Rheumatoid Arthritis: van der Heijde 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.

Schett G, Landewé R, van der Heijde D. · No affiliation provided · Ann Rheum Dis. · Pubmed #17513569 No free full text.

This publication has no abstract.

Salliot C, van der Heijde D. · Paris Descartes University, Medicine Faculty, Rheumatology B Department, Cochin Hospital, Paris, France. · Ann Rheum Dis. · Pubmed #19060002 links to  free full text

Abstract: OBJECTIVE: To perform a systematic literature review of the long-term safety of methotrexate (MTX) monotherapy in rheumatoid arthritis (RA). METHODS: A search was performed in Medline, Cochrane and EMBASE. Adults with RA who had received MTX monotherapy for more than 2 years were studied. RESULTS: 88 published studies were included. Over 12 years of treatment, the termination rate of MTX due to toxicity was less than for sulfasalazine, gold, d-penicillamine and higher than for hydroxychloroquine (level of evidence 2a-2b). Long-term use of MTX does not appear to be a risk factor for serious infections, including herpes zoster (2b-4), and could provide a survival benefit by reducing cardiovascular mortality (2b). The prevalence of raised liver enzymes (more than twice the upper limit of normal) is close to 13% of patients; 3.7% of patients stopped MTX permanently owing to liver toxicity (2b). Data on the risk for liver fibrosis/cirrhosis are conflicting: a meta-analysis showed an incidence of fibrosis of 2.7% after 4 years of MTX (2a). However, two other studies on sequential liver biopsies did not show evidence for developing severe damage (2b). Insufficient data are available to fully assess the risk of lymphoma and malignancies, although there is no strong evidence of increased risk (2b-4). CONCLUSION: This systematic literature search on MTX monotherapy with relatively low-dose use during at least 2 years shows favourable long-term safety.

Visser K, van der Heijde D. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #19033290 links to  free full text

Abstract: OBJECTIVES: To review systematically the available literature on the optimal dosage and route of administration of methotrexate in patients with rheumatoid arthritis (RA), as an evidence base for generating clinical practice recommendations. METHODS: A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and American College of Rheumatology/European League Against Rheumatism meeting abstracts, searching for randomised controlled trials evaluating various dosages or routes of administration of methotrexate in RA. Articles that fulfilled predefined inclusion criteria were systematically reviewed and the quality was appraised. Effect sizes and odds ratios for clinical, radiological and toxicity outcomes were calculated and directly or indirectly compared between study groups using methotrexate in different dosages or by different routes. RESULTS: A total of 38 publications out of 1748 identified references was included in the review. Start doses of 25 mg/week or fast escalation with 5 mg/month to 25-30 mg/week were associated with higher clinical effect sizes and more (gastrointestinal) adverse events in comparison with doses of 5-15 mg/week or slow escalation. Starting with 15 mg/week subcutaneous versus oral methotrexate was associated with higher clinical efficacy but more withdrawal due to toxicity in early RA. In longstanding RA, after failure on 15-20 mg/week orally, a switch to 15 mg/week intramuscularly with subsequent dose escalation did not result in increased efficacy. CONCLUSIONS: Starting on methotrexate 15 mg/week orally, escalating with 5 mg/month to 25-30 mg/week, or the highest tolerable dose, with a subsequent switch to subcutaneous administration in the case of an insufficient response, seems to be the optimal evidence-based dosing and routing recommendation for methotrexate in RA.

Keeling SO, Landewe R, van der Heijde D, Bathon J, Boers M, Garnero P, Geusens P, El-Gabalawy H, Inman RD, Kraus VB, Kvien TK, Mease PJ, Ostergaard M, Ritchlin C, Syversen SW, Maksymowych WP. · Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. · J Rheumatol. · Pubmed #17343310 No free full text.

Abstract: OBJECTIVE: A list of 14 criteria for guiding the validation of a soluble biomarker as reflecting structural damage endpoints in rheumatoid arthritis (RA) clinical trials was drafted by an international working group after a Delphi consensus exercise. C-reactive protein (CRP), a soluble biomarker extensively studied in RA, was then used to test these criteria. Our objectives were: (1) To assess the strength of evidence in support of CRP as a soluble biomarker reflecting structural damage in RA according to the draft validation criteria. (2) To assess the strength of recommendation for inclusion of individual criteria in the draft set. METHODS: A systematic literature review was conducted to elicit evidence in support of each specific criterion composing the 14-criteria draft set. A summary of the key literature findings per criterion was presented to both the working group and to participants in a special interest soluble biomarker group at OMERACT 8. Participants at OMERACT 8 were asked to rate the strength of evidence and the strength of the recommendation in support of each individual criterion on a 0-10 numerical rating scale. Working group members not present at OMERACT voted by a Web-based survey. RESULTS: Minimal data were extracted from the literature pertaining to those criteria listed under the category of truth. Ratings for strength of evidence were moderate to low (< 7) for CRP as a biomarker reflecting structural damage in RA; this was true for all criteria except those listed under the category of feasibility and 2 listed under the category of discrimination pertaining to assay reproducibility and evidence regarding sources of variability. Ratings for strength of recommendation for inclusion of each of the 14 criteria in the draft set were high (> 7) except for those criteria listed under the category of truth. CONCLUSION: The draft criteria serve as a useful template in the evaluation of the strength of evidence in support of a particular soluble biomarker as reflecting structural damage in RA.

Sharp JT, van der Heijde D, Angwin J, Duryea J, Moens HJ, Jacobs JW, Maillefert JF, Strand CV, Anonymous00377. · University of Washington School of Medicine, Seattle, WA, USA. · J Rheumatol. · Pubmed #16331786 No free full text.

Abstract: Measurement of radiographic abnormalities in metric units has been reported by several investigators during the last 15 years. Measurement of joint space in large joints has been employed in a few trials to evaluate therapy in osteoarthritis. Measurement of joint space width in small joints has been reported by several investigators but has not yet found a place in clinical trials in rheumatoid arthritis or osteoarthritis. We review methods for measuring joint space width in finger, toe, and wrist joints; special attention is given to how the joint edges are found, the method used to measure distance between joint margins, size of an area of the sampled joint, and reproducibility of measurements. Methods for measurement of erosion size, which have had less attention, are briefly discussed.

Boonen A, van der Heijde D. · Division of Rheumatology, Department of Internal Medicine, University Hospital Maastricht Care and Public Health Research Institute, University Maastricht, P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The Netherlands. · Rheum Dis Clin North Am. · Pubmed #16287591 No free full text.

Abstract: This article reviews radiographic data from six cohorts of patients with early inflammatory arthritis. Of the patients, 8% to 15% had erosive disease at the first encounter with the rheumatologist. Classic scoring methods were applied to quantify damage, but baseline damage was low in early inflammatory arthritis. Yearly progression in damage score was assessed only in patients with high suspicion of rheumatoid arthritis at baseline or who had a final diagnosis of rheumatoid arthritis at follow-up and varied between 0.5% and 1.7% of the maximal damage of the scoring method per year. The large number of patients with zero values for erosions and lower progression rates will influence sample sizes in clinical trials in early inflammatory arthritis when including radiographic change as an outcome.

Landewé R, van der Heijde D. · University Hospital Maastricht, Department of Internal Medicine/Rheumatology, PO Box 5800, 6202AZ Maastricht, the Netherlands. · Ann Rheum Dis. · Pubmed #16239387 links to  free full text

Abstract: Despite the advent of sophisticated imaging systems, plain radiography continues to be a valuable outcome variable in clinical trials of inflammatory disorders for a number of reasons. This paper discusses the pros and cons of the different ways in which radiographic data in trials is presented; the minimum time needed to demonstrate radiographic progression in the context of a clinical trial; and the best ways to statistically analyse radiographic data.

van der Heijde D. · Division of Rheumatology, Department of Internal Medicine, University Hospital Maastricht, P. Debyelaan 25, PO Box 5800, Maastricht 6202 AZ, The Netherlands. · Best Pract Res Clin Rheumatol. · Pubmed #15501186 No free full text.

Abstract: Quantification of radiological damage in inflammatory arthritis is important. It has proven its value in clinical trials, but its use in clinical practice is becoming more important as well. Scoring methods for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are available. These differ in the joints and features assessed. This results in differences in the scoring range, but also in the method of performance. The various methods for the three diseases are detailed in this chapter. Most information is available for rheumatoid and for this disease the relationship between radiological damage and long-term outcome is summarised.

Bruynesteyn K, Boers M, Kostense P, van der Linden S, van der Heijde D. · Department of Internal Medicine, Division of Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. · Ann Rheum Dis. · Pubmed #15286006 links to  free full text

Abstract: Progression of radiological joint damage is usually based on the simultaneous assessment of a series of films from an individual patient ("paired", with or without known sequence). In this setting the degree of progression that can be reliably detected above the measurement error is best determined by the smallest detectable change, and overestimated by the traditionally calculated smallest detectable difference. This knowledge is important for calculation of the proportion of patients showing radiographic progression in clinical trials.

van der Heijde D, Landewé R. · University Hospital Maastricht, Department of Internal Medicine/Rheumatology, and Care and Public Health Research Institute, University Maastricht, Maastricht, The Netherlands. · Ann Rheum Dis. · Pubmed #14532139 links to  free full text

Abstract: It was shown previously that reparative changes in erosions can be seen in individual joints and individual patients. Whether repair may occur at a group level, and can be induced by treatment, is not known. This manuscript describes a means of visualising data obtained in a clinical trial by the use of probability plots to better understand the results. These probability plots give a good insight into the coherence of the data. They can also be used to make the interpretation of repair at a group level easier. Probability plots also explain the hazard of using binomial cut off points to compare treatment effects. The interference of true repair with measurement error is demonstrated. Repair at a group level is suggested if the mean progression score is statistically significantly different from zero, which can be visualised by a 95% confidence interval of this mean change score below zero. Application of this technique may give us better information on the effects of new drugs on the induction of repair.

van der Heijde D. · University Hospital Maastricht, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands. · Best Pract Res Clin Rheumatol. · Pubmed #12915157 No free full text.

Abstract: Joint damage visualized on radiographs is still the hallmark of rheumatoid arthritis. With increasing duration of disease, there is an increasing relationship between joint damage and functional status. There are also other imaging techniques such as magnetic resonance imaging and ultrasound. The role of these techniques in clinical trials and clinical practice is discussed. Structural damage is an important measure of outcome for showing aspects of disease modification resulting from antirheumatic therapy. Recommendations are presented on how the results could be reported in an optimal way to ensure the correct presentation of data and comparability of the results. Joint damage is a clear sign of severe disease. More data become available that joint damage is related to several aspects of outcome, such as functional status, work disability and mortality. The significance and clinical implication of a certain magnitude of change in the modified Sharp score is discussed.

Braun J, van der Heijde D. · Rheumazentrum Ruhrgebiet, Herne, Germany. · Expert Opin Investig Drugs. · Pubmed #12831346 No free full text.

Abstract: The therapeutic options for patients suffering from severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-TNF therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on what is now several hundred AS and PsA patients, this treatment seems to be even more effective than the same therapy in rheumatoid arthritis (RA). The anti-TNF-alpha agents currently available, infliximab (Remicade); Centocor), etanercept (Enbrel); Amgen) and adalimumab (Humira; Abbott), are approved for the treatment of RA in the US; infliximab and etanercept are approved in Europe. The situation in SpA is different to RA because there is an unmet medical need, especially in AS, since no therapies with disease-controlling antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, TNF blockers might even be considered as first-line immunosuppressive agents in patients with active AS and PsA who are not sufficiently treated by non-steroidal anti-inflammatory drugs and sulfasalazine, if peripheral arthritis is present. For infliximab, a dosage of 5 mg/kg at intervals between 6 and 12 weeks was necessary to constantly suppress disease activity; this is also a major aim of long-term treatment. No dose-finding studies have yet been performed. The standard dose of etanercept is 25 mg s.c. twice-weekly. No studies on adalimumab (standard RA dose 20 - 40 mg s.c. every 2 weeks) have yet been conducted in SpA. The efficacy of etanercept was first demonstrated in PsA and etanercept is now approved for this indication. A double-blind study has also been performed in AS, with similarly clearcut efficacy. There is preliminary evidence that both agents do also work in other SpA such as undifferentiated SpA. Infliximab has recently been approved for short-term treatment of severe uncontrolled AS; the approval for etanercept is pending. Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis might be preventable but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. Tuberculosis can be mostly prevented if patients are checked for previous contact with tuberculosis. Currently, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.

