Rheumatoid Arthritis: Laan RF

Laan RF, van Riel PL, van de Putte LB. · University Medical Center Nijmegen, Department of Rheumatology, Nijmegen, The Netherlands. · Curr Opin Rheumatol. · Pubmed #11333342 No free full text.

Abstract: Methotrexate and leflunomide are both effective drugs in the treatment of patients with rheumatoid arthritis. Methotrexate has been available for many years, whereas leflunomide is a relatively new drug. Several large trials describing its efficacy and safety in comparison with both sulfasalazine and methotrexate and with placebo have been published recently. It appears that leflunomide is approximately equally effective as sulfasalazine and methotrexate. New data are also available on the mechanism of action of leflunomide especially. This drug probably acts as an immunomodulatory agent by interfering with the de novo synthesis of pyrimidines.

te Boekhorst PA, Barrera P, Laan RF, van de Putte LB. · Department of Rheumatology, University Hospital Nijmegen, The Netherlands. · Clin Exp Rheumatol. · Pubmed #10410273 No free full text.

Abstract: We report a case of severe hepatotoxic reaction during gold therapy for rheumatoid arthritis. The previous literature on this condition is reviewed and the possible mechanisms of gold-induced hepatotoxicity are discussed.

Laan RF, Jansen TL, van Riel PL. · Department of Rheumatology, University Hospital Nijmegen, The Netherlands. · Rheumatology (Oxford). · Pubmed #10334676 links to  free full text

Abstract: Glucocorticosteroids are used frequently in the management of patients with rheumatoid arthritis. Data supporting their efficacy and safety are still meagre. Glucocorticosteroids may be used systemically with different routes of administration (oral, i.m. and i.v.), in different doses and for different periods of time. The effectiveness of glucocorticosteroids in reducing inflammation in the short term has been shown for oral treatment in a dose of 7.5 mg prednisolone daily or more, for i.m. pulses (120 mg methylprednisolone every 4 weeks) and for i.v. methylprednisolone pulses. For longer periods of treatment, the evidence suggesting effectiveness of low-dose oral glucocorticosteroids is more limited. Some data suggest that different regimens of glucocorticosteroids may retard the development of erosions in patients with rheumatoid arthritis. The toxicity of short-term treatment is relatively low. For long-term treatment, the development of osteoporosis is a serious problem. Concomitant therapy with either calcitriol or bisphosphonates may reduce this risk.

Fransen J, Laan RF, Van Der Laar MA, Huizinga TW, Van Riel PL. · Department of Rheumatology, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands. · Ann Rheum Dis. · Pubmed #15361375 links to  free full text

Abstract: OBJECTIVE: To study the influence of rheumatologists' adherence to a methotrexate guideline on efficacy and toxicity in the treatment of rheumatoid arthritis. METHODS: In a 48 week randomised controlled trial of methotrexate, comparing folates with placebo, rheumatologists were advised on methotrexate dosage using a guideline reflecting daily practice. The influence of guideline non-adherence on outcome was analysed using generalised estimating equations and survival analysis. RESULTS: In 51% of the 411 study patients the guidelines were always followed. Non-adherence resulted in lower doses of methotrexate in 25% of cases, and higher doses in 24%. The reduction in the disease activity score was significantly greater (mean -0.4; p = 0.0085) in the adherent group than in the "low dose" group; the "high dose" group did not differ from the adherent group. Dropout caused by severe adverse events did not differ between the three groups. CONCLUSIONS: There is an indication that adherence to guidelines on methotrexate dosage may benefit patients with rheumatoid arthritis by improving disease activity without increasing toxicity. For definite proof, a randomised controlled trial comparing guideline supported dosing with usual care is needed.

Hartman M, van Ede A, Severens JL, Laan RF, van de Putte L, van der Wilt GJ. · Department of Medical Technology Assessment, University Medical Centre, Nijmegen, The Netherlands. · J Rheumatol. · Pubmed #15124248 No free full text.

