Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network

Carla Gaggiano; Donato Rigante; José Hernández-Rodríguez; Antonio Vitale; Maria Tarsia; Alessandra Soriano; Giuseppe Lopalco; Florenzo Iannone; Masen Abdel Jaber; Roberto Giacomelli; Ewa Wiȩsik-Szewczyk; Marco Cattalini; Micol Frassi; Matteo Piga; Gaafar Ragab; Jurgen Sota; Fiammetta Zunica; Alberto Floris; Vito Sabato; Mohamed Tharwat Hegazy; Olga Araújo; Laura Pelegrín; Alessandra Fabbiani; Alessandra Renieri; Salvatore Grosso; Claudia Fabiani; Bruno Frediani; Luca Cantarini

doi:10.1177/1759720X211037178

Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network

Ther Adv Musculoskelet Dis. 2021 Sep 9:13:1759720X211037178. doi: 10.1177/1759720X211037178. eCollection 2021.

Authors

Carla Gaggiano¹, Donato Rigante², José Hernández-Rodríguez³, Antonio Vitale⁴, Maria Tarsia⁵, Alessandra Soriano⁶, Giuseppe Lopalco⁷, Florenzo Iannone⁷, Masen Abdel Jaber⁸, Roberto Giacomelli⁹, Ewa Wiȩsik-Szewczyk¹⁰, Marco Cattalini¹¹, Micol Frassi¹², Matteo Piga¹³, Gaafar Ragab¹⁴, Jurgen Sota⁴, Fiammetta Zunica¹¹, Alberto Floris¹⁵, Vito Sabato¹⁶, Mohamed Tharwat Hegazy¹⁴, Olga Araújo³, Laura Pelegrín¹⁷, Alessandra Fabbiani¹⁸, Alessandra Renieri¹⁹, Salvatore Grosso⁵, Claudia Fabiani²⁰, Bruno Frediani⁴, Luca Cantarini²¹

Affiliations

¹ Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease, and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy; Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy.
² Department of Life Sciences and Global Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Rare Diseases and Periodic Fevers Research Centre, Università Cattolica del Sacro Cuore, Rome, Italy.
³ Vasculitis Research Unit and Autoinflammatory Diseases Clinical Unit, Department of Autoimmune Diseases, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.
⁴ Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease, and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy.
⁵ Clinical Pediatrics, Department of Molecular Medicine and Development, University of Siena, Siena, Italy.
⁶ Department of Internal Medicine, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
⁷ Rheumatology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
⁸ Rheumatology Unit, Santa Chiara Hospital, Trento, Italy.
⁹ Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
¹⁰ Department of Internal Medicine, Pulmonology, Allergy and Clinical Immunology, Central Clinical Hospital of the Ministry of National Defense, Military Institute of Medicine, Warsaw, Poland.
¹¹ Paediatric Clinic, University of Brescia and Spedali Civili di Brescia, Brescia, Italy.
¹² Rheumatology and Clinical Immunology, Spedali Civili, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
¹³ Rheumatology Unit, Department of Medical Sciences, University and AOU of Cagliari, Cagliari, Italy.
¹⁴ Rheumatology and Clinical Immunology Unit, Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
¹⁵ Rheumatology Unit, AOU University Clinic, Cagliari, Italy.
¹⁶ Faculty of Medicine and Health Sciences, Department of Immunology-Allergology-Rheumatology, University of Antwerp and Antwerp University Hospital, Antwerpen, Belgium.
¹⁷ Clinical Institute of Ophthalmology, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.
¹⁸ Medical Genetics, University of Siena, Siena, Italy.
¹⁹ Medical Genetics, University of Siena, Siena, Italy; Medical Genetics, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
²⁰ Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
²¹ Research Center of Systemic Autoinflammatory Diseases, Behçet's Disease Clinic and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Policlinico 'Le Scotte', viale Bracci n. 1, 53100 Siena, Italy.

Abstract

Background: This study aims at describing the therapeutic outcome of patients carrying the R92Q variant in the TNFRSF1A gene treated with anakinra (ANA) or canakinumab (CAN) and identifying any factors predictive of complete response to IL-1 inhibition.

Methods: Clinical data of patients treated with ANA or CAN for recurrent inflammatory attacks due to the presence of the R92Q variant were retrospectively collected and analysed.

Results: Data about 20 treatment courses with IL-1 inhibitors (16 with ANA and 4 with CAN) from 19 patients were collected. Mean age at disease onset was 20.2 ± 14.8 years. In 5 cases (26%) the R92Q variant was found in a family member affected by recurrent fever. The therapeutic response was complete in 13(68%) and partial in 2 patients (11%); treatment failure was observed in 4 cases (21%). Median AIDAI decreased from 10 (interquartile range [IQR] = 28) to 0 (IQR = 1) at the 12-month follow-up visit (p < 0.001). Mean ESR and median CRP dropped respectively from 40.8 ± 24.8 to 9.1 ± 4.5 mm/h (p < 0.001) and from 3.0 (IQR = 1.9) to 0.3 (IQR = 0.3) mg/dl (p < 0.001) after 12 months of treatment. A steroid-sparing effect was observed from the third month of treatment (p < 0.01). Thirteen patients (65%) were still on treatment at the last follow-up visit (median duration of treatment 17 (IQR = 38) months). The presence of R92Q mutation in a symptomatic relative (p = 0.022), the relapsing remitting disease course (p < 0.001) and the presence of migratory erythematous skin rashes during fever attacks (p = 0.005) were associated with complete efficacy of IL-1 inhibitors.

Conclusions: R92Q patients showed a favourable response to ANA and CAN, particularly when the mutation segregated in a family member and when a relapsing-remitting disease course or TNF-α receptor-associated periodic syndrome (TRAPS) typical skin rash were observed. In the subgroup of patients not taking advantage of IL-1 blockage different molecular mechanisms underlying the autoinflammatory picture are likely to exist.

Keywords: R92Q variant; TNF-α receptor associated periodic syndrome; anakinra; biologic therapy; canakinumab; innovative biotechnologies; interleukin-1 inhibition; personalized medicine.