Research

Sock's Rheumatoid Arthritis Page 1:

Research

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Research and production in RA medication has seen unequalled success of the past decades,and on-going clinical trials will result in future developments to benefit the RA patient. It is indeed exciting times.There are currently new medications awaiting FDA approval.

The immunomodulatory agent leflunomide (Arava) is superior in efficacy to placebo and equivalent to methotrexate and sulfasazine (in some patients).

Two biologic agents that block TNF-alpha,Etanercept (Enbrel) and Infliximab (Remicade) is also available Etanercept is superior to placebo,when used alone or with methotrexate in moderate to severe RA.

Refractory to previous DMARDs or when used in combination with methotrexate in partial responders to that drug. Infliximab is superior to placebo when used in combination with methotrexate again in partial respoders to that drug.

Long-term data on the safety of these drugs DMARDs is lacking but Enbrel- 4 years good effacicy has been proven--like wise in European studies with Remicade.--they have been well tolerated up to now. Their prohibitive cost will probably limit use to patients whose condition is refractory to standard DMARD therapy.

There have been recent infection side effects reported and concerns but careful patient selection is required for it's use in RA therapy. They are not suitable for every patient.

Biotechnology is the industry that has found ways to create new drugs from molecules that naturally exists in the human body. It's a technology that has allowed us to identify as to how disease states occur and how we can actually devise drugs to treat those new disease states in ways we couldn't think about 20 years ago.Biologic drugs are the genes or the proteins or the cells that are found to be involved in disease states that can be harnessed to use in fighting and treating the disease.

Methotrexate have been a conventional DMARD drug. It may be compared of 20 carbon atoms and yet a biotechnology drug like a monoclonal antibody or a soluable receptor might be composed of thousands of carbon atoms that are put together to create these molecules. Therefore they're much more complex.

Many of the products are produced naturally in the body and they're produced in minute amounts. In order for us to make them in sufficient amounts that they can be actually used in testing clinically we have to do what's called recombiant genetric engineering.

What we do with that content is to isolate the gene that is providing the information to the cell by which these complex molecules are made. We then tailor that gene and splice it to be used in a smaller organism. E.G. the mechanism by which genes are translated into these complex molecules known as proteins is common to all organisms on the planet.

We can actually harness that knowledge to put the gene that entices TNF receptor,e.g. into cell or smaller organism that we can control to a much greater extent for the production of these complex proteins.

Biological response modifiers work by turning off TNF-alpha,one type of tumor necrosis factor. Over the past five years,many studies around the world have identified TNF as a cause of joint destruction in RA.

Once a connection between TNF-alpha and joint erosions in humans was confirmed in the lab,researchers were able to engineer a TNF-alpha antibody-an agent that would latch onto TNF-alpha and prevent it from causing further damage. Drugs such as Remicade is chimeric monoclonal antibody."

The term "Chimeric" means the antibody has been created by putting together antibodies that would not ordinary combine. In Remicade's case both parts are required, to work-one part is required as a carrier the other is required as the TNF-alpha blocking agent.

For the first time,bio-engineers at the University of California,have fabricated cartilage tissue that imitates the structure and function of natural tissue. In the future,the synthetic tissue could be developed to replace cartilage worn down by congenital defects,age-related degeneration,joint injuries and arthritis. Research began by building a "map" of the cartilage,then growing different kinds of juvenile cartilage cells in gel. Once the gel is removed,what is left is biological tissue.

This synthetic tissue comes close to imitating the real thing. It secreates the same protein needed to lubricate a joint. It also mimics the complexity of cartilage;e.g.,The tissue at the surface much less dense than tissue in deeper areas.

Cartilage forms the body's shock absorbers and,although only a few millimetres thick,plays the important role of cushioning joints. The researchers are hopeful that the engineered tissue can be developed as an implant treatment for those with cartilge damage. Next up are animal trials to test out the implanting proceduure.

According to results from a Phase II study presented recently at the American College of Rheumatology (ACR) scientific meeting, the novel investigational biologic agent, CTLA4Ig, may have potential for treating rheumatoid arthritis patients who do not respond adequately to etanercept (Enbrel) alone.

Researchers at Stanford University Medical Center have found that selective COX-2 inhibitors – a class of medications widely prescribed for painful inflammatory conditions such as osteoarthritis and rheumatoid arthritis - interfere with the healing process after a bone fracture or cementless joint implant surgery.

Their findings, published in the November issue of the Journal of Orthopaedic Research, suggest that patients who regularly take COX-2 inhibitors should switch to a different medication, such as acetaminophen or codeine derivatives, following a bone fracture or cementless implant.

The study, conducted in rabbits, also suggests that physicians should consider changing prescribing patterns since many doctors commonly prescribe anti-inflammatory drugs including COX-2 inhibitors under the very circumstances in which the drugs should be avoided.

"It's very common. You break a bone and go to the ER. The doctor sets it in a splint and prescribes one of these anti-inflammatory drugs (including COX-2 inhibitors) for pain," said Dr. Stuart Goodman, professor of orthopaedic surgery at the Stanford School of Medicine and lead author of the study. "We now know that could actually delay healing."

According to a Stanford release, researchers confirmed years ago that nonspecific NSAIDS inhibited bone growth and healing, but the Stanford study is among the first to show that COX-2 inhibitors have the same effect.

In tests with rabbits, the researchers found that while the tissue in the control group contained 24.8 percent and 29.9 percent new bone growth, the tissue harvested after the rabbits consumed naproxen and rofecoxib contained significantly less – 15.9 percent and 18.5 percent respectively. The difference in new bone growth associated with the two drugs was statistically insignificant; suggesting the COX-2 inhibitor impeded new bone growth as much as the nonspecific NSAID.

While acknowledging the limitations of animal research, Goodman said this study "has great applicability to humans, because the healing process is virtually the same" for rabbit and human bones. Goodman is having his own patients avoid COX-2 inhibitors for six weeks after a fracture or joint implant, and he recommends other physicians do the same. "This research has very practical applications."

Goodman said his recommended six-week "time-out" period is an educated guess, because his study didn't address how long the bone-growth-suppressing effects of COX-2 inhibitors last. To answer that question, Goodman and his colleagues recently began a follow-up study

Progression Of RA:

French investigators have identified prognostic factors allowing prediction of radiologic damage and progression in rheumatoid arthritis. The investigators, from multiple institutions including the Federation d Rhumatologie,Centre Hospitalier Universitaire in Montpelier France,followed a cohort of 191 RA patients for up to three years. At the beginning og the study,all patients had a disease duration of less than 1 year.

Over the three year period,the change in total radiologic score for these patients was 6.1 + - 6.2. Seventy-one patients experienced radiologic progression out of 172 patients for whom data was available for the study.

Univariate analysis with Fisher's exact test showed that radiologic scores and progression were correlated with baseline values of erythrocyte sedemintation rate. C-reactive protein level,IgM and IgA rheumatoid factor positivity, antiperinuclear antibody positivity,radiolagic scores,duration of morning stiffness and rheumatoid arthritis associated HLA-DRB*04 genes.

Logistic analysis showed that only IgM rheumatoid factor positivity,DRB1*04 genes,pain score and total radiologic score at baseline were predictive for three-year radiologic scores. Baseline E.S.R.,IgM,R.F.,DRB*104 genes and erosions score were predictive for progression of joint damage.

Cytokine and enzymes produced by the tenosynovium contribute to tissue destruction in RA. Researchers from the Imperial College School of Medicine,London England,examined 17 specimens of encapsulating tenosynovium,invasive tenosynoviums and 17 wrist extensor tenosynovectomy.

Researchers quantified levels of tumour necrosis factor alpha (TNF), interleukin-6(IL-6),vascular endothelial growth factor (VEGF),matrix metalloproteinases (MMPs) 1,2,3, and 13 as well as tissue inhibitor of metalloproteinases 1 (TIMP-1).

MMP-1 and MMP-13 levels were approximately 2.5 fold higher in the invasive tenosynovium samples compared to the encapsulating tenosynoviums. However,MMP-13 levels as well as IL-6 expression-were lower in encapsulating tenosynoviums than the wrist synovium samples.

Morever,MMP-2 expression was around 1.5 fold higher in invasive tenosynovium compared with encapsulating tenosynoviums and wrist samples. On the other hand, VEGF,TIMP-1 and MMP-3 expressions did not significantly differ between the encapsulating tenosynovium,encapsulating tenosynovium and wrist joint samples.

Researchers assessed synovium samples from nine patients using zymography. All samples showed enzymatic activity. The authors concluded that proinflammatory cytokines and proteolytic enzymes produced by the tenosynovium contribute to the tissue destruction characteristic of RA.

The researchers argued that increased production of MMP-1,MMP-2 and MMP-13 might explain why invasive tenosynovium is assocciated with poorer prognosis and higher rupture rates than other synovium samples.

Finally,they suggested that the increased VEGF expression might suggest that agiogenesis contributes to tenosynovial proliferation and tendon invasion. --Arthritis and Rheumatism/01.

Things Important To Control RA:

Some are already implemented,others are in the laboratory stage,there are things we must consider and on some,we must investigate further

B cells,because they make certain antibodies that attack joints and tissues in RA,might be removed or destroyed,in hopes that the new population of B cells that the immune system would make to replace the troublemakers would not make these destructive antibodies.

Chemical messages come from the tissues where RA is beginning and move to the local blood vessels. There,those chemicals help to fashion proteins along the vessel lining as well as proteins on the outer membrances of the white blood cells that flow by.

The hungry macrophages,some of which are already in the tissues and the many others that are recruited from the blood,are central players in RA. They excite T cells,they pour out inflammatory chemicals (cytokines), and even assist in bone and cartilage destruction. Reducing or eliminating their numbers is the goal.

T cells are in the mainstream of immune system reactions. They recognize substances (antigens) presented to them by specialized cells such as macrophages. The T cells become activated and go on to perpetuate inflammation and damage to the joints. The T cells communicate with other cells,by sensing specific chemicals on the cell surfaces.

Each of the cytokines,those chemical messengers-TNF-alpha and IL-1 that literally run the immune system reactions are prime targets.

In the destruction of cartilage and bone,powerful enzymes that damage those tissues are secreated by cells that have been excited by cytokines. A way to reduce or eliminate that flood of corrosive chemicals would reduce or prevent the painful damage.

Scientist are already making progress in varying degrees in a attempt to accomplish the ultimate.

In rheumatoid arthritis (RA) patients, the amount of interleukin (IL)-1beta released by peripheral blood cells appears to predict the patient's response to methotrexate therapy, according to a recent report. Specifically, the amount released is directly related to the likelihood of a good or excellent response.

Dr. Michael Seitz and colleagues, from University Hospital in Bern, Switzerland, assessed the outcomes of 50 RA patients who were treated with methotrexate for 6 months. Prior to starting therapy, peripheral blood mononuclear cells (PBMC) were obtained from the patients and analyzed for cytokine expression.

Based on their clinical features at 6 months, the patients were classified as excellent, good, poor, or non-responders to methotrexate therapy. The authors' findings are published in the January issue of The Journal of Rheumatology.

Compared with nonresponders, good or excellent responders included a higher proportion of male patients. In addition, good or excellent responders had a significantly lower IL-1ra/IL-1beta ratio than did nonresponders (p < 0.00001). Further analysis revealed that the lower ratios in good or excellent responders were due to increased IL-1beta release from PBMCs.

The researchers also noted a slight, but significant increase in soluble TNF receptor p55 and p75 levels in good and excellent responders.

"Determination of cellularly produced IL-1beta and even more of the IL-1ra/IL-1beta synthesis in PBMC may be useful to predict the outcome of RA patients undergoing treatment with methotrexate and may characterize a subset of RA that is more responsive to IL-1 directed therapeutic interventions," the investigators state.