Psychological morbidity in patients with pemphigus and its clinicodemographic risk factor: A comparative study

Due to the long disease duration, impact on appearance, social stigmatization, and numerous side effects of treatment, pemphigus, an autoimmune bullous disease, often has a significant psychological impact on patients. On the other hand, mood disorders may exacerbate the disease by affecting the patient's self‐management, forming a vicious circle. To investigate anxiety and depressive disorders in patients with pemphigus, a total of 140 patients with pemphigus were recruited for this cross‐sectional retrospective study between March 2020 and January 2022. A control group of 118 patients with psoriasis, a commonly known psychosomatic dermatosis, was established. Patients were evaluated at the visiting day with the Beck Anxiety Inventory and Beck Depression Inventory second edition for mood disorders, the Dermatology Life Quality Index and the EuroQol Five Dimensions Questionnaire for disease‐related life quality, and the Visual Analogue Scale for pain and itching symptoms. In our cohort, 30.7% of patients with pemphigus suffered from either anxiety disorder (25%) or depressive disorders (14.3%). Propensity score matching was implemented to create a comparable cohort of pemphigus and psoriasis groups considering the baseline discrepancy. Thirty‐four comparable pairs of pemphigus and psoriasis patients were extracted. The prevalence and severity of depressive disorder in pemphigus patients were significantly higher than in psoriasis patients, while anxiety disorder levels appeared to be similar in two groups. Multivariate logistic regression analysis further revealed that disease‐related hospitalization history, active mucosal damage, and concomitant thyroid disease are independent risk factors for mood disorders in pemphigus patients. Our results showed that pemphigus patients had a high prevalence and severity of mood disorders. Relevant clinicodemographic indicators may be valuable for prediction and early identification of mood disorders in pemphigus. Better disease education from physicians may be important for these patients to achieve overall disease management.


| INTRODUC TI ON
Pemphigus is a group of severe autoimmune bullous diseases characterized by painful blisters of the skin and/or mucous membranes that easily rupture and form erosions.Several studies have estimated the incidence of pemphigus worldwide to be 0.6-32 per million person-years.Mean onset age is usually between 45 and 65 years. 1 Treatment of pemphigus is challenging and relies on the long-term use of high-dose systemic corticosteroids and other immunosuppressants.More recently, biologics such as Rituximab targeting CD20 have been emerging as novel treatment options. 1 However, due to the long disease duration, impact on appearance, social stigmatization, and large side effects of treatment, pemphigus has a significant psychological impact on patients.
[4][5][6][7] These skin diseases exert a negative effect on patients' social activities, interpersonal relationships, sex life, and self-estimation.On the other hand, mood disorders may exacerbate the condition by affecting the patient's self-management, forming a vicious circle.Psoriasis has been considered as a representative psychosomatic dermatosis with a well-established relationship with mood disorders.A variety of questionnaire tools have been applied to screen psoriasis patients for psychological symptoms, the improvement of which has been set as a secondary treatment objective to achieve better disease management. 4,5,8wever, probably due to the rarity of the disease, the way in which mood disorders affect patients with pemphigus has not had the attention of dermatologists.Population-based studies in Israel and Taiwan suggest that patients with pemphigus were 1.19-1.983][14] Few studies have elucidated the recognizable risk factors for psychological morbidities in pemphigus patients.
Thus, this study sought to assess the prevalence of anxiety and depressive disorders in patients with pemphigus compared with those with psoriasis and to identify the clinic-demographic risk factors.

| Dermatological assessment
General information (age, gender, body mass index [BMI], tobacco and alcohol use, comorbidities), disease characteristics (onset age, disease duration, recurrent times, lesion locations, disease stage, disease severity, treatment), and patient-reported symptoms including pruritus and pain assessed by the Visual Analogue Scale (VAS) were collected.The Pemphigus Disease Area Index (PDAI) and the Psoriasis Area and Severity Index (PASI) were performed on all pemphigus and psoriasis patients, respectively, on their visiting day.

| Mental health assessment
Patients were requested to respond to the Beck Anxiety Inventory (BAI) and Beck Depression Inventory-II (BDI), two well-established modalities to screen for anxiety and depression.Each scale included 21 representative symptoms scored from 0 to 3 according to the individual answer. 15,16Validated cut-off values of 8 for BAI and 14 for BDI were used for the definition of the presence of psychological morbidities.Notably, these scales are insufficient substitutes for a clinical diagnosis made by a specialist but are valuable for early screening by dermatologists.The scales were chosen based on their guaranteed reliability and validity in the Chinese population, and better performance compared to other questionnaires in a German study on rheumatoid arthritis. 17,18

| Life quality evaluation
Life quality was evaluated by the Dermatology Life Quality Index (DLQI) and the EuroQol Five Dimensions Questionnaire (EQ-5D-5L).DLQI was designed by Professor Finlay AY and Khan GK in 1994 and has been long applied in various dermatological disorders.The questions cover commonly affected aspects, including symptoms and feelings, daily activities and leisure, school and work, social relationships, and skincare.DLQI scores of 0-1, 2-5, 6-10, 11-20, and 21-30 represents no, mild, moderate, severe, and extremely severe impairment of life quality, respectively. 19-5D-5L is a self-reported easy-to-use questionnaire that contains a five-dimension descriptive system and an EQ-Visual Analogue Scale (EQ-VAS).It showed good validity in pemphigus patients in its first application in Hungary.20 The five questions, which take seconds to ask, cover mobility, self-care, usual activities, pain/ comfort, and anxiety/depression.Selecting from five severity levels for each aspect, each of 3125 different answer combinations is assigned a utility value based on a 5L value set developed for the Chinese population that has been adjusted for societal factors, ranging from −0.391 to 1 (the worst and best life quality scores).21 EQ-VAS is a 20-cm, vertical VAS used to assess the patients' current self-estimated health status on a scale of 0 to 100.[20][21][22]

| Statistical analysis
Depending on data distribution, continuous variables were shown as mean ± standard deviation or median and interquartile ranges (Md, 25th percentile [P25], 75th percentile [P75]), while categorical variables were reported as numbers and percentages (n, %).
To realize a rigorous comparison and to exclude the impact of confounding factors, propensity score matching using nearest-neighbor matching (caliper = 0.1) was used to obtain a comparable cohort.
Quantitative variables were compared between the two groups with the Mann-Whitney U test or the t-test according to data distribution.Analysis of categorical variables was performed with the χ 2 (chi) test or Fisher's exact test when appropriate.Ordered three-category variables, such as disease severity which is graded as mild, moderate, and severe, were analyzed by the Cochran-Armitage test.Correlations were evaluated by Spearman's rank correlation coefficient (rs).
Multivariate logistic regression analysis was performed to identify the risk factors for anxiety and depressive disorders in pemphigus.During the analysis, the Box-Tidwell test was used to assess the assumption of linearity in the logit for continuous variables such as age and disease duration.The tolerance test and variance inflation factors were used to rule out multicollinearity.Results were expressed as the odds ratio (OR) and 95% confidence interval (95% CI).
All statistical tests of the hypothesis were two-sided and performed at the 0.05 level of significance.P<0.05 are marked with *, P < 0.01 are marked with **, P < 0.001 are marked with ***.
We employed SPSS Version 26.0 statistical software and R Studio 1.3.1093for data analysis and plot design.The following R packages were used: tableone, matching, survey, reshape2, data.table, ggplot2, and forestplot.

| Patient characteristics
One hundred and forty patients with pemphigus were included in our study, with a mean age of 52.48 ± 15.17 years and a male ratio of 43.6%.We also established a control group of 118 patients with psoriasis vulgaris who were younger (mean age 46.51 ± 15.22 years) with a higher proportion of males (66.9%).There were also significant differences between the pemphigus and psoriasis groups for BMI and the rate of active or previous smokers at baseline.Psoriasis appeared to arise earlier and persisted longer than pemphigus.These differences are all in line with the common knowledge of the two diseases.Comorbidities including diabetes mellitus, hypertension, coronary heart disease, and stroke occurred equally in the two groups (Supporting Information Table S1).The mean PDAI score in the pemphigus group was 9.72 ± 12.740 and the mean PASI score in the psoriasis group was 13.05 ± 9.259.

| Demographic characteristics and comorbidities in pemphigus patients stratified according to anxiety or depressive disorders
According to psychological assessment, 43 pemphigus patients (30.7%) with anxiety or depressive disorders and 97 patients (69.3%) without anxiety or depressive disorders were divided into two groups.There were no significant differences in age, sex distribution, smoke history, BMI, and patient source (outpatient or inpatient) between the two groups.In our cohort, 58 (41.4%) pemphigus patients had comorbidities, most commonly hypertension, diabetes mellitus (DM), and autoimmune thyroiditis (AIT).Higher percentages of anxious or depressed patients were found to be comorbid with AIT (P = 0.035) (Table 2).

| Disease-related characteristics in pemphigus patients stratified according to anxiety or depressive disorders
Table 3 shows the clinical characteristics of the studied patients.
In particular, the mean onset age of pemphigus in our cohort was 49.29 ± 15.05 years and the median disease duration was 25 (8.25, 53) years.In addition, 94 (67.1%) and 46 (32.9%) patients were diagnosed as PV and PF, respectively.The mean BDI score was 7.46 ± 6.601 in the PV group and 7.06 ± 5.976 in the PF group (P = 0.728).The mean BAI score was 5.57 ± 7.110 in the PV group and 4.17 ± 6.333 in the PF group (P = 0.256).Although PV was thought to exert a heavier psychological impact than PF, patients with the diagnosis of PV or PF distributed similarly in the groups with or without anxiety or depressive disorders in our study.Among all patients, 61 (43.6%) were with active disease, 57 (40.7%) patients were in partial remission and 22 (15.7%)patients were in complete clinical remission during drug tapering or under minimal dose therapy.Unexpectedly, mood disorders in pemphigus were also independent of disease stage.Pemphigus patients with anxiety or depressive disorders were more likely to have a disease-related hospitalization history (69.8% vs 13.4%, P = 0.011).Moreover, 61 (45%) pemphigus patients had experienced at least one previous recurrence.
More than two relapses were seen in nine (20.9%) patients with anxiety or depressive disorders, compared with nine (9.3%) of those without anxiety or depressive disorders, although the difference did not reach statistical significance (P = 0.057).We assessed the disease severity by PDAI score.Anxiety or depressive disorders were associated with a higher mucosal activity score (P = 0.038), whereas other components of the index were similar between the two groups.Patients with or without anxiety or depressive disorders did not differ in terms of onset age of pemphigus, disease duration, diagnosis, disease stage, involved sites of the lesions, and pemphigus-specific antibody titers.
Most patients received corticosteroids with or without immunosuppressors (42.1% and 41.4%) as their highest level of treatment regimen, followed by topical corticosteroids alone and Rituximab (12.1% and 4.3%).Anxiety or depressive disorders in pemphigus were F I G U R E 1 Plot of standardized mean difference (SMD) on covariables between the pemphigus and psoriasis groups before and after the propensity score matching.
not associated with different treatment options.However, patients with anxiety or depressive disorders tended to have higher current prednisone doses (17.65 ± 12.21 vs 13.89 ± 10.83 mg, P = 0.071) and higher rates of treatment-related adverse events (44.2% vs 27.8%, P = 0.057), although no statistical difference was found.

| Clinical indicators of anxiety or depressive disorders in pemphigus
A multiple logistic regression analysis was performed to look for the clinical indicators of anxiety or depressive disorders in pemphigus.

| DISCUSS ION
Pemphigus significantly impaired the mental well-being of patients, which was often overlooked by clinicians.In our cohort, 30.7% of This cross-sectional retrospective study was performed in the Department of Dermatology in Ruijin Hospital from March 2020 to January 2022.Consecutive patients with pemphigus vulgaris (PV) and pemphigus foliaceus (PF), the two common subtypes of pemphigus, were enrolled.The diagnosis of pemphigus was made based on clinical presentation, serology, direct immunofluorescence, and histopathology analysis.We also established a control group of histopathologically confirmed psoriasis vulgaris.Patients with psoriatic arthritis were excluded from this study.All patients signed informed consent.Patients under 18, those with a diagnosis of anxiety or depression before the onset of dermatologic disorders, and those with severe cognitive impairment were excluded from the study.The study protocol was approved by the Ethics Committee of Shanghai Jiaotong University Affiliated Ruijin Hospital (61/2014).
Life quality of pemphigus patients.(a) and (b) show the different impaired dimensions according to DLQI and EQ-5D-5L, respectively.DLQI, Dermatology Life Quality Index; EQ-5D-5L, EuroQol Five Dimensions Questionnaire.Clinical characteristics in pemphigus patients stratified according to anxiety or depressive disorders.
tients were significantly higher than those in psoriasis, while anxietyF I G U R E 2 *P < 0.05.TA B L E 2 Demographic information and comorbidities in pemphigus patientswith or without anxiety and depressive disorders.TA B L E 3