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ID PMID Title PublicationDate abstract
28549945 Validity of the rheumatoid arthritis impact of disease (RAID) score and definition of cut- 2018 May OBJECTIVES: To assess the validity of the rheumatoid arthritis impact of disease (RAID) for measuring disease activity of rheumatoid arthritis (RA) and to determine cut-off values for defining the disease activity states. METHODS: A total of 622 RA patients from an European database have been included. Cross-validation was based on assessment of convergent and discriminant validity. Optimal cut-offs were determined against external criteria by calculating the respective 25th and 75th percentiles mean values of RAID. External criteria included definitions for remission (REM), low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA), cut-offs of the 28-joint disease activity score-C-reactive protein (DAS28-CRP) score. RESULTS: The RAID showed a moderate degree of correlation with respect to DAS28-CRP (rho=0.417; P<0.0001). The receiver operating characteristic (ROC) curves to discriminate the ability of RAID to distinguish patients with active and non-active disease was very good with an area under the curve (AUC) of 0.847 (95% confidence interval [CI]: 0.816 to 0.878; P<0.0001). Based on the distributions of RAID in the different disease activity groups, we propose the following cut-off values for REM: RAID ≤3; for LDA: RAID >3 and ≤4; for MDA: RAID >4 and ≤6; for HDA: RAID >6. Mean RAID differed significantly between patients classified as REM, LDA, MDA or HDA (P=0.001). CONCLUSIONS: The cut-offs revealed good measurement characteristics in cross-validation analysis, had great discriminatory performance in distinguishing patients with different levels of disease activity and are suited for widespread use in everyday practice application and research.
30025962 Serum retinol-binding protein 4 is associated with insulin resistance in patients with ear 2019 May OBJECTIVE: Retinol-binding protein 4 (RBP4), systemic inflammation and insulin resistance (IR) are linked, yet the determinants of RBP4 and its impact on IR in rheumatoid arthritis (RA) are incompletely understood. The aim of this study was to explore the prevalence of IR in RA and investigate whether the serum levels of RBP4 were associated with IR in patients with RA. METHODS: In this study, 403 individuals with newly diagnosed and untreated RA were consecutively recruited. We calculated the Disease Activity Score assessed using 28-joint counts for swelling and tenderness (DAS28). Levels of serum RBP4, interleukin-6 (IL-6) and tumor necrosis factor (TNF) α were tested. IR was defined as Homeostasis model assessment for insulin resistance (HOMA-IR) index greater than or equal 2.40. RESULTS: In those 403 patients, 68 (16.9%) were male and the median age was 43 years (IQR: 36-52). There was an evidently positive correlation between increased serum levels of RBP4 and increasing severity of RA (DAS28) (r = 0.403, P < 0.001). Furthermore, a modest positive correlation between levels of serum RBP4 and HOMA-IR score (r = 0.251; P < 0.0001) was found. Eighty-five patients (21.1%) in patients with RA were defined as IR (HOMA-IR ≥ 2.40), which was significantly higher than in normal cases (4.7%). In the patients with IR, serum levels of RBP4 were higher when compared with those in patients free-IR P < 0.001. The IR distribution across the quartiles of RBP4 ranged between 5.0% (first quartile) to 39.0% (fourth quartile), P for trend < 0.001. For each 1unit increase of RBP4, the unadjusted and adjusted risk of IR increased by 8% (OR: 1.08; 95% CI: 1.05-1.11, P < 0.001) and 5% (1.05; 1.02-1.09, P = 0.001), respectively. When RBP4 was added to the model containing established significant risk factors, AUROC (standard error) was increased from 0.768 (0.025) to 0.807(0.021). A significant difference in the AUC between the established risk factors alone and the addition of RBP4 was observed (difference, 0.039[0.004]; P = 0.02). CONCLUSION: Elevated serum levels of RBP4 were associated with increased risk of IR and might be useful in identifying RA at risk for IR and/or impaired glucose tolerance for early prevention strategies, especially in obese and women patients.
