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ID PMID Title PublicationDate abstract
28660550 Clinical and Economic Evaluation of Repository Corticotropin Injection: A Narrative Litera 2017 Aug INTRODUCTION: Repository corticotropin injection (RCI; H.P. Acthar(®) Gel; Mallinckrodt Pharmaceuticals Inc., Hampton, NJ) is a highly purified, prolonged-release porcine preparation of adrenocorticotropic hormone (ACTH) analogue that is FDA-approved for treatment of 19 autoimmune and inflammatory disorders. The diverse physiological actions of RCI at the melanocortin receptors (MCRs) affect processes involved in inflammation, pigmentation, steroidogenesis, and immunomodulation. Although RCI has been approved to treat inflammatory and autoimmune diseases for more than 60 years, recent progress in understanding both MCRs and the effects of RCI in modulating immune responses has led to increased interest in RCI as a therapeutic choice. The objective of this narrative literature review is to summarize key clinical and economic data on RCI treatment of seven disorders: infantile spasms (IS), multiple sclerosis (MS) relapses, proteinuria in nephrotic syndrome, rheumatoid arthritis (RA), dermatomyositis/polymyositis (DM/PM), systemic lupus erythematosus (SLE), and symptomatic sarcoidosis based on published literature and product information. An extended report is available as the Academy of Managed Care Pharmacy (AMCP) Formulary dossier for H.P. Acthar(®) Gel. METHODS: Key studies of clinical efficacy and healthcare utilization and cost from 1956 to 2016 are summarized. RESULTS: The evidence supports the efficacy of RCI across the seven indications. RCI is effective as a first-line therapy for IS. For the other six conditions, RCI may improve clinical outcomes during exacerbations or when the condition is resistant to conventional treatments. Use of RCI is associated with reduced use of biologics, corticosteroids, and disease-modifying antirheumatic drugs. Initiation of RCI therapy in patients with IS, MS, RA, SLE, or DM/PM has been associated with lower post-therapy healthcare utilization and medical costs, including decreases in hospitalizations, hospital length of stay, outpatient visits, and emergency department visits. CONCLUSION: The evidence suggests that RCI may improve inflammatory and autoimmune disease control and patient quality of life, particularly in complex patients, and yield healthcare cost savings that demonstrate the medicine's value. FUNDING: Mallinckrodt Pharmaceuticals Inc.
29247155 CXCL10 and TRAIL Are Upregulated by TXNDC5 in Rheumatoid Arthritis Fibroblast-like Synovio 2018 Mar OBJECTIVE: Thioredoxin domain containing 5 (TXNDC5) is highly expressed in synovial membranes of rheumatoid arthritis (RA). Our study aimed to investigate the pathogenic role of TXNDC5 in RA. METHODS: PCR arrays, CCK-8 assays, flow cytometry, and transwell migration assays were used to analyze cultured rheumatoid arthritis synovial fibroblasts (RASF). RESULTS: Increased CXCL10 and tumor necrosis factor-related apoptosis-inducing ligand levels were detected in RASF transfected with anti-TXNDC5 small interfering RNA (siRNA), and decreased expression was detected in RASF transfected with TXNDC5-expressing plasmids. Significantly attenuated RASF proliferation and migration, and increased RASF apoptosis, were observed in the siRNA-transfected RASF. CONCLUSION: Downregulation of TXNDC5 could contribute to RASF antiangiogenic and proapoptotic features through the suppression of CXCL10 and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand).
