Clinical Outcomes In Rheumatoid Arthritis Research Articles

Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis.

Anti-IL-6 receptor antibodies are clinically efficacious in the management of rheumatoid arthritis (RA) with an associated increase in regulatory T cells (Tregs); however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyze the relationship between these Treg subsets and the clinical outcome of RA. We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs, and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. Blocking IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favorable treatment course, and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.

Patient-physician discordance impairs outcomes in early rheumatoid arthritis through less consistent treat-to-target implementation.

We aimed to assess whether patient-physician discordance regarding disease activity affects T2T-implementation and clinical outcomes in rheumatoid arthritis (RA). This was an analysis of the 2-year T2T-guided trial Care in early RA (CareRA). During year 1, DMARD escalations were mandated by the protocol when DAS28-CRP was >3.2. During year 2, treatment was at the rheumatologists' discretion. At each visit we assessed T2T-implementation, defined as escalating DMARDs if DAS28-CRP >3.2. Patient-physician discordance was defined by the discordance score (DS), a weighted difference between patient-reported and clinical/laboratory outcomes. Using generalised linear mixed models and multilevel mediation analysis, we studied the association between time-varying DS, T2T-implementation and the odds of remission (SDAI ≤3.3), physical functioning (HAQ-score), and radiographic progression at year 2. Over 2 years, 379 patients were assessed at 3129 follow-up visits. On 445 (14%) of these visits, DAS28-CRP was >3.2, and DMARDs were escalated in 217/445 (49%) of such cases. T2T-implementation declined over time and was consistently lower during the second year (year 1: 57-66%; year 2: 17-52%). Higher DS over time was negatively associated with remission and physical functioning at year 2, partly mediated by a lower proportion of T2T-adherent visits. No such association was found for radiographic progression. Even in a trial setting, T2T was applied on only around 50% of visits. T2T was less likely to be implemented with increasing patient-physician discordance regarding disease activity, which was in turn associated with less remission and worse functional outcome, but not with radiographic progression.

Effects of metformin therapy on HMGB1 levels in rheumatoid arthritis patients

ObjectiveThe traditional treatment of rheumatoid arthritis (RA) has some side effects. We aimed to explore the effect of metformin treatment on the expression of HMGB1, cytokines, T cell subtypes and the clinical outcomes in RA patients.MethodsThe present prospective cohort study recruited 124 RA patients (metformin group) who were treated with metformin and conventional therapy (methotrexate, hydroxychloroquine sulfate and sulfasalazine) and 98 RA patients (conventional therapy group) who were only treated with conventional therapy. All subjects were admitted from December 2018 to December 2021 and continuous medication for 90 days. The serum high mobility group box 1 (HMGB1), tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β and C-reactive protein (CRP) levels were measured by enzyme-linked immunosorbent assay (ELISA). Flow cytometric were used to analyze the expression of CD4+ and CD8+. Demographic and clinical statistics including age, body mass index (BMI), sex, course of disease, erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), visual analogue score (VAS)and disease activity score (DAS)-28 were collected.ResultsThe serum levels of HMGB1, CRP, IL-6, CD4+ expression and CD4+/CD8+ ratio were significantly increased in patients with DAS-28 score ≥ 2.6. The serum HMGB1 and cytokines levels of metformin group declined more quickly during the study time. Pearson’s analysis supported that a positive correlation existed between the HMGB1 and IL-6, TNF-α, CRP, CD4+, CD4+/CD8+ ratio, and VAS scores. HMGB1 could be a potential diagnostic biomarker for RA patients in active phase. Serum HMGB1 (95% CI 1.133–1.397, P < 0.001) was a factor associated with active RA.ConclusionThe serum HMGB1 levels were significantly increased in RA patients in active phase. The serum levels of HMGB1 and inflammatory factors and VAS scores were decreased gradually with metformin treatment. HMGB1 might act as a novel therapeutic target for RA.

Rheumatoid arthritis.

