MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES RESEARCH ON CYTOKINE CHANGES AND TREATMENT EFFECTIVENESS OF GENERALIZED ERYTHRODERM[.]
MINISTRY OF EDUCATION AND TRAINING MINISTRY OF DEFENCE 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES RESEARCH ON CYTOKINE CHANGES AND TREATMENT EFFECTIVENESS OF GENERALIZED ERYTHRODERMIC PSORIASIS BY METHOTREXATE Speciality: Internal Medicine/Dermatology Code: 9720107 ABSTRACT OF MEDICAL PHD THESIS Hanoi – 2023 THE THESIS WAS DONE IN: 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES Supervisor: Assoc.Professor Đặng Văn Em MD, PhD Assoc Professor Lê Hữu Doanh MD, PhD Reviewer: Assoc.Professor Phạm Hoàng Khâm MD, PhD Assoc.Professor Bùi Thị Vân MD, PhD This thesis will be presented at Institute Council at: 108 Institute of Clinical Medical and Pharmaceutical Sciences Day Month Year The thesis can be found at: 1.National Library of Vietnam 2.Library of 108 Institute of Clinical Medical and Pharmaceutical Sciences 3.Central Institute for Medical Science Infomation and Tecnology RESEARCH PROBLEM Generalized erythrodermic psoriasis (GEP) is one of the severe forms of psoriasis characterized by extensive skin lesions covering over 90% of the body's surface area, accompanied by disruptions in biochemical, water, and electrolyte balance, as well as damage to various organs It significantly impacts aesthetics, psychological well-being, and quality of life, burdening both families and society with healthcare responsibilities Recent studies have indicated a significant increase in cytokines such as IL-2, IL-6, IL-8, IL-10, IL12, IL-17, IL-23, etc., in the serum of psoriasis patients These cytokines are believed to play a role in maintaining psoriatic lesions in general and GEP in particular These cytokines can be used as monitoring and treatment indicators for GEP patients in particular and psoriasis patients in general Several biologic drugs have been studied and applied clinically, including Infliximab-TNF-α inhibitor and Secukinumab - IL-17 inhibitor While numerous studies on GEP and post-treatment cytokine evaluation have been conducted worldwide, there is still a lack of research on post-treatment cytokine evaluation In Vietnam, there have been studies on cytokines in common psoriasis and pustular psoriasis, but none have explored the association of cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, TNF-α, INF-γ) in GEP patients before and after Methotrexate treatment Objectives: We aimed to conduct the study "Research on cytokine changes and treatment effectiveness of generalized erythrodermic psoriasis by Methotrexate " with the following objectives: Investigate relevant factors and clinical characteristics of GEP patients undergoing treatment at the Central Dermatology Hospital Determine the concentrations of cytokines: IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, TNF-α, INF-γ in GEP patients before and after Methotrexate treatment Evaluate the effectiveness of Methotrexate treatment for GEP CHAPTER DOCUMENTARY OVERVIEW 1.1 Generalized erythrodermic psoriasis 1.1.1 The situation of red psoriasis of the whole body In Vietnam, in the National Hospital of Dermatology from 2008-2010, the rate of psoriasis patients coming to the clinic accounted for 2.2%, the proportion of psoriasis patients compared to inpatients accounted for about 20.1% According to Dang Van Em, patients with psoriasis hospitalized from 1990 to 1994 at the Department of Dermatology, Hospital 103 and Central Military Hospital 108 accounted for about 6.16% GEP was confirmed in psoriasis patients with skin lesions over 90% of the body surface In Vietnam, there are currently very few studies on systemic erythrodermic psoriasis 1.1.2 Pathophysiology of erythrodermic psoriasis The pathogenesis of GEP is not fully understood, systemic erythrodermic psoriasis is a rare and severe variant of common psoriasis, however, some studies suggested this disease was associated primarily with the T helper (Th2) phenotype Th2 cytokines (IL-13, IL-5, IL-10, IL-9) may be involved in the pathogenesis of GEP This change in cytokines causes normal psoriasis to turn into GEP Th1/Th2 imbalance is also the cause of GEP Understanding this pathogenesis helps scientists to find ways to treat the disease such as using biological drugs against T cells, tumor necrosis factor-α (TNF-α), IL-12 axis /IL-23, or redirect cellular immune responses to the protective Th2 form of IL-4… 1.1.3 Clinical features of erythrodermic