Lower HbA1c in patients with type 1 diabetes and celiac disease who reached celiac-specific antibody-negativity-A multicenter DPV analysis.
ABSTRACT: OBJECTIVES:To study celiac-specific antibody status over 3?years in patients with type 1 diabetes and biopsy-proven celiac disease (T1D?+?CD). Furthermore, to determine clinical differences after diagnosis between patients reaching constant antibody-negativity (Ab-neg) and staying antibody-positive (Ab-pos). METHODS:A total of 608 pediatric T1D?+?CD patients from the multicenter DPV registry were studied longitudinally regarding their CD specific antibody-status. Differences between Ab-neg (n = 218) and Ab-pos (n = 158) patients 3?years after biopsy were assessed and compared with 26?833 T1D patients without CD by linear and logistic regression adjusted for age, gender, diabetes duration and migration background. RESULTS:Thirty-six percent of T1D?+?CD patients reached and sustained antibody-negativity 3?years after CD diagnosis. The median time until patients returned to Ab-neg was 0.86 (0.51;1.16) years. Three years after diagnosis, HbA1c was lowest in Ab-neg and highest in Ab-pos patients compared to T1D-only patients (adjusted mean (95%CI): 7.72 (7.51-7.92) % vs 8.44 (8.20-8.68) % vs 8.19 (8.17-8.21) %, adjusted P?
Project description:BACKGROUND:Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination. AIM:To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and -negative (NEG) groups. METHODS:We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8), transverse myelitis (TM = 2) n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls. RESULTS:The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies. CONCLUSION:Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.
Project description:BACKGROUND:We evaluated antidrug antibody (ADA) development in patients with chronic plaque psoriasis from three clinical trials of tildrakizumab, a humanized anti-interleukin-23p19 monoclonal antibody (P05495, reSURFACE 1 and reSURFACE 2). OBJECTIVES:To determine the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab. METHODS:In 1400 (weeks 12-16) and 780 (weeks 52-64) evaluable patients randomized to tildrakizumab 100 or 200 mg, treatment-emergent ADA-positive (TE-POS) patients were identified and characterized for neutralizing antibodies (NAbs). Pharmacokinetics, safety and efficacy were evaluated by ADA status. RESULTS:In patients treated with tildrakizumab 100 or 200 mg continuously, < 7% were inconclusive at 52-64 weeks. In long-term data through 52-64 weeks, the incidence of TE-POS was 6·5% (100 mg) and 8·2% (200 mg) and the incidence of TE-POS NAb-POS was 2·5% (100 mg) and 3·2% (200 mg). TE-POS NAb-POS patients had modestly increased median tildrakizumab clearance (36·5%) compared with ADA-NEG patients. Percentage Psoriasis Area and Severity Index improvements in TE-POS NAb-POS vs. ADA-NEG patients on continuous treatment through week 52 were 76% (n = 10) vs. 91% (n = 342) for 100 mg and 77% (n = 12) vs. 87% (n = 299) for 200 mg. The incidence of potential immunogenicity-related adverse events did not indicate a clear trend in any positive ADA patient category compared with ADA-NEG patients through weeks 52-64. The effects of ADA on pharmacokinetics, efficacy and safety at 12-16 weeks were also summarized. CONCLUSIONS:ADA development with tildrakizumab treatment for 52-64 weeks was low; around 3% of patients developed TE-POS NAb-POS ADAs and showed lower serum concentrations and corresponding reduced efficacy. No relationship between ADAs and safety was observed. What's already known about this topic? Unwanted immune responses - for example immunogenicity and antidrug antibodies (ADAs) - have been observed with therapeutic monoclonal antibodies and can affect efficacy and safety. Tildrakizumab is a humanized monoclonal antibody targeting interleukin-23 and is currently approved for patients with plaque psoriasis. What does this study add? ADA development in tildrakizumab-treated patients with psoriasis over 52 weeks was low. The small proportion of patients who had treatment-emergent ADAs and had neutralizing antibodies experienced lower serum tildrakizumab concentrations and reduced efficacy. No relationship between ADAs and safety events was observed.
