ARTICLE
Auteur(s) : Judith HJ Roelofzen1, Katja KH
Aben1,4, Ali JM Khawar1, Peter CM Van de
Kerkhof2, Lambertus ALM Kiemeney1,3,4, Pieter GM Van Der
Valk2
1Department of Epidemiology and Biostatistics,
Radboud University Nijmegen Medical Centre P.O Box 9101, 6500 HB
Nijmegen, The Netherlands
2Department of Dermatology, Radboud University Nijmegen
Medical Centre P.O Box 9101, 6500 HB Nijmegen, The Netherlands
3Department of Urology, Radboud University Nijmegen
Medical Centre; Nijmegen, The Netherlands
4Comprehensive Cancer Centre IKO, Nijmegen, the
Netherlands
accepté le 23 Mai 2007
Psoriasis and eczema are chronic skin diseases, which often require
years of treatment. Many therapies are available for these
dermatoses. In recent years, new topical therapies (e.g.
calcineurin inhibitors) and systemic therapies (e.g. biologicals)
have been introduced. Coal tar has been a well-established therapy
for psoriasis and eczema in past decades, but some reluctance to
use coal tar has evolved among dermatologists over recent years.
One of the reasons for this reluctance is the suspicion of an
increased risk of cancer after coal tar treatment in dermatological
practice. This suspicion is based on animal studies and studies in
occupational settings showing an increased risk of nonmelanoma skin
cancer after chronic exposure to coal tar [1-5]. However, the
results of epidemiologic studies on the dermatological use of coal
tar are conflicting. One study showed an increased risk of
non-melanoma skin cancer after coal tar treatment [6], but other
studies did not reveal an increased risk [7-11]. The risk of other
types of cancer is unknown. Because of a lack of large
epidemiological studies with long-term follow-up that specifically
investigated the (late) side effects of coal tar treatment,
uncertainty about the carcinogenicity of coal tar in dermatological
use remains. For this reason the LATER-study (“Late effects of coal
tar treatment in eczema and psoriasis; the Radboud study”)
started in November 2003 in the Netherlands. In this study 10,000
patients diagnosed with psoriasis or eczema before 1990 will be
included and the risk of cancer after coal tar treatment will be
evaluated.Because of the possible carcinogenicity and several
additional reasons (e.g., use is unpleasant for patients, doubts on
efficacy and difficulties in obtaining coal tar from pharmacies)
the use of coal tar in dermatological practice has decreased over
the past years. A survey was conducted among Dutch and Flemish
dermatologists with special emphasis on the use of coal tar in
order to find out the position of coal tar in the treatment of skin
diseases. The study was carried out in two countries to get an
impression of the variation between countries with respect to the
use of coal tar. This survey was conducted as part of the
LATER-study.
Methods
A questionnaire was developed and pilot-tested by three expert
dermatologists (two from the Netherlands and one from Flanders).
All dermatologists were asked to describe their treatment policy in
case of mild/moderate psoriasis, severe psoriasis, mild/moderate
eczema and severe eczema. For these questions, a list with topical,
photo-, and oral therapies was provided and dermatologists could
mark whether or not they used a listed therapy. In addition,
dermatologists could describe therapies that he/she used that were
not recorded in the list of questions. They were also asked to list
therapies that they had prescribed in the past but stopped
prescribing, including the reason(s) and year of stopping. Finally,
they were asked about prescriptions of topical therapies in the
case of pregnant patients with psoriasis or eczema. In this
questionnaire the overall terms ‘psoriasis’ and ‘eczema’ were used.
As a consequence, these terms included all the different types of
psoriasis and eczema.
The questionnaire were sent to all practising dermatologists in
the Netherlands (N = 360) and Flanders (N = 328) who were
registered as members of the Dutch or Belgian Association for
Dermatology and Venereology. The questionnaire was accompanied by
an invitational letter. In this letter we shortly introduced the
ongoing LATER-study. We explained that as part of this study (to
estimate the risk of cancer after coal tar treatment) we were
interested in the position of coal tar in the spectrum of treatment
modalities for psoriasis and eczema.
The invitational letters and questionnaires were mailed to the
dermatologists in the summer of 2004. After three weeks, a reminder
was sent. All collected data were summarised descriptively using
the statistical software program SPSS version 12.
