Terapi Takrolimus untuk Konjungtivitis Alergika

892019 Terapi Takrolimus untuk Konjungtivitis Alergika

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Therapeutic effects of 01 tacrolimus eye drops forrefractory allergic ocular diseases with proliferativelesion or corneal involvement

Atsuki Fukushima1 Yuichi Ohashi2 Nobuyuki Ebihara3 Eiichi Uchio4

Shigeki Okamoto5 Naoki Kumagai6 Jun Shoji7 Etsuko Takamura8 Yayoi Nakagawa9

Kenichi Namba10 Hiroshi Fujishima11 Dai Miyazaki12

For numbered af 1047297liations seeend of article

Correspondence toDr Atsuki FukushimaDepartment of OphthalmologyKochi Medical SchoolOko-cho Kohasu Nankoku-shiKochi 783-8505 Japanfukusimakochi-uacjp

Received 9 October 2013Revised 26 December 2013Accepted 16 March 2014

To cite Fukushima AOhashi Y Ebihara N et al Br J Ophthalmol PublishedOnline First [ please includeDay Month Year]

doi101136bjophthalmol-2013-304453

ABSTRACTBackground The objective of this study was toinvestigate the ef 1047297cacy of topical 01 tacrolimus intreating refractory allergic conjunctivitis with proliferativelesions andor corneal involvementMethods This prospective observational study included1436 patients with refractory allergic conjunctivitiswhose condition had responded poorly to conventionalantiallergic drugs andor topical steroids andor topical

cyclosporine All patients received tacrolimus eye dropstwice daily during the study period Ten clinical signsand six clinical symptoms were rated on a four-gradescale The primary endpoint was the change frombaseline in total clinical signs and symptoms score at thelast observation or following 6 months of treatmentResults Total signs and symptoms score signi1047297cantlydecreased after 1 month of treatment (plt0001) Giantpapillae and corneal lesions were also reduced bytacrolimus eye drop use (plt0001) The drug provedeffective in patients whose condition did not respondwell to topical cyclosporine therapy About 50 of allpatients using topical steroids were weaned The mostcommon adverse reaction was a transient burning

sensation (320)Conclusions Tacrolimus eye drops are highly effectivein treating refractory allergic conjunctivitis withproliferative lesions andor corneal involvement and mayreduce or replace topical steroid useTrial registration number UMIN 000008640

INTRODUCTIONSevere allergic conjunctival diseases (ACDs) suchas atopic keratoconjunctivitis (AKC) and vernal ker-atoconjunctivitis (VKC) are occasionally compli-cated by keratopathy1 Severe keratopathy such as ashield ulcer is a serious pathological conditionbecause it may result in reduced visual acuity2

Keratopathy associated with severe ACD is primar-ily caused by the histotoxic protein produced byeosinophils3 and eosinophils massively in1047297ltrategiant papillae tissue in patients with severe ACDTherefore alleviation of giant papillae with surgicalresection is a widely used treatment in the casesthat do not respond to medical treatment Drugtherapy for severe ACD often utilises topical andoral antiallergic agents or steroids However antial-lergic agents often have insuf 1047297cient ef 1047297cacy andlong-term patient management is usually required

with this therapy4

The use of ocular steroids isassociated with a serious increased risk of ocular

hypertension cataracts andor glaucoma2 5

Additionally the risk of steroid-induced ocularhypertension is particularly high in children lessthan 10 years old and a cataract-induced visualacuity reduction during infancy or early childhoodmarkedly affects a patientrsquos quality of life6

Tacrolimus is a 23-member cyclic macrolidelactone and was isolated from Streptomyces tsuku-baensis in 19847 It was initially developed as an

immunosuppressant agent for use following organtransplantation but is now clinically availableworldwide Tacrolimus ointment is also marketedfor the treatment of atopic dermatitis

Tacrolimus binds to FK506-binding proteins withinT lymphocytes and inhibits calcineurin activityCalcineurin inhibition suppresses dephosphorylationof the nuclear factor of activated T cells and its trans-fer into the nucleus which results in suppressed for-mation of T helper 1 (Th1) (interleukin (IL)-2interferon γ) and Th2 cytokines (IL-4 IL-5)8

