RxPG News : Rheumatology

Advances in genetics related to ankylosing spondylitis

Sun, 10 Jan 2010 14:50:26 PST

( from http://www.rxpgnews.com ) Work done in part by researchers at The University of Texas Health Science Center at Houston has led to the discovery of two new genes that are implicated in ankylosing spondylitis (AS), an inflammatory and potentially disabling disease. In addition, the international research team pinpointed two areas along stretches of DNA that play an important role in regulating gene activity associated with the arthritic condition.

The findings, a critical milestone in the understanding of AS, are published in the January issue of Nature Genetics, a journal that emphasizes research on the genetic basis for common and complex diseases. "This helps us better understand what is driving this disease and gives us direction for new treatments and diagnostic tests," said John D. Reveille, M.D., the study's principal investigator and professor and director of the Division of Rheumatology and Clinical Immunogenetics at The University of Texas Medical School at Houston.

Reveille, the university's Linda and Ronny Finger Foundation Distinguished Chair in Neuroimmunologic Disorders, and Matthew A. Brown, M.D., professor of immunogenetics at Australia's University of Queensland, led the research by the Triple "A" Spondylitis Consortium Genetic Study (i.e. the TASC or Australo-Anglo-American Spondylitis Consortium). Based on work from a genome-wide association scan, the team identified genes ANTXR2 and IL1R2 as well as two gene deserts, segments of DNA between genes on chromosomes 2 and 21 that are associated with ankylosing spondylitis. Importantly, the study also confirmed the Triple "A" Australo-Anglo-American Spondylitis Consortium's previously reported associations of genes IL23R and ERAP1, formerly known as ARTS1.

Reveille, chief of rheumatology at Memorial Hermann-Texas Medical Center, said the genetic discoveries bring the scientific community closer to fully understanding AS, a chronic form of arthritis that attacks the spine and also can target other joints and organs in the body. The Centers for Disease Control and Prevention for the National Arthritis Data Workgroup estimates that AS and its related diseases affect as many as 2.4 million people in the United States. It generally strikes patients in their teens, 20s or 30s and can cause a complete fusion of the spine, leaving patients unable to straighten and bend.

Steve Haskew, who has lived with AS for more than three decades, said these genetic discoveries offer hope to patients, especially those newly diagnosed.

"When I first started experiencing lower back pain and the aching joints, no one could tell me what was wrong," said Haskew, co-leader of an AS support group. "It's fascinating to see how far we've come and how much has been learned about the disease."

Laurie Savage, co-principal investigator and executive director of the Spondylitis Association of America (SAA) said, "These new breakthroughs are, indeed, good news for those whom we serve. It is very encouraging to know that the health impact and economic consequences of spondyloarthritis in the world eventually will be contained as a direct consequence of the dedication of Drs. Reveille, Brown and colleagues, and that of the many individuals affected by spondyloarthritis who have participated in these studies."

Is Devil's Claw the key to treating arthritis?

Mon, 17 Aug 2009 15:48:01 PST

( from http://www.rxpgnews.com ) Deep in Africa's Kalahari desert lies the Devil's Claw, a plant that may hold the key to effective treatments for arthritis, tendonitis and other illnesses that affect millions each year.

In the US, Devil's Claw extracts are in phase-II clinical trials for the treatment of hip and knee arthritis. Other promising uses are not far behind.

But while the demand for these beneficial compounds is increasing, the supply of natural Devil's Claw is dwindling, thanks to years of drought, which have pushed the plant towards extinction.

Scientists have now successfully reproduced active ingredients in the Devil's Claw. Their technique may eventually lead to the development of 'bio-factories' that could produce huge quantities of rare plant extracts quickly and at little cost.

Milen I. Georgiev, a scientist who organises and teaches environment protection courses and schools in Bulgaria, pointed out that for thousands of years, native populations in southern Africa have used the Devil's Claw as a remedy for a huge number of ailments, including fever, diarrhoea and blood diseases.

Today, there are dozens of medicinal and herbal products around the world that are based on chemicals derived from the plant.

In particular, studies suggest that two chemicals -- iridoid glycosides harpagoside and harpagide -- may have beneficial effects in the treatment of degenerative rheumatoid arthritis, osteoarthritis, tendonitis, and other conditions, Georgiev said.

'In Germany, 57 pharmaceutical products based on Devil's Claw, marketed by 46 different companies, have cumulative sales volumes alone worth more than $40 million,' Georgiev noted.

Currently, more than 25 percent of all prescribed medicines used in the industrialised countries are derived either directly or indirectly from plants, many of which are rare and sometimes endangered.

Hairy root, an infectious plant disease caused by the soil bacteria Agrobacterium rhizogenes, is at the core of a promising new technique that could one day lead to 'biofactories' that produce medicines derived from rare plants in huge quantities at a low cost.

Georgiev notes that hairy roots are a big improvement over traditional, greenhouse-based plant culturing. Georgiev and team are the first to induce hairy root cultures of Devil's Claw.

They took the plant's roots and infected them with the A. rhizogenes soil bacteria -- a natural genetic engineer -- to create a system of hairy roots to produce the plant's key medicinal chemicals, says a release of the American Chemical Society -.

These findings were reported at the 238th national meeting of the ACS.

Clinical studies of Regeneron's ARCALYST (rilonacept) published

Mon, 11 Aug 2008 08:28:01 PST

( from http://www.rxpgnews.com ) Regeneron Pharmaceuticals, Inc. (Nasdaq: REGN) today announced the publication of the results of three studies which supported the U.S. Food and Drug Administration (FDA) regulatory submission for ARCALYST® (rilonacept) Injection for Subcutaneous Use for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS).

Two studies were published in the August 2008 issue of Arthritis and Rheumatism, the flagship publication of the American College of Rheumatology. The first study was the preliminary trial to evaluate the impact of ARCALYST on markers of inflammation, clinical response, and safety and the second was the pivotal efficacy and safety clinical trial of ARCALYST. A third study, conducted to develop and validate a key symptoms assessment scale for CAPS patients and subsequently utilized as the primary endpoint measure in the pivotal clinical study of ARCALYST, was published online in the August 2008 issue of Current Medical Research and Opinion.

ARCALYST, also known as interleukin-1 (IL-1) Trap, is a targeted inhibitor of IL-1, which is the key driver of inflammation in CAPS. ARCALYST is the only therapy approved for patients with CAPS, including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) in adults and children 12 and older. CAPS represent a group of rare, inherited, auto-inflammatory conditions characterized by life-long, recurrent symptoms of rash, fever/chills, joint pain, eye redness/pain, and fatigue. Intermittent, disruptive exacerbations or flares can be triggered at any time by exposure to cooling temperatures, stress, exercise, or other unknown stimuli. The incidence of CAPS has been reported to be approximately one in 1,000,000 people in the United States.

"The ultimate goal of our work over the last ten years has been to find an effective therapy for Cryopyrin-Associated Periodic Syndromes. We began by characterizing the unusual clinical features and debilitating impact of CAPS and then discovered the underlying genetic basis of the disease. A major concern was whether a pharmaceutical company would expend the significant resources necessary to develop a treatment for a disease that has been diagnosed in only a few hundred patients in the United States," stated Hal Hoffman, M.D., Associate Professor, University of California, San Diego and a leading expert on CAPS. "These publications highlight that scientists, clinicians, and industry can collaborate to efficiently, yet rigorously, develop therapies for rare diseases with significant unmet medical need. As a result of this collaboration, patients with CAPS now have an approved treatment available that can help them to effectively manage their disease."

In the initial, open-label pilot evaluation of ARCALYST® (rilonacept), five patients with the Familial Cold Auto-inflammatory Syndrome (FCAS) sub-type of CAPS experienced a marked improvement in symptoms with a corresponding reduction in markers of inflammation. Based upon these convincing findings, a pivotal clinical program was designed to support a registration filing. In order to develop a basis for measuring symptom severity as reported by CAPS patients in a disease that waxes and wanes from day to day, an observational, non-pharmacologic study was conducted in 48 patients with either FCAS or Muckle-Wells Syndrome (MWS). Systematic evaluation of a series of patient-reported outcomes tools resulted in the development of a validated CAPS symptoms measurement instrument with high internal consistency and reliability.

In the pivotal, randomized, double-blind clinical study, 47 patients with FCAS or MWS were randomized to receive either ARCALYST or placebo for six weeks. Patients treated with ARCALYST experienced an 84 percent statistically significant improvement in overall symptom scores versus baseline, whereas those treated with placebo did not experience a significant improvement in their symptoms (13 percent improvement). Ninety-six percent of patients receiving ARCALYST experienced at least a 30 percent improvement in symptoms during this six-week phase of the study. All patients were subsequently given single-blind ARCALYST for nine weeks. Patients were then re-randomized to either ARCALYST or placebo and evaluated over a subsequent nine-week period. Patients remaining on ARCALYST continued to experience symptom control, whereas those receiving placebo experienced a statistically significant worsening of their CAPS symptoms. The most commonly reported adverse reactions reported with ARCALYST were injection-site reaction and upper respiratory tract infection.

"The development process for ARCALYST for the treatment of CAPS highlights Regeneron's overall approach to drug development — to develop drugs targeted at well-documented mediators of disease, focus clinical development on diseases in which those biologic mediators play a primary underlying role, establish clinical proof of concept, and then strive to conduct efficient, pivotal studies with well-validated clinical endpoints," stated George D. Yancopoulos, M.D., Ph.D., President of Regeneron Research Laboratories. "In this case, recognizing that IL-1 is an active mediator of inflammatory disease, we developed ARCALYST to potently inhibit IL-1 in the bloodstream before it can bind to its receptors. Once it was recognized that the genetic mutation associated with CAPS is associated with IL-1 overproduction, we rapidly initiated a pilot study to determine the clinical impact of IL-1 inhibition with ARCALYST. Based upon the clear-cut responses experienced by the CAPS patients in the pilot study, we then developed a validated instrument to assess the severity of CAPS symptoms over time and introduced that instrument into two randomized, placebo-controlled pivotal study phases."

High birth weight - risk for rheumatoid arthritis

Mon, 30 Jun 2008 08:39:49 PST

( from http://www.rxpgnews.com ) People who have a birthweight over 10 pounds are twice as likely to develop rheumatoid arthritis when they are adults compared to individuals born with an average birthweight, according to a study published by researchers from Hospital for Special Surgery online in advance of print in the Annals of the Rheumatic Diseases. While the mechanism for this association is unclear, the study identifies a potentially modifiable risk factor and highlights a potential way to decrease the incidence of the disease.

"There may be a relationship between being born over 10 pounds and getting rheumatoid arthritis later in life," said Lisa Mandl, M.D., MPH, who led the study and is an attending rheumatologist at Hospital for Special Surgery (HSS) in New York City. "If there was some way that you could prevent someone from getting rheumatoid arthritis by making sure their birth weight wasn't over 10 pounds, this is a risk factor that could be modifiable. You can't change someone's age. You can't change someone's gender, but potentially you could change someone's birth weight. This is however only speculative at this point."

Previously, investigators have demonstrated that an increased risk of adult onset chronic disease can be a function of the fetal environment. Strong associations between low birth weight and an increased risk of type 2 diabetes mellitus, coronary heart disease and hypertension have been documented in a number of different populations. Published in 2003, a case-control study of roughly 400 individuals in Sweden identified an association between high birthweight and rheumatoid arthritis.

To see if this association played out in a larger population, Dr. Mandl and colleagues turned to a study of 87,077 women in the Nurses' Health Study. In 1976, nurses were invited to participate in this study that involved a baseline survey and then a biennial questionnaire regarding health status, lifestyle, family medical history and health practices. The investigators excluded women who had cancer or any type of connective tissue disease at baseline or follow-up because these can cause joint swelling, symptoms that can be confused with rheumatoid arthritis. Also excluded were women who reported having rheumatoid arthritis or connective tissue disease during follow-up, but in whom the diagnosis could not be confirmed by review of their medical record. The study population included only women who answered a 1992 survey that collected information about birthweight. After these exclusions, 87,077 individuals were included in the study and 619 of them developed rheumatoid arthritis.

Through statistical analysis, the investigators discovered that a birthweight of greater than 4.54 kg doubled the risk that a person would develop rheumatoid arthritis as an adult compared with individuals who had an average birthweight.

"In utero, the fetus will react appropriately to different stressors. However, this may preprogram the fetus so that when it gets out into the world, this preprogramming is not helpful out in the 'real world'," said Dr. Mandl. In other words, the fetal environment may be preprogramming people's brains or endocrine systems to be maladapted in later life.

"There have now been two different groups, in different countries with different patients born at different times, that both suggest a similar relationship between birthweight and rheumatoid arthritis," said Dr. Mandl. "I hope that other people will think about looking for this association in other populations."

Dr. Mandl says that patients with rheumatoid arthritis are known to have a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, and this axis may be affected in utero. The HPA axis is the body's neuroendocrine system that involves the hypothalamus, pituitary and adrenal glands; this system is responsible for handling stress by regulating the production of cortisol, neurotransmitters and key hormones.

