ARTICLE
Auteur(s) : Frédéric Augey1,
Philippe Renaudier2, Jean-François
Nicolas1
1Université Claude-Bernard Lyon I, Department of
Immunoallergology, Pavillon Dufourt, Centre Hospitalier Lyon Sud,
69495 Pierre-Benite Cedex. France
2Université Claude-Bernard Lyon I, Department of
haemovigilance Hopital de la Croix-Rousse, Hospices Civils de Lyon,
France
accepté le 28 Juin 2006
Generalized pustular psoriasis (GPP), first described by Von
Zumbusch in 1910, is the most severe type of psoriasis with
possibly life-threatening complications. It is characterized by the
sudden onset of diffuse erythema, with a scattering of pustules
which often become confluent, accompanied by high fever, general
malaise and hyperleukocytosis. Histological investigations have
shown a characteristic but non specific Kogoj’s spongiform pustule
associated with the other epidermal changes seen in psoriasis
vulgaris (parakeratosis, elongation of the ridges). GPP can be the
first sign of a psoriatic disease or a complication of common
psoriasis due to hypocalcaemia, pregnancy, hypocortisolism,
infections or severe stress [1, 2]. Frequently there is no obvious
cause. Acute generalized exanthematous pustulosis is a differential
diagnosis of drug-induced GPP.To our knowledge, epidemiological
studies have only been performed in Japan. During the years
1983-1989 the estimated prevalence rate was 7.46/million with an
estimated incidence of 16.5 new cases per year [3].Herein, we
present an epidemiological study of GPP performed in France in 2004
in order to describe both its epidemiological picture and the
therapeutic strategies developed by hospital dermatologists.
Patients and methods
An exhaustive list of the 121 dermatological wards throughout
France – including the French West Indies, French Guyana and La
Reunion island – was obtained from the French dermatologists union.
In January 2005 a questionnaire was sent to each department. All
in and outpatients who visited the department in 2004 for GPP were
considered. If no answer was obtained within one month, the
department was contacted again by phone or e-mail several times
during the following four months.
Through questionnaires we asked, for each patient: i) if it was
the first pustular outbreak ii) the sex iii) the age iv) possible
complications or death because of the disease or treatment. We also
asked if the disease was recalcitrant or not, had justified
immunobiological treatments and the therapeutic habits of each
ward.
Diagnosis of GPP was made by the dermatologists according to
their own criteria. Impetigo herpetiformis, which is often
considered as a GPP of pregnancy, was included in this survey.
We also asked CNAMTS*1, the health
insurance of 90% of the French population, for the number of
patients with GPP who were declared in the CNAMTS disease registry.
The results available were for the years 1998 and 2001, not for
2004.
Estimation of incidence and prevalence of GPP in 2004 was based
on the assumption that the mean number of patients in the
university departments responding to the survey was equal to that
among departments not responding and so on for general
departments.
Statistical analysis
The statistical unit was the patient. The qualitative variables
were compared by the Pearson chi2 test or the Fischer exact test,
and the quantitative variables by the Mann Whitney U test. The
respective roles of the different factors for the therapeutic
failures was studied by logistic regression. A therapeutic failure
was defined by the successive or associated use of several systemic
therapies to control the outbreaks of GPP. The estimated odds-ratio
(OR) and the 95% confidence intervals (CI) were calculated. All the
calculations were done by SPSS/PC 11.0®.
Results
The number of GPP patients in the CNAMTS registry was: i) 40 new
patients in 1998, ii) 25 in 2001. Therefore the incidence of GPP is
0.5 to 0.8 per million. In 2001 the sex ratio was 1 and the median
age was 56.
Among the 121 dermatology departments, 112 answered the survey
(39 in university hospitals, 73 in general hospitals). The response
rate was 86.6% and 96% in university and general hospitals
respectively (mean: 92.5%). However only 17.3% answered
spontaneously after the first mail.
