1 MINISTRY OF EDUCATION AND TRAINING - MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES ------------------------------------------------- TRAN NGUYEN ANH TU EVALUATION OF HS-CRP, IL-17A LEVELS, AND EFFICACYAND SAFETY OFSECUKINUMAB IN PATIENTS WITH PSORIASIS VULGARIS Speciality: Dermatology Code: 62720152
SUMMARY OF PHD THESIS IN MEDICINE Ha Noi – 2021
2 THE THESIS WAS DONE IN108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES
Supervisors:
1. Dang Van Em, Associate professor, PhD. 2. Nguyen Trong Hao, MD, PhD.
Reviewers:
1. 2. 3.
The thesis defense was presentedtoThesis committee at: 108 Institute of Clinical Medical and Pharmaceutical Sciences. Day Month Year20 The thesis can be found at:
1. National Library of Vietnam 2. Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences
1 INTRODUCTION
recent
Psoriasis is a chronic inflammatory skin disease which affects approximately 2-3% of the population, regardless of gender and race. Historically, psoriasis was considered a disease limited to the skinbut nowadays it is recognised as a systemic inflammatory disease. Several reportshavefocussed on biomarkers indicating the systemic dimension of psoriasis and the aspect of comorbidity psoriasis shares with other chronic inflammatory diseases. Among inflammatory markers, hs-CRP has strongly attracted researchers because of its high sensitivity and direct involvement with arterosclerosis. Tracking the changes of hs-CRP serum concentration, therefore, has become an appealling topic.
Besides, some patients appear to resist to systemic medications or develop side effects due to long term exposure to such drugs. Therefore, it is necessary to seek for “targeted therapies” intervening on critical steps of psoriasis pathogenesis. Given that keratinocytes are principal targets of IL-17A, Secukinumab was approved by United States Food and Drug Admistration (FDA) in January 2015 and by Vietnam Ministry of Health in June 2016 to be prescribed for moderate to severve psoriasis vulgaris.
In Vietnam, there has not been any study with large sample size regarding change ofhs-CRP and IL-17A levels related to Secukinumab efficacy. Our study were conducted covering these problems, namely “Evaluation of hs-CRP, IL-17A levels, and efficacy and safety of Secukinumab in patients with psoriasis vulgaris”. The objectives include:
1. To studyclinical features and related factorsin patients with psoriasis vulgaris atHo Chi Minh City Hospital of Dermato- Venereology.
2. Tocompare pre-treatment and post-treatment hs-CRP and IL- treated with levelsin psoriasis vulgaris patients 17A Secukinumab. 3. To investigate the efficacy and safety of Secukinumab in the treatment of moderate to severe psoriasis vulgaris.
2 FINDINGS OF THE STUDY 1. The hs-CRP, IL-17A levels in patientswith psoriasis vulgaris
were higher than control group. 2. Thehs-CRP and IL-17A levelswere reduced by treatment with Secukinumab. 3. Secukinumab was effective and safe in the treatment of psoriasis vulgaris.
3 Chapter 1 OVERVIEW
1.1. Psoriasis vulgaris overview 1.1.1.History
From 460 B.C to 377 B.C, Hippocrates had described thoroughlyseveral skin diseases. One of them was “lopoi”, which included psoriasis and leprosy. Since 19th century, psoriasis has been distinguished from leprosy. It was firstly named “bệnh vảy nến” in Vietnamese by Dang Van Hy. 1.1.2.Epidemiology Psoriasis can affect individuals of all sexes, age groups, races
yielding a prevalance of 2-3% in world population. 1.1.3. Pathogenesis Multiple factors, related to genetics, immunology and environment, are responsible for this disease. 1.1.4. Severity classification - Psoriasis Area and Severity Index (PASI):mild: <10, moderate: 10 to <20, severe: ≥ 20.
- Dermatology Life Quality Index – DLQI:no effect on patient’s life: 0-1, small effect: 2-5, moderate effect: 6-10, very large effect: 11-20, extremely large effect: 21-30 1.1.5. Treatment Patients should be consulted about therapeutic social-economic
strategiesdepending onseverity, age, gender, status… 1.2. Psoriasis and Interleukin-17A (IL-17A)
turn involve in
fibroblasts,…IL-17A, contributes therefore,
IL-17Aplays an important role in abnormalproliferation and differentiation of epidermal cells, triggering and amplificating inflammatory cascades,which releasing in antimicrobial peptides, cytokines and chemokines. Mediators, which are activated by IL-17A as a neutrophil-depedent and Th17-depedent immune response, facilitate metalloprotease production, mobility of leukocytes and tissue repairment. IL-17A also has synergetic effects with other imflammatory mediators. This interleukin rather targets endothilia, to pathogensis of comobidities such as psoriasis arthritis, heart diseases, arterosclerosis.
4
In 2016, Oliveira revealed a significant increase in IL-17A serum concentration psoriasis patients. Takahashi found a correlation between IL-17A serum concentration and disease severity. This observation was also supported by other studies. Kyriakou, on the other hand, stated that of both groups, IL-17A serum concentrations were not different. Neither were the correlation between IL-17A and PASI established. These features are consequently still of controversial. 1.3. Psoriasis and hs-CRP
CRP is synthesizedprimarily in liver under the activation of imflamatory cytokines, namely IL-6, IL-1β và IFN-α. Besides, adipose tissue and capilary smooth muscles also synthesize such reactive protein. Evidences demonstrate that complements will not be fully activated unless CRP is sufficent. Nowadays it is possible to measure CRP concentrations, even a low of less than 2 mg/dL. Such low concentration is refered to high sensitivity CRP (hs-CRP).
index and
In addition, many authors have noticed a phenomenon callled “upgrade” and have found a proportional relation between the inflammatory the risk of systemic comorbidities. Ashishkumar, in 2013, observed a dramatical rise of hs-CRP serum concentration in psoriasis vulgaris patients and a correlation between this marker and a surogate of severity (PASI). Similar results were also reported.
Ultimately, CRP is recognised as a cardiovascular risk factor. Pepys and Ridker showed an association between CRP serum concentration and cardiovascular diseases, type 2 diabetes…Hence, monitoring hs-CRP concentration dynamics during systemic medication administration is defenitely useful in term of controlling skin lesions, systemic imflamation and cardiovascular risks. 1.4. Secukinumab overview
Secukinumab is a fully human monoclonal IgG1/k antibody that selectively neutralizes IL-17A. Recommendated dose is 300 mg for subcutanesous injection at week 0, 1, 2, 3, 4. Maintainance dose is admistered monthly. Stage 3 clinical CLEAR, SCULPTURE, FEATURE and trials, namely ERASURE, FIXTURE, JUNCTURE, have
5 indicated a Secukinumab dose of 300 mg is effective and safe in the treatment ofmoderate to severe psoriasisvulgaris patients. At the 12th week, PASI-75 was achieved by 75.9-90.1% of participants. These figures for PASI-90 and PASI-100 are 54.2-72.8%, 24.1-43.1% respectively. Another result of these studies is the predomiant effect of 300 mg dose compared to dose of 150 mg, especially regarding its longterm outcome.
Not onlyis the clinical amelioration but the evolution of IL- 17A and hs-CRP concentrations also an outcome taking attention. Akimichi Morita (2020), when studing over 34 psoriasis vulgarispatients who were on Secukinumab, reported the IL-17A serum concentration somehow increased at the time of 2nd week and 16th week. Treatment efficacy is still preserved. The author explained that IL-17A did entered the circulation system after loosing connections with tissue’receptors caused by skin Secukinumab.
