Rheumatoid Arthritis: de Vries-Bouwstra JK

de Vries-Bouwstra JK, Dijkmans BA, Breedveld FC. · Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands. · Rheum Dis Clin North Am. · Pubmed #16287595 No free full text.

Abstract: Treatment of patients with rheumatoid arthritis (RA) with disease-modifying antirheumatic drugs is started immediately after diagnosis, resulting in more effective suppression of disease activity and substantial reduction of joint damage. The development of biologic agents has enabled remission as a realistic therapeutic goal in a greater proportion of patients. The tumor necrosis factor-alpha inhibitors, infliximab, etanercept, and adalimumab, have been studied in numerous randomized clinical trials. These agents can suppress disease activity directly, slow or stop progression of radiologic damage, and prevent further loss of quality of life. Patients treated with tumor necrosis factor-alpha inhibitors show few adverse events, which together with the high clinical effectiveness is favorable for treatment compliance. The exact role of these agents in the treatment of early-stage RA is unknown.

van den Hout WB, Goekoop-Ruiterman YP, Allaart CF, de Vries-Bouwstra JK, Hazes JM, Kerstens PJ, van Zeben D, Hulsmans HM, de Jonge-Bok JM, de Sonnaville PB, Dijkmans BA, Breedveld FC. · Department of Medical Decision Making, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #19248130 No free full text.

Abstract: OBJECTIVE: To evaluate societal costs and quality-adjusted life years (QALYs) of treatment strategies for patients with recent-onset active rheumatoid arthritis (RA). METHODS: Patients (n = 508) were randomly allocated to 1 of 4 treatment strategy groups: sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination therapy with infliximab. For 2 years, patients reported cost and utility measures. RESULTS: Average QALYs (ideally 2.00) for groups 1-4 were 1.29, 1.31, 1.32, and 1.41, respectively, for the British EuroQol (P <or= 0.05 for group 4 versus groups 1-3); 1.41, 1.43, 1.44, and 1.52, respectively, for the Dutch EuroQol (P <or= 0.05 for group 4 versus groups 1-3); and 1.38, 1.38, 1.39, and 1.44, respectively, for the Short Form 6D (P <or= 0.05 for group 4 versus groups 1-3). The Time Trade-Off showed no significant differences. In the primary analysis, using the friction cost method to value productivity, the cost-utility ratio for group 4 against the next best alternative was estimated at euro 130,000 (95% confidence interval euro 27,000, euro 3,000,000) per QALY. Using the human capital method, the value of sustained productivity in group 4 largely compensated for the extra medication costs. CONCLUSION: Initial combination therapy with infliximab for patients with recent-onset active RA resulted in significantly better quality of life than other strategies. Using the friction cost method, costs to achieve this improvement are generally considered too high, and initial combination therapy with prednisone should be preferred. However, depending on the extent to which productivity is valued, infliximab costs could be largely compensated for by savings on productivity. Since patterns of infliximab use had not yet stabilized after 2 years, longer followup may change the economic conclusions.

van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Ewals JA, Han KH, Hazes JM, Kerstens PJ, Peeters AJ, van Zeben D, Breedveld FC, Huizinga TW, Dijkmans BA, Allaart CF. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #19116965 No free full text.

Abstract: OBJECTIVE: To investigate the effectiveness of 4 different treatment strategies for recent-onset rheumatoid arthritis (RA) on 2-year patient-reported outcomes, including functioning and quality of life. METHODS: A total of 508 patients with recent-onset RA were randomly assigned to 1) sequential monotherapy, 2) step-up combination therapy, both starting with methotrexate, 3) initial combination therapy, including a tapered high-dose prednisone, or 4) initial combination therapy with methotrexate and infliximab. Treatment was adjusted every 3 months if the Disease Activity Score (DAS) remained >2.4. The McMaster Toronto Arthritis Patient Preference Disability Questionnaire, the Short Form 36 (SF-36), and scores for pain, global health, and disease activity measured on a 100-mm visual analog scale (VAS) were compared between groups at baseline and every 3 months thereafter for 2 years. RESULTS: After 2 years, all patient-reported outcomes had improved significantly from baseline, irrespective of the treatment strategy. SF-36 subscale scores approached population norms for 3 physical components, and achieved population norms (P > 0.05) for bodily pain and 4 mental components. Improvement in functioning, VAS scores, and physical items of the SF-36 occurred significantly earlier in patients treated with initial combination therapies (all comparisons after 3 months: overall P < 0.001; P < 0.05 for groups 1 and 2 versus groups 3 and 4). CONCLUSION: All 4 DAS-driven treatment strategies resulted in substantial improvements in functional ability, quality of life, and self-assessed VAS scores after 2 years. Initial combination therapy led to significantly faster improvement in all patient-reported measures.

van der Kooij SM, le Cessie S, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van Zeben D, Kerstens PJ, Hazes JM, van Schaardenburg D, Breedveld FC, Dijkmans BA, Allaart CF. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #18930988 No free full text.