It is difficult to determine from ancient writings, old human specimens, and from Art over the centuries, as to when Rheumatoid Arthritis first appeared. It may be a relatively modern condition, as it was reasonably well described in the seventeenth century. Augustin Jacob Landre-Beauvais (1772-1840), University of Paris is credited, with the first clear description of the disease in his thesis. In 1859 Sir Alfred Baring Garrod (1819-1907), the "father of rheumatology", gave the disease its current name which was finally adapted in Britain by the Ministry of Health in 1922. Some forms of Juvenile Arthritis are related to adult Rheumatoid Arthritis (aka Still's disease). If untreated Rheumatoid arthritis can result in severe destructive joint damage and often there are associated severe systemic complications. Disease modifying agents have benefited the disease management, but it was the discovery of the anti TNF-alpha agents in the 1990s, and subsequently many additional Biologic agents, which have greatly changed the clinical outcome in Rheumatoid Arthritis.

Clinical Outcomes in Rheumatoid Arthritis due to Tocilizumab Stock-out during COVID-19 Epidemics: A Short Case Series Report

Clinical Outcomes in Rheumatoid Arthritis due to Tocilizumab Stock-out during COVID-19 Epidemics: A Short Case Series Report

The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis.

Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a “continuum” of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.

Addition of Fibroblast-Stromal Cell Markers to Immune Synovium Pathotypes Better Predicts Radiographic Progression at 1 Year in Active Rheumatoid Arthritis.

ObjectivesThis study aims to investigate if addition of fibroblast-stromal cell markers to a classification of synovial pathotypes improves their predictive value on clinical outcomes in rheumatoid arthritis (RA).MethodsActive RA patients with a knee needle synovial biopsy at baseline and finished 1-year follow-up were recruited from a real-world prospective cohort. Positive staining for CD20, CD38, CD3, CD68, CD31, and CD90 were scored semiquantitatively (0-4). The primary outcome was radiographic progression defined as a minimum increase of 0.5 units of the modified total Sharp score from baseline to 1 year.ResultsAmong 150 recruited RA patients, 123 (82%) had qualified synovial tissue. Higher scores of CD20+ B cells, sublining CD68+ macrophages, CD31+ endothelial cells, and CD90+ fibroblasts were associated with less decrease in disease activity and greater increase in radiographic progression. A new fibroblast-based classification of synovial pathotypes giving more priority to myeloid and stromal cells classified samples as myeloid-stromal (57.7%, 71/123), lymphoid (31.7%, 39/123), and paucicellular pathotypes (10.6%, 13/123). RA patients with myeloid-stromal pathotype showed the highest rate of radiographic progression (43.7% vs. 23.1% vs. 7.7%, p = 0.011), together with the lowest rate of Boolean remission at 3, 6, and 12 months. Baseline synovial myeloid-stromal pathotype independently predicted radiographic progression at 1 year (adjusted OR: 3.199, 95% confidence interval (95% CI): 1.278, 8.010). Similar results were obtained in a subgroup analysis of treatment-naive RA.ConclusionsThis novel fibroblast-based myeloid-stromal pathotype could predict radiographic progression at 1 year in active RA patients which may contribute to the shift of therapeutic decision in RA.

Tender and swollen joint counts are poorly associated with disability in chikungunya arthritis compared to rheumatoid arthritis

Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) are described after chikungunya virus infection. We aimed to compare the relevance of joint counts and symptoms to clinical outcomes in RA and chronic chikungunya disease. Forty patients with chronic chikungunya arthralgia and 40 patients with RA were enrolled in a cross-sectional study. The association of tenderness and swelling, clinically assessed in 28 joints, and patient evaluations of pain and musculoskeletal stiffness with modified Health Assessment Questionnaire (HAQ) and quality of life (QoL) assessments were investigated. Tender and swollen joint counts, pain and stiffness scores were all associated with the HAQ disability index in RA (all r > 0.55, p ≤ 0.0002), but only stiffness was significantly associated with disability in chikungunya (r = 0.38, p = 0.02). Joint counts, pain and stiffness were also associated with most QoL domains in RA patients. In contrast, in chikungunya disease, tender joint counts were associated only with one QoL domain and swollen joints for none, while pain and stiffness were associated with several domains. Our results confirm the relevance of joint counts in RA, but suggest that in chronic chikungunya disease, joint counts have more limited value. Stiffness and pain score may be more important to quantify chikungunya arthritis impact.

