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31300979 Abatacept retention and clinical outcomes in rheumatoid arthritis: real-world data from th 2019 Nov INTRODUCTION: AbataCepT In rOutiNe clinical practice (ACTION; NCT02109666) was an observational study of patients with rheumatoid arthritis who initiated intravenous abatacept in clinical practice. We aimed to compare abatacept retention rates and clinical outcomes in patients from Germany versus other countries. METHOD: Baseline characteristics, crude retention rates, and clinical outcomes were compared by treatment line in the German cohort at 2 years. In addition, biologic-naïve patients were compared with biologic-naïve patients pooled from other participating countries. RESULTS: In the German cohort, 677/680 (99.6%) patients enrolled were evaluable and 171/677 (25.3%) were biologic naïve. At baseline, abatacept monotherapy was received by a similar proportion of biologic-naïve and biologic-failure patients in the German cohort, but by a greater proportion of biologic-naïve patients in German versus other countries cohort (27.5 vs. 12.9%). The overall crude abatacept retention rate at 2 years in the German cohort was 39.9%; retention rate did not differ significantly by treatment line, but among biologic-naïve patients it was lower in Germany than in the other countries cohort (42.1 vs. 58.7%; log-rank test p < 0.001). At 2 years, good/moderate European League Against Rheumatism (EULAR) response rates in biologic-naïve patients were 85.5% in the German and 92.1% in other countries cohort (p = 0.163). CONCLUSIONS: In the German cohort of ACTION, abatacept retention at 2 years was similar in biologic-naïve and biologic-failure patients. Biologic-naïve patients in German cohort had a significantly lower abatacept retention rate and a trend of lower good/moderate EULAR response rate than those in the other countries cohort. KEY POINTS: • Analyses of data from national patient cohorts provide insight on local treatment patterns. • In the German cohort of the ACTION study, abatacept retention at 2 years was similar in biologic-naïve and biologic-failure patients. • Biologic-naïve patients from the German cohort had a significantly lower abatacept retention rate and a trend of lower good/moderate EULAR response rate than patients from other countries. • Data from large international studies may not be directly applicable to individual countries.
31292181 Dosage reduction and discontinuation of biological disease-modifying antirheumatic drugs i 2019 Jul 9 INTRODUCTION: The 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 ANALYSIS: A 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 DISSEMINATION: The 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 NUMBER: 2017-001970-41; Pre-results.
30295429 Brief Report: Safety and Immunogenicity of Rituximab Biosimilar GP 2013 After Switch From 2019 Jan OBJECTIVE: Comparable clinical efficacy of the rituximab (RTX) biosimilar GP2013 and reference RTX has been established in blinded randomized trials. However, when switching from a reference biologic to a biosimilar, potential safety implications are often an important consideration. Therefore, the aim of this study was to evaluate the safety of switching from reference RTX to RTX biosimilar GP2013 compared with treatment continuation with reference RTX in patients with rheumatoid arthritis (RA). METHODS: In this multinational, randomized, double-blind, parallel-group safety study, 107 patients with RA who had previously received treatment (of any duration) with reference RTX as part of routine practice and who required continuation of treatment were randomized to receive either GP2013 or to continue treatment with reference RTX. All patients received a stable dosage of methotrexate and folic acid during the study. Study assessments included the incidence of hypersensitivity, infusion-related and anaphylactic reactions, immunogenicity (antidrug antibodies), and general safety. RESULTS: Regardless of whether patients switched to GP2013 or continued treatment with reference RTX, the incidences of hypersensitivity (9.4% and 11.1%, respectively) and infusion-related reactions (11.3% and 18.5%, respectively) were similarly low. Only 1 patient (in the reference RTX group) developed antidrug antibodies to RTX after starting study treatment. No neutralizing antidrug antibodies were observed. Antidrug antibodies were not associated with adverse events (AEs). No clinically meaningful differences in the rate of AEs were observed between treatment groups. CONCLUSION: No safety risks were detected when patients switched from reference RTX to GP2013. The safety profiles of patients in both treatment groups were similar, although the study was not powered for statistical testing of equivalence in safety.
