To evaluate predictors for successful biologic tapering among patients with inflammatory arthritis using baseline characteristics from the BIODOPT trial.
Adult patients with rheumatoid arthritis, ...psoriatic arthritis or axial spondyloarthritis on stable biologic dose and in low disease activity ≥12 months were enrolled. Participants were randomized (2:1) to disease activity-guided biologic tapering or continuation of baseline biologic. Patients achieving successful tapering reduced their biologic dose by ≥50%, had no protocol deviations and were in low disease activity at 18 months. Modified Poisson regression with robust variance estimator was applied.
In total, 142 patients were randomized to tapering (n = 95) or control (n = 47). Successful tapering was achieved by 32 and 2%, respectively. Tapering group was the only statistically significant independent predictor for successful tapering, risk ratio (RR): 14.0 (95% confidence interval CI: 1.9 to 101.3, P = .009). However, higher Short Form Health Survey 36 mental component summary (SF-36 MCS) was observed to be a predictor of potential importance, RR: 1.06 (95% CI: 0.99 to 1.13, P = .097). When limiting the analyses to the tapering group only, none of the baseline variables were statistically significant independent predictors but SF-36 MCS was still considered to be of potential importance, RR: 1.05 (95% CI: 0.99 to 1.12, P = .098).
Successful tapering is a reachable target for 1 in 3 patients with inflammatory arthritis who are interested in reducing their biological therapy. No statistically significant predictors (besides allocation to tapering) were identified. Future research on mental health and tapering is encouraged.
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•Biominerals present complex hierarchical structures that we exemplify by bone structure in this review.•Bone structure can be investigated by 3D X-ray imaging through combination of ...instrumentation adapted to the given question.•Modern 3D X-ray imaging methods afford insights from the nano- to the organ-scale structure of bone.•The structure of long bones from rodents and humans differ because rodents do not present Haversian remodeling.•Local tomography provides higher resolution but better data quality is obtained with samples cut to match the field of view.
Biominerals typically have complex hierarchical structures traversing many length scales. This makes their structural characterization complicated, since it requires 3D techniques that can probe full specimens at down to nanometer-resolution, a combination that is difficult – if not impossible – to achieve simultaneously. One challenging example is bone, a mineralized tissue with a highly complex architecture that is replete with a network of cells. X-ray computed tomography techniques enable multiscale structural characterization through the combination of various equipment and emerge as promising tools for characterizing biominerals. Using bone as an example, we discuss how combining different X-ray imaging instruments allow characterizing bone structures from the nano- to the organ-scale. In particular, we compare and contrast human and rodent bone, emphasize the importance of the osteocyte lacuno-canalicular network in bone, and finally illustrate how combining synchrotron X-ray imaging with laboratory instrumentation for computed tomography is especially helpful for multiscale characterization of biominerals.
IMPORTANCE: Whether using magnetic resonance imaging (MRI) to guide treatment in patients with rheumatoid arthritis (RA) improves disease activity and slows joint damage progression is unknown. ...OBJECTIVE: To determine whether an MRI-guided treat-to-target strategy vs a conventional clinical treat-to-target strategy improves outcomes in patients with RA in clinical remission. DESIGN, SETTING, AND PARTICIPANTS: Two-year, randomized, multicenter trial conducted at 9 hospitals in Denmark. Two hundred patients with RA in clinical remission (disease activity score in 28 joints–C-reactive protein DAS28-CRP <3.2 and no swollen joints) were enrolled between April 2012 and June 2015. The final follow-up visit was April 2017. INTERVENTIONS: Patients were randomly allocated (1:1) to an MRI-guided vs a conventional treat-to-target strategy. In the MRI-guided group, the treatment goal was absence of MRI bone marrow edema combined with clinical remission, defined as DAS28-CRP of 3.2 or less and no swollen joints. In the conventional group, the treatment goal was clinical remission. MAIN OUTCOMES AND MEASURES: Co-primary outcomes were proportions of patients achieving DAS28-CRP remission (DAS28-CRP <2.6) and with no radiographic progression (no increase in total van der Heijde–modified Sharp score) at 24 months. Significance testing for the primary outcome was based on 1-sided testing. Secondary outcomes were clinical and MRI measures of disease activity, physical function, and quality of life. RESULTS: Of 200 patients randomized (133 women 67%; mean SD age, 61.6 10.5 years; median baseline DAS28-CRP, 1.9 interquartile range, 1.7-2.2; van der Heijde–modified Sharp score, 18.0 interquartile range, 7.0-42.5), 76 patients (76%) in the MRI-guided group and 95 (95%) in the conventional group completed the study. Of these, 64 (85%) vs 83 (88%), respectively, reached the primary clinical end point (risk difference, −4.8% 1-sided 95% CI, −13.6% to + ∞; 1-sided P = .19) and 49 (66%) vs 58 (62%), respectively, reached the primary radiographic end point (risk difference, 4.7% 1-sided 95% CI, −7.0% to + ∞; 1-sided P = .25). Of 10 key secondary end points, 8 were null and 2 showed statistically significant benefit for the MRI treat-to-target group. Seventeen patients (17%) in the MRI-guided treat-to-target group and 6 patients (6%) in the conventional treat-to-target group experienced serious adverse events. CONCLUSIONS AND RELEVANCE: Among patients with RA in clinical remission, an MRI-guided treat-to-target strategy compared with a conventional treat-to-target strategy did not result in improved disease activity remission rates or reduce radiographic progression. These findings do not support the use of an MRI-guided strategy for treating patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01656278
Abstract
Objective
To evaluate flare risk when tapering or withdrawing biologic or targeted synthetic DMARDs (bDMARDs or tsDMARDs) compared with continuation in patients with inflammatory arthritis ...in sustained remission or with low disease activity.
