Induction therapy in heart transplantation: A systematic review and network meta-analysis for developing evidence-based recommendations.

INTRODUCTION: Induction therapy (IT) utility in heart transplantation (HT) remains contested. Commissioned by a clinical-practice guidelines panel to evaluate the effectiveness and safety of IT in adult HT patients, we conducted this systematic review and network meta-analysis (NMA). METHODS: We searched for studies from January 2000 to October 2022, reporting on the use of any IT agent in adult HT patients. Based on patient-important outcomes, we performed frequentist NMAs separately for RCTs and observational studies with adjusted analyses, and assessed the certainty of evidence using the GRADE framework. RESULTS: From 5156 publications identified, we included 7 RCTs and 12 observational studies, and report on two contemporarily-used IT agents-basiliximab and rATG. The RCTs provide only very low certainty evidence and was uninformative of the effect of the two agents versus no IT or one another. With low certainty in the evidence from observational studies, basiliximab may increase 30-day (OR 1.13; 95% CI 1.06-1.20) and 1-year (OR 1.11; 95% CI 1.02-1.22) mortality compared to no IT. With low certainty from observational studies, rATG may decrease 5-year cardiac allograft vasculopathy (OR .82; 95% CI .74-.90) compared to no IT, as well as 30-day (OR .85; 95% CI .80-.92), 1-year (OR .87; 95% CI .79-.96), and overall (HR .84; 95% CI .76-.93) mortality compared to basiliximab. CONCLUSION: With low and very low certainty in the synthetized evidence, these NMAs suggest possible superiority of rATG compared to basiliximab, but do not provide compelling evidence for the routine use of these agents in HT recipients.

Outcomes of kidney transplantation in patients with IgA nephropathy based on induction: A UNOS data analysis.

INTRODUCTION: IgA nephropathy (IgAN) can cause end-stage kidney disease (ESKD). This study assesses the impact of induction and maintenance immunosuppression on IgAN recurrence, graft survival, and mortality in living and deceased donor kidney transplants (LDKT and DDKT). METHODS: Retrospective analysis of the UNOS database in adults with ESKD secondary to IgAN who received kidney transplants between January 2000 and June 30, 2022. Patients with thymoglobulin (ATG), alemtuzumab, or basiliximab/daclizumab induction with calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) with or without prednisone maintenance were analyzed. Multivariate logistic regression was performed to identify factors correlated with IgA recurrence. Multivariable Cox regression analyses were performed for clinically suspected risk factors. Kaplan Meir Analysis was utilized for overall graft survival. RESULTS: Compared to ATG with steroid maintenance, alemtuzumab with steroid increased the odds of IgAN recurrence in DDKTs (OR 1.90, p < .010, 95% CI [1.169-3.101]). Alemtuzumab with and without steroid increased the odds of recurrence by 52% (p = .036) and 56% (p = .005), respectively, in LDKTs. ATG without steroids was associated with less risk of IgAN recurrence (HR .665, p = .044, 95% CI [.447-.989]), graft failure (HR .758, p = .002, 95% CI [.633-.907]), and death (HR .619, p < .001, 95% CI [.490-.783]) in DDKTs. Recurrence was strongly associated with risks of graft failure in DDKTs and LDKTs and death in LDKTs. CONCLUSION: In patients with IgAN requiring a kidney transplant, Alemtuzumab induction correlates with increased IgAN recurrence. Relapse significantly affects graft survival and mortality. ATG without steroids is associated with the least graft loss and mortality.

Novel multiple sclerosis agents-associated cardiotoxicity: A real-world pharmacovigilance study.

BACKGROUND: Emerging novel therapeutics have been developed to hamper the progression of multiple sclerosis (MS). However, the adverse events related to these new agents remain largely unknown. Therefore, we sought to investigate the cardiovascular complications of these drugs. METHODS: Utilizing data from the U.S. food and drug administration (FDA) adverse events reporting system (FAERS), we comprehensively evaluated the cardiovascular complications of the newly FDA-approved anti-MS modifying therapies approved since 2015. Disproportionality signal analysis was conducted by measuring reporting odds ratio (ROR) with a 95% confidence interval of all cardiovascular adverse events since approval till 2021. RESULTS: After vetting the newly approved agents for MS, CD20 and CD25 inhibitors and sphingosine-1-phosphate receptors agonists were the latest approved medications for MS since 2015. Two CD20 (ocrelizumab, ofatumumab) and one CD25 inhibitors (daclizumab) were significantly associated with multiple cardiovascular adverse events. Among all the cardiotoxic events; coronary artery disease, cardiac failure and atrial fibrillation were the most predominant among CD20 or CD25 blockers. Interestingly, sphingosine-1-phosphate receptors (S1PR) agonists showed much fewer reported cardiac adverse events. However, fingolimod and siponimod were associated with significant AV block and bradycardia. CONCLUSIONS: Our data revealed the new MS agents are associated with various undefined cardiovascular complications. These findings potentially instigate further studies to personalize prescribing these agents for MS based on patient's cardiovascular profile.

Designing and generating a single-chain fragment variable (scFv) antibody against IL2Rα (CD25): An in silico and in vitro study.

OBJECTIVES: IL-2Rα plays a critical role in maintaining immune function. However, expression and secretion of CD25 in various malignant disorders and autoimmune diseases are now well established. Thus, CD25 is considered an important target candidate for antibody-based therapy. This study aimed to find the most suitable linker peptide to construct a functional anti-CD25 single-chain fragment variable (scFv) by bioinformatics studies and its production in a bacterial expression system. MATERIALS AND METHODS: Here, the 3D structures of the scFvs with different linkers were predicted and molecular dynamics simulation was performed to compare their structures and dynamics. Then, interactions between five models of scFv and human CD25 were calculated via molecular docking. According to MD and docking results, the anti-CD25 scFvs with (Gly4Ser)3 linker were constructed and cloned into pET-22b(+). Then, recombinant plasmids were transformed into Escherichia coli Bl21 (DE3) for expression using IPTG and lactose as inducers. Anti-CD25 scFv was purified from the periplasm and detected by SDS-PAGE and Western blot. Afterward, functionality was evaluated using ELISA. RESULTS: In silico analysis showed that the model containing (Gly4Ser)3 as a linker has more stability compared with other linkers. The results of SDS-PAGE, Western blot, and ELISA confirmed the accuracy of anti-CD25 scFv production and its ability to bind to the human CD25. CONCLUSION: Conclusively, our work provides a theoretical and experimental basis for production of an anti-CD25 scFv, which may be applied for various malignant disorders and autoimmune diseases.

Safety and efficacy of daclizumab beta in patients with relapsing multiple sclerosis in a 5-year open-label study (EXTEND): final results following early termination.

BACKGROUND: EXTEND (NCT01797965), an open-label extension study, evaluated the safety and efficacy of daclizumab beta in participants with relapsing multiple sclerosis (MS) who had completed the randomized DECIDE study. METHODS: Eligible participants who received either daclizumab beta or interferon beta-1a in DECIDE received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 5 years in EXTEND, followed by 24 weeks of post-dosing follow-up. Safety and tolerability were evaluated, as were clinical efficacy and magnetic resonance imaging (MRI). EXTEND was terminated ahead of schedule by the sponsors. RESULTS: The total safety population (N = 1203) received at least one dose of daclizumab beta in EXTEND. In the DECIDE and EXTEND combined periods, the median number of doses of daclizumab beta was 53; median time on treatment was 196 weeks. By 24 September 2018, the end of the study, 110/1203 (9%) participants had completed the protocol-specified treatment period and 1101/1203 (92%) had experienced an adverse event (AE). The most commonly reported AEs were MS relapse, nasopharyngitis, and upper respiratory tract infection. Hepatic events (18%), cutaneous events (45%), and infections (62%) were common treatment-related AEs. The incidence of serious AEs was 29%, most commonly MS relapse and infections. The incidence of immune-mediated disorders was 2%; three of seven were encephalitis. Two of six deaths were considered treatment related. In participants who received continuous daclizumab beta throughout DECIDE and EXTEND, the treatment effects on clinical and MRI outcomes were maintained for up to 6 years. CONCLUSION: Results from the combined DECIDE-EXTEND study elucidate outcomes of longer-term treatment with daclizumab beta in the clinical trial setting and underscore the importance of pharmacovigilance with immunomodulatory therapies in the real-world setting.

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.

Management of MS Patients Treated With Daclizumab - a Case Series of 267 Patients.

Daclizumab was approved by the FDA and the EMA in 2016 for the treatment of relapsing forms of multiple sclerosis (MS). Cases of severe inflammatory brain disease with fatal outcome led to the withdrawal of approval in Europe and the US on March 2, 2018. Approximately 8,000 patients worldwide received daclizumab, but little is known about the further therapy management of these patients after the withdrawal of daclizumab. The aim of this study is to further analyze therapy management in MS patients after safety warnings and market withdrawal. Data from two registries in Germany, the German MS Registry (GMSR) and REGIMS, were used for this analysis. In total, 267 patients were included in this study. For almost 25% of patients (in the GMSR) daclizumab was the initial treatment. Most common pre-treatments were fingolimod, dimethyl fumarate, and natalizumab; various injectables summed up to 25.9%. The most common follow-up therapies were ocrelizumab and fingolimod. In most patients, follow-up therapies were administered shortly after discontinuation of daclizumab. The wash-out time for subsequent therapies varied between 1.2 and 4.0 months. Warnings and decisions by authorities led to a rapid decline and termination of therapies in both cohorts, indicating that such warnings have an immediate impact on the treatment landscape. Therapies that were started within a short time after the discontinuation of daclizumab were subsequently replaced by other therapies and may be considered as bridging therapies.