29131315 TXNDC5 contributes to rheumatoid arthritis by down-regulating IGFBP1 expression. 2018 Apr The thioredoxin domain-containing 5 (TXNDC5) gene is associated with susceptibility to rheumatoid arthritis (RA) and exhibits increased expression in the synovial tissues. TXNDC5 is also associated strongly with diabetes, a metabolic disease characterized by interrupted insulin signalling. This study investigated whether TXNDC5 contributes to RA via the insulin signalling pathway. In this study, RA synovial fibroblast-like cells (RASFs) transfected with an anti-TXNDC5 small interfering RNA (siRNA) were analysed with an insulin signaling pathway RT(2) profiler polymerase chain reaction (PCR) array and an insulin resistance RT(2) profiler PCR array. The PCR arrays detected significantly increased expression of insulin-like growth factor binding protein 1 (IGFBP1) in RASFs with suppressed TXNDC5 expression. The result was verified using real-time PCR and Western blot analyses. Significantly elevated IGFBP1 expression and decreased interleukin (IL)-6 secretion were also detected in culture medium of transfected RASFs. Furthermore, decreased IGFBP1 mRNA and protein expression levels were detected in RA synovial tissues. Additionally, significantly increased apoptosis and decreased cell proliferation and cell migration were observed in RASFs transfected with the anti-TXNDC5 siRNA, whereas transfection with the anti-IGFBP1 siRNA or a mixture of the anti-IGFBP1 and anti-TXNDC5 siRNAs restored normal cell proliferation, migration and IL-6 level in RASFs. Insulin-like growth factor (IGF) has potent prosurvival and anti-apoptotic functions, and IGFBP1 can suppress IGF activity. Based on the results of the present study, we suggest that TXNDC5 contributes to abnormal RASF proliferation, migration and IL-6 production by inhibiting IGFBP1 expression.
28380678 Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: Com 2017 Jun Patients with rheumatoid arthritis often develop methotrexate-associated lymphoproliferative disorders (MTX-LPD) during MTX treatment. MTX-LPD occasionally regresses spontaneously after simply discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non-spontaneous regression have yet to be elucidated. To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTX-LPD (diffuse large B-cell lymphoma [DLBCL]-type [n = 34] and classical Hodgkin lymphoma [CHL]-type [n = 17]). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL-type MTX-LPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL-type MTX-LPD patients (76%) required additional chemotherapy. This difference was statistically significant (P = 0.001). However, overall survival was not significantly different between DLBCL-type and CHL-type (91% vs 94%, respectively; P > 0.05). Thus, the morphological differences in the pathological findings of MTX-LPD may be a factor for spontaneous or non-spontaneous regression after discontinuation of MTX.
28111965 Identification of CD4(+) T-cell-derived CD161(+) CD39(+) and CD39(+)CD73(+) microparticles 2017 Feb AIM: This study aimed to identify CD4(+) T-cell-derived microparticles (MPs) and investigate their roles in rheumatoid arthritis (RA). METHODS: Synovial fluids from 34 RA, 33 osteoarthritis patients and 42 healthy individuals were analyzed by flow cytometry. Human fibroblast-like synoviocytes and peripheral blood mononuclear cells were cultured with or without isolated MPs, chemokines and cytokines were measured by ELISA. RESULTS: CD4(+)CD161(+)CD39(+) and CD4(+)CD39(+)CD73(+) MPs were abundantly present in RA patients, which were positively or negatively correlated with RA features, respectively. Chemokines CCL20, CCL17 and CCL22, and cytokines IL-17 and IL-10 were influenced by these MPs in human fibroblast-like synoviocytes (HFLS) or PMBCs. CONCLUSION: CD4(+) T-cell-derived CD161(+)CD39(+) and CD39(+)CD73(+) MPs could serve as new reciprocal biomarkers for RA evaluation.
28477219 Reliability of ultrasound grading traditional score and new global OMERACT-EULAR score sys 2017 Dec This study aims to test the reliability of ultrasound to graduate synovitis in static and video images, evaluating separately grayscale and power Doppler (PD), and combined. Thirteen trained rheumatologist ultrasonographers participated in two separate rounds reading 42 images, 15 static and 27 videos, of the 7-joint count [wrist, 2nd and 3rd metacarpophalangeal (MCP), 2nd and 3rd interphalangeal (IPP), 2nd and 5th metatarsophalangeal (MTP) joints]. The images were from six patients with rheumatoid arthritis, performed by one ultrasonographer. Synovitis definition was according to OMERACT. Scoring system in grayscale, PD separately, and combined (GLOESS-Global OMERACT-EULAR Score System) were reviewed before exercise. Reliability intra- and inter-reading was calculated with Cohen's kappa weighted, according to Landis and Koch. Kappa values for inter-reading were good to excellent. The minor kappa was for GLOESS in static images, and the highest was for the same scoring in videos (k 0.59 and 0.85, respectively). Excellent values were obtained for static PD in 5th MTP joint and for PD video in 2nd MTP joint. Results for GLOESS in general were good to moderate. Poor agreement was observed in 3rd MCP and 3rd IPP in all kinds of images. Intra-reading agreement were greater in grayscale and GLOESS in static images than in videos (k 0.86 vs. 0.77 and k 0.86 vs. 0.71, respectively), but PD was greater in videos than in static images (k 1.0 vs. 0.79). The reliability of the synovitis scoring through static images and videos is in general good to moderate when using grayscale and PD separately or combined.