Abstract: OBJECTIVE: To determine cost-effectiveness of folic or folinic acid supplementation in patients with rheumatoid arthritis (RA) who started methotrexate (MTX) treatment. METHODS: An economic evaluation, performed alongside a randomized, double blind, placebo controlled trial with followup of 48 weeks. Patients started MTX with placebo (n = 137), folic acid (n = 133), or folinic acid (n = 141). Outcome measures were drug survival and quality-adjusted life-years (QALY), measured with the EuroQol questionnaire. Both medical and nonmedical costs were analyzed. RESULTS: Drug survival after 48 weeks was 60% for placebo, 81% for folic acid, and 87% for folinic acid. QALY during a 48 week period were 0.55 (95% CI 0.52-0.58) in the placebo group, 0.55 (95% CI 0.52-0.58) in the folic acid group, and 0.58 (95% CI 0.56-0.60) in the folinic acid group. Mean medical costs were 1398 US dollars (placebo), 1409 US dollars (folic acid), and 1776 US dollars (folinic acid). Mean total costs were 3339 US dollars, 3632 US dollars, and 3296 US dollars, respectively. CONCLUSION: In terms of resource deployment, no statistically significant difference was found between the 3 strategies. The preferred strategy consists of folic acid supplementation because of improved drug survival.

Hoekstra M, van Ede AE, Haagsma CJ, van de Laar MA, Huizinga TW, Kruijsen MW, Laan RF. · Department of Rheumatology, Medisch Spectrum Twente, Enschede, The Netherlands. · Ann Rheum Dis. · Pubmed #12695153 links to  free full text

Abstract: OBJECTIVE: To study factors associated with toxicity, final dose, and efficacy of methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

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

van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ, Thomas CM, De Boo TM, van de Putte LB. · Department of Rheumatology, University Medical Center St Radboud, Nijmegen, The Netherlands. · Rheumatology (Oxford). · Pubmed #12048292 links to  free full text

Abstract: OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Barrera P, van der Maas A, van Ede AE, Kiemeney BA, Laan RF, van de Putte LB, van Riel PL. · Department of Rheumatology and. Department of Epidemiology, University Medical Centre, Nijmegen, The Netherlands. · Rheumatology (Oxford). · Pubmed #11961174 links to  free full text

Abstract: OBJECTIVES: To compare the 48-week drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-alpha (TNF-alpha) monoclonal antibody (moAb) and methotrexate (MTX) in patients with active long-standing rheumatoid arthritis (RA). Secondary aims were to identify potential predictors for clinical response. METHODS: Patients with RA, enrolled in phase I trials with a human anti-TNF-alpha moAb and followed for at least 48 weeks at our centre, were compared with patients receiving MTX monotherapy without folate supplementation. The first 6 weeks of anti-TNF therapy were placebo-controlled and followed by an open-label study. Patients treated with MTX participated in a 48-week, double-blind, phase III study of MTX alone vs MTX with folate supplementation, which was co-ordinated by our department. The studies with anti-TNF-alpha and MTX were performed in the same period and had very similar inclusion, exclusion, response and stop criteria. RESULTS: Sixty-one patients treated with anti-TNF-alpha moAb were compared with 137 receiving MTX monotherapy. At baseline, patients in the anti-TNF-alpha group had a longer disease duration (median 108 vs 50 months, P=0.0001) and a more protracted history of second-line anti-rheumatic drugs than those treated with MTX (median 4 vs 1, P=0.0001). The 48-week dropout rate was lower among patients treated with anti-TNF (23 vs 45% in the MTX group, P<0.005). Proportional hazard analysis showed a significantly lower dropout risk among anti-TNF-treated patients [relative risk (95% confidence interval): 0.28 (0.12-0.6) uncorrected and 0.17 (0.06-0.45) corrected for confounders). The 48-week area under the curve for the disease activity score (DAS) was smaller in the anti-TNF-alpha group than in the MTX group (P=0.005). The percentage of responders was higher in the anti-TNF-alpha group over the whole study period. The median percentage of visits in which a patient fulfilled the European League Against Rheumatism (EULAR) response criteria was 83% in the anti-TNF-alpha group vs 40% in the MTX group (P=0.0001). Clinical and demographic characteristics were, in general, poor predictors for response to therapy at week 48. The clinical response after the first anti-TNF-alpha dose tended to increase the chance of prolonged efficacy of this approach [relative risk (95% confidence interval): 2 (0.75-6.0)]. The previous number of second-line drugs was the only predictive variable for response to MTX to which it was inversely related [relative risk (95% confidence interval): -0.71 (-0.57 to -0.88)]. CONCLUSIONS: In patients with active, long-standing RA, blocking TNF-alpha is more effective and better tolerated than MTX monotherapy. An early response increases the chance of a sustained effect of anti-TNF-alpha. In contrast to MTX, the response to anti-TNF-alpha is not affected by previous disease-modifying anti-rheumatic drug history.

