Abstract
Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.
Highlights
Hemorrhagic Telangiectasia (HHT) is a rare but ubiquitous hereditary vascular disease, with an estimated prevalence of 1/5000 to 1/8000
These genes both intervene in the BMP9/ALK1/ENG/SMAD pathway in endothelial cells, and it has been hypothesized that HHT is related to disequilibrium in the angiogenic balance, resulting from an increase in the factors involved in the activation phase and a decrease in those involved in the maturation phase of angiogenesis [2]
Preclinical models have shown that injections of tacrolimus decreased the number of retinal arteriovenous malformations induced by BMP9/10-immunodepletion in a mouse HHT model [11]. These results suggest that the mechanism of action of FK506 involves a partial correction of endoglin and ALK1 haplosufficiency, and may be an interesting drug for use in patients with HHT
Summary
HHT is a rare but ubiquitous hereditary vascular disease, with an estimated prevalence of 1/5000 to 1/8000. The ENG (endoglin) and ACVRL1 encoding ALK1 (activin receptor-like kinase 1) genes are responsible for 90% of cases of HHT [1]. The recognized manifestations of HHT are all due to abnormalities in vascular structure. Nosebleeds are the most frequent complication in HHT and may occur as often as several times per day They are spontaneous, very variable in time and from one patient to another, but recurrent in 90% of patients. They can be associated with severe anemia in 2–10% of patients, and blood transfusions are required sometimes or regularly (every 2 or 3 weeks) in 2–5% of patients [4]. These nosebleeds significantly reduce quality of life [5]
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