Rheumatoid Arthritis: Lems WF

van Dieten HE, Korthals-de Bos IB, van Tulder MW, Lems WF, Dijkmans BA, Boers M. · Department of Clinical Epidemiology and Biostatistics, Vrije Universiteit, Van de Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #11005773 links to  free full text

Abstract: A systematic review on the cost effectiveness of prophylactic treatments of non-steroidal anti-inflammatory drug (NSAID) induced gastropathy in patients with osteoarthritis or rheumatoid arthritis was conducted. Two reviewers conducted the literature search and the review. Both full and partial economic evaluations published in English, Dutch, or German were included. The criteria list published in the textbook of Drummond was used to determine the quality of the economic evaluations. The methodological quality of three randomised controlled trials (RCTs) in which the economic evaluations obtained probability estimates of NSAID induced gastropathy and adverse events was assessed by a list of internal validity criteria. The conclusions were based on a rating system consisting of four levels of evidence. Ten economic evaluations were included; three were based on RCTs. All evaluations studied misoprostol as prophylactic treatment: in one evaluation misoprostol was studied as a fixed component in a combination with diclofenac (Arthrotec). All economic evaluations comprised analytical studies containing a decision tree. The three trials were of high methodological quality. Nine economic evaluations were considered high quality and one economic evaluation was considered of low methodological quality. There is strong evidence (level "A") that the use of misoprostol for the prevention of NSAID induced gastropathy is cost effective, and limited evidence (level "C") that the use of Arthrotec is cost effective. Although the levels of evidence used in this review are arbitrary, it is believed that a qualitative analysis is useful: quantitative analyses in this field are hampered by the heterogeneity of economic evaluations. Existing criteria to evaluate the methodological quality of economic evaluations may need refinement for use in systematic reviews.

Nurmohamed MT, Lems WF, Dijkmans BA. · Department of Rheumatology, Slotervaart Hospital and Jan van Breemen Institute, Amsterdam, the Netherlands. · Ann Rheum Dis. · Pubmed #10381480 links to  free full text

This publication has no abstract.

van Tuyl LH, Lems WF, Voskuyl AE, Kerstens PJ, Garnero P, Dijkmans BA, Boers M. · Department of Clinical Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #18625629 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and feasibility of an intensive combination treatment in early rheumatoid arthritis (RA) combined with monitoring both disease activity and cartilage degradation. METHODS: In a pilot trial, 21 patients with active early RA (mean DAS28 5.3; mean disease duration 3 months) were treated with COBRA treatment comprising sulfasalazine, methotrexate and high-dose step-down prednisolone, intensified by adding hydroxychloroquine and continued low-dose prednisolone. In addition, based on measurements of disease activity or a marker of cartilage degradation (CTX-II), treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks; and with infliximab after 21 weeks. RESULTS: Nineteen of 21 patients (90%) were in remission (DAS28 <2.6) after 40 weeks (8 weeks, 57%; 21 weeks, 76%). American College of Rheumatology (ACR) criteria, ACR20, 50, 70 and 90 improvements rates were 100%, 95%, 71% and 43% respectively. CTX-II excretion decreased by mean (SD) 347(292) ng/mmol creatinine, but only 50% of patients reduced their CTX-II excretion below the cut-off point. The two monitoring groups showed no significant difference in remission according to DAS score or CTX-II excretion, despite a trend towards more intensive treatment in the CTX-II group. Treatment intensification was feasible according to protocol. CONCLUSIONS: This small pilot study suggests that intensified and tightly controlled COBRA treatment is uniquely effective in early RA. TRIAL REGISTRATION NUMBER: ISRCTN96372677.

Vis M, Havaardsholm EA, Haugeberg G, Uhlig T, Voskuyl AE, van de Stadt RJ, Dijkmans BA, Woolf AD, Kvien TK, Lems WF. · Department of Rheumatology, VU University Medical Centre, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #16606653 No free full text.

Abstract: OBJECTIVES: To examine whether treatment with anti-tumour necrosis factor (TNF) alpha prevents loss of bone mineral density (BMD) at the spine and hip (generalised) and in the hands (local) of patients with rheumatoid arthritis, and to study the changes in markers of bone metabolism, including receptor activator of the NFkappaB ligand (RANKL) and osteoprotegerin (OPG), during anti-TNF treatment. PATIENTS AND METHODS: 102 patients with active rheumatoid arthritis, who were treated with infliximab during 1 year, were included in this open cohort study. The BMD of the spine and hip (dual x ray absorptiometry) and hands dual x ray radiogrammetry was measured before the start of treatment and after 1 year. Changes in osteocalcin formation, beta-isomerised carboxy terminal telopeptide of type 1 collagen (beta-CTx, resorption), RANKL and OPG were determined at 0, 14, 30 and 46 weeks. RESULTS: The BMD of the spine and hip was unchanged during treatment with infliximab, whereas BMD of the hand decreased significantly by 0.8% (p<0.01). The BMD of the hip in patients with a good European League Against Rheumatism response showed a favourable change compared with patients not achieving such a response. Serum beta-CTx and RANKL were both considerably decreased compared with baseline at all time points. The decrease in beta-CTx was associated with the decrease in Disease Activity Score of 28 joints and C reactive protein during the 0-14 weeks interval. CONCLUSION: In patients with rheumatoid arthritis treated with infliximab, spine and hip bone loss is arrested, whereas metacarpal cortical hand bone loss is not stopped. The outcome of the study also supports a relationship between clinical response, in terms of reduced inflammatory activity, and changes in bone loss of the spine, hip and hands.

de Jong Z, Munneke M, Zwinderman AH, Kroon HM, Ronday KH, Lems WF, Dijkmans BA, Breedveld FC, Vliet Vlieland TP, Hazes JM, Huizinga TW. · Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #15479889 links to  free full text

Abstract: OBJECTIVE: To investigate the effect of long term high intensity weightbearing exercises on radiological damage of the joints of the hands and feet in patients with rheumatoid arthritis (RA). METHODS: Data of the 281 completers of a 2 year randomised controlled trial comparing the effects of usual care physical therapy (UC) with high intensity weightbearing exercises were analysed for the rate of radiological joint damage (Larsen score) of the hands and feet. Potential determinants of outcome were defined: disease activity, use of drugs, change in physical capacity and in bone mineral density, and attendance rate at exercise sessions. RESULTS: After 2 years, the 136 participants in high intensity weightbearing exercises developed significantly less radiological damage than the 145 participants in UC. The mean (SD) increase in damage was 3.5 (7.9) in the exercise group and 5.7 (10.2) in the UC group, p = 0.045. Separate analysis of the damage to the hands and feet suggests that this difference in rate of increase of damage is more pronounced in the joints of the feet than in the hands. The rate of damage was independently associated with less disease activity, less frequent use of glucocorticoids, and with an improvement in aerobic fitness. CONCLUSION: The progression of radiological joint damage of the hands and feet in patients with RA is not increased by long term high intensity weightbearing exercises. These exercises may have a protective effect on the joints of the feet.

Cremers SC, Lodder MC, Den Hartigh J, Vermeij P, Van Pelt P, Lems WF, Papapoulos SE, Dijkmans BA. · Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. · J Rheumatol. · Pubmed #15338492 No free full text.

Abstract: OBJECTIVE: Bisphosphonates (BP) inhibit osteoclast-mediated bone resorption, and have been reported to decrease the rate of cartilage degradation. The anti-resorptive effect of BP is determined by the amount of BP retained by the skeleton. In rheumatoid arthritis (RA) the uptake is not confined only to the skeleton, but BP is also retained in joints, which could have implications for dose regimens. We investigated the whole body retention (WBR) of pamidronate and its relationship to bone resorption and cartilage degradation in patients with active RA. METHODS: Twenty-six patients received placebo, 45 mg, or 90 mg intravenous pamidronate. Serum and urine samples were collected before and for 12 days after drug administration. Rate of bone resorption was assessed by the biochemical markers: serum carboxy terminal cross-linked telopeptide of type I collagen, urinary carboxy terminal cross-linked telopeptide of type I collagen normalized to creatinine and urinary amino-terminal telopeptide of type I collagen normalized to creatinine; and rate of cartilage degradation by urinary carboxy terminal telopeptide of type II collagen normalized to creatinine. WBR was derived from urinary excretion of pamidronate data. RESULTS: Pamidronate induced a rapid and sustained decrease in the level of biochemical markers of bone resorption and cartilage degradation. The mean WBR of pamidronate was 69% of the administered dose, and showed a remarkably wide range (41-96%). The decrease in rate of bone resorption, but also rate of cartilage degradation appeared to be related to the WBR of pamidronate. CONCLUSION: This is the first study in which the effect of BP treatment has been studied in relation to the amount of BP retained by the body in patients with active RA. The total amount of BP retained by the body shows a remarkably wide range and is comparable with literature on patients with osteoporosis. The apparent relationships between the amount of BP retained by the body and the effect could have implications for therapeutic regimens in patients with RA.

de Jong Z, Munneke M, Lems WF, Zwinderman AH, Kroon HM, Pauwels EK, Jansen A, Ronday KH, Dijkmans BA, Breedveld FC, Vliet Vlieland TP, Hazes JM. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #15077288 links to  free full text

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) are more at risk for the development of osteoporosis and osteoporotic fractures than are their healthy peers. In this randomized, controlled, multicenter trial, the effectiveness of a 2-year high-intensity weight-bearing exercise program (the Rheumatoid-Arthritis-Patients-In-Training [RAPIT] program) on bone mineral density (BMD) was compared with usual care physical therapy, and the exercise modalities associated with changes in BMD were determined. METHODS: Three hundred nine patients with RA were assigned to an intervention group, either the RAPIT program or usual care physical therapy. The primary end points were BMD of the hip and spine. The exercise modalities examined were aerobic fitness, muscle strength, and, as a surrogate for those effects not directly measured by the RAPIT program, attendance rate. RESULTS: The data on the 136 RAPIT participants and 145 usual care participants who completed the study were analyzed. The mean rate of decrease in hip BMD, but not in lumbar spine BMD, was smaller in patients participating in the RAPIT program when compared with that in the usual care group, with a mean decrease of 1.6% (95% confidence interval [95% CI] 0.8-2.5) over the first year and 0.5% (95% CI 1.1-2.0) over the second year. The change in hip BMD was significantly and independently associated with changes in both muscle strength (multivariate odds ratio [OR] 1.75, 95% CI 1.07-2.86) and aerobic fitness (OR 1.79, 95% CI 1.10-2.90), but not with the attendance rate (OR 1.00, 95% CI 0.99-1.00). CONCLUSION: A long-term high-intensity weight-bearing exercise program for RA patients is effective in slowing down the loss of BMD at the hip. The exercise modalities associated with this effect are muscle strength and aerobic fitness.

Lodder MC, Van Pelt PA, Lems WF, Kostense PJ, Koks CH, Dijkmans BA. · No affiliation provided · J Rheumatol. · Pubmed #12966622 links to  free full text

This publication has no abstract.

de Nijs RN, Jacobs JW, Bijlsma JW, Lems WF, Laan RF, Houben HH, ter Borg EJ, Huisman AM, Bruyn GA, van Oijen PL, Westgeest AA, Algra A, Hofman DM, Anonymous00207. · Department of Rheumatology and Clinical Immunology, F02.127, University Medical Center, PO Box 85500, 3508 GA Utrecht, The Netherlands. · Rheumatology (Oxford). · Pubmed #11752508 links to  free full text

Abstract: OBJECTIVE: This study was designed to determine whether the prevalence of vertebral deformities in patients with rheumatoid arthritis (RA) treated with corticosteroids (Cs) is higher than in RA patients not receiving Cs therapy. PATIENTS AND METHODS: This multicentre cross-sectional study included 205 patients with RA who were receiving Cs orally on a daily basis and 205 patients with RA who did not receive Cs, matched for sex and age. Vertebral deformities were scored according to the Kleerekoper method. RESULTS: Vertebral deformities were found in 52 (25%) patients on Cs and in 26 (13%) patients not on Cs. Sixteen (8%) patients in the group on Cs had experienced clinical manifestations of an acute vertebral fracture in the past vs only three patients (1.5%) among those not on Cs. The use of Cs tended to increase the risk of developing a vertebral deformity [adjusted odds ratio (OR) 1.56, 95% confidence interval (CI) 0.81-2.99] and symptomatic vertebral fracture (adjusted OR 1.42, 95% CI 0.24-8.32). Each 1-mg increase in the current daily Cs dose increased the risk of a vertebral deformity (adjusted OR 1.05, 95% CI 0.98-1.13) and of a symptomatic vertebral fracture (adjusted OR 1.05, 95% CI 0.89-1.24). CONCLUSION: There is a higher prevalence of vertebral deformities and clinical manifestations of vertebral fractures in patients on Cs than in those not on Cs. Our data indicate that the use of Cs and each 1-mg increase in the current daily Cs dose may increase the risk of development of a vertebral deformity and symptomatic vertebral fracture in patients with RA.

van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Kerstens PJ, Dijkmans BA, Boers M. · Department of Rheumatology, EMGO Institute, and the Department of Epidemiology and Biostatistics, VU University Medical Center, 1081 HV Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #19487259 No free full text.

Abstract: OBJECTIVE: COBRA combination therapy is well known and has uncontested efficacy in the treatment of rheumatoid arthritis (RA). However, it is infrequently applied in Dutch clinical practice. Based on qualitative research on opinions of physicians and patients towards COBRA therapy, our study describes the development and pilot testing of an implementation package to facilitate prescription and use of COBRA therapy in early RA. METHODS: The implementation package was developed to address specific barriers towards prescription of COBRA therapy and comprised informational handouts (an information booklet and leaflet for patients), preprinted prescription orders, and background information on COBRA therapy for the rheumatologists. Twenty-two rheumatologists agreed to participate, including the arthritis nurse where available. Rheumatologists, nurses, and patients were asked to record their experience. All Dutch arthritis nurses were invited to an educational session on COBRA therapy. RESULTS: Sixteen rheumatologists accompanied by 10 arthritis nurses used the material to prescribe COBRA therapy to a total of 27 patients. Rheumatologists and nurses both gave high marks to the supplied materials. Eighty-eight percent of rheumatologists reported that the material sped up the prescription process, and 65% indicated they would prescribe COBRA therapy more frequently if these materials were available routinely. Patients expressed great satisfaction with the information handouts, rating it 2.8 (standard deviation 0.5) on a scale of -3 (very negative) to +3 (very positive). Most patients (89%) planned to keep the information booklet as a reference and 70% used it as a tool to remember the correct intake of medication. The attitude and perceived capability of nurses towards the guidance of patients with RA receiving COBRA therapy was improved through a brief educational intervention. CONCLUSION: Rheumatologists, patients, and arthritis nurses all highly appreciated the implementation package and indicated that its availability would increase uptake of COBRA therapy.

van der Heijden JW, Oerlemans R, Lems WF, Scheper RJ, Dijkmans BA, Jansen G. · Departments of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands. · Clin Exp Rheumatol. · Pubmed #19327235 No free full text.

Abstract: OBJECTIVE: The proteasome is a multicatalytic proteinase complex regulating the intracellular breakdown of many proteins, including those mediating the activation of pro-inflammatory signaling pathways (e.g. NFkappaB), cell proliferation and survival. Conceptually, proteasome inhibitors may therefore elicit potential anti-inflammatory properties by inhibiting these processes and thereby impair the cellular release of pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-alpha) in RA patients. METHODS: Whole-blood from 19 RA patients (including methotrexate-responsive and non-responsive patients) and 7 healthy volunteers was incubated ex-vivo with the proteasome inhibitor bortezomib after T-cell stimulation with alphaCD3/CD28. Inhibition of cytokine production by bortezomib was measured after 24 and 72 hours by ELISA. Effects of bortezomib on apoptosis and T-cell activation (CD25 expression) were measured by FACS-analysis. RESULTS: Bortezomib proved to be a rapid (<24 hour) and potent inhibitor of the release of several NFkappaB-inducible cytokines (including TNF-alpha, IL-1Beta, IL-6 and IL-10) by activated T-cells from healthy volunteers and RA patients, regardless of their clinical responsiveness to methotrexate. Median concentrations of bortezomib required to inhibit TNF-alpha production by 50% (mIC-50) were 12 nM (range: 8-50 nM) for healthy volunteers and 46 nM (range: 18-60 nM) for RA patients. A reduction of T cell activation and a marked induction of T-cell apoptosis were revealed as late effects after bortezomib incubations beyond 24 hours. CONCLUSION: Proteasome inhibitors represented by bortezomib may elicit potential anti-inflammatory properties that deserve further exploration in experimental therapies for RA.

van der Heijden JW, Oerlemans R, Tak PP, Assaraf YG, Kraan MC, Scheffer GL, van der Laken CJ, Lems WF, Scheper RJ, Dijkmans BA, Jansen G. · VU University Medical Center, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #19248091 No free full text.

Abstract: OBJECTIVE: To determine whether multidrug-resistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF). METHODS: Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n = 17) or LEF (n = 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance-associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed. RESULTS: BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P = 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients. CONCLUSION: These findings show that the drug resistance-related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.

van der Heijden JW, Oerlemans R, Dijkmans BA, Qi H, van der Laken CJ, Lems WF, Jackman AL, Kraan MC, Tak PP, Ratnam M, Jansen G. · VU University Medical Center Amsterdam, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #19116913 No free full text.

Abstract: OBJECTIVE: To determine the expression of folate receptor beta (FRbeta) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FRbeta than methotrexate (MTX). METHODS: Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FRbeta protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FRbeta messenger RNA (mRNA) levels were determined by reverse transcription-polymerase chain reaction analysis. Binding affinities of FRbeta for folate antagonists were assessed by competition experiments for 3H-folic acid binding on FRbeta-transfected cells. Efficacy of FRbeta-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FRbeta-transfected cells. RESULTS: Immunohistochemical staining of RA synovial tissue showed high expression of FRbeta on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T cell areas or in control synovial tissue. Consistently, FRbeta mRNA levels were highest in synovial tissue extracts and RA monocyte-derived macrophages, but low in peripheral blood T cells and monocytes. Screening of 10 new-generation folate antagonists revealed 4 compounds for which FRbeta had a high binding affinity (20-77-fold higher than for MTX). One of these, the thymidylate synthase inhibitor BCG 945, displayed selective targeting against FRbeta-transfected cells. CONCLUSION: Abundant FRbeta expression on activated macrophages in synovial tissue from RA patients deserves further exploration for selective therapeutic interventions with high-affinity-binding folate antagonists, of which BCG 945 may be a prototypical representative.

van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Kerstens PJ, Dijkmans BA, Boers M. · Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. · Rheumatology (Oxford). · Pubmed #18710900 No free full text.