Induction immunosuppression and the risk of incident malignancies among older and younger kidney transplant recipients: A prospective cohort study.

BACKGROUND: Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after receiving induction. METHODS: We identified 66 700 adult KT recipients treated with anti-thymocyte globulin (ATG) (n = 40 443) or interleukin-2 receptor antagonist (IL-2RA) (n = 26 327) induction (1/1/1999-12/31/2014) using USRDS/Medicare data. We estimated the risk of first-diagnosed post-KT malignancy associated with induction (ATG vs. IL-2RA) using Cox proportional hazard models. We then tested whether these risks differed between older and younger recipients (Wald test for interaction). Models incorporated inverse probability of treatment weights to adjust for confounders. RESULTS: The 3-year cumulative incidences of any diagnosed malignancy were 11.5%. ATG was associated with a higher malignancy risk (HR = 1.12, 95%CI:1.06-1.18). This association differed (pinteraction  = 0.04) between younger (HR = 1.12, 95%CI:1.06-1.18) and older recipients (HR = 1.03, 95%CI:0.96-1.09). ATG was also associated with higher risk of skin (HR = 1.18, 95%CI:1.08-1.29), lung (HR = 1.24, 95%CI:1.05-1.47), and ovary malignancies (HR = 1.94, 95%CI:1.08-3.48). However, only the association of ATG with post-KT skin malignancy differed (pinteraction  = 0.01) between younger (HR = 1.18; 95%CI:1.08-1.29) and older (HR = 1.01; 95%CI:0.93-1.09) recipients. CONCLUSIONS: Compared with IL-2RA induction, ATG was associated with elevated post-KT malignancy risk but only among younger recipients. Transplant centers may need to tailor induction IS for younger recipients to mitigate malignancy risk.

Characterization of the Impact of Daclizumab Beta on Circulating Natural Killer Cells by Mass Cytometry.

Daclizumab beta is a humanized monoclonal antibody that binds to CD25 and selectively inhibits high-affinity IL-2 receptor signaling. As a former treatment for relapsing forms of multiple sclerosis (RMS), daclizumab beta induces robust expansion of the CD56bright subpopulation of NK cells that is correlated with the drug's therapeutic effects. As NK cells represent a heterogeneous population of lymphocytes with a range of phenotypes and functions, the goal of this study was to better understand how daclizumab beta altered the NK cell repertoire to provide further insight into the possible mechanism(s) of action in RMS. We used mass cytometry to evaluate expression patterns of NK cell markers and provide a comprehensive assessment of the NK cell repertoire in individuals with RMS treated with daclizumab beta or placebo over the course of 1 year. Treatment with daclizumab beta significantly altered the NK cell repertoire compared to placebo treatment. As previously reported, daclizumab beta significantly increased expression of CD56 on total NK cells. Within the CD56bright NK cells, treatment was associated with multiple phenotypic changes, including increased expression of NKG2A and NKp44, and diminished expression of CD244, CD57, and NKp46. These alterations occurred broadly across the CD56bright population, and were not associated with a specific subset of CD56bright NK cells. While the changes were less dramatic, CD56dim NK cells responded distinctly to daclizumab beta treatment, with higher expression of CD2 and NKG2A, and lower expression of FAS-L, HLA-DR, NTB-A, NKp30, and Perforin. Together, these data indicate that the expanded CD56bright NK cells share features of both immature and mature NK cells. These findings show that daclizumab beta treatment is associated with unique changes in NK cells that may enhance their ability to kill autoreactive T cells or to exert immunomodulatory functions.

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.

Direct T-cell Inhibition and Agents Targeting T-cell Migration and Chemotaxis.

Lymphocyte depletion and blockade of T-cell activation and trafficking serve as therapeutic strategies for an enlarging number of immune-mediated diseases and malignancies. This review summarizes the infection risks associated to monoclonal antibodies that bind to the α chain of the interleukin-2 receptor, the cell surface glycoprotein CD52, and members of α4- and ß2-integrin families acting as cell-adhesion molecules. An outline of the mechanisms of action, approved indications and off-label uses, expected impact on the host immune response, and available clinical evidence is provided for each of these agents.

90Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma.

Background: Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. Study Design and Treatment: This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled 90Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6-574.6 MBq 90Y-daclizumab and the fourth patient receiving two doses of 580.9-566.1 MBq 90Y-daclizumab followed by high-dose chemotherapy and ASCT. Results: All 4 evaluable patients treated with 90Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5-7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Discussion: Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and 90Y-daclizumab provided strong enough ß emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong ß irradiation killed normal cells in the tumor microenvironment. Conclusions: 90Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Significance: Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of 90Y-daclizumab into the preconditioning regimen for refractory and relapsed HL patients with high-dose BEAM chemotherapy and ASCT provided sustained CRs in the 4 patients studied. Two of these patients were highly refractory to multiple prior treatments with bulky disease at entry into this study, including 1 patient who never entered a remission and had failed 6 different therapeutic regimens. Despite the small number of patients treated in this study, the sustained clinical benefit in these patients indicates a highly effective treatment. The daclizumab was directed primarily not at HRS cells themselves but toward nonmalignant T cells rosetting around malignant cells. 90Y provided strong ß emissions that killed antigen nonexpressing tumor cells at a distance by a crossfire effect. Furthermore, the strong ß radiation killed normal cells in the tumor microenvironment that nurtured the malignant cells in the lymphomatous mass. The present study supports expanded analysis of 90Y-daclizumab as part of the regimen of ASCT in patients with refractory and relapsed HL.

Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis.

BACKGROUND: Interleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance immunotherapy. Secondary aims included assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection. METHODS: We conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy. Data collected were the name of the first author, journal title, year of publication, country where the study was conducted, number of patients in the IL-2 induction therapy arm and in the placebo arm, number of patients who had biopsy-proven rejection and graft survival in each arm. A random effects model was used for the meta-analysis. RESULTS: Of the 470 articles found in different databases, 7 were included in the meta-analysis. Forest plot analysis for rate of rejection during the follow-up period post-transplant showed no significant difference between the groups. There was no evidence of heterogenicity between included studies (I 2 = 21.8%, P = 0.27). The overall risk difference was -0.02 [95% confidence interval (CI) -0.05-0.01]. A random effects meta-analysis for patient and graft survival was performed using forest plot analysis and showed no significant effect of IL-2 receptor (IL-2R) antibody induction on patient or graft survival compared with placebo. The overall risk difference was -0.01 (95% CI -0.04-0.01) and 0.00 (95% CI -0.00-0.01), respectively. Three of the included studies showed no effect of basiliximab on creatinine change, two showed no effect on risk of CMV infection and two showed less risk of post-transplant diabetes in the basiliximab group. CONCLUSION: IL-2R antibody induction therapy has no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy. More randomized controlled studies are needed.

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.

Daclizumab: Mechanisms of Action, Therapeutic Efficacy, Adverse Events and Its Uncovering the Potential Role of Innate Immune System Recruitment as a Treatment Strategy for Relapsing Multiple Sclerosis.

Daclizumab (DAC) is a humanized, monoclonal antibody that blocks CD25, a critical element of the high-affinity interleukin-2 receptor (IL-2R). DAC HYP blockade of CD25 inhibits effector T cell activation, regulatory T cell expansion and survival, and activation-induced T-cell apoptosis. Because CD25 blockade reduces IL-2 consumption by effector T cells, it increases IL-2 bioavailability allowing for greater interaction with the intermediate-affinity IL-2R, and therefore drives the expansion of CD56bright natural killer (NK) cells. Furthermore, there appears to be a direct correlation between CD56bright NK cell expansion and DAC HYP efficacy in reducing relapses and MRI evidence of disease activity in patients with RMS in phase II and phase III double-blind, placebo- and active comparator-controlled trials. Therapeutic efficacy was maintained during open-label extension studies. However, treatment was associated with an increased risk of rare adverse events, including cutaneous inflammation, autoimmune hepatitis, central nervous system Drug Reaction with Eosinophilia Systemic Symptoms (DRESS) syndrome, and autoimmune Glial Fibrillary Acidic Protein (GFAP) alpha immunoglobulin-associated encephalitis. As a result, DAC HYP was removed from clinical use in 2018. The lingering importance of DAC is that its use led to a deeper understanding of the underappreciated role of innate immunity in the potential treatment of autoimmune disease.

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.

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.

Immune-mediated encephalitis with daclizumab: The final nail.

We provide clinical commentary on this edition's case report of immune-mediated encephalitis related to daclizumab therapy.