive tablets in each of the groups at this ova.•!:',o,;.;·,,
`Thus the results at the end of the first month are shown in Table I.
`· ·::,·s·::·:,,,,,.,,,.,.:,•
`
`TABLE I.-Results at the End of the First Month.
`Result.
`Tetracycline.
`.Placebo.
`Total.
`19
`Improved
`4:7
`28
`Not improved
`23
`8
`31
`36
`78
`4:2
`All
`% improved
`78
`45
`
`Thus although after the first month there was a considerable placebo effect, ·,:·;:: .... ,
`the improvement with tetracycline is statistically significant. The findings are . \::
`· equally significant if the men and women are considered separately.
`In the second phase of the investigation, after all had received ~ctive tetra-.
`cycline, the results can be expressed as shown in Table II.
`
`\.'·
`
`.::;·.,:.:_..
`
`TABLE II.-Results at the End of the Second Month.
`Results.
`Tetracycline.
`Placebo.
`17
`Improved 2nd month
`4
`Not improved
`4:
`2
`Did not complete
`4:
`All
`23
`% iroproved
`74:
`
`8
`50
`
`Again the improvement of 7 4% of those who had not previously
`tetracycline is statistically signifi.cant.
`
`Exh. 1006
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`

`
`A CLINICAL TRIAL OF TETRACYCLINE IN ROSACEA
`
`.651
`
`A review of the 6 who. did not improve revealed that there were 4 women
`&nd 2 men, .all under the age of 50, anxiety appeared a prominent feature, and
`redness rather than pustulation was the main element of the rosacea. One of
`the women was a girl of 17 who afterwards was found to be pregnant and the
`tetracycline rapidly stopped.
`Four patients who had rosacea and keratitis, 3 women and one n:ian, all
`improved steadily after initi~tion into the trial, and were free from rosacea
`&nd keratitis within 8 we~ks. As luck would have it, all had been given t4e
`place bo :first.
`Many of the patients have been followed for periods of over a year, and it has
`been observed that tetracycline has a suppressive effect on rosacea, which may
`soon pass o:ff once it has been discontinued. For instance, one patient did not
`clear on the placebo, cleared in one month on tetracycline, relapsed in two weeks
`&fter tetracyclinewas stopped, cleared again on 250 mg. b.d., relapsedon 250 mg.
`on alternate days, and :finally remained clear on- 250 mg. daily. A nurober of
`other patients have been controlled completely by tetracycline 100 mg. daily
`but if this was stopped the condition recurred.
`An attempt to estimate the relapse rate of those who had discontinued
`treatment and supervision for over six months was made by sending a question-
`. naire to 22 of those who had been clear when last seen. Nineteen replies were
`received, 5· patients were still completely clear, 8 were having slight trouble,
`and 6 reported themselves as bad as ever.
`
`DISOUSSION.
`In this investigation no attempt has been made to determine how tetracycline
`works·, yet the observation of these cases has raised a nurober of queries. There
`is no doubt that tetracycline controls not only pustulation, which one could
`accept might be of bacterial origin, but the liability to flushing and the.
`permanent dilatation of the capillaries also clear in favourable cases.
`I would
`agree with others such as Wittkower and Klaber (1939) that many rosacea
`patients are shy individuals often under great emotional stress, as instanced
`in the following case. A man aged 33 with marked rosacea of 1 year's duration.
`The onset of the rosacea coincided with the discovery that he was sterile, and
`also that the house he rented and ori which he had spent a great deal of time
`and money, was the subject of a demolition order, surely enough frustration and
`feeling of inadequacy to explain the onset of rosacea. Y et within three weeks
`of commencing tetracycline the rosacea had virtually cleared, and was com-
`pletely clear in six weeks. He remained well two months after the tetracycline
`had been discontinued, yet his circumstances were the same.
`It is difficult to avoid a placebo e:ffect in any trial. In a recent report
`(Witkowski and Simons, 1966) on a trial in acne vulgaris where every precaution
`was taken, 23% of patients on the placebo improved. In the present trial
`
`Exh. 1006
`
`

`
`652
`
`I. B. SNEDDON
`
`the. benefit of tetracycline was statistically signifioant and was
`controlling rosacea in 87% of patients. Such improvement was Tn (,, .... 4.-.:.!·
`in two-thirds of a group of patients who had discontinued treatment
`six months. The mechanism of its .bene:ficial action is as yet
`the observation that it oontrols not only pustulation but erythema
`that it is not entirely an antibacterial or antidemodectio e:ffect. Ras it
`action on intestinal absorption ~
`I would like to thank Ronald Ohurch for his help and Professor Knoweldon for his
`in designing the trial and working out the statistios.
`
`REFERENOES •
`.ARoN-BRUNETIERE, R., BoURGEors-G.A.V.A.RDIN', j, and KüHEN, I .. (1951). Bul~. Soc~ fr._qlny,
`Syph., 58, 301.
`.
`BRoWN, W. H., SMITR, M. S. and McLAo.HLAN, A. D. (1935) Brit. J. Derm., 47, 181.
`KLABER, R. and WrTTKOWER, E. (1939) Ibid., 51, 501.
`RoBINSON, T. W. E. (1965) Arch. Derm., 92, 542.
`T.HULLIEz, A. and GrLLis, E. (1954) Archs belges Derm., 10, 302.
`WATSON, W. 0., PATON, E .. and MURRAY, D. (1965) Lancet, ii, 47,
`WrTKOWSKI, J. A. and SrMONS, H. M. (1966) J. Amer med Ass., 196, 397.
`
`·
`
`Exh. 1006