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ID PMID Title PublicationDate abstract
29065699 Performance of autotaxin as a serum marker for liver fibrosis. 2018 Jul Background Because autotaxin reportedly has a better performance than hyaluronic acid as a marker for liver fibrosis for the prediction of cirrhosis caused by hepatitis C, we aimed to further evaluate the role of autotaxin in liver fibrosis of other aetiologies. Methods Autotaxin antigen was measured in serum samples from 108 patients with chronic hepatitis B and 128 patients with non-alcoholic fatty liver disease who had undergone a liver biopsy as well as healthy subjects and patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis and cardiac dysfunction. Results When evaluated using receiver operator characteristics curves, the performance of autotaxin for the prediction of significant fibrosis (F2-F4) in chronic hepatitis B patients was better than that of hyaluronic acid or type IV collagen 7S. In non-alcoholic fatty liver disease patients, however, the performance of autotaxin for the prediction of significant fibrosis was poorer than that of hyaluronic acid or type IV collagen 7S. The increase in the serum autotaxin concentrations was less notable than that of hyaluronic acid or type IV collagen in patients with chronic kidney disease, diabetes mellitus, rheumatoid arthritis or cardiac dysfunction. Food intake did not affect the serum autotaxin concentrations. Conclusions Autotaxin is useful as a serum marker for liver fibrosis caused by not only chronic viral hepatitis C but also by hepatitis B, although it was less useful in patients with non-alcoholic fatty liver disease. The increase in serum autotaxin concentrations is fairly specific for liver fibrosis, and the serum autotaxin concentrations can be analysed without consideration of food intake before blood collection.
28465139 Diagnostic potential of NETosis-derived products for disease activity, atherosclerosis and 2017 Aug OBJECTIVES: 1) To assess the association of NETosis and NETosis-derived products with the activity of the disease and the development of cardiovascular disease in RA; 2) To evaluate the involvement of NETosis on the effects of biologic therapies such as anti-TNF alpha (Infliximab) and anti-IL6R drugs (Tocilizumab). METHODS: One hundred and six RA patients and 40 healthy donors were evaluated for the occurrence of NETosis. Carotid-intimae media thickness was analyzed as early atherosclerosis marker. Inflammatory and oxidative stress mediators were quantified in plasma and neutrophils. Two additional cohorts of 75 RA patients, treated either with Infliximab (n = 55) or Tocilizumab (n = 20) for six months, were evaluated. RESULTS: NETosis was found increased in RA patients, beside myeloperoxidase and neutrophil elastase protein levels. Cell-free nucleosomes plasma levels were elevated, and strongly correlated with the activity of the disease and the positivity for autoantibodies, alongside inflammatory and oxidative profiles in plasma and neutrophils. Moreover, ROC analyses showed that cell-free nucleosomes levels could identify RA patients showing early atherosclerosis with high specificity. RA patients treated either with IFX or TCZ for six months exhibited decreased generation of NETs. Concomitantly, clinical parameters and serum markers of inflammation were found reduced. Mechanistic in vitro analyses showed that inhibition of NETs extrusion by either DNase, IFX or TCZ, further abridged the endothelial dysfunction and the activation of immune cells, thus influencing the global activity of the vascular system. CONCLUSIONS: NETosis-derived products may have diagnostic potential for disease activity and atherosclerosis, as well as for the assessment of therapeutic effectiveness in RA.
28294642 Cost-effectiveness of sequenced treatment of rheumatoid arthritis with targeted immune mod 2017 Jul AIMS: To determine the cost-effectiveness of treatment sequences of biologic disease-modifying anti-rheumatic drugs or Janus kinase/STAT pathway inhibitors (collectively referred to as bDMARDs) vs conventional DMARDs (cDMARDs) from the US societal perspective for treatment of patients with moderately to severely active rheumatoid arthritis (RA) with inadequate responses to cDMARDs. MATERIALS AND METHODS: An individual patient simulation model was developed that assesses the impact of treatments on disease based on clinical trial data and real-world evidence. Treatment strategies included sequences starting with etanercept, adalimumab, certolizumab, or abatacept. Each of these treatment strategies was compared with cDMARDs. Incremental cost, incremental quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each treatment sequence relative to cDMARDs. The cost-effectiveness of each strategy was determined using a US willingness-to-pay (WTP) threshold of $150,000/QALY. RESULTS: For the base-case scenario, bDMARD treatment sequences were associated with greater treatment benefit (i.e. more QALYs), lower lost productivity costs, and greater treatment-related costs than cDMARDs. The expected ICERs for bDMARD sequences ranged from ∼$126,000 to $140,000 per QALY gained, which is below the US-specific WTP. Alternative scenarios examining the effects of homogeneous patients, dose increases, increased costs of hospitalization for severely physically impaired patients, and a lower baseline Health Assessment Questionnaire (HAQ) Disability Index score resulted in similar ICERs. CONCLUSIONS: bDMARD treatment sequences are cost-effective from a US societal perspective.
28913596 [Perioperative management of immunosuppressive treatment in patients undergoing joint surg 2017 Nov The perioperative management of patients on immunosuppressive drugs is uncertain due to a lack of controlled studies. Continuation of medication without a pause may increase the risk of postoperative infections and wound healing disorders and when the pause is too long this can induce a flare of the underlying rheumatic disease. Additional factors, such as rheumatic disease activity, comorbidities, previous infections and the type of surgical procedure also modulate the risk. The highest risk of infection is associated with corticosteroids depending on the dose, so that a dosage as low as possible but stable in the perioperative period is recommended. Among the conventional disease-modifying antirheumatic drugs (DMARDs) only methotrexate has been sufficiently investigated and in this case a pause in treatment induces higher risks than continuation. Antimalarial agents and sulphasalazine should be continued due to the low risks, whereas leflunomide should be washed out before major surgical interventions. The perioperative risk of treatment with biologics is still far from clear; therefore, as a rule of thumb, withholding treatment for two serum half-lives before an intervention and restarting after completed wound healing are recommended.
29282305 Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression i 2018 Feb 1 Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.
28470428 Genome-wide DNA methylation analysis of articular chondrocytes identifies TRAF1, CTGF, and 2017 Oct The aim of this study is to identify osteoarthritis (OA)-associated differentially methylated genes in human articular chondrocytes from patients with OA. DNA methylation profiling of articular chondrocytes from OA patients, rheumatoid arthritis (RA) patients, and controls was performed, and candidate genes were chosen for validation of gene demethylation status. The mRNA expression levels of candidate genes in chondrocytes were detected by real-time quantitative PCR. Chondrocytes from OA and RA group were treated with 5-Aza-2-deoxycytidine (5-Aza), and then the mRNA expression levels were detected. Forty-five genes with significant methylation differences between OA and control group were identified. Tumor necrosis factor receptor-associated factor 1 (TRAF1), connective tissue growth factor (CTGF), and chemokine (C-X3-C motif) ligand 1(CX3CL1) genes were hypomethylated in chondrocytes of OA and RA patients, which verified by bisulfite sequencing analysis. The mRNA expression level of TRAF1 and CTGF was significantly increased in OA and RA group (p < 0.05), while the expression level of CX3CL1 was only increased in OA group (p < 0.05). For the chondrocytes from OA and RA treated with 5-Aza, the mRNA expression level of TRAF1 and CTGF was highly increased (p < 0.05). It is the first time to show that TRAF1, CTGF, and CX3CL1 genes were hypomethylated in OA chondrocytes and have a consistent correlation with mRNA expression, which suggests that epigenetic changes in the methylation status of TRAF1, CTGF, and CX3CL1 contribute to the pathology of OA.
28013201 Risk of serious adverse effects of biological and targeted drugs in patients with rheumato 2017 Mar 1 OBJECTIVES: To determine possible differences in serious adverse effects among the 10 currently approved biological and targeted synthetic DMARDs (b/ts-DMARDs) for RA. METHODS: Systematic review in bibliographic databases, trial registries and websites of regulatory agencies identified randomized trials of approved b/ts-DMARDs for RA. Network meta-analyses using mixed-effects Poisson regression models were conducted to calculate rate ratios for serious adverse events (SAEs) and deaths between each of the 10 drugs and control (i.e. no b/ts-DMARD treatment), based on subjects experiencing an event in relation to person-years. Confidence in the estimates was assessed by applying the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). RESULTS: A total of 117 trials (47 615 patients) were included. SAEs were more common with certolizumab compared with abatacept (rate ratio = 1.58, 95% CI: 1.18, 2.14), adalimumab (1.36, 95% CI: 1.02, 1.81), etanercept (1.60, 95% CI: 1.18, 2.17), golimumab (1.45, 95% CI: 1.00, 2.08), rituximab (1.63, 95% CI: 1.16, 2.30), tofacitinib (1.44, 95% CI: 1.03, 2.02) and control (1.45, 95% CI: 1.13, 1.87); and tocilizumab compared with abatacept (1.30, 95% CI: 1.03, 1.65), etanercept (1.31, 95% CI: 1.04, 1.67) and rituximab (1.34, 95% CI: 1.01, 1.78). No other comparisons were statistically significant. Accounting for study duration confirmed our findings for up to 6 months' treatment but not for longer-term treatment (6-24 months). No differences in mortality between b/ts-DMARDs and control were found. Based on the GRADE approach, confidence in the estimates was low due to lack of head-to-head comparison trials and imprecision in indirect estimates. CONCLUSION: Despite low confidence in the estimates, our analysis found potential differences in rates of SAEs. Our data suggest caution should be taken when deciding among available drugs. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42014014842.
29248936 Patients with Coexistence of Circulating Hepatitis B Surface Antigen and Its Antibody May 2017 Dec 17 Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients who undergo immunosuppressive drug therapy. Although the recommendation of antiviral prophylaxis made by the American Gastroenterological Association in 2015 focuses on the risk stratification of different immunosuppressive drugs, risk factors for HBV reactivation are also worth identifying in clinical practice. Recent studies have shown that the uncommon serological pattern of coexistent circulating HBV surface antigen (HBsAg) and its antibody (anti-HBs) was associated with double mutations (A1762T/G1764A) in the basal core promoter (BCP) region of the HBV genome, which is critical for HBV replication. Here, we depicted rheumatoid arthritis (RA) patients with coexistent HBsAg and anti-HBs in our medical center, who developed HBV reactivation during immunosuppressive drug therapy. DNA sequencing analysis of the HBV genome revealed triple mutations (A1762T, G1764A, and T1753V) in the BCP region, which could further enhance the ability of HBV replication. Hence, a novel hypothesis is advanced for the first time that patients with coexistent HBsAg and anti-HBs may have a strong predisposition to HBV reactivation due to specific BCP mutations. This hypothesis would, if correct, justify the concurrent detection of HBsAg and anti-HBs in HBV screening in patients with rheumatic diseases and quickly recognize patients with high risk of HBV reactivation. Further controlled studies are needed to confirm this hypothesis.
29119581 Risk of tuberculosis comparison in new users of antitumour necrosis factor-α and with exi 2018 Apr WHAT IS KNOWN AND OBJECTIVE: Patients with rheumatic disease are at risk for infections. Evaluating antitumour necrosis factor (anti-TNF) drug-associated risk of infections requires justification of baseline risk in the population at high risk of infection. We examined the incidence of active tuberculosis (TB) and its risk factors in patients with rheumatic disease started with anti-TNF-α therapy or with existing disease-modifying antirheumatic drug (DMARD) therapy. METHODS: A retrospective cohort study of anti-TNF-α therapy new users (anti-TNF-α group) and those starting with a DMARD after the failure of at least one other DMARD or who had added to existing DMARD treatment (DMARD group) for rheumatic disease in the largest medical setting in Taiwan from 1 January 2005 through 31 November 2013 was conducted to determine relative risk of TB between patient groups. Patients in the DMARD group were stratified into "mild" and "severe" disease severity as proxies for low and high background risk of infection. RESULTS AND DISCUSSION: A total of 3640 patients were enrolled (anti-TNF: 955; DMARD: 2685). The incidence of TB was 903.9/100 000 patient-years for anti-TNF-α new users and 391.7/100 000 patient-years for DMARD switchers. In Cox regression model, adjusted HR for TB in the anti-TNF-α group was higher than for the entire DMARD group (aHR, 2.41; 95% confidence interval [CI], 1.2-4.85), subgroup with mild disease (2.91; 1.31-6.47) and subgroup with severe disease (1.65; 0.68-4.03). Significant independent risk factors for TB were being male, age ≥60 years, history of respiratory disease, glucocorticoids dose >7.5 mg/d and living in a TB-prevalent region. WHAT IS NEW AND CONCLUSION: Anti-TNF-α therapy was independently associated with increased risk of TB in patients with mild disease, but it was not significantly correlated in patients with severe disease after adjusting for confounders.
28315446 Targeted delivery of morin, a dietary bioflavanol encapsulated mannosylated liposomes to t 2017 Jun The purpose of the study was to develop a liposomal drug delivery system for morin, a dietary polyphenol, in order to target the synovial macrophages and investigate the remission of disease severity in the adjuvant-induced arthritic (AIA) rats. To do so, mannose decorated liposomal morin (ML-Morin) was prepared using the thin film hydration method and the physicochemical properties were characterized. The particle size and zeta potential of liposomal morin (L-Morin) was found to be 127.9nm±2.6 and -24.5mV±0.76, whereas ML-Morin showed an increased value of 132.5nm±5.2 and -54.8mV±0.67 respectively. Further, the drug entrapment efficiency (% EE) of ML-Morin was found 86.7±3.8%. To understand the efficacy of L-Morin, ML-Morin over free-Morin; cellular uptake, production and expression of pro-inflammatory mediators, osteoclastogenic factors, and transcription factors were evaluated in primarily isolated synovial and spleen macrophages. Interestingly, confocal microscopic images showed an increased uptake of ML-Morin in the synovial and spleen macrophages than L-morin. In addition, ML-Morin significantly suppressed the production and mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-17), angiogenic factors (VEGF), an inflammatory enzyme (iNOS), and transcription factor (NF-κB-p65). Furthermore, the protein expression of TNF-α, IL-1β, IL-6, IL-17, RANKL, STAT-3, and p-STAT-3 was found to decrease with increased osteoprotegerin (OPG) expression in the ML-Morin targeted macrophages. Thus, our findings endorsed that, ML-Morin preferential internalization into the macrophages of arthritic rats effectively inhibited the inflammatory immune response and osteoclastogenesis better than the dexamethasone palmitate encapsulated mannosylated liposomes (ML-DP), a reference drug as evidenced by clinical and histological analysis.
29150565 The Role of Macrophages in the Response to TNF Inhibition in Experimental Arthritis. 2018 Jan 1 The reduction of synovial tissue macrophages is a reliable biomarker for clinical improvement in patients with rheumatoid arthritis (RA), and macrophages are reduced in synovial tissue shortly after initiation of TNF inhibitors. The mechanism for this initial response is unclear. These studies were performed to identify the mechanisms responsible for the initial reduction of macrophages following TNF inhibition, positing that efflux to draining lymph nodes was involved. RA synovial tissue and synovial fluid macrophages expressed CCR7, which was increased in control macrophages following incubation with TNF-α. Human TNF transgenic (hTNF-Tg) mice were treated with infliximab after development of arthritis. Ankles were harvested and examined by histology, immunohistochemistry, quantitative RT-PCR, ELISA, and flow cytometry. hTNF-Tg mice treated with infliximab demonstrated significant clinical and histologic improvement 3 d after the initiation of therapy, at which time Ly6C(+) macrophages were significantly reduced in the ankles. However, no evidence was identified to support a role of macrophage efflux to draining lymph nodes following treatment with infliximab. In contrast, apoptosis of Ly6C(+) macrophages in the ankles and popliteal lymph nodes, decreased migration of monocytes into the ankles, and a reduction of CCL2 were identified following the initiation of infliximab. These observations demonstrate that Ly6C(+) macrophage apoptosis and decreased ingress of circulating monocytes into the joint are responsible for the initial reduction of macrophages following infliximab treatment in hTNF-Tg mice.
29063464 Diverse patterns of anti-TNF-α-induced lupus: case series and review of the literature. 2018 Feb The induction of autoantibodies is common following therapy with anti-TNF-α agents. However, anti-TNF-α-induced lupus (ATIL) is rare. We assessed the clinical characteristics of three patients with inflammatory bowel disease (IBD) who were treated with infliximab and developed distinct subsets of ATIL. Also, we searched for similar cases in the published literature. We describe three patients with ATIL. The first patient had a classical drug-induced lupus (DIL) presented by thrombocytopenia that resolved after infliximab discontinuation. The second case experienced symmetric polyarthritis of 14 joints in rheumatoid arthritis (RA)-like distribution accompanied by lymphopenia. The third one had a severe serositis including ascites and pleural and pericardial effusions along with pancytopenia. In this patient, ATIL coexisted with anti-TNF-α-induced hepatitis. The second and third patients met the American College of Rheumatology classification criteria for SLE. Nevertheless, all three cases exhibited ANA and anti-dsDNA positivity, and only the second patient had anticardiolipin (aCL IgG) and anti-histone antibodies. The coexistence of both lupus-like syndrome and hepatitis following anti-TNF-α therapy in the same patient is very rare, and to the best of our knowledge, only four such case reports are mentioned in literature. Patients with mild ATIL may tolerate another anti-TNF-α agent without recurrence of the disease. Rheumatologists should be aware of the distinct clinical presentations of ATIL and its coexistence with other rare anti-TNF-alpha complications such as hepatitis.
28600696 Efficacy and Safety of Switching from Innovator Rituximab to Biosimilar CT-P10 Compared wi 2017 Aug BACKGROUND: CT-P10 is a biosimilar candidate of innovator rituximab (RTX) that demonstrated a comparable clinical profile to RTX in a phase I randomized controlled trial (RCT) in rheumatoid arthritis (RA) (ClinicalTrials.gov identifier: NCT01534884). OBJECTIVE: This open-label extension (OLE) study (NCT01873443) compared the efficacy and safety of CT-P10 in patients with RA who received CT-P10 from the outset (i.e., from the start of the RCT and also in the OLE; 'maintenance group') with those who received RTX during the RCT and switched to CT-P10 during the OLE ('switch group'). METHODS: Patients who completed the RCT were recruited. Based on the Disease Activity Score using 28 joints (DAS28) and predefined safety criteria, patients could receive up to two courses of CT-P10 during the OLE. Efficacy [DAS28 and European League Against Rheumatism (EULAR) response], safety and immunogenicity were assessed. RESULTS: Eighty-seven patients were enrolled; 58 and 29 had previously received CT-P10 or RTX, respectively, in the RCT. Of these, 38 (65.5%) and 20 (69.0%) were treated with CT-P10 in the OLE and therefore comprised the maintenance and switch groups, respectively. The mean change in DAS28-erythrocyte sedimentation rate (ESR) from baseline (week 0 of RCT) at week 24 of the first OLE treatment course in the maintenance and switch groups was -2.7 and -2.4, respectively. The proportion of patients with good/moderate EULAR responses was also comparable between groups. Antidrug antibodies were detected in 13.2 and 15.0% of patients in the maintenance and switch groups, respectively, at week 24 of the first OLE course. CT-P10 treatment was well-tolerated when administered for up to 2 years or after switching from RTX. CONCLUSION: In this study population, comparable efficacy and safety profiles were observed in patients who switched from RTX to CT-P10 and those maintained on CT-P10 throughout treatment.
29039054 Treatment Persistence and Healthcare Costs Among Patients with Rheumatoid Arthritis Changi 2017 Nov INTRODUCTION: After a patient with rheumatoid arthritis (RA) fails tumor necrosis factor inhibitor (TNFi) treatment, clinical guidelines support either cycling to another TNFi or switching to a different mechanism of action (MOA), but payers often require TNFi cycling before they reimburse switching MOA. This study examined treatment persistence, cost, and cost per persistent patient among MOA switchers versus TNFi cyclers. METHODS: This study of Commercial and Medicare Advantage claims data from the Optum Research Database included patients with RA and at least one claim for a TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) between January 2012 and September 2015 who changed to another TNFi or a different MOA therapy (abatacept, tocilizumab, or tofacitinib) within 1 year. The index date was the date of the change in therapy. Treatment persistence was defined as no subsequent switch or 60-day gap in therapy for 1 year post-index. RA-related costs included plan-paid and patient-paid amounts for inpatient, outpatient, and pharmacy claims. Medication costs included index and post-index costs of TNFi and different MOA therapies. RESULTS: There were 581 (38.3%) MOA switchers and 935 (61.7%) TNFi cyclers. The treatment persistence rate was significantly higher for MOA switchers versus TNFi cyclers (47.7% versus 40.2%, P = 0.004). Mean 1-year healthcare costs were significantly lower among MOA switchers versus TNFi cyclers for total RA-related costs ($37,804 versus $42,116; P < 0.001) and medication costs ($29,001 versus $34,917; P < 0.001). When costs were divided by treatment persistence, costs per persistent patient were lower among MOA switchers versus TNFi cyclers: $25,436 lower total RA-related cost and $25,999 lower medication costs. CONCLUSION: MOA switching is associated with higher treatment persistence and lower healthcare costs than TNFi cycling. Reimbursement policies that require patients to cycle TNFi before switching MOA may result in suboptimal outcomes for both patients and payers. FUNDING: Sanofi and Regeneron Pharmaceuticals.
