Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: An individual meta-analysis of 5792 patients

Objectives: To determine the impact of excluding patient global assessment (PGA) from the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission criteria, on prediction of radiographic and functional outcome of rheumatoid arthritis (RA). Methods: Meta-analyses using individual patient data from randomised controlled trials testing the efficacy of biological agents on radiographic and functional outcomes at ≥2 years. Remission states were defined by 4 variants of the ACR/EULAR Boolean definition: (i) tender and swollen 28-joint counts (TJC28/SJC28), C reactive protein (CRP, mg/dL) and PGA (0-10=worst) all ≤1 (4V-remission); (ii) the same, except PGA >1 (4V-near-remission); (iii) 3V-remission (i and ii combined; similar to 4V, but without PGA); (iv) non-remission (TJC28 >1 and/or SJC28 >1 and/or CRP >1). The most stringent class achieved at 6 or 12 months was considered. Good radiographic (GRO) and functional outcome (GFO) were defined as no worsening (ie, change in modified total Sharp score (ΔmTSS) ≤0.5 units and ≤0.0 Health Assessment Questionnaire-Disability Index points, respectively, during the second year). The pooled probabilities of GRO and GFO for the different definitions of remission were estimated and compared. Results: Individual patient data (n=5792) from 11 trials were analysed. 4V-remission was achieved by 23% of patients and 4V-near-remission by 19%. The probability of GRO in the 4V-near-remission group was numerically, but non-significantly, lower than that in the 4V-remission (78 vs 81%) and significantly higher than that for non-remission (72%; difference=6%, 95% CI 2% to 10%). Applying 3V-remission could have prevented therapy escalation in 19% of all participants, at the cost of an additional 6.1%, 4.0% and 0.7% of patients having ΔmTSS >0.0, >0.5 and >5 units over 2 years, respectively. The probability of GFO (assessed in 8 trials) in 4V-near-remission (67%, 95% CI 63% to 71%) was significantly lower than in 4V-remission (78%, 74% to 81%) and similar to non-remission (69%, 66% to 72%). Conclusion: 4V-near-remission and 3V-remission have similar validity as the original 4V-remission definition in predicting GRO, despite expected worse prediction of GFO, while potentially reducing the risk of overtreatment. This supports further exploration of 3V-remission as the target for immunosuppressive therapy complemented by patient-oriented targets

The impact of patient global assessment in the definition of remission as a predictor of long-term radiographic damage in patients with rheumatoid arthritis: protocol for an individual patient data meta-analysis

BACKGROUND: Remission is the target for management of rheumatoid arthritis (RA) and intensification of immunosuppressive therapy is recommended for those that do not achieve this status. Patient global assessment (PGA) is the single patient reported outcome considered in the American College of Rheumatology/European League Against Rheumatism remission criteria, but its use as target has been questioned. The primary aim of this study is to assess whether excluding PGA from the definition of disease remission changes the association of disease remission with long-term radiographic damage and physical function in patients with RA. METHODS: Individual Patient Data Meta-analysis using data from randomized controlled trials of biological and targeted synthetic agents, identified through ClinicalTrials.gov and PubMed. Different remission states will be defined: (i) 4v-remission [tender (TJC28) and swollen 28-joint counts (SJC28) both≤1, C-reactive protein (CRP)≤1 (mg/dl), and PGA≤1 (0-10 scale)], (ii) 4v-near-remission (TJC28≤1, SJC28≤1, CRP≤1, and PGA>1), (iii) non-remission (TJC28>1 or SJC28>1 or CRP>1), all mutually exclusive, and (iv) 3v-remission (TJC28≤1, SJC28≤1, CRP≤1). Likelihood ratios will be used to descriptively compare whether meeting the 3v and 4v-remission criteria in a single visit (at 6 or 12 months) predicts good outcome in the second year (1-2y). Differences in the predictive value of PGA in the definition of remission will be assessed by comparing the three mutually exclusive disease states using logistic regression analysis. Good outcome is defined primarily by radiographic damage (no deterioration in radiographic scores, whatever the instrument used in each trial), and secondarily by functional disability (Health Assessment Questionnaire consistently ≤0.5 and no deterioration), and their combination ("overall good outcome"). Additional analyses will consider longer periods over which to (concurrently) define remission status and outcome (between 1-5y and 1-10y), different cut-offs to define good radiographic outcome (change ≤0.5, ≤3 and ≤5 in radiographic score), sustained remission and the influence of treatment and other clinical factors. DISCUSSION: If 4v-remission and 4v-near-remission are associated with a similar probability of good outcomes, particularly regarding structural damage, the 3v-remission (excluding PGA) could be adopted as the target for immunosuppressive therapy. Patients' perspectives would remain essential, but assessed separately from disease activity, using instruments adequate to guide adjunctive therapies. Systematic review registration: PROSPERO, CRD42017057099

Multi-classifier prediction of knee osteoarthritis progression from incomplete imbalanced longitudinal data

Conventional inclusion criteria used in osteoarthritis clinical trials are not very effective in selecting patients who would benefit from a therapy being tested. Typically majority of selected patients show no or limited disease progression during a trial period. As a consequence, the effect of the tested treatment cannot be observed, and the efforts and resources invested in running the trial are not rewarded. This could be avoided, if selection criteria were more predictive of the future disease progression. In this article, we formulated the patient selection problem as a multi-class classification task, with classes based on clinically relevant measures of progression (over a time scale typical for clinical trials). Using data from two long-term knee osteoarthritis studies OAI and CHECK, we tested multiple algorithms and learning process configurations (including multi-classifier approaches, cost-sensitive learning, and feature selection), to identify the best performing machine learning models. We examined the behaviour of the best models, with respect to prediction errors and the impact of used features, to confirm their clinical relevance. We found that the model-based selection outperforms the conventional inclusion criteria, reducing by 20-25% the number of patients who show no progression. This result might lead to more efficient clinical trials.Comment: 22 pages, 12 figures, 10 table

The effect of subcutaneous and sublingual birch pollen immunotherapy on birch pollen–related food allergy: a systematic review

Background: Birch pollen–related food allergy (BPFA) is the most common type of food allergy in birch-endemic areas such as Western and Central Europe. Currently, there is no treatment available for BPFA. Due to the cross-reactivity between birch pollen and a range of implicated plant foods, birch pollen allergen immunotherapy (AIT) may be effective in the treatment of BPFA. In this study, we systematically evaluate the effectiveness of birch pollen–specific subcutaneous or sublingual immunotherapy in treating BPFA. Methods: A search was performed in the PubMed, Embase, and Cochrane libraries. Studies were independently screened by two reviewers against predefined eligibility criteria. The outcomes of interest were changes in (1) severity of symptoms during food challenge, (2) eliciting dose (ED), and (3) food allergy quality of life (FA-QoL). The validity of the selected articles was assessed using the revised Cochrane risk of bias tool. We focused on studies with the lowest risk of bias and considered studies with a high risk of bias as supportive. Data were descriptively summarized. Results: Ten studies were selected that included 475 patients in total. Seven studies were categorized into “high risk of bias” and three into “moderate risk of bias.” The three moderate risk of bias studies, with a total of 98 patients, reported on severity of symptoms during challenge and on the ED. All three studies had a control group. Compared to the control group, improvement in severity of symptoms was observed during challenge in two out of the three studies and on the eliciting dose in one out of three. Only one study investigated the effect of birch pollen AIT on FA-QoL, showing that there was no significant difference between patients receiving subcutaneous immunotherapy or a placebo. Of the seven supportive studies, four had a control group and of those, three showed improvement on both severity of symptoms and ED. None of the supportive studies investigated the effect of the therapy on FA-QoL. Conclusion: This systematic review shows that there is not enough evidence to draw firm conclusions about the effect of AIT on BPFA. Future research is warranted that uses robust clinical studies that include long-term effects, QoL, and multiple BPFA-related foods

Observations of the unidentified gamma-ray source TeV J2032+4130 by VERITAS

TeV J2032+4130 was the first unidentified source discovered at very high energies (VHE; E $>$ 100 GeV), with no obvious counterpart in any other wavelength. It is also the first extended source to be observed in VHE gamma rays. Following its discovery, intensive observational campaigns have been carried out in all wavelengths in order to understand the nature of the object, which have met with limited success. We report here on a deep observation of TeV J2032+4130, based on 48.2 hours of data taken from 2009 to 2012 by the VERITAS (Very Energetic Radiation Imaging Telescope Array System) experiment. The source is detected at 8.7 standard deviations ($\sigma$) and is found to be extended and asymmetric with a width of 9.5$^{\prime}$$\pm$1.2$^{\prime}$ along the major axis and 4.0$^{\prime}$$\pm$0.5$^{\prime}$ along the minor axis. The spectrum is well described by a differential power law with an index of 2.10 $\pm$ 0.14$_{stat}$ $\pm$ 0.21$_{sys}$ and a normalization of (9.5 $\pm$ 1.6$_{stat}$ $\pm$ 2.2$_{sys}$) $\times$ 10$^{-13}$TeV$^{-1}$ cm$^{-2}$ s$^{-1}$ at 1 TeV. We interpret these results in the context of multiwavelength scenarios which particularly favor the pulsar wind nebula (PWN) interpretation

The effect of subcutaneous and sublingual birch pollen immunotherapy on birch pollen–related food allergy: a systematic review

BackgroundBirch pollen–related food allergy (BPFA) is the most common type of food allergy in birch-endemic areas such as Western and Central Europe. Currently, there is no treatment available for BPFA. Due to the cross-reactivity between birch pollen and a range of implicated plant foods, birch pollen allergen immunotherapy (AIT) may be effective in the treatment of BPFA. In this study, we systematically evaluate the effectiveness of birch pollen–specific subcutaneous or sublingual immunotherapy in treating BPFA.MethodsA search was performed in the PubMed, Embase, and Cochrane libraries. Studies were independently screened by two reviewers against predefined eligibility criteria. The outcomes of interest were changes in (1) severity of symptoms during food challenge, (2) eliciting dose (ED), and (3) food allergy quality of life (FA-QoL). The validity of the selected articles was assessed using the revised Cochrane risk of bias tool. We focused on studies with the lowest risk of bias and considered studies with a high risk of bias as supportive. Data were descriptively summarized.ResultsTen studies were selected that included 475 patients in total. Seven studies were categorized into “high risk of bias” and three into “moderate risk of bias.” The three moderate risk of bias studies, with a total of 98 patients, reported on severity of symptoms during challenge and on the ED. All three studies had a control group. Compared to the control group, improvement in severity of symptoms was observed during challenge in two out of the three studies and on the eliciting dose in one out of three. Only one study investigated the effect of birch pollen AIT on FA-QoL, showing that there was no significant difference between patients receiving subcutaneous immunotherapy or a placebo. Of the seven supportive studies, four had a control group and of those, three showed improvement on both severity of symptoms and ED. None of the supportive studies investigated the effect of the therapy on FA-QoL.ConclusionThis systematic review shows that there is not enough evidence to draw firm conclusions about the effect of AIT on BPFA. Future research is warranted that uses robust clinical studies that include long-term effects, QoL, and multiple BPFA-related foods

Discovery of Very High Energy Gamma Rays from 1ES 1440+122

The BL Lacertae object 1ES 1440+122 was observed in the energy range from 85 GeV to 30 TeV by the VERITAS array of imaging atmospheric Cherenkov telescopes. The observations, taken between 2008 May and 2010 June and totalling 53 hours, resulted in the discovery of $\gamma$-ray emission from the blazar, which has a redshift $z$=0.163. 1ES 1440+122 is detected at a statistical significance of 5.5 standard deviations above the background with an integral flux of (2.8$\pm0.7_{\mathrm{stat}}\pm0.8_{\mathrm{sys}}$) $\times$ 10$^{-12}$ cm$^{-2}$ s$^{-1}$ (1.2\% of the Crab Nebula's flux) above 200 GeV. The measured spectrum is described well by a power law from 0.2 TeV to 1.3 TeV with a photon index of 3.1 $\pm$ 0.4$_{\mathrm{stat}}$ $\pm$ 0.2$_{\mathrm{sys}}$. Quasi-simultaneous multi-wavelength data from the Fermi Large Area Telescope (0.3--300 GeV) and the Swift X-ray Telescope (0.2--10 keV) are additionally used to model the properties of the emission region. A synchrotron self-Compton model produces a good representation of the multi-wavelength data. Adding an external-Compton or a hadronic component also adequately describes the data.Comment: 8 pages, 4 figures. Accepted for publication in MNRA

