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   Response - Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
   


2. What additional supporting information will be shared?
   Response -  Study Protocol
   Response -  Statistical Analysis Plan
   
   
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   Response - To achieve aims in the approved proposal.
   


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6. For how long will this data be available start date provided 29-10-2021 and end date provided 30-12-2025?
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Title of the topic: “ TO EVALUATE THE LEVEL OF IL-17 AND IT’S CORRELATION WITH DISEASE SEVERITY IN PSORIASIS”

BRIEF RESUME OF THE INTENDED WORK:

 INTRODUCTION AND NEED FOR THE STUDY

Psoriasis is an immune mediated disorder, mainly affecting the skin, nails as well as the joints. It has a prevalence of 0.44-2.8 per cent in India, and world prevalence of 2-3 %.¹ It commonly affects individuals in their third or fourth decade.² It is a papulosquamous inflammatory disorder, usually characterized by development of red scaly lesions, which are pruritic in nature. These are mainly found to be seen over the extensors, knees, scalp and occasionally the whole body.³

The most widely accepted tool that is used to describe the severity is the Psoriasis Area Severity Index (PASI) score.

Although the exact etiology is unknown, it can be attributed to various risk factors, like genetics, and factors like alcohol intake, smoking, psychological stress and infection.⁴

The pathogenesis can be explained by the abnormal proliferation of keratinocytes. The T helper cells and dendritic cells play a crucial role in the pathogenesis. In some genetically predisposed individuals, the keratinocytes release self DNA and RNA. The dendritic cells then start producing increased amounts of cytokines. These are then presented to naïve T cells, which then undergo differentiation into Th -1, Th-17 and Th 22 cells. Th17 cells then secrete IL-17A, IL-17F, IL-22 , and IFN-γ. As a result of this cascade, there is hyperproliferation of keratinocytes.⁵

Patients often find it frustrating and are mentally distressed due to the troublesome recurrence of lesions.⁶ Despite the availability of various treatment modalities, the role of biologicals has increased in the present time.^7,8 These may be attributed to development of intolerance to phototherapy, adverse side effects of systemic drugs and need for laboratory monitoring.

At present, the biologicals used in targeting the IL-17 pathway are Secukinumab, Ixekizumab, and Brodalumab.^9,10,11

Due to the subjective nature regarding grading of psoriasis, which focuses on history and physical examination by the consulting physician, an attempt has been made to understand the clinical correlation of disease severity of psoriasis and the level of IL-17. The study would aim to bridge the gap in the paucity of data regarding the association between the level of IL-17 and severity of psoriasis in Indian population.

 REVIEW OF LITERATURE

In psoriasis, the level of cytokines are found to be increased, which play an important role in the immunopathogenesis.

A study was done by Takahashi et al, on levels of serum cytokines in Japanese patients with psoriasis, whereby 122 cases and 78 controls were included in the study.¹² The serum levels of various cytokines like tumour necrosis factor (TNF)- α, interferon (IFN)- γ, interleukin IL-2, IL-6, IL-7, IL-8, IL-12, IL-17, IL-18 and vascular endothelial growth factor (VEGF) were evaluated and severity of psoriasis was compared using the PASI score. They found increased serum levels of TNF- α, IFN- γ, IL-12, IL-17, IL-18 and VEGF which correlated with the PASI. However IL-10 levels were decreased.

Yilmaz et al studied the levels of IL-17 in patients with psoriasis, and assessed them in various types of psoriasis.¹³ The severity of plaque psoriasis was directly proportional to IL-17 levels. Compared to other types of psoriasis, highest correlation was seen between serum and tissue mRNA levels of IL-17 and pustular psoriasis.

Morsy et al conducted a study on IL-17 levels and role of various factors constituting metabolic syndrome in patients with psoriasis.¹⁴ The role of obesity, hypertension, deranged blood glucose levels and dyslipidemia were highlighted and correlated with disease severity and levels of IL-17. Patient’s BMI, systolic and diastolic blood pressure, fasting blood glucose levels and triglycerides were recorded, and assessed. The study showed increased IL-17 levels, but no obvious difference in PASI scores in patients with or without metabolic syndrome. However, they found an association between psoriasis and hypertriglyceridemia and abdominal obesity.

