News in Review C O M M E N TA R Y A N D P E R S P E C T I V E

OCULOPLASTICS come—a reduction in prop­

New Drug Targets tosis of 2 mm or more—in
83% of the treated patients
Challenge of Thy- at 24 weeks. This compared
roid Eye Disease to 10% in the placebo group
(p < 0.001).
Early disease improve-
FOR THE FIRST TIME, A MEDICATION ment. More than half of
has been approved that can stop and the treated patients (56%)
modify the debilitating and sight- reached this study marker
threatening pathology of thyroid eye in as few as six weeks, and
disease. Teprotumumab (Tepezza) they continued to improve
gained expedited approval from the through 24 weeks, said Dr.
FDA in January. Douglas, at Cedars-Sinai
The drug is a fully human monoclo- Medical Center in Los
nal antibody inhibitor of the insulin- Angeles.
like growth factor I receptor (IGF-IR), Additional findings. The EFFECT OF TREATMENT. A patient with thyroid
which orbital fibroblasts and B and T study also found significantly eye disease before and after treatment with
cells overexpress in Graves disease and greater improvements in the teprotumumab. The drug was administered
thyroid eye disease (TED).1 treated patients’ secondary intravenously once every three weeks during
TED “is really burdensome for outcomes (p ≤ 0.001 for all), the 24-week trial; evaluation of effectiveness
patients. It impairs their vision, in ad- the researchers reported. is continuing beyond that point.
dition to causing their facial disfigure- These clinical measures in-
ment and double vision. Teprotumu­ cluded overall response (78% of treated spasms (32%), alopecia (20%), nausea
mab is the first medication that reverses patients vs. 7% of the placebo group); (15%), fatigue (12%), and diarrhea and
all of those things, and with mild to Clinical Activity Score of 0 or 1 (59% headache (both 10%), the researchers
moderate side effects,” said Raymond S. vs. 21%); the mean change in proptosis reported. There were two serious ad-
Douglas, MD, PhD, one of the principal (−3.32 mm vs. −0.53 mm); and diplo- verse events: an infusion reaction that
investigators in OPTIC, the study that pia response (68% vs. 29%). resolved with corticosteroid treatment,
led to the FDA’s approval. “My patients In addition, improvement was and pneumothorax that was considered
are just thrilled. This has been a real noted in a 16-item quality of life (QoL) unrelated to the drug.
game-changer.” questionnaire specific to Graves disease Mechanism of action. Previous
OPTIC results. Earlier this year, re- (mean change of 17.28 points in treated research has shown that teprotumumab
searchers published results of OPTIC, a patients vs. 1.80 points in the placebo blocks the pathologic immune responses
phase 3 trial.2 In this study, 41 patients group). This self-administered ques- of active TED by reducing signaling by
with TED received a total of eight in- tionnaire includes questions on visual both IGF-IR and thyrotropin receptors.1
Raymond S. Douglas, MD, PhD

travenous infusions of teprotumumab, and psychosocial functioning; a mean Unchecked, the activated receptors lead
spaced three weeks apart. They showed change of at least 6 points is considered to the formation of physical and func-
significantly greater improvement in clinically significant. tional molecular complexes that trigger
their disease at 24 weeks than did the Side effects. Adverse events associ- hyaluronan accumulation and expres-
42 participants who received placebo. ated with the drug were mild to moder- sion of cytokines, which in turn cause
The trial achieved its primary out- ate in most cases and included muscle inflammation, edema, and expansion of

EYENET MAGAZINE   •   19
extraocular muscle and adipose tissue, PUBLIC HEALTH an eye examination, with the use of a
Dr. Douglas said.
It is not clear how long the drug’s
Rapid Survey of penlight, and a fundus exam via direct
ophthalmoscopy. The exams are held
ability to inhibit the receptors will per- Blindness: RAAB in the participant’s home. “The major
sist beyond 24 weeks, Dr. Douglas said.
The drug manufacturer is conducting a
Method Accurate advantages of this method are its sim-
plicity, rapid conduct, lower cost, and
postmarketing study intended to help use of standardized assessments,” said
clarify this issue, he said. RESEARCHERS LED BY A TEAM BASED Dr. Lam.
A new paradigm? Looking ahead, in Hong Kong set out to assess the diag- In the field. This study involved
the approval of teprotumumab rep- nostic accuracy of the survey method 2,145 people aged 50 years and older
resents “a pivotal moment” in the treat- known as RAAB (for rapid assessment in 45 villages located in the Chaonan
ment of TED, Dr. Douglas said. “I con- of avoidable blindness). They found Region of southern China. All partici-
sider this a generational medication. that RAAB has high diagnostic accura- pants were examined according to the
I think our fellows who are training cy for the detection of the prevalence RAAB protocol; they were then offered
now will be hard-pressed to remember of blindness, visual impairment (VI), a more extensive examination in a
the times before teprotumu­mab came and VI due to cataract.1 “RAAB is a mobile eye clinic that was set up in a
on the market for TED, much like the valuable alternative in areas where cost village center on the same day.
times before biologics came on the and logistical factors prohibit the use of Exams in the mobile clinic included
market for rheumatoid arthritis” conventional epidemiologic surveys,” standardized visual acuity (VA) tests
and revolutionized treatment for said coauthor Dennis S.C. Lam, MD, using logMAR charts, refraction, slit-
that disease. —Linda Roach FRCOphth, at the Chinese University of lamp biomicroscopy, and a dilated
Hong Kong. fundus exam with a binocular in­dir­-
1 Smith TJ, Janssen JAMJL. Endocr Rev. 2019; A note on RAAB. This method is ect ophthalmoscope. Blindness and
40(1):236-267. endorsed by the World Health Orga- economic blindness were defined as
2 Douglas RS et al. N Engl J Med. 2020;382(4): nization for population-based surveys having VA in the better-seeing eye of
341-352. of blindness and VI in people aged 50 <20/400 and <20/200, respectively.
Relevant financial disclosures—Dr. Douglas: years and older in a specific geograph- VI was defined as having VA of <20/60
Horizon Therapeutics: C. ic area. Each RAAB survey involves in the better eye. The primary cause of

REFRACTIVE refractive cylinder up to –3.0 D.

SMILE Approval Expanded At 12 months, 95.3% of all eyes were within 0.50 D
of emmetropia, 89.0% achieved uncorrected distance
visual acuity (UDVA) of 20/20 or better, and 99.0% had
THE RESULTS OF A PIVOTAL CLINICAL TRIAL ARE OUT,
UDVA of 20/40 or better. In addition, MSE went from
paving the way for expanded FDA approval of small
–5.39 at baseline to –0.01 D, and average refractive
incision lenticule extraction (SMILE) for the correction
cylinder went from –1.53 D to 0.18 D.
of myopia and astigmatism.1
Complications. Three intraoperative events were
Since 2011, SMILE has evolved from a treatment for
associated with difficult lenticule removal and resultant
myopia to one for myopia with astigmatism up to –0.50
cap tear. All resolved without sequelae at postoperative
D—and now to one for correction of myopia with or
day one, and patients completed the study with UDVA
without astigmatism up to –3.0 D. The flapless treat-
of 20/20 or better. Eight adverse events occurred post-
ment, which reshapes the cornea using only a femto-
operatively; none had significant consequences.
second laser, proved safe and effective and demon-
Looking ahead. SMILE still does not address hypero-
strated predictable correction over the trial duration
pia, mixed astigmatism, or very high levels of astigma-
of 12 months, and patients achieved refractive stability
tism, Dr. Dishler noted. “But I would estimate that well
between three and six months.
over 90% of patients in search of refractive vision cor-
In the approved range, the procedure can be recom-
rection could be served by this procedure.” He noted
mended to patients as an alternative method of refrac-
that the U.S. military is currently completing a SMILE
tive vision correction, said Jon G. Dishler, MD, at Dishler
study, and he added, “a procedure with rapid recovery
Laser Institute in Greenwood Village, Colorado.
without the limitations of a corneal flap is appealing to
The study. Between March 2015 and July 2016, 357
both patients and doctors.” —Miriam Karmel
patients (357 eyes) underwent SMILE in one eye. (Most
fellow eyes received excimer laser treatment.) Preoper- 1 Dishler JG et al. Ophthalmology. Published online Jan. 14,
ative sphere ranged between –1.00 and –10.00 D, with 2020.
manifest spherical equivalent (MSE) up to –11.50 D and Relevant financial disclosures—Dr. Dishler: Carl Zeiss: C.

20  •   A P R I L 2020
 blindness and VI was defined according in the top decile were at a
to the cause of VI in the participant’s 15-fold in­creased risk of
better eye. advanced glaucoma and
Results. Of the 2,145 participants 21.5-fold increased risk of
who were screened with RAAB, 327 advanced high-tension glau-
(15.2%) refused to attend the mobile coma, relative to those in the
eye clinic, and two (0.1%) were unable bottom decile. What’s more,
to undergo the more in-depth exam- those in the highest decile
ination. reached an absolute risk for
Sensitivities ranged from 89.5% to glaucoma 10 years earlier
90.3%, and specificities ranged from than did participants at the
97.7% to 99.3% for detection of differ- bottom.
ent levels of VI—and these results pro- “Traditionally, genetic
vide “strong support for the diagnostic testing in glaucoma has
accuracy of the RAAB methodology for focused on rare mutations POAG RISK. The risk calculator was found to be
the detection of blindness and VI,” the such as the Gln368Ter vari- predictive of a number of factors, including earlier
researchers wrote. ant in the MYOC gene. Our age of glaucoma diagnosis, increased likelihood
With regard to blindness and VI work provides the utility of of disease progression in early-stage disease, and
owing to cataract and refractive error, mass screening,” said Xikun greater need for incisional surgery in advanced
RAAB was highly accurate for cataract Han, MSc, at the QIMR disease.
but less so for refractive error. Berghofer Medical Research
Limitations. The authors noted that Institute in Brisbane, Australia. diagnosis. Individuals in the top 10%
it is possible that their results over- “Also, importantly, the prediction of PRS distribution were, on average,
estimate the impact of cataract and can be done before damage begins, diagnosed seven years earlier than were
underestimate those of glaucoma and and people who are stratified into the those in the bottom 10%.
posterior segment diseases on the prev- high-risk group can take the necessary In addition, those in the highest
alence of blindness and VI. Nonethe- precautions.” decile had twice as many family mem-
less, they said, the RAAB methodology A new approach. Unlike existing bers affected by glaucoma as did those
“remains an important tool for inform- risk calculators, which rely on general at the bottom. Moreover, a higher PRS
ing research and policy for blindness information such as age and intraoc- was associated with a greater need for
prevention.” —Arthur Stone ular pressure (IOP), the PRS is based trabeculectomy.
on an individual’s profile of all known Room for improvement. The
1 Zhang XJ et al. Am J Ophthalmol. Published risk loci for glaucoma. In this study, researchers noted that their risk
online Dec. 14, 2019. the researchers identified 107 new gene calculator needs to be tested in other
Relevant financial disclosures—Dr. Lam: None. variants associated with glaucoma that populations­—and that it could be
increase the individual’s risk of devel- evaluated prospectively in a longitu-
oping POAG. dinal intervention study. In an effort
GLAUCOMA
To create the PRS, the researchers to improve the PRS’ predictive power,
Genetic Test identified vertical cup/disc ratio risk the researchers hope to collect DNA
Outlines POAG variants from optic nerve photographs
of 67,040 participants in the U.K.
from 20,000 people with glaucoma or
a family history of glaucoma. “While a
Risk Categories Bio­bank, which holds genotyping on more accurate PRS is unlikely to move
500,000 volunteer participants between high-risk individuals to a low-risk cat-
A MULTICOUNTRY TEAM HAS DE- the ages of 40 and 69. Thus, this investi- egory, the current PRS is less accurate
veloped a genetic test that stratifies gation is the largest genome-wide asso- for those in the moderately high-risk
in­div­iduals with glaucoma into risk ciation study of optic nerve morphol- category,” Mr. Han said. “An improved
groups.1 The researchers’ polygenic risk ogy to date. In addition to information genetic test will help split up this group
score (PRS), or genetic profiling strategy, from the U.K. Biobank, they used other more effectively, enabling more precise
determines how likely a patient is to large biobanks to provide risk variants guidance to be given to a larger number
develop primary open-angle glaucoma for IOP and POAG. of people.” —Miriam Karmel
(POAG)—and indicates which patients Age and family history mattered.
should be offered early treatment and/ The PRS, which could be approved for 1 Craig JE et al. Nat Genet. Published online Jan.
or monitoring. general use in one or two years, was sig- 20, 2020.
The PRS predicted that individuals nificantly associated with age at POAG Relevant financial disclosures—Mr. Han: None.
Xikun Han, MSc

See the financial disclosure key, page 10. For full disclosures, including category descriptions, view this News in Review at aao.org/eyenet.

EYENET MAGAZINE   •   21