INTRODUCTION Psoriasis is one of the most common dermatological condition which 1-3% population got around the world. This percentage varies in races and regions. For example, psoriasis in Northern Europe was reported up to 3%, higher than the United States of America and China with 2% and 0.3% respectively. In Viet Nam, until now there has been a serious dearth in research on the prevalence of this disease, just a few studies operated in Kinh Mon district, Hai Duong province showed this figure being 1,5% of population. Psoriasis in the obese Vietnamese shows the overexpression of inflammatory factors and adipocytokines including cytokines IL-6, TNF-α, adiponectin, and PAI-1. The level of TNF-α increases in patients with psoriasis, and is positively correlated to the BMI and insulin resistance. Controlling metabolic syndrome in patients with psoriasis is essential to reduce disease burdens. However, treating psoriasis associated with metabolic syndromes faces many challenges because of controversial pathology, progression and clinical evidence. Research on using the combination of methotrexate and metformin in psoriasis and metabolic syndrome has been done around the world but not in Vietnam so for. Therefore, it is necessary to conduct research on this type of treatment in Vietnam with the following objectives: 1. To describe some relating factors and clinical features of psoriasis concomitant with metabolic syndrome. 2. To survey the metabolic syndrome in psoriasis patient and its relationship with clinical features. 3. To identify the effectiveness of the combination of methotrexate and metformin in the treatment of mild and moderate psoriasis.
MINISTRY OF EDUCATION MINISTRY OF NATIONAL DEFENCE AND TRAINING 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES HUYNH THI XUAN TAM STUDYING THE EFFECTIVENESS OF THE COMBINED USE OF METHOTREXATE AND METFORMIN ON PSORIASIS CONCOMITANT WITH METABOLIC SYNDROME Major: Dermatology Code: 62.72.01.52 EXECUTIVE SUMMARY OF THE DISSERATION Hà Nội – 2020 The study was accomplished at: 108 INSTITUTE OF CLINICAL MEDICAL AND PHARMACEUTICAL SCIENCES Instructors: Bui Thi Van MD Ph.D Tran Ngoc Anh MD Ph.D Dissertation Committee: The dissertation will be protected in a council meeting at: 108 Institute of Clinical Medical and Pharmaceutical Sciences At hour Day Month Year 2020 The dissertation can be found in: National library of Vietnam Library of 108 Institute of Clinical Medical and pharmaceutical Sciences Central institute for Medical Science Information and Technology INTRODUCTION Psoriasis is one of the most common dermatological condition which 1-3% population got around the world This percentage varies in races and regions For example, psoriasis in Northern Europe was reported up to 3%, higher than the United States of America and China with 2% and 0.3% respectively In Viet Nam, until now there has been a serious dearth in research on the prevalence of this disease, just a few studies operated in Kinh Mon district, Hai Duong province showed this figure being 1,5% of population Psoriasis in the obese Vietnamese shows the overexpression of inflammatory factors and adipocytokines including cytokines IL-6, TNF-α, adiponectin, and PAI-1 The level of TNF-α increases in patients with psoriasis, and is positively correlated to the BMI and insulin resistance Controlling metabolic syndrome in patients with psoriasis is essential to reduce disease burdens However, treating psoriasis associated with metabolic syndromes faces many challenges because of controversial pathology, progression and clinical evidence Research on using the combination of methotrexate and metformin in psoriasis and metabolic syndrome has been done around the world but not in Vietnam so for Therefore, it is necessary to conduct research on this type of treatment in Vietnam with the following objectives: To describe some relating factors and clinical features of psoriasis concomitant with metabolic syndrome To survey the metabolic syndrome in psoriasis patient and its relationship with clinical features To identify the effectiveness of the combination of methotrexate and metformin in the treatment of mild and moderate psoriasis Chapter 1: INTRODUCTION 1.1 Clinical and subclinical features of psoriasis: 1.1.1 Clinical features: - Cutaneous lesion: A specific lesion is a non-infiltrated, erythematous, well-defined plaque with silvery scales on the surface The size of the lesion can vary from pinpoint papules to plaques covering large area of the body Psoriasis has a tendency to be symmetrical, which is a good characteristic for diagnosis However, unilateral lesion can also appear Common lesions include: macules, plaques of erythema and scale (sometime papules with scale) - Sites of lesion: Lesions are generally symmetrical The sites of predilection of the characteristic plaques include scalp, beyond the hairline, knee, elbow, extensor of the arms and legs Psoriasis lesions can appear on cutaneous injuries, irritation, rubbing (for example scratching, chafing, injection) called Kebner phenomenon - Nail lesions: Nail lesions are very common (30-50% of all cases) It happens in all or many nails symmetrically The prevalent feature is the thickening of nails or subungual hyperkeratosis The surface of the nails isn’t shiny and has pitting or grooves across 1.1.2 Subclinical features: - Histologic findings: acanthosis of the epidermis, parakeratosis and vascular dilation - Other tests: Mild anemia is commonly reported among psoriasis patients There is an increase in the risk of arthritis due to Gout Nitrogen balance is negative, presenting low albumin in the serum The level of Creactive protein, α2-macroglobulin and erythrocyte sedimentation rate rises, which indicates systemic inflammation 1.2 Psoriasis and metabolic syndrome: A number of recent research studies on lipid disorders showed ununiformed results across geographies and races These studies showed a strong correlation between psoriasis and lipid disorder A systemic review from literature on “Psoriasis and metabolic syndrome” by Rita Sales, Tiago Torres from Portal university, Portugal pinpointed that psoriasis is positively correlated to metabolic disorder Psoriasis should not be considered as a simple skin condition but a systemic inflammatory illness concomitant with some diseases, e.g an increased likelihood of cardiovascular illness Doctors should be alerted to this syndrome and find it beside skin condition It is important to screen for the proofs of metabolic disease and control them tightly All psoriasis patients are advised to change their lifestyles and exercise more frequently With the objective to evaluate the serum lipid in psoriasis patients, Nguyen Trong Hao and Tran Hau Khang conducted a case-control study on 80 psoriasis patients and 80 healthy people Diagnosis of psoriasis was based on clinical and pathological features Both group had lipid profile calculated (triglyceride, cholesterol, HDLc, LDLc) The results showed that patients had a higher triglyceride (p = 0.03) and lower HDLc (p = 0.0009) in comparison to that of healthy people The authors concluded that it is necessary to screen and treat lipid disorder as soon as possible to prevent atherosclerosis and its complications 1.3 Methotrexate and Metformin in the treatment of psoriasis with metabolic syndrome: 1.3.1 Methotrexate - Effect on DNA synthesis: MTX competitively and reversibly binds to dihydrofolate reductase within hour, with an affinity greater than that of folic acid This prevents the conversion of dihydrofolate to tetrahydrofolate Tetrahydrofolate is a necessary cofactor in the production of 1-carbon units, which are critical for the synthesis of thymidylate and purine nucleotides needed for DNA and RNA synthesis A less rapid, but partially reversible, competitive inhibition of thymidylate synthetase also occurs within 24 hours after administration of MTX - Effect on T lymphocytes: Jeffes et al demonstrated in an in vitro experiment that the effect of MTX on the proliferation of lymphoid cells is 1000 times greater than its effect on human keratinocytes Not only does MTX affect the proliferation of lymphocytes, it also blocks migration of activated T cells into certain tissues - Immunosuppression: The effect probably occurs because of inhibition of DNA synthesis in immunologically competent cells The drug can suppress primary and secondary antibody responses - Anti-inflammatory effect: the anti-inflammatory effects are predominantly mediated by adenosine This increased adenosine production is the result of a complex interaction with AICAR transformylase and ecto 5′ nucleotidase 1.3.2 Metformin Metformin is an oral diabetes medicine in biguanide group that helps control blood sugar levels It cannot decrease sugar level in normal person In diabetes patients, metformin improves blood sugar control but not cause hypoglycemia (unless the patients starve themselves or using other drugs for diabetes treatment) Metformin act through activation of adenosine monophosphate-activated protein kinase (AMPK) in extracellular signal-related kinase (ERK1/2) signaling pathway leading to cell cycle arrest and therefore inhibition of cell proliferation, hallmark of psoriasis AMPK activation not only inhibits iNOS, dendritic, and T cell and monocyte/macrophage activation but also activates IL-10 and TGF-β, thereby exerting its anti-inflammatory action The antiproliferative and anti-inflammatory effects of metformin might have resulted in reduction of psoriasis 1.3.3 Using Metformin and Methotrexate on psoriasis patients Hartmut Glossmann et al highlighted that Metformin is a good therapy in combination with methotrexate in the treatment of male patients with psoriasis concomitant with obesity and metabolic syndrome Scientists have the evidence supporting the theory in which the anti-inflammatory effect of metformin can combine with methotrexate and reduce its hepatotoxicity in experimented animals This 32 Note: The side effects in clinical features of both groups had no statistical difference with p > 0,05 - Side effects in subclinical features: Table 3.22: Cases with abnormal blood test (MTX+MET) (n = 33) Before treatment month month months n (%) n (%) n (%) n (%) 0 0 0 0 Hemoglobin (12 – 16g/dL) below 2g/dL Number of WBC (5 – 10 x 109/L) Below x 109/L 33 Below x 109/L 0 0 4 (12,1) (12,1) (9,1) 0 0 0 0 Number of RBC (4 – 6,13M/µL) Below 4M/µL Number of platelet (140 – 440 x 103/L) Below 140 x 103/L Below 100 x 103/L Note: The results showed that after months, there were patients (9.1%) with RBC below < 4M/µL 34 CHAPTER 4: DISCUSSION 4.1 Some relating factors and the clinical features of psoriasi vulgaris along with metabolic - Age of onset and duration: Patient had the mean age of onset being 36 years old The mean duration was 16 years with the longest one being 47 years (chart 3.5), which is compatible to the research of Ngo Minh Vinh (37,1 ± 14,4 years) and the youngest patient was 16 years old Our results are also equivalent to Reich and Ruiz’s research with the mean age of onset being 35 and 36.2 years old, respectively In conclusion, the proportion of cases having the age of onset before 40 was 54.5% In term of duration, at the top position was 20 years duration were very similar, at roughly 27.3% each This figure shows that psoriasis is a chronic disease which can last for years, not to mention the complicated progression affecting petients’ quality of life 35 - Severity distribution: The figure for moderate psoriasis was higher than that for severe ones, 53% compared to 47% respectively, which was supported by the results of Truong Le Anh Tuan’s study in which the percentage of moderate and severe psoriasis patient with metabolic syndrome were 68.42% and 31.58%, respectively - The relationship between the age of onset and some relating factors: The research showed that there is a statistical correlation between smoking, drinking and the age of onset in which the proportion of smoking and drinking patients had the age of onset before 40 were 1.71 and 2.21 times as high as that of non smoking and drinking ones, respectively The research also found a connection between drinking and type of disease in which the statistics of drinking patients having type psoriasis were 1.86 times higher than that of non alcoholic ones As we mentioned before, drinking and smoking play an important role in the pathogenesis of psoriasis 36 Therefore, psoriasis patients are strongly advised to quit smoking and drinking 4.2 The matabolic syndrome in psoriasis vulgaris and its relationship to clinical features The matabolic syndrome in psoriasis vulgaris patient Among five risk factors in psoriasis vulgaris patients with metabolic syndrome, abdominal obesity has the highest correlation at 93,9% high blood pressure came second at 86,4% Standing in the least correction was low HDL-cholesterol, with the percentage of 33,3% Patients with risk factors have the highest percentage, accounting for 57.6% of the samples 7.6% of patients had risk factors, which was the lowest number Based on PASI, dermatologists can evaluate the severity of psoriasis Psoriasis should not be considered as a simple skin condition but a systemic inflammatory illness concomitant with the increased risk of cardiovascular illness and other diseases Compared with the study, of Joel M et al operated in Americac 37 concluded that the percentage of metabolic syndrome in psoriasis patient was higher than that in population The connection between severe psoriasis and risk factors of metabolic syndome has been proven recently Doctor should alert to this syndrome, find it beside skin condition and notice the effectiveness and safety of the treatment in order to manage psoriasis comprehensively More studies are needed to investigate the pathogenesis and evaluate the effectiveness of psoriasis treatment on metabolic syndrome - The relationship between abdominal obesity and some relating factors: There are an association between the age of onset, type of psoriasis and abdominal obesity feature in which patients with the age of onset before 40 or type psoriasis have the rate of abdominal obesity being 0.89 and 0.9 time higher than that in late onset or type patients Waist circumference in Asian male and female ≥ 90cm and 80cm, respectively, a creteria of NCEP ATP III, is a risk factor of metabolic syndrome The result in 38 table 3.12 showed the percentage of high waist circumference in patient and control groups were 39,39% and 25,76%, respectively However there was no significant difference in high waist circumference between two groups, which was inconsistent with AlMutairi’s study result in which the figure of abdominal obesity in psoriasis and control groups were 47,7% and 19%, respectively, as well as Gisondi P.’s research (57.1% in psoriasis group and 47.6% in control group) The reasons this differnce could be explained that our sample size was not as large as that in studies conducted before and all patients had metabolic syndrome However, many research have confirmed psoriasis induces high waist circumference According to Katarina Wolk et al, one unit increase in BMI will make the risk of psoriasis onset rise 9% and PASI go up 7% Obesity (BMI ≥ 30) also increases the threat of psoriasis, almost doubling that in patients 39 4.3 Effectiveness of treating mild and moderate psoriasis with metabolic syndrome by the combination of Metformin and Methotrexate - Comparing treatment effectiveness between groups After treatment, there was a fall in PASI of both group but the difference was not statiscal We have not found any research comparing these medicines, resulting in no data for us to compare and discuss Fasting glucose monitoring showed that: fasting glucose in MET+MTX group was control tightly, in constrast, not much change in that of MTX group This result is consistent after months monitoring, which is easy to explain because metformin is highly effective in controlling fasting glucose in diabetes patients, noy MTX However, the difference between two groups was not statistical, with p>0.05 No patient had hypoglycemia, proving the safety of metformin in the treatment of psoriasis Fasting Cholesterol monitoring showed that: Cholesterol in MTX+MET group was reduced after 1- 40 weeks monitoring but no statistical difference was shown, with p>0.05 Meanwhile, the decrease of cholesterol in MTX group after 12 weeks was statistical different, with p0.05 The explanation could be before treament, the level of cholesterol in MET+MTX group was lower than that in MTX only (4.8 versus 4), so the decrement was more, resulting in statistical difference between groups 41 CONCLUSION Through the study on 66 psoriasis vulgaris patients with metabolic syndrome, we draw some conclusions: Relating factors and clinical features of psoriasis patients with metabolic syndrome 1.1 Relatimg factors: - The figure for male was 59,1%, higher than that of female, with 40,9% - The proportion of family history, smoking, drinking and doing exercise more than time/week were 15,2%, 31,8%, 28,8% and 37,9%, respectively 1.2 Clinical features: - The mean age of onset was 36 years old 54.5% of patients had the age of onset before 40 The statistic for the remaining onset was 45,5% - 11-20 years duration accounted for the highest percentage, with 40,9% - 57.6% and 56.2% patients had the onset position of psoriasis being lower limbs and head, skin fold, serially 42 - Mild psoriasis was more prevalent than severe one, with 53% compared to 47% 1.3 The relationship between some clinical features and relating factors: - By comparing different genders, it can be seen that the onset of psoriasis before 40 was more prevalent in male than that in female - In comparison with non-smoking patients, the proportion of smoking ones having the age of onset before 40 were higher - More drinking patients had the age of onset before 40 than non-drinking ones Metabolic syndrome in psoriasi vulgaris patients and its relationship to the clinical features: 2.1 Metabolic syndrome in psoriasi vulgaris patients 93.9% of patient had abdominal obesity, while the figure for hypertension and low HDL-cholesterol were lower, standing at 86.4% and 33.3%, respectively 2.2 The relationship between metabolic syndrome and some clinical features: 43 There was a correlation between abdominal obesity and the age of onset in which patient with the age of onset before 40 had a higher percentage of abdominal obesity than those below 40 The effectiveness of moderate and severe psoriasis concomitant with metabolic syndrome treatment by the combination of methotrexate and metformin: - In methotrexate+metformin group, the proportion of good, moderate and medium results were 51,6%, 24,2%, 24,2%, respectively and PASI decrement was 73,82% (19,1- 5), which was compatible to the results of methotrexate only group in which 42,5%, 33,3% and 24,2% of patients achieved good, moderate and medium results, respectively and PASI was reduced 68,84% (19,9-6,2) - Both groups had reduced triglycerid MTX+MET group had glucose reduced (from 9.2 to 6.1) and the effects on HDL-C, cholesterol of both groups were equivalent 44 - The side effects in clinical features of both groups were nausea, vomitting which did not last long and there was no need to stop treatment Liver and kidney function testspp were in normal range 45 SUGGESTION The combination of Metformin and Methotreaxate brings improvement on psoriasis and metabolic syndrome patients There is a need for further study to investigate and use this coalesence 46 ANNOUNCED CATALOF OF RESEARCHES RELATING TO THIS DISSERTATION Huỳnh Thị Xuân Tâm, Bùi Thị Vân, Trần Ngọc Ánh (2018) The clinical features and some relating factors in psoriasis patients with metabolic syndrome Clinical Medicine and Pharmacy Magazine 108,13(4),8-15 Huỳnh Thị Xuân Tâm, Bùi Thị Vân, Trần Ngọc Ánh (2018) Metabolic syndrome in psoriasis patients: A comparative study Clinical Medicine and Pharmacy Magazine 108,13(4), 65-70 Huỳnh Thị Xuân Tâm, Bùi Thị Vân, Trần Ngọc Ánh (2018) The outcome of the treatment using a combination of metformin methotrexate in psoriasis patients with metabolic syndrome Clinical Medicine and Pharmacy Magazine 108,13, 253-257 ... anti-inflammatory effects of metformin might have resulted in reduction of psoriasis 1.3.3 Using Metformin and Methotrexate on psoriasis patients Hartmut Glossmann et al highlighted that Metformin is a good... effect of metformin can combine with methotrexate and reduce its hepatotoxicity in experimented animals This suggests for the doctors that using metformin can protect the liver from methotrexate. .. treated by metformin + methotrexate, and Control group: 33 psoriasis vulgaris patients with metabolic syndrome were treated by methotrexate only - Treatment procedure: + Treatment group: Methotrexate: