TWEAK levels in psoriatic patients treated with narrowband ultraviolet B and methotrexate

Psoriasis is an autoimmune disease which has an effect on the joints and skin. Tumor Necrosis Factor‐Like Weak Inducer of Apoptosis (TWEAK) is a multi‐functional cytokine which regulates the cellular processes and has been related to a variation of conditions.


| INTRODUC TI ON
Psoriasis refers to a persistent inflammatory illness of the skin and joints.It also impacts roughly 2%-3% of the inhabitants of the universe. 1oriasis pathophysiology is still poorly understood.Several proinflammatory cytokines and cytokine receptors have been implicated in its pathophysiology. 2EAK is a transmembrane protein that is found in different subsets of skin cells and is included in a various physiologic and pathological procedures.It is stated in keratinocytes in human psoriasis lesions.TWEAK and its receptor Fn14 are upregulated by numerous human inflammatory dermal diseases. 3EAK causes cutaneous inflammation by increasing cytokine and chemokine production in collaboration with its unique receptor, Fn14, which is represented by keratinocytes and overexpressed in inflammatory situations. 4oriasis treatment must be tailored to the individual and may include a combination of several treatment approaches.Topical therapy can help treat mild to moderate psoriasis.Phototherapy, systemic therapy, or biologic treatment may be used to treat more severe psoriasis. 5e most common category of phototherapy used in the cure of the psoriasis and other skin problems are NB-UVB. 6It reduces expression of serum E-selectin. 7rthermore, it inhibits the proinflammatory cytokines secretions like interleukin (IL)-1, IL-6, IL-8, interferon gamma (IFNγ), and TNF-alpha (TNFα). 8-UVB moderately increases the systemic level of TWEAK in psoriatic patients. 9Methotrexate (MTX) is an immunosuppressive drug that has anti-proliferative and anti-inflammatory effects on psoriasis. 10It inhibits keratinocytes' growth and downregulates endothelial appearance of the intercellular adhesive molecules ICAM-1, E-selectin, 11 TNFα, IFNγ, and IL-6. 12e purpose of the work was to measure the grades of serum TWEAK in psoriatic candidate's pre-cure and post-cure with NB-UVB and MTX and its correspondence with PASI score pre-and post-cure.

| Study cohort
This study employed a randomized controlled trial design, involving a total of 60 individuals.Among them, 40 were patients diagnosed with psoriasis vulgaris, while the remaining 20 were selected as normal controls, matched in terms of age and sex.The patients were randomly assigned to two groups.A total of 20 individuals were administered NB-UVB treatment in the initial group.The second group comprised 20 candidates who were treated with MTX.
Participants with chronic syndromes such as hepatic conditions, hematologic disorders, chronic kidney impairment, infections, or malignancy, patients who have got NB-UVB phototherapy in the last 3 months, candidates who have received systemic or biologic agents, and patients who have received systemic psoriasis treatment in the last 3 months, and patients who are pregnant or lactating were excluded from this study.

| Calculating sample size
The G*power 3 program was used to figure out the sample size.
To identify a size of 0.

| Methodology
At the start of the study, all subjects were exposed to suitable history, suitable general and dermal exams, with an exploration to eliminate any other associated systemic disease, and TWEAK measurements.

| Clinical evaluation
All patients underwent a comprehensive medical history as well as suitable general and local exams.The PASI score was applied to assess psoriasis vulgaris candidates per and post therapy with NB-UVB phototherapy and MTX.The illness intensity was classified as mild if the PASI was less than 15, If the PASI was less than 15, the disease was considered mild., moderate if the PASI was between 15 and 25, and severe if the PASI was greater than 25.Treatment side effects were documented.The start dose was 0.25 J/cm 2 , and the dose was augmented by 10%-20% at every session, with a supreme dose of 5 J/cm 2 .When red skin irritation, discomfort, or blistering appeared, the doses were reduced by 20% or the sessions were halted temporarily.Diseased candidates were told to wear "UV goggles," and diseased males were told to use genitalia shield cover and avoid direct exposure to sunlight during the phototherapy course.70% of the MED was used in the initial NB-UVB calculation.

| MTX therapy
Twenty candidates with psoriasis vulgaris were injected by MTX intramuscularly at a dose of (0.3 mg/kg/week) along with folic acid supplements at a dose of 5 mg given 24 h after methotrexate for a total of 4 weeks (10-12 weeks).Every patient had liver and kidney function tests earlier the initial dose of MTX and again 12 weeks later.

| Medical photography
The patients were photographed at baseline and after 3 months of regular therapy using a high-resolution digital camera canon EOS 1300D 18 megapixels (made in Taiwan), in standard light and distance.

| Statistical analysis
The Statistical Package for Social Sciences (SPSS) software was used to analyses the data (version 22).Comparing qualitative variables that were represented as frequencies and percentages was done using the chi-square test.The student t-test was applied to equate the quantitative measures, which were shown as means and standard deviation (SD).The indicated correlation between variables and regression analysis will be performed.The value of p < 0.05, is appraised significance.

| RE SULTS
This research included 40 patients with moderate to severe psoriasis and 20 normal controls.There were no significance variations related to age and sex among subjects (p > 0.05) (Table 1).

