Rheumatoid Arthritis: van Riel P

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.

Repping-Wuts H, van Riel P, van Achterberg T. · No affiliation provided · Rheumatology (Oxford). · Pubmed #18927188 No free full text.

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van Riel P. · No affiliation provided · Neth J Med. · Pubmed #12607586 links to  free full text

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Fransen J, Stucki G, van Riel P. · No affiliation provided · Rheumatology (Oxford). · Pubmed #12048285 links to  free full text

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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.

Wells G, Anderson J, Boers M, Felson D, Heiberg T, Hewlett S, Johnson K, Kirwan J, Lassere M, Robinson V, Shea B, Simon L, Strand V, van Riel P, Tugwell P. · Department of Clinical Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada. · J Rheumatol. · Pubmed #12734920 No free full text.

Abstract: The OMERACT 6 Minimal Clinically Important Difference/Low Disease Activity Workshop was organized with the aim of meeting the many challenges that exist in determining a low disease activity in rheumatoid arthritis (RA). This article presents an overview of that workshop, including results of the voting, a summary of associated discussions, recommendations, and a proposed research agenda.

Wells G, Boers M, Shea B, Anderson J, Felson D, Johnson K, Kirwan J, Lassere M, Robinson V, Simon L, Strand V, van Riel P, Tugwell P. · Department of Clinical Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada. · J Rheumatol. · Pubmed #12734918 No free full text.

Abstract: The MCID (minimal clinically important difference) module of OMERACT 5 developed a research agenda that led to the conclusion that a state of low disease activity for rheumatoid arthritis (RA) would need to be defined. To develop such a definition the various concepts and terminologies, the process for developing an operational definition, and the availability and design of longitudinal datasets for validation needed to be considered. This article describes the process of the MCID/Low Disease Activity State Workshop at OMERACT 6 to develop such a definition.

Dougados M, Schmidely N, Le Bars M, Lafosse C, Schiff M, Smolen JS, Aletaha D, van Riel P, Wells G. · Rene Descartes University, Medicine Faculty, UPRES-EA 4058, APHP, Cochin Hospital, Rheumatology B Department, Paris, France. · Ann Rheum Dis. · Pubmed #19074177 links to  free full text

Abstract: OBJECTIVES: To evaluate different methods of reporting response to treatment or disease status for their ability to discriminate between active therapy and placebo, or to reflect structural progression or patient satisfaction with treatment using an exploratory analysis of the Abatacept in Inadequate Responders to Methotrexate (AIM) trial. METHODS: 424 active (abatacept approximately 10 mg/kg) and 214 placebo-treated patients with rheumatoid arthritis (RA) were evaluated. METHOD: of reporting included: (1) response (American College of Rheumatology (ACR) criteria) versus state (disease activity score in 28 joints (DAS28) criteria); (2) stringency (ACR20 vs 50 vs 70; moderate disease activity state (MDAS; DAS28 <5.1) vs low disease activity state (LDAS; DAS28 <or=3.2) vs DAS28-defined remission (DAS28 <2.6)); (3) time to onset (time to first ACR50/LDAS) and (4) sustainability of ACR50/LDAS for consecutive visits. Methods were assessed according to: (1) discriminatory capacity (number of patients needed to study (NNS)); (2) structural progression (Genant-modified Sharp score) and (3) patient satisfaction with treatment. Positive likelihood ratios (LR) evaluated the ability of the above methods to reflect structural damage and patient satisfaction. RESULTS: MDAS and ACR20 had the highest discriminatory capacity (NNS 49 and 69). Sustained LDAS best reflected no radiographic progression (positive LR >or=2). More stringent criteria (at least ACR50/LDAS), faster onset (<or=3 months) and sustainability (>3 visits) of ACR50/LDAS best reflected patient satisfaction (positive LR >10). CONCLUSIONS: The optimal method for reporting a measure of disease activity may differ depending on the outcome of interest. Time to onset and sustainability can be important factors when evaluating treatment response and disease status in patients with RA.

Dougados M, Emery P, Lemmel EM, Zerbini CA, Brin S, van Riel P. · Hôpital Cochin, René Descartes University, 27, Rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France. · Ann Rheum Dis. · Pubmed #15271770 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of adding sulfasalazine to leflunomide treatment compared with switching to sulfasalazine alone in patients with RA with an inadequate response to leflunomide monotherapy. METHODS: Patients with active RA ((DAS28) >3.2) who were enrolled in the first open label phase of the RELIEF study received leflunomide for 24 weeks. Inadequate responders then entered the double blind phase and received a further 24 weeks' treatment with leflunomide (20 mg once daily) plus sulfasalazine (final dose 2 g once daily), or placebo plus sulfasalazine (dose as above). The primary efficacy variable was the DAS28 response rate, and secondary efficacy outcomes were ACR 20%, 50%, and 70% response rates. Adverse events, including standard laboratory tests, were recorded. RESULTS: 106 inadequate responders entered the double blind phase; 56 received leflunomide plus sulfasalazine, and 50 placebo plus sulfasalazine. In the intention to treat population, more patients receiving leflunomide plus sulfasalazine (25/56 (45%)) achieved a DAS28 response than those receiving placebo plus sulfasalazine (17/50 (34%)) (p = 0.179). In week 24 completers, more patients receiving leflunomide plus sulfasalazine (17/56 (30%)) were DAS28 responders than those receiving placebo plus sulfasalazine (10/50 (20%)) (p = 0.081). Comparable numbers in each group were ACR 20% responders; the ACR 50% response rate was significantly higher in the leflunomide plus sulfasalazine group (8.9%) than in the placebo plus sulfasalazine group (0%) (p = 0.038). The safety profiles of both groups were comparable. CONCLUSION: Patient numbers are small and firm conclusions cannot be reached, but a non-significant benefit is indicated for combining leflunomide with sulfasalazine compared with switching to sulfasalazine alone in patients inadequately responding to leflunomide.

Dougados M, Emery P, Lemmel EM, de la Serna R, Zerbini CA, Brin S, van Riel P. · René Descartes University, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France. · J Rheumatol. · Pubmed #14719196 No free full text.

Abstract: OBJECTIVE: The RELIEF investigation was a 48-week, multicenter, international study comprising 2 phases. Results from the first phase, a 24-week open-label cohort study that evaluated the safety and efficacy of leflunomide, as well as predisposing factors to treatment response, are reported here. METHODS: Patients received leflunomide 100 mg once daily for 3 days, followed by 20 mg once daily thereafter. All adverse events were documented. Efficacy variables were the European League Against Rheumatism (EULAR) response criteria using the Disease Activity Score (DAS 28) responder rate and the response rate according to American College of Rheumatology (ACR) criteria. At Week 24, baseline data were analyzed to determine predictive factors for treatment response. RESULTS: A total of 969 patients were entered in the trial. No adverse events that have not previously been seen with leflunomide were reported. Among 968 evaluable patients, 673 (69.6%) completed 24 weeks of treatment and were responders according to DAS 28 response rate, and 587 (60.6%) completed 24 weeks of treatment and were responders according to ACR 20%. Thus, there was a high correlation between the EULAR and ACR criteria in determining treatment response. In addition, 240 (24.8%) patients had a low DAS 28 (< or = 3.2) and 123 (12.7%) patients fulfilled the disease remission criteria (DAS 28 < 2.6) at the end of the study. CONCLUSION: This study demonstrates that leflunomide is well tolerated, with a safety profile similar to that seen previously in Phase III studies, and confirms the efficacy of leflunomide across a range of patient categories.

Rau R, Sander O, van Riel P, van de Putte L, Hasler F, Zaug M, Kneer J, van der Auwera P, Stevens RM, Anonymous00147. · Department of Rheumatology, Evangelisches Fachkrankenhaus, Ratingen, Germany. · J Rheumatol. · Pubmed #12672184 No free full text.

