Management of oesophageal strictures in inherited epidermolysis bullosa: a clinical practice guideline

Recommendations

The CPG describes the diagnostic procedures, preventative measures and treatment of OS in EB. The recommendations are listed in Table 2.

Diagnosis of oesophageal strictures

R1 (↑↑) We recommend the use of radiological investigations to diagnose OS and their characteristics in patients with EB with suggestive clinical signs and symptoms.

• Radiological investigations should carefully examine the entire oesophagus, paying attention to the cervical portion, to define the location, length, diameter and number of strictures.

• Radiological modalities used for the diagnosis of OS include oesophagogram and videofluoroscopy.

OS are clinically suspected when patients with EB present with chronic dysphagia (inability to swallow solids or even liquids, sialorrhoea, regurgitation and food impaction) and odynophagia.^3,4,8,10 Strictures are most commonly seen in the cervical oesophagus, followed by the thoracic and then the abdominal tracts.^3,4,8,10 They can be single or, less commonly, multiple, and their length is variable. Although the diagnosis is suspected based on suggestive clinical signs and symptoms, radiological investigations such as oesophagogram (also known as contrast swallow) and videofluoroscopy are recommended to confirm the presence, location, length and number of strictures.¹¹

Videofluoroscopy provides a direct dynamic view of oral–pharyngeal and upper oesophageal function, while oesophagogram allows morphological evaluation of the entire oesophagus. Specifically, oesophagogram, with attention to the cervical tract, has proven effective in detecting OS in EB.^8,10–24 Moreover, this noninvasive test has very rare adverse events in standard practice. Nowadays, water-soluble contrast media are increasingly used for oesophagogram.^5,25

R2 (↓↓) We recommend against using endoscopic examination in patients with EB for a diagnosis of OS.

The endoscope may traumatize the fragile oropharyngeal and oesophageal mucosa resulting in new blister formation, and further scarring and narrowing. More serious complications, in particular oesophageal perforation, have also been reported.^26,27 Furthermore, endoscopy may be difficult to perform in patients with microstomia and oral scarring. Thus, the risks of diagnostic endoscopy are not balanced by the benefits, also considering that diagnostic radiological procedures are available, effective and safe. In very rare symptomatic cases in which properly performed radiological investigations fail to identify OS or if endoscopy is the only modality available, it should be undertaken by experienced endoscopists, familiar with EB, to prevent damage or excessive blistering. Surgical expertise and facilities should be available in case of oesophageal perforation.

R3 (↑↑) We recommend prompt detection of OS in patients with EB with suggestive signs and symptoms.

• Early signs and symptoms of OS include intermittent dysphagia for solid and sometimes liquid food, increased meal duration, intermittent regurgitation and/or sialorrhoea. Starting from an early age (ideally infancy), personalized information should be provided about the possibility of developing OS, and their early signs and symptoms, to individuals with specific EB subtypes, in particular RDEB and KEB, caregivers and their paediatrician or general practitioner. Early detection of OS may allow implementation of preventive measures, facilitating maintenance of adequate nutrition and delaying stricture progression and related complications.

• Individuals with signs and symptoms suggestive of OS should be promptly referred to an EB expert centre and managed by a multidisciplinary team, which optimally comprises a dermatologist, nutritionist or dietitian, gastroenterologist, (interventional) radiologist, digestive or paediatric surgeon, dentist, anaesthetist, psychologist and specialized nurse.

OS can occur at an early age, with reported cumulative risks of OS development of 6.7% and 35.2% by age 1 and 5 years, respectively, in severe RDEB.³

Although no literature is available comparing the benefits and risks of prompt vs. delayed diagnosis of OS, this recommendation has been based on indirect evidence,^14,28 expert³ and panel opinion, and the results of the PPI survey that scored ‘Early diagnosis of OS’ as the topic with the second highest priority (Appendix S3; Table S3a).

OS treatment: preventive and pharmacological measures, dilatations and surgical procedures

R4 (↑) We conditionally recommend considering nonpharmacological measures for preventing/or delaying the onset or progression of OS in people living with EB.

• Early referral to a dietitian or nutritionist at the point of diagnosis is recommended for appropriate dietary advice with regular follow-ups.

• Early referral to a dentist (ideally at 3–6 months of age) with regular follow-up is recommended for education of the parents and caregivers. This includes preventive advice on oral hygiene routines, fluorides and oral manifestations of EB.