28120479 Urinary haptoglobin, alpha-1 anti-chymotrypsin and retinol binding protein identified by p 2017 May The study was aimed at identification by proteomics and validation by enzyme-linked immunosorbent assay (ELISA) of potential urinary biomarkers for lupus nephritis. Study subjects comprised 88 systemic lupus erythematosus (SLE) patients and 60 controls (rheumatoid arthritis, diabetes mellitus and healthy individuals). Based on the SLE disease activity index (SLEDAI), patients were classified as active renal (AR), active non-renal (ANR) or inactive disease (ID). Urinary proteins from a group of patients with AR or ID were resolved by two-dimensional gel electrophoresis and identified by matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS/MS). The selected biomarkers were validated by ELISA using samples from all patients and controls. AR patients were followed-up for 12 months after start of therapy. Three urinary proteins, alpha-1 anti-chymotrypsin (ACT), haptoglobin (HAP) and retinol binding protein (RBP), were detected in patients with AR and not ID. Upon validation, ACT levels were higher in AR patients than the other groups (P < 0·001) and showed good correlation with renal SLEDAI (r = 0·577, P < 0·001) as well as SLEDAI (r = 0·461, P < 0·001). Similarly, HAP levels were > 10-fold higher in AR than other groups (P < 0·001) and correlated well with renal SLEDAI (r = 0·594, P < 0·001) and SLEDAI (r = 0·371, P < 0·01). RBP levels were also higher in AR patients than in other groups (P < 0·05), except diabetes, and showed moderate correlation with renal SLEDAI (r = 0·284, P < 0·008) and SLEDAI (r = 0·316, P < 0·003). Upon follow-up with treatment, levels of all three proteins declined at 6 and 12 months (P < 0·01). Multiple logistic regression identified ACT as the best marker to differentiate AR from ANR. Urinary HAP, ACT and RBP are potential biomarkers for lupus nephritis activity.
28927315 Systematic review and meta-analysis of the epidemiology of polyautoimmunity in Sjögren's 2018 Mar OBJECTIVE: The epidemiology of polyautoimmunity in Sjögren's syndrome (secondary Sjögren's syndrome - sSS) is not well defined and has not been investigated before using a systematic approach. We conducted a systematic review of the epidemiology of sSS associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma, and myositis, assessing the prevalence rates (PRs) and clinical and serological features of sSS. METHOD: A systematic literature search of PubMed and Embase databases (updated to March 2016) was performed to identify all published data on PR, demographic profile, clinical manifestations, laboratory features, and causes of death associated with sSS. The PR's of sSS were summarized with PRs and 95% confidence intervals (CIs). RESULTS: The literature search identified 1639 citations, of which 42 fulfilled the inclusion criteria. Only 19 studies were of moderate to good quality and were selected for the meta-analysis. According to a random-effects model, the pooled PR for sSS associated with RA was 19.5% (95% CI 11.2 to 27.8) and the pooled PR for sSS associated with SLE was 13.96% (95% CI 8.88 to 19.04). The female/male ratio of sSS in the RA population was 14.7 (95% CI 7.09 to 256) and in the SLE population was 16.82 (95% CI 1.22 to 32.4). CONCLUSION: Prevalence rates of sSS vary widely in different populations. Both meta-analyses conducted in the RA and SLE populations were characterized by a high degree of study heterogeneity. The results of this meta-analysis highlight the need for better quality population studies.