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 Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, de Boo TM, van de Putte LB. · University Medical Center St. Radboud, Nijmegen, The Netherlands. · Arthritis Rheum. · Pubmed #11710708 No free full text.

Abstract: OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, de Boo TM, van der Wilt GJ, Severens JL, Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de Putte LB. · University Medical Center St Radboud, Nijmegen, The Netherlands. · Arthritis Rheum. · Pubmed #11465701 links to  free full text

Abstract: OBJECTIVE: To study the effect of folates on discontinuation of methotrexate (MTX) as single-drug antirheumatic treatment due to toxicity, to determine which type of adverse events are reduced, to study the effects on the efficacy of MTX, and to compare folic with folinic acid supplementation in a 48-week, randomized, double-blind, placebo-controlled trial. METHODS: Patients with active RA (n = 434) were randomly assigned to receive MTX plus either placebo, folic acid (1 mg/day), or folinic acid (2.5 mg/week). The initial MTX dosage was 7.5 mg/week; dosage increases were allowed up to a maximum of 25 mg/week for insufficient responses. Folate dosages were doubled once the dosage of MTX reached 15 mg/week. The primary end point was MTX withdrawal because of adverse events. Secondary end points were the MTX dosage and parameters of efficacy and toxicity of MTX. RESULTS: Toxicity-related discontinuation of MTX occurred in 38% of the placebo group, 17% of the folic acid group, and 12% of the folinic acid group. These between-group differences were explained by a decreased incidence of elevated liver enzyme levels in the folate supplementation groups. No between-group differences were found in the frequency of other adverse events or in the duration of adverse events. Parameters of disease activity improved equally in all groups. Mean dosages of MTX at the end of the study were lower in the placebo group (14.5 mg/week) than in the folic and folinic acid groups (18.0 and 16.4 mg/week, respectively). CONCLUSION: Both folate supplementation regimens reduced the incidence of elevated liver enzyme levels during MTX therapy, and as a consequence, MTX was discontinued less frequently in these patients. Folates seem to have no effect on the incidence, severity, and duration of other adverse events, including gastrointestinal and mucosal side effects. Slightly higher dosages of MTX were prescribed to obtain similar improvement in disease activity in the folate supplementation groups.

Tjon SS, Geurts AC, van't Pad Bosch P, Laan RF, Mulder T. · Sint Maartenskliniek-Research, Department of Rheumatology, Nijmegen, The Netherlands. · Arch Phys Med Rehabil. · Pubmed #11083353 No free full text.

Abstract: OBJECTIVE: To investigate the use of compensatory visual and attentional control strategies for standing balance in patients with rheumatoid arthritis (RA) with severe knee joint impairment. DESIGN: Experimental 2-group design. SETTING: Specialized clinic for orthopedics, rheumatology, and rehabilitation in The Netherlands. PARTICIPANTS: Eighteen patients without comorbidity (age range, 65 +/- 7.7 yr; 16 women, 2 men) from a consecutive sample of patients with RA scheduled for total knee arthroplasty; 23 controls of the same age group also were tested (13 women, 10 men). MAIN OUTCOME MEASURES: By means of a dual-plate force platform, the velocity of center of pressure (COP) fluctuations were analyzed in the anteroposterior and lateral sway directions during quiet standing with eyes open, eyes closed, and while performing a secondary attention-demanding arithmetic task. RESULTS: Patients showed an average 80% greater COP velocity in both directions of sway compared with controls. In addition, stability deteriorated substantially more in patients than controls when deprived of visual information, which was associated with the degree of knee destruction. The effect of the arithmetic task was small and similar in patients and controls. CONCLUSION: RA patients with severe knee joint impairment can have a substantial basic postural instability; their relatively high reliance on visual information suggests impaired sensory feedback from the lower limbs. Current research is aimed at determining whether these postural deficits can be improved by total knee replacement.

Eijsbouts A, van den Hoogen F, Laan RF, Hermus RM, Sweep FC, van de Putte L. · No affiliation provided · J Rheumatol. · Pubmed #10529161 No free full text.

This publication has no abstract.

Radovits BJ, Fransen J, Eijsbouts A, van Riel PL, Laan RF. · Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. · Rheumatology (Oxford). · Pubmed #19478038 No free full text.

Abstract: OBJECTIVE: To investigate whether there is a difference in waiting time between indication and start of anti-TNF-alpha therapy in younger and older RA patients. METHODS: The study was carried out in the Nijmegen inception cohort of early RA. All patients meeting indications for anti-TNF-alpha therapy according to the Dutch reimbursement criteria were included in the analysis. Time from indication to start of anti-TNF-alpha therapy or censoring was calculated in all patients. Multivariable Cox regression analysis was used to investigate the influence of age at indication on the time to commencement of anti-TNF-alpha treatment. Hazard ratios were calculated for groups in age quartiles. The model was corrected for 28-joint disease activity score (DAS28), disease duration, gender, the Charlson comorbidity index and episodes of serious illnesses between indication and anti-TNF-alpha therapy or censoring. RESULTS: From the 487 eligible patients, 215 patients started anti-TNF-alpha treatment during their follow-up (44%). Age significantly influenced the time to receiving anti-TNF-alpha after first indication, adjusting for confounders (HR = 0.975/year, P < 0.001). The same analysis using age quartiles showed that the younger age groups had a higher chance of receiving anti-TNF-alpha treatment within an equal period of time than older patients [HR 2.67 (95% CI 1.64, 4.35); 2.30 (1.43, 3.71); 1.79 (1.14, 2.81) with increasing age; the eldest group as reference]. The eldest patients had significantly higher DAS28 values prior to anti-TNF-alpha treatment than younger patients. CONCLUSION: Elderly RA patients were less likely to receive anti-TNF-alpha treatment within an equal period of time compared with younger patients, taking disease activity, disease duration and comorbidities into account.

Radovits BJ, Popa-Diaconu DA, Popa C, Eijsbouts A, Laan RF, van Riel PL, Fransen J. · Radboud University Nijmegen Medical Centre, Department of Rheumatology, P O Box 9101, H470, 6500 HB Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #18701555 No free full text.

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease than the general population. Systemic inflammation may contribute to this risk. This study investigated whether the level of disease activity is associated with the risk of developing myocardial infarction (MI) in patients with RA. METHODS: A case-control study was performed within a large prospective cohort of patients with RA. Cases were patients who developed their first MI after the diagnosis of RA, controls were patients with RA without MI. Cases and controls had similar RA disease duration. Traditional and disease-specific risk factors for MI were collected and a time-averaged disease activity score (DAS28) was calculated. The data were analysed using conditional logistic regression analysis. RESULTS: Cases of MI were significantly older, were more often male, with higher body mass index (BMI) and total cholesterol and lower high-density lipoprotein (HDL) serum levels than controls. Time-averaged disease activity was similar for cases and controls. The raw odds ratio for MI in patients with a "high" (>4.0) versus a "low" (<or=4.0) average DAS28 was 1.2 (95% CI 0.61 to 2.36). The odds ratio corrected for age, gender, BMI, baseline Health Assessment Questionnaire and baseline HDL was 0.91 (95% CI 0.39 to 2.12). CONCLUSION: Patients with RA who developed MI had more classical risk factors but not higher disease activity over time than control patients with RA. Low levels of inflammation may be sufficient for accelerated atherogenesis and an excess risk of cardiovascular disease in RA.

Radovits BJ, Fransen J, van Riel PL, Laan RF. · Radboud University Nijmegen Medical Centre, Department of Rheumatology, PO Box 9101, HP 470, 6500 HB Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #17965425 No free full text.

Abstract: OBJECTIVES: To investigate the influence of age and gender on the components of the 28-joint Disease Activity Score (DAS28) in patients with rheumatoid arthritis (RA), and to clarify whether a high DAS28 can be equally interpreted in all age groups, independent of gender. METHODS: A prospective cohort of 553 patients with RA was studied for approximately 20 years after diagnosis. The single measures of disease activity and the share of different components of the DAS28 (eg, erythrocyte sedimentation rate; ESR) were analysed and compared between three age groups (<45, 45-65 and >65 years) and per gender, using analysis of variance (ANOVA). The performance of the DAS28 and its components was explored in moderate to high and low DAS28 categories. Linear mixed model analysis was used to design the models best predicting ESR and the share of ESR. RESULTS: ESR significantly increased with age, independent of other variables of disease activity. This increase was more pronounced in male than in female patients. Nevertheless, the share of ESR increased with age only in male patients with a low DAS28 (<3.2). If the DAS28 score was >3.2, age and gender did not have a significant effect on any components of the DAS28. C-reactive protein (CRP) and DAS28(CRP) were not influenced by age. CONCLUSIONS: A high DAS28 was found to perform equally in all age groups, in men and women, despite the elevating effect of age on ESR. In elderly men with low disease activity, remission rate could be underestimated by an elevated ESR.