Finally, Gottlieb (2014) andGerdes (2020) demonstrated hs- CRP serum concetration commenced to decrease at the 12nd week and continue falling until the week of 52.
6 Chapter 2METHODS
2.1. The study population
150 patients diagnosed with psoriasis vulgaris who were treatedatHo Chi Minh City Hospital of Dermato-Venereology from July 2017 to April 2020. 2.1.1. Diagnosis criteria
Patients were diagnosed with psoriasis vulgaris based on symptoms and signs. Atypical cases have diagnosis established by pathology. 2.1.2. Inclusion criteria 2.1.2.1. For the 1st objective: All psoriasis vulgaris patients were included. 2.1.2.2. For the 2nd objective:
- Study group:Moderate and severe psoriasis vulgaris patients who were 18 or older, not pregnant, not on non-steroid anti- inflammatory drugs, aspirin, corticosteroid, statin, beta-blockers, hormone-based drugs (contraceptives, hormone therapy,…), did not have tissuesinjured, did not suffer from other inflammatory nor infective conditions.
- Control group:sex and age-matched healthy individuals who sought medical care for nevus removals or who were volunteer participants. 2.1.2.3. For the 3rd objective: Including inclusion criteria for the 2nd objective, given
patients did not have any contraindicationto Secukinumab. 2.1.3. Exclusion criteria:
Patients who did not satisfy inclusion criteria. Patients from whom inform consents could not be obtained. Patients who did not adhere to treatment. 2.2. Study materials 2.2.1. Secukinumab:manufactured by Novartis Pharma AG, Basel, Switzerland. 2.2.2. Laboratory chemicals:IL-17A measuring kits and hs-CRP measuring kits 2.2.3. Testers: Automatic hematology analysers, biochemistry analysers
7
2.3. Methodology 2.3.1. Study design
- Objective 1: prospective cross-sectional study - Objective 2: prospective cross-sectional case control study - Objective 3: prospective pre‐post intervention study 2.3.2. Sample sizes
- Objective 1: convenience sampling, including all psoriasis vulgaris patients who sought medical services atHo Chi Minh City Hospital of Dermato-Venereology from July 2017 to April 2020. We had recruited a total of 150 participants. - Objective 2:
+ Sample size was estimated by formula proposed by World Health Organisation, which was at least 30 for each group.
[Z(1-α/2)√2P(1-P) + Zβ√P1(1-P1) + P2(1-P2)]2 n1= n2=
(P1-P2)2
+ Method: Stratified sampling. We had included 50 moderate and severe psoriasis patients and 50 sex and age-matched healthy individuals. - Objective 3: 50 patients who suffered from moderate and
severe psoriasis. 2.3.3.Study procedure 2.3.3.1. Clinical features andrelated factors
- Reception - Screening for inclusion criteria - Taking inform consents with asignments -Fullfilling medical records covering history, signs, blood tests - Extracting necessary data.
2.3.3.2.Changes of hs-CRP and IL-17Alevels in psoriasis vulgaris patients treated with Secukinumab.
- Study group: 50 patients included + First blood sampling for routine tests, hs-CRP, IL-17A + Tuberculosis screening + Secukinumab initiation + Second and third blood sampling after 12 weeks and 24
8
weeks
- Control group: 50 healthy participants included + Blood sampling for hs-CRP and IL-17A measuring
2.3.3.3. Efficacy and safety of Secukinumab in the treatment of moderate to severe psoriasis vulgaris. - 50 moderate and severe psoriasis patients were treated with Secukinumab following this regimen: + 300 mg dose for subcutaneous injection at week 0, 1, 2, 3, 4, 8, 12, 16, 20, 24.
+ Follow-up examination at week 1, 2, 3, 4, 8, 12, 16, 20, 24. + A total of 24 weeks was demanded. - Outcomes evaluation: + Improvement in PASI score (%): (pretreatment PASI –posttreatment PASI)x100%/pretreatment PASI
+Outcome classification: very good if PASI decrease 100%, good if PASI decrease 75-99%, fair if PASI decrease 50-<75%, poor if PASI decrease 25-<50%, very poor if PASI decrease <25% - Side effects monitoring based on clinical manifestations and
laboratory findings. 2.3.4.Statistical analysis:
R-studio software 2.4.Study sites and timeframe: -Ho Chi Minh City Hospital of Dermato-Venereology, Medic medical center, Pham Ngoc Thach hospital - July 2017 – April 2020 2.5.Research ethics: Participants had been informed, discussed and
joined voluntarily. No fee of blood tests was charged. Personal information was coded for privacy purpose only. 2.6. Limitations: Only pretreatment and posttreatment data was revealed. There
was no control group for comparision.
9
STUDY ALGORITHM
Inclusion (150 participants)
Clinical characteristics
50 healthy participants
50 moderate and severe patients
1st IL-17 and hs-CRP measurements
1st routine 1st routine blood tests blood tests
Secukinumab
2nd IL-17 and hs- CRP measurements
3rd routine blood tests
3rd IL-17 and hs- CRP measurements
Immunological results
Clinical and immunological results
Final results
10 RESULTS Chapter 3RESULTS factors features and related factors
Clinical features 3.1. actors 3.1.1. Related factors 3.1.1. Age group distribution (n=150) Table 3.1.Age group distribution (n=150) Table 3.1 % % n 0 0.00 0 11. 11.33 17 20.67 20. 31 16. 16.67 25 28. 28.00 42 23. 23.33 35 100 100 150
48.03 ± 14.13 13, age group of 50 age was 48.03 ± 14.13, age group of 50-59 was the . There was no patients Age group < 20 20-29 30-39 40-49 50-59 ≥ 60 Sum Mean ± SD Comments: Comments:Mean age was common group, accounting for 28.00%. There was no common group, accounting for 28.00% most common group, accounting for 28.00% most under 20 years old. under 20 years old.
Male Male
47.33%
52.67%
Female Female
Chart 3.1. Gender distribution (n=150 Chart 3.1 Gender distribution (n=150)
84%
11.33%
2.67% 2.67%
2% 2%
Mean BMI: 22.70 ± 2. 22.70 ± 2.70 Comments:52.67% of participants are f Comments: , dominating male of participants are female, dominating male of participants are f 33%). participants (47.33%). participants (47 - Mean BMI:
100 50 0
BMI classification (n=150) Chart 3.2. BMI classification (n=150) Chart 3.2 Comments: Almost participants fell into normal BMI range (84%) Comments: Almost participants fell into normal BMI range (84%), Almost participants fell into normal BMI range (84%) Almost participants fell into normal BMI range (84%) only 2% were obese. only 2%
11
17.33% 17.33%
45.34%
37.33% 37.33%
Severe (PASI>=20) Severe (PASI>=20)
psoriasis vulgaris Clinical features of psoriasis vulgaris 3.1.2. Clinical features of 3.1.2. 3.1.2.1 PASI score 3.1.2.1 PASI score - Mean PASI score: 83 Mean PASI score: 19.39 ± 8.83
Medium (=<10
outweighthe other
33%.
accounted for only 17.33%. Severe patients (45.34%)
while the mild group accounted
1.33%
15.33%
13.33%
13.33%
68.68%
Small effect (2-5)
Very large effect (11-20)
Very large effect (11
- Mean DLQI is Comments:
Comments: Severe patients
groups
groups while the mild group
3.1.2.2. DLQI score
3.1.2.2. DLQI score
Mean DLQI is 11.87 ± 4.94
1.33%
6.DLQI score distribution
68.68%.
