About pemphigus

Pemphigus is a group of autoimmune blistering diseases characterized by loss of adhesion between keratinocytes giving rise to blister formation. The intraepithelial blister formation is caused by acantholysis: the loss of adhesion between keratinocytes caused by autoantibodies directed against the intercellular adhesion structures.

The different forms of pemphigus may be distinguished by the specificity of the autoantibodies for different targets or by the location of blister formation. With the most common form, pemphigus vulgaris (PV), blisters are located just above the basal skin layer. With pemphigus foliaceus (PF), blisters occur within the upper layers of the epidermis. Other subtypes of the pemphigus group are paraneoplastic pemphigus (usually occurring in patients with lymphoma) and drug-induced pemphigus. Rare pemphigus variants include pemphigus herpetiformis and pemphigus erythematosus.

Instruments that have been used to study QOL in pemphigus

There are a wide variety of QOL measures. They may categorized as genetic, skin specific, or disease specific.

Generic measures allow for comparisons across all diseases. The Medical Outcome Study 36-item Short-form Survey (SF-36) is a generic instrument that measures health-related QOL and is thus useful in comparing QOL in patients with pemphigus with the general population. It uses a multi-item scale that assesses 8 health concepts : (1) limitations in physical activities because of health problems, (2) limitations in social activities because of physical or emotional problems, (3) limitations in usual role activities because of physical health problems, (4) bodily pain, (5) general mental health, (6) limitations in usual role activities because of emotional problems, (7) vitality, and (8) general health perceptions. A score of 0 to 100 is calculated for each domain, with higher scores correlating with better QOL.

Skin-specific measures used in dermatology allow for comparisons across skin diseases. The Dermatology Life Quality Index (DLQI) was derived from patients with a variety of skin diseases and provides a simple method of scoring the impact of skin disease on QOL. There are 10 questions covering symptoms and feelings (items 1 and 2), daily activities (items 3 and 4), leisure (items 5 and 6), work and school (item 7), personal relationships (items 8 and 9), and treatment (item 10). Each question has 4 possible responses: “not at all,” “a little,” “a lot,” or “very much,” with scores of 0, 1, 2, and 3 respectively. “Not relevant” is also scored as 0. The scores of each question are added to give a DLQI score, with a possible maximum of 30 and minimum of 0. A higher score indicates greater impairment of QOL. Healthy individuals have an average score of 0.5.

The Skindex is another skin-specific measure. It was designed to assess the effect of symptoms and the burden on social function and emotional state. The original Skindex consisted of 61 items but it has now been refined to questionnaires of 29, 17, and 16 items (Skindex-29, Skindex-17, and Skindex-16, respectively) to decrease respondent burden and improve discrimination and evaluation. With dermatologic measures focusing specifically on skin-related issues, they are useful in instances such as comparing patients with different skin diseases, or detecting changes in the effects of skin disease on patients in clinical trials or longitudinal studies.

Psychiatric-related measures are also used in the study of QOL in pemphigus. Psychiatric morbidity is important among patients with skin diseases, and the prevalence of depression among dermatologic patients is high at 25% to 40% compared with only 2% to 5% in the general population. The 12-item General Health Questionnaire (GHQ-12) measures psychological distress and can help detect nonpsychotic disorders such as depression and anxiety. Each item has a 4-point scale with questions such as, “in the last weeks, did you feel under strain?.” The higher the score, the greater the likelihood of a minor nonpsychotic psychiatric disorder. GHQ positivity is the cutoff score at which a minor psychiatric disorder such as depression or anxiety is likely.

The Ministry of Health, Labor, and Welfare in Japan has its own burden of disease measure. This questionnaire asks about the ability to independently perform common activities of daily living (ADLs) including bathing, eating, cooking, shaving or applying make-up, using a toilet, traveling by public transportation, and driving.

Instruments that have been used to study QOL in pemphigus

There are a wide variety of QOL measures. They may categorized as genetic, skin specific, or disease specific.

Generic measures allow for comparisons across all diseases. The Medical Outcome Study 36-item Short-form Survey (SF-36) is a generic instrument that measures health-related QOL and is thus useful in comparing QOL in patients with pemphigus with the general population. It uses a multi-item scale that assesses 8 health concepts : (1) limitations in physical activities because of health problems, (2) limitations in social activities because of physical or emotional problems, (3) limitations in usual role activities because of physical health problems, (4) bodily pain, (5) general mental health, (6) limitations in usual role activities because of emotional problems, (7) vitality, and (8) general health perceptions. A score of 0 to 100 is calculated for each domain, with higher scores correlating with better QOL.

Skin-specific measures used in dermatology allow for comparisons across skin diseases. The Dermatology Life Quality Index (DLQI) was derived from patients with a variety of skin diseases and provides a simple method of scoring the impact of skin disease on QOL. There are 10 questions covering symptoms and feelings (items 1 and 2), daily activities (items 3 and 4), leisure (items 5 and 6), work and school (item 7), personal relationships (items 8 and 9), and treatment (item 10). Each question has 4 possible responses: “not at all,” “a little,” “a lot,” or “very much,” with scores of 0, 1, 2, and 3 respectively. “Not relevant” is also scored as 0. The scores of each question are added to give a DLQI score, with a possible maximum of 30 and minimum of 0. A higher score indicates greater impairment of QOL. Healthy individuals have an average score of 0.5.

The Skindex is another skin-specific measure. It was designed to assess the effect of symptoms and the burden on social function and emotional state. The original Skindex consisted of 61 items but it has now been refined to questionnaires of 29, 17, and 16 items (Skindex-29, Skindex-17, and Skindex-16, respectively) to decrease respondent burden and improve discrimination and evaluation. With dermatologic measures focusing specifically on skin-related issues, they are useful in instances such as comparing patients with different skin diseases, or detecting changes in the effects of skin disease on patients in clinical trials or longitudinal studies.

Psychiatric-related measures are also used in the study of QOL in pemphigus. Psychiatric morbidity is important among patients with skin diseases, and the prevalence of depression among dermatologic patients is high at 25% to 40% compared with only 2% to 5% in the general population. The 12-item General Health Questionnaire (GHQ-12) measures psychological distress and can help detect nonpsychotic disorders such as depression and anxiety. Each item has a 4-point scale with questions such as, “in the last weeks, did you feel under strain?.” The higher the score, the greater the likelihood of a minor nonpsychotic psychiatric disorder. GHQ positivity is the cutoff score at which a minor psychiatric disorder such as depression or anxiety is likely.

The Ministry of Health, Labor, and Welfare in Japan has its own burden of disease measure. This questionnaire asks about the ability to independently perform common activities of daily living (ADLs) including bathing, eating, cooking, shaving or applying make-up, using a toilet, traveling by public transportation, and driving.

Previous QOL studies on pemphigus

There have been only 5 published studies on QOL in pemphigus. One published in Japan by Masahiro and colleagues, 1 in Germany by Mayrshofer and colleagues, another in Morocco by Terrab and colleagues, and 2 published by the same group in Rome by Paradisi and colleagues and Tabolli and colleagues.

Masahiro and colleagues administered the Japanese Ministry of Health, Labor, and Welfare burden of disease measure to 380 patients with pemphigus. Patients with pemphigus retained good ADLs. Of the patients surveyed, 99.7% were able to feed themselves and use the toilet independently, 97% were able to shave or apply make-up by themselves, 96.5% were able to bathe, 90.8% were able to use public transportation, 85.2% could cook, and 82.3% could drive. However, pemphigus was found to have a large impact on finances. Fifty-four percent of patients reported an increased expenditure because of disease, 42% reported decreased income, and 41% described themselves as being in poverty because of factors such as costly medications and expensive transport to and from hospital. These figures were increased by approximately 20% in patients described as having severe pemphigus.

Mayrshofer and colleagues studied 27 patients who attended dermatology clinics at the universities of Dresden, Erlangen, Kiel, Mannheim, Munich, and Wurzburg between January 1996 and October 2001. The patients had a primary diagnosis of PV and received the German DLQI. The average age of the patients was 55.9 years and 40% were men. The average DLQI score was 10 out of 30. Physical symptoms, such as itch, burning pain, and blistering were most responsible for impairment of QOL. Patients with itching had an average DLQI score of 11.5, compared with 7.9 for those without itching. Those with burning had an average score of 10.8, which was twice as high as patients who reported no burning sensations. Patients with blisters involving mucous membranes also had worse QOL, averaging 10.4, whereas those without had a score of 9.3.

Bullous pemphigoid (BP) and PV are similar in that they are both blistering autoimmune diseases. However, the DLQI score of 6.92 for BP is much less than that for PV, perhaps because of the rarity of mucosal membrane involvement in BP, or because it responds to lower doses of drugs, which results in fewer side effects. For example BP typically needs no more than 0.5 mg/kg/day prednisone whereas pemphigus usually needs at least 1 mg/kg/day starting dose and sometimes higher. The study concludes that the DLQI may be useful as an additional measure of response to treatment in patients with pemphigus.

However, QOL is a complex area affected by many factors, and the DLQI has some limitations in assessing pemphigus. The questionnaire was constructed using data from 120 patients and only 1 of these patients had blisters, whereas there were at least 10 cases of eczema, 14 cases of psoriasis, and 15 of acne. Thus, it is likely that the DLQI is more applicable for measuring QOL in patients with eczema, psoriasis, or acne than that of patients with pemphigus. In addition, the scoring reflects the bias of the question selection and it is possible that patients with pemphigus place emphasis on aspects of handicap not covered by the DLQI, or no emphasis on some of the questions mentioned in the DLQI. The DLQI also asks only about the previous week, which may miss flares in chronic disease. The average PV DLQI score of 10 is higher than that for BP and rosacea, but lower than that for atopic eczema, which, with an average DLQI score of 12.5, rates most highly on this scoring system. The common, non–life threatening basal cell carcinoma (BCC) does not have much effect on QOL, with an average score of 2.

Terrab and colleagues conducted another study on patients with pemphigus in Morocco using the SF-36 as well as another questionnaire on the impact of pemphigus on self-perception, social relationships, and behavior. These questionnaires were given to 30 patients with pemphigus and 60 healthy adults between January and August 2002. To be included in the pemphigus group, patients had to have bullous dermatitis with fluid-filled bullae with intraepidermal division on a cutaneous biopsy, the presence of acantholytic cells, and immunoglobulin deposition in the epidermis under direct immunofluorescence. For every person with pemphigus, there were 2 controls of the same age and sex who were seeing a dermatologist for an acute, nonhandicapping problem such as warts or benign cutaneous tumors. Because of the high illiteracy rate in Morocco, the questionnaires were filled out by investigators, not patients (the survey was originally designed for either self-administration or administration by a trained interviewer in person or by telephone). To minimize bias, 1 investigator completed the questionnaires for all participants, whether they were literate or not.

The SF-36 showed decreased mean scores for the pemphigus group compared with controls in all dimensions except for physical pain and alteration in general status of health. Most affected by pemphigus were physical and emotional statuses, particularly if there was facial involvement and large extent of lesions. Results also varied with profession. Seventy percent of affected patients were ashamed of their appearance, and 60% of those were extremely worried about what others thought of their illness. Sixty percent had lost self-confidence and 82% were very concerned with repercussions on their sex life. Popular beliefs may have been a contributing factor, because skin illnesses in Morocco are believed to be contagious, associated with poor hygiene, or linked to unconventional sexual practices, and, when treatment is unfavorable, the disease is deemed incurable. Other factors found to further decrease QOL were repeated hospitalizations, difficult or costly management, and social concerns such as marriage prospects for young women.

Because the SF-36 is a general health measure, it is likely to be less specific for pemphigus than the DLQI. It has been frequently criticized when used for documenting changes after medical intervention because it is a general health status survey that is not as responsive as a disease-specific survey. However, in the case of pemphigus, there are no disease-specific questionnaires and only generic ones are available. Another problem with the SF-36 is often seen in the subscales of (1) limitations in physical activities because of health problems, and (6) limitations in usual role activities because of emotional problems. Many patients score 0 for these scales before treatment (indicating a worst-case response), and 100 after treatment (indicating a lack of problems), limiting the ability to detect any further improvement because it is impossible to score more than 100.

Tabolli and colleagues also used the SF-36 to investigate 58 patients with either PV or PF. Two questionnaires from The Institute for Personality and Ability Testing were used to measure anxiety and depression. Similar to previous studies, Tabolli and colleagues found that mucocutaneous involvement, severe pemphigus as measured by physicians, and more recent onset correlated with worse health status as measured by the SF-36. Better health status was seen in men and patients with PF. Terrab and colleagues and Tabolli and colleagues concluded that the management of pemphigus must take into account its impact on various aspects of patients’ lives.

A fourth study by Paradisi and colleagues used a larger sample of 126 patients with pemphigus. Dermatologists scored patients’ disease severity and patients were asked to complete the SF-36, the Skindex-29 and the GHQ-12. Participating in the study were 112 patients with PV (67 women, 45 men, mean age 52.2 years), 10 with PF (8 women, 2 men, mean age 55.1 years), 2 with paraneoplastic pemphigus and 2 with linear immunoglobulin A pemphigus. Both dermatology-specific (using the Skindex-29) and general health (using the SF-36) questionnaires found a strong impact of pemphigus on QOL, with women being affected more than men. No difference was seen for age. Worse QOL was also found in those on less than 10 mg/d of steroids (compared with more than 10 mg/d), those with both mucous and cutaneous involvement, and those with 2 or more comorbidities (reflecting adverse effects of long-term treatment).

GHQ positivity was detected in 40% of patients with pemphigus, and 70% of patients with PF. These percentages are very high compared with the general population scores of 10%. GHQ positivity correlated with clinical severity. The SF-36 also correlated strongly with clinical severity of PF. However, there was weaker correlation with PV. Paradisi and colleagues suggest that psychological distress and personality disorders may play a role in disease development, maintenance, and progression, which in turn would affect QOL. They conclude that, to properly measure patients’ health status, a generic and a dermatology-specific QOL tool should be used, with a psychiatric-oriented questionnaire to help select patients who would benefit from psychological support in addition to their standard treatment.

There were several contrasts to the findings of Tabolli and colleagues. Paradisi and colleagues found that there was poorer QOL for patients with PF than PV, there was no change in role activities because of emotional problems (item 2 on the SF-36), and that QOL was most affected in patients who had had the disease for 3–4 years (not those with recent disease onset). The discrepancies between these studies further suggest the need for a disease-specific measure to accurately measure QOL in pemphigus. Although disease-specific measures cannot be used to compare with other groups of disease, they are most sensitive to changes in QOL. No disease-specific measures have yet been published for pemphigus.