Secukinumab demonstrates high efficacy and a favourable safety profile in paediatric patients with severe chronic plaque psoriasis: 52-week results from a Phase 3 double-blind randomized, controlled trial.

BACKGROUND: Secukinumab has demonstrated sustained long-term efficacy with a favourable safety profile in various psoriatic disease manifestations in adults. OBJECTIVES: Here, the efficacy and safety of two secukinumab dosing regimens [low dose (LD) and high dose (HD)] in paediatric patients with severe chronic plaque psoriasis over one year are reported. METHODS: In this multicentre, double-blind study (NCT02471144), patients aged 6 to <18 years with severe chronic plaque psoriasis were stratified and randomized by weight (<25 kg, 25 to <50 kg, ≥50 kg) and age (6 to <12 years, 12 to <18 years) to receive low-dose (LD: 75/75/150 mg) or high-dose (HD: 75/150/300 mg) subcutaneous secukinumab or placebo or etanercept 0.8 mg/kg (up to a max of 50 mg). RESULTS: Overall, 162 patients were randomized to receive secukinumab LD (n = 40) or HD (n = 40), etanercept (n = 41) or placebo (n = 41). The co-primary objectives of the study were met with both secukinumab doses (LD and HD) showing superior efficacy compared to placebo (P < 0.0001) with respect to PASI 75 response (80.0%, 77.5% vs. 14.6%) and IGA mod 2011, 0 or 1 response (70%, 60% vs. 4.9%) at Week 12. Both secukinumab doses were superior to placebo (P < 0.0001) with respect to PASI 90 response at Week 12 (72.5%, 67.5% vs. 2.4%). The efficacy of both doses was sustained to Week 52 with secukinumab achieving higher responses vs. etanercept (PASI 75/90/100: LD, 87.5%/75.0%/40.0% and HD, 87.5%/80.0%/47.5.% vs. etanercept, 68.3%/51.2%/22.0% and IGA 0 or 1: LD, 72.5% and HD, 75.0% vs. etanercept, 56.1%). The safety profile of secukinumab was consistent with the adult Phase 3 studies, with no new safety signals identified. CONCLUSIONS: Both doses of secukinumab demonstrated high and sustained efficacy up to Week 52 with a favourable safety profile in paediatric patients with severe chronic plaque psoriasis.

Secukinumab treatment leads to normalization of quality of life and disease symptoms in psoriasis patients with or without prior systemic psoriasis therapy: the PROSE study results.

INTRODUCTION: Psoriatic disease is associated with considerable impairment of quality of life (QoL). The PROSE study (NCT02752776) investigated the impact of secukinumab treatment on patient-reported outcomes (PRO) in patients with moderate to severe psoriasis stratified by their treatment history. METHODS: PROSE was a prospective, non-randomised, multicentre study. Patients were categorized at baseline according to treatment history as naïve [naïve to any systemic therapy (N = 663)], conventional systemic [previously exposed to ≥1 conventional systemic (CS) therapy (N = 673)] and biologics [previously exposed to ≥1 biologic therapy (N = 324)]. QoL PROs, efficacy and safety of secukinumab 300 mg were assessed for a period of 52 weeks. RESULTS: The primary objective was met with 70.8% patients achieving a Dermatology Life Quality Index (DLQI) 0/1 response at Week 16 (naϊve, 74.7%; CS, 71.3%; biologic, 61.7%), with effects sustained up to Week 52. Mean Family DLQI (FDLQI) score decreased from 11.5 at baseline (naϊve, 11.3; CS, 11.4; biologic, 12.1) to 2.5 at Week 16 (naϊve, 2.5; CS, 2.3; biologic: 3.5). Substantial improvements in EuroQoL 5-Dimension Health Questionnaire, Numeric Rating Scale for pain, itching and scaling, Health Assessment Questionnaire-Disability Index, Treatment Satisfaction Questionnaire for Medication, and Patient Benefit Index were also observed at Week 16. The QoL gains were associated with substantial improvements in Psoriasis Area and Severity Index and Investigator Global Assessment mod 2011 0/1 response. No meaningful difference was observed in the efficacy or QoL improvements across patient subpopulations. All QoL and efficacy parameter improvements were sustained up to Week 52. Secukinumab treatment was well-tolerated, and no new safety signals were observed. CONCLUSION: Secukinumab treatment resulted in complete normalization of QoL in a substantial proportion of psoriasis patients, and their families, regardless of their prior treatment history.

Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein-coding and untranslated regions of the IL-17A gene: results from a multicentre study of four European psoriasis cohorts.

BACKGROUND: Genetic predictors for treatment response could optimize allocation of biological treatment in patients with psoriasis. There is minimal knowledge about pharmacogenetics of anti-IL-17 agents. OBJECTIVES: To assess whether genetic variants in the protein-coding region or untranslated regions of the IL-17A gene are associated with response to IL-17A inhibitors in patients with psoriasis. METHODS: This was a multicenter European cohort study investigating pharmacogenetics of IL-17A inhibitors in patients with psoriasis. Patients with plaque psoriasis treated with secukinumab or ixekizumab in daily practice were included. For all participants, the protein-coding region and untranslated regions of the IL-17A gene were analysed using Sanger sequencing. Identified genetic variants were tested for association with response to secukinumab/ixekizumab, measured as ∆PASI, after 12 weeks (primary outcome) and after 24 weeks (secondary outcome). Association was tested using a linear regression model with correction for baseline PASI as a fixed covariate and for biological naivety and body mass index as additional covariates. RESULTS: In total, 134 patients treated with secukinumab or ixekizumab were included. Genotyping of the cohort identified genetic variants present in untranslated regions and intronic DNA, but not in the protein-coding region of the IL-17A gene. Five genetic variants in non-coding DNA with a known or suspected functional effect on IL-17A expression were selected for association analyses: rs2275913, rs8193037, rs3819025, rs7747909 and rs3748067. After 12 weeks, 62% of patients achieved PASI75 and 39% achieved PASI90. At week 24, PASI75 and PASI90 response rates were 72% and 62%, respectively. No associations were found between the five genetic variants and ∆PASI, PASI75 or PASI90 after 12 and 24 weeks of anti-IL-17A treatment. CONCLUSIONS: Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein-coding and untranslated regions of the IL-17A gene. Pharmacogenetics of IL-17A inhibitors in the treatment of psoriasis requires further exploration.

The genetic basis for most patients with pustular skin disease remains elusive.

BACKGROUND: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). OBJECTIVES: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. METHODS: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. RESULTS: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. CONCLUSIONS: The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN.

Increased microRNA-323-3p in IL-22/IL-17-producing T cells and asthma: a role in the regulation of the TGF-ß pathway and IL-22 production.

BACKGROUND: IL-22- and IL-17-producing T cells have important roles in allergic diseases. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and modulate numerous biological processes. Little is known about the functions of miRNAs in IL-22/IL-17-producing T cells. MATERIAL AND METHODS: IL-22- and IL-17-positive T cells were sorted from human peripheral blood mononuclear cells (PBMCs) by intracellular staining and dual-secretion assay. miRNA expression profiles were detected with TaqMan array microfluidic cards. T cells were transfected with miRNA mimics. Gene expression was analyzed using RT-qPCR and/or enzyme-linked immunosorbent assay in T-cell subsets and PBMCs from patients with asthma and atopic dermatitis. RESULTS: The increased expression of miR-323-3p and noncoding RNA nc886 and reduced expression of miR-93, miR-181a, miR-26a, and miR-874 were detected in IL-22-producing T cells. The pathway analysis of the putative targets suggested that these differentially expressed miRNAs could impact the proliferation, differentiation, and effector functions of T cells. Further analyses showed the highest expression for miR-323-3p in IL-22- and IL-17-double-positive T cells and its capacity to suppress multiple genes from the transforming growth factor-ß pathway and the production of IL-22 in T cells. An increased expression of miR-323-3p in PBMCs from patients with asthma and reverse correlation between miR-323-3p levels and IL-22 production in PBMCs cultured in T-cell growth conditions was observed. CONCLUSIONS: Our data suggest that miR-323-3p acts in a negative feedback loop to control the production of IL-22 in IL-22/IL-17-producing T cells and might thus impact the T-cell responses in asthma.

