Pieces of the metabolic syndrome puzzle
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New evidence links it to psoriasis, androgenetic alopecia

Researchers investigating psoriasis and androgenetic alopecia (AGA) have wondered, in recent years: Are patients with the two conditions at increased risk for cardiovascular disease (CVD)? Numerous studies have linked psoriasis with individual CVD risk factors such as obesity, dyslipidemia, hypertension, and insulin resistance. AGA research indicated an elevated risk of myocardial infarction and cardiac-related mortality. Now the concept of metabolic syndrome is providing a new framework for investigators to assess the increased risk of CVD in psoriasis and AGA patients. As a result, with mounting evidence pointing to a clear association with metabolic syndrome, psoriasis experts and researchers studying AGA are urging dermatologists to take a more active role in preventing CVD through early intervention.

Obesity drives metabolic syndrome

Metabolic syndrome is the name given to a group of familiar risk factors that occur together and increase the risk for coronary artery disease, stroke, and type 2 diabetes (see sidebar, "Metabolic syndrome defined"). “There have been 500 or 600 studies over the past 10 years indicating that when obesity is found in an individual, there’s a cluster of conditions that tend to accompany it: high blood pressure, low high-density lipoprotein [HDL] cholesterol, high triglycerides, and a high fasting glucose, almost a pre-diabetes state,” said Nehal N. Mehta, MD, director of inflammatory risk and associate scholar, Center for Clinical Epidemiology and Biostatistics, at the University of Pennsylvania’s Perelman School of Medicine. “The cluster was first called Syndrome X,’ then the dysmetabolic syndrome,’ then the metabolic syndrome. Each of these abnormalities, by itself, predisposes an individual to cardiovascular disease, but as a group their threat is greatly increased. If you have all five, your risk of heart disease increases by more than 300 percent.”

Psoriasis can be thought of as a “pre-metabolic syndrome state,” said Dr. Mehta, a preventive cardiologist whose practice is dedicated to the cardiovascular care of patients with psoriasis. “If you look at a cross section of psoriasis patients, about 80 percent of them will be overweight, and about half of those could be classified as obese,” he notes. “Of 300 patients we’ve seen in the past two years, more than 48 percent have metabolic syndrome. This is a very important public health message to communicate: there’s no population more likely to develop metabolic syndrome than this one.”

Psoriasis and metabolic syndrome

A study published in the Archives of Dermatology (2011;147(4):419-24) used data from the National Health and Nutrition Examination Survey (2003-2006) to estimate the prevalence of the metabolic syndrome among psoriasis patients and in the general U.S. population. The study participants, aged 20 to 59 years (mean age 39), included 2,385 individuals with no psoriasis and 71 who reported having been told by a health care provider that they have psoriasis. The prevalence of the metabolic syndrome was 40 percent among individuals with psoriasis and 23 percent among individuals without psoriasis. Even after adjusting for age, sex, race/ethnicity, smoking, and serum C-reactive protein levels, the odds ratio for patients with psoriasis and the metabolic syndrome was 1.96. The most common component of metabolic syndrome among individuals with psoriasis was abdominal obesity, followed by hypertriglyceridemia and low HDL cholesterol. Using the 2008 U.S. census population data, the authors estimated that 6.6 million individuals aged 20 to 59 have psoriasis and 2.7 million of those have metabolic syndrome.[pagebreak]

“This was the first broadly representative study of psoriasis, to my knowledge, in which metabolic syndrome was diagnosed in psoriasis patients in the general population,” said co-author Joel M. Gelfand, MD, MSCE, medical director of the Clinical Studies Unit and assistant professor of dermatology and epidemiology at the University of Pennsylvania’s Perelman School of Medicine. “That’s a big advantage, because most other studies have come from tertiary care centers, and we don’t know how reliable they are. We followed up this study with a separate analysis using the United Kingdom record system, where we obtained data on 4,000 patients with psoriasis.” The follow-up study (of which Dr. Mehta was also a co-author), presented in abstract form at the Society of Investigative Dermatology’s 2011 annual meeting, examined the medical records from The Health Improvement Network, a large population-based UK general practice database. The results not only confirmed a significant association of psoriasis with metabolic syndrome, but also found that “as severity of psoriasis increased, so did association with metabolic syndrome,” Dr. Gelfand noted. “Also, the individual components of the metabolic syndrome were increased in people with psoriasis, so independent of obesity, people with psoriasis were more likely to have elevations in glucose and triglycerides, again in a dose-response (i.e. disease severity) manner.”[pagebreak]

Inflammation a common thread

Although the association between psoriasis and metabolic syndrome is well established, researchers are still probing the relationship in an effort to identify the factors that might explain why the two conditions are linked. “The important thing we’ve learned is that coronary artery disease is not just atherosclerosis and lipid deposition, but is a very inflammatory condition, and a lot of those inflammatory markers are very similar to the inflammatory cytokines we see in skin and joints with psoriasis,” said Alan L. Menter, MD, chief of dermatology and chair of the psoriasis unit at the Baylor Research Institute. “If you then add obesity, hypertension, and diabetes to that, which in their own right increase the risk of coronary artery disease, you have two separate risk factors: the psoriasis per se, with inflammation, and then the diabetes/obesity issue, which is significantly higher in psoriasis than any other immune disease.”

