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Summary: Background: Methotrexate (MTX) is an efficacious treatment for psoriasis; however, its widespread application is limited by its unpredictable efficacy. Objectives: To investigate the association of clinical factors and variants of psoriasis susceptibility genes with clinical responses to MTX in a prospective cohort. Methods: A total of 221 patients with psoriasis were recruited. Patients who achieved Psoriasis Area and Severity Index (PASI) improvement ≥ 75% at week 12 were defined as responders, whereas those with PASI improvement < 50% were defined as nonresponders. In 90 screening patients, genetic variants for 18 single‐nucleotide polymorphisms in 14 susceptibility genes, and HLA‐Cw6 status were initially compared for responders and nonresponders. Statistically significant associations in genetic variants were verified in all 221 patients. Results: Overall, 49% and 45% of patients achieved PASI 75 improvement during screening and verification stages, respectively. Concomitant arthritis with psoriasis and high body mass index (BMI) negatively affect the efficacy of MTX. TT genotype of rs10036748 in TNIP1 was significantly associated with PASI 75 response at week 12 (54% and 37%, P < 0·05). A significantly higher PASI 90 response was observed in patients with TT genotype of rs10036748 (27% vs. 12%, P < 0·01) and TC/TT genotype of rs4112788 in LCE3D (25% vs. 13%, P < 0·05) at week 12 compared with those who had other genotypes. After adjustment for all confounding factors, only BMI (P < 0·05), arthritis (P < 0·05) and genotype of rs10036748 (P < 0·05) were significantly associated with clinical responses to MTX. Conclusions: Patients with psoriasis with TT genotype of rs10036748 in TNIP1, with lower BMI, without arthritis will achieve a better response to MTX. What's already known about this topic? Methotrexate is the first‐line treatment for moderate‐to‐severe psoriasis. However, there is significant heterogeneity in individual responses to methotrexate.Patients with psoriasis who are positive for HLA‐Cw6 show improved response to methotrexate treatment. What does this study add? Concomitant psoriasis and high body mass index negatively affect the efficacy of methotrexate.TT genotype of rs10036748 in TNIP1 was significantly associated with better responses to methotrexate. What is the translational message? Patients with psoriasis with TT genotype of rs10036748 in TNIP1 will demonstrate a better response to methotrexate.Treatment with methotrexate can be recommended particularly for those patients with psoriasis who have a low body mass index and do not have arthritis. Linked Comment: Cheng. Br J Dermatol 2019; 181:660–661. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

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Summary: Psoriasis is a persistent disease that causes inflammation throughout the body and affects approximately 1% to 3% of the world population. It generally appears as red scaly patches and papules over several areas of the skin. Methotrexate is an effective medication for the treatment of psoriasis; however, it is not widely used because its efficacy is unpredictable. This study aimed to determine whether clinical factors of psoriasis and the genes that make people more susceptible to it may affect the effectiveness of methotrexate. The authors identified 221 Chinese patients with psoriasis who were treated with methotrexate for 12 weeks. The patients were divided into the responder and non‐responder groups, based on whether their psoriasis improved (responded) after the 12‐weeks treatment. The responder group comprised patients with more than 75% improvement while the non‐responder group comprised those with less than 50% improvement in psoriasis. Associations between 18 common variations of 14 genes that make people susceptible to psoriasis (LCE3D, IL12B, NFKB1A, TNIP1, ERAP1, ZNF683, MTHFR, AIM2, PTTG1, GJB2, SYNE2, IKZF3, SERPINB8, ZNF816A) and the HLA‐Cw6 status were analysed, based on their response to methotrexate. The differences between the clinical factors of methotrexate responders and non‐responders were compared. Body mass index, arthritis, and rs10036748 genotype were significantly associated with the patients' response to methotrexate. The authors concluded that patients with psoriasis and the TT genotype of rs10036748 on the TNIP1 gene, those with lower body mass indices, and those without arthritis will respond better to methotrexate. Linked Article: Yan et al. Br J Dermatol 2019; 181:778–785 [ABSTRACT FROM AUTHOR]