Dupilumab levels high in tears of patients with moderate to severe ocular surface disease
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Patients with atopic dermatitis and moderate to severe ocular surface disease who were treated with dupilumab had higher levels of the biologic in their tears than those with mild or no ocular surface disease, according to study results.
Researchers also found dupilumab (Dupixent, Sanofi Genzyme/Regeneron) in conjunctival cell suspensions, Roselie Achten, MSc, MD/PhD candidate of the department of dermatology and allergology at University Medical Center Utrecht, the Netherlands, and colleagues wrote in Clinical and Translational Allergy.
The prospective, monocenter observational cohort study involved 48 patients (median age, 38 years; interquartile range [IQR], 27-48; 50% men) with moderate to severe AD.
Before treatment with dupilumab began, 89.6% of the patients had ocular surface disease (OSD), ranging from mild (39.6%) to moderate (35.4%) to severe (14.6%).
Treatment impact
The researchers did not find any correlation between levels of dupilumab in tears and Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) scores at week 4.
At week 28, the proportion of patients with mild OSD increased to 52.1%, whereas fewer had moderate (33.3%) and severe (10.4%) OSD.
Levels of dupilumab in tears appeared significantly higher among patients with moderate to severe OSD than among those with mild or no OSD (0.55 mg/L; IQR, 0.35-1.31 vs. 0.29 mg/L; IQR = 0.16-0.6; P = .02).
The correlation between levels of dupilumab in tears and UTOPIA scores at week 28 was significant as well, the researchers found (Spearman’s correlation = 0.505; P < .001).
By measuring levels of dupilumab in serum, researchers found a significant difference between patients with moderate to severe vs. no or mild OSD at week 4 (62.1 mg/L; IQR, 52-77 vs. 79.4 mg/L; IQR, 63.2-110.5l; P = .043) but not at week 28. There were no correlations between levels of dupilumab in serum and UTOPIA scores at either timepoint.
Additionally, the researchers detected levels of dupilumab in the conjunctival cell suspensions of five patients with AD who were treated with dupilumab for 4 weeks.
Using flow cytometry analysis, the researchers also confirmed IgG4 binding on CD45-epithelial cells in four of these patients after 4 weeks of treatment with dupilumab. Plus, there was a decrease in the median fluorescence intensity of IL-4R alpha on CD45-epothelial cells after 4 weeks of treatment compared with baseline.
These additional findings suggest that dupilumab on the ocular surface may directly affect the conjunctival epithelium by blocking IL-4R alpha, the researchers wrote.
Conclusions
Noting the frequency of OSD among patients with moderate to severe AD and the high levels of dupilumab in the tears of patients with moderate to severe OSD, the researchers wrote that these levels may be related.
These findings also may indicate that a disrupted blood-tear barrier in patients with AD and moderate to severe OSD may lead to these higher levels of dupilumab in their tears, compared with patients with no or mild OSD.
The researchers also questioned whether the direct binding of dupilumab on the IL-4R alpha of conjunctival cells has any biological and/or clinical consequences.
Overall, the researchers concluded, further research is necessary to investigate the implications of these increased levels of dupilumab in the tears of patients with AD.
Perspective
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This is very interesting. There is one question that jumps out at me. Half of the patients already had moderate to severe OSD. The report shows that patients with moderate to severe OSD have higher concentrations of dupilumab in their tears. The researchers propose that perhaps the blood-tear barrier is compromised in OSD, which allows more drug into the eye.
What is not clear, though, is whether patients with mild or no OSD are becoming moderate to severe and if the concentration is then high for them, too. Is this study only looking at what category patients are in at baseline and then seeing how much dupilumab gets in, or are they looking at what category they are in at the end and then seeing how much gets in? That is a little confusing.
Do patients with mild OSD, or even those who have no OSD at baseline but then develop severe OSD, have high concentrations in their tears? If not, then does the concentration even mean anything? If the suggestion is that the severe patients get more penetration, then we would expect the severe patients to get worse and the mild ones not to be as likely to progress to severe. In actuality, we see many patients who are mild initially but who get worse with the drug, so this adds to the confusion.
To really assess this, there are two separate things to look at. First is to look at concentrations at the end in the pre-existing severe group vs. the pre-existing mild group, which the researchers did. This may confirm their suggestion that the barrier is weakened in severe disease.
The second part is to look at the concentration in the severe vs. mild groups without regard to where they started from a severity standpoint. This may indicate whether the starting point is even relevant. In other words, if the pre-existing mild patients who are now severe have a high concentration, then we can suggest that tear concentration may be related to severity and may cause an increase in severity. On the other hand, if those patients have a low concentration, then concentration may not be relevant.
These are the points that need to be cleaned up. To the best that I can tell, when we look at the severe patients at the end, and note that their concentrations are higher, we do not know if these are only the pre-existing severe patients or if they also are including the formerly mild patients who turned severe. We also do not know if any severe patients became mild from dupilumab and are now in the mild group when looking at concentration.
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