Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2024;14(4):e2024280 1 Impact of Pemphigus on Sleep Quality: A Prospective Observational Single-Center Case-Control Study Vincenzo Maione1, Stefano Bighetti1, Sara Rovaris1, Chiara Cozzi1, Cesare Tomasi1, Piergiacomo Calzavara-Pinton1, Luca Bettolini1 1 Dermatology Department, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy Key words: Pemphigus, Sleep, Quality of life Citation: Maione V, Bighetti S, Rovaris S, et al. Impact of Pemphigus on Sleep Quality: A Prospective, Observational, Monocentric Case- Control Study. Dermatol Pract Concept. 2024;14(4):e2024280. DOI: https://doi.org/10.5826/dpc.1404a280 Accepted: Augus 8, 2024; Published: October 2024 Copyright: ©2024 Maione et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Dr Vincenzo Maione, Department of Dermatology, Spedali Civili, University of Brescia, Piazzale Spedali Civili, 1, 25123, Brescia (BS), Italy. Tel +39 030 3995301 Fax +39 0303995015 Email: maionevincenzo@gmail.com Introduction: Pemphigus, an autoimmune disorder, significantly impacts the quality of life for those affected. Objective: This study examined the sleep quality in patients with pemphigus, a domain for which the existing literature provides limited data without a focused analysis. Methods: A total of 156 individuals, 52 in the case and 104 in the control group, completed several questionnaires (Pittsburgh Sleep Quality Index [PSQI], General Health Questionnaire-12 [GHQ-12], and ABQOL [Autoimmune Bullous Disease Quality of Life]). Disease severity was evaluated using the Pemphigus disease area index (PDAI index). Results: The case group exhibited significantly higher levels of psychological distress, reflected in GHQ- 12 scores (P = 0.00), and notably poorer sleep quality compared to controls across various parameters (sleep latency [SL], disturbances [SDi], medication [SM], daytime sleep dysfunction [DSD]), and the global PSQI score (GS)] (P = 0.00)). Significant correlations were observed between PDAI scores and sleep dura- tion (SDu) (P = 0.01), SM (P=0.03), SL (P =0.03), and GS (P=0.00). An association was found between the equivalent steroid intake and SDu (P=0.00) as well as GS (P=0.02). No statistically significant correlation emerged between disease duration and PSQI scores. Our findings indicated a correlation between poor sleep quality and cutaneous rather than mucosal manifestations (p=0.01). Pemphigus affects sleep quality. Severe disease showed heightened SDi, correlating with higher steroid doses, and in the chronic phase, the impact seems to have been more influenced by the pro-inflammatory stage of the disease. Patients with cutaneous pemphigus exhibited reduced sleep quality compared to those with oral pemphigus. Conclusion: Understanding that pemphigus worsens sleep quality can be beneficial for the holistic management of individuals with this condition. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2024;14(4):e2024280 Introduction The quality of sleep in autoimmune diseases is a growing area of interest in medical research with sleep disturbances being prevalent among patients with autoimmune disorders. As example, patients with multiple sclerosis often experience sleep disturbances like insomnia and restless legs syndrome which may be linked to neurological damage and inflamma- tion significantly impacting the patient’s quality of life [1]. In lupus patients, sleep deprivation can exacerbate disease symptoms; sleep fragmentation and altered sleep-stage tran- sitions are common, contributing to increased fatigue and health deterioration [2]. Finally, rheumatoid arthritis is associated with a higher incidence of sleep apnea, where chronic inflammation and pain interfere with sleep, further aggravating daytime fa- tigue [3]. In dermatology, most studies on sleep quality have been dedicated to psoriasis and atopic dermatitis, and the litera- ture provides very limited data on the relationship between sleep quality and autoimmune blistering diseases [4]. In particular, pemphigus is the autoimmune blistering disease with the greatest clinical impact and, consequently, the most significant influence on patients’ quality of life (QoL). This is due to various factors, such as the chronic nature of the disease, its severe impact on sensitive areas like mucous membranes, and the necessity for long-term man- agement Several tools have been developed to standardize the evaluation of disease severity and its influence on QoL. However, there is limited literature available on the sleep quality of individuals affected by pemphigus. Our primary objective in conducting a prospective obser- vational single-center case-control study was to investigate the impact of pemphigus on this topic. Methods The study, conducted between March 2019 and November 2021, recruited participants from the outpatient clinic of the Dermatology Department at the University Hospital of Bres- cia, Italy. This hospital is a designated European Reference Network (ERN) for pemphigus. Patients with a confirmed diagnosis of pemphigus through histological examination plus serology (or serology plus positive DIF) were included in the case group, while the control group consisted of healthy individuals with no history of pemphigus or other systemic diseases or medications that could bias the study results. Both groups had to be aged between 18 and 75 years and possess the cognitive ability to complete the questionnaires provided. The case group was purposely selected, while the control group was chosen based on convenience. During the visit, demographic and clinical information such as age, sex, and comorbidities were recorded. For the case group, the age at which pemphigus was diagnosed, disease duration, type of pemphigus, and affected sites were documented through questionnaires, along with the concomitant and previous treatments administered over time for both groups. Data were collected through self-administered ques- tionnaires designed to evaluate the impact of pemphigus on patients’ quality of life and sleep quality. Both groups com- pleted the same questionnaires. Pittsburgh Sleep Quality Index Questionnaire (PSQI) The Pittsburgh Sleep Quality Index (PSQI) [5] is a self-rated tool used to evaluate various dimensions of sleep, such as sleep quality (SQ), sleep duration (SDu), sleep latency (SL), sleep disturbances (SDi), sleep efficiency (SE), daytime sleep dysfunction (DSD), sleep medications (SM), and global score (GS) over a 1-month period. It includes a cutoff score of 5 to differentiate between good and poor sleep quality. General Health Questionnaire-12 (GHQ-12) The level of mental well-being was evaluated in both the case and control groups through the GHQ-12 questionnaire [6]. The scores obtained from the questionnaire were utilized to distinguish between individuals experiencing psycholog- ical distress and those who were not. Scores exceeding 14 indicated the presence of psychological distress. Further- more, the scores were categorized into mild (15-18) and moderate-severe (19-36) ranges. Autoimmune Bullous Disease Quality of Life Questionnaire (ABQOL) The ABQOL questionnaire, used to evaluate the quality of life of patients with autoimmune bullous diseases like pem- phigus, was completed only by patients diagnosed with pemphigus. The questionnaire comprises 17 items that as- sess different aspects of the patient’s life, such as physical symptoms, psychological well-being, social functioning, and treatment-related factors [7]. During the study, the participants were provided with clear instructions on how to fill out the questionnaires. They were also given the opportunity to request further clarifica- tion if needed. Pemphigus Disease Area Index (PDAI) In the case of patients with pemphigus, an expert dermatol- ogist was responsible for assessing their Pemphigus Disease Area Index (PDAI) scores. The scores were categorized as follows: scores below 15 indicated mild pemphigus, scores between 15-45 indicated mild disease, and scores above 45 indicated extensive disease [8]. The study was approved by the local ethics committee, and all participants provided written informed consent. We conducted the study following the principles of the Original Article | Dermatol Pract Concept. 2024;14(4):e2024280 3 Declaration of Helsinki, ensuring the confidentiality of all participants’ data, and their right to withdraw from the study at any time was guaranteed. The encoded and anonymous database was formatted using Microsoft-Excel TM software and subsequently im- ported from IBM-SPSS TM ver. 27.1. Epi-Info StatCalc® software ver. 7.2 was used to cal- culate the sample size, sampling tests was calculated at the power level 1-beta = 80%, alpha = 5% two-tailed. The ratio of controls to cases is equal to 2, and the percentage of con- trols exposed is equal to 40%. Assuming an odds-ratio of 3 are calculated 42 cases and 83 controls with Kelsey test. Descriptive statistics such as mean, standard deviation, median, and range were calculated for continuous variables. The Kolmogorov-Smirnov test was used to assess the nor- mality of the distributions. The Mann-Whitney U test and Kruskal-Wallis H test were used to compare non-normally distributed continuous variables between groups, while the independent samples t-test was used to compare normally distributed continuous variables. Categorical variables are presented as frequency counts, percentages and analyzed us- ing the Chi-square test or Fisher’s exact test, when appropri- ate. The Chi-square test for 2x2 tables was used to calculate the odds ratio. A p-value of less than 0.05 was considered statistically significant for all analyses. Results The study involved 156 participants: 52 in the case group (21 males, 31 females, average age 57.96 ± 15.78 years) and 104 in the control group (46 males, 58 females, aver- age age 51.98 ± 14.01 years). The pemphigus patients were diagnosed at an average age of 52.92 ± 15.13 years and followed up for a median of 2.5 years (range: 0-22). Most patients in the case group (86.54%) had pemphigus vul- garis, while 13.46% had the foliaceous form. The majority had cutaneous involvement (69.23%), followed by mucosal involvement (26.92%), and concurrent skin and mucous membrane involvement (3.85%). The median methylpred- nisolone equivalent dose was 0.75 (range: 0–16). All but one patient received steroid therapy, either alone or with steroid- sparing agents. Azathioprine was prescribed to 23 patients, 17 received plasma exchange, one received intravenous im- munoglobulins, six were treated with rituximab, 18 with mycophenolate, and 18 with dapsone. The analysis revealed that cases had significantly poorer sleep quality than did controls, indicated by the global score (GS) and most individual domains, including sleep latency (SL), sleep disturbance index (SDi), sleep medica- tion (SM), and daytime sleep dysfunction (DSD) (Figure 1). A Pearson chi-squared test on GHQ-12 scores, stratified by 3.5 3 2.5 2 1.5 1 0.5 0 SL EE P Q U A LI TY CONTROL CASE p = .49 3.5 3 2.5 2 1.5 1 0.5 0 SL EE P D U RA TI O N CONTROL CASE p = .14 3.5 3 2.5 2 1.5 1 0.5 0 SL EE P LI TE RA CY CONTROL CASE p = .00* 3.5 3 2.5 2 1.5 1 0.5 0 SL EE P D IS TU RB A N CE CONTROL CASE p = .00* 3.5 3 2.5 2 1.5 1 0.5 0 SL EE P EF FI CI EN CY CONTROL CASE p = .63 3.5 3 2.5 2 1.5 1 0.5 0 D AY TI M E SL EE P D YS FU N C TI O N CONTROL CASE p = .00* 3.5 3 2.5 2 1.5 1 0.5 0 SL EE P M ED IC AT IO N CONTROL CASE p = .00* 25 20 15 10 5 0 G LO BA L SC O PE CONTROL CASE p = .00* Figure 1. Boxplot of PSQI for each domain examined in the study between cases and controls. The box plot lines correspond from bottom of box to top: 25th percentile, median percentile, 75th percentile. Whiskers extend from both ends of the box to the data points located within the lower quartile minus 1.5 times the interquartile range (IQR) or the upper quartile plus 1.5 times the IQR. Data points beyond these whiskers are plotted individually as points and are considered outliers. p-values presented as from a Mann–Whitney test of differences across the case/control groups. *Statistically significant difference in medians between cases and controls. 4 Original Article | Dermatol Pract Concept. 2024;14(4):e2024280 observed across PSQI subdomains regarding the localization of pemphigus symptoms. Discussion Sleep is a fundamental component of personal well-being and plays a pivotal role in the degradation of the quality of life in chronic conditions [9]. Although bullous diseases are rare, they often progress to chronic states, leading to a deterioration in various aspects of patients’ quality of life [10]. Our study sought to offer a more precise understanding of the influence of pemphigus on the sleep quality of these patients. The literature on the relationship between sleep and pemphigus is notably limited. Probable causes for this scar- city may be attributed to the rarity of the pathology and the age of patients affected by pemphigus, often younger than others affected by other chronic diseases, where the impact on sleep could be more evident. In a study by Hsu and colleagues [11] involving 130 cases, a correlation between pemphigus and insomnia was highlighted, linked to steroid intake. However, it is im- portant to note that due to the study’s structure, additional psychological distress