Browse

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

ID PMID Title PublicationDate abstract
30338640 Impact of subclinical synovitis in ankles and feet detected by ultrasonography in patients 2019 Jan OBJECTIVE: To investigate the impact of subclinical synovitis detected by ultrasonography (US) on the ankles and feet of patients with rheumatoid arthritis. METHODS: We retrospectively reviewed the data of patients (n = 59) who underwent US. RESULTS: The functional ability and quality of life (QoL) of patients in the subclinical group were impaired. While the physician visual analog scale (VAS) scores significantly decreased in the subclinical group, patient and pain VAS scores significantly decreased only in patients without synovitis. CONCLUSION: US-detected subclinical foot and ankle synovitis considerably affected patient functional status and QoL; however, it was often unnoticed by physicians.
30860322 [JAK inhibitors in the management of rheumatoid arthritis]. 2019 Mar 6 Janus kinase (JAK) inhibitors are part of the second-line therapeutic arsenal for patients with moderate to severe rheumatoid arthritis. The pivotal trials have demonstrated good efficacy, even in direct comparison to antirheumatic biotherapies. Their good efficacy is confirmed in observational studies, in particular with a good drug maintenance over time. Combination with conventional synthetic anti-rheumatic agents is probably less essential with JAK inhibitors than with some biotherapies, such as anti-TNFs. Registry studies have also confirmed the safety profile known from randomized trials, i.e. a safety profile generally close to that of antirheumatic biotherapies, with the exception of a slight increase in shingles cases.
30635392 C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmu 2019 Feb 15 The classical pathway of complement (CP) can mediate C3 opsonization of Ags responsible for the costimulation and activation of cognate B lymphocytes. In this manner, the complement system acts as a bridge between the innate and adaptive immune systems critical for establishing a humoral response. However, aberrant complement activation is often observed in autoimmune diseases in which C3 deposition on self-antigens may serve to activate self-reactive B cell clones. In this study, we use BIVV009 (Sutimlimab), a clinical stage, humanized mAb that specifically inhibits the CP-specific serine protease C1s to evaluate the impact of upstream CP antagonism on activation and proliferation of normal and autoimmune human B cells. We report that BIVV009 significantly inhibited complement-mediated activation and proliferation of primary human B cells. Strikingly, CP antagonism suppressed human Ig-induced activation of B cells derived from patients with rheumatoid arthritis. These results suggest that clinical use of CP inhibitors in autoimmune patients may not only block complement-mediated tissue damage, but may also prevent the long-term activation of autoimmune B cells and the production of autoantibodies that contribute to the underlying pathologic condition of these diseases.
31396835 High prevalence of abnormalities on chest radiography in rheumatoid arthritis. 2019 Dec INTRODUCTION: Chest radiography (CXR) is commonly performed in rheumatoid arthritis (RA), particularly for the diagnosis of pulmonary disease. However, other structures are visible on CXR, abnormalities of which may contribute to morbidity and early mortality. This study was undertaken to evaluate the extent of CXR abnormalities in RA patients. METHODS: Consecutive out-patients meeting the 2010 ACR/EULAR classification criteria for RA were included. The most recent CXR was assessed by two independent reviewers. Abnormalities identified were recorded and compared to the formal CXR report. Predictors of abnormalities on CXR were assessed using chi-squared tests. SPSS 18.0 was used for statistical analysis. RESULTS: One hundred and ninety-eight patients were included. Mean age was 62 years (range 18-90). One hundred and nine (55.1%) were current or ex-smokers. One hundred and fifty-six (79%) patients were seropositive and 123 (62.1%) had joint erosions. A recent CXR was available in 163 (82%) cases. Abnormalities were identified in 129 (79.1%). Ninety-seven (60%) had bony abnormalities. Seventy-one (43.6%) had pulmonary abnormalities; old tuberculosis in 34 (20.9%), hyperinflation in 24 (14.7%), interstitial changes in 20 (13.3%), nodules in 4 (2.4%), consolidation in 2 (1.2%), and pneumothorax in 1 (0.6%). Cardiomegaly was identified in 37 (22.7%) and aortic calcification in 24 (14.7%). Age (p = 0.001), male gender (p = 0.01), and seropositivity (p = 0.04) were significantly associated with lung abnormalities. Cardiomegaly was associated with hypertension (p = 0.012) and ischaemic heart disease (p = 0.018). CONCLUSION: Abnormalities were identified in 79% of chest radiographs in RA patients. Sixty-six percent of these were not reported. Clinicians need to be aware of the need to check for abnormalities.Key Points• RA patients have a high prevalence of CXR abnormalities.• Many of these are of clinical significance.• Age, being male, and seropositivity were associated with lung abnormalities.