"If you look at this as a theoretic biologic underpinning for why this might be true, it might give basic scientists interesting ideas to think about regarding what causes rheumatoid arthritis, and provide support for a new hypothesis," Dr. Mandl said.

According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, about 2.1 million people, or between 0.5 and 1 percent of the U.S. adult population, have rheumatoid arthritis, an autoimmune disease that causes chronic inflammation of the joints. The disease is more common in women and has no cure, but can be managed in a way that allows individuals to live productive lives.

Adalimumab- in rheumatic patients intolerant/unresponsive to other therapy

Thu, 12 Jun 2008 10:20:03 PST

( from http://www.rxpgnews.com ) Adalimumab therapy is effective and well-tolerated in ankylosing spondylitis (AS), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients with a previously inadequate response to anti-tumour necrosis factor (anti-TNF) therapies etanercept and infliximab, according to results of research presented today at EULAR 2008, the Annual European Congress of Rheumatology in Paris, France. This positive response to adalimumab was greatest for patients who had been intolerant of their anti-TNF therapies, or had lost their initial responses, compared with those who had had no response to prior anti-TNF therapies at all.

After 12 weeks of treatment with adalimumab, AS patients were found to have a mean reduction in BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) of -2.4 following previous etanercept and/or infliximab treatment, and a reduction of -2.9 in those who have not had prior anti-TNF therapy. RA patients had a mean reduction in DAS28 (Disease Activity Scale 28) of -1.9 following previous treatment with either etanercept or infliximab.

Lead researcher, Dr G R Burmester of Berlin University Hospital, commented: "An increasing number of patients with rheumatic diseases, such as AS, RA or PsA, are experiencing an inadequate response to, or are intolerant of, treatment with existing anti-TNFs including etanercept or infliximab. The results of our study show that adalimumab offers new hope for those who have tried, but not responded well, to other treatment options for their diseases."

Ankylosing spondylitis

61% of AS patients who had lost their initial responses to previous anti-TNFs reached ASAS20 (a measure of 20% improvement in 4 domains commonly affected in AS including: pain, inflammation, function, and patient's global assessment of disease activity) after twelve weeks of adalimumab therapy and 42% of patients reached ASAS40 (a 40% improvement across these domains). 54% of patients who had previously been intolerant of their medications reached ASAS20 and 37% reached ASAS40. Of those who had had no response to previous treatment, 41% reached ASAS20, and 27% achieved ASAS40.

Rheumatoid arthritis

66% of RA patients who had lost response to their previous anti-TNF treatment reached ACR20 (American Collage of Rheumatology 20% symptom improvement) after twelve weeks, and 36% reached ACR50 (50% symptom improvement). 67% of previously anti-TNF intolerant patients reached ACR20, and 39% attained ACR50. 51% of patients who had had no response to an anti-TNF in the past reached ACR20, and 26% achieved ACR50.

Psoriatic arthritis

42% of PsA patients who had previously undergone anti-TNF therapy achieved ACR50 and had a mean change in DAS28 of -2.1 after 12 weeks of adalimumab therapy.

About the Trials

Investigators examined patients with a disease duration of 9-12 years who were enrolled into three large, open-label studies: 1,250 AS patients in the RHAPSODY trial, 6,610 RA patients in ReAct, and 442 PsA patients in STEREO. All patients received 40mg adalimumab subcutaneously every other week for 12 weeks, in addition to their current antirheumatic treatment regimens. Patients with prior anti-TNF experience could only enroll into RHAPSODY or STEREO studies if infliximab therapy had been discontinued two months or longer previously and/or etanercept therapy had been discontinued three or more weeks previously. Those who entered the ReAct trial had to have discontinued etanercept and infliximab therapies two months or more prior to the start of the study.

In these three studies, adalimumab appeared to be well-tolerated in patients with prior anti-TNF treatment in all three disease groups.

Stem cells offer cartilage repair hope for arthritis sufferers

Sun, 13 Apr 2008 03:59:37 PST

( from http://www.rxpgnews.com ) Research being presented on 11th April 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”

Fibromyalgia- an indepth look

Mon, 25 Jun 2007 11:49:16 PST

( from http://www.rxpgnews.com ) Fibromyalgia, a chronic, widespread pain in muscles and soft tissues accompanied by fatigue, is a fairly common condition that does not manifest any structural damage in an organ. Twenty-five years ago, Muhammad B. Yunus, MD, and colleagues published the first controlled study of the clinical characteristics of fibromyalgia syndrome. That seminal article, published in Seminars in Arthritis and Rheumatism, led directly to formal recognition of this disease by the medical community. In the June 2007 issue of Seminars in Arthritis and Rheumatism, Dr. Yunus once again makes an enormous contribution to the field of chronic pain and fatigue by meticulously synthesizing and interpreting the extensive body of scientific literature on fibromyalgia and his own insights into the concept of central sensitivity syndromes (CSS).

Fibromyalgia, affecting approximately 2% of the US population, is an example of a class of maladies called CSS. These diseases are based on neurochemical abnormalities and include irritable bowel syndrome, migraine and restless legs syndrome.

Incorporating a critical review of over 225 publications and the authorâs broad experience in fibromyalgia and related diseases, Dr. Yunus describes 13 separate conditions that are related to central sensitization (CS), where the central nervous system (spinal cord and brain) becomes extremely sensitized on certain parts of the body, so that even mild pressure or touch would cause much pain. Such hypersensitivity may also be associated with other symptoms such as poor sleep and fatigue.

According to Dr. Yunus, âCSS are the most common diseases that are based on real neurochemical pathology and cause real pain and suffering. In some patients stress and depression may contribute to the symptoms but they are all based on objective changes in the central nervous system.â

Dr. Norman L. Gottlieb, Editor of Seminars in Arthritis and Rheumatism, believes that this article "advances our understanding of fibromyalgia, unifies and advances concepts, and suggests that this and several other common disorders have much in common in terms of their biopsychosocial development. This, hopefully, will expand both clinical and research interest in this group of diseases and lead to advances in therapy for many of them."

In an accompanying editorial John B. Winfield, MD, comments, "Without question, Muhammad Yunus is the father of our modern view of fibromyalgiaâ¦. Yunus, who took a rather more biological approach to fibromyalgia in the past, now emphasizes a biopsychosocial perspective. In my view, this is tremendously important because it is the only way to synthesize the disparate contributions of such variables as genes and adverse childhood experiences, life stress and distress, posttraumatic stress disorder, mood disorders, self-efficacy for pain control, catastrophizing, coping style, and social support into the evolving picture of central nervous system dysfunction vis-a-vis chronic pain and fatigue â¦.Science and medicine now have a rational scaffolding for understanding and treating chronic pain syndromes previously considered to be 'functional' or 'unexplained.' â¦Neuroscience research will continue to reveal the mechanisms of CS, but only if informed through a biopsychosocial perspective and with the interdisciplinary collaboration of basic scientists, psychologists, sociologists, epidemiologists, and clinicians."

Dr. Yunus concludes that CSS is an important new concept that embraces the biopsychosocial model of disease. He advocates further critical studies to fully test this concept which seems to have important significance for new directions for research and patient care involving physician and patient education. "Each patient, irrespective of diagnosis," says Dr. Yunus, "should be treated as an individual, considering both the biological and psychosocial contributions to his or her symptoms and suffering."

Remicade therapy shown to increase productivity in psoriatic patients

Sat, 03 Feb 2007 06:52:06 PST

( from http://www.rxpgnews.com ) Investigators reported yesterday at the American Academy of Dermatology annual meeting that patients with moderate to severe plaque psoriasis receiving REMICADE® (infliximab) induction and maintenance therapy experienced significant improvements in productivity at week 10, which were sustained through week 50. After 10 weeks, patients receiving REMICADE 3 mg/kg or 5 mg/kg achieved significant improvements in work and daily activities (2.9 and 3.1, respectively, from baseline) compared to little to no improvement (a mean decrease of 0.1) among placebo-treated patients (P < 0.001), as measured by the Productivity Visual Analogue Scale. Psoriasis is an inflammatory disorder characterized by raised, inflamed, red lesions, or plaques, which can cause physical pain and emotional distress. It is estimated that as many as 7.5 million people in the U.S. have psoriasis, which can present in various forms and can range from mild to severe and disabling.

"These findings show a relationship between the significant improvements REMICADE-treated patients experienced in psoriasis and improvements in productivity," said Steven Feldman, M.D., Ph.D., professor of dermatology, pathology and public health sciences, Bowman Gray School of Medicine, Wake Forest University. "Such analyses offer further insight into the impact of this chronic inflammatory disease on patient productivity and the effect of intervening with an appropriate biologic treatment, like REMICADE. We look forward to further studies to identify the economic implications of such productivity analyses in a real-world setting."

In the Evaluation of Infliximab for Psoriasis in a [REMICADE] Efficacy and Safety Study (EXPRESS II), REMICADE-treated patients demonstrated a statistically significant productivity increase of 2.9 and 3.1 in the 3 mg/kg and 5 mg/kg groups, respectively, from baseline compared with a mean decrease of 0.1 with placebo as measured by the Productivity Visual Analogue Scale (P < 0.001). The Productivity Visual Analogue Scale is a 10-cm scale with a score of zero indicating very impaired productivity and a score of 10 indicating no impairment. Baseline productivity scores among the REMICADE 3 mg/kg, REMICADE 5 mg/kg and placebo groups were comparable at 5.7, 5.6 and 5.6, respectively, indicating impaired productivity.

Increased productivity scores paralleled significant improvements in the role-physical domain (RP) and role-emotional domain (RE) scores of SF-36, an eight-domain questionnaire widely used to assess patient health-related quality of life. In EXPRESS II, at baseline, RP scores in the REMICADE 3 mg/kg, REMICADE 5 mg/kg and placebo groups were relatively low compared with the general population (47.5, 46.6 and 44.8, respectively). At week 10, significant mean increases of 4.1 and 5.1 were reported in the REMICADE 3 mg/kg and 5 mg/kg groups, respectively, compared with little increase (0.8) in the placebo group (P < 0.001). At baseline, RE scores were 47.4, 47.8, and 46.4, respectively. At week 10, significant mean increases of 4.8 and 4.4 were reported in the REMICADE 3 mg/kg and 5 mg/kg groups, respectively, compared with little increase (0.9) in the placebo group (P < 0.001).

At 14 weeks, patients in the REMICADE 3 mg/kg and 5 mg/kg induction groups were randomized to receive scheduled treatment every eight weeks or "as-needed" maintenance therapy with REMICADE. Improvement in productivity scores was better maintained in the scheduled dosing groups versus the as-needed dosing group. The greatest productivity improvement through week 50 was seen in the REMICADE 5 mg/kg every-eight-week maintenance group. Additionally, placebo patients who transitioned to REMICADE treatment at week 16 also achieved improvements in productivity through week 50.

Psoriasis is most commonly diagnosed between the ages of 20 and 30, striking in the prime of people's lives, and the extent of skin involvement varies from mild to severe and disabling. People with severe psoriasis may have large areas of their body covered by lesions, which may crack and bleed. The pain and embarrassment associated with such skin lesions may prevent people from participating in social and work-related activities, and the physical and mental effects of psoriasis have been compared to those of other chronic illnesses such as rheumatoid arthritis, hypertension, heart disease, diabetes and depression. Skin lesions associated with psoriasis often result in feelings of sadness, despair, guilt and anger, as well as in low self-esteem. A person's sense of self-worth can be affected, and in some cases, this emotional turmoil can lead to depression.

"This research further illustrates the correlation and impact of psoriasis on work productivity and demonstrates the substantial physical and emotional burdens faced by those living with this life-altering disease," says Gail Zimmerman, president and CEO, National Psoriasis Foundation. "We at the National Psoriasis Foundation encourage continued research and stress the importance of access to effective therapies, which may help manage a disease that often interferes with work and life activities."

In September 2006, REMICADE was approved in the U.S. for the treatment of adult patients with chronic severe (i.e. extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. The recommended dose is an infusion of 5 mg/kg followed by additional doses at two and six weeks after the first infusion and then every eight weeks thereafter.

Acupuncture effective in relieving low back pain, more cost-effective

Fri, 15 Sep 2006 18:04:37 PST

( from http://www.rxpgnews.com ) Acupuncture has a small but significant benefit for patients with low back pain, and appears to be cost-effective in the longer term, find two studies published on bmj.com today.

In the UK, an estimated 16% of the adult population consult their general practitioner for help with back pain in a 12-month period. The annual cost of lower back pain to the NHS has been estimated at £480 million (703million; $901million) and the burden of lower back pain is estimated at over £10 billion per year in terms of lost productivity and sickness benefits.

Acupuncture is used by an estimated 2% of adults each year for a range of conditions, including back pain. But the evidence is largely inconclusive and the best way to manage low back pain remains unclear.

