Current treatment in macrophage activation syndrome worldwide: a systematic literature review to inform the METAPHOR project
Authors: Baldo Francesco , Erkens Remco G A , Mizuta Mao , Rogani Greta , Lucioni Federica , Bracaglia Claudia , Foell Dirk , Gattorno Marco , Jelusic Marija , Anton Jordi , Brogan Paul , Canna Scott , Chandrakasan Shanmuganathan , Cron Randy Q , De Benedetti Fabrizio , Grom Alexei , Heshin-Bekenstein Merav , Horne AnnaCarin , Khubchandani Raju , Ozen Seza , Quartier Pierre , Ravelli Angelo , Shimizu Masaki , Schulert Grant , Scott Christiaan , Sinha Rashmi , Ruperto Nicolino , Swart Joost F , Vastert Sebastiaan , Minoia Francesca ,   PReS MAS/sJIA Working Party and Paediatric Rheumatology International Trial Organization, Aalto Kristiina , Mendoza Carlos Abud , Abushhaiwia Awatif , Ailioaie Constantin , Akikusa Jonathan , Aksu Guzide , Ayaz Nuray Aktay , Al Jashmi Ruqaiya Nasser , Al-Abrawi Safiya , Alessio Maria , Alexeeva Ekaterina , Al-Mayouf Sulaiman M , AlMutairi Abdulaziz , Alsuweiti Muatasem , Amalia Rizqi , Amin Iman , Anton Jordi , Armbrust Wineke , Astigarraga Itziar , Bakkaloglu Sevcan , Bakry Reima , Basaran Ozge , May Floricely Basulto , Bathia Jigna , Battagliotti Cristina , Belot Alexandre , Berg Stefan , Beutel Karin , Bica Blanca , Bolt Isabel , Boyadzhiev Martin , Boyarchuk Oksana , Boyko Yaryna , Bracaglia Claudia , Breda Luciana , Brochard Karine , Brogan Paul , Brunner Jurgen , Rivas Segundo Bujan , Calin Aurelia , Calzada Joan , Lovillo Marisol Camacho , Canna Scott , Cannizzaro Elvira , Caorsi Roberta , Carlomagno Raffaella , Cattalini Marco , Celani Camilla , Chan Kwai Yu Winnie , Chandra Sharat , Chandrakasan Shanmuganathan , Chang Chong U , Chasnyk Vyacheslav , Chyzheuskaya Iryna , Ciurtin Coziana , Garulo Daniel Clemente , Cochino Alexis-Virgil , Consolaro Alessandro , Consolini Rita , Cron Randy , da Silva Carlos Henrique M , De Benedetti Fabrizio , De Cunto Carmen , De Matteis Arianna , De Somer Lien , Dedeoglu Fatma , Deepakbabu Chellapandian , Del Giudice Emanuela , Maldonado Adriana Soraya Diaz , Dolezalova Pavla , Dressler Frank , Dzhus Marta , El Miedany Yasser , El-Ghoneimy Dalia , Emminger Wolfgang , Enciso Sandra , Estmann Anne , Etayari Hala , Fair Danielle , Fasshauer Maria , Fassi Daniel , Faugier Enrique , Federici Silvia , Feldman Brian , Filocamo Giovanni , Flato Berit , Fluchel Mark , Foell Dirk , Fotis Lampros , Frkovic Marijan , Fuhlbrigge Robert , Gaggiano Carla , Gagro Alenka , Gallizzi Romina , Cunha Ana Luiza Garcia , Garcia-Rodriguez Fernando , García-Rodríguez Fernando , Gattorno Marco , Girschick Hermann , Glerup Mia , Grebenkina Lyudmila , Guha Suparna , Suarez Raul Gutierrez , Ramirez Jaime Guzman , Hadef Djohra , Saied Mohamad Hamad , Hashad Soad , Hashkes Philip (Pinchas) , Hasle Henrik , Hays Julia Allyson , Held Martina , Henter Jan-Inge , Herrera Cristina N , Heshin-Bekenstein Merav , Ho Assunta Chi Hang , Horne Anna Carin , Horneff Gerd , Huang Jing-Long , Hufnagel Markus , Ilisson Jaanika , Islam Mohammad Imnul , Ivanova Viktoriia , Izawa Kazushi , Janda Ales , Jelusic Marija , Jeong Daechul , Jesudas Rohith , Jindal Ankur , Mendiola Karla Vanessa Jiron , Oliveira Sheila K , Kahn Robin , Kaposzta Rita , Kasapcopur Ozgur , Katsicas Maria Martha , Kavirayani Akhila , Keenan Camille , Khaosut Parichat , Khawaja Khulood , Khedr Waleed Ahmed Salaheldeen Hassan , Khubchandani Raju , Kobusinska Katarzyna , Koker Oya , Koné-Paut Isabelle , Kostik Mikhail , Kuemmerle-Deschner Jasmin , Kumar Ashish , La Rosée Paul , Ramirez Mabel Aurora Ladino , Lazar Calin , Lee Chongwei , Lehmann Hartwig , Lehmberg Kai , Li Caifeng , Li Xiaoqing , Licciardi Francesco , Lima Joana , Lorenz Zoref , Lotfy Hala , Lovell Daniel J , Lu Meiping , Lukjanoviča Kristīne , Maggio Maria Cristina , Magni-Manzoni Silvia , Maher Sheren esam maher , Majeed Mahmoud , Maritsi Despoina , Marsh Rebecca , Martini Giorgia , Masmas Tania Nicole , Mastrolia Maria Vincenza , Mauro Angela , Mehregan Fatemeh Feresteh , Mejbri Manel , Melki Isabelle , Miettunen Paivi , Miniaci Angela , Minoia Francesca , Mizuta Mao , Mondal Rakesh , Montin Davide , Ayala Zoilo Morel , Angarita Juan Manuel Mosquera , Mukusheva Zaure , Myrup Charlotte , Nakhutsrishvili Eka , Naqvi Ahmed , Narazaki Hidehiko , Nascimento Joao , Navarrete Carmen , Nordal Ellen Berit , Ogbu Ekemini A , Ogunjimi Benson , Okong'o Lawrence Owino , Oliveira-Ramos Filipa , Omenetti Alessia , Opoka-Winiarska Violetta , Orlando Francesca , Cicek Sumeyra Ozdemir , Ozen Seza , Pain Clare , Pal Priyankar , Fontana Natalia Palmou , Papadopoulou Charalampia , Pardeo Manuela , Petrovic Gordana , Picarelli Mercedes , Pilania Rakesh Kumar , Pilkington Clarissa , del Carmen Pinedo Maria , Pratsidou-Gertsi Polyxeni , Pruunsild Chris , Quarmyne Maa-Ohui , Quartier Pierre , Karami Seyed Reza Raees , Ramme Kim , Ravelli Angelo , Razanamahery Jerome , Rebane Katariina , Remesal Agustin , Retornaz Karine , Rigante Donato , Rocco Joseph , Fonseca Adriana Rodrigues , Lozano Ana Luisa Rodriguez , Rodriguez-Aguayo Sandra , Rojas Jorge , Rossano Martina , Ryhanen Samppa , Magalhaes Claudia Saad , Sadeghi Payman , Sag Erdal , Davila Blachy Javier Saldana , Salehzadeh Farhad , Sánchez-Manubens Judith , Sawhney Sujata , Schulert Grant , Schvartz Adrien , Selcuk Yuksel , Mulaosmanovic Velma Selmanovic , Sen Ethan , Sener Seher , Mohite Rachna Shanbhag , Sharma Avinash , Shehata Rawia Salama , Shimizu Masaki , Simonini Gabriele , Singh Surjit , Smerla Roubini , Šnipaitienė Aušra , Sobh Ali , Sozeri Betul , Sparchez Mihaela , Sršen Saša , Stanevicha Valda , Swart Joost , Sztajnbok Flavio , Tangcheewinsirikul Sirikarn , Temelkova Katya , Tenbrock Klaus , Toplak Natasa , Torno Lilibeth , Trevisan Matteo , Tsinti Maria , Tsitsami Elena , Twilt Marinka , Van den Berg J Merlijn , van Laar Jan A M , Rincon Camilo Andres Vargas , Varnier Giulia Camilla , Vastert Sebastiaan , Cornejo Gabriel Vega , Verdoni Lucio , Viola Diego Oscar , Vojinovic Jelena , Vyzhga Yulia , Wahlin Bjorn , Wakiguchi Hiroyuki , Weiser Peter , Wiesik-Szewczyk Ewa , Yamazaki Kazuko , Yasumura Junko , Yin Wei , Zeng Huasong , Zhang Wei , Ziaee Vahid , Ziv Amit , Zuber Zbigniew 
Published: July 2024

Abstract

Objective
To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice.

Methods
A systematic literature search was performed in both EMBASE and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure.

Results
Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatological conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported Janus kinase inhibitor in MAS.

Conclusion
High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, the global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed.