Switching from dupilumab to tralokinumab in atopic dermatitis patients with ocular surface disease: Preliminary case series.

Abstract

To the editor, Since 2018, new biological therapies that target pathways involved in the pathogenesis of atopic dermatitis (AD) are available to treat patients with moderate-to-severe AD.1, 2 Dupilumab inhibits interleukin (IL)-4 and IL-13 signalling by targeting the IL-4 receptor alpha and has proven its efficacy and safety.2 However, high rates of dupilumab-associated ocular surface disease (DAOSD) have been reported during treatment.2 In phase-3 trials with tralokinumab, a biological therapy that specifically targets IL-13, less ocular surface disease (OSD) has been reported compared to phase-3 trials with dupilumab (7.5% vs. 8.6–22.1%, respectively).1, 2 Nevertheless, the first phase-3 dupilumab trials also showed low rates of DAOSD and in addition, phase-3 dupilumab trial data cannot be compared one-to-one with the phase-3 tralokinumab trial data, since no head-to-head study is yet performed. Due to the more specific working mechanism of tralokinumab compared to dupilumab, it can be hypothesized that patients with DAOSD might benefit from switching to tralokinumab. Therefore, we compared ocular symptoms, ocular inflammation, and ophthalmic medication use in AD patients with DAOSD who were subsequently treated with tralokinumab. This prospective, monocentric, observational case series included four patients with moderate-to-severe AD (median age 40.0 years (interquartile range (IQR) 27.3–66.3), 50% male (n = 2/4)) treated at the University Medical Center Utrecht between March 2020 and December 2022. Patients discontinued dupilumab treatment due to the development of DAOSD and were switched to tralokinumab. Informed consent was provided, and this study was considered as non-interventional by the Medical Research Ethics Committee. Patients were examined by both a dermatologist and ophthalmologist prior to the start, after 4, and after 28 weeks of treatment with dupilumab and tralokinumab following a standardized protocol, in which the presence of OSD symptoms (red eyes, watery eyes, pruritus, pain, photophobia, and burning sensation) was evaluated. If needed—i.e. in case of new-onset OSD or worsening of pre-existent OSD, and after starting ophthalmic treatment for OSD—additional ophthalmologic visits were performed. The Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score, focusing on the eyelids, conjunctiva (both bulbar and tarsal) and the limbus, was assessed at all ophthalmological visits by the same ophthalmologist.3 Higher UTOPIA scores reflect more severe OSD, as described previously.3 The UTOPIA score of the most affected eye was used for analyses. Additionally, past or current use of ophthalmic medication use was reported at each visit. The patients' characteristics are available via https://zenodo.org/record/7509282. Median Eczema Area and Severity Index (EASI) before initiation of dupilumab treatment were higher compared to EASI before starting tralokinumab treatment (21.6 (IQR 5.7–26.7) vs. 4.6 (IQR 1.2–7.3, respectively)), which can be explained by the fact that all patients started treatment with tralokinumab in the wash-out period of dupilumab. Although EASI was slightly higher at week 28 when treated with tralokinumab compared to dupilumab (Table 1), patients were satisfied with the effect of treatment on AD. Additionally, at week 28 of tralokinumab treatment, less OSD symptoms were reported compared with dupilumab treatment in patients 2 and 4 (Table 1). During the course of tralokinumab treatment, UTOPIA scores decreased in patients 1, 2 and 3, indicating that ocular inflammation improved after switching from dupilumab to tralokinumab (Figure 1). However, patient 1 developed DAOSD after a longer period of treatment with dupilumab, suggesting that tralokinumab-associated OSD (TAOSD) may occur later. Nevertheless, patient 1 was able to taper down the frequency of hydrocortisone eye drops to once daily leading to controlled ocular inflammation. Patient 2 showed clear improvement in ocular inflammation during treatment with tralokinumab, which was achieved despite the discontinuation of ophthalmic medication. Patient 3 showed an improvement in his UTOPIA score during dupilumab treatment by using dexamethasone eye drops twice daily. However, this patient switched to tralokinumab treatment because of fear of long-term side effects of high-dose dexamethasone. Patient 3 still required dexamethasone eye drops during treatment with tralokinumab, although less frequently than during treatment with dupilumab. In patient 4, the UTOPIA score increased during the first weeks of treatment with tralokinumab, after which an almost equal UTOPIA score was achieved with the same ocular therapy as during treatment with dupilumab (Figure 1, Table 1). Our results suggest that some patients with DAOSD may benefit from switching to tralokinumab as fewer symptoms were reported and less ocular inflammation (i.e. lower UTOPIA scores) was observed in three out of four cases. Also, less ophthalmic steroids were needed during tralokinumab treatment in all four patients, leading to a lower risk of corticosteroid-induced glaucoma and cataract.4 As it is known that severe chronic DAOSD with involvement of the limbus may lead to irreversible limbal stem cell deficiency requiring long-term follow-up, this could also apply to TAOSD.5 Therefore, physicians should not be reluctant to prescribe anti-inflammatory ophthalmic medication. As we recently described that 90% of moderate-to-severe AD patients already have OSD before starting treatment, it is important to monitor patients ophthalmologically from the start of treatment with dupilumab or tralokinumab in order to distinguish between DAOSD/TAOSD and AD-associated OSD.6 It has been hypothesized that scarcity of goblet cells (GC) may play a role in the development of DAOSD.7 As results of a recent in-vitro study suggested that the proliferation of GCs is influenced by both IL-4 and IL-13, less TAOSD may develop due to the more specific working mechanism of tralokinumab by affecting IL-13 signalling only.8 In addition, the dual blockade of IL-4 and IL-13 signalling by dupilumab could lead to Th1/Th17 skewing, which is thought to contribute to the development of DAOSD as well.1 This study has some limitations. First, all patients were in their dupilumab wash-out period when starting tralokinumab, making it more difficult to distinguish between DAOSD and TAOSD at the early time points. However, the effect of tralokinumab monotherapy on ocular inflammation could still be evaluated due to the follow-up visits. As this study only examined four patients, larger comparable studies are needed to verify our results. In conclusion, this prospective case series showed that some patients with DAOSD may benefit from switching from dupilumab to tralokinumab treatment. All authors have made substantial contributions to the conception and design, or acquisition of data or analysis and interpretation of data. All authors have been involved in drafting the manuscript or revising it critically and have given final approval for the version to be published. None. Roselie Achten, Coco Dekkers, Joke de Boer has nothing to disclose. Daphne Bakker is a speaker for Sanofi, Janssen, Novartis and LEO Pharma. Chantal van Luijk is a speaker for Sanofi and Santen. Marlies de Graaf is a principal investigator and advisory board member and/or speaker for AbbVie, Eli Lilly, Leo Pharma, Pfizer, Regeneron Pharmaceuticals and Sanofi. Femke van Wijk is a speaker and/or consultant for Janssen, Johnson & Johnson and Takeda. Marjolein de Bruin-Weller is a consultant, advisory board member and/or speaker for AbbVie, Almirall, Aslan, Arena, Eli Lilly, Galderma, Janssen, Leo Pharma, Pfizer, Regeneron Pharmaceuticals and Sanofi. Judith Thijs is a speaker for Sanofi, LEO Pharma, Janssen and Admirall. Included patients participated in the BioDay Registry, sponsored by AbbVie, Sanofi, Lilly, Pfizer and LEO Pharma pharmaceutical company. The sponsors were not involved in the analyses, interpretation of the data and preparation of the manuscript. The data that support the findings of this study are available from the corresponding author upon reasonable request.