Assessing the Correlation Between Autoimmune Bullous Disease Quality of Life Questionnaires (ABQOL, TABQOL, DLQI) and Disease Severity Indices in Pemphigus and Bullous Pemphigoid

Background: Pemphigus and bullous pemphigoid (BP) are autoimmune blistering diseases (AIBDs) that affect the skin and mucous membranes, and adversely impact quality of life (QOL). Few studies have assessed the correlation between the severity of disease and QOL in patients with pemphigus and BP. Objectives: To identify the correlation between the severity of AIBDs and QOL using the Autoimmune Bullous Disease Quality of Life (ABQOL), Treatment Autoimmune Bullous Disease Quality of Life (TABQOL), and Dermatology Life Quality Index (DLQI) questionnaires in Chinese patients with pemphigus and BP at baseline, and after 1, 3 and 6 months of treatment. Methods: Pemphigus and BP patients were invited to complete the ABQOL, TABQOL, and DLQI questionnaires. We measured the pemphigus disease area index (PDAI), autoimmune bullous skin disorder intensity score (ABSIS), and antibodies of desmoglein1,desmoglein3 (DSG1/DSG3) for pemphigus; and the bullous pemphigoid disease area index (BPDAI), ABSIS, and antibodies of BP180/ BP230 for BP as disease severity indices. The correlations between the severity of disease and QOL were analyzed by Spearman’s correlation coecient (r). Results: Eighty-ve patients were included: 55 with pemphigus and 30 with BP. The pemphigus subtypes included pemphigus vulgaris (PV, n = 32), pemphigus foliaceus (PF, n = 22), and paraneoplastic pemphigus (PNP, n = 1). We found signicantly strong correlations between QOL (ABQOL, TABQOL, DLQI) and severity of disease (PDAI/BPDAI, ABSIS) with (r = 0.87, 0.77, 0.83; r = 0.86, 0.73, 0.80) for pemphigus and BP, respectively. Mild or strong correlations were also observed between QOL and antibody titers in pemphigus with DSG1/DSG3(r=0.32/0.36) and BP with BP180/BP230( r = 0.73/0.17) respectively. Conclusion: The QOL of patients with pemphigus and BP decreased with increased severity of the AIBDs. As the disease severity descended, so the QOL improved. The QOL indices should be used in clinical trials and to manage patients’ treatment, especially during the active disease stage, despite the mild correlation observed after 1 month of treatment.The PDAI to be better at assessing disease severity than the ABSIS in patients with pemphigus, and ABSIS are better than BPDAI in BP patients for correlation with the QOL indices.


Introduction
Pemphigus and bullous pemphigoid (BP) are the most common, life-threatening chronic autoimmune blistering diseases (AIBDs) that affect the skin and mucous membranes [1,2]. Pemphigus includes two main pemphigus variants of pemphigus vulgaris(PV) and pemphigus foliaceus(PF), PV is characterised by painful oral erosions and presented as enanthema and erosions, while PF is originated with exclusive skin lesions.Pemphigus erythematosus(PE) is a clinical subtype of PF,which presentes as erythema,erosions and so-called puff pastry-like scaling on the face,back,and trunk. Paraneoplastic pemphigus (PNP) as rare pemphigus variants accounts for about 5%of pemphigus [1]. Pneumonia and septicaemia were the most frequent causes of death,followed by cardiovascular diseases and peptic ulcer disease.Skin barrier, breakdown and infection of the oral cavity thereby affecting nutrition, and the need for steroids and immunosuppressants to treat the disease can present nancial di culties, all resulting in signi cant physical and psychological burdens for the patients [3,4]. Studies have shown that pemphigus and BP adversely affect a patient's quality of life (QOL), by impacting their emotions, physical health, and social functioning [4,5]. With different clinical manifestations, the pemphigus subtypespemphigus vulgaris (PV), pemphigus foliaceus (PF), and paraneoplastic pemphigus (PNP) [1,6] -have varying effects on patients' QOL.
The impact of the disease on QOL is now receiving more attention from doctors, and studies have been conducted to develop new QOL tools, such as the Autoimmune Bullous Disease Quality of Life (ABQOL), Treatment Autoimmune Bullous Disease Quality of Life (TABQOL), and Dermatology Life Quality Index (DLQI) questionnaires to evaluate patients and their QOL [3-5, 7, 8]. Some studies have also investigated the correlations between disease severity and QOL in different disease pro les [9]. A recent study by Krain et al. [10]showed that the autoimmune bullous skin disorder intensity score (ABSIS) was weaker than the pemphigus disease area index (PDAI) in 50 patients with mild pemphigus, and did not incorporate data on comorbid conditions. However, this study did not include all data-points, and did not investigate patients with various pemphigus subtypes, including PV,PF and PNP.
The aim of this prospective study was to investigate the correlation between disease severity and QOL in Chinese patients with pemphigus (including PV, PF, and PNP) and BP at baseline, and after 1, 3 and 6 months of treatment, with the aim to reduce administration of glucocorticoids and immunosuppressants.
A better understanding of this relationship could help in managing the treatment of patients with pemphigus and BP.
The higher the scores, the worse the QOL indices. The ABQOL and TABQOL questionnaires each consist of 17 questions for patients with AIBDs, covering topics such as pain, itch, and work discrimination [19][20][21]. The DLQI is a 10-question survey, with possible scores ranging from 0 to 30 points [4]. All patients diagnosed with pemphigus or BP, or relapsed for the rst time (baseline), were invited to participate in follow-up visits. Patients completed the ABQOL, TABQOL, and DLQI of QOL forms and were assessed by a doctor using the PDAI/BPDAI and ABSIS scoring systems at baseline, and after 1, 3 and 6 months of treatment.
Pemphigus and BP patients accompanying comorbid conditions are also need to assess whether there is a signi cant difference in scores between the 'complication' group and the 'non-complication' group.

Statistical Analysis
The correlations between the severity of the disease(PDAI/BPDAI,ABSIS,antibody titers) and QOL(ABQOL,TABQOL,DLQI) were analyzed using Spearman's correlation coe cient (r) for all components and a mixed linear model for changes of the average trend. Spearman correlation coe cient cut-offs for the absolute value of 0 − 0.19, 0.2 − 0.39, 0.4 − 0.59, 0.6-0.79, and 0.8 − 1.0 corresponded to weak, mild, moderate, strong, and very strong, respectively [22]. Statistical signi cance was de ned by a P-value < 0.05. SPSS version 24 was used to conduct the analyses.

Results
A total of 85 patients, including 55 (65%) with pemphigus and 30(35%) with BP were recruited to the study. The pemphigus group included 32 (58%) with PV, 22(40%) with PF, and one (2%) with PNP after 3 months of treatment, and 65 (76%) of the patients(35 pemphigus and 30 BP) completed the 6-month follow-up. The mean age was 56.2 (range 28 − 82) years and the male-to-female ratio was 5:6. Table 1 illustrates the total demographic and disease characteristics of the patients with pemphigus and BP. Figure 1 show the mixed linear model for the changes in median QOL (ABQOL,TABQOL,DLQI) indices and disease severity indices (PDAI/BPDAI, ABSIS) in 85 Chinese patients with pemphigus and BP at baseline, and after 1 and 3 months of treatment. Figure 2 show the changes in 65 patients with pemphigus and BP at baseline, and after 1, 3 and 6 months of treatment.
The median disease severity (median PDAI/BPDAI, ABSIS) scores are shown in Table 2. The median scores of PDAI/BPDAI, ABSIS are shown for the pemphigus and BP patients at baseline all were ≥ 45.

