Effect of Methotrexate on Inflammatory Response in Adult Atopic Dermatitis Patients

Study Overview
=================
Brief Summary
-----------------
Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with pruritus. Methotrexate can be used to treat refractory disease to conventional therapy. It will be conducted a single arm trial with twelve adult patients with moderate to severe AD on methotrexate for 24 weeks. Investigators intend to evaluate the effect methotrexate on cytokines and chemokines involved in the inflammatory response, on IgE levels, on pruritus, and on EASI and SCORAD severity scores.

Detailed Description
-----------------
Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with pruritus. Methotrexate (MTX) can be used to treat refractory disease to conventional therapy, but there are few studies showing its effect on the profile of cytokines involved in the inflammatory response. Objectives: To assess the effect of MTX on the cytokines involved in the inflammatory response of adult AD patients treated with methotrexate for 24 weeks. As specific objectives, investigators intend to assess the evolution of serum IgE levels, the EASI (Eczema Area and Severity Index) and SCORAD (Scoring Atopic Dermatitis) severity scores and pruritus in them. Methods: It will be conducted an open, prospective study with twelve adult patients with moderate to severe AD on MTX for 24 weeks. Each participant is expected to attend 7 visits during 6 months of follow-up. In clinical healthy and injured skin, two assessments will be performed: 1) mRNA expression of IL-4, IL-10, IL-17A, IL-22, IL-31, oncostatin M receptor (OSMR), alpha subunit IL-31 (IL-31RA) receptor, TNF-α, IFN-γ, TSLP, TARC and MDC by Real Time-PCR at the initial week and week 24; 2) expression of IL-31, IL-31RA, OSMR, TSLP and Ki67 by immunohistochemistry at the initial week and week 24. Skin samples from non-atopic subjects will be utilized as controls for the assays, paired by gender and age. Additional analysis of serum levels of IgE (nephelometric method) at the initial week and week 24 of the study will be performed. AD severity scores (EASI and SCORAD) will be tested and pruritus will be analyzed by a visual analog scale at the initial, week 12 and week 24.

Official Title
-----------------
Evaluation of the Effect of Methotrexate on Cytokines and Chemokines Involved in the Inflammatory Response in Adult Patients With Atopic Dermatitis

Conditions
-----------------
Atopic Dermatitis

Intervention / Treatment
-----------------
* Drug: Methotrexate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: AD (Hanifin and Rajka criteria) moderate to severe (EASI ≥ 7.1 and SCORAD ≥ 25); Age ≥ 18 years; Women without the potential to become pregnant or using an effective method of contraception and with a negative pregnancy blood test; Men without a desire of pregnancy and who use condom in sexual intercourse. Exclusion Criteria: Hepatic and / or renal insufficiency; Anemia, thrombocytopenia and / or leukopenia; Use of concomitant hepatotoxic drug; Active infection; Allergy to MTX; Excessive alcohol intake; Difficulty to understand how to take methotrexate; HIV infection or other immunosuppression condition; Therapy with UVA or UVB, corticoid, cyclosporine, immunobiological, azathioprine within 12 weeks prior to introduction of methotrexate.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methotrexate<br> | Drug: Methotrexate<br>* oral, 15 mg per week, 24 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of cytokines and chemokines expression at 24 weeks | mRNA expression of IL-4, IL-6, IL-10, IL-31, TSLP, INF-gamma, TNF-alpha, TARC and MDC by Real Time-PCR. Immunohistochemistry with antibodies against IL-31, IL-31RA, OSMR, TSLP and Ki67 | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline of IgE level at 24 weeks | Nephelometric method | week 24 | 
| Change from baseline of Pruritus at 12 weeks | Visual analogue scale (VAS). The VAS was used as a 10-cm long horizontal line with a starting point as no itch (0 points) and ending with worst imaginable itch. | week 12 | 
| Change from baseline of Pruritus at 24 weeks | Visual analogue scale (VAS). The VAS was used as a 10-cm long horizontal line with a starting point as no itch (0 points) and ending with worst imaginable itch. | week 24 | 
| Change from baseline of SCORAD severity score at 12 weeks | The SCORAD (Scoring atopic dermatitis) is a severity score used for atopic dermatitis. To measure the extent of AD, the rule of nines is applied on a front/back drawing of the patient's inflammatory lesions. The extent can be graded from 0 to 100. The intensity part of the SCORAD consists of 6 items: erythema, oedema/papulation, excoriations, lichenification, oozing/crusts and dryness. Each item can be graded on a scale from 0 to 3. The subjective items include daily pruritus and sleeplessness. The SCORAD Index formula is: A/5 + 7B/2 + C. In this formula, A is defined as the extent (0-100), B is defined as the intensity (0-18) and C is defined as the subjective symptoms (0-20). The minimal score of SCORAD is 0 and the maximal score is 103 (most severe). | week 12 | 
| Change from baseline of SCORAD severity score at 24 weeks | The SCORAD (Scoring atopic dermatitis) is a severity score used for atopic dermatitis. To measure the extent of AD, the rule of nines is applied on a front/back drawing of the patient's inflammatory lesions. The extent can be graded from 0 to 100. The intensity part of the SCORAD consists of 6 items: erythema, oedema/papulation, excoriations, lichenification, oozing/crusts and dryness. Each item can be graded on a scale from 0 to 3. The subjective items include daily pruritus and sleeplessness. The SCORAD Index formula is: A/5 + 7B/2 + C. In this formula, A is defined as the extent (0-100), B is defined as the intensity (0-18) and C is defined as the subjective symptoms (0-20). The minimal score of SCORAD is 0 and the maximal score is 103 (most severe). | week 24 | 
| Change from baseline of EASI severity score at 12 weeks | Eczema Area and Severity Index (EASI) is a tool for the measurement of severity of atopic dermatitis. It ranges from 0 (no eczema) to 72 (most severe). EASI is one of the core outcome instruments recommended to be included in all clinical trials on atopic dermatitis. | week 12 | 
| Change from baseline of EASI severity score at 24 weeks | Eczema Area and Severity Index (EASI) is a tool for the measurement of severity of atopic dermatitis. It ranges from 0 (no eczema) to 72 (most severe). | week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
atopic dermatitis, pruritus, methotrexate, inflamation, IL-31