C J Haagsma

Ziekenhuisgroep Twente, Almeloo, Overijssel, Netherlands

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Publications (36)168.3 Total impact

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    ABSTRACT: Objective: To determine whether a double dose of intraarticular triamcinolone acetonide is more effective for knee arthritis than a 40-mg dose. Methods: In this 12-week randomized controlled clinical trial, 40 mg and 80 mg of intraarticular triamcinolone acetonide were compared in patients with knee arthritis. Evaluated variables included a Likert burden scale, visual analog scale pain scale, degree of arthritis activity, presence of swelling, and presence of functional limitation. Results: Ninety-seven patients were randomized. No significant differences were observed between the groups regarding any outcomes. Conclusion: An 80-mg dose of triamcinolone acetonide had no additional benefit compared with 40 mg as treatment for knee arthritis. Trial registration: Nederlands Trial Register; trial registration number: NTR2298.
    No preview · Article · Aug 2015 · The Journal of Rheumatology
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    ABSTRACT: Background The feet are often involved in rheumatoid arthritis (RA), but physical examination of the metatarsophalangeal (MTP) joints to detect arthritis is always challenging especially in case of obesity, oedema and malalignment. Ultrasound (US) has proven to be more sensitive than physical examination to detect (subclinical) synovitis in the MTP joints. Objectives (i) To determine the frequency of subclinical synovitis in the MTP joints by US among patients in DAS28 remission or LDA, and (ii) to assess discordance between the evolution of US arthritis in the feet and DAS28 over time in newly diagnosed RA patients who are treated to target. Methods A multicentre cohort of newly diagnosed RA patients was followed prospectively for one year. Patients were treatment naïve for synthetic DMARDs, biological DMARDs and glucocorticoids, and symptom duration was less than one year. All patients were treated to target with regular visits. Demographics, clinical (SJC28, TJC28) and laboratory (ESR, RF, ACCP) parameters were recorded at each visit. US examination of the dorsal aspect of MTP2-5 joints was performed at baseline, three months and one year. Images were scored on greyscale (GS; 0-3) and power Doppler (PD; 0-3). A US positive MTP joint was defined by GS>1 and/or PD>0. Simple descriptive statistics were used and longitudinal course of both DAS28 and number of US positive MTP joints were plotted for each patient. Discordance of course was defined as crossing of slopes. Results At baseline, 174 patients were included of whom 159 completed one year follow-up. At baseline, 109 (73%) patients had at least one US positive MTP joint. Overall, mean (SD) DAS28 decreased from 4.9 (1.3) at baseline to 2.3 (1.2) at one year, while the number of US positive MTP joints decreased from median (interquartile range) 1 (0-4) at baseline to 0 (0-0) at one year. Discordance in longitudinal course of DAS28 and US positive MTP joints over one year was seen in 9 patients (6%). After one year of follow-up, 98 (62%) patients were in DAS28 remission (DAS28<2.6) of whom 23 (23%) still had at least one US positive MTP joint. Twenty-nine patients had low disease activity (DAS28≤3.2) of whom 7 (24%) had at least one US positive MTP joint. Conclusions Most patients (94%) improved both in DAS28 score and number of US positive MTP joints during follow-up. However, 23% of the early RA patients in DAS28 remission still had subclinical synovitis on US in at least one MTP joint at one year. Monitoring of MTP joints by US and subsequent steering of treatment might be considered to prevent for example progressive radiological damage. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Until now there are no unequivocal prognostic parameters predicting reliably treatment success or failure in early RA patients. Ultrasound (US) predicts progression to RA in undifferentiated patients (1,2) and flare and erosive progression in RA patients in remission.(3) In early RA patients treated to target the added value of US to predict clinical outcomes has not been investigated. Objectives We investigated whether in newly diagnosed RA patients findings of an US examination of joints at baseline added to clinical, laboratory and radiographical baseline findings would improve prediction of failure to reach DAS28 remission (<2.6) after one year. Methods A multicentre cohort of newly diagnosed RA patients was followed prospectively for one year. US of hands (longitudinal (dorsal and palmar)), wrists and feet (longitudinal (dorsal)) was performed at baseline using an Esaote MyLab 60 (LA6-18MHz). Grey scale (GS) and power Doppler (PD) US was scored semiquantitatively (0-3). A joint was considered to be ultrasonographically