28583308 An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arth 2017 Jul 13 Rheumatoid arthritis (RA) is an autoimmune joint disease maintained by aberrant immune responses involving CD4+ T helper (Th)1 and Th17 cells. In this study, we tested the therapeutic efficacy of Ligand Epitope Antigen Presentation System (LEAPSâ„¢) vaccines in two Th1 cell-driven mouse models of RA, cartilage proteoglycan (PG)-induced arthritis (PGIA) and PG G1-domain-induced arthritis (GIA). The immunodominant PG peptide PG70 was attached to a DerG or J immune cell binding peptide, and the DerG-PG70 and J-PG70 LEAPS vaccines were administered to the mice after the onset of PGIA or GIA symptoms. As indicated by significant decreases in visual and histopathological scores of arthritis, the DerG-PG70 vaccine inhibited disease progression in both PGIA and GIA, while the J-PG70 vaccine was ineffective. Splenic CD4+ cells from DerG-PG70-treated mice were diminished in Th1 and Th17 populations but enriched in Th2 and regulatory T (Treg) cells. In vitro spleen cell-secreted and serum cytokines from DerG-PG70-treated mice demonstrated a shift from a pro-inflammatory to an anti-inflammatory/regulatory profile. DerG-PG70 peptide tetramers preferentially bound to CD4+ T-cells of GIA spleen cells. We conclude that the DerG-PG70 vaccine (now designated CEL-4000) exerts its therapeutic effect by interacting with CD4+ cells, which results in an antigen-specific down-modulation of pathogenic T-cell responses in both the PGIA and GIA models of RA. Future studies will need to determine the potential of LEAPS vaccination to provide disease suppression in patients with RA.
28844418 Early results of Latitude primary total elbow replacement with a minimum follow-up of 2 ye 2017 Oct BACKGROUND: The aim of this study was to present outcomes of primary Latitude total elbow replacement (TER) with a minimum follow-up of 2 years. METHODS: A retrospective cohort study was undertaken with prospective outcome data collection for the latest outcome. Included were 63 consecutive primary Latitude TERs in 58 patients performed during a period of 5 years at a specialist orthopedic hospital. RESULTS: The mean age of the patients was 62 years (33-85 years). Five primary TERs (4 patients) were lost to follow-up. The primary diagnosis was rheumatoid arthritis in 49, osteoarthritis in 8, and trauma in 6 elbows. The mean flexion-extension arc was 75° preoperatively and 97° postoperatively. Mean postoperative Elbex pain score was 19/100, and function score was 37/100. Mean postoperative scores were 42/100 for the Quick Disabilities of the Arm, Shoulder, and Hand and 38/50 for the elbow-specific American Shoulder and Elbow Surgeons assessment. Four patients died of unrelated causes, and 8 of 63 underwent further surgical intervention, including explantation and conversion from unlinked to linked implant. On radiographic review of 41 surviving TERs, aseptic radiologic loosening was observed of the humeral component in 4 elbows and of the ulnar component in 9. Seven elbows had no radial component, and of the remaining 34 elbows, 16 (47%) had signs of loosening of the radial implant. Complications included 1 heterotopic ossification, 1 olecranon fracture, and 3 further procedures for ulnar nerve entrapment. CONCLUSION: The results indicate that the early outcome of Latitude TER is comparable to that of other prostheses. There is concern about early radiologic loosening of the radial component.
28178142 Treatment of rheumatoid arthritis with biologics may exacerbate HTLV-1-associated conditio 2017 Feb RATIONALE: There are roughly 5 to 10 million persons infected with human T-lymphotropic virus type 1 (HTLV-1) worldwide, and the safety of treating this population with biologics remains poorly understood. PATIENT CONCERNS AND DIAGNOSIS: An HTLV-1-infected 66-year-old female with HTLV-1 uveitis (HU) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Her HU had been in remission and her HAM/TSP symptoms had been managed effectively with oral steroids for years. However, she developed severe rheumatoid arthritis (RA) after failing to respond well to conventional anti-rheumatic agents. INTERVENTIONS: She was administered two intravenous 8mg/kg doses of the biologic tocilizumab. OUTCOMES: Subsequently, her RA symptoms resolved, but she suffered a recurrence of HU and exacerbation of HAM/TSP symptoms. When she was switched back to steroid-based treatment, HU and HAM symptoms both improved, but RA symptoms again worsened. Finally, an attempt to substitute the biologic abatacept and reduce the steroids failed when HAM/TSP symptoms again became aggravated. LESSONS: To the best of our knowledge, this represents the first report worldwide of a biologic aggravating HTLV-1-associated conditions. This report suggests that caution is advised when using biologics to treat HTLV-1-infected patients, though further research is required to clarify the situation.
28898115 Mannose-binding lectin deficiency and miscarriages in rheumatoid arthritis. 2017 Nov OBJECTIVE: To investigate the association between mannose-binding lectin (MBL) serum level and MBL2 polymorphisms, and the frequency of spontaneous miscarriages in rheumatoid arthritis (RA) patients. METHODS: One hundred seventy seven women (mean age 50 years) with RA from Southern Brazil were studied and 4.5% had a history of abortion (8/177). The MBL levels were determined by ELISA. MBL2 polymorphisms in the promoter (-550H/L, -221X/Y), 5' untranslated region (4 P/Q) and exon 1 (p.Gly54Asp: B allele, p.Arg52Cys: D allele and p.Gly57Glu: C allele; collectively labelled O) were genotyped by sequencing. RESULTS: Mannose-binding lectin levels of RA patients ranged from ≤100 ng/mL to 6640 ng/mL (median 541.5 ng/mL). There was a significant difference in MBL median levels (100 ng/mL vs. 625 ng/mL, respectively, p = .001) and frequency of MBL deficiency (75.0% vs. 24.1%, p = .007, OR = 10.3, 95%CI = 1.9-55.4), in patients with a history of miscarriage vs those without it. Patients with RA and miscarriage had more frequently haplotypes related with low MBL levels (p = .007, OR = 10.5, 95%CI = 1.3-84) than high producers. Moreover, LYPB haplotype and O allele were significantly associated with the occurrence of miscarriage (p = .001, OR = 9.7, 95%CI = 2.4-39.1 and p = .009, OR = 5.9, 95%CI = 1.4-23.4, respectively). CONCLUSIONS: The results suggest that MBL deficiency and the presence of MBL2 gene polymorphisms that lead to MBL deficiency are risk factors for the occurrence of miscarriage in patients with RA.
28164724 JAK inhibition in inflammatory bowel disease. 2017 Jul Current available treatments for inflammatory bowel disease (IBD) have some limitations and new options are needed. Several new molecules are being tested for the treatment of IBD and other immune-mediated inflammatory diseases. Among them, Janus kinase (JAK) inhibitors seem to have the lead, since tofacitinib has received regulatory approval in 2012 for the treatment of rheumatoid arthritis, and also it has shown a favorable risk-benefit ratio in phase 3 studies for ulcerative colitis, both in anti-TNF naïve and anti-TNF experienced patients. Other compounds with JAK inhibitory activity are also being tested with promising results. Areas covered: This review discusses the molecular aspects of the JAK-STAT pathway, which gives rationale for the use of JAK inhibitors in immune-mediated inflammatory diseases, especially in IBD. Different compounds with JAK inhibitory activity are presented, and relevant efficacy and safety data in IBD and other conditions are discussed. Expert commentary: It would not be surprising that in a foreseeable future many new orally administrated drugs will be available. This enhanced armamentarium will probably pose new dilemmas, in terms of drug positioning, escalation and de-escalation strategies, and combination therapy.
