Rheumatoid Arthritis: Aletaha D

Aletaha D, Landewe R, Karonitsch T, Bathon J, Boers M, Bombardier C, Bombardieri S, Choi H, Combe B, Dougados M, Emery P, Gomez-Reino J, Keystone E, Koch G, Kvien TK, Martin-Mola E, Matucci-Cerinic M, Michaud K, O'Dell J, Paulus H, Pincus T, Richards P, Simon L, Siegel J, Smolen JS, Sokka T, Strand V, Tugwell P, van der Heijde D, van Riel P, Vlad S, van Vollenhoven R, Ward M, Weinblatt M, Wells G, White B, Wolfe F, Zhang B, Zink A, Felson D, Anonymous00358, Anonymous00359. · Medical University of Vienna, Vienna, Austria. · Arthritis Rheum. · Pubmed #18821648 No free full text.

Abstract: OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS: Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION: These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Aletaha D. · No affiliation provided · Arthritis Res Ther. · Pubmed #19519959 links to  free full text

Abstract: Studies based on registries continue to inform us of many relevant issues in the treatment of arthritic conditions and constitute more than just a supplement of clinical trial data. We can learn about long-term aspects of therapies beyond the scope of most clinical trials and about larger-scale toxicity. The downsides need to be considered in the interpretation of the results and include mainly the biases that are inherent when routine clinical practice is just observed and not steered by a protocol. However, using steered protocols in practice not only would facilitate post hoc analyses of clinical effectiveness, but (as we have learned from research in rheumatoid arthritis) can also improve outcomes of our patients.

Smolen JS, Aletaha D. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Nat Clin Pract Rheumatol. · Pubmed #18461061 No free full text.

This publication has no abstract.

Aletaha D. · National Institutes of Arthritis, Musculoskeletal, and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. · Arthritis Res Ther. · Pubmed #16542465 links to  free full text

Abstract: Several pooled indices for the assessment of rheumatoid arthritis disease activity are available to rheumatologists. Face and criterion validity of these instruments can be assessed by determining the association of their measurements with opinions of physicians. Several confounding aspects must be considered in such analyses, especially blinding of the person(s) making the decisions to the instruments being studied and to the objective of the study in general. From several studies in the literature, there is currently no evidence that any one of the available composite indices is better or worse than any other. The choice of index in clinical practice should ideally be based on practical considerations related to the needs of the rheumatologist in the respective health care setting.

Smolen JS, Aletaha D. · No affiliation provided · Ann Rheum Dis. · Pubmed #14962951 links to  free full text

This publication has no abstract.

Aletaha D, Huizinga TW. · Division of Rheumatology, Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria. · Best Pract Res Clin Rheumatol. · Pubmed #19233051 No free full text.

Abstract: Many early arthritis clinics have been started in the past decade. A major objective of these clinics is to improve our understanding of early arthritis in its undifferentiated form and to help provide guidance, recommendations, or criteria for diagnostic and therapeutic decision-making in patients with such presentation. Increasingly, they will allow aspects of pathogenesis - including autoantibodies and potential genetic markers - to be included in the set of clinical predictors that a rheumatologist is presented with. From an analytical perspective, usually logistic regression modelling is used to identify the best predictors of potentially long-lasting and/or erosive disease. Classification tree analysis might be another way to analyse data, and has the advantage that the results are easier to interpret than statistical parameters. In the past, many such projects have been published, none of which has achieved widespread use. Currently, the American College of Rheumatology and the European League Against Rheumatism are in the process of defining new criteria for rheumatoid arthritis that will allow earlier diagnosis and treatment of patients and definition of patients with early disease for inclusion in clinical trials.

Smolen JS, Aletaha D, Steiner G. · Division of Rheumatology, Department of Internal Medicine 3, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Ann Rheum Dis. · Pubmed #19139203 No free full text.