Abstract: OBJECTIVES: To compare the clinical and radiological efficacy of initial vs delayed treatment with methotrexate (MTX) and infliximab (IFX) in patients with recent onset rheumatoid arthritis (RA). METHODS: In a post hoc analysis of the BeSt study (for Behandel Stratagieen, Dutch for treatment strategies), 117 patients who started initial MTX+IFX were compared with 67 patients who started MTX+IFX treatment after failing (disease activity score (DAS)>2.4; median delay to IFX: 13 months) on > or =3 traditional DMARDs. If the DAS remained >2.4, the protocol dictated IFX dose increases to 6, 7.5 and 10 mg/kg. In case of a DAS < or =2.4 for > or =6 months, IFX was tapered and finally stopped. We aimed to correct for allocation bias using propensity scores. Functional ability was measured by the Health Assessment Questionnaire (HAQ), radiological progression by Sharp/van der Heijde scoring (SHS). RESULTS: Baseline differences between the initial and delayed groups were no longer significant after propensity score adjustment. At 3 years after baseline, patients treated with initial MTX+IFX experienced more improvement in HAQ over time and were less likely to have SHS progression than patients treated with delayed MTX+IFX (p = 0.034). At 2 years after IFX initiation, more patients in the initial group compared with the delayed group could discontinue IFX after a good response (56% vs 29%, p = 0.008). CONCLUSIONS: The results of this post hoc analysis suggest that using MTX+IFX as initial treatment for patients with recent onset RA is more effective than reserving MTX+IFX for patients who failed on traditional DMARDs, with more HAQ improvement over time, more IFX discontinuation and less progression of joint damage.

van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Güler-Yüksel M, Zwinderman AH, Kerstens PJ, van der Lubbe PA, de Beus WM, Grillet BA, Ronday HK, Huizinga TW, Breedveld FC, Dijkmans BA, Allaart CF. · Leiden University Medical Center, The Netherlands. · Ann Rheum Dis. · Pubmed #18662933 No free full text.

Abstract: OBJECTIVES: To compare the occurrence of drug-free remission, functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis (RA). METHODS: Patients with recent-onset, active RA (n = 508) were randomly assigned to four different treatment strategies: (1) sequential monotherapy; (2) step-up combination therapy; (3) initial combination therapy with prednisone and (4) initial combination therapy with infliximab. Treatment was adjusted based on 3-monthly disease activity score (DAS) assessments, aiming at a DAS < or =2.4. From the third year, patients with a sustained DAS <1.6 discontinued treatment. RESULTS: In total, 43% of patients were in remission (DAS <1.6) at 4 years and 13% were in drug-free remission: 14%, 12%, 8% and 18% of patients in groups 1-4, respectively. The absence of anti-cyclic citrullinated peptide antibodies, male gender and short symptom duration were independently associated with drug-free remission. Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment, without significant differences between the groups. Significant progression of joint damage was observed in 38% and 31% of patients in groups 3 and 4 versus 51% and 54% of patients in groups 1 and 2 (p<0.05, group 4 versus groups 1 and 2, group 3 versus group 2). CONCLUSIONS: In patients with recent-onset active RA, drug-free remission was achieved in up to 18% of patients. DAS-driven treatment maintained clinical and functional improvement, independent of the treatment strategy. Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy.

de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Verpoort KN, Schreuder GM, Ewals JA, Terwiel JP, Ronday HK, Kerstens PJ, Toes RE, de Vries RR, Breedveld FC, Dijkmans BA, Huizinga TW, Allaart CF. · VU University Medical Center, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #18438829 links to  free full text