Welsing PM, Severens JL, Hartman M, van Gestel AM, van Riel PL, Laan RF. · Department of Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands. · Pharmacoeconomics. · Pubmed #17002483 No free full text.

Abstract: OBJECTIVE: Markov models are increasingly used in economic evaluations of (new) treatments for chronic diseases. In this study we propose a Markov model with health states defined by the disease activity score (DAS) to be used to extrapolate efficacy data from short-term clinical trials in rheumatoid arthritis to longer term cost-effectiveness results. Moreover, we perform an initial validation of this model. METHODS: To test the validity of the model, the expected disease course (according to the model) was first compared with the observed disease course in an inception cohort of newly diagnosed rheumatoid arthritis patients. Then the relationship of the health states with utility and costs was investigated. Finally, costs and QALYs were calculated for usual care of patients in the first 5 years of their disease using the model and compared with the literature. RESULTS: The model seemed to be able to extrapolate 1-year efficacy data as seen by a comparable distribution over the Markov states between the model results and the observational data. The health states had a significant relationship with costs and utility, and population characteristics had only a moderate effect on the cost and utility values of the Markov states. The distribution over the Markov states resulted in 3.266 expected QALYs per patient over 5 years. The expected medical and total costs per patient over 5 years were 6754 euro (1997 values) and 12,641 euro, respectively, for standard rheumatoid arthritis care in The Netherlands. CONCLUSION: The developed Markov model seems a valid model for use in economic evaluations in rheumatoid arthritis. The model produced similar utilities, but lower total costs, to those in previously published studies. Although the steps to develop and validate this Markov model were applied in the context of rheumatoid arthritis, they can be generalised to other chronic diseases.

Eijsbouts AM, van den Hoogen FH, Laan RF, Hermus AR, Sweep CG, van de Putte LB. · Department of Rheumatology, Endocrinology, University Medical Centre Nijmegen, Nijmegen, The Netherlands. · Clin Exp Rheumatol. · Pubmed #16173242 No free full text.

Abstract: OBJECTIVE: To study the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatoid arthritis (RA). METHODS: Fifty patients with RA participated in 3 groups: recent onset active RA (n = 20), longstanding active RA (n = 20) and long-standing RA in remission (n = 10), and were compared with 20 healthy controls. The activity of the HPA-axis was assessed under basal conditions and in response to stress (insulin tolerance test, ITT). In addition, patients with recent onset RA underwent a corticotropin releasing hormone (CRH) test and a dexamethasone suppression test. Plasma levels of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha) and IL-6 were also measured. RESULTS: Basal plasma, salivary and urinary cortisol levels and plasma adrenocorticotropic hormone (ACTH) levels were not different between patients with RA and healthy controls. During the ITT, cortisol levels were consistently lower in RA patients than in healthy controls. ACTH levels during the ITT were not different between patients with RA and healthy controls. ACTH and cortisol responses to CRH were assessed only in patients with recent onset RA and were found to be within normal limits. Basal circulating plasma IL-6 levels were significantly higher in patients with active RA than in the other groups. CONCLUSION: Under the standardized conditions of the ITT, patients with RA have decreased plasma cortisol levels compared to healthy controls, despite elevated levels of IL-6. The defect is probably located at the adrenal level and may be of pathogenetic significance for the development of chronic arthritis.

Welsing PM, Severens JL, Hartman M, van Riel PL, Laan RF. · University Medical Center Nijmegen, Nijmegen, the Netherlands. · Arthritis Rheum. · Pubmed #15593319 links to  free full text

Abstract: OBJECTIVE: To determine the cost effectiveness of treatment strategies for rheumatoid arthritis patients satisfying the indication for tumor necrosis factor (TNF)-blocking treatment. METHODS: A Markov model study was performed. The following treatment strategies were considered: 1) usual treatment; 2) treatment with leflunomide, in the case of nonresponse after 3 months, switch to usual treatment; 3) TNF-blocking treatment, in the case of nonresponse after 3 months, switch to usual treatment; 4) treatment with leflunomide, in the case of nonresponse, switch to TNF-blocking treatment, in the case of nonresponse to TNF-blocking treatment, switch to usual treatment; 5) TNF-blocking treatment, in the case of nonresponse, switch to leflunomide treatment, in the case of nonresponse to leflunomide, switch to usual treatment. Expected patient-years in the different Markov states, costs, and quality-adjusted life years (QALYs) were compared between the treatment strategies; incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: Over the 5-year period, the expected effect on disease activity and QALYs was better for treatment strategies that included TNF-blocking treatment than for the other treatment strategies. The greater effectiveness of these treatment strategies reduced medical and nonmedical costs compared with usual treatment by about 16% and 33%, respectively, omitting the costs of medication. When the costs of medication were included, the costs of strategies that started with TNF-blocking treatment were higher than those of the other treatment strategies. Treatment strategy 4 had the most favorable ICER of the treatment strategies that included TNF-blocking treatment: 163,556/QALY compared with usual treatment. CONCLUSION: Among strategies that include TNF-blocking agents, one starting with leflunomide and, in the case of nonresponse, switching to TNF-blocking treatment probably results in the most favorable ratio between incremental costs and effects.

Eijsbouts AM, van den Hoogen FH, Laan RF, Sweep CG, Hermus AR, van de Putte LB. · Department of Rheumatology, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, Netherlands. · Ann Rheum Dis. · Pubmed #15319231 links to  free full text

Abstract: OBJECTIVE: To compare basal and stimulated prolactin levels between patients with rheumatoid arthritis and healthy controls, and to assess the effects of antirheumatic treatment on prolactin concentrations. METHODS: Serum prolactin was assessed under basal conditions and during an insulin tolerance test (ITT) in 20 patients with recently diagnosed active rheumatoid arthritis and 20 age and sex matched controls. The patients were reassessed after two weeks' treatment with naproxen and after six months' additional treatment with either sulfasalazine or methotrexate. Disease activity was assessed by the disease activity score (DAS). RESULTS: Basal levels of prolactin were not significantly different between patients with rheumatoid arthritis and controls. Prolactin responses to hypoglycaemia were less in untreated rheumatoid patients than in controls. DAS scores correlated negatively with the area under the curve (AUC) for prolactin concentrations during the ITT. Treatment with naproxen for two weeks did not influence either basal or stimulated prolactin levels. After six months of antirheumatic treatment, prolactin responses to hypoglycaemia increased significantly to levels observed in controls. At the same time point, DAS had improved considerably. The improvement correlated with the increase in AUC of prolactin during the ITT (r = 0.48; p = 0.05). CONCLUSIONS: Patients with active rheumatoid arthritis have a decreased prolactin response to hypoglycaemia induced stress. The response recovers following treatment with antirheumatic drugs.

van Ede AE, Laan RF, De Abreu RA, Stegeman AB, van de Putte LB. · Department of Rheumatology, University Medical Centre St Radboud, Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #12429535 links to  free full text

Abstract: OBJECTIVES: To study (a) purine metabolism during treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine metabolism with efficacy and toxicity of MTX treatment. METHODS: One hundred and three patients with active RA who started treatment with MTX were included. The initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if necessary. The purine enzymes 5'-nucleotidase (5'NT), purine-nucleoside-phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and adenosine-deaminase (ADA) were measured before the start, after six weeks, and after 48 weeks or at study withdrawal. The laboratory results were related to measures of efficacy and toxicity of MTX treatment. RESULTS: Baseline values of 5'NT and PNP (16.9 and 206.8 nmol/10(6) mononuclear cells/h, respectively) were similar to those in former studies. Activities of HGPRT and ADA were relatively low at the start (8.7 and 80.3 nmol/10(6) mononuclear cells/h, respectively). After six weeks purine enzyme activities showed no important changes from baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of ADA (-21.6 nmol/10(6) mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/10(6) mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/10(6) mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy or toxicity of MTX treatment. In contrast, enzyme activity of 5'NT showed a decrease in the subgroup of patients discontinuing MTX treatment because of hepatotoxicity. CONCLUSION: MTX treatment in patients with RA leads to a significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that is not related to the anti-inflammatory efficacy or toxicity of MTX. Hepatotoxicity was related to a decrease in the enzyme activity of 5'NT. These changes may be explained by direct or indirect (via purine de novo and salvage metabolism and the homocysteine pathway) effects of MTX.