severity, showed significant differences between the groups (P = 0.001), indicating higher psycholog- ical distress among cases (Table 2). Table 3 demonstrated a significant correlation between PDAI scores and parameters such as SDu, SL, SM, and GS. Additionally, ABQOL scores were significantly correlated with various PSQI domains, including sleep quality (SQ), SL, SDi, DSD, and GS. We investigated the relationship between PSQI-measured sleep quality and daily steroid doses, considering known side effects. Spearman’s correlation showed significant links be- tween corticosteroid dosage and sleep quality, particularly GS (P=0.02) and SDu (P=0.00) (Table 3). The dosage also correlated significantly with disease severity (PDAI score, P=0.00). Despite aiming to assess the impact of cumulative corti- costeroid therapy on sleep quality, determining the total dose was challenging. Disease duration was used as an indirect in- dicator, but no significant correlation with PSQI was found. Further analysis indicated a significant impact of cutaneous symptoms on sleep quality (p=0.01), with no significant impact from mucosal symptoms (P=0.22). No trends were Table 1. Baseline and Demographic Characteristics. Variables Case Group (N=52) Control Group (N=104) Sex, n (%) Male 21 46 Female 31 58 Age (y), mean (DS) 57.96 (15.78) 51.98 (14.01) Age at diagnosis (y), mean (DS) 52.92 (15.13) Follow-up time (y), median (range) 2.5 (0-22) Subtype, n (%) Vulgaris 42 (86.54) Foliaceous 7 (13.46) Involvement at the visit, n (%) Cutaneous 36 (69.23) Mucosal 14 (26.92) Both 2 (3.85) Concomitant methylprednisolone equivalent dose, median (range) 0.75 (0-16) Previous therapies, n (%) Corticosteroids 51 (98) Azathioprine 23 (44) Mycophenolate mofetil 18 (34) Dapsone 18 (34) Plasmapheresis 17 (32) Rituximab 6 (11) Intravenous immunoglobulin 1 (2) Original Article | Dermatol Pract Concept. 2024;14(4):e2024280 5 It should be emphasized that in our study, steroid dosage was higher in more severe patients, potentially correlating with the deterioration of the PSQI. However, when consid- ering the duration of steroid treatment and, consequently, the cumulative role of such therapy, a direct correlation with the worsening of sleep quality is not evident. Likely, while in the acute phase of the disease, high steroid dosage may compromise the normal sleep quality, in patients with long- standing disease, the pro-inflammatory state associated with information from the sample, such as standardized extent of pemphigus, steroid dosages used, and the duration of treatment, is not obtainable. In our study, we confirm the relationship between pemphigus and sleep. Patients with more severe manifestations, and consequently a higher PDAI score, exhibit a significant deterioration in various domains of the PSQI. This finding becomes even more crucial consid- ering the overall worsening reported by patients, evaluated through specific questionnaires dedicated to the condition. Table 2. Quality of Life Comparisons Between Case and Control Groups. PSQI Case group (n=52) Control group (n=104) p-valuemean (min-max) mean (min-max) Sleep quality (SQ) 1.06 (0-3) 0.96 (0-3) .49 Sleep duration (SDu) 0.86 (0-3) 0.59 (0-3) .14 Sleep latency (SL) 1.18 (0-3) 0.61 (0-2) .00* Sleep disturbances (SDi) 1.40 (0-3) 1,00 (0.3) .00* Sleep efficiency (SE) 0.78 (0-3) 0.98 (0-3) .63 Daytime sleep dysfunction (DSD) 0.68 (0-3) 0.22 (0-3) .00* Sleep medication (SM) 0.94 (0-3) 0.39 (0-3) .00* Global score (GS) 6.90 (1-20) 4.75 (0-12) .00* Sleep quality, n (%) Good 20 (38) 64 (62) Poor 32 (62) 40 (38) GHQ-12 Case group (n=52) Control group (n=104) P-value .00*n % n % None 11 21 48 46 Mild 26 50 46 44 Moderate-severe 15 29 9 9 Abbreviations: GHQ-12: General Health Questionnaire-12. Table 3. Correlation Analysis Between PSQI And Disease Severity Scores and Steroid Intake. PDAI (n=52) ABQOL (n=52) Equivalent Steroid Intake r p-value r p-value r P-value PSQI Sleep quality (SQ) .28 .05 .37 .00* .25 .08 Sleep duration (SDu) .35 .01* .05 .76 .38 .00* Sleep latency (SL) .31 .03* .31 .03* .18 .22 Sleep disturbances (SDi) .16 .27 .33 .02* .03 .85 Sleep efficiency (SE) .05 .72 -.01 .94 .13 .38 Daytime sleep dysfunction (DSD) .19 .18 .35 .01* .29 .10 Sleep medication (SM) .30 .03* .11 .47 .05 .75 Global score (GS) .46 .00* .39 .00* .33 .02* Abbreviations: ABQOL: Autoimmune Bullous Disease Quality of Life questionnaire; PDAI: Pemphigis Disease Area Index; PSQI: Pittsburgh Sleep Quality Index questionnaire. 6 Original Article | Dermatol Pract Concept. 2024;14(4):e2024280 the inclusion of an additional control group of autoimmune diseases typically treated with steroids. Further investiga- tions in this domain are warranted to validate the identified findings. References 1. Pèrez-Carbonell L, IranzoA. Sleep disturbance in Autoimmune neurological disease. 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Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour the pathology continues to play a more significant role. This observation is supported by various studies indicating that the disruptive effect of corticosteroids on sleep appears to be dose-related and not time-related [12-13]. A more intriguing hypothesis, proposed by other authors [14], revolves around the role of bidirectional immunological interplay between pemphigus and sleep. Pemphigus is characterized by an in- crease in cytokines such as IL-6 and TNF-alpha [15], which seem to influence brain activity during the NREM and REM phases of sleep [16-17]. On the other hand, consequent sleep deprivation could potentially enhance the production of these cytokines, thereby impacting the course of the pathol- ogy and hamper the patient’s recovery. However, it should be emphasized that beyond the immunological context, in our sample of pemphigus patients, there was evident psychologi- cal distress that could have played a role in the deterioration of sleep quality. Furthermore, as our data do not allow us to date the onset of psychological distress, we cannot exclude its occurrence before pemphigus and, consequently, assess its subsequent impact. An additional aspect of our study aimed to evaluate the impact of oral lesions on the quality of sleep of pemphigus patients. In a study on oropharyngeal pemphigus, Calabria and colleagues [18] reported a lower quality of sleep in pa- tients with oropharyngeal pemphigus compared to a healthy control group. Moreover, there was no statistically signifi- cant difference in the case group when comparing patients’ presence or absence of steroid therapy, or in consideration of the cumulative time of the disease duration. These data appear interesting; however, their further analysis seems lim- ited due to the absence of a group of patients with cutaneous lesions. Differently, our data reveal that individuals with a predominant mucosal involvement experience a lesser im- pact on sleep compared to those with a predominant cuta- neous manifestation. This result could be interpreted in light of a higher expression of certain cytokines, such as IL-6, in cutaneous lesions of pemphigus compared to oral lesions, consequently leading to a greater impact on the quality of sleep in patients with skin involvement [19]. Conclusion This study underscores the imperative to investigate the quality of sleep in individuals with pemphigus, considering the enduring and substantial impact of the disease on this fundamental aspect of well-being. However, it is crucial to acknowledge the limitations inherent in this study, such as the relatively small sample size and the single-center nature of the research design. Another factor that could have influ- enced the study’s outcome was the absence of patients with pemphigus in complete remission without steroid therapy or Original Article | Dermatol Pract Concept. 2024;14(4):e2024280 7 18. Calabria E, Adamo D, Leuci S, et al. The health-related quality of life and psychological profile in patients with oropharyngeal Pemphigus Vulgaris in complete clinical remission: A case- control study. J Oral Pathol Med. 2021;50(5):510-519. DOI: 10.1111/jop.13150. 19. Timoteo RP, da Silva MV, Miguel CB, et al. Th1/Th17- Related Cytokines and Chemokines and Their Implications in the Patho- genesis of Pemphigus Vulgaris. Mediators Inflamm. 2017;2017: 7151285. DOI: 10.1155/2017/7151285. necrosis factor-alpha levels are significantly increased as com- pared to healthy subjects and correlate with disease activity. Eur Cytokine Netw. 1997;8(4):383-387. 16. Fang J, Wang Y, Krueger JM. Mice lacking the TNF 55 kDa receptor fail to sleep more after TNFalpha treatment. J Neuro- sci. 1997;17(15):5949-5955. DOI: 10.1523/JNEUROSCI.17-15 -05949.1997. 17. Späth-Schwalbe E, Hansen K, Schmidt F, et al. Acute effects of recombinant human interleukin-6 on endocrine and central ner- vous sleep functions in healthy men. J Clin Endocrinol Metab. 1998;83(5):1573-1579. DOI: 10.1210/jcem.83.5.4795.