Faculty Bibliography

OBJECTIVE:The goal was to assess the diagnostic performance of three novel autoantibodies (NA) for Sjögren's disease (SjD) by comparing NA prevalence in patients with SjD, other autoimmune rheumatic diseases (ARDs), nonspecific chronic sialadenitis (CS), and controls. METHODS:We identified rheumatology outpatients with confirmed SjD, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), CS, and healthy controls. Subjects underwent serum testing for antibodies to salivary gland protein 1 (SP-1), parotid secretory protein (PSP) and carbonic anhydrase-6 (CA-6). Subjects with SjD, CS and controls also underwent testing of saliva. Receiver operating characteristic (ROC) curve C-statistics along with sensitivity, specificity, positive and negative likelihood ratios were calculated for each serum autoantibody for SjD vs. CS or controls. RESULTS:Among 468 patients screened, 444 were analyzed including cohorts with: SjD (n=149), SLE (n=70), SSc (n=56), RA (n=73), CS (n=31) and controls (n=65). There was no statistical difference (p=0.80) in the presence of one or more NA in the serum of SjD patients compared to subjects with other ARDs, CS, or controls. ROC curves demonstrated poor discriminative ability for SjD versus CS or controls for any positive NA (0.47) or any individual NA (range 0.44 to 0.53). The positive likelihood ratio for having any positive novel autoantibody was 1.04 and 0.83 for SjD vs. CS or controls, respectively. CONCLUSION/CONCLUSIONS:Testing serum for NA demonstrated poor ability to distinguish patients with SjD from control patients or those with CS or other ARDs. This serum autoantibody panel is not likely to be useful as a diagnostic test for SjD.

PURPOSE/OBJECTIVE:To assess the prevalence of novel Sjögren's disease (SjD) autoantibodies in dry eye disease (DED) patients with or without SjD. PARTICIPANTS/METHODS:DED patients were recruited from two tertiary care clinics and categorized by SjD status per the 2016 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria. METHODS:Participants underwent a battery of DED evaluations (unanesthetized Schirmer's test, tear film break up time, corneal and conjunctival vital dye staining), and unstimulated salivary flow rate assessment. Blood specimens were tested for Salivary Protein-1 (SP-1), Carbonic Anhydrase VI (CA VI), and Parotid Secretory Protein (PSP) antibodies. Salivary gland biopsies were offered when necessary to determine SjD status. RESULTS:304 participants completed bloodwork testing and 38 (12.5 %) were diagnosed with SjD. SjD participants had significantly higher positive rates of IgA SP-1 (21 % vs. 10 %; p = 0.049), any SP-1 autoantibody isotype (42 % vs. 24 %; p = 0.02), and a higher mean number of novel autoantibody-positive results (SjD 1.5 (1.1); non-SjD 1.0 (1.0); p = 0.005). The positive labial salivary gland biopsy group had a significantly higher rate of any PSP autoantibody isotype than the negative biopsy group (47 % vs. 22 %; p = 0.04). CONCLUSIONS:SjD participants had significantly higher rates of IgA SP-1, any SP-1 autoantibody isotype, and a higher number of positive novel autoantibodies in general. Participants with positive salivary gland biopsies had a significantly higher prevalence of any PSP autoantibody isotype. Positivity of these tests may indicate the inflammatory nature of dry eye in these patients and could be useful for informing treatment and follow-up.

Neuropathic corneal pain (NCP) is an underdiagnosed ocular disorder caused by aberrant nociception and hypersensitivity of corneal nerves, often resulting in chronic pain and discomfort even in the absence of noxious stimuli. Recently, microneuromas (aberrant growth and swelling of the corneal nerve endings) detected using in vivo confocal microscopy (IVCM) have emerged as a promising biomarker for NCP. However, this process is time-intensive and error-prone, limiting its clinical use and availability. In this work, we present a new NCP screening system based on a deep learning model trained to detect microneuromas using a multisite dataset with a combined total of 103,168 IVCM images. Our model showed excellent discriminative ability detecting microneuromas (AuROC: 0.97) and the ability to generalize to data from a new institution (AuROC: 0.90). Additionally, our pipeline provides an uncertainty quantification mechanism that allows it to communicate when its predictions are reliable, further increasing its clinical relevance.

PURPOSE/UNASSIGNED:We evaluated the efficacy of varenicline solution nasal spray (VNS) in treating dry eye disease (DED) associated with moderate to severe Sjogren's disease and analyzed tear film cytokine levels of patients with DED and Sjogren's disease before and after VNS use. METHODS/UNASSIGNED:This was a pilot study involving a single-center, single-arm investigator-initiated trial. Patients with moderate to severe Sjogren's disease were given VNS 0.03 mg twice daily for 28 days. Patients were assessed on day 0 before VNS use, day 14 and day 28. Clinical exam findings, symptomatology as measured by the eye dryness score, and tear cytokines were assessed at baseline and day 28. RESULTS/UNASSIGNED:Thirty-nine subjects were included. Between day 0 and day 28, there was a statistically significant improvement in the eye dryness score (p = 0.01), corneal staining (p < 0.001), and conjunctival staining (p = 0.04). There was a statistically significant increase in tear secretion by unanesthetized Schirmer's in subjects with a baseline Schirmer's ≤5 mm (n = 35 eyes, p = 0.02) and a non-statistically significant increase in tear secretion in subjects with a baseline Schirmer's of 6-10 mm (n = 16 eyes, p = 0.79). There was a statistically significant decrease in tear film cytokine concentration of IFNγ (p = 0.0003), IL-12p70 (p < 0.0001), IL-17a (p = 0.004), IL-1β (p = 0.007), IL-2 (p < 0.0001), IL-4 (p = 0.01), and TNF-α (p = 0.02), and no significant change in IL-6 (p = 0.56) and IL-10 (p = 0.18). CONCLUSION/UNASSIGNED:Our findings add to existing evidence that VNS improves subjective dry eye symptoms, corneal and conjunctival staining, and tear secretion in a subset of tear-deficient patients, while providing new evidence that VNS reduces concentration of pro-inflammatory cytokines in the tear film. CLINICAL TRIAL REGISTRATION NUMBER/UNASSIGNED:NCT05700422.

PURPOSE/OBJECTIVE:The purpose of this study was to provide relative citation ratio (RCR) benchmark data for cornea and external diseases specialists. DESIGN/METHODS:This is a cross-sectional bibliometric analysis. SUBJECTS/METHODS:Subjects included were fellowship-trained cornea and external diseases faculty at Accreditation Council for Graduate Medical Education-accredited institutions in the United States. METHODS:Academic specialists were indexed using the National Institutes of Health iCite Web site. Publication count, mean RCR score, and weighted RCR score were obtained between October 2022 and January 2023 by examining PubMed-listed publications from 1980 to 2022. Data were compared by sex, career duration, academic rank, and acquisition of a Doctor of Philosophy. MAIN OUTCOME MEASURES/METHODS:The main outcome measures were publication count, mean RCR value, and weighted RCR value. RESULTS:The cohort included 602 specialists from 112 Accreditation Council for Graduate Medical Education-accredited institutions. These clinician-scientists produced highly impactful research with a median publication count of 15 (interquartile ranges 4-41), median RCR of 1.4 (interquartile ranges 0.91-1.88), and median-weighted RCR of 20.28 (5.3-66.69). Both academic rank and career length were associated with greater publication count and RCR values. Male sex was also associated with greater publications counts and RCR scores compared with female faculty. Acquisition of a Doctor of Philosophy was associated with greater publication counts and weighted RCR scores but no difference in mean RCR scores. CONCLUSIONS:Academic cornea and external diseases specialists conduct high-impact research, with a median RCR of 1.4, exceeding the NIH standard value of 1. These data provide RCR benchmark data for the field to inform self, institutional, and departmental evaluations. These results also highlight a significant gender disparity in the field necessitating efforts to increase female representation and ensure equal opportunities.

PURPOSE OF REVIEW/OBJECTIVE:Meibomian gland dysfunction (MGD) is one of the most common disorders encountered by ophthalmologists, and its management can prove challenging for both clinicians and patients. Intense pulsed light (IPL), which has been historically used in the field of dermatology, has emerged as a tool to help improve meibomian gland function. The goal of this review is to assess the clinical efficacy, utility, and safety of IPL for the treatment of MGD. RECENT FINDINGS/RESULTS:In recent randomized controlled trials, IPL has been shown to improve meibomian gland function, and subsequently tear film quality and dry eye symptoms. The mechanism of action still remains unclear. Recent literature suggests that IPL may also be used in conjunction with other therapies, such as meibomian gland expression, low-level light therapy, and thermal pulsation. Careful attention should be placed on each patient's Fitzpatrick skin type, as well as protecting the ocular structures to reduce the risk of adverse effects. Cost, accessibility, as well as a limited duration of efficacy may be drawbacks. SUMMARY/CONCLUSIONS:There is significant evidence supporting that IPL may be used as a potential well tolerated and effective treatment for MGD, though there are certain caveats regarding its long-term efficacy, accessibility, and cost.

INTRODUCTION/BACKGROUND:Cenegermin is approved for treatment of neurotrophic keratopathy (NK) and has been studied in patients with stage 2 or 3 NK. This study evaluated the efficacy and safety of cenegermin in adults with stage 1 NK. METHODS:This was a phase IV, multicenter, prospective, open-label, uncontrolled trial. Adults with stage 1 NK (Mackie criteria) and decreased corneal sensitivity (≤ 4 cm) received 1 drop of cenegermin 20 mcg/ml in the affected eye(s) 6 times/day for 8 weeks with a 24-week follow-up. RESULTS:Of 37 patients, corneal epithelial healing was observed in 84.8% (95% confidence interval [CI] 68.1-94.9%; P < 0.001) at week 8; 95.2% (95% CI 76.2-99.9%; P < 0.001) of those patients remained healed at the end of the 24-week follow-up (week 32). At week 8, 91.2% (95% CI 76.3-98.1%; P < 0.001) of patients experienced improved corneal sensitivity; this improvement was observed in 82.1% (95% CI 63.1-93.9%; P < 0.001) of patients at week 32. Mean best-corrected distance visual acuity change from baseline at week 8 was - 0.10 logMAR (standard deviation [SD], 0.15; 95% CI - 0.16 to - 0.05; P < 0.001) and at week 32 was - 0.05 logMAR (SD, 0.16; 95% CI - 0.11 to 0.01; P = 0.122). At weeks 8 and 32, 15.2% (95% CI 5.1-31.9%; P < 0.001) and 10.7% (95% CI 2.3-28.2%; P < 0.001) of patients, respectively, had a 15-letter gain from baseline. At least one adverse event (AE) was reported by 73.0% and 45.7% of patients during the treatment and follow-up periods, respectively. The most common treatment-related, treatment-emergent AEs were eye pain (37.8%), blurred vision (10.8%), and eyelid pain (8.1%); these were mostly mild or moderate and were only reported during the treatment period. CONCLUSIONS:These results support the potential use of cenegermin for treating patients with stage 1 NK, and future confirmatory studies would be beneficial to elaborate on these findings. TRIAL REGISTRATION/BACKGROUND:DEFENDO; NCT04485546.

PURPOSE/UNASSIGNED:This study was to assess corneal epithelial thickness (CET) in patients with Sjogren's disease (SjD). METHODS/UNASSIGNED:A retrospective chart review was conducted of SjD patients from September 2021 to January 2022. Patient demographics, unanesthetized Schirmer's test, serologic markers, and symptoms as measured by the Ocular Surface Disease Index (OSDI) were reviewed. Epithelial thickness from both eyes was measured using anterior segment OCT at the central 3mm and concentric 5mm, 7mm, and 9mm zones for the superior, temporal, inferior, and nasal corneal quadrants. Associations between corneal epithelial thickness with patient demographics, clinical characteristics, and symptoms were evaluated using regression models. RESULTS/UNASSIGNED:Fifteen SjD patients (100% female) were included with a mean age of 58.4 years. Patients with Sjogren's disease had a significantly thinner superior corneal epithelium compared to the inferior epithelium (mean 47.7mm vs 53.1mm, p = 0.001). The epithelial thickness mean standard deviation (MSD) was significantly inversely correlated with the unanesthetized Schirmer test (r=-0.39, p = 0.005), suggesting that an overall variability of CET correlates with decreased aqueous tear production. SS-A, SS-B, ANA, and RF positivity were not associated with any measures of CET. CONCLUSION/UNASSIGNED:This pilot study suggests that there is significant superior versus inferior thinning of corneal epithelium in Sjogren's patients. There was a significant correlation between variability of corneal epithelial thickness and decreased tear production in Sjogren's patients. Further larger studies are needed to understand the relationship of CET with objective and subjective measurements of ocular surface disease.

PURPOSE/UNASSIGNED:We evaluate the treatment effect of OC-01 (varenicline solution) nasal spray (VNS) in dry eye disease (DED) subjects from two randomized trials who self-reported autoimmune disease (AID). PATIENTS AND METHODS/UNASSIGNED:Post hoc subgroup analysis of subjects reporting a history of AID from the integrated OC-01 VNS 0.03 or 0.06 mg and vehicle control (VC) treatment groups of the ONSET-1 and ONSET-2 trials. Mean change in Schirmer test with anesthesia score (STS, mm) and Eye Dryness Score (EDS) from baseline to 28 days was compared between OC-01 VNS and VC groups. Consistency of treatment effect in subjects with and without AID was evaluated using treatment-subgroup interaction terms in ANCOVA models for mean changes from baseline STS and EDS, and in a logistic regression model for proportion achieving ≥10 mm STS improvement. RESULTS/UNASSIGNED:Of the 891 participants, 31 reported comorbid AID. In all models, the treatment-subgroup interaction terms were not significant (p>0.05), indicating consistency of therapeutic effect of OC-01 VNS in subjects with and without AID. In subjects with AID, the treatment difference for STS was 11.8 mm and -9.3 for EDS and difference for proportion of subjects with ≥10 mm STS improvement was 61.1%. The most common adverse event was sneeze (82-84%), graded as mild by 98% of subjects. CONCLUSION/UNASSIGNED:OC-01 VNS demonstrated consistency in improving both tear production and patient-reported symptoms in subjects with AID, consistent with pivotal ONSET-1 and 2 trial results. Further investigation is warranted, and results may further support use of OC-01 VNS for DED in AID patients.