31088167 Subcutaneous tocilizumab: recent advances for the treatment of rheumatoid arthritis. 2019 Jun INTRODUCTION: Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that is widely used to treat rheumatic arthritis (RA). When initially introduced, TCZ was administered by intravenous infusion. Since 2013, subcutaneous administration of TCZ has also been offered. Currently, we can choose the TCZ administration route according to patient preference. AREAS COVERED: We summarize TCZ therapy and review recent advances of TCZ-SC therapy. Initially, three pre-clinical phase III randomized controlled trials - MUSASHI, SUMMACTA, and BREVACTA - demonstrated the similar effectiveness and safety between subcutaneous TCZ (TCZ-SC) and intravenous TCZ (TCZ-IV). Several real-world TCZ-SC studies further confirmed these findings. These studies also focused on the influence of body weight. Since TCZ-SC is a fixed dose therapy, the efficacy of TCZ-SC 162 mg q2w was sometimes inadequate in high body weight patients. By contrast, TCZ-SC 162 mg qw therapy achieved a higher trough serum concentration of TCZ than TCZ-IV 8 mg/kg q4w. No additional safety concerns were noted. Finally, possible differences between the IL-6 inhibitor and IL-6 receptor inhibitor are discussed. EXPERT OPINION: There are no appreciable differences between TCZ-SC and TCZ-IV in clinical practice. Thus, TCZ-SC is an attractive option for RA patients.
31727137 European Network of Pregnancy Registers in Rheumatology (EuNeP)-an overview of procedures 2019 Nov 14 BACKGROUND: The collaborative initiative of the European Network of Pregnancy Registers in Rheumatology (EuNeP) aims to combine data available in nationwide pregnancy registers to increase knowledge on pregnancy outcomes in women with inflammatory rheumatic diseases (IRD) and on drug safety during pregnancy and lactation. The objective of this study was to describe the similarities and differences of the member registers. METHODS: From all registers, information about their structure and design was collected, as well as which parameters regarding demographics, maternal outcomes, treatment, course and outcome of pregnancy, and development of the child were available in the respective datasets. Furthermore, the current recruitment status was reported. RESULTS: The four registers (EGR2 (France), RePreg (Switzerland), RevNatus (Norway), and Rhekiss (Germany)) collect information prospectively and nationwide. Patients can be enrolled before conception or during pregnancy. To date, more than 3500 patients in total have been included, and data on 2200 pregnancies with an outcome are available. The distribution of diagnoses in the respective registers varies considerably, and only three entities (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) are captured by all the registers. Broad consistency was found in non-disease-specific data items, but differences regarding instruments and categories as well as frequency of data collection were revealed. Disease-specific data items are less homogeneously collected. CONCLUSION: Although the registers in this collaboration have similar designs, we found numerous differences in the variables collected. This survey of the status quo of current pregnancy registers is the first step towards identifying data collected uniformly across registers in order to facilitate joint analyses. TRIAL REGISTRATION: Not applicable.
31056653 Two populations of circulating PD-1hiCD4 T cells with distinct B cell helping capacity are 2019 Sep 1 OBJECTIVE: A novel population of B helper cells, phenotypically CD4+CXCR5-PD-1hi, has been described in the synovial tissues and peripheral blood of seropositive RA patients, and termed 'peripheral helper T' (Tph) cells. Contrary to CD4+CXCR5+PD-1hi follicular helper T (Tfh), Tph cells are not located in lymphoid organs but accumulate in inflamed tissues. Our objective was to study the frequency of circulating Tph (cTph) and circulating Tfh cell counterparts (cTfh) in patients with early RA (eRA). METHODS: Freshly isolated peripheral blood mononuclear cells from 56 DMARD-naïve eRA patients and 56 healthy controls were examined by flow cytometry. Autologous cocultures of naïve or memory B cells were established with isolated peripheral blood Tph or Tfh cells. RESULTS: Seropositive (RF+ and/or ACPA+, n = 38) but not seronegative eRA patients (n = 18) demonstrated increased frequencies and absolute numbers of cTph and cTfh cells. cTph but not cTfh cells expressed CCR2. Those eRA patients who experienced a significant clinical improvement at 12 months demonstrated a marked decrease of their cTph cell numbers whereas their cTfh cell numbers remained unchanged. Both isolated Tph and isolated Tfh cells were able to induce maturation of memory B cells, whereas only Tfh cells could differentiate naïve B cells. CONCLUSION: Two populations of PD-1hiCD4 T cells with distinct phenotype and B cell helping capacity are increased in the peripheral blood of seropositive eRA patients. Whereas cTph cells are present only in patients with an active disease, cTfh cells seem to be constitutively elevated.