Abstract: OBJECTIVE: To determine the association of HLA-DRB1, rheumatoid factor (RF), and anti-citrullinated protein antibody (ACPA) status with progression of joint damage in early rheumatoid arthritis (RA) treated according to different treatment strategies. METHODS: The present study was conducted using data from the BeSt study (Behandelstrategieën voor Reumatoide Artritis [treatment strategies for rheumatoid arthritis]), a randomized trial comparing 4 targeted (toward achievement of a Disease Activity Score [DAS] of < or =2.4) treatment strategies: sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with methotrexate, sulfasalazine, and prednisone (group 3), and initial combination therapy with methotrexate and infliximab (group 4), in 508 patients with early RA. Multivariate logistic regression analysis was used to predict progressive disease (increase of Sharp/van der Heijde score over 2 years beyond the smallest detectable change [4.6]) according to the presence or absence of the shared epitope (SE), DERAA, RF, and ACPA, with correction for other baseline characteristics. RESULTS: Progressive disease could not be predicted by presence of the SE: the odds ratio in groups 1, 2, 3, and 4, respectively, was 1.4, 2.6, 1.9, and 3.0. DERAA carriership did not protect against progressive disease (odds ratio 0.4, 1.4, 0.9, and 0.9 in groups 1, 2, 3, and 4, respectively). RF positivity and ACPA positivity predicted progressive disease in group 1 (odds ratio 4.7 [95% confidence interval 1.5-14.5] for RF and 12.6 [95% confidence interval 3.0-51.9] for ACPA), but not in groups 2-4 (for RF, odds ratio [95% confidence interval] 1.5 [0.5-4.9], 1.0 [0.3-3.3], and 1.4 [0.4-4.8] in group 2, group 3, and group 4, respectively; for ACPA, odds ratio [95% confidence interval] 3.4 [0.8-14.2], 1.7 [0.5-5.4], and 1.8 [0.5-6.8] in group 2, group 3, and group 4). CONCLUSION: In patients with early RA treated with the goal of tight control of the DAS, no significant association between HLA-DRB1 status and radiographic progression was found. RF and ACPA were predictive of progressive disease only in patients treated with sequential monotherapy. These observations suggest that effective treatment can prevent radiographic progression, even in patients with risk factors for severe damage.

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.

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.

Verpoort KN, Cheung K, Ioan-Facsinay A, van der Helm-van Mil AH, de Vries-Bouwstra JK, Allaart CF, Drijfhout JW, de Vries RR, Breedveld FC, Huizinga TW, Pruijn GJ, Toes RE. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #18050209 links to  free full text

Abstract: OBJECTIVE: In classic studies on the genetic background of antibody production, the major histocompatibility complex (MHC) has been shown to act as the most prominent immune response gene that controls the magnitude and the specificity of antibody production. The strongest genetic risk factor for rheumatoid arthritis (RA), the human MHC HLA-DRB1 shared epitope (SE) alleles, predisposes for antibodies against citrullinated proteins (ACPAs). ACPA levels are higher in SE-positive patients with RA than in SE-negative patients with RA. The aim of the present study was to determine whether SE influences not only the magnitude but also the specificity of the ACPA response. METHODS: In 2 cohorts of anti-citrullinated peptide 2-positive patients with RA, one from a study of recent-onset arthritis (n = 206) and the other from a treatment strategy study (n = 141), serum antibodies against a citrullinated peptide derived from vimentin (cVim) and antibodies against a citrullinated fibrinogen peptide (cFibr) were determined by enzyme-linked immunosorbent assay. HLA-DRB1 genotyping was performed. RESULTS: In the first cohort, SE alleles were significantly associated with the presence of antibodies against cVim (odds ratio [OR] 4.95, 95% confidence interval [95% CI] 1.87-15.3) and were not significantly associated with the presence of antibodies against cFibr (OR 1.71, 95% CI 0.70-4.14). These results were replicated in the second cohort (OR 5.05, 95% CI 1.92-13.6 and OR 1.19, 95% CI 0.30-3.97, respectively). CONCLUSION: In 2 cohorts of ACPA-positive patients with RA, SE alleles predisposed for the development of antibodies against cVim but not for the development of antibodies against cFibr. These data indicate that SE alleles act as "classic" immune response genes in the ACPA response, because they influence both the magnitude and the specificity of this RA-specific antibody response.

van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Peeters AJ, van Krugten MV, Breedveld FC, Dijkmans BA, Allaart CF. · Department of Rheumatology C-01-R, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #17947301 No free full text.

