Disease activity-guided dose optimisation including discontinuation of TNF-inhibitors in rheumatoid arthritis is effective for up to 10 years: an observational follow-up of the DRESS study.

OBJECTIVES: To investigate safety and effectiveness of disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis over 10 years. METHODS: Observational long-term extension of a randomised study of participants who completed the 3-year extension of the DRESS-study. After the randomised phase (month 0-18), disease activity-guided dose optimisation was allowed for all. Main outcomes were mean time-weighted DAS28-CRP; biological and targeted synthetic anti-rheumatic drug (b/tsDMARD) use per year as proportion of daily defined dose; proportion of patients reaching discontinuation; durability, effectiveness of subsequent dose reduction attempts; and radiographic progression between 3 and 10 years using the Sharp-van der Heijde score. RESULTS: 170 patients were included of whom 127 completed 10-year follow-up. The mean disease activity remained low (DAS28-CRP 2.13, 95% confidence interval 2.10-2.16), whilst the b/tsDMARD dose reduced from 97% at baseline (95%CI 96% to 99%, n = 170)% to56% at year 10 (49% to 63%, n = 127). 119 of 161 participants (74%) with an optimisation attempt reached discontinuation, with a median duration of 7 months (interquartile range 3-33 months), and 25 participants never had to restart their b/tsDMARD (21%, 14% to 29%). The mean dose reduction after dose optimisation was 48% (n = 159) for the first optimisation attempt and 33% for subsequent attempt (n = 86). 48% (41/86) of participants had radiographic progression exceeding the smallest detectable change (5.7 units), and progression was associated with disease activity, not b/tsDMARD use. CONCLUSION: Long-term disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis, including discontinuation and multiple tapering attempts, remains safe and effective.

Limited Diagnostic and Prognostic Value of Routine Radiographs in Newly Presenting Arthritis Suspected of Rheumatoid Arthritis: A Retrospective Study.

OBJECTIVE: Current recommendations suggest that patients with newly presenting arthritis suspected of rheumatoid arthritis (RA) should undergo routine radiographs of hands and feet (X-HF) as the presence of RA-associated erosions might be of diagnostic and prognostic value. Our objective was to investigate the prevalence, diagnostic, and prognostic value of RA-associated erosions seen on routine X-HF in a large, recent cohort of patients with newly presenting arthritis. METHODS: A retrospective cohort study was performed between 2016 and 2019 in patients with newly presenting arthritis suspected of RA. Patients were included if arthritis was present at diagnosis, rheumatoid factor and anticitrullinated protein antibodies were measured, RA was noted in the differential diagnosis, and routine X-HF were conducted. Outcomes were the prevalence of one or more RA-associated erosion(s), and whether diagnostic or prognostic classification were changed by erosivity. Seronegative patients, patients without acute phase reactants, and patients with longer symptom duration were analyzed as subgroups. RESULTS: RA-associated erosions were found in 32 of 724 patients (4.4%, 95% confidence interval [95% CI] 3.1-6.2). Erosions led to a change of diagnostic classification in two patients (0.3%, 95% CI 0.01-1.1) and changed prognostic classification in three patients (0.4%, 95% CI 0.1-1.3). Seronegative patients and patients without elevated acute phase reactants had significantly lower prevalence of erosions (χ2 9.4, P = 0.002, χ2 6.5, P = 0.01). Longer symptom duration was not associated with a different prevalence of erosions (χ2 0.4, P = 0.81). CONCLUSION: The recommendation of conducting routine X-HF in patients with newly presenting arthritis suspected of RA might be reconsidered due to low prevalence of early erosive disease and lack of diagnostic and prognostic value.

Therapy with JAK inhibitors or bDMARDs and the risk of cardiovascular events in the Dutch rheumatoid arthritis population.

OBJECTIVE: Caution has been advocated recently when using Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) patients with an unfavorable cardiovascular risk profile. We aimed to compare the incidences in cardiovascular events between JAKi or bDMARDs in a large population of RA patients. METHODS: RA patients starting a new bDMARD or JAKi between August 1st 2018 and January 31st 2022 have been selected from IQVIA's Dutch Real-World Data Longitudinal Prescription database, covering about 63% of outpatient prescriptions in the Netherlands. Study outcome was a cardiovascular event, defined as the start of platelet aggregation inhibitors during study period. The incidence densities of cardiovascular events were compared between JAKi and bDMARDs using multilevel Poisson regression, adjusted for exposition time and confounders. RESULTS: 15 191 unique patients were included, with 28 481 patient-years on treatment with either JAKi (2,373) or bDMARDs (26 108). Most patients were female (72%) and median age was 62 years. We found 36 cardiovascular events (1.52 events/100 patient years) during therapy with JAKi and 383 events (1.47 events/100 patient years) during therapy with bDMARDs, respectively, resulting in an adjusted incidence rate ratio (IRR) of 0.99 for JAKi compared with bDMARDs (95% confidence interval (CI), 0.70-1.41). Sub-analyses in patients >65 years, by sex, or separately for tofacitinib and baricitinib, yielded similar results. CONCLUSION: In a large Dutch general RA population, the risk of cardiovascular events seems not different between JAKi users and those using bDMARDs, although a small increase in higher risk patients cannot be excluded.

Beliefs of rheumatologists and general practitioners on urate lowering therapy: a cross-sectional study.

Objective: To describe beliefs of physicians and patients in primary and secondary care about urate-lowering therapy (ULT), to examine differences in physicians' medication beliefs and to examine the association of physicians' medication beliefs with the prescribed dosage of ULT, gout outcomes and patients' medication beliefs. Methods: We conducted a cross-sectional study among rheumatologists and general practitioners (GPs) and their patients using ULT in The Netherlands. All participants filled out the Beliefs About Medication Questionnaire (BMQ). Demographics of physicians were collected through questionnaires. Patient and disease characteristics were collected through questionnaires and electronic medical records. Differences between rheumatologists and GPs in the BMQ subscales Necessity and Concern and the necessity-concern difference (NCD) score were analysed by two-sample t-tests. Multilevel analyses were performed to examine the association of physicians' BMQ scores with the prescribed dosage of ULT, gout outcomes (number of gout flares, serum urate) and patients' BMQ scores. Results: A total of 28 rheumatologists, 443 rheumatology patients, 45 GPs and 294 GP patients were included. The mean NCD scores were 7.1 (s.d. 3.6), 4.0 (s.d. 4.0), and 4.2 (s.d. 5.0) for rheumatologists, GPs and patients, respectively. Rheumatologists scored higher on necessity beliefs [mean difference 1.4 (95% CI 0.0, 2.8)] and lower on concern beliefs [mean difference -1.7 (95% CI -2.7, -0.7)] compared with GPs. No associations between physicians' beliefs and prescribed dosage of ULT, gout outcomes or patients' beliefs were found. Conclusion: Rheumatologists had higher necessity and lower ULT concern beliefs compared with GPs and patients. Physicians' beliefs were not related to prescribed ULT dosage and patient outcomes. The role of physicians' beliefs in gout management in patients using ULT seems limited. Future qualitative research can provide more insights into physicians' views of gout management.

Urate-lowering therapy following a treat-to-target continuation strategy compared to a treat-to-avoid-symptoms discontinuation strategy in gout patients in remission (GO TEST Finale): study protocol of a multicentre pragmatic randomized superiority trial.

BACKGROUND: Long-term gout treatment is based on reducing serum urate levels using urate-lowering therapy (ULT). Most guidelines recommend using a lifelong continuation treat-to-target (T2T) strategy, in which ULT is dosed or combined until a serum urate target has been reached and maintained. However, a frequently used alternative strategy in clinical practice is a treat-to-avoid-symptoms (T2S) ULT discontinuation strategy, with the possibility of restarting the medication. This latter strategy aims at an acceptable symptom state, regardless of serum urate levels. High-quality evidence to support either strategy for patients in prolonged remission while using ULT is lacking. METHODS: We developed an investigator-driven pragmatic, open-label, multicentre, randomized, superiority treatment strategy trial (GO TEST Finale). At least 278 gout patients using ULT who are in remission (>12 months, preliminary gout remission criteria) will be randomized 1:1 to a continued T2T strategy (treatment target serum urate < 0.36 mmol/l) or switched to a T2S discontinuation strategy in which ULT is tapered to stop and restarted in case of (persistent or recurrent) flaring. The primary outcome is the between-group difference in the proportion of patients not in remission during the last 6 months of 24 months follow-up and will be analyzed using a two proportion z test. Secondary outcomes are group differences in gout flare incidence, reintroduction or adaptation of ULT, use of anti-inflammatory drugs, serum urate changes, occurrence of adverse events (with a special interest in cardiovascular and renal events), and cost-effectiveness. DISCUSSION: This study will be the first clinical trial comparing two ULT treatment strategies in patients with gout in remission. It will contribute to more specific and unambiguous guideline recommendations and improved cost-effectiveness of long-term gout treatment. It also paves the way (exploratory) to individualized long-term ULT treatment. In this article, we elaborate on some of our trial design choices and their clinical and methodological consequences. TRIAL REGISTRATION: International Clinical Trial Registry Platform (ICTRP) NL9245. Registered on 2 February 2021 (METC Oost-Nederland NL74350.091.20); EudraCT EUCTR2020-005730-15-NL. Registered on 11 January 2021.

[Methotrexate to prevent progression to rheumatoid arthritis?] / Methotrexaat om reumatoïde artritis te voorkomen?

The TREAT EARLIER was aimed at testing whether methotrexate could prevent the evolution from clinically suspect arthralgia to Rheumatoid Arthritis. Although the primary outcome was negative, symptoms did improve during and after use of methotrexate. Here we discuss how to interpret these findings, and place the study in the existing evidence.

The added value of predictive biomarkers in treat-to-target strategies for rheumatoid arthritis patients: a conceptual modelling study.

OBJECTIVES: To quantify the additional value of a hypothetical biomarker predicting response to treatment for RA regarding efficacy and costs by using a modelling design. METHODS: A Markov model was built comparing a usual care T2T strategy with a biomarker-steered strategy for RA patients starting biologic therapy. Outcome measures include time spent in remission or low disease activity (LDA) and costs. Four additional scenario analyses were performed by varying biomarker or clinical care characteristics: (i) costs of the biomarker; (ii) sensitivity and specificity of the biomarker; (iii) proportion of eligible patients tapering; and (iv) medication costs. RESULTS: In the base model, patients spent 2.9 months extra in LDA or remission in the biomarker strategy compared with usual care T2T over 48 months. Total costs were €43 301 and €42 568 for, respectively, the usual care and biomarker strategy, and treatment costs accounted for 91% of total costs in both scenarios. Cost savings were driven due to patients in the biomarker strategy experiencing remission or LDA earlier, and starting tapering sooner. Cost-effectiveness was not so much driven by costs or test characteristics of the biomarker (scenario 1/2), but rather by the level of early and proactive tapering and drug costs (scenarios 3/4). CONCLUSIONS: The use of a biomarker for prediction of response to b/tsDMARD treatment in RA can be of added value to current treat-to-target clinical care. However, gains in efficacy are modest and cost gains are depending on a combination of early proactive tapering and high medication costs.

Effect of metformin use on clinical outcomes and serum urate in gout patients with diabetes mellitus: a retrospective cohort study.