31009578 Attitudes towards Oral Health in Patients with Rheumatoid Arthritis: A Qualitative Study N 2019 Oct INTRODUCTION: Patients with rheumatoid arthritis (RA) present a higher incidence and severity of periodontitis than the general population. Our study, Outcomes of Periodontal Treatment in Patients with Rheumatoid Arthritis (OPERA), was a randomized waiting-list controlled trial using mixed methods. Patients randomized to the intervention arm received intensive periodontal treatment, and those in the control arm received the same treatment with a 6-mo delay. AIM: The nested qualitative component aimed to explore patients' experiences and priorities concerning oral health and barriers and facilitators for trial participation. METHODS: Using purposive sampling until thematic saturation was reached, we conducted 21 one-to-one semistructured interviews with randomized patients in either of the 2 treatment arms as well as with patients who did not consent for trial participation. RESULTS: The patients described their experiences about RA, oral health, and study participation. Previous experiences with dental care professionals shaped patients' current perceptions about oral health and the place of oral health on their list of priorities compared with other conditions. Patients also highlighted some of the barriers and facilitators for study participation and for compliance with oral health maintenance. The patients, in the control arm, presented their views regarding the acceptable length of waiting time for the intervention. CONCLUSION: The associations between periodontal and systemic health are increasingly recognized by the literature. Our study provided an insight into RA patients' experiences and perceptions about oral health. It also highlighted some of the barriers and facilitators for participating in a periodontal interventional study for this group. We hope that our findings will support the design of larger interventional periodontal studies in patients with RA. The complex challenges faced by the burden of RA and the associated multimorbidities in this patient group might highlight opportunities to improve access to oral health services in this patient population. KNOWLEDGE TRANSFER STATEMENT: This article provided insights into the experiences and perceptions of rheumatoid arthritis patients about their oral health to improve patient participation in a definitive clinical trial.
31831079 FKB327, an adalimumab biosimilar, versus the reference product: results of a randomized, P 2019 Dec 12 OBJECTIVE: To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA). METHODS: Patients were randomized 1:1 in a double-blind study (NCT02260791), received 40 mg of FKB327 or RP by subcutaneous injection every other week for 24 weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ± 13% and - 12% to + 15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54. RESULTS: A total of 730 patients were randomized in Period I (n = 367 FKB327, n = 363 RP), and 645 transitioned to Period II (n = 216 FKB327-FKB327, n = 108 FKB327-RP, n = 108 RP-FKB327, n = 213 RP-RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were - 7.9 to 4.7% and - 7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II. CONCLUSION: FKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02260791, Registered 29 July 2014. ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.
31599096 Subjective well-being among rheumatoid arthritis patients. 2019 Oct AIM: Subjective well-being (SWB) is a psychological construct that is synonymous with happiness. Many variables including age, sex, income, employment, and marital status are related to SWB. Health is also an important determinant of SWB that can be adversely affected in patients with chronic conditions such as rheumatoid arthritis (RA). In this study, we evaluate the SWB of RA patients and compare it with that of healthy controls. METHODS: We obtained the original dataset from the "Quality of Life Survey, 2013", which was conducted by the Economic and Social Research Institute, Cabinet Office, Government of Japan. In this survey, SWB was determined by asking participants to rate their happiness between 0 (very unhappy) and 10 (very happy). The survey also included a 56-point questionnaire regarding well-being-related variables. This questionnaire was administered to RA patients recruited from Kobe University Hospital, and clinical and treatment data were simultaneously collected. RESULTS: Multivariate analysis revealed that RA patients with high or moderate disease activity had SWB scores that were similar to those of controls. However, the SWB scores of RA patients in remission or with low disease activity were higher than those of controls (P = .013). SWB was associated with household income, self-assessment of living costs, self-assessment of health, depression/ anxiety, and social connection. CONCLUSIONS: For RA patients, achieving the therapeutic target can result in better SWB than that of healthy controls. Financial status, self-assessment of health, psychological stress, and social network are also important determinants for the SWB of RA patients.
31399850 Outcomes of dose reduction, withdrawal, and restart of tofacitinib in patients with rheuma 2019 Dec OBJECTIVE: This study was designed to compare outcomes of dose reduction, withdrawal, and continuation of tofacitinib in patients with rheumatoid arthritis (RA) and to examine effectiveness of rescue with an original treatment regimen for disease flare. METHODS: We prospectively enrolled 100 patients who had high or moderate disease activity and treated them with tofacitinib at 5 mg twice daily for 1 year. All patients achieving remission or low disease activity (LDA) were assigned to a withdrawal, dose-reduction, or continuation group, then followed until disease flare or end of the study. For flare cases, the original treatment regimen was reintroduced. RESULTS: During the first year, 68 patients achieved remission or LDA (median sustained time 49.0 weeks). Subsequently, disease flare occurred at the following crude incidence rates per person-year (95% confidence interval [CI]): 0.73 (0.43-1.22) after withdrawal, 0.44 (0.25-0.77) after dose reduction, and 0.04 (0.01-0.27) during continuation. Kaplan-Meier estimates of median flare-free time (95% CI) were 7.0 months (2.8-11.2) for withdrawal and 21.0 months (4.1-37.9) for dose reduction. In the Cox regression analysis, adjusted hazard ratios (95% CIs) were 18.11 (2.38-138) for withdrawal and 9.13 (1.19-70.4) for dose reduction compared with continuation. Restart of the original treatment regimen led to rapid remission in flare cases (93% for withdrawal and 100% for dose reduction). CONCLUSION: After achievement of remission or LDA, the dose-reduction strategy seems preferable to immediate withdrawal of tofacitinib. Restart of the original regimen can reinduce RA control in flare cases.Key Points• During the 1-year tofacitinib therapy, two-thirds of RA patients with high or moderate disease activity achieved rapid and sustained remission or low disease activity.• During subsequent years, the incidence rate and adjusted hazard ratio for disease flare were significantly higher following tofacitinib immediate withdrawal than following dose reduction.• Half of the patients were estimated to remain flare-free for 21 months after dose reduction and for 7 months after withdrawal of tofacitinib.• Restart of the original treatment regimen rapidly restored disease control in almost all flare cases.
30709954 Peripheral Lymphocyte Multidrug Resistance Activity as a Predictive Tool of Biological The 2019 Jun OBJECTIVE: Multidrug resistance (MDR) transporters may be used as biomarkers to monitor disease progression in RA and as a predictive tool to establish responsiveness to biological therapy. In this multicenter clinical trial, we aimed to assess the predictive value of activity measurement of transporters MDR1, MD resistance protein (MRP)1, and breast cancer resistance protein (BCRP) for biological therapeutic response in RA before the initiation of biological therapy as well as 4 to 6 and 12 weeks after. METHODS: Peripheral blood samples were collected from 27 responders and 12 nonresponders to biological disease-modifying antirheumatic drugs (bDMARD) at the indicated timepoints as well as from 35 healthy controls. MDR activity factor (MAF) of MDR1, MRP1, and BCRP was measured in CD3+ and CD19+ cells using the Solvo MDQ Kit and cell surface staining by flow cytometry following peripheral blood mononuclear cells isolation. RESULTS: At the start of therapy, MAFC (composite MAF of MRP1 and MDR1) and MAFMDR values, and at 4 to 6 weeks of treatment, MAFC, MAFMRP, and MAFMDR values of CD3 cells were higher in nonresponders compared to responders. Receiver-operation characteristic curve analysis revealed that RA patients with MAFC values above 21.3 in CD3 cells at the start of bDMARD therapy are likely to be nonresponders. At 4 to 6 weeks of treatment, these also predict unfavorable response: MAFC values above 20.3, MAFMRP values above 6.0, and MAFMDR values above 13.9 in CD3 cells. CONCLUSION: Our results indicate that the determination of MAFC values in CD3 cells of patients with RA may be of predictive value prior to the initiation of biological therapy, to establish whether the patient will demonstrate sufficient therapeutic response.
