Summary of phd thesis in medicine: evaluation of HS CRP, IL 17a levels, and efficacyand safety ofsecukinumab in patients with psoriasis vulgaris

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

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

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

INTRODUCTION

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 recent 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 17A levelsin psoriasis vulgaris patients treated with Secukinumab

IL-3 To investigate the efficacy and safety of Secukinumab in the treatment of moderate to severe psoriasis vulgaris

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

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

1.1.5 Treatment

Patients should be consulted about therapeutic strategiesdepending onseverity, age, gender, social-economic status…

1.2 Psoriasis and Interleukin-17A (IL-17A)

IL-17Aplays an important role in abnormalproliferation and differentiation of epidermal cells, triggering and amplificating inflammatory cascades,which in turn involve in releasing 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, fibroblasts,…IL-17A, therefore, contributes to pathogensis of comobidities such as psoriasis arthritis, heart diseases, arterosclerosis

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)

In addition, many authors have noticed a phenomenon callled

“upgrade” and have found a proportional relation between the inflammatory index and 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 trials, namely ERASURE, FIXTURE, CLEAR, SCULPTURE, FEATURE and JUNCTURE, have

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 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 skin tissue’receptors caused by Secukinumab

IL-Finally, Gottlieb (2014) andGerdes (2020) demonstrated CRP serum concetration commenced to decrease at the 12nd week and continue falling until the week of 52

hs-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 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

anti Control group:sex and ageanti 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

2.3 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 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

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

STUDY ALGORITHM

1st routine

blood tests

Inclusion (150 participants)

Clinical characteristics

50 moderate and

severe patients

1st IL-17 and hs-CRP measurements

Secukinumab

1st routine

blood tests

2nd IL-17 and CRP measurements

hs-3rd routine

blood tests

3rd IL-17 and CRP measurements

hs-Clinical and

immunological

results

Immunological results

Final results

50 healthy participants

Comments:Mean age was

most common group, accounting for 28.00%

under 20 years old

Chart 3.1 Gender distribution (n=150

of participants are f33%)

22.70 ± 2.70

Chart 3.2 BMI classification (n=150)

Almost participants fell into normal BMI range (84%)

13, age group of 50common group, accounting for 28.00% There was no

%

0.00 11.33 20.67 16.67 28.00 23.33

2%

- Mean PASI score:

Chart 3.4 PASI severity score distribution (n=150)

Comments: Severe patients

groups while the mild group

Extremely large effect (21

Clinical features of psoriasis vulgaris

Mean PASI score: 19.39 ± 8.83

PASI severity score distribution (n=150)

Severe patients (45.34%)

while the mild group accounted

Mean DLQI is 11.87 ± 4.94

6.DLQI score distribution

Very large effect group predominated other groups with

68.68%

of PASI score and patients’s

PASI score and BMI classification (n=150)

psoriasis vulgaris

83

PASI severity score distribution (n=150)

34%) featured to outweighaccounted for only 17.33%

DLQI score distribution (n=150)

predominated other groups with

patients’s characteristics

score and BMI classification (n=150)

PASI

11.55 ± 6.94 19.19 ± 9.01 20.37 ± 5.15 32.77 ± 7.42

significantly among BMI groups,

PASI severity score distribution (n=150)

Table 3.15 PASI score and nail lesions (n=150)

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

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)

Mann-Whitney U test

Comments: hs-CRP level in obese psoriasis patients was statistically

higher than non obese ones, p<0.05

Table 3.31.hs-CRP level and disease severity (n=50)

Marker Moderate (n = 26) Severe (n = 24) p

hs-CRP 2.53 ± 1.22 22.00 ± 27.53 <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

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 Moderate (n = 26) Severe (n = 24) p

IL-17A 34,46 ± 28,96 53,24 ± 141,48 0,08 Mann-Whitney U test

Comments:No statistically significant difference in IL-17A levels

between two groups was observed, p>0,05