Investigating the TeV Morphology of MGRO J1908+06 with VERITAS

We report on deep observations of the extended TeV gamma-ray source MGRO J1908+06 made with the VERITAS very high energy (VHE) gamma-ray observatory. Previously, the TeV emission has been attributed to the pulsar wind nebula (PWN) of the Fermi-LAT pulsar PSR J1907+0602. We detect MGRO J1908+06 at a significance level of 14 standard deviations (14 sigma) and measure a photon index of 2.20 +/- 0.10_stat +/- 0.20_sys. The TeV emission is extended, covering the region near PSR J1907+0602 and also extending towards SNR G40.5--0.5. When fitted with a 2-dimensional Gaussian, the intrinsic extension has a standard deviation of sigma_src = 0.44 +/- 0.02 degrees. In contrast to other TeV PWNe of similar age in which the TeV spectrum softens with distance from the pulsar, the TeV spectrum measured near the pulsar location is consistent with that measured at a position near the rim of G40.5--0.5, 0.33 degrees away.Comment: To appear in ApJ, 8 page

The multi-biomarker disease activity test for assessing response to treatment strategies using methotrexate with or without prednisone in the CAMERA-II trial

Objectives: The CAMERA-II trial compared two tight-control, treat-to-target strategies, initiating methotrexate with prednisone (MTX+pred) or MTX with placebo (MTX+plac), in early RA-patients. The multi-biomarker disease activity (MBDA) blood test objectively measures RA disease activity with a score of 1-100. In CAMERA-II, response profiles of the MBDA score, its individual biomarkers, and DAS28 were assessed. Methods: We evaluated 92 patients from CAMERA-II of whom clinical data and serum for MBDA testing at baseline and ≥ 1 time-point from months 1, 2, 3, 4, 5, 6, 9, or 12 were available. Changes (Δ) from baseline for DAS28 and MBDA score and comparisons of ΔDAS28 and ΔMBDA score over time within the MTX+pred versus the MTX+plac strategy were tested for significance with t tests. Changes in biomarker concentration from baseline to months 1-5 were tested with Wilcoxon signed rank test and tested for difference between treatment arms by Mann-Whitney U test. Results: MBDA and DAS28 showed similar response profiles, with gradual improvement over the first 6 months in the MTX+plac group, and in the MTX+pred group faster improvement during month 1, followed by gradual improvement. The 12 MBDA biomarkers could be grouped into 4 categories of response profiles, with significant responses for 4 biomarkers during the MTX+plac strategy and 9 biomarkers during the MTX+pred strategy. Conclusions: MBDA tracked treatment response in CAMERA-II similarly to DAS28. More individual MBDA biomarkers tracked treatment response to MTX+pred than to MTX+plac. Four response profiles could be observed. Trial registration: CAMERA-II International Standard Randomised Controlled Trial Number: ISRCTN 70365169. Registered on 29 March 2006, retrospectively registered

Deep Broadband Observations of the Distant Gamma-ray Blazar PKS 1424+240

We present deep VERITAS observations of the blazar PKS 1424+240, along with contemporaneous Fermi Large Area Telescope, Swift X-ray Telescope and Swift UV Optical Telescope data between 2009 February 19 and 2013 June 8. This blazar resides at a redshift of $z\ge0.6035$, displaying a significantly attenuated gamma-ray flux above 100 GeV due to photon absorption via pair-production with the extragalactic background light. We present more than 100 hours of VERITAS observations from three years, a multiwavelength light curve and the contemporaneous spectral energy distributions. The source shows a higher flux of (2.1$\pm0.3$)$\times10^{-7}$ ph m$^{-2}$s$^{-1}$ above 120 GeV in 2009 and 2011 as compared to the flux measured in 2013, corresponding to (1.02$\pm0.08$)$\times10^{-7}$ ph m$^{-2}$s$^{-1}$ above 120 GeV. The measured differential very high energy (VHE; $E\ge100$ GeV) spectral indices are $\Gamma=$3.8$\pm$0.3, 4.3$\pm$0.6 and 4.5$\pm$0.2 in 2009, 2011 and 2013, respectively. No significant spectral change across the observation epochs is detected. We find no evidence for variability at gamma-ray opacities of greater than $\tau=2$, where it is postulated that any variability would be small and occur on longer than year timescales if hadronic cosmic-ray interactions with extragalactic photon fields provide a secondary VHE photon flux. The data cannot rule out such variability due to low statistics.Comment: ApJL accepted March 17, 201