Abstract: OBJECTIVE: The COBRA therapy (combination therapy in early rheumatoid arthritis) has proven to be an effective treatment for early RA, but is rarely prescribed. A survey showed reluctance of Dutch reumatologists to apply COBRA therapy in early RA. The present qualitative study was carried out to further explore the reservation of Dutch rheumatologists towards prescribing COBRA therapy and include patients' view on (components of) COBRA therapy. METHODS: Two focus group discussions were undertaken for rheumatologists (n(1) = 8, n(2) = 7) and two for patients (n(1) = 4, n(2) = 8). In addition, in-depth interviews were conducted with 11 rheumatologists and 1 patient. These were taped and transcribed. Two independent researchers identified themes and these were discussed with three other researchers. RESULTS: Rheumatologists were positive concerning effectiveness of COBRA therapy, but highly concerned about their patients' possible negative reaction to the large amount of pills to be prescribed. In addition, rheumatologists perceived lack of time explaining and prescribing COBRA therapy and felt uncomfortable prescribing high doses of prednisolone. Patients were positive about an aggressive combination therapy such as COBRA, and they had no qualms taking many pills if this could improve their prognosis. Patients associated prednisolone with negative side-effects, but were also aware of the benefits and the need of prednisolone in rough times. A decrease in the amount of pills after intensive treatment was highly appreciated. CONCLUSION: Rheumatologists and patients differed in opinion about the use of COBRA therapy. Rheumatologists were particularly concerned about their patients' reaction towards them prescribing such an aggressive and complex therapy, whereas patients, while aware of the side-effects, were most interested in suppressing illness symptoms and reducing future damage regardless of the amount of pills.

Bos WH, Bartelds GM, Vis M, van der Horst AR, Wolbink GJ, van de Stadt RJ, van Schaardenburg D, Dijkmans BA, Lems WF, Nurmohamed MT, Aarden L, Hamann D. · Sanquin Research, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #18445623 No free full text.

Abstract: OBJECTIVE: To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). METHODS: IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated fibrinogen (ACF) and IgG1 : IgG4 ACPA ratios were calculated. A pilot study was performed in 28 ACF-positive patients treated with infliximab for one year. Confirmation of the results was obtained using a cohort of 180 consecutive patients treated with adalimumab for 28 weeks. RESULTS: The median reduction in ACF levels was 31% for total IgG, 29% for IgG1, 40% for IgG4 and 22% for the IgG4 : IgG1 ACF ratio in the infliximab cohort. In adalimumab-treated patients, ACF levels declined 14% for total IgG and IgG1, and 36% for IgG4 ACF; the IgG4 : IgG1 ratio was reduced by 24% (all percentage values p<0.05). The decrease in antibody levels was correlated with the clinical response; European League Against Rheumatism good responders had the greatest decline in antibody levels and this effect was most pronounced for IgG4 (48% reduction). The IgG4 : IgG1 ACF ratio preferentially decreased in patients with adequate therapeutic adalimumab levels. CONCLUSION: ACPA subclass distribution is modulated by effective anti-inflammatory treatment. The preferential decline of IgG4 ACPA, reflected by the decreased IgG4 : IgG1 ratio, suggests a beneficial effect of anti-TNF treatment on chronic antigenic stimulation by citrullinated proteins. This effect may be directly anti-TNF mediated or the result of effective dampening of the inflammation in the rheumatoid joint.

de Jong Z, Munneke M, Vilim V, Zwinderman AH, Kroon HM, Ronday HK, Lems WF, Dijkmans BA, Breedveld FC, Vliet Vlieland TP, Hazes JM, Degroot J. · Department of Rheumatology C4-R, Leiden University Medical Center, Post-box 9600, 2300 RC Leiden, The Netherlands. ; · Rheumatology (Oxford). · Pubmed #18400837 No free full text.

