Psoriasis is a common skin disease that affects approximately 3% of the population in the United States (Armstrong, 2013). This disease usually presents itself on the skin with scaly plaques; however, it is becoming more widely accepted as not only a skin disease but also a systemic chronic inflammatory disease (Boehncke, Fichtlscherer, et al., 2011). It has been shown that, because of this systemic inflammation, patients with psoriasis have an increased prevalence of cardiovascular risk factors including a greater incidence of coronary artery disease, myocardial infarction (MI), and cardiovascular death compared with the general population (Armstrong, 2013). These comorbid conditions are thought to be secondary to chronically elevated levels of cytokines resulting from systemic inflammation (Villasenor-Park, Wheeler, & Grandinetti, 2012). These cytokines may include tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-17.
With increased understanding of the systemic pathology of psoriasis, targeted treatment therapies have emerged in recent years. In attempts to target TNF-alpha, a number of biologics such as infliximab, etanercept, and adalimumab have been developed for the treatment of psoriasis and other chronic inflammatory disorders (Channual, Wu, & Dann, 2009). Ustekinumab has also been developed and targets IL-12 and IL-23, and there may be other inflammatory cytokines that play a role in psoriasis and systemic inflammation (Villasenor-Park et al., 2012). Other widely used systemic therapies include methotrexate and cyclosporine (Bissonnette et al., 2013). Other nonsystemic treatments for psoriasis include topical treatments, corticosteroids, vitamin D analogues, dithranol, and tar (Wakkee, Thio, Prens, Sijbrands, & Neumann, 2007). These are commonly reserved for milder forms of psoriasis when systemic therapy is not warranted.
Systemic treatments continue to be very effective in the treatment of psoriasis (Yost & Gudjonsson, 2009). Furthermore, these therapies are not only reducing the burden of the skin disease but, with their targeted antagonist actions on systemic inflammation, are suggesting a beneficial decrease in cardiovascular risk. With emerging data on biologic therapies and their beneficial outcomes on suppressing systemic inflammation, change in treatment of patients with psoriasis is evolving. As Armstrong (2013) states: “Whether systemic treatments for psoriasis modify the risk of major adverse cardiovascular events is a clinically significant question.” As this statement suggests, it is important to examine the best available evidence to determine this relationship and its clinical significance.
METHODS OF REVIEW
A literature search was conducted using the computerized databases of PubMed, CINAHL, Cochrane Library, UpToDate, Google Scholar, and Web of Knowledge. To identify pertinent studies within the past 5 years, various keywords and searches were utilized. Keywords used in the search included psoriasis, biologic therapy, and cardiovascular risk. To include all pertinent studies, broader and narrower topics were explored in the search. Broader topic keywords utilized included inflammatory disease, systemic treatment, and comorbidities. Narrower topic keywords utilized included plaque psoriasis, psoriasis vulgaris, infliximab, etanercept, adalimumab, ustekinumab, anti-TNF, systemic inflammation, MI, C-reactive protein (CRP), and biomarkers. An additional strategy used in the search to include all keywords was MeSH terminology in the PubMed database. Manual searches were also completed from the reference lists of various articles obtained. Inclusion criteria for research studies included systemic treatment methods as the intervention in patients with psoriasis within the past 5 years and published in peer-reviewed journals. No previous systemic reviews of the research literature were located on this topic.
STRENGTH OF EVIDENCE
To rate the strength of the studies retrieved in this review, a rating system by Melynk and Fineout-Overholt (2005) was used. These levels of evidence are the following: level 1, a systemic review or meta-analysis of randomized controlled trials (RCTs) or clinical practice guidelines based on RCTs; level 2, a well-designed RCT; level 3, well-designed non-RCTs; level 4, well-designed case control or cohort studies; level 5, systemic reviews of descriptive or qualitative studies; level 6, a single descriptive or qualitative study; and level 7, the opinion of expert authority. The seven studies reviewed are presented in Table 1 and include the appropriate ranking of level of evidence.
FINDINGS OF THIS REVIEW
Of the seven studies reviewed, one was an RCT level 2 (Bissonnette et al., 2013). Five studies were observational/cohort level 4 (Abuabara et al., 2011; Ahlehoff et al., 2013; Boehncke, Salgo, et al., 2011; Jokai et al., 2013; Wu et al., 2013). One study was a retrospective analysis of data from a RCT level 6 (Strober et al., 2008). In the studies reviewed, strengths and limitations were found. Internal validity was strengthened in the one study that used random assignment to groups (Bissonnette et al., 2013). Internal validity was also strengthened in the studies with large sample sizes, which included four studies (Abuabara et al., 2011; Ahlehoff et al., 2013; Strober et al., 2008; Wu et al., 2013). The reliability of measurement tools was noted in all the studies. For example, in one study, carotid and brachial intima-media thickness was measured by high-resolution, B-mode ultrasonography (Jokai et al., 2013). Another study strengthened internal validity with their measurement tool by using only two well-trained investigators with each participant being monitored by the same investigator at all visits (Boehncke, Salgo, et al., 2011).
Although there were many strengths to the studies reviewed, limitations were also found. The use of nonrandomized assignment to groups in many of the studies decreased internal and external validity by increasing selection bias and decreasing the generalizability of the study. As in one of the observational studies (Abuabara et al., 2011), patients were not randomized to treatment groups. One should note that there could be bias of primary differences in the patients. Decreased generalizability was seen in the study by Ahlehoff et al. because the participants included a Danish population only, which is predominantly persons of Caucasian decent. An additional weakness was that three studies had sample sizes of less than 50 participants (Bissonnette et al., 2013; Boehncke, Salgo, et al., 2011; Jokai et al., 2013).
All seven studies reviewed used outcomes of different measurements of cardiovascular risk. However, different measurements used showed an overall decrease in cardiovascular risk in patients with psoriasis being treated with systemic therapies (Bissonnette et al., 2013; Boehncke, Salgo, et al., 2011; Jokai et al., 2013; Strober et al., 2008). Abuabara et al. (2011) did not show a significant difference in MI risk between systemic treatment and phototherapy treatment. However, the risk of MI was lower in patients less than 50 years old in the systemic treatment group; a similar finding of a significant decrease of MI risk was seen with etanercept in the study by Wu et al. (2013). Cardiovascular risk was measured by CRP levels in one study, and the decrease in cardiovascular risk was seen with a decrease in CRP levels in participants treated with etanercept (Strober et al., 2008) similar to the decrease in highly sensitive-CRP (hs-CRP) levels with the adalimumab treatment group compared with a control group in a study by Bissonnette et al. In the study by Ahlehoff et al. (2013), a reduced risk of death and cardiovascular disease in participants on biologic or methotrexate treatment was found compared with other therapies. Three studies measured cardiovascular risk by other methods such as vascular inflammation (Bissonnette et al., 2013), vascular endothelial growth factor (Boehncke, Salgo, et al., 2011), and intima-medial thickness (Jokai et al., 2013). Vascular inflammation as measured by target background ratio was improved in adalimumab participants as compared with the control group (Bissonnette et al., 2013).
Nonsignificant results were also noted in the studies reviewed. No significant difference overall was seen in MI risk between systemic and phototherapy treatment groups in one study (Abuabara et al., 2011). Bissonnette et al. (2013) showed no statistically significant change over time in serum lipid levels between the treatment groups, and Jokai et al. (2013) showed no statistically significant relationship of MI risk factors with CRP or sedimentation rate.
RECOMMENDATIONS AND CLINICAL IMPLICATIONS
Overall, the review of the research studies lends support to the positive effects of systemic treatment with biologics in reducing markers of inflammation. Treatment with biological agents or methotrexate in patients with severe psoriasis was associated with lower cardiovascular disease event rates compared with patients treated with other antipsoriatic therapies (Ahlehoff et al., 2013). This should be noted as a viable option to reduce cardiovascular morbidity and mortality. It also raises the question, as addressed by Boehncke, Salgo, et al. (2011), “Would early treatment with these systemic anti-inflammatory agents lead to possible prevention of developing these cardiovascular comorbidities?” Overall, there were several biomarkers such as decreased CRP levels that were improved with systemic or biologic therapy in patients with psoriasis. As stated by Wu et al. (2013), “It is too early to determine whether TNF inhibitors should be used in psoriasis patients specifically to reduce cardiovascular events. Results of a large prospective study may help determine this. Further, there are many new biologic agents currently on the market or coming onto the market, and there will be a need to understand the relationship between treatment with these agents and the risk of MI” (p. 902). The relationship should be highly considered and discussed with patients. Collaborative practice also needs to take place as psoriasis is not simply limited to the skin. Patients should be monitored for cardiovascular risk and also treated appropriately for these risks. As commonly seen, these studies suggest a need for additional research to confirm the results.
This review of research studies contributed to the understanding of an association of psoriasis to cardiovascular risk factors and that systemic treatment with biologic agents is starting to play a vital role in reducing this risk. Although additional research and evidence must be completed, the current evidence warrants a change in practice in the way patients with psoriasis are treated and managed. Efforts should be made to educate patients on their risks and risk management. Disseminating current research in regards to biologic agents and their role in decreasing cardiovascular risks in patients with psoriasis will help progress treatment protocols and enhance collaborative practice among providers.
The author would like to thank Geri B. Neuberger, RN, MN, EdD, APRN, Professor, University of Kansas School of Nursing, for her guidance in the development and preparation of the manuscript.
Abuabara K., Lee H., Kimball A. B. (2011). The effect of systemic psoriasis therapies on the incidence of myocardial infarction: A cohort study. British Journal of Dermatology, 165 (5), 1066–1073.
Ahlehoff O., Skov L., Gislason G., Lindhardsen J., Kristensen S. L., Iversen L., Hansen P. R. (2013). Cardiovascular disease event rates in patients with severe psoriasis treated with systemic anti-inflammatory drugs: A Danish real-world cohort study. Jounal of Internal Medicine, 273 (2), 197–204.
Armstrong A. W. (2013). Do TNF inhibitors reduce the risk of myocardial infarction in psoriasis patients? Journal of the American Medical Association, 309 (19), 2043–2044.
Bissonnette R., Tardif J. C., Harel F., Pressacco J., Bolduc C., Guertin M. C. (2013). Effects of the tumor necrosis factor-alpha antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: Results of a randomized controlled trial. Circulation Cardiovascular Imaging, 6 (1), 83–90.
Boehncke S., Fichtlscherer S., Salgo R., Garbaraviciene J., Beschmann H., Diehl S., Boehncke W. H. (2011). Systemic therapy of plaque-type psoriasis ameliorates endothelial cell function: Results of a prospective longitudinal pilot trial. Archives of Dermatology Research, 303 (6), 381–388.
Boehncke S., Salgo R., Garbaraviciene J., Beschmann H., Hardt K., Diehl S., Boehncke W. H. (2011). Effective continuous systemic therapy of severe plaque-type psoriasis is accompanied by amelioration of biomarkers of cardiovascular risk: Results of a prospective longitudinal observational study. Journal of the European Academy of Dermatology and Venereology, 25 (10), 1187–1193.
Channual J., Wu J. J., Dann F. J. (2009). Effects of tumor necrosis factor-alpha blockade on metabolic syndrome components in psoriasis and psoriatic arthritis and additional lessons learned from rheumatoid arthritis. Dermatologic Therapy, 22 (1), 61–73.
Jokai H., Szakonyi J., Kontar O., Marschalko M., Szalai K., Karpati S., Hollo P. (2013). Impact of effective tumor necrosis factor-alfa inhibitor treatment on arterial intima-media thickness in psoriasis: Results of a pilot study. Journal of the American Academy of Dermatology, 69 (4), 523–529.
Melnyk B. M., Fineout-Overholt E. (2005). Evidence-based practice in nursing and healthcare: A guide to best practice. Philadephia, PA: Lippincott Williams & Wilkins.
Strober B., Teller C., Yamauchi P., Miller J. L., Hooper M., Yang Y. C., Dann F. (2008). Effects of etanercept on C-reactive protein levels in psoriasis and psoriatic arthritis. British Journal of Dermatology, 159 (2), 322–330.
Villasenor-Park J., Wheeler D., Grandinetti L. (2012). Psoriasis: Evolving treatment for a complex disease. Cleveland Clinic Journal of Medicine, 79 (6), 413–423.
Wakkee M., Thio H. B., Prens E. P., Sijbrands E. J., Neumann H. A. (2007). Unfavorable cardiovascular risk profiles in untreated and treated psoriasis patients. Atherosclerosis, 190 (1), 1–9.
Wu J. J., Poon K. Y., Bebchuk J. D. (2013). Association between the type and length of tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. Journal of Drugs in Dermatology, 12 (8), 899–903.
Yost J., Gudjonsson J. E. (2009). The role of TNF inhibitors in psoriasis therapy: New implications for associated comorbidities. F1000 Medicine Reports, 8 (1), M1–M30.