OBJECTIVE: Gout and diabetes mellitus type 2 (DM) frequently co-exist. The pharmacological effects of metformin may include anti-inflammatory and urate lowering effects. The objective of this study was to test these effects in patients with gout starting uric acid lowering treatment (ULT) in secondary care. METHODS: Retrospective cohort study including patients with gout and DM starting ULT. Differences in the incidence density of gout flares, proportion of patients reaching target sUA in the first six months after starting ULT, and difference in mean allopurinol dose at sUA target were compared between users of metformin and users of other or no anti-diabetic drugs (control group). Correction for confounding was applied. RESULTS: A total of 307 patients were included, of whom 160 (52.1%) used metformin. The incidence of flares was 1.61 and 1.70 in the first six months for respectively the metformin group and control group. The incidence rate ratio for gout flares was not significant (0.95, 95% CI 0.78 to 1.14). At six months, 62.8% and 54.9% reached target sUA in the metformin and control group respectively, corrected odds ratio of 1.09 (95% CI 0.66 to 1.80). There was no difference in mean allopurinol dose at sUA target 266 mg for metformin users and 236 mg for the control group, difference 30 mg (95% CI - 4.7 to 65.5). CONCLUSIONS: In conclusion we could not confirm a clinically relevant anti-inflammatory or urate lowering effect of metformin in patients starting ULT treatment and receiving usual care flare prophylaxis.

Extra-articular findings with FDG-PET/CT in rheumatoid arthritis patients: more harm than benefit.

Objective: Whole-body PET with CT scanning using 18F-fluorodeoxyglucose (18F-FDG) is used occasionally in RA patients to detect arthritis. FDG-PET/CT might also detect malignancies, but the amount of incidental findings and the number of relevant malignant diseases that could be missed are currently unknown. We aimed to study the malignancy screening performance of whole-body FDG-PET/CT in longstanding RA patients with low disease activity. Methods: FDG-PET/CT scanning was done in the intervention arm of the Dose REduction Strategy of Subcutaneous TNF-inhibitors (DRESS) study, a randomized controlled trial on dose-tapering of biological DMARDs. The reference standard was clinical diagnosis of malignancy during the 3-year follow-up period of the study. Prevalence of extra-articular abnormalities, follow-up and treatments were summarized post hoc. Results: One hundred and twenty-one scans were carried out in 79 patients. Extra-articular abnormalities were found in 59 of 121 (49%) scans, resulting in additional diagnostic procedures in 21 of 79 (26.6%) patients. Nine patients (7.4%) were suspected of malignancy; none turned out to be malignant. Six clinical malignancies that developed during follow-up were all negative on baseline FDG-PET/CT. Conclusion: Whole-body FDG-PET/CT scanning used in RA patients for imaging of arthritis results in frequent incidental extra-articular findings, whereas some who apparently had normal scans also developed malignancies. Trial registration: Netherlands Trial Register, www.trialregister.nl, NL6771.

[Gout: an overview of diagnostics and treatment]. / Jicht.

Gout is characterized by acute arthritis due to the deposition of urate crystals in joints in a state of hyperuricemia. Gout is a clinical diagnosis and can be confirmed with a joint aspiration to examine the synovial fluid with a polarized light microscopy. If a joint aspiration is not feasible or inconclusive, ultrasound or Dual Energy Computed Tomography (DECT) can be considered. Pharmacological treatment of gout consists of treating acute flares with anti-inflammatory drugs and, if indicated, of urate lowering therapies (ULT). (Inter)national rheumatology guidelines recommend the use of ULT indefinite by a treat-to-target approach, but there is discussion whether (certain) patients might also be treated by a treat-to-avoid-symptoms approach. Two large Dutch trials are comparing these strategies in gout patients. Most gout patients have cardiovascular and metabolic comorbidities and therefore an indication for cardiovascular risk assessment.

18F-FDG PET-CT in rheumatoid arthritis patients tapering TNFi: reliability, validity and predictive value.

