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The risk of organ-based comorbidities in psoriasis: a systematic review and meta-analysis Study conducted at the Southwest Medical University, Luzhou, Sichuan, China.

Abstract

Background:

The close relationship between psoriasis and concomitant diseases is widely accepted. However, a comprehensive analysis of organ-based comorbidities in psoriasis is still lacking.

Objective:

The authors aimed to present the risk of organ-based comorbidities in psoriasis by comparing the general population.

Methods:

The authors retrieved a search of Pubmed, EMBASE, and Cochrane databases for studies reporting organ-based comorbidities in psoriasis versus the general population. Observational studies that met the following criteria were assessed: 1) Psoriasis diagnosis; 2) Cardiovascular or kidney or liver or respiratory or cerebrovascular outcomes; 3) Comparison group of individuals without psoriasis. Pooled Relative Risks (pRRs) and 95% Confidence Intervals (CIs) were calculated by using the random-effect model.

Results:

Fifteen observational studies with 216,348 psoriatic patients and 9,896,962 individuals from the general population were included. Psoriasis showed a greater risk of organ-based comorbidities. Compared to the general population, pRR for all organ-based comorbidities was 1.20 (95% CI 1.11–1.31) in psoriasis, and pRR was lower in mild 0.61 (95% CI 0.46–0.81) than in moderate/severe patients. pRR was 1.20 (95% CI 1.11–1.30) for cardiovascular, 1.56 (95% CI 1.20–2.04), and 1.75 (95% CI 1.33–2.29) for cerebrovascular and liver diseases, respectively. pRR for coexisting renal and cardiovascular events was 1.09 (95% CI 1.01–1.18). pRR for coexisting renal and cerebrovascular events was 1.28 (95% CI 0.99–1.66). pRR for coexisting renal and liver diseases was 1.46 (95% CI 1.10–1.94). pRR for coexisting cardiovascular and liver diseases was 1.41 (95% CI 1.11–1.80).

Study limitations:

There is heterogeneity.

Conclusion:

Psoriasis has a higher risk of single and multiple organ-based comorbidities than the general population. The present study will further improve attention to psoriasis as a systemic inflammatory disease.

KEYWORDS
Comorbidity; Meta-analysis; Psoriasis; Risk; Systematic review

Introduction

Psoriasis is a chronic inflammatory disease, affecting approximately 2%–3% of the global population.11 Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361:496–509.,22 Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, et al. Psoriasis. Nat Rev Dis Primers. 2016;2:16082.,33 BoehnckeWH, Schön MP. Psoriasis. Lancet. 2015;386:983–94.,44 Furue K, Ito T, Furue M. Differential efficacy of biologic treatments targeting the TNF-α/IL-23/IL-17 axis in psoriasis and psoriatic arthritis. Cytokine. 2018;111:182–8.,55 Lima XT, Minnillo R, Spencer JM, Kimball AB. Psoriasis prevalence among the 2009 AAD National Melanoma/Skin Cancer Screening Program participants. J Eur Acad Dermatol Venereol. 2013;27:680–6.,66 Enamandram M, Kimball AB. Psoriasis epidemiology: the interplay of genes and the environment. J Invest Dermatol. 2013;133:287–9.,77 Kuh D, Ben-Shlomo Y, Lynch J, Hallqvist J, Power C. Life course epidemiology. J Epidemiol Community Health. 2003;57:778–83.,88 Parisi R, Symmons DPM, Griffiths CEM, Ashcroft DM. Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133:377–85. The pathogenesis of psoriasis is believed to be the result of the interaction of genetic, environmental, and immune factors.99 Albanesi C, Madonna S, Gisondi P, Girolomoni G. The Interplay Between Keratinocytes and Immune Cells in the Pathogenesis of Psoriasis. Front Immunol. 2018;9:1549.,1010 Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128:1207–11.,1111 Enamandram M, Kimball AB. Psoriasis epidemiology: the interplay of genes and the environment. J Invest Dermatol. 2013;133:287–9. Psoriasis has been considered to be a systemic disease that may increase risks of cardiovascular disease, metabolic syndrome, and other comorbidities.1212 Davidovici BB, Sattar N, Prinz JC, Puig L, Emery P, Barker JN, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130:1785–96.,1313 Takeshita J, Grewal S, Langan SM, Mehta NN, Ogdie A, Voorhees AS, et al. Psoriasis and comorbid diseases: Epidemiology. J Am Acad Dermatol. 2017;76:377–90.,1414 Oliveira MFSP, Rocha BO, Duarte VG. Psoriasis: classical and emerging comorbidities. An Bras Dermatol. 2015;90:9–20. The comorbidity mechanism of psoriasis may be related to the release of pro-inflammatory molecules during chronic inflammation.33 BoehnckeWH, Schön MP. Psoriasis. Lancet. 2015;386:983–94.,1515 Takeshita J, Grewal S, Langan SM, Mehta NN, Ogdie A, Voorhees AS, et al. Psoriasis and comorbid diseases: Implications for management. J Am Acad Dermatol. 2017;76:393–403.,1616 Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9.,1717 Kovitwanichkanont T, Chong AH, Foley P. Beyond skin deep: addressing comorbidities in psoriasis. Med J Aust. 2020;212:528–34. More and more evidences suggest that severe or relapsing psoriasis tends to be a systemic inflammation disease.1818 Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA. 2020;323:1945–60.,1919 Casciano F, Pigatto PD, Secchiero P, Gambari R, Reali E. T-Cell Hierarchy in the Pathogenesis of Psoriasis and Associated Cardiovascular Comorbidities. Front Immunol. 2018;9:1390. Studies have shown that 13% of psoriatic patients are associated with ischaemic heart disease, 12% associated with diabetes mellitus, and 36% associated with arterial hypertension.2020 Augustin M, Reich K, Glaeske G, Schaefer I, Radtke M. Comorbidity, and age-related prevalence of psoriasis: Analysis of health insurance data in Germany. Acta Derm Venereol. 2010;90:147–51. There are meta-analyses about psoriasis with single diseases, e.g. Chronic Obstructive Pulmonary Disease (COPD)2121 Candia R, Ruiz A, Torres-Robles R, Chávez-Tapia N, Méndez-Sánchez N, Arrese M. Risk of non-alcoholic fatty liver disease in psoriatic patients: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2015;29:656–62. and diabetes.2222 Cheng J, Kuai D, Zhang L, Yang X, Qiu B. Psoriasis increased the risk of diabetes: a meta-analysis. Arch Dermatol Res. 2012;304:119–25. However, there is no comorbidity data at levels of organs.

