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New Therapeutic Advances

Recently, many new agents to treat rheumatoid arthritis have been developed or are under investigation. Traditional antirheumatic drugs suppress the inflammatory response and slow the process of joint destruction. Yet the mechanisms of action for these drugs are nonspecific. Newer drugs have been designed to target the inflammatory process and specific components in the inflammatory cascade. The newer biotechnology agents have been designed to target components of the immune system involved in inflammation, while preserving the integrity of the immune system to fight off infection. Another relatively new approach is the use of combination therapy with various DMARDs in the hope that combining drugs with different mechanisms of action will provide added benefit.

Cox Inhibitors: The variation in GI side effect profiles of NSAIDs may be due to the COX selectivity of individual drugs. COX serves as the rate-limiting enzyme in prostaglandin production. Inhibiting this enzyme decreases prostaglandin-induced initiation and maintenance of inflammatory responses. Two isoforms of COX have been identified (COX-1 and COX-2).27 COX-1 is beneficial in helping to maintain normal cellular physiologic processes in the GI tract, kidneys, and blood. In the gut, COX-1 stimulates the secretion of bicarbonate and mucus, and reduces stomach acid secretion. All of these actions are protective for the lining of the stomach against irritants. COX-2 is involved in selectively activating pro-inflammatory cytokines and does not have a gastroprotective effect. Therefore, the ideal agent would selectively inhibit COX-2 to reduce the inflammatory response but also maintain the GI and renal protective nature of COX-1.29 NSAIDs have been developed to be COX-2 selective, or combined with synthetic prostaglandins to minimize GI intolerance. Of the NSAIDs on the market, etodolac (Lodine) and nabumetone (Relafen) are the most selective agents for COX-2 and have the lowest incidence of GI and renal side effects. Piroxicam (Feldene), indomethacin (Indocin), naproxen (Naprosyn), and sulindac (Clinoril) have a greater affinity for inhibiting COX-1 and therefore an increased risk of GI and renal problems. Flurbiprofen (Ansaid), ibuprofen (Motrin), meclofenamate sodium (Meclomen), and diclofenac (Voltaren) show equal affinity for COX-1 and COX-2 inhibition. While the clinical relevance of COX-2-selective NSAIDs is unclear, these agents may prove beneficial in patients requiring long-term NSAID therapy who are predisposed to developing adverse GI effects. COX-2 selective agents would inhibit the inflammatory response but maintain the GI protective properties of COX-1. Studies using one of the first COX-2 inhibitors, meloxicam, demonstrated that selectively inhibiting COX-2 improved GI tolerability while maintaining therapeutic effectiveness. An FDA advisory panel has recommended approval of Celecoxib (Celebra), which in Phase III trials shows promising results for pain reduction and joint swelling. In a clinical trial enrolling 300 patients with active RA, celecoxib was administered to patients experiencing an acute flare. Patients given either 200 mg BID or 400 mg BID had a statistically significant improvement. Patient global assessment scores, duration of morning stiffness, and number of painful or tender joints all improved compared to placebo. A COX-2 inhibitor by the name of Vioxx will be undergoing clinical trials in late 1998. Preliminary research shows a significant improvement in preventing GI mucosal damage when compared to aspirin and ibuprofen.

Biotechnology: Biotechnology is playing an increasing role in the development of novel approaches to manage rheumatoid arthritis. Molecular technology has permitted the identification of specific cell components and cell surface markers that contribute to the immune-mediated response in rheumatoid arthritis. Although the etiology of rheumatoid arthritis remains unknown, this increased understanding of the pathogenesis provides opportunities to target the immune system with specific therapies. Several biologic agents developed for the treatment of rheumatoid arthritis include monoclonal antibodies, recombinant interleukin-1 receptor antagonists, and recombinant soluble tumor necrosis factor receptor.

The role of cytokines in rheumatoid arthritis is a concept that has been explored for many years. Identifying a T-cell mediated immune response was the first step in targeting the inflammatory response in rheumatoid arthritis. The concept of activated T-cells both initiating rheumatoid synovitis and maintaining chronic RA has focused new attention on specific pro-inflammatory cytokines such as IL-1 and TNF-a. These cytokines are believed to be directly responsible for the clinical manifestations of rheumatoid arthritis, and therapies are being developed to specifically target these areas.

Monoclonal Antibodies: Monoclonal antibodies (MAbs) have been developed to bind to receptors on the surface of T-cells, thus interfering with their function or making the T-cells unavailable for binding. By binding to T-cells, MAbs disable the autoimmune response involved in inflammation and tissue destruction. This may slow the disease progression. Some trials of monoclonal antibodies (MAbs) have shown a resultant reversible depletion of T-cells that would prevent the patient from mounting a T-cell mediated immune response. IDEC Pharmaceuticals and SmithKline Beecham have partnered to develop a chimeric combination of human and monkey antibodies. This agent has proven to be less allergenic than previous products made with mouse antibody. Phase II trial results indicate an improvement >20% by American College of Rheumatology criteria in 42%–47% of patients receiving therapy with 40 mg and 80 mg, respectively. Dosages of 140 mg were also evaluated but had to be discontinued due to the development of rash. No other adverse effects were reported, and rash was not observed in patients receiving the lower dosages. Patients receiving this therapy sustained benefit for 2–3 months following discontinuation before arthritis symptoms worsened.
Other MAbs are being developed, such as an antibody that would be coupled with a cytotoxin that, when taken up into the target cell, would cause cell destruction and decrease the immune response. No agents are currently available using these techniques.

Cytokines: Tumor necrosis factor alpha (TNF-a) and interleukin-1 (IL-1) are two proinflammatory cytokines that appear to be dominant in the inflammatory response in rheumatoid arthritis. In patients with rheumatoid arthritis, there is an imbalance between proinflammatory and anti-inflammatory mediators, which may or may not be cytokines. This leads to increased activity of the proinflammatory components (TNF-a and IL-1) and inflammation at the site. By providing exogenous inhibitors such as antagonists or antibodies or soluble receptors, one may achieve an anti-inflammatory state within the joint. When administered over 6 months to patients with rheumatoid arthritis, IL-1 receptor antagonists have been shown to decrease C-reactive protein, as well as improve responses based on American College of Rheumatology clinical response criteria. Monoclonal antibodies to TNF provided the first evidence that TNF inhibitors may be useful agents in treating rheumatoid arthritis. Both open-label and double-blind, placebo controlled trials using MAbs to TNF have demonstrated significant decreases in CRP levels and number of swollen joints. Agents used to inhibit the activity of TNF-a and IL-1 have only been used as monotherapy. Combination biologics is in its infancy at this time.

TNF Receptors: The identification and isolation of soluble TNF receptors (sTNFRs) is also being pursued. sTNFRs are a naturally occurring counter-regulation mechanism to the activity of TNF. Levels of soluble receptors are elevated in both plasma and synovial fluid samples of rheumatoid arthritis patients and patients with other autoimmune and inflammatory conditions. A recombinant human TNFR fusion protein (TNFR:Fc) has been developed by Immunex to neutralize TNF. Etanercept (Enbrel) is a product of recombinant DNA technology in which the extracellular portion of two TNF receptors is linked to the Fc fragment of human IgG1 molecules and then expressed in mammalian cells. The product acts as a noncompetitive inhibitor of TNF, preventing binding of TNF to the cell surface receptor, thus reducing TNF activity.
Both Phase II and Phase III clinical trials have been conducted using etanercept. Etanercept was administered as 10–25 mg SC twice weekly. Subjects had active RA and had failed to respond to therapy with DMARDs at least once. Results show a statistically significant reduction in disease activity, which was determined using clinical endpoints (American College of Rheumatology clinical response criteria); biological markers (CRP, ESR); and quality of life assessments (health assessment questionnaire, visual analog pain scale). Clinical improvement was seen in these areas within 2 weeks of initiating therapy. Treatment was generally well tolerated, with the most common side effect reported as redness and discomfort at the injection site. There appeared to be an increased incidence of upper respiratory tract infections in patients receiving etanercept; however, this difference was not significant when the data was analyzed over time.

Soluble cytokine receptors such as etanercept may have a therapeutic advantage over other TNF agents since immunogenicity does not appear to be an issue. Nonhuman or chimeric MAb therapy often stimulates the production of antibodies which deactivate the therapeutic agent, limiting long-term use or inducing allergic reactions. In the previously mentioned Phase II and III studies involving etanercept, neutralizing antibodies were not detected. The information gathered on etanercept is promising in its therapeutic applications in rheumatoid arthritis. At press time etanercept was recommended for approval by the FDA arthritis advisory committee as a mono agent or in combination for the treatment of active rheumatoid arthritis.

Immunosuppression: Suppressing the immune response to a particular antigen can be induced by oral administration of certain antigens. This may be beneficial in treating rheumatoid arthritis since oral administration of antigens including collagen have been shown to be effective in blocking the induction of, or ameliorating, established disease. Proposed mechanisms of action include induction of anti-inflammatory cytokines (i.e., IL-4 and IL-10) and the stimulation of growth factor at the site of joint injury. Several studies have investigated oral collagen. Patients given chicken type II collagen showed statistically significant improvements in the number of swollen or tender joints while patients receiving bovine type II collagen showed only minor clinical response. More controlled trials are needed to evaluate the efficacy of orally administered type II collagen in treating rheumatoid arthritis.
Immunosuppressive agents are another growing area of development in treatments for rheumatoid arthritis. Leflunomide (Arava) is an isoxazole derivative similar to methotrexate. Current studies with the drug are focused on treating autoimmune diseases such as rheumatoid arthritis. The mechanism of action of leflunomide is not completely known; however, it is believed to interfere with T-cell proliferation, which then inhibits synthesis of pyrimidines. This decrease in pyrimidine synthesis leads to a reduced number of proinflammatory cytokines within the body. The mild anti-inflammatory effect seen with leflunomide may be attributed to this activity.
Leflunomide dosing is one 100 mg tablet daily for three days, followed by a maintenance dose of one 20 mg tablet each day. Data on the use of leflunomide in patients with RA are promising. Both Phase II and Phase III double-blind, placebo-controlled, clinical trials showed statistically significant improvement versus placebo. Patients receiving leflunomide had a decreased number of tender or painful joints, improved global patient assessment scores, and improved clinical response criteria. Clinically significant results were seen after 1 month of therapy and benefit was retained for up to 18 months. Side effects associated with leflunomide include diarrhea, reversible alopecia, and hypertension. Six percent of patients discontinued therapy due to these side effects. Leflunomide has now been approved by the FDA for the treatment of inflammatory arthritis. This new agent will provide yet another approach to treat RA and add to possible combination therapies with other DMARDs.

Combination Therapy: By combining several drugs with different mechanisms of action, a greater benefit may be achieved than if the same drugs were used independently. It may also be possible to use lower doses of the medications, therefore minimizing the toxicities associated with each drug. Combinations of DMARDs that have been evaluated in the literature include MTX and HCQ; MTX, AZA, and HCQ; MTX and gold; MTX and cyclosporin A; MTX and SSZ; MTX, SSZ, and HCQ; HCQ and cyclosporin A; and MTX and DP. Studies indicate that the combination of antimalarials and DP shows antagonism within the body. While the effectiveness of combination therapy is difficult to evaluate, these therapies have provided relief when other medications used alone failed to do so.

Rheumatoid arthritis: Conclusion

New therapies and modifications on old therapies are constantly being explored in order to improve the treatment of rheumatoid arthritis. As more is learned about the disease process and the pathophysiology behind it, improved, targeted therapies can be developed. While there is no cure yet for rheumatoid arthritis, the future is promising for finding the treatments necessary to control and suppress the disease, enabling rheumatoid arthritis patients to continue to work and more comfortably perform their daily activities.

Nonsteroidal Anti-inflammatory Drugs

OTC NSAIDs are indicated for self-treatment of pain rather than inflammation, and the dosing guidelines on the package should not be exceeded unless the patient is instructed to do so by a physician. Patients taking OTC products should be closely monitored for effectiveness of therapy and the development of toxicities. NSAIDs are the initial drug treatment of choice for rheumatoid arthritis since they work to reduce joint pain and swelling, and improve function. While their analgesic and anti-inflammatory properties provide benefit, NSAIDs do not alter the course of rheumatoid arthritis or prevent joint destruction. Their mechanism of action is related to the inhibition of prostaglandin (PG) synthesis. Cyclooxygenase (COX) serves as the rate-limiting enzyme in PG production. Inhibition of this enzyme decreases PG-induced initiation and maintenance of inflammatory responses. There is no significant clinical difference in efficacy among the NSAIDs, although patient response to individual agents varies greatly. The choice of NSAIDs should be based on cost, duration of action, and patient tolerability and acceptance. While the analgesic effect of NSAIDs is quick in onset, the anti-inflammatory effect may not be complete for 4–6 weeks. If a patient fails therapy with a particular NSAID at the recommended dosage, another NSAID from another chemical class should be tried. The side effects of NSAIDs should be considered in patients who are elderly, have comorbid disease states (hypertension, diabetes, congestive heart failure, renal failure, peptic ulcer disease), or may be taking concurrent medications (e.g., diuretics) that may reduce renal blood flow. The primary adverse effect of NSAIDs is a tendency to cause bleeding and ulcerations in the stomach. A strategy to manage this condition is to prescribe misoprostol (Cytotec) concurrently for patients to take with their NSAIDs. Since misoprostol is a synthetic prostaglandin, it both prevents and heals NSAID-induced ulcers. A fixed combination product of diclofenac and misoprostol is available commercially. This product has been designed for patients who are at increased risk of developing gastric or duodenal ulcers from NSAID therapy. Patients receiving this fixed combination therapy had a reported gastric ulcer rate of 3%–4%, compared to 11% with diclofenac alone. Combination products of misoprostol and other NSAIDs are also being developed.

Corticosteroids: Corticosteroids have been proven to rapidly and effectively reduce inflammation and relieve symptoms in patients with rheumatoid arthritis. However, the development of adverse effects with corticosteroids, when taken for extended periods of time and at higher doses, limits their use. Intra-articular injections of steroids are generally safe and effective when administered appropriately, and can provide patients with immediate relief. Injections directly into the joint may also allow the patient to regain more range of motion in joints that have become stiff and inflamed. Low-dose oral corticosteroids (10 mg of prednisone daily or the equivalent) are beneficial for patients during the following situations: acute flares, special life events, the period of therapy after a DMARD has been initiated but not yet reached full effect, or when unacceptable discomfort or functional limitations persist despite full-dose NSAID and/or DMARD therapy.

The patient should be closely monitored for the development of side effects such as adrenal suppression, Cushing’s syndrome, osteoporosis, glaucoma, cataracts, gastritis, and hypertension. In patients receiving steroids for only 1–2 weeks, the corticosteroid need not be tapered since adrenal suppression is minimal over such a short period of time. However, in patients receiving doses of corticosteroids for greater than one month, tapering should occur gradually and be proportional to the length of time that the patient was on corticosteroids. Slow tapering of glucocorticoids allows the body to resume its natural production of cortisol, which becomes suppressed when patients take exogenous sources of steroid. It may be necessary to decrease the dose of corticosteroid by 1 mg every 1–2 weeks if the patient experiences symptoms of rheumatoid arthritis or has other complaints. A goal of any corticosteroid therapy should be to limit the use of the corticosteroid and avoid long-term therapy if possible.

Disease-Modifying Antirheumatic Drugs: Since active disease leads to irreversible joint and bone damage, it is important to start patients on DMARD therapy as soon as possible. Initiation of DMARD therapy is crucial in the management of rheumatoid arthritis. For a patient with a confirmed diagnosis, therapy should not be delayed beyond three months if, despite full-dose NSAID therapy, he or she has continued joint pain, significant morning stiffness or fatigue, active synovitis, or persistent elevation in ESR. The goal is to intervene before joints become damaged. While NSAIDs and corticosteroids alleviate symptoms, joint damage can still occur during their use, and the disease will progress. Disease-modifying agents such as hydroxychloroquine (HCQ), sulfasalazine (SSZ), methotrexate (MTX), gold salts, d-penicillamine (DP), and azathioprine (AZA) are intended to reduce or prevent joint damage, preserve joint integrity and function, maintain patient productivity and reduce total healthcare costs of patients with rheumatoid arthritis.

DMARDs as a class have a relatively slow onset of effect (1–6 months) and each patient will respond differently to various agents. Each DMARD also has its own unique toxicities which require close monitoring in order to avoid adverse events (Table 2). Patients must be educated about the potential risks versus benefits before initiating therapy.

The best initial DMARD for treatment of rheumatoid arthritis has not been established. SSZ or HCQ is usually selected for patients with mild disease. Both are available generically and have convenient dosing schedules and favorable safety profiles. HCQ therapy requires no additional laboratory monitoring, although patients should receive eye exams every 6–12 months to detect the development of reversible retinal toxicity (i.e., decreased night vision, loss of peripheral vision). SSZ requires that patients have routine CBCs to detect possible development of blood dyscrasias. The onset of action of these therapies should be apparent within 1–6 months; if no response is seen after this time, a change in therapy is warranted.

Methotrexate is the drug of choice in patients who have a more severe form of the disease (for example, erosions or extra-articular manifestations). Low-dose, once-weekly therapy has become a mainstay of treatment because MTX is relatively inexpensive; the cost of monitoring for toxicity is less than that of monitoring with use of gold, penicillamine or immunosuppressive agents; and there is a high rate of clinical response. The onset of action is generally within several weeks of initiating therapy, and patients are likely to still be on treatment after 5 years. Other DMARDs do not have such a quick onset of effect or long-term patient tolerability.

Methotrexate therapy is usually initiated at 7.5 mg/week. This dosage may be either increased or decreased depending on efficacy or development of toxicity. The usual dose is from 7.5–15 mg/week. To aid patients in appropriately taking MTX therapy, specially designed dose packs are available. Each dose pack contains one month’s worth of MTX therapy. The tablets are grouped by weekly doses and clearly marked to improve patient adherence. All of the dose packs contain 2.5 mg MTX tablets but are available in different weekly doses.
Prior to beginning MTX therapy, it is necessary to perform baseline laboratory work. A CBC with differential, platelet count, liver function tests, hepatitis B and C studies, serum creatinine and chest x-ray should be obtained. Subsequently, every 1–2 months CBC with platelet count, AST, and albumin should be evaluated. These tests, along with routine chest x-rays, help to monitor for thrombocytopenia, leukopenia, anemia, renal insufficiency, liver fibrosis, and pulmonary changes that are associated with MTX therapy. Side effects such as nausea, vomiting, diarrhea, and stomatitis may develop. These side effects may be minimized with the administration of folic acid 1 mg/day. Concurrent administration of folic acid decreases the incidence of side effects by 50% without decreasing the clinical efficacy of MTX.20 It is also possible to split the MTX dose over 24 hours instead of taking all of the tablets at once, or administer MTX subcutaneously or intramuscularly should GI discomfort continue.

Contraindications and drug interactions are also considerations when initiating MTX therapy. Since it is highly teratogenic, MTX should not be given to pregnant or lactating females. Patients who are known alcoholics or have alcohol-associated liver disease should not receive MTX since hepatic fibrosis may develop. Methotrexate should also not be used in patients who are immunocompromised, are known to be nonadherent with therapy, or have existing blood dyscrasias. Patients should be educated to avoid excessive alcohol intake since it may contribute to the development of liver toxicity. Other drugs to be avoided include phenytoin (alters protein binding), trimethoprim/sulfamethoxazole (has anti-folate activity), aminoglycosides (is nephrotoxic) and probenecid (is nephrotoxic). Concurrent administration of any of these medications significantly increases the risk of developing toxicity.
Gold and penicillamine have been used for many years in the treatment of rheumatoid arthritis. Although neither agent is used frequently anymore, they may be utilized in refractory cases of rheumatoid arthritis. While patients respond successfully to gold therapy, many have to discontinue therapy within 1 year due to development of toxicity (anemia, leukopenia, thrombocytopenia, proteinuria) or decrease in efficacy. Penicillamine is comparable to gold in efficacy; however, side effects (nausea, vomiting, diarrhea, hypogeusia) limit its clinical use. A word of caution when using penicillamine is that 10% of patients who have an allergic reaction to penicillin will have a hypersensitivity to penicillamine; however, this is not an absolute contraindication to therapy

Immunosuppressive Agents: In addition to MTX, cyclophosphamide, cyclosporin A and AZA are immunosuppressive agents used to manage rheumatoid arthritis. These therapies are generally reserved for severe cases unresponsive to other treatments. These agents are effective in controlling the symptoms of rheumatoid arthritis but have the same toxicities associated with any chemotherapeutic agent. Side effects such as myelosuppression, hepatotoxicity, GI disturbances, and hemorrhagic cystitis are commonly seen with cyclophosphamide, cyclosporin A and AZA. Cyclosporin A has proven beneficial in patients who fail to respond to DMARD therapy but is more toxic than DMARDs. Women should be informed of the fetal risk associated with the agent being used, and appropriate measures should be taken to ensure effective contraception.

Management Rheumatoid arthritis

Both nonpharmacological and pharmacological modalities should be utilized to manage rheumatoid arthritis, including surgery, if indicated. Although there is presently no cure for rheumatoid arthritis, the goals of therapy are to control disease activity; alleviate pain; maintain function for essential activities of daily living and work; maximize quality of life; slow the rate of joint damage; and, if possible, induce complete remission.

Nonpharmacologic: Nonpharmacologic therapy is an important component of managing rheumatoid arthritis. These modalities help patients to manage their own disease and maintain their quality of life. Patient and family education should focus on the pathology and course of the disease; options for drug and nondrug therapy; potential drug interactions and side effects; and monitoring the progression of the disease. Physical therapy is important to preserve and maintain range of motion of joints and prevent muscle atrophy. Adequate rest will help decrease systemic inflammatory responses, protect the joints, and permit repair. The key is to maintain balance between proper rest and physical activity. To minimize joint instability and maintain strength, individualized exercise programs should be designed to move joints through their full range of motion. Occupational therapy teaches patients how to manage activities of daily living (ADLs) and properly use supportive devices such as canes or splints, which may become necessary as the disease advances. Support services such as the Arthritis Foundation and local patient support groups can significantly benefit patients and their families.

Pharmacologic: Agents available to manage rheumatoid arthritis continue to increase in number. Historically, the pharmacologic approach to managing rheumatoid arthritis was represented as a pyramid. Therapy was initiated with salicylates or nonsteroidal anti-inflammatory drugs (NSAIDs). When this therapy was no longer effective in providing symptom control, patients would move to the next level — disease-modifying anti-rheumatic drugs (DMARDs). DMARDs may help to slow progression of the disease or induce remission. If DMARDs do not achieve desired results or the patient develops toxicity, options are limited and patients often are placed on combination therapy or experimental protocols.
The pyramid was designed to start patients on what was believed to be the least toxic medication during the early stages of the disease. As the disease progressed, more toxic medications were used. While NSAIDs are at the bottom of the pyramid, such side effects as GI ulcerations and changes in kidney function can be problematic, especially in the elderly. It has been recently recognized that joint and bone erosion can develop after only a couple of months of experiencing rheumatoid arthritis symptoms; therefore, the pyramid approach has been largely abandoned in favor of more aggressive therapy given early in the disease.
Wilske and Healey proposed a “step-down bridge” alternative to the pyramid for the treatment of rheumatoid arthritis. They suggested that combinations of drugs given early in the disease may induce remission and prevent joint destruction. Patients were started with a fast-acting anti-inflammatory (corticosteroid). If symptoms persisted after one month, a DMARD was added to the regimen. After three months, the patient was tapered off the steroid and continued on the DMARD. In order to control acute flare-ups, patients were given methotrexate and, as needed, steroids. A variation on this treatment strategy, the “sawtooth approach,” utilizes combinations of DMARDs and substitutes new agents if benefit from the original agents is lost. Patients are then gradually tapered off the various medications, leaving them on a single DMARD. Critics of the “step-down bridge” approach state that it unnecessarily exposes patients to toxic medications. Since it is not possible to determine which patients will develop aggressive disease, exposing all patients to combination therapy adds additional costs for drugs and monitoring. The risk–benefit ratio for combination therapy is still being evaluated. Some patients displaying less than optimal response may benefit from the use of combinations of DMARDs.

Over-the-counter (OTC) salicylates and NSAIDs include aspirin, ibuprofen, magnesium salicylate, naproxen, and ketoprofen (Table 1). The anti-inflammatory response desired in rheumatoid arthritis is achieved at higher doses than those recommended on the OTC product labeling.

Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology in which the synovium, or joint lining, is attacked by the immune system; the resulting inflammation leads to destruction of the synovium and surrounding joint. A chronic disease, rheumatoid arthritis requires early diagnosis and aggressive treatment in order to minimize the morbidity associated with its advancement. Rheumatoid arthritis affects 1% of the population — approximately 2.5 million Americans. Most patients diagnosed are between the ages of 35–50; however, about 20% of patients are diagnosed with rheumatoid arthritis after the age of 60, with an overall prevalence of disease in the over-60 population of 2%–3%. Women are three times more likely than men to develop rheumatoid arthritis and typically experience a more severe and debilitating form of the disease. There appears to be a genetic tendency in developing rheumatoid arthritis since first-degree relatives of patients seropositive for rheumatoid factor have a three- to four-fold increased risk of developing rheumatoid arthritis themselves.

Rheumatoid arthritis mainly affects the small joints of the hands, wrists, and feet, although larger joints such as hips, knees, and shoulders, may also be involved. Joint swelling, erythema, stiffness, warmth, and pain are classic symptoms of early disease. As rheumatoid arthritis progresses, joint deformities such as subluxation of the wrists, swan-neck and Boutonniиre deformities of the fingers develop, resulting in permanent disfiguration and disability. Patients may also develop extra-articular manifestations, such as soft tissue nodules, pericarditis, neuropathies, muscle atrophy, and fatigue.

Rheumatoid arthritis is associated with several clinical laboratory abnormalities. Normochromic, normocytic anemia (anemia of chronic disease) is present in about half of patients. The erythrocyte sedimentation rate (ESR) is elevated in 85%–95% of patients due to the inflammatory component of rheumatoid arthritis. ESR is not diagnostic for rheumatoid arthritis, and the results should be interpreted carefully since this value may increase with normal aging, infection, or inflammatory conditions. Aspirate of the synovial fluid from affected joints will show increased numbers of white blood cells and is often turbid in appearance, another indication of inflammation. Rheumatoid factor is present in 60%–70% of patients with rheumatoid arthritis. While the test is not specific for rheumatoid arthritis, it does provide a marker to gauge the severity of disease. By performing serial dilutions, one can determine the concentration of rheumatoid factor. Higher dilutional titers usually indicate more severe disease. Patients may also have elevated C-reactive protein (CRP) and decreased serum albumin.
Rheumatoid arthritis is a difficult disease to manage due to the waxing and waning nature of the symptoms, and prognosis is directly related to onset of disease. Approximately 80% of rheumatoid arthritis patients experience a cyclical pattern, in which periods of remission lasting up to a year are followed by disease flares. About 10% of patients will have one acute episode of arthritis and then enter a spontaneous permanent remission. Another 10% have a severe, debilitating form of the disease that leads to severe bone erosion and joint deformity. Patients with a rapid, sudden onset are more likely to have remission within the first year. A more gradual onset, over 6 months, is indicative of a persistent disease that may not remit. Poor prognostic indicators include high levels of rheumatoid factor, extra-articular manifestations, diagnosis at younger than 30 years of age, and female gender.