Mixed Beri’s: High Output Heart Failure from Severe Anemia and Thiamine Deficiency

Background: Severe anemia and thiamine deficiency can independently result in high output heart failure (HOHF) through different mechanisms. Data on the threshold and timeframe at which these etiologies may precipitate HOHF is unclear. Case: A 63-year-old male with alcohol use disorder consuming 18 drinks/week presented with progressive shortness of breath and lower extremity edema for a few months. Physical exam revealed tachycardia, anasarca, jugular venous distension, Lancisi’s sign, and a midsystolic murmur. Echocardiogram demonstrated EF of 30-35%, dilated left ventricle, and cardiac index of 4.2L/min/m2. Decision-Making: Heart failure can independently precipitate anemia while severe alcoholism can induce myelosuppression and promote risk for bleeding. Thus, iron studies and endoscopy are crucial to elucidating the underlying pathophysiology to further direct therapy. Labs demonstrated hemoglobin 3.0 g/dL (baseline 11 g/dL 7 months prior), ferritin 5 ng/mL, thiamine 26 nmol/L, and hemoccult positive stool while colonoscopy revealed bleeding diverticulosis and hemorrhoids, thereby confirming critical iron deficiency anemia from lower GI bleed and thiamine deficiency. Cardiac catheterization ruled out ischemic cause of his new onset cardiomyopathy, supporting the diagnosis of HOHF in the setting of severe anemia and concomitant cardiac Beri Beri. Our patient was treated with parental thiamine infusions, intravenous iron sucrose, blood transfusions, and gradually diuresed with bumetanide. Repeat evaluation of his left ventricular function 3 months later showed recovery of EF to 50-55%. Conclusion: HOHF can generally be reversed with etiology-directed treatments. In chronic alcoholic patients, we advocate for routine testing of whole blood thiamine to assess for occult vitamin deficiency to determine whether supplementation may assist in therapy. The relative independent contributions or synergistic effects of iron deficiency and thiamine deficiency on HOHF remains unknown, but thorough investigations are essential to ensure recovery of cardiac function

Targeting effector memory T cells with alefacept in new onset type 1 diabetes: 12 month results from the T1DAL study

Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D. Methods The T1DAL study is a phase II, double-blind, placebo-controlled trial that randomised T1D patients 12-35 years old within 100 days of diagnosis, 33 to alefacept (two 12-week courses of 15 mg IM per week, separated by a 12-week pause) and 16 to placebo, at 14 US sites. The primary endpoint was the change from baseline in mean 2-hour C-peptide area under the curve (AUC) at 12 months. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings The mean 2-hour C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110 nmol/L) in the alefacept group and decreased by 0.115 nmol/L (95% CI -0.278 to 0.047) in the placebo group, which was not significant (p=0.065). However, key secondary endpoints were met: the mean 4-hour C-peptide AUC was significantly higher (p=0.019), and daily insulin use and the rate of hypoglycemic events were significantly lower (p=0.02 and p<0.001, respectively) at 12 months in the alefacept vs. placebo groups. Safety and tolerability were comparable between groups. There was targeted depletion of Tems and Tcms, with sparing of naïve and regulatory T cells (Tregs). Interpretation At 12 months, alefacept preserved the 4-hour C-peptide AUC, lowered insulin use, and reduced hypoglycemic events, suggesting a signal of efficacy. Depletion of memory T cells with sparing of Tregs may be a useful strategy to preserve beta cell function in new-onset T1D

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D

Correlation Among Hypoglycemia, Glycemic Variability, and C-Peptide Preservation After Alefacept Therapy in Patients with Type 1 Diabetes Mellitus: Analysis of Data from the Immune Tolerance Network T1DAL Trial

PURPOSE: In natural history studies, maintenance of higher levels of C-peptide secretion (a measure of endogenous insulin production) correlates with a lower incidence of major hypoglycemic events in patients with type 1 diabetes mellitus (T1D), but it is unclear whether this is also true for drug-induced C-peptide preservation. METHODS: We analyzed hypoglycemic events and glycemic control data from the T1DAL (Inducing Remission in New-Onset T1D with Alefacept) study, a trial of alefacept in new-onset T1D, which found significant C-peptide preservation at 1 and 2 years. We performed a post hoc analysis using mixed models of the association between the meal-stimulated 4-hour C-peptide AUC (4-hour AUC) and rates of major hypoglycemia, measures of glycemic control (glycosylated hemoglobin [HbA1c]; mean glucometer readings), and variability (glucometer SDs; highest and lowest readings), and an index of partial remission (insulin dose-adjusted HbA1c[ IDAA1c]). FINDINGS: Data from 49 participants (33 in the alefacept group and 16 in the placebo group) were analyzed at baseline and 12 and 24 months. We found that the 4-hour AUC at baseline and at 1 year was a significant predictor of the number of hypoglycemic events during the ensuing 12-month interval (p = 0.030). There was a strong association between the 4-hour AUC and glucometer SDs (P < 0.001), highest readings (p < 0.001), and lowest readings (p = 0.03), all measures of glycemic variability. There was a strong inverse correlation between the 4-hour AUC and 2 measures of glycemic control: HbA1c and mean glucometer readings (both p < 0.001). There was also a strong inverse correlation between the 4-hour AUC and IDAA1c values (p < 0.001), as well as a strong correlation between IDAA1c values and glucometer SDs (p < 0.001), suggesting that reduced glycemic variability is associated with a trend toward partial remission. None of these analyses found a significant difference between the alefacept and placebo groups. IMPLICATIONS: Measures of glycemic variability and control, including rates of hypoglycemia, are significantly correlated with preservation of C-peptide regardless of whether this is achieved by immune intervention with alefacept or natural variability in patients with new-onset T1D. Thus, preservation of endogenous insulin production by an immunomodulatory drug may confer clinical benefits similar to those seen in patients with higher C-peptide secretion due to slow disease progression

