Management of Psoriasis as a Systemic Disease: What Is the Evidence?

N.J. Korman

The British Journal of Dermatology. 2020;182(4):840-848.

Discussion

Given the breadth of data indicating that psoriasis is a systemic disease and should be managed as such, it seems clear that systemic treatments are needed to optimize patient outcomes. Two goals were set forth to guide practitioners towards effective management of systemic inflammation in psoriasis. Based on the available evidence, the first goal – to prevent damage associated with inflammation and prevent future damage/comorbidities – appears to be attainable for many patients with the use of biological agent therapy early in the course of disease, which targets the appropriate proinflammatory cytokines. The second, loftier, goal – to reverse existing damage/comorbid conditions caused by inflammation – has less evidence supporting its attainability. However, results from several studies in both animals and humans suggest that reversing damage may be more achievable than practitioners currently appreciate. The advancement of research on new biomarkers, which could improve either earlier diagnosis of comorbidities or clinical evaluation of comorbidities, may help practitioners better evaluate patient response to systemic therapies. In order to provide further support for the attainability of these treatment goals, efforts to collect prospective data are underway. Results from these prospective trials are expected to deliver important insights into the role that biological agents may play in treating systemic inflammation associated with psoriasis.

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Acknowledgments
Technical assistance with editing and styling of the manuscript for submission was provided by Oxford PharmaGenesis Inc. and was funded by Novartis Pharmaceuticals Corporation. The author was fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript.

Funding sources
Writing and editorial assistance funded by Novartis Pharmaceuticals Inc., East Hanover, NJ, U.S.A.

Table 1. Comorbidities associated with psoriasis
Comorbidity	Increased risk with psoriasis
CVD⁷⁷	Atherosclerosis
	• Moderate psoriasis (Adjusted OR 1·39, 95% CI 1·11–1·76)
	• Severe psoriasis (Adjusted OR 1·81, 95% CI 1·25–2·63)
	Heart failure
	• Severe psoriasis (Adjusted OR 2·98, 95% CI 1·37–6·49)
	• Moderate psoriasis (Adjusted OR 0·77, 95% CI 0·37–1·59)
	• Mild psoriasis (Adjusted OR 0·93, 95% CI 0·54–1·61)
Diabetes mellitus⁷⁸	Mild psoriasis (IRR 1·49, 95% CI 1·43–1·56)
	Severe psoriasis (IRR 2·13, 95% CI 1·91–2·37)
Obesity⁷⁹	Mild psoriasis (pooled OR 1·46, 95% CI 1·17–1·82)
	Moderate-to-severe psoriasis (pooled OR 2·23, 95% CI 1·63–3·05)
NAFLD¹¹	Overall (OR 2·15, 95% CI 1·57–2·94)
	Moderate-to-severe psoriasis (OR 2·07, 95% CI 1·59–2·71)
PsA⁸⁰	Affects 30% of patients with psoriasis
IBD⁸¹	Patients with psoriasis have a 2·9-fold higher risk of developing Crohn disease than the general population

CI, confidence interval; CVD, cardiovascular disease; IBD, inflammatory bowel disease; IRR, incidence rate ratio; NAFLD, nonalcoholic fatty liver disease; OR, odds ratio; PsA, psoriatic arthritis.

Table 2. Pathogenesis of psoriasis comorbidities
Comorbidity	Evidence of shared systemic inflammatory pathways
CVD^25,82–86	Atherosclerosis
	• IL-17A contributes to atherosclerotic lesion progression and plaque instability in murine models
	•ACS is associated with upregulation of IL-17 and T helper (Th)17 cells. Th17 cells upregulate the number of IL-17 receptors on endothelial cells and vascular smooth muscle cells
	•Cytokine product of Th1 cells (i.e. TNF-α) promotes endothelial dysfunction and movement of T cells to atherosclerotic plaques
	•Patients with psoriasis have increased levels of markers of platelet activation (spontaneous platelet hyperaggregability, mean platelet volume, plasma levels of β-thromboglobulin and platelet factor 4), which are reduced on psoriasis clearance
	Heart failure
	• Increased serum/plasma levels of TNF-α and IL-6
	• Levels of TNF-α are directly related to the New York Heart Association functional class
	• Overall functional status in patients with CHF is inversely associated with levels of IL-6
Diabetes mellitus⁸⁷	• TNF-α promotes insulin resistance by reducing tyrosine kinase activity of the insulin receptor
	• High serum levels of IL-6 (in conjunction with IL-1β), IL-8, IL-17 and IL-18 are found in diabetes and considered to contribute to insulin resistance
Obesity^88–90	• Adipose tissue of individuals with obesity promotes the development of Th17 cells
	• IL-17A expression is upregulated in obesity
	• Other cytokines, such as TNF-α and IL-6, contribute to the proinflammatory state of obesity
NAFLD91	• TNF-α exacerbates hepatic insulin resistance, resulting in increased FFA synthesis and decreased FFA oxidation, thereby promoting hepatic steatosis
PsA^92–98	• IL-23 and downstream cytokines IL-17 and IL-22 promote enthesitis in murine models
	• Increased concentrations of Th17 cells, IL-17RA, IL-17A, TNF-α and IL-1 in the synovium of patients with PsA
	• IL-17 and IL-22 linked to pannus formation in the joint, joint erosion and new bone formation
IBD⁹⁹	Crohn disease
	• Mediated by Th1 cells and their cytokine products (i.e. TNF-α and IFN-γ)
	• Increased levels of IL-17 and IL-23 found in the intestinal lamina propia of patients with Crohn disease

ACS, acute coronary syndrome; CHF, congestive heart failure; CVD, cardiovascular disease; FFA, free fatty acid; IBD, inflammatory bowel disease; IFN, interferon; IL, interleukin; NAFLD, nonalcoholic fatty liver disease; PsA, psoriatic arthritis; TNF, tumour necrosis factor.

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Management of Psoriasis as a Systemic Disease: What Is the Evidence?

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