Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis

Emma Rubenstein; Carla Maldini; Augusto Vaglio; Federica Bello; Jan Phillip Bremer; Frank Moosig; Paolo Bottero; Alberto Pesci; Renato Alberto Sinico; Julian Grosskreutz; Claudia Feder; David Saadoun; Giorgio Trivioli; Federica Maritati; Barbara Rewerska; Wojciech Szczeklik; Paolo Fraticelli; Giuseppe Guida; Gina Gregorini; Gianluca Moroncini; Bernhard Hellmich; Jochen Zwerina; Matthieu Resche-Rigon; Giacomo Emmi; Thomas Neumann; Alfred Mahr

doi:10.3899/jrheum.2023-0325

Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis

J Rheumatol. 2023 Nov;50(11):1446-1453. doi: 10.3899/jrheum.2023-0325. Epub 2023 Sep 22.

Authors

Emma Rubenstein¹, Carla Maldini², Augusto Vaglio³, Federica Bello⁴, Jan Phillip Bremer⁵, Frank Moosig⁶, Paolo Bottero⁷, Alberto Pesci⁸, Renato Alberto Sinico⁹, Julian Grosskreutz¹⁰, Claudia Feder¹¹, David Saadoun¹², Giorgio Trivioli¹³, Federica Maritati¹⁴, Barbara Rewerska¹⁵, Wojciech Szczeklik¹⁶, Paolo Fraticelli¹⁷, Giuseppe Guida¹⁸, Gina Gregorini¹⁹, Gianluca Moroncini²⁰, Bernhard Hellmich²¹, Jochen Zwerina²², Matthieu Resche-Rigon²³, Giacomo Emmi²⁴, Thomas Neumann²⁵, Alfred Mahr²⁶

Affiliations

¹ E. Rubenstein, MD, MPH, Infectious Diseases Department, Saint-Louis Hospital, Paris, France; [email protected].
² C. Maldini, MD, PhD, Catedra de Semiologia UHMI 3, Facultad de Ciencias Medicas, Universidad Nacional de Cordoba, Cordoba, Argentina.
³ A. Vaglio, MD, PhD, Department of Biomedical, Experimental and Clinical Sciences, University of Firenze, and Nephrology and Dialysis Unit, Meyer Children's Hospital, Florence, Italy.
⁴ F. Bello, MD, Internal Interdisciplinary Medicine Unit, Careggi University Hospital, and Department of Experimental and Clinical Medicine, University of Firenze, Florence, Italy.
⁵ J.P. Bremer, MD, PhD, Immunologikum Hamburg, Hamburg, Germany.
⁶ F. Moosig, MD, PhD, Rheumazentrum Schleswig-Holstein Mitte, Neumünster, Germany.
⁷ P. Bottero, MD, Allergy and Clinical Immunology, G. Fornaroli Hospital, Milan, Italy.
⁸ A. Pesci, MD, Pneumology, University of Milano Bicocca, San Gerardo Hospital, Monza, Italy.
⁹ R.A. Sinico, MD, PhD, Department of Nephrology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
¹⁰ J. Grosskreutz, MD, Precision Neurology, Excellence Cluster Precision Medicine in Inflammation, University of Lübeck, University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany.
¹¹ C. Feder, MD, Department of Internal Medicine V, Jena University Hospital, Jena, Germany.
¹² D. Saadoun, MD, PhD, Department of Internal Medicine and Clinical Immunology, Sorbonne Universités, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre national de références Maladies Autoimmunes et systémiques rares, Centre national de références Maladies Autoinflammatoires rares et Amylose inflammatoire INSERM, UMR S959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France.
¹³ G. Trivioli, MD, Department of Nephrology, Cambridge University Hospitals, Cambridge, UK.
¹⁴ F. Maritati, MD, Nephrology, Dialysis and Renal Transplant Unit, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹⁵ B. Rewerska, MD, PhD, Diamond Clinic, Diamond Medical Centre, Krakow, Poland.
¹⁶ W. Szczeklik, MD, PhD, Centre for Intensive Care and Perioperative Medicine, Jagiellonian University Medical College, Krakow, Poland.
¹⁷ P. Fraticelli, MD, PhD, Medical Clinic, Department of Internal Medicine, Marche University Hospital, Ancona, Italy.
¹⁸ G. Guida, MD, PhD, Department of Clinical and Biological Sciences, University of Turin, and Severe Asthma and Rare Lung Disease Unit San Luigi Gonzaga University Hospital, Orbassano, Turin, Italy.
¹⁹ G. Gregorini, MD, Nephrology, Spedali Civili, University of Brescia, Brescia, Italy.
²⁰ G. Moroncini, MD, PhD, Medical Clinic, Department of Clinical and Molecular Science, Marche Polytechnic University, Ancona, Italy.
²¹ B. Hellmich, MD, PhD, Internal Medicine, Rheumatology and Immunology, Medius Kliniken, University of Tübingen, Kirchheim-Teck, Germany.
²² J. Zwerina, MD, 1st Medical Department, Hanusch Hospital, Vienna, Austria.
²³ M. Resche-Rigon, MD, PhD, Clinical Research Unit, Saint-Louis Hospital, Paris, France.
²⁴ G. Emmi, MD, PhD, Internal Interdisciplinary Medicine Unit, Careggi University Hospital, Firenze, Italy, Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy, and Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Melbourne, Australia.
²⁵ T. Neumann, MD, Rheumatology and Internal Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland, and Department of Internal Medicine III, Jena University Hospital, Jena, Germany.
²⁶ A. Mahr, MD, PhD, Nephrology, Dialysis and Renal Transplant Unit, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, and Rheumatology and Internal Medicine, Kantonsspital St. Gallen, St. Gallen, Switzerland.

PMID: 37739478
DOI: 10.3899/jrheum.2023-0325

Abstract

Objective: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA.

Methods: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results.

Results: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics.

Conclusion: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Keywords: antineutrophil cytoplasmic antibody–associated vasculitis; eosinophilic granulomatous vasculitis; vasculitis.

MeSH terms

Antibodies, Antineutrophil Cytoplasmic
Churg-Strauss Syndrome* / diagnosis
Cluster Analysis
Granulomatosis with Polyangiitis* / diagnosis
Humans
Phenotype

Substances

Antibodies, Antineutrophil Cytoplasmic