OBJECTIVES: To investigate the reliability and validity of fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT scanning (FDG-PET) in RA patients with low disease activity tapering TNF inhibitors (TNFis) and its predictive value for successful tapering or discontinuation. METHODS: Patients in the tapering arm of the Dose REduction Strategies of Subcutaneous TNFi study, a randomized controlled trial of TNFi tapering in RA, underwent FDG-PET before tapering (baseline) and after maximal tapering. A total of 48 joints per scan were scored both visually [FDG-avid joint (FAJ), yes/no] and quantitatively [maximal and mean standardized uptake values (SUVmax and SUVmean)]. Interobserver agreement was calculated in 10 patients at baseline. Quantitative and visual FDG-PET scores were investigated for (multilevel) association with clinical parameters both on a joint and patient level and for the predictive value at baseline and the change between baseline and maximal tapering (Δ) for successful tapering and discontinuation at 18 months. RESULTS: A total of 79 patients underwent FDG-PET. For performance of identification of FAJs on PET, Cohen's κ was 0.49 (range 0.35-0.63). For SUVmax and SUVmean, intraclass correlation coefficients were 0.80 (range 0.77-0.83) and 0.96 (0.9-1.0), respectively. On a joint level, swelling was significantly associated with SUVmax and SUVmean [B coefficients 1.0 (95% CI 0.73, 1.35) and 0.2 (0.08, 0.32), respectively]. On a patient level, only correlation with acute phase reactants was found. FDG-PET scores were not predictive of successful tapering or discontinuation. CONCLUSIONS: Quantitative FDG-PET arthritis scoring in RA patients with low disease activity is reliable and has some construct validity. However, no predictive values were found for FDG-PET parameters for successful tapering and/or discontinuation of TNFi.

[Topical NSAIDs: ineffective or undervalued?] / Topicale NSAID's: ineffectief of ondergewaardeerd?

Topical NSAIDs are currently recommended in several national and international guidelines for knee osteoarthritis, hand osteoarthritis and acute musculoskeletal pain. However, there is still widespread skepticism about the effectiveness of this treatment. This article discusses different reasons for this skepticism, a short summary of the pharmacokinetics and pharmacodynamics of topical NSAIDs and an overview of available evidence regarding efficacy and safety. Based on this evidence topical NSAIDs have a clear place in the treatment of knee and hand osteoarthritis and acute musculoskeletal pain. Due to less systemic side effects they should be recommended before an oral NSAID is considered. Topical NSAIDs might even be an option for patients with contra-indications for oral NSAIDs. There is a large variety of available topical NSAIDs. Of the available topical NSAIDs in the Netherlands, diclofenac gel seems the most sensible choice.

Sex differences in response to allopurinol and benzbromarone in gout: a retrospective cohort study.

OBJECTIVE: Owing to lower mean uric acid excretion in women compared with men, uricosuric agents might be preferred in women over xanthine oxidase (XO) inhibitors. We therefore investigated the differences in response to two urate-lowering therapies (ULTs) with different modes of action within and between sexes. METHODS: This retrospective cohort study included patients with a clinical diagnosis of gout who started allopurinol and/or benzbromarone. The successful response to ULT, defined as reaching a serum uric acid (sUA) target of <0.36 mmol/l within 6 months after commencing ULT, was compared between allopurinol and benzbromarone in women and men. Effect modification by sex on differences in response was evaluated. RESULTS: Allopurinol was started in 255 women and 1045 men, and benzbromarone in 60 women and 205 men. After 6 months, the proportions of women reaching the sUA target were 58.4% and 66.7% for allopurinol and benzbromarone, respectively (difference, -8%; 95% CI: -22%, 5%). The respective proportions in men were 61.0% and 75.6%, respectively (difference, -15%; 95% CI: -21%, -8%). Corrected for confounding, the odds ratio (OR) of reaching the target on benzbromarone vs allopurinol within women was 0.91 (95% CI: 0.47, 1.75), and within men 1.55 (95% CI: 1.04, 2.32). Corrected for confounding, sex was not an effect modifier of the difference in allopurinol and benzbromarone response (OR, 0.59; 95% CI: 0.28, 1.24). CONCLUSION: This study did not demonstrate between-sex differences regarding the response to either a uricosuric agent or an XO inhibitor, negating different treatment choices by sex.

Therapeutic drug monitoring of adalimumab in RA: no predictive value of adalimumab serum levels and anti-adalimumab antibodies for prediction of response to the next bDMARD.

