Identification Of Role For Proteins In Children's Muscle Disease Could Open Up New Treatment Options

A study presented by Mrs. Elisabeth Elst today shows for the first time that a protein - heat shock protein 60 (HSP60) - that is present in chronic inflammations, triggers a response by T-cells (a type of white blood cells that plays a part in the body's own immune response) in children with juvenile dermatomyositis (JDM).



The specific response has earlier been observed in juvenile idiopathic arthritis, but to date, little is known about the role of HSP60 in inflammatory myositis. Inflammatory myositis (IM) is the name given to a group of diseases that cause inflammation in the muscles of the body, which is mediated by the immune system of the body. The main symptoms are pain and weakness and can cause patient disability because of damage to the muscles. The main types of IM are dermatomyositis and polymyositis.



For children, the conditions of myositis are complex and are characterized by muscle damage due to an inflammatory process of the blood vessels that lie under the skin and muscles. Some of the symptoms include skin changes around the eyelids and over the knuckles and finger joints, as well as weakness in muscles, mainly affecting the large muscles around the hips and shoulders resulting in increased difficulty with walking, climbing stairs, getting up from the floor and lifting the arms. The children also often become uncharacteristically miserable and fractious and they may complain of tummy pain.



Heat shock proteins (HSP) are a group of proteins whose expression is increased when the cells are exposed to elevated temperatures. Production of high levels of heat shock proteins can also be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exposure of the cell to toxins (e.g. ethanol, arsenic, and ultraviolet light), or water deprivation.



Mrs. Elst, pediatric immunologist at the University Medical Centre Utrecht, said, "We have shown for the first time that HSP60 plays an active part in the control of the inflammatory process in JDM. Thus, therapy aimed at the expansion of T-cells with regulatory capacities reacting to HSP60 could contribute to disease remission in patients with JDM. This conclusion opens up new perspectives for the understanding and approach for antigens in immunotherapy."







Jim Baxter - Onsite tel: +44 (0) 7900 605652

Jo Spadaccino - Onsite tel: +44 (0) 7773 271930

Mia Gannedahl - Office tel: +44 (0) 20 7331 2325



Abstract number: OP0060



About EULAR



* The European League Against Rheumatism (EULAR) is the organization 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, the 7th Annual European Congress of Rheumatology in Amsterdam (EULAR 2006) brings together more than 10,000 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/.



Contact: Mia Gannedahl

European League Against Rheumatism

Abbott Announces HUMIRA® (adalimumab) Approved In Japan For The Treatment Of Rheumatoid Arthritis

Abbott announced that it has received approval from the Japanese Ministry of Health, Labour and Welfare for HUMIRA® (adalimumab) for the treatment of rheumatoid arthritis in patients with inadequate response to conventional therapy. This approval is the first for HUMIRA in Japan, where Abbott co-developed and will co-market HUMIRA with Eisai Co., Ltd. HUMIRA is now approved in 75 countries for rheumatoid arthritis and other autoimmune disease indications.


"The approval of HUMIRA in Japan is a significant milestone for Abbott," said Glenn Warner, vice president, Pharmaceuticals, Japan, Abbott. "This approval is both good news for Japanese patients and a significant step forward for Abbott in Japan."


HUMIRA is expected to become available to patients in Japan in the coming months, following the standard pricing approval process.


"The clinical studies of HUMIRA in Japanese patients demonstrated the efficacy and safety of this medicine," said Prof. Nobuyuki Miyasaka, M.D., Department of Collagen Disease and Rheumatology, Tokyo Medical and Dental University Graduate School of Medicine, who was involved in the development of HUMIRA for the treatment of rheumatoid arthritis in Japan.


Abbott has submitted an application for approval of HUMIRA for plaque psoriasis, and is also developing HUMIRA in Japan for Crohn's disease, ankylosing spondylitis, juvenile rheumatoid arthritis and ulcerative colitis. Eisai is co-developing and will jointly market these indications with Abbott.
More Information About Rheumatoid Arthritis


Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, joint pain and stiffness, which can lead to long-term joint damage. The joints most commonly affected early in the disease are the smaller joints of the fingers, feet and wrists. The elbows, knees, ankles and hips can also be affected. Although there is no cure for RA, people continue to seek treatments that help alleviate pain and inflammation and slow disease progression.


More information on RA and current treatment options can be found at RA.


Important Safety Information


Globally, prescribing information varies; refer to the individual country product label for complete information.