Abstract: OBJECTIVE: To determine the optimal dose regimen for intravenous Ro 45-2081 (lenercept) in patients with rheumatoid arthritis (RA) by evaluating efficacy, safety, tolerability, and pharmacokinetic and pharmacodynamic characteristics. METHODS: Adult patients with longstanding RA who were taking stable doses of nonsteroidal antiinflammatory drug and/or low dose corticosteroids but who had stopped their previous disease-modifying antirheumatic drug were randomly assigned to receive 3 intravenous infusions, one every 4 weeks, of placebo or Ro 45-2081 in a double blind, placebo controlled, parallel group multicenter trial. Patients received one of the following: (1) placebo, (2) low dose Ro 45-2081 (0.05 mg/kg, maximum 5 mg), (3) middle dose (mid-dose) Ro 45-2081 (0.2 mg/kg, maximum 20 mg), or (4) high dose Ro 45-2081 (0.5 mg/kg, maximum 50 mg). Efficacy measures included change from baseline in number of swollen joints and tender joints, scores on physician and patient assessments of disease activity, and patient assessment of pain, as well as acute phase reactants. RESULTS: Patients treated with Ro 45-2081 exhibited improvement after one day of the first intravenous infusion. This treatment benefit maximized by 2 weeks but diminished thereafter. After the second and third infusion, improvement was of shorter duration as non-neutralizing anti-Ro 45-2081 antibodies developed and accelerated clearance of Ro 45-2081. There were no antibodies after the first infusion. This made efficacy transient in the mid-dose group and modest in the low and high dose groups at 12 weeks of treatment, resulting in no statistical differences at most time points or doses of Ro 45-2081. The majority of adverse experiences were mild or moderate, and were not related or only remotely related to study drug. No clinically relevant changes in mean laboratory values were reported. The third dose pharmacokinetic measurements showed that the average Ro 45-2081 clearance rate more than doubled compared with the first dosing interval, thus reducing the average Ro 45-2081 AUC by 36%. CONCLUSION: Intravenous Ro 45-2081 every 4 weeks proved to be well tolerated and transiently effective in the mid-dose group and modestly effective in the low and high dose groups in patients with longstanding RA. The interactions between Ro 45-2081, its non-neutralizing anti-Ro 45-2081 antibody, and the clinical benefit remain complex, but affected efficacy over the 12 weeks of treatment as Ro 45-2081 concentrations fell.

Emery P, Van Vollenhoven R, Ostergaard M, Choy E, Combe B, Graninger W, Krueger K, Matucci-Cerinic M, Navarro F, van Riel P, Settas L, Steinfeld S. · University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #19286904 No free full text.

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Repping-Wuts H, Hewlett S, van Riel P, van Achterberg T. · Radboud University Nijmegen Medical Centre, The Netherlands. · J Adv Nurs. · Pubmed #19243466 No free full text.

Abstract: AIM: This paper is a report of a study conducted to compare the knowledge, attitudes and current management of rheumatoid arthritis-related fatigue in British and Dutch rheumatology nurses. BACKGROUND: After pain, fatigue is the most important symptom for patients with rheumatoid arthritis, but little is known about the current management of this fatigue by healthcare professionals. METHODS: A questionnaire was mailed in 2007 to rheumatology nurses who were members of British Health Professionals in Rheumatology (N = 267) and the Dutch Society of Rheumatology Nurses (N = 227). Descriptive statistics, independent samples t-test and Pearson chi-square tests were used for statistical analysis. RESULTS: A total of 494 nurses returned questionnaires (response rate 48%). In general, their knowledge about rheumatoid arthritis fatigue was in accordance with the literature and all indicated a positive attitude towards assessing and managing rheumatoid arthritis-related fatigue. However, respondents reported contradictory views about managing fatigue. Although they believed that other team members could help patients, they seldom referred patients on to other professionals. Although nurses believed that other advice besides pacing and balance between activity and rest might help, they did not offer this to patients. Despite acknowledging that there is poor communication about fatigue between patients and nurses, respondents reported that it is patients rather than nurses who raise the issue of fatigue in consultations. CONCLUSION: British and Dutch rheumatology nurses are sympathetic but do not know how to manage rheumatoid arthritis-related fatigue. Strategies to support self-management for this fatigue, and to increase communication between healthcare professionals and patients, should be initiated to help improve patient outcomes for rheumatoid arthritis-related fatigue.

Repping-Wuts H, Repping T, van Riel P, van Achterberg T. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. · Patient Educ Couns. · Pubmed #19118972 No free full text.

Abstract: OBJECTIVE: To describe nurse-patient and rheumatologist-patient interaction in fatigue communication at the rheumatology out-patient clinic. METHODS: Consultations of 20 rheumatoid arthritis (RA) patients with the nurse specialist and the rheumatologist were videotaped and analysed using the Medical Interview Aural Rating Scale (MIARS). Subsequently, patients were asked to fill out a concern questionnaire asking how worried they felt and how satisfied they were with attention given by both healthcare professionals. Finally, patients were interviewed on reasons for being not or not completely satisfied with the care received. RESULTS: Fatigue was discussed in 42% of the rheumatologists' consultations and 83% of the nurse specialists' consultations. RA patients more often used implicit cues instead of explicit concerns related to fatigue. Almost 72% of the patients felt worried about fatigue and in general they were more satisfied with the nurse specialist's attention to fatigue than with the attention from the rheumatologist. CONCLUSION: Fatigue is not structurally communicated at the rheumatology out-patient clinic and exploring and acknowledging communication techniques can help patients to express their concerns about fatigue. PRACTICE IMPLICATIONS: Healthcare professionals must recognise fatigue as a severe problem for RA patients and start the conversation on fatigue instead of waiting for the patient to mention fatigue spontaneously.

Karonitsch T, Aletaha D, Boers M, Bombardieri S, Combe B, Dougados M, Emery P, Felson D, Gomez-Reino J, Keystone E, Kvien TK, Martin-Mola E, Matucci-Cerinic M, Richards P, van Riel P, Siegel J, Smolen JS, Sokka T, van der Heijde D, van Vollenhoven R, Ward M, Wells G, Zink A, Landewe R. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Ann Rheum Dis. · Pubmed #18791056 No free full text.

Abstract: OBJECTIVE: To use an evidence-based and consensus-based approach to elaborate recommendations on how to report disease activity in clinical trials of patients with rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: After an initial expert meeting, during which relevant research questions were identified, a systematic literature search was performed using Medline, Embase and the Cochrane Library as sources. To ensure literature retrieved was comprehensive, we emphasised search algorithms that were sensitive rather than specific. The results of the literature search were discussed by the expert panel, modified and expanded, and were used as the basis for the elaboration of the recommendation in the consensus process. Finally, an independent ACR panel approved these items with some minor modifications. RESULTS: The following pieces of evidence were obtained from the literature search: (1) timing and the sustaining of a response is relevant to achieve better outcomes; (2) composite disease activity indices have been used to define low disease activity and remission and these definitions have been validated as has the American Rheumatism Association (ARA) remission criteria. The "patient-reported symptom state" (PASS) is not yet well validated; (3) evidence was obtained to identify those measures, scales and patient-reported instruments, for which there is a documented association with relevant outcomes; (4) baseline disease activity is associated with disease activity levels at the end of follow-up; and (5) there was not sufficient evidence relating the added benefit of MRI or ultrasound over clinical assessments. Most data stemmed from observational studies rather than clinical trials and literature review was supplemented by input from experts. The results served as the basis for the elaboration of the seven recommendations by the experts. CONCLUSIONS: The approach based on scientific evidence from the literature as well as on expert input provided sufficient information to derive recommendations on reporting disease activity in RA clinical trials. The methodology, results and conclusions of this project were endorsed by EULAR and the ACR.

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. · Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · Ann Rheum Dis. · Pubmed #18791055 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 standardised 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. CONCLUSIONS: These recommendations endorsed by EULAR and ACR will help harmonise 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.

Kurreeman FA, Rocha D, Houwing-Duistermaat J, Vrijmoet S, Teixeira VH, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Vaz C, Fernandes M, Pascual-Salcedo D, Michou L, Bombardieri S, Radstake T, van Riel P, van de Putte L, Lopes-Vaz A, Prum B, Bardin T, Gut I, Cornelis F, Huizinga TW, Petit-Teixeira E, Toes RE, Anonymous00030. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #18759306 No free full text.

Abstract: OBJECTIVE: We recently showed, using a candidate gene approach in a case-control association study, that a 65-kb block encompassing tumor necrosis factor receptor-associated factor 1 (TRAF1) and C5 is strongly associated with rheumatoid arthritis (RA). Compared with case-control association studies, family-based studies have the added advantage of controlling potential differences in population structure and are not likely to be hampered by variation in population allele frequencies, as is seen for many genetic polymorphisms, including the TRAF1/C5 locus. The aim of this study was to confirm this association in populations of European origin by using a family-based approach. METHODS: A total of 1,356 western European white individuals from 452 "trio" families were genotyped for the rs10818488 polymorphism, using the TaqMan allelic discrimination assay. RESULTS: We observed evidence for association, demonstrating departure from Mendel's law, with an overtransmission of the rs10818488 A allele (A = 55%; P = 0.036). By taking into consideration parental phenotypes, we also observed an increased A allele frequency in affected versus unaffected parents (A = 64%; combined P = 0.015). Individuals carrying the A allele had a 1.2-fold increased risk of developing RA (allelic odds ratio 1.24, 95% confidence interval 1.04-1.50). CONCLUSION: Using a family-based study that is robust against population stratification, we provide evidence for the association of the TRAF1/C5 rs10818488 A allele and RA in populations of European descent, further substantiating our previous findings. Future functional studies should yield insight into the biologic relevance of this locus to the pathways involved in RA.

Repping-Wuts H, van Riel P, van Achterberg T. · Department Rheumatology/495, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Clin Rheumatol. · Pubmed #18622574 No free full text.

Abstract: To describe rheumatologists' knowledge, attitude and current management of fatigue in patients with rheumatoid arthritis (RA), a postal questionnaire was sent to all rheumatologists (N = 204) and trainees (N = 49), members of the Dutch Society of Rheumatology. The overall response rate was 44% (N = 110). In general, rheumatologists' knowledge about RA-related fatigue was in accordance with the literature but they perceive a lack of their own knowledge about aetiology and evidence-based interventions to prevent and treat fatigue. The majority of the rheumatologists believe that fatigue is a multi-disciplinary diagnosis and is preferably managed by the nurse specialist (34%). Assuming that the patient will raise the issue, most of the rheumatologists pay attention to fatigue during the first consultation and less often during follow-up consultations. There is a need for knowledge about causes and treatments for RA-related fatigue to ensure that patient outcomes are improved.

Alten R, Gram H, Joosten LA, van den Berg WB, Sieper J, Wassenberg S, Burmester G, van Riel P, Diaz-Lorente M, Bruin GJ, Woodworth TG, Rordorf C, Batard Y, Wright AM, Jung T. · Department of Internal Medicine II, Rheumatology, Schlosspark-Klinik Teaching Hospital Charité University Medicine Berlin, Heubnerweg, D-14059 Berlin, Germany. · Arthritis Res Ther. · Pubmed #18534016 links to  free full text

Abstract: INTRODUCTION: IL-1beta is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production. METHODS: ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1beta, was generated to study the potent and long-lasting neutralization of IL-1beta in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA). RESULTS: The mouse IL-1 receptor cross-reacts with human IL-1beta, and it was demonstrated that ACZ885 can completely suppress IL-1beta-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study--the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study. CONCLUSION: ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00619905.

Repping-Wuts H, Fransen J, van Achterberg T, Bleijenberg G, van Riel P. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · J Clin Nurs. · Pubmed #17931330 No free full text.

Abstract: AIM: To determine whether persistent severe fatigue in patients with rheumatoid arthritis can be predicted by inflammation and disability. METHODS: A follow-up study with a one-year duration was performed. From an existing rheumatoid arthritis cohort, 150 consecutive patients, with established rheumatoid arthritis, were asked to assess fatigue, using the subscale Checklist Individual Strength-fatigue of the Checklist Individual Strength at baseline and 12 months later. The Checklist Individual Strength-fatigue scores were classified into 'normal' (score between 8-27), 'moderate' (score between 27-34) or 'severe' (score 35 or above) fatigue. Disease-related variables were: tender joints, swollen joints, general health, disability and laboratory measures (erythrocyte sedimentation rate, rheumatoid factor and haemoglobin). Predictors of persistent severe fatigue were identified by multiple logistic regression analyses with backward selection (selection criteria: p<0.05). RESULTS: At baseline, 137 patients agreed to participate and 123 patients completed the study. Severe fatigue was experienced by as many as 50% of the patients, both at baseline and at the end of the study (n = 123). Moreover, 49 patients (40%) experienced severe fatigue at baseline as well as at follow-up, which we called 'persistent severe fatigue'. Persistent severe fatigue was predicted by mean general health and disability at baseline [odds ratio (OR) = 2.03 and 2.83, respectively] in this group of rheumatoid arthritis patients with a low-to-moderate level of disease activity and disability. CONCLUSION: The data show that severe fatigue is not resolved spontaneously in rheumatoid arthritis patients, and persistent severe fatigue is mainly predicted by general health and disability. The relation with inflammation or a low level of haemoglobin, which is often assumed in clinical practice, was not found. RELEVANCE TO CLINICAL PRACTICE: Fatigue in patients with rheumatoid arthritis has to be considered as a symptom that needs to be addressed by professionals in the same way as pain and disability. In current care, fatigue is insufficiently addressed.

Repping-Wuts H, Uitterhoeve R, van Riel P, van Achterberg T. · Department of Rheumatology, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands. · Int J Nurs Stud. · Pubmed #17662291 No free full text.

