ARTICLE
Auteur(s) : Piergiacomo
Calzavara-Pinton1, Giovanni Leone2,
Marina Venturini1, Raffaella Sala1, Delia
Colombo1, Ilaria Lesnoni LA Parola2, Nathalie
Sitzia3, Carmela Ferraro2, Mauro
Picardo2
1Department of Dermatology, Azienda Spedali Civili di
Brescia, Brescia, Italy Fax: (+39)-030-3995015.
2San Gallicano Dermatological Institute, Rome, Italy
3Section of Medical Statistics, Department of
Biosciences, University of Brescia, Brescia
accepté le 1 Juillet 2005
Phototherapy with narrow-band (312 ± 2 nm) UVB (NB-UVB) is one of
the most widely used treatments for severe forms of psoriasis but
its repeated and prolonged use is limited by the risk of cumulative
adverse effects in the long-term, namely non-melanoma skin cancer
and photo-aging. Combination and sequential treatments with other
topical or systemic anti-psoriatic therapies are a practical
approach to achieve a quick recovery and a reduction in the
cumulative NB-UVB dose [1, 2]. The term “combination therapy”
refers to the use of more than one agent at the same time and does
not imply a specific strategy for their use. NB-UVB phototherapy is
widely and successfully combined with topical, e.g. vitamin D3
analogues and tazarotene, treatments [1]. In more severe cases
systemic treatments, i.e. retinoids and methotrexate, are combined.
However both drugs have frequent adverse effects and are
contraindicated in patients with liver and dismetabolic diseases as
well as female patients of child-bearing age [1]. Cyclosporin A
(CsA) is another potent antipsoriatic treatment but its combination
with NB-UVB has been avoided because of the concern that the
immunosuppressive activity of CsA would enhance the potential
carcinogenic effects of NB-UVB, even though this has not been
assessed so far in dermatological patients treated with NB-UVB. In
order to minimize this risk, whatsoever it is, we used a sequential
treatment protocol in which administration of low dose CsA for 4
weeks was followed by a quick tapering of the drug dose and,
concomitantly, the beginning of NB-UVB phototherapy. This treatment
strategy, involving the use of specific therapeutic agents in a
deliberate sequence, aims to optimize the therapeutic outcome with
a reduction of total dose of both treatments.We report the results
of a comparative, open, pivotal pilot study of sequential
CsA-NB-UVB versus NB-UVB phototherapy alone in two groups of
patients with severe psoriasis vulgaris from two dermatological
centres. The principal end-point of the study was to test the
equivalence of efficacy of the two therapies. The secondary
endpoints were the comparisons with cumulative UVB doses, number of
exposures and duration of NB-UVB therapy, duration of treatment
period and disease-free interval.
Material and methods
Subjects
Sixty consecutive patients suffering from severe (PASI >15)
psoriasis vulgaris were enrolled from October to December 2003.
Prior to the study the experimental nature of the study was
carefully explained to patients and their written informed consent
was obtained. The study was approved by the local Ethics Committee.
The patients were allocated to receive either sequential therapy
with CsA and NB-UVB phototherapy or NB-UVB phototherapy alone by
non-random allocation. Groups included the same number of
patients.
The group sequentially treated included 30 patients (21 males
and 9 females, mean age 36.7 years, range 19-63). 5 patients had
skin type II, 16 skin type III and 9 skin type IV.
The group treated with phototherapy alone included 30 patients
(18 males and 12 females, mean age 40.3 years, range: 18-57 years).
6 patients had skin type II, 16 skin type III and 8 skin type
IV.
All patients had interrupted other topical treatments, including
phototherapy, or systemic therapies for psoriasis at least 2 months
before entering the study.
At baseline a thorough clinical examination was performed.
Disease activity was assessed with the Psoriasis Area and Severity
Index (PASI) score [3]. In addition, the presence of itching and
its localization (limited to the psoriatic plaques or widespread),
intensity (mild, moderate or intense), and frequency (intermittent,
continuous) were registered.
Serum biochemistry, full blood counts, urine analyses,
antinuclear and anti-ENA antibodies and blood pressure measurement
were evaluated in all patients. In patients taking CsA, blood
pressure was measured once a week and blood tests were repeated
after 4 weeks.
Exclusion criteria were the following: abnormal renal or liver
function, abnormal serum potassium and uric acid, pregnancy, age
younger than 18 years, hypertension, previous or concomitant
malignancy, primary or secondary immunodeficiency, active or
chronic infection, drug or alcohol abuse, concomitant therapy with
drugs interacting with CsA and nephrotoxic or photosensitizing
agents.
Radiation source
We used two Waldmann 7001 cabinets (Waldmann Lichttechnik,
Villingen-Schwenningen, Germany) equipped with 40 Philips
TL-01/100W lamps (Philips Eindhoeven, The Netherlands) with a peak
of emission at 312 ± 2 nm. Irradiance was measured with two
portable broadband UV meters (Waldmann) after calibration with a
Macam SR 9910 spectroradiometer (Macam Photometrics Ltd,
Livingston, Scotland).
Treatment protocols
In the first group, CsA was administered at a dose of 3.0 mg
kg–1 body weight (b.w.)/day for 4 weeks. Afterwards,
phototherapy was begun and the dose of CsA was gradually reduced by
1 mg kg–1 b.w./every week up to discontinuation. In both
groups phototherapy was delivered according to the same treatment
protocol [4]. The initial dose ranged between 0.1-0.4 J
cm–2 according to skin phototype. Patients were treated
3 times a week and UV doses were adjusted at each session according
to the erythema response. In short, 20%, 10% or no incremental
increases were made if, respectively, no, a barely perceptible or a
well defined, asymptomatic erythema response at 48 hours was seen.
The PASI score was evaluated weekly and treatments were given until
psoriasis cleared [4] (PASI score = 0) or until partial improvement
was achieved without further amelioration despite another week of
treatment (the same PASI score in two subsequent weekly
evaluations).
All patients were allowed to use an emollient cream, as needed.
No maintenance therapy was given and patients were followed-up at
1, 6 and 9 months intervals.
Controls
Fourteen patients (seven in each group) had psoriatic lesions in
areas that were inaccessible or poorly accessible by NB-UVB
radiation. These were located in the perineo-crural area (6
patients) in the internatal cleft (4 patients) and in the armpits
(4 patients). These lesions were chosen to serve as unirradiated or
poorly irradiated controls.
Statistical analysis
The present pilot study was a pivotal experience in severe cases of
psoriasis.
Data were recorded as mean values ± SD. Based on the study
design, statistical analysis of the therapeutic results was carried
out employing a test for equivalence with macros supported by the
computer-based statistical program SAS [5]. Total number of NB-UVB
exposures, cumulative NB-UVB dosages and duration of therapy were
compaired with Student’s t test for non-paired data. Significance
was defined as p < 0.05.
Results
At baseline, the mean (± SD) PASI score of the group receiving
CsA-NB-UVB and patients receiving phototherapy alone were similar
(28.58 ± 7.99 versus 26.69 ± 6. 67; p < 0.01)) (table 1)( Table 1 ).
Both treatments were equally highly effective with a strong
reduction of PASI after 4 weeks of therapy (12.38 ± 6.31 with
CsA-NB-UVB and 14.38 ± 7.87 with NB-UVB) and at the end (1.95 ±
3.63 with CsA-NB-UVB and 2.37 ± 2.86 with NB-UVB) in comparison
with baseline. Statistical evaluation shows that, at these time
points, the efficacy of the two treatments was equivalent at a
statistical level of p < 0.05.
The slight differences of PASI scores in favour of CsA-NB-UVB
(table 1) were mainly due to the better improvement of psoriatic
lesions of control skin areas (armpits, internatal fold and inner
part of the thighs) that were not or were poorly exposed to UVB
radiation. They were observed in 7 patients in each group and were
noted to have ameliorated or cleared in 6 patients treated in
CsA-NB-UVB group and only in 2 treated with NB-UVB alone.
Obviously, the limitation of the design of the present pilot study
does not allow ruling out spontaneous remissions or efficacy of low
doses of NB-UVB that may reach these body areas.
Statistical evaluation with the Student’s t test shows that the
cumulative UVB dosages (8.94 ± 6.41 J cm–2 versus 18.34
± 8.49 J cm–2, p < 0.01) and the total number of
exposures (12.11 ± 5.87 versus 19.59 ± 4.66, p < 0.01) in
patients given sequential therapy was lower than in the control
group (table 2)( Table 2 ). However, the
overall treatment period was shorter for patients given
phototherapy alone: 6.59 ± 1.52 versus 8.14 ± 2.00 weeks of therapy
(p < 0.01) (table 2).
Before treatment, 6 patients in the CsA-NB-UVB group and 10 in
the control group presented with itching. All these patients
described itching as intermittent, mild to moderate and strictly
limited to the psoriatic plaques. This symptom disappeared within
1-2 weeks in all patients during CsA treatment and more slowly (2-4
weeks) in patients treated with NB-UVB alone.
Four patients (two in each group) reported a single episode of
excessive phototoxic reaction that was mild and transitory in
nature. No patient experienced undesirable effects related to CsA
and there was no relevant change in laboratory tests.
After discontinuation of treatment there was a progressive
relapse of psoriasis but at follow-up examination no difference was
noted between PASI scores of patients treated with sequential
therapy or phototherapy alone, either after 1 month (6.92 ± 8.23
versus 4.00 ± 4.07; p < 0.05), 3 months (11.22 ± 9.34 versus
9.02 ± 6.77; p < 0.05) and 9 months (17.79 ± 6.83 versus 21.54 ±
21.59; p < 0.05).
Table 1 Variations of PASI scores at baseline (T0),
after 4 weeks of treatment (T1) and at the end of the treatment
cycle (T2) and after 1, 6 and 9 months of follow-up. Statistical
evaluation shows that the efficacy of the two treatment is always
equivalent at a statistical level of p < 0.05
|
PASI
|
NB-UVB
|
CsA-NB-UVB
|
p
|
|
T0
|
26.69 ± 6.67
|
28.58 ± 7.99
|
< 0.01
|
|
T1
|
14.38 ± 7.87
|
12.38 ± 6.31
|
< 0.01
|
|
T2
|
2.37 ± 2.86
|
1.95 ± 3.63
|
< 0.05
|
|
Follow-up
|
|
|
|
|
1 month
|
4.00 ± 4.07
|
6.92 ± 8.23
|
< 0.05
|
|
6 months
|
9.02 ± 6.77
|
11.22 ± 9.34
|
< 0.05
|
|
9 months
|
21.54 ± 21.59
|
17.79 ± 6.83
|
< 0.05
|
Table 2 Total number of NB-UVB exposures and cumulative
dosages and duration of tre-tment cycles (Student’s t test for
non-paired data).
|
NB-UVB
|
CSA+NB-UVB
|
p
|
|
Total number of NB-UVB exposures
|
19.59 ± 4.66
|
12.11 ± 5.87
|
< 0.01
|
|
Cumulative NB-UVB dosages (J cm-2)
|
18.34 ± 8.49
|
8.94 ± 6.41
|
< 0.01
|
|
Cumulative duration of therapy (weeks)
|
6.59 ± 1.52
|
8.14 ± 2.00
|
< 0.01
|
Discussion
Under the conditions of the present pilot study, sequential
CsA-NB-UVB therapy and NB-UVB phototherapy administered alone have
attained similar efficacy, as measured with the improvement of the
PASI score. However, in the sequential protocol, the administration
of low dose CsA for a short period allowed lowering of the total
NB-UVB doses and the cumulative number of exposures. People with
busy lifestyles or living far away from this facility greatly
appreciated the need for fewer phototherapy sessions even though
the overall duration of the sequential therapy would be longer. A
better improvement of lesions of body areas that are completely or
almost completely UV-shielded and the quick relief of itching were
two further clinically relevant advantages. Both protocols were
well tolerated and flares of psoriasis were not seen after
discontinuation of CsA. At 1, 6 and 9 month visits, progressive and
parallel increases of PASI scores were registered but, with both
therapies, mean values remained lower than at baseline.
In the present paper, low dose CsA and NB- UVB phototherapy were
administered according to a sequential protocol with only a short
overlap, in order to minimize the concern that the simultaneous
administration of CsA could enhance the potential NB-UVB related
skin carcinogenesis [6], although the degree of this risk, if any,
after therapeutical use of NB-UVB in humans has not been
established so far. On the other hand, it is well known that
long-term high-dose CsA may enhance the hazard of skin
carcinogenesis caused by chronic exposures to solar UV light. A
high incidence of skin tumors has been found in transplant patients
treated continuously for long periods with high dose CsA therapy,
often associated with other immuno-suppressive drugs [7, 8].
Multiple factors with complex interactions are probably involved in
the observed pattern of increased incidence of skin tumors in
transplantation. They include severely depressed immunity with an
impaired immune surveillance against various carcinogens and the
subsequent elimination of malignant clones, chronic stimulation of
the immune system, genetic susceptibility, environmental factors,
the activation of oncogenic viruses, and a possible mutagenic
effect of the drugs [9, 10].
Otherwise it is as yet unclear whether long-term low-dose CsA
might also increase the risk of UV-related malignancies. In
patients with rheumatoid arthritis, contrasting findings have been
found, including tumor promoting activity, protective effects and
absence of any effect [9-11]. However, the risk, if any, is
presumably even lower with the present treatment protocol because
patients were treated with short-term low-dose CsA and the overlap
period, when NB-UVB phototherapy began and CsA dose was rapidly
tapered, was very small. Indeed, in a prospective long term cohort
study of 1252 psoriasis patients treated with one or more cycles of
low-dose CsA [12], exposure to UVB or UVA phototherapy showed no
significant carcinogenic effect. In contrast, the risk of SCC is
increased by CsA administration in psoriatic patients who have been
exposed to PUVA [1, 12-14]. In these patients, the incidence of
tumors increased, mostly in regions of the body not usually exposed
to sunlight but only to PUVA, thus confirming that UV light alone
has a poor effect on CsA-induced carcinogenesis [14]. The
enhancement of the risk of carcinogenesis in PUVA – but not UVB –
treated patients could be explained by experimental in vitro
evidence suggesting that CsA hinders PUVA – but not UVB – induced
apoptosis of keratinocytes and lymphocytes [15, 16].
Therefore, at this time, it is completely unknown whether a
short treatment course of low dose CsA enhances the potential
carcinogenic risk related to NB-UVB phototherapy. On the other
hand, it is certain that lowering the NB-UVB cumulative dose and
number of exposures could help to reduce this potential risk.
In conclusion, sequential CsA-NB-UVB therapy is effective in the
treatment of severe psoriasis vulgaris. This regimen seems valuable
when less exposure sessions are desirable or if patients have
itching or lesions in UV-shielded areas.
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