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Cross-sectional Analysis of a Collaborative Web-Based Database for Lupus Erythematosus–Associated Skin LesionsProspective Enrollment of 114 Patients
Siamak Moghadam-Kia, MD;
Katherine Chilek, DO;
Elizabeth Gaines, MD;
Melissa Costner, MD;
Mathew E. Rose, MB;
Joyce Okawa, RN;
Victoria P. Werth, MD
Arch Dermatol. 2009;145(3):255-260.
ABSTRACT
Objectives To assess disease severity in subsets of patients with cutaneous lupus erythematosus (CLE) by using outcome and quality-of-life measures, and to determine treatment responsiveness by establishing a Web-based database of patients with skin manifestations of lupus.
Design Prospective, cross-sectional study.
Setting University hospital cutaneous autoimmunity outpatient clinic.
Patients One hundred fourteen patients who presented from January 15, 2007, to November 8, 2007, and met the criteria for having CLE or lupus-nonspecific skin disease.
Main Outcome Measures Scores on the CLE Disease Activity and Severity Index and the modified Skindex-29 (a quality-of-life measure) completed at each visit.
Results Seven patients (6.1%) presented with acute CLE, 21 (18.4%) with subacute CLE, 77 (67.5%) with chronic CLE, 7 (6.1%) with systemic lupus erythematosus and LE-nonspecific skin lesions, and 1 (0.9%) with LE-nonspecific skin disease only. The mean baseline CLE Disease Activity and Severity Index activity/damage scores in patients with acute, subacute, and chronic CLE were 6.4/5.1, 11.1/1.6, and 7.5/10.2, respectively. The mean baseline modified Skindex-29 scores were 76.3, 79.4, and 82.7, respectively (P = .80). The disease in 11 of the patients (9.6%) was considered refractory to conventional therapies. Significantly more patients in the refractory group than the nonrefractory group were current smokers (P = .006).
Conclusion This Web-based database should allow collection of data related to disease activity, quality of life, and response to therapy at multiple centers.
INTRODUCTION
Lupus erythematosus (LE) is a potentially disabling autoimmune disease that presents clinically as a spectrum ranging from mild involvement with only localized discoid skin lesions to life-threatening illness with severe systemic manifestations. Although the prevalence of systemic LE (SLE) is 17 to 48 per 100 000 worldwide, cutaneous LE is estimated to be as much as 2 to 3 times more common than SLE itself.1 Skin disease is the second most common clinical manifestation of LE as well as the second most common primary presenting symptom of LE.2
Skin disease in LE is diagnosed on the basis of clinical, serologic, and histologic criteria, following the Gilliam or modified Gilliam classification.3-4 According to this classification, skin disease in LE can present with either lupus-specific cutaneous LE (CLE) or lupus-nonspecific findings. Lupus-specific skin lesions are seen only in patients with LE. Lupus-nonspecific skin lesions may occur in patients with LE but also may be present among other disease processes. Lupus-specific skin manifestations are subclassified into chronic CLE (CCLE), subacute CLE (SCLE), and acute CLE (ACLE).3 The types of skin lesions in an individual patient can provide insight into the likelihood of underlying systemic disease. Both CCLE and SCLE may persist for many years and, like SLE, may lead to severe disability and limited quality of life (QOL). Cutaneous LE is considered to be the third most common cause of industrial disability from dermatologic disease, with as many as 45% of patients with CLE experiencing some form of vocational handicap.5 These data imply considerable societal and medical costs for patients.
The need for high-quality, multicenter clinical databases that enable collection and organization of information on specific diseases has been well documented. Databases enable clinicians to conduct research, plan and manage services, and obtain accurate estimates of care outcomes that can be shared with patients.6-11 Valid and reliable information is critical in chronic diseases such as LE in which patients present with a wide spectrum of symptoms requiring management during an extended period.12
At present, although a few SLE databases exist, including the Cincinnati Children's Hospital SLE Database, the National Lupus Registry, and 1000 Canadian Faces of Lupus Database,13-14 there has not been a comprehensive prospective collection of data on CLE. Because research projects depend on systematic data collection to determine feasibility and design, medical databases are a valuable tool to support new inquiries and investigations.
