Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2024;14(1):e2024041 1 The Causal Association Between Medication Intake and Increased Risk of Psoriasis Zhichen Li1 , Haobin Zhou2 , Chuxian Hu3, Zechao Lu4, Zechu Lu1, Huayao Zhang5 1 The Second Clinical College of Guangzhou Medical University, Guangzhou, Guangdong, China 2 The First Clinical College of Guangzhou Medical University, Guangzhou, Guangdong, China 3 The Sixth Clinical Medical School of Guangzhou Medical University, Guangzhou, Guangdong, China 4 Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China 5 Department of Breast Surgery, Shaoguan Maternal and Child Health Hospital, Shaoguan, Guangdong, China Key words: psoriasis, medicine intake, Mendelian randomization, risk factors Citation: Li Z, Zhou H, Hu C, Lu Z, Lu Z, Zhang H. The Causal Association Between Medication Intake and Increased Risk of Psoriasis. Dermatol Pract Concept. 2024;14(1):e2024041. DOI: https://doi.org/10.5826/dpc.1401a41 Accepted: August 29, 2023; Published: January 2024 Copyright: ©2024 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: Zhichen Li and Haobin Zhou contributed equally to this work. Corresponding Author: Huayao Zhang, Department of Breast Surgery, Shaoguan Maternal and Child Health Hospital, No.1, Yucai Road, Shaoguan, Guangdong, 512026, China. E-mail: hyzhang1988@163.com Introduction: Psoriasis is a chronic, inflammatory, and papulo-squamous skin disorder without a radical cure. Although previous observational analyses have discovered a relationship between medi- cation intake and increased risk of psoriasis, they are susceptible to confounders. Objectives: We intend to ascertain if there is a causal association between specific medication intake and increased risk of psoriasis by utilizing the Mendelian randomization (MR) method. Methods: We obtained the genome-wide association study (GWAS) data for medication intake (23 types, N = 1809) from UK Biobank samples. And we sourced the GWAS data for psoriasis from the 8th release of the FinnGen database, which included 8,075 psoriasis cases and 330,975 healthy con- trol cases. Then a two-sample MR study was performed to determine their causal association, and inverse-variance-weighted MR (IVW-MR) was applied to calculate the effect estimates. Results: The IVW-MR analysis uncovered a positive correlation between the intake of HMG CoA re- ductase inhibitors and the increased risk of psoriasis (odds ratio [OR] = 1.167, 95% confidence inter- val [CI] = 1.084-1.257). Similarly, the use of thyroid preparations (OR=1.080, 95% CI=1.026-1.138), nonsteroidal anti-inflammatory and antirheumatic products (OR=1.406, 95% CI=1.037-1.908), anilides (OR=1.379, 95% CI=1.004-1.894), antihistamines for systemic use (OR=1.341, 95% CI=1.104-1.630), and antihypertensives (OR=1.099, 95% CI=1.016-1.190) were associated with an increased risk of psoriasis. We did not find evidence from IVW-MR for other associations. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2024;14(1):e2024041 Conclusions: Our study offers a causal testimony that the intake of HMG CoA reductase inhibitors, thyroid preparations, nonsteroidal anti-inflammatory and antirheumatic products, anilides, antihista- mines for systemic use, and antihypertensives will potentially increase the risk of psoriasis. Introduction Psoriasis is a chronic, inflammatory, and papulo-squamous skin disorder. Psoriasis vulgaris is the most common subtype, accounting for approximately 90% of cases  [1]. Clinically, it is characterized by sharply demarcated salmon-pink plaques in individuals with white skin but gray plaques in those with black skin, both covered by silvery scales [2]. According to a systematic review [3], the prevalence of psoriasis varied widely across different regions, ranging from 0.09% in Tanzania to 5.1% in the USA. The distribution of psoriasis patients was also un- equal regarding race, age, and geography. For instance, it occurred more commonly in Caucasians, adults, and indi- viduals from wealthy countries [2-4]. Furthermore, psori- asis patients often experienced poor self-esteem, anxiety, depression, insomnia, and even suicidality because of their unsightly external appearance [5-8], which placed a heavy burden on individuals and society. A previous study indicated that the intake of certain medications might induce psoriatic lesions on normal skin in psoriasis patients or trigger psoriasis in predisposed individ- uals, even in those without a family history of this disease [9]. These medications included nonsteroidal anti-inflammatory drugs (NSAIDs), penicillins, antimalarial drugs, psycho- tropic drugs, and