H.L.M. Brus

The efficacy of anti‐TNF in rheumatoid arthritis, a comparison between randomised controlled trials and clinical practice

Background: Randomised controlled trials (RCTs) evaluating the efficacy of antagonists to tumour necrosis factor α (TNFα) showed high response percentages in the groups treated with active drugs. Objective: To compare the efficacy of anti-TNF treatments for rheumatoid arthritis (RA) patients in RCTs and in daily clinical practice, with an emphasis on the efficacy for patients eligible and not eligible for RCTs of anti-TNF treatments. Methods: First, randomised placebo-controlled trials written in English for etanercept, infliximab and adalimumab for patients with RA were selected by a systematic review. Second, the DREAM (Dutch Rheumatoid Arthritis Monitoring) register with patients starting for the first time on one of the TNF-blocking agents was used. Patient characteristics, doses of medication and co-medication as well as the ACR20 response percentages were compared between RCTs and DREAM data, stratified for trial eligibility. Results: In 10 of 11 comparisons, the ACR20 response percentages were lower in daily clinical practice than in the RCT active drug group, which was significant in five of 11 comparisons. Only 34–79% of DREAM patients fulfilled the selection criteria for disease activity in the several RCTs examined. DREAM patients eligible for RCTs had higher response percentages than ineligible DREAM patients. ACR20 response percentages of eligible DREAM patients were comparable with the ACR20 response percentages of the RCT active drug group in 10 of 11 comparisons. Conclusion: The efficacy of TNF-blocking agents in RCTs exceeded the efficacy of these drugs in clinical practice. However, in clinical practice more patients with lower disease activity were treated with TNF-blocking agents compared with those treated in RCTs. For daily practice patients who were eligible for RCTs, responses were more similar to responses reached in RCTs.

Effects of patient education on compliance with basic treatment regimens and health in recent onset active rheumatoid arthritis

OBJECTIVES To determine the effects of patient education on compliance and on health in patients with active, recent onset rheumatoid arthritis (RA). METHODS A randomised, controlled, assessor blinded, one year trial. The experimental group followed an education programme. All patients started on sulphasalazine therapy. Compliance with sulphasalazine was measured by pill counting. Compliance rates with regimens of physical exercise, endurance activities, and energy conservation were measured by questionnaires. Compliance with prescriptions of joint protection was scored using a test for joint protection performance. Health was measured by a Disease Activity Score (function of erythrocyte sedimentation rate, Ritchie score, and number of swollen joints), C reactive protein, Dutch-AIMS scores, and M-HAQ scores, range of motion of shoulder, elbow, and knee joints. Parameters were scored at baseline and after three, six, and 12 months. RESULTS Sixty of 65 patients gave informed consent, five of them withdrew from follow up. Compliance with sulphasalazine exceeded 80% with no differences between groups. Compliance with physical exercise (at three months), energy conservation (at three and at 12 months), and joint protection (at three months) improved significantly more in the experimental group. The improvements of health were not different in the groups. CONCLUSION Compliance with sulphasalazine among patients with active, recent onset RA is high, whether formal patient education is followed or not. Compliance with physical exercise, energy conservation, and joint protection was increased by patient education. Formal patient education did not improve health status.

The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data.

AIMnto evaluate the effects of adalimumab, etanercept and infliximab on disease activity, functional ability and quality of life and the medication costs in a naturalistic design.nnnMETHODSnAll patients from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register starting on tumour necrosis factor (TNF)alpha-blocking agents for the first time were monitored and assessed by trained research nurses every 3 months. The primary outcome was the Disease Activity Score (DAS28) course over the 12 months follow-up, analysed by linear mixed models. Secondary outcomes were the Health Assessment Questionnaire (HAQ), EuroQol five dimensions (EQ-5D) and the Short-Form 36 items (SF36) scores, and medication-related total costs.nnnRESULTSnThe DAS28 and SF-36 physical component scale decreased in all three medication groups over 12 months, but the decrease was larger for adalimumab and etanercept in comparison to infliximab (p<0.001). The analyses of the HAQ and the EQ-5D scores showed the same (non-significant) trend, namely that at 12 months, the functionality and quality of life was better for adalimumab and etanercept patients. With regard to the medication costs, infliximab treatment resulted in significantly higher costs over the follow-up period than treatments with either adalimumab or etanercept. The comparison between adalimumab and etanercept showed a significant difference in the 12-month DAS28 course (p = 0.031). There were no additional indications for differences in effectiveness or costs between adalimumab and etanercept.nnnCONCLUSIONnThe evaluation of the effectiveness and costs showed that adalimumab and etanercept are more or less equal and favourable compared to infliximab in the first year of treatment.

The Reason for Discontinuation of the First Tumor Necrosis Factor (TNF) Blocking Agent Does Not Influence the Effect of a Second TNF Blocking Agent in Patients with Rheumatoid Arthritis

Objective. To investigate whether the reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent influences the effect of a second TNF blocking agent. Methods. Data were used from 2 Dutch registries including patients with rheumatoid arthritis (RA) treated with TNF blocking agents. Patients were divided into 3 groups based on reason for discontinuation of the first: nonresponse, loss of response, or adverse events. The primary outcome was the change from baseline of the disease activity (by DAS28) at 6 months, corrected for the baseline DAS28 score. Secondary outcomes were the change from baseline at 3 months, EULAR response rates, and the percentages of patients who reached a DAS28 score ≤ 3.2 at 3 and at 6 months. Results. In total, 49 patients who failed due to nonresponse, 75 due to loss of response, and 73 due to adverse events were included. At 6 months, the change of DAS28 score from baseline did not differ significantly between the groups (−0.6 to −1.3; p ≥ 0.173) and similar good and moderate response rates were found (12% to 18%, p ≥ 0.523, and 34% to 55%, p ≥ 0.078, respectively). The secondary outcomes were also comparable between the 3 groups. Conclusion. The results of our observational study suggest that a second TNF blocking agent may be effective after failure of the first, regardless of the reason for discontinuation of the first TNF blocking agent.

Frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in daily clinical practice

To describe the frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in the treatment of rheumatoid arthritis (RA) in daily clinical practice.

The provisional ACR/EULAR definition of remission in RA : a comment on the patient global assessment criterion

OBJECTIVESnThe provisional ACR/European League Against Rheumatism (EULAR) definition of remission in RA requires a score of ≤1 on the patient global assessment (PGA, 0-10 scale). We explored the relation between the PGA criterion and the patients clinical disease state in an observational dataset.nnnMETHODSnData of 512 newly diagnosed RA patients of the Dutch Rheumatoid Arthritis Monitoring (DREAM) remission induction cohort were analysed. Both 28-joint counts and more comprehensive joint counts (tender joint count-53, swollen joint count-44) were used.nnnRESULTSnACR/EULAR remission was present in 20.1% of the patients when using 28-joint counts and in 17.4% of the patients when applying more comprehensive joint counts. In 108 patients, the PGA score was >1 despite fulfilment of the remaining criteria (TJC28, SJC28 and CRP in mg/dl ≤1). Residual disease activity was observed in 31.5% (34/108) and median (interquartile range) scores on PGA, pain and fatigue were 2.4 (1.8-4.0), 2.0 (1.1-3.0) and 2.7 (1.3-5.0), respectively. Applying more comprehensive joint counts showed comparable results. In 19.5% (100/512) of patients, disease activity was absent (TJC53u2009=u20090, SJC44u2009=u20090, and CRP ≤1). In 41% (nu2009=u200941) of these patients, the PGA score was >1. Receiver operating characteristic analysis showed moderate accuracy of the PGA to discriminate between fulfilment and no fulfilment of all remaining criteria.nnnCONCLUSIONnFrequently, patients did not meet the PGA criterion despite a good clinical disease state. Apparently the PGA is not solely influenced by RA disease activity. In patients with marked divergence between the PGA and objective clinical measurements, caution should be taken when applying the provisional ACR/EULAR definition of remission.

Predictors for the 5-year risk of serious infections in patients with rheumatoid arthritis treated with anti-tumour necrosis factor therapy: a cohort study in the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry

OBJECTIVEnThe use of TNF inhibitors leads to an increased risk of serious infections in RA. Predicting this risk would facilitate the prevention of serious infections. The objective of this study was to identify which factors are predictive of the increased risk of serious infections in RA patients treated with TNF inhibiting therapy.nnnMETHODSnData from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry of 2044 patients with RA were used for the analyses. Data were censored at stopping TNF inhibitors or end of observation time up to 5 years. Univariate and multivariate analysis of baseline variables was performed using Cox regression with time to the first serious infection as dependent variable.nnnRESULTSnDuring a follow-up time of 5 years, 128 of 2044 (6.3%) patients developed a first serious infection with a total of 141 serious infections. The incidence rate in the first year after start of TNF inhibiting therapy was 4.57 first serious infections per 100 patient-years and 2.91 per 100 patient-years over 5 years. Age, corticosteroid use, visual analogue scale (VAS) pain, HAQ, tender joint count 28 joints (TJC28) and the presence of comorbidities were significant predictors for developing a serious infection during TNF inhibiting therapy in the multivariate model.nnnCONCLUSIONnAge, corticosteroid use, VAS pain, HAQ, TJC28 and the presence of comorbidities all at baseline were significant predictors for developing a serious infection during TNF inhibiting therapy in RA patients.

Effectiveness of a third tumor necrosis factor-α-blocking agent compared with rituximab after failure of 2 TNF-blocking agents in rheumatoid arthritis.

Objective. To compare the effectiveness of a third tumor necrosis factor-α (TNF-α)-blocking agent with rituximab after failure of 2 TNF-blocking agents in patients with rheumatoid arthritis (RA) in daily clinical practice. Methods. Patients receiving a third TNF-blocking agent or rituximab after failure of 2 TNF-blocking agents were selected from a Dutch biologic registry. The primary outcome was the results from the Disease Activity Score of 28 joints (DAS28) over the first 12 months after start of the third biologic using mixed-model analyses. Secondary outcomes included the course of the Health Assessment Questionnaire (HAQ) and the separate components of the DAS28 over the first 12 months and the change from baseline in DAS28 and HAQ at 3 and 6 months. Results. The overall course of the DAS28 over the first 12 months was significantly better for rituximab (p = 0.0044), as also observed for the HAQ, although the latter results were not statistically significant (p = 0.0537). The erythrocyte sedimentation rates, C-reactive protein, and swollen joint counts showed a better course for rituximab (p = 0.0008, p = 0.0287, p = 0.0547, respectively), but not the tender joint counts or visual analog scale for general health. DAS28 decreased significantly in both groups at 3 and 6 months (p ≤ 0.024), but the change in HAQ was significant for rituximab only at 3 months (p = 0.009). Conclusion. During the first 12 months of therapy, a larger improvement in disease activity and a trend toward a larger decrease in functional disability was observed in patients receiving rituximab. Switching to a biologic with another mechanism of action might be more effective after failure of 2 TNF-blocking agents in RA.

Evaluating guidelines on continuation of anti-tumour necrosis factor treatment after 3 months: clinical effectiveness and costs of observed care and different alternative strategies