Abstract: OBJECTIVE: To investigate the utility of serum COMP level measurements as a predictor of future damage of the weight-bearing (large) joints in RA patients participating in intensive exercise. METHODS: Data of the 281 completers of a 2-yr randomized controlled trial (Rheumatoid Arthritis Patients In Training; RAPIT) comparing the effects of usual care physical therapy with high-intensity weight-bearing exercises were analysed. The primary outcome variable was defined as the change in radiological joint damage (Larsen score) of the large joints. Potential predictors of outcome were defined: baseline and change in serum level of COMP after 3 months, baseline radiological damage of the large and small joints, number of months on glucocorticoids, change in disease activity and in physical capacity (aerobic fitness and muscle strength) after 2 yrs, and participation in the exercise group. RESULTS: In cross-sectional evaluation of baseline data, we found strong association between the high serum COMP level and current damage of the large joints. Serum COMP level at baseline, however, was not associated with an increased rate of radiological joint damage after 2 yrs of follow-up. Furthermore, neither interaction between baseline COMP level and participation in exercises, nor change in COMP level after 3 months of exercising were associated with future damage of the large joints. CONCLUSION: Neither baseline serum COMP level nor its individual change after 3 months from start of intensive exercise predict longitudinal progression of damage of the large joints in this population.

Güler-Yüksel M, Allaart CF, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van Groenendael JH, Mallée C, de Bois MH, Breedveld FC, Dijkmans BA, Lems WF. · Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #18375540 No free full text.

Abstract: OBJECTIVES: To evaluate changes in bone mineral density (BMD) in the hands, hip and spine after 1 and 2 years of follow-up, in relation to antirheumatic and antiresorptive therapies and disease and demographic variables in patients with recent-onset rheumatoid arthritis (RA). METHODS: Changes in BMD measured in metacarpals 2-4 by digital x-ray radiogrammetry and in the hip and spine by dual energy x-ray absorptiometry were assessed at baseline and after 1 and 2 years of follow-up in 218 patients with recent-onset RA from the BeSt study, who received one of four treatment strategies: sequential monotherapy (group 1); step-up combination therapy (group 2); initial combination therapy with tapered high-dose prednisone (group 3); or initial combination therapy with infliximab (group 4). RESULTS: After 1 and 2 years, there was significant BMD loss in all locations, with significantly greater BMD loss in the hands than generalised BMD loss in the hip and spine. Initial combination therapy with prednisone or infliximab were associated with less hand BMD loss compared with initial monotherapy after 1 and 2 years (-0.9 and -1.6%, -0.6 and -1.4%, -1.7 and -3.3%, and -2.6 and -3.6% for group 4-1 after 1 and 2 years, overall p = 0.001 and p = 0.014, respectively). Progression in erosions was independently associated with increased BMD loss both in the hands and hip after 1 year. The use of bisphosphonates protected only against generalised BMD loss in the hip and spine. CONCLUSIONS: The association between joint damage progression and both hand and generalised BMD loss in RA suggests common pathways between these processes, with hand BMD loss occurring earlier in the disease course than generalised BMD loss.

Vis M, Bos WH, Wolbink G, Voskuyl AE, Twisk JW, Van de Stadt R, Hamann D, Dijkmans BA, Lems WF. · VU University Medical Center, Sanquin Research, and Jan van Breemen Institute, Amsterdam, The Netherlands. · J Rheumatol. · Pubmed #18322974 No free full text.

Abstract: OBJECTIVE: To investigate the effect of treatment with infliximab on serum levels of rheumatoid factor (IgM-RF), antibodies against cyclic citrullinated peptide (anti-CCP), and antibodies against deiminated human fibrinogen, a specific citrullinated peptide (ACF), and their association with disease activity and disease duration in patients with rheumatoid arthritis (RA). METHODS: The study sample included 62 consecutive patients who were treated with infliximab for at least one year. IgM-RF, anti-CCP, and ACF were measured at 0, 14, 30, and 46 weeks. RESULTS: Patients had a mean age of 54 years and median disease duration of 10 years and were predominantly female (81%). At baseline 63%, 77%, and 82% of patients were positive for IgM-RF, anti-CCP, and ACF, respectively. In terms of percentages, the levels of IgM-RF were reduced by 64% at 46 weeks, while anti-CCP and ACF levels were reduced by roughly 25%. The decrease in serum levels of these autoantibodies was not associated with the decrease in disease activity. The change in ACF was significantly related to disease duration, while the changes in IgM-RF or anti-CCP were not. CONCLUSION: In a cohort of patients with RA who responded to infliximab therapy, all autoantibodies decreased significantly, but IgM-RF showed a larger decrease than anti-CCP or ACF. These changes in levels of autoantibodies are not directly related to the change in disease activity. Early in the disease, ACF levels were best influenced by treatment with infliximab.

