Rheumatoid Arthritis: Landewé RB

Landewé RB. · Department of InternalMedicine/Rheumatology, Maastricht University Medical Center, Care and Public Health Research Institute, Maastricht, The Netherlands. · Nat Clin Pract Rheumatol. · Pubmed #19030006 No free full text.

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Landewé RB. · No affiliation provided · Arthritis Rheum. · Pubmed #12528097 links to  free full text

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Landewé RB, Boers M, van der Heijde DM. · No affiliation provided · Rheumatology (Oxford). · Pubmed #12509605 links to  free full text

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Landewé RB, van der Heijde DM. · Department of Internal Medicine and Rheumatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. · Curr Rheumatol Rep. · Pubmed #14531956 No free full text.

Abstract: Therapeutic possibilities for the treatment of early rheumatoid arthritis (RA) have expanded largely. New treatment modalities appear very effective with respect to relevant outcomes, such as radiographic progression. At the same time, the costs of disease-modifying antirheumatic drugs (DMARDs) have exponentially increased so that--given the rather high prevalence of RA--cost may become a limiting factor in the treatment of patients with RA. Therefore, there is a need to define the profile of those patients that should be treated with the most effective, and, unfortunately, the most costly, DMARDs. The authors describe herewith the heterogeneity of RA with respect to its most important outcomes, as well as the inability to predict those outcomes appropriately at the individual patient level. This heterogeneity of RA is not acknowledged in the modern landmark clinical trials that the authors base therapeutic decisions on, and the external validity of those trials is at stake. In this article, the authors discuss the consequences of the heterogeneity of RA in light of the perceived lack of external validity of evidence-generating landmark trials. The authors propose the following solutions to overcome this discrepancy: 1) earlier recognition of RA, and 2) appropriate prediction of treatment efficacy, because the most challenging scientific efforts may be taken in the near future in order to arrive at a tailor-made therapy for every individual presenting with RA.

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.

Gerards AH, Landewé RB, Prins AP, Bruyn GA, Goei Thé HS, Laan RF, Dijkmans BA, Bruijn GA. · VU Medical Centre and Jan van Breemen Instituut, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #12634224 links to  free full text

Abstract: OBJECTIVE: To compare the efficacy and toxicity of cyclosporin A (CsA) monotherapy with CsA plus methotrexate (MTX) combination therapy in patients with early rheumatoid arthritis (RA). PATIENTS AND METHODS: 120 patients with active RA, rheumatoid factor positive and/or erosive, were randomly allocated to receive CsA with MTX (n=60) or CsA with placebo (n=60). Treatment with CsA was started in all patients at 2.5 mg/kg/day and increased to a maximum of 5 mg/kg/day in 16 weeks. MTX was started at 7.5 mg/week and increased to a maximal dose of 15 mg/week at week 16. Primary outcomes were clinical remission (Pinals criteria) and radiological damage (Larsen score), at week 48. RESULTS: Treatment was discontinued prematurely in 27 patients in the monotherapy group (21 because of inefficacy, and six because of toxicity) and in 26 patients in the combination therapy group (14 and 12, respectively). At week 48, clinical remission was achieved in four patients in the monotherapy group and in six patients in the combination therapy group (p=0.5). The median Larsen score increased to 10 (25th, 75th centiles: 3.5; 13.3) points in the monotherapy group and to 4 (1.0; 10.5) points in the combination therapy group (p=0.004). 28/60 (47%) of patients in the monotherapy group v 34/60 (57%) of patients in the combination therapy group had reached an American college of Rheumatology 20% (ACR20) response (p=0.36) at week 48; 15/60 (25%) v 29/60 (48%) of patients had reached an ACR50 response (p=0.013); and 7 (12%) v 12 (20%) of patients had reached an ACR70 response (p=0.11).Their was a tendency towards more toxicity in the combination therapy group. CONCLUSIONS: In patients with early RA, neither CsA plus MTX combination therapy nor CsA monotherapy is very effective in inducing clinical remission. Combination therapy is probably better at improving clinical disease activity, and definitely better at slowing radiological progression. Combination therapy should still be compared with methotrexate monotherapy.

Landewé RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, van Denderen JC, Westedt ML, Peeters AJ, Dijkmans BA, Jacobs P, Boonen A, van der Heijde DM, van der Linden S. · Department of Internal Medicine/Rheumatology, PO Box 5800, University Hospital Maastricht, 6202 AZ Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #11840436 No free full text.

Abstract: OBJECTIVE: The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that step-down combination therapy with prednisolone, methotrexate, and sulfasalazine (SSZ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis (RA). The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time, and to determine which baseline factors could predict outcome. METHODS: All patients had participated in the 56-week COBRA trial. During followup, they were seen by their own rheumatologists and were also assessed regularly by study nurses; no treatment protocol was specified. Disease activity, radiologic damage, and functional ability were the primary outcome domains. Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method. Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat, starting with data obtained at the last visit of the COBRA trial (56 weeks after baseline). RESULTS: At the beginning of followup, patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score (DAS28) and a significantly lower median radiologic damage (Sharp) score compared with those in the SSZ monotherapy group. The functional ability score (Health Assessment Questionnaire [HAQ]) was similar in both groups. During the 4-5 year followup period, the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group. The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group. After adjustment for differences in treatment and disease activity during followup, the between-group difference in the rate of radiologic progression was 3.7 points per year. The HAQ score did not change significantly over time. Independent baseline predictors of radiologic progression over time (apart from treatment allocation) were rheumatoid factor positivity, Sharp score, and DAS28. CONCLUSION: An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy.

Dijkmans BA, Landewé RB, van den Borne BE, Breedveld FC. · Rheumatology Department, Academic Hospital Vrije Universiteit, Amsterdam, The Netherlands. · Clin Exp Rheumatol. · Pubmed #10589367 No free full text.

Abstract: Antimalarials are attractive candidates for combination therapy. In vitro experiments have revealed a synergistic mode of action of cyclosporine and chloroquine which could not, however, be confirmed in a clinical trial.

van den Borne BE, Landewé RB, Rietveld JH, Goei The HS, Griep EN, Breedveld FC, Dijkmans BA. · Department of Rheumatology, Leiden University Medical Center, The Netherlands. · Clin Rheumatol. · Pubmed #10524550 No free full text.

Abstract: If rheumatoid arthritis (RA) patients with a mild disease course could be identified early in the phase of the disease, therapy with less aggressive and probably less toxic antirheumatic drugs seems to be rational. The aim of this study was to investigate which factors at baseline could predict a clinical response (American College of Rheumatology preliminary response criteria) after treatment with chloroquine for 16 weeks. Two hundred and three early RA patients with active disease were treated with oral chloroquine sulphate (Nivaquine) at a daily dose of 300 mg during the first 4 weeks, 200 mg during the second 4 weeks and 100 mg thereafter. One hundred and eighty-three patients (90%) completed the study and 20 patients prematurely discontinued treatment. Of all the patients, 43 patients (21%) met the response criteria. A low level of C-reactive protein (CRP) was the only independent predictor for clinical response [relative risk: 0.97 (95% confidence interval: 0.95-0.98)]. It was concluded that a clinical response to chloroquine therapy in early RA patients can be predicted by a low CRP level at baseline.

Huizinga TW, Landewé RB. · Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands. · Nat Clin Pract Rheumatol. · Pubmed #16932617 No free full text.

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Geusens PP, Landewé RB, Garnero P, Chen D, Dunstan CR, Lems WF, Stinissen P, van der Heijde DM, van der Linden S, Boers M. · University Hospital, Maastricht, The Netherlands. · Arthritis Rheum. · Pubmed #16736519 links to  free full text

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation. METHODS: OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage. RESULTS: The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P < or = 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio. CONCLUSION: This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio).

