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Rituximab Treatment and Improvement of Health-Related Quality of Life in Patients With Pemphigus
Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.7 Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).8 Effective treatments may considerably improve the QOL of patients with pemphigus.6
Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.8 Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.
In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.
MATERIALS AND METHODS
Study Design
We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.
Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).
After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.
Patient-Reported Outcome Measures
The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.
The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.6
The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.16 The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.17,18 In this study, we used an MCD of a 5-point change or more between study groups.
Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).
Statistical Analysis
Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.
RESULTS
Patient Characteristics
A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.
Patient-Reported Outcomes
Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).
Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).
The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).
Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.
COMMENT
Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.
In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.21 The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis8 and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.
Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.23 These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.23
Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.
One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.
Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.
CONCLUSION
The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.
- Hammers CM, Stanley JR. Mechanisms of disease: pemphigus and bullous pemphigoid. Ann Rev Pathol. 2016;11:175-197.
- Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026.
- Mayrshofer F, Hertl M, Sinkgraven R, et al. Significant decrease in quality of life in patients with pemphigus vulgaris, result from the German Bullous Skin Disease (BSD) Study Group. J Dtsch Dermatol Ges. 2005;3:431-435.
- Terrab Z, Benckikhi H, Maaroufi A, et al. Quality of life and pemphigus. Ann Dermatol Venereol. 2005;132:321-328.
- Tabolli S, Mozzetta A, Antinone V, et al. The health impact of pemphigus vulgaris and pemphigus foliaceus assessed using the Medical Outcomes Study 36-item short form health survey questionnaire. Br J Dermatol. 2008;158:1029-1034.
- Paradisi A, Sampogna F, Di Pietro, C, et al. Quality-of-life assessment in patients with pemphigus using a minimum set of evaluation tools. J Am Acad Dermatol. 2009;60:261-269.
- Heelan K, Hitzig SL, Knowles S, et al. Loss of work productivity and quality of life in patients with autoimmune bullous dermatoses. J Cutan Med Surg. 2015;19:546-554.
- Ghodsi SZ, Chams-Davatchi C, Daneshpazhooh M, et al. Quality of life and psychological status of patients with pemphigus vulgaris using Dermatology Life Quality Index and General Health Questionnaires. J Dermatol. 2012;39:141-144.
- Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96:2343.
- Mohammad-Javad N, Parvaneh H, Maryam G, et al. Randomized trial of tacrolimus 0.1% ointment versus triamcinolone acetonide 0.1% paste in the treatment of oral pemphigus vulgaris. Iranian J Dermatol. 2012;15:42-46.
- Lunardon L, Tsai KJ, Propert KJ, et al. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol. 2012;148:1031-1036.
- Colliou N, Picard D, Caillot F, et al. Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci Transl Med. 2013;5:175ra30.
- Heelan K, Al-Mohammedi F, Smith MJ, et al. Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150:703-708.
- Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389:2031-2040
- Aryanian Z, Balighi K, Daneshpazhooh M, et al. Rituximab exhibits a better safety profile when used as a first line of treatment for pemphigus vulgaris: a retrospective study. Int Immunopharmacol. 2021;96:107755.
- Aghai S, Sodaifi M, Jafari P, et al. DLQI scores in vitiligo: reliability and validity of the Persian version. BMC Dermatol. 2004;4:8.
- Schünemann HJ, Akl EA, Guyatt GH. Interpreting the results of patient reported outcome measures in clinical trials: the clinician’s perspective. Health Qual Life Outcomes. 2006;4:62.
- Quality of life questionnaires. Cardiff University website. Accessed December 16, 2022. http://sites.cardiff.ac.uk/dermatology/quality-oflife/dermatology-quality-of-life-index-dlqi/dlqi-instructions-foruse-and-scoring/
- Kanwar AJ, Tsuruta D, Vinay K, et al. Efficacy and safety of rituximab treatment in Indian pemphigus patients. J Eur Acad Dermatol Venereol. 2013;27:E17-E23.
- Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, et al. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids. JAMA Dermatol. 2015;151:200-203.
- Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-216.
- Aghaei S, Moradi A, Ardekani GS. Impact of psoriasis on quality of life in Iran. Indian J Dermatol Venereol Leprol. 2009;75:220.
- Ware JE Jr, Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36). 1. conceptual framework and item selection. Med Care. 1992;30:473-483.
Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.7 Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).8 Effective treatments may considerably improve the QOL of patients with pemphigus.6
Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.8 Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.
In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.
MATERIALS AND METHODS
Study Design
We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.
Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).
After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.
Patient-Reported Outcome Measures
The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.
The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.6
The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.16 The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.17,18 In this study, we used an MCD of a 5-point change or more between study groups.
Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).
Statistical Analysis
Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.
RESULTS
Patient Characteristics
A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.
Patient-Reported Outcomes
Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).
Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).
The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).
Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.
COMMENT
Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.
In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.21 The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis8 and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.
Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.23 These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.23
Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.
One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.
Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.
CONCLUSION
The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.
Pemphigus is a group of autoimmune blistering diseases characterized by the development of painful and flaccid blisters on the skin and/or mucous membranes. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are 2 major subtypes and can be distinguished by the location of blister formation or the specificity of autoantibodies directed against different desmogleins.1,2 Although rare, pemphigus is considered a serious and life-threatening condition with a great impact on quality of life (QOL) due to disease symptoms (eg, painful lesions, physical appearance of skin lesions) as well as treatment complications (eg, adverse drug effects, cost of treatment).3-6 Moreover, the physical and psychological effects can lead to marked functional morbidity and work-related disability during patients’ productive years.7 Therefore, affected individuals usually have a remarkably compromised health-related quality of life (HRQOL).8 Effective treatments may considerably improve the QOL of patients with pemphigus.6
Despite the available treatment options, finding the best regimen for pemphigus remains a challenge. Corticosteroids are assumed to be the main treatment, though they have considerable side effects.9,10 Adjuvant therapies are used to suppress or modulate immune responses, leading to remission with the least possible need for corticosteroids. Finding an optimal steroid-sparing agent has been the aim of research, and biologic agents seem to be the best option.8 Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown great promise in several studies of its clinical efficacy and has become a first-line treatment in new guidelines.11-14 Rituximab treatment has been associated with notable improvement in physician-assessed outcome measures with a favorable safety profile in patients with pemphigus.11-15 However, it is important to assess response to treatment from a patient’s perspective through the use of outcome-assessment measures that encompass patient-reported outcomes to reflect the complete patient experience and establish the overall impact of RTX as well as its likelihood of acceptance by patients with pemphigus.
In our study, we compared clinical outcomes and HRQOL through the use of disease-specific measures as well as comprehensive generic health status measures among patients with PV and PF who received RTX treatment 3 months earlier and those who received RTX in the last 2 weeks. The clinical relevance of the patient-reported outcomes is discussed.
MATERIALS AND METHODS
Study Design
We conducted a single-center cross-sectional study of 96 patients with pemphigus aged 18 to 65 years of either sex who were willing to participate in this study. Patients with a confirmed diagnosis of PV or PF who received RTX 3 months earlier or in the last 2 weeks were enrolled in the study. Patients were identified using Dermatry.ir, an archiving software that contains patients’ medical data. Exclusion criteria included lack of sufficient knowledge of the concepts of the questionnaires as well as age younger than 16 years. The study was conducted from October 2019 to April 2020 by the Autoimmune Bullous Disease Research Center at Razi Hospital in Tehran, Iran, which is the main dermatology-specific center and teaching hospital of Iran. The study protocol was approved by the relevant ethics committee.
Patients were categorized into 2 groups: (1) those who received RTX 3 months earlier (3M group); and (2) those who received RTX in the last 2 weeks (R group).
After an explanation of the study to participants, informed written consent was signed by each patient, and their personal data (eg, age, sex, education, marital status, smoking status), as well as clinical data (eg, type of pemphigus, duration of disease, site of onset, prednisolone dosage, presence of Nikolsky sign, anti-DSG1 and anti-DSG3 values, Pemphigus Disease Area Index [PDAI] score, RTX treatment protocol); any known comorbidities such as hypertension, diabetes mellitus, or morbid obesity; and any chronic pulmonary, cardiac, endocrinologic, renal, or hepatic condition, were collected and recorded in a predefined Case Record.
Patient-Reported Outcome Measures
The effect of RTX on QOL in patients with pemphigus was assessed using 2 HRQOL instruments: (1) a general health status indicator, the 36-Item Short Form Survey (SF-36), and (2) a validated, Persian version of a dermatology-specific questionnaire, Dermatology Life Quality Index (DLQI). The questionnaires were completed by each patient or by an assistant if needed.
The SF-36 is a widely used 36-item questionnaire measuring functional health and well-being across 8 domains—mental health, pain, physical function, role emotional, role physical, social functioning, vitality, and general health perception—with scores for each ranging from 0 to 100. The physical component scores (PCSs) and mental component scores (MCSs) were derived from these 8 subscales, each ranging from 0 to 400, with higher scores indicating better health status.6
The DLQI, one of the most frequently used QOL measures in dermatology, contains 10 questions, each referring to the prior week and classified in the following 6 subscales: symptoms and feelings, daily activities, leisure, personal relationships, work and school, and treatment.16 The total score ranges from 0 (no impact) to 30 (very high impact), with a higher score indicating a lower QOL (eTable 1). The minimal clinically important difference (MCD) for the DLQI was considered to be 2- to 5-point changes in prior studies.17,18 In this study, we used an MCD of a 5-point change or more between study groups.
Moreover, the patient general assessment (PGA) of disease severity was identified using a 3-point scale (1=mild, 2=moderate, 3=severe).
Statistical Analysis
Data were analyzed using SPSS Statistics version 23. P≤.05 was considered significant. Mean and SD were calculated for descriptive data. The t test, Fisher exact test, analysis of variance, multiple regression analysis, and logistic regression analysis were used to identify the relationship between variables.
RESULTS
Patient Characteristics
A total of 96 patients were enrolled in this study. The mean (SD) age of participants was 41.42 (15.1) years (range, 18–58 years). Of 96 patients whose data were included, 55 (57.29%) patients had received RTX 3 months earlier (3M group) and 41 (42.71%) received RTX in the last 2 weeks (R group). A summary of study patient characteristics in each group is provided in eTable 2. There was no significant difference between the 2 groups in terms of age, sex, type of pemphigus, marital status, education, positive Nikolsky sign, smoking status, existence of comorbidities, site of lesions, and RTX treatment protocol. However, a significant difference was found for duration of disease (P=.0124) and mean prednisolone dosage (P=.001) as well as severity of disease measured by PDAI score (P=.003) and anti-DSG1 (P=.003) and anti-DSG3 (P=.021) values.
Patient-Reported Outcomes
Physical and mental component scores are summarized in eTable 3. Generally, SF-36 scores were improved with RTX treatment in all dimensions except for mental health, though these differences were not statistically significant, with the greatest mean improvement in the role physical index (75.45 in the 3M group vs 53.04 in the R group; P=.009). Mean SF-36 PCS and MCS scores were higher in the 3M group vs the R group, though the difference in MCS score did not reach the level of significance (eTable 3).
Mean DLQI scores in the R and 3M groups were 12.31 and 6.96, respectively, indicating a considerable burden on HRQOL in both groups. However, a statistically significant difference between these values was seen that also was clinically meaningful, indicating a significant improvement of QOL in patients receiving RTX 3 months earlier (P=.005)(eTable 3).
The PGA scores indicated that patients in the 3M group were significantly more likely to report less severe disease vs the R group (P=.008)(eTable 3).
Multivariate Analysis—Effect of the patient characteristics and some disease features on indices of QOL was evaluated using the multiple linear regression model. eTable 4 shows the P values of those analyses.
COMMENT
Pemphigus is a chronic disabling disease with notable QOL impairment due to disease burden as well as the need for long-term use of immunosuppressive agents during the disease course. To study the effect of RTX on QOL of patients with pemphigus, we compared 2 sets of patients. Prior studies have shown that clinically significant effects of RTX take 4 to 12 weeks to appear.19,20 Therefore, we selected patients who received RTX 3 months earlier to measure their HRQOL indices and compare them with patients who had received RTX in the last 2 weeks as a control group to investigate the effect of RTX intrinsically, as this was the focus of this study.
In our study, one of the research tools was the DLQI. Healthy patients typically have an average score of 0.5.21 The mean DLQI score of the patients in R group was 12.31, which was similar to prior analysis8 and reflects a substantial burden of disease comparable to atopic dermatitis and psoriasis.21,22 In patients in the 3M group, the mean DLQI score was lower than the R group (6.96 vs 12.31), indicating a significant (P=.005) and clinically meaningful improvement in QOL of patients due to the dramatic therapeutic effect of RTX. However, this score indicated a moderate effect on HRQOL, even in the context of clinical improvement due to RTX treatment, which may reflect that the short duration of treatment in the 3M group was a limitation of this study. Although the 12-week treatment duration was comparable with other studies19,20 and major differences in objective measures of treatment efficacy were found in PDAI as well as anti-DSG1 and anti-DSG3 values, longer treatment duration may be needed for a more comprehensive assessment of the benefit of RTX on HRQOL indices in patients with pemphigus.
Based on results of the SF-36 questionnaire, PCS and MCS scores were not substantially impaired in the R group considering the fact that a mean score of 50 has been articulated as a normative value for all scales.23 These data demonstrated the importance of using a dermatologic-specific instrument such as the DLQI instead of a general questionnaire to assess QOL in patients with pemphigus. However, better indices were reported with RTX treatment in the 3 SF-36 domains—role physical (P=.009), role emotional (P=.03), and general health perception (P=.03)—with the role physical showing the greatest magnitude of mean change (75.45 in the 3M group vs 53.04 in the R group). Notably, PCS was impaired to a greater extent than MCS in patients in the R group and showed a greater magnitude of improvement after 3 months of treatment. These results could be explained by the fact that MCS can be largely changed in diseases with a direct effect on the central nervous system.23
Our results also revealed that the dose of corticosteroid correlated to HRQOL of patients with pemphigus who recently received RTX therapy. Indeed, it is more likely that patients on lower-dose prednisolone have a higher QOL, especially on physical function and social function dimensions of SF-36. This finding is highly expectable by less severe disease due to RTX treatment and also lower potential dose-dependent adverse effects of long-term steroid therapy.
One of the most striking findings of this study was the correlation of location of lesions to QOL indices. We found that the mucocutaneous phenotype was significantly correlated to greater improvement in role emotional, role physical, and social functioning scores due to RTX treatment compared with cutaneous or mucosal types (P=.02, P=.025, and P=.017, respectively). Although mucosal involvement of the disease can be the most burdensome feature because of its large impact on essential activities such as eating and speaking, cutaneous lesions with unpleasant appearance and undesirable symptoms may have a similar impact on QOL. Therefore, having both mucosal and cutaneous lesions causes a worsened QOL and decreased treatment efficacy vs having only one area involved. This may explain the greater improvement in some QOL indices with RTX treatment.
Limitations—Given the cross-sectional design of this study in which patients were observed at a single time point during their treatment course, it is not possible to establish a clear cause-effect relationship between variables. Moreover, we did not evaluate the impact of RTX or prednisolone adverse effects on QOL. Therefore, further prospective studies with longer treatment durations may help to validate our findings. In addition, MCDs for DLQI and SF-36 in pemphigus need to be determined and validated in future studies.