psoriasis GEP is psoriasis diagnosed when the lesion area is greater than 90% of the body surface On the red skin, there are thick, infiltrated, edematous skin scales with different degrees depending on the location of the body and the severity of the disease GEP is a severe form of psoriasis and most of the time, it is converted from normal psoriasis due to the treatment process of abuse of many drugs, especially systemic corticosteroids Many patients present with fever, chills, skin pain, extreme fatigue, tachycardia, diarrhea, constipation, weight loss, left heart failure due to excessive dehydration and edema, and visual disturbances GEP include two clinical forms, dry and wet 1.1.4 Treatment of erythrodermic psoriasis The treatment strategy for psoriasis in general and GEP in particular has phases: attack (reduce or clear the psoriasis lesions) and maintenance phase (maintain the psoriasis stability of the advanced stage) public), with the drug strategy: alone, in combination, in rotation and successively, has helped psoriasis patients in general and GEP patients have a good time of disease stabilization, improving their quality of life Topical treatment drugs + Corticosteroids: For GEP, the treatment of corticosteroids needs to be strictly indicated, and often combined with moisturizers to limit dry skin and limit systemic side effects of long-term topical corticosteroids +Vitamin D: Vitamin D3 has types: calcitriol (1,25(OH)2D3, calcipotriol (MC903), a synthetic analogue of vitamin D with strong regulatory properties, very little risk of calcium and tacalciol changes (1,24(OH)2D3) Whole body medicine + Methotrexate: MTX is the preferred systemic drug for systemic erythrodermic psoriasis (details section 3.3) + Retinoid and derivatives: a synthetic derivative of vitamin A acid, which regulates proliferation and differentiation of keratinocytes + Cyclosporine A (CyA): Immunosuppressive, acting on many cell types, preventing activation of Th, reducing INF-γ will cut off the exchange between T-lymphocytes and T-cells Mycophenolate mofetil: another immunosuppressive drug that selectively inhibits activated lymphocytes that may be effective as monotherapy for moderate to severe psoriasis + Probiotics: Several types of biologics have been used to treat GEP, including TNF-α inhibitors, IL-12/IL-23 inhibitors, and most recently inhibitors IL-17A 1.2 Role of cytokines in systemic erythrodermic psoriasis Cytokines are low-molecular-weight soluble protein molecules produced by many cells in response to allergens that act as messengers to regulate inflammatory and immune function IL-4 and IL-10 are representative of Th2 cytokines IL-4 can promote Blymphocyte activation, proliferation, synthesis, and secretion of IgE antibodies, and induce inflammatory responses by circulating immune complex accumulation on blood vessel walls IL-10 is produced by activated macrophages and some keratinocyte activators, and it can inhibit the production of IL-2, IFN-γ, proinflammatory cytokines and APC antigen may promote development of Th2 cytokines 1.3 Methotrexate for the treatment of erythrodermic psoriasis 1.3.1 Role of methotrexate in systemic erythrodermic psoriasis Although there are now many biological drug classes that affect the pathogenesis of psoriasis, bringing positive effects in the stages of attack, maintenance and improvement of the quality of life for patients However, to date, Methotrexate (MTX) has been identified as a highly effective drug in the treatment of psoriasis in general 1.3.2 Studies on the treatment of systemic erythrodermic psoriasis with methotrexate Studies in the world: The study of Collins and Rogers made 7/40 patients with systemic erythrodermic psoriasis, treated with MTX at a dose of 10mg/week, with very good results, patients with patients well, patient did not respond Van Dooren-Greebe studied 10 patients, with a dose of MTX 7.7-15mg/week, with good results, average results Haustein and Rytte had 36 patients, treated with MTX dose of 7.5-40mg/week then maintained at 7.5-15mg, 28 patients had good results, patients had average results Research in Vietnam: In Vietnam, there are many studies on the use of Methotrexate in common psoriasis, but so far there is no study on the use of Methotrexate in erythrodermic psoriasis whole body skin CHAPTER SUBJECT AND RESEARCH METHODS 2.1 Subject and Research Materials 2.1.1 Research Subjects Objective 1: 112 patients diagnosed with generalized erythrodermic psoriasis (GEP) treated as inpatients and outpatients at the Central Dermatology Hospital from 01/01/2017 to 30/06/2019 Objective 2: 30 GEP patients (study group - SG) without contraindications to use MTX and 30 healthy individuals (control group - CG) matched for age and gender, without autoimmune and infectious diseases Objective 3: 30 GEP patients from SG in objective 2.1.1.1 Diagnostic criteria: Basic lesions: Red, scaly plaques covering ≥90% of the patient's body surface area: History of psoriasis vulgaris 2.1.1.2 Inclusion criteria Objective 1: All patients diagnosed with GEP treated as inpatients and outpatients at the Central Dermatology Hospital Patients agree to participate in the study Objective 2: - Study group: 30 patients - GEP patients from objective 1, aged over 12, without contraindications to Methotrexate, and agree to participate in the study - Control group: 30 healthy individuals, matched for age and gender with the patient group, without autoimmune or acute infectious diseases Objective 3: Same as the study group in objective 2.1.1.3 Exclusion criteria Objective 1: Patients who not meet the criteria Objective 2: - Study group: Patients younger than 12 years old; Patients with mental disorders; Pregnant women, breastfeeding mothers; Patients with liver, kidney, blood diseases, ongoing infectious diseases, HIV infection, tuberculosis, or cancer; Women and men planning to conceive in the next months; Abnormal complete blood count and liver function (twice higher than normal) - Control group: Not complying with the study protocol Objective 3: Same as the study group in objective 2.1.2 Research materials: - Methotrexate tablets: 2.5mg per tablet Supplied by the Pharmacy Department of the Central Dermatology Hospital, manufactured in South Korea - Reagents: Two kits and reagents for testing cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, INF-γ, TNF-α) from Bio-Rad (USA) and testing kits for IL-17 and IL-23 from Sigma (USA) + Reagent kit for testing cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, and INF-γ) from Bio-Rad (USA) + A mixture of equal quantities of different types of plastic particles, each type attached to a different microplate, especially for cytokines that stimulate colony formation of mononuclear and granulocyte cells, interferon gamma (INF-γ), and tumor necrosis factor alpha (TNF-α) + Detecting antibody mixtures containing monoclonal antibodies specific to biotin-bound cytokines + Streptavidin-Phycoerythrin (PE) conjugate + Standard mixture of 27 human cytokines with known hormones + Sample solutions, biological solutions, washing solutions, running solutions produced and provided by Bio-Rad + Bio-Plex system and accompanying control software manufactured by Rad company + Other auxiliary laboratory materials and equipment such as shakers, vacuum machines, pipettes, pipette tips, foil, blotting paper, distilled water, test tubes all meet international standards and are supplied from genuine suppliers manufacture + Biological chemicals are managed at the Department of Immunology-Military Medical Student 2.2 Research Methods 2.2.1 Research Design - Objective 1: Prospective, Cross-sectional study - Objective 2: Prospective, Cross-sectional study with a comparative control group - Objective 3: Prospective controlled interventional trials 2.2.2 Research Sample Size - Objective 1: Convenient sample - All GEP patients treated as inpatients and outpatients at the Central Dermatology Hospital, receiving direct examinations - Objectives and 3: Convenient sample (select GEP patients meeting the inclusion criteria for the study) and the final sample size must be ≥30 patients 2.2.3 Assessment of Disease Severity Based on the Psoriasis Area & Severity Index (PASI) scale: Mild: PASI < 10; Moderate: 10 ≤ PASI < 20; Severe: PASI ≥ 20 2.2.4 Treatment Outcome Evaluation - Clinical results are calculated by the percentage reduction in PASI according to the formula by Heng-Leong Chan-1993 - PASI reduction levels: Excellent: PASI reduction 100%; Good: 75 ≤ PASI reduction < 100%; Fair: 50 ≤ PASI reduction < 75%; Moderate: 25 ≤ PASI reduction < 50%; Poor, no effect: PASI reduction < 25% 2.4 Data Processing Method - Data input and analysis using Epi InfoTM7 software Data presented in frequencies, percentages, mean values, standard deviations, and medians - Use the chi-square test to find associations for categorical variables or Fisher's exact test when there are >20% expected frequencies in a table