Drugs Approved Under Deadline More Likely to Run Into Trouble Later

By Amanda Gardner
HealthDay ReporterWEDNESDAY, March 26 (HealthDay News) — New research shows that drugs that are approved quickly to meet mandated deadlines are more likely to run into trouble down the line, after they are in millions of Americans' medicine cabinets, than drugs that receive more deliberation before approval., but it may have helped to have a black box warning in the first place rather than adding one three years later," said study author Daniel Carpenter, a professor of government at Harvard University. "It's not just the fact of approval. It's approval or regulatory processes assisting clinicians and patients with optimal use down the road. That's a big part of the approval process. It's not just saying yes and no, but saying with conditions and information that help us use drugs well."The Prescription Drug User Fee Act (PDUFA), enacted in 1992, mandated that the U.S. Food and Drug Administration must act on 90 percent of all drug applications within 12 months of submission of the application or face funding cuts. That deadline was narrowed to 10 months in 1997."This study actually puts quantitative information around the question of whether the PDUFA user fee laws have resulted in a rush to approve things or to make decisions too quickly and many people, myself included, have worried about this," said Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic Foundation.Many critics have also pointed out that the tighter deadlines were not accompanied by necessary increases in funding. "Every group that has looked at the FDA says it is underfunded," said Nissen, who has advocated for repealing PDUFA. "The right answer was to provide more resources so the FDA could evaluate applications more accurately but to do so in a way that doesn't put the FDA in the bind of making decisions too quickly and without adequate consideration of the implications."Carpenter and his colleagues used a mathematical model to look at the association between PDUFA deadlines, the timing of FDA drug approval and the likelihood of post-marketing safety problems in drugs approved since 1950. The study is published in the March 27 issue of the New England Journal of Medicine.After PDUFA was initiated, approval decisions tended to be concentrated in the two months preceding the deadlines.Drugs approved before the looming deadline were more than five times more likely to be withdrawn from the market for safety reasons; more than four times more likely to have to add a black-box warning; and more than three times more likely to have one or more dosage forms voluntarily discontinued by the manufacturer.Some examples provided by Carpenter:Baycol, a statin approved exactly one day to the year after the application was submitted, and withdrawn four years later due to reports of death from rhabdomyolysis, a breakdown of muscle fibers.The diabetic drug Rezulin was given priority status, approved before the six-month deadline, then given a black-box warning, withdrawn from the market, and eventually reintroduced.The infamous arthritis drug Vioxx was also a priority drug, approved within six months and later withdrawn because of cardiac side effects, to much hoopla."In doing a lot of interviews at the FDA, they'll tell you that the culture of CDER [Center for Drug Evaluation and Review] is fairly dominated by these review deadlines," said Carpenter, who is writing a book on the FDA.But this doesn't necessarily mean the FDA should do away with deadlines altogether, Carpenter said."It strikes me we should think about deadlines less and on resources more for accelerating and maintaining FDA drug approval," he said. "Nobody wants to go back to the years where it was taking three to four years to get drugs through the FDA. Right now, 90 percent of these drugs have to be decided on in a certain time. What if we pushed that back to 60, 70, 80 percent and doubled the number of people reviewing drugs?"Nissen said: "I also think we need to distinguish between routine approval and approvals of drugs that are really breakthrough drugs. I would argue compelling reason to move drugs that have major new benefits through the process more quickly... But 'me-too' drugs — that's another drug in the same class where there are already drugs available — that may not fit the bill. What you really want to do is accelerate the novel drugs. PDUFA doesn't distinguish, but I think it's a problem." The FDA said it was performing its own analysis.Another study, this one published in the March 26 issue of the Journal of the American Medical Association, looked at differences in the approval process for two lipid-altering drugs.The first, ezetimibe, was approved in October 2002 on the basis of its ability to reduce LDL ("bad") cholesterol levels but without evidence of its effects on atherosclerosis or clinical events. A large trial to evaluate the drug more closely for major cardiovascular events began in January 2006 but is not expected to end until January 2011. Nevertheless, the drug was approved and marketed aggressively (sales reached $5 billion in 2007).On the other hand, torcetrapib, a drug developed to raise HDL ("good") cholesterol levels never made it to market because a large, well-designed trial found an increased incidence of major cardiovascular events and death. The trial was halted early and the drug was never approved."Of the two approaches, torcetrapib was clearly the more successful," wrote the study's author, Dr. Bruce Psaty of the University of Washington, in Seattle. "For drugs used to treat cardiovascular risk factors, the FDA needs to work with the sponsor, as it wisely did for the approval of torcetrapib, so that large, long-term trials evaluating new drugs that will be used by millions of U.S. individuals start early, evaluate the reduction in cardiovascular disease incidence, and are completed soon after drug approval." SOURCES: Daniel Carpenter, Ph.D., professor of government, Harvard University, Cambridge, Mass.; Steven Nissen, M.D., chairman, Department of Cardiovascular Medicine, Cleveland Clinic Foundation; March 27, 2008, New England Journal of Medicine; March 26, 2008, Journal of the American Medical Association