CONCLUSION
The results of our study demonstrated that patients with pemphigus may benefit from taking RTX, not only in terms of clinical improvement of their disease measured by objective indices such as PDAI and anti-DSG1 and anti-DSG3 values but also in several domains that are important to patients, including physical and mental health status (SF-36), HRQOL (DLQI), and overall disease severity (PGA). Rituximab administration in patients with pemphigus can lead to rapid and significant improvement in HRQOL as well as patient- and physician-assessed measures. Its favorable safety profile along with its impact on patients’ daily lives and mental health makes RTX a suitable treatment option for patients with pemphigus. Moreover, we recommend taking QOL indices into account while evaluating the efficacy of new medications to improve our insight into the patient experience and provide better patient adherence to treatment, which is an important issue for optimal control of chronic disorders.
- Hammers CM, Stanley JR. Mechanisms of disease: pemphigus and bullous pemphigoid. Ann Rev Pathol. 2016;11:175-197.
- Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026.
- Mayrshofer F, Hertl M, Sinkgraven R, et al. Significant decrease in quality of life in patients with pemphigus vulgaris, result from the German Bullous Skin Disease (BSD) Study Group. J Dtsch Dermatol Ges. 2005;3:431-435.
- Terrab Z, Benckikhi H, Maaroufi A, et al. Quality of life and pemphigus. Ann Dermatol Venereol. 2005;132:321-328.
- Tabolli S, Mozzetta A, Antinone V, et al. The health impact of pemphigus vulgaris and pemphigus foliaceus assessed using the Medical Outcomes Study 36-item short form health survey questionnaire. Br J Dermatol. 2008;158:1029-1034.
- Paradisi A, Sampogna F, Di Pietro, C, et al. Quality-of-life assessment in patients with pemphigus using a minimum set of evaluation tools. J Am Acad Dermatol. 2009;60:261-269.
- Heelan K, Hitzig SL, Knowles S, et al. Loss of work productivity and quality of life in patients with autoimmune bullous dermatoses. J Cutan Med Surg. 2015;19:546-554.
- Ghodsi SZ, Chams-Davatchi C, Daneshpazhooh M, et al. Quality of life and psychological status of patients with pemphigus vulgaris using Dermatology Life Quality Index and General Health Questionnaires. J Dermatol. 2012;39:141-144.
- Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96:2343.
- Mohammad-Javad N, Parvaneh H, Maryam G, et al. Randomized trial of tacrolimus 0.1% ointment versus triamcinolone acetonide 0.1% paste in the treatment of oral pemphigus vulgaris. Iranian J Dermatol. 2012;15:42-46.
- Lunardon L, Tsai KJ, Propert KJ, et al. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol. 2012;148:1031-1036.
- Colliou N, Picard D, Caillot F, et al. Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci Transl Med. 2013;5:175ra30.
- Heelan K, Al-Mohammedi F, Smith MJ, et al. Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150:703-708.
- Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389:2031-2040
- Aryanian Z, Balighi K, Daneshpazhooh M, et al. Rituximab exhibits a better safety profile when used as a first line of treatment for pemphigus vulgaris: a retrospective study. Int Immunopharmacol. 2021;96:107755.
- Aghai S, Sodaifi M, Jafari P, et al. DLQI scores in vitiligo: reliability and validity of the Persian version. BMC Dermatol. 2004;4:8.
- Schünemann HJ, Akl EA, Guyatt GH. Interpreting the results of patient reported outcome measures in clinical trials: the clinician’s perspective. Health Qual Life Outcomes. 2006;4:62.
- Quality of life questionnaires. Cardiff University website. Accessed December 16, 2022. http://sites.cardiff.ac.uk/dermatology/quality-oflife/dermatology-quality-of-life-index-dlqi/dlqi-instructions-foruse-and-scoring/
- Kanwar AJ, Tsuruta D, Vinay K, et al. Efficacy and safety of rituximab treatment in Indian pemphigus patients. J Eur Acad Dermatol Venereol. 2013;27:E17-E23.
- Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, et al. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids. JAMA Dermatol. 2015;151:200-203.
- Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-216.
- Aghaei S, Moradi A, Ardekani GS. Impact of psoriasis on quality of life in Iran. Indian J Dermatol Venereol Leprol. 2009;75:220.
- Ware JE Jr, Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36). 1. conceptual framework and item selection. Med Care. 1992;30:473-483.
