Previous studies in patients with rheumatoid arthritis (RA) have shown that switching to tocilizumab (TCZ) monotherapy (TCZ
) or combination therapy (TCZ
) with conventional synthetic ...disease-modifying anti-rheumatic drugs (csDMARDs) is efficacious in reducing disease activity in patients with inadequate response to csDMARDs. However, hitherto there is no consensus on whether TCZ
is as effective as TCZ
. The objective of this study was therefore to evaluate the efficacy and safety of TCZ
versus add-on TCZ
and both TCZ therapies versus continuing the current csDMARD therapy, by performing a systematic review and meta-analyses.
The MEDLINE, EMBASE and CENTRAL databases were searched until February 2016 for relevant randomized controlled trials (RCTs). We performed meta-analyses of Disease Activity Score in 28 joints (DAS28 < 2.6), American College of Rheumatology (ACR) 20/50/70 responses, adverse events (AEs) and serious AEs (SAEs) to compare the three different strategies, whereas a random-effect model was used for pooling relative risks (RR) and 95 % confidence intervals (CI). In addition, sensitivity analyses were performed for evaluating differences in study duration.
In total, 13 RCTs were included in the meta-analysis, involving 6679 patients. When comparing both TCZ strategies, a marginally greater proportion of patients achieving DAS28 < 2.6 (RR 1.21; 95 % CI 1.09, 1.36) and ACR50 response (RR 1.14; 95 % CI 1.03, 1.26) was found in favor of the TCZ
strategy. However, the risk of SAEs was also significantly higher using this strategy (RR 1.40; 95 % CI 1.03, 1.92, p = 0.03). Pooled effect estimates showed statistical superiority of switching to either TCZ strategy compared to continuing csDMARD therapy.
In the management of active RA, almost similar efficacy can be expected in patients unable to tolerate csDMARDs, who switch to TCZ
compared to inadequate responders switching to add-on TCZ
. Although TCZ
is marginally superior to TCZ
in achieving DAS28 < 2.6 and ACR50 response, this is at the cost of an increased risk of SAEs.
Objective
Longitudinal weight-bearing radiographic joint space width (JSW) and non-weight-bearing MRI-based cartilage thickness changes often show weak correlations. The current objective was to ...investigate these correlations, and to explore the influence of different factors that could contribute to longitudinal differences between the two methods.
Methods
The current study included 178 participants with medial osteoarthritis (OA) out of the 297 knee OA participants enrolled in the IMI-APPROACH cohort. Changes over 2 years in medial JSW (ΔJSWmed), minimum JSW (ΔJSWmin), and medial femorotibial cartilage thickness (ΔMFTC) were assessed using linear regression, using measurements from radiographs and MRI acquired at baseline, 6 months, and 1 and 2 years. Pearson R correlations were calculated. The influence of cartilage quality (T2 mapping), meniscal extrusion (MOAKS scoring), potential pain-induced unloading (difference in knee-specific pain scores), and increased loading (BMI) on the correlations was analyzed by dividing participants in groups based on each factor separately, and comparing correlations (slope and strength) between groups using linear regression models.
Result
Correlations between ΔMFTC and ΔJSWmed and ΔJSWmin were statistically significant (
p
< 0.004) but weak (
R
< 0.35). Correlations were significantly different between groups based on cartilage quality and on meniscal extrusion: only patients with the lowest T2 values and with meniscal extrusion showed significant moderate correlations. Pain-induced unloading or BMI-induced loading did not influence correlations.
Conclusions
While the amount of loading does not seem to make a difference, weight-bearing radiographic JSW changes are a better reflection of non-weight-bearing MRI cartilage thickness changes in knees with higher quality cartilage and with meniscal extrusion.
Treatment in general is mostly directly aimed at disease activity, and measures such as the DAS28 might therefore present important additional information. Our aim was to develop and validate a model ...that uses a combination of disease activity (DAS28) and HAQs to estimate EuroQoL 5-dimension scale (EQ5D) utilities.
Longitudinal data from a cohort study in RA patients from the Utrecht Rheumatoid Arthritis Cohort study Group (Stichting Reumaonderzoek Utrecht) who started treatment with a biologic drug were used for mapping and validation. All 702 observations, including DAS28, HAQ and EQ5D assessed at the same time points, were used. The observations were randomly divided into a subset for development of the model (n = 428 observations) and a subset for validation (n = 274). A stepwise multivariable regression analysis was used to test the association of DAS28 (components) and HAQ (domains) with EQ5D. Model performance was assessed using the explained variance (R(2)) and root mean square errors. Observed and predicted utility scores were compared to check for under- or overestimation of the scores. Finally, the performance of the model was compared with published mapping models.
Lower DAS28 score and HAQ items dressing and grooming, arising, eating, walking and activities were associated with higher EQ5D scores. The final model had an explained variance of 0.35 and a lower root mean square error as compared with other models tested. The agreement between predicted and observed scores was fair.
HAQ components estimate EQ5D better than total HAQ. Adding DAS28 to HAQ components does not result in better utility estimations.
APPROACH is an EU-wide research consortium with the goal to identify different subgroups of knee osteoarthritis to enable future differential diagnosis and treatment. During a 2-year clinical study ...images, biomarkers and clinical data are collected from people living with knee osteoarthritis and data are analyzed to confirm patterns that can indicate such different subgroups. A Patient Council (PC) has been set up at project initiation and consists of five people from Norway, The Netherlands and UK. Initially, this group of individuals had to learn how to effectively work with each other and with the researchers. Today, the PC is a strong team that is fully integrated in the consortium and acknowledged by researchers as an important sounding board. The article describes this journey looking at formal processes of involvement - organizational structure, budget, meetings - and more informal processes such as building relationships and changing researcher perceptions. It describes how the PC helped improve the experience and engagement of study participants by providing input to the clinical protocol and ensuring effective communication (e.g. through direct interactions with participants and newsletters). Furthermore, the PC is helping with dissemination of results and project advocacy, and overall provides the patient perspective to researchers. Additionally, the authors experienced and describe the intangible benefits such as a shift in researcher attitudes and a sense of community and purpose for PC members. Importantly, learnings reported in this article also include the challenges, such as effective integration of the PC with researchers' work in the early phase of the project. TRIAL REGISTRATION: US National Library of Medicine, NCT03883568 , retrospectively registered 21 March 2019.
To assess underlying domains measured by GaitSmartTMparameters and whether these are additional to established OA markers including patient reported outcome measures (PROMs) and radiographic ...parameters, and to evaluate if GaitSmart analysis is related to the presence and severity of radiographic knee OA.
GaitSmart analysis was performed during baseline visits of participants of the APPROACH cohort (n = 297). Principal component analyses (PCA) were performed to explore structure in relationships between GaitSmart parameters alone and in addition to radiographic parameters and PROMs. Logistic and linear regression analyses were performed to analyse the relationship of GaitSmart with the presence (Kellgren and Lawrence grade ≥2 in at least one knee) and severity of radiographic OA (ROA).
Two hundred and eighty-four successful GaitSmart analyses were performed. The PCA identified five underlying GaitSmart domains. Radiographic parameters and PROMs formed additional domains indicating that GaitSmart largely measures separate concepts. Several GaitSmart domains were related to the presence of ROA as well as the severity of joint damage in addition to demographics and PROMs with an area under the receiver operating characteristic curve of 0.724 and explained variances (adjusted R2) of 0.107, 0.132 and 0.147 for minimum joint space width, osteophyte area and mean subchondral bone density, respectively.
GaitSmart analysis provides additional information over established OA outcomes. GaitSmart parameters are also associated with the presence of ROA and extent of radiographic severity over demographics and PROMS. These results indicate that GaitsmartTM may be an additional outcome measure for the evaluation of OA.
Biological therapies have greatly improved the treatment efficacy in rheumatoid arthritis (RA). However, in clinical practice a significant proportion of patients experience an inadequate response to ...treatment. The aim of this study is to classify responding and non-responding rheumatoid arthritis patients treated with biological therapies, based on clinical parameters and symptoms used in Western and Chinese medicine.
Cold and Heat symptoms assessed by a Chinese medicine (CM) questionnaire and Western clinical data were collected as baseline data, before initiating biological therapy. Categorical principal components analysis with forced classification (CATPCA-FC) approach was applied to the baseline data set to classify responders and non-responders.
In this study, 61 RA patients were characterized using a CM questionnaire and clinical measurements. The combination of baseline symptoms (‘preference for warm food’, ‘weak tendon severity’) and clinical parameters (positive rheumatoid factor/anti-cyclic citrullinated peptide antibody, C-reactive protein, creatinine) were able to differentiate responders from non-responders to biological therapies with a positive predictive value of 82.35% and a misclassification rate of 24.59%. Adding CM symptom variables in addition to clinical data did not improve the classification of responders, but it did show 8.3% improvement in classifying non-responders.
No significant differences were found between the three classification models. Adding CM symptoms to the clinical parameters in the combined model improved the classification of non-responders. Although this improvement is not significant in the current study, we consider it worthwhile to further investigate the potential of adding symptom variables for improving treatment efficacy.
Blood lymphocytes of a HLA-A2 positive breast cancer patient were stimulated with either MCF-7 or MDA-MB-231, i.e., HLA-A2-matched allogeneic breast carcinoma cell lines. Several CD8
+ CTL clones ...with reactivity against the stimulator cells but not against K562 were generated. Reactivity could be blocked with monoclonal antibody (mAb) W6/32, MA2.1, and/or BB7.2, indicating that the clones are HLA-class I and HLA-A2 restricted. The CTL clones generated following stimulation with MCF-7, recognized various other allogeneic HLA-A2
+ tumor cell lines, including breast carcinoma, renal cell carcinoma, and melanoma cell lines, but not HLA-A2
− tumor cell lines. The CTL clones did not recognize normal HLA-A2
+ cells including breast epithelial cells, renal proximal tubular epithelial cells (PTEC), or EBV-transformed B cells including the autologous EBV cell line. In contrast to the CTL clones induced with MCF-7, the reactivity of the clones stimulated with MDA-MB-231, was limited to the stimulator cell MDA-MB-231. Cytotoxicity assays utilizing T2 cells loaded with peptides as target cells indicated that none of the examined CTL-epitopes derived from HER-2/neu, Muc-1, Ep-CAM-1, and p53 were recognized by the CTL clones generated. Our findings underscore that breast cancer is an immunogenic tumor and that HLA-class I-matched allogeneic tumor cells can be used as stimulator cells to generate tumor-specific CTL from peripheral blood of a breast cancer patient with specificity for an antigenic determinant that is broadly expressed on tumor cells from various origins or with specificity limited to the breast cancer stimulator cell.
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