## 2 Materials and Methods  
### Study Design and Population  
A longitudinal prospective observational study was conducted with 5 mm punch biopsy samples from skin with psoriasis. The samples were collected before treatment initiation according to the washing periods established in the exclusion criteria. Fresh tissue samples were cryopreserved in liquid nitrogen immediately after being obtained. To study the primary objective, the samples from 4 different groups of patients, all of them older than 18 years, were included according to the following inclusion criteria (Figure 1A):  
* Group 1. Moderate-severe psoriasis Vulgaris: with PASI > 10 and/or BSA > 10%. * Group 2. Predominant scalp psoriasis. The patients with a scalp involvement greater than 50%. The presence of psoriasis plaques outside the scalp is restricted up to a maximum of 5% of the body surface. * Group 3. Hyperkeratotic palmoplantar psoriasis. The patients with plaque psoriasis and predominant hyperkeratotic palmar and/or plantar lesions. The presence of psoriasis plaques outside the palms and soles is restricted up to a maximum of 5% of the body surface. * Group 4. PPP. The patients with persistent (>3 months) sterile macroscopically visible pushular palmar and/or plantar lesions, with or without psoriasis Vulgaris. The samples were analyzed in a methylation microarray. Thus, the patients were subjected to strict exclusion criteria to avoid potential bias that could affect DNA methylation. Likewise, the patients were excluded according to the following exclusion criteria: (1) pregnant or lactating women, (2) patients with malignant disease diagnosed in the previous 5 years except for non-melanoma skin cancer, (3) patients infected with human immunodeficiency virus (HIV) hepatitis B virus (HBV) and hepatitis C virus (HCV), or suffering from serious active infectious diseases, (4) patients treated with non-biological systemic treatments (methotrexate, retinoids, cyclosporine or phototherapy) 1 month before sample collection, (5) patients treated with biological drugs in the 3 months before sample collection, (6) patients treated with topical steroids in the 2 weeks before sample collection. To study the secondary objective, palmoplantar skin biopsies were taken from 6 adult patients with inflammatory diseases other than psoriasis who developed de novo PPP while being treated with TNF-blocking drugs (Figure 1A). The protocol and informed consent followed the principles outlined in the Declaration of Helsinki for all human experimental investigations and complied with Spanish legislation on biomedical and clinical research. The protocol and informed consent were approved by the Ethics Committee for Clinical Research of Hospital Universitario de la Fe (Valencia, Spain). Henceforth, sample processing and analysis were the same for the study of both objectives. Informed consent was obtained from the participants involved. Figure 1: Workflow of the analysis performed in this study. (**A**) Summary of the different comparisons that were performed. Squares show the different subgroups that were used for the analysis: Blue (a)  
Scalp and non-scalp psoriasis; Green (b) Scalp, non-scalp, and hyperkeratotic palmoplantar plaques; Orange (c) Idiopathic psoriasis including scalp, non-scalp psoriasis, hyperkeratotic palmoplantar plaques, and PPP; Red (d) Anti-TNF-induced psoriasisiform PPP. Circles show L skin. Arrows represent comparisons performed between the different types of psoriasis. Dashed arrows represent the comparison between lesional skin of idiopathic psoriasis and anti-TNF-induced psoriasisiform PPP. (**B**) Bioinformatic pipeline used to obtain CNVs from raw methylation data. It comprises different stages: (1) Bins extraction from methylation raw data with the R package conounce; (2) Statistical analysis: Normalization against control samples (minfiData); (3) T-test of the intensity levels of the bins from the groups compared; (4) Bonferroni correction; (5) Selection of the significant CNVs; (6) Annotation and identification of genes located on CNVs.