Methods
Articles were identified in the Cochrane Library, PubMed, Embase and Web of Science. Eligible trials were randomized controlled trials comparing tapering and/or withdrawal of bDMARDs and/or tsDMARDs with the standard dose in inflammatory arthritis. Random effects meta-analysis was performed with risk ratio (RR) or Peto’s odds ratio (POR) for sparse events and 95% CI.
Results
The meta-analysis comprised 22 trials: 11 assessed tapering and 7 addressed withdrawal (4 assessed both). Only trials with an RA or axial SpA (axSpA) population were identified. An increased flare risk was demonstrated when b-/tsDMARD tapering was compared with continuation RR 1.45 (95% CI 1.19, 1.77), I2 = 42.5% and potentially increased for persistent flare POR 1.56 (95% CI 0.97, 2.52), I2 = 0%. Comparing TNF inhibitor (TNFi) withdrawal with continuation, a highly increased flare risk RR 2.28 (95% CI 1.78, 2.93), I2 = 78% and increased odds of persistent flare POR 3.41 (95% CI 1.91, 6.09), I2 = 49% were observed. No clear difference in flare risk between RA or axSpA was observed.
Conclusion
A high risk for flare and persistent flare was demonstrated for TNFi withdrawal, whereas an increased risk for flare but not for persistent flare was observed for b-/tsDMARD tapering. Thus tapering seems to be the more favourable approach.
Registration
PROSPERO (CRD42019136905).
IntroductionThe The BIOlogical Dose OPTimisation (BIODOPT) trial is a pragmatic, multicentre, randomised controlled, open-label, parallel-group, equivalence study designed to evaluate tapering of ...biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) in sustained clinical remission or low disease activity (LDA). Traditionally, these patients maintain standard dosage of bDMARD lifelong; however, recent studies indicate that a significant proportion of patients in sustained remission or LDA can taper their bDMARD and maintain stable disease activity. Thus, this trial aims to evaluate whether a disease activity-guided tapering strategy for bDMARDs will enable a significant dosage reduction while maintaining disease activity compared with usual care. From the individual patient’s standpoint as well as from a societal perspective, it would be advantageous if bDMARDs could be reduced or even discontinued while maintaining disease activity.Methods and analysisA total of 180 patients with RA, PsA or axSpA treated with bDMARDs and in clinical remission/LDA during the past 12 months will be enrolled from four centres in Denmark. Patients will be randomised in a ratio of 2:1 to either disease activity-guided tapering of bDMARDs (intervention group) or continuation of bDMARDs as usual care (control group).The primary objective is the difference between the two groups in the proportion of patients who have reduced their inclusion dosage of bDMARDs to 50% or less while maintaining stable disease activity at 18 months follow-up.Ethics and disseminationThe study is approved by the ethics committee of Northern Jutland, Denmark (N-20170073) and by the Danish Medicine Agency. Patient research partner KHH contributed to refinement of the protocol and approved the final manuscript. Results will be disseminated through publication in international peer-reviewed journals.Trial registration number2017-001970-41; Pre-results.
Bipolar disorder (BD) is a mental disorder characterized by recurrent relapses of affective episodes, cognitive impairment, illness progression, and reduced life expectancy. Increased systemic ...oxidatively generated nucleoside damage have been found in some neurodegenerative disorders and in BD. As the first, this naturalistic prospective, longitudinal follow-up case-control study investigated cerebrospinal fluid (CSF) oxidative stress markers 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) that relate to RNA and DNA damage, respectively. Patients with BD (n = 86, 51% female) and gender-and-age-matched healthy control individuals (HC; n = 44, 44% female) were evaluated at baseline (T0), during (T1) and after a new affective episode (T2), if it occurred, and after a year (T3). Cerebrospinal and urine oxidative stress markers were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. CSF-8-oxoGuo was statistically significantly higher by 18% (p = 0.003) in BD versus HC at T0, and by 22% (p = 0) at T3. CSF-8-oxoGuo had increased by 15% (p = 0.042) from T0 to T3, and by 14% (p = 0.021) from T2 to T3 in patients, who experienced an episode during follow-up. CSF-8-oxodG had increased by 26% (p = 0.054) from T0 to T2 and decreased by 19% (p = 0.041) from T2 to T3 in patients, who experienced an episode during follow-up. CSF-8-oxoGuo did not show a statistically significant change in HC during the one-year follow-up. CSF and urine-8-oxoGuo levels correlated moderately. In conclusion, CSF oxidative stress marker of RNA damage 8-oxoGuo showed both state and trait dependence in BD and stability in HC. Central RNA damage may be a potential biomarker for BD.