Ninety nine cases of GPP (ages: 14-91) were collected. Thirty
six had their first outbreak in 2004 including one with an impetigo
herpetiformis. Considering the average incidence and prevalence
rates of GPP for university and non-university wards and the fact
that 9 departments did not answer the questionnaire, we added 10
prevalent cases and 4 incident cases. Therefore the estimated total
number of patients GPP in 2004 was 109. Forty patients developed
the disease in 2004. Incidence and prevalence of GPP were estimated
as 0.64 and 1.76 per 1 million person-year respectively. A higher
incidence was reported in the French West Indies (2 per million),
La Reunion island (1.3) and the rural regions (Franche-Comté,
Centre, Bourgogne, Limousin 1.2 to 1.8) (table 1( Table 1 )).
The male/female sex ratio was 0.77. The mean (and standard
deviation) age of all patients was 52.5 (18.5) and 59.7 (16.5) for
incident cases without significant difference between males and
females. A higher incidence and prevalence were observed between
the ages of 40 and 59 years ( (figure 1) ).
The 99 patients were treated in 46 different departments (70 in
university hospitals).
The first choice treatments were acitretine (used by 89% of the
46 departments), methotrexate (8%), cyclosporine or topical
treatments only (3%). Systemic steroids were never used as first
line therapy. Acitretin was used at a daily dose ranging from 0.1
to 1 mg/kg. Seventy five percent of patients received a dose
of acitretin ranging from 0.4 to 0.8 mg/kg.
Topical steroids and moisturizing ointments were associated to
the systemic treatment for 87% (n = 40) and 13% (n = 6) of
departments, respectively. Very high potency (n = 21) or high
potency (n = 17) were preferred to low potency topical
steroids.
42% of patients had a recalcitrant GPP and received two or more
systemic treatments which were given simultaneously or
successively. Immunobiologics were given in 13% of patients. The
estimated OR for therapeutic failure, their degree of significance
and their CI are presented in table 2( Table
2 ).
In univariate analysis, treatment failure was related to
different parameters: i) management in a university ward (p = 0.03)
ii) prescription of high or very high potency corticosteroids as
first line therapy (p = 0.05) iii) systemic therapies other than
retinoids as first line therapy (p = 0.04). Multivariate analysis
did not show any significant parameter associated to the
therapeutic failure.
Severe complications were reported in 17 cases (17.1% of GPP
patients). 14 were recalcitrant GPP. Infectious or/and iatrogenic
disorders were the most often reported (table 3( Table 3 )). Acitretin, steroids and infliximab were
equally involved in iatrogeny.
Two deaths occurred in elderly patients (congestive cardiac
failure and septic shock) without drug responsibility.
Table 1 Estimated geographical distribution of GPP in
the French survey and incidence rate per million (2004)
|
Region
|
Estimated cases (n)
|
Estimated incident cases (n)
|
Estimated incidence rate
|
|
Alsace
|
2
|
1
|
0.5
|
|
Antilles-Guyane
|
2
|
2
|
2
|
|
Aquitaine
|
3
|
2
|
0.6
|
|
Auvergne
|
2
|
0
|
0
|
|
Basse-Normandie
|
1
|
0
|
0
|
|
Bourgogne
|
4.38
|
2.08
|
1.3
|
|
Bretagne
|
5
|
1
|
0.3
|
|
Centre
|
4
|
3
|
1.3
|
|
Champagne-Ardenne
|
4
|
1
|
0.7
|
|
Corse
|
0
|
0
|
0
|
|
Franche-Comté
|
6
|
2
|
1.8
|
|
Haute-Normandie
|
5
|
2
|
1.1
|
|
Ile-de-France
|
22.42
|
8.315
|
0.7
|
|
Languedoc-Roussillon
|
1
|
0
|
0
|
|
La Réunion
|
2
|
1
|
1.3
|
|
Limousin
|
3
|
1
|
1.3
|
|
Lorraine
|
2
|
0
|
0
|
|
Midi-Pyrenées
|
2
|
1
|
0,4
|
|
Nord-Pas de Calais
|
8
|
5
|
1.2
|
|
Provence-Alpes-Côte d’Azur
|
13
|
4
|
0.9
|
|
Pays-de-la-Loire
|
3.93
|
1.79
|
0.5
|
|
Picardie
|
0
|
0
|
0
|
|
Poitou-Charente
|
1
|
0
|
0
|
|
Rhône-Alpes
|
11.55
|
1.71
|
0.1
|
Table 2 Analysis of factors associated to treatment
failure
|
Univariate analysis
|
|
Factors
|
Odds ratio
|
IC 95%
|
P
|
|
Age
|
0.99
|
0.97-1.01
|
0.81
|
|
Female sex
|
1.98
|
0.87-4.47
|
0.10
|
|
University ward
|
2.91
|
1.10-7.72
|
0.03
|
|
High use of DC
|
7.65
|
0.93-62.72
|
0.05
|
|
Low use of retinoids
|
5.5
|
0.06-0.92
|
0.04
|
|
Multivariate analysis (logistic regression)
|
|
Factors
|
Odds ratio
|
IC 95%
|
P
|
|
Age
|
0.99
|
0.97-1.01
|
0.64
|
|
Female sex
|
1.77
|
0.74-4.25
|
0.19
|
|
University ward
|
2.11
|
0.73-6.06
|
0.16
|
|
High use of DC
|
4.48
|
0.49-40.78
|
0.18
|
|
Low use of retinoids
|
4.03
|
0.04-1.29
|
0.09
|
Table 3 Complications in 99 patients with GPP (French
survey-2004)
|
Complication
|
No of patients
|
|
Total
|
17 (17.1%)
|
|
Death (septic shock, cardiac failure)
|
2
|
|
Superinfection
|
4
|
|
Liver diseases
|
|
|
Spontaneous
|
1
|
|
Liver biopsy (bleeding)
|
1
|
|
Toxic hepatitis (acitretin)
|
3
|
|
Other iatrogenic complications:
|
|
|
Steroids
|
|
|
Hypocortisolism
|
1
|
|
Cushing syndrome
|
1
|
|
Osteoporosis
|
1
|
|
Infliximab
|
|
|
Arthritic lupus
|
2
|
|
Arterial thrombosis
|
1
|
|
Cyclosporine
|
|
|
Renal failure
|
1
|
Discussion
The annual incidence of GPP in France both from the statistics of
the main national health insurance and our epidemiological
retrospective survey can be estimated at a minimum of 0.6-0.7 per
million. This incidence is slightly lower than that of other severe
dermatoses such as toxic epidermal necrosis (0.9/m) [4] or
pemphigus vulgaris (1.7/m) [5] but about a fifth higher than the
incidence of GPP in Japan during the eighties [6]. This lower
incidence of GPP in Japan may be related to the lower incidence of
psoriasis (all clinical forms included) (0.29-1.18 in Japan versus
1.6-4.7 in France) and other inflammatory diseases (such as
ankylosis spondylitis or inflammatory bowel diseases) in Asia
compared with Europe [7, 8]. It may also be explained by a
different methodology used in the Japanese and French studies.
In Japan 0.9% of a sample of 28,628 psoriatics from dermatology
centers had GPP [9]. In Morocco it was the clinical presentation of
17% of severe psoriasis [10].
The male/female sex ratio was 0.7 in both the Japanese and our
survey. However it was 1.3 in the 35 acute GPP reported by
Zelickson et al. [11].
In our survey the average age was in the fifth decade, even for
the incident cases (59.7 years) and was higher than in the other
surveys (table 4( Table 4 )).
GPP has a strong tendency to natural remission, especially in
the younger adult patients, and relapse. The aim of treatment is to
shorten the pustular phase of the disease, which can provoke liver
damage as neutrophilic cholangitis [12] and cardiovascular or
infectious complications, and to induce long-lasting remissions.
Among systemic therapies for GPP, retinoids are the most effective
and have the best long-term tolerance [13], compared to
methotrexate, oral steroids and cyclosporine. The broad use of
retinoids in the treatment of GPP correlated with a dramatic
decrease of mortality in the disease (table 4). In our study, 89%
of the dermatological departments used retinoids as first line
treatment. Furthermore the Japanese guideline for the GPP
recommends retinoids as first line therapy [12].
A local treatment is usually associated to systemic therapy.
Oral corticosteroids are not used in France in psoriasis because of
the fear of severe complications, death and dependence as reported
by Ryan and Baker [15]. In contrast, dermatocorticosteroids (DC),
especially high potency DC, are currently used in the treatment of
GPP in France. However, the results of our study show a correlation
between a high rate of failure and use of high potency DC,
suggesting that corticosteroids should not be used in GPP. Similar
recommendations are provided by and Japanese and Dermatological
societies which do not recommend the use of high potency DC in
psoriasis [14, 16]. Lastly, the higher rate of failure in
university wards probably reflects that these departments manage
the most severe patients.
In conclusion, GPP affects slightly less than two per million
people in France, especially middle-aged adults in rural areas.
Recalcitrant GPP cases are frequent and their management is
difficult. Oral retinoids have clearly reduced mortality but
morbidity remains high. A prospective study would be useful to
precise the best topical treatment.
Table 4 Avalailable epidemiologic studies on Von
Zumbusch GPP
|
Ryan 1969[13]
|
Zelickson 1991[11]
|
Okhawara 1996[2]
|
Present study 2004
|
|
n = 104
|
n = 35
|
n = 208
|
n = 99
|
|
Sex ratio M/F
|
|
1.33
|
0.73
|
0.77
|
|
Average age (yrs) at onset of GPP
|
|
42.5
|
34.5
|
59.7 (n = 36)
|
|
Preceding history of: psoriasis vulgaris acral or localized
pustular psoriasis
|
|
NR
|
NR
|
|
|
24 (68%)
|
65 (31%)
|
|
|
16 (45%)
|
NR
|
|
|
Average time between pso vulgaris and first onset of GPP
|
|
12 yrs
|
6 yrs
|
|
|
Deaths
|
17 (16%)
|
2 (5.7%)
|
NR
|
2 (2%)
|
Acknowledgements
This project received the support of SVR laboratory through the
Jean Darier Award 2004.
We sincerely thanks CNAMTS, especially Dr Alain Weill, SVR
laboratory, Mrs Jenny Messenger for editorial editing and all the
clinicians who participated to the survey:
Prs J Bazex, JC Beani, C Bedane, P Berbis, P Bernard, M
Beylot-Barry, JL Bonafé, JJ Bonerandi, Bonnetblanc, J
Chevrant-Breton, A Claudy, B Cribier, B Crickx, V Descamps, E
Delaporte, JP Denoueux, Y De Prost, B Dreno, L Dubertret, C
Frances, JJ Guilhou, P Humbert, D Jullien, JJ Grob, G Guillet, P
Joly, JP Lacour, D Lambert, L Laroche, D Leroy, G Lorette, L
Meunier, J Meynadier, L Misery, P Modiano, JP Ortonne, JL Schmutz,
A Taieb, L Thomas, JL Verret.
Drs S Alexandre, O Antoniotti, A Archimbaud, MF Avril, A Barrel,
H Barthelemy, D Barthelme, P Belaube, D Bitout, I Bodokh, C
Bourgeois, P Bravard, JM Bressieux, F Breuillard, D Cales-Quist, V
Callot, F Carsuzaa, P Chasseuil, G Colonna, P Combemale, P Coupié,
Courouge, A Dallot, B Ducros, C Durieux, E Estève, J Friedel, B
Fournier, J Gachon, Y Gauthier, F Giocanti, F Grange, C Graveriau,
Y Guigen, JC Guillaume, I Guillot, B Hillion, M Janier, B Lagrange,
J Larsabal, P Le Bozec, T Le Guyadec, A Lesueur, S Ledu, Lesueur, I
Lota, C Lok, C Lucciani, R Metz, F Maccari, C Magnani, S Marques, J
Martel, JP Meraud, E Moreau, JJ Morand, P Muller, J Nougué,
Pauphilet, C Pauwels, JL Paty F Pelletier, G Perceau, P Perrin, P
Plantin, F Prigent, B Remond, D Richard, S Oro, I Saint-Cyr, B
Sans, G Safa, B Schubert, R Sevy, F Skowron, F Soyer, S Sportich, R
Trillet, C Tia Tiong Fat, P Toussaint, F Truchetet, P Valignat, PY
Venencié, Y Veran, C Vernassière, A Vermesch, Villatte, R Viraben,
E Wierzbicka, A Zagnioli.