Serious infections, sepsis, rare cases of tuberculosis (TB), and opportunistic infections, including fatalities, have been reported with the use of TNF antagonists, including HUMIRA. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease could predispose them to infections. Patients must be monitored closely for infections, including tuberculosis, before, during and after treatment with HUMIRA. Treatment should not be initiated in patients with active infections until infections are controlled. HUMIRA should not be used by patients with active TB or other severe infections such as sepsis and opportunistic infections. Patients who develop new infections while using HUMIRA should be monitored closely. HUMIRA should be discontinued if a patient develops a new serious infection until infections are controlled. Physicians should exercise caution when considering use of HUMIRA in patients with a history of recurring infection or with underlying conditions that may predispose patients to infections.















TNF-blocking agents have been associated with reactivation of hepatitis B (HBV) in patients who are chronic carriers of the virus. Some cases have been fatal. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating HUMIRA.


The combinations of HUMIRA and anakinra as well as HUMIRA and abatacept is not recommended.


TNF antagonists, including HUMIRA, have been associated in rare cases with demyelinating disease and serious allergic reactions. Rare reports of pancytopenia including aplastic anemia have been reported with TNF-blocking agents. Adverse events of the haematologic system, including medically significant cytopenia have been infrequently reported with HUMIRA.


More cases of malignancies including lymphoma have been observed among patients receiving a TNF antagonist compared with control patients in clinical trials. The size of the control group and limited duration of the controlled portions of studies precludes the ability to draw firm conclusions. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation. During the long-term open-label trials with HUMIRA, the overall rate of malignancies was similar to what would be expected for an age-, gender- and race-matched general population. With the current knowledge, a possible risk for the development of lymphomas or other malignancies in patients treated with a TNF antagonist cannot be excluded. All patients, and in particular patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of PUVA treatment, should be examined for the presence of non-melanoma skin cancer prior to and during treatment with HUMIRA.


In clinical studies with another TNF antagonist, a higher rate of serious congestive heart failure (CHF) related adverse events including worsening CHF and new onset CHF have been reported. Cases of worsening CHF have also been reported in patients receiving HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. HUMIRA should not be used in patients with moderate or severe heart failure.


The most frequently reported adverse event (?‰?1/10 patients) at least possibly causally related to HUMIRA is injection site reaction (including pain, swelling, redness or pruritus). Other common adverse events (?‰?1/100 patients) at least possibly causally related to HUMIRA include lower respiratory infections (including pneumonia, bronchitis), viral infections (including influenza, herpes infections), candidiasis, bacterial infection (including urinary tract infections), upper respiratory infection, dizziness (including vertigo), headache, neurologic sensation disorders (including paraesthesias), cough, nasopharyngeal pain, diarrhea, abdominal pain, stomatitis and mouth ulceration, nausea, hepatic enzymes increased, rash, pruritus, musculoskeletal pain, pyrexia and fatigue (including asthenia and malaise).


About HUMIRA


HUMIRA is the only fully human monoclonal antibody approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn???s disease and plaque psoriasis (Ps) in the United States and Europe. HUMIRA is also approved for the treatment of juvenile idiopathic arthritis (JIA) in the United States, and review for JIA in Europe is ongoing. Clinical trials are underway evaluating the potential of HUMIRA in ulcerative colitis. To date, HUMIRA has been approved in 75 countries and more than 250,000 people worldwide are currently being treated with HUMIRA.


HUMIRA resembles antibodies normally found in the body. It works by blocking tumor necrosis factor alpha (TNF-?±), a protein that, when produced in excess, plays a central role in the inflammatory responses of many immune-mediated diseases.


In the United States, HUMIRA is approved by the FDA for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA). HUMIRA can be used alone or in combination with methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs). HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older. HUMIRA can be used alone or in combination with MTX. HUMIRA is indicated for reducing the signs and symptoms of active arthritis, inhibiting the progression of structural damage and improving physical function in patients with psoriatic arthritis. HUMIRA can be used alone or in combination with MTX or other DMARDs. HUMIRA is indicted for reducing signs and symptoms in patients with active ankylosing spondylitis. HUMIRA is indicated for reducing the signs and symptoms and inducing and maintaining clinical remission in adults with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab. HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy of phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.


In Europe, HUMIRA, in combination with MTX, is indicated for the treatment of moderate to severe, active RA in adult patients when the response to DMARDs including MTX has been inadequate, and for the treatment of severe, active and progressive RA in adults not previously treated with MTX. HUMIRA can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate. HUMIRA has been shown to reduce the rate of progression of joint damage as measured by x-ray and to improve physical function, when given in combination with MTX.


Also in Europe, HUMIRA is indicated for the treatment of active and progressive PsA in adults when the response to previous DMARD therapy has been inadequate and for the treatment of severe, active AS in adults who have had an inadequate response to conventional therapy. HUMIRA is indicated for treatment of severe, active Crohn's disease, in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. For induction treatment, HUMIRA should be given in combination with corticosteroids. HUMIRA can be given as monotherapy in case of intolerance to corticosteroids or when continued treatment with corticosteroids is inappropriate. HUMIRA is indicated for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA.


Abbott's Commitment to Immunology
Abbott is focused on the discovery and development of innovative treatments for immunologic diseases.


About Abbott


Abbott ( NYSE: ABT) is a global, broad-based health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs more than 68,000 people and markets its products in more than 130 countries. Abbott employs 2,100 people in Japan with offices in Tokyo, Osaka, Fukui, and Chiba.


Abbott

abbott


View drug information on Humira.

Can Blood Samples Predict Arthritic Rheumatism?

Levels of inflammatory proteins, so-called cytokines, are elevated in the blood even before the onset of arthritic rheumatism. This means that such blood samples could be used to predict the development of the disease and thereby make it possible to prevent the pathological process, according to an article by Umea researcher Solbritt Rantapaa Dahlqvist and her associates in the journal Arthritis and Rheumatism.


The research team analyzed blood samples from 86 individuals who donated samples to the Medical Biobank before they developed arthritic rheumatism. Of these, 69 had submitted samples at the time they were developing the disease. Moreover, blood samples were analyzed from 256 population-based matched controls from the Medical Biobank. The concentrations of 30 different cytokines and cytokine-related factors in plasma were measured using a so-called multiplex system.


The results show that individuals that later developed arthritic rheumatism had significantly elevated levels of most cytokines and that these cytokine patterns distinguished them from the control individuals. There was a connection with several different parts of the immune defense and also with specific auto-antibodies, so-called anti-cyclic citrullinated peptide antibodies. The results indicate that several years before individuals develop symptoms of arthritic rheumatism, the immune system is activated and the process that leads to arthritic rheumatism has started.


"Our findings point to the possibility of better predicting the development of arthritic rheumatism and perhaps also of preventing the development of the disease," says Solbritt Rantapaa Dahlqvist.


Arthritic rheumatism is a chronic autoimmune disorder characterized by joint inflammation that ultimately leads to the breakdown of cartilage and bone. The disease is difficult to diagnose early since its symptoms can often be diffuse at first. However, studies have shown that it is important to diagnose and treat the disease early in order to prevent severe joint damage.


Source: Expertanswer

Over 200 Genes Influenced By Vitamin D, Highlighting Links To Disease

The extent to which vitamin D deficiency may increase susceptibility to a wide range of diseases is dramatically highlighted in research just published. Scientists have mapped the points at which vitamin D interacts with our DNA - and identified over two hundred genes that it directly influences. The results are published in the journal Genome Research.



It is estimated that one billion people worldwide do not have sufficient vitamin D. This deficiency is thought to be largely due to insufficient exposure to the sun and in some cases to poor diet. As well as being a well-known risk factor for rickets, there is a growing body of evidence that vitamin D deficiency also increases an individual's susceptibility to autoimmune conditions such as multiple sclerosis (MS), rheumatoid arthritis and type 1 diabetes, as well as certain cancers and even dementia.



Now, in a study whose funders include the Medical Research Council (MRC), the MS Society, the Wellcome Trust and the MS Society of Canada, researchers at the University of Oxford have shown the extent to which vitamin D interacts with our DNA. They used new DNA sequencing technology to create a map of vitamin D receptor binding across the genome. The vitamin D receptor is a protein activated by vitamin D, which attaches itself to DNA and thus influences what proteins are made from our genetic code.



The researchers found 2,776 binding sites for the vitamin D receptor along the length of the genome. These were unusually concentrated near a number of genes associated with susceptibility to autoimmune conditions such as MS, Crohn's disease, systemic lupus erythematosus (or 'lupus') and rheumatoid arthritis, and to cancers such as chronic lymphocytic leukaemia and colorectal cancer.



They also showed that vitamin D had a significant effect on the activity of 229 genes including IRF8, previously associated with MS, and PTPN2, associated with Crohn's disease and type 1 diabetes.



"Our study shows quite dramatically the wide-ranging influence that vitamin D exerts over our health," says Dr Andreas Heger from the MRC Functional Genomics Unit at Oxford, one of the lead authors of the study.
















The first author of the paper, Dr Sreeram Ramagopalan from the Wellcome Trust Centre for Human Genetics, adds: "There is now evidence supporting a role for vitamin D in susceptibility to a host of diseases. Vitamin D supplements during pregnancy and the early years could have a beneficial effect on a child's health in later life. Some countries such as France have instituted this as a routine public health measure."



The main source of vitamin D in the body comes from exposing the skin to sunlight, although a diet of oily fish can provide some of the vitamin. Research has previously suggested that lighter skin colour and hair colour evolved in populations moving to parts of the globe with less sun to optimise production of vitamin D in the body. A lack of vitamin D can affect bone development, leading to rickets; in pregnant mothers, poor bone health can be fatal to both mother and child at birth, hence there are selective pressures in favour of people who are able to produce adequate vitamin D.



This new study supports this hypothesis, having found a significant number of vitamin D receptor binding sites in regions of the genome with genetic changes more commonly found in people of European and Asian descent. It is probable that skin lightening as we migrated out of Africa resulted from the necessity to be able to make more vitamin D and prevent rickets: vitamin D deficiency led to pelvic contraction resulting in increased risk of fatality of both mother and unborn child, effectively ending maternal lineages unable to find ways of increasing availability of the vitamin.



"Vitamin D status is potentially one of the most powerful selective pressures on the genome in relatively recent times," says Professor George Ebers, Action Medical Research Professor of Clinical Neurology and one of the senior authors of the paper. "Our study appears to support this interpretation and it may be we have not had enough time to make all the adaptations we have needed to cope with our northern circumstances."



Source:
Wellcome Trust

Sex -- A Major Predictor Of Remission In Early Rheumatoid Arthritis?

Women with rheumatoid arthritis have significantly less chance of remission than men, finds research published ahead of print in the Annals of the Rheumatic Diseases.



The authors base their findings on almost 700 adults who had been recently diagnosed with rheumatoid arthritis.



Their average age was 58, and they had had their disease for an average of six months. Two thirds of study participants were women, and they tended to be younger than the men.



After two years, the disease had gone into remission in just under four out of 10 study participants. After five years, the proportion in remission was similar, at 38.5%. But only around one in five were in remission at both time points.



Gender was a significant factor in the progress of the disease. At two years, just under a third of the women (32%) were in remission compared with almost half of the men (48%).



By five years, the gap had widened, with just under 31% of women in remission compared with 52% of the men.



Men were more than twice as likely to be in remission as women at both time points.



Women did not have more severe disease than the men initially, but it quickly became more severe and progressed more rapidly than it did among the men.



Differences in how long a person had had the disease, their age, or their drug treatment could not explain the discrepancy in remission rate, say the authors.





Contact: Emma Dickinson


BMJ Specialty Journals

Popular Painkillers Linked To Hospital Admissions For Heart Failure

A British study has shown that nonsteroidal anti-inflammatory (NSAID) drugs raise older patients' risk of a first hospital admission for heart failure by 30%. The study looked at people aged 60-84.


Popular painkillers, such as Nurofen and Voltaren are NSAIDs. This is the third study in less than one year that links NSAIDs to heart risks.


The study found, predictably, that those who had a history of heart failure, obesity, smoking, recent specialist appointments and recent hospital stays, had a higher risk of being admitted to hospital for heart failure for the first time.


You can read about this study in the journal Heart.


The study also found, however, that 14% of those being admitted for heart failure were at the time taking NSAIDs. This compares to 10% of people who would normally be taking an NSAID for that age group.



Older patients who take indomethacin (indocin), a NSAID, are three times as likely to be admitted to hospital for heart failure for the first time.


NSAIDs are most commonly taken by patients with osteoarthritis.


What does this mean in numbers of patients being admitted into hospital? For the 60-84 age group, for every 1000 people taking NSAIDs, it means one extra hospital admission for heart failure. For those over 70 taking NSAIDs, if they have diabetes or hypertension, it could mean an extra three per thousand.


The researchers said that even a small increase in risk can mean an important increase in the workload for public health services.


Their conclusion was that not only do NSAIDs raise the risk for patients with a history of cardiovascular disease, but also people without any history of heart disease.


Many health experts wonder whether NSAIDs should be available so readily in supermarkets.



The FDA is currently reviewing NSAIDs.


With Cox-2 inhibitors, such as Vioxx, taken off the market, patients suffering from osteoarthritis and in need of painkillers will be concerned at these latest findings.


Web site with information on NSAIDs


Written by:




View drug information on Vioxx.

Cigarette Smoking Is A Predictor Of RA And May Negatively Impact On Efficacy Of Anti-TNFs

Smoking cigarettes is a significant risk factor for developing rheumatoid arthritis (RA) and may have a negative impact on the effectiveness of anti-tumour necrosis factor (anti-TNF) inhibitors in RA patients taking these treatments, according to results of two studies presented at EULAR 2010, the Annual Congress of the European League Against Rheumatism in Rome, Italy. A further study has shown that smoking interferes with the expression of several genes which, when over-expressed can contribute to processes which exacerbate disease activity.



Results of a Swedish study1 showed that for both men and women, smoking at the time of study initiation was shown to be a predictor for future diagnosis with RA (Odds Ratio (OR) 1.55 95% CI 1.20-2.01). Socio-economic status also had an impact on the risk of developing RA with "Blue-collar workers" (those who do manual labour and earn an hourly wage) having an increased risk compared with white-collar workers (salaried professionals or educated workers) (OR 1.41: CI 1.02-1.94).



"The results of our study have confirmed that whether or not an individual smokes cigarettes, and the type of job that they do are surprisingly robust predictors of developing RA," said Dr Ulf Bergstr?¶m, Department of Rheumatology, Sk??ne University Hospital, Malm?¶, Sweden, and lead author of the first study. "Investigating the impact of socio-economic factors on the development of RA could help us to understand disease mechanisms and identify preventative strategies in the future."



Results of a second Swedish study2 showed that smoking predicted a poor response to anti-TNFs, as measured by two indices of disease activity: ???A 'poor' EULAR response (based on the assessment of disease activity) at 3 months (OR 0.53, (95% CI 0.32-0.87), p=0.012) ???A poor Simplified Disease Activity Index (SDAI) response at 6 months (OR 0.45 (CI 0.27-0.77), p=0.0003) and at 6 months (OR 0.47, (CI 0.25-0.88), p=0.02). Results of one further study undertaken in Switzerland3 showed that in experimental mice, the presence of smoke in the air induced the expression of the following genes:

A 2.3 fold (p=0.02) induction of the expression of vascular endothelial growth factor (VEGF) was seen. VEGF is a growth signal that, when over-expressed, can stimulate the over-production of new blood vessels which can contribute to disease progression.
A 2.7 fold (p=0.03) induction of the heat-shock protein DNAJC6 was seen. Heat shock proteins are induced in response to environmental stress and help to maintain cell function, but can also lead to activation of the immune system.

"The results of our study show that smoking (or the presence of smoke in the air) has an effect on the expression of the same genes and causes modifications in the same proteins in both mouse models and in human beings," said Dr. Caroline Ospelt, Centre of Experimental Rheumatology, University Hospital Zurich, Switzerland. "We hypothesise that this is because smoking alters the ability of certain proteins to elicit an immune response in those with a genetic pre-disposition to rheumatic conditions. This could be a contributing factor to the symptoms experienced and an individual's disease progression."



Study designs and key statistics:
The first Swedish study1 (OP0045) assessed a total of 33,346 individuals who were included in the Swedish Preventive Medicine Program (PMP) between 1974 and 1992 (male n=22,444, female n=10,902; incident RA cases n=296). The median time from inclusion to RA diagnosis was 12 years with a mean age of RA diagnosis at 60 years.
In the second Swedish study2 (OP0014) 934 RA patients from the South Swedish Arthritis Treatment Group responded to a questionnaire sent out in 2005 that covered smoking habits.


In the Swiss study3 (OP0081) investigators compared tissues samples from mice exposed to room air (n=8) compared with cigarette smoke (n=6) with samples from the joints from smoking (n=3) and non smoking (n=5) RA patients undergoing joint replacement surgery. Changes in gene expression were measured using whole genome microarrays and verified using real time Polymerase Chain Reaction (PCR, a DNA amplifying technique), and two assays to determine levels of protein presence - immunoblotting and ELISA (Enzyme-Linked Immuno Sorbent Assay).



Abstract Numbers: OP0014, OP0045, OP0081



Source:

Rory Berrie


European League Against Rheumatism