Biological Therapy in Patients with Rheumatoid Arthritis in a Tertiary Center in Portugal: A Cross-Sectional Study.

Clinical outcomes in rheumatoid arthritis have greatly improved with therapeutic advances. Despite the availability of substantial clinical trial evidence, there is a lack of real-life data. The aim of this study was to assess disease status and quality of life in an outpatient population treated with biological disease-modifying anti-rheumatic drugs. Cross-sectional study recalling all patients ever treated in our unit with biological disease-modifying antirheumatic drugs. Clinical and demographic data, compliance, disease activity, functional status, joint deformities, and comorbidities were documented, and patients queried on occupational status, education, marital status and generic health related quality of life questionnaires. Recall was attended by 77 of the original 94 patients. At recall, median age was 63 years old, 82% of the patients were female and the median disease duration was 12 years. Biological therapy was started at a median of four years following disease onset. According to the disease activity score (DAS28), the percentage of patients with high, moderate, low disease activity or remission changed from 50, 45, 0 and 5 (pre-therapy) to 11, 37, 25 and 26 at recall, respectively; functional status was significantly improved. Seventy-five per cent of the patients retained the original treatment with good compliance. Lower Short Form-36 domain scores accompanied a low EQ-5D-3L score. Deceased patients (n = 6) had a lower estimated 10-year survival rate. In this group, biological therapy was discontinued at a higher frequency during follow-up. A high disease activity and a high HAQ disability index characterized most patients at pre-bDMARD onset. Despite therapy switches and regular follow-up, a significant percentage of patients still presented with moderate disease activity, functional impairment and a poor health-related quality of life.

Treatment expectations as a possible prognostic factor for DMARD response in rheumatoid arthritis: a prospective cohort study

Background:The prediction of the individual’s response to disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is challenging and often limited. Here we evaluated the influence of patients’ expectations towards a change in treatment with DMARD on clinical outcome in RA.Methods:One hundred patients (74 female) with RA (2010 ACR/EULAR classification criteria) and an upcoming change in DMARD treatment due to non-response or adverse effects were included. Patients’ treatment beliefs, health-related quality of life and treatment expectations were measured using the Beliefs about Medicines Questionnaire (BMQ), the Short Form 36, and self-designed questions about expectations before treatment initiation (T0), and DAS28-CRP was calculated at T0 and after 4 months (T4). Associations between patients’ beliefs and expectations and changes in DAS28-CRP (T0 to T4, ΔDAS28-CRP) were explored by regression analyses after multiple imputation.Results:A total of 99 patients were included, of whom 84 completed all questionnaires. Thirty-six percent of all variability in treatment response (ΔDAS28-CRP) was explained by expectations assessed with the questionnaires and the C-reactive protein (CRP)-value at T0. Among these, the expected improvement rate, with 10.5%, as well as the CRP-value at T0, with 10.6%, had the greatest positive effect whereas the fear of adverse effects, with 11.4%, and the BMQ.concern scale, with 9.0%, had the greatest negative impact on ΔDAS28.Conclusion:Patients’ expectations towards newly induced DMARD therapies influence clinical response and may serve as possible explanatory factors for treatment response affecting subjective and objective outcome parameters.Clinical trial registration number:DRKS00017005

Addition of Fibroblast-Stromal Cell Markers to Immune Synovium Pathotypes Better Predicts Radiographic Progression at One Year in Active Rheumatoid Arthritis

Background: Current synovial assessments mainly focus on the infiltrated immune cells. Whether addition of fibroblast-stromal cell markers to a classification of synovial pathotypes improves their predictive value on clinical outcomes in rheumatoid arthritis (RA) remains unknown. Methods: Active RA patients with a knee needle synovial biopsy at baseline and finished one-year follow-up were recruited from a real-world prospective cohort. Positive staining for CD20, CD38, CD3, CD68, CD31 and CD90 were scored semi-quantitatively (0-4). The primary outcome was radiographic progression defined as a minimum increase of 0.5 units of the modified total Sharp score from baseline to one year. Findings: Among 159 recruited RA patients, 123 (77.4%) had qualified synovial tissue. Higher scores of CD20+ B cells, sublining CD68+ macrophages, CD31+ endothelial cells and CD90+ fibroblasts were associated with less decrease in disease activity and greater increase in radiographic progression. A new fibroblast-based classification of synovial pathotypes giving more priority to myeloid and stromal cells classified samples as myeloid-stromal (57.7%, 71/123), lymphoid (31.7%, 39/123), and pauci-cellular pathotypes (10.6%, 13/123). RA patients with myeloid-stromal pathotype showed the highest rate of radiographic progression (43.7% vs. 23.1% vs. 7.7%, P =0.011), and the lowest rate of Boolean remission at 3, 6, 12 months. Baseline myeloid-stromal pathotype independently predicted radiographic progression at one year (3.199, 95% CI: 1.278, 8.010). Similar results were obtained in a subgroup analysis of treatment-naive RA. Interpretation: This novel myeloid-stromal pathotype could predict radiographic progression at one year in active RA which may contribute to the shift of therapeutic decision in RA. Funding Statement: This work including data collection and conduct of experiments was supported by National Natural Science Foundation of China (81801606, 81971527 and 82001731), Guangdong Natural Science Foundation (2018A030313541 and 2018A030313690), Guangdong Medical Scientific Research Foundation (A2018062 and A2021065), Science and Technology Program of Guangzhou (201904010088 and 202102010188), and Guangdong Basic and Applied Basic Research Foundation (2019A1515011928, 2019A1515110125 and 2020A1515110061). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Ethical approval was provided by the Medical Ethics Committee of Sun Yat-sen Memorial Hospital (SYSEC-2009-06 and SYSEC-KY-KS-012). All patient consents were obtained before biopsy and collection of clinical data.

Effect of an 8-Week Yoga-Based Lifestyle Intervention on Psycho-Neuro-Immune Axis, Disease Activity, and Perceived Quality of Life in Rheumatoid Arthritis Patients: A Randomized Controlled Trial

Various external stressors and environmental challenges lead to the provocation of the immune system in autoimmune diseases like Rheumatoid arthritis (RA). The inappropriate immune response further triggers the cascade of inflammatory changes resulting in precipitation of symptoms and hampers quality of life (QOL). The underlying psycho-somatic component of the disease requires a holistic approach to its treatment dimension rather than the use of pharmacotherapy. The applicability of mind-body interventions has become essential in today’s fast-paced life. Yoga, a mind-body technique, alters the mind’s capacity to facilitate systemic functioning at multiple organ system levels. Hence, we conducted this study to evaluate the impact of 8 weeks of a yoga-based lifestyle intervention (YBLI) on psycho-neuro-immune markers, gene expression patterns, and QOL in RA patients on routine medical therapy. A total of 66 patients were randomized into two groups: yoga group or non-yoga group and were assessed for a panel of inflammatory cytokines (IL-6, IL-17A, TNF-α, and TGF-β), mind-body communicative markers (BDNF, DHEAS, β-endorphin, and sirtuin) and transcript levels of various genes (IL-6, TNF-α, NFKB1, TGF-β, and CTLA4). We assessed disease activity and QOL using the DAS28-ESR and WHOQOL-BREF questionnaire, respectively. Yoga group observed significant improvements in the levels of markers, which influenced the psycho-neuro-immune axis (p < 0.001) with an estimated effect size from small to medium range. In the yoga group, there was a significant reduction in DAS28-ESR (p < 0.001) and improvement seen in the physical health, psychological, social relationships domains (p < 0.001) of QOL, except environmental (p > 0.05). The yoga group showed downregulation of IL-6, TNF-α, and CTLA4 and upregulation of TGF-β. These results suggest that a decrease in disease activity after yoga practice is associated with a significant reduction in inflammatory cytokines, the elevation of mind-body communicative markers, and normalization of various transcript levels, which improved QOL. Thus the adoption of YBLI improves clinical outcome in RA, and decreases systemic inflammation by its beneficial effects on psycho-neuro-immune axis and normalization of dysregulated transcripts. Thus YBLI may be used for RA patients as an adjunctive therapy.

THU0186 CLINICAL EVALUATION OF THE IMMUNOGENICITY TO CT-P13 FOR SUBCUTANEOUS USE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: 1-YEAR CLINICAL RESULTS FROM A MULTICENTER, RANDOMIZED CONTROLLED PIVOTAL TRIAL

Background:Novel subcutaneous infliximab (CT-P13 SC) was developed to augment the flexibility in therapeutic use of infliximab and noninferiority (NI) of CT-P13 SC versus CT-P13 intravenous (IV) was demonstrated for efficacy in patients with rheumatoid arthritis (RA) [1]. CT-P13 SC 120mg biweekly showed consistent higher therapeutic trough levels during the treatment period, which helps in maintaining efficacy over time. Since immunogenicity has clinical importance in patients using anti-TNF alpha agents and there is a general presumption that SC route is more immunogenic than IV route, this needs careful assessment.Objectives:Immunogenicity assessment of CT-P13 SC with further impact analysis has been performed on the pivotal data set [1] to determine whether there was any correlation between the magnitude of anti-drug antibody (ADA) positivity and clinical outcomes in RA patients.Methods:The immune response against CT-P13 in human serum was detected using an electrochemiluminescence (ECL) platform with an Affinity Capture Elution (ACE) step. An ADA ECL ACE assay showed ability to detect ADA at low levels in all samples regardless of residual drug in serum (25 ng/mL ADA in the presence of 80 μg/mL of CT-P13 in RA serum). To investigate the impact of ADA titer on PK, efficacy and safety, key clinical parameters were assessed by visit based ADA titer quartile. All patients who had ‘Positive’ ADA status result at each visit were included in the analysis and categorized into 4 groups using the 25th, 50th, 75th percentiles of ADA titer result, respectively.Results:The four subgroups categorized by quartiles at each visit from week 22 to week 54 were: 1st (ADA titer ≤ 3), 2nd (3 &lt; ADA titer ≤ 9), 3rd (9 &lt; ADA titer ≤ 27) and 4th (27 &lt; ADA titer). There was a trend for pre-dose concentration to decrease as ADA titer increases for both CT-P13 SC and CT-P13 IV arms as expected (Figure 1). Patients in the 1st and 2nd subgroup maintained the sufficient therapeutic drug concentration level. Figure 2 shows the correlation between ADA titer and efficacy outcomes where the change from baseline of DAS28 (CRP) and the proportion of patients achieving ACR20 were lower in the 3rd and 4th subgroups. The ADA impact was especially apparent in the 4th subgroup where the mean pre-dose concentration of the patients was below the therapeutic drug concentration level (1 μg/mL), which led to worse efficacy outcomes in both arms, IV as well as SC. Nevertheless, no impact of ADA on safety profile in both arms was observed. A neutralizing antibody (NAb) method with enhanced drug tolerance but limited performance was also developed and clinical consequences of NAb titer in terms of PK, efficacy and safety were not different from the results with ADA.Conclusion:The analysis of both ADA positivity and titer is clinically meaningful in the prediction of PK profile and clinical response. CT-P13 SC administration did not result in a greater incidence of ADA compared to the CT-P13 IV and there were no clinical differences depending on the formulation.

Anti-inflammatory Diet In Rheumatoid Arthritis (ADIRA)—a randomized, controlled crossover trial indicating effects on disease activity

BackgroundMany patients with rheumatoid arthritis (RA) report symptom relief from certain foods. Earlier research indicates positive effects of food and food components on clinical outcomes in RA, but insufficient evidence exists to provide specific dietary advice. Food components may interact but studies evaluating combined effects are lacking.ObjectivesWe aimed to investigate if an anti-inflammatory diet reduces disease activity in patients with RA.MethodsIn this single-blinded crossover trial, 50 patients with RA were randomly assigned to an intervention diet containing a portfolio of suggested anti-inflammatory foods, or a control diet similar to the general dietary intake in Sweden, for 10 wk. After a 4-mo washout period the participants switched diet. Food equivalent to ∼50% of energy requirements was delivered weekly to their homes. For the remaining meals, they were encouraged to consume the same type of foods as the ones provided during each diet. Primary outcome was change in Disease Activity Score in 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR). Secondary outcomes were changes in the components of DAS28-ESR (tender and swollen joints, ESR, and visual analog scale for general health) and DAS28-C-reactive protein.ResultsIn the main analysis, a linear mixed ANCOVA model including the 47 participants completing ≥1 diet period, there was no significant difference in DAS28-ESR between the intervention and control periods (P = 0.116). However, in unadjusted analyses, DAS28-ESR significantly decreased during the intervention period and was significantly lower after the intervention than after the control period in the participants who completed both periods (n = 44; median: 3.05; IQR: 2.41, 3.79 compared with median: 3.27; IQR: 2.69, 4.28; P = 0.04, Wilcoxon's Signed Rank test). No significant differences in the components were observed.ConclusionsThis trial indicates positive effects of a proposed anti-inflammatory diet on disease activity in patients with RA. Additional studies are required to determine if this diet can cause clinically relevant improvements.This trial was registered at clinicaltrials.gov as NCT02941055.

THU0107 OBESITY PREDICTS RESPONSE TO NOT ALL BUT CERTAIN BIOLOGICAL / TARGETED DISEASE MODIFYING ANTI-RHEUMATIC DRUGS FOR RHEUMATOID ARTHRITIS - RESULTS FROM KANSAI CONSORTIUM FOR WELL-BEING OF RHEUMATIC DISEASE PATIENTS (ANSWER COHORT)

Background:A number of previous reports suggested that obesity is one of the baseline factors indicates refractory to biologic disease-modifying antirheumatic drugs (bDMARDs). However, difference of the significant responses appears on obesity patients depending on each kind of drug is yet unclear. However, it is yet unclear how the significant responses on obesity patients vary on each kind of drug.Objectives:To assess whether obesity affects clinical outcome in rheumatoid arthritis (RA) treated with each molecular-targeted agent including bDMARDs and tofacitinib.Methods:In Kansai consortium for well-being of rheumatic disease patients (ANSWER) cohort, which was the real-world retrospective cohort of clinical database for rheumatic diseases, RA patients who initiated biological / targeted disease modifying anti-rheumatic drugs were included and consecutively followed. Obesity was defined as BMI over than 25, and patients were divided between obese (“Ob”) and non-obese (“non-Ob”) patients. SDAI (simplified disease activity index) was compared between non-Ob and Ob at month 0, 3, 6, 9, 12 after the indicated drugs were administered. Using logistic regression analysis, odds ratio (OR) and their corresponding 95% confidence intervals (95% CIs) were further calculated to estimate achievement rate of SDAI remission defined as lower than 3.3 by obesity and other relevant clinical parameters. Once after the drugs were discontinued by any unfavorable reason, disease activities were no more scored and the Last Observation Carried Forward (LOCF) imputation method was used for SDAI at month 3 and thereafter.Results:A total of 1936 patients met in the inclusion criteria were under the analysis. In each drug, SDAI remission rate (non-Ob, Ob, p-value by Chi-square test) at month 12 was as follows; Infliximab (IFX, n=135): 43%, 38%, NS (not significant); Etanercept (ETN, n=188): 44%, 19%, p=0.0122; Adalimumab (ADA, n=169): 50%, 56%, NS; Golimumab (GLM, n=315): 36%, 30%, NS; Certolizumab pegol (CZP, n=131): 33%, 56%, p=0.0287; Tocilizumab (TCZ, n=423): 41%, 29%, p=0.0456; Abatacept (ABT, n=144): 26%, 23%, NS; Tofacitinib (TOF, n=69): 27%, 23%, NS. In multivariate analysis to predict SDAI remission at month 12, obesity was an independent protective factor in CZP (OR: 0.29, 95% CIs: 0.10 – 0.83), but was an independent risk factor in TCZ (OR: 1.9, 95% CIs: 1.01 – 3.61) irrespective of age, sex, disease duration, SDAI at month 0 or number of previous bDMARDs. Any other drug including ETN did not show significant result between non -Ob and Ob in the multivariate analysis.Conclusion:Obese patients were more resistant to TCZ but more effective in CZP than non-obese patients.

Overweight/obesity affects histological features and inflammatory gene signature of synovial membrane of Rheumatoid Arthritis

Overweight/obesity influence disease burden and clinical outcome of Rheumatoid Arthritis (RA). The impact of overweight/obesity on synovial tissue (ST) inflammation is largely unknown. Here, we investigated the histological and transcriptional signature of ST obtained from RA in different disease phases (disease onset, failure to first-line conventional DMARDs and in sustained clinical and ultrasound remission) finding that overweight/obese DMARDs naive RA showed higher likelihood of follicular synovitis, higher IHC scores for sublining inflammatory cells (CD68+, CD21+ and CD20+) and higher IL-1RA plasma levels than normal weight RA. Regardless to the synovitis pattern, overweight/obese DMARDs naive RA showed a worse clinical response to “Treat-to-target” (T2T) than normal weight RA at 6 and 12 months follow-up. Conversely, MTX-IR RA did not show significant differences in synovial inflammation based on BMI category. Overweight/obese RA in stable clinical and US remission showed higher degree of residual synovitis in terms of sublining CD68+, CD20+ cells and lining and sublining CD3+ compared to normal weight RA. Finally, gene expression profile analysis revealed that ST of overweight/obese DMARDs naive RA is enriched by CCL3 and MyD88 compared to normal weight RA in sustained disease remission, the latter correlating with BMI and IHC scores for synovial CD68+ cells. These findings suggest that indeed overweight/obese RA show higher degree of synovitis at disease onset and after remission achievement that influences the response rate to T2T and should be considered within the management of patients with RA.

Abatacept retention and clinical outcomes in rheumatoid arthritis: real-world data from the German cohort of the ACTION study and a comparison with other participating countries

IntroductionAbataCepT 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.MethodBaseline 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.ResultsIn 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).ConclusionsIn 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.

Relationship between Helicobacter pylori cytotoxin-associated gene A protein with clinical outcomes in patients with rheumatoid arthritis

IntroductionThe Helicobacter pylori(H. pylori) infection leads to intensification of symptoms and calenture of autoimmune diseases. This study aimed to evaluate the relationship between H. pylori infection and clinical outcomes in rheumatoid arthritis (RA) patients. MethodologyThis study was performed on 100 RA patients. Blood samples were collected for measuring Anti-H. pylori IgG antibodies and cytotoxin-associated gene A (CagA) protein. Fresh fecal samples were also collected and the fecal H. pylori antigen was extracted. Clinical condition as well as severity and type of RA symptoms in both groups of H. pylori positive and H. pylori negative were also compared. ResultsSerum levels of rheumatoid factor (RF), ESR, CRP, anti-cyclic citrullinated peptide (Anti−CCP), and anti-mutated citrullinated vimentin (Anti-MCV) were significantly higher in H. pylori positive patients than in H. pylori negative patients (P < 0.05). Serum RF, ESR, CRP and Anti-MCV levels were significantly higher in CagA positive patients than in CagA negative patients (P < 0.05). There were no significant differences in DAS-28 scores between H. pylori positive and H. pylori negative patients (P = 0.064) as well as between patients with positive and negative fecal H. pylori antigen (P = 0.237). However, DAS-28 score was significantly higher in CagA positive patients than in CagA negative patients (P < 0.001). Furthermore, mean VAS score was significantly higher in H. pylori positive patients (P = 0.031) and CagA positive patients (P = 0.004); however, there were no significant differences in VAS scores between patients with positive and negative fecal H. pylori antigen (P = 0.310). ConclusionFollow-up and examination of RA patients in terms of infection with serum and fecal H. pylori organism and CagA seems necessary that will contribute to better and further control and treatment of the patients.

IRF4 and IRGs Delineate Clinically Relevant Gene Expression Signatures in Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Introduction: Overactivation of the type I interferon (IFN) signature has been observed in several systemic autoimmune conditions, such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis (RA). Impaired control of Interferon-Responding Genes (IRGs) expression by their regulatory mechanisms, including Interferon Regulatory Factors (IRFs), may underlie these findings and it may explain the heterogeneity observed among these conditions. In the present study we aimed to evaluate the associations between IRF4 gene expression and those of IRGs in SLE and RA patients to gain insight about its links with the IFN signature as well as to explore the potential clinical relevance of these associations.Methods: The gene expression of IRF4 and IRGs (IFI44, IFI44L, IFI6, and MX1) in peripheral blood was analyzed in 75 SLE patients, 98 RA patients, and 28 healthy controls. A group of 13 biological-naïve RA patients was prospectively followed upon TNFα-blockade. The associations among IRF4 and IRGs were evaluated by principal component analyses (PCA), correlations and network analyses. Publicly available datasets were used for replication.Results: A broad activation of IRGs was observed in autoimmune patients, although certain heterogeneity can be distinguished, whereas IRF4 was only upregulated in RA. The differential expression of IRF4 in RA was then confirmed in publicly available gene expression datasets. PCA revealed different associations among IRF4 and IRGs in each condition, which was later confirmed by correlation and network analyses. Cluster analysis identified 3 gene expression signatures on the basis of IRF4 and IRGs expression which were differentially used by SLE and RA patients. Cluster III was associated with markers of disease severity in SLE patients. Cluster II, hallmarked by IRF4 upregulation, was linked to clinical stage and mild disease course in RA. TNFα-blockade led to changes in the association between IRF4 and IRGs, whereas increasing IRF4 expression was associated with a good clinical outcome in RA.Conclusions: The differential expression of IRF4 and IRGs observed in SLE and RA can delineate gene expression signatures associated with clinical features and treatment outcomes. These results support a clinically-relevant phenomenon of shaping of the IFN signature by IRF4 in autoimmune patients.

Practical Guidance on Biosimilars, With a Focus on Latin America: What Do Rheumatologists Need to Know?

Background/Historical PerspectiveAvailability of biologic disease-modifying antirheumatic drugs (bDMARDs) has improved clinical outcomes in rheumatoid arthritis, but it also increased the cost of treatment. Biosimilars, the regulated copies of biologic products, have a potential to reduce health care costs and expand access to treatment. However, because of a complex development process, biosimilars can be considered only those noninnovator biologics with satisfactory supporting evidence (ranging from structural to clinical), as outlined in the recommendations by the World Health Organization (WHO). In Latin America, a heterogeneous regulatory landscape and nonconsistent approval practices for biosimilars create decision-making challenges for practicing rheumatologists.Summary of LiteratureMost Latin American countries either have adopted or are in the process of adopting guidelines for the approval of biosimilars. However, among several marketed bDMARDs in the region, currently there are only 2 products that could be considered true biosimilars, based on the WHO criteria. The rest can be considered only intended copies, whose safety and efficacy are not fully established. One such product had to be withdrawn from the market because of safety concerns.Conclusions and Future DirectionsPracticing rheumatologists in Latin America need to understand the regulatory situation for biosimilars in their countries. When considering bDMARDs that are not innovator products, clinicians should use only those that have been approved according to the WHO recommendations. For clarification, local health authorities or professional associations should be contacted.