Tacrolimus has also been reported to inhibit histaminerelease from mast cells and is thought to alleviateallergic symptoms through these mechanisms9

Previously tacrolimus was administered as anin-house formulation in a solute of castor oil oliveoil or dextrin10ndash12 The ointment form of tacroli-mus was also useful in treating refractory in1047298amma-tory disease of the outer ocular area Unfortunatelythese formulations are known to cause irritationand epithelial keratitis so information on their ef 1047297-cacy is sporadic and limited13 Herein we evaluatethe ef 1047297cacy of tacrolimus eye drops in treatingrefractory allergic ocular disease in 1436 patientstreated with topical tacrolimus We show thattopical tacrolimus is highly effective in treating

AKC and VKC and may reduce or replace steroid

therapy for these conditions

METHODSEligibility criteria and diagnosis

All patients included in this study were treated withtacrolimus eye drops and the study was designed asfollows Tacrolimus ophthalmic suspension 01(Senju Pharmaceutical Co Osaka Japan) was usedin eyes with severe allergic conjunctivitis thatresponded poorly to conventional antiallergicagents such as antiallergic ophthalmic solutionstopical steroids andor cyclosporine All patientsregistered and treated with tacrolimus eye drops

between May 2008 and August 2010 were includedin the study Patients with a known sensitivity to

Fukushima A et al Br J Ophthalmol 201401ndash5 doi101136bjophthalmol-2013-304453 1

Clinical science

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Copyright Article author (or their employer) 2014 Produced by BMJ Publishing Group Ltd under licence

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tacrolimus hydrate or any tacrolimus eye drop component aninfectious eye disease or a con1047297rmed or possible pregnancywere excluded

The protocol for this study was reviewed by the EthicsCommittee of the Pharmaceuticals and Medical Devices Agencyin Japan The clinical trial registration ID is UMIN 000008640

A diagnosis was made according to published guidelines forallergic conjunctival diseases3 14 15 Patients satisfying the fol-

lowing requirements were included in analyses presence of con-junctival giant papillae limbal swelling andor Trantas dots14persistent or relapsing conjunctivitis sign14 and younger than40 years of age3 14 16

One drop of tacrolimus was administered twice a day topatients with refractory allergic ocular diseases with proliferativelesions andor corneal involvement The maximum observationperiod was 6 months Each of 10 clinical signs (table 1) wasscored on a four-point scale using the following de1047297nitions0=none 1=mild 2=moderate and 3=severe3 16 Grades were

assigned based on photographic criteria (table 1 photographicimages not shown)3 In addition each of six symptoms includ-ing itching discharge lacrimation photophobia foreign bodysensation and eye pain was scored on a four-grade scaleScoring was done at baseline (therapy initiation) and at 1 2 3and 6 months into tacrolimus eye drop therapy In cases whentacrolimus therapy was discontinued observations made on thelast day of administration were used as the last observation

Demographic variables collected and examined includedgender age allergic disease complications previously useddrugs concomitant drugs and adverse reactions The primaryef 1047297cacy endpoint was the change in total signs and symptomscores from baseline

Statistical analysesData are presented as meanplusmnSD Statistical analyses were per-formed using JMP statistical software (V9 for Windows SASInstitute Inc Cary North Carolina USA) Statistical signi1047297cancewas de1047297ned as a two-sided p value of lt005 Ef 1047297cacy assess-ments were based on measurements obtained from the eye witha higher total ocular 1047297ndings score (worse disease)17 and the

Wilcoxon signed rank test was used to compare total scoresbefore and after treatment

RESULTSPatient pro1047297leTable 2 summarises the demographic variables of the 1436patients included in analyses The percentage of male patientswas 776 Mean patient age was 158plusmn89 years at the time of enrolment and 83plusmn42 years at the time of disease onset