Objective: To study the adherence of rheumatologists to the Dutch guidelines for anti-tumour necrosis factor alpha (TNF-α) treatment. The secondary objective was to evaluate alternatives to the present guidelines with regard to the percentage of responders and costs. Methods: The response (>1.2 DAS28 decrease) in patients who started on anti-TNF-α treatment for the first time was evaluated at 3 and 6 months after initiation. How many patients continued or discontinued their initial anti-TNF-α treatment was evaluated. Possible alternative guidelines were evaluated by means of a decision tree, with regard to the expected percentage of successfully (responders) and unsuccessfully treated patients and expected costs. Results: At 3 months 56% (N u200a=u200a 306) and 44% (N u200a=u200a 233) of all 539 evaluable patients were classified as responders or non-responders, respectively. Despite the guidelines, most (81%) (N u200a=u200a 189) of the non-responders continued treatment. 37% of the non-responders who continued anti-TNF-α treatment were eventually classified as responders at 6 months. Decision analytical modelling showed that with equal expected costs all alternative strategies would result in more responders than according to theoretical full adherence with the guidelines. “Continuation in case of partial response” had the best trade-off between successfully treated patients (64%) and unsuccessfully treated patients (17%). Conclusion: There was suboptimal adherence to the Dutch guidelines for treatment with anti-TNF-α for rheumatoid arthritis patients. This seemed to be justified by the fact that a delayed response up to 6 months was shown. If treatment is continued despite a non-response at 3 months, this is only recommended in patients with at least a partial response (at least 0.6 DAS28 improvement).

FRI0345 Tapering MTX in Patients with RA Using TNFI Treatment is Possible

Background Nowadays the focus is on tapering or stopping biological treatment in patients with rheumatoid arthritis (RA) because of the cost reduction. However, the use of methotrexate (MTX) can cause considerable burden for patients, therefore the quality of life of patients would increase if the MTX could be tapered or stopped. Objectives The objective of this study was: 1. to analyse if patients taper or stop MTX in daily practice while they are using Tumor Necrosis Factor inhibitor (TNFi) treatment and 2. the effect of taper or stop MTX on the effectiveness and the long term TNFi drug survival. Methods Data was obtained from the DREAM registry. Patients with RA started TNFi treatment in combination with MTX were included in this study. Drug survival of the TNFi was analysed using Cox proportional hazard model with taper or stop MTX as time-dependent covariate. Treatment effectiveness before and after taper or stop MTX was analysed using DAS28. Linear mixed models was used to analyse the difference of DAS28 over time (variable time) between taper and not taper (interaction term = no taper*time) and stop and not stop MTX. Analyses were corrected for possible confounders. Results Of the 1331 patients starting TNFi with MTX, 487 (36.6%) patients tapered their MTX and 177 of the 1331 (13.3%) stopped their MTX treatment. On average the DAS28 scores decrease after tapering (-0.39, -0.45) and after stopping MTX (-0.26, -0.06) at 6 and 12 month respectively. About 61% of the patients shows an improvement in DAS28 (DAS28<0), 18% shows an increase between 0 and 0.6 DAS28 scores, and 21% shows an increase of >0.6. On average patients that taper or stop have both stable DAS28 scores over time, the same course over time was showed, compared to patients that do not taper or stop MTX (Interaction no taper*time: B=0.00; CI=-0.01:0.00; p=0.339 and interaction no stop*time: B=0.00; CI=-0.01:0.01; p=0.647 respectively). Moreover, the long term drug survival of TNFi is even better in patients tapering MTX and the same in patients stopping MTX, see Table. Table 1. Cox proportional regression hazard model with time-dependent covariate Hazard ratio (95%CI) p-value Tapering MTX u2003Taper MTX 0.794 (0.654–0.963) 0.019 u2003Female gender 0.998 (0.832–1.197) 0.985 u2003Rheumatoid factor positive 0.890 (0.730–1.085) 0.248 u2003Erosions present 1.324 (1.095–1.600) 0.004 u2003Age 0.997 (0.990–1.004) 0.406 u2003Disease duration 1.004 (0.992–1.015) 0.529 Stopping MTX u2003Stop MTX 0.951 (0.730–1.239) 0.709 u2003Female gender 0.975 (0.833–1.140) 0.747 Conclusions In daily practice, patients with RA do taper or stop their MTX dose when using TNFi treatment. This does not seem to influence the average DAS28 over time or the long term TNFi drug survival. This indicates that the right/correct patients are chosen to taper or stop MTX treatment in daily practice which could increase the quality of life in these patients. Disclosure of Interest None declared