29245125 Delayed-type hypersensitivity to metals in connective tissue diseases and fibromyalgia. 2018 Feb Rheumatic diseases include a group of autoimmune disorders with environmental and genetic etiology that are characterized as a subgroup of connective tissue diseases (CTD). Rheumatoid arthritis (RA) often involves the small joints of the hands in a symmetrical fashion that can lead to loss of joint function, and RA, as well as Sjögren's syndrome (SS) and other rheumatic diseases, are often accompanied by sensitivity to metals. Numerous investigations on metal sensitivity were evaluated in this review. A detailed metal exposure history was collected by different evaluation of studies. In all subjects, the main source of metal exposure was nickel, mercury, gold, palladium, titanium, and chromium. All of SLE (systemic lupus erythematosus), RA and SS patients appeared to have an increased frequency of metal delayed-type hypersensitivity (DTH) (Type IV allergy). As dental restorative materials release minor amounts of their metals (including mercury, gold, and nickel), many adults are commonly exposed to these metal ions by vapor or corrosion into saliva. Metal-related DTH in these patients will induce an inflammatory response. Such inflammations are important factors in CTD progress. It is hypothesized that metal-specific T cell reactivity can act as an etiological agent in the propagation and chronification of rheumatic inflammation. The key responses of metal delayed-type hypersensitivity in autoimmunity are precipitating as an appealing challenge for further investigations.
30352835 MiR-199a-3p inhibits proliferation and induces apoptosis in rheumatoid arthritis fibroblas 2018 Dec 21 Background Fibroblast-like synoviocytes (FLSs) that line the intimal synovium play a crucial role in the pathogenesis of rheumatoid arthritis (RA). miR-199a-3p is a highly conserved miRNA that has been shown to regulate a variety of growth behaviors in diverse cell types. However, the role of miR-199a-3p in RA-FLS is still unknown. Methods Here, we presented the first experimental evidence showing that miR-199a-3p was a critical regulator of RA-FLS function. Results miR-199a-3p expression was significantly reduced in RA-FLS compared with normal FLS. Ectopic expression of miR-199a-3p significantly inhibited RA-FLS proliferation and induced apoptosis, which was demonstrated by an increase in caspase-3 activity and Bax/Bcl-2 ratio. Our bioinformatics analysis identified Retinoblastoma 1 (RB1) gene to be a direct target of miR-199a-3p. In RA-FLS, miR-199a-3p directly targetted the 3'-UTR of RB1 mRNA and suppressed endogenous RB1 expression, whereas miR-199a-3p-resistant variant of RB1 was not affected. Silencing RB1 decreased cell proliferation and promoted apoptosis in RA-FLS, an effect comparable with miR-199a-3p overexpression. Enforced expression of RB1 partially restored cell proliferation and attenuated apoptosis in miR-199a-3p-overexpressing RA-FLSs. Conclusion In summary, miR-199a-3p is down-regulated in RA-FLS, and miR-199a-3p inhibits proliferation and induces apoptosis in RA-FLS, partially via targetting RB1. The miR-199a-3p/RB1 pathway may represent a new therapeutic target for RA.
30402834 CCL3 participates in the development of rheumatoid arthritis by activating AKT. 2018 Oct OBJECTIVE: To investigate whether CC chemokine 3 (CCL3) could exert a certain effect on rheumatoid arthritis (RA) by regulating inflammatory responses and provide a new direction for the treatment of RA. PATIENTS AND METHODS: Totally 47 RA patients (10 males and 37 females) with complete clinical data were included. Meanwhile, 27 healthy volunteers with same age and gender were recruited as healthy controls. The mRNA and protein level of CCL3 in the peripheral blood mononuclear cells (PBMCs) of RA patients and normal controls were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot, respectively. The inflammatory infiltration of synovial tissue was observed by hematoxylin and eosin (HE) staining. Immune fluorescence was used to further analyze the level of CCL3 in T and B cells of synovial tissue in RA patients. Simultaneously, real-time flow cytometry was applied to detect the level of CCL3 in T and B cells of PBMCs in the normal control group and the RA group. Western blot was used to detect the level of pAKT in RA-FLS treated with different concentrations of recombinant human CCL3. Besides, enzyme-linked immunosorbent assay (ELISA) was applied to detect the levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and receptor activator of nuclear factor kappa-B ligand (RANKL) in the culture supernatant of RA-FLS stimulated by different doses of recombinant human CCL3. RESULTS: The level of CCL3 in peripheral blood and synovial fluid of RA patients was markedly higher than that of normal controls. Inflammatory cells were infiltrated in synovial tissue of RA patients. Meanwhile, CCL3 was mainly expressed in CD4+ T cells. CCL3 treatment in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) could activate the PI3K/AKT signaling pathway to different degrees and increase the expression of cytokines including interleukin-6 (IL-6), IL-1β, TNF-α, and RANKL. These results indicated that CCL3 might participate in the progression of RA by activating AKT. CONCLUSIONS: We showed that CCL3 enhanced the expression level of pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, and RANKL by activating the PI3K/AKT signaling pathway. Besides, CCL3 could up-regulate CD4+T cells to mediate the inflammatory response of RA. These findings might provide new directions for the prevention of RA.
29574517 Impact of switching oral bisphosphonates to denosumab or daily teriparatide on the progres 2018 Jul In biologic-naïve female RA patients, switching oral BPs to DMAb significantly reduced radiographic joint destruction compared to continuing oral BPs or switching to TPTD at 12 months, which were significantly associated with a decrease of a bone resorption marker at 6 months. INTRODUCTION: The aim of this study was to clarify the effects of switching oral bisphosphonates (BPs) to denosumab (DMAb) or daily teriparatide (TPTD) on the progression of radiographic joint destruction in patients with biologic-naïve rheumatoid arthritis (RA). METHODS: A retrospective, case-controlled study involving 90 female RA patients (mean age 68.2 years, 96.7% postmenopausal, disease activity score assessing 28 joints with CRP (DAS28-CRP) 2.4, methotrexate treatment 81.1%, prednisolone treatment 68.9%, and prior BP treatment 44.8 months), who were allocated depending on each patient's and physician's wishes, to (1) the BP-continue group (n = 30), (2) the switch-to-DMAb group (n = 30), or (3) the switch-to-TPTD group (n = 30), was conducted. Patients were retrospectively selected to minimize the difference of possible clinical backgrounds that may affect the joint destruction of RA. The primary endpoint was to clarify the change of the modified total Sharp score (mTSS) from baseline to 12 months. RESULTS: After 12 months, the mean changes of the modified Sharp erosion score were significantly lower in the switch-to-DMAb group (0.2 ± 0.1; mean ± standard error) than in the switch-to-TPTD group (1.3 ± 0.5; P < 0.05), and mTSS was significantly lower in the switch-to-DMAb group (0.3 ± 0.2) than in the BP-continue group (1.0 ± 0.3; P < 0.05) and the switch-to-TPTD group (1.7 ± 0.6; P < 0.05). The logistic regression analysis showed that mTSS changes were significantly associated with the percent changes of TRACP-5b at 6 months (β = 0.30, 95% CI = 0.002-0.016; P < 0.01). CONCLUSIONS: Changes of systemic bone turnover induced by switching BPs to DMAb or TPTD may affect not only systemic bone mass, but also local joint destruction, and its clinical relevance should be considered comprehensively.
29869112 Disease activity and biologic use in patients with psoriatic arthritis or rheumatoid arthr 2018 Aug To compare disease burden and biologic use among psoriatic arthritis (PsA) or rheumatoid arthritis (RA) patients recruited to the Corrona registry. Retrospective study of patients with PsA or RA enrolled in Corrona between January 2002 and March 2013 and grouped in 2-year intervals. Clinical outcomes and biologic use were assessed. Biologic use increased over time in both cohorts, with 62 and 52% of patients with PsA and RA, respectively, receiving biologics by 2012-2013. However, 25 and 35% of patients with PsA and RA, respectively, continued to experience moderate/high disease activity. Overall, the progressive increase in biologic use accompanied progressive decreases in Clinical Disease Activity Index (from 14.2 to 10.4 for RA, and 12.4 to 8.1 for PsA) and mean Health Assessment Questionnaire score (from 0.36 to 0.34, and 0.3 to 0.24). Mean patient pain, the proportion of patients reporting morning stiffness, and the mean duration of morning stiffness remained similar for both cohorts. PsA and RA treated in the rheumatology setting had a comparable impact on patient quality of life and functional ability. Disease burden improved with increased biologic utilization in both groups; however, moderate/severe disease remains in a significant proportion of PsA and RA patients.
