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28867467 Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotre 2019 May OBJECTIVE: To assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease-modifying antirheumatic drug (DMARD). METHODS: We performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. RESULTS: A total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. CONCLUSION: Leflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints.
30945116 Population Pharmacokinetics of Upadacitinib Using the Immediate-Release and Extended-Relea 2019 Aug BACKGROUND AND OBJECTIVES: Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I-III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations. METHODS: Pharmacokinetic data from 4170 subjects taking IR doses of 1-48 mg and ER doses of 7.5-30 mg across 12 studies spanning phase I-III clinical trials, with a total of 29,372 upadacitinib plasma concentrations, were analyzed using non-linear mixed-effects modeling. The model was evaluated using bootstrap analyses and visual predictive checks. RESULTS: A two-compartment model with first-order absorption with lag time for the IR formulation, mixed zero- and first-order absorption with lag time for the ER formulation, and linear elimination, adequately described upadacitinib plasma concentration-time profiles. Population estimates of upadacitinib apparent oral clearance and steady-state volume of distribution in healthy volunteers for the ER formulation were 53.7 L/h and 294 L, respectively. The relative bioavailability of the ER formulation compared with the IR formulation was estimated to be 76.2%. Statistically significant covariates were patient population (RA subjects vs. healthy subjects), creatinine clearance, and baseline bodyweight on apparent clearance (CL/F) and bodyweight on volume of distribution of the central compartment (Vc/F). The intersubject variability for upadacitinib CL/F and Vc/F were estimated to be 21% and 24%, respectively, in the phase I studies, and 37% and 53%, respectively, in the phase II/III studies. Upadacitinib area under the concentration-time curve (AUC) was estimated to be only 5% higher or lower for RA patients who were < 60 or > 100 kg, respectively, relative to subjects with a bodyweight of 60-100 kg. RA subjects with mild or moderate renal impairment had 13% and 26% higher AUC, respectively, compared with RA subjects with normal renal function. Sex, race, concomitant use of pH-modifying drugs, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib exposure. CONCLUSIONS: A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I-III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure-response relationship of upadacitinib.
30554330 Evaluation of Physicochemical and Biological Stability of 36-Months-Aged SB5 (Adalimumab B 2019 Feb INTRODUCTION: Tumor necrosis factor (TNF-alpha) inhibitors, such as adalimumab, have shown success in treating autoimmune inflammatory diseases but are associated with substantial financial burdens to the healthcare system. Biosimilars, which are highly similar to biologic agents, offer the potential to reduce the financial burden of treatment. In the case of TNF-alpha inhibitors, they may also offer improved stability and enable prolonged use. SB5, an adalimumab biosimilar, has shown equivalent efficacy and comparable safety to its reference product in clinical trials. Currently, SB5 is approved for storage for 36 months at 2-8 °C and may be stored at room temperature (25 °C) for a maximum period of 14 days. The objective of this study was to evaluate the stability of SB5, aged to its shelf-life of 36 months, at room temperature (25 ± 2 °C) and 60 ± 5% relative humidity (RH) for a period of 4 weeks, which is longer by 14 days than that of SB5 currently approved in the European Union. METHODS: This study evaluated the stability of SB5, aged to its shelf-life of 36 months, at room temperature (25 ± 2 °C) for a period of 4 weeks. Three independent batches of 36 months-aged SB5 were stored at 25 ± 2 °C and 60 ± 5% RH for 4 weeks. Samples were tested at 0, 2, and 4 weeks. RESULTS: Color, clarity, visible particles, pH, protein concentration, and particulate matter were consistent among the batches, and all the test results met the acceptance criteria at each time point. Percent charge variance was maintained over time. Percent of high molecular weight species detected, total purity, relative binding activity by TNF-alpha, and relative potency by TNF-alpha neutralization did not change over time within each batch, and all values were within the acceptance criteria limits. CONCLUSION: SB5 aged for 36 months is physicochemically and biologically stable for 4 weeks at 25 ± 2 °C and 60 ± 5% RH, which is 2 weeks longer than the alternative storage condition as approved by the European Medicines Agency, which is at 25 °C for a period of up to 14 days. FUNDING: Samsung Bioepis Co., Ltd.
31142839 Distinct fibroblast subsets drive inflammation and damage in arthritis. 2019 Jun The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)(1,2). However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage(3-5). Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-α (FAPα)(+) fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα(+) population: FAPα(+)THY1(+) immune effector fibroblasts located in the synovial sub-lining, and FAPα(+)THY1(-) destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAPα(+)THY1(-) fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAPα(+) THY1(+) fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.
31767861 Heritability of skewed X-inactivation in female twins is tissue-specific and associated wi 2019 Nov 25 Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. Skewed XCI toward one parental X has been observed in several complex human traits, but the extent to which genetics and environment influence skewed XCI is largely unexplored. To address this, we quantify XCI-skew in multiple tissues and immune cell types in a twin cohort. Within an individual, XCI-skew differs between blood, fat and skin tissue, but is shared across immune cell types. XCI skew increases with age in blood, but not other tissues, and is associated with smoking. XCI-skew is increased in twins with Rheumatoid Arthritis compared to unaffected identical co-twins. XCI-skew is heritable in blood of females >55 years old (h(2) = 0.34), but not in younger individuals or other tissues. This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner.
30741851 Acute monoarthritis. 2019 Mar Acute monoarthritis affects a single joint and has many potential underlying causes, including crystal deposition diseases, infection, trauma, and osteoarthritis. A comprehensive health history and physical examination can help narrow the list of differential diagnoses; judicious diagnostic testing can help pinpoint the diagnosis. Clinicians also must be able to recognize which patients require emergency referral to prevent long-term adverse consequences.
30360768 Polyphenolic extract from extra virgin olive oil inhibits the inflammatory response in IL- 2019 Jan The polyphenolic extract (PE) from extra virgin olive oil (EVOO) has been shown to possess important anti-inflammatory and joint protective properties in murine models of rheumatoid arthritis (RA). This study was designed to evaluate the effects of PE on IL-1β-activated human synovial fibroblasts SW982 cell line. PE from EVOO treatment inhibited IL-1β-induced matrix metalloproteases (P<0·001), TNF-α and IL-6 production (P<0·001). Similarly, IL-1β-induced cyclo-oxygenase-2 and microsomal PGE synthase-1 up-regulations were down-regulated by PE (P<0·001). Moreover, IL-1β-induced mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB activation were ameliorated by PE (P<0·001). These results suggest that PE from EVOO reduces the production of proinflammatory mediators in human synovial fibroblasts; particularly, these protective effects could be related to the inhibition of MAPK and NF-κB signalling pathways. Taken together, PE from EVOO probably could provide an attractive complement in management of diseases associated with over-activation of synovial fibroblasts, such as RA.
30739816 Methotrexate-associated lymphoproliferative disorder with multiple pulmonary nodules and b 2019 Dec As has been well recognized, methotrexate (MTX) leads to a state of immunosuppression and can provide a basis for the development of lymphoproliferative disorders (LPDs). MTX-associated LPDs can affect nodal sites as well as extranodal sites, though the manifestation of an LPD in the form of multiple pulmonary nodules is rare. Here, we report two cases of MTX-associated LPD with multiple bilateral pulmonary nodules, which was a finding suggestive of lung cancer, and bilateral cervical lymphadenopathy. After withdrawal of MTX, the multiple bilateral pulmonary nodules and bilateral cervical lymphadenopathy disappeared without chemotherapy in both cases. From these results, patients with pulmonary nodules and cervical lymphadenopathy should be examined for head and neck malignant tumors. Also, physicians should carefully check the administration of MTX. In patients with an MTX-associated LPD, we need to make an early diagnosis and consider discontinuing the administration of MTX as soon as possible.
31146570 Outcomes of repeat two-stage exchange hip arthroplasty for prosthetic joint infection. 2019 Jun AIMS: The increasing infection burden after total hip arthroplasty (THA) has seen a rise in the use of two-stage exchange arthroplasty and the use of increasingly powerful antibiotics at the time of this procedure. As a result, there has been an increase in the number of failed two-stage revisions during the past decade. The aim of this study was to clarify the outcome of repeat two-stage revision THA following a failed two-stage exchange due to recurrent prosthetic joint infection (PJI). PATIENTS AND METHODS: We identified 42 patients who underwent a two-stage revision THA having already undergone at least one previous two stage procedure for infection, between 2000 and 2015. There were 23 women and 19 men. Their mean age was 69.3 years (48 to 81). The outcome was analyzed at a minimum follow-up of two years. RESULTS: A satisfactory control of infection and successful outcome was seen in 26 patients (57%). There therefore remained persistent symptoms that either required further surgery or chronic antibiotic suppression in 16 patients (38%). One-third of patients had died by the time of two years' follow-up. CONCLUSION: The rate of failure and complication rate of repeat two-stage exchange THA for PJI is high and new methods of treatment including host optimization, immunomodulation, longer periods between stages, and new and more powerful forms of antimicrobial treatment should be investigated. Cite this article: Bone Joint J 2019;101-B(6 Supple B):110-115.
30776645 Novel aspects of the activation of NADPH oxidase in neutrophils of rheumatic patients on b 2019 Apr The relationship between inflammation and formation of reactive oxygen species (ROS) is still not completely understood and excessive inflammatory reaction is attributed to increased yet also to reduced ROS formation. To compare ROS formation in severe and low inflammation, neutrophil oxidative burst was analyzed in rheumatic patients before and during therapy with TNFα- or interleukin-6 receptor-neutralizing antibodies. Intracellular and extracellular ROS productions were evaluated on the basis of luminol- and isoluminol-enhanced chemiluminescence in isolated peripheral neutrophils. Disease activity score DAS28 and platelet to lymphocyte ratio were used as markers of arthritis activity and the intensity of systemic inflammation. Biological therapy effectively reduced the intensity of inflammation. Of the twenty-six patients studied eighteen achieved remission or low disease activity. Highly active arthritis persisted only in one patient, though prior to the therapy it was evident in all subjects tested. In patients receiving biological therapy, intracellular chemiluminescence was significantly higher than in patients before this therapy; ROS produced by neutrophils extracellularly were not affected. The increased ROS formation associated with reduced inflammation supports the need to revise the view of the role of ROS in inflammation - from toxic agents promoting inflammation towards a more complex view of ROS as regulators of immune pathways with inflammation-limiting capacity. From this perspective, the interference with neutrophil-derived oxidants may represent a new mechanism involved in the anti-inflammatory activity of biological therapy.
30137469 S. typhi Vi capsular polysaccharide vaccine-induced humoral immunity in travellers with im 2019 Jan 1 INTRODUCTION: Typhoid fever is a global health problem, causing significant morbidity and mortality. Currently, the most widely used vaccine is the typhoid Vi capsular polysaccharide (Vi-PS) vaccine. While epidemiological studies on its efficacy have been performed in children in endemic countries, there are no efficacy studies evaluating its use in travel medicine. Response to vaccination may differ in travellers receiving immunosuppressive therapy. This study investigates the humoral response to Vi-PS vaccination in travellers receiving immunosuppressive therapy for rheumatoid disease. METHODS: We recruited patients from the LUMC rheumatology outpatient clinic and travellers from the travel clinic who had previously received Vi-PS vaccination and also immunosuppressive therapy for rheumatoid disease. We analysed blood samples acquired from 42 patients over a period of 3 years. We estimated the length of persistence of protective titres using the survival analysis using multiple cut-off values for protection and measured titre half-life and the influence of immunosuppressive medication on titre half-life using mixed models. RESULTS: Anti-Vi-PS antibody levels stayed above 10 EU/ml for a mean of 13.3 years, above 15 EU/ml for a mean of 10.1 years and above 20 EU/ml for a mean of 8.6 years after Vi-PS vaccination. Titre half-life was 7.5 years (95% CI 5.0-14.7 years, P < 0.001). No significant influence of medication on titre half-life was found. CONCLUSION: Both persistence of protective antibody titres and titre half-life are longer than expected based on other studies. This warrants further study in adult volunteers, both in healthy individuals and patients suffering from rheumatoid disease.