Allergic rhinitis and asthma were also present in 235 and176 of patients respectively Of all patients analysed 546had previously used antiallergic ophthalmic solutions such asantihistamine and mast cell stabiliser 533 had previously

used steroid ophthalmic solutions and 353 had previouslyused cyclosporine eye drop 01

Change in signs and symptoms with topical tacrolimus eyedrop useThe total score of the 10 clinical signs (range 0ndash30) and 6 clin-ical symptoms (range 0ndash18) signi1047297cantly decreased from baseline1 month after beginning tacrolimus eye drop treatment(plt0001 Wilcoxon signed rank test 1047297gure 1) The mean totalscore of clinical signs was 153plusmn50 at the start of treatmentand decreased to 59plusmn46 at the last observation (mean changefrom baseline=minus94) The total clinical symptom score

Table 1 Grading scales for clinical signs

Signs Score Definition

Palpebral conjunctivaHyperaemia

3 Impossible to distinguish individual bloodvessels

2 Dilatation of many vessels1 Dilatation of several vessels0 None

Oedema 3 Diffuse oedema with opacity2 Thinner diffuse oedema1 Slight oedema0 None

Follicles 3 20 or more follicles2 10ndash19 follicles1 1ndash9 follicles0 None

Papillae 3 Papillae size 06 mm or more

2 Papillae s ize 03ndash

05 mm1 Papillae s ize 01ndash02 mm0 None

Giant papillae ( papillaesize ge1 mm)

3 Elevated papillae in 12 or more of theupper palpebral conjunctiva

2 Elevated papillae in lt12 of the upperpalpebral conjunctiva

1 Flat papillae0 None

Bulbar conjunctivaHyperaemia

3 Diffuse dilated blood vessels over the entirebulbar conjunctiva


Oedema 3 Bullous oedema

2 Thinner diffuse oedema

1 Local ised oedema

0 None

LimbusTrantasrsquo dot

3 9 or more dots2 5ndash8 dots1 1ndash4 dots0 None

Swelling 3 Found in 23 or more of the limbalcircumference

2 Found in 13 to lt23 of the limbalcircumference

1 Found in lt13 of the limbal circumference0 None

Corneal epithelial signs 3 Shield ulcer or corneal erosion2 Exfoliation superficial punctate keratitis1 Superficial punctate keratitis

0 None

Table 2 Baseline characteristics of the patients

Sex

Male () 1115 (776)

Female 321

Mean age (years)plusmnSD 158plusmn89

Mean age of onset (years)plusmnSD 83plusmn42

Allergic complications ()

Allergic rhinitis 337 (235)

Asthma 253 (176)

Pretreatment ()

Antiallergic eye drop 784 (546)

Topical steroids 765 (533)

Topical cyclosporine 507 (353)

2 Fukushima A et al Br J Ophthalmol 201401ndash5 doi101136bjophthalmol-2013-304453

Clinical science




decreased from 81plusmn45 at baseline to 18plusmn28 at the last obser-

vation (mean change from baseline=minus63)

Giant papillae and corneal involvement score before andafter tacrolimus therapy

As shown in 1047297gure 2 872 of patients had giant papillae atbaseline with 628 of patients having active-stage giant papil-lae (score ge2) At the time of the last observation only 158of the patients had active-stage giant papillae with alleviation of giant papillae (score le1) seen in 842 of patients (plt0001Wilcoxon signed rank test) Super1047297cial punctate keratopathy(SPK) was also seen in 678 of patients at baseline ( 1047297gure 2)

At the time of the last observation the corneal epithelial dis-order score was signi1047297cantly lower than at baseline (plt0001

Wilcoxon signed rank test) with SPK prevalence lowered to223 In addition the percentage of patients with a score ge2(large impact on visual acuity) decreased from 413 at baselineto 67 at the 1047297nal evaluation

Score changes in patients unresponsive to topicalcyclosporine 01Before tacrolimus eye drop therapy 239 patients had beentreated with cyclosporine eye drop 01 for at least 1 monthbut still had giant papillae scores greater than 2 or corneal epi-thelial disorder scores greater than 2 at the time of tacrolimustherapy initiation In these patients the total clinical signs andclinical symptoms scores at the time of switching were 168

plusmn47 and 91plusmn44 respectively (1047297

gure 3) One month intotacrolimus eye drop therapy both scores had signi1047297cantly

decreased (plt0001 Wilcoxon signed rank test) to clinical signsscore of 67plusmn49 (change=minus101) and clinical symptoms scoreof 19plusmn30 (change=minus72) at the time of the last observation

Proportion of patients on steroid therapyNext we assessed the possible steroid-sparing effect of tacroli-mus eye drops The percentage of patients (n=328 patients atbaseline) using each type of steroid ophthalmic solution progres-sively decreased during the tacrolimus eye drop administrationperiod As shown in 1047297gure 4 534 of patients were success-fully weaned off topical steroids 6 months into tacrolimus treat-ment The percentage of patients using betamethasone

ophthalmic solution was 448 at baseline which decreased to165 6 months into tacrolimus treatment

Adverse reactions Adverse reactions were noted in 117 (815) of 1436 patientsanalysed (table 3) The only major adverse reaction was a transi-ent burning sensation upon drop instillation (46 cases 320)Corneal infections including bacterial keratitis (two cases014) herpetic keratitis (two cases 014) and a bacterialcorneal ulcer (one case 007) were also observed In these1047297ve patients atopic dermatitis or asthma was also noted as anunderlying condition In addition intraocular pressure elevation

occurred in three patients presumably from adjunctive topicalsteroid use

Figure 1 Change from baseline in total symptom and sign scoresduring the 6-month study period (n=1436 patients) Error barsrepresent 1 SD The statistical signi1047297cance of each score change wasevaluated using the Wilcoxon signed rank test

Figure 2 Distribution of giant papillae (A) and corneal involvement (B) scores The statistical signi1047297cance of each score change from baseline wasevaluated using the Wilcoxon signed rank test

Figure 3 Changes from baseline in total sign and symptom scores inpatients who did not respond well to prior cyclosporine ophthalmicsolution therapy Error bars represent 1 SD The statistical signi1047297canceof each score change was evaluated using the Wilcoxon signed ranktest


Clinical science




DISCUSSIONIn the past antiallergic drug andor steroid therapy has beenused to treat severe allergic conjunctivitis (VKC AKC) with pro-liferative lesions Unfortunately antiallergic drug therapy isoften insuf 1047297cient without concomitant steroid use Howevertopical steroids put patients at high risk of developing cataractsandor glaucoma For severe disease VKC most frequentlyoccurs in children and young adults while AKC typically begins

in the late teens or early twenties Unfortunately AKC canpersist into the fourth or 1047297fth decade of life18 Therefore it isdesirable to avoid long-term steroid use particularly duringchildhood to reduce the lifelong risk of developingsteroid-related complications

Tacrolimus has long been used in organ transplant patients andhas been shown to have potent immunosuppressive activityMoreover tacrolimus has also been reported to inhibit calcineurin

100 times more effectively than cyclosporine7

To evaluate therisks and bene1047297ts of tacrolimus eye drop use in patients withsevere allergic conjunctivitis the present large-scale study was con-ducted in a routine clinical setting Changes in 10 clinical signsand 6 clinical symptoms were evaluated before and after tacroli-mus eye drop therapy in 1436 patients Twice daily treatment withtacrolimus eye drops resulted in a signi1047297cant reduction in the score1 month after the start of treatment It has previously been shownthat cyclosporine ophthalmic solution has a similar ef 1047297cacy inpatients with VKC and AKC17 In accordance with the previousreport17 the present study showed that tacrolimus eye drops wereeffective in treating severe allergic ocular diseases with giant papil-lae or corneal involvement Many of our study patients had previ-ously used cyclosporine with no improvement In addition twicedaily tacrolimus eye drop treatment signi1047297cantly reduced theocular sign and symptom score 1 month into treatment even inpatients with severe allergic conjunctivitis who had a poorresponse to cyclosporine7

The onset of VKC usually occurs before puberty is morecommon in young male patients and tends to abate in the midto late teens16 18 In VKC proliferative changes such as giantpapillae formation are notable and giant papillae may alsooccur in patients with AKC19 Because vision-threatening kerato-pathy develops in an adjacent location to the giant papillae alle-viation of giant papillae seems to be an effective strategy intreating patients with proliferative lesions In the present studytwice daily treatment with tacrolimus eye drops resulted in a

marked reduction in active-stage giant papillae (score ge2) and amarked reduction in SPK The percentage of patients havingSPK decreased from 678 at baseline to 224 at the lastobservation Additionally the percentage of patients with asevere keratopathy score (ge2) decreased from 528 to 84

In the present study concomitant use of steroids was allowedand was not an exclusion criterion Steroids were used at thediscretion of the attending physician Our data showed that534 of patients using steroids were successfully weaned fromtopical steroid therapy Thus tacrolimus eye drops appear tohave a steroid-sparing or replacing effect Because those ininfancy or early childhood are at high risk for steroid-inducedelevation of intraocular pressure tacrolimus eye drops may be avery effective alternative treatment for VKC or AKC that doesnot impose the risk of developing glaucoma

Corneal infection was seen in 1047297ve patients (herpetic keratitis (twocases) bacterial keratitis (two cases) bacterial corneal ulcer (onecase)) for a total incidence of 035 This suggests that close moni-toring during topical tacrolimus therapy is necessary during pro-longed use However a previous study examining cyclosporine01 aqueous ophthalmic solution showed a similar incidence of corneal infection in which 5 (084) of 594 patients developedinfectious corneal complications (bacterial corneal ulcer (two cases)herpetic keratitis (three cases))17 This suggests that tacrolimus eyedrops are equivalent to cyclosporine for the indications studied here

Tacrolimus treatment may cause adverse reactions includingrenal failure when used systemically20 In our study no serious

systemic adverse events were observed This is likely because thepercentage of tacrolimus reaching the bloodstream with twice-

Figure 4 Proportions of patients using topical steroids at baselineand throughout the 6-month period during which the patients receivedtopical tacrolimus eye drops

Table 3 Adverse drug reactions

Adverse drug reactions Number of events ()

Transient burning sensation in eye 46 (320)

Eye irritation 34 (237)

Eye pain 10 (070)

Hordeolum 8 (056)

Conjunctival hyperaemia 6 (042)

Eye pruritus 4 (028)

Foreign body sensation in eye 3 (021)

Eye discharge 3 (021)

Lacrimation 3 (021)

Lid herpes 3 (021)

Chalazion 3 (021)

Intraocular pressure elevation 3 (021)

Photophobia 3 (021)

Corneal ulcer 2 (014)

Conjunctival oedema 2 (014)

Punctate keratitis 2 (014)

Bacterial keratitis 2 (014)

Corneal erosion 2 (014)

Transient blurred vision 2 (014)

Herpetic keratitis 2 (014)

Other events (one each of 26 cases) 1 (007)

Overall number of patients () 117 (815)


Clinical science




daily topical use is very low21 22 In conclusion we evaluatedthe ef 1047297cacy and safety of tacrolimus eye drops in patients withVKC or AKC in a clinical setting Our results suggest thattopical tacrolimus therapy is safe and effective in treatingpatients with severe allergic conjunctivitis

Author af 1047297liations1Department of Ophthalmology Kochi Medical School Kochi Japan2

Department of Ophthalmology Ehime University School of Medicine Ehime Japan3Department of Ophthalmology Juntendo University School of Medicine TokyoJapan4Department of Ophthalmology Fukuoka University School of Medicine FukuokaJapan5Okamoto Eye Clinic Ehime Japan6Kumagai Eye Clinic Yamaguchi Japan7Department of Ophthalmology Division of Visual Sciences Nihon University Schoolof Medicine Tokyo Japan8Department of Ophthalmology Tokyo Womenrsquos Medical University School of Medicine Tokyo Japan9Nakagawa Eye Clinic Osaka Japan10Department of Ophthalmology and Visual Science Hokkaido University GraduateSchool of Medicine Hokkaido Japan11Department of Ophthalmology Tsurumi University Dental Hospital KanagawaJapan12Department of Ophthalmology Tottori University School of Medicine TottoriJapan

Contributors All of the authors conception and design data acquisitioncontributed to statistical analysis and interpretation revised the article critically forimportant intellectual content AF drafted the article

Funding This study was sponsored by Senju Pharmaceutical Co Osaka Japan

Competing interests None

Ethics approval The protocol for this study was reviewed by the Ethics Committeeof the Pharmaceuticals and Medical Devices Agency in Japan

Provenance and peer review Not commissioned externally peer reviewed

Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 30) license whichpermits others to distribute remix adapt build upon this work non-commerciallyand license their derivative works on different terms provided the original work is

properly cited and the use is non-commercial See httpcreativecommonsorglicensesby-nc30

REFERENCES1 Leonardi A Motterle L Bortolotti M Allergy and the eye Clin Exp Immunol

2008117ndash212 Tabbara KF Ocular complications of vernal keratoconjuctivitis Can J Ophthalmol

19993488ndash92

3 Takamura E Uchio E Ebihara N et al Japanese guideline for allergic conjunctivaldiseases Allergol Int 201160191ndash203

4 Ohashi Y Ebihara N Fujishima H et al A randomized placebo-controlled clinicaltrial of tacrolimus ophthalmic suspension 01 in severe allergic conjunctivitis J Ocul Pharmacol Ther 201026165ndash73

5 Ang M Ti SE Loh R et al Steroid-induced ocular hypertension in Asian childrenwith severe vernal keratoconjunctivitis Clin Ophthalmol 201261253ndash8

6 Ohji M Kinoshita S Ohmi E et al Marked intraocular pressure response toinstillation of corticosteroids in children Am J Ophthalmol 1991112450ndash4

7 Kino T Hatanaka H Hashimoto M et al FK-506 a novel immunosuppressant

isolated from a Streptomyces I Fermentation isolation and physic-chemical andbiological characteristics J Antibiot (Tokyo) 1987401249ndash55

8 Sakuma S Higashi Y Sato N et al Tacrolimus suppressed the production of cytokines involved in atopic dermatitis by direct stimulation of human PBMC system(Comparison with steroids) Int Immunopharmacol 200111219ndash26

9 Zhai J Gu J Yuan J et al Tacrolimus on the treatment of ocular diseases Biodrugs20112589ndash103

10 Uno T Yamaguchi T Li XK et al The pharmacokinetics of water-in-oil-in-water-type multiple emulsion of a new tacrolimus formulation Lipids 199732543ndash8

11 Pleyer U Lutz S Juske WJ et al Ocular absorption of topically applied FK506 fromliposomal and oil formulations in the rabbit eye Invest Ophthalmol Vis Sci 1993342737ndash42

12 Yura H Yoshimura N Hamashima T et al Synthesis and pharmacokinetics of anovel macromolecular prodrug of tacrolimus (FK506) FK506-dextran conjugate J Control Release 19995787ndash99

13 Miyazaki D Tominaga T Kakimaru-Hasegawa A et al Therapeutic effects of

tacrolimus ointment for refractory ocular surface in1047298

ammatory diseases Am JOphthalmol 2008115988ndash9214 Lambiase A Minchiotti S Leonardi A et al Prospective multicenter demographic

and epidemiological study on vernal keratoconjunctivitis a glimpse of ocularsurface in Italian population Ophthalmic Epidemiol 20091638ndash41

15 Calonge M Classi1047297cation of ocular atopicallergic disorders and condition anunsolved problem Acta Ophthalmol Scand Suppl 199922810ndash3

16 Uchio E Kimura R Migita H et al Demographic aspects of allergic ocular diseasesand evaluation of new criteria for clinical assessment of ocular allergy Graefes ArchClin Exp Ophthalmol 2008246291ndash6

17 Ebihara N Ohashi Y Uchio E et al A large prospective observational study of novel cyclosporine 01 aqueous ophthalmic solution in the treatment of severeallergic conjunctivitis J Ocul Pharmacol Ther 200925365ndash71

18 Bielory L Allergic and immunologic disorders of the eye Part II ocular allergy J Allergy Clin Immunol 20001061019ndash32

19 Guglielmetti S Dart JK Calder V Atopic keratoconjunctivitis and atopic dermatitisCurr Opin Allergy Clin Immunol 201010478ndash85

20 Przepiorka D Nash RA Wingard JR et al Relationship of tacrolimus whole bloodlevels to ef 1047297cacy and safety outcomes after unrelated donor marrow transplantationBiol Blood Marrow Transplant 1999594ndash7

21 Ebihara N Ohashi Y Fujishima H et al Blood level of tacrolimus in patients withsevere allergic conjunctivitis treated by 01 tacrolimus ophthalmic suspension Allergol Int 201261275ndash82

22 Fujita E Teramura Y Shiraga T et al Pharmacokinetics and tissue distribution of tacrolimus (FK506) after a single or repeated ocular instillation in rabbits J Ocul Pharmacol Ther 200824309ndash19


Clinical science




doi 101136bjophthalmol-2013-304453 published online April 2 2014Br J Ophthalmol

Atsuki Fukushima Yuichi Ohashi Nobuyuki Ebihara et al involvementwith proliferative lesion or cornealdrops for refractory allergic ocular diseasesTherapeutic effects of 01 tacrolimus eye

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non-commercial See httpcreativecommonsorglicensesby-nc30 terms provided the original work is properly cited and the use iswork non-commercially and license their derivative works on differentlicense which permits others to distribute remix adapt build upon thisCreative Commons Attribution Non Commercial (CC BY-NC 30)This is an Open Access article distributed in accordance with the

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Articles on similar topics can be found in the following collections

Notes











tacrolimus hydrate or any tacrolimus eye drop component aninfectious eye disease or a con1047297rmed or possible pregnancywere excluded

The protocol for this study was reviewed by the EthicsCommittee of the Pharmaceuticals and Medical Devices Agencyin Japan The clinical trial registration ID is UMIN 000008640

A diagnosis was made according to published guidelines forallergic conjunctival diseases3 14 15 Patients satisfying the fol-

lowing requirements were included in analyses presence of con-junctival giant papillae limbal swelling andor Trantas dots14persistent or relapsing conjunctivitis sign14 and younger than40 years of age3 14 16

One drop of tacrolimus was administered twice a day topatients with refractory allergic ocular diseases with proliferativelesions andor corneal involvement The maximum observationperiod was 6 months Each of 10 clinical signs (table 1) wasscored on a four-point scale using the following de1047297nitions0=none 1=mild 2=moderate and 3=severe3 16 Grades were

assigned based on photographic criteria (table 1 photographicimages not shown)3 In addition each of six symptoms includ-ing itching discharge lacrimation photophobia foreign bodysensation and eye pain was scored on a four-grade scaleScoring was done at baseline (therapy initiation) and at 1 2 3and 6 months into tacrolimus eye drop therapy In cases whentacrolimus therapy was discontinued observations made on thelast day of administration were used as the last observation

Demographic variables collected and examined includedgender age allergic disease complications previously useddrugs concomitant drugs and adverse reactions The primaryef 1047297cacy endpoint was the change in total signs and symptomscores from baseline

Statistical analysesData are presented as meanplusmnSD Statistical analyses were per-formed using JMP statistical software (V9 for Windows SASInstitute Inc Cary North Carolina USA) Statistical signi1047297cancewas de1047297ned as a two-sided p value of lt005 Ef 1047297cacy assess-ments were based on measurements obtained from the eye witha higher total ocular 1047297ndings score (worse disease)17 and the

Wilcoxon signed rank test was used to compare total scoresbefore and after treatment

RESULTSPatient pro1047297leTable 2 summarises the demographic variables of the 1436patients included in analyses The percentage of male patientswas 776 Mean patient age was 158plusmn89 years at the time of enrolment and 83plusmn42 years at the time of disease onset

Allergic rhinitis and asthma were also present in 235 and176 of patients respectively Of all patients analysed 546had previously used antiallergic ophthalmic solutions such asantihistamine and mast cell stabiliser 533 had previously

used steroid ophthalmic solutions and 353 had previouslyused cyclosporine eye drop 01

Change in signs and symptoms with topical tacrolimus eyedrop useThe total score of the 10 clinical signs (range 0ndash30) and 6 clin-ical symptoms (range 0ndash18) signi1047297cantly decreased from baseline1 month after beginning tacrolimus eye drop treatment(plt0001 Wilcoxon signed rank test 1047297gure 1) The mean totalscore of clinical signs was 153plusmn50 at the start of treatmentand decreased to 59plusmn46 at the last observation (mean changefrom baseline=minus94) The total clinical symptom score

Table 1 Grading scales for clinical signs

Signs Score Definition

Palpebral conjunctivaHyperaemia

3 Impossible to distinguish individual bloodvessels


Oedema 3 Diffuse oedema with opacity2 Thinner diffuse oedema1 Slight oedema0 None

Follicles 3 20 or more follicles2 10ndash19 follicles1 1ndash9 follicles0 None

Papillae 3 Papillae size 06 mm or more

2 Papillae s ize 03ndash

05 mm1 Papillae s ize 01ndash02 mm0 None

Giant papillae ( papillaesize ge1 mm)

3 Elevated papillae in 12 or more of theupper palpebral conjunctiva

2 Elevated papillae in lt12 of the upperpalpebral conjunctiva

1 Flat papillae0 None

Bulbar conjunctivaHyperaemia

3 Diffuse dilated blood vessels over the entirebulbar conjunctiva


Oedema 3 Bullous oedema

2 Thinner diffuse oedema

1 Local ised oedema

0 None

LimbusTrantasrsquo dot

3 9 or more dots2 5ndash8 dots1 1ndash4 dots0 None

Swelling 3 Found in 23 or more of the limbalcircumference

2 Found in 13 to lt23 of the limbalcircumference

1 Found in lt13 of the limbal circumference0 None

Corneal epithelial signs 3 Shield ulcer or corneal erosion2 Exfoliation superficial punctate keratitis1 Superficial punctate keratitis

0 None

Table 2 Baseline characteristics of the patients

Sex

Male () 1115 (776)

Female 321

Mean age (years)plusmnSD 158plusmn89

Mean age of onset (years)plusmnSD 83plusmn42

Allergic complications ()

Allergic rhinitis 337 (235)

Asthma 253 (176)

Pretreatment ()

Antiallergic eye drop 784 (546)

Topical steroids 765 (533)

Topical cyclosporine 507 (353)


Clinical science






















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Eye pain 10 (070)

Hordeolum 8 (056)





Lacrimation 3 (021)

Lid herpes 3 (021)

Chalazion 3 (021)


Photophobia 3 (021)











Clinical science
















19993488ndash92

























Clinical science








These include



Open Access















CollectionsTopic




Notes





























Clinical science




















Eye pain 10 (070)

Hordeolum 8 (056)





Lacrimation 3 (021)

Lid herpes 3 (021)

Chalazion 3 (021)


Photophobia 3 (021)











Clinical science
















19993488ndash92

























Clinical science








These include



Open Access















CollectionsTopic




Notes



























Eye pain 10 (070)

Hordeolum 8 (056)





Lacrimation 3 (021)

Lid herpes 3 (021)

Chalazion 3 (021)


Photophobia 3 (021)











Clinical science
















19993488ndash92

























Clinical science








These include



Open Access















CollectionsTopic




Notes























19993488ndash92

























Clinical science








These include



Open Access















CollectionsTopic




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Terapi Takrolimus untuk Konjungtivitis Alergika

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