No effect (0-1)
10)
Large effect (6-10)
Extremely large effect (21-30)
Extremely large effect (21
(n=150)
DLQI score distribution (n=150)
Chart 3.6
Comments:
Comments: Very large effect group
predominated other groups with
Very large effect group predominated other groups with
predominated other groups with
a high percentage of 68.
a high percentage of
3.1.2.3
1.2.3 Relations of PASI score and Table 3.14.PASI
p
0.039 characteristics
patients’s characteristics
of PASI score and patients’s
score and BMI classification (n=150)
PASI score and BMI classification (n=150)
score and BMI classification (n=150)
PASI
n = 150
n = 150
11.55 ± 6.94
11.
4
19.19 ± 9.01
19.
126
126 BMI
BMI
Underweight
Underweight
Normal
Normal
Overweight
Overweight 16
16 20.37 ± 5.15
20.
Obesity
Obesity 4 32.77 ± 7.42
32.77 ± 7.
PASI scores differedsignificantly a mong BMI groups,
significantly among BMI groups, Kruskal
Kruskal-Wallis test
Comments
Comments: PASI scores differ
with p<0.05.
with p<0.
12
Table 3.15. PASI score and nail lesions (n=150)
p
< 0.001 PASI
20.34 ± 8.54
11.44 ± 7.23 n
134
16
Nail lesions
Yes
No
Mann-Whitney U test
Comments:PASI score of group with nail lesions is statistically
higher than of which without nail lesions, p<0.001.
Chart 3.7.Correlation betweenPASI score and DLQI (n=150)
Comments: There was a proportional correlation between PASI and
DLQI score.
3.2 Pretreatment and posttreatment hs-CRP and IL-17A levels in
psoriasis vulgaris patients treated with Secukinumab.
3.2.1 Pretreatment hs-CRP and IL-17A levels in psoriasis
vulgaris patients
Table 3.22.Comparision of hs-CRP levels between study group and
control group
Marker p Control group
(n = 50) <0.001 Study group
(n = 50)
11.88 ± 21.29 0.82 ± 0.37
hs-CRP
Mann-Whitney U test
Comments: hs-CRP levels in psoriasis patients were statistically
higher than control group, p<0.001. Table 3.25.hs-CRP level and BMI (n=50) BMI n hs-CRP p
0.041 Not obese
Obese 47
3 11.44 ± 21.81
18.62 ± 9.07
Mann-Whitney U test
Comments: hs-CRP level in obese psoriasis patients was statistically
higher than non obese ones, p<0.05.
13
Table 3.31.hs-CRP level and disease severity (n=50)
Marker Moderate (n = 26)
hs-CRP 2.53 ± 1.22 Severe (n = 24)
22.00 ± 27.53 p
<0.001
Mann-Whitney U test
Comments: hs-CRP level in severe patients was statistically higher
than moderate ones, p<0.001.
Chart 3.8.Correlation betweenhs-CRP level and PASI score (n=50)
Comments:hs-CRP level had a strongly proportional correlation with
PASI score, given r = 0.69 (0.52-0.82), p<0,001.
Table 3.32.Comparision of IL-17A levels between study group and
control group
Marker p Control group
(n = 50) IL-17A Study group
(n = 50)
43.48 ± 99.56 3.91 ± 1.72 <0.001
Mann-Whitney U test
Comments: IL-17A level in psoriasis patients was statistically higher
than control group, p<0.001. Table 3.40.IL-17Alevel and disease severity (n=50)
Marker
IL-17A Moderate (n = 26)
34,46 ± 28,96 Severe (n = 24)
53,24 ± 141,48 p
0,08
Mann-Whitney U test
Comments:No statistically significant difference in IL-17A levels
between two groups was observed, p>0,05.
14
Chart 3.9.Correlation between L-17A level and PASI score (n=50)
Comments:There was a moderate correlation betweenIL-17A level
and PASI score, given r = 0.38, p<0.01.
3.2.2.Posttreatment hs-CRP and IL-17A levels in psoriasis
vulgaris patients treated with Secukinumab.
Table 3.41. Change ofhs-CRP levelduring treatment (n=50)
p
Time
Before
treatment
After 12
weeks
After 24
weeks
hs-CRP 11.88 ± 21.29 4.27 ± 4.89 2.13 ± 3.40 < 0.001
Comments: hs-CRP levelsignificantly decreased after12 and 24
weeks, p<0.001.
Table 3.42. Change of IL-17Alevel during treatment (n=50)
p
Time
Before
treatment
After 12
weeks
After 24
weeks
43.48 ± 99.56 23.82 ± 55.18 6.05 ± 6.44 < 0.001
IL-17A
Comments: IL-17A levelsignificantly decreased after 12 and 24
weeks, p<0.001.
15
3.3. Efficacy and safety of Secukinumab in the treatment of
moderate to severe psoriasis vulgaris
Figure 3.12. Proportion of patients with clinical responses through
week 24
Comments: At week 4, PASI-50, PASI-75, PASI-90 responses were
achieved by100%, 82%, 22%, respectively. At week 24, PASI-100
response was achieved by 100%. Table 3.62. Adverse events (n=50)
Events
n
%
Upper respiratory infection
5
10
1
2
Candidiasis
Comments:Adverse eventsranged from 2% for Cadidiasis to 10% for
upper respiratory infection.
Table 3.63. Pretreatment and posttreatment laboratory findings
(n=50)
Tests
Before treatment
After treatment
p
RBC
4,94 ± 0,59
5,16 ± 0,55
0,18
WBC
7,58 ± 2,29
7,22 ± 2,36
0,42
PLT
246,8 ± 64,83
220,02 ± 58,97
0,02
Urea
4,00 ± 1,36
4,64 ± 1,19
0,007
Creatinin
81,34 ± 15,87
82,88 ± 13,74
0,7
ALT
30,23 ± 21,23
28,74 ± 18,93
0,77
25,33 ± 9,53
23,66 ± 13,01
0,1
AST
Comments:No noticeable change of common blood tests was
observed.
16
Chapter 4DISCUSSION
4.1. Clinical features and related factors
4.1.1. Related factors
- Age:Mean age was 48.03 ± 14.13 (table 3.1) with age group
of 51-60 taking up the highest percentage (28.67%). This was in
accordance with other studies published by Truong Thi Mong
Thuong (45.34), Takahashi (47.50), Schwensen (48.00). Mean age
generally falls into 40-50 year-old range which is regarded as larbor
age group.
- Sex:As can be seen from chart 3.1, females tended to
dominate males with 52.67% accounted by the former compared to
47.33% by the latter. Truong Le Anh Tuan reported a similar result.
In general, males and females have equal chances to develop
psoriasis.
- BMI:Our finding demonstrated by chart 3.2 revealed an
obesity percentage of 11.33, similar to a report of Nguyen Trong Hao
with 14.1%. Although such figure was not high, clinicians should
take this factor into account when consulting and educating their
patients. This is because evidences show that obesity has an
association with psoriasis.
4.1.2. Clinical features of psoriasis vulgaris
- Severity classification according to PASI: Mean PASI
score was 19.39 ± 8.83. Severe PASI was the most common group
(45.34%) as demonstrated in chart 3.4. Data have showed that one
third of patients are severe. Among the clinical indicators, PASI is
the most popular index to quantify skin injury and is recognised as
“gold standard” applying to clinical trials.
- Severity classification according to DLQI: We obtained a
mean DLQI score of 11.87 ± 4.94. The group which suffered from
very large effect had the highest percentage of 58.68%, similar with
Frandresena and Nayak’s finding. Psoriasis disease, therefore,
affectson both physical health and quality of life.
4.1.3 Relations of PASI score and clinical charactersistics
- PASI score and BMI: Table 3.14 illustrated an association
of PASI and BMI, given p<0.05. Providing that weight gain cause a
rise of proinflammatory cytokines such as IL-1, IL-6, TNF-α,…
17
related to psoriasis’s pathogenesis, PASI score would increase
parallel with BMI.
- PASI score and nail lesions: As can be seen in table 3.15,
PASI score appeared to be higher in group having nail lessions. This
finding was again in accordance with others. Rich, however, did not
established a correlation of PASI and NAPSI. Some patients actually
have serious nail lesions, but have mild skin lesions or have no such
manifestation.
in psoriasis levels
- PASI score and DLQI: Our results revealed a proportional
correlation between DLQI and PASI with r = 0.65 (p<0.001). Other
studes also reported that the more severe the disease was, the more
significant it affected to patient’s quality of life. Stress have been
proved to trigger abnormal neurological and endocrine reponses,
playing a critical role in psoriasis’s pathogenesis. As a consequence,
stress can make psoriasis more severe and render the disease
unresponsive to medications.
4.2. Pretreatment and posttreatment hs-CRP and IL-17A levels
in psoriasis vulgaris patients treated with Secukinumab
4.2.1. Pretreatmenths-CRP and IL-17A
vulgaris patients
4.2.1.2. Pretreatment hs-CRP level
in psoriasis patients and is an
- Table 3.22 shows that hs-CRP level in psoriasis patients
(11.88 ± 21.29 mg/L) was statistically higher in control group (0.82
± 0.37 mg/L), p<0.05. This data support the hypothesis stating
psoriasis is a systemic inflammatory disease, which specifically
cause changes of inflammatory markers. Our results were similar to
other studies. High hs-CRP level is a prognosis factor for coronary
heart disease
independent
cardiovascular risk factor. Pepys and Ridker reported an association
of CRP
type 2
level and heart diseases, hypertension,
diabetes…Therefore, many authors have emphasised the importance
of cormorbidities screening, especially the risk of myocardial
infarction, the leading cause of death in psoriasis patients.
- Features related to hs-CRP level: We found a relation of
hs-CRP level with obesity as demonstrated in table 3.25 and with
PASI score as demonstrated in table 3.31.
18
The former is in accordance with Andreas study. This is
because adipose tissue excretes cytokines stimulating hs-CRP
synthesis in liver. The adipose itself produces hs-CRP and thus make
hs-CRP serum concentration accelarate. Weight control, therefore, is
definitely neccessary in psoriasis patients.
The latter, as illustrated by chart 3.8, is a proportional
correlation. Domestic and foreign researchers reported the same
finding, supporting a strong relation between hs-CRP and disease
severity. Keratocytes are responsible for secreting IL-1 and TNF-α,
which stimalate hepatocytes to secrete CRP. CRP, in turn, is
recognised by circulating C1q and activates a complement cascade
which damages tissues and manifests by psoriasis lesions.
4.2.1.3. Pretreatment IL-17A level
- IL-17A level apppeared to be significantly higher in psoriasis
patients (43.48 ± 99.56 pg/mL) compared to control group (3.91 ±
1.72 pg/mL), p<0.05.
excluded psoriasis arthritis defined nor Relation between IL-17A and psoriasis is still unconclusive.
Some studies agreed with our finding. The others somehow could not
observe a significant increase. This discrepancy can be explained by
small sample sizes, different inclusion criteria. Our study only
covered patients who were moderate or severe while the others
neither
clinical
manifestations.
- Features related to IL-17A level: Table 3.40 and chart 3.9
show no correlation between IL-17A and PASI score. Few studies
about this topic is of controversial. Some factors render this issue
unconclusive. Firstly, sample sizes were not enough large. Secondly,
inclusion criteria were not identical. Our study was conducted over
moderate to severe psoriasis vulgaris patients whereas some studies
did not exclude patients with psorisasis arthritis. This type of
psoriasis together with nail psoriasis could yield an increase of IL-
17A level. Thirdly, PASI score primarily demonstrates skin injury.
This tool itself has some limitations regarding its complicity,
timewasting, low sensitivity and specificity in mild patients. Besides,
Choe found a proportional correlation of these two factors in chronic
stable patients. PASI score, therefore, is of little value for
19
inflammation,
determining severity of psoriasis during acute
especially in patients in whom an abundance macules and papules
exist.
4.2.2. Posttreatment hs-CRP and IL-17A levels in psoriasis
vulgaris patients treated with Secukinumab.
4.2.2.1. Posttreatment hs-CRP level
trials,
As can be seen in table 3.41, hs-CRP decline sharply and
statistically at week 12 (4.27 ± 4.89 mg/L) and week 24 (2.13 ± 3.40
mg/L), compared to pretreatment level (11.88 ± 21.29 mg/L),
p<0.001. The first real-world study by Wang showed a similar trend
of this marker in psoriasis patients. However, different from our
findings, hs-CRP level in Wang’s study increased to 2.5 mg/L. This
could be due to his study population, which covered mild patients
and arthritis patients. The latter can make hs-CRP difficult to
continue falling. A meta-analysis conducted by S. Gerdes including
three clinical
namely FIXTURE, ERASURE and
SCULPTURE, revealed that the higher pretreatment hs-CRP level
was, the more significant the change would be.
4.2.2.2. Posttreatment IL-17A level Table 3.42 shows the evolution of IL-17A levelduring treatment.
Given Secukinumab is a novel drug against psoriasis, only one
study evaluating the change of IL-17A after treatment was found.
The studyby Akimichi, somehow showed an opposite trend.
Amikichi reported that IL-17A had rise at second week and week 16.
To explain this elevation, Secukinumab is supposed to bind
selectively to IL-17A molecules at skin lesions and then to enter the
circulation. Measurements coud not distinguish “free IL-17A” from
“IL-17A-Secukinumab” complexes. Akimichi, like other authors, did
not exclude psoriasis arthritis patients. Another differnce is that our
participants had a higher mean PASI score (22.35) compared to his
study patients (15.05). Additional larger studies are needed to clarify
this issue.
20
4.3. Efficacy of Secukinumab in the treatment of moderate to
severe psoriasis vulgaris
4.3.1. Clinical outcomes
Our finding showed that Secukinomab could improve clinical
manifestations as early as from the second week, at which 2% of
patients achieved a PASI-50. At the third week, a total of 74% of
patients had PASI-50. At the fourth week, the percentage of PASI-
50, PASI-75, PASI-90 was 100%, 82%, 22% respectively. At the
eighth week, these corresponding figure were 100%, 100%, 90% and
as low as 42%, of whom PASI were 100, indicating the patients were
free of lesions. PASI-50, PASI-75, PASI-90, PASI-100 were
reported in 100%, 100%, 100%, 78% respectively at twelfth week.
At the very end of study point of time (week 24), a hundred per cent
of patients got a PASI-100(chart 3.12).
These results is in acordance with phase III trials ERASURE,
FIXTURE, CLEAR, SCULPTURE, FEATURE and JUNCTURE
and three real-world studies in Canada and Italy. These all proved the
efficacy and safety of Secukinumab in the treatment of psoriasis
vulgaris ranging from moderate to severe illness. This drug
specically gave a rapid amelioration.
To be more detailed, we found a more significant effecacy of
Secukinumab compared to previous data. This advanced effect could
be explained in some ways. Our population had fewer comorbidities
which could make patients less responsive. Besides, it could be due
to lower BMI, different meassure techniques and history of
biological medication exposure. In other clinical trials, patients were
strictly included, only if they failed to response to classical systemtic
drugs. As a consequence, we hypothesise that these patients tended
to be unresponsive to systemic medications. Moreover, data
supported that treatment efficacy would be more enhanced unless
they had exposed to biological medications before. Our study
population had a lower BMI (22.70 ± 2.70) than this index in other
two trials: FIXTURE (28.4 ± 6.4) and ERASURE (30.3 ± 7.2).
Although Secukinumab can be prescibed regardless of weights,
obesity patients featured to have little benefit compared to whom had
normal weights as demonstrated by FIXTURE trial and ERASURE
21
trial.
4.3.1. Adverse events
We had observed 5 patients (10%) suffuring from upper
respiratory infection and 1 patients (2%) developing candidiasis as
adverse events of Secukinumab. These adverse events were in fact
mild and transient. In comparison with some pivotal clinical trials,
namely FIXTURE, ERASURE, FEATURE, JUNCTURE, common
side effects were pharyngitits, headache and upper respiratory
infections with low incidences from 1 to 6 per cent. Besides, real-
world studies which followed patients over long periods reported low
frequencies of adverse outcomes, supporting results of previous
phase III clinical trials. A real-world study in Italy with a 84-week
follow-up period, showed only 1.8% of patients suffering from
perianal abcessess, deterioration of arthritis, eczema-like rashes,
candidiasis and only one case over 324 patients infected tuberculosis.
In our study, patients were performed routine blood testing
before treatment and after 24 weeks. As illustrated by table 3.67,
biochemical markers were still
in physiological range. This
observation was similar to core clinical trials such as FIXTURE,
ERASURE, FEATURE, JUNCTURE. Although post treatment ure
serum concentration was statistically higher than before treatment
(4.64 ± 1.19 mmol/L compared to 4.00 ± 1.36 mmol/L) and so was
platelet count (220.02 ± 58.97 K/uL compared to 246.8 ± 64.83
K/uL), these did not exceed normal ranges. Given no data published
regarding these trends, we hypothesise it was the small sample size
which lead to random differences. A study with larger sample size is
needed to confirm this finding.
Therefore, Secukinumab is a safe biological drug in the
treatment of moderate to severe psoriasis vulgaris. Neither it change
the results of routine blood tests nor it leads to serious side effects.
Adverse events, if occur, are usually mild and transient. Classical
systemic drugs, in contrast, do not have such advantages.
22
CONCLUSION
1.Clinical features and related factors
1.1.Related factors - Psoriasis was more common in individuals aging 50 years old or more (51.33%) and in female (52.67%)
- 20% of patients had family history of psoriasis; 36.66% of
patients had aduration of illness from 2 to 5 years, 53.33% had
irregular physical activities and 2% were obese.
1.2. Clinical features of psoriasis vulgaris
- Symetrically distributed skin lesions existed in 90% of
patients; psoriasis lesions also manifested athead skin in 85.33% of
patients, at nails in 89.33% and at skin folds at 20%. - Severity of psoriasis, based on PASI score, was primarily severe with a percentage of 45.34. - Patients whose quality of life was in very large effect
accounted for a significant percentage of 68.68.
2. Pretreatment and posttreatment hs-CRP and IL-17A levels in
psoriasis vulgaris patients treated with Secukinumab
- Before treatment:hs-CRP level (11.88 ± 21.29) and IL-17A
level (43.48 ± 99.50)of study group were higher than control group
(hs-CRP: 0.8 ± 0.37; IL-17A: 3.91 ± 1.72). hs-CRP levelhad an
association with both obesity and severity while IL-17A level was
related to skin fold lesions and severity.
- After treatment:hs-CRP and IL-17A levelshad decreased
gradually(hs-CRP: before treatment: 11.88 ± 21.29, after 12 weeks:
4.27 ± 4.89, after 24 weeks: 2.13 ± 3.4) and IL-17A: before
treatment: 43.48 ± 99.50, after 12 weeks: 23.82 ± 52.18, after 24
weeks: 6.05 ± 6.44).hs-CRP, IL-17A and the severity of disease
related to each other.
3. Efficacy of Secukinumab in the treatment of moderate to
severe psoriasis vulgarispatients
- Secukinumab have a highefficacy in the treatment of
moderate and severe psoriasis vulgaris, demonstrated by PASI score
23
decrease: Before treatment (22.35 ± 8.92), after 4 weeks (3.74 ±
2.71), after 8 weeks (0.71 ± 1.14), after 12 weeks (0.13 ± 0.3), after
16 weeks (0.08 ± 0.29) and after 24 weeks (0).
- Response to Secukinumab had accelerated over time:
Responseappeared after 2 weeks (poor: 2% , fair: 72%), was
prominent after 4 weeks (good: 82%, fair: 18%),after 8 weeks (very
good: 42% , good: 58%), after 8 weeks (very good: 90%, good: 10%)
and patients were free of lesions after 24 weeks.
- Adverse events: upper respiratory infection occured in 10%
of patients treated with Secukinumab, candidiasis occured in 2% and
no affect to complete blood count, liver function and kidney function
tests was observed.
24
PROPOSALS
1.Secukinumab has been proved effective and safe in the treatment
of moderate to severe psoriasis vulgaris. It should be prescribed more
commonly if applicable, especially in severe patients.
2. To determine optiomal dose for each patient, there is a need to
perform studies regarding the appropriatenessof maintainance dose.
This must be a “4-most-dose”: the lowest, the most efficient, the
safest and the cheapest dose.
LIST OF PUBLISHED ARTICLES RELATING TO THESIS
1. Tran Nguyen Anh Tu, Nguyen Trong Hao, Dang Van Em
(2020), “Related factors and clinical manifestations of patients
with psoriasis vulgaris at Ho Chi Minh city Hospital of
Dermato-Venereology”, Jounal of 108 – Clinical Medicine and
Pharmacy, (15), pp. 21–25.
2. Tran Nguyen Anh Tu, Nguyen Trong Hao, Dang Van Em
(2018), “The clinical efficacy and safety of secukinumab in the
treatment of psoriasis vulgaris”, Jounal of 108 – Clinical
Medicine and Pharmacy, (13), pp. 88 –91.
3. Tran Nguyen Anh Tu, Nguyen Trong Hao, Dang Van Em
(2020), “The study on changes of serum Il-17A and hs-CRP
treated by
concentration of psoriasis vulgaris patient
secukinumab”, Jounal of 108 – Clinical Medicine and
Pharmacy, (15), pp. 49 –54.