30421014 Automatic quantification of tenosynovitis on MRI of the wrist in patients with early arthr 2019 Aug OBJECTIVES: Tenosynovitis (inflammation of the synovial lining of the sheath surrounding tendons) is frequently observed on MRI of early arthritis patients. Since visual assessment of tenosynovitis is a laborious task, we investigated the feasibility of automatic quantification of tenosynovitis on MRI of the wrist in a large cohort of early arthritis patients. METHODS: For 563 consecutive early arthritis patients (clinically confirmed arthritis ≥ 1 joint, symptoms < 2 years), MR scans of the wrist were processed in three automatic stages. First, super-resolution reconstruction was applied to fuse coronal and axial scans into a single high-resolution three-dimensional image. Next, 10 extensor/flexor tendon regions were segmented using atlas-based segmentation and marker-based watershed. A measurement region of interest (ROI) was defined around the tendons. Finally, tenosynovitis was quantified by identifying image intensity values associated with tenosynovial inflammation using fuzzy clustering and measuring the fraction of voxels with these characteristic intensities within the measurement ROI. A subset of 60 patients was used for training and the remaining 503 patients for validation. Correlation between quantitative measurements and visual scores was assessed through Pearson correlation coefficient. RESULTS: Pearson correlation between quantitative measurements and visual scores across 503 patients was r = 0.90, p < 0.001. False detections due to blood vessels and synovitis present within the measurement ROI contributed to a median offset from zero equivalent to 13.8% of the largest measurement value. CONCLUSION: Quantitative measurement of tenosynovitis on MRI of the wrist is feasible and largely consistent with visual scores. Further improvements in segmentation and exclusion of false detections are warranted. KEY POINTS: • Automatic measurement of tenosynovitis on MRI of the wrist is feasible and largely consistent with visual scores. • Blood vessels and synovitis in the vicinity of evaluated tendons can contribute to false detections in automatic measurements. • Further improvements in segmentation and exclusion of false detections are important directions of future work on the path to a robust quantification framework.
30762968 Skin inflammation associated with arthritis, synovitis and enthesitis. Part 2: rheumatoid 2019 Feb Syndromes associated with concurrent skin and joint inflammation frequently pose a therapeutic challenge for both dermatologists and rheumatologists. In part 1 of this review, we discussed psoriatic arthritis as well as the autoinflammatory disorders SAPHO syndrome, Still's disease and Behçet's disease. Part 2 will address rheumatoid arthritis, reactive arthritis, Reiter's syndrome and Lyme borreliosis. In addition, we will discuss dermatomyositis and lupus erythematosus, two common autoimmune disorders that frequently present with both cutaneous and joint involvement. For each of the aforementioned disorders, we will highlight aspects of epidemiology, pathogenesis, clinical presentation, diagnosis and treatment.