31302858 A preliminary study of lung abnormalities on HRCT in patients of rheumatoid arthritis-asso 2019 Nov OBJECTIVE: This retrospective study evaluates lung abnormalities on high-resolution CT (HRCT) and clarifies which abnormality can predict the progressive fibrosis of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD). OBJECTS AND METHODS: We identified 1096 RA patients, and enrolled 213 patients with a diagnosis of RA-ILD who underwent serial chest HRCT. Clinical data of the patients were obtained. The presence, extent, and distribution of lung abnormalities were assessed on CT scans. Logistic regression analysis was used to determine positive indicators with predictive value for progressive fibrosis, and 2 × 2 contingency tables were constructed to assess their diagnostic efficiency. RESULT: Of 213 RA-ILD patients, 106 (49.8%) were diagnosed as progressive fibrosis. The rates of advanced age, male, smoking history, shortness of breath, and anti-CCP antibody high titer positive were higher, and RA duration was shorter in progressive fibrosis patients. Reticular pattern (RP), peribronchovascular interstitium (PBVI) thickening, interlobular septal thickening, and traction bronchiolectasis were more common in the progressive fibrosis group (84.9% vs 42.1%, P < 0.001; 79.3% vs 45.8%, P < 0.001; 74.5% vs 43.9%, P < 0.001; 67.0% vs 40.2%, P < 0.001; respectively). Lung abnormalities demonstrated subpleural predominance, and the subpleural RP and/or interlobular septal thickening had a wide distribution in the progressive fibrosis group (71.7% vs 14.0%, P < 0.001). The overall extent of lung abnormalities was more extensive in the progressive fibrosis group (18.4% vs 14.2%, P < 0.05). Logistic regression analysis showed that a wide distribution of subpleural RP and/or interlobular septal thickening (OR, 18.15) and PBVI thickening (OR, 4.98) were independent risk factors predictive of progressive fibrosis. For the combination of these two CT abnormalities, sensitivity was 63.2%, specificity was 92.5%, positive likelihood ratio was 8.5, and negative likelihood ratio was 0.4 in predicting progressive fibrosis. CONCLUSIONS: A wide distribution of subpleural RP and/or interlobular septal thickening and PBVI thickening on HRCT appear predictive of progressive fibrosis in RA-ILD. The combined evaluation of these two CT abnormalities has a good judgment value. Key Points • We designed this study to investigate the risk factors for progressive fibrosis in patients with RA-ILD. Factors including clinical, physiological, radiological and therapeutic variables were all included in the data analysis. • Our results showed HRCT abnormalities, rather than other parameters, appeared predictive of progressive fibrosis in RA-ILD. • The methods and results of image evaluation in this article would provide reference to rheumatologists in identifying early stage of progressive fibrosis which helps to improve poor prognosis of RA-ILD.
31452928 Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical 2019 OBJECTIVE: In MOBILITY (NCT01061736), sarilumab significantly reduced disease activity, improved physical function and inhibited radiographic progression at week 52 versus placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate. We report 5-year safety, efficacy and radiographic outcomes of sarilumab from NCT01061736 and the open-label extension (EXTEND; NCT01146652), in which patients received sarilumab 200 mg every 2 weeks (q2w) + methotrexate. METHODS: Patients (n=1197) with moderately to severely active RA were initially randomised to placebo, sarilumab 150 mg or sarilumab 200 mg subcutaneously q2w plus weekly methotrexate for 52 weeks. Completers were eligible to enrol in the open-label extension and receive sarilumab 200 mg q2w + methotrexate. RESULTS: Overall, 901 patients entered the open-label extension. The safety profile remained stable over 5-year follow-up and consistent with interleukin-6 receptor blockade. Absolute neutrophil count <1000 cells/mm(3) was observed but not associated with increased infection rate. Initial treatment with sarilumab 200 mg + methotrexate was associated with reduced radiographic progression over 5 years versus sarilumab 150 mg + methotrexate or placebo + methotrexate (mean±SE change from baseline in van der Heijde-modified Total Sharp Score: 1.46±0.27, 2.35±0.28 and 3.68±0.27, respectively (p<0.001 for each sarilumab dose versus placebo)). Clinical efficacy was sustained through 5 years according to Disease Activity Score (28-joint count) using C reactive protein, Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index. The number of patients achieving CDAI ≤2.8 at 5 years was similar among initial randomisation groups (placebo, 76/398 (19%); sarilumab 150 mg, 68/400 (17%); sarilumab 200 mg, 84/399 (21%)). CONCLUSION: Clinical efficacy, including inhibition of radiographic progression, reduction in disease activity and improvement in physical function, was sustained with sarilumab + methotrexate over 5 years. Safety appeared stable over the 5-year period.