31563273 The AIRE Ser196Ser synonymous variant is a risk factor for systemic lupus erythematosus. 2019 Dec The AIRE gene influences the expression of a wide array of self-antigens in the thymus, and is essential to the negative selection of self-reactive T cells and establishment of central tolerance. Single nucleotide variants (SNVs) such as rs878081C/T (Ser196Ser) and rs2075876G/T at this locus have been associated with susceptibility to rheumatoid arthritis, mainly in Asian populations, but its role in systemic lupus erythematosus (SLE) has not been documented. We performed a case-control association study with 379 SLE patients and 460 controls from central Mexico. In addition, we replicated our finding in another group of 179 SLE patients and 97 controls from the same region of Mexico. In the first group, we identified that the AIRE Ser196Ser synonymous variant was associated with SLE (OR 1.4, p = 0.009), meanwhile, in the second group we observed the following: OR 1.7, p = 0.024. No association was found between these AIRE SNVs and lupus nephritis. Our results suggest that AIRE is a risk factor for SLE in our population. This study is the first to document an association between AIRE and SLE susceptibility.
31488129 Long-term results of the iBP elbow prosthesis: beware of destructive metallosis! 2019 Sep 6 BACKGROUND: The aim of this study was to review the long-term results of the instrumented Bone Preserving (iBP) elbow prosthesis. METHODS: Thirty-one patients (10 M, 21F, 28-77 year) were retrospectively evaluated using the Oxford Elbow Score (OES), Disabilities of Arm, Shoulder and Hand Outcome Measure (DASH), Mayo Elbow Performance (MEPS), physical examination and standard radiographs. Kaplan-Meier survival analysis was used. RESULTS: Thirty-seven primary iBPs have been placed in 31 patients between 2000 and 2007. Six patients (8 prostheses) had died, 10 elbows had been revised and three patients (4 prostheses) were lost to follow-up. Fourteen patients (15 prostheses) were available for follow-up. The main indication for surgery was rheumatoid arthritis. Mean follow-up was 11 years (8-15). Kaplan-Meier survival analysis showed a survival of 81% at 10 years after surgery. Main reason for revision was particle disease and loosening due to instability and malalignment. Eleven of 14 patients were satisfied, although radiographs showed radiolucencies in 11 patients. CONCLUSION: The iBP elbow prosthesis gives a survival rate of 81% 10 years after surgery with a progressive decline beyond 10 years. However, many patients have radiolucencies. Discrepancy between clinical signs and radiological results warrants structural follow-up, to assure quality of bone stock in case revision surgery is indicated. The study was reviewed and approved by the Medical Ethical Committee of University Medical Center Groningen (METc2016/038). LEVEL OF EVIDENCE: Level IV, Case series.
30638197 Cimifugin Inhibits Inflammatory Responses of RAW264.7 Cells Induced by Lipopolysaccharide. 2019 Jan 14 BACKGROUND RAW264.7 cells are induced by lipopolysaccharide (LPS) as a rheumatoid arthritis (RA) model. The present study investigated the effect of cimifugin on the proliferation, migration, chemotaxis, and release of inflammation-related factors and inflammation-related signaling pathways of LPS-induced RAW264.7 cells. MATERIAL AND METHODS MTS assay was used to determine the proliferation of RAW264.7 cells. Transwell assay was employed to examine the migration and chemotaxis of the cells. ELISA was performed to measure the contents of chemotactic factors and inflammatory factors in cell culture supernatants. Western blotting was carried out to detect the expression of factors related with MAPKs and NF-κB signaling pathways. RESULTS Cimifugin (0-100 mg/L) had no cytotoxicity for RAW264.7 cells. LPS stimulation induced morphological differentiation of RAW264.7 cells, but intervention by cimifugin inhibited the activation effect by LPS by about 50%. Cimifugin (100 mg/L) decreased the migration and chemotaxis of RAW264.7 cells to 1/3 of that in control cells by decreasing the release of migration- and chemotaxis-associated factors by at least 30%. Cimifugin (100 mg/L) suppressed the release of inflammatory factors from RAW264.7 cells to less than 60% of that in the LPS group. In addition, cimifugin (100 mg/L) inhibited the activities of MAPKs and NF-κB signaling pathways. CONCLUSIONS The present study demonstrates that cimifugin reduces the migration and chemotaxis of RAW264.7 cells and inhibits the release of inflammatory factors and activation of related signaling pathways induced by LPS. Cimifugin may have potential pharmacological effects against RA.
32008173 Autoantibodies against P29ING4 are associated with complex regional pain syndrome. 2019 Dec INTRODUCTION: Complex regional pain syndrome (CRPS) is a complication following trauma or surgery and may be difficult to diagnose since biomarkers are lacking. Using protein array technology, we found antibodies binding to p29ING4, which we further characterized using ELISA. METHODS: Thirty-six sera of early-stage type 1 CRPS, 66 sera of rheumatoid arthritis (RA), 53 sera of axial spondyloarthritis (axSpA), 29 sera of psoriatic arthritis (PsA), 22 sera of patients after radial fractures (trauma control), and 100 sera of blood donors (BD) were analyzed for anti-p29ING4. We established ELISAs with 7 different antigens and using different secondary antibodies binding to IgG, IgG1, IgG2, IgG3, IgG4, IgA, and IgM, and 2 different tests to detect immune complexes (IC) of p29ING4 and IgG or IgG1. RESULTS: The highest likelihood ratios versus CRPS and trauma control were observed considering the A1-23 (sensitivity 19%, specificity 100%, LR > 19) using IgG as a secondary antibody, the A120-165 (sensitivity 17%, specificity 100%, LR = 17) using IgG as a secondary antibody and the A120-165 (sensitivity 31%, specificity 95%, LR = 6.2) using IgA as a secondary antibody. IC of p29ING4 and IgG were present in 11/36 (31%) CRPS sera, 17/64 (27%) RA sera, 13/53 (25%) SpA sera, 5/29 (17%) PsA sera, 1/22 (5%) trauma control sera, and 4/100 (4%) sera of BD. IC of p29ING4 and IgG1 were present in 14/36 (39%) CRPS sera, 19/64 (30%) RA sera, 13/53 (25%) SpA, 1/29 (3%) PsA, 2/22 (9%) trauma control, and 4/100 (4%) of the BD sera. CONCLUSION: Due to the lack of other biomarkers of type 1 CRPS, P29ING4 autoantibodies could be helpful in its diagnostic work-up.
30487199 Predicting outcomes in rheumatoid arthritis related interstitial lung disease. 2019 Jan The aim of this study was to compare radiology-based prediction models in rheumatoid arthritis-related interstitial lung disease (RAILD) to identify patients with a progressive fibrosis phenotype.RAILD patients had computed tomography (CT) scans scored visually and using CALIPER and forced vital capacity (FVC) measurements. Outcomes were evaluated using three techniques, as follows. 1) Scleroderma system evaluating visual interstitial lung disease extent and FVC values; 2) Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines applied to RAILD; and 3) CALIPER scores of vessel-related structures (VRS). Outcomes were compared to IPF patients.On univariable Cox analysis, all three staging systems strongly predicted outcome (scleroderma system hazard ratio (HR) 3.78, p=9×10(-5); Fleischner system HR 1.98, p=2×10(-3); and 4.4% VRS threshold HR 3.10, p=4×10(-4)). When the scleroderma and Fleischner systems were combined, termed the progressive fibrotic system (C-statistic 0.71), they identified a patient subset (n=36) with a progressive fibrotic phenotype and similar 4-year survival to IPF. On multivariable analysis, with adjustment for patient age, sex and smoking status, when analysed alongside the progressive fibrotic system, the VRS threshold of 4.4% independently predicted outcome (model C-statistic 0.77).The combination of two visual CT-based staging systems identified 23% of an RAILD cohort with an IPF-like progressive fibrotic phenotype. The addition of a computer-derived VRS threshold further improved outcome prediction and model fit, beyond that encompassed by RAILD measures of disease severity and extent.