Although the close relationship between psoriasis and concomitant diseases has been commonly accepted, and the risk of a single specific disease in psoriasis has been intensively studied.2121 Candia R, Ruiz A, Torres-Robles R, Chávez-Tapia N, Méndez-Sánchez N, Arrese M. Risk of non-alcoholic fatty liver disease in psoriatic patients: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2015;29:656–62.,2323 Upala S, Shahnawaz A, Sanguankeo A. Psoriasis increases risk of new-onset atrial fibrillation: a systematic review and meta-analysis of prospective observational studies. Journal of Dermatolog Treat. 2017;28:406–10.,2424 Li X, Kong L, Li F, Chen C, Xu R, Wang H, et al. Association between Psoriasis and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis. PLoS One. 2015;10:e0145221. However, a comprehensive analysis of comorbidities in terms of organs in psoriasis is still lacking. In this study, the authors aimed to investigate the differences between psoriasis and the general population in terms of different organ-based comorbidities. The analysis was not limited to purely merger values and tried to find association patterns between them.

Material and methods

Literature review and search strategy

This meta-analysis was registered in PROSPERO (CRD 42020211821), following the PRISMA 2020 checklist.2525 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, etal. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. The authors searched Pubmed, EMBASE, and Cochrane Library databases, including all studies from the respective inception of these databases to October 14, 2020. The investigator performed the literature retrieval, research selection, data extraction, and quality assessment.

The search strategy included a variety of terms related to psoriasis and organ-based comorbidities. The detailed search strategies of Pubmed, Embase, and Cochrane Library were put in the supplementary material.

Selection of studies

According to the PECO strategy, articles that met the following criteria would be included. Population: the authors included studies that contained both psoriasis and the general population; Exposure: psoriasis with regular diagnosis (no age limit); Comparative: the people without psoriasis and from the same research environment as psoriasis; Outcome: the record results were organ-based comorbidities (cardiovascular diseases, kidney diseases, liver diseases, respiratory diseases, spleen diseases, and cerebrovascular system-related diseases). Publications with insufficient and reduplicated data were excluded. The restriction of study type and language were not considered in the initial search.

Data extraction and assessment of study quality

Full text of articles meeting the eligibility criteria was selected for data extraction. Data was extracted by the first author, year of publication, country, demographic, number of patients, and follow-up time. For example, the authors intended to include studies that were clearly defined as diseases with the kidney, such as chronic kidney disease, etc. In addition, studies that had nothing, but abnormal testing data were excluded. If a study provided data with different types of psoriasis (mild, moderate, and severe), the authors combined them to obtain an estimate of all psoriatic patients. In order to ensure the accuracy of data extraction, any difference found in the data can be addressed by referring to the original article. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of included studies, with a maximum score of 9 points, representing the highest quality. The scale assessed the quality of each study in three areas, including (1) Case and control subjects’ recruitment; (2) Comparability between the two groups; (3) Identification of results of interest. The characteristics of the studies and evaluation results were displayed in Table 1.

Table 1
Characteristics of included studies: psoriasis and comorbidities.

Statistical analysis

Statistical analyses were performed by RevMan 5.4 (the Cochrane collaboration) and Stata version 12.0 (StataCorp LP, College Station, TX77845). The results were reflected in pooled RR (pRR) and 95% CI. All statistical tests were bilateral. The p-values of less than 0.05 were considered significant. The Inconsistency test (I2) statistic was used to assess the heterogeneity. The I2 value of 0%, 25%, 50%, and 75% indicated no, low, medium, and high heterogeneity, respectively. Sensitivity analyses, subgroup analyses, and meta-regression were performed to identify potential sources of heterogeneity. Besides, the funnel plots and Egger’s weighted regression were used to assess potential publication bias.

The pRRs and corresponding 95% CIs were estimated by a random-effect meta-analysis. A logarithmic transformation was performed for the estimated RRs of maximum adjusted effect size and the CIs. pRRs were subjected to Z-test and sensitivity analysis and used to assess the combined stability effect. Publication bias was measured by constructing funnel plots. A symmetrical inverted funnel indicated that there is no high likelihood of publication bias. Finally, a study was removed to assess its impact on the merger. The similarity of combined RRs before and after removing the study indicated that there was a high certainty in the results. When heterogeneity existed between studies, the authors applied the random-effect model and used the Mantel-Haenszel analysis method.

Results

Study selection

The search strategy (Fig. 1) produced 7,412 potentially relevant references (3,862 in Pubmed, 2,984 in EMBASE, and 566 in the Cochrane Library). Finally, fifteen retrospective cohort studies remained, containing 216,348 psoriatic patients and 9,896,962 general people. All studies were based on a managed database, relied on diagnostic codes to identify and verify the diagnosis of psoriasis and organ-based comorbidities.

Figure 1
Flow diagram of study selection.

Study characteristics

The main clinical characteristics and quality evaluation of the included studies were summarized in Table 1. These studies were conducted in seven countries: the United States, the United Kingdom, Germany, Denmark, Italy, Taiwan, and South Korea. The mean age of psoriatic patients ranged from 12.0 to 69.5 years, and females accounted for 32.58% to 59.19%. For the general population, the mean age ranged from 12.0 to 70.6 years, and females accounted from 22.14% to 67.42%. Only two studies did not report the average age,2626 Min C, Lim H, Lim JS, Sim S, Choi HG. Increased risk of migraine in psoriatic patients: A longitudinal follow up study using a national sample cohort. Medicine (Baltimore). 2019;98:e15370.,2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43. and one study mainly investigated children with psoriasis.2828 Tollefson MM, Houten HK, Asante D, Yao X, Kremers HM. Association of Psoriasis With Comorbidity Development in Children With Psoriasis. JAMA Dermatol. 2018;154:286–92. So, the span of age characteristics was large after synthesizing data. There was little specific organ-based comorbidities data of race. Therefore, no subgroup analysis was conducted on race.2828 Tollefson MM, Houten HK, Asante D, Yao X, Kremers HM. Association of Psoriasis With Comorbidity Development in Children With Psoriasis. JAMA Dermatol. 2018;154:286–92.,2929 Prasada S, Rivera A, Nishtala A, Pawlowski AE, Sinha A, Bundy JD, et al. Differential Associations of Chronic Inflammatory Diseases With Incident Heart Failure. JACC Heart Fail. 2020;8:489–98.