others [10]. Psoriasis is closely associ- ated with various comorbidities. For example, studies have demonstrated that psoriasis patients had a risk of developing metabolic syndromes such as type II diabetes, hypertension, atherogenic dyslipidemia, and nonalcoholic fatty liver, that was at least twice as high as that of healthy individuals [11]. Besides, psoriasis patients were susceptible to coronary atherosclerosis and even coronary artery disease [12,13]. Moreover, a meta-analysis indicated that psoriasis patients had a tremendously increased risk of asthma, inflammatory bowel disease, chronic kidney disease, and end-stage renal disease [14-16]. In such cases, they should treat not only the primary illness but also the associated complications. How- ever, medications used for treating its complications may, in turn, exacerbate psoriasis. Consequently, regardless of the patient’s disease control status, clinicians need to evaluate the potential effects of medication intake on the occurrence, recurrence, or aggravation of psoriasis. Objectives It is widely accepted that genetic variants are randomly dis- tributed during meiosis and scarcely influenced by environ- mental factors. Unlike traditional observational analyses, the Mendelian randomization (MR) study leverages this ad- vantage of genetic variants by utilizing them as instrumental variables, thereby mitigating limitations such as potential confounders, information biases, and reverse causality to the greatest extent [17]. Accordingly, we conducted an MR study and explored the causal association between medica- tion intake and increased risk of psoriasis in this article. Methods Source of Genome-wide Association Study (GWAS) Data and Harmonization Our MR study included 23 types of medications in the ex- posure group, derived from the GWAS data and used to quantify the future risk associated with medication use. The study samples were drawn from the UK Biobank (UKB) and consisted of 502,616 participants with medication records during their first visit to the UKB evaluation [18]. Out of the 6,745 types of medications recorded in the UKB, 1,809 were reported by at least ten individuals and subsequently included in the GWAS. These medications were integrated into 23 categories and underwent a series of quality control measures to form the aggregated GWAS data. We obtained these GWAS data and used the “format_data” function of the TwoSampleMR package to transform them into a recogniz- able format. To select instrumental variables for each med- ication GWAS, we applied the following thresholds: 1) The P -value was less than 5e-08; 2) We conducted clump analysis with an r2 = 0.001 and kb=10000 setting; 3) We calculated the F statistic for each instrumental variable, and those with an F value less than ten were eliminated [19]. The calculation formula was as follows [20] where N is the sample size and r2 the variance explained by IVs: r N r 2 2 ( 2) (1 ) – – Original Article | Dermatol Pract Concept. 2024;14(1):e2024041 3 Since we required at least four single nucleotide poly- morphisms (SNPs) as instrumental variables for subsequent analysis, we set a P -value threshold of P < 5e-07 in case the medications GWAS yielded insufficient instrumental vari- ables after screening and normalization. If still inadequate, we would adjust the cutoff point to P < 5e-06. The study focused on psoriasis as the primary out- come of interest. We obtained the GWAS data for psoriasis from the 8th release of the FinnGen database [21], where the PhenoCode for psoriasis was L12_PSORIASIS (https:// finngen.gitbook.io/documentation/). The dataset included 8,075 cases and 330,975 controls, with a total sample size of 339,050. FinnGen conducted a series of quality control measures on the GWAS data (DOI: https://doi.org/10.1101/ 2022.03.03.22271360). And we used National registries to define psoriasis cases. We harmonized the exposure and outcome groups data to ensure that the effect allele was consistently related to the same allele. This was achieved using the effect allele frequency (EAF) to deduce the orientation of all SNPs on the forward strand. SNPs with incorrect effects or reference alleles, and those with ambiguous palindromic sequences that EAF could not resolve, were excluded from further analysis. Mendelian Randomization and Sensitivity Test To validate the primary MR analysis method, we per- formed MR-PRESSO analysis [22] with an element set to 10,000 to identify and remove outliers. We simultaneously conducted MR analysis and computed p values. The data with outliers removed were the corrected data for subse- quent studies. Inverse-variance-weighted (IVW) was cho- sen as the primary MR method due to its robustness and reliability [23]. The results obtained through IVW were considered the main MR results. At the same time, we con- ducted four additional MR methods (MR‒Egger, simple mode, weighted median, and weighted mode) to comple- ment IVW and to observe if their results were consistent with those of IVW. To ensure the reliability of the MR results, we performed sensitivity analyses after obtaining them. We employed the MR‒Egger intercept method to test whether they were af- fected by horizontal pleiotropy [24]. A P value less than 0.05 was considered evidence of horizontal pleiotropy, indicat- ing unreliable results. We evaluated heterogeneity using the Cochrane Q test with IVW and MR‒Egger. A p-value less than 0.05 indicated the presence of heterogeneity among the instrumental variables. Since IVW can effectively handle heterogeneity, we should regard its results as the main MR results [23]. Results Causality of Medicine Intake on Psoriasis Occurrence After conducting IVW on 23 different types of medications, we identified six of them as significant risk factors for psori- asis (P < 0.05). Supplementary Table 1 provided all the drug IDs and their corresponding detailed names. As depicted in Figure 1, the intake of HMG-CoA reductase inhibitors (OR=1.167, 95% CI: 1.084-1.257, P < 0.001) substantially increased the risk of developing psoriasis. Thyroid prepa- rations (OR=1.080, 95% CI: 1.026-1.138, P = 0.004) and antihistamines for systemic use (OR=1.341, 95% CI: 1.104- 1.630, P = 0.003) also showed significant associations. Ad- ditionally, NSAIDs and antirheumatic products (OR=1.406, 95% CI: 1.037-1.908, P = 0.028), antihypertensives (OR=1.099, 95% CI: 1.016-1.190, P = 0.019), and anilides (OR=1.379, 95% CI: 1.004-1.894, P = 0.047) contributed to the occurrence or aggravation of psoriasis. Supplementary Table 2 provided detailed outcomes of the other four MR methods. Sensitivity Analyses For the IVW-MR analysis, the Cochran Q test indicated no heterogeneity among the reported results (P > 0.05). More- over, the MR‒Egger regression analysis demonstrated that overall horizontal pleiotropy did not significantly affect the results obtained through IVW-MR (P > 0.05). Supplementary Table 2 provided the integrated outcomes of MR PRESSO and detailed sensitivity analyses. Based on these findings, we could assert their causal relationship’s credibility. Conclusions Psoriasis is an immune-mediated chronic inflammatory skin disease mainly affecting the knees, elbow, trunk, and scalps, which presents with well-demarcated erythematous plaques covered by silvery-white scales. Medication-provoked pso- riasis can be classified into two types. Medication-induced psoriasis often occurs in patients with no family or personal history of psoriasis, whose lesions typically subsided after ceasing medication use [25]. Medication-aggravated psori- asis usually affects patients with a history of psoriasis or a genetic predisposition, generally exacerbating their existing lesions or developing new ones [25]. However, identifying medication-related triggers for psoriasis flares in clinical practice can be challenging for various reasons. For example, variations in the absorption rate and half-time period among different medications may lead to an inconspicuous tempo- ral relationship [26]. As mentioned earlier, MR analysis can 4 Original Article | Dermatol Pract Concept. 2024;14(1):e2024041 Pruritus is a common symptom experienced by most pso- riasis patients and can significantly impact their quality of life. Itching often leads to the scratching of psoriatic lesions, further intensifying the itch and creating a vicious cycle of “itching-scratching,” ultimately worsening skin inflamma- tion. In clinical practice, dermatologists use antihistamines to alleviate itch in skin disorders. Few large-scale, random- ized, controlled trials have examined whether antihistamines use increases the risk of psoriasis. Some case reports have suggested that fexofenadine and terfenadine may exacerbate psoriasis [33,34]. Our research provided theoretical evidence that antihistamines use may be a risk factor for psoriasis, but the underlying reason for this remained unclear. Further pharmacological studies are required to elucidate the mech- anism of this adverse reaction. Recent studies have shed light on the relationship be- tween psoriasis and thyroid disease. For instance, hypo- thyroidism was highly prevalent in psoriasis patients  [35]. Hashimoto’s thyroiditis was also more prevalent in pso- riasis patients (especially in females) than in healthy people [35-37]. Levothyroxine is usually used to treat hypo- thyroidism and Hashimoto’s thyroiditis. To date, few studies effectively dispose of this drawback, making it a more credi- ble tool for causal estimation between medication intake and the increased risk of psoriasis. Psoriasis patients are susceptible to developing cardio- vascular episodes [12,13]. Statins, also known as HMG-CoA reductase inhibitors, are commonly prescribed to lower cho- lesterol levels and decrease the incidence of cardiovascular dis- eases. However, there is an ongoing debate among researchers regarding the relationship between statin use and psoriasis. Some studies suggested that statins had beneficial effects on plaque psoriasis and could reduce its severity [27,28]. Con- versely, others argued that there was insufficient evidence that using oral statins as an auxiliary treatment could reduce the severity of psoriasis [29]. Psoriasis patients with hypercholes- terolemia may even worsen their pre-existing psoriasis after using statins due to the activation of signal transducer and activator of transcription 3 (STAT3) [30]. These studies also stated that statins could result in the deterioration of psoriasis lesions [31,32]. Our study found that statin intake increased the risk of triggering or exacerbating psoriasis, providing ge- netic evidence for exploring the concrete pharmacological mechanism of statins in psoriasis patients. Figure 1. The forest plot displayed the results of a two-sample Mendelian randomization analysis, investigating the relationship between the intake of 23 different types of medications and the risk of psoriasis. The effect estimates were presented as odds ratios. CI = confidence interval; OR = odds ratio. Original Article | Dermatol Pract Concept. 2024;14(1):e2024041 5 instrumental variable assumptions cannot be empirically verified, but we have conducted sensitivity analyses to ensure no heterogeneity or horizontal pleiotropy. Our study offers a causal testimony that the intake of HMG CoA reductase inhibitors, thyroid preparations, non- steroidal anti-inflammatory and antirheumatic products, anilides, antihistamines for systemic use, and antihyperten- sives are substantially associated with the increased risk of psoriasis. References 1. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370(9583):263-271. DOI: 10.1016 /S0140-6736(07)61128-3. PMID: 17658397. 2. Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker JNWN. Psoriasis. Lancet. 2021;397(10281):1301-1315. DOI: 10.1016 /S0140-6736(20)32549-6. PMID: 33812489. 3. Michalek IM, Loring B, John SM. A systematic review of world- wide epidemiology of psoriasis. 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Our study did not find a correlation between these medicines and an increased risk of psoriasis. In contrast, the remaining minorities, such as sym- patholytic agents (reserpine, clonidine), direct vasodilators (hydrazine), and α1-receptor blockers (prazosin, terazosin), were implicated. For example, a large population-based, case-control study found no connection between the use of β-blockers and an increased risk of psoriasis [40]. However, clonidine may increase the risk of psoriasiform eruption by decreasing intracellular cyclic AMP and promoting the pro- liferation of epidermal cells [41]. Taking urapidil resulted in the observation of a similar lesion [42]. These findings were consistent with the results of our study, which instructed us to choose appropriate antihypertensives medications for psoriasis patients. Acetaminophen and aspirin are two of the most widely used NSAIDs. Shaowei Wu et al. reported that regular acet- aminophen users may increase the risk of developing psori- asis and psoriatic arthritis [43]. This phenomenon may be attributed to its inhibition of arachidonic acid metabolism via the cyclo-oxygenase pathway, resulting in the accumula- tion of leukotrienes and aggravating psoriasis [10]. Notably, acetaminophen belongs to both NSAIDs and anilides. This finding aligned with our study outcomes, which indicated NSAIDs and anilides were associated with a greater risk of psoriasis. These results reminded clinicians that aspirin may be a safer alternative to acetaminophen when prescribing NSAIDs to psoriasis patients in the short term. However, clinicians should still pay attention to psoriasis occurrence when patients use NSAIDs for a long time [43]. This reliable evidence emphasizes the importance of ra- tional medication administration, which is crucial in pre- venting and managing psoriasis. 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