So, researchers identified 241 adults aged 18 to 65 with persistent non-specific low back pain. The people were provided by members of the British Acupuncture Council. Patients were randomly assigned to either usual NHS care or up to 10 acupuncture treatment sessions. All patients remained under GP care.

Pain levels were measured at intervals during the two-year study period. Satisfaction with treatment and use of pain medication were also recorded.

At 12 months, patients in the acupuncture group showed a small benefit in pain scores compared to patients receiving usual care. Stronger evidence was observed for an increased benefit at 24 months.

At three months, patients in the acupuncture group were significantly more likely to be 'very satisfied' with their treatment compared with usual care, and with their overall care, but showed no such difference in satisfaction with information received.

At 24 months, the acupuncture group were more likely to report reduced worry about their back pain, less likely to report current use of pain medication for their back, and more likely to report no pain for the past 12 months.

Although the differences in pain scores between groups were small, they represent a clinically worthwhile benefit and can be viewed as a 'moderate' effect, say the authors.

Further research is needed to investigate the optimum timing for such an acupuncture treatment package, and to assess the value of repeated courses of acupuncture for patients experiencing recurrent episodes of low back pain, they conclude.

In a separate paper, the same researchers looked at the cost effectiveness of acupuncture for lower back pain. Costs were measured from both an NHS and a societal perspective, and effectiveness was measured in terms of quality adjusted life years (QALYs) gained.

They found that total NHS costs during the two-year study period were higher on average for the acupuncture group (£460; 673; $859) than for the usual care group (£345; 506; $644).

However, the cost per QALY gained was £4,241 (6,223; $7,921). This is well below the lower threshold of £20,000 used by the National Institute for Health and Clinical Excellence (NICE) to decide whether the NHS can afford to pay for a health technology.

A short course of traditional acupuncture for the treatment of lower back pain in primary care confers a modest health benefit measured in QALYs for a relatively minor extra NHS cost relative to usual care, say the authors. The use of acupuncture for the treatment of lower back pain therefore appears to be cost-effective in the longer term.

Matrilin-3 gene discovered to prevent onset of osteoarthritis

Mon, 24 Jul 2006 19:16:37 PST

( from http://www.rxpgnews.com ) A gene that is associated with osteoarthritis and skeletal deformities in people has been shown to be responsible for preventing the onset of osteoarthritis in adult mice, according to a recent study led by Rhode Island Hospital. The matrilin-3 gene plays a role in early bone development, controls bone mineral density in adulthood and prevents osteoarthritis later in life.

Mutations in matrilin-3 have previously been linked to certain skeletal disorders and hand osteoarthritis. But this study, reported in the cover article of the August issue of the American Journal of Pathology, is the first to demonstrate that the loss of the gene leads to osteoarthritis, a joint disease that is caused by deterioration of cartilage, and usually occurs later in life.

"Clearly there is a correlation between matrilin-3 and osteoarthritis. Potentially, we could use it as a diagnostic tool or to predict whether someone is likely to develop osteoarthritis," says senior author Qian Chen, PhD, director of cell and molecular biology, and head of orthopaedic biology research at Rhode Island Hospital.

Chen is also a professor of medical science, and holds the Michael G. Ehrlich Chair in Orthopaedic Research, both at Brown Medical School.

The research has also led to an animal model that can be used to study the development of arthritis in real time, Chen says. Previous research has attempted to pinpoint causes of osteoarthritis through other means, such as looking retrospectively at the causes of the disease or inflicting an injury on a joint to mimic a sports injury or trauma.

"In the long term, it helps us understand the mechanism of human osteoarthritis development. Very few molecules have even been associated with osteoarthritis, so this is a huge deal. Now that matrilin-3 has been clearly shown to develop osteoarthritis in an animal model, we can study it further," Chen says.

There are four matrilins, or proteins, that form the extracellular matrix (ECM), which holds cartilage together. Matrilin-1 and -3 are specific to skeleton tissues, while matrilin-2 and -4 are also found in other tissues throughout the body. There has been a link between mutated forms of matrilin-3 and hand osteoarthritis, as well as skeletal disorders such as multiple epiphyseal dysplasia (MED), a disorder that begins in childhood and can include malformation of the hands, feet and knees and abnormal curvature of the spine.

In this study, researchers knocked out matrilin-1 and -3 in mice in order to study their link to osteoarthritis. When matrilin-1 was knocked out, there was no apparent effect. When matrilin-3 was removed, the mice had a normal and fertile lifespan and appeared to have normal skeletal development.

However, without matrilin-3, researchers noticed that during embryonic development, mice developed premature and extended hypertrophy the phase when cells increase in size to form bone. Later in life, those mice had higher bone mineral density (BMD) and higher rates of osteoarthritis. In people, BMD is a hallmark of certain forms of osteoarthritis.

Compared with mice whose genes had not been altered, the mice lacking matrilin-3 showed significantly higher BMD both in the knee joint and throughout the body at 18 weeks of age, the time when mice typically reach peak bone density. Clinical studies in humans have shown that the prevalence of knee and hip osteoarthritis increases with increasing BMD.

"Our study reveals an unexpected property of matrilin-3 in maintaining proper BMD, a factor that was not previously examined," the authors write. "However, the mechanism of the association between increased bone density and joint degeneration is not known. Our data show that matrilin-3 deficiency results in both the increase of BMD and joint cartilage degeneration, thereby connecting these two events together."

Researchers could not make the connection, however, between a lack of matrilin-3 and skeletal disorders, such as MED. The mice lacking matrilin-3 developed a higher incidence of osteoarthritis in adulthood without developing deformities in childhood.

The results challenge one theory of osteoarthritis that the disease is caused by degeneration from an abnormal skeletal structure.

"Our study shows that even in those normal looking skeletons, you still develop osteoarthritis. So there's not necessarily a link between those two," Chen says. "Maybe there's something else that causes it, such as stiff bone."

Osteoarthritis affects more than 20 million Americans and is the most common type of arthritis. It is characterized by a breakdown in cartilage, commonly affecting the knees, hips and lower back. While younger people can develop osteoarthritis from joint injuries, the disease most often occurs in people over 65. The causes of osteoarthritis are not known, but they are believed to be both genetic and environmental such as being overweight or suffering sports injuries.

Cyclophosphamide Improves Breathing for Scleroderma Patients

Mon, 10 Jul 2006 06:43:37 PST

( from http://www.rxpgnews.com ) An oral medication improves overall lung function and reduces lung-related inflammation associated with the deadly skin disease scleroderma, says a researcher at the University of Medicine and Dentistry of New Jersey who was part of a national study.

The 12-month, 13-site clinical trial involved 158 patients treated with the drug cyclophosphamide. The oral medication had a modest but significant effect on the lung functions of scleroderma patients stricken with alveolitis, a chronic inflammation of the lung tissue commonly diagnosed in those with systemic scleroderma, said Dr. Vivien
M. Hsu, a scleroderma specialist at the UMDNJ-Robert Wood Johnson Medical School in New Brunswick and a principal investigator in the study.

Subjects with dyspnea, or breathlessness due to interstitial lung disease, also felt better after being given daily doses of cyclophosphamide for one year, Dr. Hsu said. The study was published recently (June 22, 2006) in the New England Journal of Medicine.

"We used a double-blind, randomized, placebo-controlled clinical trial to determine the drug's ability to suppress labored breathing and restrictive lung physiology in these patients," Dr. Hsu said. "We assessed their pulmonary function every three months to
determine their forced vital capacity regarding breathing, and then closely followed the patients for one year thereafter."

The patients in the study received 2 milligrams per kilogram of body weight each day, or matching placebo, for one year. The forced vital capacity measured in these subjects at the end of two years remained stable in the majority of patients who received cyclophosphamide.

Scleroderma is a rheumatic disease that primarily affects women, and is characterized by skin thickening due to over-production of scar (collagen) and connective tissue. This disease often scars the organs, including the lungs, kidneys, gastro-intestinal tract and heart. Scleroderma frequently can damage the smallest blood vessels leading to
further damage of these vital organs.

The cause of the disease is unknown but it is widely regarded by medical experts as an autoimmune disorder. There are no proven drugs that may reverse the damage due to scleroderma-related interstitial lung disease. Different drugs may be used to treat its manifestations, but patients whose vital organs are attacked and adversely affected by
scleroderma may die from complications of this unpredictable disease.

Rituximab halts damage to joints

Thu, 22 Jun 2006 17:22:37 PST

( from http://www.rxpgnews.com ) New data, presented today at the Annual European Congress of Rheumatology show for the first time that a rheumatoid arthritis (RA) treatment, rituximab, is able to significantly inhibit the structural damage to joints caused by RA in patients who have long-standing disease and an inadequate response to one or more TNF (Tumour Necrosis Factor) inhibitors.

Prevention of joint structural damage in rheumatoid arthritis is a critical therapeutic outcome. Many patients respond well to the TNF inhibitors, a relatively new class of therapy which prevents TNF protein causing inflammation in rheumatoid arthritis, however approximately 30% - 40% of patients treated with this therapy experience either an inadequate response or are intolerant to such therapies. As such, the study was designed to investigate the effect at 1 year of rituximab (a new therapy targeting B-cells cells which create abnormal antibodies causing rheumatoid arthritis symptoms) plus methotrexate (an antimetabolite drug which inhibits the synthesis of DNA, RNA and protein, previously the gold standard in the treatment of rheumatoid arthritis) on joint structural damage, compared to methotrexate alone in rheumatoid patients with inadequate response to one or more TNF inhibitors.

The results reveal bone erosions in patients in the rituximab group were reduced by over half during the course of a year compared to patients receiving placebo (erosion scores of 0.59 and 1.32 respectively), as were the narrowing of joint spaces (scores of 0.41 and 0.99 respectively). In addition the proportion of patients with no change in erosion score was significantly higher in the rituximab group compared to placebo.

"These findings suggest that treatment with rituximab plus methotrexate is associated with significant inhibition of joint structural damage, an important finding in patients who do not currently respond to other treatments" explained Professor Edward Keystone, Rheumatology Department at the University of Toronto, Canada, one of the studies principle investigators. "Stopping joint damage indicates that the disease pathway has been interrupted, a goal we strive for in the treatment of rheumatoid arthritis. As such, today's results have the potential to offer many patients a new hope".

Tocilizumab effective in systemic juvenile idiopathic arthritis (sJIA)

Thu, 22 Jun 2006 16:43:37 PST

( from http://www.rxpgnews.com ) A new study has confirmed significant improvements after treatment with tocilizumab amongst children with systemic juvenile idiopathic arthritis (sJIA), who do not tolerate or have an inadequate response to conventional therapies. Professor Shumpei Yokota presented the encouraging results of the first double-blind, placebo controlled trial for tocilizumab at the Annual European Congress of Rheumatology in Amsterdam today (Thursday 22 June).

Juvenile Idiopathic Arthritis (JIA) is a relatively rare disease, affecting 30 to 150 children per 100,000 per year in Europe.1 "Systemic JIA is a specific type of juvenile idiopathic arthritis and it is one of the most severe types as it affects the whole body and most of the joints. As well as swollen and painful joints, the child has rashes, high fever, is severely lacking in energy and is generally very unwell", said Professor Yokota.

Tocilizumab, previously known as MRA, is currently undergoing phase III trials for moderate to severe adult onset rheumatoid arthritis (RA) as well as sJIA. Tocilizumab blocks the action of a protein, called interleukin 6 (IL-6), which provokes inflammation.

The study presented by Professor Yokota and the research team involved a total of 56 children, 35 of them were female, and the mean age was 8.3 years old. Disease activity was assessed in a number of ways such as number of active joints, number of joints with limitations of motion, physician's/parent's global assessment, two inflammatory disease parameters (ESR and CRP) and through a parental heath assessment questionnaire (CHAQ). 68% of the children had an improvement rate of 70%, while more than 85% had an improvement rate of 50%. Treatment was generally well tolerated, though two patients experienced serious adverse events; one anaphylactoid reaction and one gastrointestinal hemorrhage. Both patients returned to normal after discontinuation of tocilizumab.

"The goals of the treatment for children with arthritis are to relieve pain and inflammation, slow down or prevent the destruction of joints, as well as restore use and function of the joints to promote optimal growth, physical activity, and social and emotional development in the child. This study confirms that tocilizumab is one of the most promising therapies to treat children with sJIA who have not benefited from conventional therapies", said Professor Yokota.

Unfavourable blood fat levels predict rheumatoid arthritis up to 10 years later

Mon, 05 Jun 2006 16:58:37 PST

( from http://www.rxpgnews.com ) An unfavourable ratio of blood fats could herald the development of the inflammatory joint disease rheumatoid arthritis up to 10 years later, suggests research published ahead of print in the Annals of Rheumatic Diseases.

The authors base their findings on analysis of more than 2000 blood samples donated to a blood bank in The Netherlands.

They analysed the fat content of 1078 deep frozen blood samples from 79 people who had given blood between 1984 and 1999 and subsequently went on to develop rheumatoid arthritis 10 or more years later.