Psoriasis and all organ-based comorbidities

The risks all included organ-based comorbidities between psoriatic patients and the general population were described in Fig. 2. The authors mainly studied the involvements of the heart, kidneys, lung, brain, and liver. In 15 studies,2626 Min C, Lim H, Lim JS, Sim S, Choi HG. Increased risk of migraine in psoriatic patients: A longitudinal follow up study using a national sample cohort. Medicine (Baltimore). 2019;98:e15370.,2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,2828 Tollefson MM, Houten HK, Asante D, Yao X, Kremers HM. Association of Psoriasis With Comorbidity Development in Children With Psoriasis. JAMA Dermatol. 2018;154:286–92.,2929 Prasada S, Rivera A, Nishtala A, Pawlowski AE, Sinha A, Bundy JD, et al. Differential Associations of Chronic Inflammatory Diseases With Incident Heart Failure. JACC Heart Fail. 2020;8:489–98.,3030 Ahlehoff O, Gislason GH, Lindhardsen J, Olesen JB, Charlot M, Skov L, et al. Prognosis following first-time myocardial infarction in psoriatic patients: a Danish nationwide cohort study. J Intern Med. 2011;270:237–44.,3131 Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J. 2012;33:2054–64.,3232 Armstrong AW, Azizi S, Wu J, Harskamp CT, Farrow J, Johnson MAN, et al. Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. Arch Dermatol Res. 2013;305:891–7.,3333 Charlton R, Green A, Shaddick G, Snowball J, Nightingale A, Tillett W, et al. Risk of type 2 diabetes and cardiovascular disease in an incident cohort of people with psoriatic arthritis: a population-based cohort study. Rheumatology (Oxford). 2019;58:144–8.,3434 Chiang CH, Huang CC, Chan WL, Huang PH, Chen YC, Chen TJ, et al. Psoriasis and increased risk of ischemic stroke in Taiwan: a nationwide study. J Dermatol. 2012;39:279–81.,3535 Feldman SR, Zhao Y, Shi L, Tran MH. Economic and Comorbidity Burden Among Patients with Moderate-to-Severe Psoriasis. J Manag Care Spec Pharm. 2015;21:874–88.,3636 Khalid U, Ahlehoff O, Gislason GH, Skov L, Torp-Pedersen C, Hansen PR. Increased risk of aortic valve stenosis in psoriatic patients: a nationwide cohort study. Eur Heart J. 2015;36:2177–83.,3737 Lee S, Xie L, Wang Y, Vaidya N, Baser O. Comorbidity and economic burden among moderate-to-severe psoriasis and/or psoriatic arthritis patients in the US Department of Defense population. J Med Econ. 2018;21:564–70.,3838 Schell C, Schleich R, Walker F, Yazdi AS, Lerche H, Röcken M, et al. Restless legs syndrome in psoriasis: an unexpected comorbidity. Eur J Dermatol. 2015;25:255–60.,3939 Vena GA, Altomare G, Ayala F Berardesca E, Calzavara-Pinton P, Chimenti S, et al. Incidence of psoriasis and association with comorbidities in Italy: a 5-year observational study from a national primary care database. Eur J Dermatol. 2010;20:593–8.,4040 Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. they contained 216,348 psoriatic patients and 9,896,962 control subjects. It showed that psoriatic patients had a significantly increased risk of these organ-based comorbidities, and pRR was 1.20 (95% CI 1.11–1.31, I2 =98%, p<0.001). After removing the study involving mainly children,2828 Tollefson MM, Houten HK, Asante D, Yao X, Kremers HM. Association of Psoriasis With Comorbidity Development in Children With Psoriasis. JAMA Dermatol. 2018;154:286–92. pRR became to 1.17 (95% CI 1.08–1.27, I2 = 98%, p < 0.001).

Figure 2
Forest plot of the risks of comorbidities in psoriatic patients comparing the general population.

Psoriasis and specific organ-based comorbidities

In 14 studies,2626 Min C, Lim H, Lim JS, Sim S, Choi HG. Increased risk of migraine in psoriatic patients: A longitudinal follow up study using a national sample cohort. Medicine (Baltimore). 2019;98:e15370.,2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,2828 Tollefson MM, Houten HK, Asante D, Yao X, Kremers HM. Association of Psoriasis With Comorbidity Development in Children With Psoriasis. JAMA Dermatol. 2018;154:286–92.,2929 Prasada S, Rivera A, Nishtala A, Pawlowski AE, Sinha A, Bundy JD, et al. Differential Associations of Chronic Inflammatory Diseases With Incident Heart Failure. JACC Heart Fail. 2020;8:489–98.,3030 Ahlehoff O, Gislason GH, Lindhardsen J, Olesen JB, Charlot M, Skov L, et al. Prognosis following first-time myocardial infarction in psoriatic patients: a Danish nationwide cohort study. J Intern Med. 2011;270:237–44.,3131 Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J. 2012;33:2054–64.,3232 Armstrong AW, Azizi S, Wu J, Harskamp CT, Farrow J, Johnson MAN, et al. Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. Arch Dermatol Res. 2013;305:891–7.,3333 Charlton R, Green A, Shaddick G, Snowball J, Nightingale A, Tillett W, et al. Risk of type 2 diabetes and cardiovascular disease in an incident cohort of people with psoriatic arthritis: a population-based cohort study. Rheumatology (Oxford). 2019;58:144–8.,3434 Chiang CH, Huang CC, Chan WL, Huang PH, Chen YC, Chen TJ, et al. Psoriasis and increased risk of ischemic stroke in Taiwan: a nationwide study. J Dermatol. 2012;39:279–81.,3636 Khalid U, Ahlehoff O, Gislason GH, Skov L, Torp-Pedersen C, Hansen PR. Increased risk of aortic valve stenosis in psoriatic patients: a nationwide cohort study. Eur Heart J. 2015;36:2177–83.,3737 Lee S, Xie L, Wang Y, Vaidya N, Baser O. Comorbidity and economic burden among moderate-to-severe psoriasis and/or psoriatic arthritis patients in the US Department of Defense population. J Med Econ. 2018;21:564–70.,3838 Schell C, Schleich R, Walker F, Yazdi AS, Lerche H, Röcken M, et al. Restless legs syndrome in psoriasis: an unexpected comorbidity. Eur J Dermatol. 2015;25:255–60.,3939 Vena GA, Altomare G, Ayala F Berardesca E, Calzavara-Pinton P, Chimenti S, et al. Incidence of psoriasis and association with comorbidities in Italy: a 5-year observational study from a national primary care database. Eur J Dermatol. 2010;20:593–8.,4040 Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. summing 210,856 psoriatic patients and 9,891,470 controls. The pRR for cardiovascular events was 1.20 (95% CI 1.11–1.30, I2=97%, p < 0.001), significantly increased comparing the general population. In 9 studies2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,2929 Prasada S, Rivera A, Nishtala A, Pawlowski AE, Sinha A, Bundy JD, et al. Differential Associations of Chronic Inflammatory Diseases With Incident Heart Failure. JACC Heart Fail. 2020;8:489–98.,3030 Ahlehoff O, Gislason GH, Lindhardsen J, Olesen JB, Charlot M, Skov L, et al. Prognosis following first-time myocardial infarction in psoriatic patients: a Danish nationwide cohort study. J Intern Med. 2011;270:237–44.,3131 Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J. 2012;33:2054–64.,3434 Chiang CH, Huang CC, Chan WL, Huang PH, Chen YC, Chen TJ, et al. Psoriasis and increased risk of ischemic stroke in Taiwan: a nationwide study. J Dermatol. 2012;39:279–81.,3535 Feldman SR, Zhao Y, Shi L, Tran MH. Economic and Comorbidity Burden Among Patients with Moderate-to-Severe Psoriasis. J Manag Care Spec Pharm. 2015;21:874–88.,3636 Khalid U, Ahlehoff O, Gislason GH, Skov L, Torp-Pedersen C, Hansen PR. Increased risk of aortic valve stenosis in psoriatic patients: a nationwide cohort study. Eur Heart J. 2015;36:2177–83.,3838 Schell C, Schleich R, Walker F, Yazdi AS, Lerche H, Röcken M, et al. Restless legs syndrome in psoriasis: an unexpected comorbidity. Eur J Dermatol. 2015;25:255–60.,4040 Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. involved 135,345 psoriatic patients and 9,699,285 control subjects, pRR for renal diseases was 1.08 (95% CI 0.87–1.33, I2 =83%, p < 0.001). In 8 studies2626 Min C, Lim H, Lim JS, Sim S, Choi HG. Increased risk of migraine in psoriatic patients: A longitudinal follow up study using a national sample cohort. Medicine (Baltimore). 2019;98:e15370.,2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,3131 Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J. 2012;33:2054–64.,3232 Armstrong AW, Azizi S, Wu J, Harskamp CT, Farrow J, Johnson MAN, et al. Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. Arch Dermatol Res. 2013;305:891–7.,3333 Charlton R, Green A, Shaddick G, Snowball J, Nightingale A, Tillett W, et al. Risk of type 2 diabetes and cardiovascular disease in an incident cohort of people with psoriatic arthritis: a population-based cohort study. Rheumatology (Oxford). 2019;58:144–8.,3535 Feldman SR, Zhao Y, Shi L, Tran MH. Economic and Comorbidity Burden Among Patients with Moderate-to-Severe Psoriasis. J Manag Care Spec Pharm. 2015;21:874–88.,3737 Lee S, Xie L, Wang Y, Vaidya N, Baser O. Comorbidity and economic burden among moderate-to-severe psoriasis and/or psoriatic arthritis patients in the US Department of Defense population. J Med Econ. 2018;21:564–70.,4040 Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. with 103,300 psoriatic patients and 4,729,963 control subjects, pRR of cerebrovascular disease events was 1.56 (95% CI 1.20–2.04, I2=94%, p<0.001). In 9 studies2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,3030 Ahlehoff O, Gislason GH, Lindhardsen J, Olesen JB, Charlot M, Skov L, et al. Prognosis following first-time myocardial infarction in psoriatic patients: a Danish nationwide cohort study. J Intern Med. 2011;270:237–44.,3131 Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J. 2012;33:2054–64.,3232 Armstrong AW, Azizi S, Wu J, Harskamp CT, Farrow J, Johnson MAN, et al. Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. Arch Dermatol Res. 2013;305:891–7.,3535 Feldman SR, Zhao Y, Shi L, Tran MH. Economic and Comorbidity Burden Among Patients with Moderate-to-Severe Psoriasis. J Manag Care Spec Pharm. 2015;21:874–88.,3636 Khalid U, Ahlehoff O, Gislason GH, Skov L, Torp-Pedersen C, Hansen PR. Increased risk of aortic valve stenosis in psoriatic patients: a nationwide cohort study. Eur Heart J. 2015;36:2177–83.,3838 Schell C, Schleich R, Walker F, Yazdi AS, Lerche H, Röcken M, et al. Restless legs syndrome in psoriasis: an unexpected comorbidity. Eur J Dermatol. 2015;25:255–60.,4040 Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. with 132,791 psoriatic patients and 9,689,831 control subjects, pRR for the occurrence of pulmonary disease events was 1.05 (95% CI 0.89–1.23, I2 = 92%, p < 0.001). In 5 studies2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,2828 Tollefson MM, Houten HK, Asante D, Yao X, Kremers HM. Association of Psoriasis With Comorbidity Development in Children With Psoriasis. JAMA Dermatol. 2018;154:286–92.,3535 Feldman SR, Zhao Y, Shi L, Tran MH. Economic and Comorbidity Burden Among Patients with Moderate-to-Severe Psoriasis. J Manag Care Spec Pharm. 2015;21:874–88.,3838 Schell C, Schleich R, Walker F, Yazdi AS, Lerche H, Röcken M, et al. Restless legs syndrome in psoriasis: an unexpected comorbidity. Eur J Dermatol. 2015;25:255–60.,4040 Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. involved 46,469 psoriatic patients and 131,154 control subjects, pRR for the occurrence of liver diseases was 1.75 (95% CI 1.33–2.29, I2 = 88%, p < 0.001), and it was remarkably higher than general population (Fig. 3).

Figure 3
Forest plot of specific comorbidity risk in psoriatic patients compared with the general population (cardiovascular, renal, cerebrovascular, lung, liver diseases).

