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Abstract
Recombinant canine interferon- (KT-100) or topical
antihistamine (diphenhydramine: DH) was administered
to dogs with atopic dermatitis (AD) for 4 weeks and
their efficacies were compared using pruritus, excoriation, erythema and alopecia as evaluation criteria.
Clinical studies on 92 atopic dogs (KT-100 group: 63,
DH group: 29) were conducted at 18 animal hospitals
in Japan. KT-100 was administered subcutaneously
once a day three times a week on alternating days for
4 weeks. DH was administered topically twice daily for
4 weeks. The efficacy rates of the KT-100 group on day
28 were 72.1% for pruritus, 73.8% for excoriation,
75.4% for erythema and 60.7% for alopecia, which
were significantly higher than those of the DH group
(20.7% for pruritus, 27.6% for excoriation, 24.1% for
erythema and 24.1% for alopecia).
Accepted 21 March 2006
Introduction
Interferon (IFN)- is known to exhibit both immunoenhancing and immunoregulatory effects on the immune
system, and to be effective in cases of human atopic
dermatitis (AD).14 Various drugs for the treatment of canine
AD have been investigated, including glucocorticoids,
calcineurin inhibitors, histamine-1 receptor antagonists,
phosphodiesterase inhibitors, leucotriene inhibitors, prostaglandin analogues and inhibitors, externally applied antipruritics, immunoregulatory antibiotics, Chinese herbs and
homeopathic drugs.5 However, problems associated with the
use of these drugs can include adverse effects or low efficacy.
Dogs
1) Inclusion criteria
Dogs were included if they fulfilled the Willemses criteria for AD.13
Adverse food reactions were excluded by feeding an elimination diet
for a minimum of 4 weeks and ectoparasites by trial therapy. If present,
secondary infections with Malassezia pachydermatis infection and
pyoderma were treated before the trial commenced. In addition, in order
to standardize the severity of AD in this study, only dogs for which the
severity of pruritus was evaluated to be moderate to severe and for
which the sum of the clinical scores for excoriation, erythema and
alopecia was 19 or higher at the initial examination were included in
the study (see succeeding text for scoring system). Dogs that had
received steroids (including oral and injectable), antihistamines, or
other immunotherapeutic drugs (including Chinese herbal medicine)
were required to undergo a withdrawal period of at least 2 weeks prior
to the study, and the concomitant use of these drugs was not permitted
during the study.
2) Exclusion criteria
Dogs were excluded from the study if they had mild AD, insufficient withdrawal periods of prohibited drugs, changes to the type or frequency
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology. 17; 195200
195
Definition
0 No pruritus
1 Mild pruritus
2 Mild to moderate pruritus
3 Moderate pruritus
4 Moderate to severe pruritus
5 Severe pruritus
No pruritus observed
Occasional scratching or biting, almost no difference from normal dogs
Some scratching and biting, and slight restlessness
Frequent scratching and biting, and restlessness
Very frequent scratching and biting, and extreme restlessness
Continuous scratching and biting, and continuous restlessness causing the animal to wake his owner at night
Location
Score
Definition
Excoriation
0 No excoriation
1 Mild excoriation
2 Mild to moderate excoriation
3 Moderate excoriation
4 Moderate to severe excoriation
5 Severe excoriation
0 No erythema
1 Mild erythema
2 Mild to moderate erythema
3 Moderate erythema
4 Moderate to severe erythema
5 Severe erythema
0 No alopecia
1 Mild alopecia
2 Mild to moderate alopecia
3 Moderate alopecia
No excoriation observed
Shallow, inconspicuous wounds
Small number of wounds at lesion site
Large number of wounds at lesion site
Large number of wounds spreading over the entire area
Deep wounds with presence of blood over the entire area
No erythema observed
Some light pink zones
Sporadic light pink zones
Pink zones spreading over a moderate range
Deep pink zones spreading from the moderate range to the entire area
Red zones spreading over the entire area
No alopecia observed
Some zones of thinning hair
Zones of thinning hair spreading over a moderate range
Zones of thinning hair spreading over the entire area or zones of missing
hair spreading beyond the moderate range
Hardly any hair over the entire area or zones of missing hair over
nearly the entire area
Zones of missing hair spreading over the entire area
Erythema
Alopecia
Intervention
This study was conducted using Good Clinical Practice (GCP) standards
at 18 animal hospitals in Japan from August 2003 to January 2004.
The dogs were randomly assigned to the KT-100 and DH groups by a
third party to a ratio of 2: 1. The randomization table was prepared by
Toray Industries, Inc. after the veterinarians had verified that the dogs
met the inclusion criteria, and random assignment of the dogs to the
two groups was performed.
The dosage for the KT-100 group was based on the results of a
previous dose finding study (Hasegawa A., unpublished data). Dogs
of the KT-100 group were administered subcutaneously 10 000 units
of KT-100 per kilogram body weight once a day, three times a week,
on alternating days for 4 weeks. During the subsequent 4-week
follow-up period, the frequency of administration was adjusted at
the discretion of the veterinarian monitoring the dogs condition
while the amount administered was unchanged at 10 000 units kg1
body weight. Dogs in the DH group were sprayed twice daily for 8
weeks according to the manufacturers instructions.
sites, namely, the face, pinnae, axilla, abdomen, inguinal region and
extremities. Compared with the scores on the initial day, 75%
improvement of pruritus, excoriation, erythema or alopecia was
evaluated as excellent; 50% to < 75% improvement, as good; 0% to
< 50% improvement, as fair; no change in scores, as no effect; and
worsening of symptoms, as worsened. The efficacy rate for each
symptom was expressed as follows:
(no. of excellent cases + no. of good cases)/total no. of cases.
The same veterinarian performed the scoring of clinical signs on
days 0, 14, 21, 28 and 56.
Evaluation of efficacy
Pruritus, excoriation, erythema and alopecia were chosen as evaluation criteria by assigning a score of 05 using a simplified version of the
CADESI (canine atopic dermatitis extent and severity index) score.14
The severity of pruritus was scored as follows: 0 for no pruritus, 1 for
mild pruritus, 2 for mild to moderate pruritus, 3 for moderate pruritus,
4 for moderate to severe pruritus, and 5 for severe pruritus, as determined by the veterinarian through interviews with dog owners (Table 1).
Excoriation, erythema and alopecia were evaluated by the veterinarian
and scored as follows: 0 for no symptoms, 1 for mild symptoms, 2 for mild
to moderate symptoms, 3 for moderate symptoms, 4 for moderate to
severe symptoms, and 5 for severe symptoms (Table 2), at each of six
196
Statistical analysis
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
Breed
ELISA results
Duration of clinical signs in years
Body weight
Withdrawal period
Level
Study group
KT-100
DH
Total
Male
Female
<1
1<3
3<5
5 < 10
10
Unknown
(mean SD)
Shih Tzu
Shiba Inu
West Highland white terrier
Golden retriever
Shetland sheepdog
Labrador retriever
Other
Positive
Negative
<1
1<3
3<6
6
Unknown
(mean SD)
<6
6 < 12
12
(mean SD)
2 weeks < 1 month
1 month <
Unknown
Pruritus
Excoriation
Erythema
Alopecia
63
32
31
2
15
18
24
3
1
5.08 2.77
21
10
3
4
3
1
21
40
23
13
14
20
7
9
3.13 2.41
23
24
16
10.10 7.14
14
43
6
3.58 0.66
14.98 6.04
15.86 5.43
12.37 6.23
29
9
20
0
3
7
11
8
0
7.35 3.93
16
3
2
0
0
1
7
20
9
5
2
4
4
14
3.37 3.10
11
14
4
7.56 4.33
3
26
0
3.55 0.69
12.74 6.00
13.83 5.71
11.07 7.02
92
41
51
2
18
25
35
11
1
5.80 3.34
37
13
5
4
3
2
28
60
32
18
16
24
11
23
3.18 2.55
34
38
20
9.30 6.47
17
69
6
3.57 0.67
14.28 6.08
15.22 5.57
11.07 7.02
Significance
P = 0.0765*
P = 0.0216*
P = 0.3170*
P = 0.6086*
P = 0.4019*
P = 0.4191*
P = 0.1176*
P = 0.8543
P = 0.1007
P = 0.1050
P = 0.3752
was used for 2-grade evaluation (excellent + good and fair + no effect
+ worse). The outcome measures for efficacy analysis were assessed
per protocol. The clinical scores of all the dogs were included in the
statistical analyses, whether or not the dog had completed the study.
All missing clinical scores were replaced using the last value carry
forward rule.