30729713 Effects of vitamin D on disease activity and serum interleukin-6 in rheumatoid arthritis. 2019 May AIM: Vitamin D(3) or 25(OH)D(3) may have a potential role in rheumatoid arthritis (RA) pathogenesis by inhibiting the expression of pro-inflammatory cytokines including interleukin-6 (IL-6). The aim of this study is to determine the clinical factors of vitamin D deficiency in multi-ethnic Malaysian RA patients and its association with disease activity, functional disability and serum IL-6 levels. METHOD: One hundred RA patients and 50 healthy controls, sex- and age-matched, were recruited. Disease Activity Score of 28 joints and Health Assessment Questionnaire scores were assessed. Baseline serum 25(OH)D(3) and IL-6 were measured in all subjects. RA patients who were vitamin D deficient were given loading doses of vitamin D(3) and repeated assessments were done. RESULTS: Vitamin D deficiency (<50 nmol/L) was found in 63% of RA patients and 76% of healthy controls. Chinese RA patients and healthy controls had significantly more sufficient 25(OH)D(3) levels compared to Malays and Indians (P < 0.001). Serum 25(OH)D(3) level was still negatively associated with body mass index in RA patients (P = 0.002) after adjustment for potential confounding variables. No significant association was seen between 25(OH)D(3) levels and disease activity or serum IL-6 levels in both pre- and post-treatment groups. A negative association was observed between serum 25(OH)D(3) and functional disability, including a 33% improvement post-treatment (mean ± SD: 0.30 ± 0.46 to 0.20 ± 0.18). CONCLUSION: Vitamin D deficiency is prevalent in Malaysian RA patients. This study suggests that vitamin D is not associated with disease activity or serum IL-6 levels but it may have a role in functional disability in RA patients.
31655341 Inhibition of NET formation by polydatin protects against collagen-induced arthritis. 2019 Dec BACKGROUND: Rheumatoid arthritis (RA) is a systematic, inflammatory, autoimmune disease, associated with a high number of disabilities. Increasing evidence has demonstrated that neutrophil extracellular trap (NET) formation plays a significant role in the pathogenesis and progression of RA. In this study, we have aimed to investigate the effects of polydatin (PD) on NET formation and its effects on disease activity in a collagen-induced arthritis (CIA) mouse model. METHODS: In the presence of PD or vehicle, neutrophils isolated from RA patients and mice were treated with phorbol 12-myristate 13-acetate (PMA) for 4 h, and NET formation investigated. For in vivo experiments, PD was administered intraperitoneally (45 mg/kg per day) to collagen-induced arthritis (CIA) mice. The incidence and severity of collagen-induced arthritis were assessed and NET deposition tested. RESULTS: In vitro, PD significantly suppressed NET formation of neutrophils from RA patients. Consistently, decreased NETs were observed in PD treated bone marrow-derived neutrophils. In CIA mouse model, PD treatment delayed the onset of arthritis and attenuated arthritis severity. Compared with vehicle-treated CIA mice, the deposition of NETs in ankle joints was also reduced in PD-treated CIA mice. CONCLUSION: In this study, we found that PD treatment markedly inhibited NET formation and protected CIA mice from the development of arthritis. These findings suggest that inhibition of NET formation by PD may serve as a novel mechanism for the treatment of RA.
30821895 Impact of Patient's Global Assessment on Achieving Remission in Patients With Rheumatoid A 2019 Oct OBJECTIVE: There is an ongoing debate about excluding patient's global assessment (PtGA) from composite and Boolean-based definitions of rheumatoid arthritis (RA) remission. This study aimed at determining the influence of PtGA on RA disease states, exploring differences across countries, and understanding the association between PtGA, measures of disease impact (symptoms), and markers of disease activity (inflammation). METHODS: Cross-sectional data from the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology international database were used. We calculated the proportion of patients failing American College of Rheumatology/European League Against Rheumatism Boolean-based remission (4-variable remission) solely due to PtGA (PtGA-near-remission) in the overall sample and in the most representative countries (i.e., those with >3,000 patients in the database). Multivariable linear regression models were used to identify the main determinants of PtGA, grouped in predominantly inflammatory impact factors (28 tender joint counts, 28 swollen joint counts, and C-reactive protein level) and disease impact factors (pain and function). RESULTS: This study included 27,768 patients. Excluding PtGA from the Boolean-based definition (3-variable remission) increased the remission rate from 5.8% to 15.8%. The rate of PtGA-near-remission varied considerably between countries, from 1.7% in India to 17.9% in Portugal. One-third of the patients in PtGA-near-remission group scored PtGA >4 of 10. Pain and function were the main correlates of PtGA, with inflammation-related variables contributing less to the model (R(2) = 0.57). CONCLUSION: PtGA is moderately related to joint inflammation overall, but only weakly so in low levels of disease activity. A considerable proportion of patients otherwise in biologic remission still perceive high PtGA, putting them at risk of excessive immunosuppressive treatment.