TA B L E 1
Baseline characteristics of the studied groups.
Regarding anthropometric parameters variations among the three studied groups, there were insignificant differences as regard of weight (p = 0.958), and body mass index (BMI) (p = 0.656) (Table 1).
There were no significance differences among the studied patients as regard mean PASI score before therapy (p = 0.184).After therapy, the PASI score reduced significantly in both NB-UVB group and in MTX group (p < 0.001).For the two studied groups (NB-UVB and MTX) there were significance variations among the mean PASI score pre-and post-treatment for each group (p = 0.024) (Table 2).
At the baseline of the study, there were significant difference in the mean TWEAK between patients and controls (p < 0.001).After treatment, there was insignificant variation in the TWEAK level among all studied groups (p = 0.357).For NB-UVB and MTX groups there was a significant variation in mean TWEAK level between preand post-treatment (p < 0.001) (Table 3, Figure 1).
The percent change in the TWEAK level after treatment in the studied groups was increased in NB-UVB (57%) than Methotrexate group (46%), but there was insignificant difference between both groups (p = 0.287) (Table 3).
There was a significant positive correlation between TWEAK and PASI score before treatment (r = 0.399, p = 0.014) (Table 4).
There was a non-significant mild negative correlation between the percent change in TWEAK level and the patient's age in the NB-UVB Group (r = −0.454,p = 0.054).All other correlations were nonsignificant (p > 0.05) and ranged from weak to mildly negative.There was a remarkable high moderate negative association between the percent change in TWEAK level and the percent change in PASI score for the MTX Group (r = −0.561,p = 0.015), but all other correlations were non-significance whereas (p > 0.05) (Table 4).

| DISCUSS ION
Psoriasis is a multi-systemic inflammatory illness that impacts the skin and joints. 13The etiology of psoriasis is still not fully unidenti-   The median difference between groups was compared using Mann-Whitney U-test. b The median difference within group was compared using the Wilcoxon Signed Rank Test.
c Repeated Measure of mean difference between groups was compared using the ANOVA test across time.
F I G U R E 1 Change of TWEAK level over the treatment time between groups.
inflammatory-associated proteins like S100A8/9 and SERPINB1/B9, all were discovered to be extremely expressed in the infected skin of psoriasis candidates. 16 attracting leukocytes to the skin and promoting the inflammation response, TWEAK can cause keratinocytes to produce IFNγ and numerous chemokines like CCL2, CCL5, CCL17, CCL22, and CXCL10 that are involved in the pathogenesis of psoriasis.Additionally, TWEAK can upregulate IL-19 expression in dermal fibroblasts that influence or maintain the clinical phenotypes of psoriasis. 3Fα has a primary role in the development of the psoriasis by adjusting the interaction between dendritic cells and antigen-specific T-cells, which stimulates T-cell responses.Furthermore, it increased Th17 responses, which plays an essential part in the psoriasis cytokine network by inducing IL-23 production from dendritic cells. 17 this study, serum TWEAK grades in candidates with psoriasis vulgaris were compared to control group, as well as their association with PASI score and therapy with NB-UVB phototherapy and MTX.
In the present work, there was a significant positive correlation between TWEAK and PASI score before treatment.
These findings agree with previous researches that found significant elevated levels of PASI in severe psoriasis compared to mild, moderate, and no disease. 18 contrast, other studies found that PASI associated inversely with TWEAK levels, and that candidates with TWEAK concentrated levels below the mean value had elevated PASI than those with TWEAK concentrations above the mean value. 19ter treatment, the percent change of PASI score significantly reduced in both treatment modalities.For NB-UVB group, the percent change of PASI score significantly reduced after treatment with NB-UVB about 60%.The results of the current research are in accordance with multiple studies in the literature. 20,21Concerning MTX, percent change was 90% in our results.This is in agreement to our findings, a non-randomized controlled trial done by Elango et al., clarified that >75% decrease from baseline PASI score in 75% of psoriasis candidates after MTX administration. 22 this trial TWEAK was found to be remarkably elevated in diseased persons than control candidates, these results were in agreement with previous reports found similar results. 2,3,19In contrast to our work, Myśliwiec et al., 9 found that there were no remarkable variations in the serum TWEAK levels in psoriatic patients compared with well-being control individuals.
Our study assessed the alterations in serum TWEAK levels following treatment with NB-UVB and MTX.A significant decrease in serum TWEAK levels was observed after treatment with both NB-UVB and MTX in patients with psoriasis.Post-treatment, the levels  of serum TWEAK exhibited no substantial disparity in comparison to the control group.
In contrast to our work, Myśliwiec et al., 9 found that TWEAK level in Psoriatic patients before treatment was similar to healthy.
Moreover, they found that TWEAK level after treatment was significantly higher after treatment.This can be explained by the various means of models in their research.[25] To our knowledge, this is the first work to investigate how MTX affects serum TWEAK levels and compare the effect with NB-UVB.
We found that there was a significant reduction in serum TWEAK level after treatment with MTX in psoriatic patients.However, the difference between the two modalities after treatment was nonsignificant.The mechanism by which MTX reduces serum TWEAK levels is conjectural at this point.

| CON CLUS ION
The study findings demonstrate a robust and direct association between the extent of psoriasis severity and the levels of TWEAK in the bloodstream.The levels of TWEAK were notably decreased during NB-UVB phototherapy and MTX therapy.Furthermore, there were significant correlations observed between serum TWEAK levels and PASI scores.These findings provide evidence for the potential involvement of TWEAK in the underlying mechanisms of psoriasis and lend support to the novel treatment approach of MTX.
Measurement of serum TWEAK levels can be utilized to assess the advancement of psoriasis and the impact of treatment.
3 in the association between Serum TWEAK levels in Psoriatic candidates Before and After NB-UVB with an error possibility of 0.05 and an 80% power on a two-tailed test, an estimated minimum sample size of 60 participants was needed; an estimated minimum sample size of 60 participants were required.All participated individuals were assigned to one of two collections based on randomized coded cards.So, the study included three groups: The first is control collection, which involved 20 normal well-being candidates, and the NB-UVB phototherapy group, which included 20 patients.The third group included 20 patients who were given MTX.Ethical Committee Approval: Aswan Institutional Review Board of the Medical College with registration number (498/12/20).Approval on Clinical Trials Registration: RCT approval numbers: NCT04811911.The research followed the guidelines set up by the Helsinki Declaration.All candidates gave written informed consent just before sharing in the research.All candidates were guaranteed confidentiality.

2. 5 |
phototherapy (311 nm) twice a week (on non-successive days) for 3 months.The machine was outfitted with eight Waldmann kind F 85/100W-01 narrowband UVB lamps (TL01).The radioactivity spectrum from these lamps scaled from 310 to 315 nm, with a maximum UV-um of 313 nm 100 L. UVB lamps of type TL01 were labeled with one red and one blue band.UVB lamps (TL01lamp) from (Waldman, Villingen-Schwenningen, Germany) had a physical radiation grade (strength) of 7-10 mW/cm 2 and a biological effect (erythematous) irradiance of 0.4-0.6 mW/cm 2 .
Blood sample (about 5 cc) was drawn from the antecubital vessel of each control and psoriatic candidate before and after MTX and NB-UVB phototherapy treatment.Samples were putted in serum separator tubes, and then centrifuged at 1000g for 15 min after being leaved to clot for 30 min at chamber temperature.Before analysis, serum samples were collected and kept at 20°C.Using commercially available enzyme-linked immunosorbent assay (ELISA) kits, TWEAK blood levels in healthy control persons and psoriatic patients were evaluated.(Usage of TWEAK ELISA Kit, Sino Gene Clon Biotech, Norcross, GA) (Catalog no: SG-10751) before and after treatment with NB-UVB phototherapy and MTX.
fied.Various proinflammatory cytokines such as TNFα, interleukin IL-1, IL-6, IL-17, IL-22, and IL-23, 14 as well as various adhesive molecules such as Intercellular Adhesion Molecule (ICAM)-I and Eselectin, 15 have been implicated.TWEAK may contribute to the etiology of psoriasis and may be correlated with the severity of the condition.TWEAK intensely overlaps with IL17A and TNFα in these processes.The upregulation and expression of CXC chemokines, as well as cytokines like IL-23 and TA B L E 2 PASI Score follow up after treatment. a