In particular, they looked at levels of total cholesterol, high density lipoprotein ('good' cholesterol), triglycerides, apolipoproteins A and B, and lipoprotein (a).

The samples were then compared with those taken from 1071 randomly selected blood donors, matched for age, sex, and storage time.

They found that the samples of people who subsequently developed rheumatoid arthritis had a more unfavourable balance of circulating blood fats than the samples of those who did not develop the disease.

On average, total cholesterol was 4% higher, while high density lipoprotein levels were 9% lower. Triglycerides were 17% higher and apolipoprotein B was 6% higher.

Taken together, these figures also indicate an increased risk of ischaemic heart disease, in which the artery walls are thickened and hardened by fat deposits.

This might help to explain the link between an increased risk of cardiovascular disease among patients with rheumatoid arthritis, say the authors.

And they speculate that a poorer blood fat ratio might make a person more susceptible to inflammation or inflammatory diseases, such as rheumatoid arthritis.

Role of inflammatory leukocytes in extending tissue damage

Sun, 30 Apr 2006 23:28:37 PST

( from http://www.rxpgnews.com ) Documented in extensive studies, backed by the anecdotal evidence of professional athletes, impact injury to joints causes degeneration of cartilage. In most cases, the eventual result is the pain, stiffness, and compromised mobility of osteoarthritis (OA). Yet, questions remain surrounding the role of the inflammatory system in the cartilage destruction following mechanical trauma.

Tissue damage typically stimulates an influx of leukocytes, white blood cells known for promoting tissue regeneration and healing--to tissue protecting organs. However leukocytes can be a double edged sword. In the May 2006 issue of Arthritis & Rheumatism researchers at Baylor College of Medicine and the Michael E DeBakey Veterans Affairs Medical Center in Houston, Texas, present the results of a study to test the hypothesis that leukocytes extend the zone of damage and cell death in cartilage after an acute injury.

The research team began with a collection of dog bones--the hind knee joints of 24 fresh young adult cadaver canines. Within one hour after death, each bone was subjected to impact injury with a metal weight, determined sufficient to cause cartilage damage without shattering the bone. A comparable collection of cadaver canine bones was preserved to serve as controls. All of the knee joints were cultured with blood leukocytes from the same dogCartilage biopsies were taken at various intervals between 12 hours and 7 days.

Among the assaulted bones, approximately half of the chondrocytes, or cartilage cells, died within 7 days. In the uninjured bones, over 90 percent of the chondrocytes survived. A surprising finding was the reduced viability of cartilage cells located well outside the vicinity of direct impact. In cartilage samples taken 6 to 9 mm from the impact site, and even in samples taken 10 mm or more from the impact site, these critical cells to tissue renewal had largely been killed off by leukocytes. The real culprit, however, was the leukocytes' generation of noxious nitric oxide (NO).

Is there a way to stop the leukocyte-mediated murders of chondrocytes? To explore this critical question, the researchers conducted more experiments on the dog bone cultures. They found that the killing of cartilage cells could be averted by desferoxamine, chemical thay=t blocks production of NO, and by anti-CD18 antibodies, which block the Velcro-like adhesion molecules that white cells use to adhere to other cells.

"Our findings have interesting clinical implications," observes the study's leading author, Dr. D. M. Green. "First, we have demonstrated that acute mechanical injury of the articular surface causes death of chondrocytes located at a distance from the site of trauma. Second, up-regulation of adhesion molecules on the affected chondrocytes allows leukocytes to adhere and to extend the zone of injury beyond the impact site. Thus, the data in this study suggest that therapies to reduce acute influx of leukocytes into damaged cartilage should be considered in the future when treating osteochondral injuries."

Rituximab achieves remission in patients resistant to conventional DMARDs

Sun, 30 Apr 2006 23:12:37 PST

( from http://www.rxpgnews.com ) Drugs aimed at suppressing inflammation-provoking cytokines--specifically those linked to T-cells--have improved the treatment of rheumatoid arthritis (RA), a chronic, inflammatory autoimmune disease. Still, the frequency of remission achieved by these biologic agents remains below 50 percent. To increase the success rate of biologic therapy for RA patients, researchers have honed in on a new target: the B cell.

Rituximab, a biologic agent that selectively depletes B cells, has been successfully used to treat non-Hodgkin's lymphoma. It has also been shown to improve disease symptoms for RA patients, when injected at aggressive levels for a two-week period. To investigate this biologic's potential long-term therapeutic value, an international team of scientists set out to compare the effectiveness and safety of different rituximab doses over a 24-week period, with and without steroids. Their study focused on 465 RA patients with moderate to severe symptoms resistant to disease-modifying antirheumatic drugs (DMARDs), including other biologics. The results indicate the promise of low-dose rituximab to achieve remission for RA patients, without serious side effects and without the need for prescribing harsh steroids.

Drawn from outpatient populations in California, Texas, Arizona, Switzerland, Sweden, Poland, and England, the subjects were randomly divided into nine treatment groups. Three groups received a 1,000 mg. dose of rituximab--two infusions two weeks apart--with either intravenous steroid, oral steroid, or placebo. Three groups received a 500 mg. dose of rituximab--two infusions two weeks apart--with either intravenous steroid, oral steroid, or placebo. Three groups received a placebo with either intravenous steroid, oral steroid, or another placebo. All subjects received the DMARD methotrexate (MXT). All subjects were evaluated every four weeks for changes in the Disease Active Score (DAS), a 28-joint assessment for swelling and tenderness, as well as for overall disease improvement, with the goal of meeting the American College of Rheumatology (ACR) 20 percent improvement criteria.

At the 24-week culmination, 54 percent of the subjects in three rituximab 1,000 mg. X 2 groups and 55 percent of the subjects in the three rituximab 500 mg. X 2 groups had achieved the desired ACR20 response, compared with 28 percent of the subjects in the three placebo groups. The different dosages of rituximab did not have a statistically significant impact on the odds of achieving an ACR20 response, and analyses of the proportions of patients who achieved higher ACR improvement scores--50 percent and 70 percent--showed similar patterns. Changes in DAS28 at week 24 reflected the ACR response findings, as did the subjects reports of relief from joint pain and stiffness. What's more, subjects in the rituximab groups showed gains toward disease remission earlier in the course of treatment than subjects in the placebo group.

Steroids, whether received intravenously or orally, showed no significant correlation with disease improvement scores among the rituximab groups. Intravenous steroid, however, showed a positive correlation to improved tolerability during the first rituximab infusion in both dosage groups. Overall, adverse events associated with rituximab were mild and easily managed. Headache was the most common complaint.

Confirming the role of B cells in the inflammatory processes behind RA, this study demonstrates the effectiveness and safety of a unique biologic therapy, in moderate doses and independent of steroids. Yet, as its leading author, Dr. Paul Emery, notes, further studies are needed before applying the results to the routine treatment of RA patients. "Both doses of rituximab explored in this study warrant further differential exploration and longer-term followup," he stresses.

New hope for tissue regeneration and joint repair

Wed, 29 Mar 2006 13:12:37 PST

( from http://www.rxpgnews.com ) Inflammation, cartilage and bone erosions, joint destruction--that's the typical progression of arthritis and most rheumatic diseases. While inflammation may be controlled, and perhaps even eliminated, with early aggressive treatment, few therapeutic approaches offer hope for repairing tissue once the damage has been done. One promising strategy is the use of mesenchymal stem cells (MSCs). MSCs are capable of extensive self-renewal and adaptable to forming all kinds of connective tissues. While detected in several adult human tissues, MSCs have traditionally been obtained from bone marrow, an invasive, painful, and costly process.

Researchers in the United Kingdom and Belgium set out to investigate the characteristics of cells in the periosteum, the dense membrane at the boundary between the bone and the surrounding soft tissues. Their study, featured in the April 2006 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), is the first to identify periosteal cells as MSCs, with multipotent properties at the single cell level and the potential to regenerate cartilage, muscle, and bone in patients with inflammatory and degenerative rheumatic diseases.

Samples of periosteal cells were obtained from the tibia of 12 human donors, ranging in age from 24 to 83 years. Following enzymatic release and culture expansion, cell populations were tested for telltale markers of MSCs, as well as for their growth and differentiation potential. To assess their multipotency beyond the laboratory, the periosteal cells were then injected into one of three animal models: mice, with the goal of muscle regeneration; goats, with the goal of developing cartilage; and mice, with the goal of bone formation.

Regardless of donor age, periosteal cells expanded extensively, steadily maintaining growth curves over at least 30 population doublings. They also displayed the hallmarks of MSCs, including long telomeres, the sections of DNA at the end of a chromosome. What's more, the results of the animal experiments proved that expanded periosteal MSCs can contribute to muscle regeneration and form cartilage when implanted into a joint surface defect. The bone tissue retrieved from the last group of mice was partly human, which indicates the potential of these cells to build bone as well.

"Like MSCs derived from bone marrow, periosteal MSCs rapidly adhere to plastic and can be expanded for several passages, preserving their multipotency," notes study leader Dr. Cosimo De Bari, an MRC clinician scientist and consultant rheumatologist at King's College London, UK. "A small periosteal biopsy represents a relatively easily accessible source of MSCs."

This groundbreaking study calls attention to the need for more research into MSCs--in the periosteum and other tissues--and their practical therapeutic benefits for late-stage arthritis sufferers.

Fighting inflammation with targeted liposomal therapy

Wed, 29 Mar 2006 13:07:37 PST

( from http://www.rxpgnews.com ) Vascular endothelial cells (VECs) form the walls of blood vessels and play a critical role in inflammation. In rheumatoid arthritis (RA), VECs interact with cytokines, proteins that regulate immune response, and allow inflammation to persist, escalate, and progressively damage tissue, and joints. Recognized as potent inflammation inhibitors, corticosteroids work to control the expression of cytokines, adhesion molecules and the growth of endothelial cells. The potential of these drugs, however, has been restricted by their considerable toxicity and short half-life.

To study the impact of corticosteroids on VEC activity, researchers in The Netherlands turned to liposomes, microscopic vesicles used to deliver drugs or genetic material directly into a cell. They chose RGD peptide liposomes to deliver a dose of dexamethasone phosphate (DEXP) to VECs at the site of inflammation in rats with experimental arthritis. The results, presented in the April 2006 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), indicate the promise of targeted liposomal therapy for rheumatoid arthritis patients.

RGD peptide was selected for targeting of the liposomes based on its high chemical stability and its high affinity for proteins expressed on angiogenic VECs At sties of inflammation. To create a disease sample, rats with adjuvant-induced arthritis (AIA) and rats or mice were injected with a lipopolysaccharide (LPS)-induced inflammation were used. After disease onset, generally 12 days after the inductions, the rats were randomly divided to receive treatment. One group received a single intravenous injection of 1 milligram of DEXP encapsulated in targeted RGD peptide-exposing polyethylene glycol liposomes (RGD-PEG-L). Another group was injected with the same dosage of DEXP encapsulated in non-targeted PEG liposomes. A control group was injected with an empty liposomes. To allow examination of liposome interactions with blood vessel walls in living animals, researchers used a mouse dorsal skin flap window model and distinguished RGD-PEG liposomes by fluorescent labels.

One hour after injection of the liposomes, which was performed only four hours after the induction of the inflammation, researchers observed strong binding of the RGD-PEG liposomes to the blood vessel wall at the site of the inflammation. Besides their rapid attack on VEC activity, the binding of RGD-PEG liposomes to inflamed sites was three-fold higher than that of the liposomes without the peptide.

Disease activity and its toll were monitored among the rats with AIA. Arthritis severity was scored by grading each paw from 0 to 4, based on redness, swelling, and joint immobility, with a maximum possible score of 16 per animal. Rats treated with DEXP-containing RGD-PEG liposomes showed the lowest overall scores, the strongest anti-inflammatory effects, and delayed disease progression.

This study demonstrates the potential of corticosteroid-carrying, VEC-binding RGD liposomes to quickly relieve inflammation and significantly reduce its ravages. "Using these liposomes to deliver DEXP to VECs at sites of arthritis involvement proved very efficacious in rat AIA, indicating promise for the treatment of rheumatoid arthritis," note the study's leading authors, Gert Storm, Ph.D. and Gerben Koning, Ph.D. "Future research will focus more precisely on the mechanisms involved and may also explore delivery of other anti-inflammatory compounds by the RGD-targeted liposomes."

Snake venom could ease arthritis pain

Wed, 29 Mar 2006 12:55:37 PST

( from http://www.rxpgnews.com ) Snake venom could ease the debilitating pain from arthritis, say scientists.

Naftali Primor, research and development manager at the Shulov Institute of Sciences (SIS) in Israel where the research is being carried out, believes that an analgesic based on snake venom could be on sale within five years.

The researchers studied the Palestinian viper - the most common snake in Israel - and said people suffering from arthritis could get relief using a cream made of chemicals found in snake venom, reported the online edition of Daily Mail.

