Sunday 30 June 2013

From EatingWell:  May/June 2010 Nobody will miss the meat in this colorful, zesty vegetarian taco salad. The rice and bean mixture can be made ahead and the salad quickly assembled at mealtime. Recipe by Nancy Baggett for EatingWell.


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From EatingWell:  July/August 2007 Paella started as an outdoor dish. Grilling seafood, zesty sausage and vegetables before combining them with saffron-scented rice replicates that traditional character. This takes a little planning to get everything finished as needed, but the results are worth it. The first time, for simplicity, do the grilling and slicing before cooking the rice. If you have a side-by-side grill and burner, later you can perform both tasks simultaneously, which makes you look like a cooking wizard. Note that perfectly done paella rice will be dry and the slightest bit toothsome: it's not creamy or overly moist.


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seasonal-asthma Fall brings with it school days, crisp air, turning leaves—and a spike in asthma symptoms. But spring can be tough for people with asthma, too, particularly if they have a pollen allergy. And summer heat waves are notorious for sending asthmatics, particularly asthmatic children in urban areas, to the emergency room.

So why do asthma symptoms seem to get worse with every change in the weather? Although it seems confusing, there are some annual trends, as well as reasons why asthma symptoms are worse at particular times of the year.

For example, severe asthma episodes tend to peak during the autumn months, especially among children. A 2001 study that examined tens of thousands of asthma hospitalizations in Canada over a 12-year period, for instance, found that there were more than twice as many hospitalizations in October as there were in July or August. Other studies have discovered similar patterns.

However, one study conducted in Detroit found that when there was a rapid 10-degree rise in temperature or a 10% rise in humidity—as can happen in spring and summer—hospitalizations for children with asthma increased in the next day or two.

In truth, asthma symptoms can flare at any time of year due to well-known asthma triggers, such as pet dander, secondhand smoke, and exercise. But knowing the triggers that can vary by season—such as pollen, temperature, humidity, pollution, and viruses—can help people with asthma figure out if they should be stepping up their medication.

Fall
Cold air can cause an asthmatic’s lungs to tighten up, so you might guess that a fall peak in asthma episodes is due to cooler weather. But the patterns found in the Canadian study have also been reported in far-flung places including Hong Kong and the tropical island of Trinidad—so cold weather isn’t entirely to blame.

In fact, the main culprit is believed to be cold-and-flu season, which kicks into gear once kids head back to school. Classrooms filled with runny noses, and grimy hands are breeding grounds for cold and flu viruses, which schoolchildren inevitably spread to their families.

People with asthma aren’t more likely to catch a virus than people without asthma, but when they do, their illness tends to be longer and more severe. Respiratory tract infections aggravate the chronic lung inflammation of asthma, which can lead to wheezing, coughing, difficulty breathing, and asthma attacks. (The flu, common cold, and other respiratory infections are responsible for about 80% of wheezing episodes in children, and about 50% of such episodes in adults.)

“The old adage, ‘If you treat a cold, it lasts a week; if you ignore it, it lasts seven days’, is not true for an asthmatic,” says Bradley Chipps, MD, a pediatric pulmonologist and allergist in Sacramento, Calif. “Unless treated, the symptoms will go on for weeks sometimes.”

The flu, whether it’s swine flu (H1N1) or seasonal flu, can be even more perilous. A recent analysis of cases found that 28% of people hospitalized with swine flu had asthma. People with asthma are more vulnerable to complications stemming from the flu—such as pneumonia—and are more likely to be hospitalized, which is why the Centers for Disease Control and Prevention recommends that all people with asthma over six months old get the seasonal and swine flu shot. And it has to be the shot, whether it’s a seasonal or swine flu vaccine. (The FluMist vaccine, which is delivered via nasal spray, can cause wheezing and should be avoided by asthmatics.)

The sudden spike in asthma-related doctor’s appointments and ER visits among children that coincides with the start of the school year—a pattern that has been observed all around the Northern Hemisphere—is so predictable that it has come to be known as the September epidemic.

Allergens also are a problem in the fall. The ragweed season begins in late summer, but in some areas it can last well into October. This plant, which is found in the greatest quantities in the East and Midwest, is a nightmare for people with asthma who are sensitized to this allergen. Each plant produces up to a billion grains of pollen in a season, and the lightweight grains can carry on the wind for hundreds of miles.

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Whether you have fresh cherries or sour cherries on hand or have dried cherries to use in the off-season, these healthy cherry dessert recipes are delicious ways to eat more cherries. Our cherry pie recipes, cherry cake recipes, cherry trifle recipes and cherry cookie recipes are easy dessert recipes featuring the sweet flavor of cherries. Try our No-Bake Cherry Cheesecake for a delicious potluck dessert recipe with cherries or Almond Cherry Bites for a cherry cookie recipe to enjoy year round.

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Saturday 29 June 2013

Fresh pasta tossed with hearty vegetables, herbs and olive oil is a staple in the Mediterranean diet. We’ve lightened up traditional pasta recipes in our collection of Mediterranean pasta recipes, including penne pasta recipes, baked pasta recipes, lasagna recipes, vegetarian pasta recipes, gnocchi recipes, fettuccine recipes and more easy pasta recipes, by adding extra vegetables to round out the meal and incorporating lean meats and seafood for added protein. Escape to the Mediterranean with one of these healthy Mediterranean Diet pasta recipes.

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From EatingWell:  May/June 2010 Instead of deep-frying the fish for these fish tacos, we coat the fish with a flavor-packed chile rub and grill it instead. Make sure the fillets are no more than 1/2 to 3/4 inch thick so they cook quickly. Sometimes flipping fish on the grill can be tricky since the fish can stick to the grill or fall apart. The solution is to invest in a grill basket that easily holds 4 to 6 fish fillets and secures the fish in the basket for easy flipping. If you don’t have a grilling basket, make sure the grill is hot and well oiled before adding the fish.


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Eggplant slices are sturdy enough to stand up to the fire of a grill to serve as the basis for a hearty vegetarian entree. Grilled eggplant also can be pureed into a flavorful dip, as in our Grilled Eggplant Salsa recipe. Try one of these healthy grilled eggplant recipes the next time you’re looking for a new grilled vegetarian dinner idea.

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When the weather gets warmer, make a healthy summer salad recipe for a no-cook weeknight meal. These healthy pasta salad recipes, tortellini salad recipes, tomato salad recipes and more easy summer salad recipes are also perfect to share at picnics and potlucks. Try our Summer Succotash Salad for a summer salad using the freshest vegetables of the season or Greek Pasta Salad for a heartier salad recipe to share.

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Eggplant is a versatile vegetable that takes the place of meat in many satisfying vegetarian meals. Our baked eggplant recipes, including stuffed eggplant recipes, are delicious and healthy ways to eat more eggplant. Try our Eggplant & Chickpea Baked Pasta or Indian-Spiced Stuffed Eggplant for an easy eggplant recipe for dinner.

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From EatingWell:  January/February 2010 Both ripe and underripe mango work well in this chicken and vegetable stir-fry. If the mangoes you have are less ripe, use 2 teaspoons brown sugar. If they’re ripe and sweet, just use 1 teaspoon or omit the brown sugar altogether.


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Friday 28 June 2013

Leukotriene pathway modifiers, also known as leukotriene blockers, are a relatively new type of asthma drug. The Food and Drug Administration approved Singulair (montelukast sodium), the first drug in this class, in 1998.

These medications, which can be taken in a once-a-day pill form, improve lung function by treating the underlying inflammation of asthma over the long term. These drugs are used for persistent cases of asthma and should be taken once a day, whether or not your child is experiencing asthma symptoms.

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If you’re looking for a new recipe to make for your Fourth of July party, picnic or potluck, try making one of our healthy July 4th dessert recipes. Many of our summer dessert recipes have a patriotic flair or red, white and blue theme and are perfect for your Independence Day celebration. Try EatingWell's American Flag Cake, a healthy sheet cake decorated with strawberries and blueberries, or make Mini Cream Pies with Berries for a red, white and blue patriotic dessert. Download a FREE 4th of July Recipe Cookbook!

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If you want to make the spread at your Independence Day party look festive, be sure to include at least one of these cute, healthy red, white and blue recipes on your 4th of July menu. These recipes don't use food coloring to get their vibrant hue, instead they use naturally colorful foods such as red strawberries, raspberries, cherries and tomatoes and blue potatoes, blueberries and blue corn chips. Try one of these easy red, white and blue recipes for your 4th of July appetizers, side dishes or desserts or combine a few for an All-American spread. Download a FREE 4th of July Recipe Cookbook!

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hammock-allergy-guide Most springtime sneezers—some one in five Americans—are aware they've got allergies. But knowing how best to treat them is another story. Drugstore aisles are stacked high with an array of pills, capsules, sprays, mists, and drops, and that's before you even get to the prescription options. The upside of all those choices, though, is "there is no need to suffer with seasonal allergies—good treatment is available," says Gainesville, Georgia, allergist Andy Nish, MD. The key to finding the products that will do the most for you, he says, is to first determine the severity, frequency, and duration of your symptoms, which may include sneezing, runny nose, nasal congestion, itchy throat, and itchy, watery eyes.

• Your allergies are mild if you get a twitchy, itchy nose and watery eyes while hanging around outside during pollen season (from early spring to early summer, depending on where you live). It's a nuisance, but not really life-altering.

• Your allergies are moderate if you have sneezing fits or need tissues even when you're inside, and if you're congested enough that you have trouble sleeping or wake up with a sore throat, affecting how you feel over the course of your day.

• Your allergies are severe if you're just plain miserable all the time: Your nose is constantly congested or running, you carry tissues 24/7, you go into frequent sneezing fits, and your eyes are incredibly red, puffy, and itchy. Your throat may even get so sore and itchy that you wonder if you're sick. (You're not.) Suffice it to say, your symptoms consume your life.

Now that you know where you fall on the allergy scale, here's how to find the right remedies for your symptoms.

If your allergies are mild
It sounds like a no-brainer, but every allergy doc worth his degree will urge you to avoid exposure to pollen—produced by trees, grass, weeds, and flowers—as much as possible during peak allergy hours (generally noon through late afternoon). Of course, you can't stay inside all the time, so pop an over-the-counter antihistamine such as Zyrtec, Allegra, or Claritin every day before you head into the great outdoors. These drugs work by blocking the effects of histamine, a chemical your body produces to attack invaders like pollen—launching such immune reactions as watery eyes and sneezes. Which antihistamine should you pick? In the end, all antihistamines on the market work the same way, but different people respond differently (both positively and negatively) to each one; trial and error is the only way to find the product that's best for you, says Paul M. Ehrlich, MD, president-elect of the New York Allergy & Asthma Society.

Got a stuffy nose? Consider using an antihistamine with an added decongestant—look for a "D" or the word "sinus" in the name (think Claritin-D or Benadryl Allergy and Sinus). Decongestants relieve clogging by shrinking swollen tissues and blood vessels, which also shuts down the feedback loop that keeps mucus flowing. (Don't take decongestants if you're pregnant or have hypertension.)

Itchy eyes? Use over-the-counter eyedrops such as Zaditor or Alaway.

Still reaching for the tissues? Try using NasalCrom, a mild OTC nasal spray, especially a few hours before you know you're going to be out in nature, says Tim Mainardi, MD, senior fellow in allergy and immunology at Columbia University Medical School. It prevents mast cells—which are like "little land mines full of histamine," says Dr. Mainardi—from blowing up and releasing their symptom-causing goods.

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Indian spices flavor the eggplant in our healthy Indian eggplant recipes, including Indian eggplant stews, curries and more easy eggplant recipes. Escape to the east with these flavor-packed Indian eggplant recipes that are perfect for a meatless meal when paired with fragrant brown rice or naan.

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Thursday 27 June 2013

asthma-outdoors If you've ever seen a brown haze of pollution hanging over your city, most likely your response was, "Ugh. How can I avoid breathing that stuff?" But let's face it, even if you know it's a bad air day, you probably need to grab some sunshine, get in an outdoor run, or get to work.

Polluted air contains particulate matter, lead, ozone, nitrogen dioxide, carbon monoxide, and sulfur dioxide—all of which can cause problems in people with allergies or asthma. Even if pollution is low, airborne pollen and mold can make a trip outdoors particularly daunting for people with respiratory conditions.

How to tell if it's a bad air day
The first step toward protecting your lungs is to know your city or town. More than 115 million people nationwide still live in counties with pollution levels considered potentially harmful to their health.

Air quality varies widely around the United States. Ozone, for instance—which can pose a major problem for asthmatics—tends to be more prevalent in urban areas, though it can be found in suburban and rural areas as well. If you live in Fargo, N.D.—one of the cities with the cleanest air in the nation—you are likely to breathe easier than if you live in Los Angeles, which has the highest ozone levels in the country.

Local weather stations often provide this information on their websites, and radio stations typically give ozone alerts. In addition, many websites can tell you if pollutants, ozone, or pollen counts are high in your area on any given day.

AirNow.gov, a site run by federal government agencies, provides a daily Air Quality Index as well as other useful information on air quality.The American Academy of Allergy, Asthma & Immunology’s National Allergy Bureau has a daily mold and pollen report.The American Lung Association rates the air quality annually by state at stateoftheair.org.The Environmental Protection Agency has a feature on its website called “My Environment”, which gives you an up-to-date air-quality forecast for your zip code.Pollen.com offers a four-day allergy forecast using data from the National Weather Service.However, it’s not just pollen or air pollution that can trigger problems. Michael Benninger, MD, the chairman of the Head and Neck Institute at the Cleveland Clinic, in Ohio, says changes in barometric pressure and temperature can also spell trouble for people with allergies to pollen and mold, people with severe sinus symptoms, and even people without allergies.
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Friday 21 June 2013

By Sarah Wickline, Contributing Writer, MedPage Today Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this cohort study demonstrated several novel predictors of anxiety and depression among patients after a cancer diagnosis.Be aware that the overall prevalence of anxiety and depression was roughly 30 percent.

In the year following a cancer diagnosis, some patients showed lingering or late-onset anxiety and/or depression, although most appeared to cope relatively well, researchers found.

Among 1,154 patients followed from initial cancer diagnosis, about 20% met criteria for clinically relevant anxiety and roughly 10% were found to have depression 6 and 12 months later, according to Allison W. Boyes, PhD, of the University of Newcastle in Australia, and colleagues.

Significant predictors of development of late-onset or persistent mood disorders in the prospective study included high levels of such disorders 6 months after diagnosis, but also such factors as gender, type of cancer, and certain coping styles, the researchers reported online in the Journal of Clinical Oncology.

"This is one of the first studies to examine the prevalence and predictors of the short-term courses of anxiety and/or depression among a diverse sample of cancer survivors in early survivorship," the researchers wrote.

They noted that most cancer survivors in this group showed psychological resilience, with either no mood disruption or only transient anxiety or depression.

Boyes and colleagues asserted that targeted screening and early intervention should be considered for more vulnerable patients to prevent or reduce the severity of psychological disorders.

Participants were recruited from the ongoing Cancer Survival Study, each having been diagnosed in the past 6 months with one of the top eight incident cancer types in Australia: prostate, colorectal, female breast, lung, melanoma, non-Hodgkin's lymphoma, leukemia, or head and neck cancer.

Along with a detailed questionnaire, each participant filled out the 14-item Hospital Anxiety and Depression Scale (HADS) initially at 6 months after diagnosis and again 12 months after diagnosis. Participants were designated as anxiety or depression cases at a particular assessment if HADS scores at in the relevant domains reached at least 8 on the 21-point scales.

The personal questionnaires assessed patient health behaviors, psychological history and social support systems. Up-to-date medical and treatment records were available for each patient.

Among those asked to participate in the study, 43% agreed. Sample retention between the two assessments was 95%. Participants were 18 to 80 years old and 58% were male.

Odds ratios were adjusted based on information obtained from the patient questionnaires concerning: marital status, education, employment, health insurance coverage, size of household, geographic location, the use of complementary therapies for cancer-related purposes, and the presence of physical comorbidities and/or significant life events that could have been a source of stress.

At the 6-month assessment, 22% (95% CI 20%-25%) qualified as anxiety, and after 12 months, 21% (95% CI 19%-24%) persisted.

At both 6 and 12 months, 13% (95% CI 11%-14%) qualified as depression, and 9% (95% CI 7%-10%) had comorbid anxiety and depression.

Overall, 70% (95% CI, 68%-73%) did not develop anxiety at any time, 82% (95% CI, 79%-84%) did not develop depression, and 87% (95% CI, 85%-89%) did not develop comorbid anxiety-depression.

Boyes and colleagues found that, among patients showing anxiety or depression during the study period, the trajectories varied. About half of patients qualifying as mood disorder cases had the conditions at both assessments. The remainder were about equally divided between those who qualified for case status only at the 12-month evaluation and those who met case criteria at month six but not at month 12.

Significant predictors of anxiety at 12 months included the following: Anxiety at 6 months (relative to no anxiety at 6 months): OR 10.7, 95% CI 7.2-15.0Depression at 6 months (relative to no depression at 6 months): OR 1.9, 95% CI 1.2-3.1Female gender (relative to male): OR 1.8, 95% CI 1.3-2.6"Fighting spirit" coping (relative to other coping styles): OR 1.7, 95% 1.1-2.8

For depression, the following factors were significantly associated with case status at 12 months: Depression at 6 months: OR 6.9, 95% CI 4.0-12.2Anxiety at 6 months: OR 2.6, 95% CI 1.6-4.4Low physical activity but not sedentary (relative to "sufficiently active"): OR 2.1, 95% CI 1.2-3.6Cancer not in remission (relative to remission): OR 1.8, 95% CI 1.1-2.9Lung cancer diagnosis (relative to melanoma): OR 5.3, 95% CI 1.9-15.1"Cognitive avoidance" coping: OR 1.7, 95% CI 1.1-2.8

Patients with comorbid anxiety-depression also had physical inactivity as a significantly predictor, along with both current and past smoking, with odds ratios ranging from 1.6 to 3.7.

