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30824656 HLA-DRB1 Haplotypes, Shared Epitope, and Disease Outcomes in US Veterans with Rheumatoid A 2019 Jul OBJECTIVE: To evaluate associations of HLA-DRB1 haplotypes and shared epitope (SE) with rheumatoid arthritis (RA) severity and all-cause mortality in RA. METHODS: Patients with RA from the Veterans Affairs Rheumatoid Arthritis (VARA) registry were followed from enrollment until death or December 31, 2013. Clinical characteristics, DNA, and serum were collected at enrollment. Radiographic damage, the presence or absence of subcutaneous nodules, disease activity measures, and functional status were assessed at enrollment and updated during followup. Sixteen HLA-DRB1 haplotypes and SE status were determined from banked DNA. Associations between HLA-DRB1 haplotypes, RA disease characteristics, and mortality were assessed in multivariable regression models. RESULTS: Within VARA, 1443 participants had genotyping and accrued 6150 patient-years of followup. Haplotypes VKA, VRA, LRA, SRA, SRE, SKR, and SEA, and SE alleles were significantly associated with seropositivity for rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP). Haplotypes VKA and SKR were associated with higher RF concentrations, while VRA, DRE, and GRQ were associated with lower RF concentrations. Haplotypes VKA, VRA, and LRA were associated with higher concentrations of anti-CCP antibody, while haplotypes SRA, SRE, LEA, SKR, and SEA were significantly associated with lower anti-CCP concentrations. Haplotype VKA (OR 1.39, 95% CI 1.08-1.80) was associated with increased frequency of radiographic damage at enrollment but none of the haplotypes were associated with the presence of subcutaneous nodules. Haplotypes SKA (HR 1.52, 95% CI 1.26-1.83) was associated with higher mortality. CONCLUSION: HLA-DRB1 haplotypes are independently and variably associated with seropositivity, autoantibody concentrations, and outcomes in RA.
31588838 Identification of PBMC-expressed miRNAs for rheumatoid arthritis. 2020 Apr Post-transcriptional regulation by miRNAs plays an important role in the pathogenesis of rheumatoid arthritis (RA), however, the roles of specific miRNAs in RA pathogenesis remain largely unclear. This study performed dual-omics (miRNA and mRNA) integration analysis and in-depth cellular and molecular functional exploration to identify novel RA-associated miRNAs and to understand their underlying pathogenic mechanism. Based on the miRNA and mRNA expression profiles in peripheral blood mononuclear cells (PBMCs) from a discovery sample set (25 RA cases and 18 healthy controls), 18 differentially expressed miRNAs (DEMIRs) (|Fold-change|>2 and P < 0.05) were identified and corresponding interaction networks of DEMIRs and mRNA were constructed. After the expression validation of the DEMIRs in a validation sample set (35 RA cases and 35 healthy controls), miR-99b-5p was highlighted. The over-expression of newly discovered miR-99b-5p is able to suppress T cell apoptosis, promote cell proliferation and activation, increase expression of proinflammatory cytokines (IL-2, IL-6, TNF-α, and IFN-γ), and inhibit expression of its target genes mTOR and RASSF4. This study comprehensively identified PBMC-expressed miRNAs along with corresponding regulatory networks significant for RA and discovered miR-99b-5p as a novel post-transcriptional mediator involved in RA pathogenesis. The findings improved our understanding of RA pathogenesis and provided novel insights into the molecular mechanisms underlying RA pathogenesis.
