Rheumatoid Arthritis: Smolen JS

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.

Kalden JR, Scott DL, Smolen JS, Schattenkirchner M, Rozman B, Williams BD, Kvien TK, Jones P, Williams RB, Oed C, Rosenburg R, Anonymous00047. · Department of Internal Medicine III, University of Erlangen-Nuremberg, Germany. · J Rheumatol. · Pubmed #11550964 No free full text.

Abstract: OBJECTIVE: We previously reported that the new disease modifying antirheumatic drug leflunomide resulted in significant improvement in functional ability compared with placebo and sulfasalazine in a 6 month double blind, randomized, Phase III trial in rheumatoid arthritis (RA). The current study compared functional disability in cohorts of patients with RA from the initial study who volunteered to continue treatment with leflunomide or sulfasalazine. METHODS: The Health Assessment Questionnaire (HAQ) was used to assess functional ability in patients completing 6 months of therapy who chose to continue in double blinded 12 and 24 month extensions. Patients on active regimens continued taking leflunomide 20 mg/day or sulfasalazine 2 g/day; those taking placebo were switched at Month 6 to sulfasalazine. RESULTS: Leflunomide significantly improved patients' functional ability compared to placebo (p < or = 0.0001) and sulfasalazine (p < or = 0.01) at 6 months. These changes were seen as early as Month 1, and continued improvements were seen in 12 and 24 month cohorts. Mean HAQ scores were significantly improved with leflunomide compared with sulfasalazine at 24 months (-0.65 vs -0.36; p = 0.0149); corresponding changes in HAQ Disability Index (DI) were -0.73 vs -0.56 and were not statistically different. Leflunomide is safe and well tolerated and no unexpected adverse events were noted during the 2 year period; diarrhea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These longterm data confirm leflunomide improves functional ability as shown by reductions in HAQ scores. The benefit of leflunomide is reflected in other efficacy criteria, such as global assessments and the American College of Rheumatology response rates, all of which showed significantly more improvement with leflunomide than sulfasalazine at 24 months.

Smolen JS, Weinblatt ME. · No affiliation provided · Ann Rheum Dis. · Pubmed #18854512 No free full text.

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

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

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Smolen JS, Steiner G. · No affiliation provided · Arthritis Rheum. · Pubmed #11665960 No free full text.

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Smolen JS, Graninger WB, Emery P. · No affiliation provided · Rheumatology (Oxford). · Pubmed #10908683 links to  free full text

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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.

Scheinecker C, Redlich K, Smolen JS. · Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Immunity. · Pubmed #18400186 No free full text.

Abstract: Biological therapies targeting cytokines, T cells, or B cells have improved outcomes of inflammatory diseases. However, many issues remain open: What is the best target? How well can response be predicted? How can cure be achieved?

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.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Sieper J, Emery P, Keystone EC, Schiff MH, Mease P, van Riel PL, Fleischmann R, Weisman MH, Weinblatt ME. · David Geffen School of Medicine, UCLA - RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA. · Ann Rheum Dis. · Pubmed #17934088 No free full text.

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Keen HI, Lavie F, Wakefield RJ, D'Agostino MA, Hammer HB, Hensor E, Pendleton A, Kane D, Guerini H, Schueller-Weidekamm C, Kortekaas MC, Birrel F, Kloppenburg M, Stamm T, Watt I, Smolen JS, Maheu E, Dougados M, Conaghan PG. · Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #17704062 No free full text.

Abstract: OBJECTIVES: Painful osteoarthritis (OA) of the hand is common and a validated ultrasound (US) scoring system would be valuable for epidemiological and therapeutic outcome studies. US is increasingly used to assess peripheral joints, though most of the US focus in rheumatic diseases has been on rheumatoid arthritis. We aimed to develop a preliminary US hand OA scoring system, initially focusing on relevant pathological features with potentially high reliability. METHODS: A group of experts in the fields of OA, US and novel tool development agreed on domains and suggested scaling of the items to be used in US hand OA scoring systems. A multi-observer reliability exercise was then performed to evaluate the draft items. RESULTS: Synovitis (grey scale and Power Doppler) and osteophytes (representing activity and damage domains) were included and evaluated as the initial components of the scoring system. All three features were evaluated for their presence/absence and if present were scored using a 1-3 scale. The reliability exercise demonstrated intra-reader kappa values of 0.444-1.0, 0.211-1.0 and 0.087-1.0 for grey scale synovitis, power Doppler and osteophytes respectively. Inter-reader reliability kappa values were 0.398, 0.327 and 0.530 grey-scale synovitis, power Doppler and osteophytes respectively. Without extensive standardisation, both intra- and inter-reader reliability were moderately good. CONCLUSIONS: The draft scoring system demonstrated substantive to almost perfect percentage exact agreement on the presence/absence of the selected OA features and moderate to substantive percentage exact agreement on semi-quantitative grading. This preliminary process provides a good basis from which to further develop an US outcome tool for hand OA that has the potential to be utilised in multicentre clinical trials.

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. · Department of Rheumatology, Medical University of Vienna, Vienna, Austria. · J Rheumatol Suppl. · Pubmed #17611974 No free full text.

Abstract: The recently approved therapies abatacept and rituximab have significantly improved treatment options for patients with rheumatoid arthritis, especially for patients who have an inadequate response to tumor necrosis factor inhibitors. This article reviews the latest efficacy and safety data for both abatacept and rituximab. One-year data from abatacept and rituximab clinical trials show significantly better efficacy and reduction in radiographic damage for these therapies compared with placebo. In addition, repeated courses of rituximab confer continued efficacy for patients. The safety profile of these therapies shows that infusion reactions and infections are the most commonly reported important adverse events. Premedication with corticosteroids reduces the infusion reactions to rituximab.

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.

Schett G, Hayer S, Zwerina J, Redlich K, Smolen JS. · Medical University of Vienna, Austria. · Nat Clin Pract Rheumatol. · Pubmed #16932627 No free full text.

Abstract: Chronic inflammation and bone loss are closely linked pathophysiologic events. The most typical example of inflammatory bone loss is seen in patients with rheumatoid arthritis who develop systemic osteopenia as well as local breakdown of bone in the direct vicinity of inflamed joints. Understanding the mechanisms of arthritic bone degradation is crucial for designing therapies that can specifically protect joints from structural damage. Since osteoclast differentiation and activity are key events in arthritic bone damage, the signals that trigger osteoclastogenesis are potential therapeutic targets. Receptor activator of nuclear factor-kappaB (RANK) is activated by its ligand, RANKL, an essential molecule for osteoclast development: in the absence of RANKL or RANK, osteoclast differentiation from monocyte precursors does not occur. RANKL is expressed on T cells and fibroblasts within the synovial inflammatory tissue of patients with RA and its expression is regulated by proinflammatory cytokines. In animal models of arthritis, blockade of RANKL-RANK interactions, or a genetic absence of RANKL or RANK, protects against joint damage despite the presence of joint inflammation. Therefore, inhibition of RANKL is regarded as a promising future strategy for inhibiting inflammatory bone loss in patients with chronic inflammatory arthritis.

Smolen JS, Maini RN. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Arthritis Res Ther. · Pubmed #16899109 No free full text.

Abstract: The therapeutic success of biological agents, especially the tumour necrosis factor (TNF) inhibitors, has opened a new chapter in the book of therapies for rheumatoid arthritis. Nevertheless, more than 50% of patients may not respond by > 50% improvement. New compounds have recently entered the treatment arena. One of these is rituximab, which depletes B cells, and another, abatacept, interferes with T-cell co-stimulation. However, although these agents may be effective in a number of patients who fail to respond to TNF blockade, they only rarely induce remission and overall 50% response rates do not exceed those with the TNF inhibitors. Among the major proinflammatory cytokines, IL-6 plays a pleiotropic role both in terms of activating the inflammatory response and osteoclastogenesis. Here, we review recent phase II trials of tocilizumab, a humanized anti-IL-6 receptor antibody that achieves a significant therapeutic response rate.

Machold KP, Nell VP, Stamm TA, Smolen JS. · Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Arthritis Res Ther. · Pubmed #16719936 links to  free full text

Abstract: There is increasing evidence for beneficial effects of early DMARD (disease-modifying antirheumatic drug) therapy over delayed treatment in patients who present with arthritis of recent onset. However, no universal consensus exists concerning the choice of initial drug or whether single drugs or combinations should be given as initial treatments. Recent studies have focused on the benefits of various strategies in which treatments were tailored to achieve low levels of disease activity, as assessed using validated response criteria. These studies demonstrated superiority of 'aggressive' over 'conventional' approaches. Whether the inclusion of tumour necrosis factor antagonists or other biologic targeted therapies in such strategies confers additional benefits in terms of improved long-term outcomes must be clarified by further studies. Assessment of risks in the individual patient, allowing individual 'tailoring' of the initial treatment, would be desirable.

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.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, Dougados M, Emery P, Keystone EC, Klareskog L, Mease PJ. · 1000 Veteran Avenue Rehabilitation Centre, Room 32-59, Los Angeles, CA 90024, USA. · Ann Rheum Dis. · Pubmed #16239380 links to  free full text

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

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