Psoriasis is a common immune-mediated inflammatory skin disorder that affects up to 3.2% of adults in the United States.1 It is a TH1, TH17, and TH22 inflammatory disease resulting in increased levels of cytokines in the skin, including IFN-γ, tumor necrosis factor (TNF), IL-17, and IL-22. Dendritic antigen-presenting cells also are increased in the skin of patients with psoriasis resulting in increased levels of IL-23.2 Although skin disease often is its most prominent and sometimes its only documented manifestation, an understanding of psoriasis as a chronic multisystem inflammatory disorder is essential to optimize outcomes.1,3 Multiple comorbidities that may affect treatment selection often are associated with psoriasis, including psoriatic arthritis, cardiovascular disease, depression, obesity, metabolic syndrome, cardiovascular disease (CVD), cerebrovascular disease, and peripheral vascular disease.
As with other immune-mediated inflammatory diseases, it has been hypothesized that psoriasis may influence comorbidities through shared genetic risks, environmental factors, and pathogenic factors or inflammatory pathways.2-4 For example, emerging evidence suggests that comorbidities such as metabolic syndrome may be related to the chronic inflammation that accompanies psoriasis, a finding that has important clinical implications.3
The interplay and dependence or interdependence of psoriasis and its comorbidities is complex, and it is an area deserving of vigorous research.1 At present, observational and epidemiological data such as the present case suggest that effective treatment of psoriasis could lead to benefits “beyond the skin” and potentially even prevent future disease-associated comorbidity.1-3
Metabolic Comorbidities and Psoriasis Treatment
Although the prevalence of CVD and CVD risk factors is increased in patients with psoriasis, studies suggest that the suppression of systemic inflammation that accompanies adequate psoriasis treatment, particularly in patients with moderate to severe disease, may decrease the risk for cardiovascular comorbidities.5 For example, a number of studies have found treatment of psoriasis with methotrexate may decrease the risk for cardiovascular events, including ischemic heart disease, stroke, and cardiovascular death.6-10 Low-dose methotrexate has been shown to be particularly advantageous for decreasing CVD in patients with psoriasis.5,8
Tumor necrosis factor α inhibitors, which are frequently used for moderate to severe plaque psoriasis, also may notably decrease cardiovascular risk.5 One study showed a significant decrease in the risk for myocardial infarction in patients with psoriasis who were treated with TNF-α inhibitors (hazard ratio, 0.50; 95% CI, 0.32-0.79)11; other studies have confirmed this benefit.12-17 Moreover, the reduction in cardiovascular events may be greater with TNF-α inhibitors than with methotrexate when the former is used for psoriasis treatment, with longer duration of TNF-α inhibition leading to greater risk reduction.18,19
In patients with severe psoriasis, treatment with TNF-α inhibitors has been associated with improvements in subclinical CVD (abnormalities in echocardiogram), improved coronary microvascular function (determined by transthoracic Doppler echocardiography), and reduced progression in coronary artery disease (assessed by coronary computed tomography).20-22 Improvement in endothelial function (brachial artery reactivity) and carotid arterial stiffness also has been reported following 6 months of treatment with adalimumab for moderate to severe psoriasis.21
Data concerning potential cardiovascular risk reduction with treatment of psoriasis utilizing newer agents are continuing to emerge. To date, no increase in the incidence of major adverse cardiovascular events has been shown in patients with psoriasis treated with anti–IL-17 agents, such as secukinumab; however, additional long-term studies are needed.18,23-25
Apremilast, an oral phosphodiesterase 4 inhibitor, is another addition to the psoriasis armamentarium.26 No increase in the risk for major cardiac events has been shown in randomized controlled trials of patients with psoriasis receiving apremilast for up to 156 weeks.27,28 As with secukinumab, additional long-term, large-scale studies are needed to determine the effects of apremilast on cardiovascular risk in patients with psoriasis.5
Other Comorbidities
Effective treatment of psoriasis also appears to benefit various other comorbidities. Numerous studies have shown an increased incidence of depression in patients with psoriasis vs controls and a concurrent improvement in psychiatric symptoms with psoriasis disease control.1 For instance, a multicenter, randomized, open-label study of 352 patients with psoriasis showed treatment with etanercept, a TNF inhibitor, significantly improved scores for concomitant depression and anxiety (P<.05).29 Similarly, a double-blind, randomized clinical trial of patients with psoriasis found significant improvement in depression at 12 weeks in patients treated with adalimumab vs placebo (P<.001).30 Likewise, a multicenter phase 3 trial of more than 600 psoriatic patients showed improved Beck depression inventory and Hamilton depression rating scale scores at 12 weeks in patients with psoriasis treated with etanercept compared to placebo.31
A much larger analysis of 7490 patients with psoriasis compared the rates of depression among patients receiving biologic therapy, phototherapy, and conventional systemic therapy. The greatest impact on depression symptoms was seen with biologic therapy (incidence rate, 3.01/100 patient-years), followed by conventional systemic therapy (5.70/100 patient-years), and phototherapy (5.85/100 patient-years).32
Uveitis, or inflammation of the middle layer of the eye (the uvea), frequently is seen in patients with psoriasis. In a cohort study of 60,000 patients with mild psoriasis and more than 7000 patients with severe psoriasis, the incidence of uveitis in patients was significantly increased in both patients with severe disease and those with mild disease (P<.001 for both).33 In a case series of 8 patients with concomitant psoriasis and uveitis, 4 patients were treated with infliximab and 4 with adalimumab; 7 patients treated achieved remission of their uveitis.34
Role of the TNF-α Blockade in Sickle Cell Disease
Presently, no reported human studies have shown TNF-α blockade as a possible treatment of sickle cell disease.35 However, increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and to the severity of sickle cell disease due to their integral role in the development of vascular wall dysfunction and ischemia.35,36 Studies have shown that TNF-α is released in homozygous sickle cell anemia (HbSS) disease and impedes blood flow during sickle cell crisis, resulting in worsening ischemia and painful infarction.35,36 Moreover, cytokine analysis has shown significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in patients with HbSS vs healthy controls, suggesting a possible role of TNF-α in the pathogenesis of sickle cell crisis.36
The case patient reported a 50% reduction in pain level and the use of pain medications that overlapped with the initiation of adalimumab for treatment of her psoriasis. Moreover, although radiographs showed possible psoriatic changes of the distal metatarsal row, she described sickle cell pain and pain crises that were uncharacteristic of psoriatic arthralgia.35 Although these findings are observational in nature and limited to one patient, they do suggest an interesting hypothesis. If a common inflammatory mediator is the culprit, it is possible that TNF-α inhibitors could be the preferred treatment option for patients with psoriasis and comorbid HbSS or HbSC disease. Further studies are needed to analyze the role of TNF-α inhibition in sickle cell disease.
Bottom Line
Psoriasis may influence comorbidities through shared genetic risks, environmental factors, or inflammatory pathways. Improvement in metabolic and other comorbidities have been shown with the effective treatment of psoriasis. The case described here showed improvement in sickle cell crises and pain with treatment of psoriasis with adalimumab. Tumor necrosis factor inhibitors may be an optimal choice for patients with both psoriasis and sickle cell disease.