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #18240203 links to  free full text

Abstract: OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients. METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4). RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups. CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

Wijbrandts CA, Dijkgraaf MG, Kraan MC, Vinkenoog M, Smeets TJ, Dinant H, Vos K, Lems WF, Wolbink GJ, Sijpkens D, Dijkmans BA, Tak PP. · Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #18055470 links to  free full text

Abstract: OBJECTIVE: To determine whether the heterogeneous clinical response to tumour necrosis factor (TNF)alpha blocking therapy in rheumatoid arthritis (RA) can be predicted by TNFalpha expression in the synovium before initiation of treatment. METHODS: Prior to initiation of infliximab treatment, arthroscopic synovial tissue biopsies were obtained from 143 patients with active RA. At week 16, clinical response was evaluated using the 28-joint Disease Activity Score (DAS28). Immunohistochemistry was used to analyse the cell infiltrate as well as the expression of various cytokines, adhesion molecules and growth factors. Stained sections were evaluated by digital image analysis. Student t tests were used to compare responders (decrease in DAS28 > or =1.2) with non-responders (decrease in DAS28 <1.2) and multivariable regression was used to identify the independent predictors of clinical response. RESULTS: Synovial tissue analysis confirmed our hypothesis that the baseline level of TNFalpha expression is a significant predictor of response to TNFalpha blocking therapy. TNFalpha expression in the intimal lining layer and synovial sublining were significantly higher in responders than in non-responders (p = 0.047 and p = 0.008, respectively). The numbers of macrophages, macrophage subsets and T cells (all able to produce TNFalpha) were also significantly higher in responders than in non-responders. The expression of interleukin (IL)1beta, IL6, IL18, IL10, E-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was not associated with response to anti-TNFalpha treatment. CONCLUSION: The effects of TNFalpha blockade are in part dependent on synovial TNFalpha expression and infiltration by TNFalpha producing inflammatory cells. Clinical response cannot be predicted completely, indicating involvement of other as yet unknown mechanisms.

Swaneveld FH, van Vugt RM, de Boer JP, Dijkmans BA, Lems WF. · Department of Rheumatology, Slotervaart Hospital, Amsterdam, The Netherlands. · Clin Rheumatol. · Pubmed #17660934 links to  free full text

Abstract: Rituximab is a chimeric human-mouse anti-CD20 monoclonal antibody, which is used in the treatment of both B-cell lymphomas and rheumatic diseases. We describe a case of a previously healthy 57-year-old man developing arthritis while being treated with rituximab-CHOP chemotherapy (R-CHOP) for a non-Hodgkin lymphoma. The remittant arthritis developed at successively shorter time-intervals after R-CHOP administration and only improved after rituximab was removed from the chemotherapy schedule, suggesting a rituximab-related phenomenon, as extensive diagnostic testing ruled out any other diagnosis.

Güler-Yüksel M, Bijsterbosch J, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Hulsmans HM, de Beus WM, Han KH, Breedveld FC, Dijkmans BA, Allaart CF, Lems WF. · Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #17644545 No free full text.

Abstract: OBJECTIVES: We examined the effects of four different treatment strategies on bone mineral density (BMD) in patients with recently diagnosed, active rheumatoid arthritis (RA) and the influence of disease-related and demographic factors on BMD loss after 1 year of follow-up in the BeSt trial. METHODS: BMD measurements of the lumbar spine and total hip were performed in 342 patients with recent onset RA at baseline and after 1 year. Multivariable regression analyses were performed to determine independent associations between disease and demographic parameters and BMD loss after 1 year. RESULTS: Median BMD loss after 1 year was 0.8% and 1.0% of baseline in the spine and the hip, respectively. No significant differences between the treatment groups, including corticosteroids and the anti-tumour necrosis factor-alpha infliximab, were observed with regard to BMD loss after 1 year of treatment. Joint damage at baseline and joint damage progression according to the Sharp-van der Heijde score were independently associated with more BMD loss after 1 year. The use of bisphosphonates independently protected against BMD loss. CONCLUSIONS: After 1 year of follow-up in the BeSt study, we did not find differences in BMD loss between the four treatment strategies, including high doses of corticosteroids and anti-tumour necrosis factor-alpha. Joint damage and joint damage progression are associated with high BMD loss, which emphasises that BMD loss and erosive RA have common pathways in their pathogenesis.

Steen KS, Nurmohamed MT, Visman I, Heijerman M, Boers M, Dijkmans BA, Lems WF. · Department of Rheumatology, VU University Medical Center, Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #17604285 No free full text.

