Delayed onset hypophysitis after therapy with daclizumab for multiple sclerosis - A report of two cases.

Daclizumab (DAC), a humanized monoclonal antibody that binds to the interleukin (IL)-2-receptor alpha chain, was approved in May 2016 for treatment of relapsing-remitting multiple sclerosis (RRMS). Approval was suspended in March 2018 after occurrence of severe liver failure and fatal meningoencephalitis in several patients treated with DAC. We report the clinical, laboratory and neuroimaging findings of 2 patients, who developed hypophysitis about 4 months after cessation of therapy with DAC. This report identifies delayed onset hypophysitis as a previously unrecognized severe side effect of DAC, highlighting the importance of continuous pharmacovigilance and patient monitoring even after cessation of DAC therapy.

Induction regimens and post-transplantation lymphoproliferative disorder after pediatric intestinal transplantation: Single-center experience.

Pediatric recipients of intestinal transplants have a high incidence of PTLD, but the impact of specific induction immunosuppression agents is unclear. In this single-center retrospective review from 2000 to 2017, we describe the incidence, characteristics, and outcomes of PTLD after primary intestinal transplantation in 173 children with or without liver, after induction with rATG, alemtuzumab, or anti-IL-2R agents. Thirty cases of PTLD occurred among 28 children, 28 EBV+ and 2 EBV-. Although not statistically significant, the PTLD incidence was higher after isolated intestinal transplant compared with liver-inclusive allograft (19.3% vs 13.3%, P = .393) and after induction with anti-IL-2R antibody and alemtuzumab compared with rATG (28.6% and 27.3% vs 13.3%, P = .076). The 30 PTLD cases included 13 monomorphic PTLD, 13 polymorphic PTLD, one spindle cell, one Burkitt lymphoma, and two cases too necrotic to classify. After reduction of immunosuppression, management was based on disease histology and extent. Resection with or without rituximab was used for polymorphic tumors and limited disease extent, whereas chemotherapy was used for diffuse disease. Of the 28 patients, 11 recovered with functioning allografts (39.3%), 10 recovered after enterectomy (35.7%), and seven patients died (25%), three due to PTLD and four due to other causes. All who died of progressive PTLD had received chemotherapy, highlighting the mortality of PTLD, toxicity of treatment and need for novel agents. Alemtuzumab is no longer used for induction at our center.

Long-term safety and efficacy of daclizumab beta in relapsing-remitting multiple sclerosis: 6-year results from the SELECTED open-label extension study.

OBJECTIVE: SELECTED, an open-label extension study, evaluated daclizumab beta treatment for up to 6 years in participants with relapsing multiple sclerosis who completed the randomized SELECT/SELECTION studies. We report final results of SELECTED. METHODS: Eligible participants who completed 1-2 years of daclizumab beta treatment in SELECT/SELECTION received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 6 years in SELECTED. Safety assessments were evaluated for the SELECTED treatment period; efficacy data were evaluated from first dose of daclizumab beta in SELECT/SELECTION. RESULTS: Ninety percent (410/455) of participants who completed treatment in SELECTION enrolled in SELECTED. Within SELECTED, 69% of participants received daclizumab beta for > 3 years, 39% for > 4 years, and 9% for > 5 years; 87% of participants experienced an adverse event and 26% a serious adverse event (excluding multiple sclerosis relapse). No deaths occurred. Overall, hepatic events were reported in 25% of participants; serious hepatic events in 2%. There were no confirmed cases of immune-mediated encephalitis. Based on weeks from the first daclizumab beta dose in SELECT/SELECTION, adjusted annualized relapse rate (95% confidence interval) for weeks 0-24 was 0.21 (0.16-0.29) and remained low on continued treatment. Overall incidence of 24-week confirmed disability progression was 17.4%. Mean numbers of new/newly enlarging T2 hyperintense lesions remained low; percentage change in whole brain volume decreased over time. CONCLUSIONS: The effects of daclizumab beta on clinical and radiologic outcomes were sustained for up to ~ 8 years of treatment. No new safety concerns were identified in SELECTED. TRIAL REGISTRATION: Clinicaltrials.gov NCT01051349; first registered on January 15, 2010.

