Dystrophic epidermolysis bullosa is caused by mutations in the COL7A1 gene, which results in low type VII collagen, an essential component of anchoring fibrils at the dermal–epidermal junction. Even minor trauma leads to extensive skin and mucosal blisters with soft tissue scarring. Esophageal and pharyngeal strictures occur in more than 65% of patients with the autosomal recessive form of dystrophic epidermolysis bullosa (RDEB) causing severe dysphagia (1–4). These strictures typically arise in the proximal esophagus and are caused by minor mechanical trauma. Solid food bolus ingestion causes a shearing effect of the squamous mucosa, resulting in blister formation. Repeated blister formation and ulceration coupled with chronic inflammation can result in scarring and ultimately the development of esophageal strictures. The strictures may become so severe that the narrowing can impede the passage of saliva and swallowed liquids. Gastroesophageal reflux is also common in RDEB and may result in the formation of distal esophageal strictures (2). Proximal esophageal strictures in particular respond well to pneumatic balloon dilation. This well-described technique is fluoroscopy-assisted and involves minimal instrumentation of the esophagus with the endoscope (to reduce the risk of mechanical shearing trauma) (2). Although some patients may go for years without repeated dilation, the majority of patients with RDEB will require regular pneumatic stretches as often as every few months (2,5).
Adjunct therapy for refractory esophageal strictures include corticosteroids. Intralesional corticosteroid injections have previously been used effectively for the treatment of caustic or peptic esophageal strictures in combination with pneumatic dilation (6–8). Perioperative systemic steroids have also been used in patients with RDEB to reduce the frequency of esophageal dilation and radiation exposure (9). Topical steroids have not been used in epidermolysis bullosa for this indication. They are, however, frequently used for the treatment of eosinophilic esophagitis (EoE) (10), a chronic condition which can be associated with esophageal fibrosis and strictures (11). One such topical steroid preparation is oral viscous budesonide (OVB), a mixture of budesonide nebulizer solution (Pulmicort) mixed with maltodextrin and sucralose (Splenda), which has been shown to reverse esophageal eosinophilic inflammation (10,12). In the present report we discuss the treatment of 2 patients with epidermolysis dystrophica and proximal esophageal strictures with esophageal balloon dilation and OVB.
Between June 2004 and February 2010, a 16-year-old boy with RDEB and a severe proximal esophageal stricture underwent 19 esophageal dilations with fluoroscopic guidance. (2) At the time of dilation the stricture was usually between 1 and 3 mm in diameter and approximately 1 cm long. The esophageal stricture was dilated to between 10 and 12 mm diameter using the controlled radial expansion pneumatic balloon dilator, and from June 2004 to February 2009 he underwent 17 dilations (3–5 dilations per year). Typically after each intervention the patient would be asymptomatic but would start having recurrence of symptoms with dysphagia, oropharyngeal pain, and choking 8 to 10 weeks postdilation. He would develop dysphagia for solids and, on some occasions, would be unable to swallow saliva. In February 2009 he was started on OVB 0.5 mg (0.5 mg/2 mL budesonide nebulizer solution mixed with 5 g of sucralose and maltodextrin, and no eating or drinking for 30 minutes postingestion). He typically ingested OVB 4 to 7 times per week and also took a dose when he had a ”tight throat,” which he claimed would alleviate his symptoms. This tightness may have been caused by acute blister formation. During the 18-month therapy with OVB he required only 2 dilations and noticed a significant improvement particularly in the reduced frequency of choking episodes. He is able to eat all food textures and, 5 months after his last dilation, is still able to eat sliced steak and turkey. At the time of writing, repeat dilation had not been planned.
A 9-year-old girl with junctional epidermolysis bullosa presented with dysphagia and choking when eating food. An esophogram revealed 2 strictures, between 1 and 5 mm diameter, total length 7 cm extending from C4 to the thoracic inlet. From May 2007 to May 2010 she underwent 11 esophageal dilations (3–4 dilations per year) with fluoroscopic guidance and was dilated to 10 to 12 mm diameter each time (2). A 5-cm controlled radial expansion balloon dilator, inflated with radioopaque solution, passed over a guidewire was used and serial dilations of the whole stricture were undertaken. Adequate dilation was confirmed fluoroscopically. Typically the patient would start complaining of symptoms, particularly choking with meals, about 8 weeks after dilation and this would prompt repeat intervention. In August 2009 she was started on OVB 0.5 mg daily and has been compliant with therapy. Instructions not to eat or drink for 30 minutes after taking OVB were given. During the last 12 months she has had 2 routinely scheduled dilations at 5-month intervals, but before each procedure had been asymptomatic. She had been eating all food normally and ate a hamburger the day before the last procedure. By November 2010, 6 months following her last dilation, the subject was still symptom free. At the time of writing, during 15 months of OVB therapy, she underwent 2 dilations and has remained symptom free throughout. Her next dilation will be scheduled when she becomes symptomatic.
OVB is a topical steroid preparation, which was formulated to target the esophagus. Taken once daily at a dose of 1 to 2 mg/day, it is effective in the treatment of EoE, a condition associated with dysphagia and subepithelial fibrosis and stricturing (10,12). In EoE, fibrosis within the lamina propria is accompanied by increased numbers of transforming growth factor-β (TGF-β)–positive cells, increased expression of the TGF-β signaling transcription factor, phosphorylated Smad2/3 (pSmad2/3), and increased numbers of activated blood vessels expressing vascular cell adhesion protein-1 in the subepithelial space. Treatment with OVB for 3 to 4 months decreased fibrosis, TGF-β1 and pSmad2/3-positive cells, and decreased vascular activation (10,13,14). The exact inflammatory process involved in the formation of proximal esophageal strictures in epidermolysis bullosa (EB) is unclear, but it is likely triggered by repeated mechanical trauma caused by swallowing boluses of solid food. The clinical manifestations of EB reflect a structural defect caused by a genetically determined absence of certain collagen components and anchoring fibrils in the epidermis, resulting in repeated trauma and erosions of the mucosa. This is followed by inflammation and stricture formation as a result of incomplete healing. As such, topical steroids are unlikely to have any effect on this underlying structural abnormality. Preventing and breaking the vicious cycle of chronic inflammation and resulting continuous repair attempts with ultimate stricture formation by using OVB will likely be more beneficial long term in the management of these patients and outweigh the theoretical risk of mucosal atrophy caused by steroid absorption, particularly because the absorptive functions of the esophagus are usually highly compromised in patients with severe forms of EB (RDEB) and as such appear to be of less clinical concern.
The ability to maintain adequate oral energy intake is important in the management of EB. Malnutrition may lead to poor wound healing especially in patients without a gastrostomy feeding device. Esophageal structuring and painful oral lesions will negatively affect the patient's ability to ingest adequate energy.
Our 2 subjects have localized proximal esophageal strictures and they received approximately 25% of the age-appropriate dose of OVB that would be recommended for the treatment of EoE. Long-term daily treatment with OVB using conventional EoE treatment doses is well tolerated and complications such as oral or esophageal candida are uncommon (10,12). Neither of our subjects had evidence of candida infection, even after 15 to 18 months of OVB therapy. During OVB therapy both subjects reported a prolonged reduction in their symptoms of dysphagia and choking attacks after esophageal dilation. Both subjects required fewer pneumatic dilations during the 15- to 18-month treatment period with OVB therapy.
We have previously shown that long-term OVB therapy is safe and effective for the treatment of EoE. Topical steroid therapy using a relatively small dose of OVB therapy may reduce the rate of recurrence of esophageal stricture formation and therefore symptoms such as dysphagia in patients with EB. Further long-term studies using OVB in subjects with EB would be useful to better understand safety, efficacy, and optimal dosing for this therapy. Subjects with EB and esophageal strictures requiring frequent dilations should be considered for treatment with OVB.
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