• Collaboration between the dietitian or nutritionist, dentist and patient or parents is recommended to ensure the advice is consistent and the care is person centred.

Despite very low evidence, experts and PPIs agree that different nonpharmacological measures may contribute to delaying the onset and/or progression of OS in EB. In addition, ‘Preventive measures to avoid/delay development of OS’ was the highest-priority topic according to the PPI survey (Appendix S3; Table S3a).

Dietetic and nutritional advice may include modification of food textures to reduce trauma to the oral and oesophageal mucosa.^5,16 Attention should be paid to ensure nutritional intake is not compromised by the prolonged use of blended meals with poor nutrient content.^16,29,30 Advice may include adapting cooking methods, energy-dense, soft food choices and adding more fluids to soften foods. The advice should be individualized to reflect the patient’s EB subtype and risk of OS, nutritional requirements and personal preference. Appropriate information may prevent incorrect dietary customs due to mistaken beliefs.

Properly cared-for oral mucosa and dentition will enhance the patient’s ability to chew and swallow, optimizing their intake of a variety of foods and reducing oral and oesophageal tissue damage. For details, refer to the CPG on oral healthcare in EB.³¹

R5 (↑) We conditionally recommend considering the use of pharmacological measures for preventing or delaying the onset or progression of OS in EB.

• Pharmacological measures can include (i) topical treatment of oral lesions, (ii) fluoride-containing products applied to the teeth, and, if required, systemic supplementation, (iii) oral viscous budesonide and (iv) treatment of gastro-oesophageal reflux disease (GORD), when present.

• Prompt gastroenterology referral at the first signs and symptoms of oesophageal involvement is recommended to assess and treat GORD and to consider oral viscous budesonide.

GORD can occur in all EB types, but in particular RDEB, and might contribute to the formation of distal OS.^3,4 Independently of a pathogenic role in OS, GORD should be considered in patients with EB and treated according to current guidelines.^32–34 Typical GORD symptoms may respond to lifestyle and dietary modifications alone or, when ineffective, combined with proton pump inhibitors as first-line treatment.

Although evidence supporting the efficacy of pharmacological measures in preventing or delaying the onset or progression of OS in patients with EB is very low, oral viscous budesonide, characterized by low systemic exposure, is increasingly prescribed in expert centres,^5,6 extrapolated from its use in eosinophilic oesophagitis, a condition associated with dysphagia, subepithelial fibrosis and stricture formation.³⁵

In an open-label trial on six paediatric patients with EB, a 4-month treatment regimen of oral budesonide nebulizer solution (0.5 mg per 2 mL twice a day) led to clinical and radiological improvement of OS in five patients.²⁸ However, oesophageal Candida infection was observed in one patient,²⁸ and is also reported in a small percentage of patients during treatment of eosinophilic oesophagitis with topical corticosteroids.³⁵ Based on eosinophilic oesophagitis consensus guidelines, the suggested dose of oral budesonide varies between 1 mg and 2 mg per day in adult patients.³⁵ The availability of an orodispersible formulation of budesonide represents an additional treatment modality in adults.

Finally, pharmacological measures for oral cavity care are detailed in the CPG for oral healthcare in EB.³¹

R6 (↑↑) We recommend performing oesophageal dilatation associated, whenever needed, with surgical procedures, specifically gastrostomy, for the management of OS.

• Oesophageal dilatation and gastrostomy tube placement must be performed in EB reference centres, by experienced professionals as part of a multidisciplinary team.

• Oesophageal dilatation is recommended for patients who have not responded to pharmacological treatment with oral budesonide and continue to present chronic dysphagia, sialorrhoea, food impaction and regurgitation.

• Gastrostomy is recommended for patients who present with intractable OS, failure to thrive, major problems in the oral cavity, severe chronic constipation and high stress levels during feeding.

• Complete and personalized information about the benefits and risks must be delivered to the patient and/or parents, and written informed consent should be obtained prior to any procedure.

According to the PPI survey, OS treatment represents a priority (Appendix S3; Table S3a). Despite nonpharmacological and pharmacological measures, OS frequently progress with worsening symptoms that require invasive treatments. Such symptoms include chronic and persistent dysphagia with inability to swallow even fluids, odynophagia, food impaction, regurgitation, rumination (i.e. rechewing food returned from the oesophagus), vomiting and increased sialorrhoea.^14,27

Retrospective cohort studies and case series ^{8,10,14,15,17–19,21,23,24,36–42} stated a high success rate (> 95%) of oesophageal dilatation with immediate symptomatic improvement following the procedure (disappearance or relief of dysphagia, increased feeding, and nutrition and weight gain), and a very low rate of serious complications. In a recent multicentre cohort study, major complications such as haemorrhage, tear and chest pain were reported in a minority of dilatations (2.7%, 12 of 451 procedures).⁸

Several retrospective cohort studies^43–48 and a systematic literature review⁴⁹ have reported that gastrostomy contributes to improving the nutritional and health status of patients with EB presenting with malnutrition. Moreover, improved quality of life and satisfaction among caregivers after gastrostomy tube placement have been described.^45,47 Early gastrostomy may avert nutritional decline,⁴⁸ indicating that it should be considered timely to prevent or delay weight loss. Complications (excessive leakage, infection, pain, ulceration, chronic wounds and granulation tissue) have been reported in 20–70% of cases, leading to gastrostomy tube removal in approximately 10%.⁴⁹

Gastrostomy tube placement may be performed by either open or laparoscopic surgery or percutaneous gastrostomy.^{18,20,39,40,43,44,46,48} In turn, the latter may be carried out by a transoesophageal endoscopic approach or an image-guided nonendoscopic technique.^18,20,40,48 Recently, a retrospective cohort study has documented the effectiveness and safety of a minimally invasive laparoscopic-assisted gastrostomy approach in 32 children with EB.⁴⁶ However, the method of insertion and type of gastrostomy tube will depend on the experience within the specialist centre.

R7 (↓↓) We recommend against bougie (semirigid) dilatation for best outcomes in terms of safety in patients with EB.

Oesophageal dilatation can be performed using two main categories of devices: radial expanding balloon dilators and fixed-diameter semirigid push-type dilators (bougie dilators) (Table 3).⁵⁰

Bougie dilators are passed across the stricture and dilatation is achieved by employing bougies of progressively increased diameter. In addition to exerting radial forces, the procedure also involves longitudinal forces that generate a significant shearing effect.

Balloon dilators can be positioned over a guidewire under fluoroscopic or endoscopic guidance. When fluoroscopy is used, successful dilatation is detected by the obliteration of the ‘hourglass shape’ on the balloon, representing the stricture (Figure 2).⁵¹ Balloon dilators only exert radial forces that are delivered simultaneously over the entire length of the stricture.⁵¹

There are almost no data comparing the efficacy and safety of bougie vs. balloon dilators to treat OS in EB. However, a recent multicentre cohort study reported that only three out of 451 dilatations were carried out using bougie dilators.⁸ In addition, recent studies on oesophageal dilatation in EB employed balloon dilators almost exclusively.^{17,18,21,23,24,37–42}

It is agreed by experts that bougies in EB are very likely to increase the mechanical trauma to the hypopharynx and the shearing trauma of the oesophageal mucosa, contributing to OS recurrence and increasing the risk of oesophageal perforation.⁵² Accordingly, EB reference centres are using fluoroscopically or endoscopically guided balloon dilatation.

R8 (↑) We conditionally recommend offering fluoroscopically guided balloon dilatation as the first-line treatment option for best outcomes in terms of safety.

• Endoscopy-guided dilatation should be considered in specific situations and settings: presence of a gastrostomy tube, characteristics of the stricture, local resources and, importantly, the physician’s expertise and skills in the use of an endoscope for treatment of OS.

Placement of the balloon dilator across the stricture and hydrostatic dilatation can be carried out under fluoroscopic or endoscopic guidance or combinations of the two techniques (Table 3). There is no international consensus on how to perform these procedures, which may lead to variations between centres.

Several retrospective cohort studies^4,8,24,39,42 and case series^{15,17,18,20,21,23,36,38,40,41} reported on efficacy and safety using fluoroscopically and/or endoscopically guided balloon dilatation for treatment of OS in EB. Of these, one cohort study⁴² and four case series^21,23,38,40 routinely used the endoscopy-guided approach.

Both procedures led to OS symptom relief and quality-of-life improvement. Limited complications are described for both techniques, including transient swallowing difficulty after the procedure, pain and fever,^15,41 with only rare cases of oesophageal perforation.⁴² A single multicentre study compared the outcomes of the two procedures, concluding that they have a comparable efficacy, but more complications may occur with the endoscopic technique due to the mechanical trauma secondary to the passage of the endoscope.⁸ Overall, fluoroscopically guided balloon dilatation may be preferable for treatment of OS in EB in terms of safety.