Results
Subjects
One hundred and nine dogs (KT-100 group: 75, DH group:
34) were enrolled in the study. Seventeen dogs (KT-100
group: 12, DH group: 5) were excluded from the efficacy
analysis on day 14 and two dogs (KT-100 group) were
excluded from the efficacy analysis on day 28 because of
deviation from the study protocol. Of the excluded dogs,
three (KT-100 group: 2, DH group: 1) had heart disease;
one each (KT-100 group) had hypothyroidism, seborrhoeic
dermatitis and flea allergy dermatitis; three (KT-100 group:
1, DH group: 2) lacked clinical scores on the initial day and
two (KT-100 group) did not meet the required withdrawal
period. During the study, existing shampoo therapy was
changed or the frequency of bathing was increased in two
dogs (DH group), medication was discontinued on day 7 as
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
197
Figure 1. Time course of each clinical scores of atopic dogs administered KT-100 or DH.
Significant differences in the scores of pruritus, excoriation and erythema were observed between the KT-100 group and the DH group on days
21, 28 and 56, while that of alopecia was observed on day 56 (Students t-test).
Study
group
Excellent
Good
Fair
No
effect
Worse
Total
KT-100
DH
KT-100
DH
KT-100
DH
KT-100
DH
19
1
36
2
37
4
29
2
25
5
9
6
9
3
8
5
12
12
10
11
9
13
13
14
5
10
0
0
0
2
5
2
0
1
6
10
6
7
6
6
61
29
61
29
61
29
61
29
MannWhitneys
U-test
P < 0.0001
P < 0.0001
P < 0.0001
P = 0.0009
Efficacy rate
72.1%
20.7%
73.8%
27.6%
75.4%
24.1%
60.7%
24.1%
Chi-square
test
P < 0.0001
P < 0.0001
P < 0.0001
P = 0.0012
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
Discussion
Canine AD is a chronic disease that requires lifelong
control. Although systematic reviews of drugs for treating
canine AD have been conducted in recent years, high efficacy was noted only for glucocorticoids and cyclosporin.5
However, glucocorticoids are frequently associated with
such adverse effects as polydipsia and polyuria, although
they are commonly prescribed for symptomatic treatment
in Japan. Although mild cases can be controlled to a certain
extent with medicated shampoos, antihistamines and
Chinese herbal medicine, thereby reducing dependency on
steroids, moderate and severe cases often require steroids
at an appropriate dosage and frequency to achieve high
efficacy. Cyclosporine has been associated with vomiting
(incidence: 14 42%), diarrhoea (incidence: 1618%) and
skin infection (incidence: 29%).5 Although hyposensitization
therapy has been employed, it is not widely used in Japan
when compared with the USA or EU, because it requires
long-term and frequent injection of allergens, and because it
can induce side-effects such as systemic allergic reactions.
In this study, we showed that KT-100 is significantly
more effective for the treatment of canine AD than DH, an
antihistamine preparation currently used for the treatment
of allergic dermatitis in Japan. Compared with DH
administration, KT-100 administration for 4 weeks resulted
in significant improvement of all clinical signs assessed in
this study, including pruritus, excoriation, erythema and
alopecia. Compared with the DH group, we noted significant
reductions in the scores of pruritus, excoriation and erythema in the KT-100 group from day 21, and a significant
reduction in the score of alopecia on day 56. Obviously,
alopecia takes longer to resolve than the inflammatory
changes due to the time taken for hair regrowth. In many
clinical studies to assess the efficacy of drugs on canine
AD, the observation period is usually set between 3 and
8 weeks.1518 In our study, the administration period was
set at 4 weeks, followed by a 4-week follow-up period.
Therefore, the 4-week clinical study period for canine AD
may be sufficient. The results of the follow-up period
suggested that the effect of KT-100 might persist over the
course of 4 weeks even when the frequency of administration was reduced to once a week or less.
In this study, we used DH as the control because it is the
only drug authorized for treating canine allergic dermatitis
and pruritic dermatitis by the Japanese government. In
this regard, a blinded study is difficult due to the difference
in the route of administration, namely, injection and topical,
and therefore, a randomized trial that involved comparison
with a control drug was performed.
Acknowledgements
The authors would like to thank the following veterinarians
who collaborated in the clinical study: Drs Riko Itoh, Takuya
Kubo, Ikuo Konishi, Satoshi Saitoh, Toru Takahashi, Shingo
Torigoe, Kazutaka Takehara, Michio Yamaguchi, Kenichi
Mizoguchi, Tomiya Uchino, Satoru Yonezawa, Hirohide
Kamimura, Koji Nishida, Tetsuya Shimoda, Fumio Shibasaki,
Kaoru Kato, Masahiko Takenaka and Teruaki Amimoto. We
are grateful to Ms Toshiko Sakamoto (Toray Industries Inc.)
for her excellent help in preparing the manuscript.
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2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.