Abstract: OBJECTIVE: To assess the duration and the probability of maintaining low disease activity once a low disease activity score (DAS) is achieved in recent onset rheumatoid arthritis (RA) patients. METHODS: The BeSt study is a randomised trial comparing four different treatment strategies in patients with recent onset, active RA. Treatment adjustments were mandatory as long as the DAS was >2.4. If the DAS was <or=2.4, treatment was continued and after 6 months, tapered to maintenance dose. We analysed thrice-monthly DAS calculations in order to assess the duration and the probability of maintaining a DAS <or=2.4. RESULTS: Patients treated with initial combination therapy achieved a DAS <or=2.4 significantly earlier than patients treated with initial monotherapy. Independent of treatment strategy and without treatment adjustments, the probability of a next DAS <or=2.4 3 months after a first DAS <or=2.4 was 74%. The probability increased to 85% after two preceding DAS <or=2.4 and to 88-97% after one to two preceding DAS<1.6. The median duration of a DAS <or=2.4 was 12 months. CONCLUSION: Once recent onset RA patients achieve a low DAS, the probability of maintaining a low DAS without treatment adjustments is high. This may have implications for the monitoring of patients in daily practice.

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.

van der Bijl AE, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Ten Wolde S, Han KH, van Krugten MV, Allaart CF, Breedveld FC, Dijkmans BA. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #17599726 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy of infliximab plus methotrexate (MTX) as induction therapy in patients with early rheumatoid arthritis (RA). METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with active, early RA who were included as group 4 of the BeSt study were initially treated with infliximab (3 mg/kg) in combination with MTX (25 mg/week). The Disease Activity Score (DAS) was measured every 3 months. In patients with persistent low disease activity (DAS <or=2.4) for at least 6 months, the infliximab dosage was tapered and finally discontinued; the MTX dosage then was tapered to 10 mg/week. In patients with a DAS of >2.4, the infliximab dosage was increased (maximum 10 mg/kg), and they were subsequently switched to another DMARD. Except for intraarticular administration, corticosteroids were not permitted. Functional ability and the modified Sharp/van der Heijde score were determined after 2 years of therapy. RESULTS: Of the 120 patients, 67 responders (56%) had persistent low disease activity and discontinued infliximab after a median of 9.9 months, with a median MTX dosage of 10 mg/week after 2 years. Ten other patients experienced a disease flare after discontinuation and resumed infliximab after a median of 3.7 months. Thirteen patients did not achieve persistent low disease activity and received infliximab at various dosages. Treatment was unsuccessful in 30 patients. In the 67 responders, the progression of joint damage was lower than in the 30 patients in whom treatment failed. CONCLUSION: Fifty-six percent of patients with active early RA, initially treated with infliximab plus MTX, could discontinue infliximab after achieving a DAS of <or=2.4. Low disease activity was maintained in these patients while the MTX dosage was tapered to 10 mg/week.

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.

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, Kerstens PJ, Grillet BA, de Jager MH, Han KH, Speyer I, van der Lubbe PA, Seys PE, Breedveld FC, Dijkmans BA. · Leiden University Medical Center, Department of Rheumatology C1-R, PO Box 9600, 2300 RC Leiden, The Netherlands. · Ann Rheum Dis. · Pubmed #17405834 No free full text.

Abstract: OBJECTIVE: To determine treatment preferences among patients with recent onset rheumatoid arthritis participating in a randomised controlled trial comparing four therapeutic strategies. METHODS: A questionnaire was sent to all 508 participants of the BeSt trial, treated for an average of 2.2 years with either 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). Treatment adjustments were made every 3 months to achieve low disease activity (DAS < or =2.4). The questionnaire explored patients' preferences or dislikes for the initial therapy. RESULTS: In total, 440 patients (87%) completed the questionnaire. Despite virtually equal study outcomes at 2 years, more patients in group 4 reported much or very much improvement of general health: 50%, 56%, 46% and 74% in groups 1-4, respectively (overall, P<0.001). Almost half of the patients expressed no preference or aversion for a particular treatment group, 33% had hoped for assignment to group 4 and 38% had hoped against assignment to group 3. This negative perception was much less prominent in patients actually in group 3. Nevertheless, 50% of patients in group 3 disliked having to take prednisone, while only 8% in group 4 disliked going to the hospital for intravenous treatment. CONCLUSIONS: Within the limitations of our retrospective study, patients clearly preferred initial combination therapy with infliximab and disliked taking prednisone. After actual exposure, this preference remained, but the perception of prednisone improved. Patient perceptions need to be addressed when administering treatment.

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Peeters AJ, de Jonge-Bok JM, Mallée C, de Beus WM, de Sonnaville PB, Ewals JA, Breedveld FC, Dijkmans BA. · Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. · Ann Intern Med. · Pubmed #17371885 links to  free full text

Abstract: BACKGROUND: In patients with early rheumatoid arthritis, initial combination therapies provide earlier clinical improvement and less progression of joint damage after 1 year compared with initial monotherapies (as demonstrated in the BeSt study). OBJECTIVE: To evaluate whether the initial clinical and radiographic efficacy of combination therapies could be maintained during the second year of follow-up in patients with early rheumatoid arthritis. DESIGN: Randomized, controlled clinical trial with blinded assessors. SETTING: 18 peripheral and 2 university medical centers in the Netherlands. PATIENTS: 508 patients with early active rheumatoid arthritis. INTERVENTION: 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). Trimonthly treatment adjustments were made to achieve low disease activity. MEASUREMENTS: Primary end points were functional ability (Health Assessment Questionnaire) and Sharp-van der Heijde score for radiographic joint damage. RESULTS: Groups 3 and 4 had more rapid clinical improvement during the first year; all groups improved further to a mean functional ability score of 0.6 (overall, P = 0.257) and 42% were in remission (overall, P = 0.690) during the second year. Progression of joint damage remained better suppressed in groups 3 and 4 (median scores of 2.0, 2.0, 1.0, and 1.0 in groups 1, 2, 3, and 4, respectively [P = 0.004]). After 2 years, 33%, 31%, 36%, and 53% of patients in groups 1 through 4, respectively, were receiving single-drug therapy for initial treatment. There were no significant differences in toxicity. LIMITATIONS: Patients and physicians were aware of the allocated group, and the assessors were blinded. CONCLUSIONS: Currently available antirheumatic drugs can be highly effective in patients with early rheumatoid arthritis in a setting of tight disease control. Initial combination therapies seem to provide earlier clinical improvement and less progression of joint damage, but all treatment strategies eventually showed similar clinical improvements. In addition, combination therapy can be withdrawn successfully and less treatment adjustments are needed than with initial monotherapies.

van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, van Zeben D, Kerstens PJ, Gerards AH, van Groenendael JH, Hazes JM, Breedveld FC, Allaart CF, Dijkmans BA. · Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands. · Ann Rheum Dis. · Pubmed #17293364 No free full text.

Abstract: OBJECTIVES: To determine the efficacy of subsequent disease modifying antirheumatic drug (DMARD) therapies after initial methotrexate (MTX) failure in patients with recent onset rheumatoid arthritis (RA), treated according to the DAS for 2 years. METHODS: In groups 1 and 2 of the BeSt study, 244 RA patients were initially treated with MTX 15-25 mg/week. Patients who discontinued MTX because of insufficient clinical response (disease activity score, DAS >2.4) or toxicity were classified as "MTX failures." In group 1, these patients switched to sulfasalazine (SSA), then leflunomide and finally to MTX + infliximab (IFX). In group 2, "MTX failures" added SSA to MTX, then hydroxychloroquine (HCQ), then prednisone, and eventually switched to MTX + IFX. "MTX successes" were patients who achieved a DAS </=2.4 after 2 years while still on MTX monotherapy. Total Sharp/van der Heijde score (TSS) progression from 0-2 years was assessed in "MTX failures" versus "MTX successes." RESULTS: After 2 years, 162/244 patients (66%) had discontinued MTX because of insufficient response or toxicity. Of these, 78% also failed on SSA (adding or switching), 87% subsequently failed on leflunomide (in group 1), and 64% on MTX + SSA + HCQ (in group 2). 34 of 48 patients (71%) in groups 1 and 2 were successfully treated with MTX + IFX. After 2 years, regardless of the "success" on subsequent DMARDs, " MTX failures" had a median TSS progression of 3 units (mean 9) versus 1 unit (mean 3) in "MTX successes" (p = 0.007). CONCLUSION: After failure on initial MTX, treatment with subsequent conventional DMARDs is unlikely to result in a DAS </=2.4 and allows progression of joint damage.

van der Straaten RJ, Wessels JA, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Allaart CF, Bogaartz J, Tiller M, Huizinga TW, Guchelaar HJ. · Leiden University Medical Center, Department of Clinical Pharmacy and Toxicology, P.O. Box 9600, 2300 RA Leiden, The Netherlands. · Pharmacogenomics. · Pubmed #17286537 No free full text.

