Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
29066107 Clinical and Radiographic Outcomes at 25-30 Years of a Hip Stem Fully Coated With Hydroxyl 2018 Feb BACKGROUND: Little is known about the survival of total hip arthroplasty implants with bioactive coatings beyond the first 20 years. The authors aimed to report survival of a tapered hip stem fully coated with hydroxylapatite (HA) at follow-up of 25-30 years. METHODS: Of the original series of 320 patients (347 hips), 12 patients (12 hips) had stem and cup revisions, 54 patients (55 hips) had cup revisions, 17 patients (17 hips) had liner exchange. A total of 207 patients (225 hips) died with stems in place and 21 patients (24 hips) could not be reached. This left a cohort of 80 patients (86 hips) with their original stem for assessment. Survival was analyzed using the Kaplan-Meier (KM) method and cumulative incidence function (CIF). RESULTS: Considering stem revision as endpoint, the revision risk calculated using the KM method was 6.3%, whereas using the CIF it was 3.7%. Considering any reoperation as endpoint, the revision risk calculated using the KM method was 41.2%, whereas using the CIF it was 25.9%. The Harris Hip Score for 77 patients (18 hips) was 81.6 ± 15.2. Standard x-rays were available for 52 hips (49 patients), and 10 (19.2%) showed radiolucencies <2 mm thick. CONCLUSION: This study is the first to report outcomes of an HA-coated stem beyond 25 years. The survival of stem compares favorably with long-term survival of the Charnley cemented stem, and with shorter-term registry studies. The stem achieved its intended purpose of total osteointegration in the long-term, although the proximolateral region remains susceptible to radiolucencies.
29267905 Doses of rituximab for retreatment in rheumatoid arthritis: influence on maintenance and r 2018 Mar 1 OBJECTIVE: To investigate maintenance of rituximab (RTX) in RA patients re-treated with reduced doses compared with standard dose in a real life setting. METHODS: The Autoimmunity and Rituximab (AIR) registry is a nationwide prospective observational cohort investigating the long-term safety and efficacy of RTX in RA. The present study included patients from the AIR registry that have been re-treated with RTX after a first course of RTX standard dose (1000 mg × 2). Two groups were defined according to dose of RTX of the first retreatment course (i.e. second course): standard dose group and reduced dose group. Five years' maintenance and rate of serious infections of the retreatment period were compared between standard dose and reduced dose groups. Analyses used the inverse probability of treatment weighting propensity score adjusted method. RESULTS: Among the 1986 patients from the AIR registry, 1278 were included, 1093 (85.5%) treated with standard dose and 185 (14.5%) with reduced doses. Maintenance of RTX at 5 years in the standard and reduced groups was 55.5 and 53.8%, respectively, and did not significantly differ between groups in adjusted analyses (hazard ratio = 1.03; 95% CI: 0.81, 1.30), but the cumulative RTX dose received for retreatment [1.4 (0.6) vs 2.3 (1.0) g/year, P < 0.001] and the rate of serious infections were significantly lower in the reduced dose group (adjusted hazard ratio = 0.50; 95% CI: 0.27, 0.92; P = 0.02). CONCLUSION: Use of reduced doses of RTX for retreatment did not alter the maintenance of RTX at 5 years in RA patients, but allowed a 39% total dose reduction and a lower rate of serious infections.
