Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease

Russell C Dale; Fabienne Brilot; Lisa V Duffy; Marinka Twilt; Amy T Waldman; Sona Narula; Eyal Muscal; Kumaran Deiva; Erik Andersen; Michael R Eyre; Despina Eleftheriou; Paul A Brogan; Rachel Kneen; Gulay Alper; Banu Anlar; Evangeline Wassmer; Kirsten Heineman; Cheryl Hemingway; Catherine J Riney; Andrew Kornberg; Marc Tardieu; Amber Stocco; Brenda Banwell; Mark P Gorman; Susanne M Benseler; Ming Lim

doi:10.1212/WNL.0000000000000570

Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease

Neurology. 2014 Jul 8;83(2):142-50. doi: 10.1212/WNL.0000000000000570. Epub 2014 Jun 11.

Authors

Russell C Dale¹, Fabienne Brilot², Lisa V Duffy², Marinka Twilt², Amy T Waldman², Sona Narula², Eyal Muscal², Kumaran Deiva², Erik Andersen², Michael R Eyre², Despina Eleftheriou², Paul A Brogan², Rachel Kneen², Gulay Alper², Banu Anlar², Evangeline Wassmer², Kirsten Heineman², Cheryl Hemingway², Catherine J Riney², Andrew Kornberg², Marc Tardieu², Amber Stocco², Brenda Banwell², Mark P Gorman², Susanne M Benseler², Ming Lim²

Affiliations

¹ From the Neuroimmunology Group (R.C.D., F.B.), Children's Hospital at Westmead, University of Sydney, Australia; Boston Children's Hospital (L.V.D., M.P.G.), MA; the Division of Rheumatology (M.T., S.M.B.), The Hospital for Sick Children, University of Toronto, Canada; Children's Hospital of Philadelphia (A.T.W., S.N., B.B.), University of Pennsylvania; Paediatric Neurology and Rheumatology (E.M., A.S.), Texas Children's Hospital, Baylor College of Medicine, Houston; Assistance Publique-Hopitaux de Paris (K.D., M.T.), Hôpitaux Universitaires Paris-Sud, National Referral Center for Neuro-Inflammatory Diseases in Children, Pediatric Neurology Department and Université Paris-Sud, Inserm U1012, Le Kremlin-Bicêtre, France; Royal Children's Hospital Melbourne (E.A., A.K.), Australia; Great Ormond Street Hospital NHS Trust (M.R.E., C.H.), London; UCL Institute of Child Health (D.E., P.A.B.), London; Alder Hey Children's NHS Foundation Trust and the Institute of Infection and Global Health (R.K.), University of Liverpool, UK; Children's Hospital of Pittsburgh (G.A.), University of Pittsburgh, PA; Hacettepe University Child Neurology (B.A.), Turkey; Birmingham Children's Hospital (E.W.); John Radcliffe Hospital (K.H.), Oxford, UK; Neurosciences Unit and Mater Medical Research Institute (C.J.R.), Mater Children's Hospital, South Brisbane, University of Queensland, Australia; Alberta Children's Hospital (S.M.B.), Calgary, University of Calgary, Canada; and Evelina Children's Hospital (M.L.), London, UK. russell.dale@health.nsw.gov.au.
² From the Neuroimmunology Group (R.C.D., F.B.), Children's Hospital at Westmead, University of Sydney, Australia; Boston Children's Hospital (L.V.D., M.P.G.), MA; the Division of Rheumatology (M.T., S.M.B.), The Hospital for Sick Children, University of Toronto, Canada; Children's Hospital of Philadelphia (A.T.W., S.N., B.B.), University of Pennsylvania; Paediatric Neurology and Rheumatology (E.M., A.S.), Texas Children's Hospital, Baylor College of Medicine, Houston; Assistance Publique-Hopitaux de Paris (K.D., M.T.), Hôpitaux Universitaires Paris-Sud, National Referral Center for Neuro-Inflammatory Diseases in Children, Pediatric Neurology Department and Université Paris-Sud, Inserm U1012, Le Kremlin-Bicêtre, France; Royal Children's Hospital Melbourne (E.A., A.K.), Australia; Great Ormond Street Hospital NHS Trust (M.R.E., C.H.), London; UCL Institute of Child Health (D.E., P.A.B.), London; Alder Hey Children's NHS Foundation Trust and the Institute of Infection and Global Health (R.K.), University of Liverpool, UK; Children's Hospital of Pittsburgh (G.A.), University of Pittsburgh, PA; Hacettepe University Child Neurology (B.A.), Turkey; Birmingham Children's Hospital (E.W.); John Radcliffe Hospital (K.H.), Oxford, UK; Neurosciences Unit and Mater Medical Research Institute (C.J.R.), Mater Children's Hospital, South Brisbane, University of Queensland, Australia; Alberta Children's Hospital (S.M.B.), Calgary, University of Calgary, Canada; and Evelina Children's Hospital (M.L.), London, UK.

Abstract

Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS.

Methods: Multicenter retrospective study.

Results: A total of 144 children and adolescents (median age 8 years, range 0.7-17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05-9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1-8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0-2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0-2 was greater in patients given rituximab early in their disease course compared to those treated later.

Conclusion: While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality.

Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.

Publication types

Multicenter Study

MeSH terms

Adolescent
Aging / physiology
Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
Antibodies, Monoclonal, Murine-Derived / adverse effects*
Antibodies, Monoclonal, Murine-Derived / therapeutic use*
Autoimmune Diseases / drug therapy*
Blood Cell Count
Central Nervous System Diseases / drug therapy*
Child
Child, Preschool
Cohort Studies
Female
Humans
Immunity, Cellular / drug effects
Immunosuppressive Agents / adverse effects*
Immunosuppressive Agents / therapeutic use*
Infant
Infections / epidemiology
Infections / etiology
Inflammation / drug therapy
Infusions, Intravenous / adverse effects
Male
Retrospective Studies
Rituximab
Treatment Outcome

Substances

Anti-Inflammatory Agents, Non-Steroidal
Antibodies, Monoclonal, Murine-Derived
Immunosuppressive Agents
Rituximab

Grants and funding

K23 NS069806/NS/NINDS NIH HHS/United States