Management of nonviral mixed cryoglobulinemia vasculitis refractory to rituximab: Data from a European collaborative study and review of the literature

Clara Pouchelon; Marcella Visentini; Giacomo Emmi; Véronique le Guern; Luca Quartuccio; Maxime Samson; Nils Venhoff; Antoine Briantais; Milvia Casato; Emmanuel Chatelus; Marie Chilles; Maria C Cid; Elisabeth Diot; Mikael Ebbo; Stanislas Faguer; Bernhard Hellmich; Marie Jachiet; Thomas Moulinet; François Perrin; Thomas Quémeneur; Renato Alberto Sinico; Benjamin Terrier

doi:10.1016/j.autrev.2022.103034

Management of nonviral mixed cryoglobulinemia vasculitis refractory to rituximab: Data from a European collaborative study and review of the literature

Autoimmun Rev. 2022 Apr;21(4):103034. doi: 10.1016/j.autrev.2022.103034. Epub 2022 Jan 4.

Authors

Clara Pouchelon¹, Marcella Visentini², Giacomo Emmi³, Véronique le Guern¹, Luca Quartuccio⁴, Maxime Samson⁵, Nils Venhoff⁶, Antoine Briantais⁷, Milvia Casato², Emmanuel Chatelus⁸, Marie Chilles⁹, Maria C Cid¹⁰, Elisabeth Diot¹¹, Mikael Ebbo⁷, Stanislas Faguer¹², Bernhard Hellmich¹³, Marie Jachiet¹⁴, Thomas Moulinet¹⁵, François Perrin¹⁶, Thomas Quémeneur¹⁷, Renato Alberto Sinico¹⁸, Benjamin Terrier¹⁹

Affiliations

¹ Department of Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France.
² Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
³ Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy.
⁴ Clinic of Rheumatology, Department of Medicine (DAME), ASUFC, University of Udine, Udine, Italy.
⁵ Service de Médecine Interne et Immunologie Clinique, Centre Hospitalier Universitaire de Dijon, France.
⁶ Clinic for Rheumatology and Clinical Immunology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁷ Department of Internal Medicine, CHU Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, Aix-Marseille Université, France.
⁸ Centre National de Référence des Maladies Auto-Immunes et Systémiques Rares, Est/Sud-Ouest (RESO), France, Service de rhumatologie, Centre Hospitalier Universitaire de Strasbourg, 1 avenue Molière, 67098 Strasbourg, France.
⁹ Department of Internal Medicine, Orléans, France.
¹⁰ Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
¹¹ Service de Médecine Interne, CHRU Tours, Tours, France.
¹² Département de Néphrologie et Transplantation d'Organes, CHU de Toulouse, Toulouse, France.
¹³ Department of Internal Medicine, Rheumatology and Immunology, Medius Kliniken, University of Tübingen, Kirchheim-Teck, Germany.
¹⁴ Department of Dermatology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris.
¹⁵ Department of Internal Medicine and Clinical Immunology, Regional Competence Center for Rare and Systemic Autoimmune Disease, Nancy University Hospital, Vandœuvre-lès-Nancy, University of Lorraine, UMR 7365 CNRS, IMoPA, Vandœuvre-lès-Nancy, France.
¹⁶ Department of Internal Medicine, Saint-Nazaire Hospital, France.
¹⁷ Département de Néphrologie and Département de Médecine Interne, Centre Hospitalier de Valenciennes, Valenciennes, France.
¹⁸ Department of Medicine and Surgery, University of Milano Bicocca, and Renal Unit, ASST-Monza, Milan/Monza, Italy.
¹⁹ Department of Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France. Electronic address: benjamin.terrier@aphp.fr.

PMID: 34995764
DOI: 10.1016/j.autrev.2022.103034

Abstract

Background: Glucocorticoids (GCs) plus rituximab (RTX) represent the first-line treatment of nonviral mixed cryoglobulinemia vasculitis (CryoVas). However, data on therapeutic management and outcome of patients refractory to RTX are lacking.

Methods: We conducted a European collaborative retrospective multicenter study of patients with nonviral mixed CryoVas refractory to RTX and performed a literature review.

Results: Twenty-six original cases and 7 additional patients from the literature were included. All patients but one had type 2 cryoglobulinemia, and causes were autoimmune disease (51%), malignant hemopathy (12%) or essential CryoVas (42%). CryoVas was primary refractory to RTX in 42%, while 58% had an initial response to RTX before immune escape. After RTX failure, patients received a median of 1 (IQR, 1-3) line of treatment, representing 65 treatment periods during follow-up. Main treatments used were GCs in 92%, alkylating agents in 43%, RTX in combination with other treatments in 46%, and belimumab in 17%. Combination of anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents provided the highest rates of clinical response in 100% 82% and 73%, respectively, but showed poor immunological response, in 50%, 30% and 38%, respectively. Rates of severe infection were 57%, 9% and 0% in patients receiving anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents, respectively.

Conclusion: In patients with nonviral mixed CryoVas refractory to RTX, anti-CD20 plus belimumab, and alkylating agents associated or not with anti-CD20, provide the highest rates of clinical response. However, anti-CD20 plus belimumab was frequently associated with severe infections.

Keywords: Alkylating agents; Belimumab; Cryoglobulinemia vasculitis; Refractory; Rituximab.

Publication types

Multicenter Study
Review

MeSH terms

Cryoglobulinemia* / complications
Cryoglobulinemia* / etiology
Humans
Multicenter Studies as Topic
Retrospective Studies
Rituximab / therapeutic use
Treatment Outcome
Vasculitis* / complications
Vasculitis* / drug therapy

Substances

Rituximab