4. Tran Nguyen Anh Tu, Nguyen Trong Hao, Dang Van Em
(2019), “The serum IL-17A and hs-CRP levels in patients with
psoriasis vulgaris”, Vietnamese Journal of Dermatology, (28),
pp. 20 - 28.
outweighthe other 33%. accounted for only 17.33%. Severe patients (45.34%) while the mild group accounted
1.33%
15.33%
13.33% 13.33%
68.68%
Small effect (2-5) Very large effect (11-20) Very large effect (11
- Mean DLQI is Comments: Comments: Severe patients groups groups while the mild group 3.1.2.2. DLQI score 3.1.2.2. DLQI score Mean DLQI is 11.87 ± 4.94 1.33%
6.DLQI score distribution
68.68%.
No effect (0-1) 10) Large effect (6-10) Extremely large effect (21-30) Extremely large effect (21 (n=150) DLQI score distribution (n=150) Chart 3.6 Comments: Comments: Very large effect group predominated other groups with Very large effect group predominated other groups with predominated other groups with a high percentage of 68. a high percentage of 3.1.2.3
1.2.3 Relations of PASI score and Table 3.14.PASI
p 0.039 characteristics patients’s characteristics of PASI score and patients’s score and BMI classification (n=150) PASI score and BMI classification (n=150) score and BMI classification (n=150) PASI n = 150 n = 150 11.55 ± 6.94 11. 4 19.19 ± 9.01 19. 126 126 BMI BMI Underweight Underweight Normal Normal
Overweight Overweight 16 16 20.37 ± 5.15 20.
Obesity Obesity 4 32.77 ± 7.42 32.77 ± 7.
PASI scores differedsignificantly a mong BMI groups, significantly among BMI groups, Kruskal Kruskal-Wallis test Comments Comments: PASI scores differ with p<0.05. with p<0.
12 Table 3.15. PASI score and nail lesions (n=150)
p < 0.001 PASI 20.34 ± 8.54 11.44 ± 7.23 n 134 16
Nail lesions Yes No Mann-Whitney U test Comments:PASI score of group with nail lesions is statistically higher than of which without nail lesions, p<0.001.
Chart 3.7.Correlation betweenPASI score and DLQI (n=150) Comments: There was a proportional correlation between PASI and DLQI score. 3.2 Pretreatment and posttreatment hs-CRP and IL-17A levels in psoriasis vulgaris patients treated with Secukinumab. 3.2.1 Pretreatment hs-CRP and IL-17A levels in psoriasis vulgaris patients Table 3.22.Comparision of hs-CRP levels between study group and control group
Marker p Control group (n = 50) <0.001 Study group (n = 50) 11.88 ± 21.29 0.82 ± 0.37
hs-CRP Mann-Whitney U test Comments: hs-CRP levels in psoriasis patients were statistically higher than control group, p<0.001. Table 3.25.hs-CRP level and BMI (n=50) BMI n hs-CRP p
0.041 Not obese Obese 47 3 11.44 ± 21.81 18.62 ± 9.07
Mann-Whitney U test Comments: hs-CRP level in obese psoriasis patients was statistically higher than non obese ones, p<0.05.
13 Table 3.31.hs-CRP level and disease severity (n=50)
Marker Moderate (n = 26) hs-CRP 2.53 ± 1.22 Severe (n = 24) 22.00 ± 27.53 p <0.001
Mann-Whitney U test Comments: hs-CRP level in severe patients was statistically higher than moderate ones, p<0.001.
Chart 3.8.Correlation betweenhs-CRP level and PASI score (n=50) Comments:hs-CRP level had a strongly proportional correlation with PASI score, given r = 0.69 (0.52-0.82), p<0,001.
Table 3.32.Comparision of IL-17A levels between study group and control group
Marker p Control group (n = 50) IL-17A Study group (n = 50) 43.48 ± 99.56 3.91 ± 1.72 <0.001
Mann-Whitney U test Comments: IL-17A level in psoriasis patients was statistically higher than control group, p<0.001. Table 3.40.IL-17Alevel and disease severity (n=50)
Marker IL-17A Moderate (n = 26) 34,46 ± 28,96 Severe (n = 24) 53,24 ± 141,48 p 0,08
Mann-Whitney U test Comments:No statistically significant difference in IL-17A levels between two groups was observed, p>0,05.
14
Chart 3.9.Correlation between L-17A level and PASI score (n=50) Comments:There was a moderate correlation betweenIL-17A level and PASI score, given r = 0.38, p<0.01. 3.2.2.Posttreatment hs-CRP and IL-17A levels in psoriasis vulgaris patients treated with Secukinumab.
Table 3.41. Change ofhs-CRP levelduring treatment (n=50) p
Time
Before treatment
After 12 weeks
After 24 weeks
hs-CRP 11.88 ± 21.29 4.27 ± 4.89 2.13 ± 3.40 < 0.001
Comments: hs-CRP levelsignificantly decreased after12 and 24 weeks, p<0.001.
Table 3.42. Change of IL-17Alevel during treatment (n=50) p
Time
Before treatment
After 12 weeks
After 24 weeks
43.48 ± 99.56 23.82 ± 55.18 6.05 ± 6.44 < 0.001
IL-17A Comments: IL-17A levelsignificantly decreased after 12 and 24 weeks, p<0.001.
15 3.3. Efficacy and safety of Secukinumab in the treatment of moderate to severe psoriasis vulgaris
Figure 3.12. Proportion of patients with clinical responses through week 24 Comments: At week 4, PASI-50, PASI-75, PASI-90 responses were achieved by100%, 82%, 22%, respectively. At week 24, PASI-100 response was achieved by 100%. Table 3.62. Adverse events (n=50)
Events
n
%
Upper respiratory infection
5
10
1
2
Candidiasis Comments:Adverse eventsranged from 2% for Cadidiasis to 10% for upper respiratory infection.
Table 3.63. Pretreatment and posttreatment laboratory findings (n=50)
Tests
Before treatment
After treatment
p
RBC
4,94 ± 0,59
5,16 ± 0,55
0,18
WBC
7,58 ± 2,29
7,22 ± 2,36
0,42
PLT
246,8 ± 64,83
220,02 ± 58,97
0,02
Urea
4,00 ± 1,36
4,64 ± 1,19
0,007
Creatinin
81,34 ± 15,87
82,88 ± 13,74
0,7
ALT
30,23 ± 21,23
28,74 ± 18,93
0,77
25,33 ± 9,53
23,66 ± 13,01
0,1
AST Comments:No noticeable change of common blood tests was observed.
16 Chapter 4DISCUSSION
4.1. Clinical features and related factors 4.1.1. Related factors
- Age:Mean age was 48.03 ± 14.13 (table 3.1) with age group of 51-60 taking up the highest percentage (28.67%). This was in accordance with other studies published by Truong Thi Mong Thuong (45.34), Takahashi (47.50), Schwensen (48.00). Mean age generally falls into 40-50 year-old range which is regarded as larbor age group.
- Sex:As can be seen from chart 3.1, females tended to dominate males with 52.67% accounted by the former compared to 47.33% by the latter. Truong Le Anh Tuan reported a similar result. In general, males and females have equal chances to develop psoriasis.
