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Addressing immune-related adverse events of cancer immunotherapy: how prepared are rheumatologists?
  1. Marie Kostine1,
  2. Laura C Cappelli2,
  3. Cassandra Calabrese3,
  4. Leonard H Calabrese3,
  5. Clifton O Bingham III2,
  6. Christophe Richez1,
  7. Jacques-Eric Gottenberg4,
  8. Olivier Lambotte5
  1. 1 Rheumatology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
  2. 2 Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
  3. 3 Rheumatology/Immunology, Cleveland Clinic, Cleveland, Ohio, USA
  4. 4 Rheumatology, Hopitaux Universitaires de Strasbourg, Strasbourg, France
  5. 5 Internal Medicine and Clinical Immunology, Hopital Bicetre, Le Kremlin-Bicetre, France
  1. Correspondence to Dr Marie Kostine, Rheumatology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux 33000, France; marie.kostine{at}

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Cancer immunotherapy blocking immune checkpoints represents a major advance in oncology. Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death 1 (PD-1) or its ligand PD-L1 have become standard of care in many advanced-stage cancers. Yet an important proportion of patients experience inflammatory or autoimmune side effects, also known as immune-related adverse events (irAEs), as a consequence of dysregulated immunity. irAEs can affect almost any organ system.1 Notably, an expanding range of manifestations mimicking our classical rheumatic diseases have been described.2 3 Rheumatic irAEs, including inflammatory arthritis, pseudomyalgia rheumatica, sicca syndrome, myositis and vasculitis, are increasingly reported. Since there has been increasing emphasis on this emerging field within the last 3 years, we aimed to evaluate the knowledge of rheumatologists, as well as other specialists, regarding ICI and irAEs through an online survey.

Survey questions addressed the demographics (gender, age, practice setting and duration of medical practice), domains of awareness, clinical experience and interest in irAE-specific medical education. The survey was first distributed in the USA (2016) to healthcare provider cohorts at Johns Hopkins University (JHU) and Cleveland Clinic (CC), then in France (2018) to rheumatologists and other specialists via several national expert networks: Société Française de Rhumatologie, Club Rhumatismes et Inflammations, Société Nationale Française de Médecine Interne, Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif and Société Française d’Endocrinologie.

Overall, 153 rheumatologists from the USA (JHU n=39; CC n=114) and 349 French specialists (rheumatologists n=159; internists n=113; endocrinologists n=55; gastroenterologists n=22) participated in this study. As detailed in table 1, rheumatologists from private practices and academic institutions predominated, with various levels of experience. Half of the other specialists worked in an academic setting. In 2016, 67% of rheumatologists from the USA were unaware or have just heard of irAEs, compared with 28% of French rheumatologists and 22% of other French specialists in 2018. Of note, the majority of French participants reported some basic knowledge. This can be explained mainly by the timing of the survey and thus increasing physician exposure to patients with irAEs in 2018: 86 of 159 rheumatologists (54%) and 128 of 190 other specialists (67%) had exposure to patients with irAEs, compared with 18 of 122 rheumatologists (15%) in 2016. However, despite this 2-year time interval and the fact that the study was conducted in two different countries hardly comparable, the resulting conclusion of both surveys is the same: familiarity with ICI and irAEs had been still reported by less than 30% of rheumatologists, and less than 10% declared being very confident in treating such patients. Nevertheless, we did observe some improvement as the majority of French rheumatologists were somewhat (20%) or moderately (41%) confident managing irAEs in 2018. In France, systemic autoimmune diseases are managed by both rheumatologists and internists. We observed very similar results between French rheumatologists and internists, while endocrinologists and gastroenterologists reported more frequently to be familiar with irAEs and their management. Description and recognition of irAEs were perceived to be the biggest educational need in 2016, while in 2018 the type of educational content requested by 80% of physicians focused on treatment algorithms, more relevant for providers already engaged in managing irAEs.

Table 1

Demographics and knowledge of ICI and irAEs among rheumatologists and other specialists, n (%)

This study highlights that rheumatologists, as well as other specialists, had limited experience and lacked confidence in the management of irAEs. The same observation has been reported by our Portuguese colleagues during the last European League Against Rheumatism (EULAR) meeting, with 64% of rheumatologists being unfamiliar with these new therapies, according to a web-based questionnaire sent in November 2017.4 Since the first dissemination of the survey in 2016, shortly after the approval of ICIs, the number of patients treated with ICIs has considerably increased. The increase in ICI use, and the resultant increase in patients with irAEs, likely explains why more rheumatologists reported managing irAEs and were more familiar with them, as indicated by the second dissemination of the survey in 2018, but we are still a long way from having achieved the objective. Specific education around rheumatic irAEs has been implemented with (1) local multidisciplinary meetings in several institutions, (2) dedicated sessions during national and international meetings, and (3) guidelines published to help oncologists and organ specialists in the management of irAEs.5–7 Recommendations for the diagnosis and management of musculoskeletal irAEs due to cancer immunotherapy will be proposed by EULAR in a near future. All these educational efforts will help rheumatologists and other specialists to become more confident with this evolving clinical field.


We thank all respondents for their active participation.



  • Handling editor Josef S Smolen

  • Collaborators Société Française de Rhumatologie (SFR), Club Rhumatismes et Inflammations (CRI), Société Nationale Française de Médecine Interne (SNFMI), Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID) and Société Française d’Endocrinologie (SFE).

  • Contributors LCC, CC, LHC and COB planned and conducted the study in the USA. OL, J-EG, CR and MK conducted the study in France. MK, LCC and CC drafted the manuscript, and all the authors critically reviewed and approved the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests MK received speaking fees from BMS. LCC received research grant from BMS and reported consulting for Regeneron. COB has served as consultant for BMS, Regeneron and Genentech/Roche, and received grant support from BMS. CR received speaking fees from BMS, AstraZeneca and Genentech/Roche. J-EG received honoraries from BMS and Pfizer and research grant from BMS. OL received paid expert testimony and consultancy fees from BMS France, MSD and AstraZeneca, consultancy fees from Genzyme, and expert testimony for Janssen. CC and LHC declared no conflict of interest for this work.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.