Breakthrough Offers Potential Treatment For Rheumatoid Arthritis

A breakthrough in understanding the way atoms move across cell membranes in the human body could pave the way for the development of new treatments for inflammatory diseases such as rheumatoid arthritis.



Scientists at the University of Leeds have identified a previously unknown natural mechanism that opens ion channels - proteins at the cell surface that act as doorways into and out of cells - through the naturally occurring protein thioredoxin.



Ion channels allow movement of ions - electrically charged atoms - across the cell membrane to carry out various functions such as pain transmission, timing of the heart beat, and regulation of blood glucose. Often, they need to be stimulated to open and, until now, two main groups of activating mechanisms have been acknowledged: changes in cell voltage and binding of chemical factors.



In a paper published today (03 January) in Nature, Professor Beech and colleagues from the University's Faculty of Biological Sciences reveal that thioredoxin works in a different manner: it activates an ion channel by donating electrons to it, in a process Professor Beech likens to "an electronic on-switch".



"Thioredoxin is naturally present in cells and is secreted to help the body counter stressful chemical reactions that occur in inflammation, which can damage cells," he explains. "We already knew that inflammatory diseases cause the production of high levels of thioredoxin - in fact with rheumatoid arthritis, it's striking how much is present in affected joints. But we didn't know until now that thioredoxin can also activate ion channels, conferring additional protective potential and offering opportunities for mimicking the effect with drugs."



"It would seem that the body's own natural defences have provided us with new understanding that could be significant in the development of future treatments for arthritis and related diseases," he says.







The research has been funded by the Wellcome Trust, which has recently provided the group with further funding to expand its research into ion channels.



Source: Jo Kelly


University of Leeds

Rheumatoid Arthritis Patients Taking Enbrel® Keep Working For Longer

Patients receiving Enbrel® (etanercept) in combination with methotrexate for early Rheumatoid Arthritis (RA) are more likely to continue working, according to the COMET study published recently in Rheumatology.



One year results from the COMET study - which compared the impact of methotrexate alone with methotrexate in combination with Enbrel on work productivity - showed that active early RA patients receiving the Enbrel-methotrexate combination were nearly three times less likely to stop working compared to patients receiving methotrexate alone. Furthermore, work absenteeism was reduced by almost 50 per cent in the combination group.1



RA is a chronic and progressive disease that affects 2.9 million people across Europe.2 As the disease progresses, RA can cause permanent damage to the joints, resulting in deformity and loss of independence.



The prevention of work productivity loss represents benefit beyond the traditional measures of disease improvement. The economic impact of RA is significant, with an estimated €45 billion spent on the disease in Europe each year. Of this, 32 per cent of the total cost is likely due to work disability and decrease in work productivity.2 Results from previous studies suggest that even in the early stages of disease, RA can impact a person's ability to work.1 In the COMET study, half of the work stoppages observed occurred in the first three months of the trial.1



"Keeping a person gainfully employed represents a benefit to society, above and beyond, the clinical benefits of treatment" said Professor Aslam Anis, School of Population and Public Health, University of British Columbia and lead author of the paper. "The fact that half of the work stoppages occurred in the first three months of this trial, together with the fact that there were significantly fewer work stoppages in the Enbrel-methotrexate combination group, underscore the importance of early and aggressive treatment of RA."



During the COMET (COmbination of Methotrexate and ETanercept) study, work absenteeism was recorded over 12 months amongst 205 patients with early active RA. Total absenteeism was defined as a composite of number of missed workdays, reduced working time and number of days patients were unemployed as a result of their RA.



At the end of one year:1
The number of missed workdays in the group receiving combination treatment of Enbrel and methotrexate (14.2 days) was approximately half that of patients receiving methotrexate monotherapy (31.9 days)


In total, the Enbrel combination group missed up to 37 fewer total days due to absenteeism than the methotrexate monotherapy group


24 per cent of patients in the monotherapy group had to stop work at least once during the year, compared to 8.6 per cent of patients in the combination therapy group

Previously published data from the COMET trial showed that early treatment of RA can halt the joint damage seen as the disease progresses - 80 per cent of patients in the combination group experienced no further joint damage as measured by x-rays. Furthermore, 50 per cent of patients experienced a sustained reduction in disease activity as measured by the number of swollen joints (i.e. clinical remission) and 55 per cent achieved normal physical functioning, as measured by the Health Assessment Questionnaire.3
















About COMET

The COMET (COmbination of Methotrexate and ETanercept in early rheumatoid arthritis) study was designed to compare the clinical efficacy and safety of Enbrel (ETN) and methotrexate (MTX) combination therapy with MTX alone on clinical disease activity and progressive joint damage in patients with active early rheumatoid arthritis. The work analysis was designed to compare the impact of ETN+MTX to MTX alone on work productivity among MTX-na??ve patients with active early RA over 12 months.



Two hundred and five patients [MTX (n=100) VS ETN+MTX (n=1050], who were working full time or part time at the start of the trial and had at least one follow-up observation, were included in the analysis. Compared with the MTX group, the ETN+MTX group had a maximum of 37 fewer missed workdays or at minimum 22 fewer missed workdays.



About ENBREL

ENBREL is a fully human soluble tumour necrosis factor (TNF) receptor antagonist. ENBREL was first approved in 1998 for moderate to rheumatoid arthritis and has since been used in 505,000 patients worldwide across indications.



ENBREL is approved for the following indications:



Rheumatoid arthritis
ENBREL in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying antirheumatic drugs, including methotrexate (unless contraindicated), has been inadequate. ENBREL can be given as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. ENBREL is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. ENBREL, alone or in combination with methotrexate, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function.



Polyarticular juvenile idiopathic arthritis
Treatment of active polyarticular juvenile idiopathic arthritis in children and adolescents aged 4 to 17 years who have had an inadequate response to, or who have proved intolerant of, methotrexate. ENBREL has not been studied in children aged less than 4 years.



Psoriatic arthritis
Treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying antirheumatic drug therapy has been inadequate. ENBREL has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease.



Ankylosing spondylitis
Treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.



Plaque psoriasis
Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA. ENBREL is also licensed in the European Union for treatment of chronic severe plaque psoriasis in children and adolescents from the age of 8 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies.



About Wyeth

Wyeth Pharmaceuticals, a division of Wyeth, has leading products in the areas of women's health care, infectious disease, gastrointestinal health, central nervous system, inflammation, transplantation, haemophilia, oncology, vaccines and nutritional products.



Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing and marketing of pharmaceuticals, vaccines, biotechnology products, nutritionals and non-prescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals, Wyeth Consumer Healthcare and Fort Dodge Animal Health.



References

1. Anis A et al. The effect of etanercept on work productivity in patients with early active rheumatoid arthritis: results from the COMET study. Rheumatology doi:10.1093/rheumatology/kep239. E-Pub, 18 August 2009


2. Lundkvistet al. The burden of rheumatoid arthritis and access to treatment: health burden and costs. Eur J Health Econ 2008;8 (Suppl.2):S49-60


3. Emery P et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372:375-382



Source:

Wyeth


View drug information on Enbrel.

New Biologic Drug Is Effective Against Rheumatoid Arthritis

Abatacept, a member of a new class of drug that targets immune cells to treat rheumatoid arthritis (RA), is effective against RA, according to a new Cochrane Systematic Review. The review examines recent trials to assess safety and efficacy of the drug.



RA is an autoimmune disease affecting up to 1 in 100 people in Western countries. RA patients experience chronic pain and inflammation as a result of the body's own immune system attacking the lining of the joints. Abatacept is a new "biologic" drug that works by blocking the actions of the immune cells, called T cells, which cause joint inflammation.



The review combined data from seven trials including 2,908 patients, whose symptoms were assessed after one year of taking the drug or a placebo. Compared to placebo, patients given abatacept were twice as likely to achieve a 50% improvement in symptoms, including pain and the number of tender and swollen joints. Patients who took the drug also experienced improvements in physical ability. There was no progression in damage to joints of people who took abatacept at 12 months follow up. However, serious adverse effects increased if the drug was given in combination with other biologics.



"Like other biologics, abatacept is an expensive drug, but if the benefits are evident, it may be of great interest to patients with rheumatoid arthritis who fail standard therapy or other biologic treatment. Our review shows that it is indeed effective, and generally well-tolerated, but we would strongly recommend that it is not used with other biologics," says lead researcher, Lara Maxwell, of the Institute of Population Health at the University of Ottawa in Ontario, Canada.



"There is a need for more long term studies to determine whether the drug is safe and the effect sustained over longer periods. Better designed studies in the future are likely to have a longer follow-up and high retention rates, and it would be useful to conduct trials of one biologic versus another."



Source:
Jennifer Beal


Wiley-Blackwell

Adalimumab Proves Effective For Children With Juvenile Rheumatoid Arthritis

Adalimumab, an injectable anti-TNF therapy that has FDA approval for treating rheumatoid arthritis in adults, has proven effective in children with juvenile rheumatoid arthritis, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Washington, DC.


The immunosuppressant adalimumab, currently used to treat adults with moderate to severe rheumatoid arthritis, targets inflammation by blocking TNF (tumor necrosis factor) proteins in the body. Following studies that demonstrated safety and effectiveness in adults with rheumatoid arthritis, this study in children with juvenile rheumatoid arthritis was performed. Juvenile rheumatoid arthritis affects an estimated 285,000 children in the U.S. The disease, which starts before they reach age 16, can cause joint stiffness, reluctance or refusal to use arms or legs, reduced activity levels, persistent pain and joint swelling. If not effectively treated, it can result in joint damage, growth delay and decreased bone mineralization.


To assess the long-term effectiveness and safety of adalimumab in a younger population, researchers conducted a 48-week randomized study on 171 children, ages 4 to 17, with five or more swollen joints and three or more joints with limited range of motion at the outset of the study. The subjects were categorized as those taking and not taking methotrexate at the beginning of the study. The dose of methotrexate and all other arthritis medications remained stable throughout the trial. Adalimumab doses were based on the child's size, with participants receiving 24 mg/M2 BSA, maximum of 40 mg, given as a subcutaneous injection every 2 weeks over a 16-week period. At the end of the 16 weeks, the 83% (142) of the subjects who met the definition of "responder" for this study were randomized into a double-blind study and assigned to either continue adalimumab or switch to a placebo for the next 32 weeks or until disease flare-up.


Results demonstrated that participants receiving adalimumab had significantly fewer disease flares than those on placebo. Of those not already taking methotrexate, 43% randomized to adalimumab and 71% to placebo flared; of those already on methotrexate, 37% and 65%, respectively flared. The most common problems were mild upper respiratory infections. No tuberculosis or opportunistic infections were reported.


"Based on this data, adalimumab taken with or without methotrexate provided rapid, substantial and sustainable improvement for children with very active juvenile rheumatoid arthritis," explains Daniel J. Lovell, MD, MPH, Chairman, Pediatric Rheumatology Collaborative Study Group, Cincinnati, Ohio and an investigator in the study. "Given that the medication was generally well tolerated, adalimumab has emerged as an excellent treatment option for children with juvenile rheumatoid arthritis."















The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see rheumatology/annual.


Presentation Number: 659


Long-Term Efficacy and Safety of Adalimumab in Children with Juvenile Rheumatoid Arthritis (JRA): 48-Week Results


D. J. Lovell1, N. Ruperto2, L. Jung1, A. Reiff3, D. Nemcova2, K. Jarosova2, A. Prieur2, C. Sandborg1, J. Rovensky2, J. Bohnsack1, K. Minden2, L. Wagner Weiner1, R. Vehe1, G. Horneff2, J. Medich4, E. H. Giannini1, A. Martini2. 1PRCSG, Cincinnati, OH; 2PRINTO-IRCCS G Gaslini, Genova, Italy; 3Children's Hospital of Los Angeles, Los Angeles, CA; 4Abbott, Parsipanny, NJ


PURPOSE: This analysis evaluated long-term efficacy and safety of adalimumab (ADA) in pts with JRA.


METHODS: A multi-center, Phase III, randomized, double-blind (DB), placebo (PBO)-controlled withdrawal study was conducted in 171 polyarticular-course JRA pts 4-17 years old with >5 swollen joints and >3 joints with limitation of motion at baseline. At the end of a 16-wk OL phase, pts demonstrating an ACR Ped 30 response were randomized (DB) to either ADA 24 mg /m2 BSA (max 40 mg/dose) or PBO sc eow for an additional 32 wks or until disease flare (primary endpoint). Disease flare criteria were 1) worsening of >30% from baseline in >3 of 6 ACR Ped core criteria, 2) >2 active joints, and 3) improvement of >30% in no more than 1 of the 6 criteria. After 32 wks or at time of flare in DB, pts were allowed to receive OL ADA. Randomization was stratified by use of concomitant MTX. Efficacy and safety assessments were collected at regular intervals.


RESULTS: At the end of the 16-wk OL phase, the % of pts showing ACR Ped 30/50/70 response were 83/74/52. A total of 133 pts entered the DB phase (female, 77%, mean age, 11.2 years, and 65% taking MTX). Only 4% of those entering the DB dropped out (1 protocol violation, 1 withdrew consent, 3 other). In the DB, pts receiving ADA had significantly fewer disease flares than PBO, both without MTX (43.3% vs. 71.4%, p=0.031, primary endpoint) and with MTX (36.8% vs. 64.9%, p=0.015). In ADA pts, ACR30/50/70 responses at Wk 48 (end of DB period) were significantly greater than those in PBO pts (table). Pts who flared in the DB still had good ACR response rates (ACR30/50/70 of 73/61/24) at the time of flare because of stringent flare criteria. Most common AEs were infections (mostly mild upper respiratory). Four ADA and two PBO pts experienced SAEs during the DB phase. No TB or opportunistic infections were reported.


Pediatric ACR Responders at Week 48

ADA PBO

(n=68) (n=65)

ACR30 60%* 35%

ACR50 59%* 35%

ACR70 56%* 28%


p

Celecoxib Increases Risk Of Heart Attack, New Study Finds

A study published in the March issue of the Journal of the Royal Society of Medicine, has found celecoxib increases the risk of a heart attack by over two-fold.



Celecoxib is the most commonly used COX-2 inhibitor drug in the treatment of arthritis and acute pain. It is manufactured by Pfizer and marketed under the brand name Celebrex.



"Our evidence shows an increased risk of heart attack in patients taking celecoxib," said Professor Richard Beasley of New Zealand's Medical Research Institute.



"Drug regulatory authorities need to urgently re-examine the assessment of the drug in light of these findings."



Cyclooxygenase-2 (COX-2) inhibitor drugs are popular analgesics as they have fewer gastrointestinal side effects than traditional NSAIDs like ibuprofen and diclofenac. However, the extent to which use of COX-2 inhibitors increase the risk of cardiovascular events has been the subject of considerable debate in the last two years.



Rofecoxib, also a COX-2 inhibitor drug, was manufactured by drug company Merck under the name Vioxx but voluntarily withdrawn worldwide following evidence linking it to an increase in the risk of heart attacks and stroke.



Professor Beasley undertook a systematic review and meta-analysis of randomized double-blind clinical trials of celecoxib of at least six weeks' duration and which presented data on serious cardiovascular events.



Specifically, the researchers examined whether the increased risk of cardiovascular events with rofecoxib was also present with celecoxib and thus represented a class effect of COX-2 inhibitors.



Four placebo-controlled trials with 4422 patients were included in the primary meta-analysis comparing celecoxib with placebo. The findings show the use of celecoxib was associated with a 2.26-fold increased risk of myocardial infarction when compared to a placebo.



The second meta-analysis included a total of six studies of 12,780 patients and demonstrated a 1.88-fold increased risk of myocardial infarction when celecoxib was compared with all comparator treatment groups including ibuprofen, paracetomol and diclofenac.



"These findings are critical as the risk is similar in magnitude to the 2.24-fold increased risk of heart attack with Vioxx as reported in a comparable meta-analysis," said Professor Beasley.



"Given the popularity of celecoxib in the treatment of arthritis, drug regulators must undertake an up-to-date risk assessment based on the findings presented here."
















Currently, the European Medicines Agency's advice is COX-2 inhibitors should not be used in patients with heart disease or stroke and doctors should use the lowest effective dose of the COX-2 medicine for the shortest possible duration of treatment.



"It will be interesting to see if the drug regulators tighten restrictions and whether celecoxib is now withdrawn as occurred with Vioxx," Professor Beasley said.



JRSM Editor, Kamran Abbasi, said controversy had raged for almost two years about the safety of this class of drug.



"The early warnings on Vioxx went unheeded. We can only hope that clinicians and regulatory authorities around the world will not make the same mistake twice. This is another lesson that wonder drugs often come with a sting in the tail," Dr Abbasi said.



In contrast to the increased risk of myocardial infarction, this study did not identify a corresponding increased risk of cerebrovascular events.




'Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis' by B Caldwell, S Aldington, M Weatherall, P Shirtcliffe and R Beasley is published in the March issue (Vol. 99) of the Journal of the Royal Society of Medicine.



JRSM is the flagship journal of the Royal Society of Medicine. It has been published continuously since 1809. Its Editor is Dr Kamran Abbasi.



Founded in 1805, the Royal Society of Medicine is an independent organisation that promotes the exchange of knowledge, information and ideas in medical science and continued improvement in human health. rsm.ac.uk


View drug information on Vioxx.

Cartilage Repair Hope Offered By Stem Cells Tor Arthritis Sufferers

Research presented at the UK National Stem Cell Network Annual Science Meeting in Edinburgh could offer hope that bone stem cells may be harnessed to repair the damaged cartilage that is one of the main symptoms of osteoarthritis.



Scientists at Cardiff University have successfully identified stem cells within articular cartilage of adults, which although it cannot become any cell in the body like full stem cells, has the ability to derive into chondrocytes - the cells that make up the body's cartilage - in high enough numbers to make treatment a realistic possibility. The team have even been able to identify the cells in people over 75 years of age.



Osteoarthritis affects over 2M people in the UK and occurs when changes in the make up of the body's cartilage causes joints to fail to work properly. At its worse it can cause the break up of cartilage, causing the ends of the bones in the joint to rub against each other. This results in severe pain and deformation of the joint. One current treatment to treat damaged cartilage due to trauma in younger patients is to harvest cartilage cells from neighbouring healthy cartilage and transplant them into the damaged area. Unfortunately, only a limited number of cells can be generated.



The research team, funded by the Arthritis Research Campaign and the Swiss AO Foundation, have identified a progenitor, or a partially derived stem cell in bovine cartilage that can be turned into can be turned into a chondrocyte in culture. Their breakthrough came in identifying a similar cell in human cartilage that was more like a stem cell with characteristics that they could be used to treat cartilage lesions due to trauma but also mark the onset of osteoarthritis



Lead researcher Professor Charlie Archer from the Cardiff School of Biosciences said: "We have identified a cell which when grown in the lab can produce enough of a person's own cartilage that it could be effectively transplanted. There are limitations in trying to transplant a patient's existing cartilage cells but by culturing it from a resident stem cell we believe we can overcome this limitation.



"This research could have real benefits for arthritis sufferers and especially younger active patients with cartilage lesions that can progress to whole scale osteoarthritis."



Prof Archer commented: "We have embarked on the next stage which is to conduct and animal trial which is a necessary pre-requisite to a clinical trial which we hope to start next year if the results are positive"







This research was presented at the UK National Stem Cell Network Inaugural Science Meeting at the Edinburgh Conference Centre on 11 April 2008.



The conference is a showcase of the best and latest UK stem cell science across all stem cell disciplines.



The UK National Stem Cell Network acts as a network of the existing regional stem cell networks in the UK, to bring coordination and coherence to a range of national and regional activities in the field of stem cell research.



The UKNSCN secretariat receives financial support from four of the UK Research Councils:
Biotechnology and Biological Sciences Research Council (BBSRC)


Economic and Social Research Council (ESRC)


Engineering and Physical Sciences Research Council (EPSRC)


Medical Research Council (MRC)

The Network represents the UK stem cell research community and is run through an independent Steering Committee. Initially, the secretariat is operated by BBSRC on behalf of all the Government sponsors of stem cell research, including the Research Councils, the Department of Health and the Department for Innovation, Universities and Skills.



Source: Matt Goode


Biotechnology and Biological Sciences Research Council

Activity The Key To Managing Arthritis

"University of Queensland" researchers have shown for the first time older women who exercise are more likely to not get stiff or painful joints.


The landmark study, published in the journal Arthritis Research & Therapy, shows women in their 70s could avoid the pain of arthritis by keeping active.


Dr Kristi Heesch, Dr Yvette Miller and Professor Wendy Brown from UQ's "School of Human Movement Studies" , have used data collected over three years as part of the Australian Longitudinal Study on Women's Health, targeting middle-aged and older women who had no symptoms of arthritis.


"What we found is if women in their 70s can do as little as 75 minutes of moderate physical activity a week, they will lessen their chances of developing frequent arthritis symptoms for three years," Dr Heesch said.


"The results also suggest that engaging in at least 150 minutes of moderate-intensity physical activity per week may be even more protective.


"Our results are the first to show a dose - response relationship between physical activity and arthritis symptoms in older women."


Dr Heesch said arthritis was a debilitating health problem, which is more likely to strike as people got older and affects more women than men.


"Arthritis is almost as common as cardiovascular disease in Australia, affecting 17 percent of the population," she said.


"If preventive intervention strategies, such as increasing physical activity participation by even small amounts, could delay the onset and development of symptoms of arthritis, there could be considerable cost savings to the healthcare system and to older women themselves, not to mention reductions in pain and suffering caused by this often debilitating health problem.


She said the study also looked at middle-aged women but there seemed to be no similar advantage in women of that age.


"We were surprised to find such a difference between middle-aged and older women," she said.


"One explanation is that occupational physical activity was not included in our assessment of physical activity and that many women in the mid-age cohort of the study were in paid work, whereas the older women were not."


Dr Heesch said her team is doing further research into the link between physical activity and self-reported diagnosis or treatment for arthritis.


uq.au

Tocilizumab Provides Significant Clinical Benefit In Rheumatoid Arthritis Patients

The investigational compound tocilizumab (ActemraTM) significantly reduces disease activity in patients with moderate to severe rheumatoid arthritis (RA) who have an inadequate response to methotrexate, researchers announced at the European League Against Rheumatism (EULAR) 2007.


Josef Smolen, MD, chairman of the rheumatology department at the Medical University of Vienna, reported findings in 623 patients who had been randomized to receive tocilizumab 8 mg/kg, tocilizumab 4 mg/kg, or placebo, administered by intravenous infusion every four weeks. Tocilizumab is a novel monoclonal antibody targeting interleukin (IL)-6 signaling.


All patients enrolled in the study had moderate to severe active RA despite long- term metrotrexate treatment.


Participants in the trial continued to receive concomitant oral or parenteral methotrexate at their pre-study dose of 10 to 25 mg weekly throughout the trial and stopped all other disease-modifying anti-rheumatic drugs upon entry into the study.


The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at 24 weeks.


Results of the phase III tOcilizumab Pivotal Trial in methotrexate Inadequate respONders (OPTION) trial showed that 58.5% of patients in the 8 mg/kg group and 47.9% in the 4 mg/kg group achieved ACR20 responses at week 24 compared with 26.5% in the placebo group.


Also, 22% who received tocilizumab 8 mg/kg achieved ACR70, and 43.9% achieved ACR50. Only 2% of the placebo cohort achieved ACR70, and 10.8% achieved ACR50.


The analysis also showed a decrease in the Disease Activity Score in 28 joints (DAS28) starting the second week. At 24 weeks, the mean DAS28 score was reduced by 3.43 in the 8 mg/kg tocilizumab group, 2.63 in the 4 mg/kg tocilizumab group, and 1.55 in the placebo group.


Both doses of tocilizumab were generally well tolerated, and there was a similar rate of adverse events in the three study groups. The incidence of infections was slightly higher than with placebo but no incidence of tuberculosis was observed.


"Overall, the results show that tocilizumab in combination with methotrexate provides rapid and significant improvements in the signs and symptoms of RA," Dr. Smolen said.


He added that the high efficacy of Il-6 receptor inhibition with tocilizumab confirms the critical role of Il-6 in the pathophysiology of RA.


By Jill Stein

Jillstein03cs

Double Trouble For Rheumatoid Arthritis Patients: PLC-gamma-2 Regulates Osteoclastogenesis And B Cell Differentiation

Rheumatoid arthritis (RA) is best known as a chronic inflammatory disease caused by the immune system inappropriately attacking the joints. However, the autoimmune response also leads to the recruitment and/or differentiation of cells known as osteoclasts -- which are cells that degrade and resorb bone. Current treatments for patients with RA target either the joint-specific immune response or the osteoclast-mediated bone erosion.



Now, in a study appearing online on October 19 in advance of publication in the November print issue of the Journal of Clinical Investigation, researchers from Washington University have shown that the protein PLC-gamma-2, which was already known to regulate the differentiation of B cells (one of the immune cells crucial to the autoimmune response seen in RA), is required for normal osteoclast development and function in mice. Roberta Faccio and colleagues therefore suggest that targeting PLC-gamma-2 might lead to control of both the immune-mediated joint destruction and osteoclast-mediated bone erosion seen in RA.







TITLE: PLC-gamma-2 regulates osteoclastogenesis via its interaction with ITAM proteins and GAB2



AUTHOR CONTACT:

Roberta Faccio

Washington University School of Medicine, St. Louis, Missouri, USA.



Contact: Karen Honey


Journal of Clinical Investigation

Vioxx Heart Risk Persists One Year After Stopping Use

A new international study found that Merck's pain killer Vioxx (rofecoxib), which the drug company voluntarily withdrew from the market in 2004, found
that a near two-fold increased risk of heart, stroke and death persisted for up to one year after stopping use.


The study was the work of Dr Robert Bresalier, a professor of medicine at the MD Anderson Cancer Center in Houston, Texas, and colleagues from other research
centres in the US, Canada, Spain and the UK, is published in the 14 October 2008 issue of The Lancet.


In this latest study, Bresalier and colleagues found that the "risk was increased close to twofold, and the risk persisted for approximately a year",
according to a statement reported in the Washington Post.


But, "the good news is that, after a year, the risk seemed to go back down toward normal," Bresalier told the press.


Vioxx (rofecoxib) is a type of non-steroidal anti-inflammatory drug (NSAID). Specifically, it is a cox-2 inhibitor that targets an enzyme involved in
inflammation, the cyclooxygenase 2 (cox-2) enzyme. It was approved by the US Food and Drug Administration in 1999 for the treatment of osteoarthritis, acute
pain conditions, and dysmenorrhoea. But in 2004, Merck withdrew it because of concerns about raised risk of heart attack, stroke and death.


Other less targeted NSAIDs include ibuprofen and naproxen.


Bresalier said that he and other experts believed that all non-aspirin NSAIDs raised the risk of cardiovascular events.


"In fact, it seems to be a class effect for most if not all NSAIDs," said Bresaliers, adding that:


"There is a dose-dependent risk with Celebrex [an NSAID made by Pfizer] as well, whose magnitude was not that much different from Vioxx."


For the study, Bresalier and colleagues followed up participants who took part in the international trial APPROVe that compared Vioxx to placebo for 3 years.
APPROVe was a multicentre, randomized, placebo controlled, double blind trial involving nearly 2,600 patients with a history of colorectal adenomas (growths
or polyps in the colon) who were recruited at 108 centres worldwide during 2000 and 2001.


APPROVe, which was designed to see if Vioxx could reduce the recurrence of colon growths or polyps, was stopped in 2004 because of increased risk of heart
attack and stroke. But Bresalier and colleagues were able to get in touch with 84 per cent of the participants and follow their progress for another year
after their treatment stopped.


The analysis looked for the combined incidence of "non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular, haemorrhagic, and
unknown causes", wrote the authors.















The results showed that a year after they stopped using Vioxx, the participants still carried a 79 per cent higher risk of heart attack, stroke or death
compared to the participants who had been on placebo during the 3 year trial.


The risk of heart attack or stroke for participants on Vioxx during the trial was double that of the participants on placebo for up to year after the trial,
while the risk of death was up by 31 per cent compared to placebo.


Bresalier and colleagues said this was consistent with the increased risk observed in the trial, where the risk of having a cardiovascular event for the
participants taking Vioxx was double that of participants taking placebo.


Merck said in a statement reported by Reuters that:


"Using limited data from a prematurely terminated study needs to be interpreted very cautiously and in the context of the rest of the data from the extensive
clinical development program for Vioxx."


Bresalier and colleagues did find that Vioxx reduced the incidence of colon polyps.


Speaking to the press about NSAIDs, Bresalier said for people taking them only intermittently, for short term pain relief for example, the risk would most
likely be very small. Taking one or two pills is not going likely to give you a heart attack, and for the majority of people taking NSAIDs, they are safe
and effective. But you need to be more careful about taking high doses over a long period:



"If you have a history of cardiovascular disease, speak to your doctor to understand the relative risks and benefits. If you're somebody who really needs to
take these drugs because of chronic pain or severe arthritis, be aware of the issues. But you shouldn't be afraid to take these drugs if you need them," said
Bresalier, according to the Washington Post.


"Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial."

John A Baron, Robert S Sandler, Robert S Bresalier, Angel Lanas, Dion G Morton, Robert Riddell, Erik R Iverson, and David L DeMets.

The Lancet Early Online Publication, 14 October 2008.

DOI:10.1016/S0140-6736(08)61490-7


Click here for
Abstract.


Source: Journal Abstract, Washington Post, Reuters.


Written by: , PhD.




View drug information on Vioxx.

Emisphere Announces Recruitment Phase III Study For Oral Osteoarthritis Treatment

Emisphere
Technologies, Inc. (Nasdaq: EMIS) announced that Novartis Pharma AG
and Nordic Bioscience have completed recruitment for a multi-center Phase
III study exploring the safety and efficacy of an oral formulation of
salmon calcitonin using Emisphere's proprietary Eligen Technology to treat
patients with osteoarthritis of the knee. This study, which will be used to
support the filing with health authorities worldwide, includes more than
1,100 patients between 51 and 80 years old with a medical history and
symptoms of knee osteoarthritis. The study will be conducted mainly in
Europe and is estimated to complete second half 2010.



Osteoarthritis ("OA") is a clinical syndrome in which low-grade
inflammation results in joint pain, caused by a wearing-away of cartilage
that cushions the joints and the destruction or decrease of synovial fluid
that lubricates those joints. As OA progresses, pain can result when the
patient bears weight upon the joints, including walking and standing. OA is
the most common form of arthritis, and affects nearly 21 million people in
the United States, accounting for 25% of visits to primary care physicians,
and half of all non-steroidal anti-inflammatory drug prescriptions. It is
estimated that 80% of the population will have radiographic evidence of OA
by age 65.



"The problems associated with osteoarthritis will escalate as the
population ages," said Michael V. Novinski, President and Chief Executive
Officer of Emisphere. "This Phase III study aims at demonstrating that oral
salmon calcitonin, in combination with our Eligen drug delivery technology,
may contribute to solving this problem, and also shows that Emisphere is a
valuable partner in drug development."



About Emisphere Technologies, Inc.



Emisphere is a biopharmaceutical company that focuses on a unique and
improved delivery of therapeutic molecules using its Eligen Technology.
These molecules and compounds could be currently available or in
development. Such molecules are usually delivered by injection; in many
cases, their benefits are limited due to poor bioavailability, slow on-set
of action or variable absorption. The Eligen Technology can be applied to
the oral route of administration as well other delivery pathways, such as
buccal, rectal, inhalation, intra-vaginal or transdermal. The website is:
emisphere.



Safe Harbor Statement Regarding Forward-looking Statements



The statements in this release and oral statements made by
representatives of Emisphere relating to matters that are not historical
facts (including without limitation those regarding the timing or potential
outcomes of research collaborations or clinical trials, any market that
might develop for any of Emisphere's product candidates and the sufficiency
of Emisphere's cash and other capital resources) are forward-looking
statements that involve risks and uncertainties, including, but not limited
to, the likelihood that future research will prove successful, the
likelihood that any product in the research pipeline will receive
regulatory approval in the United States or abroad, the ability of
Emisphere and/or its partners to develop, manufacture and commercialize
products using Emisphere's drug delivery technology, Emisphere's ability to
fund such efforts with or without partners, and other risks and
uncertainties detailed in Emisphere's filings with the Securities and
Exchange Commission, including those factors discussed under the caption
"Risk Factors" in Emisphere's Annual Report on Form 10-K (file no. 1-10615)
filed on March 13, 2008 and our Quarterly Report on Form 10-Q for the
quarter ended June 30, 2008, filed on August 11, 2008.


Emisphere Technologies, Inc

emisphere

Potential Fix For Damaged Knees Identified By Study

Investigators from Hospital for Special Surgery have shown that a biodegradable scaffold or plug can be used to treat patients with damaged knee cartilage. The study is unique in that it used serial magnetic resonance imaging (MRI) and newer quantitative T2 mapping to examine how the plug incorporated itself into the knee. The research, abstract 8372, was presented during the annual meeting of the American Orthopedic Society for Sports Medicine, June 9-12, in Keystone, Colo.



"The data has been encouraging to support further evaluation of this synthetic scaffold as a cartilage repair technique," said Asheesh Bedi, M.D., a fellow in sports medicine and shoulder surgery at Hospital for Special Surgery who was involved with the study. Dr. Bedi performed analysis of MRI scans of patients primarily treated by Riley Williams, M.D., director of the Institute for Cartilage Repair at Hospital for Special Surgery. "The Trufit plug has been designed to have mechanical properties that are similar to cartilage and bone," Dr. Bedi said.



Damage to so-called articular cartilage can occur in various ways, ranging from direct trauma in a motor vehicle accident to a noncontact, pivoting event on the soccer field. "Articular cartilage lacks the intrinsic properties of healing - you are essentially born with the articular cartilage that you have," Dr. Bedi said. Left untreated, these injuries can increase loads placed on the remaining intact cartilage and increase the risk of progression to degenerative arthritis. One way to treat patients with symptomatic chondral lesions is an OATS procedure, in which cartilage is transferred from one portion of the knee to treat another. Because this is a "robbing Peter to pay Paul" situation, researchers at Hospital for Special Surgery set out to examine whether they could use a biodegradable plug, the Trufit CB plug, to fill the donor site. The goal was to monitor how the plug incorporated itself into the knee and to evaluate the quality of the repair cartilage.



The Trufit plug has two layers. The top layer has properties similar to cartilage and the lower layer has properties similar to bone. The bilayered structure has mechanical properties that approximately match the adjacent cartilage and bone. Surgeons inserted the plug in the knees of 26 patients with donor lesions from OATS procedures and followed up with imaging studies (with MRI and T2-mapping) at various intervals for a period of 39 months.



"Quantitative MRI, when combined with morphologic assessment, allows us to understand the natural history of these repair techniques and define those patients who are most likely to benefit from the surgery," said Hollis Potter, M.D., chief of the Division of Magnetic Resonance Imaging, director of Research in the Department of Radiology and Imaging at Hospital for Special Surgery and lead author of the study. "We gain knowledge about the biology of integration with the host tissue, as well as the repair tissue biochemistry, all by a noninvasive imaging technique."



"What we found was that the plug demonstrated a predictable process of maturation on imaging studies that paralleled the biology of their incorporation," Dr. Bedi said. "With increasing postoperative duration, the repair tissue demonstrated encouraging properties with T2-values that resembled native articular cartilage."



Dr. Williams, Dr. Bedi and other surgeons at Hospital for Special Surgery are involved in ongoing studies to investigate the efficacy of the TruFit plug in treating primary cartilage defects as well. "What is unique about this study is that we have serial MRI with T2 mapping at various time points after surgery, which allows us to really examine the natural history of plug incorporation," Dr. Bedi said.



Dr. Williams believes that there is a role for scaffold-based cartilage repair strategies in the treatment of symptomatic cartilage lesions. "It is our hope that we can successfully treat these cartilage problems over the long term, thus restoring normal knee function and slowing the progression of knee arthritis," Dr. Williams said.



Other authors involved in the study are Li Foong Foo, M.D., and the Cartilage Study Group.



Source:
Phyllis Fisher


Hospital for Special Surgery

European Medicines Agency Recommends Restricted Use For Piroxicam

The European Medicines Agency (EMEA) has recommended restrictions on the
use of piroxicam-containing medicinal products because of the risk of
gastrointestinal side effects and serious skin reactions. The Agency's
Committee for Medicinal Products for Human Use (CHMP) concluded that
piroxicam should no longer be used for treatment of short-term painful
and inflammatory conditions. Piroxicam can still be prescribed for the
symptomatic relief of osteoarthritis, rheumatoid arthritis and
ankylosing spondylitis. However it should not be the first choice of
non-steroidal anti-inflammatory drug (NSAID) treatment in these
conditions.



Prescription of piroxicam should always be initiated by a physician
experienced in the treatment of patients with inflammatory or
degenerative rheumatic diseases and treatment should be used in the
lowest dose (no more than 20 mg per day) and for the shortest duration
possible. In any case, the treatment should be reviewed after the first
14 days of starting.



In addition, the CHMP recommended new contraindications and strengthened
warnings for piroxicam, further details of which are provided in a
separate question-and-answer document.



Topical medicines containing piroxicam are not concerned by these
restrictions.



Further to the request of the European Commission, the CHMP initiated a
full assessment of the benefits and risks of piroxicam in September
2006, because a review of non-selective NSAIDs showed that piroxicam
could be associated with a higher risk of gastrointestinal side effects
and serious skin reactions than other non-selective NSAIDs.



The CHMP recommendations will now be forwarded to the European
Commission for adoption of a legally binding decision, applicable in all
EU Member States.


1. The safety review was conducted in accordance with Article 31 of
the Community code on human medicinal products (Directive 2001/83/EC as
amended).


2. More information about the recommendations for piroxicam is
available in a separate question- and-answer document here
here.


3. A press release announcing the start of the procedure for
piroxicam can be found
here.


4. More information about the review of NSAIDs can be found
here.


5. This press release, together with other information about the
work of the EMEA, may be found on the EMEA website:


European Medicines Agency (EMEA)

Lupus More Severe In Patients With Southern European Ancestry

Systemic lupus erythematosus (SLE) patients with a higher percentage of ancestry from southern Europe have more severe disease manifestations, according to new research presented at EULAR 2008, the Annual Congress of the European League Against Rheumatism in Paris, France.



According to the results of the research, northern European ancestry is shown to be associated with the relatively milder mucocutaneous (skin) manifestations of SLE, whereas southern European ancestry contributes to more severe manifestations of the disorder such as nephritis (inflammation of the kidneys) and increased production of specific autoantibodies (antibodies that fail to recognise and therefore attack the body's own cells, tissues or organs).



SLE is a complex autoimmune disease characterised by chronic inflammation and damage to body tissues, which occurs as a result of the production of abnormal antibodies that target and cause damage to cells of the patient's body, including immune cells. SLE has the potential to affect a variety of areas of the body, including the heart, lungs, kidneys, joints, and/or nervous system. The course of the disease is unpredictable, with periods of illness (called flares) alternating with remission. Lupus can occur at any age but is most common in women, particularly of non-European descent. Until now, the relationship between specific European ancestry and SLE severity has not been studied.



Professor Lindsey A Criswell of the University of California, San Francisco, USA, who led the study, said: "Exploring the ancestry and genetic make-up of patients in relation to their disease today helps us to better understand the complex nature of SLE and why it manifests itself differently in different people. This study shows a clear correlation between specific European ancestry and SLE disease severity and autoantibody production, which may further assist in understanding the risk factors for this condition and should help us better understand and manage this disease in the future."



Researchers in this study examined 1,270 SLE patients from four independent cohorts who had at least 90% European ancestry according to continental ancestry-informative genetic markers. 1,409 genome-wide markers informative for northern versus southern European ancestry were then analysed to estimate the percentage of northern European ancestry for each subject using the STRUCTURE programme. The association between northern European ancestry and specific SLE subphenotypes, including autoantibody production, nephritis, arthritis and mucocutaneous manifestations was then explored.



Northern European ancestry was positively associated with photosensitivity (odds ratio=2.0, p











Abstract number: AB0147



About EULAR
The European League Against Rheumatism (EULAR) is the organisation which represents the patient, health professional and scientific societies of rheumatology of all the European nations.


The aims of EULAR are to reduce the burden of rheumatic diseases on the individual and society and to improve the treatment, prevention and rehabilitation of musculoskeletal diseases. To this end, EULAR fosters excellence in education and research in the field of rheumatology. It promotes the translation of research advances into daily care and fights for the recognition of the needs of people with musculoskeletal diseases by the governing bodies in Europe.


Diseases of bones and joints, such as rheumatoid arthritis and osteoarthritis cause disability in 4 - 5 % of the adult population and are predicted to rise as people live longer.


As new treatments emerge and cellular mechanisms are discovered, EULAR 2008 brings together more than 12,000 experts - scientists, clinicians, healthcare workers, pharmaceutical companies and patients - to share their knowledge in a global endeavour to challenge the pain and disability caused by musculo-skeletal disorders.


To find out more information about the activities of EULAR, visit: eular/

Source: Rory Berrie / Camilla Dormer


European League Against Rheumatism

Patients With Rheumatoid Arthritis Benefit From Gene Therapy

Researchers have reported the first clinical evidence that gene therapy reduces symptoms in patients with rheumatoid arthritis, an important milestone for this promising treatment which has endured a sometimes turbulent past. Described in the February issue of the journal Human Gene Therapy the findings stem from a study of two patients with severe rheumatoid arthritis conducted in Germany and led by an investigator at Beth Israel Deaconess Medical Center (BIDMC).



Originally conceived as a means of treating genetic diseases, such as cystic fibrosis and hemophilia, gene therapy involves implanting a normal gene to compensate for a defective gene in the patient. The first clinical trial to test gene therapy was launched in 1990 for the treatment of a rare, genetic immunodeficiency disease.



"This study helps extend gene therapy research to nongenetic, nonlethal diseases," explains principal investigator Christopher Evans, PhD, Director of the Center for Advanced Orthopaedic Studies at BIDMC. "Rheumatoid arthritis [RA] is an extremely painful condition affecting multiple joints throughout the body. Arthritis is a good target for this treatment because the joint is a closed space into which we can inject genes," adds Evans, who is also the Maurice Muller Professor of Orthopaedic Surgery at Harvard Medical School.



A classic autoimmune disease, RA develops when, for unknown reasons, the body's immune system turns against itself, causing joints to become swollen and inflamed. If the disease is inadequately controlled, the tissues of the joint are eventually destroyed. Although anti-inflammatory agents and biologics can help to mitigate symptoms, there is no cure for the condition, estimated to affect more than 2 million individuals in the U.S. alone.



Evans has spent many years studying the molecules responsible for the breakdown of cartilage in patients with arthritis, identifying interleukin-1 as a good target. But, he adds, once he had this answer, another question was not far behind: How could he effectively reach the joints to block the actions of this protein?



Gene therapy provided the answer.



By implanting a gene in the affected joint, he was able to stimulate production of a human interleukin-1 receptor antagonist protein, which serves to block actions of the interleukin-1 protein.



"The idea is that by remaining in place, the new gene can continuously block the action of the interleukin-1 within the joints," says Evans. "In essence, the gene becomes its own little factory, continuously working to alleviate pain and swelling."



In 2005, in a study published in the Proceedings of the National Academy of Sciences (PNAS), Evans and colleagues demonstrated that the IL-1Ra gene could be safely transferred to human joints in patients with RA. In this new paper, the authors aimed to prove that the therapy was not only safe, but that it was of therapeutic benefit.
















Two study subjects were recruited. (The number reduced from six study subjects following severe adverse events in an unrelated gene therapy trial taking place elsewhere, according to Evans.) Both subjects were postmenopausal females under the age of 75 with a diagnosis of advanced rheumatoid arthritis. After tissue was removed from the subjects' knuckle joints, a harmless retrovirus was inserted into the tissue cells, in order to serve as a "vector" to transport the gene into the patients' joints. After being placed in culture to grow and replicate, the cells were injected back into the afflicted joints.



After four weeks, patients reported reduced pain and swelling, according to Evans. "In one of the two subjects, these effects were dramatic, and the gene-treated joints remained pain-free even though other joints experience flares." Subsequent laboratory tests showed that tissues removed from the subject's joint tissue synthesized lower amounts of disease-related proteins, confirming that the reduction in pain and swelling resulted from the actions of the implanted gene.



"Existing treatments for rheumatoid arthritis are costly and need to be administered regularly," says Evans, adding that in addition to risk of side effects, not all patients respond well. "This paper provides us with the first real evidence that painful symptoms can indeed be lessened through gene therapy."



Ongoing work will focus on the use of gene therapy for the treatment of osteoarthritis, as well as rheumatoid arthritis.







This study was funded, in part, by grants from the National Institutes of Health and Orthogen, a German biotechnology company.



Study coauthors include Peter Wehling, Julio Reinecke, Axel Baltzer, Marcus Granrath, Klaus Schulitz, Carl Schultz, and Rudiger Krauspe of the University of Dusseldorf School of Medicine, Germany; Theresa Whiteside, Elaine Elder and Paul Robbins of the University of Pittsburgh School of Medicine; and Steven Ghivizzani of the University of Florida College of Medicine.



Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks in the top four in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit bidmc.



Source: Bonnie Prescott


Beth Israel Deaconess Medical Center

Novel Drugs Selectively Target Pathway Important In Rheumatoid Arthritis

Methotrexate (MTX), a folate antagonist that blocks folic acid activity, is the most widely used disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It enters the cell via several pathways, one of which involves folate receptor ?? (FR??), which is highly specific for cells present in the joints of patients with rheumatoid arthritis (RA). During the last two decades, a second generation of folate antagonists has been designed to address some of the limitations of MTX, which include adverse side effects and resistance. A new study examined the capacity of several of these new drugs to determine whether they could selectively target cells that express FR??. The study was published in the January issue of Arthritis & Rheumatism (www3.interscience.wiley/journal/76509746/home).



Led by Gerrit Jansen of the VU University Medical Center in Amsterdam, researchers analyzed FR?? expression from biopsy samples from the knee joints of RA patients before and after four months of treatment with MTX and from controls. These experiments confirmed that FR?? expression is highly specific to activated macrophages (a type of immune cell that plays a role in the inflammatory response in RA) in the synovial membrane of RA patients.



The researchers went on to examine new folate antagonists to determine which ones would most likely be beneficial in treating synovial inflammation. Several of these agents showed a markedly higher binding affinity for FR?? compared to MTX, which has a high affinity for entering cells via another pathway known as reduced folate carrier (RFC). This pathway is found throughout the body, however, and is therefore not specific for synovial cells. Researchers also examined whether two of the newer drugs would inhibit growth of FR??-expressing cells and found that one of them, BCG 945, accomplished this at low concentrations. Interestingly, the uptake of BCG 945 was inhibited by the addition of folic acid. "In this context, it may be anticipated that, for example, fortification of food with folate may reduce the activity of this folate antagonist, whereas restriction in dietary folate intake could further enhance the therapeutic efficacy of these types of drugs," the authors state. BGC 945 was originally discovered at the Institute of Cancer Research in London, and is now known as ONX 0801. Onyx Pharmaceuticals has an exclusive worldwide license to this compound.



They note that although MTX is the drug of first choice in the treatment of RA, its efficacy can be improved. "Further evaluation of folate antagonists with properties of high binding affinity for FR?? and low affinity for the RFC may pave the road for a more selective targeted therapy of activated synovial macrophages," they conclude.







In an accompanying editorial in the same issue, Christoph Fiehn of the Center for Rheumatic Diseases in Germany notes that folate antagonists remain the key to RA treatment, both now and in the future. "Antifolate drugs that, unlike MTX, are FR??-specific would have a stronger effect on synovial macrophages and a weaker effect on other types of cells that take up MTX by the ubiquitously expressed RFC," he explains. "A higher therapeutic effect and a lower rate of side effects of FR??-specific antifolates as compared with MTX could possibly be the result."



Articles: "Folate Receptor ?? as a Potential Delivery Route for Novel Folate Antagonists to Macrophages in the Synovial Tissue of Rheumatoid Arthritis Patients," Joost W. van der Heijden, Ruud Oerlemans, Ben A.C. Dijkmans, Huiling Qi, Conny J. van der Laken, Willem F. Lems, Ann L. Jackman, Maarten C. Kraan, Paul P. Tak, Manohar Ratnam, Gerrit Jansen, Arthritis & Rheumatism, January 2009; 60:1; pp.12-21.



"The Future of Folic Acid Antagonist Therapy in Rheumatoid Arthritis," Christoph Fiehn, Arthritis & Rheumatism, January 2009; 60:1; pp. 1-4.



Source: Sean Wagner


Wiley-Blackwell

Genetic Connection Found Between Short Stature And Arthritis

Common genetic variants linked to arthritis may also play a role in human height, a new study shows.



The international study was co-led by the University of Michigan School of Public Health. The journal Nature Genetics published the findings online Jan. 13.



The new study confirms observations by health professionals of a connection between decreased height and increased risk of osteoarthritis, the most common form of arthritis. Researchers speculate that both extremes of height may be associated with osteoarthritis for different reasons. Shorter bones and/or less cartilage may render the joints more susceptible to damage, while longer bones may produce greater levels of damaging stress on the joints.



The findings are exciting for several reasons, said Gon?§alo Abecasis, assistant professor in the School of Public Health. For one, there are many genes that control height, but only a few associated with osteoarthritis, he said.



"In this case the gene we picked also is important in osteoarthritis and it's actually quite hard to find genes for osteoarthritis," said Abecasis, who co-directed the study with Karen Mohlke of the University of North Carolina. "One of the things we were excited about is you could study (height) in many people, and once you've done that you have a short list of genes that you can then study for what they do in terms of osteoarthritis."



The findings also add to the general understanding of height.



"It is useful to know all genes responsible for height variation, so we are reassured if our baby is shorter than others because he has a collection of "short" alleles on his DNA, and not because he has something wrong, like a metabolism disorder," said Serena Sanna, co-author who worked on the paper as a post-doctoral student in Abecasis' group and who is now at the National Research Council di Cagliari in Italy. Anne Jackson, a research specialist at U-M, is also a co-author.



To arrive at their findings, researchers from the United States and Europe analyzed the genomes of more than 35,000 people. If there were average height differences for individuals with certain genetic variants, this indicated that something in that genomic region containing the variants likely influenced height. In this particular study, researchers initially examined the effects of more than 2 million genetic variants.



The new variant accounts for less than 1 percent of the genetic basis of height, and is associated with an average difference in height of about 0.4 centimeters, or a little more than an eighth of an inch. The range went from 0.3 cm to 1.4 cm, depending on the population and whether an individual had one or two copies of the so-called taller version of the variant. A variety of factors, including genetics, diet and prenatal environment, interact to determine how tall someone grows. It is currently thought that genetic factors are responsible for at least 80 percent of the variation in height among people.
















The variants most strongly associated with height lie in a region of the human genome thought to influence expression of a gene for growth differentiation factor 5, called GDF5, which is a protein involved in the development of cartilage in the legs and other long bones. Rare variants in the GDF5 gene have been associated with disorders of skeletal development, and more common variants recently have been tied to susceptibility to osteoarthritis of the hip and knees in Asian and European populations.



The completion of the map of human genetic variation, or HapMap, has fueled a surge in this type of genome-wide association study, with most of the growth coming in the past 10 months. Researchers around the globe have now associated more than 60 common DNA variants with the risk of more than 20 common diseases or related traits.







The research received major support from National Human Genome Research Institute, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, and the National Heart, Lung and Blood Institute, all of which are part of the National Institutes of Health.



For more on Abecasis, visit: sph.umich/csg/abecasis/.



For more on the School of Public Health, visit: sph.umich/.



The University of Michigan School of Public Health has been working to promote health and prevent disease since 1941, and is consistently ranked among the top five public health schools in the nation. Faculty and students in the school's five academic departments and dozens of collaborative centers and initiatives are forging new solutions to the complex health challenges of today, including chronic disease, health care quality and finance, emerging genetic technologies, climate change, socioeconomic inequalities and their impact on health, infectious disease and the globalization of health. Whether making new discoveries in the lab or researching and educating in the field, our faculty, students and alumni are deployed around the globe to promote and protect our health.



Source: Laura Bailey


University of Michigan

Evidence Of Benefit Lacking For Many Common Ways Of Treating Osteoarthritis Of The Knee

A new scientific review released by HHS' Agency for Healthcare Research and Quality concludes that evidence of benefit is lacking for many common ways of treating osteoarthritis of the knee, including popular dietary supplement ingredients, a common surgical procedure, and injected preparations.


The review found that glucosamine and chondroitin, over-the-counter dietary supplement ingredients that are used widely because of their purported benefits to relieve knee pain caused by osteoarthritis and improve physical functioning, appear to be no more effective than placebos. A placebo is a harmless substance given to selected patients in a clinical trial that looks like the real drug or injection being studied, but which has no medical effect.


The review, which was requested and funded by HHS' Centers for Disease Control and Prevention, also failed to find convincing evidence of benefit from arthroscopic surgery to clean the knee joint with or without removal of debris and loose cartilage.


Published studies generally report that injections with hyaluronan preparations (substances that are intended to improve lubrication of the knee joint) improve scores on patient questionnaires used to measure pain and function. However, the evidence is uncertain because of variation in study quality and difficulty determining whether changes in scores translate into real clinical improvements for patients.


"Millions of Americans seek relief from the pain and reduced mobility caused by osteoarthritis of the knee," said AHRQ Director Carolyn M. Clancy, M.D. "However, they should work with their clinicians to decide the best course of treatment for them based on what has and has not been proven to work."


Osteoarthritis is a widespread, costly disease that wears away the cartilage cushioning the knee joint, causing pain and reducing mobility. Arthritic diseases, which include osteoarthritis, affect an estimated 46 million people in the United States, and at age 64 and older, one in 10 Americans is estimated to have osteoarthritis of the knee. Osteoarthritis and related arthritic conditions cost more than $81 billion a year in medical care, lost wages, and other expenses.


The authors, who were led by David J. Samson, M.S., associate director of the AHRQ-supported Blue Cross and Blue Shield Association Evidence-based Practice Center in Chicago, reviewed findings from 53 randomized clinical trials of glucosamine, chrondroitin, and injections with hyaluronan preparations and 23 studies of arthroscopy. The review scrutinized individual studies concerned with these treatments' effects as well as meta-analyses that analyzed the combined evidence of groups of studies.


According to authors, better quality randomized clinical trials are needed to clarify whether these treatments are beneficial. However, given the aging of the population and increasing prevalence of obesity - both risk factors for osteoarthritis of the knee - "research on new approaches to prevention and treatment of osteoarthritis of the knee should be a high priority."


For a copy of Treatment of Primary and Secondary Osteoarthritis of the Knee, click here.

ahrq

FDA Approves Monthly Injectable Drug For Treating Three Types Of Immune-Related Arthritis

The U.S. Food and Drug Administration today approved Simponi (golimumab), a monthly treatment for adults with moderate-to-severe rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis.


All three conditions are chronic disorders in which the immune system attacks multiple joints, causing stiffness, pain, and restricted motion.


"Today's approval provides another treatment option for patients with these three debilitating disorders," said Bob Rappaport, M.D., director of the Division of Anesthesia, Analgesia, and Rheumatology Products in the FDA's Center for Drug Evaluation and Research. "And the steps we're taking to minimize the risks will give patients the same level of safety protection required for other drugs in its class."


Simponi is injected under the skin. It is intended for use in combination with the immunosuppressant drug methotrexate in patients with rheumatoid arthritis. It also may be used with or without methotrexate for psoriatic arthritis and alone in patients with ankylosing spondylitis, a chronic inflammatory arthritis of the spine.


In clinical trials, patients who received Simponi for one of the three conditions showed improvements in the signs and symptoms common to their form of arthritis.


Simponi is in a class of drugs that target and neutralize tumor necrosis factor-alpha (TNF-?±), a protein that, when overproduced in the body due to chronic inflammatory diseases, can cause inflammation and damage to bones, cartilage and tissue. Like other TNF- ?± blockers, Simponi labeling includes a boxed warning alerting patients and health care professionals to the risk of tuberculosis and invasive fungal infections with use of the drug. The FDA also required a risk evaluation mitigation strategy (REMS) for Simponi, as it required for other TNF-?± blockers. The REMS for Simponi includes a Medication Guide for patients and a communication plan to help prescriber's understand the drug's risks.


The most common adverse reactions to Simponi include upper respiratory tract infection, sore throat and nasal congestion.


Simponi is marketed by Centocor Ortho Biotech Inc., Malvern, Pa.

Source
U.S. Food and Drug Administration


View drug information on Simponi.

Phase II Results For Low-Dose Oral Immune Tolerance Therapy (ARG201) In Systemic Scleroderma Published

arGentis Pharmaceuticals, LLC announced that the Phase II results using highly purified type 1 bovine collagen orally (now known as ARG201) in the treatment of diffuse cutaneous systemic sclerosis (scleroderma - SSc) have been published in the June issue of Arthritis & Rheumatism, a major peer-reviewed rheumatology research journal. Systemic sclerosis is an autoimmune disease causing widespread fibrosis of the skin and internal organs. ARG201 is an immunotherapy that induces low dose oral immune tolerance in SSc patients causing downregulation of the body's autoimmune response. There are no approved treatments for the underlying cause of SSc, which has a median survival of eleven years (Mayes 2004).


The article entitled, "A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Oral Type I Collagen Treatment in Patients With Diffuse Cutaneous Systemic Sclerosis," reviews the results of the 168-patient, twelve center trial in which patients were administered a precise dose of highly purified type 1 collagen or placebo for 12 months with follow up at 15 months. Two prospectively subpopulations, Early Phase SSc patients (diagnosed for ?‰¤ 3 years) and Late Phase SSc patients (diagnosed from 3 to 10 years) were included in the trial due to differences in immunologic function of the two groups. The differences were borne out in the trial results. Late Phase patients had a statistically and clinically significant decrease from baseline in modified-Rodnan Skin Scores (-7.9 units) in the collagen treated patients versus the placebo group (-2.9 units). There was no difference in skin scores in Early Phase patients; although subsequent analysis demonstrated that patients who have been diagnosed as early as 1.75 years diagnosis may benefit from type 1 collagen therapy. The trial also demonstrated a high correlation between Late Phase patients who had significant changes in skin scores and that of other clinical outcomes. There were no adverse events in the trial attributed to the therapy.


Additionally, whether patients had at least 25% improvement in MRSS depended on whether they were Early or Late Phase patients at 12 months (p=0.014) and 15 months (p=0.031). A statistically significant upregulation of IL-10 (p=0.01), a marker for tolerance induction and a potent antifibrotic cytokine, was also seen in treated Late Phase SSc patients at 12 and 15 months.


"This trial delineated both clinically and immunologically the differences between Early Phase and Late Phase diffuse SSc patients," said Arnold E. Postlethwaite, principal investigator. "The reduction in skin scores among the Late Phase patients also demonstrates clinically meaningful improvement for the first time in a large, randomized trial in systemic sclerosis."


ARG201 has been granted orphan status by the U.S. Food and Drug Administration. Phase III trials will begin in the first half of 2009.


About Systemic Sclerosis


Systemic sclerosis (SSc or systemic scleroderma), a type of Scleroderma, is an autoimmune disease causing widespread fibrosis of the skin, lungs and other organs. As SSc progresses, patients suffer increasing difficulties with digestion, breathing, joint pain and often develop pulmonary hypertension. Median survival from diagnosis is eleven years (Mayes, 2004). There are approximately 80,000 SSc patients in the U.S. with similar numbers in the European Union. No therapies are presently available to treat the underlying cause of the disease.


About arGentis


arGentis Pharmaceuticals, LLC is a diversified specialty biopharmaceutical company seeking to license and commercialize therapies with demonstrated proof of concept for chronic diseases. Our pipeline consists of mid- and late-stage platform technologies in both autoimmunity and ophthalmology. ARG201, the company's lead compound for the treatment of systemic sclerosis, will enter Phase III trials in 2009. The ophthalmology pipeline includes three therapies for dry eye syndrome which are uniquely applied to the outer upper and lower eyelids for transdermal delivery to the affected glands.

arGentis Pharmaceuticals, LLC