Study Redefines Placebo Effect as Part of Effective Treatment

/PRNewswire/ -- Researchers used the placebo effect to successfully treat psoriasis patients with one quarter to one half of their usual dose of a widely used steroid medication, according to an early study published online today in the journal Psychosomatic Medicine. Early results in human patients suggest that the new technique could improve treatment for several chronic diseases that involve mental state or the immune system, including asthma, multiple sclerosis and chronic pain.

By designing treatment regimens that mix active drug and placebo, researchers at the University of Rochester Medical Center hope to maximize drug benefits, reduce side effects, increase the number of patients who take their medicine and extend the use of drugs otherwise limited by addiction risk or toxicity. Using a fraction of the usual drug dose to get the same effect could also make possible a dramatic and timely reduction in healthcare costs, according to the authors.

The publication is a product of decades of research in the emerging field of "psychoneuro-immunology," which holds that the ability of the human immune system to fight disease is closely linked with a person's mind. Thoughts and moods are captured in neurochemicals that cause the release of hormones which interact with disease-fighting cells.

The current research team chose psoriasis for their first human experiments because it is chronic, gets worse when patients feel stress and involves the immune system. The condition causes pain and disability in four million Americans as inherited traits and irritants cause the immune system to trigger the too fast production of skin cells, resulting in red, scaly patches of dead skin.

"Our study provides evidence that the placebo effect can make possible the treatment of psoriasis with an amount of drug that should be too small to work," said Robert Ader, Ph.D., M.D. (hc), distinguished university professor in the University of Rochester School of Medicine & Dentistry. "While these results are preliminary, we believe the medical establishment needs to recognize the mind's reaction to medication as a powerful part of many drug effects, and start taking advantage of it," said Ader, professor of Psychiatry and principal investigator of the study. The placebo effect, obviously, cannot help unconscious patients, or replace substances that the body itself is unable to produce, he added. In the absence of functioning islet cells, for example, placebos cannot stimulate the release of insulin in a Type l diabetic.

Study Details

A description of the current findings requires expanding the definition of placebo effects to include phenomena that are not fully understood by modern medicine, Ader said. Although placebos, "dummy pills" that have no therapeutic effect by themselves, are prescribed by many physicians today, their use still carries a stigma. It's as if the effect of a pill containing no medication is not "real," part magic and part deception.

To accurately define and study the placebo effect, Ader and colleagues chose to frame it as an example of a well-established psychological phenomenon: the conditioned response. Nineteenth century Russian physiologist Ivan Pavlov was the first to study the phenomenon of conditioning. By ringing a bell (a conditioned stimulus) each day before giving his dogs food (an unconditioned stimulus), Pavlov found that the dogs would eventually salivate (a conditioned response) at the sound of the bell alone.

In the current study, Ader and colleagues sought to determine if a drug's therapeutic effect could be triggered by qualities associated with the drug, like its shape, color, smell and packaging, as well as by its administration by an authority figure in a white lab coat. These repeated associations, Ader argues, create conditioned responses, drug-like therapeutic effects of treatment caused, not by a drug's ingredients alone, but elicited by stimuli associated with the effects of active drug treatment. The results provide the first evidence that conditioned responses might be harnessed to influence the design of drug regimens in humans.

Research teams at the University of Rochester Medical Center and Stanford University conducted an 11 to 14-week, double-blind, randomized clinical trial in 46 patients with mild-to-moderate psoriasis. Patients were on no other medications during the study, and had signed consent forms after being informed they might receive a reduced dose of topical steroid.

At the start of the study, researchers randomly selected two "target" psoriatic lesions or sores on each patient. Twice each day during a three-week baseline period, all patients spread a lotion containing a full dose of steroid medication (0.1% Aristocort A, triamcinolone acetonide) onto one of their two study lesions. The second lesion was coated with a moisturizing cream. Medicated and unmedicated creams were distributed in coded syringes to make them indistinguishable.

Nearly all past drug studies divided patients into two groups only. One would get the full dose of the drug all of the time (a 100 percent reinforcement schedule). The other would get zero drug all of the time (zero percent reinforcement). The current study asks for the first time: what if we treat patients with something in between drug and placebo? After the three-week baseline period, patients were randomly assigned to one of three groups.

The first continued to receive 100 percent of the treatment drug at each administration for the rest of the study on his or her study lesion. A second, the partial reinforcement group, also continued to receive a full dose, but only 25 or 50 percent of the time, and a steroid-free emollient the rest of the time. The study was designed so that this second group could benefit from exposure to cues they had previously associated with active drug treatment (a conditioned therapeutic effect). A third group, the "dose control group," received active drug at every administration, but at 25 or 50 percent of the full dose used in the first and second groups. Thus, the partial reinforcement and "dose control" groups received the same total amount of active medication, but in different patterns.

Results were measured in two ways. First, a "blinded" dermatologist measured the severity of a patient's psoriasis lesions weekly using the Psoriasis Severity Scale (PSS), a standard tool used to track the redness, hardening and thickening of skin. The second measure was whether a patient experienced a "relapse" in lesion severity, defined arbitrarily as a return to a PSS score within two units of a patient's initial score.

In terms of the overall PSS severity scores, results were mixed. The Stanford study site found no group differences in PSS scores that could be attributed to the different treatment regimens. Ader believes that elevated baseline PSS scores in the randomly selected Dose Control subjects at Stanford might have obscured the differences between the dose control and partial reinforcement groups. For instance, results could have been influenced by differences in the amount of sun patients were exposed to in Upstate New York and California (ultraviolet light is an established treatment for psoriasis).

In Rochester, there were no differences between the PSS values of the Partial Reinforcement and Dose Control groups at the point in the study where experimental treatment began. In this case, partial reinforcement brought about a greater reduction in lesion severity during the experimental period than continuous reinforcement (dose control) with the same cumulative amount of drug.

The relapse results were clearer. Four of 18 patients (22.2 percent) in the 100 percent reinforcement group (full dose all the time) relapsed within the eight-week experimental period. Among patients treated with a full dose of drug, but one half or one quarter of the time (50 or 25 percent reinforcement schedule), four of 15 patients (26.7 percent) relapsed. Thus, the incidence of relapse did not differ substantially between patients receiving a full dose of drug all the time and those treated under the partial reinforcement schedules, researchers said. In contrast, eight of the 13 patients (61.5 percent) in the dose control group who received active drug each time, but not the full does, relapsed in the same period of time.

Thus, the incidence of relapse in the partial reinforcement group (26.7 percent) was significantly less than in dose control patients (61.5 percent) that received the same cumulative amount of drug. Further studies are underway, and others are planned, to confirm the effect, answer the questions raised and explore the effect in other autoimmune diseases.

The study was conducted jointly by the Departments of Psychiatry and Dermatology within the School of Medicine & Dentistry at the University of Rochester and the Stanford University School of Medicine. Along with Ader, the study was authored in Rochester by Mary Gail Mercurio, James Walton and Deborra James. Leading the effort at Stanford were David Fiorentino, Alexa Kimball, Michael Davis and Valerie Ojha. The study was funded by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health (NIH).

"The pharmaceutical industry may choose to ignore the conditioning component of drug treatment regimens," Ader said. "Alternatively, they may now consider exploring ways to exploit conditioning in the design of drug treatment protocols, especially in chronic conditions where patients acquire conditioned responses over time. I believe industry will eventually support this approach because it promises to increase safety and reduce production costs."

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FDA Approves New Drug to Treat Psoriasis

The U.S. Food and Drug Administration today approved Stelara (ustekinumab), a biologic product for adults who have a moderate to severe form of psoriasis.

Plaque psoriasis is an immune system disorder that results in the rapid overproduction of skin cells. About 6 million people in the United States have plaque psoriasis which is characterized by thickened patches of inflamed, red skin, often covered with silvery scales.

"This approval provides an alternative treatment for people with plaque psoriasis, which can cause significant physical discomfort from pain and itching and result in poor self-image for people who are self-conscious about their appearance," said Julie Beitz, M.D., director, Office of Drug Evaluation III, in the FDA's Center for Drug Evaluation and Research.

Stelara is a monoclonal antibody, a laboratory-produced molecule that mimics the body's own antibodies that are produced as part of the immune system. The biologic treats psoriasis by blocking the action of two proteins which contribute to the overproduction of skin cells and inflammation.

Three studies of 2,266 patients evaluated the biologic's safety and effectiveness.

Since Stelara reduces the immune system's ability to fight infections, the product poses a risk of infection. Serious infections have been reported in patients receiving the product and some of them have lead to hospitalization. These infections were caused by viruses, fungi, or bacteria that have spread throughout the body. There may also be an increased risk of developing cancer.

The FDA is requiring a risk evaluation and mitigation strategy or REMS for Stelara that includes a communication plan targeted to healthcare providers and a medication guide for patients.

Stelara is manufactured by Centocor Ortho Biotech Inc. of Horsham, Pa., a wholly-owned subsidiary of Johnson & Johnson of New Brunswick, N.J.

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FDA Statement on the Voluntary Withdrawal of Raptiva From the U.S. Market

Today, Genentech, the manufacturer of the psoriasis drug Raptiva (efalizumab), announced that it has begun a voluntary, phased withdrawal of the product from the U.S. market. The company is taking this action because of a potential risk to patients of developing progressive multifocal leukoencephalopathy (PML), a rare, serious, progressive neurologic disease caused by a virus that affects the central nervous system. By June 8, 2009, Raptiva will no longer be available in the United States.

Prescribers are being asked not to initiate Raptiva treatment for any new patients. Prescribers should immediately begin discussing with patients currently using Raptiva on how to transition to alternative therapies. The FDA strongly recommends that patients work with their health care professional to transition to other alternative therapies for psoriasis.

The risk that an individual patient taking Raptiva will develop PML is rare and is generally associated with long-term use. Generally, PML occurs in people whose immune systems have been severely weakened and often leads to an irreversible decline in neurologic function and death. There is no known effective treatment for PML. On Oct. 16, 2008, FDA updated the FDA-approved labeling for Raptiva to warn of the risk of life-threatening infections, including PML. On Feb. 19, 2009, the FDA issued a Public Health Advisory informing patients and prescribers of the risk of PML in patients taking Raptiva, after receiving reports of four patients with PML, three of whom died. On March 13, 2009, the FDA approved a Medication Guide for Raptiva and included additional information in Raptiva's labeling regarding PML.

Raptiva was approved by the FDA in 2003. It is a once-weekly injection for adults with moderate to severe plaque psoriasis.

Prescribers should continue to monitor patients on Raptiva for neurologic symptoms that might represent PML. Prescribers and patients may report adverse events to the FDA's MedWatch program at 800-FDA-1088, by mail at MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787, or online at www.fda.gov/medwatch/report.htm.

More information about the withdrawal of Raptiva is available on the Genentech Web site: www.gene.com/gene/products. Prescribers with questions about Raptiva may contact Genentech Medical Communications at (800) 821-8590.

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FDA Advises Public of Serious Adverse Event with Psoriasis Drug Raptiva

The U.S. Food and Drug Administration today issued a public health advisory concerning three confirmed, and one possible report of progressive multifocal leukoencephalopathy (PML), a rare brain infection, in patients using the psoriasis drug Raptiva (efalizumab). Three of those patients have died. All four patients were treated with the drug for more than three years. None of the patients were receiving other treatments that suppress the immune system.

The FDA is reviewing this latest information. The agency will take appropriate steps to:

* ensure that the risks of Raptiva do not outweigh its benefits;
* that patients prescribed Raptiva are clearly informed of the signs and symptoms of PML; and
* that health care professionals carefully monitor patients for the possible development of PML.

PML is caused by a virus that affects the central nervous system. PML usually occurs in people whose immune systems have been severely weakened. It leads to an irreversible decline in neurologic function and death. Symptoms may include unusual weakness, loss of coordination, changes in vision, difficulty speaking and personality changes. There is no known effective prevention or treatment.

Psoriasis is a chronic disease, for which a number of effective therapeutic options are available, including four other approved biologic agents, ultraviolent light therapy, and the drugs cyclosporine, acitretin, and methotrexate. Generally, treatment for psoriasis patients involves a rotation of therapies.

In October 2008, the product labeling for Raptiva was revised to highlight in a boxed warning the risks of life-threatening infections, including PML. At that time, the FDA directed Genentech, the manufacturer, to develop a risk evaluation and mitigation strategy (REMS) to include a medication guide to educate patients about the drug’s risks.

The FDA strongly recommends that health care professionals carefully monitor patients on Raptiva, as well as those who have discontinued the drug, for any signs or symptoms of neurologic disease, and that they periodically reassess the benefits of continued treatment. Patients should be aware of the symptoms of PML and contact their health care professionals immediately if they experience any such symptoms.

Raptiva is a once-weekly injection approved for adults with moderate to severe plaque psoriasis who are candidates for systemic (whole body) therapy or phototherapy. The drug works by suppressing T-cells (blood cells that help fight infection) in the immune system. These cells, when activated, migrate to the skin and cause inflammation which results in the red, inflamed and scaly patches of skin, which is associated with psoriasis. By suppressing T-cells, Raptiva decreases the function of the immune system which increases a patient’s susceptibility to infections.

Health care professionals and consumers may report serious adverse events (side effects) or product quality problems with the use of this product to the FDA's MedWatch Adverse Event Reporting program online, by regular mail, fax or phone.

--Online: www.fda.gov/MedWatch/report.htm
--Regular Mail: use postage-paid FDA form 3500 available at: www.fda.gov/MedWatch/getforms.htm and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
--Fax: (800) FDA-0178
--Phone: (800) FDA-1088

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FDA Approves Updated Labeling for Psoriasis Drug Raptiva

The U.S. Food and Drug Administration today announced labeling changes, including a Boxed Warning, to highlight the risks of life-threatening infections, including progressive multifocal leukoencephalopathy (PML), with the use of Raptiva (efalizumab). The labeling changes are based on the FDA's post-market surveillance. The FDA is also requiring the submission of a Risk Evaluation and Mitigation Strategy (REMS), which will include a Medication Guide for patients and a timetable for assessment of the REMS.

Raptiva is a once-weekly injection approved for adults with moderate to severe plaque psoriasis who are candidates for systemic (whole body) therapy or phototherapy to control their psoriasis.

The FDA's Office of Surveillance and Epidemiology, charged by the Agency with monitoring drugs once approved for the marketplace, has received reports of serious infections leading to hospitalizations, and deaths in some cases, in patients using Raptiva.

The now-required Boxed Warning will highlight the risk of bacterial sepsis, viral meningitis, invasive fungal disease, progressive multifocal leukoencephalopathy and other opportunistic infections.

Additionally, Raptiva's label will be updated to include data from juvenile animal studies in mice (age equivalent to a 1-14 year old human). These data indicate a potential risk for the permanent suppression of the immune system with repeat administration of Raptiva in this age group. Raptiva is not approved for children under 18 years of age.

"As part of FDA's monitoring of the life-cycle of approved products, the agency received reports of serious infections in some patients taking Raptiva. These reports led to our decision to highlight these risks in the drugs labeling," said Janet Woodcock, the FDA's director of the Center for Drug Evaluation and Research. "Doctors and other prescribers should carefully evaluate and weigh the risk/benefit profile of Raptiva for patients who would be more susceptible to these risks."

Raptiva works by suppressing the immune system to reduce psoriasis flare-ups, however by suppressing the body's natural defense system, it can also increase the risk of serious infections and malignancies in patients.

Patients identified to begin therapy with Raptiva should have received all their age-appropriate vaccinations before starting the drug. Vaccinations should not be administered to patients taking Raptiva because immunity to the vaccination virus may not be conferred.

Patients taking Raptiva should be educated about recognizing the signs and symptoms of infection, PML (confusion, dizziness or loss of balance, difficulty talking or walking, and vision problems), anemia (dizziness upon standing, weakness or jaundice), thrombocytopenia (bruising, bleeding gums, pin-point sized red or purple dots under the skin), or the worsening of their psoriasis or arthritis. Signs of a nervous system disorder include sudden onset of numbness, tingling or weakness in the arms, legs or face.

If any of these signs appear, Raptiva patients should seek immediate medical attention. Patients with pre-existing infections or who have a compromised immune system should notify their health care professional before beginning treatment with Raptiva.

Because reports of these adverse events were received voluntarily from populations of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug's use.

One report of PML in a Raptiva-treated patient came from an ongoing post-marketing epidemiological study of patients with psoriasis.

Health care professionals should monitor patients treated with Raptiva for the signs and symptoms of these adverse events and also instruct patients to report any such signs and symptoms to them without delay.

Consumers and health care professionals can report adverse events to the FDA's MedWatch program at 800-FDA-1088, by mail at MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787, or online at www.fda.gov/medwatch/report.htm.

Raptiva was approved in 2003. It is manufactured by Genentech, Inc. of San Francisco, Calif.

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Psoriasis: What Everyone Should Know

(NAPSI)-There’s encouraging news for the more than 6.5 million Americans who suffer from the chronic skin condition known as psoriasis: A comfortable, convenient and easy-to-use new form of topical medication has been shown to relieve many of the symptoms associated with the disease.

What Is Psoriasis?

Psoriasis is a chronic, immune-mediated condition that manifests in the skin and/or the joints. In plaque psoriasis, the most common type, patches of skin called “lesions” become inflamed and covered by silvery white scales. The severity of psoriasis can vary from person to person; however, for most people, psoriasis tends to be mild.

Psoriasis is not just a physical condition; it has an emotional impact as well.

“For those who live with it, psoriasis can be a life-altering disease,” said dermatologist and psychologist Richard Fried, M.D. “The physical discomfort and embarrassment often impact patients’ self-esteem and influence daily activities.”

No one knows exactly what causes psoriasis, but it is believed to have a genetic component. Most researchers agree that the immune system is somehow mistakenly triggered, which speeds up the growth cycle of skin cells. For most people, psoriasis has a significant and unfavorable impact on quality of life. Recent studies indicate:

• Nearly 60 percent of patients said their disease is a large problem in their everyday life.

• Psoriasis has a greater impact on quality of life in women and younger patients.

“Finding the right treatment option can be a challenge for people with psoriasis,” explained Dr. Fried. “The key to getting patients to stick with their psoriasis treatment is to find something that is effective yet easy to use and convenient.”

Treating The Condition

Many psoriasis patients--most of them with a mild form of the disease--have a low level of satisfaction with their treatment options. These include topical treatments, light therapy and oral medications. Fortunately, there’s a unique new medication--available from doctors but without a prescription--that may help patients find relief.

Called Psorent, this innovative product is a clinically proven and specially formulated topical solution to help relieve the symptoms of psoriasis such as itching, scaling, flaking, redness and irritation. The steroid-free formulation is fast drying and applies easily with a convenient, no-mess applicator.

To learn more, call (800) 628-9904 or visit www.psorent.com.

Doctors say psoriasis doesn’t have to lower a person’s self-esteem. Fortunately, topical medication can alleviate symptoms.