Topical Retinoids in Inflammatory Acne- A Retrospective, Investigator-blinded, Vehicle-controlled,...

7/30/2019 Topical Retinoids in Inflammatory Acne- A Retrospective, Investigator-blinded, Vehicle-controlled, Photographic Ass

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C li n ~ a l T h e ~ a pe u ~ i ~ s ~ V o l u m e 2 7 N u m b e ~ 2 i 2 0 0 5

T op ical R etinoids in Inf lam m atory A cne : A R etrospect ive ,Investigator-Blinded, Vehicle-Controlled, PhotographicAssessmentJ a m e s J . L e y d e n , M D , 1 A l a n S h a l i t a , M D , 2 D i a n e T h i b o u t o t , M D , 3K e n n e t h W a s h e n i k , M D , P h D , 4 a n d G u y W e b s t e r , M D , P h D s1Universi ty of Pennsylvania, P hi ladelphia, Pennsylvania, 2State Univers ity o f Ne w York Dow nstateM edical Center , Brooklyn, New York, 3Mil ton S. He rshey M edical Center , Hershey, Pennsylvania,4New York Univers i ty M edical Center , Ne w York, New York, and Sje~erson M edical College,Philadelphia, PennsylvaniaABSTRACT

B a c k g r o u n d : D e s p i t e p u b l i s h e d d a t a s h o w i n g t h ee f fi c a cy o f t o p i c a l r e t i n o id s i n t r e a t in g i n f l a m m a t o r ya c h e , i n c l i n i c a l p r a c t i c e t o p i c a l r e t i n o i d s t e n d t o b eu s e d m o s t c o m m o n l y f or n o n i n f l a m m a t o r y a ch e .

O b j e c t i v e : T h e g o a l o f t h i s s t u d y w a s t o a s s e s s t h ee f fi c a cy o f t o p i c a l r e ti n o i d s a s m o n o t h e r a p y i n i n f l a m -m a t o r y a c h e.

M e t h o d s : T h i s r e t r o s p e c t i v e , i n v e s t i g a t o r - b l i n d e d ,v e h i c l e - c o n t r o l l e d , p h o t o g r a p h i c a s s e s s m e n t s t u d yw a s c o n d u c t e d b y 5 i n v e s t i g a t o r s . T h e i n v e s t i g a t o r sr a t e d p r e t r e a t m e n t a n d p o s t t r e a t m e n t p h o t o g r a p h so f p a t i e n t s w h o h a d p a r t i c i p a t e d i n 1 2 - o r 1 5 - w e e k ,d o u b l e - b l i n d c o m p a r i s o n s o f t a z a r o t e n e 0 . 1 % g e l,a d a p a l e n e 0 . 1 % g e l, t r e t i n o i n 0 . 1 % m i c r o s p o n g e ,t r e t i n o i n 0 . 0 2 5 % g e l, a n d t a z a r o t e n e 0 . 1 % c r e a m( v e h i c l e ) . A c h e s e v e r i t y w a s r a t e d o n a 7 - p o i n t s c a l e .A p o s t t r e a t m e n t i n c r e a s e o r d e c r e a s e o f 1 g r a d e w a sc o n s i d e r e d c l i n ic a l l y m e a n i n g f u l ; _>2 g r a d e s w a s c o n -s i d e r e d a n e v e n c l e a r e r m e a s u r e o f c l i n i c a l l y s i g n i f i -c a n t i m p r o v e m e n t . I n v e s t i g a t o r s a l s o r a t e d g l o b a lr e s p o n s e t o t r e a t m e n t o n a 7 - p o i n t s c a le . A p o s t t r e a t -m e n t i n c r e a s e o f _>2 g r a d e s w a s c o n s i d e r e d a c l i n i c a l lyr e le v a n t i m p r o v e m e n t .

Results: E a c h o f t h e 5 i n v e s t i g a t o r s r a t e d p h o t o -g r a p h s o f 5 7 7 p at ie n ts ( - 5 2 % w o m e n , - 4 8 % m e n ;m e a n a g e , 1 8 - 2 0 y e a r s ) , f o r a t o t a l o f 2 8 8 5 e v a l u a t i o n s( i n a d d i t i o n t o d a i l y e v a l u a t i o n s o f t h e 2 0 c o n t r o lp a t ie n t s ). T h e t r e a t m e n t g r o u p s c o n s i s t e d o f t a z a r o t e n e(2 5 2 p a t i en t s , 1 2 6 0 ev a lu a t i o n s ) , ad ap a l en e (1 7 8 p a t i en t s ,8 9 0 e v a l u a t i o n s ) , t r e t i n o i n m i c r o s p o n g e ( 4 7 p a t i e n t s ,2 3 5 e v a l u a t i o n s ) , t r e t i n o i n g e l ( 3 9 p a t i e n t s , 1 9 5 e v a l u -a t i o n s ) , a n d v e h i c l e ( 6 1 p a t i e n t s , 3 0 5 e v a l u a t i o n s ) . I n -f l a m m a t o r y a c h e w a s i m p r o v e d w i t h a l l 4 r e t i n o i d sc o m p a r e d w i t h v e h i c l e . I n 1 9 0 5 e v a l u a t i o n s i n w h i c h

p r e t r e a t m e n t a c n e s e v e r i t y w a s g r a d e _ >3 ( m i l d to m o d -e r a t e ) , t h e i n c i d e n c e s o f c l i n i c a ll y s i g n i fi c a n t i m p r o v e -m e n t s i n t h e t a z a r o te n e , a d a p a l e n e , a n d t r e t i n o i n m i c r o -s p o n g e g r o u p s w e r e 2 4 % , 1 7 % , a n d 2 1 % , r e s p e c ti v e ly(a ll , P < 0 .0 0 1 v s v eh i c l e [7 % ] ) . Th e d i f f e r en c e i np r e v a l e n c e o f c l i n i c a l l y s i g n i f i c a n t i m p r o v e m e n t w a ss t a t is t i c a ll y s i m i l a r b e t w e e n t h e t r e t i n o i n g e l a n d v e h i -c l e g r o u p s . T h e i n c i d e n c e s o f c l i n i c a l l y r e l e v a n t i m -p r o v e m e n t i n g lo b a l r e s p o n s e t o t a z a r o te n e , a d a p a l e n e ,t r e t i n o i n m i c r o s p o n g e , a n d t r e t i n o i n g e l w e r e 3 6 % ,3 4 % , 3 1 % , a n d 2 8 % , r e s p e c t i v e ly ( P __ 0 . 0 0 1 , _ _ 0. 00 1 ,_


