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31145323 Surgical treatment of the severely damaged atlantoaxial joint with C1-C2 facet spacers: Th 2019 May RATIONALE: Atlantoaxial subluxation (AAS), caused by congenital factors, inflammation such as rheumatoid arthritis, infection, neoplasia, or trauma, is rare and severely erodes and subluxates atlantoaxial (AA) joints. For these patients, surgical reduction, and stabilization are difficult. Surgery, including anterior transoral decompression and posterior fixation, anterior endonasal decompression and fixation, and posterior decompression with AA or occipitocervical fixation, is often the only treatment available. However, there have only been 2 reports of C1-C2 facet spacer use in treating AAS. Here, we report the case histories of 3 patients with severely damaged and subluxated AA joints and symptomatic basilar invagination (BI), malalignment, or C2 root compression. PATIENT CONCERNS: The cases included 2 women with rheumatoid arthritis and 1 man with spondyloarthropathy secondary to ulcerative colitis. DIAGNOSIS: Radiographic imaging revealed severely damaged and subluxated AA joints. Their symptoms included worsening pain in the neck or occiput with or without myelopathy and neuralgia. INTERVENTIONS: After realignment with C1-C2 spacers and posterior C1-C2 screw fixation, the patient symptoms were resolved. OUTCOMES: Of note, 2 of the 3 patients were healed without complications. One patient who underwent secondary revision surgery because of rod breakage and obvious nonunion at C0-C2 was determined to be healed at 1-year follow-up after the revision surgery. LESSONS: We confirmed that C1-C2 facet spacers both reduced BI and occipitocervical coronal malalignment as well as releasing C2 root compression. Therefore, surgical restoration and fixation should be a required treatment in this very rare group of patients.
30381062 Can We Extrapolate Data from One Immune-Mediated Inflammatory Disease to Another One? 2019 Immune-mediated inflammatory diseases share several pathogenic pathways and this pushes sometimes to extrapolate from one disease or indication to others. A biosimilar can be defined as a biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product. We review the substrate for extrapolation, the current approval process for biosimilars and the pioneering studies on biosimilars performed in rheumatoid arthritis patients. A biosimilar has the same amino acid sequence as its innovator product. However, post-translational modifications can occur and the current analytical techniques do not allow the final structure. To test the efficacy in one indication, a homogeneous population should be chosen and immunogenicity features are essential in switching and interchangeability. CT-P13 (Remsima™; Inflectra™) is a biosimilar of reference infliximab (Remicade®). It meets most of the requirements for extrapolation. Nevertheless, in inflammatory bowel diseases (IBD) we need more studies to confirm the postulates of extrapolation from rheumatoid arthritis and ankylosing spondylitis to IBD. Furthermore, an effective pharmacovigilance schedule is mandatory to look for immunogenicity and side effects.
30701346 Hydroxychloroquine is a safe and effective steroid-sparing agent for immune checkpoint inh 2019 May Immunotherapy for cancer treatment continues to evolve, and immune checkpoints have proven successful therapeutic targets. With success has come the challenge of managing the commonly associated immune-related toxicities. Arthralgias and arthritis are a common immune-related adverse event (IrAE), well described in the literature (Pardoll Nat Rev Cancer 12:252-264, 2012; Diesendruck and Benhar Drug Resist Updat 30:39-47, 2017; Cappelli et al. Arthritis Care Res 69:1751-1763, 2017; Brahmer et al. J Clin Oncol 36:1714-1768, 2018; Smith and Bass (2017). The optimal management of immune checkpoint inhibitor (ICI)-induced arthritis remains unclear. We describe the first series using hydroxychloroquine as a first-line disease-modifying antirheumatic drug (DMARD) for patients without pre-existing autoimmune disease, who developed arthritis secondary to ICI's. This was a single-center retrospective observational study reporting all patients evaluated by rheumatologists affiliated with the University of Alberta, a large tertiary health care center in Northern Alberta, Canada, deemed to have inflammatory arthritis (IA) following ICIs. We identified 11 patients, without pre-existing autoimmune disease, who developed IA following ICIs. Most patients presented with a symmetrical polyarthritis with both large and small joint involvement. All patients were treated according to the outlined treatment protocol with hydroxychloroquine as a first-line steroid-sparing agent: either as monotherapy or in combination with tapering doses of systemic corticosteroids (3) or intra-articular steroid injections (6). One patient required the addition of methotrexate to control symptoms and none required biologic therapy. There were no reported adverse effects from hydroxychloroquine. Inflammatory arthritis is an important complication of ICIs leading to significant impact on patient quality of life. In our experience, in patients without pre-existing autoimmune disease, hydroxychloroquine is an effective first-line therapy for IA secondary to ICI therapy.