Psoriasis and multiple organ-based comorbidities

Psoriatic patients had been reported to suffer from two or more comorbidities simultaneously.4141 Wild J, Hobohm L, Münzel T Wenzel P, Steinbrink K, Karbach S, et al. Psoriasis and Its Impact on In-Hospital Outcome in Patients Hospitalized with Acute Kidney Injury. J Clin Med. 2020;9: 3004.,4242 Conti A, Giovannini L, Mandel VD, Odorici G, Lasagni C, Bigi L, et al. Chronic kidney disease in psoriasis: a cohort study. J Dtsch Dermatol Ges. 2020;18:438–45.,4343 Tokuyama M, Shimizu T, Yamada T Kondoh A, Mabuchi T. Case of psoriasis vulgaris with atrial fibrillation, heart failure and chronic kidney disease which were found accidentally through blood examination during apremilast treatment. J Dermatol. 2019;46:e239–40.,4444 Hu SC, Lin CL, Tu HP. Association between psoriasis, psoriatic arthritis and gout: a nationwide population-based study. J Eur Acad Dermatol Venereol. 2019;33:560–7.,4545 AlJohani R, Polachek A, Ye JY, Chandran V, Gladman DD. Characteristic and Outcome of Psoriatic Arthritis Patients with Hyperuricemia. J Rheumatol. 2018;45:213–7.,4646 Romero-Pérez D, Belinchón-Romero I, Bellot P, Francés R, Marco F, Ramos-Rincón JM. Nonalcoholic fatty liver disease puts psoriatic patients at greater cardiovascular risk. Australas J Dermatol. 2019;60:e304–10. Hence, the authors extracted data of two organs from included studies and calculated pRRs (Fig. 4). pRR for renal diseases plus cardiovascular events was 1.09 (95% CI 1.01–1.18, I2 =85%, p < 0.001). pRR for renal diseases plus cerebrovascular events was 1.28 (95% CI 0.99–1.66, I2 =87%, p < 0.001). pRR for renal diseases plus liver diseases were 1.46 (95% CI 1.10–1.94, I2 =91%, p < 0.001). pRR for cardiovascular events plus liver diseases were 1.41 (95% CI 1.11–1.80, I2 =95%, p < 0.001).

Figure 4
Forest plot of coexisting comorbidity risk in psoriatic patients compared with general population.

Organ-based comorbidity risks in mild and moderate/severe psoriasis

Three studies were subdividing psoriatic patients into mild and moderate/severe subgroups.3131 Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J. 2012;33:2054–64.,3232 Armstrong AW, Azizi S, Wu J, Harskamp CT, Farrow J, Johnson MAN, et al. Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. Arch Dermatol Res. 2013;305:891–7.,3636 Khalid U, Ahlehoff O, Gislason GH, Skov L, Torp-Pedersen C, Hansen PR. Increased risk of aortic valve stenosis in psoriatic patients: a nationwide cohort study. Eur Heart J. 2015;36:2177–83. They included 97,285 patients with mild psoriasis and 15,016 patients with moderate/severe psoriasis in total. pRR of organ-based comorbidity risk was 0.61 (95% CI 0.46–0.81, I2 = 94%, p < 0.001) for mild psoriasis, which was lower than that of moderate/severe psoriatic patients (Supplementary Fig. S1).

Sensitivity analyses

Sensitivity is an important indicator of literature quality and heterogeneity. One study was excluded to estimate the effect of pRRs at a time. There was no obvious change and a significant decrease in heterogeneity. Sensitivity analyses were performed to assess which study provided greater heterogeneity in the data by the Galbraith plot. All studies showed stable and reliable results (Supplementary Fig. S2). After careful evaluation, it was concluded that every study was not sensitive to pRRs and could not be arbitrarily excluded. As the score results were assessed by Newcastle-Ottawa Quality Assessment Scale for all included studies in Table 1. All studies scored at least 6 points, which was in line with the requirements for continuing study. Meanwhile, Stata’s Metaninf command was used to assess the impact of a single study. After excluding one study at a time, the point of estimate did not fall out of 95% CI (Supplementary Fig. S3).

Publication bias

The funnel plot was utilized to analyze the publication bias of 15 studies. The outcome of the graph showed a certain degree of publication bias. The authors further used the Egger method to check and quantify the funnel plot. The p-value was checked to determine whether there was publication bias. The T-value in bias (p = 0.854) meant that there was no publication bias (Supplementary Fig. S4).

Study quality

Regarding the quality of all studies, the NOS score ranged from 6 to 8. The authors determined that 6 studies had a low risk of bias, 7 studies had a medium risk of bias, and 2 studies had a high risk of bias (Table 1).

Subgroup analysis

The authors conducted the subgroup analyses, including regions (Western vs. Asian countries), study period (covering 2000 vs. after 2000), and funding (with vs. without). The research region of the three studies was Asia,2626 Min C, Lim H, Lim JS, Sim S, Choi HG. Increased risk of migraine in psoriatic patients: A longitudinal follow up study using a national sample cohort. Medicine (Baltimore). 2019;98:e15370.,2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,3434 Chiang CH, Huang CC, Chan WL, Huang PH, Chen YC, Chen TJ, et al. Psoriasis and increased risk of ischemic stroke in Taiwan: a nationwide study. J Dermatol. 2012;39:279–81. the rest was the West. The outcomes showed that Asian countries with pRR of 1.09 (95% CI 0.95–1.24, I2 = 98%, p < 0.001) and 1.24 (95% CI 1.12–1.37, I2 = 9 8%, p < 0.001) for Western countries. The I2 was 55.5% and p-value was 0.13 between the subgroups (Supplementary Fig. S5).

