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ID PMID Title PublicationDate abstract
32441383 Impact of persistence with tumour necrosis factor inhibitors on healthcare resource utiliz 2021 Jan AIM: To assess persistence with subcutaneous (SC) tumour necrosis factor (TNF) inhibitors as well as the impact of persistence on healthcare resource utilization (HCRU) and costs in patients with chronic inflammatory joint diseases. METHODS: In this cohort study using population-based French claims data (from 2011 to 2014), we measured persistence with SC TNF inhibitors within 12 months (M0-12) following treatment initiation in treatment-naïve and treatment-experienced users (divided into three cohorts: rheumatoid arthritis [RA], ankylosing spondylitis [AS] and psoriatic arthritis [PsA]). Persistent patients were propensity score matched to nonpersistent patients at M12. The impact of persistence status on HCRU and costs was assessed during M12-24. RESULTS: Of treatment-naïve (n = 3,804) and treatment-experienced (n = 2,279) users, only 56.1% and 46.8% were persistent at M12, respectively. Nonpersistent patients had more outpatient visits, computerized tomography scans, spine or joint magnetic resonance imaging procedures and disease-related hospitalizations, while persistent patients had more rheumatologist visits. Nonpersistent patients had lower drug costs but higher nondrug-related healthcare and hospitalization costs than persistent patients. In AS and PsA, overall healthcare costs were similar in persistent and nonpersistent patients. In RA, overall healthcare costs were lower in persistent patients (15,753€ vs 17,590€ in treatment-naïve and 17,622€ vs 21,177€ in treatment-experienced). CONCLUSION: Persistence with SC TNF inhibitors within first 12 months following treatment initiation was low in both treatment-naïve and treatment-experienced patients. Differences were observed in distribution of costs between persistent and nonpersistent patients, showing that nonpersistence with SC TNF inhibitors can lead to increased HCRU and higher costs.
33254064 A novel use of combined thermal and ultrasound imaging in detecting joint inflammation in 2021 Jan PURPOSE: To evaluate the use of combined thermal and ultrasound imaging to assess joint inflammation in rheumatoid arthritis (RA). METHOD: 22-joint (bilateral hands) thermography and ultrasonography were performed. For each patient, the MAX, MIN and AVG represent the sum of the temperature differences with a control temperature, for the respective maximum (Tmax), minimum (Tmin) and average (Tavg) temperatures at the joints. MAX (PD), MIN (PD) and AVG (PD) represent the results of combined thermal imaging with a patient's total ultrasound power Doppler (PD) joint inflammation score (Total PD) (when Total PD > median score, MAX, MIN and AVG was multiplied by a factor of 2, otherwise MAX (PD), MIN (PD) and AVG (PD) remained the same as the MAX, MIN and AVG). Pearson correlation and linear regression were used to assess correlation and characterize relationships of imaging parameters with the 28-joint disease activity score (DAS28). RESULTS: In this cross-sectional study, 814 joints were examined in 37 adult RA patients (75.7 % female, 75.7 % Chinese; mean DAS28, 4.43). Among the imaging parameters, only MAX (PD) and AVG (PD) correlated significantly with DAS28 (correlation coefficient (95 % CI): MAX (PD), 0.393 (0.079, 0.636), P = 0.016; AVG (PD): 0.376 (0.060, 0.624), P = 0.022). Similarly, only MAX (PD) and AVG (PD) demonstrated a statistically significant relationship with DAS28 (regression coefficient (95 % CI): MAX (PD), 0.009 (0.002, 0.015), P = 0.016; AVG (PD), 0.011 (0.002, 0.020), P = 0.022). CONCLUSIONS: Novel use of combined thermal and ultrasound imaging in RA shows superiority to either imaging alone in terms of correlation with DAS28.
