Rheumatoid Arthritis Disease Activity Research Articles

Rheumatoid arthritis and the risk of preterm birth.

During pregnancy, many diseases are correlated with different adverse outcomes. In turn, pregnancy affects the body, leading to increased disease susceptibility. This interplay between diseased states and pregnancy outcomes is illustrated in the effect of the chronic autoimmune disorder, rheumatoid arthritis (RA), and the adverse outcome, preterm birth (PTB). RA is a systemic disorder characterized by inflammation of the joints and other body organs. Joint pain and swelling are the most prominent manifestations of RA during pregnancy. However, the exact role of RA on PTB among pregnant women has yet to be established. This review highlighted the immunologic mechanisms involved in PTB in pregnant patients with RA. The immune cell population in pregnant women with RA exhibited higher activity of macrophages, dendritic cells, neutrophils, helper T (Th) 1 cells, and Vδ1 cells, but lower activity of CD4+CD25high T regulatory (CD24+CD25high Treg ), Th2, and Vδ2 cells. Increased pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ and decreased anti-inflammatory cytokines IL-12 and IL-10 are also exhibited by pregnant patients with RA. This review also discussed factors that may predict the risk of PTB in RA. These include disease activity and severity of RA, laboratory parameters (cytokines and immune cell population), and sociodemographic factors such as ethnicity, smoking, alcohol intake, and the level of education. Current findings on the underlying immunological mechanisms of RA can help identify possible strategies to prevent PTB.

A systematic comparison of different composite measures (DAS 28, CDAI, SDAI, and Boolean approach) for determining treatment effects on low disease activity and remission in rheumatoid arthritis.

Some composite measures for determining the treatment effects of disease-modifying antirheumatic drugs on remission and low disease activity (LDA) in rheumatoid arthritis (RA) may produce misleading results if they include an acute phase reactant (APR). To inform the choice of appropriate measure, we performed a systematic comparison of treatment effects using different composite measures. We used data generated for a systematic review of biologics in RA conducted by the Institute for Quality and Efficiency in Health Care and data from systematic reviews of newer biologics and Janus kinase (JAK) inhibitors provided by sponsors. The studies included had been conducted up to 2020 and investigated comparisons of biologics with placebo and head-to-head comparisons of biologics. Treatment effects on LDA and remission in studies investigating biologics or JAK inhibitors in RA were compared among 4 composite measures: the disease activity score 28 (DAS 28), the simplified disease activity index (SDAI), the Boolean approach (remission only), and the clinical disease activity index (CDAI)-only the latter does not include an APR. 49 placebo-controlled studies included 9 different biologics; 48 studies (16,233 patients) investigated LDA and 49 (16,338 patients) investigated remission. 11 active-controlled studies (5996 patients) investigated both LDA and remission and included 5 different head-to-head comparisons of biologics and 5 different comparisons (6 studies) of biologics with JAK inhibitors. Statistically significantly larger treatment effects were found for biologics or JAK inhibitors versus placebo or active control in 16% of pairwise comparisons of composite measures (27 of 168). Most of these larger effects were observed for composite measures with an APR, i.e. the DAS28 (19 comparisons) followed by the SDAI (n = 7). Larger effects were most frequently detected in favour of interleukin (IL)-6 inhibitors and to a lesser extent for JAK inhibitors versus treatments with different modes of action. The use of the DAS 28 and SDAI in clinical studies may generate results favouring certain treatments based on their mode of action (e.g. IL-6 inhibitors versus other biologics). To enable unbiased comparative effectiveness research, a composite measure without an APR (i.e. the CDAI) should thus be the measure of choice.

Prevalence of cognitive impairment in patients with rheumatoid arthritis: a cross sectional study.