Discussion
AIBDs are severe, chronic diseases with an enduring course that requires long-term treatment, resulting in decreased QOL [1,2]. Previous studies recruited 70 patients with AIBDs to develop a 45-item pilot ABQOL and TABQOL questionnaire to assess QOL, and concluded that the ABQOL may serve as an end-point in clinical trials with adequate validity and reliability [8,19]. Previous studies have examined QOL in patients with AIBDs using various measurement tools, such as the ABQOL in USA [3], the Chinese version of ABQOL and TABQOL [7,8]and the Polish versions of the ABQOL and TABQOL [20], thus verifying the e cacy of the Chinese version of the QOL questionnaire for this study.
Hébert et al. [11] concluded-after studying 50 patients-that the PDAI and ABSIS are effective tools to assess pemphigus activity. Ferries et al. [21]assessed the correlation between the severity of disease (PDAI/BPDAI) and QOL (ABQOL, TABQOL, DLQI, Skindes-29) in pemphigus and BP patients, with different assessment tools compared with our study. The previous studies had some limitations, such as the effect of comorbid conditions, follow-up visits, and the addition of more disease severity tools, such as antibody titers [23]. In this study, we described and evaluated the correlation between disease severity (PDAI/BPDAI, ABSIS) and QOL (ABQOL, TABQOL, DLQI) at baseline, and after 1, 3, and 6 months of treatment in Chinese patients with pemphigus and BP to exclude these limitations.
Our median PDAI/BPDAI ABSIS score and IQR in table 2 illustrated the pemphigus and BP patients can be applicable to patients with moderate to severe disease.Strong correlations were found between the QOL indices (ABQOL,TABQOL,DLQI) and the disease severity indices (PDAI/BPDAI,ABSIS), showing a decrease in QOL with increased pemphigus and BP disease severity. A notable exception was the mild correlation between disease severity indices and QOL after 1 month of treatment. The mild and moderate correlations were observed between the PDAI and ABQOL, TABQOL in the pemphigus (PV, PF) group, and between the BPDAI and TABQOL in the BP group. The patients with pemphigus (including PV and PF) tended to recover after 1 month of treatment, but the administration of steroids and immunosuppressants resulted in diet and health recovering more slowly, leading to adverse emotions and nancial worries, resulting in high QOL scores, even though the disease severity had decreased. All of the indices showed a mild or strong correlation with each other and the PDAI was greater than the ABSIS in patients with pemphigus, which is consistent with previous studies [21]; The ABSIS was greater than the BPDAI in patients with BP. The correlation between QOL and the severity of pemphigus after 6 months of treatment was 0 in the pemphigus group, which could be due to pemphigus being more severe than BP, and requiring longer treatment, with greater economic pressure. For most pemphigus patients, after 6 months of treatment the condition is under control and at the stage of drug reduction, which is why there was no obvious correlation between QOL and disease severity in pemphigus patients at Month 6.
The correlations of the subcomponents of BPDAI with ABQOL, TABQOL, and DLQI are varied. The correlations with the BPDAI erosion/blister score at baseline are the "strongest" and the correlations with BPDAI erythema/urticaria at month 1 are the "strongest". This is considered to be the result of treatment between baseline and month 1. The correlations with BPDAI mucosal blister/erosions score are all weak, due to the BP involved mucosal are few.
Dsg1 and Dsg3 are the major target antigens in pemphigus, and BP180 and BP230 are also target antigens in BP; Both autoantibodies are related to disease severity [1,2,24].As predicted, we found that the antibody titers had both mild and strong correlations with QOL. In our study,we found that mild and strong correlations were also observed between QOL and antibody titers in pemphigus with DSG1(r = 0.32),DSG3(r = 0.36) and BP with BP180(r = 0.73),BP230(r = 0.17) respectively, In particular DSG3 (for pemphigus) and BP180 (for BP) both showed "strong" correlations, which was also explained from the other side the correlation between disease severity with QOL and this phenomenon is consistent with the main pathogenic antibodies of clinical diseases.When autoantibodies decreased in the pemphigus and BP patients, the QOL scores also decreased, which shows that the improvement in the disease severity is particularly important for the improvement of the QOL. Our study illustrates that it is important for patients with pemphigus and BP to control any complications during treatment, although we found no difference between the complication and non-complication groups.
Our study also compared the PDAI/BPDAI and ABSIS using the Spearman's correlation coe cient (r). We found the PDAI was better at assessing disease severity than the ABSIS in patients with pemphigus, based on the correlation with the QOL indices. However, the ABSIS are prior to BPDAI in terms of correlation with the QOL indices. We believe the reason for this is that the BPDAI includes the main subcomponents: blisters/erosions, cutaneous urticaria/erythema, and mucosal blisters/erosions, and are also include objective measurement of pruritus with 30 scores, which may mean that the BPDAI scores are less sensitive than ABSIS.
In the future, our study needs to be repeated at a multicenter institution where more pemphigus and BP patients can be recruited, including other rare types of AIBDs patients. Our study would bene t from the addition of Skindex-S and Skindex-29 to the QOL tools to evaluate the correlations between disease severity and QOL. Despite its limitations, we have described the correlation between QOL (ABQOL, TABQOL, DLQI) and disease severity (PDAI/BPDAI, ABSIS) in Chinese patients with pemphigus (PV, PF) and BP at baseline, and after 1, 3 and 6 months of treatment.

Conclusion
We identi ed the correlation between the disease severity index (PDAI/BPDAI, ABSIS) and QOL (ABQOL, TABQOL, DLQI). QOL should be included in clinical trials and in management of the treatment of Chinese patients, especially when the disease is active, despite the mild correlation observed at 1 month. Patients' families and clinical staff should pay more attention to QOL assessments. Future studies should include the Skindex-S subscale of the Chinese version of the Skindex-29 as a QOL tool to assess disease severity indices, and the sample size should be expanded to elucidate the utility of the various disease severity tools with QOL.

ACKNOWLEDGMENTS
The authors are grateful to all participants and assessors for their contribution.

Funding
The study did not receive funding.

Availability of data and materials
The dataset supporting the conclusions of this article may be available upon request from the lead author to ensure any changes to the project do not invalidate the project's ethical approval in accordance with the Ethics Committee of Shandong Provincial Hospital for Skin Diseases approval letter.