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. 2024 Nov;12(11):2996-3013.e7.
doi: 10.1016/j.jaip.2024.07.002. Epub 2024 Aug 15.

Interleukin (IL)-1/IL-6-Inhibitor-Associated Drug Reaction With Eosinophilia and Systemic Symptoms (DReSS) in Systemic Inflammatory Illnesses

Vivian E Saper  1 , Lu Tian  2 , Ruud H J Verstegen  3 , Carol K Conrad  4 , Michal Cidon  5 , Rachel K Hopper  4 , Christin S Kuo  4 , Kazutoyo Osoegawa  6 , Kevin Baszis  7 , Catherine A Bingham  8 , Ian Ferguson  9 , Timothy Hahn  8 , Annacarin Horne  10 , Eugenia A Isupova  11 , Jordan T Jones  12 , Özgür Kasapcopur  13 , Marisa S Klein-Gitelman  14 , Mikhail M Kostik  11 , Seza Ozen  15 , Omkar Phadke  16 , Sampath Prahalad  17 , Rachel L Randell  18 , Seher Sener  15 , Cory Stingl  19 , Rabheh Abdul-Aziz  20 , Shoghik Akoghlanian  21 , Dalila Al Julandani  22 , Marcela B Alvarez  23 , Brigitte Bader-Meunier  24 , Erin E Balay-Dustrude  25 , Imelda Balboni  4 , Sarah K Baxter  25 , Roberta A Berard  26 , Sagar Bhattad  27 , Roxana Bolaria  28 , Alexis Boneparth  29 , Elaine A Cassidy  30 , Dominic O Co  31 , Kathleen P Collins  32 , Paul Dancey  33 , Aileen M Dickinson  34 , Barbara S Edelheit  35 , Graciela Espada  23 , Elaine R Flanagan  17 , Lisa F Imundo  29 , Ankur K Jindal  36 , Hyoun-Ah Kim  37 , Günter Klaus  38 , Carol Lake  39 , W Blaine Lapin  35 , Erica F Lawson  40 , Itay Marmor  41 , Joy Mombourquette  42 , Benson Ogunjimi  43 , Rebecca Olveda  40 , Michael J Ombrello  39 , Karen Onel  44 , Catherine Poholek  30 , Athimalaipet V Ramanan  45 , Angelo Ravelli  46 , Adam Reinhardt  47 , Amanda D Robinson  30 , Kelly Rouster-Stevens  17 , Nadine Saad  48 , Rayfel Schneider  49 , Velma Selmanovic  50 , Irmina Sefic Pasic  50 , Susan Shenoi  25 , Natalie R Shilo  51 , Jennifer B Soep  52 , Angeli Sura  53 , Sarah F Taber  44 , Melissa Tesher  54 , Jessica Tibaldi  55 , Kathryn S Torok  30 , Cathy Mei Tsin  4 , Natalia Vasquez-Canizares  56 , Diana S Villacis Nunez  17 , Emily E Way  57 , Benjamin Whitehead  58 , Lawrence S Zemel  35 , Surbhi Sharma  4 , Marcelo A Fernández-Viña  59 , Elizabeth D Mellins  4 ; CARRA Registry Investigators
Collaborators, Affiliations

Interleukin (IL)-1/IL-6-Inhibitor-Associated Drug Reaction With Eosinophilia and Systemic Symptoms (DReSS) in Systemic Inflammatory Illnesses

Vivian E Saper et al. J Allergy Clin Immunol Pract. 2024 Nov.

Abstract

Background: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease.

Objective: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not stopping IL-1/IL-6 inhibitors after DReSS reaction began.

Methods: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6 inhibitors with 37 cases not stopping these drugs.

Results: Before the reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease-onset age for reaction cases with preexisting cardiothoracic comorbidities. After the reaction began, increased rates of pulmonary complications and macrophage activation syndrome differentiated drug-reaction cases from drug-tolerant controls (P = 4.7 × 10-35 and P = 1.1 × 10-24, respectively). The initial DReSS feature was typically reported 2 to 8 weeks after initiating IL-1/IL-6 inhibition. In drug-reaction cases stopping versus not stopping IL-1/IL-6-inhibitor treatment, reaction-related features were indistinguishable, including pulmonary complication rates (75% [39 of 52] vs 76% [28 of 37]). Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of macrophage activation syndrome, and improved survival (P = .005, multivariate regression). Resolution of pulmonary complications occurred in 67% (26 of 39) of drug-reaction cases who stopped and in none who continued inhibitors.

Conclusions: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6 inhibitors significantly improved outcomes.

Keywords: Biologic therapy; Drug reaction with eosinophilia and systemic symptoms; Drug-induced lung disease; Hemophagocytic lymphohistiocytosis; Macrophage activation syndrome; Pulmonary hypertension; Still disease; Systemic inflammatory illnesses.

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Conflict of interest statement

Disclosure of funding sources and potential conflicts of interest: This work was supported by The Lucile Packard Foundation for Children’s Health, The Childhood Arthritis and Rheumatology Research Alliance, The Arthritis Foundation, Research Foundation Flanders, the National Institute of General Medical Sciences (award number T32GM086330), the Eunice Kennedy Shriver National Institute of Child Health & Human Development (award number T32HD104576), and the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (award number Z01AR041198) of the National Institutes of Health, and Rheumatology Research Foundation (Atlanta, Georgia USA).

AnnaCarin Horne reports support from SOBI, Marcela Alvarez reports personal fees from Novartis; Sampath Prahalad reports personal fees from Novartis; Athimalaipet Ramanan reports personal fees from Abbvie, Eli Lilly, Roche, Novartis, Pfizer, UCB, SOBI; Günter Klaus reports personal fees from Rhythm Pharmaceuticals and Fresenius Germany; Ozgur Kasapcopur reports personal fees from Novartis, Roche, Abbvie, Sanofi, SOBI; Roberta Berard reports personal fees from SOBI, Abbvie; Sarah Baxter reports employment and stock from Sanofi; Seza Ozen reports personal fees from SOBI, Novartis; Rachel Randell reports family member funding from Biogen and Merck; Rayfel Schneider reports grants from SOBI, Pfizer and personal fees from Roche, Novartis, SOBI, Innomar Strategies; Erica Lawson reports grants from Amgen, Pfizer and Abbvie; Susan Shenoi reports personal fees from Pfizer, Novartis, Amgen; Elizabeth Mellins reports grants from Glaxo Smith Kline, Codexis, Genentech. All other authors have no potential conflicting interests to report.

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