Riga Stradins University

Sanita Zigure

CHILDHOOD PSORIASIS IN LATVIA (epidemiology, clinical features, therapy )

(Speciality - Dermatovenereology)

SUMMARY OF THESIS

Supervisor of research work: professor, Dr.med.hab. Andris Rubins Head of Department of Dermatovenereology, RSU

Riga, 2006

Topicality of the work.

Psoriasis is one of the most common diseases in pediatrics and dermatology. Its prevalence is estimated at between 1 and 6 % of the population (Raychaudhuri S.P., Farber E.M. 2001; Olsen A.O. et al., 2005; Ortonne J.P. et al., 2005). In Northern and Western Europe incidence of psoriasis is extremely high - up to 5 % (Hurwitz S., 1993; Landegreen J., MibackenH., 1995; Шегай M. M, et al., 1998; Farber E. et al.,1999; Olsen A.O. et al., 2005). It represents 4.1% of all dermatoses encountered in children younger than 16 (Oranje A.P. et al., 1997; Leman J., Burden D., 2001).

In Latvia, up to now, incidence of psoriasis among children younger than 18 has not been profoundly studied. There are no statistical data on children suffering from psoriasis. Features of the course of the disease in children with psoriasis have not been studied in relation with etiopathogenic factors. Effect of the therapy on body's immune condition has not been studied as well.

Management of psoriasis is still one of the most current problems in dermatology for both adults and children. Since etiology is not known, and pathogenesis has not been fully studied, empirical methods in therapy are applied. Treating children suffering from psoriasis it is crucial to choose medication that would give a stable clinical effect and would not be dangerous for further development of a child; it should control the disease, prevent deviations, decrease extent of body lesions, prolong remission, improve quality of the patient's life.

In management of psoriasis corticosteroids of local effect are used (Gottlieb A.B., 2005; Lebwohl M., 2005). However, prolonged application of these preparations may cause side effects: dermal atrophy, teleangiectasies, striae (Howard R., Tsuchiya A., 1998; Van De Kerkhof P., 1999; Lebwohl M, 2005).

One of the recent, most effective medicines of the local effect - dihydroxy-vitaminD3

analogue - Calcipotriol is pathogenetically justified means of psoriasis local therapy. It regulates cellular differentiation, decreases proliferation, and it has anti-inflammatory effect (Christophers E., Wolff K., 1999 ; Lebwohl M., 2005).

In literature it has been reported that in treatment of psoriasis in adults, combination of calcipotriol and local corticosteroids can give good results.

It is justified with the following: the local corticosteroids activate vitamin D receptors in the skin and increase sensitivity to the therapy as well as lessen irritation caused by calcipotriol, which, in its turn, decreases risk of corticosteroid side effects (Onsun N. et al., 1998; Hughes X, Rustin M.H.A., 1999; Lebwohl M, 1997 ; Lebwohl ML, 2005).

These suggestions triggered our interest to study incidence of psoriasis among children younger than 18 in Latvia and elaborate a combined method of local therapy (calcipotriol and methylprednisolone aceponate) for children suffering from psoriasis.

Propounding of the problemIn practical pediatric dermatology psoriasis is rather commonly diagnosed disease in

children. Manifestations of the disease in the course of life change, and real incidence of the disease in Latvia is unclear.

Psoriasis is multifactoral, in its pathogenesis the immune system plays one of the most significant roles, however, its etiology is not known and it has not been fully studied. Psoriasis is known to be provoked by different factors: infection (especially streptococcus infection in children), stress, endocrine factors, medications, traumata, radiation, etc.

In Latvia, incidence of psoriasis among children has not been properly studied , and there are still several unsolved problems. Solution of them would enable to improve diagnosis and management of psoriasis, as well as to determine risk factors and prognosis:

1. Psoriasis incidence among children and adolescents is not known.2. The most common precipitating factors of psoriasis development as well as its familial

inheritance have not been studied.3. Prevalence of clinical forms of psoriasis and degree of severity in children from different

age groups are not known .4. Tactics of psoriasis management in children has not been developed. A modern efficient

method of combined local therapy for psoriatic children is necessary, which wouldimprove children's quality of life in different aspects.

5. Relation of clinical data to immunologic indices has not been assessed.6. Questionnaire survey studies have not been carried out, though, it would help in obtaining

information on each individual as to their features of the disease as well as in statisticaldata process.

Objectives of workObjectives of work were the following:

1. to study epidemiological indices of psoriasis incidence among children younger than 18; toascertain the most common precipitating factors and features of the course of psoriasis inchildren;

2. to design a special form for registration of psoriatic patients;3. to develop and justify a complex method of psoriasis management in children, applying

calcipotriol cream and methylprednisolone aceponate cream, to compare and assess the effectof the developed local combined therapy in children;

4. to study changes of patients' immunological status, their correlation with clinicalmanifestations of the disease.

Tasks of work

1. To conduct an epidemiological study of psoriasis in Latvia:• To design a questionnaire for psoriatic patients (younger than 18).

• To assess incidence of psoriasis among children of different age groups .• To determine the most common precipitating factors and familial inheritance in

psoriatic children.

2. To ascertain and assess prevalence of psoriasis clinical forms and extent of psoriaticlesions in children of different age groups.

3. To develop a new method of local combined therapy, applying calcipotriol andmethylprednisolone aceponate creams and assess its effect.

4. To study the condition of the immune system in psoriatic children before and after thelocal combined therapy (calcipotriol and methylprednisolone aceponate cream), toassess the process of trreatment and clinical and immunological indices.

Ideas put forward for defending1. The designed questionnaires for psoriatic patients significantly relieve epidemiological

studies of psoriasis.2. Assessment of clinical forms, extent of lesion and localisation in children of different

age groups help to choose an adequate therapy.3. Assessment of efficacy and influence of the elaborated local combined (calcipotriol

and methylprednisolone aceponate) therapy on the course of disease andimmunological indices.

Novelty of results1. For the first time a questionnaire form for patients has been designed, which helps to

detect psoriatic patients, to examine them, to ascertain precipitating factors, to makeaccurate diagnosis and record adverse events.

2. For the first time in Latvia epidemiological study has been conducted with psoriaticchildren of the age up to 18:

• The most common precipitating factors of psoriasis were ascertained: psycho-emotional stress 44.2 % , virus and bacterial infections 33.8 %, psoriasis in familyanamnesis 24 %.

• It was determined that the average age of psoriatic children is 12.2 + 3.9 years.

• It was ascertained that psoriasis vulgaris -66 %, psoriasis exsudativa -17 % andpsoriasis guttata - 13 % are the most common forms occurring among children.

3. For the first time in Latvia, severity of the course of the disease in psoriatic patients wasascertained by PASI and BSA %, depending on age and gender, characteristic features ofthe disease in age groups were determined as well.

4. A new method of the local combined therapy (calcipotriol and methylprednisoloneaceponate) and its influence and effect on psoriasis vulgaris clinical course and immunesystem have been developed and piloted.

Amount of work

Amount of the thesis is 105 pages of typescript, it is illustrated by 14 Tables and 47 Figures.

Material and methods

Epidemiological study.In order to obtain data for the study, special forms of questionnaire were designed for psoriatic patients. The questionnaires included information on patient's age (up to 18), gender, living place, vaccinations, allergic reactions, suffered infections, internal pathology, familial psoriasis and other chronic dermal and internal diseases in the family, data on disease causing factors, age at which psoriasis has been diagnosed, extent of dermal lesion, clinical forms, psoriasis complications and the applied therapy.

Psoriatic children at the age from 6 months to 18 years have been recorded consulting and treating dermatological patients in the Dermatology department of Children Clinical University Hospital and in outpatient consultation clinics, as well as during field sessions 4 x a year and consulting psoriatic children and adolescents together with regional dermatologists.

In the period of 1999 - 2004, 500 psoriatic children at the age from 6 months - 18 years from different districts of Latvia were consulted and interviewed. Questionnaire data and clinical parameters were computerised for further procession.

Psoriatic children were divided into age groups, taking into account developmental features in different periods:young children - children at the age of 6 mons - 3 years pre-school children - at the age of 4 - 7 years pre-puberty age - 8 - 11 years puberty age - 12-14 years adolescence - 15-18 years

Diagnoses and classifications

Psoriasis diagnosis was made basing on the typical clinical picture and characteristic psoriasis phenomena. For more accurate diagnosis in case of differential diagnosis, 30 children underwent dermal biopsy.

Determination of severity of psoriasis clinical form.Course of psoriasis, extent of dermal lesions as well as severity of the clinical signs

(desquamation, erythema, infiltrations) and effect on quality of life were assessed in 500 children according to their gender and age, applying Psoriasis Area and Severity Index (PASI), as well as determining percentage of extent of body lesions. To assess the degree of severity of psoriasis we used the guidelines of European Medical Agency on division of severity of psoriasis. We grouped our patients according to their age and determined the average PASI and percentage of the average extent of body lesions (BSA%) separately in 3 groups (see Table 1). Table 1. Degrees of psoriasis severity.

Mild form BSA 0-10 %

PASI 0-9,9

Moderate form

BSA 11-20%

PASI 10-20

Severe form BSA>21% PASI > 20

Clinical- immunological study.

In the Department of Dermatology of Children Clinical University Hospital outpatient randomised study involved 60 children and adolescents (30 girls, 30 boys) at the age of 8 - 17 (mean age 12.25 ± 2.43 years) with moderate psoriasis vulgaris form with extent of body lesions up to 20%.

The patients were randomly (drawing lots) divided into 2 groups.

Group I with local combined method of treatment - 30 patients received applications of calcipotriol cream ("Daivonex" 50 mkg/g) in the morning and 0.1% methylprednisolonc aceponate ("Advantan") cream in the evening for 2 weeks, but starting from the 3rd until the 4th week the patients used calcipotriol cream in the morning and evening on odd days, but on even days they used calcipotriol cream in the morning and 0.1% methylprednisolone aceponate cream in the evening. Totally therapy lasted for 4 weeks.

Group 2 with local calcipotriol monotherapy - 30 patients locally applied calcipotriol cream (Daivonex 50 mkg/g) in the morning and evening for 4 weeks.

To evaluate the clinical effect of the treatment method, PASI was used (lesions of scalp and neck were not included), which was determined before therapy, after the Ist, 2nd and 4th week. Clinical improvement was evaluated by 6-point scale.

Assessment of the following took place at all visits: blood count, level of calcium and phosphorus in blood, alkaline phosphotase, adverse events.

Methods of laboratory investigationImmunological investigation was conducted in the Centre of Clinical Immunology of

Stradins Clinical University Hospital. In order to assess effect of the local combined therapy not only on patients' clinical condition, but also on children's and adolescent's immune system, in 19 patients from Group 1 it was possible to determine their immune status. For assessment of immune status immunological parameters were ascertained (CD4+, CD8+, proportion coefficient CD4 +/CD8+, CD16+, CD25+, immunoglobulin IgA, IgG, IgM, IgE , complement factors C3, C4, circulating immunocomplex CIK level) in blood serum before therapy and after the received therapy, comparing to the control group - healthy children, in accordance with the intervals stated by the producer of the testing system.

Determination of lymphocyte subpopulation CD4+, CD8+, CD 16+ and CD25+ with monoclonal antibodies for lymphocyte surface markers with laser cytofluorimeter with Becton Dickinson reagents.

Determination of immunoglobulins in blood serum and of circulating immunocomplexes with nephelometry using Dade Behring reagents.

Procession of statistical and mathematical data.Statistical analysis of data was done using the computer programmes: SPSS

programme (The Statistical Package for the Social Sciences), Microsoft Excell. To analyse the data, methods of statistical analysis, widely described and used in medical research (Arhipova I., Balina S., 1999; Altman D.G. 2000; Rosner B. 2000; Teibe U., Berkis U.,2001; Krastins O., Ciemina I., 2003) were applied. Indices of central trend were assessed (arithmetical mean, median, mode) and measures of dispersion (standard deviation [SD], standard error [SE] of arithmetical mean). In the study we found also 95% confidence limits.

Results were considered statistically significantly different, if the discrepancy was

credible on

the level of significance p< 0.05.

The propounded hypotheses were assessed with methods of inference statistics:

• Student's t test to compare the mean value of two samplings.

• Analysis of variance (ANOVA) to compare the mean value of several

samplings

• Correlation analysis to ascertain firmness of relations between variables.

• 2 chi-squared test to check data distribution.

• Linear regression analysis.

• Analysis of confidence interval.

Results

Characteristics of patients.

In the period of 1999 -2004 (including) there were recorded, questioned and examined 500 children younger than 18 suffering from psoriasis.

It was ascertained that with the first-time diagnosis of psoriasis, on the average, 53.2 +21.6 new psoriatic patients have been recorded every year. Of the followed-up children and adolescents 303 (60.6%) were girls and 197 (39.4%) were boys. Girls were by 21.1% more than boys (95% confidence interval 15.1% - 27.1%). Female and male ratio is 1.54 : 1. The mean age of the patients 12.2± 3.9 years. The mean age of boys 11.8+ 4.1 years, with mean standard error 0.3, but the mean age of girls 12.4± 3.7 years with mean standard error 0.2. After independent sampling t test there was no statistically significant difference between the mean ages (t = -1.77; p = 0.08) (see Table2).

Table 2. The average age of boys and girls. Average Standard Mean

Gender Number age (years) deviation Standard errorBoys 197 11,8 4,1 0,3Girls 303 12,4 3,7 0,2

As Table 3 shows, majority of the patients is at the age of 14 -17 including. With increase in patient's age, number of children with psoriasis also is increasing.

Table 3. Division of patients by age (percentage and cumulative percentage).

Age (years) Number Percentage Cumulative percentage

<1 1 0,2 0,2

1 2 0,4 0,6

2 2 0,4 1,0

3 9 1,8 2,8

4 9 1,8 4,6

5 15 3,0 7,6

6 15 3,0 10,67 26 5,2 15,88 14 2,8 18,69 25 5,0 23,610 29 5,8 29,411 41 8,2 37,612 31 6,2 43,813 44 8,8 52,614 64 12,8 65,415 62 12,4 77,816 56 11,2 89,017 55 11,0 100,0

Totally 500 100,0

Comparing by gender, in both girls and boys psoriasis is most common in the teenager period and in adolescence. Division of children and adolescents with psoriasis in age groups is shown in Table 4.

Table 4. Division of children with psoriasis in age groups.Age group Girl Boy Totally

(years) Number % Number % Number %

0-3 6 2,0 8 4,1 14 2,84-7 36 11,9 29 14,7 65 13,08-11 65 21,5 44 22,3 109 21,8

12-14 85 28,1 54 27,4 139 27,815-18 111 36,6 62 31,5 173 34,6

Totally 303 100,0 197 100,0 500 100,0

It can be seen that with increase in children's age, number of patients is also increasing. In the age group of 15 -18 there is the greatest number of adolescents suffering from psoriasis - 173 (34.6%). The least number of patients is at the age of 0-3 - 14(2.8%) children.

Hypothesis on equality of division for girls and boys was checked with chi-squared test, it was

found that division is equal for both genders (2 = 3.57; df= 4; p =0.47).

Incidence of psoriasis among children and adolescents in regions of Latvia.In Figure 1 we can see that majority of the registered children and adolescents

suffering from psoriasis come from Vidzeme - 327 patients (65%), including 173 (34%) from Riga. It can be explained by the fact that Riga has bigger population and that majority of patients are consulted in Riga as outpatients in the Department of Dermatology of Children Hospital and in the outpatient department. Registration of the patients took place also in field-sessions in regions of Latvia, however, it was possible more rarely. Approximately similar number of patients was recorded in Zemgale - 71 (14%) , Latgale -53 (11%) and Kurzeme region -49(10%).

Figure 1. Division of children with psoriasis by regions of Latvia.

It was ascertained that the most common psoriasis precipitating factors are: psycho-emotional stress in 221 children and adolescents, viral and bacterial infections in 169 patients. Psoriasis in family anamnesis was detected in 24% (120 of 500 questioned children), in 25 cases (20.8%) of them psoriasis had affected the first-degree relatives (father, mother). Most commonly the disease was inherited from father's line, i.e., in 93 (77.5%)children, 7 children (1.4%) had in their family anamnesis eczema or neurodermatitis, 2 of them from father's line, 4 -from mother's. In some patients several precipitating factors were detected.

Comparing precipitating factors between girls and boys, we detected that psycho-emotional stress, viral and bacterial infections more commonly facilitate or deteriorate course of psoriasis in girls and adolescent females, and they also have psoriasis in family anamnesis more often than males. However, it should be taken into account that there were 1.5 times more females than males in the study.

Diagnoses and classifications.Diagnosis if psoriasis was made on the basis of the clinical picture and characteristic

psoriatic phenomena. The most common sites of psoriasis localisation in children are scalp (448 children and adolescents), forehead along the border of hair, extremity joints, thorax and back. Facial skin was also affected by psoriatic inflammation in 173 (34.6%) children. Analysing data on 500 examined children with psoriasis, it was concluded that the most common form in both boys and girls was psoriasis vulgaris form - 66%, psoriasis exsudativa 17% (83), psoriasis guttata 66 (13%), psoriasis pustulosa 2% (9), psoriasis inversa and erythrodermia only in 1 % (7 and 6 children respectively).

Psoriasis complications in children and adolescents are diagnosed rarely: arthritis only in 2 % (10) of children, nail damage (thimble phenomenon) in 41% (205) of the children.

Figure 2 shows division of psoriasis clinical forms by gender. In female group number of patients suffering from psoriasis vulgaris, psoriasis exsudativa and psoriasis guttata forms is bigger, since the study involved girls by 21.2% more than boys.

Figure 2. Clinical forms of psoriasis in boys and girls

Expressing frequency of psoriasis forms in per cents, it turns out that psoriasis vulgaris occurs in 65% of 303 girls and female adolescents suffering from psoriasis and in 67% of 197 boys and male adolescents, and on the average, in 65.8% of 500 patients (see Fig.3). Psoriasis vulgaris form is likely to be the most common clinical form in children and adolescents. 95% Confidence interval 61.5% - 69.8%. Percentage of psoriasis exsudativa is slightly higher in girls (18.8%) than in boys (13.2%), but percentage of psoriasis guttata form is almost equally frequent in both girls (12.9%) and boys (13.7%).

Figure 3. Percentage of clinical forms of pediatric psoriasis in both genders.

Psoriasis vulgaris form in girls most commonly occurs at the age of 13 -17, which corresponds to the period of teenagers and adolescents, whereas in boys - most commonly at the age of puberty, i.e. 14-15 (see Fig.4). At the age of 13 incidence of psoriasis vulgaris form does not differ statistically significantly between girls and boys, difference is 7.6%. 95% Confidence is -19.2%--40.9%.

Figure 4. Patients with psoriasis vulgaris clinical form.

Figure 5 shows a regularity, i.e., psoriasis vulgaris form occurs more frequently with increase in age in both girls and, accordingly proportionally less, in boys. In female adolescents aged 15-18 this form has been diagnosed by 1.85 times more often than in males.

Figure 5. Psoriasis vulgaris in children age groups

In girls and female adolescents psoriasis exsudativa form most commonly was detected at the age of 11 and 16 , whereas in boys at the age of 11 of all 83 patients with this form (see Fig.6).

Figure 6. Children and adolescents with psoriasis exsudativa clinical form.

Figure 7 shows incidence of psoriasis exsudativa in children and adolescents in age groups. We ascertained that in girls this form most commonly occurs at the age of 15-18, whereas in boys, starting from school age, there is no significant difference among age groups.

Figure 8 reveals that psoriasis guttata in girls most commonly occurs at the age of 14 and 15, whereas in male adolescents at the age of 16 in all 66 patients suffering from this form

Figure 7. Psoriasis exsudativa in children age groups

Figure 8. Psoriasis guttata clinical form.

Figure 9 shows that psoriasis guttata form is observed equally often in both teenagers and adolescents, whereas in boys it most commonly occurs at the age of 15-18.

Figure 9. Psoriasis guttata in children age groups.

Assessing seasonally of the disease, we ascertained that psoriasis in children most commonly occurs in winter 67% (see Fig. 10).

Figure 10. Seasonality of psoriasis in children.

Winter form is the most common seasonal form in both boys and girls. Of 303 girls winter form was observed in 194 (64%) cases, summer form in 71 (23.4%) case, but mixed form in 38 (12.5%) girls. Of 197 boys winter form was observed in 138 (70%) cases , summer form in 41 (20.8%), but mixed form in 18 (9.1%) boys (see Fig. 11).

Figure 11. Disease seasonality in girls and boys.

Adverse events were diagnosed in 222 children, i.e., 44.4% of all children examined in the study and having psoriasis. One of the most common adverse event was chronic gastro-duodenitis - in 105 children, or 21% of 500 children. The next most frequently diagnosed group was neurological diseases - in 74 children, i.e. 14.8% of the total number of children; 61 of them had neurovegetodistony, 9 - enuresis nocturna, 3 - organic CNS damage, 2 - spinal spastic paralysis, 1 -spina bifida, 1 - epilepsy. Twenty-five children had other diseases (5 -dyskinesia of bile ducts, 4 - nephritis, 4 - struma, 3 - reactive hepatitis, 3 - celiakia, 2 were pregnant, 1 - leukosis, 1 - hypothyroidism, 1 alopetia areata, 1 vitium cordis congenita).

Assessment of severity of psoriasis by means of PASI.In 500 children, followed up in the study, mean PASI was 12.53 +7.38 ,which corresponds

to moderate form. It was ascertained that almost half of the children suffering from psoriasis have it in moderate form (49.8%) . The mild form affects approximately 1/3 of the patients (36.4%) , and only 13.8% have severe form. Degrees of severity of psoriasis according to mean PASI are shown in Table 5.

Table 5. Degree of psoriasis severity in children and adolescents by mean PASI.

Mean Number PercentagePASI of

Degree of severity of psoriasis groups children

Mild 0-9,9 182 36,4Moderate 10-20 249 49,8

Severe >20 69 13,8

Totally 500 100,0

As it is seen from Table 6, the average age of patients with psoriasis corresponds to teenager period (11-12 years) irrespective of severity. However , making checking of hypotheses on equality of the average patients' age according to degree of severity with dispersion method (ANOVA), it was ascertained that mean ages of the groups differ statistically significantly (F=7.10; p=0.001).

Table 6. Descriptive statistics of patients' age in groups of clinical forms according to PASI

Degree of psoriasis severity

PASI group

Number of patients

Mean ofage

Standard deviation (SD)

Standard error(SE)

Mild 0-9,9 182 11,3 4,2 0,3

Moderate 10-20 249 12,7 3,7 0,2

Severe >20 69 12,6 3,2 0.4

Totally 500 12,2 3,9 0,2

Dividing psoriatic patients according to gender, we ascertained that both girls 50.2% and boys 49.2% mostly have moderate form of psoriasis. The next form according to severity isthe mild form of psoriasis , it was more observed in girls 40.9% than in boys 29.4%. The least number of patients suffer from severe form, girls 24.4% and boys 21.3%. According to chi-squared test, division of clinical forms (PASI) by gender differs statistically significantly (2 = 17.77; p=0.01) (see Table 7).

Table 7. Division of clinical forms of psoriasis according to gender (PASI)

Degrees of psoriasis severity Girls Boys Totally

(mean PASI) Number % Number % Number %

Mild 124 40,9 58 29,4 182 36,4

Moderate 152 50,2 97 49,2 249 49,8

Severe 27 24,4 42 21,3 69 13,8

Totally 303 100,0 197 100,0 500 100,0

Distribution of psoriasis severity in children and adolescents (according to mean PASI) in different age groups differs statistically significantly (2 = 16.44; p= 0.036). Analysing severity of psoriasis in children and adolescents in age groups, it can be seen that with increase in age, number of children with moderate psoriasis is increasing. Moderate psoriasis form starts prevailing from the pre-puberty age and majority of patients - 101 (40.6%) - with moderate psoriasis are in the adolescence age of 15-18. Children and adolescents more rarely have mild psoriasis, it is more common in puberty period - 51 child (28%) and adolescence period - 48 adolescents(26.4%). In the period from 0 to 3 years, mild form of psoriasis is prevalent, whereas severe form has not been detected. In all age groups the least number of patients is with severe form of psoriasis, but beginning from the pre-school age number of patients with this form is increasing and reaches the highest number in adolescence period from 15-18 years of age, i.e. 24 patients. It should be taken into account that majority of the patients in the study were teenagers and adolescents (see Table 8. and Fig. 12).

Table 8. Division of severity of psoriasis in age groups according to PASI

Age group(years)

Severity of psoriasis ( PASI) Totally

Mild form Moderate Severe form

Number % Number % Number % Number %0-3 9 4,9 5 2,0 0 0 14 2,8

4-7 31 17,0 27 10,8 7 10,1 65 13,0

8-11 43 23,6 50 20,1 16 23,2 109 21,8

12-14 51 28,0 66 26,5 22 31,9 139 27,8

15-18 48 26,4 101 40,6 24 34,8 173 34,6

Totally 182 100,0 249 100,0 69 100,0 500 100,0

Vecuma grupa (gadi)

Figure 12. Division of clinical forms in ape groups (PASI)

In boys up to the age of 14 mean scores of PASI increase, suggesting that in the adolescence period prevalent among boys is moderate psoriasis. In girls such trend is not observed . In teenager girls at the age of 12 -14 mean PASI is lower than in boys. In girls of all age groups PASI scores are lower than in boys, which suggests that girls have tendency to mild and moderate form (see Fig. 13). 95% confidence interval limits overlap , therefore dependence of PASI mean score on age and gender is not statistically significant.

Vecuma grupa (gadi)

Figure 13. Degree of psoriasis severity in boys and girl according to age groups (PASI)

Assessment of severity of psoriasis according to percentage extent of body lesions

Taking into consideration that there are different assessment methods of severity of psoriasis, but none of them is ideal, in our study we assessed severity of psoriasis according to percentage extent of body lesion. However, this characteristic index reveals only the area of psoriatic skin lesion , but does not evaluate symptoms of psoriasis ( desquamation, infiltration, erythema). Therefore extent of body lesions is not the main index of determination of severity, but only one of them.

We ascertained that in children and adolescents the average percentage extent of body lesions (BSA%) was 12.01 + 6.9. According to guidelines of European Medical Agency (www.emea.eu.int) this index shows also prevalence of moderate psoriasis in the examined patients. Determining severity of psoriasis according to BSA % , we confirmed that in children and adolescents the dominating form is moderate psoriasis (1.78 x more), and more commonly it occurs in teenagers at the age of 13.9 ± 2.8 . Checking hypothesis on mean age equality with dispersion analysis (ANOVA) , we ascertained that mean ages of the groups differ statistically significantly (F= 91.81; p=0.01) (see Table 9).

Table 9. Descriptive statistics of patients' age (years) in groups of severity of psoriasis

according to BSA%

Degrees of Severity

(BSA%)

Patient Mean ageStandard deviation SD Standard errorSE

Number %

Mild 203 40,6 9,8 3,7 0,3

Moderate 283 56,6 13,9 2,8 0.2

Severe 14 2,8 11,4 5,1 1,4

Totally 500 100 12,2 3,9 0,2

Chi-squared test shows that division of psoriasis severity (according to BSA%) does not differ statistically significantly by gender (2 = 1.44; p=0.49). In both girls (58.7) and boys (53.3%) prevalent is moderate psoriasis (according to BSA%) (see Table 10).

Table 10. Division of severity of psoriasis ( BSA%) according to gender.

Girl Boy Totally

BSA group Number

% Number

% Number

%Mild 117 38,6 86 43,7 203 40,6

Moderate 178 58,7 105 53,3 283 56,6Severe 8 2,6 6 3,0 9 2,8Totally 303 100,0 197 100,0 500 100,0

Division of severity of psoriasis by age groups according to BSA% is not equal 2 = 166.87; p =0.001). Analysing BSA% , one can see a tendency that in all age groups there is a small number of children and adolescents with severe psoriasis. Moderate psoriasis according to BSA% is prevalent from the age of 15 -18, i.e. 136 (48.1%) adolescents.

Mild psoriasis most commonly is recorded in the pre-puberty period, i.e. 79 (38.9%) children (see Table 11 and Fig. 14).

Table 11. Division of severity of psoriasis in age groups according to BSA%.

Age group

Degrees of psoriasis by BSA % Totally

(years) Mild Moderate SevereNumbe

r% Numbe

r% Numbe

r% Numbe

r%

0-3 9 4,4 4 1,4 1 7,1 14 2,84-7 55 27,1 7 2,5 3 21,4 65 13,08-11 79 38,9 29 10,2 1 7,1 109 21,812-14 28 13,8 107 26,8 4 28,6 139 27,815-18 32 15,8 136 48,1 5 35,7 173 34,6

Totally 203 100,0 283 100,0 14 100,0 500 100,0

Figure 14. Division of severity of psoriasis in age groups according to BSA%.

In Figure 15 we can see that limits of 95% confidence interval overlap, therefore we cannot claim that dependence of severity of psoriasis (BSA%) on age and gender is statistically significant. The Figure reveals tendency that in boys at the age up to 12-14 severity of psoriasis, according to BSA%, is increasing, and it proves that in adolescence period prevalent is moderate psoriasis. In girls such tendency has not been observed.

Figure 15. Division of severity of psoriasis according to BSA% in age groups and genders.

Table 12 and Figure 16 compare both chosen criteria of assessment of psoriasis severity -PASI and BSA%. It can be seen that by PASI and BSA% equal degree of psoriasis severity has been ascertained in 51.0 % of cases, and only in 6.2% of cases there is a big difference in evaluations by these scales.

According to Kappa criterion both evaluations are statistically significantly concordant ( = 0.135; p= 0.01), but according to rank (Spearman) correlation coefficient between PASI and BSA (r = 0.106; p=0.02) there is weak , though statistically significant correlation.

Table 12. Clinical forms assessed according to BSA and PASI ( percentage in the table is given from total number of patients).

Form of psoriasis(PASI)

Form of psoriasis (BSA %) Tota

'y

Mild Moderate SevereNumbe

r% Numbe

r% Numbe

r% Numbe

r%

Mild 92 18,4 90 18,0 - 182 36,4Moderate 80 16,0 159 31,8 10 2,0 249 49,8

Severe 31 6,2 34 6,8 4 0,8 69 13,8Totally 203 40,6 283 56,6 14 2,8 500 100,0

Psoriazes forma (pēc PASI)

Figure 16. Clinical forms assessed by BSA

and PASI .

Clinically immunological study.

In the Department of Dermatology of Children Clinical University Hospital , the clinical study involved 64 patients (33 girls and 31 boy), their mean age was 12.25 ± 2.43, and they suffered from moderate form of psoriasis vulgaris, extent of body surface lesions up to 20 %. The patients were randomly divided into 2 groups. Four patients were excluded from the randomised study as they did not follow the protocol (2 boys and 1 girl applied creams irregularly, 1 girl did not come to check-up visit after a week).

In Group 1 (combined local therapy) 30 children were included (18 girls and 12 boys), and in Group 2 (calcipotriol monotherapy) 30 children (13 girls and 17 boys).

PASI changes during therapy.

Mean PASI in Group 1 (combined local therapy) before therapy was 14.82 ± 6.0, which after

1-week therapy reduced to 8.83 ± 4.77, after 2 weeks PASI reduced to 6.2 ± 2.48, but after 4

weeks mean PASI reduced to 3.94 ± 2.61.

In Group 2 (calcipotriol monotherapy) mean PASI of the patients before therapy was 15.78 ±

4.52, after one week it decreased to 11.18 ± 3.09, after 2 weeks it decreased to 8.8 + 3.09, but

after the 4th week mean PASI decreased to 7.21 ± 2.33.

In patients of the Group 1 already after one-week therapy there was significant decrease in erythema, scaling and infiltration, which was suggested by reduction of mean PASI scores by 40.4%, in comparison to Group 2, in which mean PASI after one-week treatment reduced by 29.2%. Moreover, beginning with the first week in Group 1 reduction of PASI differs statistically significantly from the result of the Group 2 (p< 0.05).

After second week of the therapy PASI in the Group 1 reduced by more than a half from baseline - by 58.2%, but in the Group 2 PASI reduced by 44.2% from the baseline. Starting from the 3rd till the 4th week in the patients of Group 1 scheme of application of medicines changed (on odd days calcipotriol cream was applied in the morning and evening, but on even days calcipotriol cream in the morning and methylprednisolone aceponate 0.1% cream in the evening).

PublicationsZigure S. Application of Aerosol Skin-cap in the local therapy in erythematosquamous

dermatoses with manifestations in hairy part of the head in children// Riga, AML/RSU.

Comparing the results before therapy and after therapy in the patients of Groups 1 and 2, we ascertained that in the patients of the combined therapy group infiltration, scaling, and erythema in psoriatic lesions reduced better and faster, which is proved by reduction of PASI by 73.4%, whereas in monotherapy group PASI reduced by 54.4%. Percentage changes of the meanPASI in both groups are shown in Figure 17.

Figure 17. Percentage changes of mean PASI during therapy.

Assessing clinical improvement by means of 6-point scale, we ascertained that in the local therapy group 23 (76.7%) patients had significant improvement and in 2 (6.7%) adolescents clinical recovering occurred (totally 83.4%). In monotherapy group 10 (33.3%) patients, i.e. one third of Group 2 children had marked improvement of dermal inflammation after therapy. Relative frequency difference between methods is statistically significant 50.1 %. The lower limit of 95% confidence interval 25.4% , upper -66.9%. Thus, with 95% confidence we can claim that the combined therapy gives better result in at least 25.4% of cases, in comparison to monotherapy. Figure 18 shows percentage clinical improvement in the patients of combined therapy and monotherapy.

Figure I8. Percentage clinical improvement in patients of combined therapy and

monotherapy.

During the therapy no deviations in he blood count were found, blood calcium and phosphorus as well as alkaline phosphotase were in norm. Serious side effects were not observed in children of both groups. It should be noted that in Group 2 five patients noticed local side effects after calcipotriol application (in 3 adolescents skin reddening, skin itching on the hands in sites of application of the cream, if it was applied immediately after water procedures; when the time of application was changed to 30-40 minutes after water procedures, complaints disappeared; in 2 adolescents reddening appeared on facial skin, if it was touched with unwashed hands).

Determination of immune status.In 19 patients (14 girls and 5 boys) from Group 1 immune status was analysed before

therapy and after the received therapy. The mean age of the children was 13.8 ± 2.1 years.

Content of lymphocyte sub-population T helpers (CD4+), supressors (CD8+), killer-cells (CD16+) and IL 2 receptor- T lymphocyte activation markers (CD25+) in peripheral blood was determined with monoclonal antibodies to surface cellular markers with laser cytofluorimeter with Becton Dickinson reagents. Study results were expressed in percents. We also determined ratio changes between T helpers (CD4+)/T-supressors (CD8+) during therapy. It was ascertained that immunological parameters in psoriasis vulgaris patients at the age of adolescence differ both individually and by gender , but deviations are not significant in comparison to immunological features of healthy children.

Figure 19 shows that percentage of T-helpers (CD4+) before therapy (37.7 ± 8.2) and after

it (37.68 + 7.9) does not differ from that of healthy children (33-41).

Figure 19. Percentage of (CD4+) before and after therapy in comparison to healthy children. Mean percentage of T-helpers in teenagers and adolescents with psoriasis vulgaris before therapy was in norm. Only in separate individuals (4 children) this index was decreased before therapy, after therapy it remained under the lower limit of the norm, but with a tendency to increase. In 7 children percentage of CD4+ before therapy was increased, but after the combined therapy in 6 cases it remained increased above the top limit of the norm, and in 1 case it decreased. In 2 children before therapy percentage of CD4+ was at the normal top limit, whereas after therapy percentage of T-helpers increased above the norm. Figure 20 shows correlation between percentage of CD4+ before and after therapy, ascertained by means of correlation and linear regression analysis. Equation of linear regression is CD4+ % after therapy = 0.82 x CD4+ before therapy (%) + 6.9. Between CD+ 4% values before and after therapy there is close correlation ( R = 0.8; p<0.05). Determination coefficient R2 = 0.7.

Figure 20. Equation of correlation and linear regression between percentage of CD4+ before

and after therapy.

By means of non-parametric statistical method we compared individual CD+ percentage differences of the adolescents (CD4+ percentage before therapy is subtracted from CD4+ percentage after therapy). We ascertained that the bigger the figure was before treatment, the bigger it remains after it. There is no common correlation, there are only individual changes. Figure 21 shows differences in each patient. In 8 children CD4+ percentage after combined local therapy has decreased, whereas in 9 children CD4+ percentage after treatment has increased, in 2 children this figure has not changed.

Figure 21. Individual CD4+ percentage differences.

T suppressor CD8+ percentage (30.26 ± 6.56) in adolescents with moderate psoriasis vulgaris before therapy on the average was unchanged in comparison to healthy children (27-35), but after therapy CD8+ percentage is less (27.32 ± 8.81), but on the average it is in the lower limit of the norm of healthy children. In 4 children before therapy CD8+ percentage was increased above norm , which after therapy decreased and only in 1 case did not reach the top limit of the norm. In 8 adolescents CD8+ percentage before therapy was within the norm, in 3 of them after therapy CD8+ % decreased to normal, in 1 decreased under the lower limit of the norm, in 4 children CD8+ % after therapy increased. In 3 adolescents CD8+ % was above the top limit of healthy children. See Fig. 22.

Figure 22. Percentage of T-suppressor (CD8+) before and after combined local therapy.

With non-parametric statistical method we compared individual CD8+ value differences (CD8+ % after therapy is subtracted from CD8+ % before therapy). We did not ascertain common correlation , there are only individual CD8+ changes before and after therapy. Figure 23 shows changes into each patient. In 15 children CD8+ % after the combined local therapy decreases , but in 4 adolescents CD8+ % after therapy increases.

Figure 23. Individual CD8+ percentage differences.

Figure 24 reveals correlation between CD8+ % before and after therapy, using correlation and linear regression analysis. Equation of linear regression is CD8 % after therapy = 0.77 x CD8 before therapy (%) + 4.1. Between CD8+ % before and after therapy there is mean correlation (R= 0.57; p < 0.05). Determination coefficient R2 =0.3. CD8+% results have tendency to decrease under influence of the therapy, but in healthy children they are within the norm. Possibly, under the influence of the combined local therapy, CD8+ migration in the dermal inflammation takes place, which results in reduction of amount of CD8 + in blood.

Figure 24. Equation of correlation and linear regression between CD8+ % before and aftertherapy.

Figure 25 shows fluctuation of CD4+ / CD8+ ratio , which before therapy was 1.34 ± 0.5 , after the local combined therapy increased to 1.55 ± 0.63 , which is higher than the top limit of healthy children (1.1 -1.4), but increase of CD4+ / CD8+ ratio after the local combined therapy is not statistically confident.

Figure 25. Fluctuations of CD4+ /CD8+ ratio before and after the combined local therapy , comparing to healthy children.

Figure 26 shows correlation between fluctuations of CD4+/ CD8+ ratio before and after the local combined therapy, ascertained by means of correlation and linear regression analysis. Equation of linear regression is CD4+ / CD8+ after therapy = 1.01 x CD4+ / CD8+ before therapy +0.19. Between CD4+ / CD8+ ratio before and after therapy there is strong correlation (R = 0.84; p < 0.05). Determination coefficient R2 = 0.67.

Increase in CD4+ / CD8+ ratio under influence of the therapy can be explained by the fact,

that after the local therapy CD4+ amount does not change, since T- helper activation continues, but number of CD8+ after therapy decreases.

Figure 26. Equation of correlation and linear regression between fluctuations of CD4+/ CD8+ proportion before and after the local combined therapy.

Percentage of killer-cells CD16+ (12.9 ± 6.59) in adolescents with moderate form of psoriasis vulgaris before therapy was on the overage unchanged in comparison to healthy children (9.0-16). However, after therapy CD16+ % is lower (10.9 ± 5.9), but on the average it falls within the norm of healthy children. In 7 adolescents CD16+ % before therapy did not differ from that of healthy children, whereas after the local combined therapy these indices in all patients reduced within the norm, only in 2 cases under the lower norm of the age.

In 5 adolescents CD16+ % before therapy was above the top norm of the age, but after therapy in 3 children it reduced within the norm, and only in 1 case it remained unchanged and in 1 continued growing. In 7 children CD16+ % before therapy was reduced, and in 4 after therapy remained under the lower limit of the age (see Fig.27 ).

Figure 27. CD16+ % before and after local therapy in comparison to healthy children.

Figure 28 shows relation between CD 16+ % values before and after therapy ascertained by means of correlation and linear regression analysis. Equation of linear regression is CD 16+ % after therapy = 0.63 x CD16+ before therapy (%) + 2.85. Between CD16+ % values before and after therapy there is strong correlation (R =0.69; p< 0.05). Determination coefficient R2 = 0.48. Results of CD16+ % have tendency to reduce under influence of therapy, but within the norm of healthy children. Reduction of CD16+ suggests decrease in psoriatic inflammation and improvement of cytotoxic functions.

CD16 % before therapy

Figure 28. Equation of correlation and linear regression between CD16+ % before and aftertherapy .

To assess content % of IL 2 receptors - T-lymphocyte activation markers (CD25+) in peripheral blood we determined their amount % in adolescents before therapy (5.63 ± 1.98) and after therapy (5.68 ± 1.95) in relation to healthy children CD25+ % (2-5%). In teenagers and adolescents with moderate psoriasis form CD25+ % is comparatively higher than in healthy children, and there is mean correlation between CD25+ % before and after the local combined therapy ( correlation coefficient R = 0.372). In 9 teenagers CD25+ % before therapy did not differ from CD25+ of healthy children, but after therapy in 7 it remained within the norm, while in 2 increased above the top norm of the age. In 10 children CD25+ % before therapy was above top limit of age norm, which after therapy in 7 remained above norm, but in 3 fell within the age norm (see Fig.29). CD25+ reveals reactions of cellular immunity by Th 1 type in case of psoriasis. In teenagers and adolescents with moderate psoriasis form CD25+ % is comparatively higher than in healthy children, and it means that in pathogenesis of psoriasis cellular immunity reactions play a significant role.

Figure 29. CD25+ % before and after the combined local therapy.

In order to determine sensitivity of humoral immunity reaction to combined local therapy in

adolescents with moderate psoriasis vulgaris form, we assessed immuno-globulin, circulating

immunocomplex, amount of complement factors C3, C4 in peripheral blood before and after

therapy in comparison to healthy children of the corresponding age. It was ascertained that

number of IgM in children before therapy was lower 1.28 ± 0.58 (g/1), but after therapy

number of IgM increased to 1.37 ± 0.58 (g/1), not exceeding IgM of healthy children 0.4 -2.3

(g/1).

After analysis of correlation and linear regression one can see that there is strong correlation between amount of IgM before and after the local combined therapy (correlation coefficient R = 0.85) (see Fig.30).

Figure 30. IgM value before and after combined local therapy.

Amount of IgG in children before therapy was 11.76 ± 2.14 (g/1), but after therapy amount of IgG tends to decrease lo.87 ± 1.55 (g/1), but result corresponds to amount of IgG in healthy children 7.0 -16.0 (g/1). Analysis of correlation and linear regression shows that there is slight correlation between amount of IgG before and after the local combined therapy (correlation coefficient R = 0.11) (see Fig.31). Decrease in IgG suggests that chronic inflammation process is decreasing.

Figure 31. Number of IgG before and after combined local therapy.

Amount of IgA in children before therapy was 2.0 ± 0.75 (g/1), after therapy IgA tends to increase 2.29 ± 1.4 (g/1), but result corresponds to amount of IgA in healthy children 0.7 -4.0 (g/1). Analysis of correlation and linear regression reveals slight correlation between IgA before and after the local combined therapy ( correlation coefficient R = 0.11) (see Fig.32).

Figure 32. Number of IgA before and after combined local therapy.Increase in amount of CIK above norm (≤ 5.2 g/ml) was ascertained in only 1 female adolescent, in the rest 18 adolescents CIK amount before therapy was 2.49 ± 1 . 1 7 and after therapy 2.32 ± 1.77. Tendency of decrease in CIK is observed, which together with reduced IgG suggests that antigen load is decreasing. Number of C3 before therapy is comparatively lower (1.02 ± 0.2), though it is within norm of healthy children (0.9 - 1.80 g/1), but after therapy C3 results have bigger amplitude (1.03 ± 0.67), which suggests activation of complement complex. Similar changes occur with C4; before therapy 0.19+0.07, after therapy 0.2 ± 022. C4 in healthy children is 0.1 - 0.40 g/l. Changes of C3 and C4 suggest activation of complementary system in the inflammation process in order to eliminate antigen that causes inflammation.

It is interesting to note that in half of the children we ascertained increased IgE level in blood (≤100 IU/ml), which reveals allergy and , possibly, in children allergisation factor plays a role in pathogenesis.

Results of immunological investigations suggest that the local combined therapy decreases inflammation process, but does not cause immuno-supression in children and adolescents suffering from psoriasis.

Conclusions

1. Questionnaire form for psoriasis patients has been designed and introduced, which helpsand significantly eases doctor's work in examination of patients, finding out precipitatingfactors and adverse events. Early diagnosis of psoriasis, assessment of precipitating factorsand timely started therapy significantly improve course of the disease and patients' qualityof life in different aspects.

2. The study ascertained that majority of the children and adolescents suffering frompsoriasis have been recorded in Vidzeme region 65%, 34% of them are from Riga.Themean age is 12.2 + 3.9 years. Ratio of girls and boys is 1.54 : 1. With increase in agenumber of children suffering from psoriasis is increasing.

3. In children with psoriasis the precipitating factors are: psycho-emotional stress - 44.2%,viral and bacterial infections - 33.8% of cases. In 24% of cases psoriasis was detected infamily anamnesis.

• In Latvia, psoriasis vulgaris form is diagnosed 66%, psoriasis exsudativa 17% and psoriasis guttata 13% . Psoriasis vulgaris form is prevalent in children of all age groups, in both genders. Psoriatic lesions of nails were diagnosed 41%, but in 44% of the patients adverse events were detected.

4. Assessing severity of psoriasis by PASI and BSA %, we found that majority of childrenand adolescents with psoriasis have it in mild (36.4%) or moderate form (49.8%); meanPASI score is 12.53 ± 7.38, but BSA % is 12 + 6.9. Mild psoriasis (by PASI) is moredetected in puberty period - in 51 child (28%) and in adolescence period in 48 cases(26.4%). In the period of young children (6 months -3 years) prevalent is mild psoriasisform (4.9%). Number of patients with severe form increases starting from pre-school ageand reaches the highest number in adolescence period at the age of 15 -18 years (34.8%).

5. In children suffering from psoriasis the local combined calcipotriol andmethylprednisolone aceponate therapy is effective and gives marked clinical improvement76.7% and clinical recovery 6.7%.

6. Results of immunological investigation suggest that the local combined therapy(calcipotriol and methyl-prednisolone aceponate cream) decreases inflammation process,does not cause immunosuppression, and does not cause statistically confident deviationsof immunologic indices.

Practical significance and recommendations1. Questionnaire forms are introduced and used in daily work by doctors at Dermatology

department of Children Clinical University hospital (Act of Introduction No.28/3-16.02.2006.). We recommend dermatologists to use it in daily practice for assessment of clinicaldata and unified registration of psoriasis patients.

2. In Dermatology department of Children Clinical University hospital a local combined (calcipotriol and methylprednisolone aceponate) method for psoriasis treatment in childrenhas been approved and introduced (Act of Introduction No.28/3-16.02. 2006.)

Piloting of study resultsResults of the study were reported and discussed in:

• the meetings of Latvia Dermatovenereology Association (LDVA) (1999-2005,• Baltic Deramtovenereology congress in Riga, Latvia (2000),• 14th Congress of LDVA in Riga, Latvia (2002).

Poster reports on the study issue have been demonstrated in• European congress of Dermatovenereology Association (EADV), Geneva, Switzerland

(2000).

• 3rd congress of Baltic Dermatovenereologists, Riga, Latvia (2000),• scientific conferences of Medical sciences of Riga Stradins University, 2000. 2002,

2003,• 20 ' congress of World dermatologists, Paris, France (2002),• 11th congress of EADV, Prague, Check Republik (2002),• 12th congress of EADV, Barselona, Spain (2003).

Publications1. Zigure S. Application of Aerosol Skin-cap in the local therapy in erythematosquamous

dermatoses with manifestations in hairy part of the head in children// Riga, AML/RSU.Scientific articles 2000; 60-61.

2. Zigure S. Some aspects of children psoriasis in Latvia// JEADV. Abstracts of 9th congressof the EADV, Geneva, Switzerland: 2000; 14 (Suppl.l) PI 9-22, 251.

3. Zigure S. Children psoriasis : epidemiology and clinical aspects// Abstracts of the 3 thBaltic Congress of Dermatovenerology, Riga, Latvia, 2000; 67.

4. Zigure S. Psoriasis in children in Latvia. A follow -up of 252 children under the age of 18with psoriasis/I Annales de dermatologie et de venereologie, 2002, 129: P2053, 1S773

5. Zigure S., Rubins A. Study on children psoriasis in Latvia/I Acta Dermatovenerologica,Alpina, Pannonica et Adriatica, 2002, Vol. 11, 45-49.

6. Zigure S. Most common triggering factors of children psorasis// JEADV. Abstracts of1 lth congress of the EADV, Praga, Czech 2002, Vol.16, S.I, P27-57, 290.

7. Rubins A., Gutmane R., Chigorevska L., Zigure S., Rubins S. Efficience of Tacrolimus0,1% ointment in atopic dermatitis, JEADV, 2002, Vol. 16, S 1, P2-15, p 129

8. Zigure S., Rubins A. Possibilities for therapy of children psoriasis/1 Riga. RSU Scientificarticles. Publications of research work in medicine, 2002. 2003: 53-55.

9. Zigure S. Treatment of psoriasis in children// Abstracts of the 14th LDVA Congress,Riga, Latvia, 2002; 19.

10. Zigure S.. Manifestations of psoriasis in children in Latvia// Riga. RSU Scientific articles ,2002.Annual publications of research works in medicine. 2003:56-60.

11.Zigure S. The combination therapy (Calcipotriol/methylprednisolon aceponate) inpsoriatic children. JEADV. Abstracts of 12th congress of the EADV, Barcelona, Spain:2003,17, (Suppl.3), P27-29, 369.

12.Zigure S. Psoriasis: Triggering factors and immunopathology. Proceedings of the LatvianAcademy Of Sciences. Section B. Vol 57 (2003) N. 5 (628), p. 151-157.