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ID PMID Title PublicationDate abstract
30949163 P2RX7 Deletion in T Cells Promotes Autoimmune Arthritis by Unleashing the Tfh Cell Respons 2019 Rheumatoid arthritis (RA) is an autoimmune disease that affects ~1% of the world's population. B cells and autoantibodies play an important role in the pathogenesis of RA. The P2RX7 receptor is an ATP-gated cation channel and its activation results in the release of pro-inflammatory molecules. Thus, antagonists of P2RX7 have been considered to have potential as novel anti-inflammatory therapies. Although originally identified for its role in innate immunity, P2RX7 has recently been found to negatively control Peyer's patches (PP) T follicular helper cells (Tfh), which specialize in helping B cells, under homeostatic conditions. We have previously demonstrated that PP Tfh cells are required for the augmentation of autoimmune arthritis mediated by gut commensal segmented filamentous bacteria (SFB). Thus, we hypothesized that P2RX7 is required to control autoimmune disease by keeping the Tfh cell response in check. To test our hypothesis, we analyzed the impact of P2RX7 deficiency in vivo using both the original K/BxN autoimmune arthritis model and T cell transfers in the K/BxN system. We also examined the impact of P2RX7 ablation on autoimmune development in the presence of the gut microbiota SFB. Our data illustrate that contrary to exerting an anti-inflammatory effect, P2RX7 deficiency actually enhances autoimmune arthritis. Interestingly, SFB colonization can negate the difference in disease severity between WT and P2RX7-deficient mice. We further demonstrated that P2RX7 ablation in the absence of SFB caused reduced apoptotic Tfh cells and enhanced the Tfh response, leading to an increase in autoantibody production. It has been shown that activation of TIGIT, a well-known T cell exhaustion marker, up-regulates anti-apoptotic molecules and promotes T cell survival. We demonstrated that the reduced apoptotic phenotype of P2rx7 (-/-) Tfh cells is associated with their increased expression of TIGIT. This suggested that while P2RX7 was regulating the Tfh population by promoting cell death, TIGIT may have been opposing P2RX7 by inhibiting cell death. Together, these results demonstrated that systemic administration of general P2RX7 antagonists may have detrimental effects in autoimmune therapies, especially in Tfh cell-dependent autoimmune diseases, and cell-specific targeting of P2RX7 should be considered in order to achieve efficacy for P2RX7-related therapy.
30971291 Iguratimod represses B cell terminal differentiation linked with the inhibition of PKC/EGR 2019 Apr 11 BACKGROUND: This study aimed to explore the molecular mechanism and clinical relevance of iguratimod in the regulation of human B cell terminal differentiation. METHODS: An in vitro human antibody-secreting cell (ASC) differentiation system was established to test the effect of iguratimod. B cell phenotype and key transcription factors (TFs) relevant to ASC differentiation were analyzed through flow cytometry and qPCR. The COX-2 activity was measured by enzyme immunoassay (EIA). RNA sequencing was used to identify potential targets of iguratimod. We enrolled six treatment-naive rheumatoid arthritis (RA) patients whose blood samples were collected for phenotypic and molecular studies along with 12-week iguratimod monotherapy. RESULTS: Iguratimod inhibited human ASC generation without affecting B cell activation and proliferation. Iguratimod showed only weak COX-2 activity. Gene set enrichment analysis (GSEA) identified that protein kinase C (PKC) pathway was targeted by iguratimod which was confirmed by PKC activity detection. Furthermore, early growth response 1 (EGR1), a target of PKC and a non-redundant TF for ASC differentiation, was found to be the most downregulated gene in iguratimod-treated B cells. Lastly, iguratimod monotherapy decreased peripheral ASCs and was associated with improved disease activity. The expression of major ASC-related TFs, including EGR1, was similarly downregulated in patient blood samples. CONCLUSIONS: Iguratimod inhibits ASC differentiation both in vitro and in RA patients. Our study suggests that PKC/EGR1 axis, rather than COX-2, is critically involved in the inhibitory effect by iguratimod on human ASC differentiation. Iguratimod could have a broader application to treat B cell-related autoimmune diseases in clinics.
30638903 qLessons learned from patients with access to an online self-management enhancing program 2019 Jun OBJECTIVE: This study aims to explain the earlier findings of a Randomized Controlled Trial (RCT), which showed that rheumatoid arthritis (RA) patients did not benefit from an online self-management program. Moreover, less patients than expected used the program. METHODS: As part of an explorative RCT, patients were interviewed to explore their (non) usage of the program. Purposive sampling (n = 21) was used to select patients from four groups of patients (n = 49): 1) non-users; 2) low users; 3) high users basic; 4) high users plus. RESULTS: The program supported only a small group of patients because: 1) not all patients were motivated to use the program, 2) patients had no clear expectation or had differing expectations of the program, 3) there was a mismatch between individual patients' support needs and the needs included in the program, 4) reminders were only sent to fill in the diaries for pain and fatigue, not to use the program modules. CONCLUSION: This study offers insights in the (non-) usage of online programs and how usage could be increased in practice. PRACTICAL IMPLICATIONS: Health professionals should be involved in the implementation of this online programs and should inform patients what the program could bring them.
29688617 Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended-Release Formul 2019 Feb Upadacitinib is a Janus kinase 1 inhibitor under development for the treatment of several inflammatory disorders including rheumatoid arthritis (RA). Upadacitinib was administered in the phase 2 RA trials primarily as twice-daily regimens of an immediate-release (IR) formulation. The upadacitinib extended-release (ER) formulation was developed to enable once-daily dosing. In the present study, upadacitinib pharmacokinetics were characterized after the administration of single and multiple once-daily doses of the ER formulation in healthy subjects relative to single and multiple twice-daily doses of the IR formulation. Increase in upadacitinib exposure was dose-proportional over the evaluated 15- to 30-mg ER dose range. Single 15- and 30-mg ER doses provided equivalent AUC(0-inf) compared with single 12- and 24-mg IR doses, respectively. A high-fat breakfast increased upadacitinib ER C(max) and AUC(0-inf) by only 20% and 17%, respectively, relative to fasting conditions. The median time to peak plasma concentrations was 2 to 4 hours for the ER formulation, and steady state was achieved by day 4 of once-daily dosing. Doses of 15 and 30 mg once daily using the ER formulation provided equivalent AUC(0-24) , comparable C(max) and C(min) , and a fluctuation index over a 24-hour period at steady state similar to 6 and 12 mg twice daily, respectively, using the IR formulation. These results supported the use of upadacitinib 15- and 30-mg doses of the ER formulation in the phase 3 trials in RA.
30194275 Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained di 2019 Feb OBJECTIVES: This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day. METHODS: Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks. RESULTS: Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups. CONCLUSIONS: In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.
31631316 Autoimmune blistering diseases provoked during the treatment of chronic inflammatory disea 2020 May BACKGROUND: To investigate the clinical course of autoimmune blistering diseases (AIBDs) following treatment with biologic agents (BAs) for chronic inflammatory diseases. METHODS: A comprehensive review of available, published literature was performed using PubMed and CINAHL search engines. Diagnostic criteria of AIBD included positive direct immunofluorescence studies and/or positive serology with clinically suggestive features. RESULTS: A total of 22 cases of AIBDs provoked by the use of BAs were found. The most commonly implicated agents were tumor necrosis factor-alpha inhibitors (n = 14). The mean age of onset of AIBD was 59.4 years (median 61.5 years, range 31-82). Average time to onset of AIBD following initiation of the suspected BA was 33.7 ± 43.8 weeks (range 3 days to 152 weeks). Psoriasis was the most common associated condition for which the BA was prescribed (n = 11), followed by rheumatoid arthritis (n = 6) and ulcerative colitis (n = 5). Of the 21 cases reporting AIBD outcome, 17 reported remission or complete resolution upon stopping treatment with the involved BA. Four cases reported continued bullae formation without worsening of disease following cessation of the BA or systemic corticosteroids used to treat the AIBD. Five cases rechallenged the patient with the involved BA and four of the five reported recurrence, often with quicker onset and more severe symptoms. CONCLUSIONS: BAs may be suspected in patients developing AIBD while being treated for chronic inflammatory diseases. A majority of cases resolve upon cessation of the offending agent.
31599600 Mining the Proteome Associated with Rheumatic and Autoimmune Diseases. 2019 Dec 6 A steady increase in the incidence of osteoarthritis and other rheumatic diseases has been observed in recent decades, including autoimmune conditions such as rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, systemic sclerosis, and Sjögren's syndrome. Rheumatic and autoimmune diseases (RADs) are characterized by the inflammation of joints, muscles, or other connective tissues. In addition to often experiencing debilitating mobility and pain, RAD patients are also at a higher risk of suffering comorbidities such as cardiovascular or infectious events. Given the socioeconomic impact of RADs, broad research efforts have been dedicated to these diseases worldwide. In the present work, we applied literature mining platforms to identify "popular" proteins closely related to RADs. The platform is based on publicly available literature. The results not only will enable the systematic prioritization of candidates to perform targeted proteomics studies but also may lead to a greater insight into the key pathogenic processes of these disorders.
31718287 Scientific rationale underpinning the development of biosimilar rituximab in hematologica 2019 Dec Sandoz rituximab (SDZ-RTX; Rixathon(®); GP2013), a rituximab biosimilar, was approved in June 2017 in Europe in all indications of reference rituximab. The stepwise SDZ-RTX development program generated extensive physicochemical, structural, functional, and biological data demonstrating a match with reference rituximab on all clinically relevant attributes. A focused clinical development program followed, in two indications selected for sensitivity to detect potential differences versus reference rituximab: rheumatoid arthritis (pivotal pharmacokinetics and efficacy evaluation) and follicular lymphoma (pivotal efficacy/safety evaluation). These trials demonstrated highly similar pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity profiles. The totality of evidence for biosimilarity for SDZ-RTX, combined with knowledge that B-cell depletion is common to each approved indication, allowed SDZ-RTX approval for use in all indications of reference rituximab.
31257076 Use of calcium channel blockers and myocardial infarction in hypertensive patients with rh 2020 Jan BACKGROUND/PURPOSE: Rheumatoid arthritis (RA) should be regarded as a high risk factor for myocardial infarction (MI). In addition to anti-hypertensive effect, calcium channel blockers (CCBs) were frequently used as anti-angina drugs in patients with MI. However, the association between CCBs and MI in RA remains unclear. We investigated whether CCBs could decrease incidence of myocardial infarction in patients with hypertension and RA. METHODS: We identified patients from the Registry for Catastrophic Illness, a nation-wide database encompassing almost all of the RA patients in Taiwan from 1995 to 2008. The primary endpoint was MI and the median duration of follow up was 3,050 days. Propensity score matching and Cox proportional hazards regression models were used to estimate hazard ratios for MI. RESULTS: Among 27,844 patients with hypertension, 17,317 (61.5%) subjects received CCBs (mean age = 58.8 years, 72.1% female). The incidence of MI significantly decreased in patients treated with CCBs (hazard ratio [HR] 0.560; 95% confidence interval [CI] 0.494-0.634). After propensity match, subjects receiving CCBs had significantly lower risk of MI (HR 0.637, 95% CI 0.549-0.740). The protective effect of CCBs therapy was significantly better in patients taking longer duration. Of note, the effect remained robust in subgroup analyses, including dihydropyridine CCBs (HR 0.550; 95% CI 0.466-0.650) and non-dihydropyridine CCBs (HR 0.674, 95% CI 0.588-0.773). CONCLUSION: Therapy of CCBs is associated with a lower risk of MI among hypertensive patients with RA. Hence, the prescription of CCBs may be a compelling indication of BP lowering in RA population.
30299202 Long-term safety and efficacy of weekly subcutaneous tocilizumab monotherapy in patients w 2019 Sep Objective: To evaluate the long-term safety and efficacy of subcutaneous tocilizumab (TCZ-SC) monotherapy administered weekly (qw) in patients with rheumatoid arthritis who had an inadequate response to TCZ-SC every other week (q2w). Methods: Patients who completed 12 weeks of double-blind treatment with either TCZ-SC q2w monotherapy or TCZ-SC qw monotherapy were switched to or continued to receive open-label treatment with TCZ-SC qw monotherapy for 40 weeks. Safety and efficacy were assessed. Subgroup analyses of Disease Activity Score based on 28 joints using erythrocyte sedimentation rate (DAS28-ESR) were performed at 12 weeks. Results: The incidence of adverse events was 464.4/100 patient-years (PY). The incidence of infection was 121.3/100 PY. The safety profile of TCZ-SC qw monotherapy was consistent with that of prior studies of TCZ. No additional safety concerns were observed. Improvement from baseline in DAS28-ESR was maintained at week 52 in patients who continued TCZ-SC qw and improved in patients who switched from TCZ-SC q2w to qw. At week 12, the efficacy of TCZ-SC qw monotherapy was greater than that of TCZ-SC q2w monotherapy irrespective of weight and BMI subgroups. Conclusion: The long-term weekly dosing of TCZ-SC monotherapy was well tolerated and efficacy was maintained over 52 weeks.
30890897 Are There Any Common Genetic Risk Markers for Rheumatoid Arthritis and Periodontal Disease 2019 BACKGROUND: Several studies suggest that there is a biologically plausible connection between rheumatoid arthritis (RA) and periodontal diseases (PD). Both disorders are characterized as multifactorial diseases potentially sharing common risk factors. Based on the inflammatory nature of RA and PD, the impact of genetic variations of genes of the immune system on both diseases was studied in this study. MATERIALS AND METHODS: We conducted a case-control study (n = 201) comparing 101 RA patients suffering from periodontal disease of different severities (no/mild PD vs. severe PD) with 100 systemically healthy controls without RA and severe PD. The genotype, allele, and haplotype distributions of 22 SNPs of 13 pro- and anti-inflammatory cytokines were assessed applying sequence-specific PCR. RESULTS: Evaluating the impact of cytokine SNPs in RA, we identified the G allele of rs1801275 in IL4Rα (p = 0.043) and the G allele of rs361525 in TNFα (p = 0.005) as disease-associated risk factors in bivariate analyses. In multivariate analyses, these significant associations could not be proven. The A allele of rs2430561 in IFNγ was indicative for severe periodontitis among the patients with rheumatoid arthritis (p = 0.039). Investigating the impact of rs2430561 in IFNγ on comorbidity using binary logistic regression analyses, the A allele was confirmed as an independent risk factor for severe periodontal disease and RA (p = 0.024). CONCLUSIONS: These results emphasize the association of genetic variations in proinflammatory cytokines (TNFα and IFNγ) and cytokine receptor (IL4Rα) and RA and periodontal diseases. In multivariate analyses, the A allele of IFNγ was proven to be a significant marker of RA and PD comorbidities. The study broadens the knowledge about disease-specific differences in genetic composition and provides an improved understanding of a possible association of both diseases.
31706010 Cinnamtannin D1 attenuates autoimmune arthritis by regulating the balance of Th17 and treg 2020 Jan The suppression of the abnormal systemic immune response constitutes a primary strategy for treatment of rheumatoid arthritis (RA); toward this end, the identification of natural compounds with immunosuppressive activity represents a promising strategy for RA drug discovery. Cinnamtannin D1 (CTD-1), a polyphenolic compound isolated from Cinnamomum tamala, was previously reported to possess good immunosuppressive activity. However, the beneficial effect of CTD-1 on RA is currently unknown. The aim of this study was to evaluate the anti-arthritic effect of CTD-1 in collagen-induced arthritis (CIA) mice and clarify the underlying mechanisms. CTD-1 treatment significantly alleviated the severity of CIA mice, affording reduced clinical scores and paw swelling, along with reduced inflammatory cell infiltration and cartilage damage in the joints; in addition, the serum levels of IL-17, IL-6, and IL-1β were decreased whereas those of TGF-β and IL-10 were increased. CTD-1-treated mice exhibited lower frequency of Th17 cells and higher frequency of Treg cells compared to those in untreated mice, indicating that the balance of Th17/Treg cells may serve as the target for CTD-1. Consistent with this, in ex vivo assays, CTD-1 inhibited Th17 cell differentiation through the downregulation of phospho-STAT3/RORγt, whereas it promoted Treg differentiation by upregulating phospho-STAT5/Foxp3 in response to the stimulation of collagen type II. Moreover, in an in vitro naïve CD4(+) T cell differentiation assay, CTD-1 directly inhibited Th17 cell differentiation and promoted Treg differentiation, suggesting that CTD-1 regulated the balance of Th17 and Treg cells to inhibit excessive immune response. Furthermore, the regulation effect of CTD-1 on Th17 and Treg cells was dependent on Ahr expression, as this effect was abolished when Ahr was knocked down and was impaired when Ahr was overexpressed. Together, our results indicated that CTD-1 treatment benefits CIA mice by regulating Th17 and Treg differentiation through the inhibition of AHR expression, and suggested a potential application of CTD-1 toward RA treatment.
31172365 Qualitative assessment of medication adherence in patients with rheumatic diseases on biol 2019 Oct INTRODUCTION/OBJECTIVES: Despite close management in specialized clinics, medication adherence remains a significant problem for some patients. The study aims to explore factors affecting medication adherence in patients attending a biologics clinic. METHOD: Participants completed surveys including the Compliance Questionnaire Rheumatology (CQR) to quantify adherence rates. Purposive sampling targeting poorly adherent patients was used to select individuals for qualitative evaluation. Semi-structured interviews were performed and continued until saturation was achieved. Interviews were transcribed and coded using NVivo. Principles of grounded theory were used for data analysis. RESULTS: A total of 123 patients completed the survey (72 RA, 33 PsA, 18 AS). Of which, 96 patients completed all CQR items, of these 72% were identified as adequately adherent. A major theme which emerged from patient interviews was that the presence of active symptoms significantly influenced adherence. Patients tended not to prioritize medication taking until they had a recurrence of symptoms. Despite describing biologics as "life-changing", patients expressed concern regarding potential long-term side effects of these medications which affected adherence. Patients identified their relationship with their rheumatologist as pivotal and perceived diet, exercise and stress as critical. Intentional factors were the predominant drivers for non-adherence; patients made a risk-benefit analysis based on their beliefs and chose to not take their medications as prescribed. CONCLUSIONS: Medication adherence to traditional and biological therapies was lower than expected by treating clinicians in this patient group, who are closely supported in a dedicated biologics clinic. Several of the identified themes suggest that shared decision making and enhancing patient education may improve adherence in this group. Key Points • Adherence rates are suboptimal even in supported, educated, English-speaking patients in the biologics era. • Contributing factors were 'intentional' as patients chose to be non-adherent based on their beliefs. • Emergent themes suggest that enhancing patient education could improve adherence.
30672499 Macular toxicity after short-term hydroxychloroquine therapy. 2019 Feb We report an unusual case of hydroxychloroquine (HCQ) toxicity after only 2 months of starting the treatment. A 42-year-old woman presented with visual impairment. Her visual acuity was 20/20 in the right eye and 20/25 in the left eye. Ophthalmologic examination revealed a bull's eye pattern in both eyes which was more prominent in the left eye. She had received HCQ therapy (400 mg/day) for 1 month, and had been taking 200 mg/day for 1 month for the treatment of rheumatoid arthritis. HCQ macular toxicity is rarely seen in short-term use, before 5 years, and to our knowledge, there is only one other case reported in the literature.
30171597 Serum Cesium, Rhenium, and Rubidium in Rheumatoid Arthritis Patients. 2019 Jun A considerable attention has been focused on the possible association between ultra-trace elements (UTEs) status and pathogenesis of many diseases including rheumatoid arthritis (RA). UTEs have important roles in numerous metabolic processes. Serum Cs, Rb, and Re levels in RA are not studied previously. The correlation of serum Cs, Rb, and Re levels with the well-known serological parameters, anticyclic citrullinated protein antibody (ACPA), C-reactive protein (CRP), ESR, and rheumatoid factor (RF) is also not studied previously. The present study aimed to measure the level and the correlation between serum UTEs with various blood tests results in RA patients. Serum Cs, Rb, Re, ACPA, CRP, RF, and ESR were measured in Iraqi RA patients who have a positive ACPA (ACPA > 25 U/ml) and compared with healthy individuals. There were significant elevations (p < 0.05) in serum levels of all the measured parameters as compared with those of the healthy control group except Rb and uric acid which have not been changed. Subgrouping of patients according to the results of CRP and RF leads to different results. In the low-CRP group, the high-RF subgroup showed an elevation of ACPA, Cs, and ESR in comparison with the low-RF patients. In the high-CRP group, the patients with high RF showed an increase in the levels of Cs, Rb, ESR, and ACPA. The patient group with high RF and high CRP showed more significant correlations between serum UTEs and serological tests. Serum levels of UTEs were significantly altered in RA patients. The variations in the serum levels of the measured parameters in RA need more investigation to explore the possible association between these UTEs and RA. RA subgroups, according to the results of CRP and CPA, produce more and various information than taking RA as a whole group in the estimation of UTEs.
