Rheumatoid Arthritis

There are over 2.1 million people in the USA suffering from this condition. Rheumatoid Arthritis (RA) is a systemic inflammatory arthritis that can cause serious deformities. It can present symptoms at any age, even in children, and can also manifest itself with constitutional symptoms, including fevers, fatigue, and stiffness. Because other conditions may mimic Rheumatoid Arthritis, there are criteria to define this diagnosis more accurately.

In particular, joint stiffness and swelling that persists over 6 weeks can make your physician more suspicious of possible RA. There are laboratory tests that can also help in the diagnosis of RA. Over 80% of RA patients may have a positive rheumatoid factor. A newer test for RA is ‘anti-CCP’ or anti-cyclic citrullinated peptide antibody, which can be seen in more aggressive disease. Even if the rheumatoid factor is negative, anti-CCP can be positive in certain cases.

Anemia, elevated sedimentation rate or elevated C-reactive protein can also be found in RA. Systemic manifestations of RA may include inflammation of the heart, lungs, or eyes, as well as inflammation of blood vessels (vasculitis), among other manifestations. X-ray changes initially may be within normal limits, but sometimes peri-articular osteopenia (loss of calcium) around the joints may be seen in early RA. Erosions and joint damage can be evident as the condition progresses. The joints most affected include the hands and feet. In particular, the small joints closest to the palms are affected. Also, knees, neck, and wrists can be involved in RA.

A physical exam, X-rays, and lab tests are needed to diagnose RA. Although there is no cure, there are several exciting therapies that offer excellent control of the condition; these are mainly classified as ‘DMARDs’, or Disease Modifying Anti-Rheumatic Drugs. Remission may be achieved in some cases. COX-2 inhibitors, such as celecoxib (Celebrex.com) are effective against inflammation and for pain management in this condition. Traditional NSAID’s such as ibuprofen and naproxen also have proven to be effective for RA. However, celecoxib has a demonstrated advantage over traditional NSAID’s with regard to gastrointestinal safety (lower risk of severe gastric bleeds). Any of these medications must be selected in close consultation with your physician, especially if there exists a history of hypertension, cardiac disease, or chronic edema (leg swelling).

Again, the mainstay therapies for RA are the DMARD’s. Methotrexate remains the first line drug of this class, to which newer medications are compared. Leflunomide can best be described as a DMARD that is similar in efficacy and side effect profile to Methotrexate. Methotrexate or leflunomide (Arava.com) are used alone or more commonly in combination with the newer, biological DMARD’s, which include adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®), Certolizumab Pegol (Cimzia®), Golimumab (Simponi™), anakinra (Kineretrx.com), abatacept (Orencia.com), and rituximab (Rituxan.com). There are additional biological DMARD’s awaiting FDA approval for RA. In some instances, corticosteroids are needed to control the inflammation associated with RA. In cases of advanced joint damage, surgery is sometimes needed to repair or replace joints. Physical therapy and exercise are essential to preserve muscle strength and range of motion throughout rheumatoid arthritis therapy.

All these DMARD’s, like any other medication, can have significant side effects, and require careful monitoring by a rheumatologist. However, they can dramatically improve quality of life and may delay or even stop progression of RA joint damage.

Please consult your physician if you suspect signs of this serious condition.

 

Multiple-DMARD (Disease Modifying Anti-Rheumatic Drug) Therapy

 

Rheumatologists do not all take the same position on combination DMARD therapies. A small minority of rheumatologists may choose to offer only one DMARD, and it all depends on what is appropriate for each individual patient. Provided that the Rheumatologist incorporates valid disease monitoring tools, and alters the dosage and DMARD chosen to reach desired results, this may be a viable approach for a given patient. This single DMARD therapy approach is most applicable to mild rheumatologic disease.

Most American rheumatologists, including myself, recommend a weekly dose of oral methotrexate as the starting point of treatment, unless contraindicated. This is especially true in moderate to severe Rheumatoid Arthritis (RA). We would then consider combination therapy alternatives, by adding a different DMARD, to optimize control of the RA. This class of medications includes biologicals (8 biological therapies approved, with 4 distinct methods-of-action), as well as hydroxychloroquine (Plaquenil), sulfasalazine (Azulfidine), or leflunomide (Arava), as warranted. It is not unusual for the RA patient to take 2 to 3 different DMARDs, depending upon the severity of their condition. The classic "triple therapy" in the past had been methotrexate, sulfasalazine and hydrochloroquine. This combination has been replaced by the more common combination of methotrexate with a biological therapy.

As of this writing (June, 2009), the combination of one of the biological TNF blockers, either by self-injection or intravenous infusion, in conjunction with methotrexate weekly (oral or injectable) is considered the gold standard for maximum benefit. There are now five biological DMARD’s that block TNF activity: adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®), Certolizumab Pegol (Cimzia®), and Golimumab (Simponi™).   They have been proven to reduce progression of joint damage and inflammation of the joints, resulting in a reduction of permanent joint deformities, and improvement in the quality of life of the patient.  

Two non-TNF blockers that are intravenously administered have been available for several years now, namely rituximab (www.Rituxan.com) and abatacept (http://www.orencia.com), both approved in February of 2006.  FDA approval for moderate to severe RA therapy has been established for these two medications. Rituximab is a monoclonal antibody against CD-20, a protein in B cells, and is indicated for patients who have failed TNF blockers. Rituxan has also been indicated for therapy against diffuse large B-cell Non-Hodgkin’s lymphoma since 1997. In contrast, Abatacept is a recombinant human fusion protein called CTLA4-Ig. It works as a selective co-stimulation modulator of T cells through CD80/86:CD28 cytokines. Several other therapies are on the horizon, with novel approaches for RA control and joint preservation.

Only since the 2^nd quarter of 2009 have Certolizumab Pegol (Cimzia®), and Golimumab (Simponi™) been approved by the FDA for RA.  Cimzia® was approved in the 2^nd quarter of 2008 for Crohn’s disease, and now has RA indication; whereas Golimumab is approved for use in rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, as shown in the chart below.  Both of these new medicines use a subcutaneous injection. Golimumab and certolizumab are both pegylated monoclonal antibodies against tumor necrosis factor (TNF), and thus are classified with the biological DMARD therapies commonly called TNF-blockers.  Cimzia® uses either a self-injectable pre-filled syringe, or a lyophilized powder for solution, that must be reconstituted by a Physician..  Simponi™ uses either a pre-filled syringe, or a pre-filled auto-injector called SmartJect™ and is to be taken either alone, or with a complementary dosing of methotrexate.  Both are monoclonal antibodies.  As noted, Cimzia® and Simponi™ are both tumor necrosis factor (TNF)-blockers.

New biological DMARD’s are already awaiting FDA approval, such as denosumab and tocilizumab. These proposed therapies work by modulating different cytokines than the other available biological DMARDs, offering new targets to RA therapy. Some of the available DMARD therapies may have other indications (such as treating other inflammatory processes) besides RA; these may be indicated in the following table, but non-inflammatory processes will not be shown.

 

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