Wietske Kievit

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.

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

AIM to 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. METHODS All 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. RESULTS The 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. CONCLUSION The 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.

Difference in the risk of serious infections in patients with rheumatoid arthritis treated with adalimumab, infliximab and etanercept: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry

Background Tumour necrosis factor (TNF)-inhibiting therapy increases the risk of serious infections in rheumatoid arthritis (RA). However, it is not clear whether this risk differs between TNF inhibitors. Objective To analyse whether the risk of serious infections in patients with RA treated with an anti-TNF inhibitor is different for adalimumab, infliximab and etanercept. Methods Data from the Dutch RA monitoring registry were used. Incidence rates were calculated from the observed number of first serious infections and follow-up time up to 5 years. A Cox proportional hazards model with time-to-first-serious infection was used to estimate risk differences among the anti-TNF treatment groups, with correction for confounders. Results The unadjusted incidence rate of a first serious infection in patients with RA per 100 patient-years was 2.61 (95% CI 2.21 to 3.00) for adalimumab, 3.86 (95% CI 3.33 to 4.40) for infliximab and 1.66 (95% CI 1.09 to 2.23) for etanercept. Age, year of starting anti-TNF therapy, comorbidities at baseline and disease activity score 28 over time were included as confounders. No difference in risk for serious infections was found between adalimumab and infliximab with an adjusted HR (adjHR) of 0.90 (95% CI 0.55 to 1.48). The risk of serious infections was significantly lower in etanercept than in both infliximab (adjHR=0.49 (95% CI 0.29 to 0.83)) and adalimumab (adjHR=0.55 (95% CI 0.44 to 0.67)). Conclusions The risk of serious infections in patients with RA treated with adalimumab or infliximab was similar, while the risk of serious infections in patients with RA treated with etanercept was lower than with both adalimumab and infliximab.

Cost effectiveness of a new strategy to identify HNPCC patients

Background: Distinguishing hereditary non-polyposis colorectal cancer (HNPCC) from non-hereditary colorectal cancer (CRC) can increase the life expectancy of HNPCC patients and their close relatives. Aim: To determine the effectiveness, efficiency, and feasibility of a new strategy for the detection of HNPCC, using simple criteria for microsatellite instability (MSI) analysis of newly detected tumours that can be applied by pathologists. Criteria for MSI analysis are: (1) CRC before age 50 years; (2) second CRC; (3) CRC and HNPCC associated cancer; or (4) adenoma before age 40 years. Methods: The efficacy and cost effectiveness of the new strategy was evaluated against current practice. Decision analytic models were constructed to estimate the number of extra HNPCC mutation carriers and the costs of this strategy. The incremental costs and gain in life expectancy for a HNPCC mutation carrier were evaluated by Markov modelling. Feasibility was explored in five hospitals. Results: Using the new strategy, 2.2 times more HNPCC patients can be identified among a CRC population compared with current practice. This new strategy was found to be cost effective with an expected cost effectiveness ratio of €3801 per life year gained. When including the group of siblings and children, the cost effectiveness ratio became €2184 per life year gained. Sensitivity analysis showed these findings to be robust. Conclusions: MSI testing in a selection of newly diagnosed CRC patients was shown to be cost effective and a feasible method to identify patients at risk for HNPCC who are not recognised by family history.

Long-term effectiveness and safety of TNF-blocking agents in daily clinical practice: results from the Dutch Rheumatoid Arthritis Monitoring register

OBJECTIVES Experience with anti-TNF agents for a decade can be used to research the safety and effectiveness of anti-TNF agents in the long term. The objective of this article is to describe drug survival, disease activity, daily functioning, quality of life and adverse events of TNF-blocking agents in daily clinical practice after 5 years of follow-up. METHODS Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register of 1560 RA patients were used for analyses (5-year follow-up, n=174). Drug survival and time to first serious infection or malignancy were analysed by Kaplan-Meier analysis. Several outcome measures at several follow-up moments were analysed per intention to treat and per protocol. RESULTS The 5-year drug survival of the first anti-TNF was 45%, and 60% for total use of TNF-blocking agents. Baseline 28-joint DAS (DAS-28) was 5.1 (s.d. 1.3). After 5 years, the mean DAS-28 was 3.2 (s.d. 1.3) in all patients who had started with TNF-blocking agents and 2.9 (s.d. 1.1) in patients who were still on TNF-blocking agents. In the latter group, the HAQ score was 0.88 (s.d. 0.7) and the EuroQol five dimensions (EQ-5D) utility score was 0.7 (s.d. 0.2). Incidence rates of serious infections and malignancies were 2.9 and 0.6 per 100 patient-years, respectively. CONCLUSION Five-year follow-up of RA patients treated with TNF-blocking agents showed a 60% drug survival accompanied by sustained low disease activity, normalized function and quality of life similar to that in the general population. The benefit to risk ratio for long-term TNF-blocking therapy remains favourable.

The effectiveness and medication costs of three anti-TNF agentsα in the treatment of rheumatoid arthritis from prospective clinical practice data

AIM to 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. METHODS All 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. RESULTS The 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. CONCLUSION The 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.

Down-titration and discontinuation of infliximab in rheumatoid arthritis patients with stable low disease activity and stable treatment: an observational cohort study

Down-titration, or discontinuing infliximab, has proven to be feasible in RA patients. Therefore, our local treatment protocol includes tapering infliximab dose. This observational study describes the prevalence of successful down-titration in daily clinical practice and its effect on costs and quality of life (QoL). Methods Infliximab was down-titrated with 25% of the original dose (3 mg/kg) every 8–12 weeks without interval change until discontinuation or flare in all RA patients with stable low 28-joint disease activity score (DAS28) and stable treatment for >6 months. During 1 year DAS28, RA medication, outpatient clinic visits, RA related absenteeism and EuroQoL5D (European QoL questionnaire, EQ5D) were documented. Prevalence of successful down-titration and changes in DAS28, QoL and costs were described. Results In 16% (95% CI 6 to 26) and 45% (95% CI 31 to 59), respectively, infliximab could be discontinued or down-titrated. Mean infliximab dose decreased significantly from 224 mg (95% CI 212 to 236 mg) at start, to 130 mg (95% CI 105 to 154 mg) after 1 year. Median DAS28 increased from 2.5 (p25–75=2.0–2.9) to 2.8 (2.2–3.6) (p=0.002). Extra corticosteroids were given in 8% of the visits. Disease modifying antirheumatic drugs were seldom changed. There was no statistical difference in QoL after down-titration. Mean reduction in the costs was €3474 (95% CI 2457 to 4492) per patient. Conclusion In the majority of patients with stable low DAS28 and stable treatment, infliximab can be down-titrated or discontinued, which results in a considerable reduction in costs without influencing QoL.

Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial

Objective To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care. Design Randomised controlled, open label, non-inferiority strategy trial. Setting Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014. Participants 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care. Interventions Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated. Main outcome measures Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events. Results Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval −12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care. Conclusions A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients. Trial registration Dutch trial register (www.trialregister.nl), NTR 3216.

Current clinical selection strategies for identification of hereditary non-polyposis colorectal cancer families are inadequate: a meta-analysis.

Present guidelines to identify hereditary non‐polyposis colorectal cancer (HNPCC) families are criticized for limitations in accuracy. The Amsterdam criteria I and II (AC I and AC II) are used to predict a germline mutation in one of the mismatch repair genes. In families not fulfilling the AC I and AC II criteria, individual indications to test cancer specimens for microsatellite instability (MSI) are guided by the Bethesda Guidelines (BG). Germline mutation testing is then performed in patients who conform to the BG and show MSI. We investigated the sensitivity and specificity of AC I, AC II, and BG. A meta‐analysis of studies on the value of the AC I and AC II criteria for predicting germline mutation, as well as a meta‐analysis of BG for the detection of MSI was performed. For the AC I, sensitivity varied from 54 to 91% and specificity varied from 62 to 84%. For the AC II, the pooled sensitivity was 78% and specificity ranged between 46 and 68%. Post‐test probabilities of a positive test result were 0.61 and 0.46 for the AC I and AC II, respectively. Post‐test probabilities of a negative test result were 0.17 and 0.21 for the AC I and AC II, respectively. For the BG, the pooled sensitivity was 89% and pooled specificity was 53%. Post‐test probability of a positive test result was 41%, and post‐test probability of a negative test result was 9%. The sensitivity and specificity of the Amsterdam criteria for predicting a germline mutation that causes HNPCC is not sufficient. The BG are useful for the detection of MSI in a group of patients suspected of having familial colorectal cancer (CRC), but sensitivity is very low in the total group of newly diagnosed CRC patients. Therefore, a new strategy is needed for the identification of HNPCC.

'Happy' drug survival of adalimumab, etanercept and ustekinumab in psoriasis in daily practice care: results from the BioCAPTURE network

Drug survival is a marker for treatment success. To date, no analyses relating dermatological quality‐of‐life measures to drug survival have been published.