30357484 Tocilizumab-induced psoriasis-like eruption resolved by shortening the dose interval in a 2019 Jan Tocilizumab (TCZ) is a humanized antihuman interleukin-6 (IL-6) receptor antibody used for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). While TCZ could act as a therapeutic agent, it has a potential for inducing adverse drug events including psoriasis-like eruption. Seven cases with specific reference to TCZ-induced psoriasis eruption have been reported worldwide so far. In these cases, treatments with the same dosage of TCZ were either maintained or discontinued. Herein, we report a case involving a 74-year-old man diagnosed with rheumatoid factor-positive and anti-citrullinated protein antibody-positive RA with comorbidity of atopic dermatitis. TCZ was administered intravenously with oral methotrexate. After the third infusion, the patient developed TCZ-induced psoriasis-like eruptions, which were resolved by shortening the dose interval. Eruption recurrence was not observed after frequent TCZ subcutaneous injection. Our case may help physicians manage TCZ-induced psoriasis-like eruption.
31161486 Clinical predictors of remission and low disease activity in Latin American early rheumato 2019 Oct OBJECTIVES: To identify baseline predictors of remission and low disease activity (LDA) in early rheumatoid arthritis (RA) from the GLADAR (Grupo Latino Americano De estudio de la Artritis Reumatoide) cohort. METHODS: Patients with 1- and 2-year follow-up visits were included. Remission and LDA were defined by DAS28-ESR (< 2.6 and ≤ 3.2, respectively). Baseline predictors examined were gender, ethnicity, age at diagnosis, socioeconomic status, symptoms' duration, DMARDs, RF, thrombocytosis, anemia, morning stiffness, DAS28-ESR (and its components), HAQ-DI, DMARDs and corticosteroid use, and Sharp-VDH score. Multivariable binary logistic regression models (excluding DAS28-ESR components to avoid over adjustment) were derived using a backward selection method (α-level set at 0.05). RESULTS: Four hundred ninety-eight patients were included. Remission and LDA/remission were met by 19.3% and 32.5% at the 1-year visit, respectively. For the 280 patients followed for 2 years, these outcomes were met by 24.3% and 38.9%, respectively. Predictors of remission at 1 year were a lower DAS28-ESR (OR 1.17; CI 1.07-1.27; p = 0.001) and HAQ-DI (OR 1.48; CI 1.04-2.10; p = 0.028). At 2 years, only DAS28-ESR (OR 1.40; CI 1.17-1.6; p < 0.001) was a predictor. Predictors of LDA/remission at 1 year were DAS28-ESR (OR 1.42; CI 1.26-1.61; p < 0.001), non-use of corticosteroid (OR 1.74; CI 1.11-2.44; p = 0.008), and male gender (OR 1.77; CI 1.2-2.63; p = 0.036). A lower baseline DAS28-ESR (OR 1.45; CI 1.23-1.70; p < 0.001) was the only predictor of LDA/remission at 2 years. CONCLUSIONS: A lower disease activity consistently predicted remission and LDA/remission at 1 and 2 years of follow-up in early RA patients from the GLADAR cohort. Key Points • In patients with early RA, a lower disease activity at first visit is a strong clinical predictor of achieving remission and LDA subsequently. • Other clinical predictors of remission and LDA to keep in mind in these patients are male gender, non-use of corticosteroids and low disability at baseline. • Not using corticosteroids at first visit is associated with a lower disease activity and predicts LDA/remission at 1 year in these patients.
30245093 Predictors for progression of two different types of cervical lesions in rheumatoid arthri 2019 Mar BACKGROUND: Biologic agents (BAs) enabled not only a reduction of disease activity but also a slowing down of structural damage to the joints in patients with rheumatoid arthritis (RA). However, the incidence of cervical lesions in patients with RA is still high. PURPOSE: To elucidate the predictors for the progression of two different cervical lesions in patients with RA under BA treatment. METHODS: Of 151 subjects who received more than two years of continuous BA treatment, 101 subjects who had cervical X-ray images taken at baseline and final visit were enrolled. The mean disease duration and mean radiography interval were 10.6 years and 4.4 years, respectively. The existence and progression of cervical lesions (atlanto-axial subluxation [AAS], vertical subluxation [VS], and subaxial subluxation [SS]) were investigated. And predictors for the AAS or VS progression were analyzed by multivariate logistic regression analysis. RESULTS: The incidence of cervical lesions at baseline were no pre-existing cervical lesion (none) in 50 cases (50%), AAS only in 32 (32%), both AAS and VS in 12 (12%), and VS only in 7 cases (7%). In the none group, only 4 cases of AAS progression (8%) was observed during the follow-up. In contrast, in the groups with pre-existing cervical lesions, a high incidence of VS progression was observed (63% in the AAS only group, 58% in the AAS + VS group, and 71% in the VS only group). Multivariate regression analysis demonstrated that the DAS-CRP value at baseline (odds ratio [OR] = 9.23) and matrix metaloprotease-3 level at baseline (OR = 1.01) were significant predictors for the progression of AAS, and pre-existing AAS (OR = 18.38) was a sole significant predictor for the progression of VS. CONCLUSIONS: Cervical lesions progressed irrespective of disease activity after AAS development. Strict disease control before the development of AAS is crucial for preventing further progression and development of cervical lesions.
30799529 Disability due to rheumatic diseases in the city of Junín, Argentina. 2019 Apr The aim of the study is to analyze the characteristics of patients with rheumatic diseases applying for a Disability Certificate (DC). Every application for DC filed by patients of 16 years of age and older in the Health Secretariat of Junin, between 2012 and 2016, was analyzed regarding age, gender, rheumatic disease as the cause of disability, employment status, and health insurance coverage. Applications were examined as per two elements: inflammatory articular or systemic disease (IASD) versus degenerative diseases, regional or generalized pain syndromes (non-IASD). Based on the DCs accepted, a Disability Prevalence Rate (DPR) was estimated and the most common causes of disability were determined. Out of 400 applications, 68% belonged to women; applicants' median age was 61 years, only 27% were working, 42% were for DC renewal, and 46% were IASD. Overall, 83% of the applications submitted were accepted. Those patients with accepted DC applications were older (median age 62 vs 55; p < 0.001), had health insurance coverage (90% vs 65%; p <0.001), were applying for DC renewal (49% vs 12%; p < 0.001) and more frequently presented a IASD (52% vs 17%; p < 0.001). 48% of accepted DC applications had osteoarthritis (OA), 36% rheumatoid arthritis (RA), 6% psoriatic arthritis (PsA), 5% systemic lupus erythematosus (SLE) and 2% ankylosing spondylitis (AS). The DPR was 0.5%. Overall, the accepted applications for DC belong to older patients with health insurance coverage, who were submitting an application for DC renewal and suffer from a IASD. OA, RA, PsA, SLE and AS were the five most common causes of disability.
31396834 Safety of adalimumab biosimilar MSB11022 (acetate-buffered formulation) in patients with m 2019 Dec OBJECTIVES: To compare the safety, efficacy, and immunogenicity of MSB11022 (acetate-buffered formulation), an adalimumab biosimilar, with the reference product. METHOD: AURIEL-RA study was a phase 3, multicenter, randomized, double-blind, parallel group trial (NCT03052322). Patients with moderately-to-severely active rheumatoid arthritis (RA) with an inadequate response to methotrexate were randomized 1:1 to MSB11022 or reference adalimumab. The primary endpoint was the incidence of treatment-emergent adverse events of special interest (AESIs) (predefined as hypersensitivity) up to week 52. The key secondary endpoint was ACR20 (≥ 20% improvement in American College of Rheumatology core set measurements from baseline) at week 12. Other efficacy endpoints, quality of life, immunogenicity, and pharmacokinetic parameters were evaluated up to week 52. Secondary safety endpoints were evaluated up to week 52 and at a 4-month safety follow-up. RESULTS: In total, 288 patients were randomized. The proportion of patients experiencing ≥ 1 treatment-emergent AESI up to week 52 was similar between trial arms: 6 patients (4.2%; 95% CI 1.56, 8.91) receiving MSB11022, and 8 patients (5.5%; 95% CI 2.41, 10.58) receiving reference adalimumab. No clinically meaningful differences in efficacy, quality of life, or immunogenicity were seen between treatment arms up to week 52. No notable difference in the incidence of treatment-emergent adverse events was observed between treatment arms up to the end of the follow-up period. CONCLUSIONS: These results suggest MSB11022 and reference adalimumab are similar in patients with moderately-to-severely active rheumatoid arthritis in terms of safety, immunogenicity, and efficacy. AURIEL-RA provides evidence to support the similarity of MSB11022 and adalimumab.Key Points• Incidences of hypersensitivity events were similar for MSB11022 (modified buffer) and reference adalimumab.• There was no difference in local reactions between MSB11022 (modified buffer) and reference adalimumab.• AURIEL-RA confirms the equivalence in efficacy and immunogenicity of MSB11022 (modified buffer) and reference adalimumab.
31818003 GRK2 Mediated Abnormal Transduction of PGE2-EP4-cAMP-CREB Signaling Induces the Imbalance 2019 Dec 8 Rheumatoid arthritis (RA) is characterized by the massive infiltration of various chronic inflammatory cells in synovia. In synovial fluid of patients with RA, M1 macrophages are dominant among all subtypes of macrophages, the mechanisms of macrophages polarization imbalance in RA has not been fully illuminated. The prostaglandin E2 (PGE2) augments M2 polarization in part via the cyclic adenosine monophosphate (cAMP)-cyclic AMP responsive element binding (CREB) signaling. However, previous study found constant stimulus of PGE2 on fibroblast-like synovial cells of adjuvant arthritis rats induced the decrease of cAMP, which is primarily caused by G protein-coupled receptor kinase 2 (GRK2)-induced EP4 over- desensitization. Whether GRK2 mediated-EP4 over-desensitization reduces the level of cAMP and inhibits M2 polarization in RA is unclear. Here we observed M1 macrophages were dominant in peritoneal macrophages (PMs), bone-marrow-derived macrophages (BMMs) and synovial macrophages of collagen-induced arthritis (CIA) mice. PGE2 stimulated M2 polarization via the EP4-cAMP-CREB in normal mice, while failed to promote M2 polarization in the PMs of CIA mice. Further, we found the EP4 over-desensitization stimulated by PGE2 induced abnormal PGE2-cAMP-CREB signaling as well as the imbalance of macrophage polarization. Targeted disruption of GRK2 in Raw264.7 (RAW) through GRK2 siRNA or CRISPR/Cas9 downregulated the M1 macrophage markers, upregulated the M2 macrophage markers and the EP4 membrane localization. The reduced M1/M2 ratio and increased p-CREB expression were observed in BMMs and PMs of GRK2(+/-) mice. This study highlighted a novel role of GRK2 in regulating macrophages function in RA and provided new idea for precision treatment of RA.
30503342 Vascular endothelial growth factor signaling in VE-cadherin expression and tube-like forma 2019 Jan 8 An increase in the vasculature is one of most representative changes in the synovial tissue of joints in rheumatoid arthritis (RA) and is closely associated with disease progression. Although the vasculatures are believed to be a result of VE-cadherin-dependent angiogenesis and a possible therapeutic target of the disease, synovial fibroblastic cells express VE-cadherin and form tube-like structures, suggesting that vasculatures in RA synovium may not simply result from angiogenesis. This paper analyzes a mechanism of VE-cadherin expression by rheumatoid arthritic synovial fibroblast-like cells (RSFLs) and their involvement in the tube-like formation. A representative angiogenic factor, vascular endothelial growth factor (VEGF), and its binding to a predominant receptor (VEGFR2) activated VE-cadherin expression and the signaling pathways of ERK/MAPK and PI3K/AKT/mTOR. Treatment of RSFLs with signaling pathway inhibitors, VEGFR2 siRNA and a VEGF-antagonizing mimicking peptide inhibited VE-cadherin expression dose-dependently. VEGF-stimulated tube-like formation by RSFLs on Matrigel was hindered by the mimicking peptide and inhibitor treatment. This data demonstrates that RSFLs activated by VEGF binding of VEGFR2 express VE-cadherin and formed tube-like structure under the control of ERK/MAPK and PI3K/AKT/mTOR pathways suggesting that the inhibition suppresses vascular development in RA synovium.
31222078 Antibiotic treatment and flares of rheumatoid arthritis: a self-controlled case series stu 2019 Jun 20 There is emerging evidence of the impact of infections on rheumatoid arthritis pathogenesis and flares. We aimed to study the association between antibiotic use (and timing of use), and the occurrence of flares in patients with RA. We nested a self-controlled case series (SCCS) of patients who have RA flares within a newly diagnosed RA cohort (n = 31,992) from the UK Clinical Practice Research Datalink (CPRD) GOLD dataset. We determined associations between exposure to antibiotics (beta-lactam, imidazole, macrolide, nitrofurantoin, quinolone, sulphonamide and trimethoprim, and tetracycline) and the occurrence of RA flares. Conditional fixed-effects Poisson regression models were used to determine incidence rate ratios (IRR), offset by the natural logarithm of risk periods. A total of 1,192 (3.7%) of RA subjects had one or more flare/s during the study period, and were therefore included. Use of sulphonamide and trimethoprim was associated with an increased risk of RA flare at 29-90 days (IRR 1.71, CI 1.12-2.59, p = 0.012); 91-183 days (IRR 1.57, CI 1.06-2.33, p = 0.025); and 184-365 days (IRR 1.44, CI 1.03-2.02, p = 0.033) after commencement of antibiotic treatment. No other antibiotic group/s appear associated with RA flare/s risk. Usage of sulphonamide and trimethoprim antibiotics, is associated with a 70% increased risk of RA flare at 1-3 months, which decreases but remains significant up to 12 months after treatment. We hypothesise that the delayed onset of RA flares after specific antibiotics is mediated through the gut or urinary microbiomes. Further epidemiological and mechanistic research is needed to determine the role of infections in RA.
31077451 Ocular complications of tumour necrosis factor alpha inhibitors. 2020 Mar Tumour necrosis factor alpha inhibitors are a relatively recent development and are becoming increasingly common in the management of many chronic inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis and juvenile idiopathic arthritis. However, their ocular side effect profile is incomplete and poorly recognised, with mostly anecdotal cases reported in the literature. In this report we review the literature regarding ocular side effects associated with tumour necrosis factor alpha blockade.
31276975 Mechanism of action of celastrol against rheumatoid arthritis: A network pharmacology anal 2019 Sep Network pharmacology uses bioinformatics to broaden our understanding of drug actions and thereby to advance drug discovery. Here we apply network pharmacology to generate testable hypotheses about the multi-target mechanism of celastrol against rheumatoid arthritis. We reconstructed drug-target pathways and networks to predict the likely protein targets of celastrol and the main interactions between those targets and the drug. Then we validated our predictions of four candidate targets (IKK-β, JNK, COX-2, MEK1) by performing docking studies with celastrol. The results suggest that celastrol acts against rheumatoid arthritis by regulating the function of several signaling proteins, including MMP-9, COX-2, c-Myc, TGF-β, c-JUN, JAK-1, JAK-3, IKK-β, SYK, MMP-3, JNK and MEK1, which regulate the functions of Th1 and Th2 cells, macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Celastrol is predicted to affect networks involved mainly in cancer, connective tissue disorders, organismal injury and abnormalities, tissue development, cell death and survival. This network pharmacology strategy may be useful for discovery of multi-target drugs against complex diseases.
31526517 Trends of Cardiac Complications in Patients With Rheumatoid Arthritis: Analysis of the Uni 2021 Mar BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory condition. Chronic inflammation is associated with atherosclerosis, hypertension, diabetes, chronic obstructive pulmonary disease (COPD), chronic kidney disease. But sparse data are available regarding the trends of cardiovascular diseases and complications in RA. We conducted a National Inpatient Sample database analysis to demonstrate the trends of cardiac complications in patients with RA. METHODS: We used National Inpatient Sample data from 2005 to 2014 to identify admissions with the diagnosis of RA and identified who had associated cardiovascular complications also. The International Classification of Diseases-9th Revision-Clinical Modification codes were used for the diagnoses of RA; congestive heart failure (CHF), acute myocardial infarction (AMI), and atrial fibrillation (AF). RESULTS: A statistically significant increasing trend of AMI, CHF, and AF was found. Independent predictors of mortality in RA patients with AMI were age (OR 1.03, CI 1.02-1.04; P < 0.001), COPD (OR 1.67, CI 1.40-2.00; P < 0.001), cerebrovascular disease (OR 2.207, CI 1.71-2.86; P < 0.001), renal disease (OR 1.42, CI 1.16-1.75; P = 0.001), and alcohol abuse (OR 2.73, CI 1.73-4.32; P < 0.001). Independent predictors of mortality in RA patients with CHF were age (odds ratio [OR] 1.02, confidence interval [CI] 1.017-1.024; P < 0.001]), COPD (OR 1.09, CI 1.01-1.18; P = 0.023), cerebrovascular disease (OR 1.67, CI 1.44-1.95; P < 0.001), renal disease (OR 1.16, CI 1.07-1.27; P = 0.001). Independent predictors of mortality in RA patients with AF were age (OR 1.02, CI 1.02-1.03; P < 0.001), race (OR 1.16, CI 1.02-1.31; P = 0.022), COPD (OR 1.56, CI 1.42-1.71; P < 0.001), peripheral arterial disease (OR 1.34, CI 1.16-1.53; P < 0.001), cerebrovascular disease (OR 2.27, CI 1.0-2.58; P < 0.001), renal disease (OR 1.60, CI 1.44-1.80; P < 0.001). The mortality trend has increased significantly in the CHF (P = 0.025) and AF (P = 0.042) groups during this study period. CONCLUSIONS: We have found a significant increase in trend of cardiovascular complications in RA patients. The proportion of patients, with cardiovascular comorbidities, have also been increased significantly.
30943139 Antidrug antibody detection for adalimumab depends on the type of assay used: an experimen 2019 Sep OBJECTIVES: To compare different methods of antidrug antibody (ADA) against adalimumab detection in ankylosing spondylitis (AS) patients and the impact of ADA on adalimumab drug levels and mean ASDAS-CRP. METHODS: We used the acid-dissociation-radioimmunoassay (ARIA), antidrug-binding-test (ABT) and a bridging Enzyme-linked Immunosorbent Assay (ELISA) to detect ADA at 4, 12 and 24 weeks of treatment. Patients were divided into groups; all assays negative (All-neg), only ARIA positive (ARIA-only-pos), ARIA and ABT positive, bridging ELISA negative (ARIA/ABT-double-pos) and all assays positive (All-pos). RESULTS: Eighty-three consecutive AS patient were included. At week 4, 18% compared to 11% and 0% of the patients tested positive for ADA in the ARIA, ABT and bridging ELISA, respectively. At week 12 and 24, cumulative 52% and 69% patients tested positive in the ARIA, compared to 27% and 30% patients in the ABT and 2% patients in the bridging ELISA. Adalimumab levels between All-neg and ARIA-only-pos were 9.1 (5.5-12.5) and 8.5 (5.7-12.3). Drug levels differed between ARIA/ABT-double-pos (2.7 (1.3-4.4)) and All-neg (9.1 (5.5-12.5)). All-pos patients had undetectable drug levels. Mean ASDAS-CRP at week 24 differs between All-neg (1.9 (±1.2)), and All-pos (3.8 (±1.9)) and ARIA/ABT-double-pos (2.0 (±1.1)) and All-pos. CONCLUSIONS: The majority of AS patients had detectable ADA against adalimumab in the ARIA. The ARIA detects more ADA compared to the less drug tolerant ABT and bridging ELISA. The clinical relevance depends on the impact on the bio-availability of the drug. A drug level measurement therefore helps to interpret ADA data regardless of type of assay used.
31174962 Trabecular Bone Score Is a Useful Parameter for the Prediction of Vertebral Fractures in P 2020 Jul INTRODUCTION: Polymyalgia rheumatica (PMR), a benign rheumatic disorder, requires long-term glucocorticoid therapy, which could be associated with osteoporosis. In the present study, we compared bone mineral density (BMD), trabecular bone score (TBS) and frequencies of vertebral fracture (VF) among patients with PMR or rheumatoid arthritis (RA) and controls. METHODS: Fifty-three postmenopausal women with PMR aged 50 yr or older were eligible for inclusion in this study. Subjects in RA (n = 106) and control (n = 106) groups were selected by propensity score matching with controlling age, body mass index and use of anti-osteoporotic agents. RESULTS: The frequency of VF in patients with PMR (30.2%) was significantly higher than those in patients with RA (13.2 %) and controls (13.2%, p = 0.017). The mean TBS of patients with PMR (1.317 ± 0.092) was significantly lower than those of patients with RA (1.336 ± 0.089) and the controls (1.373 ± 0.073, p < 0.001). In receiver operating characteristic analysis for VF in patients with PMR, the area under the curve (AUC) was 0.759 (95% confidence interval [CI] = 0.601-0.918, p < 0.001) for TBS and 0.618 (95% CI = 0.442-0.795, p < 0.001) for L-spine BMD. The AUCs were 0.760 (95% CI = 0.630-0.891, p ≤ 0.001) and 0.767 (95% CI 0.627-0.907, p < 0.001) for femur neck and total hip BMD, respectively. Multivariate analysis identified the factor associated with VF of patients with PMR as a lower TBS (Odds ratio: 0.000, 95% CI: 0.000, 0.754, p = 0.043). CONCLUSION: TBS could be a supplementary tool for discriminating osteoporotic fractures in postmenopausal patients with PMR.
31333103 Role and Function of Adenosine and its Receptors in Inflammation, Neuroinflammation, IBS, 2019 The physiological effects of endogenous adenosine on various organ systems are very complex and numerous which are elicited upon activation of any of the four G-protein-coupled receptors (GPCRs) denoted as A1, A2A, A2B and A3 adenosine receptors (ARs). Several fused heterocyclic and non-xanthine derivatives are reported as a possible target for these receptors due to physiological problems and lack of selectivity of xanthine derivatives. In the present review, we have discussed the development of various new chemical entities as a target for these receptors. In addition, compounds acting on adenosine receptors can be utilized in treating diseases like inflammation, neuroinflammation, autoimmune and related diseases.
31342216 Modeling Combined Anti-Inflammatory Effects of Dexamethasone and Tofacitinib in Arthritic 2019 Jul 24 Tofacitinib (TOF), a Janus kinase (JAK) inhibitor, which was approved in 2012, has been recommended for the treatment of clinically active rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid, is also used in RA therapy but with limited usefulness due to dose- and time-dependent adverse effects. This pilot study examines the single and combined effects of DEX and TOF in order to explore the steroid-sparing potential of TOF. Collagen-induced arthritic (CIA) rats were subcutaneously (SC) dosed with vehicle, 1.5 mg/kg TOF, 5 mg/kg TOF, 0.225 mg/kg DEX, or a combination of 1.5 mg/kg TOF and 0.225 mg/kg DEX. Paw sizes were measured as an index of disease and drug efficacy and dynamically depicted using a logistic function for natural paw growth, a turnover model for disease progression, an indirect response model for inhibitory effects of TOF and DEX and a non-competitive interaction model for the combined effect of DEX and TOF. TOF alone exerted only a slight inhibitory effect on RA paw edema compared to DEX, which reduced edema by 40%. In combination, TOF and DEX had additive effects with an interaction factor of 0.76. Using model simulations, a single SC dose of TOF does not have a visible steroid-sparing potential, although BID oral dosing has such potential. The current study suggests an additive effect of TOF and DEX and simulations indicate that further exploration of TOF and DEX administration timing may produce desirable drug efficacy with lower DEX doses.
29635017 Impact of obesity on the efficacy of different biologic agents in inflammatory diseases: A 2019 Mar OBJECTIVE: Obesity is a worldwide epidemic and a growing body of evidence suggests that it may affect the body's response to biologic agents. We investigated the influence of obesity on the efficacy of different biologic agents used to treat inflammatory diseases. METHODS: Medline, EMBASE and the Cochrane Database were searched using relevant MeSH and keyword terms for obesity and bDMARDs. Articles were selected if they reported a clinical response in obese subjects relative to other BMI categories. Response and remission outcomes were assessed using meta-analysis and all other reported outcomes were summarized. RESULTS: Among the 3850 records retrieved, 24 articles met the inclusion criteria, including 10 on rheumatoid arthritis (RA), 4 on axial spondyloarthritis (axSpA), 4 on Crohn's disease (CD), 4 on psoriasis (Ps) and 2 on psoriasic arthritis (PsA). Four biological disease-modifying anti-rheumatic drugs (bDMARDs) - anti-TNF agents, T cell co-stimulation inhibitor (abatacept), IL-6 inhibitor (tocilizumab), and B-cell depletion therapy (rituximab) - were involved. The meta-analysis showed that the odds to reach a good response or achieve remission were lower in obese (BMI>30kg/m(2)) than non-obese (BMI≤30kg/m(2)) patients who were treated with anti-TNF agents (good responder % in RA: OR 0.34, 95% CI 0.18-0.64; remission% in RA: OR 0.36, 95% CI 0.21-0.59; BASDAI50% in axSpA: OR 0.41, 95% CI 0.21-0.83), but no significant difference between obese and non-obese was found in patients treated with abatacept (good responder % in RA: OR 0.75, 95% CI 0.42-1.36; remission% in RA: OR 0.84, 95% CI 0.65-1.09) and tocilizumab (good responder % in RA: OR 1.08, 95% CI 0.44-2.63; remission% in RA: OR 0.91, 95% CI 0.50-1.66). CONCLUSION: Obesity hampered the effect of anti-TNF agents, but not those of abatacept and tocilizumab, suggesting that a personalized treatment strategy should be considered for obese patients with inflammatory diseases.
30190154 Delay in initiation of DMARD or anti-inflammatory therapy in patients newly diagnosed with 2019 Apr OBJECTIVE: To investigate factors associated with delay in initiation of initial disease-modifying antirheumatic drug (DMARD) in patients newly diagnosed with rheumatoid arthritis (RA). METHODS: We performed a retrospective cohort descriptive study using administrative data from the US military's TRICARE program (2007-2012). We identified incident RA cases using billing codes and initial DMARD receipt using prescription fill date. We quantified the time between RA presentation and initial DMARD receipt, evaluated temporal changes in delay over the study period, and investigated predictors of treatment delay (> 90 days) using logistic regression. RESULTS: We identified 16,680 patients with incident RA that were prescribed DMARDs and mean age was 47.2 (SD 13.5) years. The mean time from initial RA presentation to first DMARD prescription receipt was 125.3days (SD 175.4). Over one-third (35.6%) of incident RA patients initiated DMARD > 90days after presentation. There was less treatment delay in later years of the study (mean days to DMARD of 144.7days in 2007; 109.7days in 2012). Patients prescribed opioids had mean time to DMARD of 212.8days (SD 207.4) compared to mean of 77.3days (SD 132.3) for those who did not use opioids (p < 0.0001). Patients prescribed opioids between RA presentation and initial DMARD receipt were more likely to have delay in initial DMARD (OR 4.07, 95% CI: 3.78-4.37). CONCLUSION: In this large US nationwide study, delays in initial DMARD receipt for incident RA were common but time to treatment improved in recent years. While further analysis using clinical data is warranted, these findings suggest that limiting opioid use in patients newly presenting with RA may decrease delay in initiating DMARDs.