29578855 A Comparison of Pharmacy Dispensing Channel Use and Adherence to Specialty Drugs Among Med 2018 Apr BACKGROUND: Nonadherence to specialty drugs has been associated with poor clinical and economic outcomes. Studies conducted using commercial health plans suggest that patients who use specialty pharmacies have higher adherence compared with patients using retail pharmacies. However, little is known about the frequency of dispensing channel use or the association of dispensing channel use with adherence to specialty drugs among Medicare Part D beneficiaries. OBJECTIVES: To (a) describe the use of pharmacy dispensing channels by patients using self-administered specialty drugs in Medicare Part D and (b) study the association between dispensing channel use and adherence to specialty drugs in this population. METHODS: This study analyzed 2010 Medicare Part D data. Specialty drugs were defined as drugs with a mean cost ≥ $600 per month. We identified the top 13 specialty medications by cost and classified patients into the following classes: anticancer, disease-modifying therapy (DMT), and tumor necrosis factor inhibitor (TNFi). Dispensing channels included retail, specialty, mail order, long-term care, and other. We included patients continuously enrolled in Medicare Part D who had ≥ 1 prescription for a specialty medication before the end of June 2010. These patients were followed until the end of 2010. Patients with proportion of days covered (PDC) ≥ 0.8 were considered adherent. Adherence rates were calculated by weighting for therapeutic class after weighting for drug mix. Multivariable logistic regression analysis examined the association between dispensing channel and adherence. RESULTS: Of 5,430 patients, 1,248 were dispensed anticancer medications, 1,723 were dispensed DMTs, and 2,459 were dispensed TNFi drugs. About 16% used specialty, 74% used retail, 4% used mail order, 4% used long-term care, and 3% used other channels. The distribution pattern was similar when stratified by therapeutic class. In the descriptive analysis, patients using the specialty channel for the anticancer and TNFi classes had 7% and 10% higher adherence rates, respectively, compared with retail. For the DMT class, the adherence rate was higher for mail order but similar for retail and specialty channels. Adjusted analysis found that overall, specialty users had 23% higher odds for being adherent compared with retail users (P = 0.0104). For the anticancer and TNFi classes, specialty users had 39% (P = 0.0311) and 55% (P = 0.0005) higher odds, respectively, for being adherent than retail users. For the DMT class, no significant association was observed between dispensing channel and adherence (P = 0.9691). CONCLUSIONS: Nearly three quarters of Medicare patients on specialty therapies included in this study used the retail channel compared with one sixth who used the specialty channel. Overall, specialty channel use was associated with higher adherence compared with retail channel use. However, this relationship varied by therapeutic class. The specialty channel was associated with higher adherence among patients from the anticancer and TNFi classes but not among the DMT class. DISCLOSURES: No funding supported this study. The authors reported no potential conflicts of interest. Kale, Patel, and Carroll were responsible for study concept and design. Data analysis was conducted by Kale, assisted by Patel. The manuscript was written primarily by Kale, with assistance from Carroll. Some findings from this study were presented during the poster presentation at the Academy of Managed Care Pharmacy Nexus held in National Harbor, Maryland, on October 4, 2016.
30575978 Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine 2019 May E6011 is a novel humanized antifractalkine (FKN) monoclonal antibody being developed as a therapeutic target for Crohn's disease, rheumatoid arthritis, and primary biliary cholangitis. This study was a randomized, double-blind, placebo-controlled single-ascending-dose study of intravenous administration of E6011 (0.0006-10 mg/kg) in healthy Japanese adult men (n = 64). The starting dose was the minimum anticipated biological effect level (MABEL). MABEL was estimated by extrapolating results of a pharmacokinetic/pharmacodynamic (PK/PD) model relating E6011 exposure and suppression of free soluble FKN using data obtained from cynomolgus monkeys. Safety assessments consisted of monitoring and recording adverse events, laboratory tests, vital signs, intensive electrocardiograms, and chest x-rays. Blood samples to determine PK, PD (serum total FKN concentration), and serum anti-E6011 antibody were collected. Noncompartmental analysis was used to derive PK parameters. Single intravenous infusions of E6011 were safe and well tolerated in healthy subjects. Serum E6011 concentrations showed triphasic elimination. An increase in serum total FKN concentration was observed, confirming target engagement. The dose strategy for patient studies is to select regimens that will attain a minimum serum E6011 exposure of 10 μg/mL, identified as the minimum concentration needed to saturate the target-mediated elimination pathway. Model-based drug development from preclinical stage was successful in identifying dose regimens for clinical testing.
29487871 Serum Soluble Vascular Cell Adhesion Molecule-1 Overexpression Is a Disease Marker in Pati 2018 OBJECTIVE: Antinuclear antibodies (ANA) serve as screening tests for connective tissue diseases but have low specificity. In this pilot study, we aimed to identify patients with first-time positive ANA and musculoskeletal complaints and correlate serum soluble vascular adhesion molecules as biomarkers. METHODS: Prospective, observational study with 100 ANA-positive patients, comparing them to age- and gender-matched healthy controls (HC, n = 75), was conducted. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), endothelial-leukocyte adhesion molecule-1 (sELAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) were measured. A subgroup of patients with systemic sclerosis (SSc) treated with immunosuppressants was followed over 10 months. RESULTS: Patients belonged to three main entities: rheumatoid arthritis (RA, n = 32), collagen diseases (CD, n = 56) also including systemic sclerosis (SSc, n = 11), and other autoimmune diseases (n = 12). sICAM-1 was similar among groups. sELAM-1 was elevated by 1.9-fold in only in SSc. sVCAM-1 was elevated by 3.1-fold in RA and by 3.3-fold in CD and in other autoimmune diseases by 3.4-fold. Seven SSc patients with immunosuppression had a 2.7-fold increased sVCAM-1 at baseline and reached the levels of healthy controls after 5 months, while CRP, ESR, and clinical parameters remained unchanged. CONCLUSION: Our study suggests that sVCAM-1 is a disease marker independent of standard serum parameters in several rheumatic diseases. This study is registered with EU PAS Register number: EUPAS22154.