van der Heijde D, Braun J, McGonagle D, Siegel J. · Department of Internal Medicine, Division of Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. · Ann Rheum Dis. · Pubmed #12381508 links to  free full text

Abstract: Emerging treatment options in ankylosing spondylitis (AS) are giving new hope to patients with this chronic and potentially disabling disease. Clinical development of new treatments requires that rigorous and well controlled trials be conducted to demonstrate safety and efficacy. A number of classification systems have been developed in recent years as a result of enhanced understanding of the pathogenesis of AS. Although new outcome measures have been developed and a consensus has been reached on the use of assessment instruments in clinical trials, there is still need for improvement and implementation. The ASsessments in Ankylosing Spondylitis (ASAS) Working Group has addressed some of these dilemmas by establishing a core set of domains for the evaluation of AS and by selecting specific assessment methods for each domain. They have also published improvement criteria for assessing short term improvement with symptom modifying antirheumatic drugs and are presently in the process of developing response criteria for disease controlling antirheumatic treatment. Various experts are also currently examining discrepancies and inadequacies of classification systems for AS. Imaging studies, magnetic resonance imaging, in particular, may provide better classification criteria in the near future. In addition to consensus on outcome assessment and classification of AS, lessons learnt from clinical trials in rheumatoid arthritis (RA) may serve as a template for AS. Guidance provided by the United States Food and Drug Administration (FDA) for clinical trials in RA may be of particular use. The FDA has defined the claims that sponsors can receive for RA products and the clinical trial data that would be expected to be submitted to support such claims.

Strand V, Landéwé R, van der Heijde D. · Stanford University, Division of Immunology, Palo Alto, CA, USA. · Ann Rheum Dis. · Pubmed #12379626 links to  free full text

This publication has no abstract.

van der Heijde D. · University Hospital Maastricht, Maastricht, The Netherlands. · Arthritis Res. · Pubmed #12110155 No free full text.

Abstract: Several agents show an effect on reducing radiographic progression in rheumatoid arthritis. It is tempting to retrospectively compare the effects of these agents on radiographic progression across clinical trials. However, there are several limitations in interpreting and comparing radiographic results across clinical trials. These limitations, including study designs, patient characteristics, durations of follow-up, scoring methodologies, reader reliability, radiograph sequence, handling of missing data, and data presentation, will be discussed. The consequences are illustrated with several examples of recent clinical trials that show an effect on radiographic progression. A guide in the interpretation and clinical relevance of radiographic results is presented, with the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy used as an example.

Strand V, Lassere M, van der Heijde D, Johnson K, Boers M. · Division of Immunology, Stanford University, San Francisco, CA 94028, USA. · J Rheumatol. · Pubmed #11327271 No free full text.

Abstract: Recent randomized controlled trials of traditional and newly developed therapies provide evidence that we have interventions that potentially slow or prevent structural damage in active rheumatoid arthritis, as measured using radiography. These trials also provide a unique opportunity for exploratory data analysis to generate hypotheses apropos the pathogenesis and determinants of radiographic progression and functional disability; they also facilitate further study of the methodological issues regarding imaging measurement.

van der Heijde D. · Department of Internal Medicine, University Hospital Maastricht, The Netherlands. · J Rheumatol. · Pubmed #10090194 No free full text.

Abstract: This article is a short overview of the development of the Sharp/van der Heijde method for scoring radiographs of hands and feet in rheumatoid arthritis, in addition to a detailed description on how to use the scoring method.

van der Heijde D, Boers M, Lassere M. · Department of Internal Medicine, University Hospital Maastricht, The Netherlands. · J Rheumatol. · Pubmed #10090191 No free full text.

Abstract: Radiographs are important endpoints in clinical trials in rheumatoid arthritis (RA). Several scoring methods exist. However, many methodological issues are unsolved and require more attention. The following issues will be addressed: the abnormalities that should be scored; joints that should be included in a scoring method; whether both right and left hands and feet should be scored; views that should be used; the order in which radiographs should be scored; how data should be evaluated; how intra/interobserver variation and sensitivity to change should be assessed; the optimum number of readers to assess radiographs; the score to be used if there are multiple readers; quality assurance, international training, a validation set of radiographs, and automated scoring of radiographs.

Smolen J, Landewé RB, Mease P, Brzezicki J, Mason D, Luijtens K, van Vollenhoven RF, Kavanaugh A, Schiff M, Burmester GR, Strand V, Vencovsky J, van der Heijde D. · Department of Internal Medicine III, Medical University of Vienna and 2nd Department of Medicine, Hietzing Hospital, Austria. · Ann Rheum Dis. · Pubmed #19015207 links to  free full text

Abstract: BACKGROUND: Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor. OBJECTIVE: To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA). METHODS: An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (n = 619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function. RESULTS: Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p< or =0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and -0.4, respectively, versus 1.2 for placebo (rank analysis p< or =0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were -0.50 and -0.50, respectively, versus -0.14 for placebo (p< or =0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis. CONCLUSION: Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression. Trial registration number: NCT00175877.

Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der Heijde D, Zhou L, Tsuji W, Newmark R, Anonymous00022. · Metroplex Clinical Research Center, Dallas, Texas 75235, USA. · Arthritis Rheum. · Pubmed #18438830 links to  free full text

Abstract: OBJECTIVE: RANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment. METHODS: RA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 180 mg (n = 72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months. RESULTS: At 6 months, the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group (mean change 0.13; P = 0.118) and significantly lower in the 180-mg denosumab group (mean change 0.06; P = 0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group (P = 0.019) as compared with placebo, and at 12 months, both the 60-mg (P = 0.012) and the 180-mg (P = 0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppression of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups. CONCLUSION: Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.

Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der Heijde D, Breedveld FC, Furst DE, Lipsky PE, Anonymous00345. · Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna and Lainz Hospital, Vienna, Austria. · Arthritis Rheum. · Pubmed #15818697 links to  free full text

Abstract: OBJECTIVE: To assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment. METHODS: Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial. RESULTS: At week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28-joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C-reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo-treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX-treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001). CONCLUSION: Even in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.

van der Heijde D, Landewé R, Klareskog L, Rodríguez-Valverde V, Settas L, Pedersen R, Fatenejad S. · Rheumatology Department, University Hospital, Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #15641062 links to  free full text

Abstract: OBJECTIVE: To evaluate different methods of presentation and analysis of radiographic data in a rheumatoid arthritis (RA) randomized controlled trial. METHODS: A double-blind randomized controlled trial including 682 patients with active RA who were treated with methotrexate, etanercept, or a combination of the 2 drugs was used for this study. Probability plots of the change from baseline to year 1 were produced to visualize progression, and were compared with usual descriptive statistics. The primary analysis of the trial (based on annualized actual mean change from baseline in total Sharp score at 1 year, using linear imputation) was challenged using various ways of handling missing information with alternative imputation methods, and by various statistical analyses including analysis of covariance (ANCOVA) and mixed model analysis on both raw and log-transformed data. RESULTS: Probability plots provided detailed insight into the differentiated treatment effects between the 3 arms of this study. As adjuncts to formal hypothesis testing, these plots were more useful for presenting data than were summary descriptive statistics or use of preset cutoff points to define lack of progression. Additional analyses presented here support the results obtained with the per-protocol analysis that showed an advantage of the combination treatment compared with the monotherapy arms and for etanercept versus methotrexate alone. Various ways of handling missing information confirmed the robustness of the results. In addition, both ANCOVA and mixed model analyses on raw and on log-transformed data produced similar results. CONCLUSION: We suggest a panel of alternative analysis methods and alternative ways of handling missing information to verify that the radiographic results reported in an randomized controlled trial are not influenced by technical factors, such as interpolation, handling of missing data, and choice of statistical tests.

Breedveld FC, Han C, Bala M, van der Heijde D, Baker D, Kavanaugh AF, Maini RN, Lipsky PE. · Department of Rheumatology, Leiden University Medical Centre, Leiden, Netherlands. · Ann Rheum Dis. · Pubmed #15286005 links to  free full text

Abstract: OBJECTIVES: To identify factors associated with poor physical function in rheumatoid arthritis and to assess whether baseline joint damage has an impact on improvement in physical function during infliximab treatment. METHODS: 428 patients with active rheumatoid arthritis despite methotrexate treatment received methotrexate alone or with infliximab (3 mg/kg or 10 mg/kg every four or eight weeks) for 54 weeks (the ATTRACT trial). Data on clinical outcomes and physical function (assessed by the health assessment questionnaire (HAQ)) were collected. Structural damage was assessed using the van der Heijde modification of the Sharp score. Odds ratios (OR) for factors associated with severe functional disability (HAQ > or =2.0) at baseline were estimated using multiple logistic regression analyses, and baseline factors related to the change in physical function after treatment at week 54 were determined. RESULTS: Baseline radiographic scores were correlated with baseline HAQ scores. After adjustment for demographic characteristics in the logistic regression model, baseline disease activity scores, radiological joint damage, fatigue, and morning stiffness were found to be associated with severe functional disability (HAQ >2.0), with OR values of 2.00 (1.53 to 2.63), 1.82 (1.15 to 2.87), 1.19 (1.05 to 1.34), and 1.07 (1.01 to 1.13), respectively. In multiple linear regression analysis, physical disability, joint damage, and fatigue at baseline were correlated with less improvement in physical function after treatment. Infliximab treatment was associated with greater improvement in physical function. CONCLUSIONS: Greater joint damage at baseline was associated with poorer physical function at baseline and less improvement in physical function after treatment, underlining the importance of early intervention to slow the progression of joint destruction.

Landewé R, Geusens P, Boers M, van der Heijde D, Lems W, te Koppele J, van der Linden S, Garnero P. · Department of Internal Medicine/Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #15146408 links to  free full text

Abstract: OBJECTIVE: To investigate in a randomized clinical trial setting with an aggressive combination-therapy arm and a mild-monotherapy arm, whether therapy-induced changes in urinary C-terminal crosslinking telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) predict 5-year radiographic progression in patients with rheumatoid arthritis (RA). METHODS: Patients had participated in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial comparing aggressive step-down combination therapy (the COBRA regimen, including temporary high-dose prednisolone, temporary low-dose methotrexate, and sulfasalazine [SSZ]) and mild monotherapy (SSZ). Urinary CTX-I and CTX-II levels were measured at baseline and 3, 6, 9, and 12 months after initiation of treatment. Radiographs were scored according to the modified Sharp/van der Heijde method (mean of 2 independent readers who were aware of the sequence). Individual long-term radiographic progression was estimated, using baseline radiographs and all radiographs obtained during the followup period, by simple linear regression analysis (curve fitting). RESULTS: Both COBRA therapy and SSZ monotherapy produced a significant decrease in urinary CTX-I and CTX-II levels at 3 months, and this decrease was amplified at 6 months. COBRA therapy suppressed CTX-II (change from baseline levels -36% and -43% at 3 and 6 months, respectively), but not CTX-I, significantly better than did SSZ (-17% and -21% at 3 and 6 months, respectively) at 3 and 6 months. The magnitude of the decrease in urinary CTX-II levels at 3 months significantly predicted long-term (5-year) radiographic progression (beta = 0.48 [95% confidence interval (95% CI) 0.13, 0.83]). This effect was independent of the change in disease activity and inflammation indices at 3 months. Patients whose CTX-II levels were normalized (<150 ng/mmoles of urinary creatinine) at 3 months had a significantly higher chance of radiographic stability (no progression over 5 years) than did patients whose CTX-II levels were increased both at baseline and at 3 months (odds ratio 4.5 [95% CI 1.5, 13]). CONCLUSION: The individual CTX-II response measured after 3 months of therapy in patients with active RA who had increased CTX-II levels at baseline independently predicts long-term radiographic progression. Urinary CTX-II levels may be used as early markers of treatment efficacy in patients with RA.