Large-Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis.

OBJECTIVE: To provide a large-scale assessment of serum protein dysregulation in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features. METHODS: We investigated serum protein profiles of 66 participants with dcSSc at baseline who were enrolled in the Scleroderma: Cyclophosphamide or Transplant Trial and 66 age- and sex-matched healthy control subjects. A panel of 230 proteins, including several cytokines and chemokines, was investigated. Whole blood gene expression profiling in concomitantly collected samples was performed. RESULTS: Among the participants with dcSSc, the mean disease duration was 2.3 years. All had interstitial lung disease (ILD), and none were being treated with immunosuppressive agents at baseline. Ninety proteins were differentially expressed in participants with dcSSc compared to healthy control subjects. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion, and diapedesis were the top overrepresented pathways. Eighteen proteins correlated with the modified Rodnan skin thickness score (MRSS). Soluble epidermal growth factor receptor was significantly down-regulated in dcSSc and showed the strongest negative correlation with the MRSS, being predictive of the scores course over time, whereas α1 -antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with the MRSS. Furthermore, higher levels of cancer antigen 15-3 correlated with more severe ILD, based on findings of reduced forced vital capacity and higher scores of disease activity on high-resolution computed tomography. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses. CONCLUSION: Diffuse cutaneous SSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells

Large‐Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis

OBJECTIVE: To provide a large-scale assessment of serum protein dysregulations in diffuse cutaneous systemic sclerosis (dcSSc) and to investigate serum protein correlates of SSc fibrotic features. METHODS: Baseline serum protein profile of 66 participants with dcSSc enrolled in the Scleroderma: Cyclophosphamide Or Transplant trial and 66 healthy, age- and gender-matched controls was investigated. A panel of 230 proteins, including several cytokines and chemokines was determined. Whole blood gene expression profiling in concomitantly collected samples was performed. RESULTS: Mean disease duration was 2.3 years, all had interstitial lung disease (ILD), and none were treated with immunosuppressive agents at baseline visit. Ninety proteins were differentially expressed compared to controls. Similar to previous global skin transcript results, hepatic fibrosis, granulocyte and agranulocyte adhesion and diapedesis were the top over-represented pathways. Eighteen proteins correlated with modified Rodnan Skin Score (mRSS). Soluble EGFR was significantly down-regulated in dcSSc and showed the strongest negative correlation with mRSS and predicted its course, whereas Alpha 1 Antichymotrypsin was significantly up-regulated in dcSSc and showed the strongest positive correlation with mRSS. Furthermore, higher CA15.3 correlated with more severe ILD, based on lower forced vital capacity and higher high-resolution CT scores. Only 14 genes showed significant differential expression in the same direction in serum protein and whole blood RNA gene expression analyses. CONCLUSIONS: dcSSc has a distinct serum protein profile with prominent dysregulation of proteins related to fibrosis and immune cell adhesion/diapedesis. The differential expression for most serum proteins in SSc is likely to originate outside the peripheral blood cells

Clinical and Molecular Findings After Autologous Stem Cell Transplantation or Cyclophosphamide for Scleroderma: Handling Missing Longitudinal Data

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/175915/1/acr24785_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175915/2/acr24785.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/175915/3/acr24785-sup-0001-Disclosureform.pd

Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2&nbsp;year results of a randomised trial.

Aims/hypothesisType 1 diabetes results from T cell mediated destruction of beta cells. We conducted a trial of antithymocyte globulin (ATG) in new-onset type 1 diabetes (the Study of Thymoglobulin to ARrest T1D [START] trial). Our goal was to evaluate the longer-term safety and efficacy of ATG in preserving islet function at 2&nbsp;years.MethodsA multicentre, randomised, double-blind, placebo-controlled trial of 6.5&nbsp;mg/kg ATG (Thymoglobulin) vs placebo in patients with new-onset type 1 diabetes was conducted at seven university medical centres and one Children's Hospital in the USA. The site-stratified randomisation scheme was computer generated at the data coordinating centre using permuted-blocks of size 3 or 6. Eligible participants were between the ages of 12 and 35, and enrolled within 100&nbsp;days from diagnosis. Subjects were randomised to 6.5&nbsp;mg/kg ATG (thymoglobulin) vs placebo in a 2:1 ratio. Participants were blinded, and the study design included two sequential patient-care teams: an unblinded study-drug administration team (for the first 8&nbsp;weeks), and a blinded diabetes management team (for the remainder of the study). Endpoints assessed at 24&nbsp;months included meal-stimulated C-peptide AUC, safety and immunological responses.ResultsFifty-eight patients were enrolled; at 2&nbsp;years, 35 assigned to ATG and 16 to placebo completed the study. The pre-specified endpoints were not met. In post hoc analyses, older patients (age 22-35&nbsp;years) in the ATG group had significantly greater C-peptide AUCs at 24&nbsp;months than placebo patients. Using complete preservation of baseline C-peptide at 24&nbsp;months as threshold, nine of 35 ATG-treated participants (vs 2/16 placebo participants) were classified as responders; nine of 11 responders (67%) were older. All participants reported at least one adverse event (AE), with 1,148 events in the 38 ATG participants vs 415 in the 20 placebo participants; a comparable number of infections were noted in the ATG and placebo groups, with no opportunistic infections nor difficulty clearing infections in either group. Circulating T cell subsets depleted by ATG partially reconstituted, but regulatory, naive and central memory subsets remained significantly depleted at 24&nbsp;months. Beta cell autoantibodies did not change over the 24&nbsp;months in the ATG-treated or placebo participants. At 12&nbsp;months, ATG-treated participants had similar humoral immune responses to tetanus and HepA vaccines as placebo-treated participants, and no increased infections.Conclusions/interpretationA brief course of ATG substantially depleted T cell subsets, including regulatory cells, but did not preserve islet function 24&nbsp;months later in the majority of patients with new-onset type 1 diabetes. ATG preserved C-peptide secretion in older participants, which may warrant further study.Trial registrationClinicalTrials.gov NCT00515099 PUBLIC DATA REPOSITORY: START datasets are available in TrialShare www.itntrialshare.orgFundingNational Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). The trial was conducted by the Immune Tolerance Network (ITN)

Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial.

BackgroundType 1 diabetes results from T-cell-mediated destruction of β cells. Findings from preclinical studies and pilot clinical trials suggest that antithymocyte globulin (ATG) might be effective for reducing this autoimmune response. We assessed the safety and efficacy of rabbit ATG in preserving islet function in participants with recent-onset type 1 diabetes, and report here our 12-month results.MethodsFor this phase 2, randomised, placebo-controlled, clinical trial, we enrolled patients with recent-onset type 1 diabetes, aged 12-35 years, and with a peak C-peptide of 0.4 nM or greater on mixed meal tolerance test from 11 sites in the USA. We used a computer generated randomisation sequence to randomly assign patients (2:1, with permuted-blocks of size three or six and stratified by study site) to receive either 6.5 mg/kg ATG or placebo over a course of four days. All participants were masked and initially managed by an unmasked drug management team, which managed all aspects of the study until month 3. Thereafter, to maintain masking for diabetes management throughout the remainder of the study, participants received diabetes management from an independent, masked study physician and nurse educator. The primary endpoint was the baseline-adjusted change in 2-h area under the curve C-peptide response to mixed meal tolerance test from baseline to 12 months. Analyses were by intention to treat. This is a planned interim analysis of an on-going trial that will run for 24 months of follow-up. This study is registered with ClinicalTrials.gov, number NCT00515099.FindingsBetween Sept 10, 2007, and June 1, 2011, we screened 154 individuals, randomly allocating 38 to ATG and 20 to placebo. We recorded no between-group difference in the primary endpoint: participants in the ATG group had a mean change in C-peptide area under the curve of -0.195 pmol/mL (95% CI -0.292 to -0.098) and those in the placebo group had a mean change of -0.239 pmol/mL (-0.361 to -0.118) in the placebo group (p=0.591). All except one participant in the ATG group had both cytokine release syndrome and serum sickness, which was associated with a transient rise in interleukin-6 and acute-phase proteins. Acute T cell depletion occurred in the ATG group, with slow reconstitution over 12 months. However, effector memory T cells were not depleted, and the ratio of regulatory to effector memory T cells declined in the first 6 months and stabilised thereafter. ATG-treated patients had 159 grade 3-4 adverse events, many associated with T-cell depletion, compared with 13 in the placebo group, but we detected no between-group difference in incidence of infectious diseases.InterpretationOur findings suggest that a brief course of ATG does not result in preservation of β-cell function 12 months later in patients with new-onset type 1 diabetes. Generalised T-cell depletion in the absence of specific depletion of effector memory T cells and preservation of regulatory T cells seems to be an ineffective treatment for type 1 diabetes