30243781 Adverse consequences of low-dose methotrexate medication errors: data from French poison c 2019 May OBJECTIVE: The objectives of this study are to carefully describe the context of methotrexate medication errors, to details medical consequences and management approaches, and to determine the rate of fatal outcome. METHODS: Data on methotrexate medication errors were obtained from the French network of poison control and pharmacovigilance centres, which collected and documented reported drug-induced adverse effects. Cases were included if the intake was more than 2-fold the intended weekly dose or a weekly cumulative dose ≥ 30 mg and a follow-up of at least 4 days after the last dose. Data were analysed for demographics, treatment indication, prescribed dose, drug interactions, clinical complications and medical outcomes. RESULTS: Seventy four patients were included. The causes of methotrexate errors resulted from an erroneous prescription renewal (23.3%), incomprehensiveness of the weekly schedule by patients or at-home caregivers (56.2%) and administration of a wrong dose by a health care professional (20.5%). Of the 70 patients who took methotrexate daily, the mean daily dose received over the whole duration of the error was 9.6 ± 4.1 mg (range 2.5-22.5) with a mean duration of the error of 11.7 ± 12.2 days (range 2 to 90). Thirteen (18%) patients remained asymptomatic and 61 (82%) developed complications of which 46 (62.2%) were severe. Nine (14.8%) patients died within 11 to 45 days after the first dosing error. Compared to patients with no or mild symptoms, those with severe symptoms were more likely to be older (75.6 ± 10.8 vs. 69.5 ± 12.9 years) and to be exposed to a higher cumulative dose (94.8 ± 46.2 vs. 68.0 ± 45.7 mg). CONCLUSIONS: This study confirms that dosing errors with methotrexate can be lethal and persisted despite several warnings from drug agencies. Further measures are awaited from the European Medicine Agency.
31646548 MicroRNA-421 promotes inflammatory response of fibroblast-like synoviocytes in rheumatoid 2019 Oct OBJECTIVE: The aim of this study was to investigate whether microRNA-421 could participate in the proliferative, migratory and inflammatory changes of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis by targeting SPRY1. PATIENTS AND METHODS: The expressions of microRNA-421 and SPRY1 in synovial tissues and FLS were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. The binding condition between microRNA-421 and SPRY1 was verified by the Dual-Luciferase reporter gene assay. MicroRNA-421 mimics and inhibitor were constructed and transfected. The levels of extracellular interleukin-1 (IL-1), IL-6, and COX2 in FLS after microRNA-421 mimics or inhibitor transfection were detected by enzyme-linked immunosorbent assay (ELISA). The regulatory effect of microRNA-421 on the proliferation and migration of FLS was detected using cell counting kit-8 (CCK-8) and transwell assay, respectively. Furthermore, collagen-induced RA mouse model was constructed to confirm the specific effect of microRNA-421 on regulating RA development. RESULTS: MicroRNA-421 was highly expressed in the synovial tissues of RA patients. SPRY1 expression in FLS was negatively regulated by microRNA-421. Moreover, the overexpression of microRNA-421 significantly promoted proliferative, invasive potentials and inflammatory response of FLS. In vivo, RA mouse model indicated that downregulated microRNA-421 and upregulated SPRY1 were observed in mice injected with cortisone and microRNA-421 inhibitor when compared with those of controls. CONCLUSIONS: MicroRNA-421 promotes the inflammatory response of fibroblast-like synoviocytes in rheumatoid arthritis by downregulating the SPRY1 expression.
30666350 Persistence and treatment-free interval in patients being prescribed biological drugs in r 2019 May AIMS: The goal of this study was to analyze persistence and the treatment-free interval in patients being prescribed biological drugs in rheumatology practices in Germany. METHODS: Patients who received a first prescription of biological drugs between 2008 and 2016 in 21 rheumatologists in Germany were included in this study (index date). The main outcome was the rate of persistence with biological drugs as a function of the duration of the treatment-free interval used to define discontinuation. The secondary outcomes were the duration of the treatment-free interval, the probability of restarting therapy, and their respective association with age, gender, and diagnosis (i.e., rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis). RESULTS: A total of 4925 patients were included in this study. After 5 years of follow-up, the rate of persistence was 32.6%, 51.1%, and 65.7% if discontinuation was defined as a gap of 90, 180, and 360 days respectively. The majority of patients restarted therapy between 91 and 180 days after the discontinuation date. Advanced age was associated with a decreased probability of restarting biological therapy after a treatment-free interval of at least 91 days, with odds ratios ranging from 0.34 in people aged 61-70 years to 0.66 in those aged 31-40 years (reference value: ≤ 30 years). Finally, patients over 70 and those suffering from ankylosing spondylitis had shorter treatment-free intervals compared to those 30 years or younger (adjusted difference of - 117 days) and those suffering from rheumatoid arthritis (- 48 days) respectively. CONCLUSION: Persistence varied widely depending on the definition of discontinuation, with the majority of nonpersistent patients restarting biological therapy shortly after discontinuation.