Abstract: BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) frequently cause gastrointestinal (GI) ulcers and complications of ulcers. In 1997 in Amsterdam, the incidence of symptomatic GI events was 2.1% (95% CI 1.0-3.1) in patients with rheumatoid arthritis (RA). We conducted a new prospective, observational study on the symptomatic GI events in our outpatient clinics, and compared the data to a previous study conducted by our group. Over the same time period, a decline of GI events over the last decade was reported for US patients. METHODS: In 2003, three questionnaires were sent to all RA patients in Amsterdam at 4-month intervals, addressing medication use, dyspepsia, and symptomatic GI events in the previous 4 months. RESULTS: The incidence of GI events in high-risk patients, defined as age >or=60 and/or history of GI event) using NSAIDs or cyclo-oxygenase 2 specific inhibitors (COXIBs) was 1.2% (95% CI 0.2-2.3), which appears to be substantially lower than the 2.1% observed in 1997; however this difference did not reach statistical significance (p = 0.3). In 64% (95% CI 61-68) of the high-risk patients, acid-suppressive drugs (ie, proton pump inhibitors, prostaglandin analogues or high dose H2 antagonists) were used. In 1997 this percentage was significantly lower at 49% (45-52; p<0.001). The compliance to the Dutch guidelines for prevention of NSAID-related gastropathy was almost 75%, with 64% of the patients using acid-suppressive drugs and 11% using COXIBs. CONCLUSION: The present study reveals a decline of NSAID-induced gastrointestinal events, which is similar to the results observed in the US. This is most likely due to a more strict adherence to guidelines for prevention of NSAID gastropathy, and better treatment of rheumatoid arthritis.

Güler-Yüksel M, Bijsterbosch J, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Ronday HK, Peeters AJ, de Jonge-Bok JM, Breedveld FC, Dijkmans BA, Allaart CF, Lems WF. · Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #17456523 No free full text.

Abstract: OBJECTIVES: Osteoporosis is a well-known extra-articular phenomenon in patients with uncontrolled, long-standing rheumatoid arthritis (RA). In the present study, the extent of osteoporosis and reduced bone mineral density (BMD) and the disease-related and demographic factors that are associated with osteoporosis and reduced BMD were examined in patients with recently diagnosed, active RA. METHODS: BMD of the total hip and the lumbar spine was measured using dual-energy x ray absorptiometry in 381 patients with recently diagnosed active RA, who had never been treated with DMARDs or corticosteroids. Osteoporosis was defined as a T score <or=-2.5 SD and reduced BMD as Z score <or=-1 SD. Multivariate logistic regression analyses were performed to detect associations of osteoporosis and reduced BMD with disease activity, functional disability, joint damage (Sharp-van der Heijde score) and demographic factors. RESULTS: Osteoporosis and reduced BMD were found in the spine and/or the hip in 11% and 25%, respectively, of the patients. Longer symptom duration and presence of rheumatoid factor (RF) were the only RA-specific markers for osteoporosis and reduced BMD. Further, postmenopausal status in women, a low body mass index, familial osteoporosis, and, remarkably, male gender, were independently associated with osteoporosis and reduced BMD. CONCLUSION: In patients with recently diagnosed active RA who had never been treated with DMARDs or corticosteroids, BMD seems to be well-preserved and predominantly related to demographic factors. Longer symptom duration and a positive RF, but not higher disease activity or more joint damage, were related to osteoporosis and reduced BMD.

van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Dijkmans BA, Boers M. · Department of Clinical Epidemiology & Biostatistics, VU University Medical Center, PO Box 7057, 1053 MB Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #17392349 No free full text.

Abstract: BACKGROUND: The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial has proved that combination therapy with prednisolone, methotrexate and sulphasalazine is superior to sulphasalazine monotherapy in suppressing disease activity and radiological progression of early rheumatoid arthritis (RA). In addition, 5 years of follow-up proved that COBRA therapy results in sustained reduction of the rate of radiological progression. Despite this evidence, Dutch rheumatologists seem reluctant to prescribe COBRA therapy. OBJECTIVE: To explore the reasons for the reluctance in Dutch rheumatologists to prescribe COBRA therapy. METHODS: A short structured questionnaire based on social-psychological theories of behaviour was sent to all Dutch rheumatologists (n = 230). RESULTS: The response rate was 50%. COBRA therapy was perceived as both effective and safe, but complex to administer. Furthermore, rheumatologists expressed their concern about the large number of pills that had to be taken, the side effects of high-dose prednisolone and the low dose of methotrexate. Although the average attitude towards the COBRA therapy was slightly positive (above the neutral point), the majority of responding rheumatologists had a negative intention (below the neutral point) to prescribe COBRA therapy in the near future. CONCLUSION: The reluctance of Dutch rheumatologists to prescribe effective COBRA therapy may be due to perceptions of complexity of the treatment schedule and negative patient-related consequences of the therapy.