"Given that feelings of vulnerability are common when active treatment is completed, it may be reassuring to give survivors in late treatment the message that most will adjust well and require only low-intensity supportive care, including information and self-management support," Boyes and colleagues wrote.

Routine psychological screening may not be necessary for all cancer survivors, the researchers suggested.

Instead, they advocated "targeted screening" of survivors with the risk factors for mood disorders identified in the study.

"Intervention trials focusing on psychological functioning, coping style, and health behaviors are warranted," Boyes and colleagues concluded.

The study was funded by the National Health and Medical Research Council, Cancer Council of New South Wales, Hunter Medical Research Institute, Honda Foundation and the University of Newcastle.

Study authors declared they had no relevant financial interests.

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By Nancy Walsh, Staff Writer, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse PlannerThis study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.High disease activity in psoriatic arthritis is associated with elevated total cholesterol and triglycerides, adding to a growing body of evidence linking psoriatic arthritis metabolically with dyslipidemia and obesity.Note that the study suggests that there may be common pathogenic mechanisms for obesity and psoriatic arthritis.

MADRID -- High disease activity in psoriatic arthritis is associated with elevated total cholesterol and triglycerides, adding to a growing body of evidence linking psoriatic arthritis metabolically with dyslipidemia and obesity, a researcher said here.

Patients considered to have high disease activity because of scores of 10 or higher on the Clinical Disease Activity Index, or the presence of enthesitis or dactylitis, were significantly more likely to have total cholesterol levels above 200 mg/dL (odds ratio 1.58, 95% CI 1.11-2.24, P=0.01), according to Anna Broder, MD, of Albert Einstein College of Medicine in New York City, and colleagues.

They also were more likely to have triglyceride levels above 150 mg/dL (OR 1.6, 95% CI 1.2-2.3, P=0.005), Broder reported at the annual meeting of the European League Against Rheumatism.

"More and more studies in recent years have reported a link between obesity and psoriatic arthritis. In addition, patients whose body mass index is high are less able to achieve or maintain low disease activity in psoriatic arthritis," she said.

The association between obesity and psoriatic is complex, but is related to the production of inflammatory cytokines such as interleukin 1 (IL1), IL6, and tumor necrosis factor (TNF) alpha.

These cytokines also cause dysregulation of lipid metabolism in obesity and type 2 diabetes, resulting in deactivation of lipoprotein lipase, increased production of fatty acids, increased triglycerides, and a shift from low- density lipoprotein (LDL) to very LDL.

This leads to a pro-atherogenic lipid profile with high triglycerides, decreased high-density lipoprotein (HDL), and high or normal LDL.

The lipid profile associated with rheumatoid arthritis (RA) is quite different, she noted, and varies according to the stage of disease.

In early and presymptomatic RA, triglycerides and total cholesterol are elevated and HDL is low, but with symptom onset, the levels of all measures of the conventional lipid profile decrease with a disproportionate decrease in HDL.

"Then, with treatment, an increase occurs in all lipid levels, and the implications of that for cardiovascular risk screening are the subject of a big debate," she said.

The relationship between lipid profiles and psoriatic arthritis has not been as well characterized as that for RA, however, so the researchers analyzed data from the prospective Consortium of Rheumatology Researchers of North America (CORRONA) registry.

CORRONA currently includes 4,500 patients with psoriatic arthritis. For inclusion in this study, patients had to have at least one visit when lipid values and disease activity were recorded.

This provided a study population of 725 patients and about 39% were considered to have medium to high disease activity.

The high disease activity group included more women (57% versus 46%, P=0.006) and smokers (12.7% versus 7.7%, P=0.029), had shorter disease duration (8.7 versus 11.2 years, P=0.001), and had higher erythrocyte sedimentation rate and C-reactive protein.

Patients with high disease activity also were more likely to be prescribed conventional disease-modifying anti-rheumatic drugs (63% versus 51%, P=0.002) and prednisone (13% versus 4.5%, P<0.001), but were less likely to be treated with TNF inhibitors (57% versus 66%, P=0.015).

Mean BMI in patients with high disease activity was 31.7 kg/m2 compared with 30.6 kg/m2 in those with low disease activity.

The presence of enthesitis or dactylitis showed a positive association with total cholesterol above 200 mg/dL, with an odds ratio of 1.6 (95% CI 1.1-2.5, P=0.02).

The researchers also performed a subgroup analysis that included 54 patients who had more than one lipid measurement while enrolled in CORRONA.

In that group, increased disease activity also was associated with lower HDL and higher triglycerides on a regression analysis after adjusting for the duration between visits.

These subgroup findings didn't reach statistical significance, but this may have related to underpowering, Broder said.

"We showed that higher disease activity in psoriatic arthritis is associated with elevated total cholesterol and triglycerides, and in a prospective subanalysis we found that disease activity was associated with high triglycerides and decreased HDL, a pattern that is similar to that observed in type 2 diabetes and metabolic syndrome and obesity, and quite different from what's seen in RA," she said.

"There may be common pathogenic mechanisms for obesity and psoriatic arthritis, and this should be studied further," she concluded.

Study limitations included possible selection bias, as lipid measurements are not required in CORRONA, and the potential for residual confounding with corticosteroids and triglycerides.

The authors reported no conflicts of interest.

Primary source: European League Against Rheumatism
Source reference:
Labitigan M, et al. "Moderate to high disease activity in psoriatic arthritis is associated with elevated total cholesterol and triglycerides" EULAR 2013; Abstract OP302.

Nancy Walsh

Staff Writer

Nancy Walsh has written for various medical publications in the United States and England, including Patient Care, The Practitioner, and the Journal of Respiratory Diseases. She also has contributed numerous essays to several books on history and culture, most recently to The Book of Firsts (Anchor Books, 2010).

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Antihypertensive agents from different classes significantly reduced beta-amyloid protein plaques in a mouse model of Alzheimer's disease. Also this week: a master gene for autoimmune disease.

Antihypertensives for Alzheimer's?

Certain antihypertensives have the unintended side effect of reducing the accumulation of beta-amyloid in the brains of mice with Alzheimer's disease, researchers found.

Giulio Maria Pasinetti, MD, PhD, of Mount Sinai School of Medicine in New York City, and colleagues screened 1,600 FDA-approved drugs to look for any that might have activity either inhibiting or promoting the formation of beta-amyloid. They identified 184 drugs that reduced levels of the protein by more than 30%, including 13 cardiovascular drugs.

Of those, seven antihypertensives in different classes -- carvedilol, propranolol, valsartan (Diovan), losartan, hydralazine, nicardipine, and amiloride -- provided concentration-dependent reductions of beta-amyloid in vitro.

Propranolol, nicardipine, and carvedilol were then given to mice with Alzheimer-like amyloid pathology. After 1 month of treatment, each drug reduced the amount of beta-amyloid in the animals' brains by about 40%.

"This line of investigation will lead to the identification of common medications that are potentially beneficial or detrimental to Alzheimer's disease as a reference for physicians to consider when prescribing the most appropriate drugs for their patients, particularly for treating chronic disorders among the growing geriatric population," the researchers wrote in PLoS ONE.

-- Todd Neale

Gene Oversees Immune Checks and Balances

Mutations in a single gene may be responsible for the immune disruptions that result in disparate conditions ranging from allergies to type 1 diabetes, lupus, and Crohn's disease, researchers from the National Institutes of Health reported.

The gene, BACH2, regulates the process by which T cells differentiate into either immune system activators -- spurring inflammation in response to external threats -- and immune system restrainers that put the brakes on those inflammatory processes when the threat has been eliminated.

Writing in Nature, the researchers, led by the scientific director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, John O'Shea, MD, demonstrated that mice lacking BACH2 developed lethal autoimmune inflammation in the lungs and spleen within months of birth, along with autoantibodies similar to those found in patients with lupus.

They then found that replacing BACH2 in these knockout mice through gene therapy restored the normal immune balance, suggesting that this gene may be a suitable target for therapeutic manipulation.

-- Nancy Walsh

One Better Than Two in GVHD

Acute graft-versus-host disease, or GVHD, occurs after allogeneic transplant of hematopoietic stem cells because donor T cells, transplanted with the graft, attack the recipient's major histocompatibility complex antigens. But it has not been clear which T cells are responsible.

Now researchers led by Paul Allen, PhD, of Washington University in St. Louis, think they may have an answer: the culprit cells are the rare ones that have two T-cell receptors on their surface. Building on experiments in mice, they report in Science Translational Medicine that stem cell transplant patients with acute GVHD have significantly more such cells than do healthy controls or patients who didn't develop GVHD.

And such cells have pathologic activity in the test tube, they reported. Dual-receptor T cells from patients with acute GVHD significantly increased production of the inflammatory cytokines interferon-gamma and interleukin-17a, compared with dual-receptor cells from healthy controls or patients without GVHD.

