0774: Deciphering Rheumatoid Arthritis-associated Interstitial Lung Disease Phenotypes Using Unsupervised Hierarchical Clustering Analysis: Results from a Large Collaborative International Study

Pierre-Antoine Juge¹, Benjamin Granger², Lina El Houari³, Gregory McDermott⁴, Tracy J. Doyle⁴, Clive Kelly⁵, Gouri M Koduri⁶, Robert Vassallo⁷, Amarilys Alarcon Calderon⁷, Umut Kalyoncu⁸, Antonio Gonzalez⁹, Natalia Mena Vazquez¹⁰, Marta Rojas¹¹, Raquel Dos-Santos¹², Miriam Retuerto-Guerrero¹³, Cristina Vadillo-Font¹⁴, PALOMA VELA¹⁵, Antonio Fernandez-Nebro¹⁶, Alejandro Escudero-Contreras¹⁷, Eva Perez-Pampin¹⁸, Charlotte Hyldgaard¹⁹, Antoine Froidure²⁰, Patrick Durez²¹, Jorge Rojas Serrano²², Coline van Moorsel²³, Jan C Grutters²³, Leticia Kawano-Dourado²⁴, Charlotte Lucas²⁵, Stephane Jouneau²⁶, Raimon Sanmarti²⁷, Raul Castellanos Moreira²⁸, Katarina Antoniou²⁹, Maria Molina molina³⁰, joshua Solomon³¹, Sophia raia³¹, Miguel A Gonzalez-Gay³², Belén Atienza-Mateo³³, Sofia Flouda³⁴, Effrosyni Manali³⁴, Boumpas Dimitrios³⁵, Spyros Papiris³⁴, THEOFANIS KARAGEORGAS³⁶, Marco Sebastiani³⁷, Andreina Manfredi³⁸, Ana Catarina Duarte³⁹, Santos Castañeda⁴⁰, Lorenzo Cavagna⁴¹, Bruno Crestani⁴², Jeffrey Sparks⁴³ and Philippe Dieudé⁴⁴, ¹Division of Rheumatology, Inflammation, and Immunity Brigham & Women's Hospital, Boston, MA, ²Sorbonne Université, INSERM, and Pitié Salpêtrière Hospital, Paris, France, ³Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris, France, ⁴Brigham and Women's Hospital, Boston, MA, ⁵James Cook University Hospital, Middlesbrough, United Kingdom, ⁶Southend University Hospitals NHS Trust, Essex, United Kingdom, ⁷Mayo Clinic, Rochester, MN, ⁸Hacettepe University, Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Ankara, Turkey, ⁹Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain, ¹⁰IBIMA, Málaga, Spain, ¹¹Hospital Universitario Reina Sofía, Cordoba, Spain, ¹²Clinical University Hospital in Santiago de Compostela, Santiago de Compostela, Spain, ¹³Rheumatology, Hospital Universitario de León, León, Spain, ¹⁴Hospital Clínico San Carlos – Instituto Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain, ¹⁵Rheumatology, Hospital General Universitario Alicante, Alicante, Spain, ¹⁶Hospital Regional Universitario de Málaga, Malaga, Spain, ¹⁷Rheumatology Department, Reina Sofia University Hospital, Cordoba/Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba, Córdoba, Spain, ¹⁸Rheumatology Department Complejo Hospitalario Universitario Santiago, Santiago de compostela, Spain, ¹⁹Silkeborg Regional Hospital, Silkeborg, Denmark, ²⁰Université Catholique de Louvain, Louvain, Belgium, ²¹UCLouvain, Brussels, Belgium, ²²Hospital Angeles Villahermosa, Ciudad de Mexico, Mexico, ²³St. Antonius Hospital, Nieuwegein, Netherlands, ²⁴Hospital do Coração (HCor), São Paulo, Brazil, ²⁵CHU, Rennes, France, ²⁶Amicus, Boca Raton, FL, ²⁷Hospital Clinic, Rheumatology, Barcelona, Spain, ²⁸Hospital Clínic de Barcelona, Madrid, Spain, ²⁹University of Crete, Heraklion, Greece, ³⁰IDIBELL Bellvitge Biomedical Research Institute, Barcelona, Spain, ³¹National Jewish Health, Denver, CO, ³²IDIVAL and School of Medicine, UC, Santander; Department of Rheumatology, IIS-Fundación Jiménez Díaz, Madrid, Santander, Spain, ³³Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain, ³⁴Unit of Attikon University Hospital, Athens, Greece, ³⁵National and Kapodistrian University of Athens, Athens, Greece, ³⁶n/a, Athina, Greece, ³⁷Azienda Policlinico di Modena, Modena, Italy, ³⁸University of Modena, Modena, Italy, ³⁹Hospital Garcia de Orta, Almada, Portugal, ⁴⁰Hospital Universitario de la Princesa, Madrid, Spain, ⁴¹Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, ⁴²Hopital Bichat, Paris University, Paris, France, ⁴³Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, ⁴⁴Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, INSERM UMR1152, University de Paris Cité, Department of Rheumatology, Paris, France

Background/Purpose: RA-associated interstitial lung disease (ILD) is not a single entity as illustrated by different HRCT patterns, different risk factors and prognoses suggesting heterogenous phenotypes. Our objective was to identify definite sub-phenotypes among a large RA-ILD dataset performing unsupervised clustering analysis.

