The Role of Inflammation and Risks of Stroke in Psoriatic Arthritis

Inflammation is a known risk factor for heart disease, and patients with inflammatory arthritis, such as rheumatoid arthritis, lupus, and psoriatic arthritis, have more cardiac events. Psoriatic arthritis patients have higher rates of atherosclerosis than the general population and those who develop it have more inflammation overall. Experts now believe that psoriatic arthritis should be considered a risk factor for cardiovascular diseases, including stroke.

Inflammation, as defined by abnormally high levels of inflammatory markers, has been associated with an increased risk of stroke. Psoriasis, which may induce inflammation beyond skin and joints, could be viewed as a systemic inflammatory disease that increases vascular inflammation, leading to myocardial infarction and stroke. Markers of inflammation, such as C-reactive protein (CRP) and sedimentation rate, are elevated in patients with psoriasis, and vascular inflammation has been reported to be increased in patients with moderate to severe psoriasis.

Severe psoriatic arthritis patients have a higher risk of developing both metabolic syndrome and insulin resistance, which increases their risk for myocardial infarction and stroke. Patients who develop psoriasis and psoriatic arthritis later in life and those who progress from skin involvement to psoriatic arthritis appear to have high rates of metabolic syndrome and insulin resistance. The chronic inflammation of psoriatic arthritis may drive the development of these conditions.

Psoriatic arthritis patients are at increased risk of developing cardiovascular diseases, including stroke, according to a review published in the April 25, 2016 issue of Arthritis Care & Research⁽¹⁾ that examined 11 high-quality, controlled trials, mostly from North America and Europe. The studies, involving nearly 33,000 psoriatic arthritis patients, took into account cardiovascular disease risk factors, including age, sex, and health conditions such as hypertension and diabetes.

All of the studies showed a significantly increased risk of cardiovascular disease in psoriatic arthritis patients, including a 22 percent increased risk of cerebrovascular disease conditions, such as stroke, as compared to the general population.

A significant proportion of patients with psoriatic disease are underdiagnosed and undertreated for traditional cardiovascular risk factors. New psoriatic arthritis treatment guidelines from The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis released earlier this year stress the importance of screening for cardiovascular disease and other common comorbidities.

Inflammation and Stroke

Various conditions that activate the immune system and an inflammatory cascade may also increase the risk of stroke. The risk of ischemic stroke is associated with systemic inflammation and inflammatory biomarkers, suggesting a causal relationship, state the authors of a review published in the Sept. 12 online issue of Nature Reviews Neurology.⁽²⁾

The review, led by Mitchell S. Elkind, a vascular neurologist and epidemiologist at Columbia University and chairman of the American Stroke Association Advisory Committee, examines the effects of the immune system as a whole on the epidemiology of stroke and the associations between specific inflammatory states, biomarkers of inflammation, and the risk of incident and recurrent ischemic stroke.

Dr. Elkind writes that acute infections activate the inflammatory cascade, which might increase the subsequent risk of stroke, and that chronic infections have been associated with an increased risk of stroke.

Inflammation, the risk of stroke and biomarkers

Some inflammatory cytokines, which are drug targets in rheumatologic diseases, including IL‑6, IL‑1β, tumor necro­sis factor (TNF), complement proteins, CRP, serum amyloid A‑1 protein, coagulation proteins and fibrinogen, have chronic effects that might contribute to the formation and maturation of atherosclerotic plaques. Inflammation is likely an important contributor to athero­sclerosis, plaque rupture, platelet aggregation and intravascular thrombosis, which all increase the risk of stroke. Evidence shows that the risk of stroke is increased by both acute and chronic inflammation.

CRP is the most studied of the inflamma­tory markers, with several large epidemiological studies associating higher circulating levels of high sensitivity CRP (hs CRP) with an increased risk of vascular events independent of tra­ditional vascular risk factors, according to a 2002 study published in the New England Journal of Medicine^.(3) “There seems to be a consistent association between hsCRP levels and vascular events, including stroke,” the authors wrote.

IL‑6 is the main driver of CRP production in the liver, and evidence suggests that this cytokine mediates atherogenesis related to classical risk factors, such as aging, hypertension, smoking and obesity, according to an article in the 2009 issue of Thrombosis and Haemostasis. “Determining whether IL‑6 is both a biomarker and mediator of pathogenic pathways is critical for the development of novel therapeutic tar­gets, and multiple clinical trials are currently assessing the effects of targeted cytokine antagonist therapies on cardiovascular events,” the authors wrote.

Lp‑PLA2 is a leukocyte-derived enzyme that is released in response to inflammation. It is thought to directly propagate atherogenesis by, in part, proinflammatory downstream signaling effects. It is unclear whether Lp‑PLA2 could be a therapeu­tic target, they wrote.

Prevention and Treatment of Inflammation

Lifestyle changes can help reduce inflammation and, in turn, reduce the risk of stroke. Prospective studies show that weight loss inter­ventions lead to reductions in serum concentrations of CRP, IL‑6, and TNF. A Mediterranean diet that is rich in polyunsaturated fatty acids, fruits, vegetables and whole grains, and includes a moderate intake of alcohol and a low intake of processed and red meat has been associated with low levels of inflammation. However, a Western diet that is rich in red meat, simple carbohydrates, high-fat dairy products, and hydrogenated fats has been associated with increased levels of inflammatory markers, including CRP and IL‑6.

Statins, now used for the primary and secondary prevention of stroke, especially for those at moderate to high risk, are thought to have both lipid-lowering and anti-inflammatory effects. “Evidence is building that the anti-inflammatory effects result from their abil­ity to interrupt isoprenoid biosynthesis and improve endothelial function, thereby lowering levels of CRP, IL‑1, IL‑6 and other inflammatory markers,” the authors of the article in Thrombosis and Haemostasiswrote.

References:

• Polachek A, et al. Risk of cardiovascular morbidity in patients with psoriatic arthritis: A meta-analysis of observational studies Arthritis Care Res (Hoboken). 2016 Apr 25. doi: 10.1002/acr.22926
• Esenwa C, et al. Inflammatory risk factors, biomarkers and associated therapy in ischaemic stroke Nature Reviews Neurology 12, 594–604 (2016) doi:10.1038/nrneurol.2016.125 Published online 12  September 2016
• Paul M. Ridker, M.D., Nader Rifai, Ph.D., et. al. "Comparison of C-Reactive Protein and Low-Density Lipoprotein Cholesterol Levels in the Prediction of First Cardiovascular Events," New England Journal of Medicine. November 14, 2002. DOI: 10.1056/NEJMoa021993
• Harald Schuett; Maren Luchtefeld, et. al. "How much is too much? Interleukin-6 and its signalling in atherosclerosis," Thrombosis and Haemostasis. August 2009. DOI:  http://dx.doi.org/10.1160/TH09-05-0297
• Laura C. Coates, Arthur Kavanaugh, et. al. "Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis," Arthritis & Rheumatology. Published online March 23, 2016. DOI: 10.1002/art.39573