30574665 Microparticles and autophagy: a new frontier in the understanding of atherosclerosis in rh 2018 Dec Microparticles (MPs) are small membrane vesicles released by many cell types under physiological and pathological conditions. In the last years, these particles were considered as inert cell debris, but recently many studies have demonstrated they could have a role in intercellular communication. Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, and autoimmune diseases, such as rheumatoid arthritis (RA). RA is an autoimmune systemic inflammatory disease characterized by chronic synovial inflammation, resulting in cartilage and bone damage with accelerated atherosclerosis increasing mortality. According to the literature data, also MPs could have a role in endothelial dysfunction, contributing to atherosclerosis in RA patients. Moreover many researchers have shown that a dysregulated autophagy seems to be involved in endothelial dysfunction. Autophagy is a reparative process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. It has been shown in many works that basal autophagy is essential to proper vascular function. Taking into account these considerations, we hypothesized that in RA patients MPs could contribute to atherosclerosis process by dysregulation of endothelial autophagy process.
29921541 Dietary Long-Chain n-3 Fatty Acid Intake and Arthritis Risk in the Women's Health Initiati 2018 Nov BACKGROUND: The prevalence of arthritis in the United States is substantial and on the rise. Long-chain n-3 polyunsaturated fatty acids, which have anti-inflammatory properties, have been shown to provide therapeutic benefit to arthritis patients; however, to date few have examined these associations with arthritis risk. OBJECTIVE: The study objective was to examine the associations of long-chain n-3 polyunsaturated fatty acids intake with osteoarthritis (OA) and rheumatoid arthritis (RA) risk among postmenopausal women. DESIGN: This was a prospective cohort study. PARTICIPANTS: The sample for this analysis consisted of 80,551 postmenopausal women, aged 55 to 79 years and with no history of arthritis, recruited into the Women's Health Initiative Observational Study and Clinical Trials cohort between 1993 and 1998. Women completed a 120-item food frequency questionnaire at baseline. MAIN OUTCOME MEASURES: After a median follow-up of 8 years, 22,306 incident OA and 3,348 RA cases were identified. STATISTICAL ANALYSES PERFORMED: Adjusted Cox regression models were used to estimate hazard ratios and 95% CI for the associations between dietary LCn-3PUFA intake and OA and RA risk. RESULTS: Individual and total long-chain n-3 polyunsaturated fatty acids (Quintile 5 vs Quintile 1: hazard ratio 1.04, 95% CI 0.99 to 1.09 for OA; hazard ratio 1.01, 95% CI 0.90 to 1.13 for RA) were not associated with OA and RA risk. Further, no associations were observed between n-6 polyunsaturated fatty acids intake and either arthritis outcome. CONCLUSIONS: This study is the first to examine associations of long-chain n-3 polyunsaturated fatty acids intake with OA risk and the largest to examine associations with RA risk. Despite their therapeutic potential, the study provides no evidence of benefit of these nutrients in relation to arthritis risk.
30174672 The Natural Agonist of Estrogen Receptor β Silibinin Plays an Immunosuppressive Role Repr 2018 Estrogens, in particular 17β-estradiol (E2), have a strong influence on the immune system and also affect pathological conditions such as autoimmune diseases. The biological effects of E2 are mediated by two intracellular receptors, i.e., estrogen receptor (ER)α and ERβ, which function as ligand-activated nuclear transcription factors producing genomic effects. Immune cells express both ERα and ERβ that play a complex role in modulating inflammation. Phytoestrogens display estrogen-like effects. Among them, silibinin, the major active constituent of silymarin extracted by the milk thistle (Silybum marianum), has been suggested to have an ERβ selective binding. Silibinin is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects; however, the role of silibinin in modulating human immune responses and its impact on autoimmunity remains unclear. Aim of this study was to dissect the ability of the ERβ natural ligand silibinin to modulate T cell immunity, taking into account possible differences between females and males, and to define its possible role as therapeutic tool in immune-mediated diseases. To this purpose, female and age-matched male healthy subjects and patients with active rheumatoid arthritis (RA) were recruited. We evaluated the ability of silibinin to modulate ERβ expression in T lymphocytes and its effects on T cell functions (i.e., apoptosis, proliferation, and cytokine production). We also analyzed whether silibinin was able to modulate the expression of microRNA-155 (miR-155), which strongly contributes to the pathogenesis of RA driving aberrant activation of the immune system. We demonstrated that silibinin upregulated ERβ expression, induced apoptosis, inhibited proliferation, and reduced expression of the pro-inflammatory cytokines IL-17 and TNF-α, through ERβ binding, in T lymphocytes from female and male healthy donors. We obtained similar results in T lymphocytes from patients with active RA in term of apoptosis, proliferation, and cytokine production. In addition, we found that silibinin acted as an epigenetic modifier, down-modulating the expression of miR-155. In conclusion, our data demonstrated an immunosuppressive role of silibinin, supporting its application in the treatment of autoimmune diseases as drug, but also as dietary nutritional supplement, opening new perspective in the field of autoimmune disease management.
30369612 Sacral Stress Fracture Complicated by L5 Radiculopathy in a Patient with Rheumatoid Arthri 2018 Oct A 60-year-old Japanese woman with severe osteoporosis presented with a history of right buttock pain and right lateral lower leg pain in an L5 distribution. She had been treated with methotrexate and methylprednisolone for rheumatoid arthritis (RA) and interstitial pneumonia. Computed tomography demonstrated a sacral stress fracture in the right sacral ala. The right L5 nerve root was compressed by the fracture site. This case is rare in that L5 radiculopathy was complicated by a sacral stress fracture. Clinicians should suspect sacral stress fractures when RA or osteoporosis is present in women who experiences lumbar pain and lumbar radiculopathy.
29264628 [Perioperative handling of immunosuppressive therapy]. 2018 Feb Every year 16 million operations are performed in Germany. Many patients have an autoimmune disorder, for example rheumatoid arthritis, psoriasis or chronic inflammatory bowel disease, which requires treatment. Immunosuppressants are widely applied. Physicians must make a risk-adapted decision whether the immunosuppressant medication can be continued perioperatively or if certain drugs must be paused and if so, with what risks. The handling of immunosuppressants during the perioperative period is very relevant as many patients, for example with rheumatoid arthritis are in need of a hip or knee replacement or patients with inflammatory bowel disease need an operation due to the chronic illness. The interruption of an immunosuppressant therapy should be discussed in an interdisciplinary board according to the underlying disease, because the continuation of immunosuppressants perioperatively can lead to an increased rate of complications, especially wound healing disorders. If a patient is on a glucocorticoid therapy the following must be considered: during the perioperative period the body has an increased demand for glucocorticoids due to the stress reaction. If glucocorticoids are administered in a dosage of more than 7.5 mg/day equivalent of prednisolone this stress reaction is inhibited. Thus, in these cases a perioperative substitution with hydrocortisone is recommended.
30293331 [Chinese expert-based consensus for methotrexate in rheumatic diseases]. 2018 Oct 1 To establish the experts consensus on the use of methotrexate in the treatment of rheumatic diseases. A consensus development panel was established. The panel of consensus was composed of 45 experts in rheumatology from the group of Chinese Association of Rheumatology and Immunology Physicians. The consensus development panel developed 7 recommendations, including the clinical status and application principles of methotrexate in the treatment of rheumatoid arthritis, optimal dosage and route, dosage adjustment, monitoring, long-term safety and management in the perioperative period and before/during pregnancy. This consensus was intended to standardize the use of methotrexate in rheumatic diseases and improve the management of rheumatoid arthritis and other rheumatic diseases.
29897007 An Economic Evaluation of Tofacitinib Treatment in Rheumatoid Arthritis After Methotrexate 2018 Oct BACKGROUND: Treatment cycling with biologic disease-modifying anti-rheumatic drugs, such as tumor necrosis factor inhibitors (TNFi), is common among patients with rheumatoid arthritis (RA) and can result in reduced clinical efficacy and increased economic burden. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. OBJECTIVE: To evaluate and compare the economic effect of tofacitinib 5 mg twice daily (BID) treatment directly after methotrexate (MTX) in the MTX-inadequate responder population, or after MTX and 1 TNFi (adalimumab [ADA] or etanercept [ETN]) or 2 TNFi (ADA and ETN) in TNF-inadequate responder patients with RA, from a U.S. payer perspective. METHODS: A decision-tree economic model was used to evaluate costs over 2 years. Treatment response was modeled as American College of Rheumatology (ACR) 20/50/70 response. ACR response rates at 6-month intervals were derived from U.S. prescribing information for monotherapy and combination therapy. Safety event rates were sourced from a meta-analysis. It was assumed that 75% of patients switched therapy after an adverse event or lack of response. Cost inputs included drugs, monitoring and administration (including physician visits), health care utilization, and treatment for adverse events. The population comprised all organization members (i.e., RA and non-RA members); RA patients receiving TNFi were estimated using epidemiologic data. Results were based on an organization size of 1 million. Economic endpoints were total 2-year costs, costs per member per month (PMPM), and costs per ACR20/50 responder. RESULTS: 1,321 patients were included for analysis. Based on ACR20 switch criteria and either 100% or 50% monotherapy rates for all treatments, total 2-year costs and costs PMPM were lower for patients receiving tofacitinib as second-line therapy after MTX and as third-line therapy after MTX and 1 TNFi; costs were highest for patients who cycled through 2 TNFi. Similar trends were observed for switch criteria based on ACR50 response and addition of 20% rebates for ADA and ETN and 0% for tofacitinib, although differences were mitigated slightly. CONCLUSIONS: A treatment strategy with tofacitinib as either second- or third-line therapy after MTX may be a lower cost treatment option, compared with fourth-line introduction of tofacitinib after cycling through 2 TNFi following MTX. DISCLOSURES: All aspects of this study were funded by Pfizer. Claxton was an employee of York Health Economics Consortium, University of York, at the time of this study. Taylor is an employee of York Health Economics Consortium, The University of York, which received funding from Pfizer to conduct this study. Soonasra, Bourret, and Gerber are employees of Pfizer and hold stock/stock options in Pfizer. A previous iteration of the data reported in this manuscript (before adjustment for recent drug price increases) was presented at the Academy of Managed Care Pharmacy 28th Annual Meeting and Expo; April 19-22, 2016; held in San Francisco, CA.
29226569 Children Born by Women With Rheumatoid Arthritis and Increased Susceptibility for Chronic 2018 Aug OBJECTIVE: Fetal exposure to maternal rheumatoid arthritis (RA) might impact the long-term risk of disease in the offspring. We examined a possible association between maternal RA and 15 selected groups of chronic diseases in the offspring. METHODS: This nationwide cohort study was based on the Danish health registries and included data on all children born alive in Denmark between January 1, 1989 and December 31, 2013. The cohort comprised 2,106 children born by women with RA (exposed), and 1,378,539 children born by women without RA (unexposed). Cox proportional hazards regression models were used, taking a large range of confounders into consideration, and the hazard ratios (HRs) of child and adolescent diseases were calculated. RESULTS: In children exposed to maternal RA in utero, the HR of thyroid diseases was 2.19 (95% confidence interval [95% CI] 1.14-4.21), epilepsy 1.61 (95% CI 1.16-2.25), and RA 2.89 (95% CI 2.06-4.05). The HRs for anxiety and personality disorders and chronic lung disease including asthma were in the range of 1.15-1.16, but these were not statistically significant associations. CONCLUSION: Our results suggest that in utero exposure to maternal RA is associated with an increased risk of thyroid disease and epilepsy in childhood and adolescence, and in particular an increased risk of RA, compared to children born to mothers without RA. These important findings should encourage pediatricians and general practitioners to have an increased awareness of certain chronic diseases in children exposed to RA in utero.
29796906 Anti-cytokine therapy and plasma DNA in patients with rheumatoid arthritis. 2018 Aug BACKGROUND: Extracellular DNA (ecDNA) is increased in inflammation and it also induces inflammation. In patients with rheumatoid arthritis (RA), plasma ecDNA is higher than in healthy controls. Due to low specificity, it cannot be used for screening, but it might be useful for monitoring and prognosis of therapy success. The effect of treatment with biological disease-modifying antirheumatic drugs (bDMARDs) on plasma ecDNA in RA patients with regards to its subcellular origin has not been analyzed yet. The aim of this study was to describe the effects of bDMARDs on plasma ecDNA and its nuclear (nDNA) and mitochondrial (mtDNA) fractions in patients with RA. METHODS: Plasma samples of 32 patients with RA were collected before, as well as 3 and 6 months after starting the treatment with bDMARDs. Total plasma ecDNA was quantified fluorometrically. The subcellular origin of ecDNA was assessed using real time PCR. Treatment success was monitored using DAS28 and C-reactive protein (CRP). RESULTS: The clinical status of patients improved. Both DAS28 and CRP decreased by 52 and 73% after 3 months of treatment. Plasma ecDNA decreased significantly only after 6 months (by 26%). Real-time PCR showed that both, nDNA and mtDNA decreased by 63 and by 45% after 6 months. CONCLUSION: Treatment with bDMARDs decreases plasma ecDNA of both nuclear and mitochondrial origin. Dynamics of ecDNA is slower than dynamics of standard clinical markers. Therefore, it is likely to be not useful for monitoring of the disease progress, at least for RA.
29781231 Triple Positivity for Anti-Citrullinated Protein Autoantibodies, Rheumatoid Factor, and An 2018 Nov OBJECTIVE: In rheumatoid arthritis (RA), anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) are commonly used to aid in the diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPAs and RF alone. In addition, anti-carbamylated protein (anti-CarP) antibodies have diagnostic and prognostic value, since their presence is associated with joint damage in RA patients and also associated with the future development of RA in patients with arthralgia. Therefore, the aim of the present study was to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA. METHODS: A literature search resulted in identification of 12 relevant studies, consisting of RA patients, pre-RA individuals, disease controls, healthy first-degree relatives of RA patients, and healthy control subjects, in which data on RF, ACPAs, and anti-CarP antibody status were available. Using these data, random effects meta-analyses were carried out for several antibody combinations. RESULTS: The individual antibodies were highly prevalent in patients with RA (34-80%) compared to the control groups, but were also present in non-RA controls (0-23%). For the classification of most subjects correctly as having RA or as a non-RA control, the combination of ACPAs and/or RF often performed well (specificity 65-100%, sensitivity 59-88%). However, triple positivity for ACPAs, RF, and anti-CarP antibodies resulted in a higher specificity for RA (98-100%), accompanied by a lower sensitivity (11-39%). CONCLUSION: As the rheumatology field is moving toward very early identification of RA and possible screening for individuals at maximum risk of RA in populations with a low pretest probability, an autoantibody profile of triple positivity for ACPAs, RF, and anti-CarP provides interesting information that might help identify individuals at risk of developing RA.
28970207 Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in pati 2018 Jan OBJECTIVES: To determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis. METHODS: In 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients not in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years. RESULTS: After 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p<0.001) achieved SDFR.Overall, mean Health Assessment Questionnaire was 0.6 (0.5), and median (IQR) damage progression was 0.5 (0-2.7) Sharp/van der Heijde points, with only five patients showing progression >25 points in 5 years. CONCLUSIONS: Five years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.
30066874 MicroRNA‑143‑3p contributes to the regulation of pain responses in collagen‑induced 2018 Sep Patients with rheumatoid arthritis (RA) suffer from pain, which is associated with inflammation, peripheral and central pain processing, and joint structure damage. The aim of the present study was to investigate a key microRNA (miR) and its target genes that are involved in the pain responses of RA, and to clarify the mechanism of pain regulation. Collagen‑induced arthritis (CIA) was induced in DBA/1 and C57BL/6 mice. The paw swelling, mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), and expression levels of tumor necrosis factor (TNF)‑α and prostaglandin (PG)E2 in the sera were investigated. Decreased MWT and TWL, and increased TNF‑α and PGE2, in the CIA model group were observed in DBA/1 and C57BL/6 mice. DBA/1 mice exhibited greater hyperalgesia and higher levels of inflammatory mediators. miR‑143‑3p expression in the blood and the dorsal root ganglion (DRG) were detected, and low miR‑143‑3p expression was demonstrated in the blood and DRG tissue of CIA mice. The target genes of miR‑143 were predicted and analyzed. A total of 1,305 genes were predicted and 55 pain‑associated genes were obtained. Prostaglandin‑endoperoxide synthase 2 (Ptgs2), MAS related GPR family member E (Mrgpre), prostaglandin D2 receptor and Tnf were selected as target genes of miR‑143. DRG cells were cultured and transfected with miR‑143‑3p inhibitor or mimic. The expression of Mrgpre, Ptgs2 and Tnf was significantly inhibited following miR‑143‑3p mimic transfection, while the expression of Mrgpre, Ptgs2 and Tnf was increased following inhibitor transfection. Additionally, the expression of pain‑associated genes in the DRG of mice was investigated and the expression of Ptgs2, Mrgpre and Tnf in the DRG of CIA mice was also significantly upregulated. These results revealed that CIA mice exhibited marked hyperalgesia and high levels of inflammatory pain mediators. Low expression of miR‑143‑3p negatively regulated the pain‑associated target genes, including Mrgpre, Ptgs2 and Tnf, thereby affecting chronic inflammatory pain and neuropathic pain in RA.
30293155 Discordance of global assessment by patients and physicians is higher in osteoarthritis th 2018 Nov The study compares patient-physician discordance in global assessment in patients with osteoarthritis (OA) versus patients with rheumatoid arthritis (RA) seen in routine care. This is a cross-sectional study conducted at an academic rheumatology center at which all patients are asked to complete a Multi-Dimensional Health Assessment Questionnaire (MDHAQ), which includes a patient global assessment (PATGL). Rheumatologists are encouraged to complete a physician questionnaire, which includes a physician global assessment (DOCGL). Patients with either OA or RA were identified using ICD9 codes and classified as positive discordance (PATGL-DOCGL ≥ 2), negative discordance (PATGL-DOCGL≤ - 2), and concordance (absolute difference between the two assessments < 2). Discordance was assessed by diagnosis. Agreement between patient and physician global assessments was evaluated using intraclass correlations. Logistic regression was performed to identify explanatory variables for positive discordance. The analysis included 243 OA and 216 RA patients. Mean PATGL was higher in OA versus RA (5.4 versus 4.2, p = 0.005), while mean DOCGL was similar (4.0 versus 3.8, p = 0.23) leading to a higher patient-physician discordance in OA (1.35 versus 0.43, p < 0.001). Positive discordance occurred in 34% of OA versus 18% of RA patients (p < 0.001). Intraclass correlation coefficients were 0.43 in OA versus 0.60 in RA patients. In logistic regressions, pain was the only statistically significant explanatory variable for discordance in both OA (OR 1.34, 95% CI 1.12-1.78) and RA (OR 1.47 95% CI 1.04-2.07). Patients with OA are more likely to be discordant with their rheumatologists than patients with RA because of a higher PATGL. Similarly to RA, the most important explanatory variable for discordance was higher pain.