References
1 Degos R. Psoriasis pustuleux généralisé. In: Degos R,
ed. Dermatologie. Paris: Flammarion, 1967: 459-60.
2 Augey F, Dissard C, Normand I, Daumont M.
Generalized pustular psoriasis (von Zumbush) following iatrogenic
hypocortisolism. Eur J Dermatol 2004; 14: 415-7.
3 Ohkawara A, Yasuda H, Kobayashi H, et al.
Generalized pustular psoriasis in Japan: two distinct groups formed
by differences in symptoms and genetic background. Acta Derm
Venereol 1996; 76: 68-71.
4 Pitche P, Padonou CS, Kombate K, Mouzou T,
Tchangai-Walla K. Syndrome de Stevens-Johnson et nécrolyse
épidermique toxique à Lomé (Togo). Profil évolutif et étiologique
de 40 cas. Ann Dermatol Venereol 2005; 132: 531-4.
5 Bastujin-Garin S, Souissi R, Blum L,
et al. Comparative epidemiology of pemphigus in Tunisia and
France: unusual incidence of pemphigus foliaceus in young Tunisian
women. J Invest Dermatol 1995; 104: 302-5.
6 Raychauhuri SP, Farber EM. The prevalence of
psoriasis in the world. JEADV 2001; 15: 16-7.
7 Yang SK, Loftus EV, Sandborn WJ. Epidemiology
of inflammatory bowel disease in Asia. Inflamm Bowel Dis 2001; 7:
260-70.
8 Hukuda S, Minami M, Saito T, et al.
Spondylarthropathies in Japan nationwide questionnaire survey
performed by the Japna Ankylosing Spondylitis Society. J Rheumatol
2001; 28: 554-9.
9 Kawada A, Tezuka T, Nakazimo Y, et al. A
survey of psoriasis patients in Japan from 1982 to 2001. J Dermatol
Sci 2003; 31: 59-64.
10 Jalal O, Houass S, Laissaoui K, Hocar O,
Chiarioui S, Amal S. Formes graves de psoriasis: 160 cas.
Ann Dermatol Venereol 2005; 132: 126-8.
11 Zelickson BD, Muller SA. Generalized pustular
psoriasis; a review of 63 cases. Arch dermatol 1991; 127:
1339-45.
12 Viguier M, Allez M, Zagdanski AM, et al.
High frequency of cholestasis in general pustular psoriasis:
evidence for neutrophilic involvement of the biliary tract.
Hepatology 2004; 40: 452-8.
13 Magis NL, Blummel JJ, Kherkof PC,
Gerritsen RM. The treatment of psoriasis with etretinate and
acitretin: a follow-up of actual use. Eur J Dermatol 2000; 10:
517-21.
14 Umezawa Y, Ozawa A, Kawasima T, et al.
Therapeutic guidelines for the treatment of generalized pustular
psoriasis based on a proposed classification of disease severity.
Arch Dermatol Res 2003; 295: S43-S54.
15 Ryan TJ, Baker H. Systemic corticosteroids and
folic acid antagonists in the treatment of generalized pustular
psoriasis. Evaluation and prognosis based on the study of 104
cases. Br J Derm 1969; 81: 134-45.
16 Williams REA. Guidelines for management of patients with
psoriasis. BMJ 1991; 303: 829-35.
1 Caisse Nationale d’Assurance Maladie des
Travailleurs Salariés.
|
Printable version
Version PDF
