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

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.