In addition, until recently there have been no adequate disease severity measures available to allow this type of study to be conducted. Skin-specific and systemic clinical outcome and QOL measures have recently become available to enable clinicians to plan future research projects that can lead to improved patient care and treatment modalities. The CLE Disease Activity and Severity Index (CLASI) was designed in 2005 to convert subjective observations seen in CLE into objective data by means of a scoring system.15 The recent development of this validated skin instrument, which has separate scores for quantifying activity and damage, has made it possible to objectively monitor patients' disease course and response to therapy. Because CLE is a relatively rare condition, data collection can be improved by multicenter collaborative efforts.
We established a collaborative, Web-based database to collect information on patients with various skin manifestations of LE to elucidate certain differences that may exist across disease subtypes. This is, to our knowledge, the first systematic epidemiologic study of CLE in the United States. The primary end points of our prospective study were (1) to establish a Web-based database of patients with skin lesions associated with LE; (2) to prospectively study patients with CLE to assess disease severity, QOL, and response to therapy; and (3) to determine the prevalence, clinical severity, and characteristics of refractory cases. Using available and validated clinical outcome measures such as the CLASI and QOL measures such as the modified Skindex-29, we evaluated the severity of disease as well as the efficacy of currently available treatments to assess the need for novel interventions and provide useful data for future clinical trials of new therapies for CLE.
METHODS
SUBJECT SELECTION
Subjects at the University of Pennsylvania, Philadelphia, were enrolled sequentially during scheduled outpatient clinic visits. All subjects at the University of Pennsylvania who were 18 years or older and who were diagnosed as having CLE or LE-nonspecific disease by clinicohistopathologic correlation were invited to enroll in the database study. Most of these patients were already receiving the established medical standard of care at the Hospital of the University of Pennsylvania. The protocol for the study was approved by the institutional review board of the University of Pennsylvania School of Medicine and was in accordance with the Declaration of Helsinki in its current form. All subjects consented by means of institutional review board–approved informed consent and Health Insurance Portability and Accountability Act forms.
STUDY PROCEDURES
Information was obtained via history, physical examinations, medical record reviews, and subject questionnaires. All subjects who agreed to participate were assessed in terms of specific variables related to their medical history and treatment. Information related to sociodemographics (age and sex), concomitant systemic illness and duration, dermatologic diagnosis and duration, smoking history, medications used, and response to therapies was recorded. The following distinct yet complementary outcome measures of the subjects' disease and therapeutic experience were used at each visit: the CLASI; the SLE Disease Activity Index (SLEDAI), which evaluates systemic disease; the modified Skindex-29, a CLE-modified QOL measure; and analog measures of itch, pain, fatigue, general health, and skin assessments. Data were collected in accordance with good clinical practice guidelines to ensure accuracy and integrity. Completeness of data and use of explicit definitions for variables were assessed and a constant effort at quality control was maintained. Data were then organized and entered into a collaborative Web-based database. Data security and confidentiality were managed carefully to ensure regulatory adherence.
Subjects were categorized according to the modified Gilliam classification4 into the various subtypes of CLE: ACLE, SCLE (annular or papulosquamous), and CCLE (classic discoid LE [DLE] [generalized or localized], hypertrophic DLE, tumid LE, chilblains, or lupus panniculitis).
STATISTICAL ANALYSIS
Conventional methods were used to generate descriptive statistical results. Groups were compared by analysis of variance (ANOVA), followed by the Newman-Keuls multiple comparison test. P < .05 was considered to represent a significant difference among population sets examined.
RESULTS
We sequentially enrolled and observed 114 patients who presented to our outpatient clinic at the Hospital of the University of Pennsylvania from January 5, 2007, to November 8, 2007, and met the criteria for having CLE or lupus-nonspecific skin disease. One of the patients had 3 types of LE-specific skin disease with ACLE, SCLE, and CCLE skin lesions. Chronic CLE was the most predominant subset seen, with 77 patients (67.5%) carrying that diagnosis (Table 1). Seven (6.1%) of the subjects presented with ACLE, 21 (18.4%) with SCLE, 7 (6.1%) with SLE and LE-nonspecific skin lesions, and 1 (0.9%) with LE-nonspecific skin disease only. Of the patients with SCLE, 17 (81%) had predominantly papulosquamous lesions, 2 (10%) had predominantly annular lesions, and 2 (10%) had a combination of the 2 types.
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Table 1. Demographics of Patients Recruited at the University of Pennsylvania
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Twenty-five subjects refused to participate in the study. Twenty-two (88%) of these subjects were women and 3 (12%) were men. Race distribution of the nonenrolled subjects was 13 (52%) white, 11 (44%) African American, and 1 (4%) Asian. Twenty-three of the nonenrolled subjects had CCLE (20 women, 3 men; 11 white, 11 African American, 1 Asian), 1 had SCLE (a white woman), and 1 had SLE (a white woman).
DEMOGRAPHICS
The racial composition of our study population was 66 (57.9%) white, 41 (36.0%) African American, 1 (0.9%) Hispanic, and 5 (4.4%) Asian (Table 1). The majority of the study population were women (93 [81.6%]). The female to male ratio was 3.2:1 in subjects with SCLE and 4.1:1 in subjects with CCLE. Within CCLE subsets, the female to male ratio was the highest (4.3:1) in subjects with localized DLE and the lowest (2.2:1) in subjects with tumid LE. All of our subjects with ACLE were women.
The mean (SEM) age at onset was the highest in subjects with SCLE (48.2 [4.1] years; P = .002 for SCLE vs ACLE and SCLE vs CCLE). The difference between the mean age at onset in subjects with ACLE and those with CCLE was not statistically significant (33.1 [5.0] vs 36.1 [1.5] years; P = .56) (Table 1). Eight (7.0%) of the subjects with CLE were younger than 20 years at the onset of disease and 5 (4.4%) were older than 60 years. Of the subjects with SCLE, 2 (10%) were younger than 20 years at disease onset, whereas 4 (20%) were older than 60 years. The proportions for CCLE were 5 subjects (6.9%) and 1 (1.4%); however, there was no significant difference in the age at disease onset between the different subsets of CCLE. Furthermore, in the CCLE group, no significant difference in age at disease onset was found between sexes (36.5 [1.6] and 33.2 [3.9] years in women and men, respectively; P = .39 [t test]).
ANALYSIS OF OUTCOME AND QOL MEASURES
For CLASI, modified Skindex-29, and SLEDAI calculations, we used data from the second visit instead of the first in 5 subjects (1 with ACLE and 4 with CCLE [localized DLE in 1 subject, generalized DLE in 2, and tumid LE in 1]) because first-visit data were unavailable. Four subjects (all with CCLE [1 each with localized DLE, generalized DLE, tumid LE, and LE panniculitis]) were excluded from the CLASI, modified Skindex-29, and SLEDAI calculations, and 2 subjects (1 with SCLE and 1 with CCLE [tumid LE]) were excluded only from SLEDAI calculations because of unavailability of data.
CLASI Analysis
The mean baseline CLASI activity score (obtained at the first visit) was highest in subjects with SCLE and higher in the CCLE than in the ACLE group; however, none of these differences was statistically significant (P = .24) (Table 2). The mean baseline CLASI damage score was highest in subjects with CCLE and higher in the ACLE than in the SCLE group (P < .001 for CCLE vs SCLE; not significant for CCLE or SCLE vs ACLE) (Table 2). Within CCLE subsets, the mean baseline CLASI activity score was the highest in generalized DLE and similar between tumid LE and localized DLE (P < .01 for generalized DLE vs localized DLE and generalized DLE vs tumid LE; not significant for tumid LE vs localized DLE). The mean baseline CLASI damage score was the highest in subjects with generalized DLE and higher in those with localized DLE than tumid LE (P < .001 for generalized DLE vs tumid LE and generalized DLE vs localized DLE, and not significant [by the Newman-Keuls multiple comparison test] for localized DLE vs tumid LE) (Table 3).
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Table 2. CLASI, Modified Skindex-29, and SLEDAI in Patients With CLE Recruited at the University of Pennsylvania
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Table 3. CLASI and Modified Skindex-29 in Patients With CCLE Recruited at the University of Pennsylvania
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Skindex-29 Analysis
The mean baseline modified Skindex-29 total score was not significantly different among the subsets of CLE (Table 2). The score was highest in subjects with generalized DLE and similar in those with tumid LE and localized DLE (P = .07 [by ANOVA] for generalized vs localized DLE and for generalized DLE vs tumid LE; not significant [by the Newman-Keuls multiple comparison test] for tumid LE vs localized DLE) (Table 3).
SLEDAI Analysis
The mean baseline SLEDAI total score was highest in our subjects with ACLE and trended to higher in the SCLE than the CCLE group; however, none of these differences was statistically significant (P = .08) (Table 2).
LE-NONSPECIFIC SKIN LESIONS
The lowest incidence (5 [24]%) of LE-nonspecific skin lesions occurred in subjects with SCLE, whereas those with CCLE had a slightly higher incidence (24 [31%]) of LE-nonspecific skin lesions. The highest incidence of LE-nonspecific skin lesions was seen among subjects with ACLE (4 [57%]) (P = .26,  2 test).
REFRACTORY CASES
Eleven subjects (9.6%) had disease that was considered refractory to conventional therapies, meaning that their skin lesions remained active despite aggressive medical treatment. Most of the refractory cases were in women. The distribution of subtypes in the refractory group was significantly different from the distribution in the whole population, and the number of refractory cases of generalized DLE was greater than that of localized DLE and SCLE (P = .04, 2 test). Significantly more subjects were current smokers in the refractory group than in the nonrefractory group (P = .006). The race distribution in the refractory group was not significantly different from that in the whole population (Table 4).
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Table 4. Characteristics of Patients With Refractory LE Recruited at the University of Pennsylvania
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COMMENT
Sontheimer et al16 found SCLE lesions in 9% of their study patients, and others have found SCLE lesions in 7% to 27% of their LE patient populations.17-23 Patients with SCLE composed 18.4% of our LE patient population, similar to previously reported ratios. Most of our patients with SCLE had papulosquamous rather than annular-polycyclic lesions, similar to previously reported results.24 In addition, most of our patients with CCLE presented with DLE (either generalized or localized) or tumid LE.
Most (81.6%) of our patients with LE were women, consistent with previous studies.25 However, more of our patients with CLE were white rather than African American (57.9% vs 36.0%). This finding is different from the previously reported higher incidence of SLE in African Americans relative to whites.26-27 The difference implies that there may be a difference between SLE and CLE and may also reflect the population of patients attending the Hospital of the University of Pennsylvania clinic. Most of the subjects with SCLE were white, which is consistent with an earlier report that indicated that 85% of the involved SCLE population is of white origin.16 Others have reported similar racial demographic data.17, 20-21,23, 28-30 Subjects with CCLE were evenly divided between whites and African Americans, which differs from previous reports. Hochberg31 showed that African Americans were seemingly affected more frequently by DLE; however, some earlier studies have found DLE to be more common in whites.32-34 These results likely reflect different populations drawn to clinics.
The mean age at onset was the highest in our SCLE group. The mean age at onset was lower in the ACLE than in the CCLE group; however, this difference was not statistically significant. Malar rash, which is the most common pattern of localized ACLE, has previously been suggested to be associated with a younger age at disease onset.17 There was no significant difference in the age at onset between different subsets of CCLE. The mean age at onset in our subjects with CCLE (36.1 years) was not significantly different between sexes. The usual age at onset of DLE has been reported as 20 to 40 years in both men and women.32-37
All of our subjects with ACLE were women, which is consistent with a previously reported female to male ratio in ACLE of 8:1.38 Malar rash has been reported more commonly in women than in men,17, 39 which correlates with the higher incidence of ACLE in women. The female to male ratio was not significantly different between subjects with SCLE and CCLE. The female to male ratio was 3.2:1 in our SCLE group. Earlier studies have shown that there is likewise a female preponderance in SCLE, with women affected 3 to 6 times more frequently than men.16, 31, 40 The female to male ratio in our CCLE group of 4.1:1 is somewhat higher than reported ratios of 3:1.34, 41-42 Other researchers have reported the female to male ratio for DLE to be between 3:2 and 3:1,33-37,41-42 lower than the ratio of females to males with SLE. In subjects with CCLE, the female to male ratio was the lowest in patients with tumid LE. Interestingly, half of our subjects with CLE with onset of disease before age 20 years were men.
The CLASI was developed because of a need for skin-based outcome measures for clinical trials in CLE. It allows for detailed measurement of the extent and severity of skin involvement. The mean baseline CLASI activity score was the highest in our subjects with SCLE and was similar between the ACLE and CCLE groups. The mean baseline CLASI damage score was the highest in our subjects with CCLE, which is not surprising because CCLE lesions typically can produce scarring and dyspigmentation as they resolve. The mean baseline CLASI damage score was higher in patients with ACLE than SCLE. This may reflect that there are African Americans who pigment with ACLE, whereas subjects with SCLE are white and thus do not exhibit damage.
The CLASI can document the distribution and severity of cutaneous symptoms in a way that allows comparison between groups of patients. In our patients with CCLE, the mean baseline CLASI activity score was the highest in subjects with generalized DLE and was similar between those with localized DLE and tumid LE. Most patients with CCLE lesions tend to have indolently progressive disease that can spread to scarring and dyspigmentation. The mean baseline CLASI damage score was the highest in subjects with generalized DLE and was higher in those with localized DLE than in those with tumid LE.
Assessment of QOL in dermatology has become a major focus for researchers. The development of new therapeutics depends on meeting the needs of patients. Therefore, using patient-rated outcome measures is one of the best methods of understanding this need. The Skindex is a commonly used index of QOL in dermatology. Because CLE is exacerbated with sun exposure, 3 questions related to photosensitivity were added to create the modified Skindex-29. The modified Skindex-29 total score was not significantly different among the ACLE, SCLE, and CCLE subsets of CLE.
In our subjects with CCLE, the mean baseline modified Skindex-29 total score was the highest in subjects with generalized DLE and was similar between those with localized DLE and tumid LE. Future studies will correlate QOL findings with elements of activity and damage in the CLASI, given the trend to worse QOL in generalized DLE.
The mean baseline SLEDAI total score was the highest in the ACLE group and was higher in the SCLE than in the CCLE group, but these differences were not statistically significant. Our subjects were at the mild end of the SLE spectrum.
Almost 10% of our patients had disease that was considered refractory to current therapies, with a disproportionate number (6 [55%]) of these patients having generalized DLE. Other studies have suggested that patients with generalized DLE have more resistant disease and involvement of cytotoxic T cells.43 The diagnosis of DLE has previously been associated with smoking.44 Smoking has been also shown to interfere with efficacy of antimalarial agents in CLE.45-46 Our data regarding the higher number of smokers in the refractory group suggest that smoking may be a risk factor for refractory CLE. This highlights the importance of smoking cessation in CLE.
Interest in CLE by pharmaceutical and biotechnology companies has increased, and, in preparation for future clinical trials of new therapies for CLE, it is crucial that the prevalence, clinical severity, and characteristics of refractory cases be measured and evaluated. This target population of patients with refractory disease will benefit the most from new therapies, and assessment of its prevalence will assist in planning future studies.
CONCLUSIONS
This pilot study demonstrates the ability to collect data prospectively by means of a Web-based design. Our data suggest significant numbers of patients with both generalized and localized DLE relative to those with SCLE and ACLE. Our data showed higher CLASI scores in patients with generalized vs localized disease, with a trend toward higher modified Skindex-29 scores in generalized DLE. Our future goals are to monitor treatment responsiveness and disease severity prospectively, to assess feasibility of using instruments to measure CLE flares, to compare skin-specific vs general QOL measures in CLE, and to expand the use of the Web-based database to incorporate participation from additional sites.
AUTHOR INFORMATION
Correspondence: Victoria P. Werth, MD, Department of Dermatology, University of Pennsylvania, 2 Rhoads Pavilion, 3600 Spruce St, Philadelphia, PA 19104-4283 (werth{at}mail.med.upenn.edu).
Accepted for Publication: September 25, 2008.
Authors Contributions: Drs Moghadam-Kia and Werth had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Gaines, Costner, Okawa, and Werth. Acquisition of data: Moghadam-Kia, Chilek, Gaines, Costner, Rose, and Okawa. Analysis and interpretation of data: Moghadam-Kia, Chilek, and Rose. Drafting of the manuscript: Moghadam-Kia. Critical revision of the manuscript for important intellectual content: Moghadam-Kia, Chilek, Gaines, Costner, Rose, Okawa, and Werth. Statistical analysis: Moghadam-Kia. Obtained funding: Werth. Administrative, technical, and material support: Rose and Okawa. Study supervision: Moghadam-Kia, Rose, and Werth.
Financial Disclosure: None reported.
Funding/Support: This study was supported in part by a Veterans Affairs Merit Review grant from the Department of Veterans Affairs Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; National Institutes of Health (NIH) grant NIH K24-AR 02207 (Dr Werth); and NIH training grant NIH T32-AR007465-25 (Dr Moghadam-Kia).
Author Affiliations: Department of Dermatology, University of Pennsylvania, Philadelphia (Drs Moghadam-Kia, Chilek, Gaines, Rose, and Werth and Ms Okawa); Department of Dermatology, University of Texas (Southwestern), Dallas (Dr Costner); and Philadelphia Veterans Affairs Hospital (Dr Werth).
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