Lyme Disease Support Group

May 2011

Scientists have long suspected that immune system cells called neutrophils play a role in lupus, a disease that occurs when the body’s immune system attacks and damages its own tissues, including the skin, joints, heart, lungs, kidneys and brain.

More than a half-century ago, scientists found that the blood serum from patients with lupus triggered alterations in the nuclei of these abundant immune system cells.

This finding was used to diagnose patients with lupus for many years, but the role of neutrophils in the disease remained elusive.

Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have now found a new role for these cells in lupus.

Their discovery, published in the journal Science Translational Medicine, could potentially lead to the identification of new therapeutic targets for the disease.

Following the discovery of an abnormal neutrophil gene expression pattern in the blood of children with lupus, Virginia Pascual, M.D., and her colleagues at the Baylor Institute for Immunology Research found that exposing neutrophils from children with lupus to anti- ribonucleoprotein (anti-RNP) autoantibodies (a type of antibody commonly made by people with lupus) caused the neutrophils to die rapidly, similar to the way neutrophils from healthy children die in response to bacterial and fungal infections.

But, perhaps more importantly, they found that in the process of dying, the neutrophils from children with lupus released material from cell nuclei, which did not happen with the neutrophils of healthy children exposed to the same autoantibodies.

The release of this material led to the activation of other immune system cells, particularly those that produce interferon-alpha (IFN-α, one of a family of potent immune proteins.

Earlier research by Dr. Pascual and her colleagues showed IFN-α to be highly elevated in patients with lupus, and likely to be involved in the immune system alteration and damage in the disease.

The scientists hope that recognizing and better understanding the process of neutrophil death, and the subsequent immune cell activation, will lead to the identification of targets to block this type of cell death and intervene in the process that ultimately leads to tissue damage in lupus.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases;

the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases.

For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, Barrat FJ, Banchereau J, Pascual V. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011 Mar 9; 3(73):73ra20.

http://www.niams.nih.gov/News_and_Events/ Spotlight_on_Research/2011/neutrophils_lupus.asp

no copyright

*****************************

The Long, Winding Road to a Lupus Drug

By Nancy Walsh, Staff Writer, MedPage Today

Published: May 28, 2011

In 1967 the Beatles released one of their most acclaimed albums, Sgt. Pepper's Lonely Hearts Club Band, which featured the song Lucy in the Sky with Diamonds.

The fantasy-strewn imagery in the song was taken from a fantastical drawing John Lennon's young son, Julian, had made, we're told, of his friend Lucy Veddon.

Lucy died at age 46 in 2009 of systemic lupus erythematosus and since then Julian Lennon has become a spokesperson for the Lupus Foundation of America, lending a famous name and a famous song to a long effort to improve the treatment of what he termed the "tragic illness" that felled his childhood friend.

On May 10, World Lupus Day, Lennon spoke passionately about his efforts and those of the foundation.

Just two months earlier, on March 9, the FDA approved the first new drug for lupus in more than 50 years, belimumab (Benlysta).

The drug was approved on the basis of two pivotal trials -- but it has been a long and winding road to market.

The Empty Pipeline

Progress in the treatment of lupus has been much slower than that for other autoimmune diseases such as rheumatoid arthritis. One reason for this is the marked variability in the way the disease manifests -- between patients and over time.

"Lupus in patient A is going to be somewhat different than lupus in patient B, and somewhat different in patient C, so in reality what we have is a collection of disorders that share certain common features, and we lump them all together and call them lupus," William Stohl, MD, PhD, of the University of Southern California in Los Angeles explained to MedPage Today.

Even in patients with apparent similarities, such as those with kidney involvement, there can be multiple pathways involved in the disease pathogenesis, and treatments targeting one pathway are unlikely to help patients where another pathway is dominant, Stohl added.

There also was a lack of interest on the part of industry.

It look roughly five years in an NIH-sponsored trial of immunosuppressive drugs for lupus nephritis to see superiority for one of the drugs.

Rheumatoid arthritis and the spondylarthropathies -- where improvements could be measured in three to six months -- were more commercially appealing, according to Daniel J. Wallace, MD, of the University of California Los Angeles.

By the mid-1980s, rheumatoid arthritis patients had methotrexate, which dramatically changed their disease course and prognosis, and little more than a decade later the biologics began to appear and revolutionized their treatment altogether.

Targeting BlyS

But some progress in lupus treatment was being made. In 1999, researchers from Human Genome Sciences in Rockville, Md., published the first report of a cytokine they named B lymphocyte stimulator (BlyS), that appeared in laboratory experiments to act as an inducer of B cell proliferation.

Because it was increasingly recognized that the pathogenesis of lupus involves the activity of B cells, which produce the various autoantibodies such as antinuclear antibodies and anti-double stranded DNA characteristic of the disease, interest grew in targeting B cells therapeutically.

In 2003, the Rockville group reported having developed a fully human monoclonal antibody that inhibited BlyS in vitro, as well as in mice and monkeys.

Five years later, a phase I dose-ranging study found significant reductions in CD20+ B cells among patients with lupus, although disease activity was unchanged after one or two doses of belimumab.

Trials and Endpoints

The investigators then undertook a phase II study evaluating several doses of belimumab in 450 patients with active disease.

In this trial, patients were randomized to receive 1 mg, 4 mg, or 10 mg/kg belimumab at baseline and on days 14 and 28 and every four weeks thereafter for a year.

The primary endpoints were percent change in a disease activity index known as SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index) at week 24 and the time to first flare.

Neither endpoint was met. "This trial was an abject failure," said one of the study investigators, Joan T. Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City.

Initially the company was unsure whether to go ahead with the drug, which at the time was called LymphoStat-B.

"But what they did was conduct a number of exploratory analyses, which can't be used for efficacy claims, but they found that there seemed to be some benefit in certain subgroups of patients," she said at a recent rheumatology meeting in New York City.

It turned out that the best results were seen in patients who were seropositive, having antinuclear antibody titers of 1:80 or higher and/or anti-double-stranded DNA levels of 30 IU/mL or higher.

A further difficulty in developing drugs for lupus has been the limitations of the endpoints used in assessing response.

For instance, Merrill explained, while SELENA-SLEDAI can measure improvements in disease activity, this tool doesn't reflect possible worsening.

So in designing the phase III studies, the investigators designed a composite endpoint that addressed multiple disease domains:

•A four-point reduction in disease activity on SELENA-SLEDAI, reflecting global improvement

•No worsening in previously unaffected organs

•Physician's global assessment, providing reassurance that improvements in the disease activity were not accompanied by deterioration of the patient's overall condition

Using this endpoint, the investigators conducted two phase III studies, enrolling almost 1,700 patients in the trials, which were known as BLISS-52 and BLISS-76. Patients in those trials were randomized to receive belimumab plus standard of care or standard of care alone for one year.

The results of those studies, presented at the 2010 annual meeting of the American College of Rheumatology, showed benefits -- though modest -- across multiple domains.

Although the results were somewhat discordant, overall improvements were seen central nervous system, vascular, musculoskeletal, dermatologic, and immunologic disease components, and less worsening of hematologic manifestations.

The findings of BLISS-52 have now been published (Lancet 2011; 377: 721-731), with these results for the 10 mg/kg dose versus placebo:

•Four or more point reduction in SELENA-SLEDAI, 58% versus 46%, OR 1.71 (95% CI 1.21 to 2.41, P=0.0024)

•No worsening on the British Isles Lupus Assessment Group score, 81% versus 73%, OR 1.62 (95% CI 1.09 to 2.42, P=0.0181)

•No worsening on physician global assessment, 80% versus 69%, OR 1.74 (95% CI 1.18 to 2.55, P=0.0048)

On the basis of the two BLISS studies, FDA approved belimumab for use in seropositive patients with active disease -- the subgroup of lupus patients that seem to respond.

Into the Clinic

"Inhibition of soluble BLyS with belimumab represents a new path forward in the management of this important autoimmune disease, " the BLISS-52 investigators concluded.

But the drug isn't the be-all and end-all for lupus, according to Stohl. In the randomized trials, 60% of patients responded -- but 40% did not. "We have a long way to go," he said.

It also isn't clear just how much of the improvement that patients had in the BLISS trials was because of belimumab, according to Merrill.

The reason for this was because all the study participants were receiving standard of care treatment, and could increase their doses of prednisone, azathioprine, and other medications.

"But I'm absolutely convinced that superiority was demonstrated, with improvements being seen at multiple time points throughout the year," Merrill said.

"What we don't know is just how good the drug is. For that we have to wait until it's in the clinic and we can figure out how well it works," she said.

But a hopeful note was expressed by Anca Askanase, MD, of New York University, who has been treating patients with the drug.

"I believe this drug is a great success, and will make a big difference to patients," she told MedPage Today.

Stohl and Merrill have received fees and honoraria from Human Genome Sciences.

*************************************

comment:

tom hennessy - May 30, 2011

Hydroxychloroquine is recommended for everyone with lupus. It is to be used when phlebotomy FAILS.

WHY has phlebotomy NEVER even been tested in lupus ?

"Hydroxychloroquine should be the preferred alternative to phlebotomy"

"Because of its broad spectrum of benefits and safety profile, hydroxychloroquine should be given to most patients with systemic lupus erythematosus (SLE) during the whole course of the disease"

"Stimulating erythropoiesis increases complement receptor expression on primate erythrocytes."

"About 2 weeks after the start of phlebotomy"

******************************

http://www.medpagetoday.com/Rheumatology/Lupus/26734? utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2011 Everyday Health, Inc. All rights reserved.

Post edited by: Bettyg, at: 06/12/2011 05:18 PM

By Nancy Walsh, Staff Writer, MedPage Today

Published: June 09, 2011

Reviewed by

Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

■Explain that the prognosis for patients with lupus nephritis who develop end-stage renal disease (ESRD) has not improved in recent years despite advances in treatment.

■Note that rates of end-stage renal disease also have risen among younger patients and African Americans and other minorities with lupus nephritis.

The outlook for patients with lupus nephritis who develop end-stage renal disease (ESRD) has not improved in recent years despite advances in treatment -- and the condition is on the rise in younger patients and African Americans -- researchers reported.

Compared with the general population, the standardized incidence ratio for ESRD among patients with lupus nephritis ages 5 to 19 years rose from 0.84 (95% CI 0.66 to 1.06) in the years 1995 to 1997 to 1.35 (95% CI 1.13 to 1.62) during 2004 to 2006 (P<0.0001), according to Karen H. Costenbader, MD, of Harvard University, and colleagues.

And compared with whites, whose standardized incidence ratio remained at 2.11 (95% CI 1.98 to 2.25) by 2006, the ratio for blacks increased from 12.80 (95% CI 11.92 to 13.74) to 15.55 (95% CI 14.64 to 16.51, P=0.008), the researchers reported in the June issue of Arthritis & Rheumatism.

Despite the development of effective immunosuppressant drugs such as azathioprine and cyclophosphamide and the availability of living kidney transplantation, some 10% to 30% of patients with lupus nephritis still develop ESRD within 15 years.

Those findings emerged from an analysis of data from the U.S. Renal Data System, which is a national registry that includes almost all patients on dialysis or who undergo kidney transplantation.

Costenbader and colleagues identified 12,344 new cases of ESRD in patients with lupus nephritis between 1995 and 2006.

The age at which ESRD develops has remained at around 40, and 80% are women.

Mean body mass index increased during those years from 23.5 to 26.5 (P<0.0001).

Serum creatinine at onset decreased from 8.6 mg/dL to 7.1 mg/dL (P<0.0001), and serum hemoglobin increased from 8.9 g/dL to 9.6 g/dL (P<0.0001).

Those laboratory findings suggest that renal replacement was being started earlier, when there was greater residual kidney function, and that erythropoiesis-stimulating agents were being used more frequently, the researchers explained.

Coexistent diabetes and hypertension also increased steadily, they observed.

Aside from African Americans, other minorities also have seen increases in rates of ESRD, including Native Americans (P=0.002) and Asians (P=0.09).

Residence in the Southeastern states also has been associated with an increase (P=0.002).

When the researchers looked at patterns of transplantation, they found that in the years 1995 to 1997, half of transplants were from living donors. This rose to 70% by 2006 (P for trend <0.0001), they reported.

Rates of patients' being placed on a waiting list within three years for transplant rose slightly, from 35.7% to 37.2%, but rates of actual transplantation declined significantly from 21.5% to 18% (P=0.005).

Moreover, three-year mortality has remained static, at 27%.

Multivariable analysis found these changes in outcomes by 2003:

•Waitlisting for transplant, HR 1.09 (95% CI 1 to 1.20, P=0.05)

•Receipt of renal transplant, HR 0.87 (95% CI 0.76 to 0.99, P=0.03)

•Mortality, HR 0.95 (95% CI 0.85 to 1.07, P=0.44)

"The slightly growing incidence of ESRD and lack of improvements in important outcomes among patients with ESRD due to lupus nephritis over the past 12 years are disappointing," observed Costenbader and colleagues.

Factors that may be contributing to this lack of progress could include a lack of access or limited use of treatment, particularly in the South, the inadequate supply of donor organs, and patient nonadherence to treatment.

"Taken together with other recent findings of increased risks of graft failure, recurrent lupus nephritis, and death after kidney transplant, the changing sociodemographics, and the lack of improvement in survival in ESRD due to lupus nephritis underscore the ongoing challenge of caring for these patients," the researchers concluded.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Office of Research on Women's Health.

One author reported receiving research grants from Amgen and another has received fees and royalties from Policy Analysis and UpToDate.

A third reported grants from Abbott and Amgen and educational course sponsorship from Bristol-Myers Squibb.

Primary source: Arthritis & Rheumatism

Source reference:

Costenbader K, et al "Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006" Arthritis Rheum 2011; 63: 1681-1688.

http://www.medpagetoday.com/Nephrology/ESRD/26969? utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2011 Everyday Health, Inc. All rights reserved.

By Nancy Walsh, Staff Writer, MedPage Today

Published: June 09, 2011

Reviewed by

Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

■Explain that the prognosis for patients with lupus nephritis who develop end-stage renal disease (ESRD) has not improved in recent years despite advances in treatment.

■Note that rates of end-stage renal disease also have risen among younger patients and African Americans and other minorities with lupus nephritis.

The outlook for patients with lupus nephritis who develop end-stage renal disease (ESRD) has not improved in recent years despite advances in treatment -- and the condition is on the rise in younger patients and African Americans -- researchers reported.

Compared with the general population, the standardized incidence ratio for ESRD among patients with lupus nephritis ages 5 to 19 years rose from 0.84 (95% CI 0.66 to 1.06) in the years 1995 to 1997 to 1.35 (95% CI 1.13 to 1.62) during 2004 to 2006 (P<0.0001), according to Karen H. Costenbader, MD, of Harvard University, and colleagues.

And compared with whites, whose standardized incidence ratio remained at 2.11 (95% CI 1.98 to 2.25) by 2006,

the ratio for blacks increased from 12.80 (95% CI 11.92 to 13.74) to 15.55 (95% CI 14.64 to 16.51, P=0.008), the researchers reported in the June issue of Arthritis & Rheumatism.

Despite the development of effective immunosuppressant drugs such as azathioprine and cyclophosphamide and the availability of living kidney transplantation, some 10% to 30% of patients with lupus nephritis still develop ESRD within 15 years.

Those findings emerged from an analysis of data from the U.S. Renal Data System, which is a national registry that includes almost all patients on dialysis or who undergo kidney transplantation.

Costenbader and colleagues identified 12,344 new cases of ESRD in patients with lupus nephritis between 1995 and 2006.

The age at which ESRD develops has remained at around 40, and 80% are women.

Mean body mass index increased during those years from 23.5 to 26.5 (P<0.0001).

Serum creatinine at onset decreased from 8.6 mg/dL to 7.1 mg/dL (P<0.0001), and serum hemoglobin increased from 8.9 g/dL to 9.6 g/dL (P<0.0001).

Those laboratory findings suggest that renal replacement was being started earlier, when there was greater residual kidney function, and that erythropoiesis-stimulating agents were being used more frequently, the researchers explained.

Coexistent diabetes and hypertension also increased steadily, they observed.

Aside from African Americans, other minorities also have seen increases in rates of ESRD, including Native Americans (P=0.002) and Asians (P=0.09).

Residence in the Southeastern states also has been associated with an increase (P=0.002).

When the researchers looked at patterns of transplantation, they found that in the years 1995 to 1997, half of transplants were from living donors. This rose to 70% by 2006 (P for trend <0.0001), they reported.

Rates of patients' being placed on a waiting list within three years for transplant rose slightly, from 35.7% to 37.2%, but rates of actual transplantation declined significantly from 21.5% to 18% (P=0.005).

Moreover, three-year mortality has remained static, at 27%.

Multivariable analysis found these changes in outcomes by 2003:

•Waitlisting for transplant, HR 1.09 (95% CI 1 to 1.20, P=0.05)

•Receipt of renal transplant, HR 0.87 (95% CI 0.76 to 0.99, P=0.03)

•Mortality, HR 0.95 (95% CI 0.85 to 1.07, P=0.44)

"The slightly growing incidence of ESRD and lack of improvements in important outcomes among patients with ESRD due to lupus nephritis over the past 12 years are disappointing," observed Costenbader and colleagues.

Factors that may be contributing to this lack of progress could include a lack of access or limited use of treatment, particularly in the South, the inadequate supply of donor organs, and patient nonadherence to treatment.

"Taken together with other recent findings of increased risks of graft failure, recurrent lupus nephritis, and death after kidney transplant, the changing sociodemographics, and the lack of improvement in survival in ESRD due to lupus nephritis underscore the ongoing challenge of caring for these patients," the researchers concluded.

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Office of Research on Women's Health.

One author reported receiving research grants from Amgen and another has received fees and royalties from Policy Analysis and UpToDate.

A third reported grants from Abbott and Amgen and educational course sponsorship from Bristol-Myers Squibb.

Primary source: Arthritis & Rheumatism

Source reference:

Costenbader K, et al "Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006" Arthritis Rheum 2011; 63: 1681-1688.

http://www.medpagetoday.com/Nephrology/ESRD/26969? utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2011 Everyday Health, Inc. All rights reserved.

Lupus (systemic lupus erythematosus) is a serious and potentially fatal disease that mainly affects young women.

The cause of the disease is not known, but it is believed to be an autoimmune disease (an illness that occurs when the body mistakenly detects its own tissue as foreign and attacks itself).

The disease often starts between the ages of 15 and 44.

The manifestations of lupus are diverse:

it can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain.

An estimated 240,000 Americans are diagnosed with lupus.

People of all races can have the disease; however, African American women have a three-times higher incidence (number of new cases) than Caucasian women.

They tend to develop the disease at a younger age than Caucasian women and to develop more serious complications.

Nine times more women than men have lupus, and it is also more common in women of Hispanic, Asian, and Native American descent.

YESTERDAY

A significant number of people diagnosed with lupus faced the prospect that they would die within 5 years of the diagnosis.

While patients who were diagnosed with lupus faced an uncertain future, they knew that, in addition, to the shortened life span, they were quite likely to have a significantly compromised quality of life.

Treatments for lupus were of limited effectiveness, typically targeting the entire immune system rather than the specific elements of the immune system involved with the disease course in lupus.

Therapies were associated with significant and often debilitating side effects.

Diagnosis of lupus was more difficult because the symptoms of lupus are similar to a number of other diseases, and sophisticated tools of molecular medicine were not yet available.

TODAY

People who are diagnosed with lupus today have hope for a significantly increased life span and improved quality of life compared with those 30 years ago.

Studies from the NIH Intramural Research Program determined that treatment with immunosuppressive drugs (cyclophosphamide and prednisone) can prevent or delay kidney failure due to nephritis, one of the most serious and life-threatening complications of lupus.

[u]Hydroxychloroquine, an antimalarial medication, is also used in the treatment of lupus and other autoimmune diseases, and is associated with a reduced risk of overall tissue damage. [/u]

Recent NIH-supported research has shown that lupus patients treated with hydroxychloroquine were less likely to develop severe kidney disease, had lower disease activity, and used less steroid medication.

A number of genes associated with lupus risk and severity have been discovered. Some are linked to patient populations at high risk for lupus, including African American and Hispanic individuals.

The Office of Women’s Health at the U.S. Department of Health and Human Services has partnered with the Ad Council, with input from patient advocacy groups and federal agencies involved in lupus research and treatment, such as the NIH, to produce a lupus awareness campaign entitled,

“Could I Have Lupus?” (http://www.couldihavelupus.gov/)

The main message of the campaign is that lupus is a life-altering disease that primarily affects young women who may be experiencing symptoms of lupus but have not been diagnosed.

TOMORROW

Genetic studies will allow the identification of those at risk for lupus so that interventions can be made earlier in the disease process.

They will also identify molecular pathways that cause lupus and its symptoms, which can be targeted in the design of new therapies.

Recent research has already revealed common disease mechanisms among different autoimmune diseases, so advances in treatment of one condition may be applicable to others.

Recent discoveries about the influence of X-chromosome genes on lupus risk may provide future explanations for female predominance of the disease.

Biological indicator molecules, or “biomarkers,” will help to predict who is likely to develop lupus, what organ systems are more likely to be targeted, and the severity of disease.

Identifying lupus patients at particular risk for severe disease before serious complications arise has implications for early diagnosis and treatment.

Blood tests that measure biomarkers may be used to predict flares of lupus activity and guide individualized treatment.

Methods to analyze patients’ blood samples are already being developed to group disease-specific gene expression patterns according to disease-causing biological mechanisms.

Therapeutics will be designed to diminish or reverse immune dysfunction and inflammation.

Similar drugs that have been approved for other autoimmune diseases will be tested for effectiveness in lupus patients.

The variations in disease course and severity that are associated with minority populations, due to genetics, environment, or social issues, will be targeted to personalize treatments and reduce health disparities.

Participation of patients in clinical research is one of the best ways to advance new knowledge and contribute to the development of new treatments.

Contact: NIAMS Information Clearinghouse toll free: 877-22-NIAMS (226-4267); email: NIAMSInfo@mail.nih.gov

National Institute on Arthritis and Musculoskeletal and Skin Diseases (NIAMS): www.niams.nih.gov

Page Last Updated on February 14, 2011

http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx? csid=47

Infections and cancer are the two leading causes of death in patients with systemic lupus erythematosus (lupus), after circulatory system diseases.

That's why it's important for patients with lupus, an autoimmune disease much more common in women, to get preventive cancer diagnostic tests and immunizations to prevent infections.

A new study found that patients with lupus did get key preventive tests and vaccinations at rates similar to that of the general population or persons with other chronic diseases.

However, patients with lupus who were younger or less educated were less likely to receive preventive services.

The researchers examined cancer surveillance (for cervical, breast, and colon cancer) and immunizations against influenza and pneumococcal diseases in patients with lupus and two comparison groups: the general population and persons with chronic conditions other than lupus. Among the women with lupus meeting the United States Preventive Services Task Force guidelines, 70 percent (vs. 73 percent for the general population) had cervical cancer screening; 70 percent (vs. 68 percent) had mammography; and 62 percent (vs. 57 percent) had colon cancer screening. Most of the women with lupus received the influenza vaccine (59 percent) and pneumococcal vaccine (60 percent), while the rates for the general population were 42 percent and 70 percent, respectively.

The study group included patients with lupus (685 women and 57 men) from the University of California–San Francisco Lupus Outcomes Study, who were interviewed about receipt of preventive services during the group's fourth annual interview (conducted between March 2005 and February 2006).

They were compared with respondents to the California Health Interview Survey—a general population sample of 18,013 English-speaking individuals at least 18 years old, and a sample of 4,515 individuals with chronic illnesses (asthma, diabetes mellitus, and heart disease) other than lupus.

The study was funded in part by the Agency for Healthcare Research and Quality (HS13893).

More details are in "Provision of preventive health care in systematic lupus erythematosus:

Data from a large observational cohort study,"

Jinoos Yazdany, M.D., M.P.H., Chris Tonner, M.P.H., Laura Trupin, M.P.H., and others, in Arthritis Research & Therapy 12:R84, 2010.

AHRQ Home | Questions? | Contact AHRQ | Site Map | Accessibility | Privacy Policy | Freedom of Information Act | Disclaimers

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Agency for Healthcare Research and Quality 540 Gaither Road Rockville, MD 20850 Telephone: (301) 427-1364

http://www.ahrq.gov/research/jul11/0711RA21.htm

By Nancy Walsh, Staff Writer, MedPage Today

Published: July 26, 2011

Reviewed by

Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

■Explain that CT coronary artery calcium scoring showed a slight regression in plaque after one year of treatment with atorvastatin (Lipitor) in cardiovascular symptom-free patients with systemic lupus erythematosus.

■Note that there was no need for anyone in the statin group to stop taking the drug, as tests revealed no changes in the activity of alanine and aspartate aminotransferase nor creatine phosphokinase.

CT coronary artery calcium scoring showed a slight regression in plaque after one year of treatment with atorvastatin (Lipitor) in cardiovascular symptom-free patients with systemic lupus erythematosus, a Polish study found.

While no significant changes were seen in calcium score or volume in those randomized to statins, those taking placebo had increases in both: from 32.1 to 59.5 in the score and 35.2 to 62.9 in the volume (P<0.05 for both), according to Wojciech Plazak, MD, of Jagiellonian University in Krakow, and colleagues.

Additionally, there was no need for anyone in the statin group to stop taking the drug, as tests revealed no changes in the activity of alanine and aspartate aminotransferase nor creatine phosphokinase, the researchers reported online in Arthritis Research & Therapy.

Inflammation has been implicated in both systemic lupus erythematosus and atherosclerosis, and cardiovascular disease today is the primary cause of mortality in patients with lupus, researchers wrote.

"Interestingly, the magnitude of the protection and decrease in mortality afforded by statins cannot be explained entirely by their cholesterol-lowering effect," observed Plazak and colleagues.

These drugs also have anti-inflammatory properties and can improve endothelial function, and have been advocated for patients with lupus who have coronary artery disease, but the recommendations were based on their efficacy in non-lupus populations.

Researchers therefore enrolled 60 patients with established but stable lupus, randomizing them to 40 mg atorvastatin or placebo each day.

The majority were women, and mean age was 42.

Baseline ECG findings were normal in all participants.

More than half were on methylprednisolone, and small numbers of patients were taking other immunosuppressive drugs such as prednisone, chloroquine, and azathioprine or cardiovascular agents such as ACE inhibitors and beta-blockers.

At baseline, SPECT showed abnormal myocardial perfusion in 50%, with persistent abnormalities in 36.7% and exercise-related anomalies in 13.3%.

The most common site of abnormality was the area perfused by the left anterior descending artery, and a median of three segments of the myocardium showed persistent abnormalities.

After one year, there were no changes to the perfusion abnormalities in either group.

Among the entire cohort, baseline coronary calcifications were present in one-quarter of patients, with a median of three plaques per patient.

Six patients on statins had plaques at baseline, which did not change over the course of the year. In the placebo group, nine had plaques at baseline, which included one additional patient at one year.

Lipid profiles remained unchanged in the placebo group, but improved in the statin group:

•Total cholesterol, 170 mg/dL versus 197 mg/dL, P<0.05

•LDL cholesterol, 89 mg/dL versus 112 mg/dL, P<0.05

•Triglycerides, 106 mg/dL versus 142 mg/dL, P<0.05

A study presented at last year's annual meeting of the American College of Rheumatology found that women with this disease do not undergo standard lipid screening.

And while 43% of the women in the study qualified for lipid-lowering drugs, only 11% were prescribed statins.

In the current study, Plazak and colleagues also found that C-reactive protein -- a marker of inflammation -- fell significantly in the atorvastatin group, from 4.4 mg/L to 2.7 mg/L (P<0.05). There was no change in the placebo group.

The decrease in inflammatory C-reactive protein with statin treatment was important, according to Plazak and colleagues, because patients were not permitted to increase their immunosuppressive treatment during the study, suggesting that the statin was responsible.

Disease activity scores remained unchanged in both groups.

The researchers noted that this is the first study showing benefits for statins in lupus patients, who are at elevated risk for early atherosclerosis.

Previous studies have suggested that by age 40, 30% to 40% of these patients already have coronary artery calcifications.

The researchers also pointed out that the rate of perfusion defects was high, at 50%, "despite normal ECG recordings at rest and lack of any clinical symptoms of myocardial ischemia."

And although the number of perfusion abnormalities in the left ventricle was low, "it has been already established that the presence of even small perfusion defects in SPECT studies strongly affects prognosis," they wrote.

One concern with the use of statins in patients is the possible development of a lupus-like syndrome, which has occurred in a few cases and may relate to alterations in cell apoptosis or effects on T cells.

No statin-related serious adverse effects were seen in this study, however.

A limitation of the study was the use of calcium scores, which have limited reproducibility to estimate the size and density of calcium deposits.

Large prospective trials of statin therapy for lupus patients should now be conducted, the researchers concluded.

The authors declared that they had no competing interests.

This study was supported by a grant from the Polish Ministry of Science and Higher Education.

Primary source: Arthritis Research & Therapy

Source reference:

Plazak W, et al "Influence of atorvastatin on coronary calcifications and myocardial perfusion defects in systemic lupus erythematosus patients: a prospective, randomized, double-masked, placebo-controlled study" Arthritis Res Ther 2011; DOI:10.1186/ar3402.

http://www.medpagetoday.com/Cardiology/Atherosclerosis/ 27733?utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2011 Everyday Health, Inc. All rights reserved.

By Nancy Walsh, Staff Writer, MedPage Today

Published: August 06, 2011

Reviewed by

Zalman S. Agus, MD; Emeritus Professor

University of Pennsylvania School of Medicine and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

■Note that vaccination of SLE patients with the influenza vaccine has become part of the standard of care, but a variable response has been noted.

■Note that in this study, response to the vaccine was variable.

Some patients, especially those with a history of hematologic disorder or those taking prednisone, as well as European-American patients (compared with African-American patients) experienced a weak response to the influenza vaccine.

■Note also that low responders were more likely to experience disease flares following vaccination.

Race and the presence of hematologic abnormalities were among the factors influencing response to influenza vaccine among patients with systemic lupus erythematosus, a prospective study found.

African-American patients were three times more likely to mount a successful response to vaccination than were patients of European ancestry (95% CI 1.07 to 9.94, P=0.03), according to Judith A. James, MD, PhD, of the University of Oklahoma in Oklahoma City, and colleagues.

However, a high response to the vaccine was seen in only one-third of patients with hematologic manifestations of lupus -- and in none of the patients with hemolytic anemia (P=0.01), the researchers reported in the August issue of Arthritis & Rheumatism.

As treatment for systemic lupus erythematosus has improved in recent years, lowering mortality rates from complications such as renal disease, infections have become a more common cause of morbidity and mortality.

Accordingly, immunization against influenza has become standard of care for lupus patients.

However, previous studies have yielded limited and conflicting data on individual responses to the vaccine and on the effects of immunization on lupus disease activity.

To more fully explore the issues involved, James and colleagues enrolled 72 patients and an equal number of healthy controls, collecting blood samples before vaccination and at two, six, and 12 weeks after the immunization.

Response to the vaccine was classified as low or high according to scores calculated from total antibody concentrations, relative affinity of serum antibodies, and levels of hemagglutination inhibition.

Among the cohort of patients, more than 90% were women and 44% were African-American.

Mean age was 43, and median age at lupus diagnosis was 31.

The median number of American College of Rheumatology (ACR) lupus criteria was 5.8.

Overall, the humoral immune response following immunization was lower among lupus patients compared with controls, although high responders to the vaccine achieved antibody responses that were closer to the responses seen in controls.

The stronger response to the vaccine among African-American patients could not be explained by differences in age, as the average ages of low and high responders were similar.

"This discrepancy in vaccine responsiveness may be due to the impact of HLA haplotypes in the different racial groups, although this requires further investigation," the researchers wrote.

Patients with low responses had more American College of Rheumatology (ACR) lupus criteria than high responders (6 versus 5, P=0.05), with almost two-thirds of low responders having six or more criteria.

Aside from hemolytic anemia, low responders also had higher prevalences of thrombocytopenia, lymphopenia, and leukopenia, although the differences were not statistically significant.

More of the high responders had a discoid rash, while no differences were seen between the low and high response groups in renal disease or arthritic complications.

The use of prednisone was associated with low response, with 67% of low responders having taken the steroid in doses of 10 mg or higher per day compared with 47% of those who had higher responses to the vaccine (P=0.04).

The use of other medications such as methotrexate and azathioprine did not appear to influence immunization response, the researchers observed.

Certain patterns of autoantibodies also differed between low and high responders.

For instance, low responders more often had an increase in antinuclear antibody (14% versus 8%), while 22% of high responders had decreases in titers of this antibody.

Low responders also were more likely to have a disease flare.

Within six weeks of vaccination, 14 patients had experienced a flare, 71.4% of whom were low responders (P=0.01).

When the researchers looked for characteristics among these patients who flared, they found no correlation for baseline disease activity, number of ACR lupus criteria, or age at diagnosis.

Certain ACR criteria were more common among patients who flared, including renal involvement, central nervous system manifestations, and hematologic abnormalities, but the numbers were inadequate for statistical analysis.

One factor that did correlate with flare was baseline serum interferon (IFN)-α activity.

The mean IFN-α activity among patients who flared was 19.3 standard deviations above the mean in healthy controls, compared with 2.7 among those without flare (P=0.04).

"The relationships between IFN activity, vaccination responses, and subsequent disease flares need to be confirmed in a larger cohort, and the biologic significance of these processes should be examined," wrote James and colleagues.

Further studies of biomarkers that might help predict vaccine responses and flares could help identify patients who could benefit from more intensive lupus treatment before they are given vaccines, they concluded.

The study was supported by the National Institutes of Health and by the Kirkland Foundation.

One co-author has received speaking fees from Pfizer, Abbott, and Forest Laboratories.

Primary source: Arthritis & Rheumatism

Source reference:

Crowe S, et al "Influenza vaccination responses in human systemic lupus erythematosus: impact of clinical and demographic features" Arthritis Rheum 2011; 63: 2396-2406.

http://www.medpagetoday.com/Rheumatology/Lupus/27925? utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2011 Everyday Health, Inc. All rights reserved.

Tuesday, August 30, 2011

NEW YORK (Reuters Health) -

Despite a commonly-held belief among many doctors who treat lupus patients, headaches -- particularly migraines -- are not a manifestation of that disease and should be treated as a separate problem, report researchers in Greece.

Previous studies that found migraines to be more common in patients with systemic lupus erythematosus (SLE) may have suffered from methodological errors, said senior author Dr. Dimos Mitsikostas from Athens Naval Hospital, and have led doctors to dismiss headaches as a neurological symptom of lupus.

Instead of being part of the disease, however, headaches may result from the stress of having the disease.

"In SLE, headaches may be associated with poor quality of life and bad mood. If an SLE patient reports headaches, please see if he or she is happy and if there is any other reason to cause secondary headaches and treat them not as an SLE feature, but like a separate disorder," Mitsikostas told Reuters Health in an email.

Although various studies of the headache question have produced conflicting results, the American College of Rheumatology includes headaches and migraine as part of the spectrum of lupus symptoms.

In a previous analysis, Mitsikostas and colleagues found no significant link between migraines and lupus.

To clarify the association (or lack thereof), they performed the current study, in which lupus patients, healthy controls and multiple sclerosis (MS) patients all kept headache diaries for a year.

Like lupus, MS is a disease in which the body's own immune system attacks its nervous system, so Mitsikostas' group included 48 MS patients for comparison.

The healthy controls in the study were matched by age and gender with the lupus patients to form 72 pairs.

All participants had similar headache frequencies in the year before the study period, except the lupus patients, who had a significantly higher number of tension-type headaches, the researchers report in the journal Headache.

Results were similar during the year of headache diaries:

the three groups suffered comparable numbers of headaches, but chronic tension-type headache continued to occur more often in the lupus patients.

Migraine attacks were less severe and tended to be of shorter duration in lupus patients, whereas the severity of the chronic tension-type headaches was milder among lupus patients than among controls (but similar between lupus and MS patients).

Among both lupus and MS patients, the presence and type of headache could not be related to any other detectable manifestation of the disease, flare-up or cumulative damage.

Lupus patients had higher levels of anxiety and lower quality of life compared to controls and MS patients, and depression status was worse in lupus and MS patients than in controls. None of these features, however, coincided with the presence of headache.

"Although there are always missed points and issues for further evaluation, we feel that this study may be the last one in a long clinical research (path), starting 15 years ago," Mitsikostas concluded. "Yet, no pathophysiological links between SLE and migraine" could be found along the way, he wrote.

Somewhere between 322,000 and one million Americans are believed to have lupus, nine out of 10 of them women, according to the U.S. Centers for Disease Control and Prevention.

The disease is difficult to diagnose and there is no cure.

Although some symptoms are treatable, approximately one third of deaths among lupus patients occur before age 45.

SOURCE: Headache, online July 28, 2011.

Reuters Health

(c) Copyright Thomson Reuters 2011.

http://www.nlm.nih.gov/medlineplus/news/ fullstory_115957.html

By Nancy Walsh, Staff Writer, MedPage Today

Published: September 30, 2011

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and

Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points

■Explain that a Danish registry study found that the incidence of cancers that have been linked to viral infections, especially human papillomavirus (HPV), is increased in patients with systemic lupus erythematosus.

■Note that the registry data, while strong for diagnostic accuracy, did not include information on viral infections, including HPV.

Patients with systemic lupus erythematosus are at elevated risk for virus-associated malignancies, data from a Danish registry showed.

For all cancers that have been linked to viral infection, the standardized incidence ratio (SIR) among a cohort of 576 lupus patients was 2.9 (95% CI 2 to 4.1), according to Lene Dreyer, MD, PhD, and colleagues from Copenhagen University Hospital.

Particularly notable was human papillomavirus (HPV)-related anal cancer -- a rare malignancy -- for which the standardized incidence ratio was 26.9 (95% CI 8.7 to 83.4), the researchers reported in the October issue of Arthritis & Rheumatism.

Previous studies have suggested that patients with systemic lupus erythematosus have a small increase in overall cancer risk, primarily relating to non-Hodgkin's lymphoma.

However, they also have higher rates of genital infections with HPV, "probably due to impaired clearance of HPV secondary to disease-related and/or therapy-induced immunodeficiency," Dreyer's group observed.

To determine if these persistent HPV infections are associated with malignancies, the researchers gathered data from eight specialized lupus centers and from the Danish Cancer Registry.

A total of 88% of the patients were women, and 96% were white.

Their median age when diagnosed with lupus was 33, and median follow-up was 13.2 years.

Among the most common lupus features in this cohort were antinuclear antibody positivity in 98%, arthritis in 68%, malar rash in 50%, proteinuria in 49%, and lymphopenia in 47%.

With regard to the high incidence of lymphopenia, the researchers wrote, "It is tempting to speculate that compromised T-cell activity may have contributed to the observed susceptibility to potentially virus-associated cancers."

During follow-up, 61 cases of cancer were observed; 38.4 cases would have been expected.

The greatest risks were during the 12 months following the diagnosis of lupus (SIR 1.6, 95% CI 1.2 to 2) and 20 years later (SIR 2.2, 95% CI 1.3 to 3.6), the researchers reported.

Risk was elevated for both women (SIR 1.5, 95% CI 1.1 to 2) and men (SIR 2.4, 95% CI 1.3 to 4.4), and for those who were younger than 50 at the time of lupus diagnosis (SIR 1.6, 95% CI 0.99 to 2.6) and those who were older (SIR 1.6, 95% CI 1.2 to 2.1).

The risk was increased for all HPV-related cancers combined (SIR 2.3, 95% CI 1.4 to 3.6) and for several other sites associated with HPV malignancy aside from anal cancer:

•Buccal cavity and pharynx, SIR 1.8 (95% CI 0.3 to 12.6)

•Vagina/vulva, SIR 9.1 (95% CI 2.3 to 36.5)

•Cervix (dysplasia and carcinoma in situ), SIR 1.8 (95% CI 1.2 to 2.7)

•Nonmelanoma skin cancer, SIR 2 (95% CI 1.2 to 3.6)

The researchers noted that the increased rates of nonmelanoma skin cancer could be ascribed to surveillance bias, as patients with lupus typically receive more intensive medical care than healthy individuals, but they also cited recent work implicating HPV in the pathogenesis of skin cancer in the immunocompetent.

If the high rates of HPV-linked cancers relate to an increased susceptibility to viral infections because of immune system dysfunction, patients with lupus also could be at risk for other virus-related cancers, they suggested.

In fact, they also found increased risks for liver cancer (SIR 9.9, 95% CI 2.5 to 39.8), non-Hodgkin's lymphoma (SIR 5, 95% CI 1.9 to 13.3), and cancer of the bladder (SIR 3.6, 95% CI 1.4 to 9.7).

Epstein-Barr virus has been linked to lymphoma in patients who are immunosuppressed, and chronic infections with hepatitis B and C viruses are associated with liver malignancy, but "it is unclear whether these viruses play an important role in the pathogenesis of cancer developing in the setting of [systemic lupus erythematosus], and our data do not provide a basis for answering these questions," wrote Dreyer and colleagues.

And for bladder cancer, some evidence has implicated polyoma virus, but all the patients in this cohort who developed this cancer had previously been treated with cyclophosphamide, which itself is a bladder carcinogen.

Strengths of the study included the validity of the lupus diagnosis from the specialized lupus centers and validity of the cancer diagnoses from the national cancer registry, while limitations were the possibility of referral bias, extra care that lupus patients receive which may increase diagnoses like nonmelanoma skin cancer, and absence of data on actual HPV or other viral infections.

Dreyer and colleagues noted that the recommendation in Denmark is for all girls ages 12 to 15 to receive the HPV vaccine at no cost, and they proposed that the vaccine be made available for all lupus patients younger than 25, although it is not known if the vaccine is as protective in immunocompromised patients.

They concluded that their study results "call for clinical alertness to oncogenic virus infections" in patients with lupus.

One author was supported by the Novo Nordisk Research Foundation.

Primary source: Arthritis & Rheumatism

Source reference:

Dreyer L, et al "High incidence of potentially virus-induced malignancies in systemic lupus erythematosus" Arthritis Rheum 2011; 63: 3032-3037.

http://www.medpagetoday.com/Rheumatology/Lupus/28823? utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=

© 2011 Everyday Health, Inc. All rights reserved.

Experimental treatments altered immune response in small, preliminary studies

Monday, November 7, 2011

SATURDAY, Nov. 5 (HealthDay News) --

Two experimental treatments take aim at the destructive immune response believed to cause lupus, according to new research presented at the American College of Rheumatology annual meeting.

One study looked at large doses of vitamin D, while the other was a trial of a potential vaccine against an immune system protein called interferon alpha.

"This is an incredibly exciting time in lupus research. The academic and pharmaceutical communities are involved in studies that will hopefully lead to more effective and safer treatments," said Dr. Cynthia Aranow, an investigator at the Feinstein Institute for Medical Research in Manhasset, N.Y. She was not involved in the current studies.

Of these latest studies, Aranow said that both appeared to have an effect on immune system cells, but neither was designed to assess whether or not there was enough of an effect to make a difference to a patient (a clinical response).

Lupus is a chronic autoimmune disease that can affect almost any part of the body, including the

skin, joints, kidneys, lungs, nervous system and other organs, according to the Office on Women's Health, part of the U.S. Department of Health and Human Services.

An autoimmune disease is one that develops because the immune system mistakenly sees healthy cells in the body as foreign invaders, such as a virus.

Instead of fending off bacteria and other invaders as they should, some immune system cells begin attacking healthy cells.

The problem in developing a treatment for lupus and other autoimmune diseases is that a treatment can't just shut down the entire immune system, because that would leave the body too vulnerable to infection.

So, researchers have been trying to find the specific immune cells involved in causing lupus.

Research has been looking for ways to slow these cells down, or maybe even destroy them without damaging the rest of the immune system.

The first study, scheduled for presentation Nov. 6 at the ACR meeting in Chicago by Dr. Benjamin Terrier of the Pitie-Salpetriere Hospital in Paris, looked at the effect large doses of vitamin D might have on the immune response.

The study included 24 people with lupus who had no or mild disease activity and low levels of vitamin D.

At the start of the study, they were given an injection of 100,000 international units of vitamin D once a week for four weeks. After that, they received a once-a-month injection of the same dose of vitamin D for another six months.

The treatment was very well tolerated, and no one developed too much calcium in their blood or calcium deposits (kidney stones), according to the researchers.

The investigators also found that the treatment boosted the activity of good immune cells, and dampened some of those believed to play a role in lupus.

"It's exciting to see that they were able to reverse some of the immunologic dysfunction associated with lupus, but we need a large randomized clinical trial to confirm this," said Aranow.

She added that the dose of vitamin D used in the study was quite large, and it's not something that people with lupus should attempt to duplicate on their own.

The second study involved 28 people with mild to moderate lupus who were given four doses of a vaccine against interferon alpha (IFNa), an immune system protein that's known to play a role in the severity of lupus.

"We were able to demonstrate that the IFNa signature (in excess in lupus patients) can be turned down by vaccinating patients against their own IFNa.

The drug is called IFNa-Kinoid. [It's] a modified IFNa, devoid of IFNa biological activity, but modified in such a way that it becomes recognized by the immune system of the patient," explained Dr. Frederic Houssiau, head of rheumatology at the Catholic University of Louvain in Brussels.

He said the patient's immune system then begins to make antibodies against their own INFa.

Houssiau's team, along with colleagues from the manufacturer of the vaccine, Neovacs, found the drug to be well tolerated with no significant side effects.

"This is an early, first step. It appears to be safe. And, the fact that they could show that they could inhibit or down-regulate the interferon signature is very promising," said Aranow.

Houssiau didn't know what the vaccine might cost if developed commercially, but said it would likely be more expensive than the standard therapies currently used.

For people living with lupus, he added, "there is hope. By unraveling more and more pathways at work in lupus patients, we are now able to develop new, much more targeted drugs to tackle the disease."

Because this research was presented at a medical meeting, the data and conclusions should be viewed as preliminary until published in a peer-reviewed journal.

SOURCES:

Frederic Houssiau, M.D., Ph.D., head of rheumatology and professor of rheumatology, Catholic University of Louvain, Brussels, Belgium;

Cynthia Aranow, M.D., investigator, Feinstein Institute for Medical Research, Manhasset, N.Y.;

American College of Rheumatology, news release, Nov. 5, 2011;

presentations, American College of Rheumatology annual meeting, Chicago

http://www.nlm.nih.gov/medlineplus/news/ fullstory_118395.html

Copyright (c) 2011 HealthDay. All rights reserved.