Ocular surface disease in moderate-to-severe atopic dermatitis patients and the effect of biological therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate-to-severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate-to-severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD-related severity biomarkers in tear fluid. The second part of this review highlights that pre-existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab-associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new-onset OSD or worsening of pre-existing OSD) is observed in approximately one-third of the dupilumab-treated AD patients. Anti-inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate-to-severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab-treated AD patients with moderate-to-severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate-to-severe AD patients, and a low-threshold referral to an ophthalmologist is recommended.

Allogeneic Serum Eye Drops: A Randomized Clinical Trial to Evaluate the Clinical Effectiveness of Two Drop Sizes.

INTRODUCTION: Allogeneic serum from blood donors is starting to be used to treat patients with dry eye disease (DED). However, the optimal dose is not known. We therefore aimed to evaluate the clinical efficaciousness and user-friendliness of micro-sized versus conventional-sized allogeneic serum eye drops (SEDs). METHODS: In a randomized trial, patients with DED first receive micro-sized SEDs (7 µl/unit) for 1 month, followed by a 1-month washout, before receiving conventional-sized SEDs (50 µl/unit) for 1 month; or vice versa. The primary endpoint was the Ocular Surface Disease Index (OSDI) score. Secondary endpoints were tear break-up time (TBT), tear production (TP), and presence of corneal punctate lesions (CP). The user-friendliness of both application systems was also compared. A linear mixed model for cross-over design was applied to compare both treatments. RESULTS: Forty-nine patients completed the trial. The mean OSDI score significantly improved from 52 ± 3 to 41 ± 3 for micro-sized SEDs, and from 54 ± 3 to 45 ± 3 for conventional-sized SEDs. Non-inferiority (margin = 6) of micro-sized SEDs was established. We demonstrate a significant improvement for TBT in case of conventional-sized SEDs and for CP in both treatment groups. TP trended towards an improvement in both treatment groups. The user-friendliness of the conventional drop system was significantly higher. CONCLUSIONS: For the first time, non-inferiority of micro-sized allogeneic SEDs was established. The beneficial effect of both SED volumes was similar as measured by the OSDI score. Although user-friendliness of the micro drop system was significantly lower, it is an attractive alternative as it saves valuable donor serum. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03539159).

Dupilumab-associated ocular surface disease in atopic dermatitis patients: Clinical characteristics, ophthalmic treatment response and conjunctival goblet cell analysis.

BACKGROUND: Dupilumab-associated ocular surface disease (DAOSD) is frequently reported as side effect in atopic dermatitis (AD) patients. Therefore, the aim of this study was to investigate the frequency and severity of DAOSD, ophthalmic treatment response and to learn more about the effect of dupilumab on conjunctival goblet cells (GC). METHODS: This prospective study included dupilumab-treated AD patients between February 2020 and June 2022 from the University Medical Centre Utrecht. Patients were examined by an ophthalmologist and a dermatologist before start (baseline), and after 4 and 28 weeks of dupilumab treatment. Ophthalmological examination was assessed by the Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score. DAOSD was defined as an increase in UTOPIA score of ≥3 points from baseline. To quantify conjunctival GCs and to investigate the percentage of Cytokeratin 19 (CK19)-CD45-Mucin 5 AC (MUC5AC)+ cells, conjunctival impression cytology samples were analysed. RESULTS: Ocular surface disease (OSD) was present in 91.3% (n = 63/69) patients at baseline. DAOSD was observed in 28.9% (n = 20/69) patients, in whom GC numbers remained stable and the percentage of CK19-CD45-MUC5AC+ cells decreased at onset of DAOSD compared with baseline. After 28 weeks of dupilumab treatment, DAOSD was seen in 14.5% (n = 10/69) patients. Of the 85.5% (n = 59/69) patients without DAOSD or with controlled DAOSD at Week 28, 40.7% (n = 24/59) patients received anti-inflammatory ophthalmic drugs. CONCLUSIONS: Ocular surface disease is common in moderate-to-severe AD patients before starting dupilumab. During treatment with dupilumab DAOSD severity improves with early ophthalmic treatment. The decrease in percentage of CK19-CD45-MUC5AC+ cells during dupilumab treatment suggests an impairment of the GC function due to dupilumab treatment.

Non-Infectious Uveitis Secondary to Dupilumab Treatment in Atopic Dermatitis Patients Shows a Pro-Inflammatory Molecular Profile.

Severe uveitis is a rare complication of interleukin-4 receptor alpha blocking by dupilumab in topic dermatitis (AD) patients. The aim of this study was to describe five moderate-to-severe AD patients who developed uveitis during dupilumab treatment and to compare the proteomic profile of aqueous humor (AqH) of dupilumab-associated uveitis (n=3/5 available samples) with non-infectious uveitis (n=27) and cataract controls (n=11). Included patients were treated at the University Medical Center Utrecht (the Netherlands). Active dupilumab-associated uveitis complicated by serous detachment, cystoid macular edema, or secondary glaucoma developed within a median of 6.0 months (interquartile range 2.3-16.5 months) after starting dupilumab. Uveitis resolved after discontinuation of dupilumab and/or treatment with local or systemic corticosteroids. Proteomic profiling of AqH revealed that the molecular profile of dupilumab-associated uveitis resembled that of non-infectious uveitis. In conclusion, dupilumab-associated uveitis is a severe adverse event of dupilumab therapy, requiring urgent referral to an ophthalmologist.

Video Grading of Descemet Membrane Endothelial Keratoplasty Surgery to Identify Surgeon Risk Factors for Graft Detachment and Rebubbling: A Post Hoc Observational Analysis of the Advanced Visualization In Corneal Surgery Evaluation Trial.

PURPOSE: The aim of this study was to explore video-graded intraoperative risk factors for graft detachment (GD) and rebubbling in Descemet membrane endothelial keratoplasty surgery. METHODS: A post hoc analysis of 65 eyes of 65 pseudophakic subjects with Fuchs endothelial dystrophy that underwent Descemet membrane endothelial keratoplasty surgery as part of the Advanced Visualization In Corneal Surgery Evaluation trial. All surgical recordings were assessed by 2 graders using a structured assessment form. A multinominal regression was performed to estimate the independent effect of video-graded intraoperative factors on the incidence of GD and rebubbling. Secondary outcomes are corrected distance visual acuity and endothelial cell density. RESULTS: In total, 33 GDs were recorded, of which 17 required rebubbling. No significant predictors for GD or rebubbling were identified. However, the results revealed 2 clinically relevant patterns. An unfavorable graft configuration (ie, wrinkled, tight scroll, or taco-shaped) and a gas-bubble size smaller than the graft diameter were associated with an increased risk of GD [odds ratio (OR) 2.5 and OR 2.26, respectively] and rebubbling (OR 2.0 and OR 2.60, respectively). Inversely, a larger gas-bubble size was associated with a reduced risk of GD (OR 0.37) and rebubbling (OR 0.36). At 3 and 6 months postoperatively, corrected distance visual acuity was poorer in subjects requiring a rebubbling and endothelial cell density loss was higher in subjects with a partial GD. CONCLUSIONS: Our analysis revealed that the gas-bubble size and graft shape/geometry seem to be relevant clinical factors for GD and rebubbling, whereas descemetorhexis difficulty, degree of graft manipulation, graft overlap, and surgical iridectomy were not associated with an increased risk.

High dupilumab levels in tear fluid of atopic dermatitis patients with moderate-to-severe ocular surface disease.

BACKGROUND: The patho-mechanism of ocular surface disease (OSD) in dupilumab-treated atopic dermatitis (AD) patients remains unclear. The aim of this study is to measure dupilumab levels in tear fluid and serum, and relate these findings to the severity of OSD during dupilumab treatment in AD patients. METHODS: This prospective study included dupilumab-treated moderate-to-severe AD patients who were seen by a dermatologist and an ophthalmologist before the start of dupilumab (baseline), and after 4 and 28 weeks of dupilumab treatment. Dupilumab levels in tear fluid and serum were measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Additionally, a pilot study was conducted to measure dupilumab on conjunctival epithelial cells using flow cytometry and LC-MS/MS. RESULTS: At baseline, 89.6% (n = 43/48) of the patients had OSD, with 50.0% having moderate-to-severe OSD. After 28 weeks of dupilumab treatment, the median dupilumab tear fluid levels were 0.55 mg/L (IQR 0.35-1.31) and 0.29 mg/L (IQR 0.16-0.60) in patients with moderate-to-severe OSD and patients with no or mild OSD, respectively (p = 0.02). Dupilumab levels could be detected on conjunctival epithelial cells of 5 AD patients treated with dupilumab for 4 weeks. CONCLUSION: Patients with moderate-to-severe OSD had higher dupilumab tear fluid levels compared to patients with no or mild OSD, indicating that dupilumab reaches the ocular surface. Dupilumab was also detected in conjunctival cell suspensions and was found to directly bind CD45-conjunctival epithelial cells. This suggests that AD-induced changes of the conjunctival epithelium may play a role in the development of OSD as well as increased local drug availability.

Identification of Risk Factors for Dupilumab-associated Ocular Surface Disease in Patients with Atopic Dermatitis.

This study identified risk factors for the development of dupilumab-associated ocular surface disease in patients with moderate-to-severe atopic dermatitis in a large prospective daily practice cohort. Data from the Dutch BioDay Registry were used to assess the risk of developing dupilumab-associated ocular surface disease, by performing univariate and multivariate logistic regression analyses. A total of 469 patients were included, of which 152/469 (32.4%) developed dupilumab-associated ocular surface disease. Multivariate analysis showed a statistically significant association of the development of dupilumab-associated ocular surface disease with a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at the start of dupilumab (odds ratio 5.16, 95% confidence interval 2.30-11.56, p < 0.001). In conclusion, a history of any eye disease (history of self-reported episodic acute allergic conjunctivitis excluded) combined with the use of ophthalmic medication at baseline was associated with the development of dupilumab-associated ocular surface disease in patients with atopic dermatitis.

Intraoperative Optical Coherence Tomography-Assisted Descemet Membrane Endothelial Keratoplasty: Toward More Efficient, Safer Surgery.

PURPOSE: To evaluate the clinical value of intraoperative optical coherence tomography (iOCT) and prolonged overpressure in Descemet membrane endothelial keratoplasty for surgical safety, efficiency, and outcome. METHODS: All Descemet membrane endothelial keratoplasties performed by the same surgeon from November 2016 through April 2018 at the University Medical Center Utrecht were included, including 6 months of follow-up. The primary outcome was the prevalence of adverse events, and the secondary outcomes included critical decision-making and surgery time. Surgeries that included prolonged (ca. 12 minutes) overpressurization of the globe were classified as group 1, and those without prolonged overpressurization of the globe were classified as group 2. In all cases, iOCT was used to determine the graft orientation, apposition, and assessment of interface fluid. RESULTS: A total of 38 cases were included for analysis. In groups 1 and 2, 7 (43.6%) and 4 (18.1%) adverse events, respectively, were recorded (P = 0.29). Specifically, in groups 1 and 2, 4 and 3 cases, respectively, required rebubbling because of graft dislocation (P = 0.15). In 43% of surgeries, iOCT proved to be of value for surgical decision-making. Surgery time differed significantly between groups 1 and 2 (P < 0.001) and was the result of a shortened pressurization time in group 2. CONCLUSIONS: iOCT provides a direct assessment of the graft orientation and apposition, allowing the surgeon to refrain from prolonged pressurization of the globe after graft insertion. Optimizing the surgical protocol using iOCT can lead to a significant reduction in surgery time without compromising surgical safety or outcome.

[Corneal melting after moving a tropical aquarium]. / Wegsmeltende hoornvliezen na de verhuizing van een zeeaquarium.

BACKGROUND Keeping exotic pets can lead to dangerous situations. We describe an ophthalmological injury caused by Palythoa, an anemone that produces palytoxin when irritated. Palytoxin is one of the most poisonous marine toxins ever described. CASE This case concerns a healthy, 44-year-old man who had rubbed his eyes after setting up a tropical aquarium, which contained sea-anemones among other species. This resulted in bilateral corneal melting, or keratolysis. The injury turned out to be caused by palytoxin. As a consequence, this patient was permanently visually impaired. CONCLUSION The anemone described in this case (Palythoasp) can easily be purchased online with no warnings whatsoever. When working with an aquarium, it is important to know about the species it contains and to wear protective clothing if necessary.

Prospective evaluation of clinical outcomes between pre-cut corneal grafts prepared using a manual or automated technique: with one-year follow-up.

PURPOSE: Posterior lamellar corneal surgery is considered the standard of care for irreversible endothelial cell dysfunction. Pre-cut grafts can be prepared either manually (Descemet stripping endothelial keratoplasty; DSEK) or mechanically (Descemet stripping automated endothelial keratoplasty; DSAEK). We performed a head-to-head clinical comparison between DSEK and DSAEK grafts. METHODS: All DSEK and DSAEK procedures performed by two corneal specialists at the University Medical Center Utrecht from 1 January 2016 through 31 October 2016 were prospectively included. Pre-cut grafts were delivered by two eye banks, which either exclusively prepared the DSEK or DSAEK grafts. Preoperative and postoperative measurements were obtained, and all surgical events and adverse events were recorded. RESULTS: A total of 21 DSEK and 53 DSAEK procedures were included for analysis; the two groups were similar at baseline, with the exception of graft endothelial cell density, which was 2531 ± 67 versus 2748 ± 148 cells/mm2 , respectively (p < 0.001). At the one-year follow-up visit, corrected distance visual acuity and endothelial cell loss were similar between the groups. Mean pachymetry was significantly lower in the DSEK group (521 ± 39 versus 588 ± 59 µm; p < 0.001), whereas the rebubbling rate was significantly higher in the DSEK group (47.6% versus 18.9%; p = 0.001). Finally, three grafts in the DSEK group experienced failure compared to one graft in the DSAEK group (14% versus 1.9%, respectively). CONCLUSION: Manually dissected and microkeratome-dissected grafts performed similarly with respect to vision and endothelial cell loss assessed one year after surgery. The higher incidence of graft failure among manually dissected (i.e. DSEK) grafts may be attributable to reduced relative thickness compared to DSAEK grafts and/or the resulting differences in tissue handling and the surgeon's learning curve.

Combined chlorhexidine and PVP-I decontamination of human donor eyes prior to corneal preservation.

The aim of this study was to report the efficacy of adding chlorhexidine to the protocol for decontamination of human donor globes prior to excision of corneo-scleral rims for future keratoplasty procedures. In 2005, chlorhexidine was introduced by our eye bank as an additional step in the protocol for decontaminating human donor globes. After 5 years, we prospectively evaluated the number of contaminations. Out of 2,891 globes included in our study, 2,663 globes were processed, of which 36 (1.4%) were considered contaminated. Seventeen contaminations (0.6%) were detected by culturing limbal swabs, directly after decontamination, eight (0.3%) by visible discoloration of the culture medium carrying a corneo-scleral rim, and eleven (0.4%) after inoculation of the culture medium on blood agar plates. Importantly, after 4 weeks of incubation, none of the aerobic and anaerobic cultures taken from the secondary 'transport medium' (dextran containing medium used to transport corneal tissue to the transplantation centre) showed microbiological growth. In conclusion, the combined use of 0.02% chlorhexidine and 0.5% povidone-iodine may allow decontamination of donor globes to a level at which the risk of tissue contamination at the time of transplantation is minimized, while corneal viability is preserved.

Back-up procedure for graft failure in Descemet membrane endothelial keratoplasty (DMEK).

AIM: To evaluate the efficacy of a secondary Descemet stripping endothelial keratoplasty (DSEK) as a back-up procedure for managing graft failure after primary Descemet membrane endothelial keratoplasty (DMEK). DESIGN: Non-randomised prospective clinical study. METHODS: A first group of 50 cases with Fuchs endothelial dystrophy underwent DMEK. Two to five weeks after the DMEK, 10 cases showed no corneal clearance, so a secondary DSEK was performed. To evaluate the eyes of these 10 cases, best corrected visual acuity (BCVA) and endothelial cell density at 6 and 12 months were used as outcome parameters. RESULTS: At 6 months after secondary DSEK, 87% of the cases had a BCVA of > or = 20/40 (> or = 0.5) and one eye reached 20/25 (> or = 0.8). Donor DSEK grafts endothelial cell densities averaged 2617+/-152 cells/mm2 before surgery, 1510+/-799 cells/mm2 at 6 months and 1602+/-892 cells/mm2 at 12 months after surgery. CONCLUSION: In the event of a DMEK graft failure, a secondary DSEK may be an effective back-up procedure, as it may give a clinical outcome similar to that after a primary DSEK. Particularly during the surgeon's learning curve, patient information may be provided not only on visual outcomes after DMEK, but also after DSEK. TRIAL REGISTRATION NUMBER: NCT00521898.

Endothelial cell density after descemet membrane endothelial keratoplasty: 1- to 2-year follow-up.

PURPOSE: To evaluate donor endothelial cell density (ECD) after Descemet membrane endothelial keratoplasty (DMEK). DESIGN: Nonrandomized, prospective clinical study. METHODS: From a larger group of patients who underwent DMEK for Fuchs endothelial dystrophy or pseudophakic bullous keratopathy, complete ECD measurements were available of 26 patients with 6 and 12 months of follow-up, of whom 7 also had 24 months of follow-up. RESULTS: For the group with 24 months of follow-up, ECD averaged 2700 (+/- 260) cells/mm(2) before surgery, 2200 (+/- 460) cells/mm(2) at 6 months after surgery, 2050 (+/- 330) cells/mm(2) at 12 months after surgery, and 1780 (+/- 390) cells/mm(2) at 24 months after surgery. For the group with 12 months of follow-up, ECD averaged 2620 (+/- 210) cells/mm(2) before surgery, 1850 (+/- 540) cells/mm(2) at 6 months after surgery, and 1680 (+/- 550) cells/mm(2) at 12 months after surgery. In both groups, the ECD decreased significantly between the preoperative and 6-month measurement (P < .05). CONCLUSIONS: Similar to earlier endothelial keratoplasty techniques, DMEK may be associated with a decrease in donor ECD of approximately 25% in the early postoperative phase.