Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
32789817 Interleukin 6, interleukin 17, disease-related and contextual factor association with depr 2021 Mar OBJECTIVE: Depression is very prevalent in rheumatoid arthritis (RA) compared with the general population and may be associated with poor clinical outcomes. Identifying factors associated with depression could improve outcomes for this at risk group. However, few studies have comprehensively examined the association of contextual and disease-related factors as well as pro inflammatory cytokines interleukin 6 (IL-6) and interleukin 17 (IL-17) with depression in RA. Therefore, we aimed to identify the factors significantly associated with depression and severe depression in RA, thus providing a reference for applying clinical care interventions for patients with RA. METHODS: An observational cross-sectional study was conducted on 120 RA patients. Potential determinants included contextual and disease-related factors and laboratory variables. Enzyme-linked immunosorbent assay was used to measure serum IL-6 and IL-17 levels. Depression was assessed using the Arabic version of the Beck Depression Inventory-II questionnaire. RESULTS: A total of 120 patients were included, and up to 67.5% had some degree of depression with 60% having moderate to severe depression. The severity of disease activity of RA (DAS28-ESR (OR, 1.63; 95% CI, 0.899-3.755), HAQ scores (OR, 1.27; 95% CI, 0.702-2.933), and VAS scores for pain (OR, 2.2; 95% CI, 1.251-5.223)), besides elevated serum IL-6 (OR, 1.51; 95% CI, 0.832-3.475), IL-17 (OR, 1.28; 95% CI, 0.706-2.947), and CRP levels (OR, 1.20; 95% CI, 0.923-2.882) were significantly associated with depression and its severity in the multivariate analysis. CONCLUSION: Depression is frequent in RA and is strongly associated to elevated serum IL-6, IL-17, CRP levels, and disease activity-related factors. Key Points • RA patients are at increased risk of developing depression, particularly if their level of disease activity scores, serum IL-6, and IL-17 levels increases. • Patient characteristics associated with depression in RA include living without family, without employments, and with co-morbid hypertension, while RA disease factors are pain, functional disability, and high disease activity. • A multidisciplinary cooperative approach to RA patient care with regular assessments of these factors associated with depression should be incorporated into routine care programs to improve patients' self care capabilities and mitigate or prevent depression in these patients.
34324641 Imaging of bone and joints in vivo: pathological osteoclastogenesis in arthritis. 2021 Nov 25 Osteoimmunology highlights the reciprocal interactions between the skeletal and immune systems. Over the past two decades, many molecules that link the two have been identified, including cytokines, receptors and transcription factors, leading to successful translation of research into therapeutic approaches to autoimmune diseases such as rheumatoid arthritis. The development of an intravital imaging system using two-photon microscopy, combined with a variety of fluorescent probes and reporter mouse strains, has provided valuable insights into the real-time dynamics of osteoclasts and immune cells in the bone marrow. This technique is now applied to the synovial tissue of arthritic mice to investigate the pathogenesis of osteoimmune diseases and enables direct observation of complex biological phenomena in vivo. In addition, rapid progress in the next-generation sequencing technologies has provided important insights into the field of osteoimmunology through characterizing individual cells in the synovial microenvironment. Single-cell RNA sequencing (scRNA-seq) dissects cellular heterogeneity within a biological system and enables the identification of specific cells differentiating into mature osteoclasts within the previously defined 'osteoclast precursor-containing population'. In this review, we will explain the cellular interactions and cytokine milieu involved in inflammatory bone destruction and update how the novel technologies, such as scRNA-seq and intravital imaging, have contributed to better understand the pathogenesis of bone destruction in arthritis.
32810256 Lymphoma risks in patients with rheumatoid arthritis treated with biological drugs-a Swedi 2021 Feb 1 OBJECTIVES: To estimate the association between biological DMARDs (bDMARDs; overall and by drug) as used in RA and the risk of malignant lymphomas including subtypes. METHODS: By linking nationwide Swedish registers we identified cohorts of patients with RA initiating treatment with a bDMARD (n = 16 392), bDMARD-naïve (n = 55 253), an age- and sex-matched general population comparator cohort (n = 229 047), and all incident lymphomas 2001-16. We used Cox regression to calculate hazard ratios (HRs) of lymphoma taking calendar period and other factors into account. RESULTS: There were 82 lymphomas among the bDMARD-treated patients with RA, crude incidence rate 76/100 000 person-years, and 310 lymphomas among the bDMARD-naïve patients with RA, crude incidence rate 90/100 000 person-years. This resulted in an adjusted HR (aHR) associated with bDMARD treatment (vs not) of 1.08 (95% CI: 0.83, 1.41). The corresponding aHR for bDMARD-treated and bDMARD-naïve vs the general population was 1.65 (95% CI: 1.31, 2.08) and 1.56 (95% CI: 1.37, 1.78) respectively. Restricting follow-up period to after 2006, the aHR of lymphoma for patients with RA starting a first bDMARD vs bDMARD-naïve was 0.69 (95% CI: 0.47, 1.00), and for bDMARD treated vs patients with RA switching from one conventional synthetic DMARDs to another, aHR was 0.46 (95% CI: 0.28, 0.73). There were no signals of different risks with any particular TNF inhibitor (TNFi) agent. We found no different lymphoma subtype pattern following bDMARD therapy. CONCLUSION: Treatment with bDMARDs, including both TNFi and non-TNFi bDMARDs, does not further increase the lymphoma risk in RA; instead, bDMARD treatment may actually reduce the excess lymphoma risk in RA.
33034006 Real-World Evidence to Contextualize Clinical Trial Results and Inform Regulatory Decision 2021 Jan INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To provide additional clinical evidence in regulatory submissions for a modified-release (MR) once-daily (QD) tofacitinib formulation, we compared real-world adherence and effectiveness between patients initiating the MR QD formulation and patients initiating an immediate-release (IR) twice-daily (BID) formulation. METHODS: Two noninterventional cohort studies were conducted. First, adherence and two effectiveness proxies were compared between patients with RA who newly initiated tofacitinib MR 11 mg QD or IR 5 mg BID in the IBM(®) MarketScan(®) Commercial and Medicare Supplemental US insurance claims databases (March 2016-October 2018). Second, using data collected in the Corrona US RA Registry (February 2016-August 2019), two Clinical Disease Activity Index (CDAI)-based measures of effectiveness were compared between tofacitinib MR 11 mg QD and IR 5 mg BID, and against noninferiority criteria derived from placebo-controlled clinical trials of the tofacitinib IR formulation. Multiple sensitivity analyses of the registry data were conducted to reassure regulators of consistent results across different assumptions. RESULTS: In each study, approximately two-thirds of patients initiated the MR formulation. In the claims database study, improved adherence and at least comparable effectiveness were observed with tofacitinib MR vs IR over 12 months, particularly in patients without prior advanced therapy. In the registry study, the noninferiority of tofacitinib MR vs IR was demonstrated for both CDAI outcomes at ~6 months; this finding was robust across multiple sensitivity analyses. CONCLUSION: These results demonstrate the value of real-world evidence from complementary data sources in understanding the impact of medication adherence with a QD formulation in clinical practice. These analyses were suitable for regulatory consideration as an important component of evidence for the comparability of tofacitinib MR 11 mg QD vs IR 5 mg BID in patients with RA. TRIAL REGISTRATION: Claims database study: ClinicalTrials.gov identifier NCT04018001, retrospectively registered July 12, 2019. Corrona US RA Registry study: ClinicalTrials.gov identifier NCT04267380, retrospectively registered February 12, 2020.
34553902 Se-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl] 4-Chlorobenzoselenolate Attenuates Inflammator 2021 Oct 6 Despite major advances, not all patients achieve rheumatoid arthritis (RA) remission, thus highlighting a pressing need for new therapeutic treatments. Given this scenario, this study sought to evaluate Se-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl] 4-chlorobenzoselenolate (Se-DMC) potential on a complete Freund's adjuvant (CFA)-induced unilateral arthritis model. The effects of Se-DMC (5 mg/kg; oral dose) and meloxicam (5 mg/kg; oral dose), both administered to animals daily for 14 days, on paw edema, mechanical sensitivity, neurobehavioral deficits (anxiogenic- and depressive-like behaviors), Na(+)/K(+)-ATPase activity, oxidative stress, and inflammation were evaluated in male Swiss mice exposed to CFA (intraplantar injection of 0.1 mL; 10 mg/mL). Se-DMC reduced the paw withdrawal threshold and CFA-induced paw edema. Histopathological results revealed the antiedematogenic potential of the compound, which was evidenced by lower quantities of dilated lymphatic vessels compared with the CFA group. Se-DMC reduced mRNA relative expression levels of tumor necrosis factor-α (TNF-α) and nuclear factor-κB (NF-κB) in the hippocampus and paw of CFA mice. The CFA-induced anxiogenic- and depressive-like behaviors were reversed by Se-DMC to the control levels in the elevated plus-maze and tail suspension tests. Se-DMC reduced the paw reactive species levels and restored the superoxide dismutase (hippocampus and paw) and Na(+)/K(+)-ATPase (hippocampus) activities previously increased by CFA. Moreover, CFA administration inhibited serum creatinine kinase activity, albeit the Se-DMC effects did not appear to involve the modulation of this enzyme and were equal to or greater than meloxicam. Se-DMC attenuates CFA-induced inflammatory response, nociception, and neurobehavioral deficits in mice.
34006137 Evaluation of biomarkers related to zinc nutritional status, antioxidant activity and oxid 2022 Jun BACKGROUND: Oxidative stress (OS) is an important process related to the pathophysiology of rheumatoid arthritis and can be increased by the low intake of antioxidants. Zinc (Zn) is an important antioxidant trace-element for human health and the assessment of the nutritional status of this micronutrient in these patients is of relevance. AIM: This study aimed to evaluate Zn nutritional status in rheumatoid arthritis patients and its relation to OS. METHODS: A case-control study was carried out with 51 patients diagnosed with rheumatoid arthritis (RA group) recruited in Hospital São Paulo (São Paulo, Brazil) and 55 healthy women (CO group) from the campus of the University of São Paulo. Blood and 24-hour urine collection were used for biochemical parameters related to Zn status and OS. The assessment of dietary Zn was performed by three 24-hour dietary recalls. RESULTS: The RA group presented significative low Zn intake (p < 0.001) and plasma concentration (p = 0.040) of this mineral compared to the CO group. However, both groups were Zn deficient and the disease activity (DAS28 score) for RA patients did not influence Zn biomarkers. In addition, the antioxidant enzymes (superoxide dismutase and glutathione peroxidase) activity and the urinary 8-isoprostanes were reduced in RA patients. CONCLUSION: The evaluation of dietary intake and biochemical biomarkers indicates that rheumatoid arthritis patients are zinc deficient and have increased OS.
35126351 The Expression of Inflammasomes NLRP1 and NLRP3, Toll-Like Receptors, and Vitamin D Recept 2021 Activated rheumatoid arthritis (RA) synovial fibroblasts (SFs) are among the most important cells promoting RA pathogenesis. They are considered active contributors to the initiation, progression, and perpetuation of the disease; therefore, early detection of RASF activation could advance contemporary diagnosis and adequate treatment of undifferentiated early inflammatory arthritis (EA). In this study, we investigated the expression of nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain containing (NLRP)1, NLRP3 inflammasomes, Toll-like receptor (TLR)1, TLR2, TLR4, vitamin D receptor (VDR), and secretion of matrix metalloproteinases (MMPs) in SFs isolated from patients with RA, osteoarthritis (OA), EA, and control individuals (CN) after knee surgical intervention. C-reactive protein, general blood test, anticyclic citrullinated peptide (anti-CCP), rheumatoid factor (RF), and vitamin D (vitD) in patients' sera were performed. Cells were stimulated or not with 100 ng/ml tumor necrosis factor alpha (TNF-α) or/and 1 nM or/and 0.01 nM vitamin D3 for 72 h. The expression levels of NLRP1, NLRP3, TLR1, TLR2, TLR4, and VDR in all examined SFs were analyzed by quantitative real-time PCR (RT-qPCR). Additionally, the secretion of IL-1β by SFs and MMPs were determined by ELISA and Luminex technology. The expression of NLRP3 was correlated with the levels of CRP, RF, and anti-CCP, suggesting its implication in SF inflammatory activation. In the TNF-α-stimulated SFs, a significantly lower expression of NLRP3 and TLR4 was observed in the RA group, compared with the other tested forms of arthritis. Moreover, upregulation of NLRP3 expression by TNF-α alone or in combination with vitD3 was observed, further indicating involvement of NLRP3 in the inflammatory responses of SFs. Secretion of IL-1β was not detected in any sample, while TNF-α upregulated the levels of secreted MMP-1, MMP-7, MMP-8, MMP-12, and MMP-13 in all patient groups. Attenuating effects of vitD on the expression of NLRP3, TLR1, and TLR4 suggest potential protective effects of vitD on the inflammatory responses in SFs. However, longer studies may be needed to confirm or fully rule out the potential implication of vitD in SF activation in inflammatory arthritis. Both VDR and NLRP3 in the TNF-α-stimulated SFs negatively correlated with the age of patients, suggesting potential age-related changes in the local inflammatory responses.
33907904 Factors associated with long-term retention of treatment with golimumab in rheumatoid arth 2021 Oct BACKGROUND: Retention of biological treatment provides a marker of drug effectiveness and patient satisfaction. Retention of golimumab was high in clinical trial extensions and real-world studies up to 5 years in patients with immune-mediated rheumatic diseases. OBJECTIVE: To assess the probability of real-world long-term retention of treatment with golimumab up to 7 years after treatment initiation. METHODS: This retrospective noninterventional study involved analysis of the Spanish biological drugs registry, BIOBADASER. Adults who had ever received golimumab for rheumatoid arthritis (RA), axial spondyloarthritis (SpA), or psoriatic arthritis (PsA), and had initiated it > 6 months before the analysis date, were included. RESULTS: Among 685 patients (28.5% RA, 42.9% SpA, 28.6% PsA), the overall probability of retention of golimumab treatment since initiation was 71.7% (95% confidence interval 68.1-74.9) at year 1, 60.5% (56.5-64.2%) at year 2, 55.6% (51.5-59.5%) at year 3, 50.6% (46.2-54.8%) at year 4, 45.1% (40.1-50.0%) at year 5, 44.2% (39.0-49.3) at year 6, and 39.5% (32.8-46.2) at year 7. Retention was greater in patients with axial SpA or PsA versus RA (p < 0.001) and when golimumab was used as first-line treatment versus third or later lines (p < 0.001). Factors associated with greater golimumab retention in Cox regression included use as first-line biological therapy, having axial SpA or PsA rather than RA, and concomitant methotrexate therapy. Steroids were associated with lower retention. CONCLUSION: In this real-world study of RA, axial SpA, and PsA patients, the retention rate of golimumab was 39.5% at year 7. Key Points • Retention of biological treatment provides a marker of drug effectiveness and patient satisfaction. • This real-world study of 685 patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA), or psoriatic arthritis (PsA) showed that golimumab treatment had a retention rate up to 39.5% at year 7. • Greater golimumab retention was associated with use as first-line biological therapy, having axial SpA or PsA rather than RA, and concomitant methotrexate therapy.