inflamed if GS>1 and/or PD>0. Clinical, laboratory and radiographical parameters were recorded. Primary outcome was the absence of DAS28 remission 12 months after diagnosis, analysed using logistic regression. Results 194 patients were included, of whom 174 patients were left for the analysis, with complete data for 158. The addition of US results (OR (95% CI) 0.96; 0.89-1.04) to a multivariate model already including DAS28 at time of diagnosis (OR (95% CI) 1.6; 1.2-2.2), female gender (OR (95% CI) 1.9; 0.91-4), presence of rheumatoid factor (OR (95% CI) 2.3; 1.1-5.1) and type of monitoring strategy (OR (95% CI) 0.2; 0.05-0.85), did not significantly improve prediction of failure to reach DAS28 remission. This resulted in a non-significant Likelihood ratio test: 1.04 (p=0.31). Conclusions In conclusion, in an early RA population, treated according to the “treat to target” paradigm, adding an ultrasound examination of joints at baseline to the prognostic workup did not improve prediction for not reaching DAS28 remission. References Acknowledgements Dr. Naredo and the Ultrasound School of the Spanish Society of rheumatology, for use of their GSUS scoring system Funding: This work was supported by an unrestricted grant from Roche Nederland B.V. Roche had no involvement in the study design; in collection, analysis and interpretation of data; writing of the report; and decision to submit for publication. The corresponding author had full access to all data and had final responsibility for the decision to submit for publication. The US machines were granted by (in alphabetical order) Abbott, MSD, Pfizer, Schering Plough and UCB. These companies did not have any involvement in the study design; in collection, analysis and interpretation of data; writing of the report; and decision to submit for publication. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Recently, new classification criteria and new remission criteria for RA have been published, requiring accurate detection of arthritis, which could be improved using ultrasonography (US) when compared to assessment by physical examination only. Although a gold standard for presence or absence of arthritis is lacking, US might be a valuable tool when identifying early RA and true remission. Objectives To clarify whether US can improve the establishing of the diagnosis RA and the evaluation of remission, and, if so, which set of joints should be assessed by US. Methods A systematic literature search was performed using the keywords RA, arthritis and ultrasonography in PubMed and Embase. Relevant articles were obtained and their reference lists were screened to find additional studies. One reviewer screened titles and abstracts, and extracted data; uncertainties regarding study assessment were resolved by discussion in the study group. Results Our search yielded 1251 initial hits; 1018 papers were excluded reading the title, 199 were excluded on the basis of the abstract, and a further 41 were excluded after reading the full text of the article. There was a wide variability in the design of these studies, prohibiting pooling of the results. Five papers evaluated US in the diagnosis process of early RA, assessing 12 to 38 joints by US.1-5 US was more sensitive than clinical examination in detecting arthritis, and US predicted progression better to persistent arthritis (OR 5.5 (95%CI: 2.6-11.9) or RA (OR 2.3 (95%CI: 1.1-4.8) than clinical examination. The data suggests that to diagnose early RA, one should at least scan bilateral MCP, wrists and MTP joints. We found 11 papers on remission, scanning sets of joints ranging in number from 6 to 44.6-16 Often, US inflammation was detected in patients in clinical remission, irrespective of the specific set of remission criteria used. Power Doppler (PD) signs of synovitis predicted radiological progression of joint damage (OR’s ranging from 1.4 (95%CI: 1.1-1.9) to 12 (95%C: 3.3-44) and flare in patients clinically in remission (OR’s ranging from 6.3 (95%CI: 2.0-20) to 13 (95%CI 1.6-104)). To confirm or falsify remission, data suggests scanning at least wrist and MCP joints of the dominant hand. Conclusions Both for the diagnosis of RA as well as the evaluation of remission, US appears to be more sensitive than clinical exam. Power Doppler ultrasound predicts radiological progression of joint damage, flare of RA patients in remission, and in patients with early RA persistence of arthritis and progression to RA better than better than grey scale ultrasound. For the diagnosis of early RA, data suggests to at least scan bilateral MCP, wrists and MTP joints, while findings from the remission studies suggest including at least wrist and MCP joints of the dominant hand. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: OBJECTIVE: To investigate whether the degree and the duration of the response to an intra-articular treatment with triamcinolone acetonide in patients with arthritis is influenced by the addition of lidocaine. DESIGN: Retrospective observational cohort study. METHODS: The study population consisted of intramural and extramural patients from the rheumatology outpatient clinic of the Medical Spectrum Twente. All participants were treated with intra-articular triamcinolone acetonide and were divided into two groups based on simultaneous use of lidocaine during injection or not. The degree of pain was recorded the week before, and two weeks after treatment on a 100 mm visual analogue scale for pain intensity (VAS-PI). As a measure of the duration of treatment effect the time to re-treatment was recorded. RESULTS: The 110 patients treated with triamcinolone acetonide and lidocaine, have shown a mean reduction in pain of 32 ± 28 mm VAS-PI, versus 22 ± 25 mm VAS-PI for the 43 patients with triamcinolone acetonide alone. This difference of 31% compared to the combination therapy was not statistically significant (P = 0.31). The number of patients who did not receive a second injection, was 62 (50%) for the combination group and 20 (44%) for the triamcinolone acetonide group. Time to re-treatment was not significantly different in the first two years (P = 0.18) or in the period after two years (P = 0.35). CONCLUSION: Intra-articular administration of triamcinolone acetonide in combination with lidocaine gives a similar response compared to treatment with triamcinolone acetonide alone.
    No preview · Article · May 2013
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    ABSTRACT: Introduction Ultrasonography (US) might have an added value to clinical examination in diagnosing early rheumatoid arthritis (RA) and assessing remission of RA. We aimed to clarify the added value of US in RA in these situations performing a systematic review. Methods A systematic literature search was performed for RA, US, diagnosis and remission. Methodological quality was assessed; the wide variability in the design of studies prohibited pooling of results. Results Six papers on the added value of US diagnosing early RA were found, in which at least bilateral metacarpophalangeal (MCP), wrists and metatarsophalangeal (MTP) joints were scanned. Compared to clinical examination, US was superior with regard to detecting synovitis and predicting progression to persistent arthritis or RA. Eleven papers on assessing remission were identified, in which at least the wrist and the MCP joints of the dominant hand were scanned. Often US detected inflammation in patients clinically in remission, irrespective of the remission criteria used. Power Doppler signs of synovitis predicted X-ray progression and future flare in patients clinically in remission. Conclusions US appears to have added value to clinical examination for diagnosing of RA when scanning at least MCP, wrist and MTP joints, and, when evaluating remission of RA, scanning at least wrist and MCP joints of the dominant hand. For both purposes primarily power Doppler US might be used since its results are less equivocal than those of greyscale US.
    Full-text · Article · Jan 2013 · Arthritis research & therapy
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    ABSTRACT: There is strong evidence from clinical trials that a 'treat to target' strategy is effective in reaching remission in rheumatoid arthritis (RA). However, the question is whether these results can be translated into daily clinical practice and clinical remission is a reachable target indeed. The study aims to investigate whether in early RA a treatment strategy aiming at Disease Activity Score (DAS) 28 <2.6 is more effective than 'usual care' treatment for reaching clinical remission after 1 year. Two early RA inception cohorts from two different regions including patients who fulfilled the American College of Rheumatology criteria for RA were compared. Patients in the tight-control cohort (n=126) were treated according to a DAS28-driven step-up treatment strategy starting with methotrexate, addition of sulphasalazine (SSZ) and exchange of SSZ by anti-tumour necrosis factor in case of failure. Patients in the usual-care cohort (n=126) were treated with methotrexate or SSZ, without DAS28-guided treatment decisions. The primary outcome was the percentage remission (DAS28<2.6) at 1 year. Time to first remission and change in DAS28 were secondary outcomes. After 1 year, 55% of tight-control patients had a DAS28<2.6 versus 30% of usual care patients (OR 3.1, 95% CI 1.8 to 5.2). The median time to first remission was 25 weeks for tight control and more than 52 weeks for usual care (p<0.0001). The DAS28 decreased with -2.5 in tight control and -1.5 in usual care (p<0.0001). In early RA, a tight control treatment strategy aiming for remission leads to more rapid DAS28 remission and higher percentages of remission after 1 year than does a usual care treatment.