Primor said: "About 99 percent of the venom is non-toxic, which leaves us with a great source of possible drug components. A snake venom pain-relieving cream could be on sale within five years."

The researchers believe that other chemicals found in snake venom could be exploited to make drugs to treat diseases such as cancer.

They found that out of every 1,000 molecules present in the venom, only four or five were poisonous. They isolated one of the molecules which had analgesic properties and made a safe, synthetic copy called VeP-3.

The Arthritis Research Campaign said they had heard of examples of people with arthritis being bitten by snakes and having their pain reduced.

"Similarly, others have reported the same effect from bee stings and nettles and it appears that all venom and stings have some kind of pain-relieving properties," spokesperson Jane Tadman added.

"Obviously people shouldn't seek out adders to bite them on the off-chance that it might help their arthritis, but a synthetic form of venom minus the toxins might be the answer," she said.

Sodium Hyaluronate Can Fill the gap left by Cox-2 inhibitors

Sat, 25 Mar 2006 15:51:37 PST

( from http://www.rxpgnews.com ) After the rise in safety concerns surrounding Vioxx and other Cox-2 inhibitors, people suffering from chronic shoulder pain were left with just two therapy options at opposite extremes - take Advil, or have surgery. But a new study from Columbia University Medical Center shows that sodium hyaluronate, a drug that is FDA-approved for osteoarthritis of the knee, is also effective for shoulder pain.

The study was presented today at the American Academy of Orthopaedic Surgeons annual meeting in Chicago by Theodore Blaine, M.D., assistant professor of orthopaedic surgery at Columbia University Medical Center and an attending surgeon at NewYork-Presbyterian Hospital.

The study showed that in patients with osteoarthritis of the shoulder, sodium hyaluronate was effective in reducing chronic pain by nearly 50 percent. The results were comparable to the 1998 study that led the FDA to approve the drug's use in treating knee pain. The FDA is currently reviewing the results in shoulder pain.

"Chronic shoulder pain is a common problem that can not adequately be treated with existing FDA-approved therapies," said Dr. Blaine, who was the principal investigator of the study. "The results of the trial were very encouraging, and we hope will lead to this drug's approval as an effective therapy for thousands of suffering patients."

According to the National Institute of Musculoskeletal and Skin Diseases, shoulder problems account for about 1.5 million visits to orthopaedic surgeons annually. The pain can be caused by a variety of problems, including osteoarthritis or rotator cuff tears.

Sodium hyaluronate is a vital building block of normal cartilage. It is marketed under the name Hyalgan by Sanofi Aventis.

All of the patients in the study had previously tried nonsurgical clinical interventions - including physical therapy, at least one steroid injection, and various oral pain medications - but the pain persisted. At the beginning of the study patients received an x-ray of the shoulder to confirm the diagnosis of osteoarthritis and rule out fractures or other exclusionary criteria, as well as an MRI to diagnose soft tissue and bony pathology or a tear in the rotator cuff.

The 602 patients who comprised the study population were broken up into three groups. One group received five injections of the drug over six months. A second group received three injections, followed by two saline injections, and the third group received just a placebo of five saline injections.

Throughout the six month trial, the patients were asked to record their level of pain on a scale of one to 100 -- with 100 being the worst pain imaginable. All three groups began with an average baseline score of 65. Patients with osteoarthritis who received sodium hyaluronate saw the greatest decrease in their pain scores, which was reduced to a score of 35 in six months. The patients who received three injections ended up with a pain score of around 37.

The patients who received saline also saw a decrease, to around 43. The improvement in the saline group could be the result of the placebo effect, as well as the possible therapeutic benefit of irrigating the joint. Similar saline results were seen in the study that led to the drug's approval for knee pain.

No safety concerns arose during the study, which is particularly notable given that the patients were older and more likely to be on other medications and have additional diseases. Sixty percent of the patients were taking cardiac medications, approximately 55 percent took Cox-2 inhibitors prior to joining the study, and up to 14 percent were taking medication for diabetes.

Patients with severe Rheumatoid arthritis are at increased risk of developing lymphoma - New Study

Mon, 27 Feb 2006 17:53:37 PST

( from http://www.rxpgnews.com ) An inflammatory disease of the immune system, rheumatoid arthritis (RA) is associated with increased occurrence of lymphoma--or cancers of the lymphatic system, which plays an integral role in the body's ability to fight infection. While various studies have affirmed this link, none have been able to pinpoint the specific effects of disease activity on lymphoma risk, let alone distinguish them from the effects of disease treatment.

Are certain RA patients more vulnerable to developing lymphoma? Do certain RA therapies--from standard NSAIDs (nonsteroidal anti-inflammatory drugs) and DMARDs (disease-modifying antirheumatic drugs) to novel immunosuppressive agents like TNF (tumor necrosis factor) blockers--work to alleviate or aggravate lymphoma risk? On a quest for answers, researchers in Sweden conducted the largest investigation of the link between RA and lymphoma to date. Their findings, featured in the March 2006 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), indicate a substantially increased risk of lymphoma among patients with severe RA. Very high and prolonged inflammatory activity, not its treatment, is the major risk factor.

Drawing their sample from a national register of nearly 75,000 RA patients, the research team analyzed the medical records and case histories of 378 RA patients afflicted with malignant lymphoma between 1964 and 1995 and 378 individually matched, lymphoma-free controls. Using statistical analysis, the relative risks or odds ratios for lymphoma were assessed for three different levels of overall disease activity--low, medium, or high--based on disease duration and swollen and tender joint counts. Odds ratios for lymphoma were also compared to treatment in broad categories: any DMARD, any NSAID, aspirin, oral steroids, injected steroids, and cytotoxic drugs. No patient in the sample had received anti-TNF therapy. In addition, lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV).

Compared with low RA activity, medium RA activity was associated with an 8-fold increase in the risk for lymphoma. The odds ratio rose dramatically for high RA activity--to a 70-fold increase in lymphoma risk. The researchers also observed increased risks of lymphoma associated with pronounced, irreversible joint damage in the hands, feet, and knees documented in the last year before lymphoma diagnosis.

More than 70 percent of the RA patients in the sample, both cases and controls, had received DMARD treatment--including the popular drug methotrexate (MTX), which was recently linked to increased risk of EBV-positive lymphomas by researchers in France. In this study, however, MTX and other standard DMARDs were not associated with any increase in lymphoma risk, nor were NSAIDS, aspirin, or steroids. Interestingly, lymphoma risk was particularly low among patients who had received frequent corticosteroid injections in inflamed joints, indicating a possible lymphoma-protective role of potent anti-inflammatory drugs. Of all the medical treatments assessed, researchers observed increased lymphoma risk associated only with azathioprine (AZA), which is not regarded as a traditional DMARD for RA and rarely used in current treatment.

Given the many uncertainties surrounding the link between lymphoma and chronic inflammatory diseases, this study has substantial clinical implications. As its lead author, Dr. Lars Klareskog of Karolinska University Hospital in Stockholm, observes, since lymphoma risk is strongly associated with exceptionally severe and longstanding RA activity, aggressive treatment may reduce the risk by reducing cumulative inflammation. "From a drug safety perspective," he notes, "our results provide background data that should be considered essential for the evaluation of lymphoma risk following therapy with TNF blockers, for example, as well as other new drugs."

The link between meniscal damage and early onset osteoarthritis

Mon, 27 Feb 2006 17:48:37 PST

( from http://www.rxpgnews.com ) Cartilage loss is a major component of osteoarthritis (OA), a joint disease that affects over 20 million Americans. In knee OA, cartilage loss is influenced by knee injury, as well as obesity and age. Every healthy knee is supported and protected by a pair of meniscus. This C-shaped tissue has many functions in the knee, including load bearing, shock absorption, and stability enhancement. The onset of knee OA after meniscectomy, the surgical removal of all or part of a torn meniscus, is fairly common and traditionally considered a result of the joint injury that leads to the operation in the first place.

While meniscectomy appears to be a significant risk factor for OA, researchers know little about the effect of meniscal damage and abnormalities on cartilage loss in knees with a predisposition for the disease. The March 2006 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis) shares the results of a study that sheds new light on the importance of an intact and functioning meniscus for patients with symptomatic knee OA.

The study, led by David Hunter of Boston University School of Medicine, focused on 257 subjects enrolled in the Boston Osteoarthritis of the Knee Study. The majority, 58 percent, were men and the mean age was 66.6 years. All subjects met the American College of Rheumatology criteria for symptomatic knee OA, confirmed by X-rays and self-reports of frequent knee pain and stiffness. At the study's onset and follow-up examinations at 15 and 30 months, participants underwent magnetic resonance imaging (MRI) of the more symptomatic knee. Using the MR images, researchers measured the position of the meniscus, as well as evaluated and scored the severity of meniscal damage. Among the MRI-assessed knees, 29% had a previous injury, 27% had a previous surgery, and 5% had a previous meniscectomy.

The researchers, as expected, found a high correlation between meniscal malposition and meniscal damage. The impact of meniscal abnormality on cartilage lost was most pronounced in the medial tibiofemoral joint--the inner joint connecting the knee to the lower leg. Each measure of meniscal misalignment was associated with an increased risk of cartilage loss. There was also a strong association of meniscal tears with cartilage loss. Reductions in the coverage and height of the meniscus, provoked by partial dislocation of the meniscus, also increased the risk of cartilage loss.

This study does not distinguish the type of meniscal tear that may propel cartilage loss or implicate meniscus damage as a cause of OA. However, it does call attention to the potential of a strong, whole meniscus to protect the knee from rapid devastation in the early stages of OA, and perhaps even mitigate the need for need replacement surgery. "At present, efforts are being made to preserve a damaged meniscus rather than remove it, and an industry of meniscal replacement is developing," Dr. Hunter notes. "Our study points to the need for critical, prospective evaluation of these new therapeutic options."

Selective COX-2 inhibitors may still be best option for arthritis

Thu, 19 Jan 2006 17:53:37 PST

( from http://www.rxpgnews.com ) Scientists believe that despite the current concerns around anti-inflammatory drugs like Vioxx, they may still be the best option for treating some forms of arthritis.

In a Nature Reviews of Drug Discovery article this month the researchers from Imperial College London and Queen Mary, University of London examine the use of selective inhibitors of cyclo-oxygenase-2 (COX-2).

They argue that although this class of drugs, which includes Vioxx, has been associated with an increase in the risk of cardiovascular events such as heart attacks and strokes in some patients, the same may be true for traditional non-steroid anti-inflammatory drugs (NSAIDs).

All NSAIDs, including COX-2 inhibitors, work by blocking the actions of both COX-1 and COX-2 enzymes. Blocking COX-2 relieves inflammation and pain, but blocking COX-1 can increase the risk of gastric ulcers and bleeds. For this reason COX-2 selective drugs were developed with the simple aim that they would retain the therapeutic actions of NSAIDs (linked to inhibition of COX-2) but lose the gastric side effects (linked to inhibition of COX-1).

The researchers reviewed over one hundred papers on the subject and looked at the latest recommendations from organisations such as the American Federal Drugs Administration on the use of COX-2 inhibitors and NSAIDs.

The researchers point out that the calls for the removal of COX-2 inhibitors, and a return to using NSAIDs, may cause additional problems. Although NSAIDs have been marketed for a number of years, they have never been required to meet the clinical trial standards now set for COX-2 inhibitors, meaning they may not be any safer.

Professor Jane Mitchell, from Imperial College London, and one of the reviews authors, said: "Although some COX-2 drugs have been reported to increase the risk of heart attack and stroke, they may still remain the best option for treating arthritis in some patients without cardiovascular risk factors who cannot tolerate traditional NSAIDs because of gastric side effects."

Professor Mitchell added: "This review shows us that despite the large scale use of NSAIDs and COX-2 inhibitors for a number of years, we still need more information on their benefits and potential risks and that more research needs to be done in this area. Looking at existing evidence, however, it would seem COX-2 inhibitors may be the best option for some patients. They are as effective as traditional NSAIDs, but with less gastric side effects than some older drugs."

Support for combination therapy for achieving remission of early rheumatoid arthritis

Wed, 04 Jan 2006 05:34:37 PST

( from http://www.rxpgnews.com ) A chronic and potentially crippling inflammatory disorder, rheumatoid arthritis (RA) progressively wears away the cartilage and bone. Joint erosions are routinely seen within 6 months of RA's onset, and occur more rapidly earlier in the course of the disease. Moderate disability within 2 years of diagnosis is not uncommon. While conventional DMARD (disease-modifying antirheumatic drug) therapies have been shown to slow joint destruction, they are powerless to stop RA's progression or reverse joint damage.
As researchers widely agree, early intervention offers RA patients the most promise for preventing irreversible joint damage and avoiding severe disability. In addition to early treatment, combination treatment, with DMARDs as well as with biologic agents, has been shown to yield more favorable outcomes than a single treatment. The January 2006 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis) presents the first study to compare the effectiveness of DMARD therapy alone, anti-TNF (tumor necrosis factor) therapy alone, and a combination of DMARD and anti-TNF therapy. The compelling results affirm the long-term benefits of early combination therapy for women and men afflicted with aggressive RA.

The study was sponsored by Abbott Laboratories and conducted at 133 sites throughout North America, Europe, and Australia. It focused on patients with active RA for less than 3 years who had never been treated with the DMARD methotrexate (MTX). A total of 799 patients were enrolled in the study. The majority were women. The mean age was 52 years. 57 percent of the participants had RA for 6 months or less. The subjects were randomly divided into one of 3 treatment groups: MTX, in pill form, starting with 20 milligrams weekly; the anti-TNF adalimumab, administered by injection, starting with 40 milligrams every other week; and a combination of adalimumab plus MTX, starting at the same dosage levels as the single treatment groups. For all groups, treatment effectiveness was thoroughly evaluated after 6 months, 1 year, and 2 years. 539 of the participants completed 2 years of their assigned treatment.

In all outcome measured, the combination of treatments was clinically and statistically superior to both adalimumab and MTX alone. Following 1 year of treatment, 62 percent of patients in the combination therapy group had 50 percent improvement in disease symptoms, according to the standard American College of Rheumatology criteria, compared with 41 percent of patients in the adalimumab only group and 46 percent of patients in the MTX only group. In addition, there was significantly less radiographic disease progression at 6 months, 1 year, and 2 years among patients in the combination treatment group than among those in either single treatment group. What's more, after 2 years of treatment, nearly half the patients in the combination therapy group exhibited a major clinical remission, rates approximately twice those found among patients receiving either single therapy.

The combination of DMARD and anti-TFN therapy proved safe and well tolerated by patients. The incidence of infections and other adverse events were low and comparable in all 3 treatment groups. What's more, increasing the dosages of either adalimumab or MTX alone failed to yield the improvements experienced by patients receiving both treatments in relatively low dosages.

As spokesperson George T. Spencer-Green points out, the study's participants had an unusually high level of radiographic damage present at baseline for their average disease duration of under one year. Early RA patients with milder forms of the disease may benefit from early DMARD therapy under a clinician's supervision. "For the patient with early, aggressive and erosive, RA," he notes, "treatment with combination therapy is superior to treatment with MTX alone."

Role of Type II Collagen in rheumatoid arthritis

Mon, 05 Dec 2005 04:10:38 PST

( from http://www.rxpgnews.com ) Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints, which gradually erodes the cartilage and bone. The agents of destruction include inflammatory cells, cytokines, and protein-degrading enzymes known as matrix metalloproteinases (MMPs). The vicious cycle begins when inflammatory cells infiltrate the tissue lining the joints and consume excess oxygen. In addition to unleashing MMPs, the oxidative stress provokes non-enzymatic glycation â a chemical binding of sugar molecules and proteins. Telltale signs of glycation have been found in blood, urine, and synovial fluid of RA patients.

The primary protein in cartilage, Type II Collagen (CII) is crucial to joint health and function. Yet, the involvement of CII in the process of joint inflammation has proven difficult to substantiate. To gain a clearer understanding of CII's role in the pathogenesis of RA, researchers at Queen Mary, University of London and others studied its behavior within an inflamed joint, when modified by oxidants linked to inflammation or by ribose, a five-carbon sugar common to all living cells. Featured in the December 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), their findings support CII's potential contribution to antibody binding and RA's devastating progression.

For their investigation, the researchers collected blood serum samples from 31 RA patients. Between the ages of 65 to 93 years, the patients had disease in varying stages and were receiving different treatments. For control purposes, serum samples were also collected from 41 patients with other inflammatory joint diseases, including osteoarthritis and lupus, as well as back pain, osteoporosis, and gout. Both RA and non-RA samples were analyzed for their ability to bind to pure and natural CII, obtained from bovine cartilage, and to CII that had been chemically modified. The modified CII included three oxidants present in the rheumatic joint â hydroxyl radical, hypochlorous acid, and peroxynitrite â and ribose. The results were evaluated by a state-of-the-art 3-D fluorescent profile, followed by enzyme-linked immunosorbant assay (ELISA) and Western blotting.

Of the 31 RA serum samples analyzed, only 3 showed antibody binding to natural CII â affirming this protein as an innocent bystander in autoimmunity and its inflammatory toll on the joints. However, the percentage of samples that exhibited antibody binding increased 4-fold when tested with modified CII. In fact, 45 percent of all RA samples were assessed with moderate to strong antibody binding reactions. CII treated with hypochlorous acid was the most reactive, followed by CII treated with peroxynitrite, glycation, and hydroxyl radical, respectively. In contrast, only 1 non-RA sample showed strong antibody binding to modified CII.

"The present findings support the possibility that chemical modification of self antigens, in RA in particular and in inflammation in general, is the cause of formation of neoepitopes," reflects the study's leading author, Ahuva Nissim, Ph.D. "We propose that the oxidative modification of CII creates a CII autoantigen." This hypothesis has important implications for the further study and enhanced understanding of the pathology of RA â a complex autoimmune disease.

Study shows long-term benefits of initial combination therapy in RA

Sun, 30 Oct 2005 14:15:38 PST

( from http://www.rxpgnews.com ) A progressive, inflammatory disease affecting the joints and organs, rheumatoid arthritis (RA) claims more than two million Americans, mostly women over age 40, among its victims. While a cure has yet to be found, the treatment of RA patients has changed considerably over the last two decades. Today, the goal of therapy is not simply symptom relief, but the prevention of long-term structural damage and functional decline. Toward this end, various disease-modifying antirheumatic drugs (DMARDs) have been proven effective in clinical trials, on their own and in tandem with various tumor necrosis factor (TNF) antagonists. While the recent increase in therapeutic options offers much promise, it has left doctors grappling with the question: What is the best treatment strategy for a patient newly diagnosed with RA?

The results of a long-term study, featured in the November 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), provide clear answers. A team of researchers in the Netherlands compared the four most widely sanctioned and commonly prescribed treatment strategies for very early RA on 508 patients. Primarily women, with a mean age of 54, the patients had suffered disease symptoms for an average of 23 weeks before entering the trial. After randomly assigning the patients to one of four treatment strategies, the researchers closely monitored the effects and benefits for each group over the course of one year.

Group 1 (126 patients) received standard DMARD therapy, starting with methotrexate. Group 2 (121 patients) was assigned to step-combination therapy, starting with methotrexate only, adding other DMARDs and prednisone. Group 3 (133 patients) started with a combination of methotrexate, sulphasalazine and prednisone. Group 4 (128 patients) started with a combination of methotrexate and infliximab. For all groups, drug dosages were increased or switched to other (combinations of) drugs according to the treatment protocol to achieve a state of low disease activity.

At the end of the year, every group demonstrated measurable improvements, with 32 percent of all the patients achieving clinical remission of their disease. However, patients who had received initial combination therapy--either with prednisone (group 3) or with infliximab (group 4)--had significantly less progression of radiographic joint damage than did patients treated with DMARDs only (group 1), or patients assigned to step-up combination therapy (group 2). The number of patients without any progression of radiographic joint damage was also higher in groups 3 and 4 than in groups 1 and 2. Furthermore, RA patients in both initial combination therapy groups experienced earlier functional improvement than did patients in either the DMARD monotherapy or step-up combination therapy group, according to scores of the Dutch version of the Health Assessment Questionnaire. Overall, patients who received initial combination therapy experienced no more side effects than patients in the other two groups.

"Patients in groups 3 and 4 had the benefit of a more rapid relief of symptoms and improvement of physical function," observes the author, B. A. C. Dijkmans, M.D. "In addition, there is the possibility that effective suppression of disease activity during the early phases of the disease may ameliorate the long-term joint damage and poor physical function and, ideally, even induce true clinical remission without the need for ongoing DMARD treatment."

Should any patient with newly diagnosed RA be treated with a single DMARD? Would choosing this established course always make a patient vulnerable to increased disease severity? That question can only be answered with further research.

Exercise May Strengthen Knee Cartilage in OA Patients

Sun, 30 Oct 2005 14:07:38 PST

( from http://www.rxpgnews.com ) Osteoarthritis (OA) is the leading cause of disability among adults. As the population ages, increased intervention efforts are vital to controlling the individual and public health toll of this chronic, crippling joint disease. Along with early diagnosis, moderate exercise is one of the most effective ways to reduce pain and improve function in patients with OA of the knee and hip. Yet, more than 60 percent of U.S. adults with arthritis fail to meet the minimum recommendations for physical activity.

Based on the "wear and tear" nature of OA, the commonly held belief is that exercise will not strengthen joint cartilage and may even aggravate cartilage loss. Until recently, investigators were unable to put that belief to the test. Radiographs, the standard measure of OA's progression, made it impossible to assess cartilage before severe cartilage damage had occurred. Advances in magnetic resonance imaging (MRI) now make it possible to study cartilage changes earlier in the course of OA. Two researchers in Sweden, Leif Dahlberg, M.D., Ph.D., and Ewa M. Roos, P.T., Ph.D., used a novel MRI technique to determine the impact of moderate exercise on the knee cartilage of subjects at high risk for developing OA--middle-aged men and women with a history of surgery for a degenerative meniscus tear. In the November 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), they share evidence to support the therapeutic value of exercise for OA patients, for improving not only joint symptoms and function, but also the quality of knee cartilage.

Working with the Department of Orthopedics at Malmö and Lund University Hospitals and the medical faculty of Lund University, Drs. Dahlberg and Roos recruited 29 men and 16 women, between the ages of 35 and 50, who had undergone meniscus repair within the past 3 to 5 years. Subjects were randomly assigned to either an exercise group or a control group. The exercise group was enrolled in a supervised program of aerobic and weight-bearing moves, for 1 hour, 3 times weekly for 4 months. At the study's onset and follow-up, subjects from both groups underwent MRI scans to evaluate knee cartilage. The technique used focused specifically on the cartilage's glycosaminoglycan (GAG) content, a key component of cartilage strength and elasticity. Subjects also answered a series of questions about their knee pain and stiffness, as well as their general activity level. Of the original 45 subjects, 30--16 in the exercise group and 14 in the control group--completed the trial and all post-trial assessments.

In the exercise group, many subjects reported gains in physical activity and functional performance tests compared with subjects in the control group. Improvements in tests of aerobic capacity and stamina affirmed the self-reported changes. What's more, MRI measures of the GAG content showed a strong correlation with the increased physical training of the subjects who had regularly participated in moderate, supervised exercise.

"This study shows compositional changes in adult joint cartilage as a result of increased exercise, which confirms the observations made in prior animal studies but has not been previously shown in humans," notes Dr. Dahlberg. "The changes imply that human cartilage responds to physiologic loading in a way similar to that exhibited by muscle and bone, and that previously established positive symptomatic effects of exercise in patients with OA may occur in parallel or even be caused by improved cartilage properties."

As Drs. Dahlberg and Roos acknowledge, the study does have limitations--its small sample size and narrow focus on meniscectomized knee joints--and makes no claims for predicting the long-term effects of exercise on cartilage. The conclusion, however, remains worthy of serious consideration: "Exercise may have important implications for disease prevention in patients at risk of developing knee OA."

Synthetic protein PLAD shows potential in arthritis treament

Tue, 04 Oct 2005 20:01:38 PST

( from http://www.rxpgnews.com ) A lab-made version of a human protein alleviates symptoms of both acute and chronic arthritis in mice and could be the basis for a new arthritis drug for people, report scientists from the National Institute of Allergy and Infectious Disease (NIAID), part of the National Institutes of Health (NIH). The protein prevents the assembly of a cell surface receptor, thus blocking transmission of chemical signals that lead to arthritis symptoms.

"This study opens a new research avenue to better understand and, perhaps, to treat rheumatoid arthritis, a condition that causes suffering in more than two million Americans," says NIAID Director Anthony S. Fauci, M.D.

Investigators from NIAID's Laboratory of Immunology, led by Michael Lenardo, M.D., published their findings in the October issue of Nature Medicine, now available online. The idea that the protein, called pre-ligand assembly domain protein or PLAD, might play a role in thwarting the joint inflammation characteristic of rheumatoid arthritis--one of the most common autoimmune diseases--grew out of their research on a very rare autoimmune disease called autoimmune lymphoproliferative syndrome (ALPS).

Previously, Dr. Lenardo and his colleagues showed that in ALPS a form of PLAD blocks a cell surface receptor and prevents a needed chemical signaling pathway from functioning correctly. In ALPS, the signal pathway interrupted by PLAD leads to disease symptoms. But, the scientists reasoned, PLAD might also be able to block a related cell surface receptor--one involved in passing signals that lead to inflammation. In theory, inhibiting this pathway might benefit people with rheumatoid arthritis, who suffer from excessive inflammation.

A key promoter of inflammation is a chemical called tumor necrosis factor alpha (TNF-alpha). TNF-alpha starts a chemical chain reaction leading to inflammation by binding to two cell surface receptors, TNFR-1 and TNFR-2. Naturally occurring PLAD helps both forms of TNFR assemble and prepare to receive TNF-alpha. Synthetic PLAD, the scientists hypothesized, would bind to its natural counterpart and prevent it from performing its usual task.

The scientists used a variety of techniques (including injection of TNF-alpha) to induce arthritis symptoms in mice. Researchers also injected some of the animals with lab-made PLAD (P60 PLAD). "We found that P60 PLAD protein powerfully inhibited the symptoms of TNF-alpha-induced arthritis," says Dr. Lenardo. P60 PLAD also lessened the effects of arthritis induced by other means. Moreover, he adds, P60 PLAD appeared to inhibit disease symptoms in mice with established as well as acute arthritis. The scientists did not detect any obvious toxicity in the PLAD-treated mice.

"We're very hopeful that this could be good news for arthritis sufferers," says Dr. Lenardo. In particular, the researchers are intrigued by P60 PLAD's apparent specificity: it seems to block the binding of TNF-alpha to TNFR-1, while allowing TNFR-2 to continue to function. This is important, notes Dr. Lenardo, because it may represent an advantage over some currently used arthritis drugs, which directly block TNF-alpha by binding to both TNFRs and thereby inhibit beneficial actions mediated by TNFR-2.

The scientists next aim to develop a more stable form of P60 PLAD. Ultimately, they hope to test the protein in clinical trials.

Is the Disease Course of Rheumatoid Arthritis Becoming Milder?

Sun, 04 Sep 2005 08:13:38 PST

( from http://www.rxpgnews.com ) Rheumatoid arthritis (RA) is a chronic inflammatory disease, marked with joint pain and erosion. The course of RA can vary considerably, from mild to crippling, and is difficult to predict. On the strength of patient case histories and clinical trials, rheumatologists have suggested that the majority of today's RA patients are suffering less severe symptoms and less functional disability compared with RA patients in past decades.

Is the course of RA becoming milder? If so, why? Intrigued by these questions, researchers in The Netherlands decided to seek out the answers through a rigorous investigation. Published in the September 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), their findings indicate a positive trend. "Patients with early RA presenting in recent years have less severe disease activity at presentation, as well as a more favorable course of their disease, compared with patients in earlier years," states the study's leading author, Paco M. J. Welsing, MSc.

What is the reason for this improving trend? Welsing and his colleagues found no clear, conclusive cause, and even uncovered some contradictory evidence. However, the team found a concurrent tendency toward a shorter duration of symptoms at the time of diagnosis and more aggressive use of drug therapy--for instance, methotrexate, today's preferred disease-modifying anti-rheumatic drug (DMARD) and/or prednisone--over the course of the disease.

The study included all newly diagnosed, early RA patients enrolled in the department of rheumatology clinic of Radboud University Nijmegen Medical Centre since 1985. Patients were divided into four groups based on the date of enrollment. Patients enrolled between 1985 and 1990 (167 total) comprised Group 1. Patients enrolled between 1990 and 1995 (132 total) comprised Group 2. Patients enrolled between 1995 and 2000 (114 total) comprised Group 3. And patients enrolled between 2000 and 2005 (112 total) comprised Group 4. In all groups, the majority of patients were women. The mean age at the time of enrollment was 54 years for Group 1; 55 years for both Groups 2 and 3; and 57 years for group 4.

Researchers set out to compare disease activity and functional disability among the groups over a 5-year progression (but 4-years, maximum, for Group 4). They also compared treatment strategies among the groups. All patients were assessed for signs of RA activity--namely, swelling and tenderness--in 28 joints every 3 months, a laboratory measure for inflammation and a measure of general well being by the Disease Activity Score 28 (DAS28). All patients were assessed for functional disability--covering difficulties with walking and conducting everyday activities--using the Health Assessment Questionnaire disability index (HAQ DI) every 6 months. In addition, all patients were periodically evaluated for pain in general.

The DAS28 scores at baseline and over the course of the study were consistently lower, indicating milder disease activity, in the more recent groups--that is, patients diagnosed with RA within the last ten years. At the 5-year culmination, the DAS28 scores were lowest in the most recent, complete group--Group 3, patients diagnosed between 1995 and 2000--compared with both Group 2 (1990-1995) and Group 1 (1985-1990). The average disease activity over time per patient showed similar trends of improvement. The average DAS28 score improved from 4.1 to 3.4 from the Group 1 to Group 3.

However, the HAQ DI scores at baseline and over time were not lower among patients enrolled later in the study, and even showed some evidence of a worsening trend. "This contradictory result may be partly a distinction between measures of physical examination, laboratory results, and patient-assessed outcomes," notes Welsing, "which can be influenced by internal standards or attitudes of patients."

Researchers did find a correlation between more aggressive treatment strategies and milder disease activity in the more recent groups of patients. While suggesting the effectiveness of early treatment with methotrexate, for instance, and/or prednisone for managing RA's symptoms and destructive progression, this connection calls for further investigation.

New findings on menopausal arthritis

Sun, 04 Sep 2005 07:22:38 PST

( from http://www.rxpgnews.com ) One of the most effective new treatments for breast cancer is a hormone therapy. Aromatase inhibitors work by powerfully blocking the conversion of androgen precursors into estrogens, which lowers estradiol levels in the bloodstream and estrogen levels in peripheral tissues. Because aromatase inhibitors reduce the rates of recurrence in women with early-stage postmenopausal breast cancer, these agents are not only becoming widely used in breast cancer treatment, but also being explored for their potential to prevent the disease in women at high risk. While focusing on this therapy's promise, advocates have tended to downplay one of its drawbacks. Women treated with aromatase inhibitors often experience joint pain and musculoskeletal aching--severe enough, in some cases, to make them stop the treatment.

Two noted researchers, David T. Felson, M.D., of Boston University Clinical Epidemiology Unit, and Steven R. Cummings, M.D., of California Pacific Medical Center Research Institute and University of California, San Francisco, have thoroughly examined the evidence linking aromatase inhibitors and, more broadly, estrogen deprivation joint pain. In the September 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), they share their insights to alert oncologists, primary care physicians, and other health care professionals to this widely overlooked, potential problem for women.

"Estrogen's effects on inflammation within the joint are not well known," Dr. Felson and Dr. Cummings observe. Yet, as they note, estrogen has well-established tissue-specific effects on inflammatory cytokines. Estrogen's role in joint inflammation could account for the increased sensitivity to pain that some women suffer with estrogen depletion. Citing studies of pharmacological suppression of estrogen and studies of natural menopause, the authors offer a look at compelling evidence associating estrogen deprivation with joint pain, including:

# Aromatase inhibitors have been linked to higher rates of joint and muscle pain than tamoxifen and placebo in various clinical trials for breast cancer treatment and prevention. One example: In a National Cancer Institute of Canada study, 5,187 postmenopausal women who completed a 5-year course of tamoxifen therapy for breast cancer were randomized to a further 5 years receiving the aromatase inhibitor letrozole or a placebo. 21 percent of women taking letrozole reported joint pain compared with 16 percent of the women receiving placebo.

# In a study of leuprolide, a hormonal agent used to treat infertility and a variety of gynecological disorders, 102 premenopausal women experienced symptoms of estrogen deprivation, such as vaginal dryness, after 2 weeks of treatment, and suffered joint pain between weeks 3 and 7 of treatment. Overall, 25 percent of the women developed persistent joint pain, affecting the knees, elbows, ankles, and other areas, during the study. The pain was resolved in all women between 2 and 12 weeks after stopping the leuprolide therapy.

# In a postmenopausal estrogen/progestin intervention trial, women who received estrogen had a significantly decrease chance of musculoskeletal symptoms--between 32 and 38 percent--compared with women randomly assigned placebo. Symptoms reported in the placebo group included joint pain, muscle stiffness, and skull and neck aching. In other studies, however, estrogen replacement therapy had no beneficial effect on musculoskeletal pain.

Dr. Felson and Dr. Cummings also highlight recent data showing that Asian women undergoing menopause have lower estradiol levels than Caucasian women and seem to be more vulnerable to a syndrome commonly known as "menopausal arthritis." They also note the high rate of both osteoarthritis and rheumatoid arthritis in postmenopausal women. They conclude by stressing the need for further research into the contribution of estrogen deficiency to arthritis, as well as for recognizing the risks of musculoskeletal syndrome when prescribing aromatase inhibitors and other estrogen-depleting treatments.

Brightly-coloured fruit and veg may protect against arthritis

Thu, 18 Aug 2005 02:16:38 PST

( from http://www.rxpgnews.com ) Researchers from The University of Manchester's Medical School have discovered that eating more brightly-coloured fruits and vegetables like oranges, carrots and sweetcorn may help reduce the risk of developing inflammatory disorders like rheumatoid arthritis.

Rheumatoid arthritis currently affects around 1% adults in the UK. Previous studies have suggested that vitamin C and the pigment beta-cryptoxanthin, both of which are found in brightly-coloured fruit and veg, may act as antioxidants, and protect the body against the oxidative damage which can cause inflammation.

The Manchester team, based in the Arthritis Research Campaign's Epidemiology Unit, worked with researchers from the Institute of Public Health at the University of Cambridge to analyse health questionnaires and diet diaries by over 25000 45-74 year-olds; completed as part of the EPIC (European Prospective Investigation of Cancer) Norfolk study of diet and chronic disease in the 1990s. They then followed-up the participants over a nine year period to identify new cases of inflammatory polyarthritis (IP), including rheumatoid arthritis.

Dr Dorothy Pattison, who led the research, said: "We found that the average daily beta-cryptoxanthin intake of the 88 patients who had developed inflammatory polyarthritis was 40% lower than those who hadn't, and their intake of another carotenoid, zeaxanthin, was 20% lower.

"Those in the top third for beta-cryptoxanthin intake were only half as likely to develop IP as those in the lowest third, and vitamin C was also found to be an important factor."

The findings appear to confirm previous evidence that a modest increase in fruit and vegetables containing beta-cryptoxanthin and vitamin C, equivalent to one glass of freshly-squeezed orange juice each day, might help to protect against developing inflammatory joint diseases.

Dr Pattison has previously published research which found that both low intakes of fruit and vegetables (in particular those high in vitamin C), and high levels of red meat consumption were associated with an increased risk of developing IP.

Biologic drug adalimumab is effective in treating rheumatoid arthritis

Wed, 20 Jul 2005 15:06:38 PST

( from http://www.rxpgnews.com ) There is good evidence that adding adalimumab (Humira) to the treatment of people with long-standing rheumatoid arthritis is more effective than using oral methotrexate alone.

Adalimumab is a relatively new antibody-based therapy. Patients given 24 weeks of therapy with adalimumab and methotrexate had decreased pain and swelling and an increased ability to perform normal daily activities compared with those given methotrexate alone or no disease modifying anti-rheumatic drugs (DMARDs). X-ray damage to the joints is also slowed. Side effects in the short-term are well-tolerated. Rare and long-term side effects are not yet known.

"The drug is relatively new and so it is not surprising that there is little data from long-term studies, but the evidence so far is encouraging," says lead author Federico Navarro-Sarabia, Chair of Rheumatology at the Hospital Universitario Virgen Macarena, Seville, Spain.

In the UK, the National Institute for Health and Clinical Excellence ( NICE) is currently assessing adalimumab for use in rheumatoid arthritis.

Losing a pound results in a 4-pound reduction in knee-joint load for each step

Wed, 29 Jun 2005 13:03:38 PST

( from http://www.rxpgnews.com ) The leading cause of disability in the United States, osteoarthritis (OA) is a complex, degenerative joint disease with several established risk factors. For OA of the knee, the most important modifiable risk factor is obesity. Both the American College of Rheumatology and the European League Against Rheumatism recommend weight loss and exercise to reduce the painful and incapacitating symptoms of knee OA.

As part of a long-term study of the effects of diet and exercise on knee OA, researchers at Wake Forest University found that an average weight loss of 5 percent in overweight and obese older patients brought an 18 percent gain in overall function. Drawing from that study population, the researchers set out to investigate the specific, direct relationship between weight loss and knee-joint stress while walking. Featured in the July 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), their findings indicate that moderate weight loss results in knee-joint load reduction of a cumulative amount with considerable clinical implications.

Conducted over an 18-month period, the study focused on 142 overweight and obese adults with radiographic evidence of knee OA. Ranging in age from 60 to 89, the subjects were mostly female (74 percent) and white (75 percent); all were considered sedentary. Each subject's weight and body mass index (BMI), as well as scores on standard scales of function and pain, were obtained at baseline and again at 6-months and at 18-months. At baseline and both follow-up visits, each subject also underwent gait analysis and a battery of biomechanical tests to assess changes in knee-joint forces, both compressive and resultant, and moments, both abduction and rotation. Over the course of the study, all participants followed a prescribed weight loss plan, some through diet only, some through exercise only, and some through a combination of healthy living habits.