31225891 Association of Genetic Risk for Rheumatoid Arthritis With Cognitive and Psychiatric Phenot 2019 Jun 5 IMPORTANCE: The association of rheumatoid arthritis (RA) with cognitive and psychiatric phenotypes has been recognized. However, it is not known whether these phenotypes are a consequence of disease-related factors, such as pain, or reflect shared etiological factors. OBJECTIVE: To investigate whether genomic risk for RA is associated with cognitive and psychiatric symptoms in children and adolescents. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data from 3296 to 5936 adolescents (depending on outcome) from the Avon Longitudinal Study of Parents and Children. Clinical and questionnaire data were collected periodically from September 6, 1990, with collection ongoing, and analyzed from August 21, 2017, to May 21, 2018. EXPOSURES: Polygenic risk scores (PRSs) for RA. MAIN OUTCOMES AND MEASURES: Measures of cognition (including IQ, working memory, verbal learning, processing speed, problem solving, selective attention, and attentional control) and psychopathology (including anxiety, depression, negative symptoms, psychotic experiences, attention-deficit/hyperactivity disorder, and hyperactive and inattentive symptoms) in childhood and adolescence. RESULTS: Polygenic risk scores for RA were generated for 7977 children and adolescents (3885 [48.7%] female). Of these 7977 participants, 9 (0.11%) had a known diagnosis of RA at age 22 years. Increased PRS for RA was associated with lower total IQ (β, -0.05; 95% CI, -0.07 to -0.02; P < .001), performance IQ (β, -0.03; 95% CI, -0.06 to -0.005; P = .02), and verbal IQ (β, -0.05; 95% CI, -0.08 to -0.02; P < .001) at age 8 years (mean [SD] age at measurement, 8.6 [0.3] years) and symptoms of hyperactivity and inattention from ages 4 to 16 years, with the strongest evidence of association at age 13 years (mean [SD] age at assessment, 13.2 [0.2] years). The odds ratio at this age per SD increase in PRS was 1.25 (95% CI, 1.12-1.39) (P < .001). There was little evidence of association between the RA PRS and other measures of cognition and psychopathology. Gene-based analyses indicated that polygenic signal for RA was enriched for immune pathways (q ≤ 0.05). No equivalent associations were seen for polygenic risk associated with inflammatory bowel disease or multiple sclerosis. CONCLUSIONS AND RELEVANCE: These findings support an association between genetic risk for RA and neural phenotypes, suggesting that cognitive impairment in RA is not simply secondary to disease-related processes or treatment effects. These results may suggest that genetic susceptibility for RA might affect psychological well-being in early life and reinforce the emerging link between mental health and the immune system.
30915067 Effector Functions of CD4+ T Cells at the Site of Local Autoimmune Inflammation-Lessons Fr 2019 Infiltration of memory CD4+ T cells in synovial joints of Rheumatoid Arthritis (RA) patients has been reported since decades. Moreover, several genome wide association studies (GWAS) pinpointing a key genetic association between the HLA-DR locus and RA have led to the generally agreed hypothesis that CD4+ T cells are directly implicated in the disease. Still, RA is a heterogeneous disease and much effort has been made to understand its different facets. T cell differentiation is driven by mechanisms including antigen stimulation, co-stimulatory signals and cytokine milieu, all of which are abundant in the rheumatic joint, implying that any T cells migrating into the joint may be further affected locally. In parallel to the characterization and classification of T-cell subsets, the contribution of different effector T cells to RA has been investigated in numerous studies though sometimes with contradictory results. In particular, the frequency of Th1 and Th17 cells has been assessed in the synovial joints with various results that could, at least partly, be explained by the stage of the disease. For regulatory T cells, it is largely accepted that they accumulate in RA synovial fluid and that the equilibrium between regulatory T cells and effector cells is a key factor in controlling inflammation processes involved in RA. Recent phenotypic studies describe the possible implication of a novel subset of peripheral T helper cells (Tph) important for T-B cell cross talk and plasma cell differentiation in the RA joint of ACPA+ (autoantibodies against citrullinated proteins) RA patients. Finally, cytotoxic CD4+ T cells, historically described as increased in the peripheral blood of RA patients have attracted new attention in the last years. In view of the recently identified peripheral T-cell subsets, we will integrate immunological data as well as information on genetic variants and therapeutic strategy outcomes into our current understanding of the width of effector T cells. We will also integrate tissue-resident memory T cell aspects, and discuss similarities and differences with inflammatory conditions in skin (psoriasis) and mucosal organs (Crohn's disease).
30430957 Diets high in n-3 fatty acids are associated with lower arterial stiffness in patients wit 2019 Jan Supplementation with n-3 fatty acids can influence inflammation and markers of arterial stiffness that are increased in patients with rheumatoid arthritis (RA). However, it is unknown whether specific patterns of dietary fatty acid intake are similarly associated. In a longitudinal study, eighty-six RA patients reported their dietary intake and had arterial stiffness measured using the augmentation index (AIx) at baseline and 8 months. Latent profile analysis (LPA) was performed to characterise patterns of fatty acid intake using sixteen major fatty acids. Models for two to six profiles were compared using the Akaike and Bayesian information criteria. Associations between AIx and the profiles were adjusted for age, sex, disease activity, fish oil supplementation, medications, physical activity and socio-economic status. LPA identified five distinct profiles. Profile 1 subjects (n 7) reported significantly higher intake of palmitoleic acid (16 : 1), arachidonic acid (20 : 4n-6), EPA (20 : 5n-3), DHA (22 : 6n-3) and docosapentaenoic acid (22 : 5n-3) (P<0·001 for each) than profiles 2 (n 14), 3 (n 19), 4 (n 23) and 5 (n 23) and significantly higher grilled and tinned fish consumption. The AIx varied significantly across the five profiles (P=0·023); subjects in profile 1 had a significantly lower AIx than those in profile 3 (β=-7·2 %; 95 % CI -11·5, -2·9; P=0·001) who had the lowest reported intake of n-3 fatty acids. Fish oil supplementation was also independently associated with lower AIx (β=-4·15 %; 95 % CI -6·73, -1·56; P=0·002). A diet characterised by a higher reported intake of n-3 fatty acids, palmitoleic acid (16 : 1) and arachidonic acid (20 : 4n-6) is associated with a lower AIx in RA patients.
31056910 Role of Liposome Size, Surface Charge, and PEGylation on Rheumatoid Arthritis Targeting Th 2019 Jun 5 Rheumatoid arthritis (RA) is a chronic, systemic, progressive autoimmune disease. The vascular permeability of inflamed joints in RA makes it a natural candidate for passive targeting, similar to the enhanced permeability and retention (EPR) effect in solid tumors. Thus, various therapeutic drugs have been encapsulated in nanocarriers to achieve longer in vivo circulation times and improve RA targeting. Although liposomes are the most widely used nanocarriers for RA treatment, the effects of physical and chemical characteristics of liposomes, such as particle sizes, surface charge, polyethylene glycol (PEG) chain length, and PEG concentration, on their passive RA targeting effect have not been fully elucidated. Here, we systematically investigated the effects of physical and chemical properties of liposomes on circulation time and conducted preliminary studies on their passive targeting mechanisms. A series of liposomes with different particle sizes (70, 100, 200, and 350 nm), surface charges (positive, negative, slight positive, and slight negative), PEG chain lengths (1, 2, and 5 kDa), and concentrations (5, 10, and 20% w/w of total lipid) were prepared by lipid film dispersion and extrusion. The pharmacokinetics of liposomes with different formulas were evaluated with a fluorescence microplate reader. A collagen-induced arthritis (CIA) mouse model was utilized to mimic RA pathological conditions and to evaluate the targeting and efficacy of liposomes with different properties using a near-infrared fluorescence imaging system. Uptake of fluorescent liposomes by various synovial cells was measured by flow cytometry. The results indicated that liposomes with 100 nm diameter, a slight negative charge, and 10% incorporation of 5 kDa PEG had better in vivo circulation time and inflamed joint targeting than did other liposomes. Dexamethasone (Dex) was encapsulated into optimized liposomes as an active ingredient for RA treatment. Pharmacodynamic studies demonstrated that Dex liposomes could significantly improve the antiarthritic efficacy of Dex in a CIA mouse model of RA. This study also found that the retention mechanism of RA was mainly increased because of the uptake of liposomes by fibroblasts and macrophages in inflamed joints. This study provides a persuasive explanation for passive RA targeting by liposomes and advances our ability to treat RA with nanomedicine.
30811898 Affinity Maturation of the Anti-Citrullinated Protein Antibody Paratope Drives Epitope Spr 2019 Apr OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA). While epitope spreading of the serum ACPA response is believed to contribute to RA pathogenesis, little is understood regarding how this phenomenon occurs. This study was undertaken to analyze the antibody repertoires of individuals with RA to gain insight into the mechanisms leading to epitope spreading of the serum ACPA response in RA. METHODS: Plasmablasts from the blood of 6 RA patients were stained with citrullinated peptide tetramers to identify ACPA-producing B cells by flow cytometry. Plasmablasts were single-cell sorted and sequenced to obtain antibody repertoires. Sixty-nine antibodies were recombinantly expressed, and their anticitrulline reactivities were characterized using a cyclic citrullinated peptide enzyme-linked immuosorbent assay and synovial antigen arrays. Thirty-six mutated antibodies designed either to represent ancestral antibodies or to test paratope residues critical for binding, as determined from molecular modeling studies, were also tested for anticitrulline reactivities. RESULTS: Clonally related monoclonal ACPAs and their shared ancestral antibodies each exhibited differential reactivity against citrullinated antigens. Molecular modeling identified residues within the complementarity-determining region loops and framework regions predicted to be important for citrullinated antigen binding. Affinity maturation resulted in mutations of these key residues, which conferred binding to different citrullinated epitopes and/or increased polyreactivity to citrullinated epitopes. CONCLUSION: These results demonstrate that the different somatic hypermutations accumulated by clonally related B cells during affinity maturation alter the antibody paratope to mediate epitope spreading and polyreactivity of the ACPA response in RA, suggesting that these may be key properties that likely contribute to the pathogenicity of ACPAs.
31611200 Deletion of miR-15 Protects Against Rheumatoid Arthritis via Deregulating its Target Gene 2019 Sep OBJECTIVE: MiR-15 is involved in modulating many cellular processes that are normally destroyed in disease. The regulation of the cell cycle, angiogenesis, and responses to cellular stress are notable processes influenced by MiR-15. MiR-15 plays a critical role in the model of inflammation-related angiogenesis defects. However, its role in rheumatoid arthritis (RA) remains unclear. In this paper, we questioned the potential effects miR-15 has on RA. METHODS: Synthetic mimics of miR-15 were transfected into human RA fibroblast-like synoviocyte (FLS) cell line MH7A cells. Cell proliferation was detected by a Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was determined by flow cytometry. MH7A cells, stimulated by interleukin-1β (IL-1β), were transfected with miR-15 mimics and inhibitors. Western blot and quantitative real time (qRT)-PCR were used to detect gene and protein expressions. Bioinformatic software analysis and luciferase reporter assays were used to predict and validate miR-15 targets. RESULTS: We found that the miR-15 experienced down-regulated expression in MH7A cells, after they were stimulated with IL-1β. MiR-15 inhibited inflammatory cell proliferation and promoted inflammatory cell apoptosis. BCL2L2 was identified as a target of miR-15 by luciferase assay. Additionally, NF-κB signaling pathway related proteins were inhibited by miR-15 overexpression. CONCLUSION: These findings contribute to an understanding of the impact that miR-15 possesses on inflammatory injury, and provide a basis for RA treatment.
30611246 Association of fish intake and smoking with risk of rheumatoid arthritis and age of onset: 2019 Jan 5 BACKGROUND: Prior studies suggest that fish may be protective for rheumatoid arthritis (RA) risk perhaps through the anti-inflammatory effect of omega-3 fatty acid, but this relationship has not been clearly established. Therefore, we investigated fish intake and RA risk by serologic status, age of onset, and smoking using a prospective cohort study with large sample size, repeated measures of dietary intake, and lengthy follow-up. METHODS: We studied fish intake and RA risk among 166,013 women in two prospective cohorts, the Nurses' Health Study (NHS, 1984-2014) and NHSII (1991-2015). Fish intake was assessed using food frequency questionnaires at baseline and every 4 years. Incident RA during follow-up and serologic status were determined by medical record review. Pooled Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for RA (overall and by serologic status and age at diagnosis) for fish intake frequency. We tested for a smoking-fish interaction for RA risk. RESULTS: During 3,863,909 person-years of follow-up, we identified 1080 incident RA cases. Increasing fish intake was not associated with all RA (≥4 servings/week: multivariable HR 0.93 [95%CI 0.67-1.28] vs. < 1 serving/month; p for trend = 0.42), seropositive RA (p for trend = 0.66), or seronegative RA (p for trend = 0.45), but had increased risk for RA diagnosed > 55 years old (p for trend = 0.037). Among women ≤55 years old, frequent fish intake (vs. infrequent) had HRs (95%CIs) of: 0.73 (0.52-1.02) for all RA, 0.85 (0.55-1.32) for seropositive RA, and 0.55 (0.32-0.94) for seronegative RA. Ever smokers with infrequent fish intake had highly elevated risk for RA onset ≤55 years (HR 2.59, 95%CI 1.65-4.06), while ever smokers with frequent fish intake had modestly elevated RA risk (HR 1.29, 95%CI 1.07-1.57; vs. never smokers/frequent fish intake; p for smoking-fish interaction = 0.039). CONCLUSION: In this large prospective cohort study, we found no clear protective effect of fish or marine omega-3 fatty acid intake on RA risk, overall or by serologic status. We found that fish intake attenuated the strong association of smoking for RA diagnosed ≤55 years of age, but this requires further study.