Dr. Mehta, whose past research includes the study of inflammation induced in healthy human subjects, concurs with the theory that inflammation is at the root of both conditions. “Psoriasis is not thought to be just a skin disease, it’s a whole-body disease,” he maintained. “What it comes down to is that each of those TH-1 and TH-17 cells are the richest source of these pro-inflammatory cytokines (IL-1, IL-6, and TNF-a), and all of those are causing disruptions of signaling level. So I think it may be the chronic inflammation seen in psoriasis that’s driving all of these problems, and the obesity and the insulin resistance could be byproducts of that.”

Researchers are also looking for genetic factors that psoriasis and metabolic syndrome might share. “We have nine genes identified in psoriasis, called PSORS1 through PSORS9. PSORS1, which is based on chromosome 6, is the gene responsible in that area for all autoimmune diseases like diabetes,” Dr. Menter said. “All these things are genetically linked; the question is, how? So whether the obesity gene specifically is linked to the psoriasis gene is being researched as we speak.”

The issue of how the systemic treatments for one condition might affect the other has been studied in recent years, with some encouraging results. “Some small studies have shown that methotrexate improves HDL function,” Dr. Mehta said. “Also, methotrexate has been shown in a handful of studies to improve blood pressure and vascular blood sugars.” Dr. Menter added that methotrexate “has definitively been shown to reduce the incidence of coronary artery disease in both psoriasis and rheumatoid arthritis.” Results from a study of 24,081 psoriasis patients at Kaiser Permanente Southern California, presented at the American Academy of Dermatology’s 2011 Annual Meeting by Jashin J. Wu, MD, indicated that patients treated with TNF-a inhibitors (etanercept, adalimumab, and infliximab) had a 48 percent lower risk of myocardial infarction during four years of follow-up than patients not receiving one of these drugs. “That’s a very, very significant new finding, and I think it’s going to be a huge factor in allowing us to get better access to those drugs for patients with more severe psoriasis,” Dr. Menter said.

The effect on psoriasis of drugs prescribed to treat cardiovascular risk factors seems minimal, Dr. Mehta said. “There have been some small, anecdotal studies that suggest certain drugs such as ACE inhibitors or beta blockers make psoriasis worse, but I don’t believe that,” he stated. “I’ve used some statin drugs and blood pressure drugs in a very small population of patients, and I have not seen any worsening of psoriasis.”[pagebreak]

Broader role for dermatologists

The wealth of evidence linking the two disorders puts dermatologists who treat psoriasis on the front lines of preventing CVD in their patients, experts say. In a “Practice Gaps” commentary immediately following Dr. Gelfand’s study in Archives, Michael L. Shelling, MD, and Robert S. Kirsner, MD, PhD, suggested that “while the average dermatologist is conversant with this topic, it is the unusual dermatologist who has acted on it.” They recommended creation of a pocket card or electronic template to include the diagnostic criteria for metabolic syndrome and urged dermatologists to incorporate screening for the five risk factors into routine practice.

“I would say that even among dermatologists who have an interest in psoriasis, probably less than 5 percent do anything actively or prospectively about metabolic syndrome. We have to convince dermatologists that this is something they should be taking care of, because often the only doctor a patient sees is his or her dermatologist,” said Dr. Kirsner, who is vice chairman and Stiefel Laboratories chair of the department of dermatology and cutaneous surgery and chief of dermatology at the University of Miami Miller School of Medicine. “Also, we should be making sure that our psoriasis patients get engaged with someone who has an interest in this area, whether it’s an internist, or a cardiologist, or a vascular management specialist.” At the University of Miami, Dr. Kirsner and his colleagues have launched the Psoriasis Vascular Medicine Clinic, where psoriasis patients receive a comprehensive evaluation for cardiovascular risk factors and referral, as appropriate, to a vascular medicine specialist. “Over time, the data we will generate will be robust enough so we can say, in real life practice these are the people who are most likely to develop cardiovascular problems,’ and these are the most likely patients to benefit from referral,’” he said.

AGA and metabolic syndrome

Research into a possible link between androgenetic alopecia and myocardial infarction dates from the mid-20th century, and evidence of the connection may go back as far as 1812, according to a dermatologist with expertise in hair disorders. “When Napoleon invaded Russia, his bald soldiers died first. In the past, there was speculation that perhaps they were less brave, as baldness can affect self-esteem; or, that they suffered more from the cold, as they had no hair,” said Antonella Tosti, M.D., professor of dermatology at the University of Miami Miller School of Medicine. “We still do not know if the deaths were cardiac-related, but this is the new speculation based on scientific data.” Several studies published in the 1960s showed an association between AGA and heart attacks, and researchers began evaluating androgen and lipid levels and more recently, androgen and metabolic syndrome, Dr. Tosti said. She pointed to a report published in Acta Dermato-Venereologica (2010;90:485-870) which found that male and female patients with AGA had significantly higher triglyceride, total cholesterol and LDL cholesterol values versus controls.[pagebreak]

Dr. Tosti, who studied the relationship between early-onset AGA, metabolic syndrome, and polycystic ovary disease in European women, said she does not refer all her female patients with AGA for metabolic screening. “The ones who show other signs of hyperandrogenism, such as irregular menses and hirsutism, these are the ones who have polycystic ovary syndrome and possibly metabolic syndrome, and should be referred to an endocrinologist,” she said.

Three recent studies which looked specifically at the presence of metabolic syndrome in patients with AGA studied somewhat different patient populations, but all found a positive association. Publishing in the Singapore Medical Journal (2010;51(12):931-936), Turkish investigators examined the frequency of insulin resistance, hyperinsulemia, and metabolic syndrome in 80 men with early AGA (developed before age 35) and 48 healthy male control subjects. The frequency of both insulin resistance (using the homeostatic model assessment) and metabolic syndrome were found to be significantly higher in the group with AGA. The authors cited earlier studies suggesting that insulin resistance is the main mechanism for atherosclerosis. Finally, they suggested that further study might clarify “whether early AGA causing coronary artery disease can be attributed to dyslipidemia due to androgens, insulin resistance alone, or metabolic syndrome due to insulin resistance.”

A group of dermatologists at a university hospital in Granada, Spain, noted a dearth of studies addressing the association of AGA and cardiovascular disease in women. Their study, published in the Journal of the American Academy of Dermatology (2010;63(3):420-9), included 40 male and 37 female subjects with early-onset AGA (women with polycystic ovary disease were excluded), matched with 77 healthy control subjects. Metabolic syndrome was found in 54.5 percent of the patients with AGA versus 10.4 percent of the control subjects, and was not significantly more frequent in male patients with AGA than with female patients with AGA. In a discussion of the pathogenic mechanisms that might explain the AGA-metabolic syndrome connection, the authors pointed to the higher frequency of both hyperinsulemia and chronic inflammation parameters found in the patients with AGA. The role of insulin resistance was reinforced in an earlier study cited by the authors which found an association between early-onset AGA and insulin resistance in male patients. In addition, they said patients with AGA reported a higher frequency of a family history of both AGA and early cardiovascular disease, indicating a possible genetic role. Finally, they suggested that cardiovascular screening by metabolic syndrome criteria assessment and carotid ultrasound in men and women with early-onset AGA might help detect patients who could benefit from preventive treatment.

Noting that the literature regarding AGA and metabolic syndrome has yielded inconsistent findings, the authors of a community-based study of the two conditions in Taipei, Taiwan, maintained that most previous studies had not controlled for family history of AGA or other possibly confounding factors. Their study, published in the British Journal of Dermatology (2010;163(2):371-7), indicated a higher prevalence of metabolic syndrome in subjects with moderate or severe AGA (Norwood type IV or greater) than in those with no hair loss or mild AGA, particularly among subjects aged 60 to 69. After adjusting for age, family history, and smoking status, the results revealed that severe AGA (grade V or above) conferred a 2.6-fold higher risk of metabolic syndrome compared with moderate AGA. Conversely, subjects with metabolic syndrome were significantly more likely to have AGA type IV or greater than those without metabolic syndrome. Although the pathophysiological link between metabolic syndrome and AGA is still not well understood, “we concluded that it would be very helpful to identify the risk of metabolic syndrome in our male patients with AGA,” said co-author Christina Lin-Hui Su, MD, PhD, chief of the department of dermatology at Far Eastern Memorial Hospital in New Taipei City. “Facilitating early intervention for metabolic syndrome is critical to reducing the risk and complications of cardiovascular and type 2 diabetes later in life.”

While patients with AGA and those with psoriasis have been shown to be at higher risk for metabolic syndrome, experts examining both conditions emphasize that more research is needed to thoroughly understand the connections. In the meantime, dermatologists can be proactive in helping their at-risk patients head off CVD by arranging for screening tests and referral to appropriate specialists. “We are the appropriate people to be the focal point for this effort,” Dr. Kirsner insisted. “Right now practitioners have a certain approach to caring for their patients, and that doesn’t include screening for or talking about cardiovascular disease. Change takes time, but I’m confident that 10 years from now, this will be different, and dermatologists will make screening part of their routine.”

Metabolic syndrome defined

According to the American Heart Association and the National Heart, Lung and Blood Institute, an individual with at least three of the following conditions meets the criteria for metabolic syndrome:

Abdominal obesity: a waist circumference of over 40 inches (102 cm) in men and 35 inches (88 cm) in women

Serum triglycerides equal to or higher than 150 mg/dL

Blood pressure equal to or higher than 130/85 mmHg

Fasting blood glucose equal to or higher than 100 mg/dL

Low HDL cholesterol: under 40 mg/dL in men and under 50 mg/dL in women



Metabolic syndrome defined