To explore the role of chronic inflammation in rheumatoid arthritis (RA) on cognition. Six hundred sixty-one men and women aged ≥55 years who fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for RA were recruited from three healthcare trusts in the United Kingdom (UK) between May 2018 and March 2020. Study participants took part in interviews which captured sociodemographic information, followed by an assessment of cognition. RA specific clinical characteristics were obtained from hospital medical records. Participants were cognitively assessed using the Montreal Cognitive Assessment (MoCA) and were classified as cognitively impaired if they scored ≤27/30 points. Linear regression analyses were conducted to identify which demographic and clinical variables were potential predictors of cognitive impairment. The average age of participants was 67.6 years and 67% (444/661) were women. 72% (458/634; 95% CI 0.69 to 0.76) of participants were classified as cognitively impaired (MoCA≤27). Greater cognitive impairment was associated with older age (p= .006), being male (p= .041) and higher disease activity score (DAS28) (with moderate (DAS28 > 3.1) (p= 0.008) and high (DAS28 > 5.1) (p= 0.008)) compared to those in remission (DAS28 ≤ 2.6). There was no association between MoCA score and education, disease duration, RF status, anti-cyclic citrullinated peptide (anti-CCP) status, RA medication type or use of glucocorticoids or non-steroidal anti-inflammatory drugs (p> 0.05). This study suggests that cognitive impairment is highly prevalent in older adults with RA. This impairment appears to be associated with higher RA disease activity and supports the concept that chronic systemic inflammation might accelerate cognitive decline. This underlines the importance of controlling the inflammatory response.

Circulating methylation level of HTR2A is associated with inflammation and disease activity in rheumatoid arthritis.

HTR2A is previously identified as a susceptibility gene for rheumatoid arthritis (RA). In this study, we performed the association analysis between DNA methylation of HTR2A with RA within peripheral blood samples. We enrolled peripheral blood samples from 235 patients with RA, 30 osteoarthritis (OA) patients, and 30 healthy controls. The DNA methylation levels of about 218 bp from chr13: 46898190 to chr13: 46897973 (GRCh38/hg38) around HTR2A cg15692052 from patients were analyzed by targeted methylation sequencing. We measured methylation status for 7 CpGs in the promoter region of HTR2A and obseved overall methylation status are signficantly increased in RA compared with normal inviduals (FDR= 9.05 x 10-5). The average cg15692052 methylation levels (methylation score) showed a positive correlation with CRP (r=0.15, P=0.023). Compared with the OA group or HC group, the proportion of haplotypes CCCCCCC (FDR=0.02 and 2.81 x 10-6) is signficantly increased while TTTTTCC (FDR =0.01) and TTTTTTT(FDR =6.92 x 10-3) are significantly decreased in RA. We find methylation haplotypes combining with RF and CCP could signficantly enhance the performance of the diagnosing RA and its comorbidities (hypertension, interstitial lung disease, and osteoporosis), especially in interstitial lung disease. In our study, we found signficant hypermethylation of promoter region of HTR2A which indicates the potential clinical diagnostic role in rheumatoid arthritis.

Estrogen receptors, ERK1/2 phosphorylation and reactive oxidizing species in red blood cells from patients with rheumatoid arthritis.

Red blood cells (RBCs) are recognized to be important pathogenetic determinants in several human cardiovascular diseases (CVD). Undergoing to functional alterations when submitted to risk factors, RBCs modify their own intracellular signaling and the redox balance, shift their status from antioxidant defense to pro-oxidant agents, become a potent atherogenic stimulus playing a key role in the dysregulation of the vascular homeostasis favoring the developing and progression of CVD. Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a significantly increased risk of cardiovascular mortality with a prevalence from two to five more likely in woman, mainly attributed to accelerated atherosclerosis. The purpose of this study was to correlate the RA disease activity and the RBCs functional characteristics. Thirty-two women (aged more than 18years) with RA, and 25 age-matched healthy women were included in this study. The disease activity, measured as the number of swollen and painful joints (DAS-28), was correlated with 1) the expression of RBCs estrogen receptors, which modulate the RBC intracellular signaling, 2) the activation of the estrogen-linked kinase ERK½, which is a key regulator of RBC adhesion and survival, and 3) the levels of inflammatory- and oxidative stress-related biomarkers, such as the acute-phase reactants, the antioxidant capacity of plasma, the reactive oxidizing species formation and 3-nitrotyrosine. All the biomarkers were evaluated in RA patients at baseline and 6months after treatment with disease-modifying anti-rheumatic drugs (DMARDs). We found, for the first times, that in RA patients 1) the DAS-28 correlated with RBC ER-α expression, and did not correlate with total antioxidant capacity of plasma; 2) the RBC ER-α expression correlated with systemic inflammatory biomarkers and oxidative stress parameters, as well as ERK½ phosphorylation; and 3) the DMARDs treatments improved the clinical condition measured by DAS-28 score decrease, although the RBCs appeared to be more prone to pro-oxidant status associated to the expression of survival molecules. These findings represent an important advance in the study of RA determinants favoring the developing of CVD, because strongly suggest that RBCs could also participate in the vascular homeostasis through fine modulation of an intracellular signal linked to the ER-α.

