Dupilumab Use Associated With Increased IL-4 and IL-18 Production

Asian woman pinches her brow, highlighted red for concept of rhinosinusitis pain

In 2019, dupilumab was approved to treat refractory chronic rhinosinusitis with nasal polyps (CRSwNP). Dupilumab is a monoclonal antibody that binds to interleukin 4 receptor-α (IL-4Rα), which inhibits the signaling of both IL-4 and IL-13. Those are key cytokines in driving type 2 inflammatory response.

Therefore, Stella E. Lee, MD, director of the Sinus Center in the Division of Otolaryngology–Head & Neck Surgery at Brigham and Women’s Hospital, and Jymirah Morris, BS, and Tolani F. Olonisakin, PhD, of the University of Pittsburg, and colleagues speculate that global IL-4Rα inhibition could have immune consequences. In a research note published in International Forum of Allergy & Rhinology, they report preliminary data on how targeting IL-4Rα with dupilumab changes the local inflammatory milieu.


The researchers conducted a prospective, observational study of 15 adults, ages 52 to 62, with bilateral CRSwNP who used dupilumab between 2019 and 2020. The median treatment duration was five months (interquartile range, nine months). The patients also used intranasal corticosteroids.

All participants returned for a follow-up visit 12 to 52 weeks after initiating dupilumab. Nasal mucus secretions were collected before and after starting dupilumab and were analyzed for cytokine levels. At both visits patients completed disease severity questionnaires and had fractional exhaled nitric oxide (FeNO) measured.

T Helper 1 Cytokines

  • IL-18: Increased from 56 pg/mL pre-treatment to 110 pg/mL post-treatment (P=0.042)
  • Tumor necrosis factor-α: Undetectable in most samples
  • Interferon-γ: Undetectable in most samples

T Helper 2 Cytokines

  • IL-4: Increased from 23 pg/mL to 78 pg/mL (P=0.042)
  • IL-13: No significant change
  • IL-5: No significant change


There was no significant pre- to post-treatment change in chemokine ligand 2 or chemokine ligand 5. C-X-C motif chemokine ligand 8/IL-8, a neutrophilic chemoattractant, increased from 75 pg/mL to 160 pg/mL, but the change was not statistically significant.

Clinical Outcomes

Pre- to post-treatment change in FeNo was not significant, but there were significant dupilumab-associated improvements in:

  • The nasal polyp score
  • Lund–Kennedy endoscopic score
  • The 22-item Sino-Nasal Outcome Test
  • The University of Pennsylvania Smell Identification Test

Continued Scrutiny Needed

The fact that levels of IL-4 increased during dupilumab therapy suggests constitutive production of this cytokine that is independent of IL-4Rα stimulation. IL-18 modulates both type 1 and type 2 inflammation in CRS; particularly, it’s a strong inducer of interferon-γ release from T helper 1 cells.

This study was exploratory, and the power of the statistical analyses was limited, but these data emphasize the need to explore the consequences of inhibiting the type 2 inflammatory pathway.

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