    Full-text · Article · Dec 2011 · Annals of the rheumatic diseases
  • G Maarten F Ruinemans · Cees J Haagsma · Ron Hendrix
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    ABSTRACT: Tenosynovitis caused by a Pseudallescheria boydii infection is an extremely rare complication after a dog bite and is easily misdiagnosed, leading to a delay in treatment. Careful history taking and adequate cultures can lead to a timely diagnosis, and longstanding antimycotic treatment can successfully eradicate the fungus.
    No preview · Article · Oct 2011 · Journal of clinical rheumatology: practical reports on rheumatic & musculoskeletal diseases
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    ABSTRACT: Clinical remission is the ultimate therapeutic goal in rheumatoid arthritis (RA). Although clinical trials have proven this to be a realistic goal, the concept of targeting at remission has not yet been implemented. The objective of this study was to develop, implement, and evaluate a treat-to-target strategy aimed at achieving remission in very early RA in daily clinical practice. Five hundred thirty-four patients with a clinical diagnosis of very early RA were included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Treatment adjustments were based on the Disease Activity Score in 28 joints (DAS28), aiming at a DAS28 of <2.6 (methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with biologic agents in case of persistent disease activity). The primary outcome was disease activity after 6 months and 12 months of followup, according to the DAS28, the European League Against Rheumatism (EULAR) response criteria, and the modified American College of Rheumatology (ACR) remission criteria. Secondary outcomes were time to first DAS28 remission and outcome of radiography. Six-month and 12-month followup data were available for 491 and 389 patients, respectively. At 6 months, 47.0% of patients achieved DAS28 remission, 57.6% had a good EULAR response, and 32.0% satisfied the ACR remission criteria. At 12 months, 58.1% of patients achieved DAS28 remission, 67.9% had a good EULAR response, and 46.4% achieved ACR remission. The median time to first remission was 25.3 weeks (interquartile range 13.0-52.0). The majority of patients did not have clinically relevant radiographic progression after 1 year. The successful implementation of this treat-to-target strategy aiming at remission demonstrated that achieving remission in daily clinical practice is a realistic goal.
    Full-text · Article · Jun 2011 · Arthritis & Rheumatology

  • No preview · Article · Feb 2011 · Rheumatology
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    ABSTRACT: To compare the efficacy and tolerability of allopurinol 300-600 mg/day versus benzbromarone 100-200 mg/day used to attain a target serum urate concentration (sUr) < or =0.30 mmol/l (5 mg/dl). A randomised, controlled, open-label, multicentre trial in gout patients with renal function defined as a calculated creatinine clearance > or =50 ml/min. Patients were treated with 300 mg allopurinol or 100 mg benzbromarone once a day (stage 1). If sUr < or =0.30 mmol/l was not attained after 2 months, the dose was doubled to allopurinol 300 mg twice a day or benzbromarone 200 mg once a day (stage 2). The primary end point was treatment success in either of the two stages, defined as clinical tolerability and attainment of biochemical target sUr. Sixty-five patients were enrolled in stage 1; 36 received allopurinol and 29 received benzbromarone. Fifty-five patients (85%) were analysed at stage 1: the success rates were 8/31 (26%) and 13/25 (52%), respectively, and the difference was -0.26 (95% CI from -0.486 to -0.005), p = 0.049. At stage 2, the success rates were 21/27 (78%) and 18/23 (78%), respectively, and the difference was -0.005 (95% CI from -0.223 to 0.220), p = 1.00. Two patients stopped receiving allopurinol and three stopped receiving benzbromarone because of adverse drug reactions. Increasing the allopurinol dose from 300 to 600 mg/day and the benzbromarone dose from 100 to 200 mg/day according to the target sUr produced significantly higher success rates (both 78% successful in attaining sUr < or =0.30 mmol/l). No significant differences in treatment success between benzbromarone and allopurinol were found after dose escalation. Trial registration number: ISRCTN49563848).