Interleukin-10 family cytokines pathway: genetic variants and psoriasis.

BACKGROUND: Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20 and IL-24 have been implicated in autoimmune diseases and we have previously reported that genetic variants in the IL10 gene cluster were associated with psoriasis. OBJECTIVES: To analyse the relationship between genetic polymorphisms in the IL10 gene cluster and psoriasis. This study also explores whether there are gene-gene interactions among these genetic polymorphisms. METHODS: A total of 377 patients with psoriasis and 403 matched healthy controls were enrolled to carry out a case-control study for 48 single-nucleotide polymorphisms (SNPs) of the IL10 gene cluster. Genotyping for the SNPs was conducted on the Applied Biosystems 3730 DNA Analyzer using SNPlex® technology. Generalized multifactor dimensionality reduction (GMDR) analysis was applied to discover a likely gene-gene interaction model among the SNPs. RESULTS: The results showed that the allele distributions of IL10 gene cluster SNPs are significantly different between the case and control groups. Carriers of the IL10 T allele (rs1554286) and the IL20 T allele (rs1400986) conferred protection from psoriasis [odds ratio (OR) = 0·63, corrected P-value (Pc) = 0·007; OR = 0·62, Pc = 0·038, respectively]. GMDR analysis displayed a significant gene-gene interaction between IL10 (rs1554286) and IL20 (rs1518108) variants. The strongest protective effect was found with the block 1 haplotype ACATA in the IL10 gene (Pc = 0·004). CONCLUSIONS: This study presents a novel finding that the combination of the two SNPs, IL10 (rs1554286) and IL20 (rs1518108), is associated with a reduced risk of psoriasis. Our results indicate that genetic variants of the immunomodulatory IL10 and IL20 genes may offer a protective effect in Europeans from Russia. Independent studies are required to verify the results and find a possible functional explanation.

The EGALITY study: a confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis.

BACKGROUND: GP2015 is a proposed etanercept biosimilar. OBJECTIVES: To demonstrate equivalent efficacy, and comparable safety and immunogenicity of GP2015 and the etanercept originator (ETN, Enbrel® ) in patients with moderate-to-severe chronic plaque-type psoriasis. METHODS: In total, 531 eligible patients were randomized 1 : 1 to self-administer GP2015 or ETN twice weekly subcutaneously. Patients with ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 12 were rerandomized to continue the same treatment on a once-weekly dosing schedule or to undergo a sequence of three treatment switches between GP2015 and ETN until week 30. Thereafter, patients continued treatment with the product they had been assigned to last, up to week 52. RESULTS: The difference in PASI 75 (75% improvement from baseline PASI score) response rates at week 12 between GP2015 and ETN (primary end point) was -2·3%. The 95% confidence interval (-9·85 to 5·30) was well contained within the prespecified margin range of -18 to 18. The incidence of treatment-emergent adverse events up to week 52 was comparable between continued GP2015 (59·8%) and ETN (57·3%); switching treatments revealed comparable safety profiles. Antidrug antibodies, all non-neutralizing, were limited to five patients on ETN during treatment period 1, and one patient in the switched ETN group, who had been treated with GP2015 for 12 weeks at the time of the finding. CONCLUSIONS: The EGALITY study demonstrated equivalent efficacy and comparable safety and immunogenicity of GP2015 and ETN. The study results provide the final clinical confirmation of biosimilarity and contribute to the totality of the evidence proposing that GP2015 is an etanercept biosimilar.

European consensus statement on phenotypes of pustular psoriasis.

Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co-incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [Saurat Dermatologie 2016, Rook's Dermatology 2016, Fitzpatrick's 2012 and Braun-Falco 2012], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials. The European Rare and Severe Psoriasis Expert Network (ERASPEN) was founded to define consensus criteria for diagnosis, deeply phenotype large groups of PP patients, analyse the genetics and pathophysiology and prepare for prospective clinical trials. This work reviews historical aspects of these conditions, new genetic findings and presents our initial considerations on the phenotypes of PP and a consensus classification of clinical phenotypes that will be used as a baseline for further, prospective studies of PP. Generalized pustular psoriasis (GPP) is defined as primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques). GPP can occur with or without systemic inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (>3 months) condition. Acrodermatitis continua of Hallopeau (ACH) is characterized by primary, persistent (>3 months), sterile, macroscopically visible pustules affecting the nail apparatus. Palmoplantar pustulosis (PPP) has primary, persistent (>3 months), sterile, macroscopically visible pustules on palms and/or soles and can occur with or without PV.

Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE).

BACKGROUND: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, demonstrated efficacy and safety in moderate-to-severe plaque psoriasis when administered via subcutaneous injection. Self-administration by pre-filled syringe (PFS) can offer patients clinical benefits of a drug, with increased convenience. OBJECTIVES: To assess efficacy, safety and usability of secukinumab administration via PFS in subjects with moderate-to-severe plaque psoriasis. MATERIALS AND METHODS: Subjects in this phase 3 trial were randomized 1 : 1 : 1 to secukinumab 300 or 150 mg or matching placebo. Results to week 12 are presented here. Each treatment was delivered using a PFS once weekly to week 4, and again at week 8. Co-primary endpoints were secukinumab superiority over placebo for week 12 PASI 75 (≥ 75% reduction in Psoriasis Area and Severity Index) and IGA mod 2011 (2011 modified Investigator's Global Assessment) 0/1 response rates. Secondary endpoints included PFS usability, determined by observer rating of successful, hazard-free self-injection and subject rating of acceptability by the Self-Injection Assessment Questionnaire (SIAQ). RESULTS: Co-primary endpoints were met, with demonstration of superiority for each secukinumab dose vs. placebo at week 12 (PASI 75: 75·9%, 69·5% and 0% for secukinumab 300 mg, 150 mg and placebo; IGA mod 2011 0/1: 69·0%, 52·5% and 0%, respectively; P < 0·0001 for all comparisons vs. placebo). PFS usability was high: 100% of subjects successfully self-administered treatment at week 1, and subjects reported high SIAQ-assessed acceptability of the PFS throughout the trial. No new/unexpected safety signals were observed. CONCLUSIONS: Secukinumab administration by PFS was effective, with an acceptable safety profile and high usability. The PFS provides a reliable, convenient form of secukinumab administration in subjects with moderate-to-severe plaque psoriasis.

Differences between familial and sporadic cases of vitiligo.

BACKGROUND: Most cases of vitiligo are sporadic, but about 10-36% of the patients have positive family history. OBJECTIVE: The aim of our study was to describe differences between familial and sporadic cases of vitiligo. METHODS: A total of 186 adult vitiligo patients were examined, in 173 of whom the level of thyroid peroxidase antibodies, gastric parietal cell antibodies (PCA), antinuclear antibodies (ANA), anti-adrenal cortex antibodies and rheumatoid factor in blood was measured. All patients were divided in two groups: the cases with positive family history of vitiligo (51) and the sporadic cases (135). RESULTS: The risk of onset of the disease up to 20 years of age was higher in the familial group (P=0.008). Patients in familial group showed more widespread depigmentation compared with sporadic cases [body surface area (BSA) over 10%: P=0.004; BSA over 50%: P=0.001]. In familial group, patients had darker skin phototype (P=0.045) and the disease had started more often as a vulgar vitiligo (P=0.008). In sporadic vitiligo group, female gender was a risk factor for more widespread depigmentation (BSA over 10%, P=0.001). Extensive depigmentation was associated with reported triggering factors and mucosal involvement in both groups and with leukotrichia only in familial group. Widespread depigmentation related to the risk of presence of autoantibodies (P=0.03) in sporadic cases of vitiligo (especially of PCA: P=0.04 and ANA: P=0.0002). CONCLUSIONS: In this study, we demonstrated first time that patients with familial vitiligo have a higher risk for vulgar type at the beginning of the disease and female gender increases the risk for more extensive depigmentation in sporadic cases.

