Rheumatoid Arthritis

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[edit] Rheumatoid Arthritis

Tammi L. Shlotzhauer

James L. McGuire✢

Deceased. Rheumatoid arthritis (RA) is a chronic inflammatory arthritis characterized by symmetric, erosive synovitis.The etiology of RA is unknown, with several factors under consideration.Genetic influences are suspected because human leukocyte antigens HLA-DR4 and HLA-DR1 have been associated with RA.Many theories suggest an infectious agent acting as an environmental trigger without persisting in the host.These arthritogenic agents may induce autoimmunity in the genetically susceptible individual.The initiation and perpetuation of chronic inflammation may be influenced by other factors, including cytokine activity and hormonal influences.

Once considered as a benign disorder, RA is now known to cause significant morbidity and decreased life expectancy.Prompt aggressive treatment is warranted in patients with RA, particularly those with poor prognostic factors.^[1] RA affects about 1% to 2% of the adult U.S.population, an estimated 3 to 5 million Americans.Women are three times as likely as men to develop RA.The peak onset is ages 30 to 50, with all races affected.^[2]

[edit] PATHOPHYSIOLOGY

Previously the pathophysiology within the joint in patients with RA was broadly divided into inflammatory and proliferative phases.It was assumed that the inflammation occurred first, usually in response to a series of external agents (infectious, hormonal, environmental) in the susceptible individual.The inflammatory response became chronic and supported the development of the proliferative phase in the synovium, which resulted in the invasive pannus.A variety of cells, especially lymphocytes (both B and T cells), macrophages, and fibroblasts, could be identified in the established lesion.However, this pathophysiologic separation is oversimplified.Both the inflammatory and the proliferative components represent a continuum of interrelated events driven by cellular interaction and disequilibrium between proinflammatory and antiinflammatory cytokines.Tumor necrosis factor and interleukin-1 are proinflammatory cyto kines believed to be most responsible for rheumatoid injury.The pathophysiologic processes involved in RA have been correlated with clinical manifestations.The five phases incorporate the dominant pathophysiologic events that can be observed during the first few years of established disease (Table 133-1).^[3] These events can be targeted therapeutically.

Table 133-1 Stages of Rheumatoid Arthritis

[edit] PATIENT EVALUATION

[edit] History

RA is a heterogenous disorder that varies in presentation and clinical course.The onset of RA may be gradual or sudden, involving one or many joints.Most often the onset is insidious, presenting as slowly progressive pain and stiffness in the joints over weeks to months.Small joints of the hands and feet are usually involved at the onset.Swelling may not be apparent initially despite significant arthralgias.The pain tends to increase slowly, and swelling eventually becomes manifest.This may take months or rarely years.In most patients, RA involves several joints symmetrically, although monoarticular or asymmetric arthritis may be the first sign.

In the geriatric population, significant morning stiffness with nonspecific muscle aching, particularly in the shoulders and hips, is a common form of onset, often mimicking polymyalgia rheumatica.It may take weeks to months before joint swelling occurs.In addition to joint and muscular complaints, fatigue is the most prominent presenting feature of RA, often more debilitating than the arthritis itself.Fortunately, the acute and intense onset of arthritis presenting with systemic features (e.g., severe fatigue, low-grade fever, anorexia, weight loss) is rare.RA that presents in this manner must be differentiated from sepsis, paraneoplastic syndromes, and hypersensitivity reactions.Although impressive in its intensity, this presentation is not predictive of a poor prognosis.

The natural history of RA is also varied and may even change over time in the same person.The presentation often helps predict the subsequent course.RA can take one of four general courses: spontaneous remission, palindromic or remitting, remitting-progressive, or progressive (Table 133-2).RA can go into a spontaneous remission over weeks to months in 10% to 20% of patients.A majority of these patients experience a recurrence of RA.Thus permanent remission without treatment is unlikely.Recurrent flare-ups of arthritis with return to normal health between attacks are the hallmark of the remitting or palindromic course.These attacks are usually treated with nonsteroidal antiinflammatory drugs (NSAIDs).Disease-modifying antirheumatic drugs (DMARDs) may not be required if signs of joint damage are absent and the patient returns to normal joint function between flare-ups.If attacks are frequent, protracted, or debilitating, DMARDs should be considered to prevent recurrences.In the remitting-progressive course, complete return to a normal state between attacks does not occur.Ongoing destructive changes result from persistent active synovitis.DMARD therapy should be strongly considered for these patients.The most common course of RA is characterized by an ongoing synovitis with progressive pain, swelling, and joint damage.The progression of synovitis is generally insidious but may result in a rapid decline of function.Early DMARD therapy is recommended in an attempt to halt the progression of arthritis in these patients.

Table 133-2 Clinical Course of Rheumatoid Arthritis (RA)

The literature of the past decade has emphasized that patients with chronic RA experience progressive disability and premature mortality.This is in contrast with previous clinical impressions that RA had a relatively benign course.Recent studies suggest that patients who develop more severe disease develop erosive lesions within the first 2 years of diagnosis.Efforts to identify and treat this subset of patients are ongoing.Prognosis is being evaluated from the perspective of genetics, earlier onset of disease, educational level, and articular cartilage damage evidenced on magnetic resonance imaging (MRI).These factors are being integrated with traditional predictors of disease severity, including positive rheumatoid factor (RF), elevated erythrocyte sedimentation rate (ESR), subcutaneous nodules, insidious onset of joint disease, and erosion of bone on plain radiographs.

[edit] Physical Examination

The examination usually reveals some synovitis.Early in the disease course, however, the classic symmetric arthritis involving the hands, wrists, knees, and feet, which is typical of well-established disease, may not be present.The examination may reveal a single swollen joint or an asymmetric pattern of oligoarthritis.Observable changes include warmth, soft tissue swelling, effusion, tenderness, and diminished range of motion in involved joints.Potentially involved joints include the neck, shoulders, elbows, wrists, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, hips, knees, ankles, metatarsophalangeal (MTP) joints, and tarsal joints.Less frequently involved joints include the sternoclavicular, acromioclavicular, temporomandibular, and cricoarytenoid joints.

Changes specific to the shoulder include rotator cuff injury with superior migration of the humeral head.Loss of full extension is an early change noted in the elbow.Early hand and wrist changes include diffuse puffiness of the digits, with MCP and PIP soft tissue swelling (Fig.133-1).Ulnar deviation at the MCP joint is a result of connective tissue injury and mechanical factors.The swan-neck deformity is frequently observed with flexion of the distal interphalangeal (DIP) and MCP joints and hyperextension of the PIP joints.Extensor hood damage can result in fixed flexion of the PIP joint and hyperextension of the DIP joint, resulting in boutonniére deformity.Evidence of tenosynovitis may also be present, particularly in the wrists and dorsum of the hands.Patients with marked proliferative tenosynovitis may experience tendon rupture.Lower extremity signs include knee synovitis with effusion, quadriceps atrophy, and popliteal cysts.Patients often have ankle and foot deformities.Valgus of the ankle, pes planus, and forefoot varus deformity frequently exist simultaneously.MTP joints are often involved with downward subluxation of the metatarsal heads, cock-up deformities, hammer toes, and hallux valgus.

Figure 133-1 A, Bony proximal interphalangeal (PIP) hypertrophy of osteoarthritis. B, Synovial PIP hypertrophy of rheumatoid arthritis. (Courtesy American Rheumatism Association.)

[edit] DIAGNOSIS

In 1987 the American Rheumatism Association revised criteria for the classification of RA.To make a diagnosis ofRA, criteria 1 through 4 must have been present for at least 6 weeks, and four or more criteria must be met (Box 133-1).^[4]

[edit] Diagnostic Procedures

Early in the course of RA, clinical history and examination may be more definitive than laboratory analysis.Nonspecific inflammatory indices are often present, such as elevations of ESR, C-reactive protein, and γ-globulins, as well as the presence of normocytic anemia, leukocytosis, and thrombocytosis.RF, frequently absent in the first year of symptoms, eventually converts to a positive status in approximately 80% of patients.Antinuclear antibody (ANA) is frequently present in RA.

Synovial fluid analysis is helpful in the diagnosis of RA and other forms of inflammatory arthritis.Synovial cell counts typically range from 2000 to 50,000/mm³in affected joints, with a predominance of polymorphonuclear neutrophil leukocytes (PMNs).Early in the course of RA, counts may be lower with a relative monocytosis.Synovial fluid glucose levels are usually equal to but can be lower than serum glucose levels in chronic, severely inflamed joints.Synovial fluid from these joints or from those of monoarticular presentation should also be examined with Gram's stain and culture for bacterial infection.Synovial glucose is routinely extremely low in infected joints.

Synovial tissue biopsy may be useful when the diagnosis of RA is elusive.This is particularly important in chronic monoarticular arthritis of unclear etiology.Tissue is best obtained arthroscopically but can also be obtained blindly using needle biopsy.

[edit] Differential Diagnosis

It is often difficult on initial presentation to differentiate RA from other forms of inflammatory arthritis.Frequently, laboratory analysis is not revealing, and historic clues are particularly important.Four determinants are consistently used in the differential diagnosis of arthritis: gender, age at presentation, pattern of joint involvement, and clinical course.For example, classic RA occurs in women during their fourth decade and is a symmetric, progressive arthritis.

The presence of low back and sacroiliac discomfort should suggest the HLA-B27–associated diseases, or seronegative spondyloarthropathies (see Chapter 137 ).Ankylosing spondylitis in women often is not accompanied by the marked back stiffness and discomfort observed in men.With Reiter's syndrome the physician should seek evidence of insertional tendinitis, fasciitis, “sausage” digits, conjunctivitis, genital lesions, or urethral symptoms.Reactive polyarthritis can also be associated with psoriasis, inflammatory bowel disease, Whipple's disease, and Behçet's disease.

The common crystal arthropathies are frequently confused with RA.Chronic gout may mimic RA, with symmetric polyarthritis, tophaceous nodules, and recurrent attacks.Calcium pyrophosphate dihydrate deposition disease or pseudogout may be difficult to differentiate from RA because both conditions can involve similar joints and develop subacutely.Radiographic evidence of chondrocalcinosis is helpful.Arthrocentesis and examination of synovial fluid for crystals usually confirm definitive diagnosis of gout and pseudogout.

Other forms of diffuse connective tissue disease, including systemic lupus erythematosus (SLE), vasculitis, scleroderma, polymyositis, and mixed connective tissue disease, may resemble RA on initial presentation.Primary Sjögren's syndrome is frequently confused with RA clinically and sero logically.Significant eye and mouth dryness and the presence of ANA, including SSA and SSB (found in Sjögren's), help determine the correct diagnosis.

In the systemically ill patient with inflammatory arthritis, the physician should also consider the possibilities of bacterial endocarditis, septic arthritis, Lyme disease, and malignancy if historic or physical clues are present.Other, less acute systemic conditions that can present as polyarthritis include thyroid disease, sarcoidosis, amyloidosis, and paraproteinemias.

Three additional entities are occasionally confused with RA because of patients' similarities in age, gender, morning stiffness, and periodic joint attacks. Fibromyalgia is a clinical syndrome of multiple aches and pains, prominent morning stiffness, and nonrestorative sleep that occurs predominantly in middle-aged women.Synovitis is not present, but classic muscle tender points are associated with normal blood counts, ESR, and blood chemistries.Prominent myalgias and morning stiffness are also characteristic of polymyalgia rheumatica, but this presents almost exclusively after age 55.Synovitis can be present in some patients.The ESR is generally significantly elevated, and response to corticosteroids is almost immediate. Palindromic rheumatism may be a presentation of RA but can exist as an independent clinical entity.Observation over time, often years, may be necessary to make this differential diagnosis.

[edit] MANAGEMENT

[edit] Nonpharmacologic Therapy

[edit] Rehabilitation Issues: Joint Protection.

When joints are inflamed, cartilage is prone to injury and irreversible damage.During this vulnerable period, it is critical that principles of joint protection are understood and practiced.MCP and wrist joints are particularly prone to deformity.Special attention to protecting these joints during daily activities is indicated.An occupational therapist can teach methods of joint protection, giving specific examples on the use of these guidelines as they relate to each joint (Box 133-2).^[5]

Splinting plays an important role in joint protection.Splints can be designed to reduce inflammation through immobilization, to protect a vulnerable joint, or to improve function of a damaged joint.Splints should be worn only if they diminish pain and inflammation or improve function.No reliable evidence has documented that splints prevent deformity, but this is a common belief.Inappropriate or prolonged use of splints may cause increased stiffness, decreased strength, and decreased motion.An occupational therapist with expertise in hand therapy can be particularly helpful in devising appropriate upper extremity splints.

Assistive equipment can facilitate joint protection.Examples of equipment available for upper extremity problems include built-up handles, faucet levers, key adapters, buttonhooks, elastic shoelaces, use of Velcro in place of buttons and laces, door-opening levers, and extended handles on utensils.Useful assistive equipment for lower extremity problems includes elevated seats with armrests, raised toilet seats, shower benches, long-handled reachers, tub grab bars, and walking aids.

Proper footwear is crucial to protect the feet and ankles.RA may cause significant foot deformities and dysfunction.Swelling and secondary ligamentous laxity may result in a broad forefoot with toe deformities.A poorly fit shoe can create foot discomfort and further deformity.With mild arthritis in the feet a good supportive walking shoe or an athletic shoe usually suffices.When choosing shoes, the following features should be considered: light weight, deep enough to clear the top of toes (deeper if an insert is needed), wide enough not to pinch the toes together, 1 inch or less heel, good shock absorption, support along the inside of the shoe with an adequate arch, durable, stiff back for support, and breathable and supple uppers.If foot deformities are present, an insert or orthosis may be required.Orthotic supports are designed to relieve pressure caused by deformities or to correct foot deformity.If deformity is severe, orthopedic shoes or custom-made shoes can be fabricated from a cast of the feet.

Concepts of energy conservation should accompany principles of joint protection.Activities that cause fatigue in the patient without having an aerobic or strengthening benefit should be eliminated if possible.Discussions on the value of rest during the day are important.An occupational or physical therapist can help to teach methods of task minimization.The Arthritis Foundation has pamphlets available that review energy conservation and joint protection.

[edit] Exercise.

Appropriate exercise with adequate rest is a mainstay of the treatment of RA.Exercise recommendations have changed significantly over the past 30 years.For many years, patients were treated with prolonged bed rest to reduce active arthritis.Since inflammation improves with immobilization, the practice had some merit.It has become evident, however, that the negative effects of muscle atrophy, osteoporosis, and generalized deconditioning outweigh the benefits.Range of motion (ROM), specific strengthening, and low-impact aerobic fitness exercises can be prescribed with positive effects.Appropriate exercise can improve stamina, decrease fatigue, reduce time lost from work, and enhance the level of function.Appropriate exercise can also increase joint stability, help prevent joint deformities, decrease pain, improve function, promote self-esteem, improve sleep, and lessen muscle tension and anxiety.Compliance with exercise can be increased and joint damage avoided if guidelines are followed (Box 133-3).^[5]

The recommended amount and type of exercise depend on the degree of inflammation and the pattern of joint involvement.Gentle ROM exercises are prescribed for patients with very active inflammation.Moving affected joints through approximately five repetitions of ROM helps to maintain motion.Joints should not be stretched to the point of increased pain.Muscle setting can be performed if it does not cause significant discomfort.Muscles surrounding affected joints can be contracted, with tension maintained for 6 seconds each day to prevent muscle weakening.Moderately inflamed or subacute joints should also be taken through ROM exercise.Isometric strengthening exercise with contraction against a fixed resistance can be added.Elastic bands or other forms of fixed resistance can be used.Approximately 75% of maximum strength for 6 seconds should be used with less force when pain occurs.Slow addition of endurance exercises may be appropriate at this stage.Adding a swimming program is often recommended because the buoyancy of water tends to relieve mechanical stress on joints.

In cases of controlled synovitis, exercise recommendations vary depending on the amount of damage in the joints.General guidelines include continuing ROM exercises daily with a maximum of 10 repetitions.Isometric strengthening exercises may be performed as they would with moderately inflamed joints.Once maximum ROM and strength are achieved, more time can be devoted to aerobic exercise.Endurance exercises are most important at this stage as a means of regaining aerobic conditioning that is lost when the disease is more active.Although swimming is still the best form of exercise, other forms of low-impact aerobics (e.g., walking, bicycling, simulated ski machines, low-impact dancing) may be considered if lower extremity joints are not severely involved.Thirty minutes of aerobic exercise three times weekly increases fitness.

[edit] Nutrition.

In determining whether a relationship exists between nutrition and RA, data suggest that fewer than 5% of patients with predominantly seronegative RA have a food allergy.Improvement in arthritis through elimination diets supports these data.Specific foods to avoid in various re ports include milk products, lactose-containing foods, corn, cereals, shrimp, and nitrates.

The foremost nutritional question is whether diet modification can alter the abnormal immune response in RA.Studies of hypocaloric diets show improvement in symptoms of RA.This improvement is usually temporary and is poorly understood.Diets low in saturated fats and high in omega-3 fatty acids have also been shown to have some therapeutic benefit.Supplemental fish oils containing omega-3 fatty acids have been shown to have modest antiinflammatory activity in RA.

A well-balanced diet, with total caloric intake calculated to maintain lean body weight, and limited stress on weight-bearing joints are recommended.Adequate protein is advised to prevent muscle atrophy.Calcium and vitamin D supplementation, particularly for patients taking corticosteroids, should be considered in view of the increased risk of osteoporosis in patients with RA.Estrogens for postmenopausal women should also be considered.Sodium restriction may be necessary to limit fluid retention and secondary hypertension in patients who take NSAIDs or corticosteroids.

[edit] Pharmacologic Therapy

Traditionally, medical treatment for RA was outlined according to a pyramid approach, beginning with nonpharmacologic modalities and NSAIDs at the base.In the distant past, frank destructive changes on radiographs were man dated before physicians moved up the therapeutic pyramid to DMARDs.Usually, 2 to 3 years elapsed before DMARDs were even considered.It is now appreciated that cartilage erosions and resultant irreversible damage can occur within 2 years of the diagnosis of RA.Since progressive disability and premature mortality occur with RA, DMARDs are used earlier in the clinical course.Moreover, combinations of DMARDs have been advocated for progressive disease.Current rheumatology practice supports prompt, aggressive intervention with DMARDs in an effort to halt early, irreversible damage.Usually a single DMARD is initiated within weeks of a clear diagnosis of RA.If ineffective, serial DMARDs are attempted until control is achieved.Others propose that low doses of multiple DMARDs be initiated simultaneously; drug synergy may provide rapid improvement with less dose-related toxicity.After control is achieved, therapy is slowly withdrawn, and the patient is maintained on the least toxic DMARD that subdues the inflammatory process.

For the primary care physician, this information could translate into the following therapeutic plan.After 1 to 3months of arthritis treatment with an NSAID alone, a low-toxicity DMARD such as hydroxychloroquine should be considered if the patient remains symptomatic.If, after an additional 3 to 6 months of an NSAID/hydroxychloroquine combination, evidence of significant synovitis persists, an additional DMARD should be considered.If the physician is not comfortable with the second DMARD option, a rheumatology consultation is appropriate, particularly if methotrexate, cyclosporine, leflunomide, or etanercept is considered.This aggressive approach to patients with RA may be difficult to justify because of the potential toxicity of medications and the uncertainty of the disease course.RF and subcutaneous nodules suggest aggressive disease but are often not present in early disease.HLA-DR4 has been reported to correlate with disease severity, but testing is not readily available and has not yet been incorporated into DMARD treatment decisions.Until trial genetic tests are proven to predict severity and become readily available, treatment decisions must rely on physical and radiographic evidence of progressive synovitis and on the presence of acute-phase reactants in early disease, when RF is often negative.In a managed care system the primary care physician is likely to make the diagnosis of RA and to initiate the first NSAID and DMARD based on the clinical features.This is complicated by similarities in the presentations of several different rheumatic disorders.Consultation with a rheumatologist may be helpful for cases that present diagnostic difficulty.

Agents used for treating RA are divided into four major groups: NSAIDs, DMARDs, corticosteroids, and biologic response modifiers.

[edit] Nonsteroidal Antiinflammatory Drugs.

NSAIDs are used as the first-line therapy to decrease pain and inflammation promptly.Because of significant interpatient variability in efficacy, multiple agents may need to be prescribed before the most effective NSAID is discovered for an individual.NSAID efficacy generally requires 1 to 3 weeks to assess.With few exceptions, NSAIDs work by inhibiting the production of inflammatory prostaglandins.Despite their efficacy in reducing the symptoms of arthritis, these drugs probably do not change the natural history of RA.It is important to prescribe antiinflammatory dosages of the NSAID and not analgesic dosages, which are generally lower.

Toxicity of aspirin and NSAIDs is well described (Box 133-4).The major toxicity is to the gastrointestinal (GI) tract, with potential gastritis, erosive change, and gastric ulceration.Risk factors for toxicity in RA include advanced age, concomitant corticosteroid use, tobacco, alcohol, and a history of ulcers.Patients with prominent risk factors should be strongly considered for prophylactic treatment with the synthetic prostaglandin misoprostol (Cytotec) or use of the newest class of NSAIDs, the cyclooxygenase II (COX-II) inhibitors.By blocking COX-II significantly more than COX-I, their use is expected to be associated with less GI toxicity.Celecoxib (Celebrex) and rofecoxib (Vioxx) have recently been approved, and others are expected to be available soon.

[edit] Disease-modifying Antirheumatic Drugs.

DMARDs are aimed at altering the course of rheumatoid synovitis, thus preventing joint damage.^[6] These agents often need to be administered for several weeks to months before positive results can be seen.It is postulated that DMARDs are effective in modulating the immune process of RA.

The choice of initial second-line agent depends on the physician's judgment and preference as well as the severity of disease.Patients with severe, aggressive disease should be treated with methotrexate, leflunamide, or less often, injectable gold salts by a physician familiar with these medications.Patients with lesser symptoms may be treated with hydroxychloroquine, auranofin, or sulfasalazine, often by the primary care physician.When the initial DMARD does not result in the expected efficacy, a second agent may be added or may replace the first.^[7] More than one DMARD may be initiated from the onset of second-line therapy, with eventual step-down to a simplified regimen once control is achieved.Three other DMARDs—penicillamine, azathioprine, and cyclophosphamide—have efficacy for RA but should be prescribed only by physicians familiar with their toxicities.

[edit] Injectable Gold Salts.

Gold sodium thiomalate (GSTM) and gold sodium thioglucose (GSTG) are the two forms of injectable gold used in the United States.GSTM is a water-based solution and has limited availability; GSTG has a sesame oil vehicle and has become the preferred agent (Box 133-5).Gold was first introduced as a treatment for infections, particularly for tuberculosis, in the early 1900s.Although hailed as the DMARD of choice for several years, the efficacy of gold therapy has been questioned.Despite this controversy, many rheumatologists still believe that intramuscular (IM) gold has a role in the treatment of RA, although its use has largely been replaced by methotrexate.

Initially, IM gold is given in the form of weekly injections.Two test doses are administered; the first is a 10-mg injection, and the second weekly dose is 25 mg.Thereafter the prescribed dosage is 50 mg per week.After improvement is noted or a cumulative dose of 1000 mg is attained, the interval between injections is increased to 2 weeks.If improvement continues, the interval can be further lengthened, generally to a maximum of 1 month.IM gold therapy frequently requires 6 weeks to 6 months before maximum effectiveness is evident.

Gold therapy is often associated with toxicity, resulting in discontinuation of treatment in approximately 30% ofpatients.Rash and stomatitis are reported most often.With renal toxicity, the most common problem is proteinuria.In less than 1% of patients treated with parenteral gold, serious renal insufficiency occurs.The major toxicity is nephrotic syndrome.Hematuria may also occur.The vast majority of kidney problems are reversible.Fortunately, gold-induced hematologic problems are rare.In 1% to 3% of patients, leukopenia or thrombocytopenia may develop.If no other obvious cause is found, gold therapy should be discontinued.Eosinophilia is common in RA, but a marked increase in the eosinophil count may indicate impending toxicity, and gold should be withheld until the eosinophilia resolves.In less than 0.5% of patients, aplastic anemia may result; the mortality is in excess of 50%.The most effective therapy for aplastic anemia appears to be antithymocyte globulin.Nitritoid reaction may occur with GSTM, the water-based gold preparation that is rapidly absorbed.This reaction occurs immediately or within 20 minutes after an injection.Flushing, fainting, dizziness, and sweating usually characterize it.Because of this toxicity, the oil-based GSTG is used more often.

In view of potential renal and hematologic toxicities, weekly preinjection complete blood counts (CBCs) and urinalyses (U/As) are suggested for the first 20 weeks.Since toxicity is less likely after the first 6 months, laboratory tests may be obtained before every injection or every other injection.

[edit] Oral Gold.

The introduction of auranofin (Ridaura) in the 1980s allowed physicians to prescribe an oral form of gold.Many rheumatologists believe that auranofin is not as effective as injectable gold, but the compound can be effective if used for very early disease.A trial of 6 months may be required before a determination is made that auranofin is definitely not efficacious in a given patient.The recommended dosage is 3 mg twice a day.If no improvement is noted in 6 months, a trial of 3 mg three times per day may be considered.Recommended laboratory monitoring for toxicities requires CBC with manual differential and U/A every 4 to 12 weeks.Unlike injectable gold, auranofin has a low incidence of serious toxicities.The most prominent side effects are abdominal cramps, diarrhea, nausea, and changes in appetite.Most of these problems can be treated by starting with 3 mg a day administered with meals and by prescribing a high-fiber, bulk-inducing agent.Rash and stomatitis are uncommon; renal and hematologic toxicities are rare.

[edit] Antimalarial Drugs.

The medicinal qualities of quinine have been recognized for more than a century.Antimalarial agents include hydroxychloroquine, chloroquine, and quinacrine.Quinacrine was introduced in the 1950s as the first antimalarial used to treat RA.Chloroquine and hydroxychloroquine are used today in the treatment of RA.Hydroxychloroquine has become the antimalarial agent of choice because of its lower toxicity profile (Box 133-6).Hydroxychloroquine is contraindicated in patients allergic to the medication or to quinine.Hydroxychloroquine is given in initial dosages of 400 mg/day (200 mg orally twice a day).If an excellent response occurs, the dosage can be decreased to 200 mg/day.A trial for a minimum of 6 to 10 weeks is required to determine efficacy.

Hydroxychloroquine is probably the safest DMARD.Patients should have a baseline ophthalmologic examination before starting therapy.Only an estimated 5% of patients discontinue hydroxychloroquine because of side effects.GI effects are reported most frequently.Thrombocytopenia and other forms of bone marrow suppression are rare.The principal concern regarding antimalarial drugs is the risk of retinopathy with long-term use.The risk of retinopathy for patients taking the standard dose of 400 mg/day of hydroxychloroquine is very low.If ophthalmologic evaluation is performed routinely every 3 to 6 months as recommended and hydroxychloroquine discontinued at the earliest sign of retinal change, the risks for permanent eye damage are negligible.When loss of vision is the first sign of damage, continued loss can progress despite drug withdrawal, emphasizing the importance of routine examination.Chloroquine has a higher risk of retinopathy than hydroxychloroquine.When hydroxychloroquine is initiated, blurring of vision may occur; this is transient and caused by smooth muscle relaxation rather than retinal pathology.Corneal deposits may also occur but do not present a risk to vision.

[edit] Penicillamine.

Penicillamine is an oral preparation with a delayed onset of action and side effect profile similar to gold.Penicillamine therapy has numerous potential side effects that limit its use to uniquely refractory cases (Box 133-7).Toxicity is frequently related to dosage and generally appears in the first year of treatment.Serious side effects are similar to those of injectable gold.The chief concern is the development of hematologic toxicity.Thrombocytopenia occurs most frequently, affecting approximately 4% of patients, and leukopenia occurs in approximately 2% of patients.These side effects are largely reversible but can be life threatening in rare situations.Renal toxicity, especially nephritis with proteinuria, may occur but usually can be halted if detected early.Nephrotic syndrome is more common than with injectable gold.If significant proteinuria (greater than 1 gm) is documented by 24-hour urine evaluation, penicillamine therapy should be discontinued.The rare development of other autoimmune conditions, such as myastheniagravis, pemphigus, Goodpasture's syndrome, and SLE, may also result from penicillamine therapy.

Penicillamine therapy is initiated with 125 to 250 mg/day taken on an empty stomach.Incremental increases of 125 to 250 mg (depending on tolerance) are made every 3 months until the desired beneficial response or a daily maximum of 750 mg is reached.Higher doses occasionally are used but generally are discouraged.CBC and U/A should be monitored every 2 weeks until dosage stable, then every 1 to 3 months.

[edit] Sulfasalazine.

Sulfasalazine was originally developed in the 1930s specifically for the treatment of RA (Box 133-8).Since the 1980s, sulfasalazine use has had a resurgence because several studies demonstrated its effectiveness.Sulfasalazine is usually given as 2 gm/day divided into two to four equal doses.If no benefit is noted in 3 to 6 months, the dosage can be increased to 3 gm/day for an additional 2 to 3 months.Efficacy is generally apparent after 2 to 6 months of therapy.Baseline testing should include CBC, aspartate transaminase (AST), alanine transaminase (ALT), and in patients at risk, glucose-6-phosphate dehydrogenase (G6PD).Monitoring for toxicity includes requesting CBC with differential every 2 to 4 weeks for the first 3 months, then CBC (with or without liver function tests) every 12 weeks.

Sulfasalazine is contraindicated in patients who are allergic to sulfa compounds or salicylates.The most frequently observed side effect of sulfasalazine is GI intolerance, which is reduced with the use of enteric-coated tablets taken with meals.Starting therapy at a low dose with gradual increases also improves tolerance.Rash also occurs.Serious toxicity is rare and generally occurs early in treatment.Severe hypersensitivity reactions include pneumonitis and hepatitis, and cytopenias include thrombocytopenia and leukopenia.Spermatogenesis may be affected, causing reversible sterility.Most side effects are reversed uneventfully with discontinuation of the medication.

[edit] Methotrexate.

Methotrexate was introduced in the 1940s as a form of chemotherapy and later became popular in the treatment of psoriasis and psoriatic arthritis.Since the early 1980s, use of methotrexate for treatment of RA has increased dramatically (Box 133-9).This increased popularity is explained by the increased efficacy and relatively rapid onset of action of methotrexate compared with previously available DMARDs.Clinical improvement may be observed as early as 2 to 3 weeks, with 8 to 12 weeks of therapy required for full evaluation of efficacy.Administration of methotrexate is convenient; it allows a weekly dosage regimen.Routine laboratory monitoring is needed less frequently than that required for gold and penicillamine.

The dosage of methotrexate is 5 to 15 mg/week, with an average weekly dosage of 7.5 mg (three 2.5-mg tablets).Folic acid is often prescribed in a dosage of 1 mg/day to decreasepotential toxicity.Safety monitoring requires baseline CBC, platelet count, renal function tests, liver function tests (LFTs), and chest x-ray studies.In high-risk patients, hepatitis B and C studies should also be evaluated.A CBC should be performed again within the first 1 to 2 weeks of therapy and monthly initially.When stable, CBC, platelet count, AST, albumin, and creatinine should be monitored every 4 to 8 weeks.Methotrexate is excreted by the kidney and should not be used in the setting of renal function impairment.

As with other immunosuppressants, methotrexate has potential side effects.Those most often reported relate to GI intolerance.Nausea, vomiting, and diarrhea can usually be minimized by dividing the weekly dosage throughout the day of administration, taking the medication with food, adjusting the dosage, or using antiemetics.IM methotrexate is better tolerated.The most frequent serious side effect is hepatotoxicity.Inflammation and fibrosis of the liver can occur with long-term use.Changes in LFTs do not always correlate with liver damage.Cirrhosis of the liver is rare but has been described, particularly in patients with psoriasis.Fibrosis and cirrhosis appear to be much less common in RA patients who take methotrexate.The risk of liver toxicity can be greatly reduced by eliminating alcohol and staying as close to lean body weight as possible.Routine surveillance liver biopsies are not recommended.Biopsy may be indicated if liver function abnormalities persist during treatment.Risk of cytopenia also exists.At the dosages used for RA, cytopenia is unusual and almost always reversible with discontinuation of methotrexate.Rare atypical infections include Pneumocystis carinii pneumonia caused by immunosuppressive effects.Methotrexate also may rarely cause pneumonitis, most often in smokers, with cough, shortness of breath, and interstitial infiltrates on chest films.Pneumonitis is generally reversible but can be life threatening, requiring treatment with corticosteroids.

[edit] Cyclosporine.

Cyclosporine (cyclosporin A, Neoral) is indicated for the treatment of severe, active RA in patients who do not respond to methotrexate (Box 133-10).Only physicians experienced in management of systemic immunosuppressive therapy for RA should prescribe this agent.Cyclosporin A is most often prescribed in combination therapy with methotrexate but is also used as monotherapy.Patients with severe RA and only partial responses to methotrexate show improvement with a combination of methotrexate and cyclosporine.In controlled studies, side effects were not substantially increased compared with methotrexate alone.^[8] Long-term evaluation of this combination is needed to assess toxicity in clinical practice.

Initial therapy with cyclosporine is 2.5 mg/kg/day taken in two divided doses.The dose is then titrated by 0.5-to 0.75-mg/kg increments every 4 to 8 weeks as indicated.The maintenance dose should be the lowest effective dose and should not exceed 4.0 mg/kg.If adverse effects occur, the dose should be reduced by 25% to 50%.Cyclosporin A should be discontinued if no benefit is seen at 16 weeks or if dose reduction does not eliminate side effects.The principal adverse reactions associated with cyclosporine in RA are renal dysfunction, hypertension, headache, GI disturbances, and hirsutism/hypertrichosis.

[edit] Azathioprine.

Azathioprine (Imuran) was the first immunosuppressant approved by the U.S.Food and Drug Administration (FDA) for use in RA (Box 133-11).Although effective, toxicity issues may be prohibitive for most primary care physicians.Many rheumatologists reserve this therapy for patients who have failed treatment with other DMARDs, although azathioprine is used in many combination therapies.

Azathioprine requires 6 weeks to 6 months of use tobecome effective.An initial dosage of 1 mg/kg/day or 100 mg for the first 3 months is generally prescribed.The dosage can be increased every 3 months in increments of 25 mg, to a maximum of 150 mg, when lower dosages prove ineffective.Baseline CBC, platelet count, creatinine, and AST should be performed.Safety screening consists of monitoring CBCs every 1 to 2 weeks with changes in dosage, then every 1 to 3 months.LFTs should be performed sporadically if indicated.

The toxicity of azathioprine largely depends on the dosage.Of most concern is the development of cytopenias, often leukopenia.As with other immunosuppressants, azathioprine frequently results in macrocytosis without anemia.Marked hepatotoxicity is rare, but low-grade liver function abnormalities are more common.Azathioprine therapy increases the risk for atypical infections, which may develop without leukopenia.Less common hematologic complications include thrombocytopenia and anemia.These complications are largely reversible.Life-threatening complications are rare when vigilant monitoring is performed.The potential increased risk of subsequent malignancy, particularly lymphoma, with prolonged use has received much attention.Recent long-term studies of RA patients taking azathioprine are reassuring.Any additional risk of cancer in patients receiving azathioprine compared with others with RA appears to be small.Well-controlled studies are lacking, however, and patients should be informed of the potential risk when considering this therapy.

[edit] Cyclophosphamide.

Cyclophosphamide (Cytoxan) is the most potent and toxic immunosuppressive drug used to treat RA (Box 133-12).Although its effectiveness as a DMARD is undisputed, its potential toxicity prohibits its use in the vast majority of RA patients.Its use is limited to severe complications of RA, such as vasculitis and other severe organ involvement.Cyclophosphamide therapy should be monitored by a rheumatologist because of the seriousness of the rheumatoid and medication complications.Cytopenias appear to be related to the dosage.Risk of an atypical infection also is increased.Interstitial cystitis may occur, and adequate hydration and morning therapy are crucial to reduce cystitis.Pulmonary toxicity has been observed.Cyclophosphamide therapy is associated with an increased risk of bladder cancer and hematologic malignancy.Since cyclophosphamide is given almost exclusively for severe, un remitting RA or for life-threatening complications, this increased risk is usually justified.

[edit] Leflunomide.

Introduced inlate 1998, leflunomide (Arava) is the newest of the DMARDs (Box 133-13).It represents a new generation of low-molecular-weight immunoregulatory agents.Leflunomide appears to have an efficacy profile similar to other DMARDs, comparing favorably with sulfasalazine and methotrexate.The onset of action may be as early as 4 weeks.Leflunomide is administered orally, with an initial loading dose of 100 mg for 3 days, usually followed by 20 mg daily as a single dose.A 10-mg tablet is available for decreased dosage.As with methotrexate, concomitant administration of folic acid (1 mg/day) is recommended to decrease GI effects.Potential toxicity includes GI symptoms, rash, reversible alopecia, weight loss, and moderate LFT elevations.Leflunomide should not be used in women or men attempting pregnancy because of maternal and male-mediated fetal toxicity.Male or female patients who wish to initiate a pregnancy should discontinue leflunomide andundergo a drug elimination procedure with cholestyramine, 8 gm three times daily for 11 days.Plasma levels less than 0.02 mg/L are verified by two separate tests at least 14 days apart.Without the elimination procedure, it may take up to 2 years to lower plasma levels adequately.Definitive guidelines for laboratory monitoring have not been confirmed.At a minimum, ALT determinations are performed.

[edit] Corticosteroids.

Corticosteroids have been used for patients with RA since the 1940s (Box 133-14).Corticosteroids have prominent antiinflammatory properties that result in dramatic improvement of symptomatic arthritis and systemic complaints.The ability to modify the rheumatoid disease course with low-dose corticosteroids continues to be debated.Low-dose corticosteroids, given in a single morning dose, are popular among many rheumatologists as a form of bridge therapy after NSAIDs have been prescribed and before DMARDs become effective.During this period, corticosteroids are used to relieve symptoms while awaiting therapeutic efficacy of DMARD therapy.Corticosteroids should not be used as the sole therapy for RA in most circumstances because of their long-term toxicity.Dosage escalation for the antiinflammatory effects and a shift of dosing to the evening increases the risks of hypercortisolism.Every effort should be made to restrict the dosage to no more than 5 mg of prednisone taken in the morning.

Corticosteroid intraarticular injections are an important adjunct to therapy in RA, particularly in a persistently inflamed joint.“Depo” preparations such as methylprednisolone acetate and triamcinolone hexacetonide may give up to 1 month of relief as sole therapy.Benefits may persist much longer when the steroid injection is combined with systemic therapy.Care must first be taken to rule out a joint infection by aspiration and fluid analysis before injection.The primary care physician can often easily inject large joints (e.g., knees).Systemic absorption occurs and can temporarily suppress the hypothalamic-pituitary-adrenal axis.This may be clinically relevant in patients who have received multiple recent injections and are undergoing joint replacement or other surgery.Preoperative and postoperative corticosteroid stress dosage requires consultation with the surgeon or anesthesiologist.

[edit] Biologic Response Modifiers.

The role of cellular inter action and cytokine disequilibrium in rheumatoid synovitis and resultant cartilage damage is becoming more clearly defined.This opens the door for targeted biologic response modifiers (BRMs).Broadly, BRMs fall into four categories: monoclonal antibodies, soluble receptors, receptor antagonists, and antiinflammatory cytokines.Multiple trials are currently under way studying these biologic targeted treatments.

[edit] Etanercept (Enbrel).

Tumor necrosis factor (TNF) has been found to be a major regulator of inflammation in the rheumatoid joint.TNF communicates its proinflammatory effects by binding to specific cell receptors on white blood cells and synovial cells.Soluble TNF receptor levels are elevated in the serum of patients with RA but not in adequate amounts to inhibit the proinflammatory effects of TNF.Etanercept (Enbrel) is a dimeric soluble form of the TNF receptor that can bind two TNF molecules, rendering them biologically inactive thus also modulating the biologic responses that are induced or regulated by TNF (Box 133-15).In randomized, double-blind trials, this has translated into significant reductions in disease activity in patients with RA, even in those who had failed previous DMARD therapy.^[9] Clinical responses can occur within 1 to 2 weeks after initiating therapy, significantly faster than most DMARDs.After discontinuation of etanercept, symptoms generally returned within a month.

Etanercept is self-administered by subcutaneous injection twice weekly and requires reconstitution by the patient.Patients may self-inject only after proper training and demonstration of appropriate injection technique.Because of the extraordinary cost of this agent, managed care guidelines will likely be forthcoming.The most frequently reported adverse effect is injection site reactions.Long-term studies are required to determine if there is significantly increased immunogenicity, chronic infections, or malignancy.Close observation for evidence of bacterial infection is suggested because treatment may increase mortality in patients with sepsis.

[edit] Surgery

RA can result in persistent inflammation and joint deformity, despite timely medical therapy.Surgical techniques provide several alternatives to ensure that patients with RA continue to maintain function.Surgical options are considered tocontrol severe pain resulting from inflammation or damaged joints, to repair ruptured ligaments or tendons, to remove inflamed synovial tissue that has not responded adequately to medical therapy and is threatening joint damage or tendon rupture, and to retain or restore function in an affected joint.

Synovectomy facilitates the removal of proliferating pan nus in an effort to preserve cartilage and surrounding soft tissue structures.Synovectomy should not be viewed as a corrective procedure, since complete resection of all synovial tissue is rarely possible and synovial tissue can grow back.Synovectomy can be performed using arthroscopy or an open procedure.Recovery from arthroscopic synovectomy is generally quite rapid.Although more invasive, open surgical synovectomy has the advantage of improved access, facilitating a more thorough removal of the inflamed synovial tissue.

RA may result in damage to and occasionally rupture of surrounding tendons and ligaments.Rupture of finger extensors secondary to dorsal tenosynovitis occurs most often.If rupture occurs, reconstruction is possible with tendon transfer. Arthrodesis(joint fusion) is performed only on painful and unstable joints, most often the wrists, feet, ankles, and thumbs.Although effective in decreasing pain and improving stability, fusion permanently sacrifices motion.For this reason, it is rarely performed on the shoulder or hip.With longstanding RA, atlantoaxial subluxation and other cervical instability can occur because of ligament and bone loss caused by synovitis.In severe cases with neurologic deficits, fusion may be required to increase stability. Osteotomy can be performed to improve joint alignment and to compensate for deformity.This procedure is rarely done now because of improved joint replacement procedures.

New techniques for joint replacement have dramatically improved the outlook for even the most severely disabled patients.Traditionally, total joint replacement was performed only in older, inactive individuals who had less chance of outliving the replacement.Current trends reveal an increased use of artificial joints in younger, more active patients.Total joint replacement is frequently performed in the knees, hips, and shoulders with excellent results.Replacements for the elbows, wrists, and ankles are available but have more variable outcomes.Newer designs will likely provide better and more consistent results.

Before surgery, several precautions must be considered.Ruling out cervical subluxation is imperative if tracheal intubation is anticipated.NSAIDs should be discontinued for at least 1 week in most patients; aspirin should be discontinued 2 weeks before surgery.Stress doses should be considered for patients taking corticosteroids or those who recently had multiple intraarticular injections.Whether to stop methotrexate is controversial, but some evidence indicates a lower postoperative infection rate if methotrexate is stopped for the surgery and held for several weeks after the procedure.

[edit] SPECIAL ISSUES

[edit] Complications

Musculoskeletal complications of RA can include significant cervical spine involvement with atlantoaxial subluxation or impaction and subaxial impaction.Cervical spine involvement should be considered in all rheumatoid patients with painless sensory loss, paresthesias, severe neck or shoulder girdle pain, or weakness in the upper extremities, particularly if deficits increase with neck motion (see Chapter 124 ).More serious symptoms of myelopathy, such as loss of sphincter control, dysphagia, vertigo, or syncopal episodes, require immediate intervention.MRI is the radiographic technique of choice to assess for cervical cord compression.Evaluation for cervical spine stability with plain radiographs of the lateral neck in flexion and extension is recommended for any patient with advanced RA who is being considered for general anesthesia with intubation and concomitant hyperextension of the neck.The sudden onset or progression of hoarseness should prompt laryngoscopic evaluation for cricoarytenoid joint involvement.Inspiratory stridor should be considered a medical emergency.

Extraarticular complications of RA may vary in severity.Rheumatoid nodules, generally found on extensor surfaces, are noted in up to one third of patients with RA.Nodules rarely cause more than cosmetic problems but can be painful if traumatized.Other systemic features include sicca syndrome secondary to inflammatory changes in lacrimal and salivary glands and in other exocrine glands.Diffuse lymphadenopathy may also be a feature of RA.Lymph node biopsy should be considered if malignancy is a concern.

Hematologic abnormalities include anemia of chronic disease, eosinophilia, and thrombocytosis.Felty's syndrome, a triad of seropositive RA, significant hypersplenism, and granulocytopenia, occurs infrequently.Such patients may be susceptible to infection.If infections are recurrent, corticosteroid, DMARD, or immunosuppressive therapy may be required after the existing infection is eradicated.Splenectomy has been performed on many patients without clear evidence of benefit.Drugs used to treat RA may also cause hematologic abnormalities, including anemia from GI bleeding and bone marrow suppression.

Systemic vasculitis can occur in patients with severe, deforming RA and high RF titers.Vascular damage can range from small vessel involvement, causing palpable purpura, to a necrotizing, medium-sized arteritis.Periungual nail infarcts are common and require no specific treatment.In contrast, systemic vasculitis, with signs of mononeuritis multiplex, visceral vasculitis, cutaneous ulceration, digital infarction, or other organ involvement, requires prompt aggressive treatment.

Peripheral nerve pathology can occur in addition to the structural cervical neurologic complications previously described.Compressive neuropathies, particularly carpal tunnel syndrome, are common.Peripheral nerve damage can also result from angiopathic, amyloid, and monoclonal antibody–induced inflammatory polyneuropathy.

Pulmonary involvement includes pleural diseases, interstitial fibrosis, nodules, pneumonitis, vasculitis, and airways disease.Pleural involvement is frequent but generally asymptomatic.Large pleural effusions may cause shortness of breath.In rare instances a progressive form of pulmonary fibrosis occurs.Finding large numbers of PMNs in bron choalveolar lavage can support the diagnosis.

Symptomatic cardiac complications are rare.Pericarditis is frequently described but rarely results in cardiac tamponade.Less frequent cardiac involvement includes myocarditis, endocardial changes, arteritis, and conduction defects.

Ocular manifestations range from those that are relatively innocuous to those resulting in blindness.Severity often parallels activity, intensity, and chronicity of RA.Mostcommon is keratoconjunctivitis sicca.Less common and more severe complications include keratitis, episcleritis, scleritis, uveitis, and retinopathy.Visual changes or eye pain should be promptly evaluated by an ophthalmologist who is familiar with RA.

[edit] Psychosocial and Family Issues

RA can have an impact on all aspects of daily living, including interpersonal relationships, family dynamics, and sexuality.The perceived loss of independence and control can create fear, anger, and loss of self-esteem.The physician should not overlook this aspect of the patient's care.Since depression directly affects outcome negatively, helping the patient cope with these issues is beneficial.Sexual issues should be addressed with frankness and sensitivity, since patients are often reluctant to share problems in this area.The Arthritis Foundation provides pamphlets concerning sexual issues, coping strategies, and other practical matters.Other resources include counselors with expertise in chronic disease, self-help groups, social workers, vocational counselors, and nurse educators.Many communities have support groups for RA patients.

[edit] Pregnancy and Childbirth

Since RA predominantly affects women of childbearing age, counseling of this group is extremely important.Fortunately, pregnancy has an ameliorating effect on rheumatoid synovitis in 75% of women with RA.Most remissions occur during the first trimester but can occur at any point.Medications can usually be discontinued without adverse sequelae.Methotrexate, with its known teratogenic effects, should be discontinued long before pregnancy is attempted.As discussed, leflunomide requires an elimination procedure.Antimalarials are generally stopped 6 to 12 months before conception because of potential neurotoxicity to the fetus.Postpartum exacerbations often occur, however, most often within the first 6 months.This often presents the most significant problem, considering the physical challenges of caring for an infant.If possible, this issue should be addressed with the prospective mother and her partner before pregnancy.Prolonged breast-feeding is not always possible because antiarthritic medication, most of which is secreted in breast milk, is frequently required in the postpartum period.However, RA activity is not associated with obstetric complications or adverse fetal health.

[edit] Disability Issues

RA can interfere with the ability to work.Stiffness, pain, decreased mobility, and particularly fatigue may present serious obstacles during an 8-hour workday.Practical advice regarding open communication with employers, increased flexibility of job hours, work-site modifications, energy conservation, and possible job-sharing programs can be a valuable resource to patients trying to remain at work.Continued employment should be encouraged for financial and health insurance benefits, as well as for self-esteem.

In certain situations, continued employment may prove impossible, especially physically demanding jobs that require repetitive motion of inflamed joints.Alternative employment, a change of job description, or an application for disability benefits should be considered.This decision is highly individualized and must consider the patient's age, work experience, educational resources, financial responsibilities, and severity of arthritis.Disability benefits vary greatly in eligibility and policy definition of disability.Many private companies offer short-or long-term disability insurance as part of their benefits packages.Some states provide short term disability benefits.Patients may be eligible for federal Social Security benefits.This program is not designed to cover short-term or partial disability and is based on the present and projected inability to perform any form of work.

[edit] FUTURE DIRECTIONS

Current treatment of RA is multidisciplinary and is likely to remain that way.With managed care constraints, primary care physicians will be involved in initial diagnostic and therapeutic decisions, including the timing of DMARDs.It is hoped that genetic markers will predict severity of arthritis and help direct aggressiveness of therapy.The first of many BRMs has been released.Several cells and cytokines have been targeted for modification.As more of the critical cellular and cytokine interrelationships involved in the pathogenesis of RA are known, newer biologic agents will be tested.Expense will be a consideration for the use of these parenteral agents for chronic disease.The future therapy of RA will likely emphasize the timing of DMARDs already in widespread clinical practice, as well as BRMs in patients with aggressive disease.The primary care physician will become familiar with DMARDs, particularly methotrexate.The total cost of medications will be scrutinized in the managed care environment and will include the cost of monitoring for adverse effects.

[edit] REFERENCES