- BMI:Our finding demonstrated by chart 3.2 revealed an obesity percentage of 11.33, similar to a report of Nguyen Trong Hao with 14.1%. Although such figure was not high, clinicians should take this factor into account when consulting and educating their patients. This is because evidences show that obesity has an association with psoriasis. 4.1.2. Clinical features of psoriasis vulgaris
- Severity classification according to PASI: Mean PASI score was 19.39 ± 8.83. Severe PASI was the most common group (45.34%) as demonstrated in chart 3.4. Data have showed that one third of patients are severe. Among the clinical indicators, PASI is the most popular index to quantify skin injury and is recognised as “gold standard” applying to clinical trials.
- Severity classification according to DLQI: We obtained a mean DLQI score of 11.87 ± 4.94. The group which suffered from very large effect had the highest percentage of 58.68%, similar with Frandresena and Nayak’s finding. Psoriasis disease, therefore, affectson both physical health and quality of life. 4.1.3 Relations of PASI score and clinical charactersistics
- PASI score and BMI: Table 3.14 illustrated an association of PASI and BMI, given p<0.05. Providing that weight gain cause a rise of proinflammatory cytokines such as IL-1, IL-6, TNF-α,…
17 related to psoriasis’s pathogenesis, PASI score would increase parallel with BMI.
- PASI score and nail lesions: As can be seen in table 3.15, PASI score appeared to be higher in group having nail lessions. This finding was again in accordance with others. Rich, however, did not established a correlation of PASI and NAPSI. Some patients actually have serious nail lesions, but have mild skin lesions or have no such manifestation.
in psoriasis levels
- PASI score and DLQI: Our results revealed a proportional correlation between DLQI and PASI with r = 0.65 (p<0.001). Other studes also reported that the more severe the disease was, the more significant it affected to patient’s quality of life. Stress have been proved to trigger abnormal neurological and endocrine reponses, playing a critical role in psoriasis’s pathogenesis. As a consequence, stress can make psoriasis more severe and render the disease unresponsive to medications. 4.2. Pretreatment and posttreatment hs-CRP and IL-17A levels in psoriasis vulgaris patients treated with Secukinumab 4.2.1. Pretreatmenths-CRP and IL-17A vulgaris patients 4.2.1.2. Pretreatment hs-CRP level
in psoriasis patients and is an
- Table 3.22 shows that hs-CRP level in psoriasis patients (11.88 ± 21.29 mg/L) was statistically higher in control group (0.82 ± 0.37 mg/L), p<0.05. This data support the hypothesis stating psoriasis is a systemic inflammatory disease, which specifically cause changes of inflammatory markers. Our results were similar to other studies. High hs-CRP level is a prognosis factor for coronary heart disease independent cardiovascular risk factor. Pepys and Ridker reported an association of CRP type 2 level and heart diseases, hypertension, diabetes…Therefore, many authors have emphasised the importance of cormorbidities screening, especially the risk of myocardial infarction, the leading cause of death in psoriasis patients.
- Features related to hs-CRP level: We found a relation of hs-CRP level with obesity as demonstrated in table 3.25 and with PASI score as demonstrated in table 3.31.
18
The former is in accordance with Andreas study. This is because adipose tissue excretes cytokines stimulating hs-CRP synthesis in liver. The adipose itself produces hs-CRP and thus make hs-CRP serum concentration accelarate. Weight control, therefore, is definitely neccessary in psoriasis patients.
The latter, as illustrated by chart 3.8, is a proportional correlation. Domestic and foreign researchers reported the same finding, supporting a strong relation between hs-CRP and disease severity. Keratocytes are responsible for secreting IL-1 and TNF-α, which stimalate hepatocytes to secrete CRP. CRP, in turn, is recognised by circulating C1q and activates a complement cascade which damages tissues and manifests by psoriasis lesions. 4.2.1.3. Pretreatment IL-17A level
- IL-17A level apppeared to be significantly higher in psoriasis patients (43.48 ± 99.56 pg/mL) compared to control group (3.91 ± 1.72 pg/mL), p<0.05.
excluded psoriasis arthritis defined nor Relation between IL-17A and psoriasis is still unconclusive. Some studies agreed with our finding. The others somehow could not observe a significant increase. This discrepancy can be explained by small sample sizes, different inclusion criteria. Our study only covered patients who were moderate or severe while the others neither clinical manifestations.
- Features related to IL-17A level: Table 3.40 and chart 3.9 show no correlation between IL-17A and PASI score. Few studies about this topic is of controversial. Some factors render this issue unconclusive. Firstly, sample sizes were not enough large. Secondly, inclusion criteria were not identical. Our study was conducted over moderate to severe psoriasis vulgaris patients whereas some studies did not exclude patients with psorisasis arthritis. This type of psoriasis together with nail psoriasis could yield an increase of IL- 17A level. Thirdly, PASI score primarily demonstrates skin injury. This tool itself has some limitations regarding its complicity, timewasting, low sensitivity and specificity in mild patients. Besides, Choe found a proportional correlation of these two factors in chronic stable patients. PASI score, therefore, is of little value for
19
inflammation, determining severity of psoriasis during acute especially in patients in whom an abundance macules and papules exist.
4.2.2. Posttreatment hs-CRP and IL-17A levels in psoriasis vulgaris patients treated with Secukinumab. 4.2.2.1. Posttreatment hs-CRP level
trials,
As can be seen in table 3.41, hs-CRP decline sharply and statistically at week 12 (4.27 ± 4.89 mg/L) and week 24 (2.13 ± 3.40 mg/L), compared to pretreatment level (11.88 ± 21.29 mg/L), p<0.001. The first real-world study by Wang showed a similar trend of this marker in psoriasis patients. However, different from our findings, hs-CRP level in Wang’s study increased to 2.5 mg/L. This could be due to his study population, which covered mild patients and arthritis patients. The latter can make hs-CRP difficult to continue falling. A meta-analysis conducted by S. Gerdes including three clinical namely FIXTURE, ERASURE and SCULPTURE, revealed that the higher pretreatment hs-CRP level was, the more significant the change would be. 4.2.2.2. Posttreatment IL-17A level Table 3.42 shows the evolution of IL-17A levelduring treatment.
Given Secukinumab is a novel drug against psoriasis, only one study evaluating the change of IL-17A after treatment was found. The studyby Akimichi, somehow showed an opposite trend. Amikichi reported that IL-17A had rise at second week and week 16. To explain this elevation, Secukinumab is supposed to bind selectively to IL-17A molecules at skin lesions and then to enter the circulation. Measurements coud not distinguish “free IL-17A” from “IL-17A-Secukinumab” complexes. Akimichi, like other authors, did not exclude psoriasis arthritis patients. Another differnce is that our participants had a higher mean PASI score (22.35) compared to his study patients (15.05). Additional larger studies are needed to clarify this issue.
20 4.3. Efficacy of Secukinumab in the treatment of moderate to severe psoriasis vulgaris 4.3.1. Clinical outcomes
Our finding showed that Secukinomab could improve clinical manifestations as early as from the second week, at which 2% of patients achieved a PASI-50. At the third week, a total of 74% of patients had PASI-50. At the fourth week, the percentage of PASI- 50, PASI-75, PASI-90 was 100%, 82%, 22% respectively. At the eighth week, these corresponding figure were 100%, 100%, 90% and as low as 42%, of whom PASI were 100, indicating the patients were free of lesions. PASI-50, PASI-75, PASI-90, PASI-100 were reported in 100%, 100%, 100%, 78% respectively at twelfth week. At the very end of study point of time (week 24), a hundred per cent of patients got a PASI-100(chart 3.12).
These results is in acordance with phase III trials ERASURE, FIXTURE, CLEAR, SCULPTURE, FEATURE and JUNCTURE and three real-world studies in Canada and Italy. These all proved the efficacy and safety of Secukinumab in the treatment of psoriasis vulgaris ranging from moderate to severe illness. This drug specically gave a rapid amelioration.
To be more detailed, we found a more significant effecacy of Secukinumab compared to previous data. This advanced effect could be explained in some ways. Our population had fewer comorbidities which could make patients less responsive. Besides, it could be due to lower BMI, different meassure techniques and history of biological medication exposure. In other clinical trials, patients were strictly included, only if they failed to response to classical systemtic drugs. As a consequence, we hypothesise that these patients tended to be unresponsive to systemic medications. Moreover, data supported that treatment efficacy would be more enhanced unless they had exposed to biological medications before. Our study population had a lower BMI (22.70 ± 2.70) than this index in other two trials: FIXTURE (28.4 ± 6.4) and ERASURE (30.3 ± 7.2). Although Secukinumab can be prescibed regardless of weights, obesity patients featured to have little benefit compared to whom had normal weights as demonstrated by FIXTURE trial and ERASURE
21
trial.
4.3.1. Adverse events
We had observed 5 patients (10%) suffuring from upper respiratory infection and 1 patients (2%) developing candidiasis as adverse events of Secukinumab. These adverse events were in fact mild and transient. In comparison with some pivotal clinical trials, namely FIXTURE, ERASURE, FEATURE, JUNCTURE, common side effects were pharyngitits, headache and upper respiratory infections with low incidences from 1 to 6 per cent. Besides, real- world studies which followed patients over long periods reported low frequencies of adverse outcomes, supporting results of previous phase III clinical trials. A real-world study in Italy with a 84-week follow-up period, showed only 1.8% of patients suffering from perianal abcessess, deterioration of arthritis, eczema-like rashes, candidiasis and only one case over 324 patients infected tuberculosis. In our study, patients were performed routine blood testing before treatment and after 24 weeks. As illustrated by table 3.67, biochemical markers were still in physiological range. This observation was similar to core clinical trials such as FIXTURE, ERASURE, FEATURE, JUNCTURE. Although post treatment ure serum concentration was statistically higher than before treatment (4.64 ± 1.19 mmol/L compared to 4.00 ± 1.36 mmol/L) and so was platelet count (220.02 ± 58.97 K/uL compared to 246.8 ± 64.83 K/uL), these did not exceed normal ranges. Given no data published regarding these trends, we hypothesise it was the small sample size which lead to random differences. A study with larger sample size is needed to confirm this finding.
Therefore, Secukinumab is a safe biological drug in the treatment of moderate to severe psoriasis vulgaris. Neither it change the results of routine blood tests nor it leads to serious side effects. Adverse events, if occur, are usually mild and transient. Classical systemic drugs, in contrast, do not have such advantages.
22
CONCLUSION
1.Clinical features and related factors 1.1.Related factors - Psoriasis was more common in individuals aging 50 years old or more (51.33%) and in female (52.67%)
- 20% of patients had family history of psoriasis; 36.66% of patients had aduration of illness from 2 to 5 years, 53.33% had irregular physical activities and 2% were obese. 1.2. Clinical features of psoriasis vulgaris
- Symetrically distributed skin lesions existed in 90% of patients; psoriasis lesions also manifested athead skin in 85.33% of patients, at nails in 89.33% and at skin folds at 20%. - Severity of psoriasis, based on PASI score, was primarily severe with a percentage of 45.34. - Patients whose quality of life was in very large effect
accounted for a significant percentage of 68.68. 2. Pretreatment and posttreatment hs-CRP and IL-17A levels in psoriasis vulgaris patients treated with Secukinumab
- Before treatment:hs-CRP level (11.88 ± 21.29) and IL-17A level (43.48 ± 99.50)of study group were higher than control group (hs-CRP: 0.8 ± 0.37; IL-17A: 3.91 ± 1.72). hs-CRP levelhad an association with both obesity and severity while IL-17A level was related to skin fold lesions and severity.
- After treatment:hs-CRP and IL-17A levelshad decreased gradually(hs-CRP: before treatment: 11.88 ± 21.29, after 12 weeks: 4.27 ± 4.89, after 24 weeks: 2.13 ± 3.4) and IL-17A: before treatment: 43.48 ± 99.50, after 12 weeks: 23.82 ± 52.18, after 24 weeks: 6.05 ± 6.44).hs-CRP, IL-17A and the severity of disease related to each other. 3. Efficacy of Secukinumab in the treatment of moderate to severe psoriasis vulgarispatients
- Secukinumab have a highefficacy in the treatment of moderate and severe psoriasis vulgaris, demonstrated by PASI score
23 decrease: Before treatment (22.35 ± 8.92), after 4 weeks (3.74 ± 2.71), after 8 weeks (0.71 ± 1.14), after 12 weeks (0.13 ± 0.3), after 16 weeks (0.08 ± 0.29) and after 24 weeks (0).
- Response to Secukinumab had accelerated over time: Responseappeared after 2 weeks (poor: 2% , fair: 72%), was prominent after 4 weeks (good: 82%, fair: 18%),after 8 weeks (very good: 42% , good: 58%), after 8 weeks (very good: 90%, good: 10%) and patients were free of lesions after 24 weeks.
- Adverse events: upper respiratory infection occured in 10% of patients treated with Secukinumab, candidiasis occured in 2% and no affect to complete blood count, liver function and kidney function tests was observed.
24 PROPOSALS 1.Secukinumab has been proved effective and safe in the treatment of moderate to severe psoriasis vulgaris. It should be prescribed more commonly if applicable, especially in severe patients. 2. To determine optiomal dose for each patient, there is a need to perform studies regarding the appropriatenessof maintainance dose. This must be a “4-most-dose”: the lowest, the most efficient, the safest and the cheapest dose.
LIST OF PUBLISHED ARTICLES RELATING TO THESIS
1. Tran Nguyen Anh Tu, Nguyen Trong Hao, Dang Van Em (2020), “Related factors and clinical manifestations of patients with psoriasis vulgaris at Ho Chi Minh city Hospital of Dermato-Venereology”, Jounal of 108 – Clinical Medicine and Pharmacy, (15), pp. 21–25.
2. Tran Nguyen Anh Tu, Nguyen Trong Hao, Dang Van Em (2018), “The clinical efficacy and safety of secukinumab in the treatment of psoriasis vulgaris”, Jounal of 108 – Clinical Medicine and Pharmacy, (13), pp. 88 –91.
3. Tran Nguyen Anh Tu, Nguyen Trong Hao, Dang Van Em (2020), “The study on changes of serum Il-17A and hs-CRP treated by concentration of psoriasis vulgaris patient secukinumab”, Jounal of 108 – Clinical Medicine and Pharmacy, (15), pp. 49 –54.
4. Tran Nguyen Anh Tu, Nguyen Trong Hao, Dang Van Em (2019), “The serum IL-17A and hs-CRP levels in patients with psoriasis vulgaris”, Vietnamese Journal of Dermatology, (28), pp. 20 - 28.
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