Methods: In this international collaborative study (22 centers from 13 countries), we included patients with RA (ACR/EULAR 2010 classification criteria) having ILD defined by high-resolution computed tomography (HRCT) chest scan. Clinical, biological, imaging, and functional data were retrospectively collected from extensive chart review. Missing data were handled using multiple imputation with chained equations. A multiple correspondence analysis was performed on each sample to reduce dimensions and a non-parametric Bayesian algorithm was used to attribute a cluster to each patient. The clusters were aggregated over the multiple imputations using weighted Non-negative Matrix Factorization.MUC5B rs35705950 T risk allele distribution in the identified clusters was investigate for patients with available genotype. A surrogate decision tree was conducted using the non-imputed dataset to predict a cluster for each patient. The prediction error rate of the tree was estimated using cross-validation.

Results: A total of 1696 patients with RA-ILD were included in the cluster analysis; Table 1. Among the 37 collected variables, 20 active variables were used to construct clusters. The non-parametric Bayesian clustering algorithm detected 2 definite clusters: cluster 1 (n=1015) and cluster 2 (n=681); Table1, Figure 1. Compared to cluster 2, patients from cluster 1 were more frequently male (45.5% vs 38.3%, p=0.003), older at RA onset (56.9 ± 13.3 vs 53.8 ± 14.5, p< 0.001) and at ILD onset (65.5 ± 10.1 vs 61.9 ± 12.3, p< 0.001), more frequently with European ethnicity (85.9% vs 68.3%, p< 0.001), more frequently ever smokers at ILD onset (64.2% vs 55.7%, p< 0.001) and had less Sjogren syndrome (10.8% vs 20.6%, p< 0.001). They were more frequently positive for anti-citrullinated peptides antibodies (90.7% vs 70.0%, p< 0.001) and for rheumatoid factor (95.8% vs 67.4%, p< 0.001). UIP HRCT pattern was predominant in cluster 1 (72.5%) whereas various patterns were observed in cluster 2 (UIP = 30.8%, NSIP = 17.2%), p< 0.001. There was no difference in lung function at ILD onset between the 2 clusters. MUC5B rs35705950 genotype was available for 444 patient (26.2%) with a higher minor allele frequency (MAF) in cluster 1 (33% compared to 18%, p< 0.001). Figure 2 shows the decision tree that can be used to predict the cluster for a new patient with a prediction error rate of 9.8%.

Conclusion: Our results provide evidence that RA-ILD is a heterogeneous disease and allow the identification of at least two distinct subsets. This heterogeneity is illustrated by a contribution of the MUC5B promoter variant restricted to cluster 1, promoting the identification of specific risk scores for each RA-ILD subset. This heterogeneity underlies distinct physio pathological mechanisms which could influence not only the prognosis of patients with RA-ILD but also their therapeutic management.








P. Juge: None; B. Granger: Bristol-Myers Squibb(BMS), 2; L. El Houari: None; G. McDermott: None; T. Doyle: None; C. Kelly: None; G. Koduri: None; R. Vassallo: None; A. Alarcon Calderon: None; U. Kalyoncu: None; A. Gonzalez: None; N. Mena Vazquez: None; M. Rojas: None; R. Dos-Santos: None; M. Retuerto-Guerrero: None; C. Vadillo-Font: None; P. VELA: AbbVie/Abbott, 5, AstraZeneca, 5, Eli Lilly, 5, 6, GlaxoSmithKlein(GSK), 6, Novartis, 5, Pfizer, 5; A. Fernandez-Nebro: None; A. Escudero-Contreras: None; E. Perez-Pampin: None; C. Hyldgaard: None; A. Froidure: None; P. Durez: None; J. Rojas Serrano: None; C. van Moorsel: None; J. Grutters: None; L. Kawano-Dourado: None; C. Lucas: None; S. Jouneau: None; R. Sanmarti: None; R. Castellanos Moreira: None; K. Antoniou: None; M. Molina molina: None; j. Solomon: None; S. raia: None; M. Gonzalez-Gay: AbbVie/Abbott, 5, 6, Amgen, 5, 6, Pfizer, 5, 6; B. Atienza-Mateo: None; S. Flouda: None; E. Manali: None; B. Dimitrios: None; S. Papiris: None; T. KARAGEORGAS: None; M. Sebastiani: None; A. Manfredi: None; A. Duarte: None; S. Castañeda: None; L. Cavagna: None; B. Crestani: None; J. Sparks: AbbVie, 2, Amgen, 2, Boehringer Ingelheim, 2, Bristol-Myers Squibb, 2, 5, Gilead, 2, Inova Diagnostics, 2, Janssen, 2, Optum, 2, Pfizer, 2, ReCor, 2; P. Dieudé: AbbVie, 2, 6, Boehringer Ingelheim, 1, 2, 6, Bristol-Myers Squibb, 1, 2, 5, 6, Chugai, 5, Galapagos, 5, 6, Janssen, 2, 6, Novartis, 2, Pfizer, 1, 2, 5, 6.