Sex ratio and age of onset in AQP4 antibody-associated NMOSD: a review and meta-analysis
Authors: Arnett Simon , Chew Sin Hong , Leitner Unnah , Hor Jyh Yung , Paul Friedemann , Yeaman Michael R. , Levy Michael , Weinshenker Brian G. , Banwell Brenda L. , Fujihara Kazuo , Abboud Hesham , Dujmovic Basuroski Irena , Arrambide Georgina , Neubrand Veronika E. , Quan Chao , Melamed Esther , Palace Jacqueline , Sun Jing , Asgari Nasrin , Broadley Simon A. ,   the Guthy Jackson International Clinical Consortium*, Abboud Hesham , Aktas Orhan , Alroughani Raed , Altintas Ayse , Apiwattannakul Metha , Arrambide Georgina , Avasarala Jagannadha , Banwell Brenda , Blaschke Terrence F. , Bowen James , Contentti Edgar Carnero , Chitnis Tanuja , de Seze Jerome , Delgado-Garcia Guillermo , Dujmovic Basuroski Irena , Flores Jose , Fujihara Kazuo , Galleguillos Lorna , Greenberg Benjamin M. , Han May , Havla Joachim , Hellwig Kerstin , Hor Jyh Yung , Jarius Sven , Jimenez Jorge Andres , Kissani Najib , Kleiter Ingo , Lana-Peixoto Marco , Leite M. Isabel , Levy Michael , Mariotto Sara , Mealy Maureen A. , Neubrand Veronika E. , Oreja-Guevara Celia , Pandit Lekha , Planchon Sarah M. , Pröbstel Anne-Katrin , Qian Peiqing , Quan Chao , Repovic Pavle , Riley Claire , Ringelstein Marius , I.Rojas Juan , Rotstein Dalia , Ruprecht Klemens , Sá Maria José , Saiz Albert , Salama Sara , Siritho Sasitorn , Siva Aksel , Smith Terry J. , Sotirchos Elias S. , de Castillo Ibis Soto , Tenembaum Silvia , Villoslada Pablo , Willekens Barbara , Wingerchuk Dean , Yamout Bassem I. , Yeaman Michael 
Published: July 2024

Abstract
Background
Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data.

Methods
A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases.

Results
A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78–10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01–8.03) and for late-onset cases, it was 5.48 (95% CI 4.10–7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder.

Conclusions
The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy.