BJD
British Journal of Dermatology
S Y S TE M A T IC R E V IE W
Topical therapies for the treatment of plaque psoriasis:
systematic review and network meta-analyses
E.J. Samarasekera,1 L. Sawyer,2 D. Wonderling,1 R. Tucker3 and C.H. Smith4
1
National Clinical Guideline Centre, Royal College of Physicians of London, 11 St Andrews Place, London NW1 4LE, U.K.
Symmetron Ltd, Kinetic Centre, Theobald St, Borehamwood WD6 4PJ, U.K.
3
Faculty of Health and Social Care, University of Hull, Hull HU6 7RX, U.K.
4
Division of Medicine and Molecular Genetics, St John’s Institute of Dermatology, Guy’s Hospital, London SE1 9RT, U.K.
2
Summary
Correspondence
Catherine H. Smith.
E-mail:
[email protected]
Accepted for publication
10 February 2013
Funding sources
National Institute for Health and Clinical Excellence, and National Institute for Health Research.
Conflicts of interest
All authors were members of the NICE Psoriasis
Guideline Development Group (C.H.S chaired the
group, E.S was the research fellow, L.S and O.W
were the health economists, and R.T was the pharmacist). After completing the guideline analysis
but before its publication, L.S joined Symmetron
Limited.
DOI 10.1111/bjd.12276
The majority of people with psoriasis have localized disease, where topical therapy forms the cornerstone of treatment. We set out to summarize evidence on
the relative efficacy, safety and tolerability of different topical treatments used in
plaque psoriasis. We undertook a systematic review and meta-analyses of randomized trial data of U.K.-licensed topical therapies. The primary outcome was
clear or nearly clear status stratified for (i) trunk and limbs; and (ii) scalp.
Network meta-analyses allowed ranking of treatment efficacy. In total, 48 studies were available for trunk and limb psoriasis, and 17 for scalp psoriasis
(22 028 patients in total); the majority included people with at least moderate
severity psoriasis. Strategies containing potent corticosteroids (alone or in combination with a vitamin D analogue) or very potent corticosteroids dominated
the treatment hierarchy at both sites (trunk and limbs, scalp); coal tar and retinoids were no better than placebo. No significant differences in achievement of
clear or nearly clear status were observed between twice- and once-daily application of the same intervention or between any of the following: combined
vitamin D analogue and potent corticosteroid (applied separately or in a single
product), very potent corticosteroids, or potent corticosteroids (applied twice
daily). Investigator and patient assessment of response differed significantly for
some interventions (response rates to very potent corticosteroids: 78% and 39%,
respectively). No significant differences were noted for tolerability or steroid
atrophy, but data were limited. In conclusion, corticosteroids are highly effective in psoriasis when used continuously for up to 8 weeks and intermittently
for up to 52 weeks. Coal tar and retinoids are of limited benefit. There is a lack
of long-term efficacy and safety data available on topical interventions used for
psoriasis.
Psoriasis is a common chronic inflammatory skin condition
and, although generally not life threatening, it can have a profound impact on physical, psychological and social wellbeing.1 While recent advances and investment in high-cost
biological therapies have revolutionized outcomes for people
with severe disease, comparatively little attention has been
paid to topical therapy, which forms the cornerstone of management for the majority of people with psoriasis.2 Furthermore, the degree of disability does not necessarily correlate
with objective measures of disease extent or severity,3 and
people with minimal involvement (less than the equivalent of
three palm areas) state that psoriasis has a major effect on
954
British Journal of Dermatology (2013) 168, pp954–967
their life,4 underscoring the importance of effective treatment
in this group.
Corticosteroids, vitamin D3 and its analogues, calcineurin
inhibitors, retinoids, tar, dithranol and keratolytic agents such
as salicylic acid and urea are all used,5 and come in a vast
array of formulations, combinations and potencies. Choice of
treatment is tailored to the needs of the patient and includes
consideration of the nature of the psoriasis (type, site, extent)
and practical aspects such as cosmetic acceptability and time
available for application. How these factors, as well as
patients’ mood, beliefs and perceptions about psoriasis, might
impact on treatment adherence is also relevant.6 However, in
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 955
the context of these considerations, prescribers need reliable
evidence on the relative efficacy, tolerability and safety of the
available topical agents in order to devise a management strategy that delivers the best chance of achieving a satisfactory
outcome. The aim of this analysis is therefore twofold: (i) to
summarize the evidence on topical treatments in chronic
plaque psoriasis (stratified for trunk and limbs, and scalp) to
allow comparison of their efficacy, tolerability and safety; and
(ii) to synthesize data on efficacy to inform original costeffectiveness modelling.7 Data arising from this work were
used to inform recommendations on the use of topical therapy
for the National Institute for Health and Clinical Excellence
guideline on Assessment and Management of Psoriasis.8
PGA. The secondary outcome was clear or nearly clear status
as assessed by either the Patient’s Assessment of Overall Global
Improvement (PAGI) or the static patient’s global assessment.
Consistent data extraction for the outcome of clear or nearly
clear across the different scales was achieved by aligning the
descriptors as follows: ‘clear’, ‘nearly clear’, ‘75% improvement’, ‘excellent improvement’, ‘marked improvement’ or
‘minimal’ for dynamic scales; and ‘minimal’ or ‘very mild’ for
static scales. Other outcomes were duration of remission or
time to relapse, skin atrophy and withdrawal due to adverse
events (as a marker of tolerability).
Materials and methods
Data were extracted according to a standard template. Assessment of methodological quality and methods of analysis are
reported elsewhere.8
Search strategy and selection criteria
A systematic literature search was conducted according to a
predefined protocol for randomized, placebo-controlled or
head-to-head trials of U.K.-licensed topical therapies for plaque
psoriasis. Outcomes for the scalp were considered separately
from those of the trunk and limbs because the scalp is considered a high need, difficult-to-treat site due to difficulties with
application of topical therapies, differences in formulations,
and acceptable frequencies of application. Comprehensive
searches of Medline, Embase, Cinahl and The Cochrane Library
were conducted and last updated on 8 March 2012, restricted
to articles published in English (see Table S1, Supporting Information, for full search strategy). Abstracts were screened, and
articles that appeared to meet the inclusion criteria were
assessed further. Studies were excluded if they were not published as full reports, due to high risk of bias. Reference lists of
relevant articles were scrutinized to identify additional reports.
Eligible studies were required to have at least 25 people in
each study arm and to report induction or maintenance of
remission. The unit of randomization could be the individual
patient or one side of the body. Interventions included were:
vitamin D and vitamin D analogues (henceforth referred to as
vitamin D analogues), potent or very potent corticosteroids,
combined application of vitamin D analogue and potent corticosteroid either as a two-compound formulation (TCF) product (DovobetTM; LEO Pharma, Princes Risborough, U.K.) or
applied separately, one in the morning and one in the evening
[two-compound application; TCA (am/pm)], tar, dithranol
and retinoids. The included comparisons for the pairwise analyses for trunk and limb psoriasis were (i) any of the topical
monotherapies compared with vitamin D analogues or with
placebo or vehicle; and (ii) combined vitamin D analogue and
potent corticosteroid [TCF or TCA (am/pm)] compared with
the constituent monotherapies. For scalp psoriasis all comparisons were included in the pairwise analysis.
The primary outcome was the proportion of patients
achieving clear or nearly clear status on either the Investigator’s Assessment of Overall Global Improvement (IAGI) or
dynamic Physician’s Global Assessment (PGA), or the static
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
Data extraction and quality assessment
Statistical analysis
Data were stratified according to the site of psoriasis: (i) trunk
and limbs; and (ii) scalp. Given the number of different interventions, data on all agents within a drug class were pooled
into one analysis; however, once- and twice-daily applications
were kept as separate comparators for the network meta-analysis (NMA). Additionally, although it was not possible to
adjust data from within-patient comparison trials for the
correlation coefficient relating to the comparison of paired
data, within- and between-patient data were pooled. This
provided a conservative estimate, accepting that it may result
in underweighting of the within-patient studies.
A series of pairwise meta-analyses for the primary and secondary outcomes for induction of remission produced 12
direct comparisons for trunk and limb psoriasis and 10 for
scalp psoriasis. To synthesize all data (both direct and indirect
comparisons) into a single, coherent set of effect sizes, a hierarchical Bayesian NMA was performed.9 This produced odds
ratios (and 95% confidence intervals) for each treatment compared with all the others. We then derived relative risks and
absolute risks for each treatment from these odds ratios using
the absolute risk from data on twice-daily vehicle or placebo.
The analysis was performed in WinBUGS 19 (Medical Research
Council, Cambridge, U.K.) using a multi-arm, random-effects
logistic regression model, with parameters estimated by Markov
chain Monte Carlo Simulation (Appendices S1 and S2; see
Supporting Information). The model used the assumption that
the between-trial heterogeneity was equal across all comparisons.
For each analysis, 20 000 burn-in simulations were run for
convergence followed by a further 40 000 simulations to
produce the outputs. Full details of the analysis methods have
been published elsewhere.8 Inconsistency in the direct evidence
was assessed using Bucher’s method,10 comparing the odds ratios
from the pairwise meta-analysis wherever a loop of direct
evidence was available. We also compared estimates of effect
from the pairwise meta-analyses and NMAs. No significant inconsistency was identified.
British Journal of Dermatology (2013) 168, pp954–967
956 Topical therapies for plaque psoriasis, E.J. Samarasekera et al.
studies60,62,63,65,68,70–73 included those with moderateto-severe scalp involvement, with three64,67,69 stipulating
mild-to-moderate scalp disease and three61,66,74 allowing any
severity to be included.
Results
Search results and study characteristics
Of 2619 abstracts retrieved, 48 studies11–59 were included for
trunk and limb psoriasis and 1760–76 for scalp psoriasis (see
Fig. 1 for full selection process). Details of the included studies for trunk and limb psoriasis and scalp psoriasis are summarized in Tables S2 and S3, respectively (see Supporting
Information). There was variation in methodology and reporting between the studies, for example in treatment duration
(range: 2–12 weeks for trunk and limbs; 2–8 weeks for scalp;
maintenance studies up to 52 weeks). Evidence quality varied
between outcomes and comparisons (range: very low to
high); common limitations were unclear allocation concealment and blinding, and imprecise estimates for safety or tolerability measures. There were also differences in the baseline
disease severity. For trunk and limb psoriasis approximately
half of the studies included populations with moderate-tosevere psoriasis assessed by PASI, PGA or body surface area
(BSA), while others included either mild-to-moderate psoriasis, any disease severity or did not specify severity as an
inclusion criterion. Therefore, there would have been a
range from limited to more widespread disease among the
studies included. For scalp psoriasis, the majority of
(a) TRUNK & LIMBS
Pairwise results (investigator and patient assessments)
Tables 1 and 2 summarize the individual study results; the
outputs of the direct pairwise meta-analysis that were used as
inputs for the NMA are available in Figures S1 and S2 (see
Supporting Information) for psoriasis of the trunk and limbs,
and scalp, respectively. Time to remission varied among the
interventions (Table S4; see Supporting Information), and
variations in study length and frequency of application made
direct comparisons difficult. Overall, the most rapid improvement in response occurred during the first 2–4 weeks for
corticosteroids, and the first 4 weeks for vitamin D analoguecontaining interventions, dithranol and coal tar. Data from
long-term or ‘maintenance’ studies were not included in the
NMA (see Tables 3 and 4), and a separate NMA for long-term
data was not possible as only two studies were available for
each of trunk and limb57–59 and scalp75,76 psoriasis, and one
of these76 did not report the primary outcome.
(b) SCALP
2619 Records identified
2586 Records excluded
2470 Records excluded
101 Full-text articles excluded
Achievement of clear or nearly clear
149 Full-text articles
assessed for eligibility
33 Full-text articles assessed
for eligibility
30 Insufficient sample size
16 Full-text articles excluded
19 Incorrect outcomes
10 Incorrect outcomes
22 Incorrect comparison
2 Incorrect comparison
22 Incorrect study/article type
2 Incorrect population
4 Inadequate reporting
2 Incorrect study/article type
4 Not English language
48 Studies included in
quantitative synthesis
17 Studies included in
quantitative synthesis
9 Excluded from NMA
4 Excluded from NMA
Did not report primary or
secondary outcomes, or longterm maintenance studies
Did not report primary
outcome, or long-term
maintenance studies
39 Studies included in NMA
13 Studies included in NMA
Fig 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow chart for selection of studies; (a) for trunk and limb psoriasis and
(b) for scalp psoriasis. NMA, network meta-analysis.
British Journal of Dermatology (2013) 168, pp954–967
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 957
Table 1 Trunk and limb psoriasis – Investigator’s Assessment of Overall Global Improvement (IAGI), Physician’s Global Assessment (PGA) and
Patient’s Assessment of Overall Global Improvement (PAGI) efficacy data for induction of remission
Study
11
Barker 1999
Perez 199612
Fleming 201013
Kaufmann 200214
Langley 201115
Medansky 198716
Decroix 200417
Weinstein study A 200318
Weinstein study B 200318
Langner 199219
Langner 199320
Highton 199521
Dubertret 199222
Harrington 199623
Oranje 199747,a
Papp 200324,b
Guenther 200225
Wortzel 197526
Sears 199727
Lowe 200528
Gottlieb 200329
Lebwohl 200230
Jarratt 200631
IAGI or PGA ‘clear/
nearly clear’
PAGI ‘clear/nearly
clear’
r
n
%
15
137
216
316
14
35
69
157
480
476
490
64
163
171
96
285
454
645
21.9
215
404
13
148
16
21
13
99
195
223
26
117
98
164
71
291
34
43
107
308
312
301
206
227
150
234
18.3
509
47.1
48.8
121
321
625
741
126
515
653
701
2
12
83
78
2.4
15.4
36
79
1
8
140
139
20
61
257
568
5.0
13.1
Topical
Dose
r
n
%
Placebo
Vitamin D
Placebo
Vitamin D
Placebo
Vitamin D
Potent corticosteroid
Combined vitamin D and potent corticosteroid
Placebo
Vitamin D
Potent corticosteroid
Combined vitamin D and potent corticosteroid
Placebo
Vitamin D
Combined vitamin D and potent corticosteroid
Placebo
Potent corticosteroid
Placebo
Very potent corticosteroid
Placebo
Retinoid
Placebo
Retinoid
Placebo
Vitamin D
Placebo
Vitamin D
Placebo
Vitamin D
Placebo
Vitamin D
Placebo
Vitamin D
Placebo
Vitamin D
Placebo
Vitamin D
Potent corticosteroid
Combined vitamin D and potent corticosteroid
Placebo
Vitamin D
Combined vitamin D and potent corticosteroid
Combined vitamin D and potent corticosteroid
Placebo
Potent corticosteroid
Placebo
Potent corticosteroid
Placebo
Very potent corticosteroid
Placebo
Very potent corticosteroid
Placebo
Very potent corticosteroid
Placebo
Very potent corticosteroid
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
OD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BDc
BD
BD
OD
BDc
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
1
13
0
37
0
9
14
44
16
107
176
276
5
33
73
7
18
5
144
7
24
2
26
9
21
13
24
23
87
11
46
26
28
84
84
40
79
83
162
157
480
476
490
91
184
183
45
50
33
189
229
439
214
421
29
29
32
32
123
124
62
62
3.8
46.4
0.0
44.0
0.0
11.4
16.9
272
102
223
370
563
5.5
179
399
15.6
36.0
15.2
762
31
55
09
62
31.0
72.4
40.6
75.0
187
702
17.7
74.2
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
15
26
8
103
174
229
19
115
95
172
4
15
1
12
0
84
27
85
1
10
2
47
43
43
107
308
312
301
206
227
150
234
37
39
83
78
29
162
125
120
20
61
60
60
34.9
60.5
75
334
558
761
92
507
633
735
10.8
38.5
1.2
15.4
0.0
519
216
708
5.0
16.4
3.3
78.3
British Journal of Dermatology (2013) 168, pp954–967
958 Topical therapies for plaque psoriasis, E.J. Samarasekera et al.
Table 1 (Continued)
IAGI or PGA ‘clear/
nearly clear’
PAGI ‘clear/nearly
clear’
Study
Topical
Dose
r
n
%
r
n
%
Kragballe 199832
Vitamin D
Vitamin D
Concurrent vitamin D and potent corticosteroid
Vitamin D
Combined vitamin D and potent corticosteroid
Vitamin D
Potent corticosteroid
Vitamin D
Potent corticosteroid
Vitamin D
Potent corticosteroid
Vitamin D
Potent corticosteroid
Vitamin D
Potent corticosteroid
Combined vitamin D and potent corticosteroid
Vitamin D
Concurrent vitamin D and potent corticosteroid
Vitamin D
Coal tar
Vitamin D
Coal tar
Vitamin D
Coal tar
Vitamin D
Dithranol
Vitamin D
Dithranol
Vitamin D
Dithranol
Vitamin D
Dithranol
Potent corticosteroid
Coal tar
Very potent corticosteroid
Combined vitamin D and potent corticosteroid
OD
BD
49
69
73
43
143
67
81
119
116
172
172
172
252
249
128
130
205
207
285
401
424
171
574
523
623
580
560
46
69
89
44
135
172
172
174
252
249
267
401
511
175
542
281
237
123
101
140
183
248
342
342
201
200
365
363
369
822
693
612
505
384
504
672
93
65
180
123
153
131
231
227
608
496
779
542
Ortonne 200433
Camarasa 200334
Molin 199735
Kragballe 199136
Cunliffe 199237
Douglas 200238
Ruzicka 199839
Tham 199440
Alora-Palli 201041
Pinheiro 199742
Hutchinson 200043
Wall 199844
Berth-Jones 199245
Christensen 199946
Thawornchaisit 200749,d
Menter 200948,e
OD
OD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BD
BDc
BD
BD
OD
BD
BD
BD
BD
BD
OD
BD
OD
BD
OD
BD
OD
BD
BD
BD
OD
142
169
251
22
27
13
3
6
14
47
28
23
24
92
67
180
116
6
4
23
7
32
32
365
363
369
49
39
27
27
28
27
65
57
60
54
153
131
231
227
89
77
30
28
44
49
389
466
680
44.9
69.2
48.1
11.1
21.4
51.9
72.3
49.1
38.3
44.4
601
511
779
511
6.7
5.2
76.7
25.0
72.7
65.3
OD, once daily; BD, twice daily. Bold text denotes data included only in the sensitivity analysis of the network meta-analysis. aOranje 1997
evaluated treatments in a paediatric population. bData from Papp 2003 for IAGI/PGA were included in the base case, but only PAGI data
were included in the sensitivity analysis because they were excluded from the clinical review of direct evidence, given that in the paper they
were reported graphically. cTwice-daily combined vitamin D and potent corticosteroid was included only as a comparator in the sensitivity
analysis given that it is currently unlicensed in the U.K. at this dose. dThe protocol for the clinical review of direct evidence included only
comparisons of single topical therapies with either placebo/vehicle or vitamin D; therefore, the comparison of potent corticosteroid and coal
tar was included only in the sensitivity analysis. eThe protocol for the clinical review of direct evidence included only comparisons of combination therapies with either vitamin D or potent corticosteroid; therefore, the comparison of combined vitamin D and potent corticosteroid
and very potent corticosteroid was included only in the sensitivity analysis.
Network meta-analysis results for trunk and limb psoriasis
Investigator’s assessment of response Thirty four stidues11–35,38–46
were available for the base-case network for the primary outcome of investigator’s assessment of achieving clear or nearly
clear status, including 11 604 patients randomized to 14
interventions. Seventeen of these studies included people with
at least moderate disease severity, most commonly measured
by having over 10% BSA coverage. There was a notable
British Journal of Dermatology (2013) 168, pp954–967
absence of trials comparing the TCF product with TCA (am/
pm) (see Fig. S3, Supporting Information, showing direct
comparisons forming the network). All active interventions
were significantly more effective than placebo twice daily,
except coal tar used once daily and retinoids (Fig. 2). Very
potent steroids were the most effective treatment option (calculated response rate of 782% when applied twice daily). For
other active interventions, response rates ranged from 122%
for once-daily coal tar to 709% for once-daily TCF product
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 959
Table 2 Scalp psoriasis – Investigator’s Assessment of Overall Global Improvement (IAGI), Physician’s Global Assessment (PGA) and Patient’s
Assessment of Overall Global Improvement (PAGI) efficacy data for induction of remission
Study
61
Buckley 2008
Franz 199962
Franz 200063
Green 199464
Jarratt 200465
Jemec 200866
Klaber 199467
Kragballe 200968
McKinnon 200069
Olsen 199170
Reygagne 200571
Sofen 201172
Tyring 201073
van de Kerkhof 200974
Topical
Dose
Potent corticosteroid
Combined vitamin D and potent corticosteroid
Placebo
Potent corticosteroid
Placebo
Very potent corticosteroid
Placebo
Vitamin D
Placebo
Very potent corticosteroid
Placebo
Vitamin D
Potent corticosteroid
Combined vitamin D and potent corticosteroid
Vitamin D
Potent corticosteroid
Vitamin D
Combined vitamin D and potent corticosteroid
Vitamin D
Coal tar polytherapy
Placebo
Very potent corticosteroid
Vitamin D
Very potent corticosteroid
Placebo
Very potent corticosteroid
Placebo
Combined vitamin D and potent corticosteroid
Vitamin D
Potent corticosteroid
Combined vitamin D and potent corticosteroid
OD
OD
BD
BD
BD
BD
OD
OD
OD
OD
OD
OD
OD
OD
BD
BD
BD
OD
BD
OD
BD
BD
BD
OD
BD
BD
OD
OD
OD
OD
OD
IAGI or PGA ‘clear/
nearly clear’
PAGI ‘clear/nearly
clear’
r
r
n
%
91
100
10
71
4
77
110
108
57
115
63
125
827
926
17.5
617
6.3
616
28
104
348
371
136
171
136
272
556
541
236
232
206
382
626
686
576
737
23
36
75
76
30.7
47.4
15
84
128
227
395
42
135
286
562
567
35.7
622
448
404
697
12
68
5
86
4
15
1
40
31
100
356
385
138
175
33
142
120
79
16
129
21
38
5
35
17
97
124
343
388
n
57
115
63
125
24
25
47
95
136
272
556
541
236
232
105
207
210
213
189
188
75
76
40
41
42
135
286
562
567
%
21.1
591
7.9
688
16.7
60.0
2.1
42.1
228
368
640
712
585
754
314
686
571
371
85
686
28.0
50.0
12.5
85.4
40.5
719
434
610
684
OD, once daily; BD, twice daily. Bold text denotes data not included in the network meta-analysis.
(Fig. 3 and Table S5; see Supporting Information). The probability distributions for the rank order of each intervention
within the treatment hierarchy are shown in Figure S4 (see
Supporting Information).
When comparing the odds of response between different
active interventions, for the majority of comparisons there
were no significant differences, including between TCF product and TCA (am/pm) (Fig. S1; see Supporting Information).
However, the TCF product was significantly more effective
than once-daily application of vitamin D analogues, potent
corticosteroids, retinoids or coal tar. There was a trend to suggest that twice-daily application of any given intervention was
more effective than once-daily application (especially for coal
tar), but any differences were not statistically significant when
comparing odds of response.
A sensitivity analysis investigating the impact of including
three studies excluded from the base case (one paediatric
study47 and two studies48,49 with comparisons that did not
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
match the protocol) did not alter the overall findings, with
twice-daily application of a very potent steroid still being the
most effective treatment compared with vehicle twice daily
[relative risk (RR) 610 in base case vs. 573 in sensitivity
analysis]. The only notable difference was that the estimated
efficacy of twice-daily coal tar was reduced markedly by the
inclusion of a study with shorter duration (6 weeks vs.
8–12 weeks in base-case studies); see also Reference 8 for full
details of this analysis.
Patient’s assessment of response For the secondary outcome of patient
assessment of response, 14 studies were available
(n = 7644),14,15,23,25,27,29,30,32,33,36–38,44–46 substantially fewer
than for investigator assessment (Fig. S5; see Supporting Information). Regarding the hierarchy of efficacy, notable differences from the outcomes based on the investigators’
assessment included very potent corticosteroid twice daily
being ranked much lower by the patient assessment (sixth vs.
British Journal of Dermatology (2013) 168, pp954–967
960 Topical therapies for plaque psoriasis, E.J. Samarasekera et al.
Table 3 Long-term maintenance of remission
IAGI or PGA ‘clear/
nearly clear’
Study
Trunk and limbs
Kragballe 200658,a
Katz 199157,b
r
n
%*
52 weeks
52 weeks
80
62
104
89
769
69.7
OD
52 weeks
78
104
75
–
–
6 months
6 months
27
7
46
44
58.7
15.9
Topical
Dose
Duration of follow-up
Combined vitamin D and potent corticosteroid
Combined vitamin D and potent corticosteroid
(4 weeks) then vitamin D (48 weeks)
Alternating 4-week periods of combined vitamin
D and potent corticosteroid, and vitamin D
Potent corticosteroid
Placebo
OD
OD
IAGI, Investigator’s Assessment of Overall Global Improvement; PGA, Physician’s Global Assessment; OD, once daily. aThis maintenance study
enrolled patients with plaque psoriasis of at least moderate severity and allowed treatment once daily according to the randomized intervention schedule for up to 52 weeks for application when required. bThis maintenance study included participants who achieved remission after
3–4 weeks’ treatment with betamethasone dipropionate. The maintenance regimen was intermittent betamethasone dipropionate applied to
the site of the healed lesion (three consecutive applications 12 h apart, once a week for a maximum treatment period of 6 months).
first) and once-daily application of potent corticosteroid or
placebo appearing to be more effective than twice-daily application of the same agent (Fig. 4). There was also a trend
across the majority of interventions showing that the patient
assessment of response produced a lower estimate of the proportion responding than the investigator’s assessment (Table
S5; see Supporting Information). This difference was most
pronounced for twice-daily application of potent corticosteroid and once-daily dithranol.
Sensitivity analysis showed that including two studies initially excluded from the protocol for direct comparisons, one
in a paediatric population47 and one because the results were
presented only graphically,24 did not alter the overall findings,
with the TCF product still being the most effective compared
with vehicle twice daily (RR 463 in the base case vs. 428 in
sensitivity analysis). See also Reference 8 for full details of this
analysis.
Network meta-analysis results for scalp psoriasis
Investigator’s assessment of response Thirteen studies62–74 were available in the base-case network for the primary outcome of
investigator’s assessment of achieving clear or nearly clear status, including 5640 patients randomized to 10 different interventions (Fig. S6, see Supporting Information, showing direct
comparisons forming the network). Ten of the studies
reported on scalp psoriasis of at least moderate severity.
All active interventions were more efficacious than placebo
applied twice daily, although there was uncertainty about this
for coal-tar shampoo and vitamin D analogues used once daily
(see Fig. 5 for relative risks and Fig. 6 for absolute risks of
each intervention compared with the baseline risk of
response). As with psoriasis of the trunk and limbs, very
potent steroids were the most effective treatment option
(response rates 7835% for twice-daily and 6926% for oncedaily applications). Twice-daily coal-tar shampoo was no better than placebo (1892% and 1809%, respectively). The
British Journal of Dermatology (2013) 168, pp954–967
probability distribution of being ranked in a certain position
in the treatment hierarchy for each intervention is shown in
Figure S7 (see Supporting Information).
Considering comparisons between different active interventions, very few demonstrated a statistically significant
difference (Fig. S2). Exceptions were that once-daily application of potent corticosteroid or the TCF product was significantly more effective than vitamin D analogues once daily,
and very potent corticosteroids were significantly better than
vitamin D analogues regardless of frequency of application.
Additionally, very potent corticosteroids and the TCF product were significantly more effective than coal-tar shampoo
once daily. Unlike the results for trunk and limb psoriasis,
across all interventions there was no consistent trend that
increasing treatment frequency was linked to improved efficacy.
It was not possible to analyse the patient-assessed outcomes
as no single connected network could be formed based on
published comparisons.
Duration of remission
Clear evidence regarding the duration of remission was lacking, with only seven studies, three for trunk and limbs57,67,68
and four for scalp,15,34,46,75 reporting this outcome (Table 4).
One study for scalp68 and one for trunk and limb34 psoriasis
suggested that the relapse rate was greater for interventions
containing steroids compared with vitamin D analogues. The
proportion relapsing following treatment withdrawal across all
interventions ranged from 20% to 80% in the short term, up
to 88% after 6 months, with no consistent evidence for superiority of any one intervention.
Tolerability and adverse effects
Withdrawals from trials due to toxicity (as a proxy marker of tolerability) and reported cases of skin atrophy (as the principal local
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 961
Table 4 Duration of remission and relapse rates
Study
Trunk and limbs
Langley 201115
Camarasa 200334
Definitions
Intervention
Remission: clear/nearly clear on IAGA.
Relapse: reduction in PASI improvement
from baseline
Dovobetc OD
Remission: clear/nearly clear.
Relapse: requiring retreatment
(not maintaining clear/nearly clear)
Christensen 199946 Remission: at least 50% improvement.
Relapse: requiring retreatment
(loss of response)
Katz 199157,a
Scalp
Klaber 199467
Kragballe 200968
Poulin 201075,b
Remission: clear or slight on a 4-point scale
(clear, slight, moderate, severe).
Relapse: moderate or severe disease
or TSS 25 at two consecutive visits
Relapse rate
8 weeks post-treatment:
28/67 responders (42%)
Tacalcitol OD
8 weeks post-treatment:
7/31 responders (23%)
Placebo
8 weeks post-treatment:
3/5 responders (60%)
Calcitriol BD
8 weeks post-treatment:
30/58 responders (52%)
Betamethasone
8 weeks post-treatment:
dipropionate BD 55/73 responders (75%)
Calcipotriol BD
8 weeks post-treatment:
50/62 responders (81%)
Dithranol OD
8 weeks post treatment:
19/33 responders (58%)
Intermittent
During 24-week
betamethasone
maintenance: 16/46
dipropionate
(35%)
Placebo
During 24-week
maintenance: 35/44
(80%)
Remission: not applicable – no relapse among
responders only.
Relapse: increase in the total sign score to
at least 50% of the score at the start of
double-blind treatment
Remission: ‘clear’ or ‘minimal’ disease
according to PGA.
Relapse: recurrence of at least moderate disease
according to PGA
Calcipotriol BD
Remission: at least mild on PGA.
Relapse: PGA > 2 (moderate, severe or
very severe scalp psoriasis)
Clobetasol
propionate
twice weekly
Betamethasone
valerate BD
Xamiolc OD
Calcipotriol BD
Placebo
Time to relapse
Median: 63 days
Median: 61 days
Median: 61 days
Mean: 234 days
Mean: 253 days
Median: 29 days
Median: 56 days
Hazard ratio
037 (95%
CI 021–067)
4 weeks post-treatment:
75/99 (76%)
4 weeks post-treatment:
102/129 (791%)
–
8 weeks post-treatment:
73/135 responders
(541%)
8 weeks post-treatment:
10/29 responders (34%)
Number still in remission
after 6 months of
maintenance: 27/67
(40%)
Number still in remission
after 6 months of
maintenance: 8/69 (12%)
Median: 35 days
Median: 58 days
Median: 141
days
Median: 305
days
IAGA, Investigator’s Assessment of Overall Global Improvement; PASI, Psoriasis Area and Severity Index; OD, once daily; BD, twice daily; TSS,
total severity score; CI, confidence interval; PGA, Physician’s Global Assessment. aThis was a maintenance study that included participants who
achieved remission after 3–4 weeks’ treatment with betamethasone dipropionate. The maintenance regimen was intermittent betamethasone dipropionate applied to the site of the healed lesion (three consecutive applications 12 h apart, once a week for a maximum treatment period of
6 months). bThis was a maintenance study with treatment for up to 6 months among those who had achieved clear, very mild or mild disease
during a 4-week induction phase with once-daily clobetasol propionate. During the maintenance phase clobetasol propionate was used twice
weekly (3 days apart), but once-daily dosing was permitted for up to 4 weeks if relapse occurred. cLeo Pharma, Princes Risborough, U.K.
adverse effect associated with corticosteroids) across all comparisons and both populations showed low event rates, even in the
long term and in maintenance studies up to 52 weeks. The relative estimates were very imprecise, but in absolute terms demonstrated precise evidence of no clinically relevant differences
between the interventions because the numbers involved were so
low. There was no statistically significant increased risk of steroid
atrophy with corticosteroid use compared with other interventions, although the majority of cases of steroid atrophy reported
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
did occur in people who received corticosteroids, and
greater numbers of withdrawals due to adverse effects were seen
with twice-daily potent corticosteroid compared with once-daily
use. See also Reference 8 for full details of these outcomes.