Serum Collagen Triple Helix Repeat Containing-1 Levels are Related to Radiological Affection and Disease Activity in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a common systemic inflammatory disease. Collagen triple helix repeat containing-1 (CTHRC1) is a unique gene product able to reduce collagen deposition. The present study aimed to assess CTHRC1 level in RA patients and to uncover its relation to clinical, laboratory and radiological findings. The study included 60 adult RA patients. In addition, there were 60 control subjects who included patients with osteoarthritis (n = 20) and reactive arthritis (n = 20) and healthy controls (n = 20). Serum CTHRC1 levels were assessed by Enzyme-Linked Immunosorbent Assay (ELISA). Disease activity was calculated using the Disease Activity Score (DAS28-CRP). Radiological damage was evaluated using the Simple Erosion Narrowing Score (SENS). There was significantly higher serum CTHRC1 levels in RA patients when compared to OA, ReA and control groups [median (IQR): 4.66 (1.68-11.7) versus 1.88 (1.14-2.94), 1.55 (0.98-3.15) and 1.14 (0.85-1.3) mg/dL, respectively, p < 0.001]. There was significantly higher CTHRC1 levels in patients with higher disease activity [median (IQR): 2.23 (1.4-4.73) versus 6.55 (4.66-12.0) mg/dL, p = 0.004]. Patients with higher SENS had significantly higher CTHRC1 [median (IQR): 1.99 (1.4-4.66) versus 9.75 (4.39-12.63) mg/dL, p < 0.001] and DAS28 [median (IQR): 4.25 (2.9-5.2) versus 5.4 (4.65-5.8), p = 0.01]. Serum CTHRC1 levels are related to disease severity and radiological affection in RA patients.

SERUM HEPCIDIN AS A MARKER OF INFLAMMATION IN SEROPOSITIVE RHEUMATOID ARTHRITIS- THE NEW KID ON THE BLOCK?

Introduction: Assessment of disease activity in Rheumatoid Arthritis (RA) is required for the 'treat to target' strategy and includes clinical assessment as well as laboratory markers. These markers have fallacies, and thus confound disease activity scores. The search for an objective marker of inammation continues. T Aims And Objectives: his study is designed to evaluate if serum hepcidin can fulll the role of a marker of inammation in seropositive RA. Eighty two cases of seropositive RA Materials And Methods: fullling the inclusion and exclusion criteria for the study, and twenty ve apparently healthy controls were taken into the study. Disease activity was assessed clinically and Clinical Disease Activity Index (CDAI) was calculated. Cases were also divided into 4 groups based on CDAI. C - Reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), Serum Ferritin, and Serum Hepcidin levels were measured. Data was tabulated using MS-Excel worksheet. Appropriate statistical tests were used to compare the parameters among cases and controls and across various disease activity groups. The cases and controls were matched to age. Serum Results: Hepcidin was signicantly higher in the cases than in the controls. They also differed signicantly between various disease activity groups. They correlated positively and signicantly with CRP and ESR. Serum Ferritin levels did not vary signicantly between cases and controls. Serum Hepcidin has the potential to be a marker of Conclusion: inammation, though more studies including prospective ones will be required. Greater acceptance and availability will bring down the cost of testing.

Quantifying Rheumatoid Arthritis Disease Activity Using a Multimodal Sensing Knee Brace.

Rheumatoid arthritis (RA) is a chronic inflammatory syndrome that features painful and destructive joint disease. Aggressive disease-modifying treatment can result in reduced symptoms and protection from irreversible joint damage; however, assessment of treatment efficacy is currently based largely on subjective measures of patient and physician impressions. In this work, we address this compelling need to provide an accurate and quantitative capability for monitoring joint health in patients with RA. Joint acoustic emissions (JAEs), electrical bioimpedance (EBI), and kinematics were measured noninvasively from 11 patients with RA over the course of three weeks using a custom multimodal sensing brace, resulting in 49 visits with JAE recordings and 43 with EBI recordings. Features derived from all sensing modalities were fed into a linear discriminant analysis (LDA) model to predict disease activity according to the validated disease activity index (the DAS28-ESR). Erythrocyte sedimentation rate (ESR) was predicted using ridge regression and classified into a high or low class using LDA. DAS28-ESR level was predicted with an area under the receiver operating characteristic curve (AUC) of 0.82. With JAEs alone, we were able to track intrasubject differences in the disease activity score as well as classify ESR level with an AUC of 0.93. The majority of patients reported both an interest and ability to use the brace at home for longitudinal monitoring. This work demonstrates the ability to detect RA disease activity using noninvasive sensing. This system has the potential to improve RA disease activity monitoring by giving treating clinicians objective data that can be acquired independent of a face-to-face clinic visit.

Assessment of Vitamin D3 level in patients of rheumatoid arthritis and its relationship with disease activity using DAS 28-CRP in tertiary care center of Bihar, India

Background: Rheumatoid arthritis (RA) is most common type of inflammatory arthritis. It is chronic autoimmune disease that affects joints as well as extra-articular structures. The prevalence of this condition could be due to both genetic and non-genetic factors (e.g., environmental, viral, and hormonal). Aims and Objectives: The aim of the study was to determine and correlate 25(OH) D level with disease severity in patients of RA. Materials and Methods: The prospective observational study consists of 70 patients of RA and 70 healthy controls. Assessed level of 25(OH) D, C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP), erythrocyte sedimentation rate (ESR), and Disease Activity Score (DAS) 28-CRP score were compared in both cases and controls. Correlation of Vitamin D level with parameters such as CRP, Anti-CCP, and ESR was performed. Correlation between Vitamin D level deficiency and disease activity among the RA patients was assessed. Results: The mean age of patients in the RA group was 37.77±13.31 years. The mean CRP in cases was 40.57±25.94 mg/L and in controls was 3.26±1.95 mg/L with significant intergroup difference (P&lt;0.001). The mean anti-CCP in cases was 62.18±27.21 U/mL and in controls was 4.99±1.52 U/mL with significant intergroup difference (P&lt;0.001). The mean 25(OH) D level in cases was 12.65±5.88 and in controls was 32.18±10.22. The 25(OH) D was significantly decreased in cases than controls (P&lt;0.001). A significant inverse relationship between serum 25(OH) D levels and DAS28 was observed. Receiver operating characteristic (ROC) curves results showed that 25(OH) D&lt;11.7 ng/mL indicates severe disease activity (Area under ROC curve=84%, Sensitivity 77.78%, and specificity 83.33%,). 25(OH) D between 11.7 ng/mL and 19.83 ng/mL indicates moderate disease activity. 25(OH) D˃19.83 ng/mL indicates low disease activity value below 4.13 is alarming situation. Conclusion: The study reveals high prevalence of Vitamin D deficiency and insufficiency in RA patients. There is also significant inverse correlation exist between serum Vitamin D levels and RA disease activity. Vitamin D level is good disease activity predictor in patients of RA.

Relation of some clinical composite indices of disease activity in rheumatoid arthritis to a simplified 12 joint power Doppler ultrasound activity index

Aim of the workTo assess the association of some clinical composite disease activity indices with a simplified 12 joint power Doppler ultrasound (PDUS) activity index in rheumatoid arthritis (RA). Patients and methodsOne hundred RA patients who fulfilled the 2010 European league against rheumatism/American college of Rheumatology (EULAR/ACR) classification criteria for RA were recruited from the Rheumatology outpatient clinic, Cairo University Hospitals. Disease activity score (DAS28), the simplified disease activity index (SDAI), clinical disease activity index (CDAI) as well as mean overall index for RA (MOI-RA) were assessed. Grey Scale Ultrasonography (GSUS) and PDUS activity assessment was performed using a simplified 12-joint score. ResultsThe 100 patients were 80 females and 20 males (F:M 4:1). Their mean age was 44.4 ± 10.8 years with disease duration of 6.3 ± 4.7 years. Rheumatoid factor was positive in 77 %. DAS28 was 4.5 ± 1.3, SDAI 27.7 ± 22.7, CDAI 17.5 ± 13.2 and MOI-RA 86.8 ± 25.1. On US, tenosynovitis was present in 10 %, irregularity in 23 % and erosion in 62 %. The mean 12-point PDUS was 3.53 ± 4.16 and the overall US score 10.34 ± 9.3. A significant correlation was found between the US findings of overall synovitis, degree of PD and US score with DAS28 (r = 0.3, p < 0.0001; r = 0.4, p < 0.0001 and r = 0.3, p < 0.0001) with SDAI (r = 0.3, p < 0.0001; r = 0.4,p < 0.0001; r = 0.4, p < 0.0001) and with MOI-RA score (r = 0.3, p < 0.0001; r = 0.4, p < 0.0001 and r = 0.4, p < 0.0001 respectively) but the highest correlations was with CDAI (r = 0.4, p < 0.0001; r = 0.5, p < 0.0001 and r = 0.4, p < 0.0001 respectively). ConclusionSimplified 12 -joint PDUS score is well correlated with activity indices in RA patients.

Validity of clinical disease activity index (CDAI) to evaluate the disease activity of rheumatoid arthritis patients in Sri Lanka: A prospective follow up study based on newly diagnosed patients.

Routine use of the Disease Activity Score-28 (DAS28) to assess the disease activity in rheumatoid arthritis (RA) is limited due to its dependency on laboratory investigations and the complex calculations involved. In contrast, the clinical disease activity index (CDAI) is simple to calculate, which makes the "treat to target" strategy for the management of RA more practical. We aimed to assess the validity of CDAI compared to DAS28 in RA patients in Sri Lanka. A total of 103 newly diagnosed RA patients were recruited, and their disease activity was calculated using DAS 28 and CDAI during the first visit to the clinic (0 months) and re-assessed at 4 and 9 months of follow-up visits. The validity of the CDAI, compared to DAS 28, was evaluated. Patients had a female preponderance (6:1) and a short symptom duration (mean = 6.33 months). Internal consistency reliability of CDAI, as assessed by Cronbach's α test, was 0.868. Convergent validity was assessed by correlation and Kappa statistics. Strong positive correlations were observed between CDAI and DAS 28 at the baseline (0 months), 4 and 9 months of evaluation (Spearman's r = 0.935, 0.935, 0.910, respectively). Moderate-good inter-rater agreements between the DAS-28 and CDAI were observed (Weighted kappa of 0.660, 0.519, and 0.741 at 0, 4, and 9 months respectively). Discriminant validity, as assessed by ROC curves at 0, 4th, and 9th months of the evaluation, showed the area under the curve (AUC) of 0.958, 0.979, and 0.910, respectively. The suggested cut-off points for different CDAI disease activity categories according to ROC curves were ≤ 4 (Remission), > 4 to ≤ 6 (low), > 6 to ≤ 18 (moderate), > 18 (high). These findings indicate that the CDAI has good concordance with DAS 28 in assessing the disease activity in RA patients, in this study sample.

Glycobiology of rheumatic diseases.

Glycosylation has a profound influence on protein activity and cell biology through a variety of mechanisms, such as protein stability, receptor interactions and signal transduction. In many rheumatic diseases, a shift in protein glycosylation occurs, and is associated with inflammatory processes and disease progression. For example, the Fc-glycan composition on (auto)antibodies is associated with disease activity, and the presence of additional glycans in the antigen-binding domains of some autoreactive B cell receptors can affect Bcell activation. In addition, changes in synovial fibroblast cell-surface glycosylation can alter the synovial microenvironment and are associated with an altered inflammatory state and disease activity in rheumatoid arthritis. The development of our understanding of the role of glycosylation of plasma proteins (particularly (auto)antibodies), cells and tissues in rheumatic pathological conditions suggests that glycosylation-based interventions could be used in the treatment of these diseases.

Increased serum IL-41 is associated with disease activity in rheumatoid arthritis

BackgroundInterleukin (IL)-41 is upregulated in the synovial tissue of rheumatoid arthritis (RA) patients, but its serum level has not been reported. The present study aimed to determine IL-41 expression in serum from RA patients and to clarify the relationships between IL-41 and disease-related parameters in RA patients. MethodsThe study included 46 RA patients and 32 healthy controls (HC). Baseline data were obtained by routine physical examinations and immune-related parameters were measured by an automated chemiluminescent immunoassay analyzer. The correlations between IL-41 and disease activity score in 28 joints (DAS28) and serum clinical data were analyzed using the Pearson correlation test. ResultsSerum IL-41 concentrations were higher in RA patients than in HC. Serum IL-41 was positively correlated with DAS28 based on C-reactive protein (DAS28-CRP), CRP, erythrocyte sedimentation rate (ESR), mean platelet volume (MPV), and CRP-to-albumin ratio (CAR) and negatively correlated with platelet count, while rheumatoid factor was significantly correlated with ESR, CRP, and CAR. Receiver operating characteristic curve analysis showed that IL-41 had diagnostic value for RA, especially when combined with MPV. ConclusionsThe present findings suggest that IL-41 is increased in the serum of RA patients and may be a potential new diagnostic biomarker for RA.

A meta-analysis of methotrexate polyglutamates in relation to efficacy and toxicity of methotrexate in inflammatory arthritis, colitis and dermatitis.

In immune-mediated inflammatory diseases (IMIDs), early symptom control is a key therapeutic goal. Methotrexate (MTX) is the first-line treatment across IMIDs. However, MTX is underutilized and suboptimally dosed, partly due to the inability of making individualized treatment decisions through therapeutic drug monitoring (TDM). To implement TDM in clinical practice, establishing a relationship between drug concentration and disease activity is paramount. In this meta-analysis, we investigated the relationship between concentrations of MTX polyglutamates (MTX-PG) in erythrocytes and efficacy as well as toxicity across IMIDs. Studies analysing MTX-PG in relation to disease activity and/or toxicity were included for inflammatory arthritis (rheumatoid [RA] and juvenile idiopathic arthritis [JIA]), inflammatory bowel disease (Crohn's and ulcerative colitis) and dermatitis (psoriasis and atopic dermatitis). Meta-analyses were performed resulting in several summary effect measures: regression coefficient (β), correlation coefficient and mean difference (of MTX-PG in responders vs. nonresponders) for IMIDs separately and collectively. Twenty-five studies were included. In RA and JIA, higher MTX-PG was significantly associated with lower disease activity at 3months (β: -0.002; 95% confidence interval [CI]: -0.004 to -0.001) and after 4months of MTX use (β: -0.003; 95% CI: -0.005 to -0.002). Similarly, higher MTX-PG correlated with lower disease activity in psoriasis (R: -0.82; 95% CI: -0.976 to -0.102). Higher MTX-PG was observed in RA, JIA and psoriasis responders (mean difference: 5.2nmol/L MTX-PGtotal ; P< .01). We showed that higher concentrations of erythrocyte MTX-PG were associated with lower disease activity in RA, JIA and psoriasis. These findings are an important step towards implementation of TDM for MTX treatment across IMIDs.

SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is a complex autoimmune disease with multiple etiological factors, among which aberrant memory CD4 T cells activation plays a key role in the initiation and perpetuation of the disease. SIGIRR (single immunoglobulin IL-1R-related receptor), a member of the IL-1 receptor (ILR) family, acts as a negative regulator of ILR and Toll-like receptor (TLR) downstream signaling pathways and inflammation. The aim of this study was to investigate the potential roles of SIGIRR on memory CD4 T cells in RA and the underlying cellular and molecular mechanisms.MethodsSingle-cell transcriptomics and bulk RNA sequencing data were integrated to predict SIGIRR gene distribution on different immune cell types of human PBMCs. Flow cytometry was employed to determine the differential expression of SIGIRR on memory CD4 T cells between the healthy and RA cohorts. A Spearman correlation study was used to determine the relationship between the percentage of SIGIRR+ memory CD4 T cells and RA disease activity. An AIA mouse model (antigen-induced arthritis) and CD4 T cells transfer experiments were performed to investigate the effect of SIGIRR deficiency on the development of arthritis in vivo. Overexpression of SIGIRR in memory CD4 T cells derived from human PBMCs or mouse spleens was utilized to confirm the roles of SIGIRR in the intracellular cytokine production of memory CD4 T cells. Immunoblots and RNA interference were employed to understand the molecular mechanism by which SIGIRR regulates TNF-α production in CD4 T cells.ResultsSIGIRR was preferentially distributed by human memory CD4 T cells, as revealed by single-cell RNA sequencing. SIGIRR expression was substantially reduced in RA patient-derived memory CD4 T cells, which was inversely associated with RA disease activity and related to enhanced TNF-α production. SIGIRR-deficient mice were more susceptible to antigen-induced arthritis (AIA), which was attributed to unleashed TNF-α production in memory CD4 T cells, confirmed by decreased TNF-α production resulting from ectopic expression of SIGIRR. Mechanistically, SIGIRR regulates the IL-1/C/EBPβ/TNF-α signaling axis, as established by experimental evidence and cis-acting factor bioinformatics analysis.ConclusionTaken together, SIGIRR deficiency in memory CD4 T cells in RA raises the possibility that receptor induction can target key abnormalities in T cells and represents a potentially novel strategy for immunomodulatory therapy.

Assessment of risk factors in patients with rheumatoid arthritis-associated interstitial lung disease.

To assess the risk factors for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) and to evaluate the association of ILD with the use of methotrexate as well as with joint disease activity. A retrospective, cross-sectional study conducted between March and December 2019 at a tertiary healthcare center, in a follow-up of RA patients who had undergone pulmonary function tests (PFT) and chest computed tomography. We evaluated the tomographic characteristics, such as the presence of ILD and its extension, as well as joint disease activity. Functional measurements, such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), were also assessed. After this, a multivariate logistic regression analysis was applied in order to identify risk factors associated with ILD. We evaluated 1.233 patients, of which 134 were eligible for this study. The majority were female (89.6%), with a mean age of 61 years old and with a positive rheumatoid factor (86.2%). RA-associated ILD (RA-ILD) was detected in 49 patients (36.6%). We found an association of RA-ILD with age ≥= 62 year, male sex, smoking history and fine crackles in lung auscultation and a decreased DLCO. The indicators of being aged ≥ 62 years old and having moderate or high RA disease activity were both independent factors associated with RA-ILD, with an odds ratio of 4.36 and 3.03, respectively. The use of methotrexate was not associated with a higher prevalence of ILD. Age and RA disease activity are important risk factors associated with RA-ILD. Methotrexate was not associated with the development of RA-ILD in the present study.

Methotrexate, leflunomide and tacrolimus use and the progression of rheumatoid arthritis-associated interstitial lung disease.

To examine the association between MTX, LEF and tacrolimus use and the progression of RA-associated interstitial lung disease (ILD). The Korean RA-ILD cohort prospectively enrolled patients with RA-associated ILD at multiple centres from 2015 to 2018 and followed up with them for 3 years. ILD progression was defined by any of the followings: a decrease of ≥10% in forced vital capacity, a decrease of ≥15% in the diffusing capacity of the lung for carbon monoxide, or death from respiratory failure. Of 143 patients, 64 patients experienced ILD progression during a median follow-up period of 33 months. The use of MTX [adjusted hazard ratio (aHR), 1.06; 95% CI, 0.59, 1.89], LEF (aHR, 1.75; 95% CI, 0.88, 3.46) and tacrolimus (aHR, 0.94; 95% CI, 0.52, 1.72) did not increase the risk of ILD progression. However, the association between LEF use and the risk of ILD progression was significant in subgroups with poor lung function (aHR, 8.42; 95% CI, 2.61, 27.15). Older age, male sex, a shorter RA duration, higher RA disease activity and extensive disease at baseline were independently associated with ILD progression. None of the three treatments increased the risk of RA-associated ILD progression, except for LEF, which increased the risk of ILD progression in patients with severe ILD. The appropriate use of conventional synthetic disease-modifying antirheumatic drugs considering RA disease activity and ILD severity would be important for the management of RA-associated ILD.

Follicular dendritic cell differentiation is associated with distinct synovial pathotype signatures in rheumatoid arthritis.

Follicular dendritic cells (FDCs) fundamentally contribute to the formation of synovial ectopic lymphoid-like structures in rheumatoid arthritis (RA) which is associated with poor clinical prognosis. Despite this critical role, regulation of FDC development in the RA synovium and its correlation with synovial pathotype differentiation remained largely unknown. Here, we demonstrate that CNA.42+ FDCs distinctively express the pericyte/fibroblast-associated markers PDGFR-β, NG2, and Thy-1 in the synovial perivascular space but not in established follicles. In addition, synovial RNA-Seq analysis revealed that expression of the perivascular FDC markers was strongly correlated with PDGF-BB and fibroid synovitis, whereas TNF-α/LT-β was significantly associated with lymphoid synovitis and expression of CR1, CR2, and FcγRIIB characteristic of mature FDCs in lymphoid follicles. Moreover, PDGF-BB induced CNA.42+ FDC differentiation and CXCL13 secretion from NG2+ synovial pericytes, and together with TNF-α/LT-β conversely regulated early and late FDC differentiation genes in unsorted RA synovial fibroblasts (RASF) and this was confirmed in flow sorted stromal cell subsets. Furthermore, RASF TNF-αR expression was upregulated by TNF-α/LT-β and PDGF-BB; and TNF-α/LT-β-activated RASF retained ICs and induced B cell activation in in vitro germinal center reactions typical of FDCs. Additionally, FDCs trapped peptidyl citrulline, and strongly correlated with IL-6 expression, and plasma cell, B cell, and T cell infiltration of the RA synovium. Moreover, synovial FDCs were significantly associated with RA disease activity and radiographic features of tissue damage. To the best of our knowledge, this is the first report describing the reciprocal interaction between PDGF-BB and TNF-α/LT-β in synovial FDC development and evolution of RA histological pathotypes. Selective targeting of this interplay could inhibit FDC differentiation and potentially ameliorate RA in clinically severe and drug-resistant patients.

Rheumatoid Arthritis Effects on Kidney and Liver and their Correlations with CDAI

Rheumatoid arthritis (RA) is a disease characterized by chronic autoimmune inflammation of body joints, causing movement disability, loss of functions, joint damage, and many complications. Persistent usage of anti-rheumatic drugs has several side effects, which may cause heart, kidney, or liver diseases. This study aims to assess the influence of RA duration on kidney and liver enzymes and study the correlation between these enzyme levels and RA disease activity (CDAI). This study collected a total of 150 blood samples. 100 samples for RA patients (61 were seropositive, 39 were seronegative), and 50 for healthy Control. throughout the period from November 2021 to February 2022. The blood samples were collected from Baghdad Teaching Hospital / Rheumatology Consulting Clinic. General information had been collected from each subject according to a questionnaire that had been applied for this purpose. The age groups of patients and control were between 22-72 years, and 26-62 years old, respectively. The female participants were more than the male counterparts. The blood samples were taken from patients and control groups to screen liver and kidney functions by an automated biochemical system using the SELECTRA PRO X2 device, in addition to the ESR test. The study showed that the levels of urea, creatinine, GPT, and GOT were either normal or slightly elevated and they are non-significantly associated with RA disease activity, the little effect of RA on kidney and liver may be related to the low doses of methotrexate and corticosteroid therapy which used mostly for these patients and didn’t reach to toxicity.

Using the derived 28-joint disease activity score patient-reported components (DAS28-P) index as a discriminatory measure of response to disease-modifying anti-rheumatic drug therapy in early rheumatoid arthritis

BackgroundThe 28-joint disease activity score (DAS28) is a widely used measure to assess disease activity in rheumatoid arthritis (RA). The DAS28-P index, a derived proportion of the patient-reported components (joint tenderness and patient global assessment) within the DAS28, has been utilized as a discriminatory measure of non-inflammatory pain mechanisms in RA. This study aimed to evaluate the use of the DAS28-P index as a predictor of treatment response in early RA.MethodsPatients with early RA enrolled in a supplemental fish oil clinical trial received a combination of disease-modifying anti-rheumatic drugs (DMARDs) according to a ‘treat-to-target’ protocol. First, consecutive measures of the DAS28-P index, derived from the DAS28-erythrocyte sedimentation rate (DAS28-ESR), at each visit over a 1-year period were estimated for each patient. Then, distinct subgroups of treatment responders based on the trajectories of the DAS28-P indices were identified using bivariate k-means cluster analysis. Data on baseline predictors as well as longitudinal outcomes of disease impact and DMARD use over a 1-year period and radiographic progression over a 3-year period were collected and analyzed using a random intercept, population-averaged generalized estimating equation model.Results121 patients were included (74% female; mean age of 57; median of 16 weeks of active disease) and a 3-cluster model was identified—the ‘Responders’ group (n = 58; 48%), the ‘Partial Responders’ group (n = 32; 26%), and the ‘Non-Responders’ group (n = 31; 26%). The ‘Partial Responders’ group had consistently higher proportions of the DAS28-P index throughout the study period and had minimal radiographic progression over time, with the lowest joint erosion score of 0.9 [95% confidence interval (CI) 0.2, 1.6], observed at the 3-year follow-up. At 52 weeks, the methotrexate dose was higher for both ‘Partial Responders’ and ‘Non-Responders’ groups (18.5 mg [95% CI 15.5, 21.5] and 18.6 mg [95% CI 15.3, 21.8] respectively), when compared with the ‘Responders’ group (12.8 mg [95% CI 14.7, 20.9]).ConclusionsPersistently high DAS28-P index scores are useful to distinguish poor patient global assessment and excessive treatment escalation in early RA, suggestive of underlying non-inflammatory pain contributing to higher disease activity score. Early identification of patients with discordant subjective and objective components of composite disease activity measures may allow better tailoring of treatment in RA.