Abstract: Rheumatoid arthritis (RA) is characterised by both inflammation, as manifested by pain and swelling, and destruction of the joints. Unequivocal evidence indicates that disease activity, and thus the inflammatory response, is linked to joint damage. From this viewpoint we suggest that, vice versa, joint damage might be a cause of the active disease process, thus leading to a vicious cycle of events. The background to this notion stems from the known autoimmune response in RA, the potential of cartilage and bone breakdown products to elicit inflammation and notions that in joints that have undergone surgery with cartilage removal RA does not flare. However, the clinical evidence for this relationship is still to be provided as proof of the concept.

Smolen JS, Aletaha D, Grisar J, Redlich K, Steiner G, Wagner O. · Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Arthritis Res Ther. · Pubmed #18557991 links to  free full text

Abstract: Rheumatoid arthritis is a heterogeneous disease with respect to clinical manifestations, serologic abnormalities, joint damage and functional impairment. Predicting outcome in a reliable way to allow for strategic therapeutic decision-making as well as for prediction of the response to the various therapeutic modalities available today, especially biological agents, would provide means for optimization of care. In the present article, the current information on biological and clinical markers related to disease activity and joint damage as well as for predictive purposes is reviewed. It will be shown that the relationship of many biomarkers with disease characteristics is confounded by factors unrelated to the disease, and that only few biomarkers exist with some predictive value. Moreover, clinical markers appear of equal value as biomarkers for this purpose, although they likewise have limited capacity in these regards. The analysis suggests the search for better markers to predict outcomes and therapeutic responsiveness in rheumatoid arthritis needs to be intensified.

Smolen JS, Aletaha D. · Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Austria. · Curr Opin Rheumatol. · Pubmed #18388523 No free full text.

Abstract: PURPOSE OF REVIEW: To describe the importance of assessing disease activity in general, aiming for significant improvement particularly low disease activity and remission, and the value of employing simplified instruments toward this end in rheumatoid arthritis RECENT FINDINGS: Various instruments have either been newly developed, validated or assessed in the recent two years. Additional insights relate to the frequency of attainment of low disease activity and remission in clinical trials and clinical practice, as well as to therapeutic strategies, which involve comprehensive and tight evaluation of disease activity in the adaptation of therapy, including biologicals. All studies assessing these instruments reveal that simplified scores perform at least similar compared with more complex indices, and often better, in the evaluation of disease activity and response to treatment. SUMMARY: Simplified indices can be routinely used in clinical practice and trials and adaptation of therapy on the basis of tight control of disease activity will lead to improved outcomes of rheumatoid arthritis.

Smolen J, Aletaha D. · Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Eur J Health Econ. · Pubmed #18157733 No free full text.

Abstract: As part of the investigation into the burden of rheumatoid arthritis (RA) and the access to treatment, this article reviews the medical aspects of the disease. RA is mediated by a variety of pathogenic events which culminate in the activation of B-cells, T-cells and other cell populations and lead to secretion of proinflammatory cytokines. These events result in signs and symptoms of active disease, such as pain and swelling, joint damage and disability, the three cornerstones of the clinical expression of RA. Active disease leads to joint damage and both to disability, whereby joint destruction is associated with the irreversible portion of disability. The diagnosis of RA is based on characteristic clinical and laboratory features, however, these may not be obvious in early disease. Therapy aims at interfering with disease activity, ideally leading to remission, as well as at retarding, ideally holding or even healing, joint destruction. This can be achieved by using disease modifying anirheumatic drugs (DMARDs). Among the chemical DMARDs, methotrexate is the anchor drug, although there exist many more such agents. Among the biological compounds, TNF-inhibitors have been in use for more than one decade, and co-stimulation blockade and B-cell targeted therapy have been recent additions to the armamentarium. Therapeutic outcome can be predicted by clinical means.

Dougados M, Aletaha D, van Riel P. · Hopital Cochin, Descartes University, Service de Rhumatologie B, Paris, France. · Clin Exp Rheumatol. · Pubmed #17977485 No free full text.

Abstract: Rheumatoid arthritis (RA) is an inflammatory autoimmune and progressive disease. In patients with RA, persistent disease activity ultimately results in irreversible radiographic damage of the joints with persistent functional loss as a consequence. Disease activity measures assess a disease state at a particular time point. In order to evaluate the course of the disease in daily clinical practice or to judge the efficacy of a treatment in a clinical trial, a measure should also comprise the dimension of time. Composite indices provide a comprehensive view of disease activity and include the Disease Activity Score 28, the American College of Rheumatology criteria and newer indices such as the Clinical Disease Activity Index, the Rheumatoid Arthritis Disease Activity Index, and the Simplified Disease Activity Index. The target of RA treatment is to suppress disease activity as completely as possible, with remission being the ultimate goal. The composite index chosen should, therefore, be applicable to the circumstance in which it will be used, with different requirements in clinical practice versus clinical trials. In addition to the choice of an assessment index, novel disease monitoring strategies have been used to optimize treatment and disease control, as in the TICORA and BeST studies. It is clear that the best benefit for the patient can be obtained by combining the optimal treatment strategy and the most appropriate outcome measure. Low disease activity, intensive monitoring, and rapid adjustments in treatment seem to promise the greatest benefit. Further studies are required to better evaluate the clinical relevance of methods for assessing disease activity in patients with RA.

Aletaha D, Strand V, Smolen JS, Ward MM. · Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Austria. · Ann Rheum Dis. · Pubmed #17644550 No free full text.

Abstract: BACKGROUND: Physical function in rheumatoid arthritis (RA) has reversible and irreversible components, and is typically assessed by the Health Assessment Questionnaire Disability Index (HAQ). Since irreversible components are expected to increase with longer duration of RA and reduce the ability for improvement in physical function, we analysed responsiveness of HAQ scores in patient populations with differing RA durations in randomised controlled trials (RCTs). METHODS: Data from all RCTs published between 1980 and 2005 that reported changes from baseline in HAQ at 6 and/or 12 months were analysed. Treatments were grouped as "biologics", or "traditional" disease modifying antirheumatic drugs (DMARDs), and "placebo". We computed effect sizes of HAQ in each trial, and contrasted the association between these effects and duration of RA among treatment groups using regression models. RESULTS: We identified 42 RCTs with complete data for the statistical models. The models indicate that discrimination of functional improvement between active drug groups and placebo is reduced in patients with a longer duration of RA (p = 0.02 for the change in discrimination over time). The placebo-adjusted HAQ responses decreased on average by 0.37 per year of RA duration. CONCLUSION: Responsiveness in HAQ scores is inversely associated with mean disease duration in RA. This impacts assessment of physical function, a key outcome measure in RCTs and practice, and impacts the ability to discriminate active treatment from placebo.

Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. · Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Lancet. · Pubmed #17570481 No free full text.

Abstract: Rheumatoid arthritis is characterised by pain, swelling, and destruction of joints, with resultant disability. Only disease-modifying antirheumatic drugs can interfere with the disease process. In the past few years, biological agents, especially inhibitors of tumour necrosis factor, have allowed for hitherto unseen therapeutic benefit, although even with these drugs the frequency and degree of responses are restricted. Therefore, new agents are needed, and three novel biological compounds for treatment of rheumatoid arthritis have already been used in practice or are on the horizon: rituximab (anti-CD20), abatacept (cytotoxic T-lymphocyte antigen 4 immunoglobulin), and tocilizumab (anti-interleukin 6 receptor). We discuss the targets of these drugs, the roles of these targets in the pathogenesis of rheumatoid arthritis, and the efficacy and adverse effects of these agents from clinical trial data. Novel therapeutic strategies in conjunction with optimised disease assessment for better treatment of rheumatoid arthritis and an outlook into potential future targets are also presented.

Aletaha D, Smolen JS. · Department of Rheumatology, Medical University of Vienna, Vienna, Austria. · Clin Exp Rheumatol. · Pubmed #17083763 No free full text.

Abstract: A state of remission can be achieved in more and more rheumatoid arthritis (RA) patients. The combination of several RA disease activity measures seems to be important to provide an overall view of disease activity. Remission can be defined by two different approaches: one using a categorical model, requiring criteria for multiple variables to be fulfilled, each with its own threshold value (remission "criteria"); the other using a dimensional model, providing single measures of activity, which allow definition of remission by a single cut point (remission cut points for composite indices). The face validity of remission as defined by composite indices surpasses the one for the "criteria". Likewise, the ones that are not weighted seem to surpass the weighted ones, as can be seen by the significant proportion of patients that continues to have considerable swollen joint counts despite being in Disease Activity Score (DAS)-28 remission. All composite indices seem to perform similarly well as tests for remission using expert judgments as the gold standard.

Smolen JS, Aletaha D. · Department of Rheumatology, Medical University of Vienna; Second Department of Medicine, Lainz Hospital, Vienna, Austria. · Clin Exp Rheumatol. · Pubmed #17083756 No free full text.

Abstract: Remission should be the treatment aim in management of rheumatoid arthritis (RA) today because joint damage may progress in RA patients with low disease activity but presumably does not progress in patients in clinical remission. However, stringent criteria are needed to define remission status, as some criteria in current use allow for considerable residual disease activity. Even using stringent criteria, remission is achievable in a sizable proportion of patients in clinical trials and practice. Defining remission requires an additional consideration: Should a patient who is receiving medication be regarded as in remission if disease is absent, or must the patient be off treatment to be considered to be in remission? A case is made for aiming for a definition of remission that includes patients who continue medication therapy.

Pincus T, Kavanaugh A, Aletaha D, Smolen J. · Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232-4500, USA. · Clin Exp Rheumatol. · Pubmed #17083755 No free full text.

Abstract: The rheumatology community has devoted increasing attention to the subject of remission over the past 2 decades, on the basis of greater appreciation of the long-term severity of inflammatory rheumatic diseases and availability of new therapies and approaches to improve outcomes. Nonetheless, description of remission in rheumatic diseases is complex, compared to many nonrheumatic diseases. Recognition of remission requires a set of measures or an index rather than a single "gold standard." Spontaneous remission is not infrequent in people with early inflammatory arthritis, including some who may meet criteria for rheumatoid arthritis (RA) over less than a few months, and may be confused with a drug-induced remission. Remission may be transient in many patients over short periods, and the length of time required to maintain remission status varies in different reports. Maintenance of a state of remission in autoimmune diseases that result from dysregulatory processes, rather than invasion of foreign cells or toxins, generally requires ongoing therapy indefinitely. Patients who have organ damage or functional disability may be described as "in remission," although they are free of disease activity only, but not necessarily free of disease consequences. A status of "low disease activity" or "near remission" with 70% to 90% of the features of an ideal remission may be adequate for many people with rheumatic diseases to avoid risks that may be required to reach 100% remission status. Thus, the subject of remission remains under active discussion in the rheumatology community.

Machold KP, Nell V, Stamm T, Aletaha D, Smolen JS. · Department of Rheumatology, Internal Medicine III, Vienna Medical University, Austria. · Curr Opin Rheumatol. · Pubmed #16582693 No free full text.

Abstract: PURPOSE OF REVIEW: This review provides novel and updated information on pathogenesis, referral, and clinical characteristics as well as therapeutic approaches in early rheumatoid arthritis. RECENT FINDINGS: Early referral is important, but new classification criteria for early rheumatoid arthritis need to be elaborated. Predictive markers for rheumatoid arthritis are still confined to autoantibodies; respective algorithms have been presented. Other biomarkers will still have to prove their usefulness. Magnetic resonance imaging and sonography do not appear to sufficiently distinguish between early rheumatoid and nonrheumatoid arthritis. Rheumatoid arthritis has become milder at presentation in recent years. In its very early stages, the cytokine profile reflects T-cell activation and switches to abundant proinflammatory cytokines thereafter. Disease-modifying antirheumatic drugs plus glucocorticoids are highly effective, as is early use of tumor necrosis factor blockers plus methotrexate. Tight control of disease activity and subsequent therapeutic adjustments are highly effective. Disease activity indices that are simple to calculate have been presented and validated. Early intensive therapy may lead to decrease in disability and cost reduction in rheumatoid arthritis. SUMMARY: Understanding of early arthritis is increasing, especially in prognostic and therapeutic respects, and new treatment strategies appear to improve the outcome in patients with early arthritis. Nevertheless, much remains to be studied to better address the issue of early rheumatoid arthritis.

Aletaha D, Smolen JS. · Department of Rheumatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Rheum Dis Clin North Am. · Pubmed #16504819 No free full text.

Abstract: This article focuses on measures that are used to evaluate disease activity, damage, and function in three major inflammatory musculoskeletal disorders. The instruments used in rheumatoid arthritis, where most of the methodologic work has been done, are extensively discussed and instruments for the respective domains in psoriatic arthritis and ankylosing spondylitis are likewise presented.

Machold K, Nell V, Aletaha D, Smolen J, Stamm T. · Klinische Abt. für Rheumatologie, Universitätsklinik für Innere Medizin III, Wien. · Z Rheumatol. · Pubmed #16496075 No free full text.

Abstract: Disease activity scores for rheumatoid arthritis have been developed and validated in recent years. They allow the longitudinal documentation of the effectiveness of treatment. Application of these scores in routine daily practice could significantly improve the effectiveness of therapy with relatively little effort. This review presents evidence for the benefits of the application disease activity scores in clinical routine.

Aletaha D, Stamm T, Smolen J. · Klinische Abt. für Rheumatologie, Universitätsklinik für Innere Medizin III, Wien. · Z Rheumatol. · Pubmed #16496073 No free full text.

Abstract: Rheumatoid arthritis (RA) is the most common systemic inflammatory joint disease. It can be treated effectively with disease modifying antirheumatic drugs, and the currently propagated treatment strategy is to treat RA consequently, and revise the therapeutic approach frequently on the basis of proper disease activity evaluation. In the current review, we focus on the instruments and measures used in the assessment of RA disease activity. We will first consider the so-called core set measures of activity, prividing comprehensive overviews on joint count scales, global scales, pain scales, biomarkers, and functional assessment instruments. The second part of the review focuses on the value of composite measures of disease activity; a term under which we subsume activity indices using various formulae, self-assessment tools of disease activity, and response criteria. Among the inflammatory rheumatic diseases, RA is the one for which the most intensive research is done, and usually instruments that work for RA are further tested for other joint diseases. However, there is still a research agenda for the assessment of disease activity, even for RA. One important aspect is to assess the reliability and utility of all available instruments, including the very low end of disease activity, since remission has become an achievable goal. Another focus of disease activity assessment is to derive measures that work in clinical trials and in daily practice, but are also well understood by patients and physicians.This will further improve our ability to care for patients with RA consequently.

Aletaha D, Smolen J. · Department of Rheumatology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Clin Exp Rheumatol. · Pubmed #16273793 No free full text.

Abstract: Composite indices or pooled indices are useful tools for the evaluation of disease activity in patients with rheumatoid arthritis (RA). They allow the integration of various aspects of the disease into a single numerical value, and may therefore facilitate consistent patient care and improve patient compliance, which both can lead to improved outcomes. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) are two new tools for the evaluation of disease activity in RA. They have been developed to provide physicians and patients with simple and more comprehensible instruments. Moreover, the CDAI is the only composite index that does not incorporate an acute phase response and can therefore be used to conduct a disease activity evaluation essentially anytime and anywhere. These two new tools have not been developed to replace currently available instruments such as the DAS28, but rather to provide options for different environments. The comparative construct, content, and discriminant validity of all three indices--the DAS28, the SDAI, and the CDAI--allow physicians to base their choice of instrument on their infrastructure and their needs, and all of them can also be used in clinical trials.

Smolen JS, Aletaha D, Keystone E. · Medical University of Vienna and Lainz Hospital, Vienna, Austria. · Arthritis Rheum. · Pubmed #16200577 links to  free full text

This publication has no abstract.

Smolen JS, Redlich K, Zwerina J, Aletaha D, Steiner G, Schett G. · Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Austria. · Clin Rev Allergy Immunol. · Pubmed #16129908 No free full text.

Abstract: Therapy of rheumatoid arthritis (RA) aims at interfering with the disease process, namely inflammation and destruction of the joints, and thus at preventing long-term disability. Proinflammatory cytokines play a decisive role in the generation of the inflammatory and destructive response. Aside from traditional disease-modifying anti-rheumatic drugs and tumor necrosis factor-blocking agents, a number of targeted therapies are currently in evaluation, such as abatacept (interfering with co-stimulation), rituximab (an anti-B-cell agent) and tocilizumab (an anti-interleukin-6 receptor antibody). In phase II trials, all these agents have resulted in significant clinical improvement, and phase III trials have been partly completed with similar results and are partly on the way. Because none of these agents lead to good clinical responses in all patients and many patients have only relatively low degrees of response, it will still be a challenge to find the best therapeutic paths to combat the "inflammatory house of cards" of RA.

Smolen JS, Aletaha D, Machold KP. · Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Best Pract Res Clin Rheumatol. · Pubmed #15588977 No free full text.

Abstract: Rheumatoid arthritis (RA) therapy rests primarily on the use of disease-modifying antirheumatic drugs (DMARDs). It has been unequivocally shown that DMARD therapy early in the course of RA retards progression of damage and disability to a larger degree compared with delayed institution; the most effective DMARD is methotrexate (MTX). Moreover, combination therapy including intermediate to high doses of glucocorticoids and combinations of MTX with tumour necrosis factor blockers are more effective than monotherapies. However, early DMARD treatment requires early referral of patients and early diagnosis. This is hampered by the current lack of classification criteria for early RA, since the aim is to prevent destruction from occurring, while RA is typically characterized by the presence of erosions. Novel treatment strategies and therapeutic agents allow us to aim for remission rather than improvement of disease activity. Whether a 'window of opportunity' exists during which effective therapy might lead to cure is still an open issue and will be the focus of clinical trials in the near future.

Pincus T, Yazici Y, Sokka T, Aletaha D, Smolen JS. · Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. · Clin Exp Rheumatol. · Pubmed #14969073 No free full text.

Abstract: The two major advances over the 1990s in the treatment of rheumatoid arthritis (RA) were a shift in strategy from a "pyramid", in which disease modifying anti-rheumatic drugs (DMARDs) were deferred for several years, to the early aggressive use of DMARDs and widespread acceptance of methotrexate as the DMARD with the most long-term effectiveness and safety. Methotrexate courses are continued far longer than those of any other DMARD, an excellent indicator of greater effectiveness and safety. In one recent series, methotrexate was the first DMARD used in more than 80% of patients with RA. Studies which document the superiority of combinations of methotrexate with biological agents to methotrexate monotherapy select for only a minority of contemporary patients with RA who have severe disease activity and incomplete responses to methotrexate. In one locale, only 5% of patients met criteria for the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy (ATTRACT) trial and only 30% met the criteria for the Early Rheumatoid Arthritis (ERA) trial. In studies comparing methotrexate directly with biological agents, the biological agents have greater efficacy in patients with very severe disease, but the best results are seen in patients who take a combination of methotrexate and biologic agents. These data establish that methotrexate is the anchor drug and probably should be the first DMARD used in the majority of patients with RA at this time.