Results
A total of 236 questionnaires were returned by Dutch dermatologists
(response rate 62.5%) and 153 questionnaires by Flemish
dermatologists (response rate 45.7%). Fourteen dermatologists were
retired or left the questionnaire blank and were therefore excluded
from the study.
Large differences exist in the work setting of Dutch and Flemish
dermatologists; the majority of Dutch dermatologists practise in a
general hospital (77%) while most Flemish dermatologists practise
in a private clinic (51%). The percentage of dermatologists
practising in a university hospital is about the same in both
countries (16% in the Netherlands, 17% in Flanders).
Treatment of psoriasis (table
1)
As expected, almost all dermatologists initially prescribe topical
corticosteroids and vitamin D3 analogues to patients
with psoriasis. The majority of dermatologists (91%) use class 3
corticosteroids (e.g., bethametasone dipropionate) for patients
with mild/moderate psoriasis. In case of severe psoriasis,
dermatologists prefer class 4 corticosteroids (e.g., clobetasol
dipropionate) (93%). In addition to corticosteroids and vitamin
D3 analogues, 49% of all dermatologists also apply tar
products to patients with psoriasis. Overall, the most frequently
used tar product is solutio carbonis detergens; Flemish
dermatologists apply this much more frequently than Dutch
dermatologists (56% vs. 30%, respectively). The majority of the
Flemish dermatologists prescribe solutio carbonis detergens in both
mild/moderate psoriasis and severe psoriasis (68%), while a
considerable number of the Dutch dermatologists prescribe this coal
tar product only to patients with mild/moderate psoriasis (42%).
Pix liquida (wood tar) is not used by Flemish dermatologists and is
used by only 5% of the Dutch dermatologists. Dermatologists
practising in a general hospital treat patients less frequently
with tar products than their colleagues from the university
hospitals or private clinics (44% vs. 52% and 58%). Next to coal
tar, dithranol is applied as a second choice therapy. Overall, 46%
of all dermatologists use dithranol although it is more frequently
applied by Dutch dermatologists compared to Flemish dermatologists
(56% vs. 30%). Dutch dermatologists prefer to use dithranol in both
mild/moderate psoriasis and severe psoriasis (52% compared to 41%
of the Flemish dermatologists), whereas the Flemish dermatologists
prescribe dithranol more frequently to patients with mild psoriasis
(25% vs. 15%). Dermatologists in university hospitals and in
general hospitals prescribe dithranol more often than the
dermatologists practising in private clinics (62% and 53% vs. 17%).
When topical therapies appear to be insufficiently effective or
when skin lesions are increasing, almost all dermatologists will
treat their patients with phototherapy. Flemish dermatologists
prefer to use PUVA (93% vs. 63% of the Dutch dermatologists)
whereas the Dutch dermatologists prefer to use UVB as first-choice
phototherapy (99% compared to 83% of the Flemish dermatologists).
In both countries, the majority of the dermatologists apply UVB in
both severe psoriasis and mild/moderate psoriasis (79%). In case of
PUVA, a small majority of dermatologists apply this
photochemotherapy in severe psoriasis as well as in mild/moderate
psoriasis (58%); a considerable number of dermatologists only use
this therapy in patients with severe psoriasis (41%).
When psoriasis is resistant to topical therapy or phototherapy,
dermatologists can apply oral therapies. Several oral therapies are
available for the treatment of psoriasis. In the Netherlands first
choice oral therapies include methotrexate and retinoids (81% and
76%) whereas in Flanders first choice therapies are retinoids and
cyclosporine (83% and 70%). Fumarates are less frequently used
compared to other oral therapies. In addition to the
above-mentioned therapies, approximately 15% of the Dutch and
Flemish dermatologists reported to apply therapies that were not
listed in the questionnaire. Most frequently reported were
emollients, salicylic acid containing ointments and
Dovobet® (containing betamethasone dipropionate and
calcipotriol hydrate). The recently introduced biologicals (e.g.,
infliximab and efalizumab) were mentioned by 6 dermatologists.
Because these agents were not registered and reimbursed at the time
of this survey, these agents are likely to be prescribed within a
clinical trial setting.
Table 1 Therapies used in the treatment of psoriasis
reported by dermatologists in the Netherlands and Flanders by
severeness and country. The first column shows the percentages and
numbers of dermatologists prescribing specific therapies. The next
columns shows the percentages of the prescribing dermatologists who
prescribe the therapy only in case of mild/moderate psoriasis, only
in severe psoriasis or in both mild/moderate psoriasis and severe
psoriasis
|
All Dutch and Flemish dermatologists (n = 375)
|
the Netherlands (n = 225)
|
Flanders (n = 150)
|
|
Therapy
|
Total of dermatologists % (n)
|
Only mild/moderate psoriasis %
|
Only severe psoriasis %
|
Both %
|
Total of dermatologists % (n)
|
Only mild/moderate psoriasis %
|
Only severe psoriasis %
|
Both %
|
Total of dermatologists % (n)
|
Only mild/moderate psoriasis %
|
Only severe psoriasis %
|
Both %
|
|
Topical
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Topical corticosteroids
|
100 (374)
|
3
|
1
|
96
|
100 (225)
|
4
|
-
|
96
|
99 (149)
|
2
|
1
|
97
|
|
Vitamin D3 analogues
|
100 (374)
|
16
|
-
|
84
|
100 (224)
|
19
|
-
|
81
|
100 (150)
|
12
|
-
|
88
|
|
Tar products
|
49 (183)
|
23
|
15
|
62
|
41 (93)
|
22
|
24
|
54
|
60 (90)
|
23
|
7
|
70
|
|
Pix lithantracisa
|
20 (73)
|
12
|
43
|
45
|
24 (54)
|
11
|
43
|
46
|
14 (19)
|
16
|
42
|
42
|
|
Solutio carbonis detergensb
|
40 (151)
|
33
|
11
|
56
|
30 (67)
|
42
|
18
|
40
|
56 (84)
|
26
|
6
|
68
|
|
Pix liquida (wood tar)
|
3 (11)
|
9
|
45
|
46
|
5 (11)
|
9
|
45
|
46
|
-
|
-
|
-
|
-
|
|
Dithranol
|
46 (169)
|
18
|
33
|
49
|
56 (125)
|
15
|
33
|
52
|
30 (44)
|
25
|
34
|
41
|
|
Phototherapy
|
|
|
|
|
|
|
|
|
|
|
|
|
|
UVB
|
93 (346)
|
6
|
15
|
79
|
99 (222)
|
6
|
12
|
82
|
83 (124)
|
7
|
21
|
72
|
|
PUVA
|
75 (280)
|
1
|
41
|
58
|
63 (141)
|
1
|
46
|
53
|
93 (139)
|
1
|
35
|
64
|
|
Oral
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Methotrexate
|
72 (269)
|
1
|
72
|
27
|
81 (182)
|
1
|
67
|
32
|
58 (87)
|
2
|
83
|
15
|
|
Retinoids
|
80 (297)
|
3
|
53
|
44
|
76 (172)
|
3
|
47
|
50
|
83 (125)
|
4
|
61
|
35
|
|
Cyclosporine
|
66 (247)
|
1
|
74
|
25
|
63 (142)
|
1
|
68
|
31
|
70 (105)
|
1
|
83
|
16
|
|
Fumarates
|
28 (106)
|
5
|
50
|
45
|
43 (96)
|
5
|
48
|
47
|
7 (10)
|
-
|
70
|
30
|
aPix lithantracis is most frequently used in
concentrations of 1.5%-5%; 1 g of 1.5% or 5% pix lithantracis
contains 15 mg or 50 mg tar, respectively.
bSolutio carbonis detergens is most frequently used
in concentrations of 10%; 1 g of 10% solution carbonis detergens
contains approximately 16 mg tar.
