Oral doxycycline shows improvement of Thyroid-Associated Ophthalmopathy -related symptoms: Study

Thyroid-associated ophthalmopathy (TAO), also known as
Graves orbitopathy, is a sight-threatening immune inflammatory disease that
occurs in almost 50% of patients with Graves disease. Mild TAO accounts for
more than 70% of all cases of TAO and its prevalence is increasing. Patients
with mild TAO often experience severe cosmetic disfigurement, photophobia,
tearing, and blurred vision, negatively impacting physical and psychological
health.

Early intervention from endocrinologists and
ophthalmologists is advised to alleviate mild TAO-associated signs and
symptoms, and to prevent deterioration to moderate-severe TAO or even
blindness. Currently, topical treatments such as artificial tears and ointments
are the main interventions for mild TAO, which do not address the underlying
cause of disease. Glucocorticoids, immunosuppressants, biologics, orbital
radiotherapy, and rehabilitative surgery are not commonly recommended for mild
TAO due to severe adverse effects and potential risks.

Tetracyclines, including doxycycline, have nonantibiotic
activities via reduction of proinflammatory cytokines and inhibition of
T-cells, and have demonstrated anti-inflammatory and immunomodulatory effects
in multiple studies at doses ranging from 40mg to 200mg daily. Doxycycline has
been effective in treating immune-inflammatory disorders, including rosacea,
bullous pemphigoid, multiple sclerosis, and rheumatoid arthritis.

In this study, Yuan Pan and team aimed to investigate the
efficacy of doxycycline, 50 mg daily, in patients with mild TAO. E The results
of this study indicate that oral doxycycline, 50 mg daily, resulted in greater
improvement of TAO-related symptoms at 12 weeks compared with placebo in
patients with mild TAO.

In this placebo-controlled multicenter randomized
double-masked trial, 148 patients were assessed for eligibility. After
exclusions (patients who were pregnant or lactating, had an allergy to
tetracyclines, or had uncontrolled systematic diseases), 100 patients with mild
TAO (orbital soft tissue affected mildly) at 5 centers in China were enrolled
from July 2013 to December 2019 and monitored for 12 weeks. Participants were
randomly assigned 1:1 to receive doxycycline (50 mg) or placebo once daily for
12 weeks.

The primary outcome was the rate of improvement at 12 weeks
compared with baseline assessed by a composite indicator of eyelid aperture
(reduction 2 mm), proptosis (reduction 2 mm), ocular motility (increase 8°),
and Graves ophthalmopathy-specific quality-of-life (GO-QOL) scale score
(increase 6 points). Adverse events were recorded.

A total of 50 participants were assigned to doxycycline and
50 to placebo. Medication compliance was checked during participant interviews
and by counting excess tablets.

At week 12, the improvement rate was 38.0% (19 of 50) in the
doxycycline group and 16.0% (8 of 50) in the placebo group (P = .01) in the
intention-to-treat population.

The per-protocol sensitivity analysis showed similar results
(P = .009).

No adverse events other than 1 case of mild gastric acid
regurgitation was recorded in either group.

In this multicenter randomized double-masked placebo controlled
trial, treatment with doxycycline over 12 weeks showed a higher improvement
rate of mild TAO signs and symptoms compared with placebo. These findings
suggest that doxycycline may be an effective treatment for mild TAO, although
the relatively short-term duration of follow-up and small sample size would
warrant longer-term studies with larger cohorts to confirm efficacy for
patients similar to those enrolled in this trial. Doxycycline is relatively
affordable and is a promising therapy to tackle the public health burden
associated with TAO.

During 12 weeks of this trial, there was only 1 adverse
event of reversible mild gastric acid regurgitation in the doxycycline group.
The relatively low-dose and short-term administration of doxycycline and
protective measures to lower adverse events may account for the low adverse
event rate in this trial.

There is an abundance of evidence supporting the use of
doxycycline in patients with mild TAO. The early pathogenic stage of TAO is
characterized by infiltration of immune and inflammatory cells and molecules
into orbital soft tissues, leading to a wide array of responses mediated by
lymphocytes, matrix metalloproteinases, and cytokines. Inhibiting these complex
immune-inflammatory processes is key to treating TAO. Doxycycline has been
shown to target these processes, notably by inhibiting proliferation and
activation of lymphocytes and downregulating the proinflammatory cytokines
mentioned above. The increased rate of improvement by doxycycline in our trial
builds on the literature that doxycycline is involved in suppressing immune inflammatory
processes.

In this placebo-controlled multicenter randomized
doublemasked trial, doxycycline, 50 mg taken orally once daily over 12 weeks,
was demonstrated to have superior efficacy compared to placebo, measured by the
rate of improvement via the composite indicator of eyelid aperture, proptosis,
ocular motility, and GO-QOL at week

Source: Yuan Pan,
Yu-Xi Chen, Jian Zhang; JAMA Ophthalmol.

doi:10.1001/jamaophthalmol.2022.377

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