Abstract: The enzyme folylpoly-gamma-glutamase synthethase (FPGS) plays an important role in the intracellular polyglutamation of the disease-modifying antirheumatic drug methotrexate (MTX) and the length of the polyglutamated MTX product correlates with the time that MTX resides in the cell. The glutamates are released from MTX by activity of the enzyme gamma-glutamyl-hydrolase (GGH), thereby allowing the efflux of MTX. GGH 452C>T has been associated with decreased catalytic activity and higher accumulation of long-chain MTX-polyglutamate. However, single nucleotide polymorphisms (SNPs) in FPGS and GGH genes have not yet been explored for association with MTX efficacy or toxicity. We selected for SNPs with frequencies higher than 10% or, in case of FPGS 114G>A, causing an amino acid change with no known frequencies. In this study, frequencies of two SNPs in FPGS (1994A>G and 114G>A, rs10106 and rs10760502, respectively) and GGH genes (452C>T and 16T>C, rs11545078 and rs1800909, respectively), were determined using a newly developed method in rheumatoid arthritis patients (n = 352) and in a group of healthy controls (n = 360). Next, the SNPs were associated with response to MTX in rheumatoid arthritis patients treated with MTX monotherapy. In rheumatoid arthritis patients, allele frequencies of FPGS 1994A>G were 0.534 (A) and 0.466 (G), and for FPGS 114G>A 0.714 (G) and 0.286 (A). Allele frequencies of GGH 16T>C were 0.737 (T) and 0.263 (C) and for GGH 452C>T 0.912 (C) and 0.088 (T). No significant differences in allele frequencies between rheumatoid arthritis patients and healthy controls were found. In addition, the SNPs were not associated with good clinical response to MTX. Only patients with the GGH 16C-allele and one or no copies of the GGH 452C-16T haplotype were associated with good clinical improvement at 3 months upon treatment with MTX. No associations with efficacy at 6 months and MTX-induced toxicity were found. Therefore we conclude that despite the positive association of the GGH 16C-allele and one or no copies of the GGH 452C-16T haplotype with good clinical improvement at 3 months upon treatment with MTX, the tested SNPs in GGH and FPGS genes are suggested not to be clinically important for MTX treatment outcome.

de Vries-Bouwstra JK, Goekoop-Ruiterman YP, Wesoly J, Hulsmans HJ, de Craen AJ, Breedveld FC, Dijkmans BA, Allaart CF, Huizinga TW. · Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands. · Ann Rheum Dis. · Pubmed #17223662 No free full text.

Abstract: OBJECTIVES: (1) To assess innate ex vivo production of interleukin 1beta (IL1beta) and interleukin 1 receptor antagonist (IL1Ra) in patients with recent-onset rheumatoid arthritis (RA) as compared with healthy controls; (2) to assess the association of ex vivo IL1beta and IL1Ra production with progression of joint damage in RA; (3) to determine whether differences in ex vivo IL1beta production are explained by distribution of the IL1beta single nucleotide polymorphism C-511T. METHODS: Levels of IL1beta and IL1Ra (measured by ELISA after whole-blood stimulation with lipopolysaccharide) and distribution of IL1beta C-511T were compared in 76 patients with recent-onset RA who had received no disease-modifying antirheumatic drugs (DMARDs), and 63 healthy controls. ORs for RA based on ex vivo IL1beta and IL1Ra production were calculated. Association of ex vivo IL1beta and IL1Ra production with progression of joint damage (Sharp-van der Heijde score over 2 years) was determined by linear regression with correction for baseline characteristics. RESULTS: Patients with recent-onset RA showed lower ex vivo IL1beta and higher ex vivo IL1Ra production than healthy controls (p<0.001), with ORs for RA of 2.4 (95% CI 1.2 to 4.9) for low IL1beta-producers and 7.6 (95% CI 3.2 to 18.0) for high IL1Ra-producers. High ex vivo IL1Ra production was associated with progression of joint damage (p = 0.01). The IL1beta C-511T genotype distribution was not significantly different between patients and controls. CONCLUSIONS: Patients with recent-onset RA had decreased ex vivo IL1beta production and increased ex vivo IL1Ra production compared with controls. Ex vivo IL1Ra production is an independent predictor of progression of joint damage in recent-onset RA.