BACKGROUND: After adalimumab treatment failure, tumour necrosis factor inhibition (TNFi) and non-TNFi biological disease-modifying anti-rheumatic drugs (bDMARDs) are equally viable options on a group level as subsequent treatment in rheumatoid arthritis (RA) based on the current best evidence synthesis. However, preliminary data suggest that anti-adalimumab antibodies (anti-drug antibodies, ADA) and adalimumab serum levels (ADL) during treatment predict response to a TNFi as subsequent treatment. OBJECTIVE: To validate the association of presence of ADA and/or low ADL with response to a subsequent TNFi bDMARD or non-TNFi bDMARD. Sub-analyses were performed for primary and secondary non-responders. METHODS: A diagnostic test accuracy retrospective cohort study was done in consenting RA patients who discontinued adalimumab after >3 months of treatment due to inefficacy and started another bDMARD. Inclusion criteria included the availability of (random timed) serum samples between ≥8 weeks after start and ≤2 weeks after discontinuation of adalimumab, and clinical outcome measurements Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) between 3 to 6 months after treatment switch. Test characteristics for EULAR (European League Against Rheumatism) good response (DAS28-CRP based) after treatment with the next (non-)TNFi bDMARD were assessed using area under the receiver operating characteristic and sensitivity/specificity. RESULTS: 137 patients were included. ADA presence was not predictive for response in switchers to a TNFi (sensitivity/specificity 18%/75%) or a non-TNFi (sensitivity/specificity 33%/70%). The same was true for ADL levels in patients that switched to a TNFi (sensitivity/specificity 50%/52%) and patients that switched to a non-TNFi (sensitivity/specificity 32%/69%). Predictive value of ADA and ADL were similar for both primary and secondary non-responders to adalimumab. CONCLUSIONS: In contrast to earlier research, we could not find predictive value for response to a second TNFi or non-TNFi for either ADA or random timed ADL.

[Medicines: what has the last decade given us and what can we expect in the coming 10 years?] / Geneesmiddelen: 10 jaar terug en vooruitkijken.

Recent years have seen important changes in pharmacology. New techniques have been developed which are increasingly aimed at smaller groups of patients or even individual patients. In the past, thousands of chemical molecules were tested on a potential molecular target and the most effective molecules were selected. Nowadays a growing number of drugs are designed to aim at a specific molecular target, an example being monoclonal antibodies. There are developments that go fundamentally further and enable patients to be treated in an increasingly targeted and individual manner. These new therapies (i.e., Advanced Therapy Medicinal Products) are based on different principles than those of classical pharmacotherapy, and require different risk assessments as well as a different regulatory system. In this paper we discuss a selection of the developments in pharmacotherapy that have taken place during the past decade. In addition, we look into what sort of developments can be expected in the future.

Down-titration and discontinuation strategies of tumour necrosis factor-blocking agents for rheumatoid arthritis in patients with low disease activity.