31312989 Cytokines (IL-15, IL-21, and IFN-γ) in rheumatoid arthritis: association with positivity 2019 Nov INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial membrane damage and autoantibody production. RA is a heterogeneous disease, where cytokines such as IL-15, IL-21, and IFN-γ have been associated. However, their association with the autoantibodies has not been clearly described. The aim of this study was to evaluate the relationship between the cytokines IL-15, IL-21, and IFN-γ with the autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) in RA and disease activity. METHODOLOGY: This study included 153 RA patients and 80 control subjects (CS). The levels of IL-15, IL-21, IFN-γ, anti-CCP, anti-MCV, and anti-PADI4 were quantified by ELISA, whereas RF was quantified by turbidimetry. The disease activity was evaluated by the indices disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), clinical disease activity index (CDAI), and simple disease activity index (SDAI). RESULTS: The serum levels of IL-15, IL-21, and IFN-γ, and autoantibodies were increased in RA patients, compared with CS (p < 0.05). A correlation was found between IL-21 and anti-CCP and anti-MCV (p < 0.05). According to RA evolution, RF, anti-CCP, and anti-MCV had higher levels in early RA. In addition, increased levels of IL-21 were observed in RA seropositive patients (RF/anti-CCP/anti-MCV). The higher levels of both cytokines and autoantibodies were observed in moderate activity, evaluated by the three indices. CONCLUSIONS: Our results suggest that the increased soluble levels of IL-15, IL-21, and IFN-γ are involved in the inflammatory network in RA. However, IL-21 serum levels are associated with higher titers of autoantibodies (RF, anti-CCP, and anti-MCV) and IL-15 with moderate activity. Key Points • IL-15, IL-21, and IFN-y are associated with the immunopathology of RA, but not significantly with the evolution of the disease. • RF, anti-CCP, and anti-MCV had higher levels in early than established RA. • IL-21 has an association with RF, anti-CCP, and anti-MCVand, for this reason, could be proposed as a disease biomarker. • Patients with activity moderate of disease showed higher levels of RF, anti-CCP, anti-MCV, and IL-15.
31249276 Predictors and causes of first-line biologic agent discontinuation in rheumatoid arthritis 2019 Jan OBJECTIVES: To assess the discontinuation of first-line biological treatment and to evaluate the reasons and predictors thereof in patients with rheumatoid arthritis (RA) from daily clinical practice. METHODS: RA patients registered in the Rheumatic Diseases Portuguese Register (Reuma.pt) starting treatment with biologic DMARDs (bDMARDs) were included in this prospective observational study. The main outcome was the time to discontinuation (in years) due to any cause. Discontinuation was defined as a 90-day discontinuation of treatment or the occurrence of any switch to another bDMARD during follow-up. Baseline and time-varying sociodemographic and clinical characteristics were tested as possible predictors of discontinuation using multivariable Cox models. RESULTS: Of the 1,851 RA patients included in the study, 871 (47%) discontinued their first bDMARD. The median overall persistence of the first bDMARD was 5.5 years and the leading cause of discontinuation was inefficacy [N=476 (55%)], followed by adverse events [N=262 (30%)], other causes [N=69, (8%)] and unknown causes [N=64 (7%)]. Patients with a higher HAQ score (more disability) at baseline were more likely to discontinue their first bDMARD [hazard ratio (HR):1.39 (95% CI: 1.17-1.64)], as were patients with a higher number of comorbidities [HR: 1.17 (1.05-1.29)] and patients starting treatment from 2007 onwards [HR:1.89 (1.5-2.38)]. On the contrary, receiving TNFi bDMARD [HR:0.74 (0.57-0.94)] as opposed to non-TNFi was associated with less discontinuation. Expectedly, the higher the DAS28 during follow-up the higher the likelihood to discontinue bDMARD [HR:1.08 (1.06-1.1)]. No other time-varying predictor was found. CONCLUSION: In the Portuguese RA population, maintenance of first-line bDMARD was shown to be relatively high. Inefficacy was the leading cause of discontinuation. Features found to predict drug discontinuation (e.g. baseline disability) may contribute to inform clinician's decisions in clinical practice.