Dupilumab use correlates with S. aureus reductions, atopic dermatitis improvements

Key takeaways:

• Staphylococcus aureus abundance fell significantly with 3 days of dupilumab treatment.
• These reductions correlated with improvements in atopic dermatitis severity and reductions in CCL17.

Treatment with dupilumab reduced Staphylococcus aureus colonization and infection in patients with atopic dermatitis, correlating with improved outcomes, according to a study published in The Journal of Allergy and Clinical Immunology.

These reductions are due to blocked IL-4 and IL-13 signaling, Eric L. Simpson, MD, MCR, professor and director of clinical research, department of dermatology, Oregon Health & Science University, and colleagues wrote.

The study included 71 adults (mean age, 36.9 years; 66% men; 48% white) with moderate to severe AD, with 45 receiving a 600 mg loading dose of dupilumab (Dupixent; Sanofi/Regeneron) followed by 300 mg every 2 weeks, in addition to 26 receiving placebo, both for 6 weeks. A 10-week open label extension followed.

At baseline, all the participants had S. aureus colonies on their skin. Based on relative and viable colony-forming units, the dupilumab group experienced a reduction in S. aureus abundance that was separate from the placebo group by a factor of approximately 7.5 as early as day 3 (P = .02), and this separation continued at later time points.

Reductions in the plate counts of viable S. aureus plateaued at a factor of approximately 100 after 28 days of treatment, with no further reductions through the open label extension. The patients in the placebo group experienced similar reductions once they began receiving dupilumab during the open label extension.

Additionally, there was a 10-fold reduction in S. aureus cytotoxins in lesional skin in the dupilumab group by day 7, with a maximum reduction by a factor of 100 by day 27. Nonlesional skin had more modest reductions, with differentiation with the placebo group achieved by day 21.

Meanwhile, the dupilumab group experienced a greater absolute reduction in SCORing AD (SCORAD) than the placebo group by day 14 that remained lower at all later time points (P = .04).

Similarly, Eczema Area and Severity Index (EASI), pruritis Numerical Rating Scale (NRS) and Investigator Global Assessment (IGA) measures in the dupilumab group also significantly separated from the placebo group by day 21.

Improvements continued for the dupilumab in each severity measure through the open label extension (P .005), with clinical improvements for the placebo group when they began taking dupilumab during the open label extension in all severity measures as well (P < .001).

Changes in S. aureus abundance were associated with changes in AD severity as measured by SCORAD on days 3, 7 and 14, with a statistically significant correlation between S. aureus on lesional skin in the dupilumab group (0.39; 95% CI, 0.2-0.56) but no association in the placebo group.

Similar associations were found between reductions in S. aureus abundance and improved EASI and validated IGA measurements, but not with pruritis NRS, suggesting that patients in the dupilumab group with the most significant early reductions in lesional S. aureus were most likely to experience the greatest early improvements in AD.

Within 3 days, the researchers said, dupilumab treatment led to increases in Shannon microbial alpha diversity in lesional skin, with maximal effects by day 28. The placebo group experienced similar changes during the open label extension.

As S. aureus abundance declined, S. epidermidis, Cutibacterium acne, S. hominis and Micrococcus luteus abundances increased during dupilumab treatment. The novel lantibiotics that these bacteria produce kill S. aureus, the researchers said.

The patients in the placebo group had stable bacterial composition until the open label extension, when they experienced changes that were similar to the dupilumab group.

The dupilumab group appeared to have a significant reduction in transepidermal water loss at day 3 that did not appear during later time points in the study, with modest reductions at day 42. The placebo group had similar reductions during the open label extension.

Additionally, the dupilumab group had significant reductions in serum CCL17 compared with the placebo group by day 7 (P = .04), with precipitous and significant decreases through day 21 (P < .001) and slower decreases afterward.

These reductions in this type 2 serum in the dupilumab group also correlated with greater reductions in lesional S. aureus as early as day 7 (P = .04) and most significantly at day 14 (P = .01).

RNA sequencing from skin biopsies revealed 27 downregulated differentially expressed genes (DEGs) in dupilumab-treated lesional skin, including 11 related to type 2 inflammation with six of them also reduced in nonlesional skin.

Also, the researchers said, dupilumab did not affect or, paradoxically, lead to reduced expression of some of the antimicrobial peptides that are believed to be active against S. aureus. Only two were upregulated with treatment.

Lesional and nonlesional skin alike in the dupilumab group had five T_H17-cell/neutrophil-related genes that were upregulated, although the nonlesional skin also had 24 other T_H17 cells/neutrophil genes that were upregulated too.

The researchers observed increased expression of genes relevant for IL-17, neutrophil and complement pathways at day 7 as well.

These and other molecular changes at the host-microbe interface may explain the early changes in S. aureus abundance that the researchers observed, they said, as the inhibition of IL-4 and IL-13 enhance the host’s ability to fight S. aureus through various mechanisms.

Therapies that reduce the abundance of S. aureus and reduce type 2 immunity may be very beneficial, the researchers said, adding that reducing S. aureus alone may not provide enough clinical benefit.

The researchers called for additional studies into whether these reductions in S. aureus abundance persist after treatment has been withdrawn as well as whether these reductions may contribute to benefits in other diseases driven by type 2 inflammation.