Association analysis of IL20RA and IL20RB genes in psoriasis.

The interleukin-20-receptor I complex (IL-20-RI) is composed of two chains, IL20RA and IL20RB. Its ligands are the three members of the IL19 subfamily of cytokines, IL-19, IL-20 and IL-24. These cytokines are important in the manifestation of psoriatic lesions and, recently, an association of polymorphisms of IL20 with psoriasis has been described. In the present study we tested the hypotheses that genetic variations of the IL-20-RI influence susceptibility to psoriasis and investigated single nucleotide polymorphisms (SNPs) in the IL20RA and IL20RB genes in psoriasis patients (n=254) and healthy controls (n=224). We found no association of any of the investigated SNPs with the disease. Analysis of pairwise linkage disequilibrium (LD) across studied markers revealed a strong level of LD between SNPs within the IL20RA gene and SNPs within the IL20RB gene, and, for both genes six common haplotypes were identified with an estimated frequency >or=1%. Haplotype analyses suggested that the IL20RA haplotype CCG (rs1184860, rs1167846, rs1167849) is significantly associated with psoriasis (OR 3.14, 95% CI 1.61-6.14), whereas the TTG haplotype had a protective effect (OR 0.20, 95% CI 0.07-0.55). The risk haplotype defining SNPs 1167846 and 1184860 were found to modify paired box 5 and homeobox A9 sites, respectively, two transcription factors related to the differentiation of immune cells. Further studies are needed to confirm the genetic association and to investigate the functional relevance of IL20RA haplotypes in psoriasis.

Gene expression study of IL10 family genes in vitiligo skin biopsies, peripheral blood mononuclear cells and sera.

BACKGROUND: Vitiligo is a pigmentation disorder, the cause of which is complex and not yet fully understood. There is a significant change of epidermal cytokines in involved skin of patients with vitiligo compared with uninvolved skin and skin of healthy controls, thus suggesting a possible involvement of cytokines in the pathogenesis of vitiligo. OBJECTIVES: To evaluate potential roles of IL10 family cytokines (IL10, IL19, IL20, IL22 and IL24) in vitiligo. Along with the selected cytokines, we investigated subunits of the receptors (IL10RA, IL10RB, IL20RA and IL22RA1) which are involved in the signalling pathway of the cytokines. METHODS: Quantitative real-time polymerase chain reaction was used to detect mRNA expression levels in samples extracted from skin biopsies and peripheral blood mononuclear cells and an enzyme-linked immunosorbent assay was used to measure protein concentrations in serum from patients with vitiligo and healthy controls. RESULTS: IL22 is significantly associated with vitiligo, especially with the active stage of vitiligo, as shown by results of mRNA expression and supported by results of protein level in sera. IL22 may provoke inflammation which leads to destruction of melanocytes. CONCLUSIONS: The actual role of IL22 during pathogenesis of vitiligo remains to be better characterized. Signal transductions of other investigated cytokines seem to be regulated on the expression level of their receptor complex subunits.

Whole Transcriptome Analysis (RNA Sequencing) of Peripheral Blood Mononuclear Cells of Vitiligo Patients.