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acne . ~ The subse quen t d i scovery o f spec i f i c r e t i no i dr e c e p t o r s l e d t o t h e d e v e l o p m e n t o f 2 n e x t - g e n e r a t i o nre t i no i ds , t azaro t e ne and ada pa l ene , wh i ch a l so havebeen sh ow n t o be e f f ec t ive aga i ns t acne . Ret i no i dsc o u n t e r a c t t h e a b n o r m a l d e s q u a m a t i o n p r o c e s s , a n dt he i r u se r esu l t s in s i gn i f ican t r educ t i ons i n non i n f l am-m at o r y l es i on coun t s . 2 -7 Conseq uen t l y , derm at o l og i s t suse t h is c l ass o f d rug p r i m ar i l y i n pa t i en t s w i t h a p re-d o m i n a n c e o f n o n i n f l a m m a t o r y l e si o n s. H o w e v e r ,c l i ni ca l tr i a ls w i t h t op i ca l r e t i no i ds hav e a l so r epo r t eda subs t an t i a l decrease i n i n f l ammat o ry l es i ons , i nd i -ca t i ng t ha t t op i ca l r e t i no i ds a r e benef i c i a l i n bo t hi n f l a m m a t o r y a n d n o n i n f l a m m a t o r y a c n e . 2 -7

Fo l l owi ng the i n t roduct i on o f t azaro t ene an d adapa -l e n e , P h a s e 4 t r i a l s w e r e c o n d u c t e d t o c o m p a r e t h eef f i cacy o f var i ous fo rm ul a t i ons o f t op i ca l r e t ino i ds ,a n d t h e e f f e c ts o f t r e a t m e n t w e r e d o c u m e n t e d p h o t o -graphical ly . In th is ar t icle, we descr ibe the resul t s ofa n e v a l u a t io n o f p h o t o g r a p h s f r o m t h e s e t ri a ls t ode t e rm i ne t he e f f ec t o f t op i ca l r e t i no i ds as mon o t her -a p y f o r i n f l a m m a t o r y a c n e .M A T ER IA L S A N D M E T H O D SC o l l e c t i o n o f P h o t o g r a p h s

P r e t r e a t m e n t a n d p o s t t r e a t m e n t p h o t o g r a p h s o fpa t i en t s wi t h f ac i a l acne vu l gar i s were co l l ec t ed f rom7 Phase 4 , mu l t i cen t er , doub l e-b l i nd , r andomi zed ,para l l e l -g roup t r ia l s c om par i ng t op i ca l r e t i no i ds . 2~ ,7 ,sA l l c o m p l e t e d c o m p a r a t i v e s t ud i e s a v a i la b l e f r o m t h es p o n s o r w e r e i n c l u d e d i n w h i c h b o t h p r e t r e a t m e n ta n d p o s t t r e a t m e n t p h o t o g r a p h s o f e v a l u a b l e p a t ie n t sw e r e a v a i l a b l e . T h e s e s t u d i e s c o m p a r e d t a z a r o t e n e0 .1% ge l , adapa l ene 0 .1% ge l , t r e t i no i n 0 .1% mi -c r o s p o n g e , t r e t i n o i n 0 . 0 2 5 % g e l , a n d t a z a r o t e n e0 .1% cream (veh ic le ). Beca use no pho t og r aph s o fpa t i en t s undergo i ng t r ea t men t wi t h veh i c l e ge l fo r anyof t he r e t i no i d fo rm ul a t i ons were a va i l ab l e ( ie , nonew e r e t a k e n ) , p h o t o g r a p h s o f tr e a t m e n t w i t h v e h ic l ec r e a m ( a s u s e d i n t a z a r o t e n e c r e a m f o r m u l a t i o n s )w e r e u s e d . T h e s e p h o t o g r a p h s w e r e o b t a i n e d f r o mp i v o t a l t r i a l s c o m p a r i n g t a z a r o t e n e 0 . 1 % c r e a m w i t hveh i c l e c r eam. The met hodo l og i c de t a i l s o f a l l t r i a l swere pub l i shed p rev i ous l y .2~ ,7 ,8 M ed i ca t i ons wereapp l i ed once da i l y fo r 12 o r 15 weeks , excep t fo ra l t e rna t e -da y dos i ng o f t azaro t en e i n one t r ia l , s

A l l p h o t o g r a p h s w e r e t a k e n u s i n g a s t a n d a r d i z e dp r o t o c o l p r e s c r i b e d b y C a n f i e l d S c i e n t i f i c , I n c . ,Fa i r f i e l d , New Jer sey ( i nc l ud i ng use o f a s t e r eo t ac t i cd e v i ce to p o s i t i o n t he h e a d a n d a s t a n d a r d iz e d c a m e r a

sys t em wi t h a ca l i b ra t ed l ens se t fo r a f i xed r ep roduc-t i on r a t i o ) . Pho t og rap hs o f a ll pa t ien t s i n t he t ri a l swere i nc l uded fo r eva l ua t i on i n t h i s s t udy , p rov i dedt ha t a compl e t e se t o f r i gh t , f ron t , and l e f t v i ew pho-t o g r a p h s w e r e a v a il a b le b o t h b e f o r e t re a t m e n t ( w e e k0) and a f t e r t r ea t men t (week 12 o r 15 ) . A l l Phase 4s t ud i es were ap p rov ed by t he in s t i t u t i ona l r ev i ewb o a r d a t e a c h s t u d y s i te .D i s p la y o f P h o t o g r a p h s

Pho t og raphs were d i sp l ayed i n s l i de fo rm i n abl inded fashion to each of 5 invest igators in 3 sessionsover 3 consecu t i ve days . No d i scuss i on was a l l owedbet ween i nves t i ga t o r s wh i l e t he pho t og raphs werebe i ng d i sp l ayed . Fo r each pa t i en t , t he d i sp l ay con -s i s t ed o f 6 pho t og raphs shown s i mu l t aneous l y : r i gh t ,f ron t , and l e f t v i ews befo re and a f t e r t r ea t men t .

T h e s e ri e s o f c o n t r o l p h o t o g r a p h s w a s d i s p l a y e d3 t i mes , once each day , t o a l l ow assessmen t o f i n t r a -i nves t i ga t o r and i n t e r i nves t i ga t o r g rad i ng p rec i s i on .R a n d o m i z a t i o n

Pho t og raphs o f each pa t i en t were p resen t ed i n ar andom i zed f ash i on , r egard less o f t r ea t men t g roup ,acco rd i ng t o a compu t er -genera t ed r andomi za t i on code .The i den t i f i ca t i on codes were kep t a t a l oca t i on sepa-r a t e f rom t he s t udy s i t e . To r educe t he po t en t i a l fo rbias , the s l ides were loaded in to carousels and project -ed by s taf f f rom Canf ield Scienti fic , Inc. N o pat ient -i den t i f i ca t i on codes appeared on t he pho t og raphs ;i nves t i ga t o r s i den t i f i ed pho t og raphs by t he carouse lnumber and s l i de number wi t h i n t ha t carouse l .A s s e s s m e n t o f P h o t og r a p h s

Each i nves t i ga t o r assessed t he overa l l sever i t y o fe a c h p a t i e n t ' s i n f l a m m a t o r y a c n e b e f o r e a n d a f t e rt r e a t m e n t a n d g l o b a l r e s p o n s e t o t r e a t m e n t . O v e r a l lacne sever i t y was assessed us i ng a mod i f i ed ver s i on o fa sca l e pub l i she d by A l l en and Smi t h 9 (~ab l e i 9 ). Th i sassessmen t r a t es sever i t y on a 7 -po i n t sca l e (g rade 0 =no acne , t o g rade 6 = severe acne) . The pane l cons i d -e r e d a 1 - g r a d e i m p r o v e m e n t o r d e t e r i o r a t i o n o n t h i ssca l e t o be c l i n i c a l l y m e a n i n g f u l . In add i t i on , an i m-p r o v e m e n t o r d e t e r i o r a t i o n o f > 2 g ra d e s w a s c o n -s i dered c l e a r l y c l i n i c a l l y s ig n i f i c a n t ( ~igure 1).

G l o b a l r e s p o n s e t o t r e a t m e n t w a s a s s e s s e d u s i n g a7 -po i n t sca l e (Tab l e i i ) i n wh i ch r esponses r angedf rom a c l i n i ca l l y r e l evan t worsen i ng i n i n f l ammat o ryl es i ons (g rade -2 ) t o c l ear / near l y c l ear (g rade +4) . A


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C li n i~a l ~er a p e U~ i C S

Table I . Overal l inf lamm atory acne severity scale. Reproduced w ith permission. 9Grade Descripcion Def3nicion0 None Clear, no inflam maco ry lesionsI * Only an occasio nal small inflammaE ory lesion2 Mi ld Few scaEEered smal l infla mma Eory lesions, wiEh mild eryEhema presenE on less Ehan ha lf

oFEhe Face3 * Moderace numb er oF inflam mac ory lesions over a wide area oFche Face, wk h increasing

eryt:hema4 Mod erate Mode rate numb er oF inf lam mat ory lesions, some large, over a wide area oFche Face,

wich increasing erychema5 * Papules and pust:ules wit:h larger infl ame d lesions over muc h oFt:he Face, wit:h

pronounced eryt:hema6 Severe Large papule s and pust:ules wit:h pro nou nce d eryt:hema invo lvin g most: oFt:he Face Grades 1, 3, and 5 were used to designate intermediate evaluations.

:Zii

C : :~ . . . . . . ! i i ii l

iiiN

: i!l#

D

Figure 1. Varyin g acne severities before and after 12 or 15 weeks oFtrea tme nt wit h a retinoid: A-C ; Typical pre-sentat ions oF pretreatm ent acne severity grade 5 ( leFt panels), with cl inical im provem ent to grade 3(r ight panels). D: Typical presentat ion oF pretreatm ent acne grade 4 ( leFt panel), with cl inical improv e-ment to grade 3 (r ight panel). Mean overal l inf lam mato ry acne severity scores among investigators: A,4.8; B, 4.4; C, 5.6; D, 4.0 (see Table I For overall in fla mm ato ry acne severity scale). (A, Cou rtesy oF ZoeDraelos, MD; B, Courtesy oF Emil Tanghecd, MD; C, Courtesy oFYves Poul in, M D.)


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Tab le I I . Global response to t r e a tme nt scale.Grade Desc r ip t ion De f in i t i on

4 Very s ign i f i can t improvemen t , w i th few in f l amm ato ry l es ions rema in ing excep tfor residual macular erythema

3 S ign i f i can t improvemen t , some in f l amm ato ry l es ions rema in

I0

- I-2

Clear /nearly clearM a r k e di m p r o v e m e n tCl in ica l ly re levanti m p r o v e m e n tS l i gh t improvemen tN o i m p r o v e m e n tS l i gh t de te r i o ra t ionCl in ica l ly re levantdecer io ra t io n

Improvemen t be tween marked and s l i gh tSome improvemen t , b u t s ign i f ican t i n f l amm ato ry l esions rema inNo detectable change from preCreaCmenCSome worsening, w i th a def in i te increase in in f lammatory les ionsS ign i f i can t worsen ing , w i th numerous add i t i ona l i n f l am ma to ry l es ions

pos t t re a tm en t increa se o f _>2 g rades w as co ns idered ac l i n i ca l l y re l evan t i mprovemen t . ( ie, grad e _>2; T ab le i i ) o n th is scale wer e also ana-lyzed using the P _ 0 .01 level .S t a t i s t ic a l A n a l y s i sA s s e s s m e n t o f n t r a in v e s t i g a to r C o n s i s te n c y

U n p a i r e d t t e st s w e re u s e d t o c o m p a re i n v e s t ig a t o rr a t i n g s o f t h e c o n t ro l p h o t o g ra p h s o n e a c h o f t h e 3eva luat io n da ys. ~ Th e te s t for s tat is t ical s ignificancewas set at P < 0 .05. SAS vers io n 8 .02 (SAS Inst i tu teInc . , Cary , No r th Caro l ina) w as used fo r a l l s ta t i s ti ca lana lyses .A s s e s s m e n t o f n t e r in v e s t i g a to r C o n s i s te n c yCorre la t ion ana lys is ( the Pearson c o rre la t ion coeff i -c ien t ) was used to de te rm ine cons i s tency o f ra tings byeach inves t iga to r over the 3 -day pe r io d ) Spec if ica lly,t h e p r e t r e a t m e n t d a i l y r a t i n g s o f t h e c o n t ro l p h o t o -g ra p h s m a d e b y e a c h i n v e s t i g a t o r w e re a n a l y z e d fo rco rre la t ion .

R E S U L T SP h o t o g r a p h s

Ea c h o f t h e 5 i n v e s t i g a t o r s r a t e d p h o t o g ra p h s o f5 7 7 pa t ie n ts ( - 5 2 % w o m e n , - 4 8 % m e n ; m e a n a ge ,18 -20 years ) , fo r a to ta l o f 2885 ev a lua t ions ( in add i -t ion to da i ly eva lua t ions o f the 20 con t ro l pa t i en t s ).Th e t r e a t m e n t g ro u p s c o n s i s t e d o f t a z a ro t e n e (252pat ien t s , 1260 eva lua t ions ) , adapa lene (178 pa t ien t s ,890 eva lua t ions ) , t re t ino in microsponge (47 pa t i en t s ,235 eva lua t ions ) , t re t ino in ge l (39 pa t i en t s , 195 eva l -ua t ions ) , and veh ic le (61 pa t i en t s , 305 eva lua t ions ) .I n t r a i n v e s t i g a t o r C o n s i s t e n c y

N o s i g n i f i c a n t d a y - t o -d a y d i f f e r e n c e s w e re fo u n dbetween each inves t iga to r ' s ra t ings o f the con t ro lp h o t o g ra p h s .

T r e at m e n t E f f e ctTh e s t u d y w a s p o w e re d to 9 5 % t o d e t e c t a 1 -g r a d e

d i f f e r e n c e i n i n f l a m m a t o ry a c n e s c o re . B e t w e e n -g ro u p d i f fe r e n c e s i n t h e p ro p o r t i o n o f e v a l u a t io n si n d i c a t i n g a n i m p ro v e m e n t o f 1 o r > 2 g r a d e s o r adec l ine o f 1 g rade in overa l l acne sever i ty sco re wereana lyz ed us ing the ch i -square t es t . ~ To c on t r o l fo rm u l t i p l e b e t w e e n -g ro u p c o m p a r i s o n s , a s t r i n g e n tleve l fo r s t a t i s t i ca l s ign i f i cance (P < 0 .01 ) was se ta c c o rd i n g t o t h e B o n fe r ro n i a d j u s t m e n t . B e t w e e n -g ro u p d i f fe r e n c e s i n t h e p ro p o r t i o n o f e v a l u a t io n sind ica t ing a t l eas t a c l in ica l ly re levan t imp rov em en t

I n t e r i n v e s t i g a t o r C o n s i s t e n c yCorre la t ion coeff ic ien t s be tw een pa i rs o f inves tiga-

to rs ranged f rom 0 .648 to 1 .000 (Tab le ii i ) .T r e a t m e n t E f f e c tC h a n g e n O v e r a l l In f l am m a t o r y A c n e S e v e r i t y

The p ropor t ions o f eva lua t ions showing c l in ica limproveme n t wi th each re t ino id a re shown in } igu res 2and 3 and Ta ble i~ . Across 2 clin ical mea sures (clin i-cal ly meaningful improvement and cl in ical ly s ignifi -can t im provemen t ) , top ica l re t ino id therapy resu l ted inc l in ica l ly and s ta t i s t i ca l ly s ign i f i can t ly g rea te r im-


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C l i n #a l ~ e ~ a p e u i c s

Table I I I. P ears on 's correlat ion coeff icien ts be twe en pa i rs o f invest igators .*I n v e s r i g a r o r N o .I n v e s r i g a r o r ....................................................................................................................................................................................................................

N o . I 2 3 4 51 1 . 0 0 0 0 . 7 1 4 0 . 8 3 6 0 . 8 2 4 0 . 7 0 92 0 . 7 1 4 1 . 0 0 0 0 . 7 8 0 0 . 7 0 3 0 . 6 4 83 0 . 8 3 6 0 . 7 8 0 1 . 0 0 0 0 . 7 8 5 0 . 7 0 84 0 . 8 2 4 0 . 7 0 3 0 . 7 8 5 1 . 0 0 0 0 . 6 6 15 0 . 7 0 9 0 . 6 4 8 0 . 7 0 8 0 . 6 6 1 1 . 0 0 0* S ix t y o b s e r v a t i o n s w e r e u s e d i n t h e s e c o m p u t a t i o n s ( p h o t o g r a p h s o f 2 0 p a t i e n t s w e r e a s s e s s e d o n e a c h o f "

3 c o n s e c u t i v e d a y s ) .

p r o v e m e n t s i n a c n e s e v e r i t y c o m p a r e d w i t h v e h i c l e .Ov era l l , 46% (1 1 7 8 /2 5 7 6 ) o f ev a lu a t i o n s o f t h e t o p i ca lr e t i n o i d g r o u p s s h o w e d c l i n i c a l l y m e a n i n g f u l i m -p r o v e m e n t in a c h e s e v e ri ty c o m p a r e d w i t h 2 8 % ( 8 5 /3 0 5 )o f t h e v eh i c l e g ro u p (P _< 0 .0 0 1 ) . T h e p e rcen t ag es o f ev a l-u a t i o n s s h o w i n g c l i n i c a l l y m e a n i n g f u l i m p r o v e m e n t i nach e sev er i t y i n each r e t i n o id g r o u p w ere g rea t e r r e l a t i v eto the vehicle gro up (al l, P _< 0 .001) ( ~ igure 2A).

O v e r a l l, 1 4 % ( 3 6 9 / 2 5 8 0 ) o f e v a l u a t i o n s s h o w e dc l i n ic a l l y s i g n i f i c a n t i m p r o v e m e n t i n a c h e s e v e r i t yw i t h a t o p i c a l r e t i n o i d c o m p a r e d w i t h 5 % ( 1 6 / 3 0 5 )w i t h v e h i c l e ( P _ 0 . 0 0 1 ) . T h e i n c i d e n c e o f c l i n i c a l l ys i g n if i c a n t i m p r o v e m e n t w a s h i g h e r i n th e t a z a r o t e n e ,a d a p a l e n e , a n d t r e t i n o i n m i c r o s p o n g e g r o u p s c o r n -

p a r e d w i t h t h e v e h i c l e g r o u p ( P _ 0 . 0 0 1 , _ __ 0.0 1, a n d___0.001 , resp ect iv ely) ( ~ igure 2]~ ) . Th is d i f fe ren ce w asm o s t p r o n o u n c e d i n t h e t a z a r o t e n e a n d t r e t i n o i nm i c r o s p o n g e g r o u ps , w h i c h s h o w e d a - 3 - f o l d h i g h e ri n c i d e n c e o f c l i n i c a l l y s i g n i f i c a n t i m p r o v e m e n t c o m -p a r e d w i t h t h e v e h i c l e g r o u p . B e t w e e n - r e t i n o i d c o m -p a r i s o n s s h o w e d s i g n if i c a nt l y g r e a t e r i n c i d e n c e s o fc l i n i c a l l y s i g n i f i c a n t i m p r o v e m e n t i n t h e t a z a r o t e n eg r o u p c o m p a r e d w i t h t h e g r o u p s r e c ei v in g a d a p a l e n e( P _ 0 . 0 0 1 ) o r t r e t i n o i n g e l ( P _ 0 . 0 1 ) .Gl obal Response

O n g l o b a l r e s p o n s e t o t r e a t m e n t , o v e r a l l , 3 4 %( 8 8 4 / 2 5 8 0 ) o f e v a l u a t i o n s o f r e t i n o i d - t r e a t e d p a t i e n t s

A B 30

60

.o 40 - or~ r~> >k u k u2 0 -

0 - Tazarotene Adapalene Tretinoin Tretinoin Ve hicle0 . 1% g e l 0 . 1 % g e l 0 . 1 % M S 0. 0 25 % g e i ( n = 3 0 5 )( n = 1 26 0 ) ( n = 8 8 6 ) ( n = 2 3 5 ) ( n = 1 9 5 )Tazarotene Adapalene Tretinoin Tretinoin Ve hicle0 . 1% g e l 0 . 1 % g e l 0 . 1 % M S 0 .0 2 5 % g e i ( n = 3 0 5 )( n = 1 26 0 ) ( n = 8 9 0 ) ( n = 2 3 5 ) ( n = 1 9 5 )

F i g u re 2 . E v a l u a t i o n s s h o w i n g c l i n ic a l l y m e a n i n g f u l ( A ) o r c l i n ic a l l y s i g n i f i c a n t ( B ) i m p r o v e m e n t i n a cn e s e v e r it ya f t e r 1 2 o r I S w e e k s o f t r e a t m e n t w i t h a r e t in o i d o r ve h i c le . M S = m i c r o s p o n g e . *P


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A B3 0 1 * ~

2 0 -Or~

> 1 0 -

0 -

Or~r~>ii i

Tazarotene Adapalene Tretinoin Tretinoin Vehicle Tazarotene Adapalene Tretinoin Tretinoin Vehicle0 .q%gel 0 .q% gel 0 .1%M5 0 .025%gel (n=230 ) 0 .q%gel 0 .q%g el 0 .1%M5 0 .025%gel (n=11 5)( n =8 2 1 ) ( n =5 6 6 ) ( n = 1 6 1 ) ( n = 1 2 7 ) ( n =3 8 3 ) ( n =2 4 1 ) ( n = 7 2 ) ( n = 6 6 )F i g u r e 3 . R e l a t i o n s h i p b e t w e e n p r e t r e a t m e n t a c n e s e v e r it y a n d c l in ic al i m p r o v e m e n t a f t e r 1 2 o r 1 5 w e e k s o f t r e a t -

m e n t w i t h a r e t in o i d o r v e h i cl e . E v a l u a t i o n s o f p r e t r e a t m e n t a c n e s e v e r i ty g r a d e s > 3 ( A ) a n d > 4 ( B )s h o w i n g c l i n ic a ll y s i g n i f i c a n t i m p r o v e m e n t . M S = m i c r o s p o n g e . * P < 0 . 0 0 1 v e r s u s v e h ic l e; * P < 0 . 0 0 1 v e r -s u s a d a p a l e n e 0 . 1 % g el ; * P < 0 .0 1 v e r s u s t r e t in o i n 0 . 0 2 5 % g e l; P < 0 .0 0 1 v e r s u s t r e t in o i n 0 . 0 2 5 % g e l.

s h o w e d a t l e a s t a c l i n i c a l l y r e l e v a n t i m p r o v e m e n t ( T a b l ei i ) c o m p a r e d w i t h 1 7 % (51/305) o f v e h i c l e e v a l u a t i o n s( P < 0 . 0 0 1 ) . T h e i n c i d e n c e s o f c l i n i c a l l y r e l e v a n ti m p r o v e m e n t w e r e s i g n i f i c a n t l y h i g h e r i n t h e t a z a r o -t e n e ( 3 6 % ) , a d a p a l e n e ( 3 4 % ) , t r e t i n o i n m i c r o s p o n g e( 3 1 % ) , a n d t r e ti n o i n g e l ( 2 8 % ) g r o u p s c o m p a r e d w i t ht h e v e h i c le g r o u p ( P < 0 . 0 0 1 , < 0 . 0 0 1 , < 0 . 0 0 1 , a n d< 0 . 0 1 , r e s p e c t iv e l y ) ( T a b l e i ~ .D e t e r i o r a t i o n

T h e n u m b e r o f e v a l u a t i o n s s h o w i n g s l ig h t d e t e r i o -r a t i o n i n a c n e s e v e r i t y w a s s m a l l a n d w a s n o t s ig -

n i f i c a n t l y d i f f e r e n t b e t w e e n t h e r e t i n o i d a n d v e -h ic le g r o u p s - - 1 3 % ( 3 2 4 / 2 5 8 0 ) ve r s us 1 7 % (51/305)( } i g u r e 4 ) .R e l a t i o n s h i p B e t w e e n P r e t r e a t m e n t A c n eS e v e r i t y a n d C l i n i c a l I m p r o v e m e n tO v e r a l l In f l a m m a t o r y A c n e S e v e r i ty

C l i n ic a l i m p r o v e m e n t i n c r e a s e d a s p r e t r e a t m e n ta c n e s e v e r i t y i n c r e a s e d ( } i g ur e 3 ). O f e v a l u a t i o n s w i t hp r e t r e a t m e n t a c n e s e v e r i ty g r a d e > 3 ( T a b l e i ), 2 0 %( 3 4 3 / 1 6 7 5 ) s h o w e d c li n ic a l ly s i g n i fi c a n t i m p r o v e m e n tw i t h a t o p i c al r e ti n o id , c o m p a r e d w i t h 7 % ( 1 6 / 2 3 0 )

T a b l e IV . E v a l u a t i o n s s h o w i n g a t l e a s t a c l in i c a l ly r e l e v a n t i m p r o v e m e n t ( > 2 g r a d e s ) o n t h e g l o b a l r e s p o n s e tot r e a t m e n t s c a l e .

P r e t r e a t m e n t A c n e S e v e r i t y G r a d e *T r e a t m e n t > 3 > 4 > 5 A l l E v a l u a t i o n sT a z a r o t e n e 0 . 1% g e lA d a p a l e n e 0 . 1% g elT r e t i n o i n 0 . 1 % m i c r o s p o n g eT r e t i n o i n 0 . 0 2 5 % g e lV e h i c l e

3 7 9 / 8 2 1 ( 4 6 % ) * *2 3 8 / 5 6 6 ( 4 2 % ) *6 0 / 1 6 1 ( 3 7 % ) *4 2 / 1 2 7 ( 3 3 % )

4 7 / 2 3 0 ( 2 0 % )

224/383 (58%)**141/241 (59%)**36/72 (50%)25/66 (38%)32/115 (28%)

82/114 (72%)*44/60 (73%)*15/18 (83%)*6/21 (29%)9/28 (32%)

456/1260 (36%)*301/890 (34%)*73/235 (31%)*54/195 (28%)51/305 (17%)

* S e e T a b l e I f o r o v e r a ll i n f l a m m a t o r y a c n e s e v er it y s c a le .fP _< 0 .0 0 1 ve r su s ve h i c l e .S P _< 0 .0 1 ve r su s t r e t i n o i n 0 .0 2 5 % g e l .P _< 0 .01 versus v eh ic le .


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C l i n ~ ~ e r a p e u i c s

Tazaro tene Adapa lene Tre t ino in Tre t in o in0 .1% g e l 0 .1 % e l 0 .1 % MS 0 .025% ge l Veh ic le

0

0~ 1 0r~_=r~>u J

20

Figure 4. Evaluations s h o w i n g s l i g h t d e t e r i o r a t i o n i n a c n e s e v e r i t y af te r 12 o r 15 weeks o f t rea tme n t wi th ar e t i n o i d o r v e h i c l e . All evaluations a r e i n c l u d e d r e g a r d l e s s o f p r e t r e a t m e n t a c n e s e v e ri ty . MS =m i c r o s p o n g e .

with veh ic le (P < 0 .001) . The inc idences o f c l in ica l lys ign i f ican t impr ovem en t we re s ta t is t i ca lly s ign i f ican tlyh i g h e r i n t h e t a z a ro t e n e (2 4 % ) , a d a p a l e n e (1 7 % ) ,a n d t r e t i n o i n m i c ro s p o n g e (2 1 % ) g ro u p s c o m p a re dwi th the veh ic le g roup (a ll , P < 0 .001) (} igu re 3A) .Betw een-re t ino id com par i sons sho we d a sign i f ican tlyg rea te r f requency o f c l in ica l ly s ign i f ican t improve-m e n t i n t h e t a z a ro t e n e g ro u p c o m p a re d w i t h t h e a d a p a -lene and t re t ino in ge l g roups (P < 0 .001 and -4 (mo dera te sever i ty ) (Tab le i) , 33 % (248 /762)s h o we d c l i n i c a l l y s i g n i f i c a n t i m p ro v e m e n t w i t h at o p i ca l r e t in o i d c o m p a re d w i t h 1 0 % (1 1 /1 1 5 ) w i t hvehicle (P < 0 .001). Th e inc idenc e of cl in ical ly s ignifi-c a n t i m p ro v e m e n t wa s -3 - t o 4 - fo l d g re a t e r in t h et a z a ro t e n e , a d a p a l e n e , a n d t r e t i n o i n m i c ro s p o n g egroups compared wi th the veh ic le g roup (a l l , P -5 befo re t rea tm en t , 5 2% (110 /213)show ed c l in ica lly s ign i f ican t imp rove me n t wi th a top -ica l re t ino id , compared wi th 14% (4 /28) wi th veh ic le(P < 0 .001) . There were too few pa t ien t s wi th p re-t rea tmen t acne sever i ty g rade > -5 to make be tween-r e t i n o id c o m p a r i s o n s .

Gl obal ResponseThis increasing prevalence of cl in ical improvement

with increasing pretreatm ent ache severi ty was paral leledin eva lua tions o f g loba l response to t rea tme n t l i ab le i ~ .The greatest d ifference in the prop ort ion of evaluat ionsof ret inoid-treated pat ients versus vehicle pat ients sh ow-ing cl in ical ly relevant impr ovem ent was in pat ients w ithpretreatment acne severi ty grade >_5 (69% [147/213]vs 32% [9/28]; P < 0.001), followed by grade >-4 (56%[426/762] vs 28% [32/115]; P < 0 .001) and grade>-3 (43% [719/1675] vs 20% [47/230]; P < 0.001).Betwe en-ret inoid comp arisons show ed a s ignificantlygreater frequ ency of cl in ical ly relevant imp rovem ent onthe global response to t reatment scale in the tazarotenegroup com pared wi th the t re t ino in ge l g roup in pa t ien t swith pretre atme nt acne severity grade >-3 (P < 0 .01). Inpat ients w ith g rade >-4 ache be fore t reatm ent , a s ignifi-cantly greater frequency of cl in ical ly relevant improve-ment on the global response to t reatment scale wasfound in the tazarotene and adapalene groups versusthe t ret inoin gel group (P < 0 .01). There were toofew pa t ients with pretre atm ent acne severi ty grad e >-5 tomak e such be tween-re t ino id compar i sons .D I S C U S S I O NT h i s r e t ro s p e c t iv e a s s e s s m e n t o f p h o t o g ra p h i c d o c u -men ta t ion f rom c l in ica l t r i a l s sugges t s tha t mono ther-apy w i th top ica l re t ino ids ma y p rov ide c l in ica l benef i ti n t h e i n f l a m m a t o r y p h a se o f a c n e . T h e i n v e s t ig a t o rra t ings in th i s s tudy showed in t ra inves t iga to r and i n -


8/9

t e r inves t iga to r cons i s tency .11 Using a s tringent cri te-r i o n o f a n i m p ro v e m e n t in i n f l a m m a t o ry a c n e s e ve r it y_>2 grade s, cl in ical ly s ignificant im pro ve m ent was seenwi th 3 o f the 4 re t ino ids s tud ied . In add i t ion , top ica lr e t i n o id t h e ra p y w a s n o t a s s o c ia t e d w i t h wo r s e n i n g o fi n f l a m m a t o ry a c n e a f t er 1 2 o r 1 5 we e k s o f t h era p y .

Of in te res t , the percen tage o f eva lua t ions showingcl in ica l ly re levan t improve me n t was h igher in the m oresevere cases , perhaps because the eva lua t ions wi thl e ss e r g ra d e s o f i n f l a m m a t o ry a c n e h a d l es s ro o m fo ri m p ro v e m e n t t h a n t h o s e w i t h m o re s e v e re g r a d e s . T h en u m b e r o f p a t ie n t s w i t h s e v e re a c n e b e fo re t r e a t m e n twas smal l (n = 29 ) ; therefo re , conc lus ions regard ingth i s g roup o f pa t ien t s cou ld no t be made .

Between-re t ino id compar i sons ind ica ted tha t theg rea tes t e f f icacy occurred on the overa l l in f lamm ato ryacne sever i ty and g loba l response sca les w i th t azaro tene0.1% gel, whic h show ed stat is t ically and cl in ical ly s ig-n i f ican t improvemen t over veh ic le fo r a l l measures o fcl in ical improvement as well as s tat is t ical ly and cl in i-ca l ly sign if ican t impro vem en t re la tive to adapa lene andtret inoin gel on measures of acne severi ty . However, ahead- to -h ead tr i a l compar ing a l l 4 t rea tmen ts wou ld berequ i red to de te rmine the re la tive e f f icacy o f these ther-ap ies in t rea t ing in f lam mato ry acne .

Th is ph o tograp h ic assessmen t s tudy i s l imi ted by i tsre t rospec t ive des ign . How ever , the resu l t s a re in ag ree-men t wi th pub l i shed da ta f rom c l in ica l t r i a l s in wh icht h e i n f l a m m a t o ry p h a se o f a c n e wa s s h o w n t o b e i m -proved wi th re t ino id t rea tm en t . 2 -6 The conce rn i s tha ttop ica l re t ino ids migh t in tens i fy in f lammat ion and bed i f f icu l t to use in pa t ien t s wi th in f lammato ry acne .Th is con cern was no t ev iden t in these ana lyses : c l in ica lde te r io ra t ion was seen in 12% to 14% of pa t ien t scom pare d wi th 17% rece iv ing veh icle . How ever , anyi r r i t a t ion in the ear ly phase o f these stud ies wo u ld no thave been seen in these pho togra phs , w h ich were t akenbefo re and a f te r 12 o r 15 weeks o f t rea tm en t .