BACKGROUND: Anti-tumour necrosis factor (TNF) agents are effective in treating people with rheumatoid arthritis (RA), but are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. This is an update of a Cochrane Review published in 2014. OBJECTIVES: To evaluate the benefits and harms of down-titration (dose reduction, discontinuation, or disease activity-guided dose tapering) of anti-TNF agents on disease activity, functioning, costs, safety, and radiographic damage compared with usual care in people with RA and low disease activity. SEARCH METHODS: We searched MEDLINE, Embase, Web of Science and CENTRAL (29 March 2018) and four trial registries (11 April 2018) together with reference checking, citation searching, and contact with study authors to identify additional studies. We screened conference proceedings (American College of Rheumatology and European League Against Rheumatism 2005-2017). SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in people with RA and low disease activity. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: One previously included trial was excluded retrospectively in this update because it was not an RCT/CCT. We included eight additional trials, for a total of 14 studies (13 RCTs and one CCT, 3315 participants in total) reporting anti-TNF down-titration. Six studies (1148 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Eight studies (2111 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (three studies assessed both anti-TNF discontinuation and dose reduction), and three studies assessed disease activity-guided anti-TNF dose tapering (365 participants). These studies included data on all anti-TNF agents, but primarily adalimumab and etanercept. Thirteen studies were available in full text, one was available as abstract. We assessed the included studies generally at low to moderate risk of bias; our main concerns were bias due to open-label treatment and unblinded outcome assessment. Clinical heterogeneity between the trials was high. The included studies were performed at clinical centres around the world and included people with early as well as established RA, the majority of whom were female with mean ages between 47 and 60. Study durations ranged from 6 months to 3.5 years.We found that anti-TNF dose reduction leads to little or no difference in mean disease activity score (DAS28) after 26 to 52 weeks (high-certainty evidence, mean difference (MD) 0.06, 95% confidence interval (CI) -0.11 to 0.24, absolute risk difference (ARD) 1%) compared with continuation. Also, anti-TNF dose reduction does not result in an important deterioration in function after 26 to 52 weeks (Health Assessment Questionnaire Disability Index (HAQ-DI)) (high-certainty evidence, MD 0.09, 95% CI 0.00 to 0.19, ARD 3%). Next to this, anti-TNF dose reduction may slightly reduce the proportion of participants switched to another biologic (low-certainty evidence), but probably slightly increases the proportion of participants with minimal radiographic progression after 52 weeks (moderate-certainty evidence, risk ratio (RR) 1.22, 95% CI 0.76 to 1.95, ARD 2% higher). Anti-TNF dose reduction may cause little or no difference in serious adverse events, withdrawals due to adverse events and proportion of participants with persistent remission (low-certainty evidence).Results show that anti-TNF discontinuation probably slightly increases the mean disease activity score (DAS28) after 28 to 52 weeks (moderate-certainty evidence, MD 0.96, 95% CI 0.67 to 1.25, ARD 14%), and that the RR of persistent remission lies between 0.16 and 0.77 (low-certainty evidence). Anti-TNF discontinuation increases the proportion participants with minimal radiographic progression after 52 weeks (high-certainty evidence, RR 1.69, 95% CI 1.10 to 2.59, ARD 7%) and may lead to a slight deterioration in function (HAQ-DI) (low-certainty evidence). It is uncertain whether anti-TNF discontinuation influences the number of serious adverse events (due to very low-certainty evidence) and the number of withdrawals due to adverse events after 28 to 52 weeks probably increases slightly (moderate-certainty evidence, RR 1.46, 95% CI 0.75 to 2.84, ARD 1% higher).Anti-TNF disease activity-guided dose tapering may result in little or no difference in mean disease activity score (DAS28) after 72 to 78 weeks (low-certainty evidence). Furthermore, anti-TNF disease activity-guided dose tapering results in little or no difference in the proportion of participants with persistent remission after 18 months (high-certainty evidence, RR 0.89, 95% CI 0.75 to 1.06, ARD -9%) and may result in little or no difference in switching to another biologic (low-certainty evidence). Anti-TNF disease activity-guided dose tapering may slightly increase proportion of participants with minimal radiographic progression (low-certainty evidence) and probably leads to a slight deterioration of function after 18 months (moderate-certainty evidence, MD 0.2 higher, 0.02 lower to 0.42 higher, ARD 7% higher), It is uncertain whether anti-TNF disease activity-guided dose tapering influences the number of serious adverse events due to very low-certainty evidence. AUTHORS' CONCLUSIONS: We found that fixed-dose reduction of anti-TNF, after at least three to 12 months of low disease activity, is comparable to continuation of the standard dose regarding disease activity and function, and may be comparable with regards to the proportion of participants with persistent remission. Discontinuation (also without disease activity-guided adaptation) of anti-TNF is probably inferior to continuation of treatment with respect to disease activity, the proportion of participants with persistent remission, function, and minimal radiographic damage. Disease activity-guided dose tapering of anti-TNF is comparable to continuation of treatment with respect to the proportion of participants with persistent remission and may be comparable regarding disease activity.Caveats of this review are that available data are mainly limited to etanercept and adalimumab, the heterogeneity between studies, and the use of superiority instead of non-inferiority designs.Future research should focus on the anti-TNF agents infliximab and golimumab; assessment of disease activity, function, and radiographic outcomes after longer follow-up; and assessment of long-term safety, cost-effectiveness, and predictors for successful down-titration. Also, use of a validated flare criterion, non-inferiority designs, and disease activity-guided tapering instead of fixed-dose reduction or discontinuation would allow researchers to better interpret study findings and generalise to clinical practice.