33050760 A pooled safety analysis of peficitinib (ASP015K) in Asian patients with rheumatoid arthri 2021 May OBJECTIVE: To evaluate the safety of peficitinib for the treatment of rheumatoid arthritis (RA) in Asian patients. METHODS: Safety data from one Phase 2b, two Phase 3, and one open-label long-term extension study [data cut-off 31 May 2018] were pooled into Phase 3 studies (peficitinib 100 and 150 mg/day, and placebo) and Phase 2/3 studies (all peficitinib-treated patients). Incidence rates per 100 patient-years (PY) of adverse events (AEs) of special interest were calculated. RESULTS: Overall, 1052 patients received peficitinib for 2336.3 PY of exposure (median 2.1 years); four deaths occurred, including one death after the studies. AE incidence was similar across peficitinib 100 and 150 mg/day groups (Phase 3 studies). Respective peficitinib and placebo incidence rates (95% confidence interval) per 100 PY were 2.9 (1.9, 4.6) and 0.0 for serious infections, 5.7 (4.2, 7.9) and 2.3 (0.6, 9.4) for herpes zoster-related disease, and 0.6 (0.2, 1.6) and 1.2 (0.2, 8.3) for malignancies (excluding non-melanoma skin cancer) (Phase 3 studies), and 0.1 (0.0, 0.3) for venous thromboembolism in all peficitinib-treated patients (Phase 2/3 studies). CONCLUSION: Peficitinib was well tolerated in Asian patients with RA over a median of 2 years, with no observed dose or temporal dependency for AEs with prolonged administration.
34406709 Passive Smoking Throughout the Life Course and the Risk of Incident Rheumatoid Arthritis 2021 Dec OBJECTIVE: To investigate passive smoking throughout the life course and the risk of rheumatoid arthritis (RA), while accounting for personal smoking. METHODS: We analyzed the Nurses' Health Study II prospective cohort, using information collected via biennial questionnaires. We assessed the influence of 1) maternal smoking during pregnancy (in utero exposure), 2) childhood parental smoking, and 3) years lived with smokers since age 18. Incident RA and serostatus were determined by medical record review. Using the marginal structural model framework, we estimated the controlled direct effect of each passive smoking exposure on adult incident RA risk by serologic phenotype, controlling for early-life factors and time-updated adulthood factors including personal smoking. RESULTS: Among 90,923 women, we identified 532 incident RA cases (66% seropositive) during a median of 27.7 years of follow-up. Maternal smoking during pregnancy was associated with RA after adjustment for confounders, with a hazard ratio (HR) of 1.25 (95% confidence interval [95% CI] 1.03-1.52), but not after accounting for subsequent smoking exposures. Childhood parental smoking was associated with seropositive RA after adjustment for confounders (HR 1.41 [95% CI 1.08-1.83]). In the controlled direct effect analyses, childhood parental smoking was associated with seropositive RA (HR 1.75 [95% CI 1.03-2.98]) after controlling for adulthood personal smoking, and the association was accentuated among ever smokers (HR 2.18 [95% CI 1.23-3.88]). There was no significant association of adulthood passive smoking with RA (HR 1.30 for ≥20 years of living with a smoker versus none [95% CI 0.97-1.74]). CONCLUSION: We found a potential direct influence of childhood parental smoking on adult-onset incident seropositive RA even after controlling for adulthood personal smoking.
33155486 Time Course of Quality of Life Improvement Between Resection Arthroplasty and Metatarsopha 2021 Feb BACKGROUND: Resection arthroplasty has long been a major treatment option for forefoot deformity caused by rheumatoid arthritis (RA). However, metatarsophalangeal (MTP) joint-preserving surgery is now surpassing classic resection arthroplasty. This study was performed to compare the postoperative results of these 2 operative methods. METHODS: Fifty-one toes of 40 patients with RA who underwent resection arthroplasty (resection group) or MTP joint-preserving arthroplasty (preservation group) from 2014 to 2017 for forefoot deformity were followed up for >1 year and were retrospectively analyzed. In the preservation group, open reduction of joint dislocation was performed if needed, and the deformity was corrected by metatarsal shortening osteotomy. The mean follow-up period was 21 months. The Japanese Society for Surgery of the Foot (JSSF) scales (objective outcome measures), the Self-Administered Foot Evaluation Questionnaire (SAFE-Q) (subjective outcome measure), and radiographic indices were compared between the groups. The resection group and preservation group comprised 15 toes of 11 patients and 36 toes of 29 patients, respectively. RESULTS: There were no significant differences in the preoperative radiographic indices, JSSF scales, or SAFE-Q results between the 2 groups. The preservation group showed better JSSF scores at the last follow-up (median hallux scale, 89 vs 74; median lesser scale, 87 vs 79). In the preservation group, the SAFE-Q scores gradually improved with time until 12 months postoperatively. In the resection group, the scores decreased 3 months postoperatively and then improved and reached a plateau 6 months postoperatively. At 12 months postoperatively, there was no significant difference in the SAFE-Q scores between the 2 groups. CONCLUSIONS: MTP joint-preserving arthroplasty resulted in superior objective scores to resection arthroplasty in patients with RA forefoot deformity. Although the subjective scores did not differ between the groups at the last follow-up, the time course of postoperative quality of life improvement was different between the 2 surgeries. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
33879708 Low levels of anti-cyclic citrullinated peptide (CCP) 3.1 associated with diseases other t 2021 Apr 23 Our aim was to investigate the newest generation anti-cyclic citrullinated peptide (CCP) antibody 3.1 assay in diagnosing rheumatoid arthritis (RA) compared with other autoimmune and non-autoimmune diseases. We performed a retrospective observational chart review of patients with a positive CCP level over a one-year period at a single academic institution and assessed the associated diagnoses after at least six-months of follow-up. Of the 281 CCP positive patients during that period, 48% had a diagnosis of RA. The positive predictive value of RA in patients with a high CCP 3.1 assay was 0.619 compared to 0.248 with a low positive CCP 3.1 assay (P < .0001). Overall, there was a lower than expected positive predictive value of CCP 3.1 level with an RA diagnosis, though the likelihood of having an RA diagnosis was higher with a higher CCP level.
33394305 Establishment and verification of an osteoporosis risk model in patients with rheumatoid a 2021 Jan 4 To establish a model for osteoporosis risk in patients with rheumatoid arthritis and validate the model. A newly generated predictive model has been suggested to have good differentiation, calibration, and clinical validity and may be a useful clinical model for predicting osteoporosis in patients with rheumatoid arthritis. PURPOSE: To establish a prediction model for osteoporosis risk in patients with rheumatoid arthritis and validate the model internally and externally. METHODS: A total of 270 patients with rheumatoid arthritis who underwent bone mineral density measurement at our hospital from June 2019 to June 2020 were enrolled in the study. The patients were divided into two groups according to their entry time: a training set containing the first 2/3 of the patients (n = 180) and a validation set containing the remaining 1/3 of the patients (n = 90). Binary logistic regression analysis was used to establish the regression models, and the concordance index (C-index), calibration plot, and decision curve analysis were used to evaluate the prediction model. RESULTS: Five variables, including age (X1), course of disease (X2), the disease activity score using 28 joint counts (DAS28) (X4), anti-cyclic citrullinated peptide antibody (CCP) (X7), and 7-joint ultrasonic bone erosion (X14), were selected to enter the model. The prediction model is Logit Y = - 12.647 + 0.133X1 + 0.011X2 + 0.754X4 + 0.001X7 + 0.605X14. The model had good differentiation; the C-index in the internal verification was 0.947 (95% CI is 0.932-0.977) and the C-index in the external verification was 0.946 (95% CI is 0.940-0.994). The calibration plot of the model showed excellent consistency between the prediction probability and actual probability. When > 0.483 was taken as the cutoff value for the diagnosis of osteoporosis, the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and Jordan index of the model were 90.24%, 87.76%, 7.37, 0.11, and 78.00%, respectively. CONCLUSION: A newly generated predictive model has been suggested to have good differentiation, calibration, and clinical validity and may be a useful clinical model for predicting osteoporosis in patients with rheumatoid arthritis.
33958258 Longitudinal Changes in Knee Joint Synovial Vascularity in a Rabbit Model of Rheumatoid Ar 2021 Aug We studied a rabbit model of rheumatoid arthritis (RA) to examine the time course of changes in synovial neovascularization based on quantitative power Doppler ultrasound and contrast-enhanced ultrasound (CEUS). Twenty-five male New Zealand rabbits were in the ovalbumin-induced arthritis (OIA) group, and 5 were in the control group. Both rear knee joints of all rabbits were examined using conventional US and CEUS over 16 weeks. The knee synoviums of OIA rabbits were sampled by US-guided biopsy, and expression of CD31 and vascular endothelial growth factor (VEGF) was determined by immunohistochemistry. The correlation of joint damage based on multimodal US with microvessel density (CD31 positivity) and VEGF expression at different times was analyzed. OIA rabbits had increased synovial expression of CD31 and VEGF from weeks 6 to 12 (p < 0.01). During the early stage of CEUS enhancement, "dot enhancement" was more common at weeks 6 and 8, and "stripe enhancement" was more common at weeks 12 and 16 (p < 0.05). There were significant positive correlations of synovial CD31 and VEGF expression with power Doppler image grade, CEUS grade and peak intensity (p < 0.05 for all). Thus, OIA rabbits mimicked early-stage RA at 6 to 8 weeks, middle-stage RA at 8 to 12 weeks and late-stage RA at 12 to 16 weeks. Power Doppler image grade, CEUS grade and peak intensity, especially when combined with CD31 expression data, accurately characterized the extent of synovial vascularization in a rabbit model of RA. Increased vascularity based on CEUS may have value for the early diagnosis of RA.
34787226 Prevalence of rheumatoid arthritis in South America: a systematic review and meta-analysis 2021 Rheumatoid arthritis (RA) is among the most prevalent chronic autoimmune and inflammatory diseases worldwide. The aim of this study was to establish a pooled estimate of the RA prevalence in South America by means of a meta-analysis of the available epidemiologic studies. Systematic searches in PubMed, Lilacs, SciELO, Scopus, and Web of Science databases (updated May 2019) were done followed by a systematic grey literature search to identify original research articles and reports, published after 2000, providing data of RA prevalence in any South American country. Proportion meta-analysis of weighted pooled was performed, with between-trial heterogeneity assessed by the inconsistency relative index. Sensitivity analyses and sub-group analyses were also done. A total of 25 articles, representing 27 population-based studies were included. Pooled prevalence of RA resulted in 0.48% with 591,981 cases in a population of 114,537,812 individuals (I2=99%). Brazil and Colombia presented the lowest rates of RA prevalence 0.22%, and 0.24%, respectively. RA prevalence in indigenous population was higher 1.45%, and studies using COPCORD method reported also the highest rates 1.07%.
33246326 Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bon 2021 May 14 OBJECTIVES: While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. METHODS: We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. RESULTS: Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. CONCLUSION: Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.
34789535 Predictors of response to TNF inhibitors in rheumatoid arthritis: an individual patient da 2021 Nov OBJECTIVE: To identify patient characteristics associated with responsiveness to tumour necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). MATERIALS AND METHODS: Individual patient data from 29 randomised controlled trials (RCTs) evaluating the efficacy of a TNFi versus placebo or conventional therapy were obtained. Response to treatment was assessed in subgroups according to the following baseline characteristics: smoking status, physical activity, sex, age, body mass index, autoantibody profile, disease duration, high initial disease activity defined by Disease Activity Score on 28 joints (DAS28)(C reactive protein (CRP)) >5.1. The primary outcome was the between-treatment group difference in DAS28(CRP) change from baseline to 6 months. The secondary endpoints were the between-treatment group difference in final DAS28(CRP) measured until 6 months and EULAR response criteria until 6 months. Data from each RCT were then pooled by the Mantel-Haenszel method using a random effects model. A linear metaregression was also carried out on two data-sharing platforms separately to support the results. RESULTS: Individual data of 11 617 patients from 29 RCTs were analysed. Until 6 months, a significantly higher EULAR non-response rate was observed in obese patients (OR 0.52 vs 0.36 for non-obese, p=0.01). A multivariable regression model performed on 7457 patients indicated that patients treated by TNFi had a final DAS28(CRP) decreased by 0.02 for each year of disease duration (p<0.001), and a 0.21 decreased for patients with a baseline DAS28(CRP) >5.1 (p<0.001). CONCLUSIONS: In RA, patients who are more responsive to TNFi are those who are non-obese, have a long disease duration and have a high initial disease activity.
34554329 Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arth 2021 Nov Janus kinase (JAK) inhibitors have been developed as disease-modifying antirheumatic drugs. Despite the positive therapeutic impacts of JAK inhibitors, concerns have been raised regarding the risk of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE). A recent post hoc safety analysis of placebo-controlled trials of JAK inhibitors in rheumatoid arthritis (RA) reported an imbalance in the incidence of VTE for a 4-mg daily dose of baricitinib versus placebo. In a recent postmarketing surveillance trial for RA, a significantly higher incidence of PE was reported in treatment with tofacitinib (10 mg twice daily) compared with tofacitinib 5 mg or tumor necrosis factor inhibitors. We also experienced a case of massive PE occurring 3 months after starting baricitinib (4 mg once daily) for multiple biologic-resistant RA. Nevertheless, the evidence to support the role of JAK inhibitors in VTE risk remains insufficient. There are a number of predisposing conditions and risk factors for VTE. In addition to the known risk factors that can provoke VTE, advanced age, obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking can also contribute to its development. Greater VTE risk is noted in patients with chronic inflammatory conditions, particularly RA patients with uncontrolled disease activity and any comorbidity. Prior to the initiation of JAK inhibitors, clinicians should consider both the number and strength of VTE risk factors for each patient. In addition, clinicians should advise patients to seek prompt medical help if they develop clinical signs and symptoms that suggest VTE/PE. Key Points • Patients with rheumatoid arthritis (RA) are at increased risk of venous thromboembolism (VTE), especially those with uncontrolled, high disease activity and those with comorbidities. • In addition to the well-known risk factors that provoke VTE events, advanced age and cardiovascular risk factors, such as obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking, should be considered risk factors for VTE. • Although a signal of VTE/pulmonary embolism (PE) risk with JAK inhibitors has been noted in RA patients who are already at high risk, the evidence is currently insufficient to support the increased risk of VTE during RA treatment with JAK inhibitors. • If there are no suitable alternatives, clinicians should prescribe JAK inhibitors with caution, considering both the strength of individual risk factors and the cumulative weight of all risk factors for each patient.
33788911 Effectiveness and tolerability of oral vs subcutaneous methotrexate in patients with rheum 2021 Dec 24 OBJECTIVES: The aim of this study was to compare the effectiveness and tolerability between oral MTX and s.c. MTX in a large group of RA patients in a real-life setting. METHODS: In this retrospective cohort study, adult patients with clinical diagnosis of RA who started MTX treatment (monotherapy or combined with HCQ) started with either oral or s.c. MTX. The primary outcome was superiority testing of between group difference in change in DAS28CRP between baseline and 3-6 months, and subsequent non-inferiority (non-inferiority margin 0.6) testing analyses in case of non-superiority. Secondary outcomes included MTX dose, side effects, laboratory abnormalities and use of comedication. RESULTS: Six hundred and forty RA patients were included: 259 started with oral MTX and 381 with s.c. MTX. There was no significant difference in ΔDAS28CRP [after adjusting for confounding, 0.13 (95% CI: -0.14, 0.40)], and oral MTX strategy was non-inferior to s.c. The mean MTX dose was slightly lower for the oral strategy [18.0 (6.9) vs 19.9 (8.2), P = 0.002], which was accompanied by a lower cumulative incidence of adverse events (41% vs 52%, P = 0.005). No differences were seen in use of other comedication. CONCLUSION: Starting with oral MTX in RA in a real-life setting is non-inferior to a s.c. MTX treatment with regard to disease activity control, at least when used in dosages up to 25 mg and on a background of HCQ co-treatment and a treat-to-target approach. In addition, tolerability was better. This supports the strategy of starting with oral MTX.
34054878 Autoantibodies in Rheumatoid Arthritis - Laboratory and Clinical Perspectives. 2021 Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment.