Advances in the Management of Rheumatoid Arthritis
Advances in the Management of Rheumatoid Arthritis
Author: Keith Colburn, MD, Rheumatology Division, Department of Veterans Affairs, Jerry L. Pettis Memorial VA Hospital, Loma Linda, Calif.
Editor’s Note—Since the American College of Rheumatology (ACR) first developed guidelines for the management of rheumatoid arthritis (RA) and monitoring of drug therapy in 1996,1,2 there have been major advances in the understanding of the pathogenesis and the treatment of RA, including clear evidence of benefit of aggressive early treatment on the course and outcomes of the disease. Furthermore, new classes of therapeutic agents, including biologic agents, have been introduced.
Recently, the ACR updated the guidelines to reflect these new advances in management and treatments of RA.3 This review is adapted from the 2002 update to enhance primary care physicians’ understanding of current evidence-based management of RA. We will also discuss the new biologic agents and their economic implication for the individual patient as well as for society.
RA is a chronic progressive polyarthritis of unknown etiology diagnosed by presence of at least 4 of 7 following criteria (see Table 1) set up by the ACR: 1) morning stiffness of at least 1 hour; 2) arthritis of 3 or more joint areas; 3) arthritis of hand joints; 4) symmetric arthritis; 5) rheumatoid nodules; 6) positive serum rheumatoid factor (RF); and/or 7) radiographic changes typical of RA.4 In some cases, patients will have extraarticular involvement, including Sjögren’s syndrome, interstitial lung disease, systemic vasculitis, episcleritis and scleritis, pericardial involvement, and Felty’s syndrome.5
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RA affects 0.3-1.5% of the adult population in North America.6 The prevalence is about 2.5 times higher in women than in men. Most patients experience a chronic fluctuating course of disease that, despite therapy, may result in progressive joint destruction, deformity, disability, and even premature death. RA results in more than 9 million physician visits, more than 250,000 hospitalizations per year, 2.7-30 days absent per year from work, and estimated lifetime direct medical care costs of $93,296.7
Management Goals
The goals in managing RA are to control signs and symptoms, restore physical function, prevent or control the development of joint damage, and induce a complete clinical remission. Complete clinical remission is defined as at least 2 consecutive months of 5 or more of following requirements: 1) duration of morning stiffness not exceeding 15 minutes; 2) no fatigue; 3) no joint pain; 4) no joint tenderness or pain on motion; 5) no soft tissue swelling in joints or tendon sheaths; and 6) Westergren erythrocyte sedimentation rate (ESR) less than 30 mm/h for a female or 20 mm/h for a male.1
However, despite the wide array of drugs and biologic agents, it may not be possible in all cases to achieve complete clinical remission. If complete remission is not achieved, the management goals are the next best, that is to relieve pain, improve joint motion, limit functional loss, and incur a minimum of adverse effects.
Management Principles
The initial step in managing RA consists of the early diagnosis of RA, documenting baseline disease activity and damage, and estimating prognosis. This is followed by the initial therapy, which consist of patient education, starting disease-modifying antirheumatic drugs (DMARDs) within 3 months of disease onset, nonsteroidal anti-inflammatory drugs (NSAIDs), local or low-dose systemic steroids, and physical and/or occupational therapy.
Once therapy is initiated, patients should be regularly reassessed for disease activity and for treatment side effects. Primary care physicians can be involved in this assessment, but evaluation and periodic follow-up by a rheumatologist is strongly recommended, especially in the early stages of the disease in which it may be difficult to determine the appropriateness and effectiveness of aggressive treatment. Much of the joint damage, which ultimately results in disability, begins early on in the course of the disease.8,9 In one study, for example, more than 80% of patients with RA of less than 2 years duration had joint space narrowing on plain x-rays of the hands and wrists, while two thirds had erosions.9 An appreciation of the pathogenic mechanisms of RA and the poor outcomes with conventional therapy led to the recent realization that an aggressive approach to treatment of newly diagnosed or early disease is essential to suppress ongoing inflammation and prevent joint injury.
Methotrexate (MTX) is the standard treatment by which all other DMARDs are measured. Generally, patients initially are treated with MTX, or if the disease is very aggressive, MTX in combination therapy with other DMARDs. If patients have an inadequate response, described as ongoing active disease after 3 months of maximal initial therapy, the DMARD should be changed or a new one added. If not treated early and aggressively, reconstructive surgery may be needed for patients with end-stage joint damage manifested by unacceptable pain, limitation of function, and significant alteration of joint anatomy.
Patients should be involved in development of their treatment plan. Good care mandates that the physician discuss with the patient the likely disease course, prognosis, and treatment options. The patient needs to know what the treatment costs, the adverse effects, expected time for response, risk factors, comorbid conditions, monitoring requirements of pharmacologic agents, and their own preferences. Expectations for treatment and potential barriers to carrying out the recommendations should be discussed.
Initial Evaluation
The baseline evaluation of disease activity and damage in patients with RA outlined in Table 2 includes documentation of patients’ subjective complaints, physical examination, laboratory and radiographic examinations, as well as standardized assessment tools.
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Subjective findings include degree of joint pain, duration of morning stiffness, duration of fatigue, and limitation of function. The physical examination documents actively inflamed joints; tender and swollen joint counts; mechanical joint problems, including loss of motion, crepitus, instability, malalignment, and/or deformity; and extraarticular manifestations. Appropriate laboratory and evaluation includes ESR and/or C-reactive protein level (CRP), RF titer, complete blood cell count, electrolyte levels, creatinine level, hepatic enzyme levels (AST, ALT, and albumin), urinalysis, synovial fluid analysis, stool guaiac, and radiographs of selected involved joints. Furthermore, functional status or quality-of-life assessments using standardized questionnaires, known as the Modified Health Assessment Questionnaire (HAQ) and the physician’s and patient’s global assessment of disease activity are as helpful as the laboratory tests in monitoring disease activity in RA.1
Assessment of Disease Activity
At each visit, the physician evaluates the patient for subjective and objective evidence of active disease, including degree of joint pain by visual analog scale, duration of morning stiffness, duration of fatigue, and presence of actively inflamed joints on examination by tender and swollen joint counts. Periodically, the patient needs to be evaluated for disease progression by looking for evidence of loss of motion, joint instability, malalignment, and/or deformity, by checking for ESR or CRP elevation, and by progression of radiographic damage of involved joints. Other parameters for assessing response to treatment include re-evaluation of the physician’s and patient’s global assessment of disease activity and functional status or quality of life assessment with the standardized questionnaires mentioned above.
The ACR 20 criteria for clinical improvement requires a 20% or more decrease in the number of tender and swollen joints plus improvement in 3 of the following 5: 1) the patient pain assessment; 2) patient global assessment; 3) physician global assessment; 4) patient self-assessed disability; and 5) an acute-phase reactant (ESR or CRP).1 These criteria have been expanded to include criteria for 50% and 70% improvement measures (ie, ACR50, ACR70).
Nonpharmacologic Treatments
Optimal management of RA involves pharmacologic as well as nonpharmacologic treatments. Education and counseling are important parts of the nonpharmacologic treatment of RA. Patients should be encouraged to seek information and care from health care professionals other than their physicians. As an example, the Arthritis Foundation is an important source of educational material and programs for those suffering with RA. They may include general information, teaching illness self-management skills, training in biofeedback, the use of cognitive-behavioral and other psychotherapeutic techniques, and enhanced social support. Such programs have been shown to reduce pain, depression, and disability. They also allow patients to share in management decisions, thereby regaining some control over their illness.10
Resting an inflamed joint as well as resting the body may be beneficial. Physical and occupational therapists focus on reducing disability and improving function by exercises, joint protection, and use of orthotics and adaptive devices. Furthermore, an interdisciplinary team approach, including physicians, nurses, physical therapists, occupational therapists, social workers, health educators, health psychologists, and orthopedic surgeons should be a part of the comprehensive management of RA.
Pharmacologic Treatment
Pharmacologic therapy for RA often consists of combinations of NSAIDs, DMARDs, and/or glucocorticoids. The dosing schedules and toxicity of these medications are summarized in Tables 3 and 4.
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NSAIDs. NSAIDs, including salicylates and selective cyclooxygenase 2 (COX-2) inhibitors, reduce joint pain and swelling and improve joint function, but they do not prevent tissue injury or progressive joint damage. Thus, NSAIDs are not considered primary or sole treatment for RA.
Patients with RA are nearly twice as likely, as patients with osteoarthritis, to have a serious complication from NSAID treatment.11 Risk factors for the development of NSAID-associated gastroduodenal ulcers include advanced age, history of previous ulcer, concomitant use of corticosteroids or anticoagulants, higher dosage of NSAID, use of multiple NSAIDs, or a serious underlying disease.12
In 2 recent large trials comparing highly selective COX-2 agents with traditional NSAIDs, the patients in the selective COX-2 agent group had significantly fewer GI events and had no effect on platelet adhesion or aggregation.13,14 However, COX-2 agents are no more effective than nonselective NSAIDs and may cost as much as 15-20 times more per month of treatment than generic NSAIDs. Furthermore, the use of a certain selective COX-2 agent was reported to be associated with a higher rate of thrombotic events (including more myocardial infarctions) compared with traditional NSAIDs. However, these thrombotic events were not significantly different from the placebo-controlled group.13
Glucocorticoids. Low-dose oral glucocorticoids (< 10 mg of prednisone daily, or the equivalent) and local injections of glucocorticoids are highly effective for relieving symptoms in patients with active RA. The benefits of low-dose systemic glucocorticoids, however, must be weighed against their adverse effects, including osteoporosis, hypertension, weight gain, fluid retention, hyperglycemia, cataracts, and skin fragility, as well as the potential for premature atherosclerosis. For long-term disease control, the glucocorticoid dosage is best kept to a minimum.
Patients taking glucocorticoids at dosages as low as 5 mg/d have an increased risk of osteoporosis. Densitometry to assess bone loss should be performed at regular intervals (every 1-2 years) for the duration of glucocorticoid treatment.15 Glucocorticoid-treated patients need 1500 mg of elemental calcium per day (including dietary calcium and calcium supplements) and 400-800 IU of vitamin D per day.16,17 Antiresorptive agents, especially bisphosphonates, prevent bone loss and should be considered at the time long-term glucocorticoid therapy is initiated.17
A patient who has a disease flare in only 1 or a few joints can be treated successfully by injecting the affected joint(s), without requiring a major change in the prescribed treatment regimen. In general, the same joint should not be injected more than once within 3-4 months to avoid corticosteroid induced joint damage. The need for repeated injections in the same joint or for injections in multiple joints indicates the need to reassess the adequacy of the overall treatment program.
DMARDs. As mentioned above, much of the joint damage of RA ultimately resulting in disability begins early on in the course of the disease. DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function, and ultimately, reduce the total costs of health care, thus maintaining the economic productivity of patients with RA. Therefore, most if not every patient with established active RA deserves to be treated with DMARD therapy at the earliest stage of the disease, ideally within 3 months of onset. In general, patients with more severe active disease and/or poor prognostic signs should be treated more aggressively than those with mild disease. A poor outcome is particularly associated with an earlier age of disease onset, persistent swelling of the PIP joints, flexor tenosynovitis of the hands, a high ESR or CRP, a large number of swollen joints, a high RF titer, extraarticular disease, radiographic evidence of bone erosions or cartilage loss, subcutaneous nodules, and an early decline in joint function.18,19
The DMARDs commonly used in RA include hydroxychloroquine (HCQ), sulfasalazine (SSZ), methotrexate (MTX), leflunomide, etanercept, and infliximab. Those used less frequently include azathioprine (AZA), D-penicillamine, gold salts, minocycline, cyclophosphamide, and cyclosporine. Unless the primary care physician is familiar with the indications and side effects of these drugs, it is prudent to consult a rheumatologist once the diagnosis of RA is suspected and treatment with DMARDs needs to be initiated.
Initial DMARD selection is based on the relative efficacy, convenience of administration, costs of the medication and monitoring, and the frequency and potential seriousness of adverse reactions. Besides considering an effective contraception for women of childbearing age, the drug regimen will need to be modified if pregnancy or breastfeeding is contemplated.2
Based on considerations of safety, convenience, and cost, many rheumatologists select HCQ or SSZ first for mild-to-moderate disease activity. For the patient with active disease or with indicators of a poorer prognosis, MTX alone or in combination with other DMARDs is usually preferred for first-line treatment. For patients in whom MTX is contraindicated or has failed to achieve satisfactory disease control either because of lack of efficacy (in doses up to 25 mg/wk) or intolerance, treatment with other DMARDs alone or in combination, including the new biologic agents is indicated.
HCQ and SSZ. Although HCQ alone does not slow radiologic damage, early treatment with HCQ has a significant effect on long-term outcome for patients with early, milder disease. Rash, abdominal cramps, and diarrhea are infrequent adverse effects. HCQ is generally well tolerated and requires no routine laboratory monitoring, although patients need yearly ophthalmologic examinations for early detection of reversible retinal toxicity.20 The length of time to clinical benefit may vary from 1 month to as long as 6 months.
SSZ may act more quickly than HCQ, with benefit sometimes as early as 1 month after beginning therapy. More importantly, SSZ has been shown to retard radiographic progression of RA.21 SSZ is usually well tolerated, with most side effects, including nausea and abdominal discomfort, occurring in the first few months of therapy. Starting at a low dosage and then gradually increasing the dosage lessens the incidence of these side effects. Leukopenia is an occasional, more serious toxic effect that may occur at any time, and periodic laboratory monitoring every 3-4 months is therefore necessary. Clinical response should be apparent within 4 months, and the need for a change in therapy may be determined at that time.
MTX. Many rheumatologists select MTX as the initial DMARD for the majority of their patient with RA, especially for those patients with more active disease. Because of its favorable efficacy and toxicity profile, low cost, and established track record in the treatment of RA, MTX has become the standard by which other DMARDs are evaluated. Longitudinal observational studies and randomized, controlled trials show that MTX can retard the progression of radiographic erosions in many patients.21
Observational studies indicate that more than 50% of patients who take MTX continue the drug beyond 3 years, which is longer than any other DMARD.22 RA patients taking MTX are more likely to discontinue treatment because of adverse reactions than because of lack of efficacy.23 Stomatitis, nausea, diarrhea, and, perhaps, alopecia caused by MTX may decrease with concomitant folic acid24 or folinic acid25 treatment without significant loss of efficacy. Relative contraindications for MTX therapy are preexisting liver disease, renal impairment, significant lung disease, or alcohol abuse.
Since the most frequent laboratory abnormality in patients treated with MTX is elevation of liver enzyme levels, liver function must be monitored every 4-8 weeks. The risk of liver toxicity, however, is low.26 Based on the ACR guidelines for monitoring liver toxicity in patients receiving MTX,26 a liver biopsy should be performed in patients who develop abnormal findings on liver function studies that persist during treatment or after discontinuation of the drug. Rare but potentially serious and even life-threatening pulmonary toxicity may occur at any time with any dosage of MTX but is reversible on stopping the drug. Lymphoproliferative disorders including lymphomas may rarely occur in patients taking MTX.27 The relationship of these disorders to the medication is unclear, although some cases have regressed or resolved with discontinuation of MTX. Since MTX is potentially teratogenic, appropriate contraceptive measures during MTX treatment are mandatory.2
Leflunomide. Several randomized, controlled clinical trials have established leflunomide as an alternative to MTX as monotherapy, especially for patients who cannot tolerate MTX or are experiencing an inadequate response to MTX.28 The reduction in RA disease activity and in the rate of radiologic progression achieved by leflunomide appears to be at least equivalent to that of MTX. Leflunomide is also beneficial as combination therapy with MTX.
Five percent of patients receiving leflunomide and up to 60% of patients receiving MTX plus leflunomide have elevated liver enzyme levels. There are reported cases of liver failure, especially in patients with poor follow-up.29 Therefore, liver function must be monitored every 4-8 weeks, and patients taking MTX plus leflunomide should have liver function monitored at least monthly. In case of leflunomide overdose or toxicity, the elimination of drug can be enhanced by cholestyramine. Leflunomide is a potent teratogen, and women taking leflunomide who wish to conceive must discontinue leflunomide and undergo cholestyramine washout before attempting conception. Obstructive biliary disease, liver disease, viral hepatitis, severe immunodeficiency, inadequate birth control, and rifampin therapy (which raises leflunomide serum levels) are all contraindications to the use of leflunomide.
Anti-tumor necrosis factor alpha (anti-TNFa) therapy. The development of genetically engineered biologic agents that selectively block cytokines (anticytokine therapy) represents a major advance in the treatment of RA. The most clinically effective anti-cytokine agents studied to date are antagonists to TNFa, an essential mediator of the cytokine inflammatory cascade in RA. Two anti-TNFa agents are available in the United States: etanercept, a recombinant soluble TNF-Fc fusion protein; and infliximab, a chimeric (mouse-human) anti-TNF monoclonal antibody.
Randomized, double-blind, placebo-controlled trials have demonstrated the superior efficacy of etanercept and infliximab in improving clinical symptoms and signs in patients with RA, according to the ACR20, ACR50, and ACR70 improvement criteria.30-36 Patients with early RA36 and those with active RA in whom previous DMARD therapy had failed30 showed impressive improvement with etanercept therapy. Both etanercept34 and infliximab32,33,35 are shown to be beneficial when used in combination with MTX in patients with active RA despite optimal doses of MTX alone. Infliximab is currently recommended for use in combination with MTX therapy, because of its potential to initiate anti-idiotypic antibodies, which in turn might cause other forms of autoimmunity in the absence of MTX.
In these trials of etanercept and infliximab, many patients improved rapidly, even during the first 2 weeks of treatment. Randomized trials have demonstrated that patients treated with etanercept alone or with infliximab plus MTX have less radiographic progression after 1 year than patients treated with MTX alone.33,36 In a trial of patients with early RA,36 the symptoms and signs of the disease improved more rapidly with etanercept treatment than with MTX treatment over the first 6 months. There was comparable efficacy of the 2 agents at 12 months.
Although data from randomized trials have not shown an increased frequency of serious adverse effects, such as serious infections or malignancies, for either of the anti-TNFa agents, concerns about the short- and long-term safety of these agents continue. TNFa plays an important role in host protection against infection and tumor genesis. Postmarketing experience with etanercept and infliximab shows rare hospitalizations and deaths from serious infections in patients treated with these agents. Most of the patients who died while being treated with anti-TNFa had significant chronic infections or risk factors for infection. Anti-TNFa agents should therefore be used with caution in patients with susceptibility to infection or a history of tuberculosis. They should be avoided in patients with significant chronic infections, and discontinued temporarily in all patients with acute infection.
Postmarketing surveillance of the anti-TNFa agents yielded reports of sepsis, tuberculosis, atypical mycobacterial infections, fungal infections, other opportunistic infections, demyelinating disorders, and aplastic anemia. Risk of latent tuberculosis should be assessed with a PPD skin test prior to initiation of a TNFa antagonist. While the follow-up period with these new agents is still relatively short, thus far there have been no demonstrated increases in the incidence of malignancy in patients treated with etanercept or infliximab compared with the expected rates of RA in the general population.37 At this time, there appears to be no need for routine laboratory monitoring with the anti-TNFa agents, but patients should be alerted to report any signs or symptoms of infection. Regular observation of patients on these drugs is still essential.
In addition to the absence of long-term safety data, the disadvantages of anti-TNFa agents include the need for parenteral administration and their high cost. Furthermore, not all patients with RA respond to anti-TNFa therapy, and disease flares are expected after therapy is discontinued.34
Interleukin-1 receptor antagonist (IL-1Ra) therapy. Anakinra is a recombinant human form of IL-1Ra. IL-1ß is a cytokine that, along with TNFa, is thought to play an essential role in the synovial inflammation and joint destruction seen in RA. IL-1Ra acts to block the binding of IL-1a and IL-1 ß to the IL-1 receptor, thus preventing the activation of target cells. Randomized, double-blind, controlled trials of anakinra, at a dosage of 150 mg administered as a once-daily subcutaneous injection, showed it to be superior to placebo in improving the clinical signs and symptoms of RA, as assessed by the ACR20 criteria.38 Anakinra also improved the Health Assessment Questionnaire score38 and reduced radiographic progression39 compared with placebo. A recent study demonstrated that combination treatment with anakinra, at a dosage of 1.0 mg/kg or 2.0 mg/kg, plus MTX was more beneficial than treatment with MTX alone.40
Anakinra is approved for use in RA as a 100 mg self-administered subcutaneous daily dose. Injections are simplified with the use of a specially designed injector device that is provided by the manufacturer. Injection site reactions were the most common adverse effect reported. These most often occur during the first 4 weeks and may disappear in days to weeks. As with other biologic therapies, there is concern about the risk of serious infections and malignancy, but the available safety data are limited. Patients with asthma or chronic obstructive pulmonary disease had a higher rate of pulmonary infections; thus, anakinra should be used with caution in patients with these comorbid conditions. Anakinra should not be given to patients with active infections of any type. Anakinra is the newest biologic agent commercially available in the management of RA.
Older DMARDs. Azathioprine (AZA), a purine analog myelosuppressant, has demonstrated benefits in controlling RA and can be used as an alternative to MTX. AZA is best not used in combination with MTX because of increased side effects without increase in efficacy. D-penicillamine is effective,41 but its use is limited, in part, by a slow rate of efficacy (ie, 6 months or longer) and a high rate of unacceptable side effects including nausea, vomiting, rash, loss of taste, proteinuria and bone marrow suppression. Rare, but potentially serious, complications, including autoimmune diseases, such as Goodpasture’s syndrome and myasthenia gravis also can occur as the result of D- penicillamine therapy. Intramuscular gold treatment is effective.42 Injections are required every week for 22 weeks before less-frequent maintenance dosing is initiated. Side effects include oral ulcers, rash, proteinuria, and bone marrow suppression. Only 30% of patients started on gold were still on it after 2 years. Furthermore, certain intramuscular gold preparations are no longer being manufactured and difficult to obtain. Although oral gold is more convenient than injectable gold, there is a long delay (up to 6 months) before benefits are evident, and the oral form is far less efficacious.43 Minocycline is effective in improving the clinical parameters of mild RA.44 Further research is necessary to define the mechanism of action and exact role of tetracyclines, like minocycline, in the treatment of RA. Cyclosporine is beneficial as combination or mono-therapy,45 and has short-term efficacy similar to that of D- penicillamine.46 The use of cyclosporine, however, has been limited by its toxicity, especially hypertension and dose-related loss of renal function.47
Combination DMARD therapy. Conventional treatment of RA with a single DMARD often fails to adequately control clinical symptoms or to prevent disease progression. As a result, rheumatologists are increasingly prescribing combination DMARD therapy analogous to the treatment of Hodgkin’s disease.48 Controversy remains about whether to initiate this type of treatment in a sequential "step-up" approach in patients with persistently active disease in whom single agents have failed or whether to initiate combination therapy early in the disease course and then apply a "step-down" approach once adequate disease control is attained.49 In either case, a rheumatology referral is strongly recommended for patients being considered for initiation of combination therapy.
Early open-label studies of combination DMARD therapy showed promising results.50 A randomized, controlled clinical trial demonstrated that the triple-DMARD combination of MTX, HCQ, and SSZ had substantially increased efficacy compared with MTX alone and without increased toxicity.51 Recently, the triple-DMARD combination of MTX, SSZ, and HCQ was shown to be superior to the double-DMARD combinations of MTX plus SSZ or MTX plus HCQ in both early52 and more advanced53 RA.
Using a "step-down" approach, a recent randomized controlled trial compared SSZ alone or in combination with a 6-month tapering dosage of high-dose, short-term prednisolone and MTX in patients with early disease.54 Patients who took triple therapy had less radiographic progression, fewer withdrawals because of either toxicity or lack of efficacy, and lower disease activity scores than did patients who took SSZ alone.
The studies cited above all predate the introduction of leflunomide and biologic agents and their use in combination with other DMARDs. The combinations of infliximab, etanercept, or leflunomide with MTX have all been studied in patients who had a partial response to MTX, and found to be very beneficial.33,34
Over the last several years, combination DMARD therapy has played a significant role in improving the ability to control the disease activity of RA. The role of combination DMARD therapy continues to evolve.
Surgical treatment of RA
Surgical procedures may be considered in patients who have unacceptable levels of joint pain, loss of range of motion, or limitation of function because of structural joint damage, Examples of surgical procedures used for patients with RA include synovectomy, resection of the metatarsal heads, total joint arthroplasty, carpal tunnel release, and joint fusion. New prosthetic materials and cements for fixing joint prostheses have greatly advanced the prevention of aseptic loosening and increased the longevity of total joint prostheses in patients with RA.55
Cost Considerations
RA has significant economic implications for the individual patient as well as for society. Individuals with RA have 3 times the direct medical costs, twice the hospitalization rate, and 10 times the work disability rate of an age- and sex-matched population.56 Indirect costs related to disability and work loss have been estimated to be 3 times higher than the direct costs associated with disease.
For many years, relatively low-cost options have been available for the treatment of RA. However, the advent of COX-2 inhibitors, newer DMARDs, including biologic agents, and the increasing use of combination therapy have all brought cost considerations to the forefront. Although intuitively one would think therapeutically well treated patients without substantial disabilities would be less of a financial drain on society.
At present, insufficient longitudinal data exist to determine whether such increased expenditures will eventually be offset by lower total costs of a well-managed disease. A recent analysis has examined the relative cost-effectiveness of 6 different treatment options for RA patients in whom MTX therapy has failed:57 etanercept monotherapy, etanercept plus MTX, cyclosporine plus MTX, triple therapy with HCQ, SSZ, and MTX, continued MTX monotherapy, and no second-line agent. Triple therapy was the most cost-effective option, as determined by the ACR20 improvement criteria or a weighted proportion of patients achieving ACR20, ACR50, and ACR70 improvement. However, as with all cost-effectiveness analyses, there were assumptions that may limit the applicability of the results. For example, the time horizon for this model was limited to the first 6 months of therapy. In addition, only a limited number of treatment options were considered in the model. Neither leflunomide nor infliximab was considered. More data about the effect of newer DMARDs on outcomes such as work capacity and radiographic progression are also needed.
In today’s cost-constrained environment, whenever the efficacy and toxicity of treatment options are equivalent, the lower-cost agent is likely to be used. However, practitioners are increasingly facing situations in which therapies are no longer equivalent, there is only a partial response to treatment, treatment toxicity or comorbid conditions contraindicate the use of more traditional agents, or high-risk or severe disease requires the use of newer agents, either alone or in combination. Providers with sufficient numbers of RA patients in their practice and with longitudinal experience in treating this disease will, in consultation with their patients, be the best qualified to balance these delicate cost issues with the frequently progressive and debilitating natural course of this disease.
Summary
RA is a chronic, progressive disease, with systemic features, associated with substantial disability and economic losses, affecting about 1% of adult population. Successful treatment, early diagnosis and timely initiation of disease-modifying agents are needed to limit joint damage and functional loss. Patients may benefit from nonpharmacologic, pharmacologic, and if necessary, surgical interventions. Optimal longitudinal treatment requires comprehensive coordinated care and the expertise of a number of health care providers. Essential components of management include systematic and regular evaluation of disease activity, patient education/rehabilitation interventions, use of DMARDs, possible use of local or low-dose oral glucocorticoids, minimization of the effect on the individual’s function, assessment of the adequacy of the treatment program, and general health maintenance.
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