Two studies had not clearly pointed out the study duration,3838 Schell C, Schleich R, Walker F, Yazdi AS, Lerche H, Röcken M, et al. Restless legs syndrome in psoriasis: an unexpected comorbidity. Eur J Dermatol. 2015;25:255–60.,4040 Yeung H, Takeshita J, Mehta NN, Kimmel SE, Ogdie A, Margolis DJ, et al. Psoriasis severity and the prevalence of major medical comorbidity: a population-based study. JAMA Dermatol. 2013;149:1173–9. and the rest studies were divided into two groups for further discussion. Four researches’ periods were over the year of 2000,3131 Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J. 2012;33:2054–64.,3333 Charlton R, Green A, Shaddick G, Snowball J, Nightingale A, Tillett W, et al. Risk of type 2 diabetes and cardiovascular disease in an incident cohort of people with psoriatic arthritis: a population-based cohort study. Rheumatology (Oxford). 2019;58:144–8.,3434 Chiang CH, Huang CC, Chan WL, Huang PH, Chen YC, Chen TJ, et al. Psoriasis and increased risk of ischemic stroke in Taiwan: a nationwide study. J Dermatol. 2012;39:279–81.,3636 Khalid U, Ahlehoff O, Gislason GH, Skov L, Torp-Pedersen C, Hansen PR. Increased risk of aortic valve stenosis in psoriatic patients: a nationwide cohort study. Eur Heart J. 2015;36:2177–83. and pRR was 1.04 (95% CI 0.89–1.21, I2 =97%, p < 0.001). pRR of the rest researches (after 2000) was 1.31 (95% CI 1.17–1.47, I2 =99%, p < 0.001). The I2 was 82.7% and the p-value was 0.02 between the subgroups (Supplementary Fig. S6).

There was some research that had no funding,2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,3232 Armstrong AW, Azizi S, Wu J, Harskamp CT, Farrow J, Johnson MAN, et al. Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. Arch Dermatol Res. 2013;305:891–7. while the rest of the studies were funded. The analysis showed that pRR of unfunded research was 1.33 (95% CI 1.10–1.62, I2 = 99%, p < 0.001), and pRR of funded ones was 1.18 (95% CI 1.09–1.29, I2 = 98%, p < 0.001), The I2 was 18.7% and p-value was 0.27 between the subgroups (Supplementary Fig. S7).

These results of subgroup analyses, including regions (Western vs. Asian countries), study period (covering 2000 vs. after 2000), and funding (with vs. without), had not provided any specific source of heterogeneity.

Meta-regression

According to the characteristics of included studies, new concomitant variables were generated after dummy variables were assigned according to regions (Western vs. Asian countries), study period (covering 2000 vs. after 2000), and funding (with vs. without). The logarithmic LogRR of each study effect indicator RR was the dependent variable. The meta regressions were all carried out (p > 0.05), but there was no source of heterogeneity.

Discussion

The present study is the first meta-analysis of comorbidity risk in terms of organs in psoriatic patients. These risks of organ-based comorbidity were consistent with the previously published data at single-disease level. For example, previous studies showed that psoriatic patients had a higher risk of hypertension (OR = 1.58, 95% CI 1.42–1.76),4747 Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and hypertension: a systematic review and meta-analysis of observational studies. J Hypertens. 2013;31:433–42. end-stage renal disease (RR = 1.29, 95% CI 1.05–1.60),4848 Ungprasert P, Raksasuk S. Psoriasis and risk of incident chronic kidney disease and end-stage renal disease: a systematic review and meta-analysis. Int Urol Nephrol. 2018;50:1277–83. stroke (OR = 1.08, 95% CI 1.00–1.16),4949 Wiseman SJ, Ralston SH, Wardlaw JM. Cerebrovascular Disease in Rheumatic Diseases: A Systematic Review and Meta-Analysis. Stroke. 2016;47:943–50. non-alcoholic fatty liver disease (OR = 2.15, 95% CI 1.57–2.94),2424 Li X, Kong L, Li F, Chen C, Xu R, Wang H, et al. Association between Psoriasis and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis. PLoS One. 2015;10:e0145221. and COPD (OR = 1.90, 95% CI1.36–2.65).2121 Candia R, Ruiz A, Torres-Robles R, Chávez-Tapia N, Méndez-Sánchez N, Arrese M. Risk of non-alcoholic fatty liver disease in psoriatic patients: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2015;29:656–62. The authors found that psoriatic patients had a significantly higher risk of organ-based comorbidities than the general population. For example, comorbidity pRR was 1.20 for the overall cardiovascular organ, 1.75 for the whole liver, 1.56 for the whole cerebrovascular organ, 1.08 and 1.05 for the entire kidney organ and lung organs, respectively. In the cardiovascular, liver, and cerebrovascular, organ-based comorbidity risks of psoriasis were remarkably higher than in the general population. Although there was no significant difference between psoriasis and controls in relation to renal and pulmonary diseases, the results can also provide some reference for future research. In addition, compared with mild psoriatic patients, the authors demonstrated that moderate/severe psoriatic patients had a more notably increased risk of organ-based comorbidities.

Previous studies had shown that psoriatic patients may suffer from two or more comorbidities simultaneously, e.g., heart failure combined with chronic kidney disease,4343 Tokuyama M, Shimizu T, Yamada T Kondoh A, Mabuchi T. Case of psoriasis vulgaris with atrial fibrillation, heart failure and chronic kidney disease which were found accidentally through blood examination during apremilast treatment. J Dermatol. 2019;46:e239–40. gout or acute kidney injury combined with hypertension, liver cirrhosis, or cerebrovascular disease.4444 Hu SC, Lin CL, Tu HP. Association between psoriasis, psoriatic arthritis and gout: a nationwide population-based study. J Eur Acad Dermatol Venereol. 2019;33:560–7.,4545 AlJohani R, Polachek A, Ye JY, Chandran V, Gladman DD. Characteristic and Outcome of Psoriatic Arthritis Patients with Hyperuricemia. J Rheumatol. 2018;45:213–7.,4646 Romero-Pérez D, Belinchón-Romero I, Bellot P, Francés R, Marco F, Ramos-Rincón JM. Nonalcoholic fatty liver disease puts psoriatic patients at greater cardiovascular risk. Australas J Dermatol. 2019;60:e304–10. To find out these combined comorbidity risks in psoriasis, the authors pooled data from multiple organs. The authors found that pRR for renal diseases plus cardiovascular events in the same psoriatic patient was 1.09 (95% CI 1.01–1.18), 1.28 (95% CI 0.99–1.66) for renal diseases plus cerebrovascular events, 1.46 (95% CI 1.10–1.94) for renal diseases plus liver diseases, and 1.41 (95% CI 1.11–1.80) for cardiovascular events plus liver diseases. These values showed that psoriatic patients had significantly higher risks of multiple organ-based comorbidities, not only single organ-based comorbidities.

In order to further analyze the relationship between organ-based comorbidity risks of psoriasis and study year and patients’ region, the authors compared several sets of data. Due to the diverse characteristics of the years included in the studies, the authors took the year 2006 as the demarcation point, based on the principle of pursuing maximum similarity. Six groups of meaningful data were selected,2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,3030 Ahlehoff O, Gislason GH, Lindhardsen J, Olesen JB, Charlot M, Skov L, et al. Prognosis following first-time myocardial infarction in psoriatic patients: a Danish nationwide cohort study. J Intern Med. 2011;270:237–44.,3131 Ahlehoff O, Gislason GH, Jørgensen CH, Lindhardsen J, Charlot M, Olesen JB, et al. Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study. Eur Heart J. 2012;33:2054–64.,3232 Armstrong AW, Azizi S, Wu J, Harskamp CT, Farrow J, Johnson MAN, et al. Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. Arch Dermatol Res. 2013;305:891–7.,3535 Feldman SR, Zhao Y, Shi L, Tran MH. Economic and Comorbidity Burden Among Patients with Moderate-to-Severe Psoriasis. J Manag Care Spec Pharm. 2015;21:874–88.,3737 Lee S, Xie L, Wang Y, Vaidya N, Baser O. Comorbidity and economic burden among moderate-to-severe psoriasis and/or psoriatic arthritis patients in the US Department of Defense population. J Med Econ. 2018;21:564–70. and pRR was 0.23 (95% CI 0.05–1.00, I2 = 100%, p < 0.001) after merging data (Supplementary Fig. S8). This suggested that psoriatic patients after the year of 2006 were more likely to suffer from organ-based comorbidities. As few studies were included in the East, three groups matched with the characteristics of studies in East were used for comparative study.2626 Min C, Lim H, Lim JS, Sim S, Choi HG. Increased risk of migraine in psoriatic patients: A longitudinal follow up study using a national sample cohort. Medicine (Baltimore). 2019;98:e15370.,2727 Yang YW, Keller JJ, Lin HC. Medical comorbidity associated with psoriasis in adults: a population-based study. Br J Dermatol. 2011;165:1037–43.,3232 Armstrong AW, Azizi S, Wu J, Harskamp CT, Farrow J, Johnson MAN, et al. Psoriasis, electrocardiographic characteristics, and incidence of atrial fibrillation. Arch Dermatol Res. 2013;305:891–7.,3333 Charlton R, Green A, Shaddick G, Snowball J, Nightingale A, Tillett W, et al. Risk of type 2 diabetes and cardiovascular disease in an incident cohort of people with psoriatic arthritis: a population-based cohort study. Rheumatology (Oxford). 2019;58:144–8.,3434 Chiang CH, Huang CC, Chan WL, Huang PH, Chen YC, Chen TJ, et al. Psoriasis and increased risk of ischemic stroke in Taiwan: a nationwide study. J Dermatol. 2012;39:279–81.,3939 Vena GA, Altomare G, Ayala F Berardesca E, Calzavara-Pinton P, Chimenti S, et al. Incidence of psoriasis and association with comorbidities in Italy: a 5-year observational study from a national primary care database. Eur J Dermatol. 2010;20:593–8. After merging data, pRR was 1.73 (95% CI 1.07–2.77, I2 = 100%, p < 0.001) (Supplementary Fig. S9). The result suggested that Asian psoriatic patients were more likely to suffer from organ-based comorbidities. These conclusions need more data for further confirmation.

The pathogenesis of psoriasis and organ-based comorbidities may be mediated by certain representative cytokines, e.g., Interleukin-17 (IL-17),5050 Stebut E, Boehncke WH, Ghoreschi K, Gori T, Kaya Z, Thaci D, et al. IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications. Front Immunol. 2020;10:3096.,5151 Hugh J, Voorhees AS, Nijhawan RI, Bagel J, Lebwohl M, Blauvelt A, et al. From the Medical Board of the National Psoriasis Foundation: The risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies. J Am Acad Dermatol. 2014;70:168–77.,5252 Schön MP, Erpenbeck L. The Interleukin-23/Interleukin-17 Axis Links Adaptive and Innate Immunity in Psoriasis. Front Immunol. 2018;9:1323.,5353 Blauvelt A, Chiricozzi A. The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis. Clin Rev Allergy Immunol. 2018;55:379–90. Interleukin-23 (IL-23),5454 Dolgin E. New anti-IL-23 drugs raise hopes for psoriasis plaque clearance. Nat Biotechnol. 2016;34:1218–9. and Tumour Necrosis Factor-a (TNF-a).5555 Campanati A, Paolinelli M, Diotallevi F, Martina E, Molinelli E, Offidani A. Pharmacodynamics OF TNF α inhibitors for the treatment of psoriasis. Expert Opin Drug Metab Toxicol. 2019;15:913–25.,5656 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244–79. They can reach the body anywhere through the blood circulation and may mediate systemic inflammatory responses in psoriasis.5757 Korman NJ. Management of psoriasis as a systemic disease: what is the evidence? Br J Dermatol. 2020;182:840–8.,5858 Lockshin B, Balagula Y, Merola JF. Interleukin 17, inflammation, and cardiovascular risk in psoriatic patients. J Am Acad Dermatol. 2018;79:345–52.,5959 Gisondi P, Bellinato F, Girolomoni G, Albanesi C. Pathogenesis of Chronic Plaque Psoriasis and Its Intersection With Cardio-Metabolic Comorbidities. Front Pharmacol. 2020;11:117.,6060 Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies. J Am Heart Assoc. 2013;2:e000062.,6161 Raaby L, Ahlehoff O, Thurah A. Psoriasis and cardiovascular events: updating the evidence. Arch Dermatol Res. 2017;309:225–8. Whether the inflammatory cytokines act on each system together or singly? Whether the effects are generated by the same molecular mechanism and immune-inflammatory pathway? These questions are unclear and still need further study. Actually, the cytokines behind the pathogenesis of each organ may be the same or absolutely different. The existing research has shown that main inflammation cytokine behind psoriasis with joints or diabetes is TNF-a.6262 Braun J, Sieper J. Role of novel biological therapies in psoriatic arthritis: effects on joints and skin. BioDrugs. 2003;17: 187–99.,6363 Maneiro JR, Souto A, Gomez-Reino JJ. Impact of treatment with TNF antagonists on total cholesterol in patients with ankylosing spondylitis and psoriatic arthritis. Clin Rheumatol. 2017;36:1167–72.,6464 Lubrano E, Scriffignano S, Perrotta FM. TNF-alpha inhibitors for the six treatment targets of psoriatic arthritis. Expert Rev Clin Immunol. 2019;15:1303–12.,6565 Wang C, Guan Y, Yang J. Cytokines in the Progression of Pancreatic β-Cell Dysfunction. Int J Endocrinol. 2010;2010:515136.,6666 Wilcox NS, Rui J, Hebrok M, Herold KC. Life and death of β cells in Type 1 diabetes: A comprehensive review. J Autoimmun. 2016;71:51–8. However, the cytokine in psoriasis involving the cardiovascular system may be IL-17 or IL-23.6767 Egeberg A, Gisondi P, Carrascosa JM, Warren RB, Mrowietz U. The role of the interleukin-23/Th17 pathway in cardiometabolic comorbidity associated with psoriasis. J Eur Acad Dermatol Venereol. 2020;34:1695–706.,6868 Brembilla NC, Senra L, Boehncke WH. The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond. Front Immunol. 2018;9:1682.,6969 Lowes MA, Russell CB, Martin DA, Towne JE, Krueger JG. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol. 2013;34:174–81. All these still need further investigation.