29208852 Extremely High Serum Ferritin: An Instrumental Marker of Masquerading Adult-Onset Still's 2017 Dec 6 BACKGROUND Adult-onset Still's disease (AOSD) is a rare multi-systemic inflammatory disorder of unknown etiology characterized by spiking fever, characteristic rash, and arthritis. It often associates with high serum ferritin levels. CASE REPORT An 88-year-old woman had fever of over 39°C without response to extended-spectrum antibiotics for 6 days. She had non-specific erythema with infiltration on her trunk. She had leukocytosis with neutrophilia of 80%, mild hepatic dysfunction, normal level of rheumatoid factor and antinuclear antibody, thrombocytopenia, elevated d-dimer and soluble interleukin2 receptor, extremely high serum ferritin (78 662 ng/mL), and splenomegaly. Although she had no arthritis or specific erythema, we made the diagnosis of AOSD according to Yamaguchi's criteria with disseminated intravascular coagulation (DIC) and hemophagocytic syndrome (HPS) after ruling out infections, malignancies, or other connective tissue diseases. Twelve percent of AOSD patients have HPS. The mean serum ferritin of AOSD with HPS was reported at 18 179 ng/mL, which supported the diagnosis of AOSD because only a few other diseases could show such extremely high serum ferritin. Although she was treated with prednisolone (30 mg/day), her condition deteriorated and her left pleural effusion increased. Therefore, methylprednisolone 500 mg/day for 3 days was started followed by prednisolone 30 mg/day and immunosuppressive agent (Cyclosporine 50 mg/day), which improved her general condition, elevated C-reactive protein levels, and extremely high serum ferritin levels. CONCLUSIONS We report the case of an elderly patient with severe AOSD, who developed HPS and DIC, whose extremely high serum ferritin level was useful in diagnosis.
28733303 Oral glucocorticoid use and osteonecrosis in children and adults with chronic inflammatory 2017 Jul 21 OBJECTIVES: We studied oral glucocorticoids and osteonecrosis, a rare but serious bone disease, in individuals with various chronic inflammatory diseases. We hypothesised that we would find stronger associations in adults versus children and in people with autoimmune diseases. DESIGN: Retrospective cohort study. SETTING: Population-representative data (1994-2013) from general practices in the UK. PARTICIPANTS: Children and adults diagnosed with asthma; inflammatory bowel disease; juvenile, psoriatic or rheumatoid arthritis; psoriasis; or systemic lupus. EXPOSURES: Oral glucocorticoid patterns. PRIMARY AND SECONDARY OUTCOME MEASURES: Diagnosed osteonecrosis (primary) and osteonecrosis plus clinical features (eg, symptoms, pain medication, surgical repair) (secondary). Discrete time failure models estimated the adjusted hazard ratio (aHR) of incident osteonecrosis following oral glucocorticoid exposure. Hypothesis testing was one sided (with corresponding 90% CI) since glucocorticoids were unlikely protective. RESULTS: After adjusting for demographic, disease-related and health utilisation factors, glucocorticoid exposure was associated with osteonecrosis in adults (ages 18-49, aHR 2.1 (90% CI 1.5 to 2.9); ages ≥50, aHR 1.3 (90% CI 1.01 to 1.7)). However, low-dose glucocorticoids, corresponding to average doses <7.5 mg prednisolone daily and maximum doses <30 mg daily, were not associated with osteonecrosis in adults. Furthermore, even at high glucocorticoid doses, there was no evidence of increased osteonecrosis among glucocorticoid-exposed children (p=0.04 for interaction by age) (any glucocorticoid exposure, ages 2-9: aHR 1.1 (90% CI 0.7 to 1.7); ages 10-17: aHR 0.6 (90% CI 0.3 to 1.6)). Arthritis, inflammatory bowel disease and lupus were independently associated with osteonecrosis, but there was a similar dose relationship between glucocorticoids and osteonecrosis among adults with low-risk and high-risk diseases. CONCLUSIONS: Glucocorticoid use was clearly associated with osteonecrosis in a dose-related fashion in adults, especially young adults, but this risk was not detectable in children. The absolute risk of glucocorticoid-associated osteonecrosis in the general paediatric population and in adults taking low glucocorticoid doses is at most extremely small.
28497221 Evaluation of the Cross-reactivity of Antidrug Antibodies to CT-P13 and Infliximab Referen 2017 Jun BACKGROUND: During two pivotal clinical trials of the infliximab biosimilar CT-P13 (PLANETAS and PLANETRA), antidrug antibodies (ADAs) and neutralising antibodies (NAbs) were detected in the sera of patients treated with CT-P13 and the reference product (RP; Remicade). OBJECTIVE: The aim was to assess the comparability of Remicade- and CT-P13-tagged immunoassays for the detection of ADAs and NAbs using data from these trials, in order to determine the cross-reactivity of CT-P13 and RP ADAs. METHODS: Sera from patients with rheumatoid arthritis and ankylosing spondylitis were analysed using an electrochemiluminescence (ECL) bridging assay or Gyros immunoassay, tagged with Remicade or CT-P13 at screening, weeks 14, 30 and 54, and the end of study visit. NAb titre was compared at screening and weeks 14 and 30. The proportion of cross-reactive samples was determined and an inter-rater agreement analysis performed to assess the concordance of results between assays. RESULTS: In PLANETAS, 93.1% (94/101) of RP ADA-positive samples and 93.0% (93/100) of RP NAb-positive samples cross-reacted with CT-P13; 99.0% (103/104) of CT-P13 ADA-positive and 98.0% (98/100) of CT-P13 NAb-positive samples cross-reacted with the RP. In PLANETRA, 94.7% (426/450) of RP ADA-positive samples and 94.3% (415/440) of RP NAb-positive samples cross-reacted with CT-P13, and 96.6% (458/474) of CT-P13 ADA-positive and 96.4% (452/469) of CT-P13 NAb-positive samples cross-reacted with the RP. In both studies, there was strong agreement in outcome between assays at all post-screening time points (PLANETAS: Cohen's κ 0.89-0.98 for ADA, 0.86-0.98 for NAb; PLANETRA: 0.92-0.94 for both ADA and NAb, all p < 0.001). Significant concordance between assays was observed for NAb titre at weeks 14 and 30 (PLANETAS: Spearman's ρ 0.73 and 0.74, respectively; PLANETRA: 0.61 and 0.72, respectively; all p < 0.001). CONCLUSIONS: This study has demonstrated that ADAs and NAbs against CT-P13 and RP are cross-reactive, indicating that CT-P13 and RP share immunodominant epitopes.
27766916 A real-world risk analysis of biological treatment (adalimumab and etanercept) in a countr 2017 May OBJECTIVES: Few studies on tumour necrosis factor (TNF) inhibitor-associated tuberculosis (TB) and hepatic events have been performed in regions where these risks are elevated. This study aimed to provide a direct comparison between adalimumab and etanercept in a high-risk population and to address the implications for physicians working with patients in such an environment. METHOD: Data collected from the National Health Insurance Research Database (NHIRD) in Taiwan between 2007 and 2011 were analysed retrospectively for incidences of eight adverse events associated with TNF-α inhibitors. Hazard ratios (HRs) of adalimumab vs. etanercept were calculated using a Cox proportional hazards model. RESULTS: During this 5-year period, 86 events of TB were reported after 5317 person-years of exposure to adalimumab (1.62 events per 100 person-years), compared to 44 events after 7690 person-years of exposure to etanercept (0.57 events per 100 person-years). For serious hepatic events that led to hospitalization, 0.75 events were reported per 100 person-years of exposure to adalimumab compared to 0.39 events per 100 person-years of exposure to etanercept. Adjusted HRs for TB [aHR 3.06, 95% confidence interval (CI) 2.09-4.49, p < 0.0001], hospitalization due to a hepatic event (aHR 2.05, 95% CI 1.27-3.30, p = 0.0035), and serious infection (aHR 1.48, 95% CI 1.19-1.84, p = 0.0005) attained significance. CONCLUSIONS: TNF-α-targeting therapies with the monoclonal antibody adalimumab confers significant added risk of TB and serious hepatic events compared to therapies with the soluble fusion protein etanercept. Tailored strategies to attenuate these risks are warranted in high-risk regions such as Taiwan.