29670920 Methotrexate Combined with 4-Hydroperoxycyclophosphamide Downregulates Multidrug-Resistanc 2018 OBJECTIVE: Rheumatoid arthritis (RA) multidrug resistance is associated with P-glycoprotein (P-gp) overexpression. We investigated the effects of methotrexate (MTX) alone and combined with 4-hydroperoxycyclophosphamide (4-HC) on P-gp expression in fibroblast-like synoviocytes (FLSs) from patients with RA and examined the signaling pathway involved. METHODS: RA-FLSs were treated with MTX, MTX + 4-HC, AG490 + MTX, or AG490 + MTX + 4-HC for 72 h. Proliferation inhibition rates were determined by MTT assay; P-gp expression was measured by flow cytometry and real-time polymerase chain reaction (RT-PCR); JAK2 and STAT3 were measured by RT-PCR and cell-based ELISA to assess STAT3 signaling. RESULTS: MTX alone significantly induced P-gp expression and mRNA production in RA-FLSs. P-gp expression and mRNA levels were lower in the MTX + 4-HC group than in the MTX-alone group. In contrast to MTX, MTX + 4-HC reduced the STAT3 phosphorylation and downregulated JAK2 and STAT3 mRNA production. Inhibition of constitutively active STAT3 accompanied by 4-HC suppressed P-gp levels in RA-FLSs. The MTT assays revealed no significant differences in proliferation inhibition rates among groups. CONCLUSIONS: The increased anti-P-gp effect of MTX + 4-HC versus MTX alone in RA-FLSs was mediated via inhibition of the JAK2/STAT3 pathway and may have helped reverse MDR in refractory RA patients with high-P-gp levels.
30572963 Meta-analysis of Immunochip data of four autoimmune diseases reveals novel single-disease 2018 Dec 20 BACKGROUND: In recent years, research has consistently proven the occurrence of genetic overlap across autoimmune diseases, which supports the existence of common pathogenic mechanisms in autoimmunity. The objective of this study was to further investigate this shared genetic component. METHODS: For this purpose, we performed a cross-disease meta-analysis of Immunochip data from 37,159 patients diagnosed with a seropositive autoimmune disease (11,489 celiac disease (CeD), 15,523 rheumatoid arthritis (RA), 3477 systemic sclerosis (SSc), and 6670 type 1 diabetes (T1D)) and 22,308 healthy controls of European origin using the R package ASSET. RESULTS: We identified 38 risk variants shared by at least two of the conditions analyzed, five of which represent new pleiotropic loci in autoimmunity. We also identified six novel genome-wide associations for the diseases studied. Cell-specific functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants may act by deregulating gene expression in different subsets of T cells, especially Th17 and regulatory T cells. Finally, drug repositioning analysis evidenced several drugs that could represent promising candidates for CeD, RA, SSc, and T1D treatment. CONCLUSIONS: In this study, we have been able to advance in the knowledge of the genetic overlap existing in autoimmunity, thus shedding light on common molecular mechanisms of disease and suggesting novel drug targets that could be explored for the treatment of the autoimmune diseases studied.
30408628 Liposomes encapsulated dimethyl curcumin regulates dipeptidyl peptidase I activity, gelati 2018 Dec Rheumatoid arthritis (RA) is an autoimmune disease and characterized by the excessive cell proliferation, abnormal cell cycle of lymphocytes and synovial cells. The therapeutic effects of curcumin in active RA patients were reported, but limited by its insolubility and rapid systemic elimination. Dimethyl curcumin (DiMC) is a metabolically stable analogue of curcum with anti-inflammatory property. In this study, liposomes encapsulated dimethyl curcumin (Lipo-DiMC) was prepared to improve the bioavailability and metabolic-stability; collagen induced arthritis (CIA) rat model was employed to investigate the effects of Lipo-DiMC treatments during CIA progress. Physical assessments and routine-blood-test were performed. Fresh spleen lymphocytes were isolated from normal, CIA and Lipo-DiMC-treated CIA rats; flow-cytometry for cell-cycle analysis, western-blotting for intracellular signal pathway protein expressions, gelatin-zymography for matrix-metalloproteases 2/9 (MMP-2/9) and GF-AFC for dipeptidyl-peptidase I (DPPI) activity assay. Compared with untreated CIA rats, Lipo-DiMC treatments relieved paw-swellings, suppressed the increments of immunocytes numbers and inhibited DPPI and MMP-2/9 over-activity in blood. Lipo-DiMC adjusted CIA-induced cell cycle dysfunction at G0/G1-phase and S-phase of spleen lymphocytes for CIA rats. The intracellular expression-trends of P38, P21, Bcl-2, JNK-1 and DPPI of spleen lymphocytes were observed during CIA progress with and without Lipo-DiMC administrations. Lipo-DiMC exhibited its therapeutic functions by attenuating CIA development in rats, associated with down-regulating CIA-induced lymphocytes numbers, inhibiting over-expressed of DPPI and MMP-2/9, and adjusting cell cycles. These findings provide a new insight into the mechanism of Lipo-DiMC treatment in CIA rat model and suggest that Lipo-DiMC could be considered as a potential drug for RA treatment.
30289018 The findings of musculoskeletal ultrasonography on primary Sjögren's syndrome patients in 2019 Sep Objective: We researched the findings of musculoskeletal ultrasound sonography (MSUS) on primary Sjogren's syndrome in childhood (pSS-C) with articular manifestations. The correlation of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) were investigated to evaluate the usefulness of MSUS on their articular prognosis. Method: The objective patients are pSS-C cases who visited our hospital complaining joint pain and/or joint swelling and for whom MSUS was performed. Result: Eight patients included 6 female and 2 male, 5 RF-positive patients and 3 ACPA- positive patients. The mean age of onset was 11.1 ± 3.0 years (352 physical joint findings and 284 MSUS findings. The number of joints found clinical articular manifestations was 58/352 joints, and arthritis detected by MSUS was 30/284 joints). In multivariate analysis, the odds ratio of clinical articular manifestations was significant high in RF-positivity (2.9, 95%CI 1.5-6.2). The odds ratio of arthritis detected by MSUS in ACPA-positivity was significant high (3.7, 95%CI 1.5-11.6), although odds ratio in RF-positivity had no statistical significance and a similar trend was seen in odds ratios of subclinical arthritis (4.9, 95%CI 1.6-18.0). Conclusion: It was indicated that MSUS is useful for pSS-C. ACPA-positive pSS-C patients have arthritis and subclinical arthritis more frequently than ACPA-negative patients.
29457982 Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhib 2018 Mar 22 Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.
28782180 Down-regulation of miR-10a-5p in synoviocytes contributes to TBX5-controlled joint inflamm 2018 Jan MicroRNAs are considered to play critical roles in the pathogenesis of human inflammatory arthritis, including rheumatoid arthritis (RA). The purpose of this study was to determine the relationship between miR-10a-5p and TBX5 in synoviocytes and evaluate their contribution to joint inflammation. The expression of miR-10a-5p and TBX5 in the synovium of RA and human synovial sarcoma cell line SW982 stimulated by IL-1β was determined by RT-qPCR and Western blotting. The direct interaction between miR-10a-5p and TBX5 3'UTR was determined by dual-luciferase reporter assay in HeLa cells. Mimics and inhibitors of miR-10a-5p were transfected into SW982 cells. TBX5 was overexpressed by plasmid transfection or knocked down by RNAi. Proinflammatory cytokines and TLR3 and MMP13 expressions were determined by RT-qPCR and Western blotting. Down-regulated expression of miR-10a-5p and up-regulation of TBX5 in human patients with RA were found compared to patients with OA. IL-1β could reduce miR-10a-5p and increase TBX5 expression in SW982 cells in vitro. The direct target relationship between miR-10a-5p and 3'UTR of TBX5 was confirmed by luciferase reporter assay. Alterations of miR-10-5p after transfection with its mimic and inhibitor caused the related depression and re-expression of TBX5 and inflammatory factors in SW982 cells. Overexpression of TBX5 after pCMV3-TBX5 plasmid transfection significantly promoted the production of TLR3, MMP13 and various inflammatory cytokines, while this effect was rescued after knocking down of TBX5 with its specific siRNA. We conclude that miR-10a-5p in a relation with TBX5 regulates joint inflammation in arthritis, which would serve as a diagnostic and therapeutic target for RA treatment.
28958658 A Minimum Ten Years of Follow-Up of Alumina Head on Delta Liner Total Hip Arthroplasty. 2018 Feb BACKGROUND: In the early days when delta ceramics were developed, there was a period of using delta ceramic liner and alumina ceramic head. Therefore, the purpose of this study is to investigate the clinical and radiological outcomes of total hip arthroplasty using delta ceramic liner on alumina ceramic head after a minimum of 10 years of follow-up and to evaluate problems of early delta ceramic liner. METHODS: Alumina on delta cementless total hip arthroplasty was performed in 92 hips (85 patients) from August 2005 to March 2007 at our hospital. Bilateral total hip arthroplasty were performed in 7 patients, 30 patients on the left side and 48 patients on the right side. Preoperative diagnosis was osteonecrosis of the femoral head in 34 hips (37%), degenerative arthritis in 31 hips (33.7%), femur neck fracture in 21 hips (22.8%), and rheumatoid arthritis in 6 hips (6.5%). All surgeries were carried out with anterolateral approach. For the clinical evaluation, Harris hip score (HHS), pain, and range of motion were assessed. Radiographs were reviewed by the authors to search for any signs of osteolysis, loosening of implants, and heterotopic ossification. RESULTS: HHS was compared between preoperative and final follow-ups. The mean HHS improved from preoperative 58.3 points (range 27-76) to 92.7 points (range 78-98) on the final follow-up (P = .02). The mean range of hip motion at the final follow-up was flexion 116.9°, adduction 23.8°, abduction 34.6°, internal rotation 16.3°, and external rotation 39.2°. As for the postoperative pain, 1 patient complained of inguinal pain and 4 patients complained of thigh pain. Because of trauma, 3 cases of dislocation were observed in all cases. There are 3 cases with dislocation and 2 cases were treated with conservative treatment without recurrence, but 1 case was required for surgical treatment due to eccentric rim wear of delta liner. The aseptic loosening of acetabular cup and femoral stem was each 1 hip. CONCLUSION: Alumina head-on-delta liner cementless THA, using a large femoral head 32-36 mm in diameter, demonstrated satisfactory clinical and radiological results in the minimum 10 years of follow-up. Eccentric rim wear can occur even in delta ceramic liners that are known to have high strength, and this can lead to dislocation which can, in turn, increase the possibility of linear fracture.
28924986 Supplementing electronic health records through sample collection and patient diaries: A s 2018 Feb PURPOSE: To describe a novel observational study that supplemented primary care electronic health record (EHR) data with sample collection and patient diaries. METHODS: The study was set in primary care in England. A list of 3974 potentially eligible patients was compiled using data from the Clinical Practice Research Datalink. Interested general practices opted into the study then confirmed patient suitability and sent out postal invitations. Participants completed a drug-use diary and provided saliva samples to the research team to combine with EHR data. RESULTS: Of 252 practices contacted to participate, 66 (26%) mailed invitations to patients. Of the 3974 potentially eligible patients, 859 (22%) were at participating practices, and 526 (13%) were sent invitations. Of those invited, 117 (22%) consented to participate of whom 86 (74%) completed the study. CONCLUSIONS: We have confirmed the feasibility of supplementing EHR with data collected directly from patients. Although the present study successfully collected essential data from patients, it also underlined the requirement for improved engagement with both patients and general practitioners to support similar studies.
29093159 CNTO6785, a Fully Human Antiinterleukin 17 Monoclonal Antibody, in Patients with Rheumatoi 2018 Jan OBJECTIVE: To evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of CNTO6785, a fully human monoclonal antibody that binds to human interleukin 17A, in patients with active rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX) therapy. METHODS: This randomized, double-blind, placebo-controlled, dose-ranging study enrolled patients aged 18 to 80 years (inclusive) with active RA (≥ 6/66 swollen and ≥ 6/68 tender joints) who were refractory to MTX treatment (7.5-25 mg weekly, inclusive). The study duration was 38 weeks, containing a 10-week safety followup. Patients were randomized 1:1:1:1:1 to receive CNTO6785 15, 50, 100, or 200 mg every 4 weeks + MTX or placebo + MTX. The primary endpoint was American College of Rheumatology 20 (ACR20) response at Week 16. RESULTS: There were no significant differences from placebo in the proportion of patients treated with CNTO6785 in the primary endpoint of ACR20 response at Week 16. There were no significant findings in any additional efficacy variables through Week 32. No dose-response relationships or specific patterns were observed in adverse event profiles among CNTO6785 treatment groups. Infections occurred with similar frequency across all groups, and injection site reactions were mild or moderate and did not demonstrate a dose-response relationship. Median serum CNTO6785 concentration increases through Week 38 were about dose-proportional; the incidence of neutralizing antidrug antibodies was 19.4% and was not associated with study drug dose level. CONCLUSION: CNTO6785 was well tolerated, but did not demonstrate clinical efficacy in patients with active RA with inadequate response to MTX.
30417018 Anti-ICOSL New Antigen Receptor Domains Inhibit T Cell Proliferation and Reduce the Develo 2018 Lymphocyte costimulation plays a central role in immunology, inflammation, and immunotherapy. The inducible T cell costimulator (ICOS) is expressed on T cells following peptide: MHC engagement with CD28 costimulation. The interaction of ICOS with its sole ligand, the inducible T cell costimulatory ligand (ICOSL; also known as B7-related protein-1), triggers a number of key activities of T cells including differentiation and cytokine production. Suppression of T cell activation can be achieved by blocking this interaction and has been shown to be an effective means of ameliorating disease in models of autoimmunity. In this study, we isolated specific anti-ICOSL new antigen receptor domains from a synthetic phage display library and demonstrated their ability to block the ICOS/ICOSL interaction and inhibit T cell proliferation. Anti-mouse ICOSL domains, considered here as surrogates for the use of anti-human ICOSL domains in patient therapy, were tested for efficacy in a collagen-induced mouse model of rheumatoid arthritis where they significantly decreased the inflammation of joints and delayed and reduced overall disease progression and severity.
29887869 Inhibitory Role of Growth Hormone in the Induction and Progression Phases of Collagen-Indu 2018 Evidence indicates an intimate connection between the neuroendocrine and the immune systems. A number of in vitro and in vivo studies have demonstrated growth hormone (GH) involvement in immune regulation. The GH receptor is expressed by several leukocyte subpopulations, and GH modulates immune cell proliferation and activity. Here, we found that sustained GH expression protected against collagen-induced arthritis (CIA); in GH-transgenic C57BL/6 (GHTg) mice, disease onset was delayed, and its overall severity was decreased. The anti-collagen response was impaired in these mice, as were inflammatory cytokine levels. Compared to control arthritic littermates, immunized GHTg mice showed significantly lower RORγt (retinoic acid receptor-related orphan receptor gamma 2), IL-17, GM-CSF, IL-22, and IFNγ mRNA expression in draining lymph nodes, whereas there were no differences in IL-21, IL-6, or IL-2 mRNA levels. Data thus suggest that Th17/Th1 cell plasticity toward a pathological phenotype is reduced in these mice. Exogenous GH administration in arthritic DBA/1J mice reduced the severity of established CIA as well as the inflammatory environment, which also shows a GH effect on arthritis progression. These results indicate that GH prevents inflammatory joint destruction in CIA. Our findings demonstrate a modulatory GH role in immune system function that contributes to alleviating CIA symptoms and underlines the importance of endocrine regulation of the immune response.
29247146 Synoviocytes-derived Interleukin 35 Potentiates B Cell Response in Patients with Osteoarth 2018 Apr OBJECTIVE: Elevated expression of interleukin 35 (IL-35) is associated with autoimmune disease, including rheumatoid arthritis (RA). The present study was undertaken to determine the functional interaction among IL-35, B cells, and stromal cells residing in the synovium of patients with RA and osteoarthritis (OA). METHODS: IL-35 (EBI-3/p35) expression was investigated in RA and OA synovium using quantitative real-time PCR (qRT-PCR) and immunohistochemistry. IL-35 receptor (IL-35R) expression on B cells dissociated from synovium and periphery of patients with RA, OA, and healthy donor controls (HC) was determined by flow cytometry. The degree of B cells activation after IL-4 and/or IL-35 stimulation was measured by flow cytometry and qRT-PCR. Synovial fibroblasts (SF) purified from RA and OA synovium were cocultured with peripheral HC B cells in the presence/absence of tumor necrosis factor-α (TNF-α) and with/without anti-IL-35-blocking antibodies. RESULTS: EBI-3/p35 transcripts were expressed in close proximity to B cells residing in RA and OA synovium. IL-35R subunits, gp130 and IL-27Rα, but not IL-12Rβ2, were expressed in B cells extracted from the synovium and periphery of patients with RA/OA. Notably, RA synovium expressed the highest level of IL-27Rα on their cell surface. IL-35 induced proliferation and IgG production in HC B cells. Cocultures of HC B cells with RASF, but not OASF, exhibited significantly elevated B cells activation. TNF-α-induced, RASF-dependent secretion of IgG in B cells is partly IL-35-dependent. CONCLUSION: To our knowledge, for the first time we demonstrated that synovial/peripheral B cells expressed IL-35R and were responsive to IL-35 stimulation. SF residing in RA synovium can be linked to B cell activation and maintenance in RA synovium through IL-35.
29247149 Two-year Efficacy and Safety of Subcutaneous Tocilizumab in Combination with Disease-modif 2018 Apr OBJECTIVE: To evaluate the longterm efficacy and safety of subcutaneous tocilizumab (TCZ-SC) every 2 weeks (q2w) over 2 years in patients with rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS: Patients (n = 656) were randomized 2:1 to TCZ-SC 162 mg q2w or placebo-SC q2w plus DMARD. After a 24-week double-blind period, patients (n = 457) were rerandomized to open-label TCZ-SC q2w by means of prefilled syringe or autoinjector. Escape therapy with weekly TCZ-SC was available for patients with inadequate efficacy from Week 12. Maintenance of response and safety to 2 years was assessed. Analyses used nonresponder imputation. RESULTS: The American College of Rheumatology (ACR) 20 response after TCZ-SC was maintained beyond Week 24 and was > 70% at each timepoint. ACR50/70, 28-joint Disease Activity Score remission, and ≥ 0.30 decrease from baseline in the Health Assessment Questionnaire-Disability Index response rates were also maintained after Week 24 in the TCZ-SC arm (≥ 50%, > 25%,> 32% and > 56%, respectively). Following escape for inadequate efficacy, many patients achieved ACR20 at the end of the study, 35% after escape from TCZ-SC, and 63% from placebo. The rates of serious adverse events [(11.20/100 patient-years (PY)] including serious infections (3.25/100 PY) were stable through Week 96. No association between anti-TCZ antibody development and loss of efficacy or adverse events was observed. CONCLUSION: Efficacy and safety of TCZ-SC q2w was maintained up to 2 years and remained comparable with previously published data for intravenous TCZ. Dose escalation to weekly TCZ-SC was associated with ACR responses in prior nonresponders and was well tolerated.
27567553 Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α 2018 Jan Tumor necrosis factor (TNF)-α is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-α therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-α full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-α antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-α agents on neutralization of soluble TNF-α, each anti-TNF-α agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-α agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-α and lymphotoxin, (2) effects toward transmembrane TNF-α-expressing cells, (3) effects toward Fcγ receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-α agents to enhance the clinical efficacy in inflammatory diseases.
30547287 Measurement of IL-17AA and IL-17FF as Pharmacodynamic Biomarkers to Demonstrate Target Eng 2018 Dec 13 The interleukin (IL)-17 pathway has been implicated in the pathophysiology of many autoimmune diseases. MCAF5352A is a humanized monoclonal antibody which targets both IL-17A and IL-17F, thereby inhibiting the activity of IL-17 dimers (IL-17AA, IL-17AF, and IL-17FF). The pharmacokinetic profile of MCAF5352A has been characterized in both a Phase Ia single ascending dose study and a Phase Ib multiple ascending dose study. Two qualified enzyme-linked immunosorbent assays were used to measure total IL-17AA and IL-17FF levels in serum as pharmacodynamic biomarkers in the Phase I studies. The two assays demonstrated specificity for IL-17AA or IL-17FF with sensitivity at low picogram/milliliter levels. The assay precision and accuracy also met acceptance criteria. Although total serum IL-17AA and IL-17FF levels were below the assay detection limits prior to administration of MCAF5352A, post-treatment levels in both the single and multiple dose cohorts became detectable and increased in a dose-dependent manner. These data are consistent with target engagement by MCAF5352A. Our work highlights bioanalytical challenges encountered while developing biomarker assays requiring high sensitivity and specificity. Data generated using these assays enabled the confirmation of target engagement during early clinical drug development.