Michalak-Stoma et al conducted a study involving 60 patients of psoriasis and 30 healthy controls.¹⁵ The concentration of IL-6, IL-12, IL-17, IL-20, IL-22, and IL-23 in venous blood samples were estimated using ELISA kits .They also correlated the cytokine levels with the severity of psoriasis by employing various scales like PASI , body surface area (BSA) and physicians global assessment (PGA). The study had shown a positive correlation between IL-17, IL-23, IL-20, IL-22 levels which were comparable with disease severity.

AIMS OF THE STUDY:

The aim of this study is to evaluate the level of IL-17 and it’s correlation with disease severity in patients with psoriasis.

 OBJECTIVES OF THE STUDY:

1. To measure the level of IL-17 in patients affected with psoriasis and to compare it with the levels in healthy individuals.

2. To correlate the levels of IL-17 to severity of psoriasis .

 MATERIALS AND METHODS:

Source of data

Cases - A minimum of 30 patients with a clinical diagnosis of psoriasis satisfying inclusion and exclusion criteria attending the outpatient department of Dermatology over a duration of 24 months at Father Muller Medical College Hospital, Mangalore.

Controls - A minimum of 30 age and sex matched healthy individuals will be taken as controls over a duration of 24 months.

Sample size calculation

Method of sampling- Simple random sampling

Calculation of sample size – Based on the study by H. Takahashi et al¹²

N = 2 ( Z α + Zβ) 2σ2

( X1- X2 ) 2

Z α = 1.96 at 95% C.I.

Zβ = 1.281 at 80% power

X1 ± σ1 = 79.4 ± 6.61

X2 ± σ2 = 62.2 ± 7.39

Therefore, n= 26 per group ( minimum )

Study design : Observational analytic cross sectional study

 Method of collection of data-

Selection Criteria:

CASES -

1. Inclusion Criteria

· All the patients with clinical diagnosis of psoriasis

· Patients above the age of 18 years willing to participate in the study.

2. Exclusion Criteria

· Patients with psoriasis – already on IL-17 inhibitors.

· Patients with other pre-existing skin disorders.

· Patients who are not willing to participate in the study.

CONTROLS-

1. Inclusion Criteria

· All age and sex matched healthy volunteers willing to participate in the study.

2. Exclusion Criteria

· Individuals with active inflammatory dermatological conditions.

· Individuals on IL-17 inhibitors.

· Individuals who are not willing to participate in the study.

Data will be collected over a duration of 24 months with a sample size of 60, after obtaining approval from the institutional scientific committee and ethics committee.

· All participants will be explained about the need for the study and it’s requirements.

· A written and informed consent will be taken from each person enrolled in the study.

Methodology

A minimum of 30 patients clinically diagnosed with psoriasis will be taken up for study. Thirty age and sex matched healthy volunteers, will also be recruited after taking due consent. A detailed history and physical examination will be done.

The patient will also be examined for the extent and severity of lesions will be calculated by the consulting physician using Psoriasis area severity index (PASI).

In order to calculate the PASI Score, the following steps will be done:-

The body will be divided into four areas – head (H), arms (U), trunk to groin (T), and legs to top of buttocks (L). An average score for erythema , thickness and scaling for each area will be allotted as follows: 0-nil, 1-slight, 2-mild, 3-moderate, and 4- severe.

Following which a sum of erythema (E), induration (I) and desquamation (D) will be done for each area.

Percentage of skin covered with psoriasis will be assessed and converted to a scale of 0-10 .

SCORE AREA INVOLVED

0 - 0%

1 <10 %

2 - 10-29 %

3 - 30-49 %

4 - 50-69 %

5 - 70-89 %

6 > 90 %

Formula for PASI Score = 0.1 (Eh + Ih + Dh ) Ah + 0.2 (Eu + Iu + Du ) Au + 0.3 (Et + It + Dt ) At + 0.4 (El + Il + Dl ) Al .

Under aseptic precautions, venous blood samples will be collected from all the participants of the study. These will then be subjected to sandwich ELISA , using a commercially available kit from Biovendor, USA. The readings will be taken in BIORAD microplate readers, which will be performed in the Father Muller Research Laboratory.

The levels of IL-17 and PASI score of the participants will be assessed at the same time on a single visit.

STATISTICAL ANALYSIS:

· Collected data will be analyzed by frequency, percentage, mean, standard deviation, ‘t’ and Chi-Square test.

HYPOTHESIS : IS SEVERITY OF PSORIASIS ASSOCIATED WITH INCREASED IL-17 LEVELS ?

IMPLICATIONS OF THE STUDY:

With this study, a deeper perspective will be studied about the role of IL-17 in the pathogenesis of psoriasis.

The role of IL-17, can be used as an important parameter, in order to detect the disease, and follow up the severity of disease. It can also be used for monitoring the patient who are receiving treatment for the same. Hence it can be employed effectively as a guide in future treatment modalities.

LIST OF REFERENCES:

1. Dogra S, Yadav S. Psoriasis in India: Prevalence and pattern. Indian J Dermatol Venereol Leprol 2010;76:595-601.

2. Pariser DM, Bagel J, Gelfand JM, Korman NJ, Ritchlin CT, Strober BE, et al. National Psoriasis Foundation Clinical Consensus on Disease Severity. Arch Dermatol 2007;143;239-42.

3. Dogra S, Mahajan R. Psoriasis: Epidemiology, clinical features, co-morbidities, and clinical scoring. Indian Dermatol Online J 2016;7:471-80.

4. Kamiya K, Kishimoto M, Sugai J, Komine M, Ohtsuki M. Risk Factors for the Development of Psoriasis. Int J Mol Sci 2019;20:4347.

5. Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil S. Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol 2014;71:141-50.

6. Sampogna F, Tabolli S, Abeni D. Living with psoriasis: Prevalence of shame, anger, worry and problems in daily activities and social life. Acta Derm Venereol 2012;92:299-303.

7. Kaushik SB, Lebwohl MG. Psoriasis: Which therapy for which patient: Focus on special populations and chronic infections. J Am Acad Dermatol 2019;80:43-53.

8. Smith CH, Jabbar-Lopez ZK, Yiu ZZ, Bale T, Burden AD, Coates LC, et al. British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017. Br J Dermatol 2017;177:628-36.

9. Bhat RM, Leelavathy B, Aradhya SS, Gopal MG, Pratap DV, Mubashir M, et al.Secukinumab efficacy and safety in indian patients with moderate-to-severe plaque psoriasis: Sub-analysis from FIXTURE, a randomized, placebo-controlled, phase 3 study. Indian Dermatol Online J. 2017;8:16-24.

10. Craig S, Warren RB. Ixekizumab for the treatment of psoriasis: up-to-date. Expert Opin Biol Ther 2020;20:549-57.

11. Galluzzo M, D’adamio S, Bianchi L, Talamonti M. Brodalumab for the treatment of psoriasis. Expert Rev Clin Immunol. 2016;12:1255-1271.

12. Takahashi H, Tsuji H, Hashimoto Y, Ishida-Yamamoto A, Iizuka H. Serum cytokines and growth factor levels in Japanese patients with psoriasis. Clin Exp Dermatol. 2010;35:645-9.

13. Yilmaz SB, Cicek N, Coskun M, Yegin O, Alpsoy E. Serum and tissue levels of IL-17 in different clinical subtypes of psoriasis. Arch Dermatol Res 2012;304:465-9.

14. Morsy H, Hasaballa A, Awad S. Interleukin-17 levels in patients with psoriasis with or without metabolic syndrome. J Egypt Womens Dermatol Soc 2019;16:164-9.

15. Michalak-Stoma A, BartosiÅ„ska J, Kowal M, Raczkiewicz D, Krasowska D, Chodorowska G. IL-17A in the Psoriatic Patients’ Serum and Plaque Scales as Potential Marker of the Diseases Severity and Obesity. Mediators Inflamm. 2020;35:625-31.