34370276 Budget Impact of Sequential Treatment with Biologics, Biosimilars, and Targeted Synthetic 2021 Sep BACKGROUND: Targeted treatment of rheumatoid arthritis (RA) includes biological DMARDs (bDMARDs) and JAK inhibitors (JAKi). These agents are recommended at the same level on the basis of their efficacy and safety data. However, no local evidence of the impact of RA treatment regimens on total budget spending is available to date. This study aimed to explore the budget impact of different sequential targeted treatments in Thai patients with RA who failed at least three conventional synthetic DMARDs. METHODS: We used the adapted model to evaluate the budget impact of adding tofacitinib in different order to RA targeted treatment regimens. The Thai RA population eligible for treatment was assessed on the basis of local prevalence and experts' opinion. Cost-impact analysis was evaluated for the treatment sequences of four different lines of targeted therapies using inputs like clinical efficacy, safety, and costs. The model used a decision tree structure with treatment nodes corresponding to treatment response outcomes for a cohort of patients. The comparisons included five bDMARDs [etanercept (ETN), infliximab (IFX), golimumab (GOL), rituximab (RTX), tocilizumab (TCZ) intravenous formulation], two JAKi [tofacitinib (TOF) and baricitinib (BAR)], and two IFX biosimilars (PF-06438179/GP1111 and CT-P13). A total of 80 treatment sequences within each containing four sequential first-, second-, third-, and fourth-line options were generated. RESULTS: The findings of the base case scenario indicated the treatment sequence with RTX as first-line, followed by IFX biosimilar (PF-06438179/GP1111), TOF, and TCZ, respectively, produced the lowest budget impact of US $693.54 million. Sensitivity analyses confirmed the robustness of our findings. CONCLUSION: The order of targeted therapy starting with RTX, then IFX biosimilar, TOF, and finally TCZ incurred the lowest budget impact over a 5-year time horizon for treating moderate to severe RA. Our findings may help payers and policy makers consider appropriate budget allocation on chronic non-communicable diseases, especially RA.
33577605 High-throughput analysis of lung immune cells in a combined murine model of agriculture du 2021 Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1, Oas2, Ifit3, Gbp2, Ifi44, and Zbp1), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden.
33779767 [Atypical arthritis of the hands : Collagenosis-part 1]. 2021 May BACKGROUND: Systemic lupus erythematosus (SLE) is a gynecotropic autoimmune vasculitis with manifestations in various organ systems including the skin, internal organs, and joints. OBJECTIVE: Presentation of the atypical arthritis patterns of the hands in SLE as the most common autoimmunologic rheumatologic disease from the group of collagenoses in the context of clinical and serological findings and considering the classification criteria of the American College of Rheumatology compared to rheumatoid arthritis (RA) and psoriatic arthritis (PsA). MATERIALS AND METHODS: Narrative review based on the current literature on the subject from a radiological and rheumatological point of view. RESULTS: In 80-90% of all SLE cases, hand joint manifestations can be detected, mostly in the form of non-erosive oligo- or polyarthralgias with the picture of so-called luxation arthropathies and with the pattern of a so-called Jaccoud's or Lupus' syndrome, which are accompanied by "carpal instability" in 15% of cases. In association with an antiphospholipid antibody syndrome, ischemic osteonecrosis may occur in 5-50% of SLE, predominantly in weight-bearing areas of the skeleton, and less frequently in the carpal bones or metacarpal heads. The rare rhupus syndrome comprises patients with overlap of RA and SLE features. CONCLUSIONS: Due to the heterogeneity of the symptoms and the often individually very different courses, the diagnosis of SLE can be difficult. Since new drug therapy concepts have significantly increased the 5‑year survival rates of SLE from 0% in the 1950s to 70-90% in recent decades, a timely and definite diagnosis is necessary, to which radiologists can also contribute by correctly classifying the image morphological SLE arthritis patterns in the hands.