-- Michael Smith

Naturalistic Model for Parkinson's Disease

Mice bred to overexpress a protein that drives progression of Parkinson's disease developed many of the age-related motor symptoms and changes in sleep seen in patients with Parkinson's disease.

The mice overproduced alpha-synuclein, the essential building block for the characteristic Lewy bodies that form in the nerves of humans with Parkinson's disease. As compared with normal mice, aging transgenic animals with a specific mutation of the alpha-synuclein gene developed progressively worse motor function on a standardized test.

The transgenic mice also exhibited fragmented nighttime behavior, consistent with disturbed sleep that occurs in many patients with Parkinson's disease. However, the animals did not exhibit signs of increased anxiety and depression that often affects patients.

Currently, most preclinical Parkinson's research is conducted in rodents injected with chemical toxins that destroy dopaminergic neurons, which reproduces the motor symptoms of the human disease but not its spontaneous onset, molecular pathology, or progressive course.

Though not a perfect mimic of human Parkinson's, the transgenic mice may prove useful in studying certain aspects of Parkinson's disease, Sarah M. Rothman, PhD, of the National Institute on Aging, and colleagues reported in the Journal of Parkinson's Disease.

-- Charles Bankhead

Sweetening T Cells to Fight Cancer

Giving a little sugar to T cells might enhance their ability to fight cancer cells, researchers reported.

When cancer cells consume much of the available sugar in the same dish as T cells, the latter are rendered impotent to make inflammatory, tumor-fighting compounds, said researchers at Washington University in St. Louis.

But when the researchers fortified the T cells with extra sugar, they produced twice as much of their inflammatory weaponry, according to a report in the June 6 edition of Cell.

"It's like an on-off switch, and all we need to do to flip it is change the availability of sugar," said lead researcher Erika Pearce, PhD, in a press release. "T cells often can go everywhere -- tumors, inflammation, infections -- but sometimes they don't do anything. If we can confirm that this same switch is involved in these failures in the body, we might be able to find a way to put the fight back into those T cells."

-- Kathleen Struck

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By Crystal Phend, Senior Staff Writer, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San FranciscoThe combination of two monoclonal antibodies, ipilimumab and nivolumab, may boost response rates against metastatic melanoma without excessive toxicity.Point out that fully 65% of the patients showed some evidence of clinical activity, whether by conventional World Health Organization response criteria, unconfirmed response, immune-related response, or stable disease for 24 weeks or more.

CHICAGO -- The combination of two monoclonal antibodies -- ipilimumab (Yervoy) and nivolumab -- may boost response rates against metastatic melanoma without excessive toxicity, a phase I trial showed.

Concurrent therapy with the PD-1 receptor antibody and the CTLA-4 antibody produced an objective response in 40% of patients overall, Jedd Wolchok, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York City, and colleagues found.

At the maximum doses with acceptable toxicity (1 mg/kg nivolumab and 3 mg/kg ipilimumab), 53% saw their tumor burden shrink by at least 80%, including three complete responses among the 17 patients, the group reported here at the American Society of Clinical Oncology (ASCO) annual meeting.

The combination yielded "a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy," the group wrote in a paper released simultaneously online in the New England Journal of Medicine.

The speed of response was notable too, occurring within 12 weeks, commented Michael Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

"That's something we've never seen before with an immune therapy in melanoma and it's a rare thing to see in a solid tumor," he told MedPage Today.

Both drugs target so-called immune checkpoints subverted by tumor cells.

Ipilimumab blocks the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) pathway used by tumors to activate immune response-limiting regulatory T cells.

Nivolumab is one of a new class of agents that block tumor cells from using programmed death 1 (PD-1) receptors to "exhaust" the killer T cell response against the cancer.

The new trial included 53 patients with unresectable stage III or IV melanoma put on intravenous nivolumab and ipilimumab given together every 3 weeks for four doses, followed by nivolumab alone every 3 weeks for four doses, then the two drugs together every 12 weeks for up to eight doses.

Fully 65% of these patients showed some evidence of clinical activity, whether by conventional World Health Organization response criteria, unconfirmed response, immune-related response, or stable disease for 24 weeks or more.

Another 33 patients patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses, dubbed sequential treatment.

Sequential treatment with nivolumab after progression on ipilimumab yielded an objective response rate of 20%, including one complete response.

Treatment-related grade 3 or 4 adverse events occurred in 53% of combination-group patients "but were qualitatively similar to previous experience with monotherapy and were generally reversible."

The most common of these were elevated levels of lipase (13%), aspartate aminotransferase (13%), and alanine aminotransferase (11%).

The maximum doses with "acceptable" toxicity was associated with one case of grade 3 uveitis and one case of grade 3 elevated levels of aspartate aminotransferase and alanine aminotransferase among 17 patients treated with 1 mg/kg nivolumab and 3 mg/kg ipilimumab.

The treatment-related grade 3 or 4 adverse event rate was 18% with nivolumab after ipilimumab failure.

In a separate phase I study also released at the meeting and in the NEJM, lambrolizumab, another novel PD-1 blocker, produced a 38% response rate as monotherapy after resistance to ipilimumab in advanced melanoma.

"The results of these trials are striking and complementary," James Riley, PhD, of the University of Pennsylvania in Philadelphia, wrote in an accompanying editorial.

"Surprisingly and importantly, the use of ipilimumab and either one of two PD-1 monoclonal antibodies -- whether the PD-1 and CTLA-4 antibodies were given sequentially or together -- resulted in a rate and severity of adverse events that were no higher than those observed with the individual drugs alone," he stated.

The synergy in anti-tumor effect might be due to targeting separate pathways or by preferentially impacting distinct types of immune cells to the same end, Riley noted.

The immune checkpoint blockade strategy might be effective against a wide array of other solid tumor types as well, and the results open the door to studies adding further immune modulators, he suggested.

However, not every combination appears to be as safe and effective. A phase I trial of concurrent vemurafenib (Zelboraf) and ipilimumab by Wolchok's group was halted over liver toxicity earlier this year.

The researchers acknowledged patient selection bias and the small number of patients as limitations that suggest caution in interpreting the phase I results.

The next step will be a phase III trial to formally compare ipilimumab alone, nivolumab alone, and the combination in advanced melanoma, they suggested.

Durability will also be important to follow, Atkins noted.

The study was sponsored by Bristol-Myers Squibb.

Wolchok reported receiving consulting fees from Bristol-Myers Squibb, Ziopharm Oncology, Polynoma, and Merck and grant support from Bristol-Myers Squibb, GlaxoSmithKline, and MedImmune on behalf of his institution.

Riley reported having consulted for Bristol-Myers Squibb regarding PD-1 blockade at a single 2-day meeting, having grant support from the NIH, and holding a patent with the Walter Reed Army Institute of Research regarding CTLA-4 in HIV infection.

Crystal Phend

Staff Writer

Crystal Phend joined MedPage Today in 2006 after roaming conference halls for publications including The Medical Post, Oncology Times, Doctor's Guide, and the journal IDrugs. When not covering medical meetings, she writes from Silicon Valley, just south of the San Francisco fog.

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By John Gever, Deputy Managing Editor, MedPage Today

WASHINGTON -- Up to three scans using 18F-fluorodeoxyglucose-enhanced positron emission tomography (FDG-PET) technology can be covered by Medicare for oncology treatment planning, the Centers for Medicare and Medicaid Services (CMS) announced Tuesday.

The agency's final decision expands significantly on its earlier proposal, which would have allowed reimbursement for only a single FDG-PET scan and excluded prostate cancer as a covered indication.

Both limitations were dropped in CMS's final coverage determination. The agency said it now agrees with numerous comments it received on the draft proposal, which argued that FDG-PET scans are valuable in treatment planning in prostate cancer as they are for other tumor types.

Moreover, the final decision to cover up to three scans applies to all Medicare beneficiaries nationwide, whereas the draft proposal had left coverage determinations to local Medicare contractors. CMS also said that coverage of additional FDG-PET scans beyond the initial three can be reimbursed in individual cases at local contractors' discretion.

The scans measure rates of glucose metabolism within tissues. Cancer cells typically metabolize glucose at a higher rate than normal cells. Thus, tumors essentially light up to become visually distinct and quantifiable in FDG-PET imaging.

At issue was the extent to which CMS would allow Medicare coverage of these scans to inform treatment planning decisions after initial surgical or medical anti-tumor therapies, in that the scans are intended to show the presence of residual tumor cells.

Prior to the agency's final decision, FDG-PET scans were covered only under the "coverage with evidence determination" procedure, which pays for services only when provided in rigorous clinical studies.

CMS had received hundreds of comments on the draft memo, most of which complained about the one-scan limit and the exclusion of prostate cancer.

Many of the comments cited published research that documented the value of these scans in planning follow-up treatments in cancer patients, with CMS ultimately agreed.

The agency noted that the research does not yet establish that the scans "meaningfully improve health outcomes." But, because it was satisfied that FDG-PET results can and do make a difference in physicians' treatment plans, CMS decided that was enough to warrant routine coverage.

