Bath-psoralen plus UVA therapy changes inflammatory proteomic signatures for systemic effects beyond the skin

To the Editor, Although excess sun exposure has deleterious effects, some exposure to UV radiation can be beneficial, and UV-based therapies are safe and effective treatments for many dermatologic conditions [[1]Yones S.S. Palmer R.A. Garibaldinos T.T. Hawk J.L. Randomized double-blind trial of the treatment of chronic plaque psoriasis: efficacy of psoralen-UV-A therapy vs narrowband UV-B therapy.Arch. Dermatol. 2006; 142: 836-842Crossref PubMed Scopus (114) Google Scholar]. Psoriasis is a cutaneous and systemic chronic inflammatory disease closely associated with multiple comorbidities, including cardiovascular disease, diabetes, and metabolic syndrome. Boehncke et al. [[2]Boehncke W.H. Boehncke S. Tobin A.M. Kirby B. The 'psoriatic march': a concept of how severe psoriasis may drive cardiovascular comorbidity.Exp. Dermatol. 2011; 20: 303-307Crossref PubMed Scopus (415) Google Scholar] conceptualized the "psoriatic march", describing a causal link between psoriasis, obesity, and metabolic syndrome. Skin and joint inflammation in psoriatic patients contributes to systemic inflammation via peripheral blood circulation, which is further promoted by obesity-associated adipokines and leads to insulin resistance, the main pathophysiology underlying metabolic syndrome [[2]Boehncke W.H. Boehncke S. Tobin A.M. Kirby B. The 'psoriatic march': a concept of how severe psoriasis may drive cardiovascular comorbidity.Exp. Dermatol. 2011; 20: 303-307Crossref PubMed Scopus (415) Google Scholar]. These inflammatory cascades trigger endothelial cell dysfunction, potentially leading to atherosclerosis, myocardial infarction, and stroke. Psoriasis is an independent risk factor for cardiovascular disease and mortality, compared with mild psoriasis, severe psoriasis is associated with an increased risk of cardiovascular mortality [[3]Armstrong E.J. Harskamp C.T. Armstrong A.W. Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies.J. Am. Heart Assoc. 2013; 2e000062Crossref Scopus (334) Google Scholar] Therefore, tight control of psoriatic skin lesions, e.g., PASI90 or PASI100, might reduce future comorbidities. Here we focused on the systemic effects of bathwater delivery of PUVA (bath-PUVA) therapy and comprehensively analyzed serum proteins to clarify changes in mainly inflammatory- and cardiovascular system-associated protein levels before and after therapy. The study included 20 patients with psoriasis for whom bath-PUVA therapy was first initiated between 2007 and 2011. These patients comprised the same cohort reported previously [[4]Kanayama Y. Torii K. Ikumi K. Morita A. Bath psoralen plus UVA therapy suppresses keratinocyte-derived chemokines in pathogenetically relevant cells.JID Innov. 2021; 1100027Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar] All experiments with human samples complied with the ethical principles of the Declaration of Helsinki and were approved by the Institutional Review Board of Nagoya City University (approval numbers 312, 325-4, and 325-5). Levels of 92 inflammatory- and cardiovascular system-associated proteins (Olink Target 96 Cardiovascular II, Olink Proteomics, Uppsala, Sweden) were assessed by high-throughput proteomic assays of serum. Of the 20 patients, serum samples from 19 met the assay performance quality requirements (the data from Case 12 was excluded) (Supplementary Table S1). Supplementary Table S2 shows the baseline characteristics of these 19 patients (14 men, 5 women; age 27–75 [mean: 52.4] years; disease duration 0.160–30 [median: 9.0] years). Approximately 90 % of patients achieved PASI75, 50 % achieved PASI90, and 5 % achieved PASI100 (Supplementary Table S3). First, to investigate whether the severity of psoriatic skin influences the blood marker levels, we correlated serum proteins with the PASI before bath-PUVA therapy. Nine proteins positively correlated with pre-treatment PASI scores (r > 0.4; Fig. 1). The correlation between CCL17 and pre-treatment PASI was described previously [[4]Kanayama Y. Torii K. Ikumi K. Morita A. Bath psoralen plus UVA therapy suppresses keratinocyte-derived chemokines in pathogenetically relevant cells.JID Innov. 2021; 1100027Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Eight of these proteins could serve as new biomarkers, as we found no previous reports of these proteins in blood samples of psoriasis patients; 6 of these proteins (not MARCO and CA5A) were previously reported to be associated with atherosclerosis and cardiovascular disease (supplementary Table S4). THBS2 correlated highly with the pre-treatment PASI. In a multiple linear regression analysis, the levels of THBS-2 were independently and significantly associated with a history of atrial fibrillation, homeostatic model assessment for insulin resistance, high-sensitivity C-reactive protein, and N-terminal prohormone brain natriuretic peptide in a general population [[5]Morikawa N. Adachi H. Enomoto M. Fukami A. Kumagai E. Nakamura S. et al.Thrombospondin-2 as a potential risk factor in a general population.Int. Heart J. 2019; 60: 310-317Crossref PubMed Scopus (12) Google Scholar] THBS2 was also recently reported to be a biomarker for nonalcoholic steatohepatitis (NASH) [[6]Kozumi K. Kodama T. Murai H. Sakane S. Govaere O. Cockell S. et al.Transcriptomics identify thrombospondin-2 as a biomarker for NASH and advanced liver fibrosis.Hepatology. 2021; 74: 2452-2466Crossref PubMed Scopus (56) Google Scholar]. Serum THBS-2 levels are significantly higher in patients with NASH than in those with nonalcoholic fatty liver (NAFL), and increase in parallel to the fibrosis stage [[6]Kozumi K. Kodama T. Murai H. Sakane S. Govaere O. Cockell S. et al.Transcriptomics identify thrombospondin-2 as a biomarker for NASH and advanced liver fibrosis.Hepatology. 2021; 74: 2452-2466Crossref PubMed Scopus (56) Google Scholar]. THBS2 might be a significant predictor of the severity of heart disease and liver fibrosis as complications of psoriasis. Next, we detected differentially expressed proteins before and after bath-PUVA therapy. Compared with before treatment levels, median after treatment levels of 88 of the 92 proteins were decreased. We identified 38 proteins with significantly decreased levels (adjusted p-value < 0.05); Fig. 2a; supplementary Table S5). Serum CCL17 and SPON2 levels correlated with pre-treatment PASI, and decreased after treatment. Serum CCL17 is independently associated with coronary artery disease. Furthermore, serum CCL17 levels positively associate with the type and severity of coronary artery disease [[7]Ye Y. Yang X. Zhao X. Chen L. Xie H. Zeng Y. et al.Serum chemokine CCL17/thymus activation and regulated chemokine is correlated with coronary artery diseases.Atherosclerosis. 2015; 238: 365-369Abstract Full Text Full Text PDF PubMed Google Scholar]. In psoriasis or atherosclerosis, detailed mechanisms of SPON2 are not yet clear. We also performed functional enrichment analysis in the webtool Metascape for gene sets coding these 38 proteins [[8]Zhou Y. Zhou B. Pache L. Chang M. Khodabakhshi A.H. Tanaseichuk O. et al.Metascape provides a biologist-oriented resource for the analysis of systems-level datasets.Nat. Commun. 2019; 101523Google Scholar]. The “cytokine-cytokine receptor interaction”, “inflammatory response”, and “lipid and atherosclerosis” processes were among the top 10 processes (Fig. 2b; supplementary Table S6). Of the 38 proteins, CD40LG, CXCL1, IL-6, IL-18, SOD2, NEMO, and TNFRSF10A are involved in "lipid and atherosclerosis" processes (supplementary Table S7). CXCL1, IL-6, and IL-18 are chemo/cytokines involved in disease progression in both psoriasis and atherosclerosis. A meta-analyses showed that a 1-standard deviation higher baseline level for each IL-6, IL-18, and TNF-α associated with a 10–25 % higher risk of non-fatal myocardial infarction or death due to CHD in initially healthy people [[9]Kaptoge S. Seshasai S.R. Gao P. Freitag D.F. Butterworth A.S. Borglykke A. et al.Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis.Eur. Heart J. 2014; 35: 578-589Crossref PubMed Scopus (451) Google Scholar] IL-6 and IL-18 are secreted by keratinocytes and immune cells in psoriasis. UVA irradiation may suppress the secretion of these proteins in psoriasis, thereby reducing the progression of plaque formation by vascular endothelial cells, vascular smooth muscle cells, and immune cells. Serum protein levels associated with the cardiovascular risk in psoriasis patients decreased by ustekinumab [[10]Koschitzky M. Navrazhina K. Garshick M.S. Gonzalez J. Han J. Garcet S. et al.Ustekinumab reduces serum protein levels associated with cardiovascular risk in psoriasis vulgaris.Exp. Dermatol. 2022; https://doi.org/10.1111/exd.14582Crossref PubMed Scopus (4) Google Scholar] Following treatment of psoriasis skin lesions with ustekinumab for 12 weeks, 43 of 273 proteins were downregulated in an Olink Target 96 Cardiovascular II, Cardiovascular III, and inflammation panel (Olink Proteomics, Uppsala, Sweden). Compared with our results, 4 proteins (CCL17, IL-6, BMP-6, ADM) were common, suggesting that decreasing the serum levels of these proteins might contribute to improving psoriasis, whereas differences in the sets of reduced markers between bath-PUVA therapy and ustekinumab might be due to their different mechanisms. In conclusion, bath-PUVA therapy might have systemic effects beyond the skin to improve systemic inflammation and cardiovascular risk associated with psoriasis. This work was funded by a Grant-in-Aid for Scientific Research B 20H03703 (AM) from the Japan Society for the Promotion of Science. and AMED under Grant Number JP22km0405217.