30932440 Occult HBV infection may negatively impact on drug survival in patients with rheumatoid ar 2019 Apr 1 We performed a retrospective analysis to evaluate the survival on first line biologic drug of rheumatoid arthritis (RA) patients with potential occult HBV infection (pOBI). We analysed longitudinal data of 486 consecutive RA patients starting a first biological drug in a time frame from 1st January 2008 to 31st December 2014. Demographic and disease related characteristics were collected at baseline and at the last observation visit. Baseline serological markers of HBV infection and causes of treatment discontinuation were also recorded. Primary endpoint was the influence of pOBI on drug survival, estimated by Kaplan-Meier life table analysis. Estimates hazard ratios (HRs) of drug discontinuation, adjusted for disease characteristics, biological drug class and HBcAb status were computed by Cox-regression models. The retention rate was significantly lower in pOBI positive patients (58.2%) when compared to pOBI negative ones (67.8%) and this data was confirmed also when only discontinuation due to ineffectiveness was considered (pOBI positive 66.4% vs pOBI negative 75.3%, long rank 7.93, p=0.005). Cox regression models showed a significant association between HBcAb-neg (HR 0.58, 0.41-0.84), higher ESR-DAS28 at baseline (HR 1.07, 1.03-1.11) or RF/ACPA-neg (HR 1.46, 1.04-2.06) and drug discontinuation. Occult HBV infection seems to influence negatively the effectiveness of biological therapies in RA patients.
29998520 ALIGNed on adherence: subanalysis of adherence in immune-mediated inflammatory diseases in 2019 Jan BACKGROUND: Non-adherence to medication is a challenging problem in daily clinical practice. OBJECTIVE: To assess reasons for non-adherence in patients with chronic immune-mediated inflammatory diseases (IMIDs) in a direct comparison including evaluation of treatment necessity and concerns. METHODS: ALIGN was a non-interventional, multicountry, multicentre, self-administered, cross-sectional, epidemiologic survey study. Here, we investigate the German, Austrian and Swiss (DACH) cohort. Six hundred thirty-one patients with different IMIDs (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease and ulcerative colitis) under systemic therapies were evaluated concerning adherence, beliefs of necessity and concerns towards treatment in patients with IMIDs. RESULTS: The DACH cohort had significantly different levels of adherence depending on the IMID (P < 0.05) and the type of therapy (P < 0.05). Based on the significant influence of concerns on treatment adherence (P < 0.05) and the high belief of treatment necessity, patients could be classified in four attitudinal segments, which were unequally distributed throughout various IMIDs. High concerns had a significant influence on non-adherence, whereas necessity did not. Older age, female sex, TNFi mono-, conventional combination and TNFi combination therapy are positively associated with adherence. CONCLUSIONS: In the DACH region, patients are less concerned about medication and believe in the necessity of treatment. Therefore, we suggest adapting the communication in the various patient groups.
30275261 Relationship Between Insulin Sensitivity and β-Cell Secretion in Nondiabetic Subjects wit 2019 Mar OBJECTIVE: In nondiabetic healthy individuals, insulin secretion and sensitivity are linked by a negative feedback loop characterized by a hyperbolic function. We aimed to study the association of traditional insulin resistance (IR) factors with insulin secretion and sensitivity, and to determine whether the hyperbolic equilibrium of this relation is preserved in patients with rheumatoid arthritis (RA). METHODS: This was a cross-sectional study encompassing 361 nondiabetic individuals: 151 with RA and 210 controls. Insulin, C-peptide, and IR indices by homeostatic model (HOMA2) were assessed. A multivariable analysis was performed to evaluate the differences in the correlation of traditional IR-related factors with glucose homeostasis molecules, as well as IR indices between patients and controls. Nonlinear regression analysis was used to assess the hyperbolic relation of insulin sensitivity and secretion. RESULTS: HOMA2-IR indices were higher in patients with RA than controls. Hepatic insulin extraction, as assessed by the insulin:C-peptide molar ratio, was lower in patients with RA after multivariable analysis (0.08 ± 0.02 vs 0.14 ± 0.07, p < 0.001). Traditional IR-related factors showed significantly lower adjusted correlation coefficients with IR indices in patients with RA. The association between insulin sensitivity and secretion showed a different hyperbolic relation in patients with RA: the variability explained by the curve was lower in RA (nonlinear r(2) = 0.845 vs r(2) = 0.928, p = 0.001) and β coefficients (-0.74, 95% CI -0.77 to -0.70 vs -1.09, 95% CI -1.17 to -1.02, ng/ml, p < 0.001) were different in RA. CONCLUSION: The traditional factors associated with IR in healthy individuals are less related to IR in patients with RA. Insulin sensitivity and secretion yield a different hyperbolic equilibrium in RA.
31243259 Tocilizumab and rituximab have similar effectiveness and are both superior to a second tum 2019 Apr OBJECTIVES: To compare the effectiveness of a 2nd TNF inhibitor (TNFi), Tocilizumab (TCZ) and Rituximab (RTX), measured by drug retention and by response rates, in RA patients after discontinuing a first-line TNFi and to clarify the reasons and predictors for discontinuation of a second-line biologic. MATERIAL AND METHODS: Non-interventional prospective study of RA patients exposed to a 2nd TNFi, TCZ or RTX after previous TNFi discontinuation using real-world data from Reuma.pt database. Drug retention was estimated using Kaplan-Meier analysis and Cox models. Crude and LUNDEX adjusted response rates were evaluated at 6 months, 1 and 2 years and reasons for discontinuation were compared according to biologic class. RESULTS: In total, 643 patients were included, 88.8% females, with a mean age of 59.4±12.8 years. Of those, 390 (60.7%) initiated a 2nd TNFi, 147 (22.9%) TCZ and 106 (16.5%) RTX. Drug retention was significantly greater among patients who initiated TCZ (76.4±4.3 months) or RTX (80.8±4.8 months), compared with those who initiated a 2nd TNFi (52.7±2.6 months) (log rank test, p < 0.001). In the adjusted Cox model, hazards of discontinuation were significantly lower for TCZ (HR 0.39, 95% CI 0.23-0.64, p < 0.001) and RTX (HR 0.42, 95% CI 0.25-0.72, p=0.001). Smokers had a significantly higher risk for discontinuation (HR 2.43, 95%CI 1.50-3.95, p < 0.001) as well as patients with higher HAQ at baseline (HR 1.51, 95%CI 1.14-2.00, p=0.004). The proportion of patients in remission or low disease activity according to Clinical Disease Activity Index (CDAI) at 6 months, 1 and 2 years was, respectively, 46.5%/50.0%/61.2% for TNFi, 52.9%/53.6%/ 69.2% for TCZ and 37.7%/48.0%/50.0% for RTX. After LUNDEX adjustment, response rates were, respectively, 33.0%/31.0%/31.8% for 2nd TNFi, 42.8%/41.8%/53.3% for TCZ and 32.0%/39.4%/39.0% for RTX. The main reasons for discontinuation were inefficacy for 2nd TNFi and RTX and adverse events for TCZ (p < 0.001). CONCLUSIONS: Our findings showed a significantly higher drug retention for TCZ and RTX, compared with 2nd TNFi, and similar persistence among TCZ and RTX, in patients who discontinued a first-line TNFi. These data corroborate the notion that switching to a biologic with a different mode of action is more effective than to a second TNFi.