Biological response modifiers (BRMS) are drugs that target inflammatory pathways in rheumatoid arthritis (RA) and represent a relatively new approach to the treatment of RA.

Medications that block tumor necrosis factor alpha (TNF-a), a pro-inflammatory cytokine important in the pathogenesis of RA, were among the first to be developed and approved for the treatment of RA. Several anti-TNF-a medications including Enbrel, Humira, and Remicade are currently marketed for the treatment of RA.

Actemra (tocilizumab) differs from currently marketed biological response modifiers that block TNF-a, since it targets interleukin-6 (IL-6), a cytokine that is also over-produced in the joints of RA patients.

Il-6 is believed to contribute to inflammation, swelling and joint damage and possibly the anemia and platelet elevation counts seen in RA.

Actemra is a humanized anti-human IL-6 receptor monoclonal antibody that works by competitively blocking the binding of IL-6 to its receptor. In essence, it inhibits the deleterious effects of IL-6, which lead to inflammation and proliferation of inflammatory cells and the destructive organ potential in RA.

Multiple clinical trials have examined the efficacy and safety of Actemra.

The largest of these trials was the OPTION (TOcilizumab Pivotal Trial in Methotrexate Inadequate RespONders), a three-arm, randomized, double-blind, controlled study designed to compare the safety and efficacy of Actemra plus methotrexate with methotrexate plus placebo in RA patients who had an inadequate response to methotrexate alone.

Results from the OPTION trial demonstrated that rheumatoid arthritis (RA) patients not only achieved greater improvement of symptoms but also a higher quality-of-life with Actemra compared with methotrexate, a commonly used RA treatment.

In the OPTION trial, which was a three-arm, double-blind, controlled Phase III study, 623 patients were randomized to receive Actemra intravenously (either 4mg/kg or 8mg/kg) every four weeks plus methotrexate weekly or placebo infusions plus methotrexate weekly. The study was conducted in 73 trial sites in 17 countries outside the United States.

A rapid decrease in disease activity was seen as early as two weeks in a greater proportion of patients treated with Actemra plus methotrexate, with 27.5% achieving clinical remission by 24 weeks.

Additionally, results showed that 80% of patients in the Actemra plus methotrexate group responded with moderate to good improvements in RA symptoms, compared with 35% for those treated with placebo and methotrexate at 24 weeks.

The OPTION trial also assessed physical function and quality-of-life at baseline and every four weeks thereafter. Patients receiving Actemra achieved significantly greater improvement in areas of fatigue and mental function at 24 weeks, and achieved normal levels of hemoglobin (red blood cell count)and C-reactive protein (CRP), a marker of inflammation due to RA, compared with patients receiving placebo plus methotrexate. In addition, platelets, blood cells that often increase in number during the inflammation that accompanies RA, seemed to drop as well.

According to Dr. Nathan Wei, “The advantage of Actemra is that it offers treating rheumatologists another weapon in our arsenal for treating rheumatoid arthritis. Nowadays, it is my expectation that when I see a patient with rheumatoid arthritis, I can count on getting them into remission. It may be only a short time into the future that we will be able to cure this disease.”

Roche, the manufacturer of Actemra in the United States, announced that the Arthritis Advisory Committee of the U.S. Food and Drug Administration (FDA) by a near unanimous (10-1) vote recommended approval of Actemra (tocilizumab), a novel interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody, for reducing the signs and symptoms in adults with moderate to severe rheumatoid arthritis (RA).

Biologic therapy has revolutionized our approach to the treatment of rheumatoid arthritis (RA). Less than 10 years ago, the best we could hope for was to “modify disease” or slow it down and also help with symptoms. Now the goal is to not only control symptoms, it is to get RA into complete remission. Biologics are protein-based medicines that are synthesized in a laboratory. They act like laser beams to target the immune abnormalities that are felt to cause RA.

First generation biologics such as etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) are known as TNF-inhibitors and have done wonders for many patients. Second generation biologic such as rituximab (Rituxan) which acts against B cells and abatacept (Orencia) which works on T cells are both welcome additions to the arsenal of weapons available to combat RA.

Cimzia (certolizumab) is an investigational TNF-inhibitor. It differs from the current crop of TNF-inhibitors since it is “pegylated.” This means that a substance called polyethylene glycol has been attached to the molecule. This pegylation lengthens the half-life of the drug- meaning the drug stays in the system longer. Cimzia also has had a piece of protein removed from the molecule. The piece of protein that has been removed contained a small amount of mouse protein (yes… these drugs are often created using mouse proteins). By removing the piece of mouse protein, it is hoped that Cimzia will cause fewer adverse reactions.

A recent presentation on June 14, 2007 at the annual meeting of the European Congress of Rheumatology (EULAR) described data on Cimzia.

The team studied 2 dose regimens, which patients received subcutaneously as add-on therapy to methotrexate.

In a phase 3, multicenter, double-blind, placebo-controlled, parallel-group study, the investigators recruited 992 patients with RA who received either the study drug or placebo. The investigators wanted to know the rate at which people had a 20% improvement, as defined by the American College of Rheumatology criteria (ACR 20).

The patients, who had previously been treated for at least 6 months with methotrexate, were randomized to treatment with either pegylated certolizumab or placebo. Those on treatment received 3 400-mg doses every 2 weeks, followed by 200 or 400 mg doses of certolizumab pegol every 2 weeks. The patients continued methotrexate as usual. The investigators assessed the efficacy and safety parameters at 2-week intervals.

In an early analysis at 24 weeks, the investigators found that 581 patients completed the study: 259 of the 397 on 200 mg of the drug, 278 of the 394 on 400 mg, and 44 of the 201 on placebo. The ACR20 response rate was 59.2% in the 200 mg group, 61.2% in the 400 mg group, and 13.5% of those who received methotrexate and placebo. The proportion of patients who experienced a significant side effect was 74.0% in the 200 mg group, 76.1% in the 400 mg group, and 57.7% in the placebo group. The majority of adverse events were mild to moderate.

“Pegylated certolizumab adds significant benefit in reducing the signs and symptoms of RA in combination with methotrexate, compared to using methotrexate alone,” said lead investigator Edward C. Keystone, MD, professor of medicine at the University in Toronto, and director of the Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, in Ontario.

Bottom line: Pegylated certolizumab works like a TNF blocker and appears to treat the signs and symptoms of RA. Whether it’s better than the TNF blockers that are currently available is still no known. It is better than placebo.

Rheumatoid arthritis is one of 100 different types of arthritis. This disease is somewhat different as it is also considered an auto immune disease. An immune disease is caused when the bodies own immune system begins attacking itself. When a patient has rheumatoid arthritis the joints are primarily affected, but other organs of the body are also attacked. This disease progresses at a different rate with every patient, and can become so severe by deforming the bones, that a patient unable to walk, or use their hands. A proper treatment for rheumatoid arthritis has to be carried out by a rheumatologist, a specialist in this field of arthritis.

Some symptoms of rheumatoid arthritis include, the joints being red, swollen or warm to the touch, limited range of motion, severe pain and ability to move in the mornings. If these symptoms occur, a visit to the doctor is highly recommended.

Treatment for rheumatoid arthritis can vary greatly. The rheumatologist will put together a treatment plan, and this can change as the disease progresses. One class of drugs used as a treatment for rheumatoid arthritis is the DMAR drugs (Disease Modifying Anti Rheumatic drugs). These medications are thought to slow down the progression of the disease, but may not fully put it in remission. The medications in this class of treatment for rheumatoid arthritis include, Gold shots, Methotrexate, Plaquenil, Penicillamine and Sulfasalazine. These medications have been in use for many decades, and seem very efficient for many patients.

As with any drug protocol, the treatment for rheumatoid arthritis with this group of drugs is associated with some possible side effects. It is important to always discuss possible side effects with a doctor. Another group of drugs used for the treatment of rheumatoid arthritis is a group known as Biologics. These include Enbryl, Humira and Remicade.

Often, patients with rheumatoid arthritis can end up taking a combination of drugs to help with this disease. The treatment of rheumatoid arthritis can change as the condition changes. In addition to the two main groups of drugs, there are also steroids that can be used and NSAIDs(non-steroid anti inflammatory) group of medications. These can be used in conjunction with other treatment for rheumatoid arthritis to help control the joint swelling and pain.

Getting on the right treatment for rheumatoid arthritis can help patients not only feel better, but slow this progressive disease down.

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