The po ten t ia l c l in ica l benef i t o f re t ino id t rea tmen ti n t h e i n f l a m m a t o ry p h a se o f a c n e m a y b e t h e r e s u lto f the an t i - in f lam ma to ry e f fec t o f th i s d rug c lass . ~2qsIn vi tro ~3 and anim al ~2 s tudies suggest th at ret inoid sm a y h a v e i n h e re n t " a n t i - i n f l a m m a t o ry a ct i v it y " a n da p p e a r t o i n h i b i t t h e r e l e a s e o f p ro i n f l a m m a t o ryc y t o k i n e s t h ro u g h d o wn - re g u l a t i o n o f t h e e x p re s s io nof to l l - l ike recep to rs on monocy tes .TM Ac t i v a t i o n o fthese recep to rs , l ead ing to a t r igger ing o f in f lam-ma to ry cy to k ine responses , is be l ieved to be a m echa-n ism b y wh ich bac te r ia can in i t i a te in f lamm at ion . ~s

Pep t idog lycans in the ce l l wal l s o f Prop i on i ba c t e r i umacnes appear to ac t iva te to l l - l ike recep to r 2 on mono-cy tes , resu l t ing in the re lease o f p ro in f lammato rycy tok ines , inc lud ing in te r leuk ins 1 , 8 , and 12 andtumor necrosis factor-~.~4,~5 By dow n-re gula t ing theexpress ion o f these to l l - l ike recep to rs , re t ino ids mayre d u c e t h e r e l e a se o f p ro i n f l a m m a t o ry c y t o k in e s a n du l t i m a t e l y r e d u c e t h e i n f l a m m a t o ry c o m p o n e n t o facne .C O N C L U S I O N SThe resu l t s o f th i s s tudy sugges t tha t top ica l re t ino idt h e ra p y h a s b e n e f i t i n i n f l a m m a t o ry a c n e wh e n u s e da s m o n o t h e ra p y . A l t h o u g h t o p i c a l r e t i n o i d s o f f e rpo ten t ia l e f f icacy aga ins t in f la mm ato ry acne les ions ,these resu l t s do no t ind ica te tha t t rea tmen t shou ldcons i s t o f re t ino id therapy a lone .A C K N O W L E D G M E N T SThis s tudy was suppor ted by Al le rgan , Inc . , I rv ine ,Cal i fo rn ia .

We thank Gi l l Shears , PhD, fo r her ed i to r ia l as s i s -t a n c e i n t h e d e v e l o p m e n t o f th e m a n u s c r i p t .

Dr . Leyden has se rved as a consu l ta n t and p ar t i c i -pa ted in adv iso ry boards and c l in ica l t r ia l s , fo r Or t hoDe rm a t o l o g i c a l (R a r i t a n , Ne w J e r s e y ) , Ga l d e rm aLabora to r ies , L .P . (For t W orth , Texas ) , Al le rgan , Inc . ,Dermik Labora to r ies , Inc . (Berwyn , Pennsy lvan ia) ,a n d M e d i c i s P h a rm a c e u t i c a l C o rp o ra t i o n (S c o tt sd a l e,Ar izona) . Dr . Sha l i t a has se rved as a consu l tan t andpar t i c ipa ted in adv iso ry boards and c l in ica l t r i a l s fo rOr t h o De rm a t o l o g i c a l , Ga l d e rm a L a b o ra t o r i e s , L .P . ,Al le rgan , Inc . , Dermik Labora to r ies , Inc . , Med ic i sPharmaceu t ica l Corpora t ion , and S t ie fe l Labora to r ies ,Inc . (Cora l Gab les , F lo r ida) . Dr . Th ibou to t has par-t i c ipa ted in adv iso ry boards and c l in ica l t r i a l s fo rGalderma Labora to r ies , L .P . , Al le rgan , Inc . , andDermik Labora to r ies , Inc . Dr . Washen ik has se rveda s a c o n s u l t a n t a n d s p e a k e r a n d p a r t i c i p a t e d i n a d -v i so ry boards and c l in ica l t r i a l s fo r Al le rgan , Inc . ,M e d i c i s P h a r m a c e u t i c a l C o r p o r a t i o n , C o l l a G e n e xPharm aceu t ica l s Inc . (Newto wn , Pennsy lvan ia) , W yethP h a rm a c e u t i c a l s (M a d i s o n , Ne w J e r s e y ) , a n d M e rc k& Co . , Inc . (Rahway , New Jersey ) . Dr . Webs ter hasrece ived research g ran ts f rom and /o r se rved as ac o n s u l t a n t f o r A l l e rg a n , I n c . , Or t h o De rm a t o l o g i -c a l, G a l d e rm a L a b o ra t o r ie s , L .P . , De rm i k L a b o ra t o -r ies , Inc . , and Roche Labora to r ies , Inc . ( Ind ianapo l i s ,I n d i a n a ) .


9/9

C l i n i ~ a l ~ e ~ a p e U i C S

R E F E R E N C E S1 . K l igma n AM . Pa thogenes is o f acne

v u l g a r is . I I. H i s t o p a t h o l o g y o f c o m e -d o n e s i n d u c e d i n t h e r a b b i t e a r b yh u m a n s e b u m . Arch Dermatol. 1968 ;9 8 : 5 8 - 6 6 .

2 . W eb s t e r GF , Ber son D, S t e in L F, e ta l . E f f i ca c y a n d t o l e r a b i l i t y o f o n c e -d a i l y t a z a r o t e n e 0 . 1 % g el v e r s u so n c e - d a i l y t r e t i n o i n 0 . 0 2 5 % g e l int h e t r e a t m e n t o f fa c i a l a c n e v u l g a ri s :A r a n d o m i z e d t r i a l . Cutis. 2 0 0 1 ; 6 7( S u p p l 6 ) : 4 - 9 .

3 . L eyden JJ , T an ghe t t i E A, M i l l e r B ,e t a l. O n c e - d a i l y t a z a r o t e n e 0 . 1 %g e l v e r s u s o n c e - d a i l y t r e t i n o i n 0 . 1 %m i c r o s p o n g e g e l f o r t h e t r e a t m e n to f f a c i al a c n e v u l g a r i s : A d o u b l e -b l i n d r a n d o m i z e d t r i a l . Cutis. 2 0 0 2 ;6 9 ( S u p p l 2 ) : 1 2 - 1 9 .

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A c a d e m y o f D e r m a t o l o g y ; J u l y 2 8 - ' ...................................................................................................................................................................... ....................................................A u gu st l , 2 0 0 1 ;A n a h e i m , C alif. A d d r e s s c o r r e s p o n d e n c e t o : J a m e s ] . L e y d e n , M D , D e p a r t m e n t o f

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