Daclizumab beta (Zinbryta▼): risk of immune-mediated encephalitis – some cases several months after stopping treatment

Monitoring for encephalitis should continue for 12 months following discontinuation of daclizumab. Inform all patients who have discontinued daclizumab and their caregivers of the common symptoms of encephalitis and the need to contact their doctor immediately if they occur.

Advice for healthcare professionals:

  • cases of immune-mediated encephalitis, including anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, have occurred several months after discontinuation of daclizumab
  • prescribers should contact patients who have discontinued daclizumab and their caregivers and advise them to make contact immediately if any of the common prodromal symptoms or early common neuropsychiatric, behavioural, neurological, cognitive, or movement-related symptoms develop (see description and publications below)
  • in patients presenting with atypical neuropsychiatric symptoms, a high index of clinical suspicion should be given for autoimmune encephalitis
  • clinicians are advised to be vigilant for any symptoms suggestive of autoimmune encephalitis; monitoring for encephalitis should continue for 12 months following discontinuation of daclizumab
  • be aware of a case of Glial fibrillary acidic protein (GFAP)α immunoglobulin G (IgG)-associated encephalitis in a patient being treated with daclizumab recently reported in the literature
  • if you suspect encephalitis in a patient who has discontinued daclizumab, consider testing for a broad panel of autoantibodies (eg, antigens for neuronal cell surface and synaptic proteins), including anti-NMDA receptor antibody in cerebrospinal fluid (CSF) and serum as early as possible
  • ensure review of all suspected cases by a specialist in diagnosis and management of autoimmune encephalitis
  • report suspected adverse drug reactions, including those which occur after the withdrawal of a medicine, to the Yellow Card Scheme without delay

Background

In March 2018 the marketing authorisation for Zinbryta (daclizumab beta) was suspended and the medicine recalled from the EU market following reports of serious and potentially fatal immune reactions affecting the brain (including encephalitis and meningoencephalitis), liver, and other organs (see Drug Safety Update, March 2018). Physicians were advised to monitor patients at least monthly and more frequently as clinically indicated, for up to 6 months after the last dose.

In August 2018, the EMA was informed by the marketing authorisation holder of cases of immune-related encephalitis occurring following discontinuation of Zinbryta (see description below). In August 2018, a letter was issued by the marketing authorisation holder to healthcare professionals to inform them of this risk and of the updated recommendations. MHRA is issuing further advice in this article, following the recommendations of the UK’s Pharmacovigilance Expert Advisory Group.

Cases of anti-NMDA receptor encephalitis, including presenting symptoms

As of 10 July 2018, 7 cases of encephalitis have been reported after discontinuation of daclizumab; 2 of them were confirmed as anti-NMDA receptor encephalitis (including 1 patient from the UK). Some of the other encephalitis cases were reported to have involved widespread rash, eczema, elevated liver enzymes, skin involvement, eosinophilia, and/or eosinophilic infiltrates.

The reported cases of anti-NMDA receptor encephalitis occurred around 3–4 months after discontinuation of Zinbryta. The patients with anti-NMDA receptor encephalitis presented with headache, fever, vomiting, confusion, tremor, visual disturbances, and seizures.

Autoimmune encephalitis can be a severe and persistently debilitating disorder. It can be fatal but is treatable with full or substantial recovery especially if diagnosed early and with prompt multidisciplinary management.123 Where the outcome was reported, most patients in these cases have not fully recovered. The frequency of autoimmune encephalitis in association with daclizumab is unknown.

Case of GFAPα IgG-associated encephalitis

On 15 July 2018, a publication4 described a case of steroid-responsive GFAPα IgG-associated encephalitis in a patient on treatment with daclizumab. The patient demonstrated aggressive behaviour and occasionally expressed suicidal thoughts, then 4 months later was admitted to hospital due to fluctuating dysarthria, progressive memory loss, fatigue, and depression. The patient was treated with methylprednisolone and plasma exchange and partially improved.

Diagnosis of autoimmune encephalitis

Clinicians are advised to be vigilant for any symptoms suggestive of autoimmune encephalitis and to inform all patients previously treated with daclizumab and their caregivers about the possible presenting symptoms and what to do if they occur.

If patients with multiple sclerosis present with atypical symptoms, especially neuropsychiatric symptoms, a full drug history should be taken and if found to be previously exposed to daclizumab, a high index of clinical suspicion should be given to autoimmune encephalitis.

If a case of encephalitis is suspected in a patient who has discontinued daclizumab, physicians should perform NMDA receptor antibody tests in cerebrospinal fluid and serum. Since a recent case of anti-GFAP encephalitis has also been reported,4 testing for a broad panel of autoantibodies should also be conducted (eg, antigens for neuronal cell surface and synaptic proteins).

Ensure review of all suspected cases by a specialist in the diagnosis and management of autoimmune encephalitis. It is important to be aware that many patients may not have typical autoimmune encephalitis antibodies, thus a clinical diagnosis may be necessary and not consistently supported by investigations.

Call for reporting

Report suspected adverse drug reactions, including those occurring after cessation of treatment, to the Yellow Card Scheme without delay.

Article citation: Drug Safety Update volume 12, issue 2; September 2018: 3.

  1. Graus F, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016; 15: 391–404. 

  2. Liu H, et al. Anti-N-methyl-D-aspartate receptor encephalitis associated with an ovarian teratoma: two cases report and anaesthesia considerations. BMC Anesthesiol 2015; 15: 150. 

  3. Newman MP, et al. Autoimmune encephalitis. Intern Med J 2016; 46: 148–57. 

  4. Luessi F, et al. GFAPα IgG-associated encephalitis upon daclizumab treatment of MS. Neurol Neuroimmunol Neuroinflamm 2018; 5: e481. 

Published 25 September 2018