Rheumatoid Arthritis (RA) Pharmacological Strategies

There are three general classes of drugs commonly used in the treatment of rheumatoid arthritis: non-steroidal anti-inflammatory agents (NSAIDs), corticosteroids, and disease modifying anti-rheumatic drugs (DMARDs). NSAIDs and corticosteroids have a short onset of action while DMARDs can take several weeks or months to demonstrate a clinical effect. DMARDs include methotrexate, sulfasalazine, leflunomide (Arava®), etanercept (Enbrel®), infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), golimumab (Simponi®), abatacept (Orencia®), rituximab (Rituxan®), tocilizumab (Actemra®), anakinra (Kineret®), antimalarials (e.g. Plaquenil®). Other immunomodulators are occasionally used including azathioprine (Imuran) and cyclosporine. Because cartilage damage and bony erosions frequently occur within the first two years of disease, rheumatologists now move aggressively to a DMARD agent early in the course of disease, usually as soon as a diagnosis is confirmed. Analgesic drugs are also sometimes helpful in decreasing pain until DMARDs take effect. A summary table of how to monitor drug treatment in rheumatoid arthritis is included.

Non-steroidal Anti-inflammatory Agents (NSAIDs)

The major effect of these agents is to reduce acute inflammation thereby decreasing pain and improving function. All of these drugs also have mild to moderate analgesic properties independent of their anti-inflammatory effect. It is important to note however that these drugs alone do not change the course of the disease of rheumatoid arthritis or prevent joint destruction.

Aspirin is the oldest drug of the non-steroidal class, but because of its high rate of GI toxicity, a narrow window between toxic and anti-inflammatory serum levels, and the inconvenience of multiple daily doses, aspirin’s use as the initial choice of drug therapy has largely been replaced by other NSAIDs. There are a large number of NSAIDs from which to choose, and at full dosages all are potentially equally effective. Likewise, the toxicities of the currently available NSAIDs are similar. However, there is a great deal of variation in tolerance and response to a particular NSAID. Many different NSAIDS are available, some over the counter including ibuprofen (Advil ®, Motrin®, Nuprin ®) and naproxen (Alleve®) and many others are available by prescription including meloxicam (Mobic®), etodolac (Lodine®), nabumetone (Relafen®), sulindac (Clinoril®), tolementin (Tolectin®), choline magnesium salicylate (Trilasate®), diclofenac (Cataflam®, Voltaren®, Arthrotec®), diflusinal (Dolobid®), indomethacin (Indocin®), ketoprofen (Orudis®, Oruvail®), meloxicam (Mobic®), oxaprozin (Daypro®), and piroxicam (Feldene®). Longer acting NSAIDs that allow daily or twice daily dosing may improve compliance. The NSAID class also includes drugs known as COX-2 inhibitors that are also effective in controlling inflammation. Only one of these agents is currently available in the United States (celecoxib, Celebrex®) while additional compounds are available in other countries (etoricoxib, Arcoxia®; lumiracoxib, Prexige®). These drugs were designed to decrease the gastrointestinal risk of NSAIDS, but concerns of possible increases in cardiovascular risk with these agents has led to the withdrawal of two of these drugs from the market (rofecoxib, Vioxx®; valdecoxib, Bextra®).

Mechanism:

NSAIDs inhibit the generation of prostaglandins by blocking cyclooxygenase enzymes, COX-1 and COX-2. Prostaglandins are mediators of inflammation and pain but also have important roles in maintenance of normal body functions including protection from stomach acid, maintenance of kidney blood flow, and contributing to platelet stickiness and vascular function. COX-2 selective inhibitors selectively block prostaglandins generated via COX-2 which have prominent roles in inflammation.

Dosage:

While in some cases, lower doses of NSAIDS are effective, in rheumatoid arthritis and other forms of inflammatory arthritis a higher dose is often required to decrease inflammation. A lower dosage can initially be used if inflammation is mild, if mechanical pain is the major problem, if the patient is elderly or if the patient suffers from conditions that increase the risk for toxicity (see below). If a particular preparation is ineffective after a 4-week trial or is not tolerated, then another NSAID can be initiated. No one NSAID has been demonstrated to be better than another for the treatment of rheumatoid arthritis nor have the COX-2 agents been shown to be superior to traditional NSAIDS in terms of effectiveness.

Usual Time to Effect:

Although these agents have anti-inflammatory effect within hours, a reasonable trial period is a few weeks to 1 month.

Side Effects:

The most common toxicity of NSAIDs is gastrointestinal disturbance which may clinically include burning, belching, or irritation, but which can represent irritation of the lining of the stomach, erosions, and even ulcerations that can result in bleeding.  While taking the medication with food may eliminate some of these symptoms, this does not decrease a risk of bleeding. The co-administration of medications known as proton pump inhibitors such as omeprazole (Prilosec®), Lansoprazole (Prevacid®), Esomeprazole (Nexium®),  Pantoprazole (Protonix®), and Rabeprazole (Aciphex®),  and a medication that provides back protective prostaglandins called misoprostol (Cytotec®) can also decrease gastrointestinal bleeding associated with these medications.  Misoprostol is combined in a single pill with the NSAID diclofenac (Arthrotec®). Selective COX-2 inhibitors exhibit safer GI profiles than conventional non-selective NSAIDs.

Because prostaglandins play a role in the regulation of the blood flow in the kidneys and maintenance of glomerular filtration, NSAIDs can also impair renal function in certain patients leading to salt retention, edema, and increased blood pressure. The patients at highest risk are those with fluid imbalances or with compromised kidney function (e.g., heart failure, diuretic use, cirrhosis, dehydration, and renal insufficiency). NSAIDs may also increase cardiovascular risks by their effects on blood pressure and additional effects on vascular beds.  Thus the use of this class of medications must into account their relative risks in an individual patient of gastrointestinal damage versus potential cardiovascular risk factors.

Corticosteroids

Corticosteroids (such as prednisone; methylprenisolone, Medrol®) have both anti-inflammatory and immunoregulatory activity. They can be given orally, intravenously, intramuscularly or can be injected directly into the joint. Corticosteroids are useful in early disease as temporary adjunctive therapy while waiting for DMARDs to exert their antiinflammatory effects. Corticosteroids are also useful as chronic adjunctive therapy in patients with severe disease that is not well controlled on NSAIDs and DMARDs. The usual dose of predinisone is 5 to 10mg daily. Although prednisone can be started at higher doses (15 to 20mg daily), attempts should be made to taper the dose over a few weeks to less than 10mg daily. Once started, corticosteroid therapy may be difficult to discontinue and even at low doses. Some patients are very sensitive to the tapering of prednisone which may be done slowly over a few weeks.

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