Treatment of eczema (table 2)
Similar to psoriasis, topical steroids are the first choice topical
therapy in eczema. Class 2 corticosteroids are mostly prescribed to
patients with mild to moderate eczema (91%). In severe eczema,
dermatologists prefer class 3 corticosteroids (89%). Other first
choice therapies include calcineurin inhibitors tacrolimus
(Protopic®) and pimecrolimus (Elidel®). Dutch
dermatologists prefer the use of tacrolimus (92% and 40%,
respectively) while Flemish dermatologists appear to have no
preference (96% vs. 93%). Dutch dermatologists use tar products
more frequently compared to Flemish dermatologists (72% versus
48%). As with psoriasis, the most frequently used tar product is
solutio carbonis detergens. In both countries, most dermatologists
apply this therapy in both mild/moderate eczema and severe eczema
(55%), while pix lithantracis is mainly prescribed to patients with
severe eczema (60%). In contrast to psoriasis, Dutch dermatologists
practising in a general hospital prescribe tar products more often
than their colleagues practising in a university hospital or a
private clinic (74% vs. 69% and 63%). In Flanders, tar products are
more frequently prescribed in a private clinic compared to a
university or a general hospital (56% versus 40% and 40%).
The next step in the treatment of eczema is phototherapy. In
both countries, UVB appears to be the first-choice phototherapy.
UVB is frequently applied by Dutch dermatologists in both
mild/moderate eczema and severe eczema (65%) while Flemish
dermatologists prefer to use UVB only in patients with severe
eczema (61%). Similar to psoriasis, PUVA is more frequently used by
Flemish dermatologists than by their Dutch colleagues (52% vs.
31%). In both countries, it is mainly prescribed in patients with
severe eczema. In patients with severe eczema or when topical or
phototherapy is not effective, oral therapies are applied. In both
countries, dermatologists prescribe cyclosporine and oral
corticosteroids approximately as frequently (62% and 59%,
respectively). The most frequently reported therapies that were not
listed in the questionnaire were emollients, oral/topical
antibiotics and antihistamines.
Table 2 Therapies used in the treatment of eczema
reported by dermatologists in the Netherlands and Flanders by
severeness and country. The first column shows the percentages and
numbers of dermatologists prescribing specific therapies. The next
columns shows the percentages of the prescribing dermatologists who
prescribe the therapy only in case of mild/moderate eczema, only in
severe eczema or in both mild/moderate eczema and severe eczema
|
Therapy
|
All Dutch and Flemisch dermatologists (n = 375)
|
Dermatologists from the Netherlands (n = 225)
|
Dermatologists from Flanders (n = 150)
|
|
Total of dermatologists % (n)
|
Mild/moderate eczema %
|
Severe eczema %
|
Both %
|
Total of dermatologists % (n)
|
Mild/moderate eczema %
|
Severe eczema %
|
Both %
|
Total of dermatologists % (n)
|
Mild/ moderate eczema %
|
Severe eczema %
|
Both %
|
|
Topical
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Topical corticosteroids
|
100 (374)
|
1
|
-
|
99
|
100 (225)
|
-
|
-
|
100
|
99 (149)
|
1
|
1
|
98
|
|
Calcineurin inhibitors
|
95 (355)
|
21
|
8
|
71
|
92 (208)
|
25
|
9
|
66
|
98 (147)
|
16
|
6
|
78
|
|
Tar products
|
63 (234)
|
20
|
11
|
69
|
72 (163)
|
19
|
9
|
72
|
48 (71)
|
22
|
16
|
62
|
|
Pix lithantracisa
|
30 (109)
|
5
|
60
|
35
|
38 (86)
|
6
|
59
|
35
|
16 (23)
|
4
|
61
|
35
|
|
Solutio carbonis detergensb
|
59 (218)
|
36
|
9
|
55
|
66 (149)
|
38
|
7
|
55
|
47 (69)
|
33
|
13
|
54
|
|
Pix liquida (wood tar)
|
9 (34)
|
21
|
35
|
44
|
13 (30)
|
13
|
37
|
50
|
3 (4)
|
75
|
25
|
-
|
|
Phototherapy
|
|
|
|
|
|
|
|
|
|
|
|
|
|
UVB
|
82 (308)
|
2
|
42
|
56
|
91 (205)
|
2
|
33
|
65
|
69 (103)
|
1
|
61
|
38
|
|
PUVA
|
39 (146)
|
2
|
71
|
27
|
31 (69)
|
3
|
71
|
26
|
52 (77)
|
1
|
72
|
27
|
|
Oral
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Corticosteroids
|
59 (222)
|
1
|
87
|
12
|
66 (148)
|
1
|
86
|
13
|
50 (74)
|
-
|
89
|
11
|
|
Cyclosporine
|
62 (234)
|
1
|
86
|
13
|
65 (146)
|
1
|
84
|
15
|
59 (88)
|
1
|
91
|
8
|
aPix lithantracis is most frequently used in
concentrations of 1.5%-5%; 1 g of 1.5% or 5% pix lithantracis
contains 15 mg or 50 mg tar, respectively.
bSolutio carbonis detergens is most frequently used
in a concentration of 10%; 1 g of 10% solution carbonis detergens
contains approximately 16 mg tar.
Topical treatment in pregnant patients
Most dermatologists are reluctant to prescribe tar products to
pregnant women with psoriasis or eczema (table
3). Topical corticosteroids appear to be the most
prescribed treatment for psoriasis and eczema during pregnancy. A
few dermatologists use dithranol when treating pregnant women with
psoriasis or eczema.
Table 3 Percentages of dermatologists prescribing
topical therapies in pregnant women
|
Yes, during the whole pregnancy (%)
|
Yes, but not during the 1st trimester (%)
|
No (%)
|
|
Tar products
|
9
|
9
|
82
|
|
Dithranol
|
3
|
4
|
93
|
|
Corticosteroids
|
77
|
17
|
6
|
Therapies used in the past
Approximately one-third of all dermatologists reported using one or
more therapies in the past which they less frequently, or not at
all, apply now (table 4). The most
frequently mentioned therapy was coal tar. Several reasons were
given for stopping or minimizing the use of coal tar. Most
frequently reported reasons were 1) the difficulty of obtaining
coal tar from the pharmacy (42 times) 2) the unpleasant use for
patients (11 times) 3) possible carcinogenicity (10 times) and 4)
difficulties in using tar at home (10 times). Other therapies that
are no longer/less used by dermatologists are dithranol, with the
main reason its unpleasant use for patients, and cyclosporine and
PUVA, both because of the adverse effects.
Table 4 Therapies no longer/less prescribed by Dutch
and Flemish dermatologists
|
Therapy
|
Number of dermatologists
|
Most reported reason for stopping
|
|
Coal tar
|
92
|
Difficulties in obtaining tar from pharmacies
|
|
Dithranol
|
26
|
Unpleasant use for patients
|
|
Retinoids
|
6
|
Unsatisfactory effect
|
|
Cyclosporine
|
12
|
Adverse effects/carcinogenicity
|
|
Fumarates
|
2
|
Unsatisfactory effect
|
|
Methotrexate
|
2
|
Adverse effects, better alternatives
|
|
PUVA
|
9
|
Adverse effects/carcinogenicity
|
|
Vitamin D3 analogues
|
3
|
Unsatisfactory effect
|
|
Other
|
16
|
-
|
Discussion
In psoriasis, topical corticosteroids and vitamin D3
analogues are applied by almost all dermatologists. Tar products
and dithranol are second choice therapies. This is in accordance
with European surveys conducted in the past among patients with
psoriasis [12-15]. American surveys also showed that topical
corticosteroids and vitamin D3 analogues are the most
frequently prescribed topical therapies [16, 17].
Phototherapy is mainly applied in patients with severe psoriasis
or when topical therapy is not effective. In the past, several
studies showed an increased risk of non-melanoma skin cancer after
PUVA-therapy [18-21]. Still, more than 60% of the Dutch
dermatologists and even more than 90% of the Flemish dermatologists
prescribe this photochemotherapy for psoriasis. PUVA and UVB have a
comparable efficacy but the long-term safety of UVB therapy is more
favourable [22]. Almost all studies that investigated the risk of
cancer after UVB therapy did not show an increased risk [23]. PUVA
may be considered where UVB treatment has an insufficient effect
[24].
In the case of oral therapy for the treatment of psoriasis,
retinoids are frequently applied by dermatologists in both
countries. In Flanders, it is the most frequently applied oral
therapy. This is remarkable because of the moderate efficacy of
retinoids as a monotherapy in psoriasis vulgaris, the most common
type of psoriasis [25-27]. The guidelines of the Dutch Association
for Dermatology and Venereology recommend that methotrexate, and
not a retinoid, should be the first choice oral therapy [22].
Fumarates are the least frequently prescribed oral therapies by
dermatologists, especially in Flanders. This oral therapy is not
licensed in either the Netherlands or Flanders, which is probably
the main reason for the limited use of fumarates.
As in psoriasis, in eczema, topical corticosteroids are
prescribed by almost all dermatologists. The recently introduced
calcineurin inhibitors are also frequently applied by both Dutch
and Flemish dermatologists. The European Task Force on atopic
dermatitis recommend topical corticosteroids as first choice
therapy and they state that calcineurin inhibitors are useful
second choice agents [28]. The guidelines from the American
Association of Dermatology on the treatment of atopic dermatitis
also prescribe topical corticosteroids and calcineurin inhibitors
as the most useful agents [29]. A major advantage of calcineurin
inhibitors, compared to topical steroids, is that these agents do
not cause skin atrophy [30, 31]. There is a theoretical risk of the
promotion of skin cancer because these agents modify the
immunoregulatory functions of the skin [31, 32]. These agents were
introduced only a few years ago. Therefore, results of
epidemiological studies with long-term follow up that have assessed
the risk of (skin) cancer after the use of calcineurin inhibitors
are not available. So far, available data suggest that the use of
calcineurin inhibitors is safe, but a definite place for these
agents in the treatment for eczema has still to be established
[30].
The use of coal tar products is under discussion. Some
dermatologists have stopped using it and other dermatologists still
regard tar products as part of the therapeutic spectrum. The main
reason for stopping is the difficulty in obtaining coal tar
preparations from pharmacies. Due to stringent rules from the Dutch
government for preparing coal tar products, many pharmacies are no
longer capable of preparing these products. These rules are derived
from the rules of the European Union concerning the protection of
employees against the risk of exposure to carcinogens and mutagenic
agents in the work place (rule 2004/37/EG). PAH are recorded as
carcinogenic and mutagen agents by the European Union and,
therefore, exposure to these agents during work comes under these
rules. Another reason is the difficulty of using tar at home.
Because coal tar stains furniture and clothes, it is not always
possible to use tar preparations at home. Another reason for
stopping is the possible carcinogenicity of coal tar (but mentioned
by no more than 10 dermatologists). Studies carried out so far on
the long-term effects of coal tar in patients with psoriasis or
eczema have shown conflicting results [6-11] and therefore
large-scale epidemiologic studies are needed that include a large
number of patients and have sufficient follow-up. Studies conducted
so far mainly focused on the risk of skin cancer after coal tar
treatment. However, coal tar penetrates the skin, which leads to
systemic absorption of PAHs. Therefore it is important that future
studies not only investigate the risk of skin cancer but also the
risk of internal tumors after exposure to coal tar.
Many dermatologists hesitate to prescribe coal tar preparations
during pregnancy. Also dithranol is not frequently prescribed to
pregnant women. In general, topical corticosteroids are prescribed
during pregnancy while the safety of some preparations during
pregnancy is questionable. According to the Swedish classification
of risk of drug use during pregnancy and lactation, preparations
like betamethasone, fluticasone and triamcinolone are classified in
group C which means that the pharmacological action of the drug may
have undesirable effects on the human fetus or newborn infant.
However, when the duration and area of application are limited and
a mild preparate is used, corticosteroids can be prescribed during
pregnancy, even in the first trimester of pregnancy [33].
The present study has indicated that the major part of
dermatologists in two European countries still use tar products in
the treatment of psoriasis and eczema. The variation between the
Netherlands and Flanders with respect to the use of coal tar
products is intriguing. However, no guidelines or treatment
recommendation of the national or European dermatological societies
are available, which explains the highly variable use of topical
treatments in psoriasis and eczema, especially with respect to coal
tar and dithranol.
Despite the clear or suggested unfavourable effects, many
dermatologists still prescribe coal tar preparations. So far coal
tar remains an important therapy for psoriasis and eczema. Future
research has to assess the risk of (late) side effects of coal tar
and compare this to the risks of other therapies that are available
for the treatment of these dermatoses.
Acknowledgements
The authors thank Prof.dr. J. Lambert (Department of Dermatology,
University Hospital Antwerp, Belgium) for his help in the
development of the questionnaire.
We thank Ursula Oldenhof for her practical help during this
study.
The LATER-study is supported by the Dutch Cancer Society, grant
number KUN 2003-2890.
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