32475039 Obesity and the Risk of Incident Chronic Opioid Use in Rheumatoid Arthritis. 2021 Oct OBJECTIVE: The present study was undertaken to evaluate whether the rate of incident chronic opioid use is higher in obese patients with rheumatoid arthritis (RA). METHODS: Participants with RA in the FORWARD databank were asked about their use of weak and strong opioid medications on semiannual surveys. Incident chronic opioid use was defined as new reported use extending over 2 contiguous surveys (~7-12 months). Cox proportional hazards models were used to evaluate associations between body mass index (BMI) at enrollment and incident chronic opioid use (overall use and strong opioid use). Models adjusted for demographics, smoking, disease duration, RA treatments, household income, and education level. The predicted 5-year cumulative incidence was calculated from Cox models. RESULTS: Among 19,794 participants, 2,802 experienced an incident episode of chronic opioid use over 93,254 person-years of follow-up. Higher BMI was associated with higher risk of chronic opioid use. Severe obesity (BMI >35 kg/m(2) ) was associated with a higher risk of overall use (adjusted hazard ratio [HR(adj) ] 1.74 [95% confidence interval (95% CI) 1.72-2.04], P < 0.0001) and strong opioid use (HR(adj) 2.11 [95% CI 1.64-2.71], P < 0.001) compared to normal BMI. This association was partially explained by greater comorbidity, pain, and disability in obese groups. The attributable risk for obesity was 15% of overall opioid use and 24% of strong opioid use. CONCLUSION: Obesity is associated with a substantially higher risk of incident chronic opioid use. Approximately 1 in 4 cases of incident use of strong opioids may be attributable to obesity, suggesting a major public health impact. Interventions to prevent or reduce obesity could have an important impact on the use of opioids.
34752939 Estimates of minimal clinically important improvments vary with the responsiveness of the 2022 Feb OBJECTIVE: Minimal clinically important improvements (MCII) are known to vary with the baseline level in the sample. We examined if MCIIs are also larger in samples with higher responsiveness. STUDY DESIGN AND SETTING: In a prospective longitudinal study of patients with active rheumatoid arthritis, we assessed arthritis activity before and after new treatments. We estimated anchor-based MCIIs for three outcomes (pain severity, physical functioning by the Health Assessment Questionnaire, and Simplified Disease Activity Index, a composite measure) using receiver operating characteristic curves. We compared MCIIs among patients treated with three interventions of different impact (dose escalation, new disease-modifying medication, or prednisone). Separately, we used simulations to estimate MCIIs in five groups of responsiveness. RESULTS: Among 250 patients, standardized response means (SRMs) increased across the dose escalation, disease-modifying treatment, and prednisone treatment groups (-0.74, -1.00, and -1.53, respectively). MCIIs were also highest in the prednisone group. For example, corresponding MCIIs were -5.5, -8.9, and -13.8 for the composite measure. In the simulations, MCIIs (range -4.6 to -11.9) varied directly with SRMs (range -0.40 to -1.33). Results were similar for pain and the Health Assessment Questionnaire. CONCLUSION: The MCII is not an intrinsic measurement property but varies directly with sample responsiveness.
33594167 A two-herb formula inhibits hyperproliferation of rheumatoid arthritis fibroblast-like syn 2021 Feb 16 Fibroblast-like synoviocytes (FLS) play a pathogenic role in rheumatoid arthritis (RA). STAT3 signaling is activated in FLS of RA patients (RA-FLS), which in turn causes RA-FLS hyperproliferation. RL is a traditional remedy for treating inflammatory diseases in China. It comprises Rosae Multiflorae Fructus and Lonicerae Japonicae Flos. A standardized ethanolic extract of RL (RLE) has been shown to exert anti-arthritic effects in collagen-induced arthritis (CIA) rats. Some constituents of RLE were reported to inhibit JAK2/STAT3 signaling in rat FLS. Here, we determined whether RLE inhibits FLS hyperproliferation, and explored the involvement of STAT3 signaling in this inhibition. In joints of CIA rats, RLE increased apoptotic FLS. In IL-6/sIL-6R-stimulated RA-FLS, RLE reduced cell viability and evoked cell apoptosis. In synovial tissues of CIA rats, RLE lowered the protein level of phospho-STAT3. In IL-6/sIL-6R-stimulated RA-FLS, RLE inhibited activation/phosphorylation of STAT3 and JAK2, decreased the nuclear localization of STAT3, and downregulated protein levels of Bcl-2 and Mcl-1. Over-activation of STAT3 diminished RLE's anti-proliferative effects in IL-6/sIL-6R-stimulated RA-FLS. In summary, RLE inhibits hyperproliferation of FLS in rat and cell models, and suppression of STAT3 signaling contributes to the underlying mechanisms. This study provides further pharmacological groundwork for developing RLE as a modern anti-arthritic drug.
33725091 Comparing cost-utility of DMARDs in autoantibody-negative rheumatoid arthritis patients. 2021 Dec 1 OBJECTIVES: To evaluate the 1-year cost-effectiveness between three different initial treatment strategies in autoantibody-negative RA patients, according to 2010 criteria. METHODS: For this analysis we selected all RA patients within the intermediate probability stratum of the treatment in the Rotterdam Early Arthritis Cohort (tREACH) trial. The tREACH had a treat-to-target approach, aiming for low DAS <2.4, and treatment adjustments could occur every 3 months. Initial treatment strategies consisted of MTX 25 mg/week (initial MTX, iMTX), iHCQ 400 mg/day or an oral glucocorticoids tapering scheme without DMARDs (iGCs). Data on quality-adjusted life-years, measured with the European Quality of Life 5-Dimensions 3 Levels (EQ-5D-3L), healthcare and productivity costs were used. RESULTS: Average quality-adjusted life-years (s.d.), for iMTX, iHCQ and iGCs were respectively 0.71 (0.14), 0.73 (0.14) and 0.71 (0.15). The average total costs (s.d.) for iMTX, iHCQ and iGCs were, respectively, €10 832 (14.763), €11 208 (12.801) and €10 502 (11.973). Healthcare costs were mainly determined by biological costs, which were significantly lower in the iHCQ group compared with iGCs (P < 0.05). However, costs due to presenteeism were the highest in the iHCQ group (55%) followed by iMTX (27%) and iGCs (18%). The incremental cost-effectiveness ratios did not differ between treatment strategies. At a willingness-to-pay level of €50 000, the Dutch threshold for reimbursement of medical care, iHCQ had the highest probability (38.7%) of being cost-effective, followed by iGCs (31.1%) and iMTX (30.2%). CONCLUSION: iHCQ had the lowest healthcare and highest productivity costs, resulting in a non-significant incremental cost-effectiveness ratio. However, iHCQ had the highest chance of being cost-effective at the Dutch willingness-to-pay threshold for healthcare reimbursement. Therefore, we believe that iHCQ is a good alternative to iMTX in autoantibody-negative RA patients, but validation is needed. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN26791028.
32898607 Assessment of interleukin 6 gene polymorphisms with rheumatoid arthritis. 2021 Jan 10 BACKGROUND: Rheumatoid arthritis (RA) is complex autoimmune system disease and significant impact on the health of population in our world. Numerous studies confirmed that genetic factors play a crucial role in the pathogenesis of RA. In this current study, we aimed to investigate IL-6 polymorphisms and RA risk in Chinese Han population. METHODS: 508 RA patients and 494 age- and gender- matched healthy controls were recruited, all subjects were genotyped with an Agena MassARRAY platform. Subsequently, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression after adjusting for age and gender. RESULTS: Our results suggested that IL-6 rs2243289 allele and genotype frequencies were associated with reduced RA risk under all genetic models (all p < 0.05). Stratification analysis revealed that IL-6 rs2243289 polymorphism was significant associated with decreased the risk of RA in the old groups (age > 54) (all p < 0.05). However, IL-6 rs2069837 and rs1800796 polymorphisms were associated with increased risk of RA among the young groups (age ≤ 54) (all p < 0.05). In addition, subgroup analysis by gender suggested that IL-6 rs2069837 and rs1800796 polymorphism were interacted with increased the risk of RA in males (all p < 0.05). Besides, IL-6 rs2243289 was associated with reduced RA risk in females. CONCLUSIONS: In conclusion, our results demonstrated the correlation between IL and 6 polymorphisms and RA susceptibility and confirmed for the first time that the relationship was restricted to age and gender in Chinese Han population.
34684370 The Role of Bioactive Compounds of Nigella sativa in Rheumatoid Arthritis Therapy-Current 2021 Sep 25 Black cumin (Nigella sativa, NS) is included in the Ranunculaceae family and is classified as a medicinal plant due to very high levels of various bioactive compounds. They determine its therapeutic effects, including anti-inflammatory, anti-allergic, anti-cancer, hypoglycemic, antioxidant, hypotensive, hypolipidemic, and immunomodulating properties. The results of scientific studies indicate a supporting role of black cumin in the treatment of autoimmune diseases, including rheumatoid arthritis, due to the health-promoting properties of its bioactive ingredients. The aim of the current article is to analyze the results of scientific publications on the role of bioactive ingredients contained in black cumin in the treatment of rheumatoid arthritis.
34583676 Myrtenal and β-caryophyllene oxide screened from Liquidambaris Fructus suppress NLRP3 inf 2021 Sep 28 BACKGROUND: Liquidambaris Fructus (LF) is the infructescence of Liquidambar formosana. In Traditional Chinese Medicine, LF has been used to treat joint pain, a common symptom of arthritis and rheumatism; however, a lack of pharmacological evidence has limited its applications in modern clinics. Therefore, this study aims to explore the protective effect of LF on rheumatoid arthritis (RA) and to identify its active ingredients. METHODS: Rats with adjuvant-induced arthritis (AIA) were divided into 4 groups and administered petroleum ether extract of LF (PEL), ethyl acetate extract of LF (EEL), water extract of LF (WEL), or piroxicam (PIR) respectively for 3 weeks. Two additional groups were used as normal control (NC) and model control (MC) and administered distilled water as a placebo. The clinical scores for arthritis, bone surface, synovial inflammation and cartilage erosion were used to evaluate the therapeutic efficacy of each treatment. The serum IL-1β and TNF-α level and the expression of NLRP3, IL-1β and caspase-1 p20 in the synovial tissue of AIA rats were evaluated by ELISA and Western blot. The active ingredients of LF were investigated using network pharmacology and molecular docking methods, and their inhibition of NLRP3 inflammasome activation was verified in the human rheumatoid arthritis fibroblast-like synovial cells (RA-FLS) model. RESULTS: PEL could alleviate paw swelling, bone and joint destruction, synovial inflammation and cartilage erosion in the AIA rats, with significantly superior efficacy to that of EEL and WEL. PEL reduced IL-1β and TNF-α serum levels, and attenuated the upregulation of NLRP3, IL-1β and caspase-1 p20 expression in the synovial tissue of AIA rats. Network pharmacology and molecular docking results indicated that myrtenal and β-caryophyllene oxide were the main two active ingredients of PEL, and these two compounds showed significant inhibition on TNF-α, NLRP3, IL-1β and caspase-1 p20 expression in RA-FLS. CONCLUSIONS: Myrtenal and β-caryophyllene oxide screened from PEL could suppress the activation of NLRP3 inflammasome, thereby alleviating RA symptoms.
33559714 Effects of one-year tofacitinib therapy on bone metabolism in rheumatoid arthritis. 2021 Aug Janus kinase (JAK) inhibitors are used to treat rheumatoid arthritis (RA). We assessed the effects of tofacitinib on bone density and bone markers in association with clinical and laboratory parameters in RA. Tofacitinib stabilized bone density and resulted in a positive balance of bone turnover. INTRODUCTION: Janus kinase (JAK) inhibitors emerged as new therapeutic options in rheumatoid arthritis (RA). We have little information on how it affects areal and volumetric bone mineral density (BMD) and bone turnover markers. The aim of this study was to assess the effects of 1-year tofacitinib therapy on bone metabolism in RA. METHODS: Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) levels, as well as serum levels of sclerostin, osteocalcin (OC), P1NP, DKK-1, OPG, RANKL, and 25-hydroxy-vitamin D3. Areal and volumetric BMD were assessed by DXA and peripheral quantitative CT (QCT), respectively. RESULTS: Twenty-six patients (13 on each arm) completed the study. Tofacitinib was clinically effective by suppressing DAS28, CRP, and HAQ. This was accompanied by the attenuation of further bone loss. Tofacitinib therapy significantly increased OC, OPG, and vitamin D3, while decreased CTX levels (p < 0.05). Age and multiple bone markers (OC, CTX, P1NP, RANKL) inversely correlated with L2-4 and femoral neck BMD by DXA. CRP, DAS28, and RANKL inversely determined volumetric BMD by QCT. Age, CRP, anti-CCP, and DKK-1 influenced the effects of tofacitinib therapy on BMD changes. CONCLUSIONS: One-year tofacitinib treatment stabilized BMD in RA patients and resulted in a positive balance of bone turnover as indicated by bone biomarkers. Further studies are needed to evaluate the potential beneficial effects of JAK inhibitors on inflammatory bone loss.
33757643 Does being exposed to an educational tool influence patient preferences? The influence of 2021 Oct OBJECTIVES: There is an increased interest in patient preferences informing the development and authorisation of medical products. A requirement for robust and meaningful results of such studies is that patients adequately understand the risks and benefits associated with treatments for which their preferences are elicited. This study aims to determine the influence of an educational tool, compared with traditional written information on patient preferences elicited in a discrete choice experiment (DCE). METHODS: Treatment preferences of Swedish patients with rheumatoid arthritis (RA) were assessed using a DCE. Patients were recruited via clinics, a research panel, and the Swedish Rheumatism Association. Respondents received training materials either as plain written text or as an online educational tool. The educational tool was designed to enhance understanding of the written text by using graphics, pictograms, icon arrays, spoken text, and click-on functions. Data were analysed using random parameter logit models. RESULTS: 675 patients with RA were included in the analysis. The patients received either a written information (n = 358) or information via an educational tool (n = 317). Respondents receiving the educational tool placed relatively more importance on all included side effects in their decision making, compared to respondents receiving the written text, who placed greater importance on treatment effectiveness and administration methods. CONCLUSION: Compared to the respondents receiving the written text, the decisions of respondents receiving the educational tool were more influenced by medication side effects. Further research is needed to provide guidance on how and when to use educational tools to inform and elicit patients' preferences. PRACTICE IMPLICATIONS: The ways in which attributes are presented to patients significantly impacts preferences measured in a DCE.
33871596 Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthri 2021 Nov 3 OBJECTIVE: The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis). METHODS: Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive. RESULTS: Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg. CONCLUSION: In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years. TRIAL REGISTRATION: TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652.
33337815 Efficacy, Safety, and Immunogenicity of Biosimilar Etanercept (Enerceptan) Versus Its Orig 2021 Sep 1 BACKGROUND: Enerceptan (EtaBS) has been developed as a proposed biosimilar of etanercept. METHODS: This randomized, multicenter, evaluator-blinded, noninferiority study conducted in Argentina included adults with active, moderate, and severe rheumatoid arthritis with inadequate response to methotrexate. Subjects were randomly assigned to 32 weeks treatment with EtaBS (n = 99) or etanercept (n = 51) at a weekly 50-mg dose administered subcutaneously. Patients were categorized according to prior use of biologic disease-modifying antirheumatic drugs and concomitant use of steroids. The primary efficacy endpoint was ACR20 response rate at week 32. Safety, immunogenicity, and steady-state concentration of both drugs were evaluated. The noninferiority margin for ACR20 was estimated at 12%. RESULTS: In the per-protocol population, 85 subjects (92.4%) treated with EtaBS and 44 subjects (93.6%) treated with etanercept achieved ACR20 (difference, -1.2%; 95% confidence interval, -10.1% to 7.6%). Frequent adverse drug reactions occurred in 34.3% and 38% of subjects treated with EtaBS and etanercept, respectively. The most common reaction was upper respiratory tract infection. Six and 3 serious adverse events occurred in 4 and 3 subjects treated with EtaBS and etanercept, respectively. Injection site reactions occurred in 67.7% and 66.0% of subjects treated with EtaBS and etanercept, respectively. Two subjects treated with EtaBS and 1 subject treated with etanercept developed antibodies by week 32. CONCLUSIONS: Efficacy outcomes for EtaBS were noninferior to original etanercept in patients with moderate-to-severe rheumatoid arthritis with inadequate response to methotrexate. Safety and immunogenicity results were comparable between the two. This study is a major step toward improving access to biologics in Latin America.
32828147 Receptor activator of nuclear factor kappa-Î’ ligand (RANKL) serum levels are associated w 2021 May OBJECTIVES: The aim of this study was to establish whether serum RANKL levels in early inflammatory arthritis (IA) were associated with rheumatoid arthritis (RA) diagnosis at follow-up, and to evaluate the added value of RANKL for RA diagnosis. METHODS: Serum from 298 patients was collected. Demographic and clinical (swollen/tender joint counts, CRP, DAS28-CRP, RF, ACPA and shared-epitope data were recorded. Baseline ultrasound of 26 joints was performed, including total power Doppler (PD). An ELISA was used to measure RANKL. Predictors of progression were identified using multivariable logistic regression analysis. Area under the receiver operating characteristics (AUROC) was used to assess the performance of the prediction models and quantify the added value of RANKL in RA diagnosis. RESULTS: 151 patients developed RA and 147 were non-RA (undifferentiated IA, other inflammatory diagnoses or non-persistent inflammation). RANKL levels were significantly higher in RA (median [IQR]: 474.1 [270.8-1430.6]) than in non-RA (median [IQR]: 301.0 [174.1-477.5]. Three clinical factors (age, SJC and PD) were identified by multivariable logistic regression with model performance AUROC of 77.9% (95% CI 72.1-83.8%). Adding RANKL resulted in a relative increase of 6.5% in the model classification performance of an AUROC of 83.0% (95% CI 77.9-88.1%). In ACPA-negative patients, the model performance increased from 77.6% (95% CI 69.5-85.7%) with clinical data only to 81.9% (95% CI 73.7-89.8%) with added value of RANKL and imaging. CONCLUSIONS: RANKL levels can predict RA diagnosis over clinical biomarkers alone, both seropositive and particularly in seronegative IA patients.
33931806 [Gigantic prepatellar "tumor" in rheumatoid arthritis-a case report]. 2021 Dec In soft tissue tumors of the extremities it is of utmost importance to differentiate between benign and malignant entities. The majority of the swellings vary from benign tissue changes through soft tissue sarcomas up to pseudotumors. Because of the low incidence of malignancy and the predominantly benign alterations together with a high heterogeneity, there is a need for a reproducible diagnostic and therapeutic concept for the treatment of all tumors of the extremities. This article reports the case of a 59-year-old patient with longstanding rheumatoid arthritis who presented to the orthopedic rheumatologic consultation with a massive swelling directly ventral to the knee joint. At that point the tumor had already grown very slowly for 5 years. The staged diagnostic process (patient history, clinical, laboratory tests, sonographic examinations, X‑ray, MRI with contrast medium) revealed no trace of malignancy whatsoever. The treatment then consisted of the complete surgical excision in accordance with the recommendations for tumor surgery. Histopathological findings confirmed the diagnosis of a massive prepatellar bursitis. Initially, the extreme and solid prepatellar swelling was suspected of being malignant; however, this could already be broadly excluded preoperatively. This article presents the rationale and the orthopedic rheumatologic approach for addressing unclear space-occupying lesions of the musculoskeletal system in patients with rheumatism. In the inflammatory systemic disease in the differential diagnosis periarticular swellings can ultimately also have benign causes, such as an organized bursitis.
34713972 Inflammation-induced left ventricular fibrosis is partially mediated by tumor necrosis fac 2021 Nov OBJECTIVE: To determine the mechanisms of inflammation-induced left ventricular (LV) remodeling and effects of blocking circulating tumor necrosis factor alpha (TNF-α) in a model of systemic inflammation. METHODS: Seventy Sprague-Dawley rats were divided into three groups: the control group, the collagen-induced arthritis (CIA) group, and the anti-TNF-α group. Inflammation was induced in the CIA and anti-TNF-α groups. Following the onset of arthritis, the anti-TNF-α group received the TNF-α inhibitor, etanercept, for 6 weeks. LV geometry and function were assessed with echocardiography. Circulating inflammatory markers were measured by ELISA and LV gene expression was assessed by comparative TaqMan® polymerase chain reaction. RESULTS: The LV relative gene expression of pro-fibrotic genes, transforming growth factor β (TGFβ) (p = 0.03), collagen I (Col1) (p < 0.0001), and lysyl oxidase (LOX) (p = 0.002), was increased in the CIA group compared with controls, consistent with increased relative wall thickness (p = 0.0009). Col1 and LOX expression in the anti-TNF-α group were similar to controls (both, p > 0.05) and tended to be lower compared to the CIA group (p = 0.06 and p = 0.08, respectively), and may, in part, contribute to the decreased relative wall thickness in the anti-TNF-α group compared to the CIA group (p = 0.03). In the CIA group, the relative gene expression of matrix metalloproteinase 2 (MMP2) and MMP9 was increased compared to control (p = 0.04) and anti-TNF-α (p < 0.0001) groups, respectively. CONCLUSION: Chronic systemic inflammation induces fibrosis and dysregulated LV extracellular matrix remodeling by increasing local cardiac pro-fibrotic gene expression, which is partially mediated by TNF-α. Inflammation-induced LV diastolic dysfunction is likely independent of myocardial fibrosis.
33878476 Reactive oxygen species-responsive dendritic cell-derived exosomes for rheumatoid arthriti 2021 Jul 1 Although tolerogenic dendritic cell-derived exosomes (TolDex) have emerged as promising therapeutics for rheumatoid arthritis (RA), their clinical applications have been hampered by their poor in vivo disposition after systemic administration. Herein, we report the development of stimuli-responsive TolDex that induces lesion-specific immunoregulation in RA. Responsiveness to reactive oxygen species (ROS), a physiological stimulus in the RA microenvironment, was conferred on TolDex by introducing a thioketal (TK) linker-embedded poly(ethylene glycol) (PEG) on TolDex surface via hydrophobic insertion. The detachment of PEG following overproduction of ROS facilitates the cellular uptake of ROS-responsive TolDex (TKDex) into activated immune cells. Notably, TolDex and TKDex downregulated CD40 in mature dendritic cells (mDCs) and regulated secretion of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) at the cellular level. In the collagen-induced arthritis (CIA) mouse model, PEG prolonged the blood circulation of TKDex following intravenous administration and enhanced their accumulation in the joints. In addition, TKDex decreased IL-6, increased transforming growth factor-β, and induced the CD4(+)CD25(+)Foxp3(+) regulatory T cells in CIA mice. Overall, ROS-responsive TolDex might have potential as therapeutic agents for RA. STATEMENT OF SIGNIFICANCE: Tolerogenic dendritic cell-derived exosomes (TolDex) are emerging immunoregulators of autoimmune diseases, including rheumatoid arthritis (RA). However, their lack of long-term stability and low targetability are still challenging. To overcome these issues, we developed reactive oxygen species (ROS)-responsive TolDex (TKDex) by incorporating the ROS-sensitive functional group-embedded poly(ethylene glycol) linker into the exosomal membrane of TolDex. Surface-engineered TKDex were internalized in mature DCs because of high ROS-sensitivity and enhanced accumulation in the inflamed joint in vivo. Further, for the first time, we investigated the potential mechanism of action of TolDex relevant to CD40 downregulation and attenuation of tumor necrosis factor (TNF)-α secretion. Our strategy highlighted the promising nanotherapeutic effects of stimuli-sensitive TolDex, which induces immunoregulation.