RxPG News : Rheumatiod Arthritis

DNA-covered submicroscopic bead used to deliver genes to treat rheumatoid arthritis

Tue, 15 May 2012 07:23:08 PST

( from http://www.rxpgnews.com ) A DNA-covered submicroscopic bead used to deliver genes or drugs directly into cells to treat disease appears to have therapeutic value just by showing up, researchers report.

Within a few hours of injecting empty-handed DNA nanoparticles, Georgia Health Sciences University researchers were surprised to see increased expression of an enzyme that calms the immune response.

In an animal model of rheumatoid arthritis, the enhanced expression of indoleomine 2,3 dioxygenase, or IDO, significantly reduced the hallmark limb joint swelling and inflammation of this debilitating autoimmune disease, researchers report in the study featured on the cover of The Journal of Immunology.

"It's like pouring water on a fire," said Dr. Andrew L. Mellor, Director of the GHSU's Medical College of Georgia Immunotherapy Center and the study's corresponding author. "The fire is burning down the house, which in this case is the tissue normally required for your joints to work smoothly," Mellor said of the immune system's inexplicable attack on bone-cushioning cartilage. "When IDO levels are high, there is more water to control the fire."

Several delivery systems are used for gene therapy, which is used to treat conditions including cancer, HIV infection and Parkinson's disease. The new findings suggest the DNA nanoparticle technique has value as well for autoimmune diseases such as arthritis, type 1 diabetes and lupus. "We want to induce IDO because it protects healthy tissue from destruction by the immune system," Mellor said.

The researchers were exploring IDO's autoimmune treatment potential by inserting the human IDO gene into DNA nanoparticles. They hoped to enhance IDO expression in their arthritis model when Dr. Lei Huang, Assistant Research Scientist and the paper's first author, serendipitously found that the DNA nanoparticle itself produced the desired result. Exactly how and why is still being pursued. Early evidence suggests that immune cells called phagocytes, white blood cells that gobble up undesirables like bacteria and dying cells, start making more IDO in response to the DNA nanoparticle's arrival. "Phagocytes eat it and respond quickly to it and the effect we measure is IDO," Mellor said.

Dr. Tracy L. McGaha, GHSU immunologist and a co-author on the current study, recently discovered that similar cells also prevented development of systemic lupus erythematosus in mice.

Follow-up studies include documenting all cells that respond by producing more IDO. GHSU researchers already are working with biopolymer experts at the Massachusetts Institute of Technology, the University of California, Berkeley and the Georgia Institute of Technology to identify the optimal polymer.

The polymer used in the study is not biodegradable so the researchers need one that will eventually safely degrade in the body. Ideally, they'd also like it to target specific cells, such as those near inflamed joints, to minimize any potential ill effects.

"It's like a bead and you wrap the DNA around it," Mellor said of the polymer. While the DNA does not have to carry anything to get the desired response in this case, DNA itself is essential to make cells express IDO. To ensure that IDO expression was responsible for the improvements, they also performed experiments in mice given an IDO inhibitor in their drinking water and in mice genetically altered to not express IDO. "Without access to the IDO pathway, the therapy no longer works," Mellor said.

Drs. Andrew Mellor and David Munn reported in 1998 in the journal Science that the fetus expresses IDO to help avoid rejection by the mother's immune system. Subsequent studies have shown tumors also use IDO for protection and clinical trials are studying the tumor-fighting potential of an IDO inhibitor. On the flip side, there is evidence that increasing IDO expression can protect transplanted organs and counter autoimmune disease.

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

Mon, 05 Jun 2006 16:59:00 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.

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

Mon, 27 Feb 2006 17:54:00 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."

Support for combination therapy for achieving remission of early rheumatoid arthritis

Wed, 04 Jan 2006 05:35:00 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 04:11:00 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.

Is the Disease Course of Rheumatoid Arthritis Becoming Milder?

Sun, 04 Sep 2005 08:14:00 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.