Therapeutic Strategies for Rheumatoid Arthritis
【关键词】 Strategies
Rheumatoid arthritis, a chronic, systemic, inflammatory autoimmune disease, has as its primary target the synovial tissues. When the disease is unchecked, it leads to substantial disability and premature death.1 It affects approximately 0.8 percent of adults worldwide,2 is more common in women (by a ratio of 3 to 1), and has an earlier onset in women, frequently beginning in the childbearing years.3 Recent advances in understanding the cytokine networks that are responsible for the ongoing inflammatory response in rheumatoid arthritis4 have led to the successful use of therapies that target tumor necrosis factor (TNF-) and interleukin-1.5 (These therapies were discussed in a recent review in the Journal.6)
During the past 10 years, improved understanding of the pathophysiology of rheumatoid arthritis has led to several key changes in the approach to therapy. First, early diagnosis and treatment are important. Second, the use of disease-modifying antirheumatic drugs (DMARDs) in combination is highly effective. Third, the use of agents that target cytokines, such as TNF- and interleukin-1, is an effective strategy. And fourth, recognition is growing that the assessment of treatment outcomes should include an analysis of important coexisting illnesses (particularly cardiovascular disease and osteoporosis). In this article, I will discuss the clinical application of these principles, which has resulted in a marked improvement in clinical outcomes.7,8
Early Diagnosis and Treatment
Joint damage occurs early in the course of rheumatoid arthritis; 30 percent of patients have radiographic evidence of bony erosions at the time of diagnosis, and this proportion increases to 60 percent by two years.9 Unfortunately, bony erosions and deformities are largely irreversible. Initiation of therapy with DMARDs within three months after the diagnosis of rheumatoid arthritis is crucial; a delay of as little as three months in the introduction of these medications results in substantially more radiographic damage at five years.10,11,12 Therefore, early diagnosis, although challenging,13 is critical.14,15
The diagnosis cannot be established by a single laboratory test or procedure but is aided by the use of seven diagnostic criteria16 that favor clinical factors and, therefore, depend on the clinician's asking insightful questions and recognizing the often-subtle early physical findings. The diagnostic criteria are the presence of morning stiffness, arthritis of three or more joint areas, arthritis of the hand joints, symmetric arthritis, rheumatoid nodules, elevated levels of serum rheumatoid factor, and radiographic changes. Many other syndromes, including self-limiting viral conditions lasting several weeks, mimic rheumatoid arthritis. Therefore, the first four criteria must be present for a minimum of six weeks before a diagnosis of rheumatoid arthritis can be made. This approach, however, leads to diagnostic uncertainty that may delay appropriate therapy for months or years. Serum antibodies have been detected that may help define subgroups of patients.17 Antibodies to cyclic citrullinated peptides (CCPs) appear to have a high specificity (90 to 98 percent) and thus may prove useful in early diagnosis, even though the sensitivity of the test for them is approximately 50 to 65 percent at presentation.18,19 Interestingly, these antibodies may appear in the serum years before the onset of clinical disease.20 In any event, many patients present initially to primary care physicians, so these providers need to recognize patients with potential inflammatory arthritis and be aware of the importance of referral to a specialist within the first three months after the appearance of symptoms.
General Therapeutic Principles
Guidelines concerning therapy for rheumatoid arthritis have been published recently by the American College of Rheumatology (Figure 1).21 No treatment cures rheumatoid arthritis; therefore, the therapeutic goals are a remission of symptoms involving the joints, a return of full function, and the maintenance of remission with DMARD therapy. A useful intermediate goal is to have all patients evaluated by a rheumatologist within three months after the onset of symptoms, so that essentially all patients will be receiving DMARDs by the time they have had symptoms for three months.
Figure 1. Management of Rheumatoid Arthritis.
Since many patients with rheumatoid arthritis present initially to primary care physicians, these providers need to suspect this diagnosis early and promptly refer the patient to a rheumatologist. Optimal care of patients with rheumatoid arthritis requires close collaboration between rheumatolgists and primary care physicians. DMARD denotes disease-modifying antirheumatic drug, NSAID nonsteroidal antiinflammatory drug, and MTX methotrexate. Adapted from American College of Rheumatology guidelines.21
To evaluate the success of interventions, investigators have used a number of clinical measures. They include the number of joints that are tender and swollen, markers of inflammation (including the erythrocyte sedimentation rate and C-reactive protein level), and patients' responses to questions about their pain, their global assessment of disease activity, and their physical function. The American College of Rheumatology criteria for improvement can be used by clinicians to quantify patients' improvement after treatment (Table 1).22 Most clinical studies have required a benchmark of 20 percent improvement in these criteria, a result that is known as ACR 20; now that better treatments are being initiated earlier in the course of the disease, 50 percent improvement (ACR 50) is becoming a more frequent target.
Table 1. American College of Rheumatology Preliminary Definition of 20 Percent Improvement in Rheumatoid Arthritis (ACR 20).
Medications
Medications that are used to treat rheumatoid arthritis are divided into three main classes: nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and DMARDs (both synthetic and biologic).
NSAIDs
NSAIDs are particularly helpful during the first few weeks in which a patient has symptoms, because the drugs provide partial relief of pain and stiffness until a definitive diagnosis of rheumatoid arthritis can be established. NSAIDs have not been shown to slow the progression of the disease; therefore, in long-term care, NSAIDs should be used together with DMARDs.21 Although both these classes of medications are well tolerated for short periods, long-term administration may result in gastrointestinal ulcer, perforation, and hemorrhage. Every year 1.5 percent of patients with rheumatoid arthritis are hospitalized with gastrointestinal problems.23 The risk of these complications increases with older age, corticosteroid use, and a history of peptic ulcer disease.
Recently, cyclooxygenase-2 (COX-2) inhibitors, which decrease the incidence of gastric and duodenal ulcers by approximately 50 percent as compared with traditional NSAIDs, have been introduced.24,25,26 To a similar degree, the addition of proton-pump inhibitors to therapy with NSAIDs also decreases the incidence of bleeding ulcers associated with traditional NSAIDs.27 The efficacy of the COX-2 inhibitors is no better than that of the older and less expensive NSAIDs.24 Both traditional NSAIDs and COX-2 inhibitors have been associated with increased fluid retention, exacerbation of hypertension, and impairment of renal function in susceptible patients.24,28 Thrombotic events have been reported in patients who are taking COX-2 inhibitors29,30,31 and may occur more frequently than with traditional NSAIDs.29,30
Corticosteroids
Corticosteroids are potent suppressors of the inflammatory response in rheumatoid arthritis and in many other diseases; unfortunately, their dose-dependent side effects are familiar to all clinicians. Controversy continues about when, if, and how these compounds should be used to treat rheumatoid arthritis.32,33 Studies conducted more recently34,35,36 have corroborated findings from older trials37,38 by clearly establishing that corticosteroids decrease the progression of rheumatoid arthritis as detected radiographically. Corticosteroids in low doses (e.g., 10 mg of prednisone per day) are used to treat 30 to 60 percent of patients.21,32 The majority of patients who were enrolled in recent pivotal clinical trials were receiving corticosteroids at baseline.39,40,41,42,43,44 Table 2 presents some useful guidelines for corticosteroid use in patients with rheumatoid arthritis.
Table 2. Keys to Optimizing the Outcome of Treatment.
Predictable side effects of corticosteroid drugs include thinning of the skin, cataracts, osteoporosis, hypertension, and hyperlipidemia.45,46 The latter three conditions may be preventable with aggressive management of osteoporosis and cardiovascular risk factors. Essentially, all patients taking corticosteroids should receive supplemental calcium (1 to 1.5 g per day) and vitamin D (800 IU per day).47 Bisphosphonates appear to be very effective in reducing vertebral fractures in patients taking corticosteroids47 (offering a reported 70 percent reduction in incidence) and should be prescribed for patients who have low bone density (e.g., a T score of 2 or lower). Recent evidence suggests that inflammation plays a major role in atherosclerosis48,49,50,51; the ability of corticosteroids to decrease inflammation rapidly may offset some of the potentially detrimental effects of the drugs on the vascular endothelium.51
Synthetic DMARDs
Optimal management of rheumatoid arthritis requires rapid and sustained suppression of inflammation with DMARDs, which are defined as medications that retard or halt the progression of disease. Disease modification is most convincingly demonstrated by the ability of the medications to decrease radiographic progression. A meta-analysis of blinded clinical trials has suggested that the relative efficacy of methotrexate, sulfasalazine, intramuscular gold, and penicillamine is similar.52 Antimalarial drugs (e.g., chloroquine and hydroxychloroquine) are less effective. Penicillamine, because of concern about its toxicity, and oral gold, because of its marginal efficacy,52 are rarely used today.53
Since observational trials have clearly identified methotrexate as the synthetic DMARD that is most likely to induce a long-term response,54,55 it is most often selected for initial therapy.53 It has demonstrated efficacy and durability,56 a long-term track record of acceptable toxicity, and low cost. An important observational study has shown that patients with rheumatoid arthritis who have been treated with methotrexate have significantly lower mortality (odds ratio for death, 0.4) than patients who have not been treated with methotrexate.57 Methotrexate has become so much the standard of care that most of the recent pivotal trials of its use in patients with established disease (Figure 2) have listed active disease despite methotrexate therapy as an inclusion criterion.39,42,43,44 Concomitant administration of folic acid (1 to 3 mg per day) or folinic acid (2.5 to 5 mg given 12 to 24 hours after methotrexate) significantly decreases many toxic effects without a measurable decrease in efficacy and has improved the tolerability of methotrexate,61,62 a finding that has permitted clinicians to administer 20 to 30 mg of methotrexate per week when necessary. Most data suggest that methotrexate is most effective at a dose of 17.5 to 30 mg per week63,64 but that oral absorption may be highly variable.65,66 Therefore, if oral methotrexate produces a suboptimal response, a trial of subcutaneous or intramuscular methotrexate is indicated.21
Figure 2. Responses to Drug Therapy in Seven Studies Involving Patients Receiving Methotrexate.
All the patients in these seven studies were already receiving methotrexate, to which the other medication was added. Responses were measured in terms of an improvement of at least 20 percent in symptoms, as defined by the American College of Rheumatology (ACR 20). Numbers above the bars are response rates.
Leflunomide, a new synthetic DMARD, has an efficacy similar to that of sulfasalazine or moderate-dose methotrexate.67,68 Hydroxychloroquine, considered the least potent but best tolerated of the DMARDs,52 is the DMARD that is most commonly combined with methotrexate.53 Sulfasalazine was the first DMARD that was developed specifically to treat rheumatoid arthritis69 and has an efficacy similar to that of methotrexate.52 Sulfasalazine is most commonly used in the United States as part of combination DMARD therapy.53 Intramuscular gold is more likely both to produce a remission and to result in toxic effects as compared with methotrexate.70 Its cumbersome administration and toxicity have limited its use.53
Historically, concern about the toxicity of DMARDs has delayed their use in treating rheumatoid arthritis. It is now accepted that the consequences of delaying therapy far outweigh the possible toxic effects for the majority of patients.21,71 Safe administration of DMARDs requires critical and careful monitoring (Table 3).72 Detailed monitoring guidelines have been published to help avert damage to the liver,73 which was a major concern when use of the drug for rheumatoid arthritis became popular in the mid-1980s.74,75,76,77 Since then only one case of cirrhosis has been reported in patients whose physicians were following the guidelines for monitoring.78 These guidelines include measuring serum albumin and aminotransferase levels every four to eight weeks. Doses of methotrexate should be decreased when aminotransferase levels are elevated above the upper limit of normal, and treatment should be stopped if the elevation persists. Obtaining complete blood counts and measuring serum creatinine are also recommended,72 since a decrease in renal function may precipitate toxic effects in a patient in previously stable condition who is taking methotrexate.79
Table 3. Guidelines for Monitoring the Treatment of Rheumatoid Arthritis.
Both methotrexate and leflunomide have a substantial potential for teratogenesis,80,81 so women of childbearing potential who require these medications should be using reliable birth control. Subacute pneumonitis is rare with methotrexate (51 cases have been reported worldwide) but may be life-threatening.82 If pneumonitis is suspected on the basis of clinical findings or a chest radiograph, methotrexate should be promptly discontinued and not reintroduced. As the best tolerated of all the DMARDs, hydroxychloroquine83 ― if it is used at doses below 6.5 mg per kilogram of lean body mass per day ― requires only yearly visits to the ophthalmologist to prevent the rare occurrence of retinal toxic effects.84
Four double-blind, controlled trials have now shown that minocycline is effective in treating rheumatoid arthritis.85,86,87,88 In patients with long-standing disease, a small but statistically significant benefit was observed.85,86 Minocycline that was used as initial therapy in patients who tested positive for rheumatoid factor was superior to placebo (response rate, 65 percent, as compared with 13 percent for placebo87) and superior to hydroxychloroquine (60 percent vs. 33 percent88 ) when measuring ACR 50. The mechanism by which minocycline works is incompletely understood but probably involves immunomodulation,89 suppression of matrix metalloproteinases,90 and suppression of nonspecific infections that would otherwise stimulate inflammatory cytokine production.88 Reversible hyperpigmentation is seen in up to 30 percent of patients who are receiving long-term minocycline therapy.
Biologic DMARDs
Three biologic products that inhibit the actions of TNF- (infliximab, etanercept, and adalimumab) and one that inhibits the action of interleukin-1 (anakinra) are now available to treat rheumatoid arthritis.6 Other agents are being tested; some have targeted cytokines in ways that are similar to those previously mentioned. There is also renewed interest in products that target the activation of T cells or B cells,91,92 including anti-CTLA4Ig93,94 and anti-CD20 (rituximab).95 (A report on a study of rituximab appears elsewhere in this issue of the Journal.96)
Combination Therapy with DMARDs
Ten years ago, the use of combinations of DMARDs was rare; now at least one third of patients with rheumatoid arthritis who are treated by rheumatologists in the United States are receiving combination therapy.53 Trials that have compared combinations of DMARDs head-to-head with methotrexate40,97 and trials that have shown the additional benefit of adding drugs to methotrexate for patients who have active disease despite methotrexate39,42,43,44,58,59,60 (Figure 2) have fueled the rise of combination DMARD therapy.
One of the first randomized studies that directly compared combination DMARD therapy with methotrexate was a two-year, double-blind trial in which patients were assigned to three groups: those who took methotrexate alone (at 17.5 mg per week), those who took a combination of sulfasalazine (at 1 g per day) and hydroxychloroquine (at 400 mg per day), and those who took all three medications.40 At two years, the end point of 50 percent improvement in composite symptoms of arthritis was reached by 77 percent of patients who were treated with all three drugs but by only 33 percent of patients who were treated with methotrexate alone. Patients who received combination therapy did not have more side effects than those who received methotrexate alone. In another study, the triple combination of methotrexate (at 17.5 mg per week), sulfasalazine (at 2 g per day), and hydroxychloroquine (at 400 mg per day) was superior to either the combination of methotrexate and sulfasalazine or the combination of methotrexate and hydroxychloroquine.59
In patients who have early disease, three critical trials have all shown that initial combination therapy is superior to therapy with a single DMARD.96,98,99 The Combinatietherapie Bij Reumatoide Artritis (COBRA)98 trial compared sulfasalazine alone with the combination of sulfasalazine, low-dose methotrexate (which was stopped at 40 weeks), and prednisolone (which was given initially at 60 mg per day but tapered off by 28 weeks). Patients in the combination group had a more rapid response to treatment, fewer withdrawals from the study because of toxicity, and most important, less radiographic evidence of progression at five years.100 Other trials involving patients with early disease have demonstrated the superiority of triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) over sulfasalazine alone,99 double therapy (methotrexate and sulfasalazine or methotrexate and hydroxychloroquine), and monotherapy.96 However, no trials have compared initial combination therapy with a rapid step-up to combinations only in patients with active disease despite monotherapy.
In the much-studied group of patients with active disease despite taking methotrexate, a number of trials with similar designs have been completed. In these trials, patients continue taking methotrexate plus either the active treatment or placebo. Figure 2 details the ACR 20 responses seen in seven trials involving patients with these characteristics. This summary of the data is not intended to imply that a specific level of response in one trial can be directly compared with that in another trial. These seven effective therapies have not yet been compared head to head.
Initial Treatment
Establishing a diagnosis as early as possible and then starting DMARD therapy is the foundation for successful treatment of patients with rheumatoid arthritis. Many questions remain, including the following: Which drug should be used first? Can drug toxicity or a patient's response be predicted by pharmacogenomics? Should drug combinations be used initially? Should we try to induce rapid disease suppression with corticosteroids or TNF inhibitors? Are there biologic markers that should be used to monitor outcome in place of or in addition to standard assessment?
Until these questions are answered, most rheumatologists select methotrexate as the initial therapy for most patients.53 The characteristics and personal choices of patients influence this decision.21 Methotrexate should not be used in patients who have underlying liver or renal disease, who consume alcohol, who plan to become pregnant in the near future, or who do not want to undergo regular laboratory monitoring. Whether to start a course of low-dose corticosteroids initially along with the chosen DMARD is controversial; many clinicians start treatment with prednisone at 5 to 7.5 mg per day as bridge therapy until the slower-acting DMARDs have a chance to work. Once the DMARD begins working, corticosteroids should be tapered (Table 2).
Methotrexate is started at a dose of 7.5 to 15 mg, given orally once weekly. If patients continue to have active disease (as indicated by swollen and tender joints), as most do, the dose should be increased in 5-mg increments each month or two to 20 to 30 mg per week. If patients continue to have active disease, consideration should be given to switching to subcutaneous administration.21,65,66 If active disease persists despite optimal methotrexate therapy, other DMARDs should be added.21
Compelling data from the COBRA trial98,100 ― in which patients with active early rheumatoid arthritis were given either sulfasalazine alone or the combination of sulfasalazine, methotrexate, and either a high or a low dose of oral prednisolone for 28 weeks ― have raised the question of whether therapy to suppress the disease rapidly should be given immediately after the diagnosis. The rapid suppression of rheumatoid arthritis by corticosteroids has been recognized since the middle of the 20th century.101 The Early Rheumatoid Arthritis (ERA) trial102 is an important study that compared methotrexate (at a dose that escalated to 20 mg per week) with etanercept in patients with disease diagnosed within the preceding three years. Both treatments were very effective in controlling the disease at one year, but etanercept (administered at 25 mg subcutaneously twice a week) was more effective in rapidly suppressing disease activity. In both the ERA and COBRA trials, markers of inflammation (including the erythrocyte sedimentation rate and the C-reactive protein level) were dramatically reduced after two weeks of therapy. If, in fact, it is important to control disease in days, rather than in weeks or months, then corticosteroids and TNF inhibitors (both of which appear to be capable of stopping active disease) should be examined in trials to test the concept of induction therapy (i.e., medication that is administered initially and then withdrawn).
Therapy for Established Rheumatoid Arthritis
If patients continue to have active disease after two to three months of methotrexate at a dose of 20 to 30 mg per week, or if they cannot tolerate higher doses of methotrexate despite folate replacement, the current standard practice is to add another DMARD to methotrexate21; all the trials included in Figure 2 address this patient population.
To date, clinically significant differences have not emerged with regard to toxicity for the treatments shown in Figure 2, with the exception of poor long-term tolerability of combining methotrexate and cyclosporine.103 Until there are studies that compare the relative efficacy of these effective therapies, the most economical initial choice104 for the patient who has active disease despite taking methotrexate is the addition of sulfasalazine, hydroxychloroquine, or both. Data from the United Kingdom have shown that if conventional DMARDs are optimized and used in combination, control of the disease can be achieved in more than half of patients who would otherwise be candidates for TNF inhibitors.105 If active disease (manifested by swollen and tender joints) persists after three months of these DMARD combinations, leflunomide or a TNF inhibitor should be added to methotrexate.
If DMARD therapy is started within three months after the onset of symptoms and escalated with the goal of achieving remission, the majority of patients will have their disease well controlled within a year while taking conventional single or combination DMARD therapy.106 If inflammatory disease is inadequately controlled, therapy with TNF inhibitors should be started.
Coexisting Illnesses
The long-term prognosis for patients with rheumatoid arthritis depends not only on how well their joint disease is treated but also on how well their coexisting illnesses are addressed.107,108 The three coexisting conditions that have the greatest effect on morbidity and mortality in rheumatoid arthritis are infection (particularly pulmonary infection), osteoporosis, and cardiovascular disease.
Rheumatoid arthritis is associated with approximately a doubling of the risk of infection, as compared with the risk in age-matched controls,109 and the degree of increase in this risk correlates with the severity of the disease.110 Although some studies suggest that corticosteroids may increase the risk of infection,111 controversy exists about whether such an increase is due to the use of corticosteroids itself or to the fact that patients who are at higher risk are more likely to use corticosteroids. Whether the new TNF inhibitors increase the risk of infection is a matter for debate since the drugs have been associated with a change in the spectrum of infections112 ― specifically, increased tuberculosis, histoplasmosis, and listeria.6
The clinician who is caring for patients with rheumatoid arthritis should be aware of the risk of infection. All patients should have yearly influenza vaccinations and should receive the pneumococcal vaccine at appropriate intervals. Since patients may have a better immunologic response to vaccination before taking methotrexate,113 it seems prudent to vaccinate before starting DMARD treatment, when possible. Live vaccines should be avoided in patients who are receiving immunosuppressive medications. When considering TNF inhibitors, clinicians should recommend that all patients be tested for prior exposure to tuberculosis. Both clinicians and patients with rheumatoid arthritis should be vigilant with regard to avoiding infections and treating them early and aggressively. Stopping or withdrawing drug treatment during infections is critical.112
The advent of diagnostic tools that are accurate and easy to use and the availability of effective therapies for osteoporosis have been tremendous advances in the treatment of rheumatoid arthritis.114 The incidence of osteoporosis is doubled in patients with rheumatoid arthritis,114,115 and baseline bone-density studies should be performed in all patients, particularly those who will receive corticosteroids. If osteoporosis is present, bisphosphonate therapy, which is reported to decrease the risk of fracture by 70 percent despite the coadministration of corticosteroids,47 should be used.
Cardiovascular disease accounts for most of the excess mortality associated with rheumatoid disease.49 The newer concepts of the pathogenesis of atherosclerosis suggest that inflammation is a key factor in causing vascular endothelial damage.49,50,116 It has been hypothesized that the systemic inflammation that characterizes rheumatoid arthritis may play a key role in the excess atherosclerosis seen in patients with this disease.49,50 Risk factors for atherosclerosis should be aggressively sought and addressed. In particular, smoking cessation may be fruitful, since smoking has been associated with increased severity of arthritis.117 Current trials of statin therapy in patients with rheumatoid arthritis may address the risk of cardiovascular disease, since statins should decrease both atherosclerosis and inflammation.118,119
Current Challenges
Caring for patients with rheumatoid arthritis poses significant challenges. Three issues deserve special mention: the lack of an accurate method for making an early diagnosis, which permits early treatment; inadequate predictors of the differential response to available therapy, as well as too few studies comparing effective therapies; and the enormous cost of new therapies, which has made them unavailable to many patients. Since musculoskeletal disease accounts for one quarter of all visits to the offices of primary care physicians,120 formal training in rheumatic disease needs to be included in the education of all primary care physicians. Preliminary studies suggest that genetics might be useful in predicting responses to DMARDs.121 Until these research efforts come to fruition, studies that directly compare current therapies are urgently needed. Many of our new therapies are expensive, with initial costs that may exceed $1,500 per month. However, these up-front costs may be justified in the long term by savings that result from an improved quality of life and enhanced productivity.
The treatment of rheumatoid arthritis has improved dramatically in the past decade,7,8 thanks to early diagnosis and the availability of DMARDs. Physicians can now have the goal of eradicating active disease and aggressively intervening to address coexisting illnesses. Remission in patients who are receiving therapy is now a realistic goal. Recent reports that only a small minority of patients (i.e., 5 percent) who are being treated by rheumatologists have disease that is active enough to qualify them for current clinical trials are a testament to the success of these therapies.107
Supported by the Albert G. and Bernice F. Hansen Charitable Foundation.
Dr. O'Dell reports having received consulting fees from Amgen, Abbott, Centocor, Wyeth, and Bristol-Myers Squibb and lecture fees from Thompson, Armand Scott, and Maritz.
I am indebted to Renee Crosby and Lucie Case for their assistance in the preparation of the manuscript; to Drs. Arthur Weaver, Lynell Klassen, Iain McInnes, Gerald Moore, Ted Mikuls, Joel Bessmer, and David O'Dell for their support and thoughtful and candid review of the manuscript; and to Donna O'Grady, Colleen Buescher, and Claire Haire for their support.
Source Information
From the Department of Internal Medicine, University of Nebraska Medical Center; and the Omaha Veterans Affairs Medical Center ― both in Omaha.
Address reprint requests to Dr. O'Dell at the Department of Internal Medicine, 983025 Nebraska Medical Center, Omaha, NE 68198-3025, or at jrodell@unmc.edu.
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