At the study's culmination, participants lost an average of 2 percent of their weight and lowered their BMI by 3 percent. After adjusting for baseline body mass and baseline knee-joint force, researchers found a significant association between weight loss and reduction in compressive knee-joint loads. In fact, the force reduction was 4-times greater than the actual weight reduction. In other words, their findings indicated that, for every 1 pound of weight lost, there is a 4-pound reduction in the load exerted on the knee for each step taken during daily activities.

"The accumulated reduction in knee load for a 1-pound loss in weight would be more than 4,800 pounds per mile walked," notes Stephen P. Messier, Ph.D., the leading author of the study. "For people losing 10 pounds, each knee would be subjected to 48,000 pounds less in compressive load per mile walked. Although there are no longitudinal studies indicating that weight loss in humans slows the progression of knee OA, a reduction of this magnitude would appear to be clinically relevant."

Supporting the positive impact of weight loss on knee OA, this compelling study suggests the need for further research into the potential of weight loss--whether achieved through diet alone or in tandem with exercise--to slow, and perhaps even prevent, the crippling outcome of a disease too common among older Americans.

Study shows effectiveness of doxycycline in slowing osteoarthritis progression

Wed, 29 Jun 2005 13:01:38 PST

( from http://www.rxpgnews.com ) A tetracycline antibiotic, doxycycline, has been successfully used to treat a wide-range of bacterial infections. In addition to its effects as an antibiotic, doxycycline has other actions as a drug and, in laboratory studies with animals and with human tissue, can inhibit the degradation of cartilage in a way that could be useful for the treatment of osteoarthritis (OA). OA is a common form of arthritis associated with pain and disability related to the breakdown of cartilage, the tissue in the joint that absorbs shock and promotes smooth movement

On the strength of preclinical evidence, a team of rheumatologists affiliated with six clinical research centers across the United States conducted the first long-term clinical trial to determine the benefits of doxycycline in the treatment of OA--particularly, OA of the knee. Their findings, featured in the July 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), suggest that doxycycline may slow the progression of joint damage and point to the need for further research into the drug's effect on the signs and symptoms of this disease.

For the trial, the team recruited 431 overweight women between the ages of 45 and 64 with moderately advanced OA in one knee. The subjects were randomly assigned to receive either 100 milligrams of doxycycline or a placebo twice a day for 30 months. At baseline, the 2 treatment groups were roughly equal with respect to all demographic variables, body mass index, and types of drugs taken for pain, as well as for the x-ray severity of OA in the affected knee and the level of knee pain and functional impairment. OA progression was assessed by measuring joint space narrowing in the medial tibiofemoral compartment through X-rays obtained at baseline, 16 months and 30 months. Severity of joint pain was assessed every 6 months after a washout period of all nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics.

71 percent of the subjects completed the treatment protocol. Radiographs were obtained from 85 percent of all subjects at 30 months. After 16 months of treatment, the mean loss of joint space width in the diseased knee in the doxycycline group was 40 percent less than in the placebo group. After 30 months, it was 33 percent less. Yet, despite significantly slowing disease progression, doxycycline did not reduce the severity of joint pain. However, mean pain scores at baseline were low in both treatment groups, leaving only limited opportunity to demonstrate improvement in joint pain. On the other hand, the drug significantly reduced the frequency with which subjects reported increases in knee pain 20 percent or greater than the level of pain they had at their previous semi-annual visit.

Notably, doxycycline seemed to have no effect on joint space narrowing or pain in the relatively disease-free knee. In both knees in both treatment groups, the rate of joint space narrowing was more than twice as rapid in subjects who reported frequent increases in pain than in those with a stable pain score. "Joint pain may serve as an indicator of synovitis that leads to cartilage destruction," observes the study's leading author, Kenneth D. Brandt, M.D.

Throughout the trial, fewer than 5 percent of all subjects reported side effects. In general, doxycycline seemed to be well tolerated. Subjects in the active treatment group experienced the unexpected side benefits of fewer urinary tract and upper respiratory tract infections than their placebo counterparts.

In conclusion, in this study, doxcycyline showed benefits in slowing the rate of joint space narrowing in knees with established OA. Whether this drug has any value in the early treatment and symptomatic management of OA, however, will require further investigation.

Knee injury causes decrease in lubrication

Fri, 03 Jun 2005 16:56:38 PST

( from http://www.rxpgnews.com ) Researchers have found an association between inflammation from knee injuries and a progressive loss of joint lubrication, which may predispose people to arthritis. They have also found a way to quantify how much lubrication is lost following injury.

It is known that injury is a risk factor for osteoarthritis, a common condition that erodes cartilage and primarily affects people later in life, and that putting weight on an injured knee can result in increased friction and cause cartilage damage. But it is not known how changes in lubrication can positively or negatively impact cartilage damage.

"If you injure a joint, or have been injured in the past, it would be useful to have a test that could indicate your level of risk for developing arthritis," says author Gregory D. Jay, MD, PhD, research director in emergency medicine at Rhode Island Hospital and associate professor of emergency medicine and engineering at Brown University. "In this study, we were able to quantify loss of lubrication which has important implications for preventing osteoarthritis."

Researchers first looked at rabbits with injured knees. They withdrew synovial fluid surrounding the knee cartilage and measured lubricin, a naturally-produced substance that protects the joint from wear. They found that lubricin completely disappeared from the rabbits in three weeks.

An observation of emergency room patients supported many of the findings observed with rabbits. Researchers took a retrospective look at the synovial fluid drawn from injured knees of emergency room patients to alleviate swelling. There was a wide range of lubricating ability, but overall, there was greater friction than in patients with no injuries. In addition, the study found an increase in production of CII peptides, which indicates early damage to joint cartilage.

At the opposite end of the spectrum, researchers looked at patients with rheumatoid arthritis, chronic inflammation caused by an autoimmune reaction against the body's own tissues. They found that patients with rheumatoid arthritis had no lubricating ability. The findings indicate that the deterioration of lubricating ability and its possible association to cartilage damage "is not a unique feature of early stages of a knee injury, but rather a common feature in inflammatory conditions, both acute and chronic," the paper states.

In order to measure the breakdown of lubricin, researchers developed a simple test that can be performed in any hospital laboratory, Jay says. Previously, friction tests were conducted with complex machines that are not easily accessible to physicians.

The next step is to conduct a study with patients, Jay says, to determine whether patients with injuries should stay off their feet.

"Our ultimate goal is to determine how much lubrication is lost after a knee injury. If you're walking on a non-lubricated joint, it's very likely you'll develop osteoarthritis or induce damage to other areas of the knee," Jay says.

Study links TNF to androgen deficiency in rheumatoid arthritis

Thu, 02 Jun 2005 15:58:38 PST

( from http://www.rxpgnews.com ) A protein involved in multiple cell functions, tumor necrosis factor (TNF) is perhaps best known for provoking destructive inflammation. Recently, drugs blocking the action of TNF have shown promise in the early treatment of rheumatoid arthritis (RA).

To expand the understanding of TNF's function in chronic inflammatory diseases, researchers at University Hospital Regensburg in Germany and the National Institute of Rheumatic Diseases in the Slovak Republic decided to take a closer look at this cytokine's impact on androgen production. Androgens are thought to play a critical anti-inflammatory role in rheumatic diseases, including various forms of arthritis and lupus, based on extensive clinical trials and animal models. For their study, the team investigated the role of TNF in the conversion of biologically inactive DHEAS--short for dehydroepiandrosterone sulfate--to biologically active DHEA, the steroid hormone parent of androgen, estrogen, and testosterone. Their findings, featured in the June 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), shed new light on suppression of androgen by TNF in RA patients, as well as on the different nature of inflammation in RA from the most common inflammatory disease: osteoarthritis (OA).

To get a clear picture of how TNF affects hormone production and regulation, the research team analyzed samples of inflamed synovial tissue--obtained immediately after opening the knee joint capsules of 37 patients who underwent elective joint replacement surgery. 15 of the patients had a longstanding history of RA, with disease duration averaging 15 years. 22 of the patients were OA sufferers. Using tools for biochemical analysis, the team assessed the process of converting DHEAS to DHEA. The results revealed marked differences in the cellular activity of RA and OA patients.

On the evidence of both synovial cell and synovial fluid analysis, levels of DHEA from DHEAS were significantly lower among RA patients than OA patients. In addition, researchers found a negative correlation between converted DHEA and markers of inflammation among RA patients but not in patients with OA. They also found evidence that TNF inhibits the activity of steroid sulfatase, the key enzyme in DHEAS-to-DHEA conversion.

"This is the first study to demonstrate that the conversion of DHEAS to DHEA is decreased in patients with RA as compared with that in patients with OA," notes leading contributor Claudia Weidler. "In the present study, we were fortunate to demonstrate that TNF is also a strong inhibitor of the conversion of DHEAS to DHEA in synovial cells from patients with RA but absolutely not in patients with OA."

Providing the full picture of androgen deficiency in RA, this study affirms the need for further research into early anti-TNF antibody therapy in the treatment of this particular inflammatory disease.

Continuous NSAID use beneficial in ankylosing spondylitis

Thu, 02 Jun 2005 15:48:38 PST

( from http://www.rxpgnews.com ) A widely under-recognized form of arthritis, ankylosing spondylitis (AS) is a chronic, progressive disease targeting the spine. Commonly striking in young adulthood, before age 35, AS causes inflammation, pain, and stiffness in the spinal joints--the vertebrae--and the sacroiliac joint, where the spinal column meets the pelvis. In advanced cases, this disease can result in deforming, crippling spinal fusion and organ damage. According to expert estimates, AS afflicts at least half a million people in the United States.

While there is no cure for AS, numerous studies have affirmed the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) for improving physical function, as well as providing rapid relief from back pain and stiffness. Yet, physicians generally recommend taking NSAIDs on a short-term basis, only as needed for severe AS symptoms, due to the risk of gastrointestinal complications associated with long-term use. Inspired by the improved gastoprotective safety profile of COX-2-selective NSAIDs, an international team of rheumatologists set out to explore the impact of ongoing NSAID treatment, over a 2-year span, on the course of AS. Featured in the June 2005 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), their study offers hope for decreasing the progression of AS, without increasing the risk of peptic ulcers or other adverse events.

The clinical trial began with 215 outpatients, drawn from the records of 76 hospitals and private practices in France, with a history of AS. Using a computer-generated randomization list, the patients were divided into two treatment groups. The first group, comprised of 111 patients, was prescribed twice-daily treatment with a NSAID, regardless of symptoms. The second group, comprised of 104 patients, was also prescribed a NSAID, but instructed to take it only when they suffered pronounced pain or stiffness. Both groups started treatment with celecoxib at a dosage of 100 milligrams. All patients were allowed to increase their dosage to 200 milligrams, if necessary, or switch to another NSAID, as long as they maintained their assigned treatment strategy--either continuous or on-demand. Compliance was assessed by pill count.

At baseline, after 1 month, at 7 follow-up visits conducted at 3-month intervals, and at the final visit, patients in both groups were thoroughly evaluated, through questionnaires and laboratory tests, for clinical signs and symptoms of AS, as well as for any adverse events. X-rays of the spine were taken at the study's onset and 24-month culmination.

Overall, differences in hallmarks of disease activity--including spinal pain, night pain, morning stiffness, fatigue, and restricted mobility--were not statistically significant between the two treatment groups. There were also no significant differences in the gastrointestinal, respiratory, cardiovascular, and other health problems experienced by the groups, with the exception of symptoms of depression, which occurred more frequently in the continuous-treatment group. Only a single adverse event--a case of severe abdominal pain requiring hospital admission in the on-demand group--was deemed directly related to NSAID use, by the treating physician. There were, however, statistically significant differences in the X-ray evidence of AS progression between the continuous-treatment and the on-demand groups.

Complete sets of radiographs were available for 76 of the patients in the continuous-treatment group and for 74 of the patients in the on-demand group. Scored by a single observer blinded to treatment strategy, using the modified Stoke Ankylosing Spondylitis Spine Score (SASS), the X-rays showed both more pronounced disease progression and in a greater proportion of patients among patients who had taken NSAIDs only as needed for pain management. In fact, twice as many patients in the on-demand group were scored as having moderate to high levels of spinal joint damage at the 2-year mark than patients in the continuous-treatment group. The between-group difference in radiographic progression remained stable and significant after adjusting for baseline values of joint damage and disease-activity variables.

As noted by Professors Maxime Dougados and Desiree van der Heijde, the study's leading authors and participating rheumatologists, the findings have implications for both the treatment of AS and the application of NSAIDs. On the strength of the data, inflammation and progression of joint damage may be two separate processes in AS, which may be different from the situation in rheumatoid arthritis. And NSAIDs, generally considered symptom modifiers, may have unexplored disease-controlling properties.

"We conclude that a strategy of continuous use of NSAIDs decreases the radiographic progression in patients with AS without substantially increasing toxicity," Prof. Dougados states. "While awaiting confirmation of these results, we carefully recommend that if patients need treatment with NSAIDs to reduce the signs and symptoms of AS, they should take NSAIDs continuously instead of as needed based on symptoms."