“Quality of Life in Epidermolysis Bullosa” and “Epidermolysis Bullosa Burden of Disease”: Italian translation, cultural adaptation, and pilot testing of two disease-specific questionnaires

Inherited epidermolysis bullosa (EB) comprises a clinically and genetically heterogeneous group of rare fragility disorders of the skin and mucous membranes due to defects in protein components mediating epithelial adhesion [1, 2]. EB manifests with blister formation after minor trauma, more frequently at birth or in the first days of life (Fig. 1a, b). Four major types of EB are distinguished based on the level of blister formation: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB) [1, 2]. In addition, more than 30 subtypes with an extremely wide range of clinical features and severity are recognized, including syndromic variants. Depending on the level of skin cleavage, blister rupture results in superficial erosions or wounds, the latter frequently becoming chronic overtime and healing with scarring (Fig. 1b, c). In addition, blisters can involve mucous membranes, primarily the oral cavity, but also the esophagus, anus, eye, upper respiratory tract, and genito-urinary mucosa [2, 3]. Disease complications include recurrent infections, chronic anemia, malnutrition, failure to thrive and growth delay, hand and foot mitten deformities (Fig. 1d), joint flexion contractures, microstomia and ankyloglossia, esophageal and anal strictures. Furthermore, osteopenia and osteoporosis, delayed puberty, cardiomyopathy, renal failure, and increased susceptibility to aggressive skin squamous cell carcinomas may be present [2‐4]. Thus, some EB forms are associated with a reduced life expectancy, while others are even early lethal [1, 2]. Among EB symptoms, wound-related acute and chronic pain is particularly severe and debilitating [2‐4]. Moreover, chronic itching is a frequent complain, it can affect both wounds and intact skin resulting in an itch–scratch vicious cycle with further skin lesion worsening [2‐4].

Disease manifestations, symptoms and complications strongly affect quality of life (QoL) of the patients and their families. As no curative treatment is yet available, EB management relies on symptomatic measures, including wound care, nutritional support, gastrostomy, esophageal dilation, hand surgery, and squamous cell carcinoma treatment [2‐4]. Importantly, wound care is a crucial aspect of EB management that must be performed regularly: it is highly painful and time-consuming, thus feared by patients and distressing for their caregivers [3, 4]. In addition, many patients require frequent follow-up visits and hospitalization in reference centers, which are not always close to their residence, with financial implications and missed school/work days for patients and caregivers [5]. Finally, EB manifestations alter the physical appearance and affect the self-perception of patients [5].

The impact of the disease and patient care on QoL has been at first evaluated by specialty-specific questionnaires, in particular the Skindex-29, the Dermatology Life Quality Index (DLQI) and the Family Dermatology Life Quality Index (FDLQI) [6‐10]. More recently, disease-specific instruments have been developed to assess more precisely the impact and consequences of the different EB types [11, 12]. Specifically, the “Quality of Life in Epidermolysis bullosa” (QOLEB) aims to accurately evaluate functional and emotional aspects of QoL in EB patients [11]. It has been translated and validated in several languages including Mexican Spanish, Dutch, Brazilian-Portuguese, Castilian Spanish, Farsi, and Hindi [13‐20]. The second questionnaire, “Epidermolysis bullosa Burden of Disease” (EB-BoD) is intended to appraise family disease burden, in particular aspects concerning family and child’s life, disease and treatment, as well as social impact [12]. It has been developed and validated in French, and then translated into English.

The aim of our study was to develop an Italian translation of the English and French original versions of the QOLEB and EB-BoD questionnaires, respectively, and to pilot test them in a group of patients and caregivers, representative of all EB types.

The forward translation of the questionnaires was performed independently by an experienced dermatologist (GZ for QOLEB, and MEH for EB-BoD) and a professional translator. The translations were evaluated for reconciliation by the expert committee, which comprised an epidemiologist (DA), 4 dermatologists (AD, CC, GZ, MEH), a psychologist (TS), and language professionals.

Among the 17 items of the QOLEB, complete agreement was observed in five items between translators, aligning with the original English version. However, for the remaining 12 items, minor discrepancies in wording emerged between the translations. In particular, for 10 of these items (nine questions and one answer), there existed comparable meaning between the translations. The expert committee opted to prioritize wording that closely mirrored the original questionnaire while ensuring clarity and comprehensibility in both questions and answers. For questions with quantitative answer options (e.g., not at all, a little, a lot, etc.), the generic English term “How”, has been translated more specifically with “How much” or “To what extent”. Notably, in five of these 12 items, the translators chose a different Italian wording to achieve semantic, idiomatic, or cultural equivalence. The details about the reconciliation for these five items are shown in Table 1.

Following reconciliation, one English mother tongue translator and an expert dermatologist fluent in English (AD) independently back translated the Italian text. There was complete agreement between the two translators on one item, linguistic equivalence for 11 items. Specifically, in the five items mentioned above, the original meaning of questions and/or answers was preserved though using a slightly different wording, which reflected the Italian choices (see Table 1). The authors of the QOLEB approved the initial back translation. The committee then revised the original questionnaire and all translations, and evaluated equivalence between the source and the translated questionnaires. The pre-pilot version was approved by the QOLEB authors.

As to the EB-BoD instrument, there was full agreement in 13 out of 20 items between the translators and with the original French version, and in three additional items, there was meaning correspondence between both versions. The wording of the remaining four items was slightly modified to clarify the questions in relation to the different answer options (items 19 and 20) or to obtain semantic/idiomatic/cultural equivalence of the Italian version with the French one (items 13 and 15) (Table 1). Following reconciliation, one French mother tongue translator and a French mother tongue clinical expert (FF) back translated the Italian text. There was complete agreement between the two translators. The authors of the EB-BoD approved the initial back translation. The committee then followed the same procedure described above for the QOLEB, and the pre-pilot version was approved by the EB-BoD authors.

Questionnaire cognitive debriefing was performed on 17 families with at least one individual affected with EB (Table 2). All EB subtypes were represented: four EBS, three JEB, nine DEB and one KEB. Specifically, the QOLEB was administered to 10 patients aged > 11 years (1 EBS, 3 JEB, 5 DEB, and 1 KEB), and the EB-BoD to 12 parents of 11 children affected with different EB types (4 EBS, 1 JEB, 6 DEB). Interestingly, 10 out of 12 caregivers who filled the questionnaire and cognitive debriefing forms were the mothers of affected individuals, and the remaining two were the fathers. Table 2 also summarizes other information about parents: median age was 39 years (minimum 34, maximum 51), most of them were highly educated, and 11/12 were employed (one retired). All patients and all caregivers completed their respective questionnaires in 15 min or less (details in Table 3).

During the cognitive debriefing, most respondents demonstrated a clear understanding of both questionnaires, except for an issue raised regarding the last answer to question five in the QOLEB questionnaire: "I rely on my gastrostomy tube for nutrition." Specifically, one adult patient, affected by an intermediate form of JEB, did not know the term "gastrostomy," and thus did not understand the answer. Additionally, regarding the QOLEB questionnaire, there was a suggestion to add “when” to questions 8 and 15, thus becoming “How and when…”. The rationale behind this was to account for occasional feelings of frustration and depression, emphasizing the relevance of a temporal aspect in both questions. While intriguing, this suggestion was deemed to significantly alter the original question, falling outside the intended scope of the questionnaire translation and cross-cultural validation. Consequently, it was not integrated into the questionnaire.

Regarding EB-BoD question 9, "My family does not come to see us because of my child’s skin disease," a parent proposed a positive rephrasing: "My family comes to see us despite my child’s skin disease." Similarly, there was a suggestion to positively modify question 15 from “I have great difficulty in finding child care for my child on account of his/her skin disease” to “I easily find child care for my child despite his/her skin disease.” However, both proposed changes couldn't be accepted due to their substantial alteration of the original meaning and text, which would also impact the scoring system.

Overall, the expert committee did not modify the Italian version of the two questionnaires following cognitive debriefing. The validated Italian texts (Tables 4. and 5) were forwarded again to the respective developers for final approval.

To date, no disease-specific validated questionnaires for the measure of QoL and family disease burden for EB are available in Italian. Indeed, previous studies on QoL and family impact in EB have employed generic instruments, such as the Short Form-36 and the General Health Questionnaire-12, as well as dermatology-specific questionnaires: Skindex-29, DLQI and its version for children (CDLQI), and FDLQI [6‐10]. Although these validated instruments offer valuable measures for comparison with other diseases, both dermatological and non-dermatological, they do not fully encompass the complexity of disease manifestations and symptoms, and consequently their impact on the QoL for patients with EB and their caregivers.

Disease-specific questionnaires translated into national languages are a relevant tool to assess QoL and socio-economic impact in different nations and across cultural backgrounds. They can be exploited, also, to evaluate QoL changes overtime and, more importantly, during multicenter international therapeutic trials [22]. Indeed, the availability of such tools is one of the aims of the European Reference Network for Rare Skin Disorders (ERN-Skin) [https://​ern-skin.​eu/​what-is-the-ernskin/​]. Rare and chronic skin diseases pose a major burden on patient and family QoL [6‐10, 22‐26]. Therefore, questionnaires designed to measure the impact of diseases such as EB on family daily life, education and working activities, economic load, and psychological and social effects are valuable and necessary instruments [22].

The development of the Italian version of the QOLEB presented minor adaptation issues related to semantic and linguistic differences between English and Italian languages. For the EB-BoD the process was even smoother, given the significant linguistic and cultural similarities between Italy and France.

Although we did perform cognitive debriefing on only a small sample of patients and caregivers in a single center, our population was representative of the EB disease spectrum, as all disease types were included. Moreover, the validation process has followed the guidelines for cross-cultural adaptation of health-related QoL measures [21], and a remarkable agreement between both the researchers/translators and the caregivers was registered. Ten out of twelve caregivers who evaluated the Italian version of EB-BoD were patient’s mothers, further confirming the crucial role of the mother as main informal caregiver in rare diseases [27, 28].

Finally, we plan to further validate the QOLEB and EB-BoD questionnaires, including the verification of the psychometric properties of our version, on a larger Italian patient cohort in the framework of a European online survey. This survey will be carried out in the next months, as part of an ongoing European project (“Changes in the socio-economic burden of epidermolysis bullosa in Europe” -BUR-EB) involving eight EU countries [29].

The validity and reliability of the QOLEB instrument in quantifying functional and emotional aspects in patients with various EB types has already been shown for the original version, as well as for the Dutch, Spanish, Brazilian-Portuguese, Farsi, and Hindi translations [11, 13‐20, 30]. Moreover, QOLEB has been successfully employed in an online English cross-sectional survey on features and impact of EBS [31], and in a short-term prospective study on correlation between disease severity score, wound evolution, and QoL in DEB patients [32]. Concerning the EB-BoD instrument, preliminary analysis indicated that it could also discriminate between specific EB types [12].

Of note, the first two treatments for EB skin wounds have been recently approved by regulatory agencies. The first one, Oleogel-S10, is a gel containing triterpenes extracted from birch bark that proved effective and safe in accelerating healing of EB wounds and reducing pain [33]. Oleogel-S10 has been approved by the European Medicine Agency (EMA) and the Food and Drug Administration (FDA) for use in DEB and JEB patients aged > 6 months. The second treatment is a topical in-vivo gene therapy gel containing a replication defective herpes simplex virus type 1 carrying two copies of COL7A1 cDNA (Beremagene geperpavec) that showed efficacy in achieving healing of RDEB wounds and reducing pain [34]. Beremagene geperpavec has obtained approval by the FDA in RDEB patients aged > 6 months. Disease-specific questionnaires, in particular QOLEB and EB-BoD, will be useful tools to measure the impact on patient and family daily life of newly approved therapies. In addition, several multicenter international trials on different treatment approaches (i.e., pharmacological, cell- gene- and protein-therapy) are ongoing or about to start [35, 36]. Thus, the availability of validated Italian questionnaires contributes to provide meaningful patient-reported outcome measures for ongoing and future controlled clinical trials.

Ultimately, these tools can also serve as valuable assets in the everyday clinical practices of specialized centers. They enable the identification of particular psychological and socioeconomic challenges for EB patients and their families, guiding targeted interventions to ensure appropriate and timely care.