    Full-text · Article · Jun 2009 · Annals of the rheumatic diseases
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    ABSTRACT: To study the bioavailability of a divided higher oral dose of methotrexate (MTX), in comparison to a single dose, in adult patients with rheumatoid arthritis (RA). A pharmacokinetic analysis was performed in 10 patients with RA taking a stable dose (25-35 mg weekly) of MTX. Separated by one week, a pharmacokinetic analysis was performed in each patient after an oral single dose, and after an equal but split dose separated by 8 hours. MTX serum concentrations were measured by a fluorescence polarization immunoassay technique. Analysis was performed by calculation of the area under the curve (AUC) by the trapezoidal rule and by means of an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters. For the population analysis, data from 15 patients in our previous study comparing oral and subcutaneous administration of MTX were also used. The median MTX dose was 30 mg weekly (range 25-35 mg). The bioavailability of the split dose was 28% higher compared to the single dose (p = 0.007). In the population pharmacokinetic modeling, a 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after single-dose and split-dose MTX was 0.76 and 0.90, respectively, compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 oral administration regimens (p = 0.008). The bioavailability of oral higher dose MTX in adult patients with RA can be improved by splitting the dose.
    No preview · Article · Apr 2006 · The Journal of Rheumatology
  • H Baan · C J Haagsma · M A F J van de Laar
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    ABSTRACT: Symptomatic rheumatoid nodules are frequently surgically treated. Injection with steroids might be an alternative treatment. To determine whether injection with triamcinolon acetonide reduces the size of rheumatoid nodules, we randomized twenty patients with symptomatic nodules to either triamcinolon acetonide 40 mg/ml plus lidocaine 2% or lidocaine 1% (placebo). We measured the nodules before injection and 2, 4, 8, and 12 weeks after injection. Possible side effects were recorded. We found that the volume of the nodules injected with triamcinolon acetonide reduced significantly (p = 0.011), from 130 to 8 mm(3) (median calculated size) at 12 weeks, compared with baseline. Furthermore, at 12 weeks, the difference between the groups was significant (p = 0.03). The median size of the placebo nodules diminished as well, from 358 to 237 mm(3), but this was not significant. Pain at injection was the only side effect, equally distributed in both treatment groups. Injection with triamcinolon acetonide seems to be an alternative for surgery of rheumatoid nodules. No adverse events occurred but the limited sample does not allow definitive conclusions.
    No preview · Article · Mar 2006 · Clinical Rheumatology
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    ABSTRACT: To investigate the effect of higher weekly maintenance dose methotrexate (MTX) (> or =25 mg/week) on plasma homocysteine concentrations in adults with RA. Patients with RA were treated with high doses of MTX with adjuvant folic acid. Plasma homocysteine was determined at baseline and 1, 2, 4, 8, 12, and 48 hours after subcutaneous MTX administration. Maximum homocysteine concentrations after MTX administration were compared with baseline concentrations. Fifteen patients with RA (11 women) were included, with a median age of 61 years (range 31-72) and median disease duration 7 years (range 2-32). Median MTX dose was 30 mg (range 25-40). All patients received folic acid supplementation (5-30 mg/week). Median plasma homocysteine concentration at baseline was 10.1 mumol/l (range 6.6-12.7; normal 6-15). Homocysteine concentrations increased after MTX administration by a median of 2.5 mumol/l (range 0.7-5.1). Median maximum plasma homocysteine was significantly higher than at baseline. Peak homocysteine was reached after 12 hours. No relation between serum folate concentrations and plasma homocysteine concentrations was found. In patients with RA higher MTX doses with adjuvant folic acid do not increase baseline concentrations of homocysteine. An intermittent significant rise in plasma homocysteine occurs in the 48 hours after MTX administration.
    Full-text · Article · Feb 2005 · Annals of the Rheumatic Diseases
  • Cees J. Haagsma
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    ABSTRACT: In 1942 Nanna Svartz [1] published an important paper that has since become the benchmark for the present development of drugs: designing antirheumatic drugs based on notions of pathogenesis. She tried to link an antibacterial to an antiinflammatory agent in order to achieve simultaneous elimination of a putative infectious organism causing rheumatoid arthritis (RA) and suppression of inflammation. A number of compounds were developed and the one containing the antibiotic sulfapyridine and the anti-inflammatory salicylate 5-aminosalicylic acid linked by an azo bond (Structure 1) appeared to be the most promising.
    No preview · Chapter · Jan 2005
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    ABSTRACT: To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (> or = 25 mg weekly). Separated by 2 weeks, a pharmacokinetic analysis was performed in each patient after oral and subcutaneous administration of the same dose of MTX. MTX serum concentrations were measured by a fluorescence polarization immunoassay. Pharmacokinetic analysis was performed with an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters. The median MTX dose was 30 mg weekly (range 25-40 mg). A 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after oral MTX was 0.64 (range 0.21-0.96) compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 administration regimens. Bioavailability of a higher oral dose of MTX in adult patients with RA is highly variable, and on average two-thirds that of the subcutaneous administration. To improve efficacy of MTX at dosages of 25 mg weekly or more, a change to parenteral administration should be considered.
    No preview · Article · May 2004 · The Journal of Rheumatology
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    ABSTRACT: To study which factors are associated with longterm methotrexate (MTX) use in rheumatoid arthritis (RA). All patients with RA who had started MTX after January 1, 1993, were selected from a regional hospital based registration system. Data on demographic and clinical features were retrieved through chart review. By means of life table analysis and Cox regression analysis, MTX survival and the relation between demographic variables, clinical features, and MTX survival were studied. A total of 1072 MTX treatment episodes in 1022 patients were analyzed. The cumulative MTX survival probability after 5 years was 64%, and after 9 years was 50%. Univariate analysis showed a significant relation between MTX survival probability and folic acid supplementation, attending rheumatologist, concurrent prednisolone use, concurrent sulfasalazine use, and the number of previous disease modifying drugs. In the multivariate analysis folic acid supplementation, attending rheumatologist, and concurrent prednisolone use remained significantly related to MTX survival. Age, disease duration, and creatinine clearance were not. In this retrospective study of 1022 patients with RA the cumulative MTX survival probability was 64% after 5 years and 50% after 9 years. Folic acid supplementation and to a lesser extent prednisolone were associated with a longer MTX survival. In addition, treatment strategies of individual rheumatologists influenced MTX survival.
    No preview · Article · Dec 2003 · The Journal of Rheumatology
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    ABSTRACT: To study factors associated with toxicity, final dose, and efficacy of methotrexate (MTX) in patients with rheumatoid arthritis (RA). Data were used from a randomised clinical 48 week trial on 411 patients with RA all treated with MTX, comparing folates and placebo. Logistic regression was used to study the relation between baseline variables and various dependent factors, including hepatotoxicity (alanine aminotransferase >/=3 x upper limit of normal), MTX withdrawal, final MTX dose >/=15 mg/week, and MTX efficacy. Addition of folates to MTX treatment was strongly related to the lack of hepatotoxicity. Next to this, high body mass index was related to the occurrence of hepatotoxicity. Prior gastrointestinal (GI) events and younger age were related to the adverse event, diarrhoea. Hepatotoxicity and GI adverse events were the main reason for MTX withdrawal, which in turn was associated with the absence of folate supplementation, body mass index, prior GI events, and female sex. Renal function (creatinine clearance >/=50 ml/min) was not associated with toxicity. Reaching a final dose of MTX of >/=15 mg/week was related to folate supplementation and the absence of prior GI events. Efficacy of MTX treatment was associated with low disease activity at baseline, male sex, use of non-steroidal anti-inflammatory drugs (NSAIDs), and lower creatinine clearance. MTX toxicity, final dose, and efficacy are influenced by folate supplementation. Baseline characteristics predicting the outcome of MTX treatment are mainly prior GI events, body mass index, sex, use of NSAIDs, and creatinine clearance.
