Teprotumumab for TED: early response not required for benefit
Ugradar S et al.
Review: This is a follow-up analysis to the initial phase 2 and phase 3 trials, previously published in The New England Journal of Medicine, comparing the effectiveness of teprotumumab (Tepezza), a monoclonal antibody against insulin-like growth factor 1 receptor (IGF-1R) that is critical in the pathogenesis of thyroid eye disease (TED), against a placebo in patients with active TED. Teprotumumab has been shown to be more effective than placebo in reducing proptosis, diplopia and inflammation and led to a rapid reduction in clinical activity score (CAS) in approximately 50% of trial patients. Teprotumumab is now approved for TED treatment in the US.
This post-hoc analysis included 48 patients (24 each in treated and placebo groups), who did not show a reduction ≥2mm in proptosis halfway through the treatment protocol, which were eight infusions of teprotumumab given intravenously at three-weekly intervals. While none of the patients in the placebo group had clinically significant improvement in proptosis at 12 weeks and 24 weeks, 15 patients (63%) in the teprotumumab group demonstrated a reduction in proptosis ≥2mm at 24 weeks, even though they were deemed not to have responded at 12 weeks. With regard to CAS, 11 out of 24 patients (46%) in the placebo group had a clinically significant reduction (≥ 2 points) by 12 weeks and 10 patients achieved this at 24 weeks. In comparison, 22 out of 24 patients (92%) in the treatment group had this reduction and all patients responded by 24 weeks. Three out of 15 patients (20%) with diplopia in the placebo group demonstrated improvement in diplopia score by 12 weeks and four patients (27%) achieved this by 24 weeks. In comparison, 12 out of 22 patients (55%) with diplopia in the treatment group responded by 12 weeks and 16 patients (73%) achieved this by 24 weeks.
Comment: This retrospective study suggests that clinical response time to teprotumumab varies and a lack of initial clinical response does not preclude a significant response later if treatment is continued. Nevertheless, the majority of patients in the treatment group had already demonstrated some response to teprotumumab by 12 weeks, as evident in the reductions in CAS and diplopia scores. It should also be noted that TED is a self-limiting disease and some patients in the placebo group also demonstrated a reduction in CAS, although none showed a reduction in proptosis. It remains unclear how teprotumumab compares to intravenous methylprednisone in the treatment of active TED and whether it should be used instead of, or in addition to, methylprednisone. The current cost of teprotumumab (around US$343,000 for a six-month course) is also prohibitive. It is not available in Australasia at present. More studies on this medication may clarify its role in the treatment paradigm of TED.
Association of public health measures during the Covid-19 pandemic with the incidence of infectious conjunctivitis
Lavista Ferres et al.
JAMA Ophthalmol. Published online 18 November 2021
Review: The potential effect of Covid-19-associated public health measures on the epidemiology of infectious conjunctivitis was studied in two ways. Firstly, the researchers appraised Google trends data on search terms associated with conjunctivitis, corneal abrasions and floaters between 2016 and 2021, as well as community mobility reports between Feb 2020 and Jan 2021 in both the US and Australia. Secondly, the researchers accessed electronic health records pertaining to emergency department encounters at the University of Washington in Seattle from 2015 to 2021, comparing monthly diagnoses of non-allergic conjunctivitis, corneal abrasions and posterior vitreous detachments. These data were analysed with a counterfactual model of a time series observed before and after social-distancing measures were implemented, which provided a Bayesian time-series estimate of the outcome had no lockdowns occurred.
While there were similar findings in online search interest from Jan 2016 to Dec 2019, the mean search interest for conjunctivitis abruptly decreased in March 2020 and remained low throughout the year, even when seasonal variations were taken into account. There was a notable exception in Nov 2020, at the time of the US vice presidential debate, when then US vice president Mike Pence appeared to suffer from conjunctivitis. There was no difference in mean search interest for corneal abrasions and floaters. Based on the Bayesian model, the researchers quantified the decrease in conjunctivitis related online search activity at 32.4%, which occurred 2-3 weeks after Covid-19 restrictions were instigated. Similar results were seen in Australia, with a 40.2% decline in search interest.
Out of 1,156 emergency encounters for non-allergic conjunctivitis at the University of Washington, the mean number of presentations was 17.1 per month prior to March 2020 and 8.4 per month after March 2020. Even after controlling for a decline in total ED encounters, Bayesian modeling suggested a decrease in emergency department encounters by 37.3%, whereas the diagnoses of PVD and corneal abrasion did not show a decline with the same modeling.
Comment: This study suggests that Covid-19-related public health measures appear to have reduced the incidence of infectious conjunctivitis in the community, as demonstrated in a reduction in online search activity as well as emergency department presentations. There was no corresponding reduction in non-communicable ophthalmic presentations and search activities.
While it may seem obvious that social distancing and hand-hygiene measures would reduce the likelihood of contracting infectious conjunctivitis in the community, this is the first study to quantify this decline during the current pandemic and sets out a methodology to measure the effect of public health measures by combining search metrics and mobility data that are widely available.
Smartphone use and refractive error in teenagers: The Myopia.app study
Enthoven CA et al.
Ophthalmology, 128(12), 2021
Review: The Myopia.app is a smartphone application which measures the duration of smartphone use and face-to-screen distance, and asks questions on outdoor exposure twice weekly. Smartphone exposure is calculated as both mean hours per day and the number of episodes of uninterrupted use in excess of 20 minutes.
The study included 525 Dutch patients aged 12-16 years who underwent cycloplegic refraction and ocular biometry measurements. Only 272 participants had valid smartphone and ocular measurements for analyses. Smartphone use was measured over a five-week period, with days when the phone was used less than five minutes or over five hours (given the likelihood of the phone being left on unintentionally) excluded. Face-to-screen distance was measured with the front camera.
Myopia prevalence (defined as spherical equivalent less than -0.5D) was 18.9% in this cohort. The teenagers spent on average 3.71 hours on their smartphone on school days and 3.82 hours on non-school days, with average face-to-screen distance of 29.1cm. Participants with myopia had longer axial length as well as larger axial length to corneal radius ratio, but no difference to non-myopic subjects with regard to smartphone use, continuous use, face-to-screen distance and outdoor exposure.
Linear regression analysis showed that continuous smartphone use during school days was associated negatively with spherical equivalent and higher axial length to corneal radius ratio, with outdoor exposure also associated positively with spherical equivalent (hence outdoor exposure was associated negatively with myopia), but other associations did not reach statistical significance.
Comment: While this study demonstrated some association between continuous smartphone use and myopia, and a possible protective effect from outdoor activities, it is substantially limited by its design as a cross-sectional study which measures smartphone exposure and ocular parameters at the same time. As such, causality cannot be proven and the effect of previous smartphone usage on current refraction (as well as current usage on future refraction) is unknown. Much of the data was discarded by the researchers given unrealistic measurements and low participation rates, which may have led to inconclusive results. Nonetheless, it may indeed be of concern that teenagers in Europe are now spending almost four hours per day on their smartphones. The authors recommended limiting smartphone use, which was not entirely supported by their data, but more robust work on this subject is definitely indicated given the increased morbidity and risk to vision associated with pathological myopia.
Dr Kenneth Chan is a consultant ophthalmologist practicing in Wellington, with special interests in oculoplastics and dry eye disease. He is the current treasurer and Qualification and Education Committee chair for the New Zealand branch of RANZCO.