EXPERT ANALYSIS AT PDA 2015
PARK CITY, UTAH (FRONTLINE MEDICAL NEWS) –Evidence is mounting that the use of biologic therapies is associated with certain cardiovascular benefits in patients with psoriasis.
However, until the strength of the evidence becomes more robust, Dr. Jashin J. Wu does not recommend that patients are prescribed tumor necrosis factor (TNF) inhibitors specifically to reduce the risk of cardiovascular disease. “If systemic therapy is a consideration in the setting of CVD [cardiovascular disease] risk, it would appear that TNF inhibitors and methotrexate offer the best evidence of benefit,” Dr. Wu, director of the psoriasis clinic and director of dermatology research in the department of dermatology at Kaiser Permanente Los Angeles Medical Center, said at the annual meeting of the Pacific Dermatologic Association.
The National Psoriasis Foundation recently published a consensus statement about the potential impact of current therapies on cardiovascular disease, including the risk of diabetes ( J Am Acad Dermatol. 2014;70[1]:168-77 ). In a retrospective study of 121,280 patients with rheumatoid arthritis (RA) or psoriasis, drug regimens were categorized into four mutually exclusive groups: TNF inhibitors with or without other disease-modifying antirheumatic drugs (DMARDs), methotrexate without TNF inhibitors or hydroxychloroquine, hydroxychloroquine without TNF inhibitors or methotrexate; and other nonbiologic DMARDs without TNF inhibitors, methotrexate or hydroxychloroquine (referent group). The researchers found that adjusted Cox proportional hazards for the risk of diabetes were lower among those on TNF inhibitors (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91) and hydroxychloroquine (HR, 0.54; 95% CI, 0.36-0.80), compared with those on methotrexate (HR, 0.77, 95% CI, 0.53-1.13) ( JAMA. 2011 Jun 22;305[24]:2525-31 ).
Increased carotid intimal media thickness (IMT) is also an independent predictor of CVD. In a prospective, observational study, 20 psoriasis patients received a 12-week treatment of TNF inhibitors ( Ann Rheum Dis. 2011 Apr;70[4]:705-6 ). After 12 weeks, 9 patients continued on their TNF-inhibitor regimen (group 1), while 11 discontinued treatment because of financial constraints (group 2). Another 20 psoriasis patients who did not receive biologic therapy served as controls (group 3). The researchers measured IMT by carotid ultrasound at baseline, week 12 and at 2 years. They found that between baseline and 2 years, IMT decreased from 0.70 mm to 0.63 mm in group 1, from 0.71 to 0.67 in group 2, and increased from 0.79 to 0.82 in group 3. “This seems to suggest that the use of TNF inhibitors may improve atherosclerosis,” said Dr. Wu, who is currently running seven clinical trials of psoriasis patients. Similar findings were seen in a larger study that examined 224 patients with psoriatic arthritis and followed them for a mean of 55 months: 124 on TNF inhibitors, 104 on DMARDs, and 305 matched controls ( Arterioscler Thromb Vasc Biol. 2011 Mar;31[3]:705-120 ).
In a separate study of 16 psoriasis patients treated with TNF inhibitors, researchers used ultrasound to measure IMT of carotid and brachial arteries after 6 months of therapy ( J Am Acad Dermatol. 2013 Oct;69[4]:523-9 ). At baseline, all 16 patients had an IMT greater than normal. In those without initial calcified atherosclerotic plaques, 13 of 16 had a significant decrease of IMT (P = .0002). In those with initial calcified atherosclerotic plaques, 3 of 16 patients had a nonsignificant increase in IMT.
Increased arterial stiffness is another independent predictor of CVD. In a controlled study of 55 patients with psoriatic arthritis, RA, or ankylosing spondylitis, researchers used aortic pulse-wave velocity to measure aortic stiffness. Almost 35% of the patients (36) received TNF inhibitors while the remaining 19 did not receive treatment ( Am J Hypertens. 2012 Jun;25[6]:644-50 ). After 1 year of follow-up, use of TNF inhibitors was associated with a significant improvement in aortic pulse-wave velocity (P = .02) and reduced carotid IMT progression (P = .04).
Other evidence suggests that systemic therapy with TNF inhibitors is associated with the reduction of cardiovascular events, including myocardial infarction. In a study led by Dr. Wu, 8,845 Kaiser Permanente patients with psoriasis were evaluated between Jan. 1, 2004, and Nov. 30, 2010, and placed into one of three groups: treatment with a TNF inhibitor, treatment with oral therapy or phototherapy, or treatment with a topical agent (referent group) (Arch Dermatol. 2012 Nov;148[11]:1244-50 ). On multivariate analysis, the investigators found that the use of TNF inhibitors was associated with a significant reduction in the rate of incident MI (HR, 0.50; P = .003), compared with the use of topical agents.
Dr. Wu went on to note that C-reactive protein (CRP) is a predictor of CVD such as MI, peripheral arterial disease, and sudden cardiac death. In a retrospective cohort study, Dr. Wu and his associates evaluated Kaiser Permanente patients with psoriasis, psoriatic arthritis, or RA who were treated with a combination of TNF plus methotrexate, or with methotrexate alone from Jan. 1, 2002, to July 31, 2011 ( J. Am. Acad. Dermatol. 2015;72[5]:917-9 ). Only patients in the combination therapy group had a clinically and statistically significant decrease in CRP, compared with baseline (a mean decrease of 5.18 mg/dL). No significant changes between the two groups were observed in terms of BMI, blood pressure, fasting glucose, hemoglobin A1C, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, or alanine aminotransferase.
HDL cholesterol composition and function have also been studied in psoriasis patients. In one trial, HDL cholesterol was isolated from 15 psoriasis patients at baseline and after effective topical and/or systemic psoriasis therapy, and from 15 healthy controls matched for age and sex ( J. Invest. Dermatol. 2014;134[3]:635-42 ). The researchers found that HDL cholesterol from psoriasis patients showed a significantly impaired capability to mobilize cholesterol from macrophages. However, psoriasis therapy recovered HDL cholesterol composition and function, but had no effect on serum HDL cholesterol levels.
A better understanding of the cardiovascular effects of biologic therapy should be gleaned from the Vascular Inflammation in Psoriasis Trial , which includes $3.8 million in funding from the National Institutes of Health, to prospectively study the effect of therapy on biomarkers and on positron emission tomography with 18fluorodeoxyglucose (FDG-PET)/CT scan. The 1-year study just completed enrolling patients into one of three treatment groups: adalimumab, UVB phototherapy, or placebo. Biomarkers such as CRP, lipids, and imaging will be assessed at baseline, weeks 4, 8, 12, and then every 12 weeks. “The theory is that adalimumab, but not UVB phototherapy, will improve biomarkers and reduce vascular inflammation as measured by FDG-PET/CT scan,” Dr. Wu said. “Aggressive systemic therapy may alter the natural history of cardiovascular disease.”
Current recommendations from the National Psoriasis Foundation call for an assessment of blood pressure, pulse, and body mass index every 2 years, and an assessment of fasting blood glucose and lipid levels every 5 years, or every 2 years if the patient has additional risk factors.
Dr. Wu reported that he has received research and consulting fees from numerous pharmaceutical companies, including AbbVie and Amgen. These go to his employer.
