Topical sirolimus solution for lingual microcystic lymphatic malformations in children and adults (TOPGUN): study protocol for a multicenter, randomized, assessor-blinded, controlled, stepped-wedge clinical trial.

BACKGROUND: Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a "watchful waiting" approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment). METHODS: This is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters. DISCUSSION: Given the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04128722 . Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours - CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33.

Specific features of amoxicillin-associated Drug Reaction with Eosinophilia and Systemic Symptoms syndrome: a nationwide study.

BACKGROUND: Growing evidence indicates that amoxicillin induces herpesvirus replication in vitro. As these play a central pathophysiological role in Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (DRESS), amoxicillin could present with specific DRESS features. OBJECTIVE: To characterize the onset patterns of amoxicillin-associated DRESS. METHODS: All cases of DRESS (Kardaun score ≥4) involving amoxicillin and reported in the French Pharmacovigilance Database between January 1, 2004 and November 30, 2019 were included. Onset circumstances for these cases were categorized considering the onset delay from amoxicillin initiation, and the presence of concomitant medications with a compatible time to onset. RESULTS: A total of 146 probable cases or definite cases of DRESS were included. Three onset circumstances were identified: (i) 'amoxicillin clear culprit' where amoxicillin was the sole suspect drug or when concomitant drugs of compatible time to onset were not reported to cause DRESS (n = 62); (ii) 'amoxicillin possible culprit' in the presence of other potentially culprit drugs in addition to amoxicillin (n = 44) and (iii) 'flare' where amoxicillin, used after DRESS onset, induced flare-up reactions (n = 40). The median time to onset was 5 days (IQR 2-11) in 'clear culprit', and 18 days (IQR 7-26) in 'possible culprit' cases. In 'flare' cases, the median latency between amoxicillin initiation and flare-up reactions was 3 days (IQR 2-5). CONCLUSIONS: Amoxicillin can induce DRESS with a specific early onset and exacerbate DRESS from another drug.