Abstract Background A substantial proportion of patients with bipolar disorder remain symptomatic during inter-episode periods, and mood instability is associated with high risk of relapse and ...hospitalization. Few studies have investigated long-term daily illness activity and none has compared bipolar type I and II using daily data. The objectives were to investigate differences in daily illness activity between bipolar disorder type I and II. Methods A smartphone-based system for self-monitoring was developed. A total of 33 patients treated in a mood clinic used the system for daily self-monitoring during a median period of 310 days IQR 189; 437. Data presented summarize over 8500 observations. Results Patients with bipolar disorder type II ( n =20), compared to patients with bipolar disorder type I ( n =13), experienced a significant lower mean level of mood on a scale from −3; +3 (−0.54 (95% CI: −0.74; −0.35) versus −0.19 (95% CI: −0.35; −0.02), p =0.02), less time euthymic (51.0% (95% CI: 36.4; 65.7) versus 74.5% (95% CI: 62.4; 86.7), p =0.03) and a higher proportion of time with depressive symptoms (45.1% (95% CI: 30.6; 59.5) versus 18.8% (95% CI: 6.9; 30.7), p =0.01). The proportion of time spent with (hypo)manic symptoms did not differ (2.7% (95% CI: 0.1; 5.5) versus 5.5% (95% CI: 3.1; 7.8), p =0.17). Limitations Patients received different types, doses and combinations of psychopharmacological treatment. Conclusion Euthymia was obtained for a substantial proportion of time in patients with bipolar disorder type I, but despite on-going treatment only for half of the time for patients with bipolar disorder type II. This emphasizes the need for improving treatment strategies for bipolar disorder type II.
Abstract Background Abnormalities in psychomotor activity are a central and essential feature of affective disorder. Studies measuring differences in psychomotor activity between unipolar and bipolar ...disorder show divergent results and none have used a combined heart rate and movement monitor for measuring activity during free-living conditions. Objective To compare objectively measured psychomotor activity in patients with unipolar and bipolar disorder in a remitted or mild/moderate depressive state. Further, both groups were compared to a healthy control group. Methods A cross-sectional study of outpatients suffering from unipolar (n = 20) and bipolar (n = 18) disorder and healthy controls (n = 31), aged 18–60 years. For three consecutive days a combined acceleration (m/s2 ) and heart rate (beats per minute) monitoring was used in conjunction with a step test to estimate activity energy expenditure (J/min/kg) as measures of psychomotor activity and physical fitness. Results Overall score on Hamilton-17 items ranged between 0 and 22. Patients had higher sleeping heart rate (p < 0.001), lower fitness (p = 0.02), lower acceleration (p = 0.004), and lower activity energy expenditure (p = 0.004) compared to controls. Comparing unipolar and bipolar patients and adjusting for differences in Hamilton-17 revealed lower acceleration (p = 0.01) and activity energy expenditure in bipolar patients (p = 0.02); the difference was most prominent in the morning. Conclusions Electronic monitoring of psychomotor activity may be a promising additional tool in the distinction between unipolar and bipolar affective disorder when patients present in a remitted or depressive state.
Cognitive impairment is present in bipolar disorder (BD) during the acute and remitted phases and hampers functional recovery. However, there is currently no clinically available treatment with ...direct and lasting effects on cognitive impairment in BD. We will examine the effect of a novel form of cognitive remediation, action-based cognitive remediation (ABCR), on cognitive impairment in patients with BD, and explore the neural substrates of potential treatment efficacy on cognition.
The trial has a randomized, controlled, parallel-group design. In total, 58 patients with BD in full or partial remission aged 18-55 years with objective cognitive impairment will be recruited. Participants are randomized to 10 weeks of ABCR or a control group. Assessments encompassing neuropsychological testing and mood ratings, and questionnaires on subjective cognitive complaints, psychosocial functioning, and quality of life are carried out at baseline, after 2 weeks of treatment, after the end of treatment, and at a six-month-follow-up after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and 2 weeks into treatment. The primary outcome is a cognitive composite score spanning verbal memory, attention, and executive function. Two complete data sets for 52 patients will provide a power of 80% to detect a clinically relevant between-group difference on the primary outcome. Behavioral data will be analyzed using mixed models in SPSS while MRI data will be analyzed with the FMRIB Expert Analysis Tool (FEAT). Early treatment-related changes in neural activity from baseline to week 2 will be investigated for the dorsal prefrontal cortex and hippocampus as the regions of interest and with an exploratory whole-brain analysis.
The results will provide insight into whether ABCR has beneficial effects on cognition and functioning in remitted patients with BD. The results will also provide insight into early changes in neural activity associated with improvement of cognition, which can aid future treatment development.
Clinicaltrials.gov , NCT03295305 . Registered on 26 September 2017.
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