Vitiligo is an idiopathic disorder characterized by depigmented patches on the skin due to a loss of melanocytes. The cause of melanocyte destruction is not fully understood. The aim of this study was to detect the potential pathways involved in the vitiligo pathogenesis to further understand the causes and entity of vitiligo. For that the transcriptome of peripheral blood mononuclear cells of 4 vitiligo patients and 4 control subjects was analyzed using the SOLiD System platform and whole transcriptome RNA sequencing application. Altogether 2,470 genes were expressed differently and GRID2IP showed the highest deviation in patients compared to controls. Using functional analysis, altogether 993 associations between the gene groups and diseases were found. The analysis revealed associations between vitiligo and diseases such as lichen planus, limb-girdle muscular dystrophy type 2B, and facioscapulohumeral muscular dystrophy. Additionally, the gene groups with an altered expression pattern are participating in processes such as cell death, survival and signaling, inflammation, and oxidative stress. In conclusion, vitiligo is rather a systemic than a local skin disease; the findings from an enormous amount of RNA sequencing data support the previous findings about vitiligo and should be further analyzed.

Association analysis of IL19, IL20 and IL24 genes in palmoplantar pustulosis.

BACKGROUND: Interleukin (IL) 19, IL-20 and IL-24 belong to the IL-10 cytokine family and have been identified to play a role in the regulation of epidermal functions and in inflammation. The genes encoding IL-19, IL-20 and IL-24 are located within a gene cluster on chromosome 1q31-32 and carry frequent genetic variations. OBJECTIVES: This study investigated whether variations in the IL19, IL20 and IL24 genes that have previously been associated with plaque-type psoriasis may also play a role in palmoplantar pustulosis (PPP). PATIENTS: Fifteen polymorphisms were analysed in 43 patients with PPP and in 149 healthy control subjects. RESULTS: The rare allele of IL20 1380 A-->G (rs2981573) was less frequent in patients with PPP compared with healthy controls (OR 1 x 95, 95% CI 1 x 00-3 x 79). Haplotype analyses of IL19 and IL20 suggested an increased risk for PPP associated with IL20 haplotype GAA (OR 2 x 39, 95% CI 1 x 17-4 x 86) and a reduced risk for PPP associated both with IL19 haplotype GATGATA (OR 0 x 41, 95% CI 0 x 16-1 x 05) and IL20 haplotype GGG (OR 0 x 48, 95% CI 0 x 23-0 x 98). Extended haplotype analysis revealed an association of IL19/IL20 haplotype GACACCGGAA with a higher risk for PPP (OR 2 x 31, 95% CI 1 x 05-5 x 10) and of IL20/IL24 haplotype CAAAC with a reduced risk for PPP (OR 0 x 12, 95% CI 0 x 02-0 x 82). CONCLUSIONS: This exploratory study supports the hypothesis that variations of genes of the IL-19 subfamily of cytokines influence susceptibility to PPP. However, due to the limited size of the study samples, this current concept should be considered as preliminary and the results need to be confirmed in future independent studies.

Possible relations between the polymorphisms of the cytokines IL-19, IL-20 and IL-24 and plaque-type psoriasis.

The aim of present study was to elucidate the role of the interleukin (IL)-24 gene in predicting risk for plaque-type psoriasis and to describe the linkage disequilibrium (LD) pattern emerging from the genes of IL-19, IL-20 and IL-24. Genes encoding IL-19, IL-20 and IL-24 locate in the region q32 of chromosome 1. The association between the single-nucleotide polymorphisms (SNPs) or haplotypes of the IL-24 gene and the susceptibility of psoriasis was not found. However, a significant protective effect of the combined haplotype CAAAC of IL-20 and IL-24 genes against plaque-type psoriasis was established (OR 0.154). Protective effect against psoriasis was also observed with haplotype TGGGT (OR 0.591) and haplotype CGAGT (OR 0.457). Performing a comprehensive analysis using the data regarding SNPs of IL-24 gene together with the previously published data regarding IL-19 and IL-20 SNPs, we identified two haplotype blocks within the region q32 of chromosome 1. The main result of the present study is that while the IL-19/IL-20 extended haplotype CACCGGAA is a significant susceptibility factor for psoriasis (previous study), IL-20/IL-24 haplotypes CAAAC, TGGGT and CGAGT have a significant protective effect. Nevertheless, family-based studies are required to confirm the impact of IL-19, IL-20 and IL-24 genes in the genetic predisposition for psoriasis.

IL-10 promoter polymorphisms influence disease severity and course in psoriasis.

We analyzed three single-nucleotide polymorphisms (SNPs) at the interleukin-10 (IL-10) 5' flanking region (positions -1082 A/G, -819 C/T and -592 C/A) in an association case-control study involving 248 patients with plaque type of psoriasis and 148 unrelated healthy volunteers using ARMS (amplification refractory mutation system)-PCR (Polymerase Chain Reaction) method. No difference was found in the frequencies of haplotype distribution between healthy controls and patients with psoriasis. There were no significant differences in the IL-10 haplotype distribution depending on the age of onset and family history of psoriasis. However, the results of our study demonstrate that the IL-10 haplotype has a role in determining severity and course of plaque type of psoriasis. IL-10 ACC haplotype (P<0.05) is likely to be defining lower activity of disease (PASI

Combined haplotype analysis of the interleukin-19 and -20 genes: relationship to plaque-type psoriasis.

There is increasing evidence to suggest that the newly discovered cytokines interleukin (IL)-19 and -20 have a role in the function of epidermis and in psoriasis. The genes encoding these cytokines locate into the genomic IL-10 region on human chromosome 1. The aim of the present study was to analyze whether single-nucleotide polymorphisms (SNPs) in these genes have an impact on the susceptibility for psoriasis. From pairwise linkage disequilibrium (LD) matrix of the IL-19 and -20 gene polymorphisms, what reflects the nonrandom association of alleles at these markers, it was apparent that IL-19 and -20 genes form one block of LD. We found that the HT3 CACCGGAA haplotype of the IL-19 and -20 genes was associated with an increased risk of psoriasis, reflecting its role in determining susceptibility to plaque-type psoriasis. Although association analysis of the IL-19 gene indicated that minor alleles of the IL-19 gene SNPs (rs2243188, rs2243169 and rs2243158) revealed protective effect to psoriasis and haplotype analysis of the IL-19 gene proved significant protective effect of the TGATA haplotype in case of late-onset disease, combined haplotype analysis of the IL-19 and -20 genes demonstrated that protective effect of the IL-19 gene is secondary to the susceptibility effect of the IL-20 gene.

Polymorphisms in the interleukin-20 gene: relationships to plaque-type psoriasis.

We analyzed the frequency of single-nucleotide polymorphisms (SNPs) at positions -1053 (rs 2981572), 1380 (rs 2981573), 1462 (rs 2232360), and 3978 (rs 1518108) of the human interleukin-20 (IL-20) gene by tetraprimer ARMS-PCR method. A significant association between patients with psoriasis and the G allele at position -1053 (P<0.05) was established. The pairwise linkage disequilibrium (LD) matrix showed that the nearly complete LD was present within the polymorphisms at positions -1053, 1380, and 1462 of the IL-20 gene. We found that patients with plaque psoriasis had a higher frequency of the HT3 GAA haplotype (P<0.01, OR 2.341, 95% CI: 1.346-4.074) compared to the control group. Likewise, the HT3 GAA haplotype was associated with an increased risk of early-onset psoriasis (P<0.01, OR 2.305, 95% CI: 1.285-4.132), late onset of disease (P<0.01, OR 2.542, 95% CI: 1.266-5.102), familial psoriasis (P<0.02, OR 2.220, 95% CI: 1.249-3.945), and sporadic disease (P<0.01, OR 2.523, 95% CI: 1.390-4.580). Our data indicate that IL-20 gene polymorphisms should have a role in determining susceptibility to plaque-type psoriasis. The possible role of the studied SNPs in the regulation of the expression of IL-20 is unknown yet and needs further studies.