The present study can provide a reference for effective clinical treatments. Lately, biological antibody therapy plays a promising role in the control of psoriatic morbidity and mortality.7070 Loft ND, Vaengebjerg S, Halling AS, Skov L, Egeberg A. Adverse events with IL-17 and IL-23 inhibitors for psoriasis and psoriatic arthritis: a systematic review and meta-analysis of phase III studies. J Eur Acad Dermatol Venereol. 2020;34:1151–60.,7171 Mylle S, Grine L, Speeckaert R, Lambert JLW, Geel N. Targeting the IL-23/IL-17 Pathway in Psoriasis: the Search for the Good, the Bad and the Ugly. Am J Clin Dermatol. 2018;19:625–37.,7272 Gooderham MJ, Papp KA, Lynde CW. Shifting the focus – the primary role of IL-23 in psoriasis and other inflammatory disorders. J Eur Acad Dermatol Venereol. 2018;32:1111–9.,7373 Hawkes JE, Chan TC, Krueger JG. Psoriasis pathogenesis and the development of novel targeted immune therapies. J Allergy Clin Immunol. 2017;140:645–53.,7474 Kim J, Krueger JG. Highly Effective New Treatments for Psoriasis Target the IL-23/Type 17 T Cell Autoimmune Axis. Annu Rev Med. 2017;68:255–69.,7575 Canavan TN, Elmets CA, Cantrell WL, Evans JM, Elewski BE. Anti-IL-17 Medications Used in the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review. Am J Clin Dermatol. 2016;17:33–47. If molecular mechanisms and dysregulated target cytokines in involved organs are different, then the choice of biological antibody should be totally different.7676 Loft N, Halling AS, Egeberg A, Skov L. Efficacy of a second interleukin 17 inhibitor in psoriatic patients: A systematic review and meta-analysis. J Am Acad Dermatol. 2021;84:130–8.,7777 Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil S. Interleukin 17A: toward a new understanding of psoriasis pathogenesis. J Am Acad Dermatol. 2014;71:141–50.,7878 Conrad C, Gilliet M. Psoriasis: from Pathogenesis to Targeted Therapies. Clin Rev Allergy Immunol. 2018;54:102–13.,7979 Boehncke WH, Brembilla NC. Unmet Needs in the Field of Psoriasis: Pathogenesis and Treatment. Clin Rev Allergy Immunol. 2018;55:295–311.,8080 Kaushik SB, Lebwohl MG. Psoriasis: Which therapy for which patient: Psoriasis comorbidities and preferred systemic agents. J Am Acad Dermatol. 2019;80:27–40. No biological antibody is a panacea,8181 Dauden E, Blasco AJ, Bonanad C, Botella R, Carrascosa JM, González-Parra E, et al. Position statement for the management of comorbidities in psoriasis. J Eur Acad Dermatol Venereol. 2018;32:2058–73.,8282 Boehncke WH, Boehncke S, Schön MP. Managing comorbid disease in psoriatic patients. BMJ. 2010;340:b5666.,8383 Kaushik SB, Lebwohl MG. Psoriasis: Which therapy for which patient: Focus on special populations and chronic infections. J Am Acad Dermatol. 2019;80:43–53.,8484 Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, et al. Evidence-based Recommendations for the Management of Comorbidities in Rheumatoid Arthritis, Psoriasis, and Psoriatic Arthritis: Expert Opinion of the Canadian Dermatology-Rheumatology Comorbidity Initiative. J Rheumatol. 2015;42:1767–80. and the authors should try to provide patients with more individualized treatment plan according to organ-based comorbidities that psoriasis involved.

There are several limitations in the meta-analysis. First, there is heterogeneity. It was considered that heterogeneity was normally distributed and acceptable. The statistical heterogeneity did not affect the outcome. It was observed that the rate of heterogeneity in meta-analysis of general prevalence was always high. It was related to a huge number of study objects and the nature of observational studies. In this study, subgroup analysis and meta-regression were conducted to try to find the source of heterogeneity. The authors also used a random-effects model to address potential heterogeneity. However, each study was qualitatively similar to the analysis of all organ-based comorbidities and individual organ-based comorbidities. Secondly, some systematic analyses, meta-regression, and subgroup analyses lacked high statistical power because of the small number of included studies. Care should be taken when analyzing these data. Thirdly, the topic of the present study is novel, and there is no study on organ-based comorbidities of psoriasis. For the PECO approach, it is different from the traditional PECO expression and may cause confusion. The study population included the exposure group plus the control group, i.e., the Population contains Exposure and Comparative. However, the present study’s results can still provide a reference for clinicians in the management of psoriasis comorbidities.

Conclusions

The authors show that psoriatic patients have increased risks of both single and multiple organ-based comorbidities. None of these has been reported in published literature. These results suggest that systemic inflammation control should be observed in the treatment, especially for moderate/severe patients.

Supplementary Material.

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.abd.2021.10.007.

  • Financial support
    This study was supported in part by the National Natural Science Foundation of China (nº 81771783, 82073444).
  • Study conducted at the Southwest Medical University, Luzhou, Sichuan, China.

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Publication Dates

  • Publication in this collection
    30 Sept 2022
  • Date of issue
    Sep-Oct 2022

History

  • Received
    05 July 2021
  • Accepted
    04 Oct 2021
  • Published
    15 July 2022
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