Swinkels HL, Laan RF, van 't Hof MA, van der Heijde DM, de Vries N, van Riel PL. · Department of Rheumatology, University Medical Centre Nijmegen, The Netherlands. · Semin Arthritis Rheum. · Pubmed #11740798 No free full text.

Abstract: BACKGROUND AND OBJECTIVES: In rheumatoid arthritis, joint radiography is still the most frequently used instrument to assess the progression of joint damage. Unfortunately, the poor quality of the radiographic scoring methods available has a negative impact on the power in clinical trials. This study focuses on the influence of the following 4 factors on radiographic scores according to van der Heijde's modification of the Sharp method: intraobserver variation, interobserver variation, follow-up time, and number of measurement occasions within a patient series. METHODS: One hundred and seventy-two patients in the early stages of rheumatoid arthritis were followed up. During the first 3 years, radiographs of the hands and feet were taken twice yearly and scored by 3 observers. The scoring process was repeated after an additional 3-year period. Correlation coefficients and differences between observers were calculated to define variability. The influence of the 4 factors on variability was studied. RESULTS: One observer assigned a significantly higher score than the other 2, who had been trained together. Interobserver variability decreased as follow-up time increased. Interobserver correlation coefficients became higher, with smaller differences between observers for progression scores than for absolute scores. Increasing the number of measurements within a patient series led to higher scores. Intraobserver correlation coefficients were high, and a training effect occurred when the time between measurements was 1 year, resulting in lower scores. CONCLUSIONS: This study demonstrates that, and shows how, the investigated factors influence the variability of the modified Sharp method. It is extremely important to take interobserver variation into account when designing protocols for multicenter clinical trials. A progression scoring method is recommended for studies assessing radiographic damage or clinical trials.

van Heereveld HA, Laan RF, van den Hoogen FH, Malefijt MC, Novakova IR, van de Putte LB. · Department of Rheumatology, University Hospital, Nijmegen, The Netherlands. · Ann Rheum Dis. · Pubmed #11557656 links to  free full text

Abstract: The need for prevention of venous thromboembolism (VTE) after total hip or knee replacement is obvious. However, the optimal regimen to achieve this remains to be defined. In patients with rheumatoid arthritis (RA) long term coumarins may not be necessary owing to the use of non-steroidal anti-inflammatory drugs (NSAIDs). 103 patients in whom 151 surgical procedures were performed (55 hip and 96 knee prostheses) were treated only with short term subcutaneous heparin. NSAIDs were used daily in 85% of the patients, and they were continued after hospital discharge. Only one patient developed symptomatic deep venous thrombosis during one year follow up. Bleeding complications were seen in 20/151 (13%) of the surgical procedures, all clinically judged as minor, and recovery was not delayed except in one case. Short term (low molecular weight) heparin appears to be an adequate, simple, and safe method for prevention of symptomatic VTE in patients with RA after knee or hip replacement, though further studies are necessary to confirm these preliminary findings.

Bullens PH, van Loon CJ, de Waal Malefijt MC, Laan RF, Veth RP. · Department of Orthopaedic Surgery, and Department of Rheumatic Diseases, University Hospital Nijmegen, Nijmegen, The Netherlands. · J Arthroplasty. · Pubmed #11547372 No free full text.

Abstract: We used a visual analog scale (VAS) to assess the satisfaction after total knee arthroplasty (TKA) in a group of 108 patients (126 TKAs) with short-term to medium-term follow-up. We also used the Knee Society scoring system, Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC), pain VAS, and survival analysis. A comparison between the subjective and objective outcome systems revealed only poor correlations. This comparison suggests that the concerns and priorities of patients and surgeons differ. The outcome assessed with the satisfaction VAS revealed a significantly better subjective outcome in rheumatoid arthritis patients compared with osteoarthritis patients, whereas Knee Society scores were not different. The satisfaction VAS provides additional information about subjective outcome after TKA.