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

N.J. Korman

Disclosures

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

In This Article

Goals for Treating Systemic Inflammation in Psoriasis

Studies in other immune-mediated inflammatory diseases (IMIDs), including Crohn disease and rheumatoid arthritis (RA), have demonstrated the significant benefits of early treatment with approved biologics to improve outcomes and suggest that similar approaches may be helpful in controlling systemic inflammation and optimizing long-term outcomes in psoriasis.[15] Notably, several of the same biological agents are approved for the treatment of moderate-to-severe psoriasis and RA (etanercept, adalimumab, certolizumab and infliximab) and/or Crohn disease (adalimumab, infliximab, certolizumab and ustekinumab) owing to the centrality of their targets in disease pathogenesis.

As practitioners more readily recognize psoriasis as a systemic disease and place more emphasis on controlling systemic inflammation, treatment goals can be separated into two distinct categories based on the feasibility of achieving desired outcomes. The first and most practically implementable goal is potentially preventing damage associated with systemic inflammation while simultaneously potentially preventing the progression of psoriasis and its comorbidities. The second, perhaps loftier and more forward-thinking, goal is potentially reversing existing inflammatory damage and signs and symptoms of comorbidities.

Goal 1: Prevent Damage Associated With Inflammation and Prevent Future Damage/Comorbidities

Numerous biomarkers of inflammation have been identified.[26] Some of the most commonly utilized markers of inflammatory damage and cardiovascular risk in active psoriasis include C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).[26] CRP levels are positively correlated with disease severity as measured by the Psoriasis Area and Severity Index (PASI).[27,28] CRP is also an independent predictor of CVD risk and is implicated in the development of atherosclerotic lesions because it reduces expression of nitric oxide synthase and prostacyclin synthase, binds low-density lipoprotein cholesterol stimulating its uptake by macrophages and upregulates expression of adhesion molecules on endothelial cells.[29] As levels of CRP decrease, cardiovascular risk lowers.[29] However, there is evidence that questions the clinical usefulness of CRP for evaluating cardiovascular risk among individuals with inflammatory conditions such as psoriasis, indicating a need for alternative CVD risk biomarkers in patients with underlying inflammatory conditions.[30,31]

Treatment with biological agents decreases systemic inflammation as measured by the ESR and CRP levels in several different disease states. For example, TNF-α inhibitors significantly reduce both ESR and CRP levels in RA.[32,33] TNF-α inhibitors also significantly reduce CRP levels in patients who have either metabolic syndrome or Crohn disease.[34,35] Similarly, the IL-12/23 inhibitor ustekinumab reduces ESR and CRP levels in Crohn disease,[36] and the IL-17A inhibitor secukinumab reduces CRP levels in ankylosing spondylitis and reduces ESR levels in PsA.[37,38] In patients with moderate-to-severe psoriasis treated with systemic therapies, including methotrexate, adalimumab, etanercept, infliximab and ixekizumab, studies have reported reductions in ESR and/or CRP levels.[39–47]

Data from retrospective studies support the concept that certain biological agents targeting relevant proinflammatory cytokines involved in psoriasis pathogenesis may be the best treatment options to reduce the likelihood that patients with psoriasis will develop CVD. A large U.S. retrospective analysis of cardiovascular event rates in patients with psoriasis (severity not reported) found that patients receiving TNF-α inhibitors (etanercept, infliximab or adalimumab; percentages not specified) had significantly lower risks for myocardial infarction (MI) compared with patients receiving topical therapies [adjusted odds ratio 0·50, 95% confidence interval (CI) 0·32–0·79],[48] and that treatment with these therapies decreased the risk of major cardiovascular events compared with methotrexate over 12 months of follow-up [adjusted hazard ratio (HR) 0·55, P < 0·001].[49] Furthermore, over 24 months of follow-up, cumulative exposure to TNF-α inhibitors was associated with an 11% reduction in cardiovascular risk for every 6 months of treatment (P = 0·02).[49] Another retrospective study utilizing a U.S. administrative claims database that included information from approximately 25 million patients and their dependents, compared over 11 000 patients with psoriasis who were given TNF-α inhibitors with over 12 000 patients with psoriasis who were treated with phototherapy.[50] They found that the TNF inhibitor cohort had a lower risk for major cardiovascular events when compared with the phototherapy cohort (adjusted HR 0·77, 95% CI 0·60–0·99; P = 0·046). Similarly, another large retrospective U.S. study with information from over 7·5 million patients with a mean follow-up time of 4·7 years found that individuals with psoriasis who received TNF-α inhibitors had a lower risk for major cardiovascular events than those receiving oral/phototherapy or topical therapy.[51] In a systematic review and meta-analysis of patients with psoriasis and/or PsA, systemic therapy was associated with a significantly decreased risk of cardiovascular events compared with no systemic therapy or topical therapy.[52] Importantly, a prospective study of 220 patients with moderate psoriasis found that improvement in PASI score, predominantly via treatment with TNF-α inhibitors (particular agents were unspecified), was associated with reduced aortic vascular inflammation measured using 18F-FDG PET/CT.[53]

Although most research on the cardiovascular effects of treatment with TNF-α inhibitors in psoriasis has reported improvements in outcomes, not all studies suggest a positive correlation between treatment with biological agents and a reduced cardiovascular risk. A retrospective study of over 25 000 patients with moderate-to-severe psoriasis evaluated those treated with systemic therapies, including methotrexate, ciclosporin, alefacept, efalizumab, adalimumab, etanercept and infliximab, and compared them with patients who received ultraviolet B phototherapy. In this study, no significant difference was found in overall MI risk between the two groups (adjusted HR 1·33, 95% CI 0·90–1·96).[54] Additionally, a retrospective study of 6902 patients with severe psoriasis reported similar risk for cardiovascular events with TNF-α or IL-12/23 inhibition (adjusted HR 0·58, 95% CI 0·30–1·10) compared with methotrexate (adjusted HR 0·53, 95% CI 0·34–0·83).[55]

There have also been two small prospective studies of treatment with adalimumab in moderate-to-severe psoriasis. One study evaluated the effects of adalimumab compared with placebo for 16 weeks followed by open-label adalimumab treatment for 1 year.[56] The other study examined adalimumab, phototherapy and placebo for 12 weeks followed by open-label adalimumab therapy for 1 year.[57] Neither study demonstrated reduced vascular inflammation in the patients treated with adalimumab compared with placebo either at 12 weeks[57] or 16 weeks[56] or with phototherapy at 12 weeks[57] as measured by 18F-FDG PET/CT. However, one of these studies evaluated several biomarkers and found decreased levels of glycoprotein acetylation, a novel composite biomarker of systemic inflammation, in patients treated with adalimumab compared with those treated with phototherapy.[57] Additionally, a small prospective study of ustekinumab in a Korean population observed significantly decreased vascular inflammation in individuals who achieved ≥ 75% improvement in PASI over a mean treatment period of 5 months.[58] Ongoing prospective studies include Vascular Inflammation in Psoriasis (VIP) trials that are currently evaluating the effects of ustekinumab (VIP-U; NCT02187172), secukinumab (VIP-S; NCT02690701) and apremilast (VIP-A; NCT03082729) on aortic inflammation as measured by 18F-FDG PET/CT and on levels of biomarkers associated with metabolic and cardiovascular risk. Results from studies of biological agents in IMIDs other than psoriasis support the hypothesis that biological agents can reduce systemic inflammation and prevent cardiovascular damage.[59,60]

In addition to having the potential to prevent damage associated with vascular inflammation and preventing CVD,[48,49,53] treatment with TNF-α inhibitors may play an important role in reducing inflammatory damage in other psoriasis comorbidities. In patients with psoriasis, increased systemic inflammation and dysregulation of adipocytokines, including leptin, resistin and adiponectin, increase the risk for insulin resistance that can progress to the development of diabetes mellitus and metabolic syndrome.[25,61] This risk increases with psoriasis severity and decreases with TNF-α inhibitor therapy.[44,62,63] In a small study (N = 89) that compared treatment with etanercept vs. psoralen and ultraviolet A (PUVA) therapy in moderate-to-severe psoriasis, NAFLD and metabolic syndrome, Campanati et al. observed that etanercept therapy was associated with significant reductions in transaminases, CRP and fasting insulin, and an increase in insulin sensitivity, whereas treatment with PUVA did not lead to significant reductions in these markers.[62] These results support the concept that treatment with etanercept may have a more beneficial role than traditional therapies in preventing the progression of NAFLD to hepatic fibrosis via both its anti-inflammatory and glucose homeostatic properties.

Obesity is a well-known comorbidity of psoriasis, and in obesity, as in psoriasis and PsA, there is dysregulation of the levels and/or functions of ILs, TNF-α and other adipocytokines.[25] However, a possible role for biological agents in mitigating obesity in psoriasis has not been observed to date. In fact, TNF-α inhibitors have induced modest weight gain in patients with moderate-to-severe psoriasis.[64–67] No evidence of clinically significant weight gain has been reported in studies of ustekinumab or ixekizumab in moderate-to-severe psoriasis.[67,68] The ongoing ObePso-S trial (NCT03055494) is prospectively exploring the effects of IL-17A inhibition with the use of secukinumab on adipose tissue and skin inflammation in moderate-to-severe psoriasis.

Goal 2: Reverse Existing Damage/Comorbid Conditions Caused by Inflammation

Evidence supporting the reversal of existing damage and/or comorbid conditions caused by systemic inflammation in patients with psoriasis is encouraging but not as well developed as evidence supporting the first stated goal of preventing damage and preventing future comorbidities. A study of ustekinumab treatment in patients with moderate-to-severe psoriasis (N = 46) showed regression of subclinical inflammatory entheseal and synovial abnormalities, suggesting the possibility that PsA development could be inhibited by biological treatment of psoriasis.[69] Additionally, a study of 105 patients with varying degrees of psoriasis severity used CT angiography to show that treatment with systemic or biological agents was associated with improvement in noncalcified coronary plaque burden.[70] Furthermore, a study of 53 patients with moderate-to-severe psoriasis reported that methotrexate and ustekinumab significantly decreased carotid intima-media thickness levels.[71] Other studies have shown improvement in measures of cardiovascular function with systemic psoriasis therapies.[72–75] The effect of secukinumab on endothelial dysfunction in moderate-to-severe psoriasis without severe CVD is currently being evaluated in the prospective CARIMA study (NCT02559622).

Although it was hypothesized in most of these studies that the use of systemic anti-inflammatory treatment in psoriasis would lead to a decrease in the severity of comorbidities, studies published to date have been limited in size and scope, and larger well-designed studies are needed to provide a definitive link between these types of improvements and reductions in systemic inflammation. Overall, these findings are encouraging and suggest that early treatment with biologics has the potential, at least in the short term, to reverse damage caused by inflammatory comorbidities associated with psoriasis.

processing....