Novel compound heterozygous mutations of the COL7A1 gene in a Chinese patient with recessive dystrophic epidermolysis bullosa pruriginosa and digestive symptoms successfully treated with tofacitinib

Dystrophic epidermolysis bullosa pruriginosa (DEBP) is characterized by intense pruritus and lichenoid, nodular prurigo-like lesions. The intractable itching often decreases the life quality of DEBP patients. Current effective treatments for DEBP are limited. Here, we reported a Chinese recessive DEBP (RDEBP) patient who carried novel COL7A1 compound heterozygous mutations with digestive symptoms improved in pruritus and mucocutaneous findings after treatment with tofacitinib. A 27-year-old Chinese man had developed erythema, with mechanically induced blisters all over the body since birth. He also had intense itching from childhood. Odynophagia and dysphagia (grade I)1 were present at 7 years old. He visited the gastroenterology department due to worsening dysphagia (grade III) 1 year ago. Upper gastrointestinal endoscopy showed esophageal stenosis, and endoscopic esophageal dilatation was performed (Supporting Information Figure S1a–c). Dysphagia was relieved postoperatively (grade I). Mutation analysis revealed the patient carried compound heterozygous mutations in the COL7A1 gene: two splicing mutations, c.4980+2T>G (father was a heterozygous carrier) and c.4198-1G>A (mother was a heterozygous carrier) (Supporting Information Figure S2a,b). The patient was diagnosed as RDEBP. Five months ago, he came to our department again since itching was preventing him from falling asleep. His eating status had deteriorated (dysphagia of grade II) accompanied with obvious odynophagia. Nasopharyngoscopy showed a hypopharynx ulcer (Supporting Information Figure S3a,b). As the itching seriously affected him, we treated him with tofacitinib 5 mg twice daily. Within 4 weeks of therapy, the patient reported a marked improvement not only in pruritus, but also in skin lesions. During the subsequent 8 weeks, his condition continued to improve. On his latest visit at week 28 (March 2, 2023), he showed a stabilized general condition (Figure 1a–d). No erosions were observed on the esophagus (Supporting Information Figure S1d–f) or throat (Supporting Information Figure S3c,d), and no adverse events were reported during the treatment. RDEBP is a rare form of dystrophic epidermolysis bullosa (DEB) caused by COL7A1 gene mutation. The c.4980+2T>G and c.4198-1G>A identified in this patient affected splicing, which is predicted to cause frameshift results (Supporting Information Figure S4). Both variants were novel, absent in the gnomAD database (v2.1.1), and classified as pathogenic. The patient experienced significant relief of pruritus and also did not experience odynophagia (experienced two or three times a month before treatment) during the 28-week treatment period of tofacitinib. Taken together, Janus kinase inhibitors (JAKi)–tofacitinib may be an effective clinical management for RDEBP-related symptoms. Dysregulation of itch-related mediators interleukin 13 receptor subunit ajpha 1 IL13RA and interleukin 4 receptor, and upregulation of helper T cell (Th) 1, Th2 and Th17 cytokines, including interleukin (IL)-1b, -2, -6, tumor necrosis factor (TNF)-β, and interferon (IFN)-γ, have been reported in DEB patients.2-4 Tofacitinib could block out the downstream signal transduction for IL-2, -4, -6, -7, -9, -15, and IFN-γ, and thus may alleviate pruritus and inflammation of DEB patients. Moreover, JAKi could also inhibit the direct connection between pruritus-related factors like IL-31, TNF-α, and skin sensory neurons,5 and thereby also alleviate itching. Since there are no effective drugs for epidermolysis bullosa at present, the rapid development in small molecule drugs may provide an option for patients with epidermolysis bullosa to get maximum clinical benefits. More studies should be performed to verify this finding. This work was supported by the 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYJC18003) and the postdoctoral fund of Sichuan University (No. 2023SCU12065). None declared. Consent for the publication of recognizable patient photographs or other identifiable material was obtained by the authors and included at the time of article submission to the journal, stating that the patient gave consent with the understanding that this information may be publicly available. Figures S1–S4. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.