31105703 Restored and Enhanced Memory T Cell Immunity in Rheumatoid Arthritis After TNFα Blocker T 2019 TNFα inhibitors have shaped the landscape of rheumatoid arthritis (RA) therapy with high clinical efficiency. However, their impact on T cell recall responses is not well-elucidated. We aimed to analyze the immune profiles of memory T cells in RA patients undergoing TNFα inhibitor Golimumab (GM) treatment. Frequencies of peripheral T cell subsets and cytokine expression profiles in memory T cells (T(M)) upon PMA/Ionomycine stimulation were determined by flow cytometry. Antigen-specific CD8 T cell immunity was analyzed through stimulating PBMCs with CMV-EBV-Flu (CEF) viral peptide pool and subsequent intracellular IFNγ staining. Both peripheral CD8 and CD4 T cells from GM treated patients had a shift pattern characterized by an enlarged effector T(M) and a reduced central T(M) cell population when compared to GM untreated group. An increase in the frequencies of TNFα(+), IL-2(+), and IL-17(+) CD8 T(M) cells was observed whereas only TNFα(+)CD4 T(M) cells increased in GM treated patients. Moreover, GM treated patients contained more peripheral IFNγ-producing CD8 T cells specific to CEF viral peptides. Together, these results show a distinct T cell subset pattern and enhanced memory T cell immunity upon GM treatment, suggesting an immunoregulatory effect of TNF inhibitor Golimumab on peripheral memory T cell responses.
30297331 Identification of a distinct imaging phenotype may improve the management of palindromic r 2019 Jan OBJECTIVES: To use high-resolution imaging to characterise palindromic rheumatism (PR) and to compare the imaging pattern observed to that seen in new-onset rheumatoid arthritis (NORA). METHODS: Ultrasound (US) assessment of synovitis, tenosynovitis and non-synovial extracapsular inflammation (ECI) was performed during and between flares in a prospective treatment-naive PR cohort. MRI of the flaring region was performed where possible. For comparison, the same US assessment was also performed in anticyclic citrullinated peptide (CCP) positive individuals with musculoskeletal symptoms (CCP+ at risk) and patients with NORA. RESULTS: Thirty-one of 79 patients with PR recruited were assessed during a flare. A high frequency of ECI was identified on US; 19/31 (61%) of patients had ECI including 12/19 (63%) in whom ECI was identified in the absence of synovitis. Only 7/31 (23%) patients with PR had synovitis (greyscale ≥1 and power Doppler ≥1) during flare. In the hands/wrists, ECI was more prevalent in PR compared with NORA and CCP+ at risk (65% vs 29 % vs 6%, p<0.05). Furthermore, ECI without synovitis was specific for PR (42% PR vs 4% NORA (p=0.003) and 6% CCP+ at risk (p=0.0012)). Eleven PR flares were captured by MRI, which was more sensitive than US for synovitis and ECI. 8/31 (26%) patients with PR developed RA and had a similar US phenotype to NORA at progression. CONCLUSION: PR has a distinct US pattern characterised by reversible ECI, often without synovitis. In patients presenting with new joint swelling, US may refine management by distinguishing relapsing from persistent arthritis.
31391326 Metabolic syndrome is not uncommon in treatment-naïve rheumatoid arthritis patients. 2019 Aug OBJECTIVES: Rheumatoid arthritis (RA) is an independent risk factor for cardiovascular disease (CVD). Glucocorticoids are often used in the management of RA and might also contribute to the increased risk of metabolic syndrome (metS). Identifying metabolic alterations earlier and treating them together with disease-modifying therapy may be associated with better outcomes. Here, we aimed to investigate the frequency of metS and its components in treatment-naïve RA patients. METHODS: Fifty-three newly diagnosed treatment-naïve RA patients and 55 control subjects were enrolled. MetS was diagnosed using Adult Treatment Panel III report-defined criteria. We evaluated the metS-related metabolic and anthropometric alterations between the groups. RA patients were subdivided and those with and without metS were also compared with respect to disease-related parameters. RESULTS: MetS was more common in treatment-naïve newly diagnosed RA patients compared to controls (25 of 53 (47.1%) vs 9 of 55 (16.4%), respectively (p = 0.001; OR, 4.56; 95% CI 1.86-11.16). All evaluated anthropometric and metabolic parameters were similar in both groups. However, there was a trend to lower LDL and HDL cholesterol levels in RA patients. Furthermore, among those with metS, the number of fulfilled metS criteria items were higher in RA patients, compared to controls (p < 0.001). Interestingly, more RA patients fulfilled metS criteria with a glucose measurements item compared to controls (p < 0.001). CONCLUSION: MetS was more common in newly diagnosed and treatment-naïve RA patients compared to controls. MetS, along with tendency to present paradoxical and atherogenic lipid profiles in RA patients, may be among the underlying mechanisms of increased CVD.
31072166 An emerging role of interleukin-23 in rheumatoid arthritis. 2019 Apr Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disease and is characterized by destruction of the articular cartilage. A number of pro-inflammatory cytokines work sequentially and in concert with one another to induce the development of RA. IL-23, a member of IL-12 family, is composed of p19 and p40 subunits and it interacts with IL-23 receptor complex to trigger plethora of biochemical actions. A number of preclinical studies have shown the role of IL-23 in the development of RA in rodents. IL-23 receptor signaling is primarily linked to the activation of JAK-STAT, tyrosine kinase 2, NF-kB, and retinoic acid receptor-related orphan receptors. IL-23 produces its osteoclastogenic effects, mainly through IL-17 and Th17 cells suggesting the importance of IL-23/IL-17/Th17 in the joint inflammation and destruction in RA. Monoclonal antibodies targeted against IL-23, including tildrakizumab and guselkumab have been developed and evaluated in clinical trials. However, there are very limited clinical studies regarding the use of IL-23 modulators in RA patients. The present review discusses the different aspects of IL-23 including its structural features, signal transduction pathway, preclinical, and clinical role in RA.
30900933 Vaccination against autoimmune diseases moves closer to the clinic. 2020 Biologicals, e.g. TNF inhibitors, have improved dramatically the efficacy of medical interventions in autoimmune diseases, such as in rheumatoid arthritis (RA). However, although progressive inflammation can be halted in this way, no drug-free remissions or lasting cures are reached. For this to become real, therapies based on induction antigen-specific immune tolerance are sought. This review describes mechanisms of tolerance and the current possibilities for induction of therapeutic tolerance through antigen-specific vaccination approaches. And despite the fact that for various diseases the search for appropriate autoantigens is ongoing, pioneering studies are now already developed that use more broadly inflammation associated antigens. Through their capacity to preferentially induce regulatory T cells, heat shock proteins are an attractive source of such broadly inflammation associated antigens.
30714436 Survival of lymphocytes is not restricted by IDO-expressing fibroblast from rheumatoid art 2019 Apr Objective: Rheumatoid arthritis (RA) is characterized by expansion of fibroblast-like synoviocytes (FLS) in inflamed joints and activation of lymphocytes. Tryptophan (trp) is an essential amino acid indispensable for the biosynthesis of proteins and critical for survival of lymphocytes. Indoleamine 2,3-dioxygenase (IDO) that initiates the degradation of trp and tryptophanyl-tRNA synthetase (TTS) essential for tryptophan synthesis, regulate trp bioavailability. Here, we tested the hypothesis that triggered by cytokines, enhanced IDO activity modulate regulatory function of otherwise non-tolerogenic FLS isolated from RA patients. Materials and methods: IDO and TTS mRNA expression were evaluated by RT-PCR. IDO enzymatic activity was confirmed using HPLC. Resting or PHA-activated PBMC from healthy volunteers and RA patients were co-cultured with IDO expressing untreated (FLS(C)) or IFNγ-treated (FLS(IFNγ)) RA FLS. Lymphocyte survival and proliferation were evaluated by flow cytometry analysis and tritiated thymidine incorporation, respectively. Results: RA FLS(IFNγ) produce functionally active IDO and constitutively express TTS. RA FLS(C) and FLS(IFNγ) increased survival of resting lymphocytes in both studied groups, and decreased proliferation of healthy, but not RA, PBMC. Only FLS(IFNγ) diminished survival of activated CD3(+)CD4(-), but not CD3(+)CD4(+), healthy T cells and similar tendency was observed in rheumatoid cells. Importantly, IDO inhibitor, 1-methyl-DL-tryptophan (1-MT), failed to reverse this effect. PBMC, irrespective of their state (resting versus activated) or origin (healthy or RA), expressed high level of TTS mRNA. Conclusions: We suggest that RA FLS express functionally active IDO but control survival and expansion of healthy cells in IDO-independent mechanism and exert weaker, if any, suppressive effect on rheumatoid cells.
31701185 Periodontal disease and influence of periodontal treatment on disease activity in patients 2020 Mar The aim of this study was to assess the prevalence of periodontal disease and the effect of periodontal treatment in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). Forty-four RA patients, thirty SpA patients and thirty-nine healthy volunteers were recruited to the study. Periodontal examination included the approximal plaque index (API), bleeding on probing (BoP), probing depth (PD) and number of teeth. Samples from the deepest periodontal pockets were taken for the detection of Porphyromonas gingivalis DNA with the use of the polymerase chain reaction. All subjects with periodontitis, who completed the study, received periodontal treatment consisting of scaling/root planing and oral hygiene instructions. Disease activity scores, clinical and laboratory parameters were assessed before and 4-6 weeks after periodontal treatment. No significant difference in the prevalence of periodontal disease and the presence of P. gingivalis DNA were found in RA and SpA patients compared to healthy controls. Significantly higher API (80% vs 63%; p = 0.01) and a lower number of teeth (20 vs 25, p = 0.001) were found in RA patients. BoP was significantly elevated in SpA patients (51% vs 33%, p = 0.02). Disease activity measured by the DAS28(CRP) was significantly reduced in RA patients after periodontal treatment (p = 0.002). Clinical and biochemical parameters were not improved in SpA patients. Nonsurgical periodontal treatment had an impact on the decrease in RA activity. Periodontal examination is necessary in patients with RA to detect and treat periodontitis at an early stage.
31140396 CD74 is a T cell antigen in spondyloarthritis. 2020 Mar OBJECTIVES: Spondyloarthritis (SpA) is a chronic inflammatory disease of unknown aetiology. Previously, we identified autoantibodies against CD74 in sera of SpA patients. The aim of this study was to evaluate CD74 as a T cell antigen in SpA. METHODS: Recombinant CD74 protein and a panel of selected peptides representing its amino acid residues were examined for their capability to stimulate peripheral blood mononuclear cells from patients with SpA. In particular, cytokine production by CD4+ T cells was evaluated with flow cytometric detection of intracellular TNF-α, IFNγ, TGFβ and IL-17A. Patients' sera were tested for antibodies against CD74 using ELISA. Samples from patients with rheumatoid arthritis and healthy blood donors were similarly tested as controls. RESULTS: Significantly more CD4+ T cells from SpA patients produced TNF-α, IFNγ and IL-17A in response to recombinant CD74 than patients with rheumatoid arthritis or healthy blood donors. Among evaluated epitopes, the most promiscuous one lies within the peptide of the amino acid residues 142-185, which appeared more immunogenic. Further, the proportion of cytokine producing CD4+ T cells was significantly higher among SpA patients with autoantibodies against CD74. CONCLUSIONS: CD74 is a T cell antigen in SpA, eliciting Th1 and Th17 responses, which may be relevant in disease pathogenesis. Recognition of the highly immunogenic amino acid residues of CD74 may contribute to our understanding of autoimmune responses of T helper cells in SpA.
30696478 Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outc 2019 Jan 29 BACKGROUND: Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. METHODS: Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. RESULTS: PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. CONCLUSIONS: Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.
30615300 Profiling of Gene Expression Biomarkers as a Classifier of Methotrexate Nonresponse in Pat 2019 May OBJECTIVE: Approximately 30-40% of rheumatoid arthritis (RA) patients who are initially started on low-dose methotrexate (MTX) will not benefit from the treatment. To date, no reliable biomarkers of MTX inefficacy in RA have been identified. The aim of this study was to analyze whole blood samples from RA patients at 2 time points (pretreatment and 4 weeks following initiation of MTX), to identify gene expression biomarkers of the MTX response. METHODS: RA patients who were about to commence treatment with MTX were selected from the Rheumatoid Arthritis Medication Study. Using European League Against Rheumatism (EULAR) response criteria, 42 patients were categorized as good responders and 43 as nonresponders at 6 months following the initation of MTX treatment. Data on whole blood transcript expression were generated, and supervised machine learning methods were used to predict a EULAR nonresponse. Models in which transcript levels were included were compared to models in which clinical covariates alone (e.g., baseline disease activity, sex) were included. Gene network and ontology analysis was also performed. RESULTS: Based on the ratio of transcript values (i.e., the difference in log(2) -transformed expression values between 4 weeks of treatment and pretreatment), a highly predictive classifier of MTX nonresponse was developed using L2-regularized logistic regression (mean ± SEM area under the receiver operating characteristic [ROC] curve [AUC] 0.78 ± 0.11). This classifier was superior to models that included clinical covariates (ROC AUC 0.63 ± 0.06). Pathway analysis of gene networks revealed significant overrepresentation of type I interferon signaling pathway genes in nonresponders at pretreatment (P = 2.8 × 10(-25) ) and at 4 weeks after treatment initiation (P = 4.9 × 10(-28) ). CONCLUSION: Testing for changes in gene expression between pretreatment and 4 weeks post-treatment initiation may provide an early classifier of the MTX treatment response in RA patients who are unlikely to benefit from MTX over 6 months. Such patients should, therefore, have their treatment escalated more rapidly, which would thus potentially impact treatment pathways. These findings emphasize the importance of a role for early treatment biomarker monitoring in RA patients started on MTX.
29782424 The Profile of Serum Transferrin Isoforms in Rheumatoid Arthritis. 2019 Jun INTRODUCTION: Transferrin, a microheterogeneous iron-transporting N-glycoprotein, is an optimal model for the analysis of the glycosylation profile in rheumatoid arthritis (RA). The aim of this study was to assess the transferrin isoforms profile in RA patients at the time of diagnosis and then look into their associations with disease activity. METHODS: Serum samples were collected from 48 patients with RA. The patients were males (6) and females (42) (age range: 33-85 years). Control group consisted of 30 healthy volunteers. Transferrin isoforms were analysed by capillary electrophoresis on MINICAP electrophoretic system. RESULTS: There was a significant decrease in the relative concentrations of trisialo- (mean ± SD; 2.130 ± 1.112) and pentasialotransferrin (13.562 ± 3.088), and significant increase in tetrasialotransferrin (83.640 ± 3.165) in RA patients when compared to the control group (3.615 ± 1.156; 76.840 ± 5.621; 18.610 ± 6.027, respectively) (U Mann-Whitney test: p < 0.001 for all comparisons). There were no significant changes in the disialotransferrin concentrations in RA patients. Trisialotransferrin concentration correlated with RA activity expressed as DAS 28 in RA patients (p < 0.001). The low trisialotransferrin concentration was also associated with high platelet count and high ESR (p < 0.001 for both). Disialo-, tetrasialo- and pentasialotransferrin concentrations did not correlate with DAS 28. CONCLUSIONS: In patients with RA the serum profile of transferrin isoforms is altered. We predict that the levels of trisialylated isoforms of transferrin will serve as a useful biochemical marker of the RA activity.