- Hammers CM, Stanley JR. Mechanisms of disease: pemphigus and bullous pemphigoid. Ann Rev Pathol. 2016;11:175-197.
- Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026.
- Mayrshofer F, Hertl M, Sinkgraven R, et al. Significant decrease in quality of life in patients with pemphigus vulgaris, result from the German Bullous Skin Disease (BSD) Study Group. J Dtsch Dermatol Ges. 2005;3:431-435.
- Terrab Z, Benckikhi H, Maaroufi A, et al. Quality of life and pemphigus. Ann Dermatol Venereol. 2005;132:321-328.
- Tabolli S, Mozzetta A, Antinone V, et al. The health impact of pemphigus vulgaris and pemphigus foliaceus assessed using the Medical Outcomes Study 36-item short form health survey questionnaire. Br J Dermatol. 2008;158:1029-1034.
- Paradisi A, Sampogna F, Di Pietro, C, et al. Quality-of-life assessment in patients with pemphigus using a minimum set of evaluation tools. J Am Acad Dermatol. 2009;60:261-269.
- Heelan K, Hitzig SL, Knowles S, et al. Loss of work productivity and quality of life in patients with autoimmune bullous dermatoses. J Cutan Med Surg. 2015;19:546-554.
- Ghodsi SZ, Chams-Davatchi C, Daneshpazhooh M, et al. Quality of life and psychological status of patients with pemphigus vulgaris using Dermatology Life Quality Index and General Health Questionnaires. J Dermatol. 2012;39:141-144.
- Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96:2343.
- Mohammad-Javad N, Parvaneh H, Maryam G, et al. Randomized trial of tacrolimus 0.1% ointment versus triamcinolone acetonide 0.1% paste in the treatment of oral pemphigus vulgaris. Iranian J Dermatol. 2012;15:42-46.
- Lunardon L, Tsai KJ, Propert KJ, et al. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch Dermatol. 2012;148:1031-1036.
- Colliou N, Picard D, Caillot F, et al. Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci Transl Med. 2013;5:175ra30.
- Heelan K, Al-Mohammedi F, Smith MJ, et al. Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150:703-708.
- Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389:2031-2040
- Aryanian Z, Balighi K, Daneshpazhooh M, et al. Rituximab exhibits a better safety profile when used as a first line of treatment for pemphigus vulgaris: a retrospective study. Int Immunopharmacol. 2021;96:107755.
- Aghai S, Sodaifi M, Jafari P, et al. DLQI scores in vitiligo: reliability and validity of the Persian version. BMC Dermatol. 2004;4:8.
- Schünemann HJ, Akl EA, Guyatt GH. Interpreting the results of patient reported outcome measures in clinical trials: the clinician’s perspective. Health Qual Life Outcomes. 2006;4:62.
- Quality of life questionnaires. Cardiff University website. Accessed December 16, 2022. http://sites.cardiff.ac.uk/dermatology/quality-oflife/dermatology-quality-of-life-index-dlqi/dlqi-instructions-foruse-and-scoring/
- Kanwar AJ, Tsuruta D, Vinay K, et al. Efficacy and safety of rituximab treatment in Indian pemphigus patients. J Eur Acad Dermatol Venereol. 2013;27:E17-E23.
- Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, et al. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids. JAMA Dermatol. 2015;151:200-203.
- Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-216.
- Aghaei S, Moradi A, Ardekani GS. Impact of psoriasis on quality of life in Iran. Indian J Dermatol Venereol Leprol. 2009;75:220.
- Ware JE Jr, Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36). 1. conceptual framework and item selection. Med Care. 1992;30:473-483.
PRACTICE POINTS
- Pemphigus is an autoimmune blistering disease that can negatively affect patients’ lives.
- Assessing the impact of treatment from a patient’s perspective using outcome assessment measures is important and relevant in trials of new pemphigus treatments including rituximab.
- Rituximab administration in pemphigus patients led to rapid and notable improvement in health-related quality of life and patient-assessed measures.