John Gever

Senior Editor

John Gever, Senior Editor, has covered biomedicine and medical technology for 30 years. He holds a B.S. from the University of Michigan and an M.S. from Boston University. Now based in Pittsburgh, he is the daily assignment editor for MedPage Today as well as general factotum on the reporting side. Go Pirates/Penguins/Steelers!

Thursday 20 June 2013

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By Salynn Boyles, Contributing Writer, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse PlannerMohs micrographic surgery is the only recommended treatment option for high-risk facial nonmelanoma skin cancers.Note that Mohs micrographic surgery involves examining 100% of the surgical margins in three dimensions during surgery in an effort to remove as much cancerous tissue as possible while preserving healthy surrounding skin.

Mohs micrographic surgery is the only recommended treatment option for high-risk facial nonmelanoma skin cancers, according to new guidelines.

When researchers from the University of Virginia reviewed data on the removal of close to 500 facial lesions, they concluded that margins of at least 8-mm are needed to excise 95% of basal cell carcinoma (BCCA) lesion using conventional surgical excision and a 13.25-mm margin would be required to remove 95% of high-risk squamous cell carcinomas (SCCA).

"This margin may be unreasonable on most areas of the face," lead researcher Amy E. Schell, MD, and colleagues wrote in the June 6 issue of JAMA Facial Plastic Surgery.

They added that, owing to the variability in margins found among high-risk nonmelanoma skin cancers as well as the relatively large margins needed to completely excise 95% of these lesions, "we continue to recommend the referral of high-risk cases for Mohs micrographic surgery."

The researchers further concluded that a 5-mm margin is required to remove at least 95% of low-risk nonmelanoma skin cancers and should be considered a minimum for primary excision.

Tumor grade, stage, and larger lesion size are associated with a higher risk of incomplete excision, the researchers wrote.

Other characteristics, such as a patient's age, sex, immune and disease status, and past sun exposure, have also been suggested as predictors of outcome, as has the location of the lesion on the face.

For basal cell carcinomas, the periorbital, perinasal, and preauricular regions as well as the ears and temple have been considered by some to be high-risk zones for lesions that are deeper and have greater lateral extensions.

These facial areas plus perioral tissue have been considered by some to be high-risk zones for squamous cell carcinoma, but the relevance of lesion location on patient outcome is still debated.

Mohs micrographic surgery (MMS) involves examining 100% of the surgical margins in three dimensions during surgery in an effort to remove as much cancerous tissue as possible while preserving healthy surrounding skin.

"Although MMS may be considered the gold standard for cutaneous nonmelanoma skin cancer removal, it is not always available or practical," the researchers wrote.

In their review, Schell and colleagues examined 495 lesions removed using MMS from 180 men and 119 women treated through the University of Virginia Health System from 2005 to 2011.

Based on history and histologic subtype, all lesions were grouped into either high-risk or low-risk categories, with high-risk lesions including those that were large, recurrent, or included aggressive subtypes: Lesions greater than or equal to 2 cm in either length or width were considered high risk, as were recurrent lesions.Moderately and well differentiated squamous cell cancers in situ were placed in the low-risk category.Nodular basal cell lesions were considered low risk.Infiltrative, morpheaform, micronodular, metatypical, sclerotic,

basosquamous, and multifocal and/or mixed basal cell carcinomas were considered high risk, as were superficial basal cell lesions.

Face location was not used to classify lesions as high- or low-risk because of the conflicting data.

"Overall, lesions required at least one high-risk attribute (recurrent status, large size, or aggressive histologic subtype) to be included in the high-risk group for either basal cell carcinoma or squamous cell carcinoma," Schell and colleagues wrote.

The mean margins for low-risk BCCAs, high-risk BCCAs, low-risk SCCAs, and high-risk SCCAs were 2.4 mm, 3.7 mm, 2.6 mm and 5.3 mm, respectively.

Among the other findings: Margins were significantly larger for lesions larger than 2 cm for both BCCA (5.6 mm and 2.7 mm, respectively; P<.001) and SCCA (4.5 mm and 3.1 mm, respectively; P=.02).This was also true for high-risk histologic subtypes versus low-risk histologic subtypes for BCCA (3.6 mm versus 2.7 mm; P<.001) as well as SCCA (6.2 mm versus 2.9 mm; P=.03).Recurrent BCCA lesions had significantly larger margins than primary lesion (4.3 mm and 2.8 mm, respectively; P=.03). Margins were larger for recurrent SCCA lesions (6.1 mm) versus primary lesions (3.1 mm), but the difference was not considered statistically significant (P=.06)

Lesion location appeared to have no significance for SCCA. Margins within the area of the face considered a high-risk zone were similar in size to those on other areas of the face (3.2 mm versus 3.5mm, respectively; P=.50).

For BCCA, margins in the high-risk zone were actually smaller than those outside the zone. (2.7 mm versus 3.4 mm, respectively; P=.01).

"The high-risk zones for BCCA and SCCA encompass perinasal, periocular, and auricular lesions, which, once removed, pose significant reconstructive challenges in terms of preserving function and cosmesis," the researchers wrote. "Practically speaking, most lesions within the high-risk zones for nonmalignant skin cancer will be candidates for Mohs micrographic surgery for this reason."

This study was previously reported at the American Academy of Facial Plastic and Reconstructive Surgery Combined Otolaryngological Spring Meeting in San Diego, April 20, 2012.

The authors report no conflict of interest.

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By Rick Lange, MD, and Elizabeth Tracey, Johns Hopkins Medicine

PodMed is a weekly podcast from Johns Hopkins Medicine. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine, and Rick Lange, MD, professor of medicine at Johns Hopkins and vice chairman of medicine at the University of Texas Health Science Center at San Antonio, look at the top medical stories of the week.

This week's topics include vegan diets and mortality, metabolic surgery for diabetes, sunscreen and aging, and the health effects of fructose.

Program notes:

0:31 Sunscreen and photoaging of skin

1:33 Four groups and looked at microtopography

2:31 SPF and UVA and UVB labeling

3:05 Benefits of vegetarian diets

4:05 Followed over 6 years for 12% reduction in mortality

5:05 Metabolic surgery for diabetes

6:05 Half had surgery and about half of them met guidelines

7:05 One year data only but long term many failures

7:50 Fructose health effects

8:50 Disadvantages of glucose and fructose

9:50 Very refined foods rather than sugars

10:47 End

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By Charles Bankhead, Staff Writer, MedPage Today Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.Note that this randomized controlled trial of an immune-stimulating agent for advanced stage melanoma demonstrated efficacy in terms of durable response rate, at the price of a high frequency of (typically mild) adverse events.Be aware that overall survival was not different between the two arms of the trial, though only 6-month survival data was available for analysis.

CHICAGO -- Intralesional injection of an oncolytic therapy significantly increased the durable response rate in advanced melanoma compared with a control therapy, according to results of a randomized trial.

Patients treated with the virus-derived talimogene laherparepvec (T-VEC) had a 16.3% rate of durable responses, defined as partial or complete response maintained for at least 6 months. That compared with 2% of patients treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) who had durable responses.

Subgroup analysis showed durable responses in 33% of patients with IIIB-C (nonvisceral) disease and in 24% of patients who received T-VEC as first-line therapy, Howard L. Kaufman, MD, of Rush University Medical Center in Chicago, reported at the American Society of Clinical Oncology meeting.

"T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III trial," said Kaufman. "The only grade 3/4 adverse event that occurred in more than 2% of patients was cellulitis. We observed a trend toward improved overall survival with T-VEC at interim analysis."

Despite recent advances in the treatment of melanoma, patients with stage IIIB/C disease have a 5-year disease-free survival of 30% to 35%. Survival in stage IV melanoma is less than 15%.

Immunotherapeutic agents, such as interleukin-2 and ipilimumab (Yervoy), have demonstrated efficacy in metastatic melanoma, providing a rationale for continued investigation of immunology-based treatment strategies.

T-VEC consists of an attenuated herpes simplex virus, resulting from deletion of the viral neurovirulence gene and replacement of ICP47 with the human GM-CSF gene, said Kaufman. After direct injection into a melanoma lesion, T-VEC causes lysis of tumor cells and induces local and systemic immune responses that are enhanced by expression of GM-CSF.

Kaufman reported results from a trial involving 436 patients with unresectable stage IIIB/C and IV melanoma. Investigators at 64 sites in four countries randomized the patients 2:1 to intralesional T-VEC administered every 2 weeks or to subcutaneous GM-CSF.

T-VEC was injected into cutaneous, subcutaneous, or nodal lesions but not visceral lesions, said Kaufman. The volume injected depended on the size of the lesion, but any number of lesions could be treated in a single visit. At each treatment session, new lesions had treatment precedence, followed by larger lesions.

The primary endpoint was durable response. Secondary endpoints included overall survival, objective response rate, time to treatment failure (TTF), and safety.

About 30% of the patients had stage IIIB/C, and another 30% had stage IV M1a. T-VEC was administered as first-line therapy in 47% of the patients.

Analysis of the primary outcome showed a durable response rate of 16.3% with T-VEC and 2.1% with GM-CSF, which translated into an unadjusted odds ratio of 8.9 (P<0.0001). The overall response rates were 26.4% with T-VEC (10.8% complete responses) and 5.7% with GM-CSF (0.7% CR rate).

T-VEC consistently led to higher rates of the primary endpoint, regardless of prior treatment, performance status, sex, and HSV status.

The median TTF was 8.2 months with T-VEC and 2.9 months with GM-CSF (P<0.0001). An interim analysis of overall survival showed a trend in favor of T-VEC (23.3 months versus 19.0 months, HR 0.79, P=0.07). According to Kaufman, the final analysis of overall survival will occur in about 6 months.

The most common adverse events (all grades) with T-VEC were fatigue (50.3%), chills (48.6%), pyrexia (42.8%), nausea (35.6%), influenza-like illness (30.5%), injection-site pain (27.7%), and vomiting (21.2%). The most frequent grade 3/4 adverse event was cellulitis (2.1%).

The next step in evaluation of T-VEC will be directed toward building on the activity demonstrated in the trial, said principal investigator Robert Hans Ingemar Andtbacka, MD, of the University of Utah in Salt Lake City.

"Moving forward, the question is whether we can improve the response by combining talimogene laherparepvec with other immunotherapies and other agents," Andtbacka told MedPage Today. "There is a study ongoing where talimogene laherparepvec is being combined with ipilimumab (Yervoy) to try to activate the immune system from two different mechanisms."

The favorable adverse event profile demonstrated thus far makes T-VEC a good candidate to combine with other therapies in patients with advanced and metastatic melanoma, he added.

Better understanding of the molecular mechanisms of melanoma has led to a boom in the development of targeted agents and immunotherapies for the disease, said Gary Schwartz, MD, of Memorial Sloan-Kettering Cancer Center in New York. The challenge for local therapies, such as T-VEC, will be to achieve adequate systemic activity that can match or exceed those seen with other new agents.

"I haven't really been convinced that this approach will lead to better responses or survival, and we already have other new therapies that activate immunity specifically against particular targets," Schwartz, who was not involved in the T-VEC study, told MedPage Today. "I think we might have moved beyond this with current immunotherapy."

T-VEC could have potential as part of combination therapy, he added. Adding the agent to other therapies that have different or complementary mechanisms of action could lead to enhanced activity in melanoma.

The study was supported by Amgen.

Kaufman disclosed relationships with Amgen and BioVex. One or more co-investigators disclosed relationships with Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Morphotek, Roche/Genentech, and BioVex.

Schwartz reported no relevant disclosures.

Primary source: American Society of Clinical Oncology
Source reference:
Andtbacka RHI, et al "OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous granulocyte-macrophase colon-stimulating factor for the treatment of unresected stage IIIB/C and IV melanoma" ASCO 2013; Abstract LBA9008.

Charles Bankhead

Staff Writer

Working from Houston, home to one of the world's largest medical complexes, Charles Bankhead has more than 20 years of experience as a medical writer and editor. His career began as a science and medical writer at an academic medical center. He later spent almost a decade as a writer and editor for Medical World News, one of the leading medical trade magazines of its era. His byline has appeared in medical publications that have included Cardio, Cosmetic Surgery Times, Dermatology Times, Diagnostic Imaging, Family Practice, Journal of the National Cancer Institute, Medscape, Oncology News International, Oncology Times, Ophthalmology Times, Patient Care, Renal and Urology News, The Medical Post, Urology Times, and the International Medical News Group newspapers. He has a BA in journalism and MA in mass communications, both from Texas Tech University.

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By Michael Smith, North American Correspondent, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San FranciscoThis study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.A therapy aimed at reviving the immune response to advanced melanoma, nivolumab, generated durable responses in long-term follow-up of an early clinical trial.Point out that the drug caused adverse events in 82% of patients, with grades 3 and 4 events in 21%, most commonly lymphopenia, fatigue, and increased lipase.

CHICAGO -- A therapy aimed at reviving the immune response to advanced melanoma generated durable responses in long-term follow-up of an early clinical trial, a researcher said here.

About a third of the 107 patients in the dose-finding trial had an objective response to the monoclonal antibody nivolumab, and the rate reached 41% among patients who got the dose now being studied in phase III trials, according to Mario Sznol, MD, of the Yale Cancer Center.

In contrast, historical response rates to immunotherapy in advanced melanoma have been no better than 10%.

"We're really in an era of remarkable advances in melanoma," Sznol told reporters at the annual meeting of the American Society of Clinical Oncology.

The drug targets a molecule dubbed PD-1 -- part of a so-called immune checkpoint -- on the surface of killer T cells. PD-1 is activated by a corresponding molecule, PD-L1, on the surface of tumor cells, with the effect of turning off the immune response to the cancer.

Nivolumab is one of several drugs under investigation whose goal is to interrupt that activation and keep the immune response active. The meeting is expected to see reports on others that block PD-1, as well as some that block PD-L1 on the tumor side of the interaction.

For the near future, the study emphasizes the importance of getting patients into clinical trials of new drugs, commented Lynn Schuchter, MD, of the University of Pennsylvania in Philadelphia, a melanoma expert who speaks for ASCO.

"Patients with melanoma getting access to these new agents is really the most critical part of care," she told reporters.

But "when PD-1 antibodies get approved, it will definitely be practice-changing," she said.

"Melanoma patients are living longer and better with these new treatments," she said in a statement.

The industry-sponsored study tested nivolumab in several types of advanced disease, but for this report, Sznol and colleagues focused on the 107 patients with advanced melanoma.

All patients had disease that worsened despite earlier standard systemic treatment. Indeed, 25% had three or more prior therapies and 63% had two or more, Sznol reported.

The drug was given intravenously every 2 weeks at doses ranging from 0.1 to 10 mg per kg of body weight.

Overall, 31% of the patients -- 33 of the 107 -- saw their tumors shrink by at least 30%, with at least some responses at each dose level.

The researchers chose a dose of 3 mg per kg for further study because of a 41% response rate, including one patient with a complete response, Sznol reported.

That dose also had a median overall survival rate of 20.3 months, compared with 16.8 months for the study as a whole.

The drug caused adverse events in 82% of patients, with grades 3 and 4 events in 21%, most commonly lymphopenia, fatigue, and increased lipase.

"The high level of activity observed with this drug opens up a number of avenues for future research to understand and challenge the ways tumors evade the immune system," Sznol said in a statement.

"We're very excited that there is potential for even more activity in combination with other drugs," he said.

He noted that the study was not randomized, but "it had a considerable number of patients and the durability of responses is a sign of very promising clinical activity."

He also said that patients were representative of typical patients with advanced melanoma, rather than being selected for the best chance to respond.

The findings are a "real breakthrough in the treatment of melanoma and possibly other cancers," commented Michael Atkins, MD of Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

Physicians have been able to stimulate the immune system in nonspecific ways for several years, he told MedPage Today, but the treatments were associated with "a lot of toxicity." The highly specific nature of the PD-1 antibody approach appears to yield better efficacy with lower toxicity, he said.

But he cautioned it remains unclear if the approach will work in all patients and in all tumor types.

The study was supported by Bristol-Myers Squibb. Sznol reported financial links with the company and several authors reported holding equity positions in the firm.

Primary source: American Society of Clinical Oncology
Source reference:
Sznol M, et al "Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538)" ASCO 2013; Abstract CRA9006.

Michael Smith

North American Correspondent

North American Correspondent for MedPage Today, is a three-time winner of the Science and Society Journalism Award of the Canadian Science Writers' Association. After working for newspapers in several parts of Canada, he was the science writer for the Toronto Star before becoming a freelancer in 1994. His byline has appeared in New Scientist, Science, the Globe and Mail, United Press International, Toronto Life, Canadian Business, the Toronto Star, Marketing Computers, and many others. He is based in Toronto, and when not transforming dense science into compelling prose he can usually be found sailing.

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By Nancy Walsh, Staff Writer, MedPage Today Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.Ustekinumab yielded significant and sustained improvements in signs and symptoms of psoriatic arthritis in both anti-TNF-naive and anti-TNF-experienced patients.

MADRID -- The monoclonal antibody ustekinumab (Stelara) had sustained benefits through a year of treatment among patients with active psoriatic arthritis, even for those who had previously not done well on a tumor necrosis factor (TNF) inhibitor.

Among those who had not previously received anti-TNF treatment, patients who saw a 20% improvement in their symptoms according to the criteria of the American College of Rheumatology (ACR20) ranged from 59% to 73% on ustekinumab (Stelara), Christopher Ritchlin, MD, of the University of Rochester in New York, reported here at the annual meeting of the European League Against Rheumatism.

And even among those who had already been given anti-TNF treatment but had stopped, whether for a lack of efficacy or adverse events, 50% to 55% showed ACR20 responses at week 52, Ritchlin and his colleagues found.

"Little has been known about treatment options for patients with psoriatic arthritis who haven't responded to either methotrexate or anti-TNF treatment -- patients who don't really have any good alternatives," Ritchlin said at a press briefing.

A previous study found that patients with active psoriatic arthritis who had not had an adequate response to methotrexate showed benefits with ustekinumab.

This agent is a monoclonal antibody targeting interleukins 12 and 23, which binds to p40 on natural killer and T cells and blocks subsequent immune events, he explained.

To see if the response extended to patients who also had failed on other biologics, he and his colleagues enrolled 312 patients, randomizing them to receive ustekinumab 45 mg or 90 mg at baseline, 1 month, and then every 3 months.

A control group was given placebo at baseline, 1 month, and month 4 followed by crossover to 45 mg ustekinumab at weeks 24, 28, and 40.

After 4 months, patients who had less than 5% improvement in their tender and swollen joint counts were switched. If they had been on placebo, they were given ustekinumab 45 mg, and if they had been on the 45 mg dose, they were switched to the 90 mg dose.

A total of 180 of the patients had previously received anti-TNF therapy. Of those, the baseline tender and swollen joint counts were 25 and 14, respectively.

At week 24, 43.8% of patients receiving ustekinumab had ACR20 responses compared with 20.2% of patients on placebo (P<0.001), said Ritchlin.

By 1 year, among patients receiving the 45 mg dose, 47% had ACR20 responses, while 28% and 13% had ACR50 and ACR70 responses.

For patients given the 90 mg dose, the corresponding numbers were 48%, 26%, and 18%.

The ACR20 responses among patients who had been anti-TNF naive were 40% in patients originally randomized to placebo and then switched, 60% in the original 45-mg group, and 58.5% in the 90-mg group, while that response was seen in 37% and 41% of the TNF-experienced group.

Even among patients who had received three or more anti-TNF agents, 29% of the 45-mg group had ACR20 responses, as did 13% of the 90-mg group.

Improvements in psoriasis skin scores of 75% or more were seen in 56% of patients originally receiving placebo and then given 45 mg, while that degree of improvement was seen in 57% and 64% of the initial 45 and 90 mg groups, respectively.

Serious adverse events were seen in 5.8% of both dose groups, which was similar to the placebo group, and events leading to discontinuation occurred in 5.8% and 3.8% of the 45-mg and 90-mg groups.

Two patients, both of whom had previously been treated with anti-TNF therapy, developed malignancies. One of these was breast cancer, in a patient receiving the 45 mg dose, and the other was squamous cell carcinoma in a patient on 90 mg.

Serious infections occurred in 0.7% of patients receiving ustekinumab, and three patients with multiple cardiovascular risk factors and previous anti-TNF treatment had mild myocardial infarctions, Ritchlin said.

There were no deaths, he added.

"This study showed that for patients who have had to stop an anti-TNF agent for some reason, ustekinumab is effective. So we now have an alternative for these patients, and it represents a major advance for those of us who treat this disease," he said.

"Moreover, for dermatologists who treat patients with psoriasis and who may also have joint involvement, they can be reassured that this agent has effects on the joints as well," he added.

"In some of these patients in the dermatologists' offices, they have arthritis that's not been diagnosed. So for those patients, whether or not they've been exposed to anti-TNF, there's a reasonable chance that this agent will not only work for their skin but also for their joints," he told MedPage Today.

The study was supported by Janssen Research and Development.

The investigators disclosed receiving support from Janssen R&D and being employees of the company.

Primary source: European League Against Rheumatism
Source reference:
Ritchlin C, et al "Maintenance of efficacy and safety of ustekinumab in patients with active psoriatic arthritis despite conventional nonbiologic and anti-TNF biologic therapy: 1-year results of the P-SUMMIT 2 trial" EULAR 2013; Abstract OP1.

Nancy Walsh

Staff Writer

Nancy Walsh has written for various medical publications in the United States and England, including Patient Care, The Practitioner, and the Journal of Respiratory Diseases. She also has contributed numerous essays to several books on history and culture, most recently to The Book of Firsts (Anchor Books, 2010).

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By Michael Smith, North American Correspondent, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San FranciscoThe investigational immune therapy lambrolizumab had a 38% response rate in patients with advanced melanoma, including those who had prior treatment with ipilimumab.Point out that the drug, the second entry of blockers of the PD-1/PD-L1 immune checkpoint, was safe and well tolerated.

CHICAGO -- An investigational immune therapy was safe and well tolerated in patients with advanced melanoma, a researcher reported here.

In addition, lambrolizumab had a 38% response rate and several patients saw their tumors disappear, according to Antoni Ribas, MD, PhD, of the Jonsson Comprehensive Cancer Center at the University of California Los Angeles.

The drug, which is aimed at reviving the immune response to cancer, also appeared to yield long-lasting responses, Ribas reported at the annual meeting of the American Society of Clinical Oncology and online in the New England Journal of Medicine.

The drug is the second entry in a class that is attracting increasing interest, namely blockade of the PD-1/PD-L1 immune checkpoint, which renders tumor cells immune to the attack of activated T cells.

PD-1, on the surface of killer T cells, is activated by a corresponding molecule, PD-L1, on the surface of tumor cells, with the effect of turning off the immune response to the cancer.

In essence, the T cells are muzzled so that they cannot attack the tumor.

Earlier, researchers reported here that the first entrant in the field, nivolumab, also had a good safety profile and durable responses among patients with advanced melanoma.

Taken together, the results show "the effectiveness of this approach in patients with advanced melanoma," commented Lynn Schuchter, MD, of the University of Pennsylvania in Philadelphia, a melanoma expert who speaks on the topic for ASCO.

Time will tell whether the drugs have different properties, if one is better than another, and if so in what patients, she told MedPage Today. But she called the PD-1 approach a "remarkable advance" for melanoma patients.

The PD-1 immune checkpoint can also be attacked from the other side, and drugs are under development that block the PD-L1 molecule on tumor cells.

Ribas and colleagues tested lambrolizumab in a large international multi-center phase I trial, aimed at establishing the safety and tolerability of the drug in several dosing regimens -- 10 mg per kg body weight every 2 or 3 weeks or 2 mg/kg every 3 weeks.

They included 135 patients with advanced disease, including those who had been previously treated with the immune checkpoint inhibitor ipilimumab (Yervoy) and those who had not.

The researchers also assessed tumor responses every 12 weeks, Ribas and colleagues reported.

Overall, the drug had on limited toxicity; common adverse events attributed to the drug included fatigue, rash, pruritus, and diarrhea, but most of the adverse events were grades 1 and 2.

Remarkably, however, the overall objective response rate, confirmed by radiology, was 38% across all dose cohorts, and 52% in the 52 patients who received the highest dose of 10 mg/kg every 2 weeks.

Moreover, responses were durable -- 42 of the 52 patients who responded were still on treatment when the data were analyzed in March 2013.

Overall, the median progression-free survival among the 135 patients was longer than 7 months.

Prior exposure to ipilimumab had no effect on the benefit of the therapy, Ribas and colleagues reported.

"The striking anticancer activity observed with lambrolizumab requires confirmation in larger studies," they wrote.

The study was supported by by Merck Sharp and Dohme. Ribas reported financial links with Merck, as well as with Amgen, GlaxoSmithKline, Novartis, Roche, and MedImmune.

Michael Smith

North American Correspondent

North American Correspondent for MedPage Today, is a three-time winner of the Science and Society Journalism Award of the Canadian Science Writers' Association. After working for newspapers in several parts of Canada, he was the science writer for the Toronto Star before becoming a freelancer in 1994. His byline has appeared in New Scientist, Science, the Globe and Mail, United Press International, Toronto Life, Canadian Business, the Toronto Star, Marketing Computers, and many others. He is based in Toronto, and when not transforming dense science into compelling prose he can usually be found sailing.

Wednesday 19 June 2013

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By John Gever, Deputy Managing Editor, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse PlannerAnxiety, not depression, is the most common mental health issue facing long-term cancer survivors and their spouses.Note that the study suggests that efforts should be made to improve the identification and treatment of anxiety in long-term cancer survivors and their spouses.

Anxiety, not depression, is the most common mental health issue facing long-term cancer survivors and their spouses, a large meta-analysis found.

With data pooled from 26 studies, rates of depression in people surviving at least 2 years after a cancer diagnosis did not differ significantly from those seen in controls (relative risk 1.11, 95% 0.96-1.27, P=0.17), whereas anxiety was significantly more frequent in the survivors (RR 1.27, 95% CI 1.08-1.50, P=0.0039), according to Alex J. Mitchell, MD, of Leicester Partnership Trust in Leicester, England, and colleagues.

Rates of both depression and anxiety were similar among long-term survivors and their spouses included in 17 studies, although the data from those analyses suggested that women worried more than men irrespective of whether they were survivors or spouses.

"Our findings underline the importance of detection and treatment of anxiety disorders, not only depression," Mitchell and colleagues wrote in Lancet Oncology, adding that future research should address these conditions among patients receiving noncurative, palliative care.

