Journal of Dermatology 2016; 43: 402405

doi: 10.1111/1346-8138.13158

ORIGINAL ARTICLE

Proactive treatment with calcipotriol reduces recurrence of

plaque psoriasis
Kotaro ITO, Monji KOGA, Yoshitsugu SHIBAYAMA, Saori TATEMATSU, Juichiro
NAKAYAMA, Shinichi IMAFUKU
Department of Dermatology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

ABSTRACT
Topical calcipotriol is a widely used treatment for plaque-type psoriasis worldwide, and has been shown to
improve psoriatic plaques as well as very potent corticosteroids. However, there remains the practical question
of whether calcipotriol application should continue on healed pigmentation/depigmentation associated with psoriatic plaques. Therefore, we conducted a pilot clinical study to answer this question. Plaque-type psoriatic patients
not receiving systemic treatment were enrolled and treated with calcipotriol for 8 weeks (stage I) to achieve maximum effect. The patients were then divided into two groups: group A continued to apply calcipotriol to the
entirety of the previous lesion (including pigmentation/depigmentation) regardless of whether skin was healed or
not, while group B applied calcipotriol to the remaining lesion only. Patients were followed for 12 weeks (stage II)
and dates of plaque recurrence were recorded. A total of 29 patients (13 men, 16 women) were enrolled. During
stage I, reductions in scores for redness, induration and scale occurred in 40%, 47% and 55% of patients,
respectively. After stage II was completed, group A (n = 19) showed a significantly better KaplanMeier curve of
non-recurrence than group B (n = 8, P < 0.01). The mean non-recurrence duration was 76.8 11.8 in group A and
35.0 12.0 in group B. Our study showed that applying topical calcipotriol on seemingly healed psoriatic plaque
lesions suppresses recurrence better than applying it only on remaining plaques. This finding may be important
for instructing psoriatic patients on topical calcipotriol treatment.

Key words: calcipotriol, proactive treatment, psoriasis, recurrence, topical therapy.

INTRODUCTION
Calcipotriol (CP) is one of the most frequently used medications for the treatment of plaque-type psoriasis. There is clinical evidence to support the use of CP; according to a
systematic review by Mason et al.,1 it has similar efficacy as
potent to very potent topical corticosteroids when used over
8 weeks, its efficacy is enhanced when used in association
with ultraviolet light (UV) irradiation and it has better efficacy
when applied twice daily compared with once daily.
When using CP topical therapy against plaque psoriasis
with/without corticosteroids, we frequently observe that large
plaques shrink, become divided into small plaques and heal,
leaving behind areas of pigmentation or depigmentation. At this
point, clinical questions arise regarding where and for how long
CP application should continue; that is, should patients apply
CP to the remaining plaques alone or also on the seemingly
healed pigmented areas? Accordingly, in this study, we examined whether applying CP to pigmented areas suppresses
plaque recurrence in psoriatic subjects.

METHODS
Patients
Psoriatic patients with mild to moderate plaque psoriasis with
at least one plaque larger than 3 cm in diameter, and agreed
to participate in the study and gave written consent, were
enrolled at Fukuoka University and its affiliated clinics. Patients
being treated with cyclosporin, retinoid, methotrexate and/or
biologic agents were excluded. Patients with a previous history
of not tolerating topical vitamin D3 analogs well and those with
renal insufficiency were also excluded.

Study design
The study design was a randomized comparison. Patients were
first treated with CP, with or without topical corticosteroids
(those of submaximal potency), for 8 weeks to achieve maximum efficacy of CP (stage I). The potency of any corticosteroids used by patients was fixed throughout the stage. Next,
the patients were randomized into two groups and followed for
another 12 weeks (stage II): in group A, CP was applied to all

Correspondence: Shinichi Imafuku, M.D., Ph.D., Department of Dermatology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan
Ward, Fukuoka 814-0180, Japan. Email: dermatologist@mac.com
Received 14 July 2015; accepted 25 August 2015.

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Proactive calcipotriol for plaque psoriasis

parts of the previous lesion, including seemingly healed pigmented/depigmented areas; while in group B, CP was applied
twice daily to areas with remaining plaques only. If patients
plaques healed during stage I, they entered stage II. In group
B, if plaques healed during stage II, CP application was terminated but the patients were monitored for recurrence. In stage
II, topical steroid of mild or less potency was allowed to be
used but not allowed to be changed throughout the stage.
Patient visits were set every 4 weeks. Because this study
required administering detailed instructions to patients and closely observing them, randomization was performed by pre-allocating the participating clinics into groups A or B to minimize
the risk of protocol violation. Psoriatic plaques of the arms,
trunk and legs were evaluated by a skin score similar to the
Psoriasis Area and Severity Index but with a wider range
(employing 010-point scores for erythema, induration and
scale). In stage I, the total skin score was calculated by simply
adding the scores for the arms, trunk and legs. In stage II, at
least one clear representative plaque larger than 3 cm was
selected on extremities or trunk and evaluated in each patient.
When the skin score of the target lesion became 0 or 1, the

Table 1. Demographic data of the patients enrolled in stage II

Group

No. of patients

19 (10 men, nine women)

8 (3 men, 5
women)
74.5  4.3

Age (years,
57.6  3.1
mean  SD)
Skin score (mean  SD)
0 week
14.1  1.1
8 week
7.9  1.3
Disease duration (years)
15
5
610
3
1120
6
>20
0
Unknown
5
Comorbidities
9
(yes)
Hypertension, 3;
hyperlipidemia, 2; others,
4

14.1  1.6
6.4  1.6
1
1
2
0
4
4
Hypertension,
1; others, 3

SD, standard deviation.

Figure 1. Flow chart for the study.

2015 Japanese Dermatological Association

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K. Ito et al.

lesion was judged to be healed; skin scores of more than 2

indicated remaining lesions. Recurrence was judged when a
lesion acquired skin scores of 2 or larger (e.g. erythema, 1;
induration, 1; and scale, 0). The primary end-point, which was
compared between the groups, was the duration of lesions,
measured from the beginning of stage II to the date of recurrence in the area where CP was being applied. This study was

approved by the internal review board of Fukuoka University

Hospital.

Statistics
Statistical analysis utilized Students t-test for comparison of
parametric items, the MannWhitney U-test for non-parametric
items and the logrank test for comparing KaplanMeier curves
of non-recurrence. Values of P < 0.05 were considered statistically significant.

RESULTS
Patient demographics

Figure 2. Changes in total skin scores. Group A, calcipotriol

ointment applied to the entire former lesion; group B, calcipotriol applied only on residual areas. **P < 0.01, *P < 0.05
for comparisons with week 0 scores (by paired Students ttest); see Methods for details. S.E., standard error.

A total of 29 patients were enrolled: 21 in group A and eight in

group B. The patient flow chart is shown in Figure 1. The
imbalance in the number of subjects between the groups
occurred because of the different numbers of patients enrolled
in pre-allocated clinics. After two dropouts during stage I and
three dropouts during stage II in group A, 16 and 8 patients
were eligible for analyses of efficacy and safety in groups A
and B, respectively. The demographic data of patients who
entered stage II are summarized in Table 1. Groups A and B
had 19 (10 men, nine women) and eight (three men, five
women) patients, respectively. The mean age was
57.6  3.1 years in group A and 74.5  4.3 years in group B;
an unexpected age bias was observed (P = 0.0073, Mann
Whitney U-test).
The total skin scores before stage I were 14.1  1.1 and
14.1  1.6 in groups A and B, respectively, and decreased to
7.9  1.3 (P < 0.01) and 6.4  1.6 (P < 0.05), respectively,
after stage I (comparisons were performed using paired Students t-tests) (Fig. 2). In group A, individual skin scores were
significantly reduced after stage I for erythema (from 5.5  0.4

Figure 3. Changes in individual skin

scores. Group A, calcipotriol ointment
applied to the entire former lesion; group
B, calcipotriol applied only on residual
areas. **P < 0.01, *P < 0.05 for comparisons with week 0 scores (by paired Students t-test); see Methods for details.
S.E., standard error.

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Proactive calcipotriol for plaque psoriasis

Figure 4. KaplanMeier curves of non-recurrence during stage

II. Group A (calcipotriol ointment applied to the entire former
lesion) showed significantly better non-recurrence than group
B (calcipotriol applied only on residual areas). For details, see
Results.

tinue on seemingly healed areas. We obtained the clear result

that CP application on pigmented/healed areas suppresses
plaque relapse.
This observation may indicate that seemingly healed skin
still has a psoriatic nature and is prone to relapse. In practice,
we often encounter plaque relapses that start within the previously affected site and expand to exactly the same shape. This
phenomenon implies that these areas have a memory of psoriasis.2 Kiil et al.3 clinically observed that dermatome shaving
of plaques resulted in an absence of psoriatic plaque recurrence, suggesting that the memory is within the upper dermis.4 Suarez-Farinas et al.5 biopsied skin from previous lesions
that had been healed by tumor necrosis factor-a inhibitor treatment and showed that the expression of several inflammatory
genes remained elevated. These authors also found decreased
expression of lymphatic vessel-related genes. These observations provide a possible cellular/molecular mechanism for this
memory; it is possible that CP suppresses such skewed
gene expression, thereby preventing relapse, but further study
is needed to clarify this issue.
Our study had some limitations. First, the sample size was
small, and there was an imbalance in number between the
groups. We recommend that a larger study be conducted in
the future. Second, randomization was not complete because
we employed a pre-allocation method.
In general, topical therapy is one of the most negative
aspects of psoriasis treatment,68 and plaque recurrence
engenders feelings of frustration and helplessness among
patients.2 Our results may provide a better practical direction
for topical CP therapy and should prove useful for practitioners
in helping them to encourage and educate patients regarding
the use of CP.

Figure 5. Mean duration of non-recurrence in stage II. Group

A showed a significantly longer duration of non-recurrence
compared with group B. S.E., standard error.

CONFLICT OF INTEREST:

to 3.4  0.4, P < 0.01), induration (from 4.3  0.4 to 2.1  0.5,
P < 0.01), and scale (from 4.3  0.5 to 2.4  0.4, P < 0.01). In
group B, individual skin scores were also significantly reduced
after stage I for erythema (from 5.0  0.5 to 3.4  0.4,
P < 0.05), induration (from 4.3  0.4 to 2.1  0.5, P < 0.05)
and scale (from 4.3  0.5 to 2.4  0.4, P < 0.05) (Fig. 3).
Finally, curves of non-recurrence during stage II were compared; as illustrated in Figure 4, group A showed significantly
better non-recurrence than group B (logrank test, P = 0.0005).
The mean time to recurrence was significantly longer in group
A (5.0  0.5) compared with group B (35.0  12.0, P < 0.05)
(Fig. 5). There have not been any serious adverse events
during the trial.

REFERENCES

DISCUSSION
The efficacy of CP is widely known and based on solid evidence.1 However, many practical questions remain regarding
the optimal protocol for applying it topically. In this study, we
addressed the question of whether CP application should con-

2015 Japanese Dermatological Association

S. I. receives a research fund

and honoraria from Torii Yakuhin.

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