Predictive value of serum calprotectin (S100A8/A9) for clinical response after starting or tapering anti-TNF treatment in patients with rheumatoid arthritis.

OBJECTIVES: Calprotectin (S100A8/A9) has been correlated with disease activity in rheumatoid arthritis (RA). The aim of this study was to investigate the predictive value of serum calprotectin for clinical response after starting and tapering anti-tumour necrosis factor treatment in RA. METHODS: Serum samples and clinical outcomes were derived from two longitudinal RA studies.At baseline (starting or tapering of adalimumab or etanercept), calprotectin levels were determined by ELISA. In the Biologic Individual Optimised Treatment Outcome Prediction (BIO-TOP) study, treatment effect was assessed after 6 months using the European League Against Rheumatism (EULAR) response criteria. In the Dose Reduction Strategies of Subcutaneous TNF Inhibitors (DRESS) study, patients were classified at 18 months as being successfully dose reduced, discontinued or not able to reduce the dose. Area under the receiver operating characteristic curves (AUC) were generated to evaluate the predictive value of calprotectin and logistic prediction models were created to assess its added value. RESULTS: In the BIO-TOP study, calprotectin levels were higher in responders (n=50: 985 ng/mL (p25-p75: 558-1417)) compared with non-responders (n=75: 645 ng/mL (p25-p75: 415-973), p=0.04).AUC for predicting EULAR good response was 0.61 (95% CI 0.50 to 0.71). The prediction model with calprotectin (AUC 0.77, 95% CI 0.68 to 0.85) performed similarly to the baseline model (AUC 0.74, 95% CI 0.65 to 0.82, p=0.29). In the DRESS study, calprotectin levels were similar between the three groups (n=47; n=19; n=36) and calprotectin was not predictive for clinical response after tapering. CONCLUSIONS: Serum calprotectin has some predictive value for clinical response after starting anti-TNF treatment, although it has no added value to other clinical factors. In patients with low disease activity, serum calprotectin is not predictive for clinical response after tapering anti-TNF treatment. TRIAL REGISTRATION NUMBER: NTR4647 (BIO-TOP study) and NTR3216 (DRESS study); Pre-results.

Therapeutic drug monitoring of biologicals in rheumatoid arthritis: a disconnect between beliefs and facts.

PURPOSE OF REVIEW: To give an overview of recently published articles covering therapeutic drug monitoring (TDM) of biological DMARDs (bDMARDs) in rheumatoid arthritis. RECENT FINDINGS: In the last 18 months, two clinical studies and nine reviews were found after a systematic literature search. Most (narrative) reviews conclude that TDM should be used to improve biological treatment in rheumatoid arthritis patients, whereas most of the clinical studies (including 13 studies identified earlier) whenever scrutinized do not support this conclusion. This disconnect between sobering data from prediction studies and test-treatment diagnostic studies and optimistic TDM beliefs in reviews is caused by failure to recognize incorrect study designs, false positives because of lack of validation after explorative multiple testing, cherry picking of studies, and incorrect interpretation of test characteristics. SUMMARY: Serum (anti)-drug level monitoring has been extensively studied in rheumatoid arthritis, but correctly designed and executed interventional prediction studies or test-treatment intervention studies are sparse and mostly negative. In contrast, many reviews advocate use of biological TDM in rheumatoid arthritis. On the basis of current evidence, therapeutic drug monitoring of biologicals cannot be recommended in the treatment of rheumatoid arthritis patients, although two clinical scenarios deserve further study.