Health-related quality of life and its determinants in pemphigus: a systematic review and meta-analysis

Dear Editor, The growing interest in exploring the impact of pemphigus on health‐related quality of life (HRQoL) is reflected in the increasing number of studies in the area. Two reviews can be found in the literature on HRQoL impairment related to pemphigus; however, neither of them applied a systematic search strategy or meta‐analysis.1 2 Also, the latest study included was published in 2009. Therefore, the objectives of this paper were to perform a systematic review of the literature on HRQoL in pemphigus, to perform a meta‐analysis on the most frequently used instruments, and to identify the possible determinants of HRQoL. We searched in Ovid Medline, Embase, Web of Science, CINAHL, PsycINFO and the Cochrane Library up to 6 October 2014. The search strategy included a combination of terms related to pemphigus, general HRQoL and the names of generic and dermatology‐specific instruments. No language limits were applied. Eligible studies were screened by two independent reviewers (F.R. and V.B.), and references were also tracked. Inclusion criteria were (i) the study population included adult patients with pemphigus; (ii) the study reported HRQoL of pemphigus assessed by any instrument (not aggregated results for a group of skin diseases); and (iii) publications were original articles. For all studies the following data were extracted: patient characteristics (sample size, pemphigus type, mean age, disease duration, sex ratio, current therapy and geographical location), applied HRQoL instruments and HRQoL scores. Determinants of general or dermatology‐specific HRQoL analysed statistically in the studies were retrieved. For meta‐analysis, the number of patients and mean HRQoL scores and SDs were extracted, and 95% confidence intervals (CIs) were calculated. Meta‐analysis was performed on Dermatology Life Quality Index (DLQI) total scores or individual domains of HRQoL instruments, on which results were reported in at least three separate studies including patients of similar characteristics. Where significant heterogeneity was detected between studies (Cochran's Q P <0·01 or I2 > 50%), random‐effects meta‐analysis (inverse‐variance method) was applied; otherwise the fixed‐effects approach was employed. Sixteen studies from eight different countries were identified assessing HRQoL in 1465 patients with pemphigus with eight different instruments (Table 1). Our systematic search strategy yielded nine further papers published since the former reviews, and two additional studies that were not included in the earlier reviews despite being published before 2009. There were 11 cross‐sectional studies,3 4 5 6 7 8 9 10 11 12 13 four case–control studies14 15 16 17 and a prospective cohort18 with a 4‐month follow‐up period. The patient populations varied between seven and 380, with only five studies enrolling > 100 participants.3 4 9 13 15 Selected studies ADLs, Activities of Daily Living; AI, Anxiety Index; ASQ, Anxiety Scale Questionnaire; ATT, attitude to appearance scale; BP, bodily pain; CDQ, Clinical Depression Questionnaire; COMDQ, Chronic Oral Mucosal Diseases Questionnaire; DLQI, Dermatology Life Quality Index; GH, general health; GHQ, General Health Questionnaire; HRQoL, health‐related quality of life; IMPACT, Impact of Skin Disease Scale; MADRS, Montgomery–Åsberg Depression Rating Scale; MCS, mental component summary; MH, mental health; NR, not reported; PCS, physical component summary; PF, physical functioning; PGA, Physician's Global Assessment; PV, pemphigus vulgaris; RE, role‐emotional; RP, role‐physical; SF, social functioning; SF‐36, Short Form‐36; SSQ, Social Support Questionnaire; VT, vitality; WHOQOL‐BREF, World Health Organization Quality of Life‐BREF; WHODAS 2.0, World Health Organization Disability Assessment Schedule 2.0. For SF‐36 and WHOQOL‐BREF higher scores refer to better HRQoL, for all other measures higher scores represent worse HRQOL. aGhodsi5 inclusion > 12 years; Kumar6 inclusion ≥ 15 years. bIn the study of Wysoczyńska et al.17 the mean score of the other six dimensions of SF‐36 was not reported. cThe most common comorbidities in the study were hypertension, osteoporosis, diabetes, obesity and glaucoma. Selected studies ADLs, Activities of Daily Living; AI, Anxiety Index; ASQ, Anxiety Scale Questionnaire; ATT, attitude to appearance scale; BP, bodily pain; CDQ, Clinical Depression Questionnaire; COMDQ, Chronic Oral Mucosal Diseases Questionnaire; DLQI, Dermatology Life Quality Index; GH, general health; GHQ, General Health Questionnaire; HRQoL, health‐related quality of life; IMPACT, Impact of Skin Disease Scale; MADRS, Montgomery–Åsberg Depression Rating Scale; MCS, mental component summary; MH, mental health; NR, not reported; PCS, physical component summary; PF, physical functioning; PGA, Physician's Global Assessment; PV, pemphigus vulgaris; RE, role‐emotional; RP, role‐physical; SF, social functioning; SF‐36, Short Form‐36; SSQ, Social Support Questionnaire; VT, vitality; WHOQOL‐BREF, World Health Organization Quality of Life‐BREF; WHODAS 2.0, World Health Organization Disability Assessment Schedule 2.0. For SF‐36 and WHOQOL‐BREF higher scores refer to better HRQoL, for all other measures higher scores represent worse HRQOL. aGhodsi5 inclusion > 12 years; Kumar6 inclusion ≥ 15 years. bIn the study of Wysoczyńska et al.17 the mean score of the other six dimensions of SF‐36 was not reported. cThe most common comorbidities in the study were hypertension, osteoporosis, diabetes, obesity and glaucoma. Four different generic measures were used: Short Form‐36 (SF‐36), Activities of Daily Living, World Health Organization Quality of Life‐BREF and World Health Organization Disability Assessment Schedule 2.0. Four types of dermatology‐ or oral‐disease‐specific tools were applied: DLQI, Skindex‐29, Skindex‐17 and Chronic Oral Mucosal Diseases Questionnaire. The most frequently used measures were SF‐36 (eight of 16),9 11 12 14 15 16 17 18 DLQI (five of 16)4 5 7 8 17 and Skindex‐29 (four of 16).9 11 15 17 The meta‐analysis showed the highest deterioration in the role‐physical dimension of SF‐36 (38·1, 95% CI 20·4–55·9), followed by role‐emotional (47·5, 95% CI 21·9–73·2) and vitality (50·7, 95% CI 43·6–57·7) (Fig. 1a). The mean total DLQI score of patients with pemphigus ranged from 4·0 to 13·8.4 5 7 8 17 Newly diagnosed or untreated patients scored on average 12·0 (95% CI 11·1–12·9) (Fig. 1b). The greatest impairments were reported in the symptoms and feelings, and daily activities dimensions of DLQI (2·8–3·0 and 1·9–2·2, respectively).5 8 The meta‐analysis indicated similar mean scores in the symptoms (35·8, 95% CI 32·7–38·9) and emotions (36·5, 95% CI 33·8–39·2) domains of Skindex‐29, whereas they were slightly lower for social functioning (32·8, 95% CI 29·9–35·6) (Fig. 1c).9 11 15 Meta‐analysis of studies with the Short Form‐36 (SF‐36), Dermatology Life Quality Index (DLQI) and Skindex‐29. The sizes of the dots refer to sample sizes. (a) SF‐36 dimension scores in medically treated and/or hospitalized patients with pemphigus. Random‐effects models were used for each dimension. Scores range from 0 (worse health‐related quality of life, HRQoL) to 100 (better HRQoL). The studies of Paradisi et al.9 and Wysonczyńska et al.17 were not included in the meta‐analysis because they did not report results for each dimension of the SF‐36. The study of Timoteo et al.18 was excluded as it reported results only graphically. (b) The total DLQI score of newly diagnosed or untreated patients with pemphigus. Fixed‐effects model. DLQI ranges from 0 to 30, where higher scores indicate worse HRQoL. The study of Wysonczyńska et al.17 was not included in the meta‐analysis as 77% of the participants reported a disease duration of > 2 years. (c) Skindex‐29 dimension scores of medically treated and/or hospitalized patients with pemphigus. A random‐effects model was used in the symptoms dimension, and fixed‐effects models in the emotions and social functioning dimensions. Scores range from 0 to 100, where higher scores indicate worse HRQoL. CI, confidence interval; df, degrees of freedom. Overall, 41 possible determinants of HRQoL were identified (Table S1; see Supporting Information), of which reduced HRQoL was clearly associated with higher disease severity, anxiety and depression in at least two separate studies. However, the impact of several factors on HRQoL, such as age, sex, type of pemphigus, disease duration, mucocutaneous involvement, clinical activity, itching, skin burning or being treated by adjuvant drugs, cannot be clearly stated. This paper provides the first systematic review and meta‐analysis of HRQoL studies in pemphigus. The various HRQoL instruments applied, the different sample sizes and the geographical locations hinder the comparison of the 16 studies. Only five studies used both generic and dermatology‐specific measures.6 9 11 15 17 The eight different tools capture different aspects of HRQoL and yet do not necessarily explore all the dimensions that are important for patients with pemphigus. However, our meta‐analysis confirmed that even the same instrument may lead to rather different HRQoL findings in patients with similar characteristics in terms of age, disease duration and disease severity. This was especially apparent for studies using SF‐36 and Skindex. Presumably several other factors – such as differences in patients' disease perception, treatment practice, presence of comorbidities and country‐ or culture‐specific factors – also influence HRQoL and, as a result, HRQoL scores across the patient settings. The great heterogeneity of the HRQoL measures and scores highlights the need for standardizing HRQoL assessment in pemphigus. None of the studies applied pemphigus‐ and/or autoimmune bullous disease‐specific HRQoL measures. However, recently two disease‐specific questionnaires have been developed, namely Autoimmune Bullous Disease Quality of Life and Treatment of Autoimmune Bullous Disease Quality of Life. There is only one prospective cohort studied in the literature; therefore, little is known on the disease course of pemphigus in terms of HRQoL. No randomized controlled trials with an HRQoL end point were found, a point that should be considered in drug development in the future. We find it important to highlight the lack of health‐state utility studies. Utilities reflect the preference or desirability of a health state and are essential for economic evaluations of health interventions. The application of costly biological drugs, such as rituximab or etanercept, and in addition the ongoing phase 3 clinical trials with new biologics, support the need for utility results in pemphigus. This would also facilitate exploration of the disease burden of pemphigus compared with other dermatological conditions. Further investigations are needed, enrolling larger patient numbers, preferably in a longitudinal framework and applying pemphigus‐specific or preference‐based measures. These would contribute to the more precise evaluation of the HRQoL improvement achieved with different therapies for pemphigus. The authors are grateful to Ms Mahshid Moradi, a PhD student at Corvinus University of Budapest, for her assistance in translation. Funding sources: none. Conflicts of interest: none declared. Table S1. Determinants of health‐related quality of life in pemphigus assessed in the studies.