Wells GA, Boers M, Shea B, Brooks PM, Simon LS, Strand CV, Aletaha D, Anderson JJ, Bombardier C, Dougados M, Emery P, Felson DT, Fransen J, Furst DE, Hazes JM, Johnson KR, Kirwan JR, Landewé RB, Lassere MN, Michaud K, Suarez-Almazor M, Silman AJ, Smolen JS, Van der Heijde DM, van Riel PL, Wolfe F, Tugwell PS. · Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada. · J Rheumatol. · Pubmed #16206362 No free full text.

Abstract: Agreement on response criteria in rheumatoid arthritis (RA) has allowed better standardization and interpretation of clinical trial reports. With recent advances in therapy, the proportion of patients achieving a satisfactory state of minimal disease activity (MDA) is becoming a more important measure with which to compare different treatment strategies. The threshold for MDA is between high disease activity and remission and, by definition, anyone in remission will also be in MDA. True remission is still rare in RA; in addition, the American College of Rheumatology definition is difficult to apply in the context of trials. Participants at OMERACT 6 in 2002 agreed on a conceptual definition of minimal disease activity (MDA): "that state of disease activity deemed a useful target of treatment by both the patient and the physician, given current treatment possibilities and limitations." To prepare for a preliminary operational definition of MDA for use in clinical trials, we asked rheumatologists to assess 60 patient profiles describing real RA patients seen in routine clinical practice. Based on their responses, several candidate definitions for MDA were designed and discussed at the OMERACT 7 in 2004. Feedback from participants and additional on-site analyses in a cross-sectional database allowed the formulation of 2 preliminary, equivalent definitions of MDA: one based on the Disease Activity Score 28 (DAS28) index, and one based on meeting cutpoints in 5 out the 7 WHO/ILAR core set measures. Researchers applying these definitions first need to choose whether to use the DAS28 or the core set definition, because although each selects a similar proportion in a population, these are not always the same patients. In both MDA definitions, an initial decision node places all patients in MDA who have a tender joint count of 0 and a swollen joint count of 0, and an erythrocyte sedimentation rate (ESR) no greater than 10 mm. If this condition is not met: * The DAS28 definition places patients in MDA when DAS28 < or = 2.85; * The core set definition places patients in MDA when they meet 5 of 7 criteria: (1) Pain (0-10) < or = 2; (2) Swollen joint count (0-28) < or = 1; (3) Tender joint count (0-28) < or = 1; (4) Health Assessment Questionnaire (HAQ, 0-3) < or = 0.5; (5) Physician global assessment of disease activity (0-10) < or = 1.5; (6) Patient global assessment of disease activity (0-10) < or = 2; (7) ESR < or = 20. This set of 2 definitions gained approval of 73% of the attendees. These (and other) definitions will now be subject to further validation in other databases.

Landewé RB, Geusens P, van der Heijde DM, Boers M, van der Linden SJ, Garnero P. · Department of Internal Medicine/Rheumatology, University Hospital Maastricht, Netherlands. · Ann Rheum Dis. · Pubmed #16126801 links to  free full text

Abstract: BACKGROUND: Markers of collagen type I (CTX-1) and type II (CTX-II) degradation, reflecting bone and cartilage breakdown, appear to predict long term radiographic progression in chronic persistent arthritis. OBJECTIVE: To analyse longitudinally whether changes in arthritis severity are linked to immediate changes in the level of CTX-I and CTX-II degradation. METHODS: CTX-I and CTX-II were measured in urine samples from 105 patients with early rheumatoid arthritis who had participated in the COBRA trial at baseline and at 3, 6, 9, and 12 months after the start of treatment. The course of the biomarkers over time was compared with the course of ESR, swollen and tender joint counts, and 28 joint disease activity score (DAS28), measured at the same time points, with adjustment for rheumatoid factor, treatment, and baseline radiographic damage, by generalised estimating equations (GEE) with first order autoregression. RESULTS: GEE showed that CTX-I was longitudinally associated with DAS28, but not with ESR, swollen joint count, or tender joint count. CTX-II, however, was longitudinally associated with ESR, swollen joint count and DAS28, but not with tender joint count. The longitudinal association implies that an increase in the extent of arthritis is immediately followed by an increase in collagen type II degradation, and to a lesser extent collagen type I degradation. CONCLUSIONS: Cartilage degradation as measured by CTX-II and to a lesser extent bone degradation as measured by CTX-I closely follows indices of arthritis. Clinically perceptible arthritis is responsible for immediate damage, which will become visible on plain x rays only much later.

Welsing PM, Landewé RB, van Riel PL, Boers M, van Gestel AM, van der Linden S, Swinkels HL, van der Heijde DM. · University Medical Center Nijmegen, Nijmegen, The Netherlands. · Arthritis Rheum. · Pubmed #15248205 links to  free full text

Abstract: OBJECTIVE: Radiologic progression in rheumatoid arthritis (RA) is considered the consequence of persistent inflammatory activity. To determine whether a change in disease activity is related to a change in radiologic progression in individual patients, we investigated the longitudinal relationship between inflammatory disease activity and subsequent radiologic progression. METHODS: The databases of the University Medical Center Nijmegen (UMCN) cohort and the Maastricht Combination Therapy in RA (COBRA) followup study cohort were analyzed. The UMCN cohort included 185 patients with early RA who were followed up for up to 9 years. Patients were assessed every 3 months for disease activity and every 3 years for radiologic damage. The COBRA cohort included 152 patients with early RA who were followed up for up to 6 years. Patients were assessed at least every year for disease activity and every 12 months for radiologic damage. Disease activity was assessed with the Disease Activity Score (DAS) (original DAS in the UMCN cohort, DAS28 in the COBRA cohort). Radiologic damage was measured by the Sharp/van der Heijde score in both cohorts. Data were analyzed with longitudinal regression analysis (generalized estimating equations [GEE]), using autoregression for longitudinal associations and radiologic damage as the dependent variable. Time, time(2) baseline predictors for radiologic progression and their interactions with time, as well as DAS/DAS28 (actual values or interval means and interval SDs of the means) were subsequently modeled as explanatory variables. RESULTS: Data analyzed by GEE showed a decrease in radiologic progression over time (regression coefficient for time(2) -1.0 [95% confidence interval -1.4, -0.6] in the UMCN cohort and -0.4 [95% confidence interval -0.8, 0.0] in the COBRA cohort). After adjustment for time effects and baseline predictors of radiologic progression and their interactions with time, a positive longitudinal relationship was indicated by autoregressive GEE between the mean interval DAS and radiologic progression in the UMCN cohort (regression coefficient 5.4 [95% confidence interval 2.1, 8.6]), and between the DAS28 and radiologic progression in the COBRA cohort (regression coefficient 1.4 [95% confidence interval 0.8, 2.0]). In the UMCN cohort, the SD of the mean interval DAS was independently longitudinally related to the radiologic progression over the same periods (regression coefficient 20.2 [95% confidence interval 7.2, 33.3]). In both cohorts, the longitudinal relationships between (fluctuations in) disease activity and radiologic progression were found selectively in rheumatoid factor (RF)-positive patients. CONCLUSION: Radiologic progression is not linear in individual patients. Fluctuations in disease activity are directly related to changes in radiologic progression, which supports the hypothesis that disease activity causes radiologic damage. This relationship might only exist in RF-positive patients.

Verburg RJ, Sont JK, Vliet Vlieland TP, Landewé RB, Boers M, Kievit J, van Laar JM. · Department of Rheumatology and Medical Decision Making, Leiden University Medical Center, The Netherlands. · J Rheumatol. · Pubmed #11327241 No free full text.

Abstract: OBJECTIVE: To evaluate the effect of high dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) in comparison to conventional pharmacological therapy in the treatment of patients with refractory, progressively erosive rheumatoid arthritis (RA). METHODS: Decision analysis using a Markov model with a 5.5 year time horizon. Probabilities of transition towards 5 different health states, ranging from 70% improvement to death, were derived from published case reports, patient series, and expert panels. Quality of life (QOL) estimates were obtained from 2 RA clinical trials. Patients were hypothetical cohorts of 50-year-old female patients with progressively erosive, active RA, who failed treatment with methotrexate, combination therapy, and tumor necrosis factor blocking agents. Interventions were HDC + ASCT versus conventional pharmacological treatment with a (combination) therapy of disease modifying antirheumatic drugs. As main outcome measures, we included the number of quality adjusted life years (QALY) after HDC + ASCT compared to conventional therapy. Sensitivity analysis was performed to investigate the influence of treatment related mortality (TRM) and the influence of QOL during HDC + ASCT, and to assess the minimal desired effectiveness of HDC + ASCT for a given TRM of 1% and 10%. RESULTS: HDC + ASCT and conventional pharmacological treatment were equally effective in the base-case analysis (3.48 vs 3.46 QALY). A TRM of less than 3.3% favored HDC + ASCT as the preferred treatment. The analysis showed that when TRM was set at 1%, a relatively short period of efficacy was sufficient to remain the preferred strategy, whereas a TRM of 10% would require a sustained response for several years. CONCLUSION: This model predicted equally favorable effects of HDC + ASCT and conventional therapy in the treatment of refractory RA in the base-case. The minor differences in terms of QALY seem to indicate that clinical decision making should be guided by patient preferences. However, better clinical efficacy might be achieved by adaptation of the treatment regimen of HDC + ASCT and patient selection. The model supports the need for randomized clinical trials and may contribute to an optimal study design.

van den Borne BE, Landewé RB, Goei The HS, Breedveld FC, Dijkmans BA. · Department of Rheumatology, Leiden University Medical Centre, The Netherlands. · Rheumatology (Oxford). · Pubmed #10325664 links to  free full text

Abstract: OBJECTIVES: To investigate (1) whether the increase in serum creatinine observed during cyclosporin A (CsA) therapy was reversible in a group of patients with rheumatoid arthritis (RA) treated before the current guidelines for safe use in RA were developed and (2) whether the application of these guidelines prevents serum creatinine increases in the long term. PATIENTS AND METHODS: Eighty-three RA patients who had started low-dose CsA therapy between September 1990 and October 1992, and who were treated according to guidelines that allowed a 50% rise in serum creatinine, were tested for serum creatinine levels in December 1995 if they had discontinued CsA for at least 3 months. Predictors for irreversibility of renal function were determined by using multiple regression analysis. RESULTS: The mean level of serum creatinine gradually increased from 69+/-14 (mean+/-S.D.) micromol/l when starting CsA therapy to 88+/-23 micromol/l (28% above baseline) at the moment of CsA discontinuation, and had decreased to 80+/-17 micromol/l (16% above baseline) at follow-up, 35+/-14 months after drug discontinuation. During CsA therapy, the mean level of serum creatinine had increased to 82+/-19 micromol/l (26% above baseline) at 6 months and to 87+/-22 micromol/1 (39% above baseline) at 42 months. The mean CsA dose had decreased from 3.1+/-0.9 mg/kg/day at 6 months to 1.9+/-0.8 mg/kg/day at 42 months. The absolute number of months that serum creatinine levels were > 30% above baseline was an independent predictor for a persistent increase of the serum creatinine after CsA discontinuation. More than 2 months with a serum creatinine increase of > or = 30% resulted in a higher percentage irreversible increase than for less than 2 months with a > or = 30% increase: 27 and 6%, respectively (P < 0.0001). CONCLUSION: Long-term low-dose CsA administration in RA patients was associated with an increase in serum creatinine which was partially irreversible after drug discontinuation. The increase in serum creatinine was completely reversible in the patient group that was treated according to the current guidelines for safe use of CsA.

Landewé RB, Breedveld FC, Dijkmans BA. · No affiliation provided · Lancet. · Pubmed #12384009 No free full text.

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Landewé RB, van den Borne BE, Breedveld FC, Dijkmans BA. · No affiliation provided · Lancet. · Pubmed #10821370 No free full text.

Abstract: Methotrexate, an antirheumatic drug that may increase serum homocysteine, significantly increases mortality in patients with rheumatoid arthritis and cardiovascular comorbidity.