Allaart CF, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Breedveld FC, Dijkmans BA, Anonymous00205. · Department of Rheumatology, Leiden University Medical Center, RC Leiden, The Netherlands. · Clin Exp Rheumatol. · Pubmed #17083767 No free full text.

Abstract: AIM: To evaluate the efficacy and safety of four different treatment strategies for patients with early rheumatoid arthritis (RA).METHODS:In the BeSt study, 508 patients with newly diagnosed (< 2 years) active RA were randomised to be treated according to four treatment strategies: 1. sequential monotherapy, 2. step up to combination therapy (both starting with methotrexate), 3. initial combination therapy with methotrexate, sulphasalazine, and a tapered high dose of prednisone, and 4. initial combination therapy with methotrexate and infliximab. Three-monthly therapy adjustments were dictated by calculation of the Disease Activity Score (DAS), with the goal to achieve and maintain a DAS <or= 2.4. Functional ability was measured every 3 months with the Health Assessment Questionnaire. Radiographs of hands and feet were assessed yearly, blinded for patient identity and treatment, and in random order, to measure joint damage progression (Sharp/van der Heijde score).RESULTS:After 2 years of treatment, 80% of all patients achieved the goal of DAS <or= 2.4, and 42% reached clinical remission (DAS < 1.6). Initial combination therapy, either with prednisone (group 3) or with infliximab (group 4), resulted in earlier improvement in functional ability, more continuous clinical remission (DAS < 1.6), and less joint damage progression than initial monotherapy (groups 1 and 2). Patients in groups 1 and 2 needed more therapy adjustments, including introduction of combination therapy with prednisone or infliximab, to achieve a DAS <or= 2.4, whereas many patients in groups 3 and 4 were able to taper their medication to sulphasalazine or methotrexate, respectively, monotherapy. The adverse events profile was comparable in all groups. The presence or absence of rheumatoid factor, HLA DR4, or anti-CCP was not associated with radiologic damage progression.CONCLUSION:In patients with early, active RA, remarkable clinical improvement and suppression of joint damage progression can be achieved with frequent, objectively steered treatment adjustments. The best chance for an early clinical and radiologic response lies with initial combination therapy with either methotrexate, sulphasalazine and prednisone or with methotrexate and infliximab, which can be tapered to DMARD monotherapy once low disease activity is achieved.

Wessels JA, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YP, Allaart CF, Kerstens PJ, van Zeben D, Breedveld FC, Dijkmans BA, Huizinga TW, Guchelaar HJ. · Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #16572443 links to  free full text

Abstract: OBJECTIVE: To determine associations of methotrexate (MTX) efficacy and toxicity with single-nucleotide polymorphisms (SNPs) in genes coding for folate pathway enzymes in patients with early rheumatoid arthritis (RA). METHODS: Patients (n=205) with active RA received MTX at an initial dosage of 7.5 mg/week, which was increased to 15 mg/week and combined with folic acid (1 mg/day) after 4 weeks. If the Disease Activity Score in 44 joints (DAS44) was >2.4 at 3 months, MTX was increased to 25 mg/week. MTX efficacy was evaluated at 3 and 6 months and compared for genotypes in 3 analyses: patients with and without good response (DAS44<or=2.4), patients with and without good improvement (DeltaDAS44>1.2), and patients with and without moderate improvement (DeltaDAS44>0.6). The association between MTX-related adverse drug events (ADEs) and genotype was evaluated by comparing genotypes between patients with and without ADEs, specifically pneumonitis, gastrointestinal ADEs, skin and mucosal ADEs, and elevated liver enzyme levels. The following SNPs were analyzed: methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, dihydrofolate reductase (DHFR) -473G>A, DHFR 35289G>A, and reduced folate carrier 80G>A. In case of significant differences, odds ratios (ORs) were calculated. RESULTS: At 6 months, MTHFR 1298AA was associated with good improvement relative to 1298C (OR 2.3, 95% confidence interval [95% CI] 1.18-4.41), which increased with increased copies of the MTHFR 677CC haplotype. In contrast, MTHFR 1298C allele carriers developed more ADEs (OR 2.5, 95% CI 1.32-4.72). CONCLUSION: Patients with MTHFR 1298AA and MTHFR 677CC showed greater clinical improvement with MTX, whereas only the MTHFR 1298C allele was associated with toxicity. In the future, MTHFR genotypes may help determine which patients will benefit most from MTX treatment.

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, PO Box 9600, 2300 RC Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #16258899 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.