    Full-text · Article · May 2003 · Annals of the Rheumatic Diseases
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    ABSTRACT: To study (i) the influence of methotrexate (MTX) therapy on homocysteine and folate metabolism in patients with rheumatoid arthritis (RA), (ii) the influence of the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) on the change in plasma homocysteine levels during MTX treatment, and (iii) the interference of folate and homocysteine metabolism with the efficacy and toxicity of treatment with MTX. The 113 patients enrolled in this study were participating in a 48-week, multicentre, double-blind, placebo-controlled study comparing the efficacy and toxicity of MTX treatment with and without folic or folinic acid supplementation. The MTX dose was 7.5 mg/week initially and increased to a maximum of 25 mg/week if necessary. Concentrations of total folate, 5-methyl tetrahydrofolate (in serum and in erythrocytes) and of homocysteine, cysteine and cysteine-glycine and the MTHFR genotype were determined before the start of the study, after 6 weeks, and after 48 weeks or on withdrawal from the study. Blood was drawn from fasting patients at a standardized time in the morning, 16 h after intake of MTX. The laboratory results were related to parameters of efficacy and toxicity of MTX treatment. Baseline values were distributed equally in the three treatment groups. The mean plasma homocysteine level (normal range 6-15 micromol/l) before the start of MTX was relatively high in all groups: 15.4 micromol/l [95% confidence interval (CI) 13.5 to 17.2] in the MTX plus placebo group (n=39), 14.3 micromol/l (95% CI 12.2 to 16.4) in the MTX plus folic acid group (n=35) and 15.9 micromol/l (95% CI 13.7 to 18.1) in the MTX plus folinic acid group (n=39). After 48 weeks of MTX therapy, the mean homocysteine level showed an increase in the placebo group (+3.6 micromol/l, 95% CI 1.7 to 5.6). In contrast, a decrease was observed in the groups supplemented with folic or folinic acid (folic acid, -2.7 micromol/l, 95% CI -1.4 to -4.0; folinic acid, -1.6 micromol/l, 95% CI -0.1 to -3.0). The differences in the change in plasma homocysteine level between the placebo group and each of the two folate-supplemented groups were statistically significant (P<0.0001), contrary to the difference between the folic and folinic acid groups (P=0.26). Linear regression analysis showed that the change in plasma homocysteine level was statistically significantly associated with folic or folinic acid supplementation (P=0.0001) but not with the presence or absence of the C677T mutation in the MTHFR gene. Homozygous mutants had a higher plasma homocysteine concentration at baseline. No relationship was found between the change in disease activity and the change in homocysteine concentration or the mean homocysteine concentration after 48 weeks of MTX therapy. Toxicity-related discontinuation of MTX treatment was not associated with the change in homocysteine concentration. Low-dose MTX treatment in RA patients leads to an increased plasma homocysteine level. Concomitant folate supplementation with either folic or folinic acid decreases the plasma homocysteine level and consequently protects against potential cardiovascular risks. No relationship was found between the change in homocysteine concentration and the presence or absence of the C677T mutation in the MTHFR gene. Homocysteine metabolism was not associated with efficacy or toxicity of MTX treatment.
    No preview · Article · Jun 2002 · Rheumatology
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    ABSTRACT: To study the possible relationship between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the toxicity and efficacy of treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA). Genotype analysis of the MTHFR gene was done in 236 patients who started MTX treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation. Outcomes were parameters of efficacy of MTX treatment, patient withdrawal due to adverse events, discontinuation of MTX treatment because of elevated liver enzyme levels, and the total occurrence of elevated liver enzyme levels during the study. Multivariate logistic regression analysis was used to study the relationship between the presence of the MTHFR C677T mutation and toxicity outcomes of MTX treatment. Forty-eight percent of the patients showed the homozygous (T/T) or heterozygous (T/C) mutation. The presence of the C677CT or C677TT genotypes was associated with an increased risk of discontinuing MTX treatment because of adverse events (relative risk 2.01; 95% confidence interval 1.09, 3.70), mainly due to an increased risk of elevated liver enzyme levels (relative risk 2.38; 95% confidence interval 1.06, 5.34). Efficacy parameters were not significantly different between the patients with and those without the mutation. The C677T mutation is the first identified genetic risk factor for elevated alanine aminotransferase values during MTX treatment in patients with RA. We postulate that the incidence of clinically important elevation of liver enzyme levels during MTX treatment is mediated by homocysteine metabolism. Supplementation with folic or folinic acid reduced the risk of toxicity-related discontinuation of MTX treatment both in patients with and in patients without the mutation.
    No preview · Article · Dec 2001 · Arthritis & Rheumatology

Publication Stats

2k Citations
168.30 Total Impact Points

Institutions

  • 2009-2015
    • Ziekenhuisgroep Twente
      Almeloo, Overijssel, Netherlands
  • 1998-2004
    • Medisch Spectrum Twente
      • Rheumatology Department
      Enschede, Overijssel, Netherlands
  • 1995-1998
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1997
    • Rijnstate Hospital
      Arnheim, Gelderland, Netherlands