Addition of Epigallocatechin Gallate 400 mg to Sofosbuvir 400 mg + Daclatisvir 60 mg With or Without Ribavirin in Treatment of Patients with Chronic Hepatitis C Improves the Safety Profile: A Pilot Study.

Emergence of new molecules acting directly on the hepatitic C virus (HCV) has improved treatment outcomes. However, there is a risk of selecting viral escape mutants, so a new combination is needed using different inhibitors that target different steps of the HCV infectious cycle. Novel single tablet formulations were developed: Dactavira, composed of sofosbuvir (SOF) 400 mg/daclatisvir (DCV) 60 mg/epigallocatechin gallate (EGCG) 400 mg without ribavirin (RBV); and Dactavira plus, which includes RBV 800 mg. A randomized, open-label study was carried out on treatment-naïve non-cirrhotic (Group A, n = 50) and treatment-naïve cirrhotic (Group B, n = 22) patients with genotype 4 HCV infection. Group A was randomly assigned to receive a single daily fixed-dose (Dactavira, n = 25) or the standard of care [SOF 400 mg/DCV 60 mg] (n = 25) daily for 12 weeks. Group B was randomly assigned to receive a single daily fixed-dose (Dactavira plus, n = 11) or the standard of care + RBV 800 mg (n = 11) daily for 12 weeks. Patients receiving Dactavira or Dactavira plus had a significantly more rapid rate of viral load decline as compared to patients receiving the standard of care therapy. Sustained virological response for 12 weeks for Dactavira or Dactavira plus showed no statistically significant difference when compared to the standard of care. Also, they did not affect normal hemoglobin levels (p < 0.001) versus the standard of care. The incorporated EGCG interferes with the viral entry mechanisms, as reported by several investigators, and in turn enhances efficacy and prevents relapse as compared to the standard of care. Also, its antihemeolytic and antifibrotic activities may improve the safety and tolerability of the therapy.

Rash developing after cessation of Daclizumab for relapsing remitting MS; a case series.

Daclizumab, a monoclonal antibody directed against CD25, a subunit of the high-affinity IL-2 receptor, was licensed as a disease modifying therapy (DMT) for relapsing remitting multiple sclerosis in 2017. Interference with IL-2 signalling is hypothesised to modulate T cell function. For example it results in a preferential shift of innate lymphoid cell (ILC) into CD56bright natural killer cells and a decrease in regulatory T Cells. We present three patients who developed urticarial papulovesicular rashes at a median of 3 months after discontinuation of Daclizumab. We propose an unexpected T cell mediated immune reaction as the cause.

The development of sarcoidosis in patients receiving daclizumab: A case series from multiple clinical trials.

INTRODUCTION: Several drugs have been associated with druginduced sarcoidosis-like reactions (DISRs) that are clinically indistinguishable from sarcoidosis. Daclizumab is a humanized monoclonal IgG1 antibody that binds to CD25 that has been studied for the treatment of multiple sclerosis (MS). During MS clinical trials of daclizumab, 12 subjects developed clinical conditions potentially consistent with sarcoidosis. Therefore, an independent adjudication committee of individuals with expertise in sarcoidosis was organized to determine the likelihood of these cases representing sarcoidosis. METHODS: The adjudication committee consisted of a pulmonologist, pathologist, and radiologist with clinical experience in sarcoidosis. The committee had access to the subjects' laboratory data, narratives of all suspect adverse reaction reports, radiographic imaging and histology from biopsies. A priori, a grading system was developed to determine criteria to establish the likelihood that the patient had developed sarcoidosis. RESULTS: The adjudication confirmed sarcoidosis in 11/12 subjects. The committee's decisions were unanimous in all cases. Biopsies were available in 7/11 of these. In the 4 subjects who did not have a biopsy, they all had presentations, clinical findings, and/or laboratory findings that were highly specific for sarcoidosis. Alternative causes for these clinical findings were reasonably excluded in all cases. The lung (8/11) and skin (6/11) were the most common organs involved. The mean daclizumab dose given when signs or symptoms of sarcoidosis occurred was 5413 ±â€¯2704 mg and the median time from first daclizumab dose was 996 days. The incidence rate of developing sarcoidosis in those participating in these daclizumab trials was 154/100,000 patient-years compared with incidence rates of sarcoidosis in the United States of 3.2-17.8/100,000/year. These data suggest that these sarcoidosis cases may have represented DISRs related to daclizumab therapy. CONCLUSIONS: Given the clinical presentation and subsequent evaluation of these 11 subjects, we suspect that they had DISRs from daclizumab.

Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis.

BACKGROUND: Daclizumab is a monoclonal antibody that binds the high-affinity interleukin-2 receptor and was approved for the treatment of relapsing multiple sclerosis. Due to severe inflammatory brain disorders, the approval was suspended in March 2018. OBJECTIVE AND METHODS: This retrospective cohort study summarizes clinical, laboratory, radiological, and histological findings of seven patients who developed meningo-/encephalitis after daclizumab therapy. RESULTS: Patients presented with encephalitis and/or meningitis and suffered from systemic symptoms such as fever (5/7), exanthema (5/7), or gastrointestinal symptoms (4/7). Secondary autoimmune diseases developed. Blood analysis revealed an increase in eosinophils (5/7). Six patients fulfilled the diagnostic criteria for a drug reaction with eosinophilia and systemic symptoms (DRESS). Magnetic resonance imaging (MRI) showed multiple contrast-enhancing lesions, and enhancement of the ependyma (6/7), meninges (5/7), cranial or spinal nerves (2/7), and a vasculitic pattern (3/7). Histology revealed a pronounced inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils, and densely infiltrated vessels. Most patients showed an insufficient therapeutic response and a high disability at last follow-up (median Expanded Disability Status Scale (EDSS) 8). Two patients died. CONCLUSION: Meningoencephalitis and DRESS may occur with daclizumab therapy. This potential lethal side effect is characterized by a dysregulated immune response. Our findings underline the importance of postmarketing drug surveillance.

FDA-approved drugs for multiple sclerosis have no efficacy or disability data in non-Caucasian patients.

Pharmacotherapy of multiple sclerosis (MS) is evolving rapidly. Despite impressive gains over the past 2 decades in the approval of multiple drugs for MS, lack of recruitment of minorities with MS in phase 3 clinical studies is a persistent concern and skews efficacy and disability data.

A case of immune-mediated encephalitis related to daclizumab therapy.

This report will detail a case of immune-mediated encephalitis in the context of daclizumab therapy. Daclizumab is a humanised monoclonal antibody which, prior to its recent worldwide withdrawal due to safety concerns, was utilised as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The withdrawal of this therapy was prompted by concerns over 12 cases of serious immune-mediated adverse reactions in the central nervous system. We report an additional case, including clinical data and results of neuroimaging, cerebrospinal fluid (CSF) examination and brain biopsy.

Does Induction Type Influence Outcomes in Kidney Transplant Recipients at Different Phases of Hepatitis B Infection?

OBJECTIVES: Immunosuppressive therapy in kidney transplant recipients with hepatitis B virus infection may increase the risk of disease progression. Here, we compared outcomes of depleting (antithymocyte globulin/alemtuzumab) versus nondepleting (basiliximab/daclizumab) antibody induction in kidney transplant recipients at different serologic phases of hepatitis B virus infection. MATERIALS AND METHODS: We used the Organ Procurement and Transplantation Network/United Network for Organ Sharing database to identify adult kidney transplant recipients at different serologic phases of hepatitis B virus infection (transplants received from 2001-2011 after patients received perioperative induction with discharge on calcineurin inhibitors/mycophenolate mofetil with/without steroids). We used a Cox model to compare outcomes among patient groups. RESULTS: Median follow-up was 50.7 months (range, 28.6 to 82.6 mo). Serologic phase for the 7681 study patients were as follows: 1098 at HBsAg+/anti-HBc- (depleting = 652, nondepleting = 446), 446 at HBsAg+/anti-HBc+ (depleting = 250, nondepleting = 216), and 6117 at HBsAg-/anti-HBc+ (depleting = 3562, nondepleting = 2555) (where anti-HBc denotes hepatitis B core antibody, HBsAg denotes hepatitis B surface antigen, and +/- denote positive/negative). When we compared those with depleting versus nondepleting agents, hazard ratios (95% confidence intervals) for adjusted overall graft, death-censored graft, and patient survival were 0.97 (0.78-1.26; P = .86), 1.20 (0.83-1.60; P = .44), and 0.92 (0.66-1.30; P = .51) in the HBsAg+/anti-HBc-; 0.81 (0.55-1.18; P = .27), 0.59 (0.32-1.12; P = .11), and 0.95 (0.60-1.49; P = .83) in the HBsAg+/anti-HBc+; and 0.96 (0.86-1.05; P = .37), 0.95 (0.60-1.49; P = .97), and 0.92 (0.80-1.05; P = 0.22) in the HBsAg-/anti-HBc+ groups. CONCLUSIONS: Our study did not show adverse graft and patient outcomes associated with depleting versus nondepleting antibody induction in kidney transplant recipients at different phases of hepatitis B virus infection. This supports the selection and use of induction agents based on immunologic risk in such patients.

Drug reaction with eosinophilia and systemic symptoms after daclizumab therapy.

OBJECTIVE: To report on 2 women with multiple sclerosis (MS) who developed severe neurologic deterioration and a drug reaction with eosinophilia and systemic symptoms (DRESS) after treatment with 2 and 4 subcutaneous injections of daclizumab, respectively. METHODS: This report includes clinical, MRI, and histopathologic data. RESULTS: Daclizumab is a humanized monoclonal antibody that binds the interleukin-2 receptor. It was approved for the treatment of relapsing MS. DRESS is an immunologic reaction to various medications that is characterized by eosinophilia as well as cutaneous and visceral manifestations. Following daclizumab treatment, both patients showed fulminant neurologic deterioration along with blood eosinophilia and skin changes, and both fulfilled the clinical criteria for the diagnosis of DRESS. They presented with multiple gadolinium-enhancing supra- and infratentorial lesions, with lesions in the basal ganglia, mesencephalon, and cerebellum. Brain biopsies revealed a pronounced inflammatory infiltrate including numerous eosinophils infiltrating demyelinating lesions, a feature that is atypical for MS but compatible with DRESS. In addition, numerous plasma cells and changes reminiscent of vasculitis were evident. CONCLUSIONS: Neurologic deterioration and DRESS occurred as severe adverse drug effects of daclizumab treatment. Early diagnosis and treatment of DRESS are essential because it is associated with complications such as new autoimmune diseases and liver failure, and may even be lethal. Because of its potential serious side effects, daclizumab was recently suspended for use in the European Union.

Daclizumab in multiple sclerosis. / Daclizumab en la esclerosis multiple.

INTRODUCTION: Daclizumab is a monoclonal antibody directed against the CD25 subunit of the interleukin-2 receptor, investigated as a disease-modifying therapy in relapsing-remitting multiple sclerosis. The present review addresses how the drug was developed, the known mechanism of action of the drug and the up-to-date data of efficacy and safety. DEVELOPMENT: Daclizumab has shown superiority in prevention of relapses against placebo and low-dose interferon beta-1a at a level that puts it on par with the rest of current first-line drugs. The effect on the progression of the disease and on neurodegeneration parameters, however, is not clear. On the other hand, it presents safety problems (mainly risk of autoimmunity phenomena including fulminant hepatopathy and encephalitis) that have supposed eventually its withdrawn from marketing. Daclizumab introduces a new mechanism of action through the blocking of a key interleukin in immune regulation and its effect on a population of cells with regulatory ability, such as the NK CD56(bright) cells. CONCLUSIONS: Daclizumab has shown efficacy in slowing the inflammatory process of multiple sclerosis, although the appearance of potentially serious side effects has not allowed its use to significantly impact current clinical practice. The development of new drugs in multiple sclerosis must be contingent on maintaining or improving the risk-benefit profile with respect to those already in use.

TITLE: Daclizumab en la esclerosis multiple.Introduccion. El daclizumab es un anticuerpo monoclonal dirigido contra la subunidad CD25 del receptor de la interleucina-2, investigado como terapia modificadora de la evolucion de la enfermedad en la esclerosis multiple. La presente revision aborda como se desarrollo el farmaco, cual es su mecanismo de accion conocido y los datos que se han obtenido hasta la fecha acerca de su eficacia y seguridad. Desarrollo. El daclizumab ha mostrado superioridad en prevencion de brotes frente a placebo e interferon beta-1a de baja dosis en un nivel que lo situa a la par del resto de farmacos de primera linea actuales. El efecto sobre la progresion de la enfermedad y sobre parametros de neurodegeneracion, no obstante, no esta aclarado. Por otro lado, presenta problemas de seguridad (riesgo de reacciones autoinmunes que incluyen hepatopatia fulminante y encefalitis) que han supuesto finalmente su retirada del mercado. El daclizumab introduce un nuevo mecanismo de accion a traves del bloqueo de una interleucina clave en la regulacion inmune y por su efecto sobre una poblacion de celulas con capacidad reguladora, como son las celulas NK CD56(bright). Conclusiones. El daclizumab ha demostrado eficacia para frenar el proceso inflamatorio de la esclerosis multiple, aunque la aparicion de efectos secundarios potencialmente graves no ha permitido que su uso impacte de manera significativa en la practica clinica actual. El desarrollo de nuevos farmacos en la esclerosis multiple debe estar supeditado a mantener o mejorar el perfil riesgo-beneficio respecto a los ya en uso.

Circulating lymphocyte levels and relationship with infection status in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta.

BACKGROUND: Reversible lymphocyte count reductions have occurred following daclizumab beta treatment for relapsing-remitting multiple sclerosis. OBJECTIVE: To analyse total and differential lymphocyte levels and relationship with infection status. METHODS: In DECIDE, blood samples were collected at 12-week intervals from daclizumab beta- ( n = 919) or intramuscular interferon beta-1a-treated ( n = 922) patients. Infections/serious infections were assessed proximate to grade 2/3 lymphopenia or low CD4+/CD8+ T-cell counts. Total safety population (TSP) data were additionally analysed from the entire clinical development programme ( n = 2236). RESULTS: Over 96 weeks in DECIDE, mean absolute lymphocyte count (ALC), CD4+ and CD8+ T-cell counts decreased <10% (7.1% vs 1.6%, 9.7% vs 2.0%, 9.3% vs 5.9%: daclizumab beta vs interferon beta-1a, respectively); shifts to ALC below lower limit of normal occurred in 13% versus 15%, respectively. Grade 3 lymphopenia was uncommon (TSP: <1%) and transient. Lymphocyte changes generally occurred within 24 weeks after treatment initiation and were reversible within 12 weeks of discontinuation. In DECIDE, mean CD4+/CD8+ T-cell counts were similar regardless of infection status. TSP data were consistent with DECIDE. CONCLUSION: When observed, ALC and CD4+/CD8+ T-cell count decreases in daclizumab beta-treated patients were generally mild-to-modest, reversible upon treatment discontinuation and not associated with increased risk of infections, including opportunistic infections.