Discussion
Overall, the NMA hierarchy of effectiveness for topical therapy
for trunk and limb psoriasis indicated that, discounting very
British Journal of Dermatology (2013) 168, pp954–967
962 Topical therapies for plaque psoriasis, E.J. Samarasekera et al.
Very potent corticosteroid BD: 6·10 (4·48–7·14)
TCF OD: 5·55 (3·49–6·88)
Very potent corticosteroid OD: 5·31 (1·44–7·38)
TCA (am/pm): 5·12 (2·87–6·78)
Potent corticosteroid BD: 4·90 (3·40–6·14)
Coal tar BD: 4·23 (1·90–6·49)
Vitamin D BD: 4·26 (3·06–5·42)
Potent corticosteroid OD: 3·78 (1·46–6·14)
Vitamin D OD: 3·44 (1·56–5·63)
Dithranol OD: 3·38 (1·71–5·34)
Retinoid OD: 2·17 (0·43–5·57)
Coal tar OD: 0·98 (0·12–4·18)
Placebo OD: 0·78 (0·21–2·29)
0·1
1·1
2·1
3·1
4·1
5·1
6·1
7·1
8·1
Risk Ratio
Fig 2. Summary of relative risk of response for all interventions compared with twice-daily placebo for trunk and limb psoriasis based on
investigator’s assessment of response. BD, twice daily; TCF, two-compound formulation product containing potent corticosteroid and vitamin D
analogue; OD, once daily; TCA (am/pm), two-compound application of potent corticosteroid and vitamin D analogue, one in the morning and
one in the evening.
90%
80%
Once daily
78·20%
Twice daily
70·90%
Probability of response
70%
62·40%
60%
54·90%
65·40%
67·90%
54·20%
47·90%
50%
43·50%
42·80%
40%
27·30%
30%
20%
10%
0%
12·50%
9·70%
Vehicle
12·20%
Tazarotene
Dithranol
Coal tar
Vitamin D
Potent
TCA (am/pm)
corticosteroid
TCF product
Very potent
corticosteroid
Fig 3. Absolute response rates for trunk and limb psoriasis based on investigator’s assessment of response. TCF, two-compound formulation
product containing potent corticosteroid and vitamin D analogue; TCA (am/pm), two-compound application of potent corticosteroid and vitamin
D analogue, one in the morning and one in the evening.
potent steroids (which many dermatologists would not
consider a suitable option for most patients based on clinical
experience of local adverse effects), the combination of potent
British Journal of Dermatology (2013) 168, pp954–967
corticosteroid and vitamin D analogue, either applied once
daily in a single TCF product or applied separately, was the
most effective intervention, with no significant difference
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 963
TCF OD: 4·63 (2·86–5·86)
TCA (am/pm): 4·22 (1·85–5·92)
Potent corticosteroid OD: 3·85 (1·50–5·82)
Vitamin D BD: 3·56 (2·16–4·92)
Potent corticosteroid BD: 3·29 (1·73–4·97)
Very potent corticosteroid BD: 2·65 (1·09–4·65)
Vitamin D OD: 2·45 (0·99–4·43)
Dithranol OD: 2·29 (0·83–4·43)
Placebo OD: 1·54 (0·45–3·80)
0·1
2·1
4·1
6·1
Risk Ratio
Fig 4. Summary of relative risk of response for all interventions compared with twice-daily placebo for trunk and limb psoriasis based on patient’s
assessment of response. TCF, two-compound formulation product containing potent corticosteroid and vitamin D analogue; OD, once daily; TCA
(am/pm), two-compound application of potent corticosteroid and vitamin D analogue, one in the morning and one in the evening; BD, twice
daily.
Very potent corticosteroid BD: 6·96 (5·62–7·96)
Very potent corticosteroid OD: 6·15 (2·99–8·31)
TCF OD: 5·71 (2·35–7·95)
Potent corticosteroid OD: 5·04 (1·61–7·79)
Potent corticosteroid BD: 4·38 (2·22–6·68)
Vitamin D BD: 3·10 (1·31–5·94)
Vitamin D OD 3·07 (0·71–6·59)
Placebo OD: 1·74 (0·37–4·89)
Coal tar polytherapy OD: 1·68 (0·42–5·29)
0·1
1·1
2·1
3·1
4·1
5·1
6·1
7·1
8·1
9·1
Risk Ratio
Fig 5. Summary of relative risk of response for all interventions compared with twice-daily placebo for scalp psoriasis based on investigator’s
assessment of response. BD, twice daily; OD, once daily; TCF, two-compound formulation product containing potent corticosteroid and vitamin D
analogue.
between these application methods. No important differences
in terms of tolerability or toxicity were evident between these
treatment options. The rank order of efficacy (confined to
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
investigator’s assessment) was similar for the scalp; however,
perhaps not surprisingly given difficulties with application,
there was a lack of any consistent trend linking frequency of
British Journal of Dermatology (2013) 168, pp954–967
964 Topical therapies for plaque psoriasis, E.J. Samarasekera et al.
90%
Once daily
80%
78·35%
Twice daily
69·26%
Probability of response
70%
64·24%
60%
56·75%
49·31%
50%
40%
34·59%
34·89%
30%
20%
18·92%
18·09%
11·26%
10%
0%
Vehicle
Coal tar polytherapy
Vitamin D
Potent corticosteroid
TCF product
Very potent corticosteroid
Fig 6. Absolute response rates for scalp psoriasis based on investigator’s assessment of response. TCF, two-compound formulation product
containing potent corticosteroid and vitamin D analogue.
application to improved efficacy. Very potent steroids were
the most effective treatment and vitamin D analogues and
coal-tar shampoo were the least effective overall, with coal-tar
shampoo showing similar response rates to placebo. This
effect estimate was based on just one study for coal tar69 and
may be unreliable, but the absence of evidence for efficacy is
important to note given that coal-tar shampoo is commonly
prescribed in primary care.77,78
For trunk and limb psoriasis, some discordance was evident
between results for physician- and patient-assessed outcomes,
which may be caused by the relative paucity of evidence to
inform the effect estimates for the patient-assessed outcome.
However, for most interventions, patients were less positive in
their evaluation of response than investigators, particularly for
twice-daily application of potent corticosteroid and once-daily
dithranol. This may indicate differences between patients’ and
physicians’ perception of ‘clear or nearly clear’ and highlights
the importance of including both outcomes when evaluating
topical interventions. Similarly, the nonsignificant trend
towards twice-daily applications being more effective than
once-daily application was not seen in the patient-assessed
data, which might reflect the preference of patients for oncedaily applications to reduce the burden of treatment.
Strengths of this study include the additional power afforded by synthesizing all of the available data in one coherent
network. Additionally, the assumption that between-trial
heterogeneity is equal across all comparisons may allow heterogeneity to be more accurately estimated for comparisons
with few studies. For example, for the comparison of TCF vs.
vitamin D twice daily the confidence interval from the direct
evidence (based on only two trials) was narrower than that
based on the NMA. In this case the NMA estimate is more
conservative than the direct evidence, but if more trials were
conducted we might find that the existing direct evidence is
underestimating heterogeneity.
British Journal of Dermatology (2013) 168, pp954–967
A recognized limitation of this analysis is that for the
majority of trunk and limb studies included, the severity of
psoriasis was recorded as moderate to severe. Consequently,
our results may not be wholly generalizable to patients with
mild-to-moderate disease for which topical therapy is the
mainstay of treatment. Nevertheless, our analysis did include
12 studies with mild-to-moderate disease, which represents
the majority of patients for whom topical therapy is appropriate. Additionally, generalizability may be further limited by
the common risk of recruitment bias, meaning that the clinical
trial participants may not be representative of those in clinical
practice, owing to the restrictions on those included, although
in the majority of studies the exclusion criteria were not
excessively stringent.
This review highlights important gaps in the evidence.
There were no direct comparisons between TCA (am/pm)
and TCF products. More importantly, the majority of the trials
focused on achievement of remission, with very limited data
on key outcomes of relevance to psoriasis such as relapse
rates, the optimal point at which to reinstate treatment on
relapse and strategies to maintain remission. The data do not
suggest any major risk associated with corticosteroid use, even
in the context of moderate or severe disease. While this is
reassuring, these data should be interpreted with caution:
most of the studies were short term and may be inadequately
powered to accurately determine true risk. Furthermore, presence or absence of steroid atrophy was a key outcome in only
a minority of studies, and no study used validated objective
measures for assessment (e.g. skin ultrasound). Patients and
clinicians should therefore remain vigilant for potential local
(and systemic) sequelae associated with corticosteroids in psoriasis. However, nonsteroid-based treatments such as retinoids,
coal tar and vitamin D are less effective, and so a strategy for
the safe and effective long-term use of treatments for the
maintenance of disease control in psoriasis is urgently needed.
© 2013 The Authors
BJD © 2013 British Association of Dermatologists
Topical therapies for plaque psoriasis, E.J. Samarasekera et al. 965
Future studies should ensure that patients’ evaluations of treatment are included as outcomes.
What’s already known about this topic?
●
Topical treatments are widely available and prescribed
for plaque-type psoriasis.
What does this study add?
●
●
●
Explicit rank order of efficacy, showing that treatment
strategies containing potent or very potent corticosteroids are the most effective.
Investigator and patient evaluation of efficacy may differ.
Twice-daily application of the same intervention offers
no important benefit over once-daily application for
most treatments.
Acknowledgments
This work was undertaken by the National Clinical Guideline
Centre, which received funding from the National Institute for
Health and Clinical Excellence. The views expressed in this
publication are those of the authors and not necessarily those
of the Institute. No funding was received that directly influenced the preparation or decision to publish this review. This
research was supported by the National Institute for Health
Research Biomedical Research Centre at Guy’s and St Thomas’
NHS Foundation Trust and King’s College London. The views
expressed are those of the authors and not necessarily those of
the NHS, NIHR or the Department of Health.
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Supporting Information
Additional Supporting Information may be found in the online
version of this article at the publisher’s website:
Fig S1. Trunk and limb psoriasis – odds ratios for clear/
nearly clear as measured by IAGI or PGA, results of conventional and network meta-analyses.
Fig S2. Scalp psoriasis – odds ratios for clear/nearly clear as
measured by IAGI or PGA, results of conventional and network meta-analyses.
Fig S3. Network of evidence for investigator’s assessment
of clear or nearly clear status for trunk and limb psoriasis
(base case).
Fig S4. Rank density plots for investigator assessed response
– trunk and limb psoriasis.
Fig S5. Network of evidence for patient’s assessment of clear
or nearly clear status for trunk and limb psoriasis (base case).
Fig S6. Network of evidence for investigator’s assessment of
clear or nearly clear status for scalp psoriasis (base case).
Fig S7. Rank density plots for investigator assessed response
– scalp psoriasis.
Table S1. Full search strategy (using Embase (OVID) as an
example).
Table S2. Included study characteristics – trunk and limb
psoriasis.
Table S3. Included study characteristics – scalp psoriasis.
Table S4. Proportion achieving clear or nearly clear at different time-points during the trials.
Table S5. Absolute response rates for all interventions for
psoriasis of the trunk and limbs.
Appendix S1. WinBUGS code for investigator assessment of
trunk and limb psoriasis.
Appendix S2. WinBUGS code for investigator assessment of
scalp psoriasis.
British Journal of Dermatology (2013) 168, pp954–967