Effect of Drug Withdrawal on Interleukin-1 or Interleukin-6 Inhibitor Associated Diffuse Lung Disease

Vivian Saper¹, Sampath Prahalad², Scott Canna³, Rabheh Abdul-Aziz⁴, Marcela Alvarez⁵, Catherine Bingham⁶, Brigitte Bader-Meunier⁷, Imelda Balboni⁸, Roberta Berard⁹, Roxana Bolaria¹⁰, Alexis Boneparth¹¹, Alicia Casey¹², Elaine Cassidy¹³, Joyce C. Chang¹⁴, Michal Cidon¹⁵, Kathleen Collins¹⁶, Aileen M. Dickenson¹⁷, Graciela Espada⁵, Martha Fishman¹², Elaine Flanagan¹⁸, Timothy Hahn¹⁹, Ankur K. Jindal²⁰, Ozgur Kasapcopur²¹, Marisa Klein-Gitelman²², Timothy Klouda¹², Mikhail Kostik²³, Carol Lake²⁴, Mariana Marques²⁵, Michael Ombrello²⁶, Karen Onel²⁷, Omkar Phadke²⁸, Angelo Ravelli²⁹, Adam Reinhardt³⁰, Amanda D. Robinson³¹, Kelly Rouster-Stevens³², Nadine Saad²⁷, Grant Schulert³³, Susan Shenoi³⁴, Cory Stingl¹⁴, Anjali Sura³⁵, Melissa Tesher³⁶, Jessica Tibaldi³⁷, Kathryn Torok³⁸, Cathy Tsin³⁹, Natalia Vasquez-Canizares⁴⁰, D. Sofia Villacis-Nunez⁴¹, Ben Whitehead⁴², Holly Wobma¹², Lawrence Zemel⁴³ and Elizabeth Mellins¹, ¹Stanford University, Stanford, CA, ²Emory + Children's Pediatric Institute, Atlanta, GA, ³Children's Hospital of Philadelphia, Philadelphia, PA, ⁴University at Buffalo, Buffalo, NY, ⁵Hospital de Niños Dr Ricardo Gutierrez, Buenos Aires, Argentina, ⁶Penn State Children's Hospital, Allentown, PA, ⁷Pediatric Immuno-hematology, Necker Hospital, APHP, Paris, France, ⁸Stanford University, Palo Alto, CA, ⁹London Health Sciences Centre, London, ON, Canada, ¹⁰Self, Victoria, BC, Canada, ¹¹Columbia University Medical Center, New York, NY, ¹²Boston Children's Hospital, Boston, MA, ¹³University of Pittsburgh Medical Center Medical Education, Pittsburgh, PA, ¹⁴Children's Hospital of Phildelphia, Philadelphia, PA, ¹⁵Children's Hospital Los Angeles, Los Angeles, CA, ¹⁶LeBonheur Children's Hospital, Memphis, TN, ¹⁷Children's Hospital of Los Angeles, Los Angeles, CA, ¹⁸Emory University and Children's Healthcare of Atlanta, Atlanta, GA, ¹⁹Penn State Childrens Hospital, Hershey, PA, ²⁰Postgraduate Institute of Medical Education and Research, Chandigarh, India, ²¹Istanbul University-Cerrahpasa, Cerrahpasa Medical School, İstanbul, Turkey, ²²Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, ²³Saint-Petersburg State Pediatric Medical University, Saint Petersburg, Russia, ²⁴National Institutes of Health, Gaithersburg, MD, ²⁵UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, ²⁶National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, ²⁷Hospital for Special Surgery, New York, NY, ²⁸EMORY, Atlanta, GA, ²⁹Istituto Giannina Gaslini, Genoa, Italy, ³⁰Boys Town National Research Hospital, Omaha, NE, ³¹UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, ³²Emory University/Children's Healthcare of Atlanta, Atlanta, GA, ³³Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ³⁴Seattle Children's Hospital, Seattle, WA, ³⁵SUNY Upstate Medical University, Syracuse, NY, ³⁶University of Chicago, Chicago, IL, ³⁷IRCSS Istituto G. Gaslini University of Genoa, Genoa, Italy, ³⁸University of Pittsburgh, Pittsburgh, PA, ³⁹Stanford University, Stanford, ⁴⁰Children's Hospital at Montefiore, Bronx, NY, ⁴¹Children's Healthcare of Atlanta - Emory University, Atlanta, GA, ⁴²Queensland Children's Hospital, Brisbane, Australia, ⁴³CCMC, Hartford, CT

Meeting: ACR Convergence 2021

Keywords: Biologicals, Drug toxicity, interstitial lung disease, Mortality, Still's disease

Session Information

Date: Tuesday, November 9, 2021

Title: Pediatric Rheumatology – Clinical Poster III: Miscellaneous Rheumatic Disease (1614–1644)

Session Type: Poster Session D

Session Time: 8:30AM-10:30AM

Background/Purpose: Severe delayed hypersensitivity reactions (DHR) are under-recognized in inflammatory conditions, particularly drug reaction with eosinophilia and systemic symptoms (DRESS). Previous work has shown this reaction to occur implicating inhibitors of IL-1 and IL-6 during treatment of Stills disease.¹ The purpose of the present analysis of newly identified cases is to assess outcomes based on timeliness of recognizing drug reaction and withdrawal of the implicated medications.

Methods: This is a retrospective observational study of subjects with Stills disease who experienced a DRESS reaction implicating one or more of anakinra, canakinumab, tocilizumab or rilonacept. Classification as DHR required scoring as probable or definite using the validated scoring system RegiSCAR for DRESS.² Cases with and without diffuse parenchymal lung disease during treatment (DLD) were included. Variables included duration of drug exposure, development of diffuse lung disease, lung disease status at data close and death. Lung disease resolution was defined as absence of respiratory symptoms without supplemental oxygen, normal chest CT and resolution or absence of digital clubbing. DLD improvement differed from resolution by allowing improved chest CT or digital clubbing with neither worsening. Comparisons were made using Fishers exact test and odds ratios with 95% confidence intervals. 59 subjects met inclusion criteria for DHR implicating inhibitors of IL-1 and/or IL-6. Class II HLA associations were considered as available.

Results: Median age at Stills onset was 4 years (range 0.5-17.7 years), 69% (41/59) had DLD and 61% (36/59) were female. Fatalities occurred solely in subjects developing DLD (12/41,29%). Median latency from drug initiation to detection of DLD was 1.3 yrs (range 2 weeks-4.3 years). When biopsied, pathology in DLD was pulmonary alveolar proteinosis, as described.¹ Three cases resolved lung disease; all 3 had permanently discontinued IL-1 and IL-6 inhibitors within 6 weeks of DLD detection. DHR subjects without DLD who stopped IL-1 or IL-6 inhibitors did not develop DLD, during median follow-up of 1 year after drug stop (range 0.2-6.5 years). Drug withdrawal improved outcomes (table). HLA-DRB1*15 was present in 31/37(84%), strikingly exceeding population frequencies.³

Conclusion: Timely recognition of DRESS reactions and withdrawal of all IL-1 and IL-6 inhibitors improve outcomes in Stills disease, lessens risk of the often fatal drug-associated lung disease and may allow resolution of DLD. Mechanisms underlying cross reactions between these structurally different drugs are not known. Determination of HLA may limit the incidence of DHR.

1. Saper et al. Emergent high fatality lung disease in systemic juvenile arthritis. Ann Rheum Dis. Dec 2019;78(12):1722-1731

2. Kardaun et al. DRESS: an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. Nov 2013;169(5):1071-80.

3. Hollenbach et al. IL-1 and IL-6 inhibitor hypersensitivity link to common HLA-DRB1*15 alleles. https://www.medrxiv.org/content/10.1101/2020.08.10.20172338v3

Disclosures: V. Saper, None; S. Prahalad, Novartis, 1; S. Canna, Simcha Therapeutics, 2, Novartis, 5, AB2Bio, Ltd, 5, IMMvention Therapeutix, 5; R. Abdul-Aziz, None; M. Alvarez, None; C. Bingham, None; B. Bader-Meunier, None; I. Balboni, None; R. Berard, Sandoz, 2, SOBI, 2, Roche, 2; R. Bolaria, None; A. Boneparth, None; A. Casey, None; E. Cassidy, None; J. Chang, None; M. Cidon, None; K. Collins, None; A. Dickenson, None; G. Espada, None; M. Fishman, None; E. Flanagan, None; T. Hahn, None; A. Jindal, None; O. Kasapcopur, Novartis, 6, Pfizer, 6, Roche, 6, Abbvie, 6; M. Klein-Gitelman, None; T. Klouda, None; M. Kostik, None; C. Lake, None; M. Marques, None; M. Ombrello, None; K. Onel, None; O. Phadke, None; A. Ravelli, Abbvie, 2, 6, BMS, 2, 6, Pfizer, 2, 6, Hoffmann-La Roche, 2, 6, Novartis, 2, 6, Centocor, 2, 6, Anjelini Holding, 2, 6, Reckitt Benckiser, 2, 6; A. Reinhardt, None; A. Robinson, None; K. Rouster-Stevens, None; N. Saad, None; G. Schulert, Novartis, 6; S. Shenoi, Pfizer, 2; C. Stingl, None; A. Sura, None; M. Tesher, None; J. Tibaldi, None; K. Torok, None; C. Tsin, None; N. Vasquez-Canizares, None; D. Villacis-Nunez, None; B. Whitehead, None; H. Wobma, Immplacate Inc, 4, 8; L. Zemel, None; E. Mellins, Genentech, 5.

To cite this abstract in AMA style:

Saper V, Prahalad S, Canna S, Abdul-Aziz R, Alvarez M, Bingham C, Bader-Meunier B, Balboni I, Berard R, Bolaria R, Boneparth A, Casey A, Cassidy E, Chang J, Cidon M, Collins K, Dickenson A, Espada G, Fishman M, Flanagan E, Hahn T, Jindal A, Kasapcopur O, Klein-Gitelman M, Klouda T, Kostik M, Lake C, Marques M, Ombrello M, Onel K, Phadke O, Ravelli A, Reinhardt A, Robinson A, Rouster-Stevens K, Saad N, Schulert G, Shenoi S, Stingl C, Sura A, Tesher M, Tibaldi J, Torok K, Tsin C, Vasquez-Canizares N, Villacis-Nunez D, Whitehead B, Wobma H, Zemel L, Mellins E. Effect of Drug Withdrawal on Interleukin-1 or Interleukin-6 Inhibitor Associated Diffuse Lung Disease [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/effect-of-drug-withdrawal-on-interleukin-1-or-interleukin-6-inhibitor-associated-diffuse-lung-disease/. Accessed .

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