27998042 Ultrasound Features of the Posterior Tibialis Tendon and Peroneus Brevis Tendon Entheses: 2017 Oct OBJECTIVE: Limited literature exists on the sonographic appearance of the posterior tibialis tendon (PTT) and the peroneus brevis tendon (PBT) entheses. We determined the anatomic features and best imaging techniques of normal PTT and PBT using musculoskeletal ultrasound and compared these findings to subjects with inflammatory arthritis. METHODS: Adult subjects were enrolled as healthy controls (HCs), rheumatoid arthritis (RA) patients, or spondyloarthropathy (SpA) patients. Bilateral PTT and PBT entheses were imaged longitudinally, comparing 2 angles of insonation: perpendicular to the skin surface and 45° cephalad. Images were scored on semiquantitative scales assessing pathology. RESULTS: A total of 78 subjects were enrolled (37 HC, 21 RA, and 20 SpA). Complete enthesis visualization was achieved more frequently in the perpendicular than in the cephalad view for the PBT (76.3% versus 58.7%), but more frequently in the cephalad view for the PTT (58.0% versus 19.6%). RA and SpA subjects had higher rates of PTT fiber disruption (P < 0.001), PTT tenosynovial effusion (P < 0.001), and Doppler signal (P < 0.001) than HCs. No significant differences existed at the PBT enthesis. In multivariate analysis, RA and SpA subjects were found to be 5.1 times (P < 0.001) and 3.6 times (P < 0.001) more likely to exhibit ultrasound-detected pathology, respectively, than HCs. CONCLUSION: The perpendicular transducer aim is optimal for imaging the PBT, while the cephalad transducer orientation was more effective for evaluation of the PTT. Unlike distal PBT imaging, PTT imaging distinguished healthy and disease states, with both RA and SpA patients showing features of PTT enthesopathy. Distal PTT imaging is a useful technique for musculoskeletal ultrasound.
28282491 Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with 2017 Mar 10 BACKGROUND: Biologic disease-modifying anti-rheumatic drugs (DMARDs: referred to as biologics) are effective in treating rheumatoid arthritis (RA), however there are few head-to-head comparison studies. Our systematic review, standard meta-analysis and network meta-analysis (NMA) updates the 2009 Cochrane overview, 'Biologics for rheumatoid arthritis (RA)' and adds new data. This review is focused on biologic or tofacitinib therapy in people with RA who had previously been treated unsuccessfully with biologics. OBJECTIVES: To compare the benefits and harms of biologics (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab) and small molecule tofacitinib versus comparator (placebo or methotrexate (MTX)/other DMARDs) in people with RA, previously unsuccessfully treated with biologics. METHODS: On 22 June 2015 we searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, and Embase; and trials registries (WHO trials register, Clinicaltrials.gov). We carried out article selection, data extraction, and risk of bias and GRADE assessments in duplicate. We calculated direct estimates with 95% confidence intervals (CI) using standard meta-analysis. We used a Bayesian mixed treatment comparison (MTC) approach for NMA estimates with 95% credible intervals (CrI). We converted odds ratios (OR) to risk ratios (RR) for ease of understanding. We have also presented results in absolute measures as risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB). Outcomes measured included four benefits (ACR50, function measured by Health Assessment Questionnaire (HAQ) score, remission defined as DAS < 1.6 or DAS28 < 2.6, slowing of radiographic progression) and three harms (withdrawals due to adverse events, serious adverse events, and cancer). MAIN RESULTS: This update includes nine new RCTs for a total of 12 RCTs that included 3364 participants. The comparator was placebo only in three RCTs (548 participants), MTX or other traditional DMARD in six RCTs (2468 participants), and another biologic in three RCTs (348 participants). Data were available for four tumor necrosis factor (TNF)-biologics: (certolizumab pegol (1 study; 37 participants), etanercept (3 studies; 348 participants), golimumab (1 study; 461 participants), infliximab (1 study; 27 participants)), three non-TNF biologics (abatacept (3 studies; 632 participants), rituximab (2 studies; 1019 participants), and tocilizumab (2 studies; 589 participants)); there was only one study for tofacitinib (399 participants). The majority of the trials (10/12) lasted less than 12 months.We judged 33% of the studies at low risk of bias for allocation sequence generation, allocation concealment and blinding, 25% had low risk of bias for attrition, 92% were at unclear risk for selective reporting; and 92% had low risk of bias for major baseline imbalance. We downgraded the quality of the evidence for most outcomes to moderate or low due to study limitations, heterogeneity, or rarity of direct comparator trials. Biologic monotherapy versus placeboCompared to placebo, biologics were associated with clinically meaningful and statistically significant improvement in RA as demonstrated by higher ACR50 and RA remission rates. RR was 4.10 for ACR50 (95% CI 1.97 to 8.55; moderate-quality evidence); absolute benefit RD 14% (95% CI 6% to 21%); and NNTB = 8 (95% CI 4 to 23). RR for RA remission was 13.51 (95% CI 1.85 to 98.45, one study available; moderate-quality evidence); absolute benefit RD 9% (95% CI 5% to 13%); and NNTB = 11 (95% CI 3 to 136). Results for withdrawals due to adverse events and serious adverse events did not show any statistically significant or clinically meaningful differences. There were no studies available for analysis for function measured by HAQ, radiographic progression, or cancer outcomes. There were not enough data for any of the outcomes to look at subgroups. Biologic + MTX versus active comparator (MTX/other traditional DMARDs)Compared to MTX/other traditional DMARDs, biologic + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50, function measured by HAQ, and RA remission rates in direct comparisons. RR for ACR50 was 4.07 (95% CI 2.76 to 5.99; high-quality evidence); absolute benefit RD 16% (10% to 21%); NNTB = 7 (95% CI 5 to 11). HAQ scores showed an improvement with a mean difference (MD) of 0.29 (95% CI 0.21 to 0.36; high-quality evidence); absolute benefit RD 9.7% improvement (95% CI 7% to 12%); and NNTB = 5 (95% CI 4 to 7). Remission rates showed an improved RR of 20.73 (95% CI 4.13 to 104.16; moderate-quality evidence); absolute benefit RD 10% (95% CI 8% to 13%); and NNTB = 17 (95% CI 4 to 96), among the biologic + MTX group compared to MTX/other DMARDs. There were no studies for radiographic progression. Results were not clinically meaningful or statistically significantly different for withdrawals due to adverse events or serious adverse events, and were inconclusive for cancer. Tofacitinib monotherapy versus placeboThere were no published data. Tofacitinib + MTX versus active comparator (MTX)In one study, compared to MTX, tofacitinib + MTX was associated with a clinically meaningful and statistically significant improvement in ACR50 (RR 3.24; 95% CI 1.78 to 5.89; absolute benefit RD 19% (95% CI 12% to 26%); NNTB = 6 (95% CI 3 to 14); moderate-quality evidence), and function measured by HAQ, MD 0.27 improvement (95% CI 0.14 to 0.39); absolute benefit RD 9% (95% CI 4.7% to 13%), NNTB = 5 (95% CI 4 to 10); high-quality evidence). RA remission rates were not statistically significantly different but the observed difference may be clinically meaningful (RR 15.44 (95% CI 0.93 to 256.1; high-quality evidence); absolute benefit RD 6% (95% CI 3% to 9%); NNTB could not be calculated. There were no studies for radiographic progression. There were no statistically significant or clinically meaningful differences for withdrawals due to adverse events and serious adverse events, and results were inconclusive for cancer. AUTHORS' CONCLUSIONS: Biologic (with or without MTX) or tofacitinib (with MTX) use was associated with clinically meaningful and statistically significant benefits (ACR50, HAQ, remission) compared to placebo or an active comparator (MTX/other traditional DMARDs) among people with RA previously unsuccessfully treated with biologics.No studies examined radiographic progression. Results were not clinically meaningful or statistically significant for withdrawals due to adverse events and serious adverse events, and were inconclusive for cancer.
28387942 The balance between Treg and TH(17) cells: CD11b and interleukin-6. 2017 Apr One of the gold standards for animal models of rheumatoid arthritis is the murine collagen-induced arthritis model. Native type II collagen together with CFA is injected into susceptible mouse strains. Unfortunately, only mice with H-2(q) or H-2(r) MHC haplotypes are susceptible, making the widely used C57BL/6 mouse strain, which carries the H-2(b) haplotype, resistant against the disease. In this issue of the European Journal of Immunology, Stevanin et al. [Eur. J. Immunol. 2017. 47: 637-645] now convincingly show that although WT C57BL/6 mice are resistant to collagen-induced arthritis, mice with a homozygous deletion of CD11b on the same genetic background are fully susceptible in this important animal model of rheumatoid arthritis. They clearly demonstrate that the injection of type II collagen together with CFA leads to early onset of the disease with high incidence and with sustained severity. The authors further characterize this disease with an increase of leukocyte infiltration and enhanced TH(17) differentiation.
28635960 Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diag 2017 Jun 21 Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.
28371921 Work ability in rheumatoid arthritis patients: a register study on the prospective risk of 2017 Jul 1 OBJECTIVES: The aim was to study work ability in patients with RA compared with the general population by investigating the rates and risks of long-term sickness absence, unemployment and disability pension, and the chance of returning to work and the changes in these risks over time (1994-2011). METHODS: This was a cohort study with up to 17 years of follow-up (mean 6.95 years/person) including 6677 RA patients of working age (identified in the nationwide DANBIO registry) and 56 955 matched controls from the general population. A multi-state model was used to analyse all shifts between the work-related states (long-term sickness absence, unemployment and disability pension, as well as the chance of returning to work) and calculate hazard rates (HRs). Analyses were stratified by disease duration and controlled for socio-demographic factors, physical job exposure and somatic and psychiatric co-morbidities. RESULTS: RA patients had increased risk of long-term sickness absence (e.g. early RA: HR = 4.00, 95% CI: 3.64, 4.30) and disability pension (e.g. established RA: HR = 2.75, 95% CI: 2.54, 2.98) relative to controls. From 1994-99 to 2006-11, a decrease in the effect of established RA was observed [long-term sickness absence: from HR = 2.25 (95% CI: 1.99, 2.54) to 1.63 (95% CI: 1.51, 1.75); and disability pension: from HR = 3.49 (95% CI: 2.83, 4.32) to 2.40 (95% CI: 2.15, 2.69)]. RA patients had a lower chance of returning to work from long-term sickness absence or unemployment (HR = 0.60, HR=0.80), and this did not change over time. CONCLUSION: RA patients remain at high risk for long-term sickness absence and disability pension, despite a positive development between 1996-99 and 2006-11. Returning to work after sick leave or unemployment remains a challenge for RA patients.
28270195 Lapachol, a compound targeting pyrimidine metabolism, ameliorates experimental autoimmune 2017 Mar 7 BACKGROUND: The inhibition of pyrimidine biosynthesis by blocking the dihydroorotate dehydrogenase (DHODH) activity, the prime target of leflunomide (LEF), has been proven to be an effective strategy for rheumatoid arthritis (RA) treatment. However, a considerable proportion of RA patients are refractory to LEF. Here, we investigated lapachol (LAP), a natural naphthoquinone, as a potential DHODH inhibitor and addressed its immunosuppressive properties. METHODS: Molecular flexible docking studies and bioactivity assays were performed to determine the ability of LAP to interact and inhibit DHODH. In vitro studies were conducted to assess the antiproliferative effect of LAP using isolated lymphocytes. Finally, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models were employed to address the anti-arthritic effects of LAP. RESULTS: We found that LAP is a potent DHODH inhibitor which had a remarkable ability to inhibit both human and murine lymphocyte proliferation in vitro. Importantly, uridine supplementation abrogated the antiproliferative effect of LAP, supporting that the pyrimidine metabolic pathway is the target of LAP. In vivo, LAP treatment markedly reduced CIA and AIA progression as evidenced by the reduction in clinical score, articular tissue damage, and inflammation. CONCLUSIONS: Our findings propose a binding model of interaction and support the ability of LAP to inhibit DHODH, decreasing lymphocyte proliferation and attenuating the severity of experimental autoimmune arthritis. Therefore, LAP could be considered as a potential immunosuppressive lead candidate with potential therapeutic implications for RA.
28690029 High levels of soluble GPR56/ADGRG1 are associated with positive rheumatoid factor and ele 2018 Aug BACKGROUND: GPR56/ADGRG1 is a member of the adhesion-class G protein-coupled receptor (aGPCR) family important in brain development, oncogenesis and tumor metastasis. Like other aGPCRs, GPR56 is cleaved at the GPCR proteolysis site (GPS) motif into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Existence of soluble GPR56 (sGPR56) has been shown in vitro, however the underlying mechanism and its pathophysiologic role remains undetermined. OBJECTIVE: To assess the presence of sGPR56 in human serum using ELISA assay and compare the serum sGPR56 levels among patients of various chronic inflammatory diseases and healthy subjects. PATIENTS AND METHODS: In this study, serum samples from patients with systemic lupus erythematosus (SLE) (n = 57), rheumatoid arthritis (RA) (n = 95), Sjögren's syndrome (SS) (n = 29), ankylosing spondylitis (AS) (n = 51), and normal controls (n = 81) were analyzed using sGPR56-specific ELISA. RESULT: We show that serum sGPR56 levels are increased in patients of RA, but not in those with SLE, SS and AS. Intriguingly, serum sGPR56 levels in RA patients correlated with positive rheumatoid factor, a marker of bone erosion and poor outcome. In addition, an elevated sGPR56 level is also noted in RA patients with higher tumor necrosis factor level. CONCLUSION: we conclude that sGPR56 is present in vivo and sGPR56 level is elevated in certain chronic inflammatory diseases such as RA. Hence, sGPR56 might be considered a potential biomarker for RA disease progression.
27748083 Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis 2017 Apr OBJECTIVE: To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with methotrexate (MTX) in patients with moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to MTX. METHODS: In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging trial, patients with RA (n = 378) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg plus MTX, or matching placebo plus MTX once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. RESULTS: ACR20 response rates at week 12 were 43.9%, 61.5% (P < 0.05 versus placebo), 46.4%, 57.7%, and 44.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Significant decreases from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level were seen in the peficitinib 50 mg (P < 0.05) and 150 mg (P < 0.01) groups compared with placebo at week 12. Overall, the incidence of adverse events (AEs) was similar between peficitinib and placebo. The most common AEs were urinary tract infection (n = 22 [6%]), upper respiratory tract infection (n = 16 [4%]), and diarrhea (n = 16 [4%]). There were 3 cases of herpes zoster infection (2 in the peficitinib 100 mg group and 1 in the 150 mg group) and 2 cases of serious infection (viral infection in the peficitinib 100 mg group and erysipelas in the 150 mg group). CONCLUSION: The ACR20 response rate in the group receiving peficitinib 50 mg plus MTX was significantly different compared with the rate in patients receiving placebo, but there were no apparent dose-dependent responses, and the placebo response rate was high. Peficitinib plus MTX in patients with moderate-to-severe RA was well tolerated, with limited safety signals emerging.
29255968 A surgical case of methotrexate-associated lymphomatoid granuloma. 2018 Jul We reported a surgical case of methotrexate-associated lymphomatoid granuloma. A 69-year-old female had been treated with methotrexate for rheumatoid arthritis for 35 months. The patient underwent partial resection of the right upper pulmonary lobe for lung cancer when she was 67 years old. A nodule was detected in the left lung field on a chest radiograph performed during the postoperative follow-up period. Computed tomography revealed a 28-mm nodule in the lower left pulmonary lobe. A transbronchial biopsy examination did not lead to a diagnosis. The pulmonary nodule subsequently increased in size. We suspected a malignant tumor and performed lower left lobectomy. A pathological examination revealed lymphomatoid granuloma. Finally, the patient was diagnosed with methotrexate-associated lymphomatoid granuloma based on her history of oral methotrexate treatment.