In an accompanying commentary, Julia Addington-Hall, MD, of the University of Southampton in England, said the study sheds light on an under-recognized psychological effect of cancer survivorship.

"Much of this [past] research has been focused on depression, with anxiety being neglected by comparison," she wrote.

"The increased risk of anxiety [shown in the current analysis] in long-term cancer survivors justifies taking a fresh look at anxiety in these patients, including methods for identification of those at high risk, and provision of appropriate care and treatment."

Another cancer specialist, Ashley Sumrall, MD, of Carolinas Healthcare's Levine Cancer Institute in Charlotte, N.C., said anxiety needs to be addressed in cancer patients.

"Most of our cancer patients suffer from anxiety and depression that impact their quality of life," she told MedPage Today. "In the past, we tended to lump these two together, when, in fact, anxiety can impact the patient's care more than depression can. Anxiety increases levels of stress in the body and can also correlate with poorer outcomes. We've seen that time and time again."

In the study, Mitchell and colleagues searched the published literature for studies on prevalence of mood disorders among spouses and patients who had survived at least 2 years with a cancer diagnosis. They found a total of 16 that compared prevalences of depression and/or anxiety in cancer survivors versus healthy controls, and another 12 assessing these conditions in survivors and their spouses.

Some of these studies were based on national registry data and were quite large -- one drew on the U.K. General Practice Research Database and included data on more than 26,000 patients and 104,000 matched controls.

Pooled data from the studies on survivors versus controls yielded the following results: Depression prevalence: 11.6% in survivors (95% CI 7.7%-16.2%), 10.2% in controls (95% CI 8.0%-12.6%)Anxiety prevalence: 17.9% in survivors (95% CI 12.8%-23.6%), 13.9% in controls (95% CI 9.8%-18.5%)

For both calculations, excluding one study that Mitchell and colleagues considered to be a "methodological outlier" did not change the findings.

However, when the researchers included data from the component studies on patients diagnosed with cancer less than 2 years previously, they found that depression was significantly increased in that group relative to those with less recent diagnoses (RR 1.74 relative to diagnoses 2 to 10 years previously, P=0.0009).

The comparisons of depression and anxiety in survivors versus their spouses yielded the following: Depression prevalence: 26.7% in survivors (95% CI 19.8%-34.2%), 26·3% in spouses (95% CI 18.4%-35.0%)Anxiety prevalence: 28.0% in survivors (95% CI 22.3%-33.9%), 40.1% in spouses (95% CI 25.4%-55.9%)

Neither the prevalence of depression nor the prevalence of anxiety differed significantly between cancer patients and their spouses

The difference in anxiety prevalence did not reach statistical significance (RR 0.71, 95% CI 0.44 to 1.14), but that appeared to be because one of the five studies contributing to the analysis was sharply at odds with the other four.

That one study -- involving gynecologic cancer survivors -- showed a tripled rate of anxiety in the patients versus their spouses (RR 3.26, 95% CI 1.64-6.78), whereas the other four all showed reduced rates of anxiety in the patients relative to their spouses.

When the outlier study was excluded, the analysis of the remaining four showed significantly less anxiety among the cancer survivors (RR 0.54, 95% CI 0.42-0.69).

And of those four studies, the one with the largest patient-spouse imbalance in anxiety prevalence, with a relative risk of 0.36, involved prostate cancer survivors -- suggesting that wives may suffer from cancer-related anxiety more than their husbands, regardless of which one of them is the cancer patient.

Limitations to the study cited by Mitchell and colleagues included the usual caveats attached to meta-analyses, as well as a frequent lack of detail in the original studies on patients' mental status or on recruitment methods for healthy controls. Matching of controls to patients was variable in the studies, the researchers also noted. Overall, heterogeneity among studies was high, but there was no evidence of publication bias and excluding methodological outliers had no impact on most results.

The study had no external funding.

Study authors and the editorialist declared they had no relevant financial interests.

John Gever

Senior Editor

John Gever, Senior Editor, has covered biomedicine and medical technology for 30 years. He holds a B.S. from the University of Michigan and an M.S. from Boston University. Now based in Pittsburgh, he is the daily assignment editor for MedPage Today as well as general factotum on the reporting side. Go Pirates/Penguins/Steelers!

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By Nancy Walsh, Staff Writer, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.A year of treatment with apremilast, which targets inflammatory mediators, led to significant long-term reduction in disease activity among patients with psoriatic arthritis.Note that there were no new safety signals after 6 months regarding cardiac events, malignancies, or opportunistic infections, and no significant laboratory abnormalities were seen throughout the study.

MADRID -- A year of treatment with apremilast, which targets inflammatory mediators, led to significant long-term reduction in disease activity among patients with psoriatic arthritis, a researcher reported here.

At week 52 in a trial known as PALACE 1, 63% of patients receiving 20 mg of the new oral agent twice daily had experienced a 20% reduction in symptoms according to the criteria of the American College of Rheumatology, as had 54.6% of those receiving 30 mg of the drug, according to Arthur Kavanaugh, MD, of the University of California San Diego, and colleagues.

In addition, improvements of 50% were seen in 24.8% and 24.6% of the two dosage groups, respectively, while improvements of 70% were seen in 15.4% and 13.8%, Kavanaugh reported at the annual meeting of the European League Against Rheumatism.

Apremilast is a phosphodiesterase 4 inhibitor that breaks down cyclic AMP. "Cyclic AMP tends to be anti-inflammatory, and keeping it elevated seems to decrease some pro-inflammatory cytokines like tumor necrosis factor and interleukin 6 and to allow other anti-inflammatory cytokines like interleukin 10 to be increased," he explained during a press briefing.

The phase III trial included 504 patients with active psoriatic arthritis despite treatment with conventional disease-modifying anti-rheumatic drugs or biologic agents.

One-quarter of the patients had already been exposed to biologic treatment.

At baseline, patients were randomized to one of the two doses of apremilast or placebo. At week 16, those who had not reached a 20% improvement in swollen and tender joints were re-randomized to one of the active treatments if they had been in the placebo group, or remained at the same dose if in the active treatment groups.

After 4 months, 31.3% of patients receiving 20 mg of apremilast twice daily experienced a 20% reduction in symptoms according to criteria of the American College of Rheumatology (ACR), compared with 19.4% of those given placebo (P=0.0140).

In addition, 40% of patients receiving 30 mg of the drug twice daily had ACR20 responses, compared with placebo at that time point (P<0.0001).

At 6 months, all patients were re-randomized to 20 mg or 30 mg of apremilast, and they have now been followed for 1 year, with results for their arthritic symptoms that are "very respectable," Kavanaugh said.

"Another important outcome for patients with arthritis of the hands and feet is functional status, as measured on the Health Assessment Questionnaire, or HAQ, with scores from zero to 3," he said.

"Zero means 'I can do everything I want to do,' and 3 means 'I can't take care of myself at all,' and the baseline HAQ of 1.21 in this study reflects considerable functional impairment," he said.

After 52 weeks, there was a .35 point improvement in HAQ, "which is a level at which patients can certainly say they feel better and can do their daily activities," he noted.

The investigators also assessed effects of the treatment on the skin manifestations of disease using the Psoriasis Area and Severity Index (PASI).

In the 30 mg group, 37% had 75% improvements in PASI scores, as did 25% of those in the 20 mg group. Those improvements were sustained out through a year, Kavanaugh said.

With regard to safety, "the overall safety profile of apremilast appears to be pretty good," he noted.

All phosphodiesterase inhibitors can cause gastrointestinal adverse effects, but generally these occur early and decrease in frequency over time.

In this study, events such as diarrhea and nausea occurring in the second 6 months ranged from 0.6% to 3% in the 20 mg group and from 0% to 1.8% in the 30 mg group.

There were no new safety signals after 6 months regarding cardiac events, malignancies, or opportunistic infections, and no significant laboratory abnormalities were seen throughout the study.

"One tangible result of this could be that, if this drug is approved, we won't have to monitor lab tests to look for toxicity issues," Kavanaugh said.

"These results are encouraging for us as clinicians as well as for our patients. We have had more therapies in the past 10 years than we ever had, but success breeds success and we're happy to see even more new treatments," he said.

Apremilast is also being evaluated for use in psoriasis, ankylosing spondylitis, and rheumatoid arthritis.

The study was sponsored by Celgene.

The investigators reported financial relationships with a variety of companies, including Celgene, AstraZeneca, Amgen, Pfizer, Abbott, Novartis, and Genentech. Several are employees of Celgene.

Primary source: European League Against Rheumatism
Source reference:
Kavanaugh A, et al "Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis" EULAR 2013; Abstract LB1.

Nancy Walsh

Staff Writer

Nancy Walsh has written for various medical publications in the United States and England, including Patient Care, The Practitioner, and the Journal of Respiratory Diseases. She also has contributed numerous essays to several books on history and culture, most recently to The Book of Firsts (Anchor Books, 2010).