FDA Checks Into Singulair Suicide Risk

Font Size A A A FDA Checks Into Singulair Suicide Risk Possible Link Between Singulair Use and Suicide Risk Isn't Certain; Investigation May Take 9 MonthsBy Miranda Hitti
WebMD Medical News
March 27, 2008 — The FDA today announced that it is working with the drug company Merck to investigate a possible link between Merck's asthma and allergy drug Singulair and behavior/mood changes, suicidality (suicidal thinking and behavior), and suicide. The FDA's investigation may take nine months. As of now, there's no proof that Singulair directly affects suicide risk. Meanwhile, the FDA calls Singulair "effective" and advises patients with questions not to stop taking Singulair before talking to their doctor. The FDA also asks health care professionals and caregivers to monitor patients taking Singulair for suicidality and changes in behavior and mood. Singulair is used to treat asthma and the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose) and to prevent exercise-induced asthma. It's in a class of drugs called leukotriene receptor antagonists. Other leukotriene modifying medications include the asthma drugs Accolate, Zyflo, and Zyflo CR. The FDA is reviewing postmarketing reports it has received of behavior/mood changes, suicidality, and suicide in patients who took Accolate, Zyflo, and Zyflo CR and will assess whether further investigation is warranted. Singulair Time Line The FDA notes that over the past year, Merck has updated Singulair's prescribing information and patient information to include the following postmarketing adverse events: tremor (March 2007), depression (April 2007), suicidality (October 2007), and anxiousness (February 2008). In February 2008, the FDA and Merck discussed how best to communicate these labeling changes to prescribers and patients. According to the FDA, Merck plans to highlight the recent changes in the prescribing information in face-to-face interactions with prescribers and to provide prescribers patient information leaflets about Singulair. In response to inquiries received by the FDA, the FDA has asked Merck to evaluate Singulair study data for more information about suicidality and suicide. The FDA is also reviewing its postmarketing reports of behavior/mood changes, suicidality, and suicide in patients who took Singulair. Singulair's web site includes the most current prescribing information and patient information for Singulair, according to the FDA. Drug Companies Respond "The notification by FDA is not an indication that they believe that health care providers should change their prescribing practices based on this alert," George Philip, MD, Merck's senior director of clinical research and chair of the product development team for Singulair worldwide, tells WebMD. "Instead, if patients have questions, they should contact their doctor before making any changes in their use of Singulair and should not stop Singluair on the basis of this report." Philip notes that postmarketing reports "can be quite sketchy and difficult to make solid conclusions and certainly not sufficient for us to conclude that Singulair has caused any particular effect." In 40 clinical studies of some 11,000 patients who took Singulair as part of a placebo-controlled trial, there were no reports of suicide, according to Philip. And in other studies comparing Singulair to other types of asthma therapies including inhaled corticosteroids and long-acting beta agonists, out of roughly 3,900 patients taking Singulair and 3,400 using other asthma treatments, one patient taking Singulair and three patients taking other asthma treatments attempted — but did not complete — suicide. Accolate is made by AstraZeneca. "AstraZeneca is aware of the posting by the FDA, but to date has not been asked for any further information," Blair Hains, AstraZencea spokesman, tells WebMD. Zyflo and Zyflo CR are made by Critical Therapeutics. "We are actively reviewing our current safety database and will take appropriate action if deemed necessary," Linda Lennox, Critical Therapeutics' vice president for investor and media relations, tells WebMD via email. Report Adverse Events The FDA urges health care professionals and patients to report side effects from the use of Singulair, Accolate, Zyflo, and Zyflo CR to the FDA's MedWatch Adverse Event Reporting program. MedWatch reports can be filed the following ways: On the FDA's web siteBy returning the postage-paid FDA form 3500 to 5600 Fishers Lane, Rockville, MD 20852-9787By faxing the form to 800-FDA-0178By phone at 800-332-1088 SOURCES: FDA: "Early Communication About an Ongoing Safety Review of Montelukast (Singulair)." George Philip, MD, senior director of clinical research; chairman, Product Development Team, Singulair Worldwide, AstraZeneca. Blair Hains, spokesman, AstraZeneca. Email from Linda Lennox, vice president for investor and media relations, Critical Therapeutics.

Now-Banned Hair Dyes Linked to Bladder Cancer

By Steven Reinberg
HealthDay ReporterWEDNESDAY, March 26 (HealthDay News) — Hairdressers and barbers who used now-banned hair dyes that had high concentrations of coloring ingredients appear to be at a slightly elevated risk of bladder cancer, a new report contends.

The authors said the findings confirm what was first suspected back in the 1970s — that hair dyes appear to increase the risk of cancer. These coloring agents were discontinued in the 1970s when they tested positive for cancer in rodents."This report updates an earlier review done in the 1990s, which called the evidence inadequate to determine the risk of cancer," said Dr. Michael J. Thun, head of epidemiological research at the American Cancer Society.There is a question, however, whether the same cancer risk exists with the chemicals currently used in hair dyes, Thun said. "These studies were done over years, and cancer takes years to develop. So the relevant exposures would have been in the past, and the products have changed," Thun said. "So this report doesn't provide any evidence about the risk of current exposure."The new report is published in the April issue of The Lancet Oncology.Dr. Robert Baan, of the International Agency for Research on Cancer, in Lyon, France, and his colleagues reviewed studies on cancers in hairdressers, beauticians and barbers that were done after 1993.Hair dyes are classified as permanent, semi-permanent or temporary. Permanent dyes make up about 80 percent of the market. These dyes contain chemicals that, when mixed with peroxide, cause a chemical reaction that produces the dye. Dark hair dyes have the highest concentration of coloring agents, Baan's group noted.The researchers found that the use of these dyes was linked to a small but discernible increased risk of bladder cancer. "Bladder cancer is not rare, but it's not common," Thun said. "A small, but consistent, risk of bladder cancer was reported in male hairdressers and barbers. Because of few supporting findings by duration or period of exposure, the Working Group considered these data as limited evidence of carcinogenicity and reaffirmed occupational exposures of hairdressers and barbers as 'probably carcinogenic' to humans," the researchers wrote.Baan's team also looked at whether people using hair dyes at home had similar risks for cancer. They found there wasn't enough evidence to make a definitive conclusion about the personal use of hair dyes and the potential for cancer.The researchers also looked at other chemicals that belong to the same chemical group as hair dyes. They noted that one chemical — ortho-toluidine, which is used in making dyes, pigments and rubber chemicals — is classified as carcinogenic to humans. Thun noted that people are exposed to naturally occurring carcinogens all the time — in food, in air and water. "The goal is not to increase that load. So the goal here is to have these products be free of substances that are potential carcinogens and to minimize the exposure of people who work with them," he said.

Don't Let Hair Loss Tangle You Up - Dermatologists Can Identify Common Hair Disorders and Offer Solutions

Noticing a few extra hairs in your comb lately. Is your new hairstyle a result of trying to conceal areas of thinning hair rather than a fashion choice. Are you paying more attention to the multitude of advertisements promoting hair growth. If you answered yes to any of these questions, you might be one of the millions of people experiencing some form of hair loss. But to whom should you turn for help. The key to managing the condition is to consult a dermatologist, a physician trained in the diagnosis and treatment of all forms of hair loss.

Speaking today at the 66th Annual Meeting of the American Academy of Dermatology, dermatologist Amy J. McMichael, MD, FAAD, associate professor of dermatology at Wake Forest School of Medicine in Winston-Salem, N.C., discussed the most common forms of hair loss, current treatment options and possible futuristic therapies.

"For both men and women, hair loss can be devastating and adversely affect one's overall quality of life," said Dr. McMichael. "As with most medical conditions, the key to controlling the hair loss cycle is to seek treatment early. The problem is that most people tend to ignore the first signs of hair loss or delay treatment, hoping that their hair will regrow on its own. Since there are many types and causes of hair loss, it is vital that patients seek a proper evaluation by a dermatologist at the first sign of a problem."

Androgenetic Alopecia (Pattern Hair Loss)
The most common form of hair loss, androgenetic alopecia (commonly referred to as male- or female-pattern hair loss) is a hereditary condition that affects men and women. In male-pattern hair loss, a receding hairline is common, as well as hair loss on top of the scalp. Women, on the other hand, typically maintain their frontal hairline but tend to have visible thinning over the front and top of the scalp. However, occasionally a man will experience female-pattern hair loss and a woman will show signs of male-pattern hair loss for reasons unknown to researchers.

A significant amount of research in male-pattern hair loss has identified the enzyme that can be blocked to stop the production of dihydrotestosterone (DHT), which is a byproduct of the male hormone testosterone that is linked to baldness in men. This research has led to the development of finasteride, the FDA-approved medication for treating male-pattern hair loss.

While the cause of female-pattern hair loss is not as clearly understood as male-pattern hair loss, Dr. McMichael discussed several treatment options that work well for many women. Currently, minoxidil 2 percent is the only FDA- approved treatment for female-pattern hair loss. Available over the counter in 2 percent and 5 percent solutions, minoxidil must be applied topically and works on hair follicles to reverse the shrinking process and stimulate new growth on the top of the scalp. Minoxidil also is FDA-approved for use by men.

"There are some cases where dermatologists will use other treatments off-label to treat hair loss in women, such as the anti-androgens spironolactone and flutamide that work by blocking the male hormone testosterone at the cellular level of the hair follicle," said Dr. McMichael. "Even higher doses of finasteride have been used in women to regrow hair. But it is important that women - and especially younger women - see their dermatologist for hair loss, especially if other symptoms such as acne or abnormal menstrual cycles also are present. In some cases, hair loss along with these other symptoms may indicate a more serious medical condition, such as a tumor or polycystic ovary disease."

Another proven technique for men and women looking to restore their hair is hair transplantation. Dr. McMichael noted that the technology involved in this surgical procedure has improved significantly over the years, with tiny hair grafts now being implanted through various new techniques to create a natural look that is virtually undetectable. However, Dr. McMichael cautioned that hair transplants are simply filling in lost hair and should still be used in conjunction with a topical or oral medical therapy to prevent further hair loss.

Recently, a new light treatment based on the technology of Low Level Laser Therapy (LLLT), also known as Laser PhotoTherapy, was approved by the FDA to regrow hair. This technology was developed after it was noted that some patients undergoing laser hair removal would experience increased hair growth in spots surrounding the treatment area. As such, the concept of scattering light to generate hair growth was born - albeit with only a small percent of patients undergoing the light procedure actually growing more hair. However, Dr. McMichael believes more studies need to be done to validate its effectiveness. "Unfortunately, I don't think the new light therapy lives up to its promise of regrowing hair for most patients," said Dr. McMichael. "But as we gain a better understanding of this technology, it is possible that we can refine it to be more effective in the future."

Telogen Effluvium
Typically triggered by a event - such as an illness, child birth, loss of a loved one or surgery - telogen effluvium is a form of hair loss that occurs as a result of the body's natural physiologic response to a stressor. As a result, there is a sharp increase in the amount of hair that is shed. Dr. McMichael noted that patients might not link an event to their hair loss, since hair typically doesn't shed for about three months after a stressful event due to the slow hair loss cycle.

"In about 75 percent of patients experiencing hair shedding, we can link the cause to a past event," said Dr. McMichael.

While in most cases, hair will fully regrow on its own in a few months without any medical intervention, Dr. McMichael adds, "In other cases, iron deficiency, a thyroid problem or even improper nutrition may be the source of this type of hair loss, which is why it is important to see a dermatologist for proper diagnosis and treatment."

Alopecia Areata
Alopecia areata is an autoimmune condition in which the body makes antibodies to its own hair, causing patches of complete hair loss on the scalp or other parts of the body. Specifically, the white blood cells attack the hair follicles and put them in a sleeping state, causing the hair to fall out. While it cannot be predicted who will develop alopecia areata, the condition is thought to have some component that is a genetically inherited. Patients with another autoimmune disease or a family history of a known autoimmune disease seem to be prone to this form of hair loss.

Despite the lack of FDA-approved treatments for alopecia areata, Dr. McMichael said that dermatologists may use combination therapies off-label such as injectable steroids, topical steroids or minoxidil 5 percent to regrow hair in affected areas. In limited cases, potent oral corticosteroids can be used to slow hair loss and jumpstart hair regrowth.

In addition, dermatologists use two other forms of treatment to restore hair growth which involve the deliberate manipulation of the body's white blood cells. In irritant treatment, dermatologists trick the immune system into sending white blood cells to the scalp to get in the way of those white blood cells that are trying to cause hair loss. In contact sensitization, dermatologists apply irritants to the scalp to create a small allergic reaction. When this happens, white blood cells are again tricked into rising to the surface of the scalp to fight this inflammation - in essence diverting their attention away from the hair follicles.

Central Centrifugal Scarring Alopecia
A common form of hair loss that affects mostly African-American women is known as central centrifugal scarring alopecia. This type of hair loss is characterized by hair loss on the top of the scalp and is commonly accompanied by hair loss in the area in front of the ears, which is called traction hair loss. In Dr. McMichael's practice, the African-American patients she treats for this condition are between 25 and 65 years of age. Many patients delay treatment for this condition as they think their hair loss will be temporary and not a sign of a more serious and potentially permanent condition. Unfortunately, this delay in treatment can lead to progressive hair loss that, in some cases, is irreversible.

"Even though we are seeing more and more cases of central centrifugal scarring alopecia in our practices, there are very few published studies on the condition and its treatment," said Dr. McMichael. "Once diagnosed, we can use anti-inflammatory medications, such as steroids and oral antibiotics, to reduce the inflammation. Topical minoxidil also works in some cases to stimulate hair growth in unscarred hair follicles."

Dr. McMichael added that she expects more novel therapies to be used in the future to reverse or prevent hair loss, which may include alternative medicines, nutritional supplements and new combination therapies.

"There is interesting cellular biology research taking place throughout the world in which researchers are figuring out how to grow human hair cells in a lab so they can be produced from one or two cells and transplanted into patients," said Dr. McMichael. "In the meantime, we have many effective treatments that we can use once a patient's hair loss is properly diagnosed."

Headquartered in Schaumburg, Ill., the American Academy of Dermatology (Academy), founded in 1938, is the largest, most influential, and most representative of all dermatologic associations. With a membership of more than 15,000 physicians worldwide, the Academy is committed to: advancing the diagnosis and medical, surgical and cosmetic treatment of the skin, hair and nails; advocating high standards in clinical practice, education, and research in dermatology; and supporting and enhancing patient care for a lifetime of healthier skin, hair and nails. For more information, contact the Academy at 1-888-462-DERM (3376) or www.aad.org.

DNA-Based HPV Tests More Accurate Than Pap Smears

(HealthDay News) -- A new study confirms previous findings that human papillomavirus (HPV) DNA-based tests are more accurate than Pap smears in detecting precancerous lesions. It was already known that the HPV test uncovered more infections and precancerous lesions than Pap smears (cytology), but it wasn't clear whether HPV tests would lead to the treatment of patients whose immune systems would fight off infections -- meaning that these women didn't require treatment, anyway. In this study of almost 50,000 women, Italian researchers found that the HPV test identified almost twice as many premalignant lesions compared to Pap smears. Among women ages 35 to 60, the HPV test was more likely to detect cervical lesions. In women ages 25 to 34, the HPV test seemed to identify more infections that eventually resolved themselves. Based on their findings, the researchers said it may be best for younger women with a positive HPV test to be retested in 12 months, rather than being immediately referred for a more intensive examination called colposcopy. "It seems clear that an HPV DNA-based approach to primary screening is a very attractive option that should be actively developed and evaluated," wrote Dr. Guglielmo Ronco, from CPO Piemonte, in Torino, Italy, and colleagues. The findings of this study, which were published in the Journal of the National Cancer Institute, reinforced similar findings in a study published in 2006 by Ronco and team. That earlier study of 33,364 women, ages 35 to 60, found that HPV testing combined with liquid-based Pap testing detected 47 percent more precancerous lesions than conventional Pap smears. However, the combination testing increased the chance of false positives by 60 percent. HPV accounts for almost all cases of cervical cancer.

How does understanding the allergic cascade help?

How can we put this new understanding of allergic reaction to good use? By looking closely at the complex steps involved in this chain of events, scientists have been able to find new and innovative treatments for common and troublesome allergic illnesses. The most basic, and best, approach to caring for allergies is avoidance of the substances causing them, the allergens. Some allergens such as pet dander, foods, and medications are relatively easy to avoid. However, many other allergens, such as dust mites, molds, and pollens are more difficult to evade. Measures to reduce exposure to them, however, are still essential for the optimal treatment of allergies. The most convenient approach to the treatment of allergies involves taking various medications. A classic example of an allergic medication is the standard antihistamine. The importance of histamine in allergic disease is illustrated by the effectiveness of antihistamines (medically termed H1 receptor blockers) in preventing certain allergic symptoms. They are effective in curtailing itching, sneezing, and runny nose. However, the more severe allergic reactions and symptoms of asthma require different treatments. Anti-inflammatory medications, such as steroids and leukotriene antagonists, may be required. Medications that widen the airways through the lungs (bronchial dilators) have also been a mainstay in the treatment of asthma and are particularly useful in controlling the immediate or early phase reaction. Current research is aimed at finding medications that are targeted at specific steps in the allergic cascade. The last approach to the management of allergies attempts to interfere with the allergic antibody immune response. Allergy shots (immunotherapy) involve desensitizing a patient by injecting increasing amounts of the allergens to which the person is allergic. Over time, the immune system becomes less reactive to these allergens, generates less IgE in response to them, and becomes more tolerant upon re-exposure to them.

What are the consequences of the allergic cascade?

Now that we understand how the allergic reaction develops, let's review the various changes that occur in the body as a result of these early and late phase reactions. When histamine is injected into the skin, a technique used in diagnosing allergies, a reaction that can mimic an allergic reaction occurs. The histamine injection prompts the development of a pale, central swollen area that is caused by fluid leaking out of local blood vessels into the adjacent tissues. This localized reaction is called a "wheal." A red "flare," which sometimes has a warm feeling due to inflammation, surrounds this "wheal." Itching occurs because histamine irritates the nerve endings in the skin. This early or immediate response peaks at about 15 minutes and fades within 90 minutes. Sometimes, the immediate effects are followed by a late phase reaction that occurs about 4 to 6 hours later and can last up to a day. Allergens, such as ragweed pollen, react with the tissues lining the inner surfaces (membranes) of the nose and eyes, thereby stimulating mast cells to release chemical mediators, including histamine. The chemical mediators cause a leakage of fluid and the production of mucous, causing a runny nose, itching, and sneezing. The late reaction also causes the tissues to swell and the nose to become congested. In the lungs, exposure to inhaled allergens causes wheezing, shortness of breath, and coughing within seconds or minutes. These symptoms tend to subside after about an hour. However, after about 4 hours, the late phase reaction can cause a worsening of shortness of breath, wheezing, and coughing. This phase can last for up to 24 hours. The late phase reaction involves an influx of a variety of inflammatory cells to the affected area (eosinophils, neutrophils, lymphocytes, and mast cells) and, if repeated inhalations of allergens cause recurrent reactions, reactions may merge into each other leading to chronic or persistent allergic asthma. Lastly, allergens can be absorbed into the bloodstream and travel to many sites (including the nose, lungs, throat, skin, and digestive tract), causing multiple symptoms that are typical of a severe allergic reaction (anaphylaxis). Blood vessel dilation may occur throughout the body causing a drop in blood pressure and shock. Although rare, this type of anaphylactic reaction can be caused by medications, insect venoms, and foods.

What are cytokines?

Cytokines are small proteins that can either step-up or step-down the immune response. One of the cytokines, interleukin 4 (IL4), is essential for the production of IgE. Interleukin 5 (IL5) and others are important in attracting other cells, particularly eosinophils, which then promote inflammation. This spectrum of cytokines is also released by the TH2 lymphocytes, thus further promoting allergic inflammation. What is the "early phase" of an allergic reaction?

We have seen how the first encounter with ragweed pollen sensitizes the body with the help of lymphocytes and results in the IgE coating of the mast cells and basophils. Subsequent exposure results in the immediate release of the chemical mediators that cause the various symptoms of allergy. This process is the "early phase" of the allergic reaction. It can occur within seconds or minutes of exposure to an allergen. This is also known as an immediate hypersensitivity reaction, which in this case is to the ragweed pollen allergen. In the context of allergy, hypersensitivity refers to a condition in a previously exposed person in which tissue inflammation results from an immune reaction upon re- exposure to an allergen sensitizer. What is the "late phase" of an allergic reaction?

About 50% of the time, the allergic reaction progresses into a "late phase." This "late phase" occurs about 4 to 6 hours after the exposure. In the late phase reaction, tissues become red and swollen due to the arrival of other cells to the area, including the eosinophils, neutrophils, and lymphocytes. Cytokines that are released by the mast cells and basophils act as tiny messengers to call these other cells to the area of inflammation. Additional cytokines are released by the TH2 lymphocytes and they attract even more of these cells of inflammation. The eosinophils appear to be particularly troublesome cells of inflammation. Eosinophils evolved to defend the body against parasites, much like IgE. Nevertheless, they are often present in great numbers in the blood of people with allergies. When they arrive at the site of the allergic reaction, they release chemicals that cause damage to the tissues and continue to promote the inflammation. Repeated episodes of this "late phase" reaction contribute to chronic allergic symptoms and make the tissues even more sensitive to subsequent exposure!

What about a more detailed look at the "players?"

Lymphocytes - T's & B's

Lymphocytes are part of the white blood cell family and consist of T and B varieties. Each T lymphocyte, or T cell, is like a specially trained detective. The T cell examines the evidence that is exposed by the APC. When specific T cells come into contact with the ragweed pollen fragment on the APC and recognize it as foreign, an army of specialized T cells called "helper" cells (actually TH2 cells) is activated, thus releasing chemicals (cytokines) that stimulate B lymphocytes. B lymphocytes produce IgE antibodies that bind to the allergens (such as the pollen fragment). Once the IgE is produced, it specifically recognizes the ragweed pollen and will recognize it on future exposure. The balance between allergy-promoting TH2 cells and infection-fighting TH1 cells has recently been found to be a critical component of our immune system. Whereas allergy reactions involve large numbers of TH2 cells, infections generate an army of TH1 cells, which then release chemicals that help destroy microbes. Allergy and asthma rates have been increasing in recent decades. One currently favored theory explaining the increase is that it is a consequence of inadequately "geared up" human immune systems because of the relatively sterilized environment of modern man, possibly due to antibiotics and vaccinations! This has been referred to as the "hygiene hypothesis." What this concept implies is that the immune systems of individuals who have been exposed to sufficient microbes make TH1 cells when stimulated. But, if an individual's immune system is inadequately stimulated to produce TH1 cells by exposure to microbes, it will instead lean toward the allergy-producing system and make TH2 cells. A tendency toward allergic reactions is the result. Although this appears complicated, an understanding of the different lymphocyte responses is important in treating allergies. Ideally, we would like to respond to ragweed pollen with TH1 lymphocytes and not TH2 lymphocytes, which promote allergic reactions and produce IgE in large amounts. Allergic individuals summon a large number of TH2 cells in response to allergens, whereas non-allergic people do not. Finally, the tendency to develop allergic conditions (i.e., to develop strong TH2 responses to allergens) is thought to be partially inherited from our parents. At birth, there seems to be a balance between the infection-fighting TH1 cells and the allergy-promoting TH2 cells. Current thinking is that allergy develops after birth when a child is exposed to certain substances in the environment. The immune system is stimulated by these exposures so that the scales are now tipped toward the production of allergy-promoting TH2 cells. They are especially tipped toward allergy promotion in individuals that have inherited the genetic tendency from their parents. Mast Cells & Basophils

Mast cells and basophils are the next key players in the allergic cascade. They are volatile cells with potentially explosive behavior. Mast cells reside in tissues while basophils are found in the blood. Each of these cells has over 100,000 receptor sites for IgE, which binds on their surfaces. The binding of IgE to these cells acts like the fuse on a bomb. The cells are now sensitized or primed with the IgE. When this allergic or sensitized individual is exposed to ragweed pollen again, the IgE is ready to bind to this pollen. When this occurs, the mast cells and basophils are activated and explosively release a number of chemicals that ultimately produce the allergic reaction we can see and feel. Wherever these chemicals are released in the body will display the allergy symptoms. In the ragweed pollen example, when the mast cells are activated in the nose by exposure to the pollen, the release of chemicals will likely result in sneezing, nasal congestion, and a runny nose - the typical symptoms of hay fever. Once sensitized, mast cells and basophils can remain ready to ignite with IgE for months or even years! Chemical Mediators

Each mast cell and basophil may contain over 1000 tiny packets (granules). Each of these granules holds more than 30 allergy chemicals, called chemical mediators. Many of these chemical mediators are already prepared and are released from the granules as they burst in an allergic response. The most important of these chemical mediators is histamine. Once released into the tissues or blood stream, histamine attaches to histamine receptors (H1 receptors) that are present on the surface of most cells. This attachment results in certain effects on the blood vessels, mucous glands, and bronchial tubes. These effects cause typical allergic symptoms such as swelling, sneezing, and itching of the nose, throat, and roof of the mouth. Some chemical mediators are not formed until 5 to 30 minutes after activation of the mast cells or basophils. The most prominent of these are the leukotrienes. Leukotriene D4 is 10 times more potent than histamine. Its effects are similar to those of histamine, but leukotriene D4 also attracts other cells to tarea, thereby aggravating the inflammation. Allergy Facts Leukotrienes were initially discovered in 1938 and were called the "slow reacting substances of anaphylaxis (SRS-A)." Forty years later, Samuelsen in Sweden identified them as playing an important role in allergic inflammation.Recently, a new family of medicines, called leukotriene modifiers, have been found to be helpful in treating asthma. Examples are Singulair (monlelukast) and Accolate (zafirlukast). The other group of inflammation-causing chemical mediators that form after mast cell stimulation is the prostaglandins. Prostaglandin D2, in particular, is a very potent contributor to the inflammation of the lung airways (bronchial tubes) in allergic asthma.

Allergic Cascade

The immune system is very specific and goal oriented. Although you may be allergic to a number of substances, allergic reactions are directed at specific allergens. For example, you may be allergic to Bermuda grass, but not oysters. At times, however, two or more foreign substances might appear similar in nature to the immune system, which may mistake one for the other and react to both. For example, if you are allergic to birch trees, your immune system may also react to apples or other fruits, which it mistakes for birch pollen. These cross-reactions occur because of similar allergens that are produced by a variety of plants. The allergic response, however, is by no means vague or ill-defined. It is a definite, vigorous attack aimed, unfortunately, at harmless agents. The end result is well-defined symptoms and disorders. The deeper our understanding of the intricate nature of the allergic reaction, the more likely we are to find more effective treatments. We need to look more closely at the chain of events from the initial response to allergens to the many symptoms that may result. Although misguided, it is an efficient, well-orchestrated, and potentially explosive sequence of cellular and chemical interactions. This is the so-called "allergic cascade." Who are the "players" in the allergic cascade?

Our body's immune system is designed to constantly be on the lookout for intruders. It has the remarkable ability to distinguish between "self" and "non-self" (foreign substances, which it tirelessly protects us from). Let us look more closely at this complex process. Take for example an exposure to ragweed pollen. Once in the body, the ragweed pollen is engulfed by the immune system's scouts, the so-called Antigen Preventing Cells or APC's. These APC's slice up the ragweed pollen into small fragments, which then combine with special proteins in the cell, called human leukocyte antigens or HLA's. HLA's function like a guideline to help the body distinguish "self" from "non-self." When combined with the HLAs, the fragments become visible to a key player in the allergic cascade (the lymphocytes), which recognizes them as foreign. This ragweed pollen fragment-HLA combination is exposed on the surface of the APC's in full view of these specialized white blood cells. Before we review details of how the various players in the allergic cascade fulfill their roles, let's note these basic concepts of types of important cells and messenger proteins of the immune reaction: The term white blood cells or leukocytes is derived from Greek words "leukos" meaning white and "cytes" meaning cells. The white blood cells are essential to the immune system and include the monocytes, macrophages, neutrophils, and lymphocytes. Lymphocytes are white blood cells that play a key role in both immunity and allergy. They are divided into two types, the T and B lymphocytes. Each type is responsible for a particular branch of the immune system. It is the duty of the T-lymphocytes to be ready to directly shift into action to attack foreign substances (cell-mediated immunity). Some T-lymphocytes are experts at "killing" (cytotoxic or killer T cells) while others assist the immune response and are termed "helper" cells (TH cells). The TH cells are further divided into TH1 (infection fighters) and TH2 (allergy promoters), depending on the proteins they release. The partners of the T-lymphocytes are the B-lymphocytes. B-lymphocytes are tiny antibody factories that produce antibodies to help destroy foreign substances when stimulated to do so by the TH cells. Basophils and eosinophils are other white blood cells that play an important role in allergy. T cells often call these cells into action in allergic conditions. Blood levels of eosinophils are commonly elevated in people with asthma and other allergic diseases. Cytokines are a diverse group of proteins that are released by lymphocytes and macrophages in response to an injury or activation, such as by an allergen. They act as chemical signals that "step up" or "step down" the immune reaction.

Identifying the Symptoms of Ricin Exposure

Medical Author: Melissa Conrad Stöppler, MD
Medical Editor: William C. Shiel Jr., MD, FACP, FACR Concern about the use of the toxin ricin as a terrorist weapon have surfaced following media reports of isolated findings and poisonings related to this substance. Ricin is a naturally occurring toxin that is found in castor beans. Ricin poisoning may occur from chewing and swallowing castor beans, and the toxic substance can also be obtained the waste material that remains after processing castor beans to produce castor oil. Ricin can take many forms: It can be a powder, a mist, a pill or pellet, and can be dissolved in water and other liquids. This means that a person can contract ricin poisoning via inhalation or ingestion; the initial symptoms of ricin poisoning depend upon both the degree and route of exposure. Accidental exposure to ricin unrelated to the ingestion of castor beans would be extremely unlikely to occur. If ricin is inhaled, symptoms typically begin within eight hours of exposure and include difficulty breathing, fever, cough, nausea, sweating, and a feeling of tightness in the chest. The skin may turn blue due to the decreased oxygenation of blood resulting from fluid buildup (edema) in the lungs. Low blood pressure and respiratory failure may ultimately occur. Ricin exposure by ingestion (swallowing) typically results in symptoms in less than six hours following exposure. Symptoms include vomiting and diarrhea that may contain blood, possibly resulting in dehydration severe enough to cause low blood pressure, and blood in the urine. Ricin ingestion can also cause disturbances in the central nervous system, potentially leading to hallucinations or seizures. Within several days, multi-organ failure can result. Depending on the degree of exposure, death can result within 36 to 72 hours from both inhalation and ingestion of ricin. Skin contact with ricin powder is not likely to cause serious damage, since ricin is not generally well absorbed through normal skin. However, contact with ricin powder or products may cause pain and redness of the skin and the eyes. Ricin poisoning is not contagious and cannot be spread from one affected person to another by casual contact. There is no antidote for ricin poisoning, and medical treatment consists of supportive measures (such as breathing support, intravenous fluids, and medications to control blood pressure and seizures) to try to counteract or reduce the effects of the toxin on the body. Reference: U.S. Centers for Disease Control and Prevention (CDC), "Facts About Ricin," Mar. 5, 2008.

What is the Arthritis Foundation?

The Arthritis Foundation is the only national voluntary health organization whose purpose is directed solely to all forms of arthritis. The Arthritis Foundation has national and international programs involving support for scientific research, public information and education for affected patients and their families, training of specialists, public awareness, and local community assistance. Local branch chapters of the Arthritis Foundation serve to disseminate information about arthritis and rheumatic diseases as well as functioning as referral centers. Moreover, many of the various forms of arthritis have their own foundations that serve as information and referral resources for local communities. Summary It is the ultimate goal of scientific arthritis research that optimal treatment programs are designed for each of the many form of arthritis. This field will continue to evolve as improvements develop in the diagnosis and treatment of arthritis and related conditions. Arthritis At A Glance Arthritis is inflammation of one or more joints.Symptoms of arthritis include pain and limited function of joints.Arthritis sufferers include men and women, children and adults.A rheumatologist is a medical arthritis expert.Earlier and accurate diagnosis can help to prevent irreversible damage and disability. REFERENCES: The Arthritis Foundation (http://www.arthritis.org), "Arthritis Prevalence: A Nation in Pain," "The Facts About Arthritis."

What is the national financial impact of arthritis?

It has been estimated that the total cost of the arthritis bill for the United States, in terms of hospitalization, doctor visits, medications, physical therapies, nursing home care, lost wages, early death, and family discord is over $50 billion dollars annually. This does not include the nearly $2 billion spent each year in the United States on unproven remedies by patients addressing their symptoms on their own. What is a rheumatologist? A rheumatologist is a medical doctor who specializes in the nonsurgical treatment of rheumatic illnesses, especially arthritis. Rheumatologists have special interests in unexplained rash, fever, arthritis, anemia, weakness, weight loss, fatigue, joint or muscle pain, autoimmune disease, and anorexia. They often serve as consultants, acting like medical detectives at the request of other doctors. Rheumatologists have particular skills in the evaluation of the over 100 forms of arthritis and have special interest in rheumatoid arthritis, spondylitis, psoriatic arthritis, systemic lupus erythematosus, antiphospholipid syndrome, Still's disease, dermatomyositis, Sjogren's syndrome, vasculitis, scleroderma, mixed connective tissue disease, sarcoidosis, Lyme disease, osteomyelitis, osteoarthritis, back pain, gout, pseudogout, relapsing polychondritis, Henoch-Schonlein purpura, serum sickness, reactive arthritis, Kawasaki disease, fibromyalgia, erythromelalgia, Raynaud's disease, growing pains, iritis, osteoporosis, reflex sympathetic dystrophy, and others. Classical adult rheumatology training includes four years of medical school, one year of internship in internal medicine, two years of internal medicine residency, and two years of rheumatology fellowship. There is a subspecialty board for rheumatology certification, offered by the American Board of Internal Medicine, which can provide board certification to approved rheumatologists. Pediatric rheumatologists are physicians who specialize in providing comprehensive care to children (as well as their families) with rheumatic diseases, especially arthritis. Pediatric rheumatologists are pediatricians who have completed an additional two to three years of specialized training in pediatric rheumatology and are usually board-certified in pediatric rheumatology.

Who is affected by arthritis?

Arthritis sufferers include men and women, children and adults. Approximately 350 million people worldwide have arthritis. Nearly 40 million persons in the United States are affected by arthritis, including over a quarter million children! More than 21 million Americans have osteoarthritis. Approximately 2.1 million Americans suffer from rheumatoid arthritis. More than half of those with arthritis are under 65 years of age. Nearly 60% of Americans with arthritis are women. How is arthritis diagnosed and why is a diagnosis important? The first step in the diagnosis of arthritis is a meeting between the doctor and the patient. The doctor will review the history of symptoms, examine the joints for inflammation and deformity, as well as ask questions about or examine other parts of the body for inflammation or signs of diseases that can affect other body areas. Furthermore, certain blood, urine, joint fluid, and/or x-ray tests might be ordered. The diagnosis will be based on the pattern of symptoms, the distribution of the inflamed joints, and any blood and x-ray findings. Several visits may be necessary before the doctor can be certain of the diagnosis. A doctor with special training in arthritis and related diseases is called a rheumatologist (see below). Many forms of arthritis are more of an annoyance than serious. However, millions of patients suffer daily with pain and disability from arthritis or its complications. Earlier and accurate diagnosis can help to prevent irreversible damage and disability. Properly guided programs of exercise and rest, medications, physical therapy, and surgery options can idealize long-term outcomes for arthritis patients. It should be noted that both before and especially after the diagnosis of arthritis, communication with the treating doctor is essential for optimal health. This is important from the standpoint of the doctor, so that he/she can be aware of the vagaries of the patient's symptoms as well as their tolerance to and acceptance of treatments. It is important from the standpoint of patients, so that they can be assured that they have an understanding of the diagnosis and how the condition does and might affect them. It is also crucial for the safe use of medications.

Arthritis

What is arthritis? Arthritis is a joint disorder featuring inflammation. A joint is an area of the body where two different bones meet. A joint functions to move the body parts connected by its bones. Arthritis literally means inflammation of one or more joints. Arthritis is frequently accompanied by joint pain. Joint pain is referred to as arthralgia. There are many forms of arthritis (over 100 and growing). The forms range from those related to wear and tear of cartilage (such as osteoarthritis) to those associated with inflammation resulting from an overactive immune system (such as rheumatoid arthritis). Together, the many forms of arthritis make up the most common chronic illness in the United States. The causes of arthritis depend on the form of arthritis. Causes include injury (leading to osteoarthritis), abnormal metabolism (such as gout and pseudogout), inheritance, infections, and unclear reasons (such as rheumatoid arthritis and systemic lupus erythematosus). Arthritis is classified as one of the rheumatic diseases. These are conditions that are different individual illnesses, with differing features, treatments, complications, and prognosis. They are similar in that they have a tendency to affect the joints, muscles, ligaments, cartilage, tendons, and many have the potential to affect internal body areas. What are symptoms of arthritis? Symptoms of arthritis include pain and limited function of joints. Inflammation of the joints from arthritis is characterized by joint stiffness, swelling, redness, and warmth. Tenderness of the inflamed joint can be present. Many of the forms of arthritis, because they are rheumatic diseases, can cause symptoms affecting various organs of the body that do not directly involve the joints. Therefore, symptoms in some patients with certain forms of arthritis can also include fever, gland swelling, weight loss, fatigue, feeling unwell, and even symptoms from abnormalities of organs such as the lungs, heart, or kidneys.

Studies Back New RA Drug

By Miranda Hitti
WebMD Medical News Reviewed By Louise Chang, MD Latest MedicineNet News Lower Body Temps and Blood Loss During SurgeryVoluven Helps Minimize Surgical Blood LossHealth Tip: Buying Athletic ShoesIn-the-Field Facial Surgery Helps Injured Troops Experts Issue Guidelines on Diagnosing Seizure March 20, 2008 — Actemra, an experimental biologic drug, shows promise in treating rheumatoid arthritis and juvenile idiopathic arthritis (formerly called juvenile rheumatoid arthritis, or JRA). That news comes from the drug's phase III trials, which test safety and effectiveness. Biologic drugs, such as Actemra, target specific parts of the immune system that lead the inflammation that causes joint damage in RA. Current biologic drugs used to treat RA include Enbrel, Humira, Orencia, Remicade, and Rituxan. Actemra is not yet available. It works on a different area of the immune system than the other biologic drugs. One trial covered rheumatoid arthritis; the other focused on juvenile idiopathic arthritis. Results for both trials appear in the March 22 edition of The Lancet. A related editorial voices "cautious optimism" but calls for more studies on Actemra's possible effects on cholesterol, and for head-to-head comparisons of Actemra and other biologic arthritis drugs. Rheumatoid Arthritis Study The rheumatoid arthritis study included 621 patients with moderate to severe rheumatoid arthritis who had already tried the drug methotrexate for their RA. The patients got injections of a higher dose of Actemra, a lower dose of Actemra, or a placebo every four weeks for six months. At the end of the study, 59% of the patients who got the higher Actemra dose, 48% of those taking the lower Actemra dose, and 26% of those who got the placebo had at least a 20% improvement in their signs and symptoms of RA, which is considered significant improvement. Upper respiratory tract infections were the most common side effects seen in the Actemra group. Liver enzyme levels also rose for some Actemra patients, but those were typically one-time events and weren't linked to symptoms of liver disease, according to the researchers. Total cholesterol and LDL ("bad") cholesterol levels rose in the Actemra users. The reason for that isn't clear. Major heart "events" — such as heart attacks — weren't more common with Actemra use, but the study only lasted for six months, which may not have been long enough to detect cardiovascular risk. WebMD reported on the study last June, when researcher Josef Smolen, MD, of Austria's Medical University of Vienna, presented the findings in Barcelona, Spain, at the European League Against Rheumatism's annual meeting. The study, which didn't look at the drug's long-term safety, was funded by Hoffmann-La Roche and Japan's Chugai Pharmaceutical Co., which are developing Actemra. Juvenile Idiopathic Arthritis Study The juvenile idiopathic arthritis trial included 56 children in Japan who had tried other drugs to treat their arthritis. First, all of the children got three doses of Actemra every two weeks for six weeks. Then 43 kids whose arthritis had improved with Actemra treatment kept getting Actemra; all in all, they took Actemra for four months. Actemra trumped the placebo and "might be a suitable treatment in the control of this disorder, which has so far been difficult to manage," write Yokohama City University's Shumpei Yokota, MD, and colleagues. Adverse events were typical of other biologic drugs and included upper respiratory-tract infections and stomach flu. Anaphylactic allergic reactions and increases in liver enzyme levels were rarer. The study was funded by Chugai Pharmaceutical Co. Expert: Head-to-Head Trials Needed Editorialist Tim Bongartz, MD, who works at the Mayo Clinic College of Medicine in Rochester, Minn., writes that he is "excited about the ongoing expansion of therapeutic options for rheumatoid arthritis and, especially, systemic [juvenile idiopathic arthritis]." But he cautions that the evidence doesn't show how Actemra's risks and benefits stack up against other treatment choices. "In an ideal world, comparative trials of new drugs with other effective treatments, powered to detect important safety and efficacy endpoints, would provide this information, which I regard as essential," writes Bongartz. "It is not clear that these trials will be available before the likely approval of tocolizumab [Actemra], and it may be up to investigators to initiate the head-to-head comparisons needed to address these issues," adds Bongartz. SOURCES: Smolen, J. The Lancet, March 22, 2008; vol 371: pp 987-997. WebMD�Medical News:�"New RA�Drugs Show Promise." Yokota, S. The Lancet, March 22, 2008; vol 371: pp 998-1006. Bongartz, T. The Lancet, March 22, 2008; vol 371: pp 961-963. News release, The Lancet.