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Transplantation Dec 2016Graft-versus-host-disease (GVHD) after liver transplantation (LT) is a deadly complication with very limited data on risk factors, diagnosis and management. We report a... (Review)
Review
BACKGROUND
Graft-versus-host-disease (GVHD) after liver transplantation (LT) is a deadly complication with very limited data on risk factors, diagnosis and management. We report a case series and a comprehensive review of the literature.
METHODS
Data were systematically extracted from reports of GVHD after LT, and from the United Network for Organ Sharing database. Group comparisons were performed.
RESULTS
One hundred fifty-six adult patients with GVHD after LT have been reported. Median time to GVHD onset was 28 days. Clinical features were skin rash (92%), pancytopenia (78%), and diarrhea (65%). Six-month mortality with GVHD after LT was 73%. Sepsis was the most common cause of death (60%). Enterobacter bacteremia, invasive aspergillosis, and disseminated Candida infections were frequently reported. Recipient age over 50 years is a risk factor for GVHD after LT. Hepatocellular carcinoma was overrepresented, whereas chronic hepatitis C was underrepresented, in reported United States GVHD cases relative to all United Network for Organ Sharing database LT cases. Mortality rate with treatment of GVHD after LT was 84% with high-dose steroids alone, 75% to 100% with regimens using dose increases of calcineurin inhibitors, and 55% with IL-2 antagonists. Mortality was 25% in small case series using the CD2-blocker alefacept or TNF-α antagonists.
CONCLUSIONS
Age older than 50 years and hepatocellular carcinoma appear to be risk factors for GVHD. Hepatitis C may be protective. High-dose steroids and calcineurin inhibitors are ineffective in the treatment of GVHD after LT. CD2-blockers and TNF-α antagonists appear promising. We propose a diagnostic algorithm to assist clinicians in managing adults with GVHD after LT.
Topics: Adolescent; Adult; Aged; Algorithms; Carcinoma, Hepatocellular; Databases, Factual; Diabetes Complications; Female; Graft vs Host Disease; Humans; Iowa; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Risk Factors; United States; Universities; Young Adult
PubMed: 27495762
DOI: 10.1097/TP.0000000000001406 -
Clinical Therapeutics Jun 2016In natural history studies, maintenance of higher levels of C-peptide secretion (a measure of endogenous insulin production) correlates with a lower incidence of major... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adolescent; Adult; Alefacept; Blood Glucose; C-Peptide; Child; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immune Tolerance; Insulin; Male; Recombinant Fusion Proteins; Young Adult
PubMed: 27209482
DOI: 10.1016/j.clinthera.2016.04.032 -
Immunotherapy (Los Angeles, Calif.) Dec 2015Current anti-retroviral treatment (ART) for HIV is effective in maintaining HIV at undetectable levels. However, cessation of ART results in immediate and brisk rebound...
Current anti-retroviral treatment (ART) for HIV is effective in maintaining HIV at undetectable levels. However, cessation of ART results in immediate and brisk rebound of viremia to high levels. This rebound is driven by an HIV reservoir mainly enriched in memory CD4 T cells. In order to provide any form of functional HIV Cure, elimination of this viral reservoir has become the focus of current HIV cure strategies. Alefacept was initially developed for the treatment of chronic plaque psoriasis. Alefacept is a chimeric fusion protein consisting of the CD2-binding portion of human leukocyte function antigen-3 (LFA3) linked to the Fc region of human IgG1 (LFA3-Fc). Alefacept was designed to inhibit memory T cell activation that contributes to the chronic autoimmune disease psoriasis by blocking the CD2 coreceptor. However, it was found to deplete memory T cells that express high levels of CD2 via NK cell-mediated antibody dependent cell cytotoxicity (ADCC) . Phase II and phase III clinical trials of alefacept with psoriasis patients demonstrated promising results and an excellent safety profile. Subsequently, alefacept has been successfully repurposed for other memory T cell-mediated autoimmune diseases including skin diseases other than psoriasis, organ transplantation and type I diabetes (T1D). Herein, we review our specific strategy to repurpose the FDA approved biologic alefacept to decrease and hopefully someday eliminate the HIV reservoir, for which CD2 memory CD4 T cells are a significant contributor.
PubMed: 27110598
DOI: 10.4172/imt.1000104 -
Rheumatology International May 2016The diverse clinical picture of PsA suggests the need to identify suitable therapies to address the different combinations of clinical manifestations. This review aimed... (Review)
Review
The diverse clinical picture of PsA suggests the need to identify suitable therapies to address the different combinations of clinical manifestations. This review aimed to classify the available biologic agents and new small molecule inhibitors (licensed and nonlicensed) based on their proven efficacy in treating different clinical manifestations associated with psoriasis and PsA. This review presents the level of evidence of efficacy of different biologic treatments and small molecule inhibitors for certain clinical features of treatment of PsA and psoriasis, which was graded in categories I-IV. The literature searches were performed on the following classes of biologic agents and small molecules: TNF inhibitors (adalimumab, etanercept, infliximab, golimumab, certolizumab), anti-IL12/IL23 (ustekinumab), anti-IL17 (secukinumab, brodalumab, ixekizumab), anti-IL6 (tocilizumab), T cell modulators (alefacept, efalizumab, abatacept, itolizumab), B cell depletion therapy (rituximab), phosphodiesterase 4 inhibitor (apremilast) and Janus kinase inhibitor (tofacitinib). A comprehensive table including 17 different biologic agents and small molecule inhibitors previously tested in psoriasis and PsA was generated, including the level of evidence of their efficacy for each of the clinical features included in our review (axial and peripheral arthritis, enthesitis, dactylitis, and nail and skin disease). We also proposed a limited set of recommendations for a sequential biologic treatment algorithm for patients with PsA who failed the first anti-TNF therapy, based on the available literature data. There is good evidence that many of the biologic treatments initially tested in psoriasis are also effective in PsA. Further research into both prognostic biomarkers and patient stratification is required to allow clinicians the possibility to make better use of the various biologic treatment options available. This review showed that there are many potentially new treatments that are not included in the current guidelines that can be used for selected categories of patients based on their disease phenotype, clinician experience and access to new biologic therapies.
Topics: Antirheumatic Agents; Arthritis, Psoriatic; Biological Products; Humans; Interleukins; Precision Medicine; Psoriasis; Tumor Necrosis Factor-alpha
PubMed: 26892034
DOI: 10.1007/s00296-016-3436-0 -
The Journal of Clinical Investigation Aug 2015Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
METHODS
In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses.
RESULTS
A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01).
CONCLUSIONS
In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy.
TRIAL REGISTRATION
https://clinicaltrials.gov/ NCT00965458.
FUNDING
NIH and Astellas.
Topics: Adolescent; Adult; Alefacept; C-Peptide; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Child; Dermatologic Agents; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Humans; Immunologic Memory; Male; Recombinant Fusion Proteins; Time Factors
PubMed: 26193635
DOI: 10.1172/JCI81722 -
Biology of Blood and Marrow... Oct 2015Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory... (Clinical Trial)
Clinical Trial
Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory T cells, which drive alloimmunization, are relatively resistant to commonly used conditioning agents. Alefacept, a recombinant leukocyte function antigen-3/IgG1 fusion protein, targets CD2 and selectively depletes memory versus naive T cells. Three multiply transfused pediatric patients with NMD received a short course of high-dose i.v. alefacept (.25 mg/kg/dose on days -40 and -9 and .5 mg/kg/dose on days -33, -26, -19, and -12) before undergoing unrelated allogeneic transplant in the setting of reduced-intensity pretransplant conditioning and calcineurin inhibitor-based post-transplant graft-versus-host disease (GVHD) prophylaxis. Alefacept infusions were well tolerated in all patients. Peripheral blood flow cytometry was performed at baseline and during and after alefacept treatment. As expected, after the 5 weekly alefacept doses, each patient demonstrated selective loss of CD2(hi)/CCR7(-)/CD45RA(-) effector memory (Tem) and CD2(hi)/CCR7(+)/CD45RA(-) central memory (Tcm) CD4(+) and CD8(+) T cells with relative preservation of the CD2(lo) Tem and Tcm subpopulations. In addition, depletion of CD2(+) natural killer (NK) cells also occurred. Neutrophil recovery was rapid, and all 3 patients had 100% sorted (CD3/CD33) peripheral blood donor chimerism by day +100. Immune reconstitution (by absolute neutrophil, monocyte, and lymphocyte counts) was comparable with a cohort of historical control patients. All 3 patients developed GVHD but are all now off immune suppression and >2 years post-transplant with stable full-donor engraftment. These results suggest that alefacept at higher dosing can deplete both memory T cells and NK cells and that incorporating CD2-targeted depletion into a reduced-intensity transplant regimen is feasible and safe in heavily transfused patients.
Topics: Alefacept; Anemia, Aplastic; Blood Component Transfusion; Bone Marrow Transplantation; CD2 Antigens; Child; Cord Blood Stem Cell Transplantation; Dyskeratosis Congenita; Fanconi Anemia; Female; Graft Survival; Graft vs Host Disease; Historically Controlled Study; Humans; Immunologic Memory; Immunophenotyping; Infant; Killer Cells, Natural; Lymphocyte Depletion; Male; Pilot Projects; Recombinant Fusion Proteins; T-Lymphocyte Subsets; Transplantation Conditioning; Unrelated Donors
PubMed: 26095669
DOI: 10.1016/j.bbmt.2015.06.005 -
World Journal of Hepatology Apr 2015Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α...
Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α blockers. The biologic agents currently used in psoriasis include alefacept, efalizumab, and the TNF-α antagonists etanercept, infliximab, and adalimumab. Infections and cancer are the main possible consequences of intended or unexpected immunosuppression. We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-α therapy; the patient was firstly hospitalized for an acute cholestatic toxic hepatitis, which we supposed to be related to adalimumab. The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease. The correct diagnosis of T cell/histiocyte- rich large B cell lymphoma (T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy. T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents. In psoriatic patients, treated with biologic immunosuppressive agents, the suspect of abdominal lymphoma should always be included as differential diagnosis. Abdominal ultrasound evaluation need therefore to be included in the pre-treatment screening as in the follow-up surveillance.
PubMed: 25914782
DOI: 10.4254/wjh.v7.i5.814 -
American Journal of Transplantation :... Mar 2015Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of...
Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of antibody-mediated rejection (AMR) and graft injury. Our clinical data suggest correlation of increased serum B cell activating factor/survival factor (BAFF) with increased risk of antibody-mediated rejection in alemtuzumab treated patients. In the present study, we tested the ability of BAFF blockade (TACI-Ig) in a nonhuman primate AMR model to prevent alloantibody production and prolong allograft survival. Three animals received the AMR inducing regimen (CD3-IT/alefacept/tacrolimus) with TACI-Ig (atacicept), compared to five control animals treated with the AMR inducing regimen only. TACI-Ig treatment lead to decreased levels of DSA in treated animals at 2 and 4 weeks posttransplantation (p < 0.05). In addition, peripheral B cell numbers were significantly lower at 6 weeks posttransplantation. However, it provided only a marginal increase in graft survival (59 ± 22 vs. 102 ± 47 days; p = 0.11). Histological analysis revealed a substantial reduction in findings typically associated with humoral rejection with atacicept treatment. More T cell rejection findings were observed with increased graft T cell infiltration in atacicept treatment, likely secondary to the graft prolongation. We show that BAFF/APRIL blockade using concomitant TACI-Ig treatment reduced the humoral portion of rejection in our depletion-induced preclinical AMR model.
Topics: Animals; Antibodies, Neutralizing; Antibody Formation; B-Cell Activating Factor; Graft Survival; Humans; Kidney Transplantation; Lymphocyte Depletion; Macaca mulatta; Male; Models, Animal; Recombinant Fusion Proteins; T-Lymphocytes; Tumor Necrosis Factor Ligand Superfamily Member 13
PubMed: 25675879
DOI: 10.1111/ajt.13045 -
Indian Journal of Dermatology Sep 2014The advent of biologics in dermatologic treatment armentarium has added refreshing dimensions, for it is a major breakthrough. Several agents are now available for use.... (Review)
Review
The advent of biologics in dermatologic treatment armentarium has added refreshing dimensions, for it is a major breakthrough. Several agents are now available for use. It is therefore imperative to succinctly comprehend their pharmacokinetics for their apt use. A concerted endeavor has been made to delve on this subject. The major groups of biologics have been covered and include: Drugs acting against TNF-α, Alefacept, Ustekinumab, Rituximab, IVIG and Omalizumab. The relevant pharmacokinetic characteristics have been detailed. Their respective label (approved) and off-label (unapproved) indications have been defined, highlighting their dosage protocol, availability and mode of administration. The evidence level of each indication has also been discussed to apprise the clinician of their current and prospective uses. Individual anti-TNF drugs are not identical in their actions and often one is superior to the other in a particular disease. Hence, the section on anti-TNF agents mentions the literature on each drug separately, and not as a group. The limitations for their use have also been clearly brought out.
PubMed: 25284845
DOI: 10.4103/0019-5154.139859 -
Experimental and Clinical... Mar 2014Induction therapy after kidney transplantation is intensive immunosuppression in the initial days after transplant when the immune system of the recipient has the first... (Review)
Review
Induction therapy after kidney transplantation is intensive immunosuppression in the initial days after transplant when the immune system of the recipient has the first contact with donor antigens. Initial intensive immunosuppression may be required to prevent acute rejection and graft loss, and subsequent immunosuppression may be decreased to minimize adverse events associated with immunosuppressive drugs. Induction agents include lymphocyte-depleting antibodies such as rabbit antithymocyte globulin, alemtuzumab, muromonab-CD3, rituximab, and bortezomib; lymphocyte-nondepleting antibodies such as interleukin 2 receptor antibodies; and other discontinued or investigational agents such as efalizumab and alefacept. Induction therapy may be adjusted for special situations such as living-donor kidney transplant, pediatric transplant, hepatitis C virus-seropositive recipients, recipients who require desensitization, patients who are at risk for developing delayed graft function, and old donors. The optimal immunosuppressive regimen may vary, and clinical practice guidelines are available.
Topics: Acute Disease; Drug Administration Schedule; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Patient Selection; Risk Factors; Time Factors; Treatment Outcome
PubMed: 24635795
DOI: 10.6002/ect.25liver.l58