Inherited blistering diseases

The inherited blistering diseases consist of the variety of skin fragility syndromes classified under the general heading of epidermolysis bullosa (EB). The main subtypes include EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB), with other conditions such as Kindler syndrome, skin fragility–ectodermal dysplasia syndrome, and laryngoonychocutaneous syndrome recently reclassified as forms of EB on the basis of genetic and ultrastructural characteristics.

The burden of disease in inherited blistering disorders is known to be high, although it does vary considerably between subtypes. A 2002 study by Horn and Tidman of 116 Scottish patients with EB demonstrated that the QOL impairment in EBS and nongeneralized severe dystrophic subtypes (previously known as non–Hallopeau-Seimens syndrome) were comparable to moderate to severe psoriasis and atopic eczema as measured by the Dermatology Life Quality Index (DLQI) questionnaire with an average DLQI score of 10.7/30 for adults and 15/30 for children. Generalized severe subtypes of EB had greater QOL impairment than any disease previously assessed, with average DLQI scores of 18/30 for adults and 22/30 for children.

Fine and colleagues attempted to quantify the functional impairment and pain levels of an EB cohort using patient rating scales, demonstrating in their 2004 study that the subjective clinical severity of the disease did correlate with increased mobility and functional impairment and increased pain levels. Again, individuals with generalized severe recessive DEB (GS-RDEB) had the highest levels of pain and impairment across the EB cohort. This is demonstrated by 32% of all children with GS-RDEB rating their daily cutaneous pain greater than 5 out of 10 on a visual analog scale as opposed to 14% to 19% in all other subtypes of EB. More than 90% of the individuals with EBS surveyed by Fine and colleagues were rated as independent for activities of daily living (ADLs) in contrast to 73% of individuals with JEB or GS-RDEB who required full assistance with ADLs. The most problematic ADLs were identified as grooming and bathing across all EB subtypes, with toileting and feeding the most problematic in JEB and GS-RDEB subtypes.

These early studies were essential starting points to begin to assess the impact of EB on QOL; however, as subjective patient rating scales, they provided only semiqualitative data demonstrating a snapshot of QOL at one specific time point. These studies did give valuable insight into areas in patients’ lives that were not previously thought to have a great impact on QOL.

These areas were then further explored in later studies, particularly with Fine and colleagues’ report on the impact of a child with EB on parental interpersonal relationships and the birth of subsequent children. This study described the significant impact of having a child with EB on parental relationships, including divorce rates of 31% in parents of a child with JEB and the contribution a child with EB has on parental decisions to not have further children, with 26% and 64% of parents with a child with EBS or GS-RDEB, respectively, choosing not to have further children because of the potential risks of having a subsequently affected child. Fine’s study demonstrated the wide impact of the disease, not just on the individual but also on family and caregivers alike.

A recent study by Tabolli and colleagues has evaluated an Italian cohort of 125 patients with EB using several generic questionnaires, including the SF-36, Skindex-29, 12-item General Health Questionnaire (GHQ), EuroQol 5-dimension questionnaire (EQ-5D) or EQ-5D child, Family Strain Questionnaire, and a 5-point Patient Global Assessment scale. The results mirror the results of earlier studies showing the significant burden on families and caregivers, as well as the variation in QOL and burden of disease, with those individuals with GS-RDEB and some forms of JEB having much lower QOL than milder forms of EBS. The investigators’ results on the psychological impact of EB stated that mental health scores as measured by the SF-36 were only slightly lower than that in the general population.

A recent psychiatric study by Margari and colleagues contradicts these findings, stating that 80% of all individuals within their EB cohort had psychiatric symptoms, the most common being anxiety/paranoia and depression. Such psychiatric symptoms were present but partially compensated for by well-developed psychological strategies and coping mechanisms. The investigators state that the role of family and caregiver support was instrumental in the facilitation of coping mechanisms to prevent exacerbations of psychiatric conditions in individuals with EB. This highlights the importance of the holistic management of the patient, with attention being paid to not only the physical and functional but also the psychological and emotional aspects of the condition.

In the past 5 years, QOL research has moved from evaluation using preexisting generalized dermatologic and QOL questionnaires to a more qualitative approach through ascertaining areas of impact and burden from a grassroots level. The last decade has seen an increase in the use of qualitative methodologies in the medical field, and dermatology has been no exception. Although preexisting generalized dermatologic questionnaires have many uses in being able to compare quantitative scores between individuals and different diseases, the level of validity and reliability of such questionnaires can be brought into question when they are used for specific conditions such as EB. In severely affected individuals with GS-RDEB, lack of content validity and the presence of ceiling effects in general questionnaires such as the DLQI are significant in providing erroneous pictures and underestimates of disease burden, although these affect all EB subtypes to a greater or lesser degree. Our research group based in Sydney, Australia, has demonstrated that DLQI scores in patients with EBS are highly similar to EB-specific QOL scores, whereas more burdensome subtypes such as GS-RDEB and JEB show definite ceiling effects, particularly with functional questions that hold preexisting assumptions regarding an individual’s ability to go shopping, bathe oneself, or have an active sex life, which many individuals with severe EB subtypes are unable to perform.

Another source of error in previous measurements of QOL in EB has been the way in which pediatric patients with EB have been approached. As with any inherited disorder, a large proportion of the patient cohort is understandably pediatric. The use of traditional pediatric dermatologic questionnaires has the same potential pitfalls as adult QOL questionnaires with poor content validity; ceiling effects; and, if inappropriately administered, increased potential for parental bias. The differences in understanding, vocabulary, and interpretation of questions geared toward QOL between adults and children have led to the use of more creative methodologies to assess burden of disease in pediatric populations. This is best demonstrated by van Scheppingen and colleagues’ recent qualitative study identifying specific issues that affect the QOL in children with EB, including itch, pain, the sense of feeling different, and difficulties in joining in other activities with children. A second qualitative study by Dures and colleagues in 2011 gave further focus to the psychosocial impact of EB with themes such as learning to live with EB, talking to others, and understanding EB contributing significantly to the degree of impact EB has on patients’ psychosocial well-being. The investigators also touch on the coping strategies mentioned by Margari and colleagues, which individuals with EB use, and how these can lessen the psychosocial impact of the disease, with the identification of social support and maintaining focus on abilities as opposed to disabilities being key components of these mechanisms.

The use of more qualitative approaches to overcome the downfalls of previous questionnaires has allowed the beginning of EB-specific QOL questionnaires and accurate quantification of burden of disease in this patient population. Our research group has designed and validated an EB-specific QOL questionnaire (the QOLEB questionnaire) specifically for use with individuals with EB. The QOLEB was devised using an exhaustive item generation process with 26 patients with EB of various types and severities, their families, and experts in the field. A pilot questionnaire was devised and distributed to 130 patients with EB, and, from the data obtained, the instrument was revised using various methods, including factor analysis, to a 17-item questionnaire. The QOLEB has been shown to be a statistically valid and reliable means to evaluate QOL in EB, correlating well with existing QOL instruments and distinguishing EB subtypes by score. The QOLEB has been shown to have a high validity, specific enough to capture the QOL concerns particular to EB and broad enough to encompass the different subtypes of EB. Results from the QOLEB questionnaire conform with previous research regarding the varied impacts different EB subtypes have on QOL, with average QOLEB scores (with standard deviations in parentheses) of 13.7/51 (8.7) for EBS, 31.5 (17.6) for JEB, 18.1 (10.9) for dominant DEB, and 35.5 (12.7) for RDEB. The QOLEB has the potential to be a sensitive disease-specific tool to assess QOL in EB in future studies and has been used in a recent randomized control trial of cell therapy for recessive DEB. At present, only an adult form of this questionnaire exists, although validation of the questionnaire in other languages, such as Spanish, Portuguese, Dutch, and French, are forthcoming. A pediatric form of this questionnaire is required to address the needs of the pediatric population, and further statistical validation is underway through anchor- and distribution-based banding methods to determine mild, moderate, severe, and extreme QOL impairment for ease of interpretation of this valid score and definition of a minimal clinically important difference in the QOLEB score. This would aid in use of the score as a longitudinal measurement tool and for use in evaluating new interventions in EB.

Autoimmune blistering disease

Studies exploring QOL in autoimmune bullous dermatoses have primarily focused on pemphigus (namely pemphigus vulgaris and pemphigus foliaceus) and bullous pemphigoid with a paucity of information regarding QOL in other forms of pemphigus as well as other acquired bullous diseases such as mucous membrane pemphigoid, EB acquisita, and linear IgA bullous dermatosis.

The earliest study exploring QOL in autoimmune blistering disease (AIBD) involved 380 patients with pemphigus in Japan. Patients were stratified according to disease severity (with most patients [67.7%] having mild disease) and asked to complete a survey reviewing their ADLs and the financial impact of their condition. Patients were found to be independent in most ADLs; however, they experienced a considerable economic burden due to their disease. In the cohort, 41.9% described a decrease in income because of lost work time (60.0% in severe disease) and 41.3% described their financial status as being in poverty (57.9% in severe disease). However, only 2.2% of patients were in the active stage of disease, with the remainder in varying phases of remission, and, accordingly, the results illustrated that with appropriate treatment pemphigus does not significantly impinge upon the ADLs of patients. In contrast, the financial impact of pemphigus may be burdensome even if the patient shows clinical improvement, probably because of extensive loss of time at work when the disease is in its visible state and takes weeks to months to come under control, and this should be remembered in the assessment of these patients.

Another study evaluating QOL in pemphigus was conducted using the SF-36 to compare QOL in patients with pemphigus with that in the wider population in Morocco. The study cohort included 30 consecutive patients with pemphigus presenting to dermatology clinics or admitted to the hospital, and the control cohort consisted of 60 patients presenting with nondebilitating conditions such as verrucous warts. The SF-36 was translated into the Moroccan dialect, and, given the low literacy rate in Morocco, the questionnaires were administered by a single investigator rather than being patient administered. The investigators identified a significant difference between cohorts with the pemphigus group displaying decreased mean scores across all dimensions except for “Physical Pain” and “Change Compared to the Previous Year.” Physical status and emotional status were the domains most affected by pemphigus, with facial involvement and the extent of lesions correlating well with overall scores. Within the group, 70% expressed enormous shame about their appearance, 60% were anxious about what others thought of their disease, and 63% reported a significant loss of confidence (N = 30). Repercussions for sexual function were also important, with 81% of patients reporting concerns in this domain. Cultural factors were noted to play an important role in the detrimental effect of pemphigus on QOL in these patients because of the misconceptions that existed within the community associating skin pathologies with poor hygiene or sexual practices that go against cultural mores. Auxiliary considerations include the disease’s onerous and costly management and social issues such as the limitations placed on marriage prospects for young women. Using a generic QOL instrument, the investigators identified a significant impact of pemphigus on QOL and highlighted that beyond functional aspects of disease burden, the SF-36 also explores social domains and self-image issues, which are particularly relevant in pemphigus.

The QOL of patients with pemphigus vulgaris was also evaluated in one study of 27 German participants using a dermatology-specific instrument. The DLQI score for the study cohort averaged 10.1 ± 6.6 compared with healthy individuals with a mean score of 0.5 ± 1.1, and the investigators concluded that a diagnosis of pemphigus conferred a large impairment in QOL. Patients with mucosal involvement were found to have a higher DLQI, averaging 10.4 ± 7.3, than those with mucosal sparing who averaged 9.3 ± 5.1, indicating a poorer QOL. Itching was also associated with decreased QOL as patients with itch scored 11.5 ± 7.5 compared with those without itch who scored 7.9 ± 4.8. Similarly, burning was found to impair QOL, with patients scoring 10.8 ± 6.6. This score was compared with that in those without burning, who scored almost half of that with an average DLQI of 5.5 ± 5.7. Possibly because of the small cohort size, none of the results achieved statistical significance, and, notably, 22.2% of patients felt that their QOL was not impaired by their illness at all. The mean DLQI for pemphigus was higher than the mean scores for similar blistering diseases such as bullous pemphigoid (6.92 ± 3.8) as well as other dermatologic pathologies such as basal cell carcinoma (2.0 ± 2.2) but lower than that of atopic eczema (12.5 ± 5.8), a comparison facilitated by the use of a skin-specific QOL instrument to compare severity.

A study reviewing the health status of 58 Italian inpatients undergoing treatment of pemphigus also demonstrated a significant decrease in QOL compared with the greater population. Participants were issued the SF-36, Clinical Depression Questionnaire (CDQ), and the Institute for Personality and Aptitude Testing Anxiety Scale Questionnaire (ASQ). As expected, pemphigus had a larger impact on SF-36 scores than normative data. Patients with disease duration of 5 years or more, recent-onset disease, disease that had worsened compared with the previous year, mucocutaneous involvement, higher anti-Dsg3 antibodies, and more severe disease subjectively had worse SF-36 scores ( P <.05). The ASQ and CDQ values demonstrated a strong negative correlation with the SF-36 scores, indicating that poorer QOL scores were associated with higher levels of anxiety and depression.

Another study from Italy used generic and dermatology-specific QOL instruments in 126 inpatients with pemphigus. Most patients had pemphigus vulgaris (N = 112), although the cohort included patients with pemphigus foliaceus (N = 10), paraneoplastic pemphigus (N = 2), and IgA pemphigus (N = 2). Patients completed the SF-36, the Skindex-29, and the GHQ-12 to assess QOL with the Ikeda index and Physician Global Assessment and autoantibody titers used to assess disease severity. The SF-36 and Skindex-29 scores of patients with pemphigus were adversely affected compared with normative scores for the general Italian population ( P <.05). Disease severity was significantly associated with poorer QOL scores as was female sex, which had not been identified in previous QOL studies in pemphigus, although has been described in other dermatologic conditions. No correlation was found between Dsg antibody titers, clinical severity, or QOL scores. GHQ positivity (suggesting probable minor nonpsychotic psychiatric conditions) was detected in 39.7% of participants compared with a general population prevalence of 10% to 12% and was significantly correlated with clinical severity. Patients with pemphigus foliaceus were found to have slightly poorer QOL than those with pemphigus vulgaris using the Skindex-29, with a significant difference in the symptom scale with 70% of patients with pemphigus foliaceus GHQ positive. However, there were only 10 patients with pemphigus foliaceus in this study compared with 112 patients with pemphigus vulgaris, and, as this study was completed in an inpatient setting, it is plausible that patients with pemphigus foliaceus were more severe at presentation. As no objective disease extent score, such as the Autoimmune Bullous Skin Disease Intensity Score or Pemphigus Disease Activity Index, was provided with this study, it is not known if this was the case.

Another cross-sectional study from Iran compared the QOL in 76 patients with pemphigus for at least 3 months and 86 healthy controls who accompanied them to clinic appointments (ie, most likely relatives), so their environment and social status was similar using Farsi translations of the SF-36 and the Sweden Quality of Life instrument. It is not reported whether the investigators used validated Farsi translations of the SF-36 and Swedish QOL instruments or the proficiency of patients in Farsi given the ethnic diversity in Iran. As expected, patients with pemphigus were found to have significantly lower QOL scores across all parameters, with a mean score of 69.38 compared with the control mean of 85.43 ( P <.0001). Factors associated with poorer QOL scores included age greater than 50 years ( P <.04), longer disease duration ( P <.01), repeated hospitalization ( P <.001), and treatment protocol (steroid and adjuvant, P <.001). Of note, better QOL scores were demonstrated amongst patients with a university education ( P <.01) and with particular professions. Housekeepers had a higher number of poor QOL scores; however, this may have been because of confounding because all housekeepers within the study were women and, as mentioned previously and also found in this study, women had worse QOL scores. No significant difference in QOL was identified between patients with higher and lower incomes, although the latter had slightly better scores. The reason may be the low number of patients in the study with high incomes.

The importance of QOL in the setting of AIBD is becoming increasingly appreciated, and many studies are now including this as an important outcome measure. For instance, a small study of Brazilian patients with pemphigus recently investigated the effects of physiotherapy with QOL, the only outcome of interest. Seven patients received a 4-month course of 25 physiotherapy sessions with QOL assessed using the SF-36 at baseline and at the completion of the study. Patients who participated in the intervention showed a tendency for improvement in the symptom component of the SF-36 but not the social or psychological aspects. The only statistically significant improvement was in pain scores ( P <.005); however, further studies are warranted with larger numbers before the effects of physiotherapy on QOL in pemphigus can be determined definitively. QOL is also appearing with increasing frequency as an outcome in clinical trials, and, accordingly, it is important that reliable validated instruments are available to evaluate this construct.

To our knowledge, no QOL instrument specific to AIBD has yet been developed, and our research group has been working on the development of such a measure: the Autoimmune Bullous Disease Quality of Life Questionnaire (ABQOL). Following a comprehensive item-generation process, a pilot instrument was established that was administered to 73 patients with autoimmune bullous disease across Australia along with the DLQI. Results obtained from this pilot questionnaire were evaluated using factor analysis and review by experts in bullous disease to refine the measure to the final ABQOL questionnaire consisting of 17 questions. Psychometric evaluation of the ABQOL has shown it to be a valid and reliable instrument that may be used to monitor disease activity and serve as an end point in clinical trials. This measure has been presented at various conferences and is being submitted for publication.