Abstract: OBJECTIVE: Interest in fatigue research has grown since the finding that fatigue is, besides pain, the symptom most frequently reported by patients with rheumatoid arthritis (RA). The aim of this study was to explore the experience of fatigue from the patients' perspective. METHODS: Twenty-nine patients with RA filled-out written questionnaires on fatigue severity, disability, quality of life and sleep disturbance, and disease activity was calculated using the Disease Activity Score (DAS28). All patients were individually interviewed and asked about fatigue. Qualitative analyses were completed using software program "The Observer". Basic codes, a code plan and coding rules were developed by two researchers through a consensus-based review process. Frequencies of the central codes were calculated by the program SPSS. RESULTS: RA fatigue is verbalised as a physical everyday experience with a variety in duration and intensity. Its sudden onset and exhausting nature is experienced as frustrating and causing anger. Patients mentioned having RA as the main cause of their fatigue. The consequences of fatigue are overwhelming and influence patients' everyday tasks, attitudes and leisure time. Patients described how they have to find their own management strategies by trial and error and described pacing and rest, relaxation and planning activities as the most appropriate interventions. Downward comparison and acceptance as part of the disease are also reported as successful coping strategies for fatigue. Most patients did not discuss fatigue with clinicians explicitly, accepting that they were told that fatigue is part of the disease and believing that they have to manage it alone. CONCLUSION: The results show that RA fatigue is experienced as being different from "normal" fatigue. Patients do not expect much support from health care professionals, assuming that they have to manage fatigue alone as it is part of the disease. These results will help professionals caring for RA patients to communicate about fatigue, to explore the nature of fatigue individually and to develop tailored interventions.

van Ede A, den Broeder A, Wagenaar M, van Riel P, Creemers MC. · Department of Rheumatology, University Medical Centre Nijmegen, Nijmegen, The Netherlands. · J Rheumatol. · Pubmed #17610313 No free full text.

Abstract: OBJECTIVE: Although nodulosis is a common extraarticular manifestation of rheumatoid arthritis, accelerated pulmonary nodulosis is a rare event. The etiology of rheumatoid nodules is still unknown. Nodulosis is not necessarily associated with active joint inflammation, suggesting different pathogenic mechanisms for nodule formation and synovial tissue inflammation. We describe a patient with extensive pulmonary nodulosis, probably related to etanercept treatment. Our case emphasizes the need for careful monitoring for adverse events during treatment with biologicals, especially since the differential diagnosis often includes a broad spectrum of diseases.

Welsing PM, Borm GF, van Riel P. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · J Rheumatol. · Pubmed #16511919 No free full text.

Abstract: OBJECTIVE: To estimate a threshold for minimal clinically important radiological progression of joint damage using its longitudinal relation with functional disability in patients with rheumatoid arthritis (RA). To validate existing estimates of minimal clinically important difference (MCID) using this relation with functional disability. METHODS: We reanalyzed published data of 185 patients with early RA followed for a maximum of 9 years. Longitudinal regression (mixed models) was used, relating radiological damage (modified Sharp score) to functional disability (HAQ-DI), correcting for age (age at diagnosis and increasing disease duration), disease activity (DAS28), and demographic variables. Several shapes of the relation were investigated. Based on the observed relationship between radiological damage, functional disability, and the minimal clinically relevant increase in functional disability found in earlier studies, MCID for progression of joint damage was discussed. Existing estimates of MCID were evaluated for their influence on functional disability over the disease course. RESULTS: A longitudinal relation between the modified Sharp score and the HAQ-DI was found. Significant covariates were age, gender, and disease activity. The model indicated that the relation between the Sharp score and the HAQ-DI was dependent on the amount of damage (a threshold effect) and on patients' age. With lower age, no effect of joint damage on functional disability could be demonstrated and with higher age the effect of joint damage increased. With a typical patient from our cohort (age at diagnosis 55 yrs, some baseline damage, and an expected disease duration of 30 yrs), a (constant) progression of 6 points per year led to an increase of about 0.2 on the HAQ score, solely related to damage, over the disease course. This estimate of MCID was close to estimates based on expert opinion and equal or smaller than most estimates based on the smallest detectable difference. CONCLUSIONS: The MCID, defined using longitudinal effect on functional disability, is dependent on age and (progression of) joint damage. However, with a typical patient population this MCID was similar to thresholds based on expert opinion, adding to the validity of these estimates.

Riksen NP, Rongen GA, Smits P, van Riel P, Barrera P. · No affiliation provided · Arthritis Rheum. · Pubmed #17265507 links to  free full text

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