Endoscopy-guided balloon dilatation can be considered in specific conditions:

• Patients with a gastrostomy can have a retrograde approach for OS balloon dilatation using an endoscope passed through the existing gastrostomy.^8,41 However, the retrograde approach may be exploited also for fluoroscopically guided dilatation. Indeed, this approach makes it possible to overcome difficulties related to microstomia, common in RDEB.

• Strictures that are both narrow and tortuous require attention and expertise to avoid iatrogenic oesophageal injury. In these cases, passing the guidewire under endoscopic visualization may reduce the risk of perforation and allow dilatation.⁵²

• The physician’s expertise in the use of an endoscope for treatment of OS should be considered, and available local resources.

The available techniques and their preferential use are summarized in Table 3 and illustrated in Figures 2 and 3. Independently of the method for dilatation balloon positioning, fluoroscopy should be employed during all dilatation procedures to verify the guidewire placement. Finally, a crucial factor in the choice of technique remains the local expertise.

R9 (↑) We conditionally recommend considering pharmacological and nonpharmacological measures for preventing OS relapse.

• Pharmacological and nonpharmacological measures include dietary interventions, adherence to standard GORD treatment if required, and corticosteroid therapy.

• Gastroenterologists should assess the possibility of incorporating pharmacological treatments on a case-by-case basis, tailoring interventions to individual needs and circumstances.

• Information about the possibility of stricture relapses and related preventive measures should be provided to the patients, their parents and the primary care paediatricians and general practitioners. Patients should undergo regular follow-ups to check adherence to preventive measures, as well as to promptly detect and treat OS relapses.

Although there is scarce evidence to substantiate the efficacy of nonpharmacological measures in preventing or postponing OS relapses in EB, the panel members and PPI survey findings suggest the relevance of dietary interventions. However, it is essential to customize these measures on a case-by-case basis to avert nutritional complications. Recommendations for oral healthcare measures should be provided.³¹

In the realm of pharmacological interventions, adhering to standard GORD treatment in EB remains essential.^4–6 Several centres employ short-term systemic corticosteroids immediately after dilatation to alleviate post-procedural pain and swelling, potentially minimizing the inflammation that contributes to subsequent scarring and restenosis. However, there is a lack of data to substantiate their effectiveness as a preventive method for restenosis.^8,17,32 Oral viscous budesonide, previously reported in a few cases to decrease stricture indices and to space the need for dilatation,^5,8,28 is increasingly used in reference centres.⁶ Finally, losartan, a sartan antihypertensive drug with inhibitory effects on the profibrotic factor transforming growth factor-β1, has recently been reported to reduce OS relapses in the short term in a small case–control study.⁵³ However, further studies are needed to support its efficacy.

R10 (↑↑) We recommend that oesophageal dilatations be used for the treatment of OS recurrence in individuals with EB.

• In the case of OS relapse, patients should be referred to an EB expert centre for complete re-evaluation, and planning of dilatation and follow-up, also taking into account patient preferences.

Recurrence of OS is well described in patients with EB and frequently requires repeat dilatations.^{8,17,20,21,24,37,39,40,42,54} Although controlled prospective studies comparing the effects of repeated dilatations vs. no dilatation are lacking, retrospective cohort studies and case series reported that repeated dilatations are effective and relatively safe.^{8,17,20,21,24,37,39,40,42,54} According to the literature, the median interval between dilatation varies largely, ranging from 7 months (interquartile range 4–12) to 18 months (interquartile range 14 days to 24.5 months).^8,21 The median number of dilatations per patient is also highly variable.^17,20,21 In a large cohort study, relapses were associated with long (≥ 1 cm) segment strictures and multiple OS, suggesting the need for closer follow-up and a lower threshold for treatment in the presence of symptoms.⁸

Fluoroscopically guided balloon dilatations for treatment of recurrent OS are effective and well tolerated, with minimal risk of severe complications.^17,23,41,55 However, due to the susceptibility to squamous cell carcinoma development in this population, protocols should be implemented to reduce the radiation exposure in individuals with recurrent strictures.¹⁷ Finally, oesophageal squamous cell carcinoma has been rarely reported in patients with RDEB with chronic OS.^3,56 Thus, patients reporting worsening of acute symptoms should undergo prompt endoscopy and/or imaging re-evaluation.