Project description:We aimed to understand early alterations in kinin-mediated migration of circulating angio-supportive cells and dysfunction of kinin-sensitive cells in type-1 diabetic (T1D) patients before the onset of cardiovascular disease.Total mononuclear cells (MNC) were isolated from peripheral blood of 28 T1D patients free from cardiovascular complications except mild background retinopathy (age: 34.8+/-1.6 years, HbA(1C): 7.9+/-0.2%) and 28 age- and sex-matched non-diabetic controls (H). We tested expression of kinin receptors by flow cytometry and migratory capacity of circulating monocytes and progenitor cells towards bradykinin (BK) in transwell migration assays. MNC migrating towards BK (BK(mig)) were assessed for capacity to support endothelial cell function in a matrigel assay, as well as generation of nitric oxide (NO) and superoxide (O(2) (-)*) by using the fluorescent probes diaminofluorescein and dihydroethidium.CD14(hi)CD16(neg), CD14(hi)CD16(pos) and CD14(lo)CD16(pos) monocytes and circulating CD34(pos) progenitor cells did not differ between T1D and H subjects in their kinin receptor expression and migration towards BK. T1D BK(mig) failed to generate NO upon BK stimulation and supported endothelial cell network formation less efficiently than H BK(mig). In contrast, O(2) (-)* production was similar between groups. High glucose disturbed BK-induced NO generation by MNC-derived cultured angiogenic cells.Our data point out alterations in kinin-mediated functions of circulating MNC from T1D patients, occurring before manifest macrovascular damage or progressed microvascular disease. Functional defects of MNC recruited to the vessel wall might compromise endothelial maintenance, initially without actively promoting endothelial damage, but rather by lacking supportive contribution to endothelial regeneration and healing.
Project description:Pain is a frequent symptom in aquaporin-4-immunoglobulin-G-positive neuromyelitis optica spectrum disorders (AQP4-IgG-pos. NMOSD). Data on pain in myelin-oligodendrocyte-glycoprotein-immunoglobulin-G autoimmunity with a clinical NMOSD phenotype (MOG-IgG-pos. NMOSD) are scarce.The objective of this paper is to investigate pain in MOG-IgG-pos. NMOSD, AQP4-IgG-pos. NMOSD and NMOSD without AQP4/MOG-IgG detection (AQP4/MOG-IgG-neg. NMOSD).Forty-nine MOG-IgG-pos. (n?=?14), AQP4-IgG-pos. (n?=?29) and AQP4/MOG-IgG-neg. (n?=?6) NMOSD patients were included in this cross-sectional baseline analysis from an ongoing observational study. We identified spinal cord lesions on magnetic resonance imaging, assessed pain by the painDETECT and McGill Pain questionnaires, quality of life by Short Form Health Survey, and depression by Beck Depression Inventory.Twelve MOG-IgG-pos. NMOSD patients (86%), 24 AQP4-IgG-pos. NMOSD patients (83%), and all AQP4/MOG-IgG-neg. NMOSD patients (100%) suffered from pain. MOG-IgG-pos. NMOSD patients had mostly neuropathic pain and headache; AQP4-IgG-pos. and AQP4/MOG-IgG-neg. NMOSD patients had mostly neuropathic pain. A history of myelitis was less frequent in MOG-IgG-pos. NMOSD than in AQP4-IgG-pos. NMOSD patients. Pain influenced quality of life in all patients. Thirty-six percent of patients with pain received pain medication; none of them were free of pain.Pain is a frequent symptom of patients with MOG-IgG-pos. NMOSD and is as important as in AQP4-IgG-pos. and AQP4/MOG-IgG-neg. NMOSD. Despite its impact on quality of life, pain is insufficiently alleviated by medication.
Project description:BACKGROUND AND AIMS:ARC-520, the first an RNA interference (RNAi) therapeutic, was designed to reduce all RNA transcripts derived from covalently closed circular DNA, leading to a reduction in viral antigens and hepatitis B virus (HBV) DNA. APPROACH AND RESULTS:We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC-520 compared to placebo (PBO) in two randomized, multicenter studies in nucleoside/nucleotide analogue reverse-transcriptase inhibitor (NUC)-experienced patients with hepatitis B early antigen (HBeAg)-negative (E-neg) or HBeAg-positive (E-pos) disease. A total of 58 E-neg and 32 E-pos patients were enrolled and received four monthly doses of PBO (n = 20 E-neg, 11 E-pos), 1 mg/kg ARC-520 (n = 17 E-neg, 10 E-pos), or 2 mg/kg ARC-520 (n = 21 E-neg, 11 E-pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC-520 dose were compared to PBO. Both E-neg and E-pos high-dose groups significantly reduced HBsAg compared to PBO, with mean reductions of 0.38 and 0.54 log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and >85 days after the last dose in E-neg and E-pos patients, respectively. The low-dose groups did not reach statistical significance in either study. E-pos patients showed a dose-dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 log Paul Ehrlich IUs/mL in the low-dose and high dose ARC-520 groups respectively. ARC-520 was well tolerated, with only two serious adverse events of pyrexia possibly related to study drug observed. CONCLUSIONS:ARC-520 was active in both E-neg and E-pos, NUC-experienced HBV patients; but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin.
Project description:The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.
Project description:Minimal residual disease (MRD) is associated with adverse outcome in acute myeloid leukemia (AML) after myeloablative (MA) hematopoietic cell transplantation (HCT). We compared this association with that seen after nonmyeloablative (NMA) conditioning in 241 adults receiving NMA (n=86) or MA (n=155) HCT for AML in first remission with pre-HCT bone marrow aspirates assessed by flow cytometry. NMA patients were older and had more comorbidities and secondary leukemias. Three-year relapse estimates were 28% and 57% for MRD(neg) and MRD(pos) NMA patients, and 22% and 63% for MA patients. Three-year overall survival (OS) estimates were 48% and 41% for MRD(neg) and MRD(pos) NMA patients and 76% and 25% for MA patients. This similar OS after NMA conditioning was largely accounted for by higher non-relapse mortality (NRM) in MRD(neg) (30%) compared with MRD(pos) (10%) patients, whereas the reverse was found for MRD(neg) (7%) and MRD(pos) (23%) MA patients. A statistically significant difference between MA and NMA patients in the association of MRD with OS (P<0.001) and NRM (P=0.002) but not relapse (P=0.17) was confirmed. After adjustment, the risk of relapse was 4.51 times (P<0.001) higher for MRD(pos) patients. These data indicate that the negative impact of MRD on relapse risk is similar after NMA and MA conditioning.
Project description:OBJECTIVE: Celiac disease (CD) is associated with type 1 diabetes (T1D). In the current study, we examined whether CD affects the risk of diabetic retinopathy (DRP) in patients with T1D. RESEARCH DESIGN AND METHODS: This was a population-based cohort study. Through the Swedish National Patient Register, we identified 41,566 patients diagnosed with diabetes in 1964-2009 and who were ?30 years of age at diagnosis. CD was defined as having villous atrophy (Marsh stage 3) according to small intestinal biopsies performed between 1969 and 2008, with biopsy reports obtained from Sweden's 28 pathology departments. During follow-up, 947 T1D patients had a diagnosis of CD. We used Cox regression analysis with CD as a time-dependent covariate to estimate adjusted hazard ratios (aHRs) for DRP in patients with T1D and CD and compared them with patients with T1D but no CD. RESULTS: Duration of CD correlated with the risk of DRP. When results were stratified by time since CD diagnosis, individuals with T1D and CD were at a lower risk of DRP in the first 5 years after CD diagnosis (aHR 0.57 [95% CI 0.36-0.91]), followed by a neutral risk in years 5 to <10 (1.03 [0.68-1.57]). With longer follow-up, coexisting CD was a risk factor for DRP (10 to <15 years of follow-up, aHR 2.83 [95% CI 1.95-4.11]; ?15 years of follow-up, 3.01 [1.43-6.32]). CONCLUSIONS: Having a diagnosis of CD for >10 years is a risk factor for the development of DRP in T1D. Long-standing CD in patients with T1D merits intense monitoring of DRP.
Project description:Using Gfi1b conditional mice, deletion of gfi1b in the hematopietic system was induced by injecting MxCre tg Gfi1bfl/fl mice with pIpC. 30 days after injection, Cd150 pos, Cd 48 neg, Lin neg Sca and c-kit pos stem cells were sortrted from Gfi1bfl/fl and Mxcre tg Gfi1bfl/fl mice and analysed. We used the mouse Affymetrix Gene ST Array. Overall design: The study should determine whether loss of Gfi1 alters the gene expression pattern in the hematopietic stem cells.
Project description:Human papillomavirus-negative (HPV-neg) oropharyngeal squamous cell carcinomas (OPSCCs) are associated with poorer overall survival (OS) compared with HPV-positive (HPV-pos) OPSCCs. The major obstacle in improving outcomes of HPV-neg patients is the lack of robust biomarkers and therapeutic targets. Herein, we investigated the role of centrosome amplification (CA) as a prognostic biomarker in HPV-neg OPSCCs. A quantitative evaluation of CA in clinical specimens of OPSCC revealed that (a) HPV-neg OPSCCs exhibit higher CA compared with HPV-pos OPSCCs, and (b) CA was associated with poor OS, even after adjusting for potentially confounding clinicopathologic variables. Contrastingly, CA was higher in HPV-pos cultured cell lines compared to HPV-neg ones. This divergence in CA phenotypes between clinical specimens and cultured cells can therefore be attributed to an inaccurate recapitulation of the in vivo tumor microenvironment in the cultured cell lines, namely a hypoxic environment. The exposure of HPV-neg OPSCC cultured cells to hypoxia or stabilizing HIF-1? genetically increased CA. Both the 26-gene hypoxia signature as well as the overexpression of HIF-1? positively correlated with increased CA in HPV-neg OPSCCs. In addition, we showed that HIF-1? upregulation is associated with the downregulation of miR-34a, increase in CA and expression of cyclin- D1. Our findings demonstrate that the evaluation of CA may aid in therapeutic decision-making, and CA can serve as a promising therapeutic target for HPV-neg OPSCC patients.