31619175 Incorporating adjustments for variability in control group response rates in network meta- 2019 Oct 16 BACKGROUND: The importance of adjusting for cross-study heterogeneity in control group response rates when conducting network meta-analyses (NMA) was demonstrated using a case study involving a comparison of biologics for the treatment of moderate-to-severe rheumatoid arthritis. METHODS: Bayesian NMAs were conducted for American College of Rheumatology (ACR) 50 treatment response based upon a set of randomized controlled trials (RCTs) identified by a recently completed systematic review of the literature. In addition to the performance of an unadjusted NMA, a model adjusting for cross-study heterogeneity of control group response rates using meta-regression was fit to the data. Model fit was evaluated, and findings from both analyses were compared with regard to clinical interpretations. RESULTS: ACR 50 response data from a total of 51 RCTs and 16,223 patients were analyzed. Inspection of cross-study variability in control group response rates identified considerable differences between studies. NMA incorporating adjustment for this variability was associated with an average change of 38.1% in the magnitude of the ORs between treatment comparisons, and over 64% of the odds ratio changed by 15% or more. Important changes in the clinical interpretations drawn from treatment comparisons were identified with this improved modeling approach. CONCLUSIONS: In comparing biologics for moderate to severe rheumatoid arthritis, failure to adjust for cross-trial differences in the control arm response rates in NMA can lead to biased estimates of comparative efficacy between treatments.
31858341 A retrospective study on the predictive implications of clinical characteristics and thera 2020 May BACKGROUND: Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is associated with significant morbidity and is a critical cause of mortality in patients with RA. OBJECTIVE: Our aim was to evaluate predictive and prognostic factors for RA-ILD and to describe the therapeutic management of the condition from a large China cohort. METHODS: This was a retrospective cohort study. We collected data of 1121 RA patients who underwent chest HRCT from 2008 to 2017. Patients without ILD at RA diagnosis were included in the analysis. The development and evolution of ILD in RA patients were followed up. Determinants of ILD development and progression were identified through multivariable logistic analysis. Cox hazards analysis was used to determine significant variables associated with survival. RESULTS: A total of 923 patients without ILD at RA diagnosis were identified and enrolled. Among them, 278 cases (30.12%) were diagnosed as ILD during follow-up. Logistic regression analysis showed that advanced age (> 60 years old) at RA onset (OR: 1.485), male (OR: 1.882), short duration of RA (0~5 years) (OR: 2.099), RF positive (OR: 1.728), elevated lactate dehydrogenase (LDH) (OR: 3.032), and no medication (OR: 1.833) were closely correlated to the development of RA-ILD. No correlation was found between ILD development and traditional DMARDs such as methotrexate and leflunomide. According to the follow-up data, 83 RA-ILD patients were identified as interstitial lung disease (ILD) progression, and 102 participants were stable. Logistic regression modeling demonstrated that DLCO% < 45% (OR: 3.025) and UIP possible pattern on HRCT (OR: 3.476) were independent risk factors for the ILD progression. No correlation was found between ILD progression and traditional DMARDs such as methotrexate and leflunomide. A total of 53 RA-ILD deaths occurred during follow-up. Cox hazards analysis revealed that advanced age (> 60 years old) at RA-ILD diagnosis (HR: 3.181) and extensive lung involvement on HRCT (HR: 2.401) were associated with worse survival. Treatment with cyclophosphamide (HR: 0.210) was associated with better survival. CONCLUSIONS: Advanced age, male, short duration of RA, RF positive, elevated LDH, and no medication are closely correlated with RA-ILD. No correlation was found between traditional DMARDs and ILD development. DLCO% < 45% and UIP possible pattern are predictive factors for ILD progression. No correlation was found between traditional DMARDs and ILD progression. Advanced age and extensive lung involvement on HRCT independently predict mortality; cyclophosphamide treatment helps to improve the prognosis of RA-ILD.Key Points• We designed this study to investigate the predictive and prognostic factors for RA-ILD and to explore the potential role of DMARDs in the evolution of RA-ILD from the development to progression and death.• Patients without ILD at RA diagnosis were enrolled and followed up retrospectively.• Our results showed that no correlation was found between traditional DMARDs and the development and progression of ILD, and regular treatment may improve the development of RA-ILD.• Our results revealed that clinical variables appeared predictive implications for the diagnosis of ILD and physiological and radiological variables appeared predictive implications for the prognosis of ILD, which can provide reference to rheumatologists and help to improve poor prognosis of RA-ILD.
31242943 Higher baseline global leukocyte DNA methylation is associated with MTX non-response in ea 2019 Jun 26 BACKGROUND: Low-dose methotrexate (MTX) is the first-line therapy in early rheumatoid arthritis (eRA). Up to 40% of eRA patients do not benefit from MTX therapy. MTX has been shown to inhibit one-carbon metabolism, which is involved in the donation of methyl groups. In this study, we investigate baseline global DNA methylation and changes in DNA methylation during treatment in relation to clinical non-response after 3 months of MTX treatment. METHODS: Two hundred ninety-four blood samples were collected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, ISRCTN26791028), a multicenter, stratified single-blind clinical trial of eRA patients. Global DNA (hydroxy)methylation was quantified using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and validated with a global DNA LINE-1 methylation technique. MTX response was determined as ΔDAS28. Additionally, patients were stratified into two response groups according to the European League Against Rheumatism (EULAR) response criteria. Associations between global DNA methylation and response were examined using univariate regression models adjusted for baseline DAS28, baseline erythrocyte folate levels, and body mass index (BMI). RESULTS: Higher baseline global DNA methylation was associated with less decrease of DAS28 (β = 0.15, p = 0.013) and with MTX non-response (OR = 0.010, 95% CI = 0.001-0.188). This result was validated in LINE-1 elements (β = 0.22, p = 0.026). Changes in global DNA (hydroxy)methylation were not associated with MTX response over 3 months. CONCLUSIONS: These results show that higher baseline global DNA methylation in treatment naïve eRA patients is associated with decreased clinical response after 3 months of treatment of eRA patients and can be further evaluated as a predictor for MTX therapy non-response. TRIAL REGISTRATION: ISRCTN, ISRCTN26791028 , registered 23 August 2007-retrospectively registered.
31585842 Suspected inflammatory rheumatic diseases in patients presenting with skin rashes. 2019 Aug Skin lesions occur, often at very early stages, in many of the most frequent inflammatory rheumatic diseases such as in systemic lupus erythematosus (SLE), dermatomyositis (DM), systemic sclerosis (SSc), Sjögren's syndrome, rheumatoid arthritis (RA), and psoriatic arthritis. It is important to recognize the different specific cutaneous lesions in SLE (e.g., "butterfly" rash in acute, annular or psoriasiform photosensitive lesions in the subacute form, and discoid lesions in the chronic form) for an early diagnosis and to estimate the associated risks of internal disease, whereas nonspecific lesions (exanthema, vasculitis, and alopecia) can be part of SLE flares. Cutaneous lesions in DM (Gottron's papules and sign, heliotrope rash, dystrophic cuticles, and nailfold capillary abnormalities) may occur before any clinically evident muscular or systemic organ involvement and are of utmost importance for early diagnosis. The pattern of cutaneous lesions and associated autoantibodies also allow the distinction of different phenotypes, either more prone to life-threatening interstitial lung disease (MDA-5) or with higher risk for neoplasia (TIF1-γ). Many other skin lesions, although not specific, require further investigation to look for a possible underlying inflammatory rheumatic disease: non-pruritic urticarial lesions in anti-C1q-associated urticarial vasculitis, Still's disease or hereditary auto-inflammatory syndromes, transient macular purpura of vasculitis in Sjögren's syndrome, Behçet's disease, or RA, Raynaud's phenomenon in SSc and mixed connective tissue disease, erythema nodosum or other panniculitis in RA, Behçet's disease and SLE, pustular eruptions in Behçet's disease, psoriasis, and hereditary auto-inflammatory syndromes. After reviewing in detail the cutaneous manifestations of the most frequent inflammatory rheumatic diseases, we describe a topographic and morphological approach to skin rashes, calling attention to facial rashes, hand involvement, scalp, nail, or leg lesions or to some morphological aspects of skin lesions (annular, pustular, urticarial, or exanthematous) that may be the initial manifestations of inflammatory rheumatic diseases. The importance of skin lesions is confirmed by their presence as part of the classification criteria of many inflammatory rheumatic diseases. They also contribute to early diagnosis, to characterize disease phenotypes, to aid in effective patient management, and, ultimately, to impact on disease prognosis.
31292886 B7-H3 modulates endothelial cell angiogenesis through the VEGF cytokine. 2019 Jun B7-H3 is a cell surface molecule in the immunoglobulin superfamily that has been shown to perform both immunological and non-immunological functions. It has also been found that vascular endothelial growth factor (VEGF) is an important molecule in the modulation of endothelial cell behavior. In this study, we analyzed the serum expression of B7-H3 in 113 rheumatoid arthritis and systemic lupus erythematous patients using the ELISA and found a positive correlation between B7-H3 and VEGF. Next, we investigated the involvement of B7-H3 in angiogenesis using human umbilical vein endothelial cells (HUVECs) with transient knockdown of B7-H3 and an in vivo Matrigel model. Data from the in vitro experiments showed that B7-H3 increased cell proliferation, migration, and tube formation, and correlated with the expression of VEGF. Furthermore, B7-H3 affected the formation of functional vascular networks in Matrigel plugs, which were dissected from mice injected with different HUVECs. Our data suggest that B7-H3 promotes angiogenesis through the enhancement of VEGF secretion. This is the first study proposing a significant role for B7-H3 in the promotion of angiogenesis and may provide further understanding of this gene's biological function.
31036012 Health outcomes and unmet needs in patients with long-standing rheumatoid arthritis attend 2019 Apr 29 BACKGROUND: No previous studies have characterized a patient's experience of rheumatoid arthritis (RA) management in Greece and unmet needs may exist despite a broad range of available treatments. Therefore, we assessed quality of life (QoL), functional ability, and healthcare resource utilization in patients with established RA and receiving treatment in a tertiary care setting in Greece. METHODS: This was a prospective, observational cohort of patients aged ≥18 years, receiving any type of treatment for RA, and followed for 12 months at 7 rheumatology referral centers across mainland Greece (NCT01001182). Patient data were collected at the initial visit and 3, 6, and 9 months. QoL was evaluated using the Euro Quality of Life-5 dimensions questionnaire (EQ-5D) and functional ability was evaluated using the Health Assessment Questionnaire (HAQ). RESULTS: A total of 210 patients with RA were enrolled (76.7% women, mean ± standard deviation [SD] age: 59.1 ± 12.6 years, median [interquartile range] disease duration: 11.9 [5.0-16.0] years). Baseline mean ± SD EQ-5D and HAQ scores were 0.57 ± 0.32 and 0.75 ± 0.63, respectively, and remained largely unchanged throughout the study. Post-hoc comparison showed that patients receiving non-biologic disease-modifying antirheumatic drugs (non-bDMARDs) had significantly higher EQ-5D and lower HAQ-DI scores compared with those receiving biologic DMARDs. A majority of patients reported having difficulty doing housework or other duties (61.4 and 61.9%, respectively), and 55.2% reported needing external support for these tasks. Positive correlation was observed between QoL and functional ability. Hospitalization at least once during the study occurred in 9.5% of the patients, and 12.5% of these cases were due to exacerbation of RA. At baseline, 52.4% of the patients were retired, with 38.5% of retirees having retired early due to RA. Among the patients who were retired at baseline, the mean ± SD period from actual retirement to expected retirement age was 12.1 ± 8.1 years. CONCLUSION: QoL and functional ability were positively correlated in patients with long-standing RA, with a large proportion showing impairments in both. Timely, target-oriented treatment initiated as soon as possible after diagnosis may help to improve patient-reported outcomes and limit the burden of RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01001182 . Registered 23 October 2009.
30644097 Long noncoding RNA MEG3 regulates rheumatoid arthritis by targeting NLRC5. 2019 Aug Rheumatoid arthritis (RA) is one of the chronic systemic autoimmune diseases that cardinally affect the joints. Many people all over the world suffer from the disease. Fibroblast-like synoviocytes (FLSs) play a significant role in the occurrence and development of RA. The long noncoding RNA maternally expressed gene 3 (MEG3) is an imprinted gene, which participates in various cancers as a tumor suppressor. Previous studies have shown that nucleotide oligomerization domain (NOD)-like receptors 5 (NLRC5) plays a key role in inflammatory and autoimmune diseases. Nonetheless, we know very little about the biofunctionality of MEG3 during the development of RA. In this paper, we used complete Freund's adjuvant (CFA)-induced rats as RA animal models. The level of MEG3 significantly reduced in CFA-induced synovial tissues and FLSs, whereas the NLRC5 levels were increased. Enforced expression of MEG3 may be responsible for the decreased level of NLRC5 and inflammatory cytokine level. The results of methylation-specific PCR suggested that the MEG3 gene promoter was significantly methylated in CFA-induced synovial tissues and FLSs. More important, hypermethylation of MEG3 promoter could be inhibited by 5-aza-2-deoxycytidine (5-azadC; methylation inhibitor). Besides, the expression of NLRC5 significantly decreased followed by 5-azadc. Furthermore, DNA methyltransferases 1 (DNMT1) increased in CFA-induced synovial tissues and cells. These results indicated that MEG3 regulates RA by targeting NLRC5 potentially.
30507066 Association of Baseline Peptidylarginine Deiminase 4 Autoantibodies With Favorable Respons 2019 May OBJECTIVE: To determine if the baseline presence of autoantibodies to peptidylarginine deiminase 4 (PAD4) predicts therapeutic response to biologic and conventional disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) in whom methotrexate (MTX) monotherapy was unsuccessful. METHODS: Baseline serum from 282 RA patients in whom MTX monotherapy was unsuccessful was screened for the presence of anti-PAD4 antibodies by immunoprecipitation. Clinical response to either triple DMARD (MTX, sulfasalazine, and hydroxychloroquine) or MTX/etanercept combination therapy was determined at 24 and 48 weeks post-treatment initiation. Disease activity was measured using the Disease Activity Score 28-joint assessment (DAS28), and erosive disease was quantified using the Sharp/van der Heijde scoring method. Generalized estimating equations (GEEs) were used to model the clinical responses to treatment in patients with and those without baseline anti-PAD4 antibodies. RESULTS: Anti-PAD4 antibody positivity was associated with male sex, a history of never smoking, and anti-citrullinated protein antibodies. At baseline, patients with anti-PAD4 antibodies had longer disease duration and significantly more radiographic joint damage than anti-PAD4-negative patients, but did not differ in disease activity according to the DAS28. In unadjusted analyses and multivariable GEE models, patients with anti-PAD4 antibodies exhibited greater improvements in DAS28 (adjusted P = 0.02 and P = 0.008, respectively) and less radiographic progression (adjusted P = 0.01 and P = 0.002, respectively) compared to anti-PAD antibody-negative patients, independent of treatment received. CONCLUSION: Although anti-PAD4 antibodies were associated with worse baseline radiographic joint damage, suggesting a history of active or undiagnosed disease, treatment escalation therapy was more effective in reducing disease activity and slowing the progression of joint damage in this patient subset.
31261953 Post-Translational Modifications of Proteins: Novel Insights in the Autoimmune Response in 2019 Jun 29 Post-translational modifications (PTM) are chemical changes mostly catalyzed by enzymes that recognize specific target sequences in specific proteins. These modifications play a key role in regulating the folding of proteins, their targeting to specific subcellular compartments, their interaction with ligands or other proteins, and eventually their immunogenic properties. Citrullination is the best characterized PTM in the field of rheumatology, with antibodies anticyclic citrullinated peptides being the gold standard for the diagnosis of rheumatoid arthritis (RA). In recent years, growing evidence supports not only that a wide range of proteins are subject to citrullination and can trigger an autoimmune response in RA, but also that several other PTMs such as carbamylation and acetylation occur in patients with this disease. This induces a wide spectrum of autoantibodies, as biomarkers, with different sensitivity and specificity for diagnosis, which may be linked to peculiar clinical manifestations and/or response to treatment. The purpose of this review article is to critically summarize the available literature on antibodies against post-translationally modified proteins, in particular antibodies against citrullinated proteins (ACPA) and antibodies against modified proteins (AMPA), and outline their diagnostic and prognostic role to be implemented in clinical practice for RA patients.
30878552 Regulation of fibroblast-like synoviocyte transformation by transcription factors in arthr 2019 Jul Inflammation in the synovium is known to mediate joint destruction in several forms of arthritis. Fibroblast-like synoviocytes (FLS) are cells that reside in the synovial lining of joints and are known to be key contributors to inflammation associated with arthritis. FLS are a major source of inflammatory cytokines and catabolic enzymes that promote joint degeneration. We now know that there exists a direct correlation between the signaling pathways that are activated by the pro-inflammatory molecules produced by the FLS, and the severity of joint degeneration in arthritis. Research focused on understanding the signaling pathways that are activated by these pro-inflammatory molecules has led to major advancements in the understanding of the joint pathology in arthritis. Transcription factors (TFs) that act as downstream mediators of the pro-inflammatory signaling cascades in various cell types have been reported to play an important role in inducing the deleterious transformation of the FLS. Interestingly, recent studies have started uncovering that several TFs that were previously reported to play role in embryonic development and cancer, but not known to have pronounced roles in tissue inflammation, can actually play crucial roles in the regulation of the pathological properties of the FLS. In this review, we will discuss reports that have been able to impart novel arthritogenic roles to TFs that are specialized in embryonic development. We also discuss the therapeutic potential of targeting these newly identified regulators of FLS transformation in the treatment of arthritis.
30739130 Toreforant, an orally active histamine H(4)-receptor antagonist, in patients with active r 2019 Apr OBJECTIVE/DESIGN: In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant. PATIENTS/TREATMENT: Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52). METHODS: Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics. RESULTS: Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected. CONCLUSIONS: While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.
31168404 Interplay between obesity and smoking with regard to RA risk. 2019 OBJECTIVES: Previous studies on rheumatoid arthritis (RA) and body mass index (BMI) have yielded diverging results. We aimed to clarify the influence of BMI on the risk of developing anticitrullinated peptide antibody (ACPA)-positive and ACPA-negative RA by taking into consideration gender, smoking habits and human leukocyte antigen (HLA-DRB1) shared epitope (SE) status. METHODS: The present report is based on a Swedish population-based, case-control study with incident cases of RA (3572 cases, 5772 matched controls). Using logistic regression models, overweight/obese subjects were compared with normal weight subjects regarding risk of developing RA, by calculating ORs with 95% CIs. RESULTS: We observed diverging results for women and men. Among women, the risk of both ACPA-positive and ACPA-negative RA increased with increasing BMI, whereas an inverse association was observed among men for ACPA-positive RA. The results were similar regardless if RA onset before or after the age of 55 years was considered. When the analyses were stratified by smoking habits, the influence of BMI on RA risk was mainly restricted to smokers. Among women, a significant interaction was observed between smoking and overweight/obesity with regard to both subsets of RA. No interaction was observed between HLA-DRB1 SE and overweight/obesity with regard to RA risk. CONCLUSIONS: The interaction between smoking and obesity regarding risk for RA in women warrants efforts to reduce these risk factors in those at risk for RA. The sex differences concerning the influence of obesity on RA risk merit further studies to verify these results and understand underlying mechanisms.
30767864 The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricit 2019 Jul Numerous cytokines have been implicated in the pathogenesis of inflammatory diseases, and their dysregulation is a main feature of rheumatoid arthritis (RA). Cytokines stimulate signal transduction through several intracellular pathways, including Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways, leading to changes in cell activation, proliferation and survival. Consequently, agents that selectively target elements of the JAK/STAT pathways have received significant attention in recent years as potential new treatments for the disease. Baricitinib, an oral selective inhibitor of JAK1 and JAK2, offers an effective treatment for RA in a wide range of patients. The in vitro selectivity of different JAK inhibitors is an important consideration given that key cytokines, growth factors and hormone receptors involved in the pathogenesis of RA signal through specific JAKs. However, it is complex and far from understood how the in vitro effects of JAK inhibitors extrapolate into in vivo and clinical effects in individual patients. This narrative review focuses on the clinical efficacy and safety of baricitinib, but also provides an overview of its mechanism of action in relation to JAK1/JAK2 signalling and discusses the possible clinical implications in patients with RA.
30679758 FOXO3 is involved in the tumor necrosis factor-driven inflammatory response in fibroblast- 2019 May Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Forkhead box O 3 (FOXO3) perturbations in immune cells are increasingly linked to RA pathogenesis. Here, we show that FOXO3 is distinctly inactivated/phosphorylated in the FLS of rheumatoid synovitis. In vitro, stimulation of FLS with tumor necrosis factor-alpha α (TNFα) induced a rapid and sustained inactivation of FOXO3. mRNA profiling revealed that the inactivation of FOXO3 is important for the sustained pro-inflammatory interferon response to TNFα (CXCL9, CXCL10, CXCL11, and TNFSF18). Mechanistically, our studies demonstrate that the inactivation of FOXO3 results from TNF-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Thus, we identified FOXO3 and its modulator PIK3IP1 as a critical regulatory circuit for the inflammatory response of the resident mesenchymal cells to TNFα and contribute insight into how the synovial tissue brings about chronic inflammation that is driven by TNFα.
31375130 Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine s 2019 Aug 2 BACKGROUND: The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level. METHODS: Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC(50)) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects. Time above IC(50) and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type. RESULTS: Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC(50) values and increased time above IC(50) translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees. CONCLUSIONS: Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.
30572779 Age at the time of hip fracture in patients with rheumatoid arthritis is 4 years greater t 2020 Jan Objective: To investigate the characteristics of hip fractures in patients with rheumatoid arthritis (RA).Methods: Between 2012 and 2015, 789 hip fractures were treated at our hospital. Patients with RA were checked and their characteristics were compared with data recorded 10 years before, and with the general population.Results: There were 11 patients with RA, who were all female, and the mean age was 76 ± 7.0 years. The age at the time of hip fracture was 4 years older than that recorded 10 years before (72 ± 4.5 years, p < .05), but was younger than that of the general population (84 ± 8.0 years, p < .001). The mean prednisolone dose of 2.5 ± 2.6 mg/day was lower than that recorded 10 years before (4.8 ± 2.9 mg/day, p < .05). The rate of patients treated with anti-osteoporotic medications at fracture (73%) was higher than 10 years before (42%); however, the difference was not significant. The incidence of secondary fracture was not high compared to the general population. No mortality was recorded at 1 year, and no infective complications occurred.Conclusion: The age at the time of hip fracture in RA patients is increasing, but is still younger than that of the general population.
30136633 Biologic treatment in comparison to methotrexate has positive effect on trabecular bone sc 2019 Apr INTRODUCTION: Biologic treatment may influence activity of rheumatoid arthritis (RA), as well as areal bone mineral density (aBMD). Decreased aBMD explains the fracture risk in RA patients only partially. The trabecular bone score (TBS), novel texture parameter reflects degradation of trabecular bone and therefore could be used as a further parameter to predict the risk of fragility fracture. OBJECTIVE: To compare the effects of biological disease-modifying antirheumatic drugs (bDMARDs) and conventional synthetic (cs) DMARDs (methotrexate) on aBMD and TBS in patients suffering from active RA. METHODS: A 12 month prospective trial was performed in 105 active RA patients. The cohort was divided into two groups: group 1 (n = 84, mean age 54 yrs) treated with bDMARDs and group 2 (n = 21, mean age 53 yrs) treated with csDMARDs. The mean daily dose of prednisone at baseline was 6.2 and 6.6 mg (NS) between group 1 and 2, respectively. Patients with anti-osteoporotic treatment were not included. All patients received calcium (600 mg) and cholecalciferol (800IU). Lumbar spine (LS) and FN aBMD (by DXA, Hologic) were measured at baseline and after 1 year of treatment. TBS was generated using TBS Insight software (Medimaps, Switzerland). RESULTS: Treatment with bDMARDS led to decrease in mean prednisone dose and to increase of 1.7% (p < 0.05) in TBS and OC levels of 26% (p < 0.001) but not on aBMD and CTX after treatment. The greatest TBS increase (2.7%, p < 0.05) was observed in premenopausal females within group 1. No effect of csDMARDS on measured parameters was observed. CONCLUSION: Treatment of patients suffering from active RA with bDMARDs in comparison to csDMARDS led to increase of TBS, with greater increment of TBS in premenopausal women, despite no change in aBMD.
31461658 Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response 2019 Aug 27 There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage.