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The significant changes in the way rheumatoid arthritis has been managed include earlier, more aggressive treatment with combination therapy.
Significant changes have taken place in the way rheumatoid arthritis (RA) has been managed over the past 15 years. Most notably, studies have shown that early, aggressive treatment to a target value of at least low disease activity and, preferably, remission improves long-term outcomes of patients with RA. In addition, combination therapy has been used more frequently and earlier in the disease course.
The exact choice of which agents to combine is still a matter of debate, but in patients who have not had an adequate response to methotrexate (MTX), the value of a combination disease-modifying antirheumatic drug (DMARD), with or without a biologic agent, is not in dispute. Such treatments work well for a large number of patients, and new medications on the market offer hope for many more persons with this disease.1 In this article, I review the current state of RA treatment and monitoring.
MTX was the drug of choice
MTX emerged as the drug of choice in the mid 1980s. However, most patients also were treated with a combination of parenteral gold and other modestly effective drugs, such as d-penicillamine, sulfasalazine (SSZ), and hydroxychloroquine (HCQ). Patients typically stopped taking the ineffective DMARD and started a new one. The process was repeated as needed.
Initially, DMARDs were reserved for patients who showed evidence of advanced disease or erosions and for those for whom NSAIDs were not successful. Aggressive treatment programs evolved with the introduction of MTX, although physicians initially were worried about toxicities, which have been shown to be milder than previously assumed.2 Early on, MTX was not the initial DMARD used. Until recently, SSZ was the most frequently used DMARD in Europe.3
A new and different paradigm evolved during the early to mid 1990s. The Tight Control for Rheumatoid Arthritis (TICORA) study demonstrated that with tight control of disease activity, high degrees of remission could
be achieved with traditional DMARDs.4 The following important factors have led to this more aggressive approach in the modern treatment of patients with RA:
•The disease is now associated with significant mortality, morbidity, diminished quality of life, and disability.
•Aggressive treatment effectively improves symptoms and quality-of-life measures.
•DMARD therapies effectively retard the radiographic progression of disease.
TNF inhibitors provide
MTX was, and still is, the cornerstone of DMARD regimens. Recent trials that used biologic agents offered valuable information about MTX and its efficacy in RA treatment. In one study, when trials of tumor necrosis factor Î± (TNF-Î±) inhibitors versus MTX in MTX-naive patients (those who had not been treated with MTX before) were examined, MTX was not as effective as the TNF-Î± inhibitors in controlling the disease activity and radiographic progression.5
The introduction of TNF-Î± inhibitors in 1998 provided new options for RA management. Remission has become a possibility for more patients, especially when these drugs are used in combination with MTX. This development was demonstrated in the PREMIER study, in which a combination of adalimumab with MTX was more effective in controlling radiologic progression and symptoms than MTX or adalimumab alone.6
When evaluating results from randomized clinical trials (RCTs) of all new and upcoming treatments, keep in mind that patients enrolled in trials rarely are similar to patients seen in routine care, the majority of patients with RA.7-10 Thus, data from RCTs may have limited applicability to some patients seen in routine care.
Mode of action (MOA) biologics
In addition to the initial 3 TNF-Î± inhibitors, other MOA biologics have come on the market and have been shown to be equally effective. As the field has advanced, the choice of medications has grown with it, providing powerful therapeutic tools and more treatment options for patients with RA. These agents are abatacept; rituximab; more recently, golimumab and certolizumab, 2 new TNF-Î± inhibitors; and this year, the interleukin-6 blocker tocilizumab.
Current RA treatment for new patients often begins with MTX, the anchor drug for RA at the start of treatment or within the first 3 months. The dosage is increased from 7.5 to 10 mg/wk to 20 to 25 mg/wk to achieve maximum response within 3 to 6 months.
Disease progress should be monitored by measuring disease activity levels with one of the many composite indices, such as the 28-joint Disease Activity Score (DAS 28), Clinical Disease Activity Index (CDAI), or Routine Assessment of Patient Index Data 3 (RAPID3).11 I prefer the RAPID3 because it is the simplest to use in routine patient care, requiring 5 to 10 seconds to perform rather than 100 to 120 seconds, without the need for a formal joint count12; also, it is strongly correlated with the DAS 28 and the CDAI.13
RA treatment is a fast-changing and advancing area. Use of existing drugs is improving, new medications are available, and more are on the way. The main challenge is to identify the patients who are responding to the treatments. Objective quantification of the response or nonresponse also is needed.
The imporance of monitoring
The TICORA and Behandel Strategien (BeST) studies have demonstrated the importance of close monitoring of patients.14 However, few rheumatologists use quantitative measures in making clinical decisions. In fact, fewer than 10% of US rheumatologists use questionnaires in routine clinical care, and fewer than 15% perform a formal joint count at each visit.15
The Health Assessment Questionnaire (HAQ) and its derivatives have been shown to be the best predictors of functional and work disability, costs, need for joint replacement surgery, and mortality. They are at least as useful for predicting these outcomes as joint counts, radiographs, and laboratory tests.16 In addition, patient questionnaires may be used for all rheumatologic diseases, including osteoarthritis, systemic lupus erythematosus, fibromyalgia, scleroderma, and ankylosing spondylitis.17
The American College of Rheumatology (ACR) core data set was developed to provide a consistent set of outcome measures for RA. Seven measures thought to be important in all RA trials are (1) tender joint count, (2) swollen joint count, (3) function, (4) pain, (5) patient global assessment, (6) physician global assessment, and (7) laboratory marker for inflammation (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP] level). ACR 20, 50, and 70 responses-measures of a medication’s efficacy evidenced by at least a 20%, 50%, or 70% improvement in various ACR core measures, respectively-are useful tools. Opinions differ as to which one is more clinically relevant18; as a group, they are cumbersome to use in real-world clinical care, leading to a need for alternatives to be developed for both RCTs and clinical care.
of disease activity
The DAS and its derivatives, the DAS 28 and the DAS-CRP (using the CRP level in place of the ESR), are used widely in RCTs. The advantage of providing a score for current disease activity, rather than a change score as in the ACR 20, 50, and 70 responses, makes these measures a truer reflection of disease activity. However, a calculator is required to compute the score, with a complicated formula. A scoring tool is provided by a Web site (http://www.reuma-nijmegen.nl/www.das-score.nl/index.html), but because of the difficulties and the need for at least a 28-joint count for the score, this tool is rarely used in clinical practice.
The simplified disease activity index (SDAI) and its simpler version, the CDAI (no measurement of acute-phase reactant level needed), have been proposed. Both are strongly correlated with the DAS, but because they share most of the components of the DAS, that is to be expected. The CDAI has the advantage of allowing for calculation right at the time of the patient visit because it does not require a laboratory test.
The RAPID3 instrument was developed with the aim of solving an important problem in monitoring of patients in clinical care, meeting the need for easy use by both patients and rheumatologists while performing as well as or better than the other available scores. This index of only 3 patient-reported outcome measures from the core data set-physical function, pain, and global estimate-distinguishes active from control treatments in clinical trials as effectively as do ACR and DAS criteria.19,20 The calculation of the score requires no gadgets, blood test results, or joint count. It takes less time than the DAS 28 or HAQ scoring and is highly correlated with the DAS 28 and the CDAI in routine clinical practice.
The need to use a tool to assess patients is obvious, and all the measures just discussed perform within the same range of response and are robust. The most “user friendly”measures have the best chance of succeeding and improving both patient care and rheumatologists’ efficient use of time. We currently use the RAPID3 instrument in our clinics and some of the private practices, and we teach our fellows to do the same. With more hands-on experience, most rheumatologists probably would find this a useful and acceptable tool.
The usual next step
Despite all these advances, about 30% to 40% of patients with RA do not have a satisfactory response to their initial treatment with MTX and other DMARDs.1 The usual next step is to add a biologic agent to MTX. Four biologic agents that currently are candidates for first-line biologic therapy, in chronological order of FDA approval in the United States, are etanercept, infliximab, adalimumab, and abatacept. There is adequate evidence of significant responses to these agents in patients with RA who had an inadequate response to MTX or combinations of DMARDs.21
Even after this first round of biologics in these combinations, 20% to 30% of patients with RA continue to have active disease.1 Among patients who have good initial disease control, with MTX alone or in combination with a biologic agent, some will lose this favorable response.22 The question then is, which biologic agent is next?
Experience from published reports suggests that switching from one TNF-Î± inhibitor to another is effective in some patients to a degree similar to that with switching to another MOA biologic DMARD, such as abatacept, rituximab, or tocilizumab.23 In addition to available efficacy data, adverse-effect profiles and ease of use issues contribute to what the next choice should be for treatment of patients with RA who have tried multiple medications.
A good alternative:
Triple therapy that combines MTX, SSZ, and HCQ has been used for the past 15 years as a good alternative to DMARD monotherapy or a combination with a biologic agent. Some data in 6- to 12-month trials suggest that at least in a small group of patients, triple therapy is as effective as MTX and a biologic agent combination; such therapy may be an option for patients who are not willing to use a biologic agent. The use of multiple medications and the frequent pill-taking with triple therapy may adversely affect treatment adherence, but the cost is much less than that of a biologic combination. All these factors should be kept in mind when a treatment decision is being made.
Offering the best treatment
Emphasis on “best care”for patients with RA is appropriate, and “care that you would give your mother”even may be substituted as the gold standard, which may help place things into perspective. Cost is always a concern, but the greatest consideration is to offer the best treatment.
Currently, the best strategy for managing RA arguably is to start with MTX, with or without low-dose corticosteroids, and treat the patient aggressively. Monitoring of patient response with one of the available instruments-such as the DAS 28, SDAI, CDAI, RAPID3-is needed, and treatment should be adjusted according to these scores. To optimize treatment results, patients with inadequate response after 3 to 6 months should receive one of the biologic agents in addition to MTX. Current data suggest that if MTX is not successful, a combination of MTX and a TNF-Î± inhibitor or abatacept would be a good option. Therefore, rather than change to another drug, the right action would seem to be to add a new DMARD.
In spite of the very good results seen with MTX and TNF-Î± inhibitor combinations, about 10% to 15% of patients still do not have an adequate response to treatment.1 The new medications on the market and the newer ones coming out, like new cytokine inhibitors with a different mode of action, will be the next treatment options for these patients.
After some time, when all these agents have been in use long enough, the main determinant as to which agent to use will be patient preferences, adverse-event profiles, ease of use, and the most likely pharmacogenomic profile of each patient. Treatments currently are working for a large number of patients, and the future of treatment looks promising for the rest of the patients who have RA.
1. Yazici Y. Treatment of rheumatoid arthritis: we are getting there. Lancet. 2009;374:178-180.
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3. Pincus T, Yazici Y, Sokka T, et al. Methotrexate as the “anchor drug”for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol . 2003;21(suppl 31):S179-S185.
4. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004;364:263-269.
5. Yazici Y, Yazici H. Tumor necrosis factor alpha inhibitors, methotrexate or both? An inquiry into the formal evidence for when they are to be used in rheumatoid arthritis. Clin Exp Rheumatol. 2008;26:449-452.
6. Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.Arthritis Rheum. 2006;54:26-37.
7. Sokka T, Pincus T. Eligibility of patients in routine care for major clinical trials of anti-tumor necrosis factor alpha agents in rheumatoid arthritis. Arthritis Rheum.2003;48:313-318.
8. Sokka T, Pincus T. Most patients receiving routine care for rheumatoid arthritis in 2001 did not meet inclusion criteria for most recent clinical trials or American College of Rheumatology criteria for remission. J Rheumatol . 2003;30:1138-1146.
9. Gogus F, Yazici Y, Yazici H. Eligibility for inclusion criteria in use for rheumatoid arthritis clinical trials in a Turkish cohort. Arthritis Rheum. 2003;48(9 suppl):S128.
10. Yazici Y, Kulman I. Majority of rheumatoid arthritis patients in routine care do not meet inclusion criteria for RA clinical trials. Ann Rheum Dis. 2004;63(suppl 1):S183.
11. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum.2008;59:762-784.
12. Yazici Y, Bergman M, Pincus T. Time to score quantitative rheumatoid arthritis measures: 28-Joint Count, Disease Activity Score, Health Assessment Questionnaire (HAQ), Multidimensional HAQ (MDHAQ), and Routine Assessment of Patient Index Data (RAPID) scores. J Rheumatol. 2008;35:603-609.
13. Pincus T, Swearingen CJ, Bergman M, Yazici Y. RAPID3 (Routine Assessment of Patient Index Data 3), a rheumatoid arthritis index without formal joint counts for routine care: proposed severity categories compared to disease activity score and clinical disease activity index categories. J Rheumatol. 2008;35:2136-2147.
14. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005;52:3381-3390.
15. Pincus T, Segurado OG. Most visits of most patients with rheumatoid arthritis to most rheumatologists do not include a formal quantitative joint count. Ann Rheum Dis.2006;65:820-822.
16. Pincus T, Sokka T. Quantitative measures for assessing rheumatoid arthritis in clinical trials and clinical care.Best Pract Res Clin Rheumatol. 2003;17:753-781.
17. Pincus T, Wolfe F. Patient questionnaires for clinical research and improved standard patient care: is it better to have 80% of the information in 100% of patients or 100% of the information in 5% of patients? J Rheumatol. 2005;32:575-577.
18. Felson DT, Anderson JJ, Lange ML, et al. Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? Arthritis Rheum.1998;41:1564-1570.
19. Pincus T, Yazici Y, Bergman M, et al. A proposed approach to recognise “near-remission”quantitatively without formal joint counts or laboratory tests: a patient self-report questionnaire routine assessment of patient index data (RAPID) score as a guide to a “continuous quality improvement.” Clin Exp Rheumatol. 2006;24(6 suppl 43):S60-S65.
20. Pincus T, Chung C, Segurado OG, et al. An index of patient reported outcomes (PRO-Index) discriminates effectively between active and control treatment in 4 clinical trials of adalimumab in rheumatoid arthritis. J Rheumatol .2006;33:2146-2152.
21. Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. Lancet. 2007;370:1861-1874.
22. Duclos M, Gossec L, Ruyssen-Witrand A, et al. Retention rates of tumor necrosis factor blockers in daily practice in 770 rheumatic patients. J Rheumatol.2006;33:2433-2438.
23. Hjardem E, Ãstergaard M, PÃ¸denphant J, et al. Do rheumatoid arthritis patients in clinical practice benefit from switching from infliximab to a second tumor necrosis factor alpha inhibitor? Ann Rheum Dis. 2007;66:1184-1189.