Association of discoid lupus erythematosus with clinical manifestations and damage accrual in a multiethnic lupus cohort

Authors


Abstract

Objective

To determine the clinical manifestations and disease damage associated with discoid rash in a large multiethnic systemic lupus erythematosus (SLE) cohort.

Methods

SLE patients (per American College of Rheumatology [ACR] criteria) ages ≥16 years with a disease duration of ≤10 years at enrollment and defined ethnicity (African American, Hispanic, or white) from a longitudinal cohort were studied. Socioeconomic–demographic features, clinical manifestations, and disease damage (per the Systemic Lupus International Collaborating Clinics/ACR Damage Index) were determined. The association of discoid lupus erythematosus (DLE) with clinical manifestations and disease damage was examined using multivariable logistic regression.

Results

A total of 2,228 SLE patients were studied. The mean ± SD age at diagnosis was 34.3 ± 12.8 years and the mean ± SD disease duration was 7.9 ± 6.0 years; 91.8% were women. DLE was observed in 393 patients with SLE (17.6%). In the multivariable analysis, patients with DLE were more likely to be smokers and of African American ethnicity and to have malar rash, photosensitivity, oral ulcers, leukopenia, and vasculitis. DLE patients were less likely to be of Hispanic (from Texas) ethnicity and to have arthritis, end-stage renal disease, and antinuclear, anti–double-stranded DNA, and antiphospholipid antibodies. Patients with DLE had more damage accrual, particularly chronic seizures, scarring alopecia, scarring of the skin, and skin ulcers.

Conclusion

In this cohort of SLE patients, DLE was associated with several clinical features, including serious manifestations such as vasculitis and chronic seizures.

INTRODUCTION

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that presents with a wide spectrum of clinical manifestations ranging from skin rashes to severe and life-threatening complications. Skin involvement occurs in 70–85% of SLE patients and is classified according to morphology and histopathologic characteristics as specific and nonspecific cutaneous lupus erythematosus (CLE) (1). Specific lesions include chronic CLE, subacute CLE, and acute CLE. Discoid lupus erythematosus (DLE) is the most common form of chronic CLE and may be the initial presentation of SLE in up to 10% of cases (2).

Skin lesions of DLE are mainly localized in sun-exposed areas and may lead to scarring and disfigurement. These patients rarely present with significant organ involvement and generally have a good prognosis (3, 4). Nevertheless, the evolution to SLE has been reported in 5–10% of cases (3, 5). Previous works have focused on studying patients with isolated DLE; however, data evaluating the characteristics of SLE patients with DLE are limited. Therefore, we sought to determine the association of DLE with clinical manifestations and disease damage in a large multiethnic cohort of SLE patients.

Significance & Innovations

  • Studies assessing the clinical features of systemic lupus erythematosus (SLE) patients with discoid lupus erythematosus are limited.

  • This is the largest study examining the clinical associations of discoid rash in patients with SLE.

  • These patients were more likely to have malar rash, photosensitivity, oral ulcers, integument damage, leukopenia, vasculitis, and chronic seizures, while having a lower frequency of arthritis, end-stage renal disease, and immunologic abnormalities.

PATIENTS AND METHODS

As previously described, the Genetic Profile Predicting the Phenotype (PROFILE) is a well-characterized multiethnic prospective cohort of SLE patients constituted from multiple sites, including the University of Alabama at Birmingham, John Hopkins University, Northwestern University, the University of Texas Health Science Center at Houston, and the University of Puerto Rico Medical Sciences Campus (6). The Institutional Review Board of each institution approved this study and written informed consent was obtained from all participating subjects according to the Declaration of Helsinki.

PROFILE patients meet the American College of Rheumatology (ACR) revised and updated criteria (7, 8), are ages ≥16 years, and have a disease duration of ≤10 years at the time of enrollment. They are of defined ethnicity (Hispanic of Mexican ancestry [residing and enrolled in Texas, hence Texan Hispanics], Hispanic of Puerto Rican ancestry [residing and enrolled in Puerto Rico, hence Puerto Rican Hispanics], African American, and white), having reported all 4 grandparents to be of the same ethnic background. A total of 2,228 SLE patients are followed longitudinally in PROFILE.

Variables.

The PROFILE database consists of variables common to the individual cohorts identified after carefully mapping the different cohorts' databases (6). As previously described, this database includes variables from the socioeconomic–demographic, clinical, immunologic, and genetic domains. Only the variables included in this study will be described. DLE was ascertained according to the ACR classification criteria, based on morphologic characteristics (erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions) as documented by qualified and experienced rheumatologists during the physical examination (7).

Socioeconomic–demographic variables evaluated included age at SLE diagnosis, age at last study visit, sex, ethnicity, years of education, health insurance, and smoking status. Time of SLE diagnosis was defined as the date at which a patient met at least 4 ACR criteria. Disease duration was defined as the time between SLE diagnosis and the last study visit.

The clinical variables included cumulative SLE-related clinical manifestations, autoantibodies, medications, comorbidities, and disease damage assessed with the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI) (9). Clinical manifestations were examined as per the ACR classification criteria, as well as other selected clinical manifestations such as vasculitis and Raynaud's phenomenon. Antinuclear antibodies (ANAs), anti–double-stranded DNA (anti-dsDNA) antibodies, anti-Sm antibodies, and antiphospholipid antibodies were locally measured. Cumulative exposure to glucocorticoids, hydroxychloroquine, cyclophosphamide, methotrexate, mycophenolate mofetil, and azathioprine was also examined. Selected comorbidities were recorded, including hypertension (recording of 3 abnormal readings and/or the use of antihypertensive medications), coronary artery disease, cerebrovascular events, peripheral artery disease, venous thromboembolism, pulmonary hypertension, and hypothyroidism. The SDI score as well as the individual components of the SDI were also assessed.

Statistical analyses.

Using a cross-sectional case-only approach, descriptive analyses were performed to compare the socioeconomic–demographic features, clinical variables, and disease damage in SLE patients with and without DLE. The relationship between variables was examined by Student's t-tests or chi-square tests, as appropriate. The association of DLE with clinical manifestations and disease damage was examined using multivariable logistic regression adjusted for pertinent socioeconomic–demographic variables. Final multivariable models included independently selected variables with a P value of less than or equal to 0.10 and pertinent socioeconomic–demographic variables, and were fit using maximum likelihood ratio methods. Variables with a P value of less than or equal to 0.05 in these analyses were considered to be significant. All analyses were performed using SAS software, version 9.1.

RESULTS

At the time of analysis, 2,228 patients were included in the PROFILE cohort. The mean ± SD age at diagnosis was 34.3 ± 12.8 years and the mean ± SD disease duration was 7.9 ± 6.0 years; 91.8% were women. The distribution of ethnic populations was as follows: 43.3% were white, 35.7% were African American, 9.9% were Puerto Rican Hispanic, 9.3% were Texan Hispanic, and other ethnic groups represented 1.8% of the cohort. DLE was observed in 393 SLE patients (17.6%). Of those with discoid rash, 75.8% were diagnosed prior to or at the time of SLE diagnosis. Of those with discoid rash diagnosed after SLE diagnosis, the mean ± SD time to diagnosis was 3.8 ± 5.1 years.

Table 1 shows the socioeconomic–demographic features in SLE patients with and without DLE. SLE patients with DLE were predominantly women (92.1%), with a mean ± SD age at diagnosis of 34.5 ± 12.4 years. DLE was more common in African Americans (28.6%), followed by whites (12.6%), Puerto Rican Hispanics (10.9%), and Texan Hispanics (6.2%; P < 0.001). DLE patients were more likely to have a longer disease duration (9.4 versus 7.6 years; P < 0.001), fewer years of formal education (13.2 versus 13.8 years; P < 0.001), and a positive history of smoking (23.2% versus 13.7%; P < 0.001) compared to SLE patients without DLE. No significant differences were observed for age, sex, and health insurance.

Table 1. Socioeconomic–demographic features as a function of the presence of DLE*
 SLE with DLE (n = 393)SLE without DLE (n = 1,835)P
  • *

    Values are the number (percentage) unless otherwise indicated. DLE = discoid lupus erythematosus; SLE = systemic lupus erythematosus.

Ethnicity  < 0.001
 African American (n = 793)227 (28.6)566 (71.4) 
 White (n = 966)122 (12.6)844 (87.4) 
 Hispanic   
  Puerto Rico (n = 220)24 (10.9)196 (89.1) 
  Texas (n = 209)13 (6.2)196 (93.8) 
 Other (n = 40)7 (17.5)33 (82.5) 
Age at diagnosis, mean ± SD years34.5 ± 12.434.3 ± 12.90.829
Disease duration, mean ± SD years9.4 ± 6.97.6 ± 5.8< 0.001
Female sex362 (92.1)1,682 (91.7)0.793
Years of education, mean ± SD years13.2 ± 3.013.8 ± 3.0< 0.001
Has health insurance (n = 1,580),  no./total (%)235/257 (91.4)1,189/1,323 (89.9)0.459
Current smoker91 (23.2)251 (13.7)< 0.001

In Table 2 we show the association of DLE with clinical manifestations, immunologic features, selected comorbidities, and damage accrual in SLE patients after adjusting for ethnicity, sex, disease duration, education, and smoking. DLE was associated with malar rash (odds ratio [OR] 1.28, 95% confidence interval [95% CI] 1.02–1.62), photosensitivity (OR 1.66, 95% CI 1.30–2.13), oral ulcers (OR 1.35, 95% CI 1.07–1.70), leukopenia (OR 1.46, 95% CI 1.16–1.83), and vasculitis (OR 1.62, 95% CI 1.22–2.13). Immunologic abnormalities such as positive ANAs (OR 0.52, 95% CI 0.31–0.88), antiphospholipid antibodies (OR 0.71, 95% CI 0.52–0.98), and elevated anti-dsDNA antibodies (OR 0.64, 95% CI 0.51–0.80) were less common among patients with DLE. Furthermore, arthritis was also less frequent in SLE patients with DLE (OR 0.73, 95% CI 0.54–0.99). In addition, DLE patients were more likely to have a higher overall SDI score (OR 1.07, 95% CI 1.02–1.13), indicative of greater cumulative damage. There were no significant differences in the pharmacologic profile among SLE patients with and without DLE after adjusting for ethnicity, sex, disease duration, education, and smoking (data not shown).

Table 2. Multivariable analyses of the association of discoid lupus erythematosus with cumulative SLE manifestations, immunologic features, selective comorbidities, and damage accrual*
FeatureOR (95% CI)P
  • *

    SLE = systemic lupus erythematosus; OR = odds ratio; 95% CI = 95% confidence interval; ACR = American College of Rheumatology; CNS = central nervous system; anti-dsDNA = anti–double-stranded DNA; SDI = Systemic Lupus International Collaborating Clinics/ACR Damage Index.

  • Adjusted OR for ethnicity, sex, disease duration, education, and smoking.

ACR criteria  
 Malar rash1.28 (1.02–1.62)0.037
 Photosensitivity1.66 (1.30–2.13)< 0.001
 Oral ulcers1.35 (1.07–1.70)0.011
 Arthritis0.73 (0.54–0.99)0.040
 Serositis0.95 (0.76–1.19)0.665
 Renal involvement0.80 (0.62–1.02)0.067
 CNS involvement1.23 (0.88–1.72)0.226
  Seizures1.26 (0.85–1.86)0.249
  Psychosis1.31 (0.79–2.18)0.299
 Hematologic involvement  
  Hemolytic anemia0.95 (0.65–1.39)0.786
  Leukopenia1.46 (1.16–1.83)< 0.001
  Lymphopenia0.85 (0.67–1.06)0.154
  Thrombocytopenia0.91 (0.68–1.21)0.528
Immunologic features  
 Antinuclear antibodies0.52 (0.31–0.88)0.016
 Anti-dsDNA antibodies0.64 (0.51–0.80)< 0.001
 Anti-Sm antibodies1.15 (0.89–1.49)0.287
 Antiphospholipid antibodies0.71 (0.52–0.98)0.040
Other SLE manifestations  
 Vasculitis1.62 (1.22–2.13)< 0.001
 Raynaud's phenomenon1.00 (0.80–1.25)0.989
 Transverse myelitis
Comorbidities  
 Hypertension1.02 (0.81–1.28)0.879
 Coronary artery disease1.34 (0.77–2.32)0.304
 Stroke1.21 (0.72–2.02)0.477
 Peripheral artery disease1.12 (0.66–1.90)0.679
 Venous thrombosis0.83 (0.55–1.26)0.382
 Pulmonary hypertension0.97 (0.52–1.81)0.924
 Hypothyroidism0.79 (0.53–1.19)0.257
SDI1.07 (1.02–1.13)0.007

Because the SDI score was associated with DLE, we determined the relationship with the individual components of the SDI, again adjusting for ethnicity, sex, disease duration, education, and smoking (Table 3). Chronic seizures (OR 1.84, 95% CI 1.08–3.13), scarring alopecia (OR 5.71, 95% CI 3.91–8.35), extensive scarring of the skin (OR 14.66, 95% CI 8.67–24.81), skin ulcers (OR 2.43, 95% CI 1.06–5.60), and diabetes mellitus (OR 1.68, 95% CI 1.10–2.56) were associated with DLE. However, SLE patients with DLE were less likely to present with end-stage renal disease (ESRD; OR 0.42, 95% CI 0.19–0.93).

Table 3. Multivariable analyses of the association of discoid lupus erythematosus with the individual components of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index*
FeatureOR (95% CI)P
  • *

    OR = odds ratio; 95% CI = 95% confidence interval; GFR = glomerular filtration rate; GI = gastrointestinal.

  • Adjusted OR for ethnicity, sex, disease duration, education, and smoking.

  • Variables statistically significant.

Ocular  
 Cataracts1.19 (0.83–1.70)0.345
 Retinal changes or optic atrophy0.93 (0.51–1.72)0.820
Neuropsychiatric  
 Cognitive impairment1.03 (0.71–1.48)0.891
 Chronic seizures1.84 (1.08–3.13)0.025
 Cerebrovascular accidents1.21 (0.76–1.92)0.423
 Cranial or peripheral neuropathy0.53 (0.28–1.00)0.051
 Transverse myelitis
Renal  
 GFR <50%0.86 (0.49–1.51)0.590
 Proteinuria 24 hours, ≥3.5 gm1.00 (0.66–1.51)0.993
 End-stage renal disease0.42 (0.19–0.93)0.033
Pulmonary  
 Pulmonary hypertension1.04 (0.55–1.96)0.895
 Pulmonary fibrosis1.00 (0.56–1.78)0.997
 Shrinking lung0.40 (0.05–3.14)0.381
 Pleural fibrosis1.18 (0.52–2.69)0.691
 Pulmonary infarction
Cardiovascular  
 Angina or coronary artery bypass1.48 (0.73–2.99)0.274
 Myocardial infarction1.82 (0.95–3.47)0.071
 Cardiomyopathy1.62 (0.90–2.91)0.110
Valvular disease or replacement0.44 (0.17–1.14)0.090
 Pericarditis or pericardiectomy0.74 (0.25–2.17)0.577
Peripheral vascular  
 Claudication0.73 (0.15–3.59)0.696
 Minor tissue loss1.40 (0.59–3.33)0.450
 Significant tissue loss0.88 (0.25–3.09)0.841
 Venous thrombosis0.45 (0.17–1.19)0.109
GI  
 Infarction or resection of bowel1.16 (0.73–1.83)0.527
 Mesenteric insufficiency0.79 (0.08–7.83)0.840
 Chronic peritonitis1.93 (0.34–11.02)0.460
 Stricture or upper GI tract surgery0.36 (0.05–2.84)0.330
 Pancreatitis1.03 (0.21–5.01)0.966
Musculoskeletal  
 Atrophy or weakness0.91 (0.43–1.94)0.805
 Deforming or erosive arthritis1.06 (0.59–1.88)0.848
 Osteoporosis with fracture1.19 (0.75–1.89)0.454
 Avascular necrosis0.95 (0.59–1.52)0.829
 Osteomyelitis0.57 (0.19–1.72)0.315
 Ruptured tendons0.39 (0.11–1.39)0.147
Skin  
 Scarring alopecia5.71 (3.91–8.35)< 0.001
 Extensive scarring of the skin14.66 (8.67–24.81)< 0.001
 Skin ulcers2.43 (1.06–5.60)0.037
Premature gonadal failure1.03 (0.64–1.66)0.908
Diabetes mellitus1.68 (1.10–2.56)0.016
Malignancy0.95 (0.52–1.72)0.861

In Table 4 we show the results of the multivariable analysis, including significant variables in the previous analysis plus ethnicity, sex, disease duration, and smoking. Model 1 includes SLE manifestations and the overall SDI. The following variables retained significance: Texan Hispanic ethnicity (OR 0.48, 95% CI 0.25–0.89), African American ethnicity (OR 3.57, 95% CI 2.70–4.71), disease duration (OR 1.04, 95% CI 1.02–1.06), education (OR 0.95, 95% CI 0.91–0.99), smoking (OR 1.89, 95% CI 1.41–2.54), photosensitivity (OR 1.85, 95% CI 1.40–2.46), arthritis (OR 0.65, 95% CI 0.48–0.89), leukopenia (OR 1.46, 95% CI 1.15–1.85), anti-dsDNA antibodies (OR 0.71, 95% CI 0.56–0.91), antiphospholipid antibodies (OR 0.70, 95% CI 0.50–0.98), vasculitis (OR 1.53, 95% CI 1.13–2.05), and SDI score (OR 1.08, 95% CI 1.02–1.14). In model 2, which included SLE manifestations plus the individual components of the SDI (but not the overall SDI), Texan Hispanic ethnicity (OR 0.41, 95% CI 0.20–0.81), African American ethnicity (OR 3.18, 95% CI 2.38–4.24), disease duration (OR 1.05, 95% CI 1.03–1.07), smoking (OR 1.65, 95% CI 1.20–2.27), photosensitivity (OR 1.59, 95% CI 1.18–2.13), arthritis (OR 0.67, 95% CI 0.48–0.94), leukopenia (OR 1.41, 95% CI 1.09–1.81), anti-dsDNA antibodies (OR 0.66, 95% CI 0.51–0.85), chronic seizures (OR 1.92, 95% CI 1.03–3.60), ESRD (OR 0.30, 95% CI 0.13–0.74), scarring alopecia (OR 3.42, 95% CI 2.17–5.37), and extensive scarring of the skin (OR 10.76, 95% CI 5.89–19.66) remained significant.

Table 4. Variables independently associated with discoid lupus erythematosus by multivariable analyses*
FeatureModel 1Model 2
OR (95% CI)POR (95% CI)P
  • *

    OR = odds ratio; 95% CI = 95% confidence interval; anti-dsDNA = anti–double-stranded DNA; SDI = Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index.

  • Model 1 includes systemic lupus erythematosus (SLE) manifestations and the overall SDI.

  • Model 2 includes SLE manifestations and the individual components of the SDI. Sex was also included in both multivariable models.

Ethnicity    
 African American3.57 (2.70–4.71)< 0.0013.18 (2.38–4.24)< 0.001
 Hispanic, Puerto Rico1.04 (0.63–1.70)0.4080.87 (0.52–1.46)0.203
 Hispanic, Texas0.48 (0.25–0.89)< 0.0010.41 (0.20–0.81)< 0.001
 Other1.65 (0.68–3.99)0.4251.85 (0.77–4.46)0.193
 WhiteReference group Reference group 
Disease duration1.04 (1.02–1.06)< 0.0011.05 (1.03–1.07)< 0.001
Education0.95 (0.91–0.99)0.0180.96 (0.92–1.01)0.091
Smoking1.89 (1.41–2.54)< 0.0011.65 (1.20–2.27)0.002
Malar rash1.21 (0.93–1.56)0.1521.13 (0.86–1.48)0.383
Photosensitivity1.85 (1.40–2.46)< 0.0011.59 (1.18–2.13)0.002
Oral ulcers1.15 (0.89–1.47)0.2821.13 (0.87–1.47)0.355
Arthritis0.65 (0.48–0.89)0.0080.67 (0.48–0.94)0.019
Leukopenia1.46 (1.15–1.85)0.0021.41 (1.09–1.81)0.008
Antinuclear antibodies0.59 (0.34–1.03)0.0660.59 (0.32–1.07)0.083
Anti-dsDNA antibodies0.71 (0.56–0.91)0.0060.66 (0.51–0.85)0.001
Antiphospholipid antibodies0.70 (0.50–0.98)0.0400.73 (0.51–1.04)0.077
Vasculitis1.53 (1.13–2.05)0.0051.26 (0.91–1.74)0.171
SDI1.08 (1.02–1.14)0.011
SDI components    
 Chronic seizures1.92 (1.03–3.60)0.041
 End-stage renal disease0.30 (0.13–0.74)0.009
 Scarring alopecia3.42 (2.17–5.37)< 0.001
 Extensive scarring of skin10.76 (5.89–19.66)< 0.001
 Skin ulcers0.90 (0.31–2.64)0.853
 Diabetes mellitus1.27 (0.77–2.07)0.346

DISCUSSION

SLE patients presenting with DLE generally have been regarded as having a mild form of disease mainly characterized by mucocutaneous involvement. Some studies have suggested that life-threatening manifestations are uncommon among these patients and that usually they have a better prognosis compared to SLE patients without DLE (4, 10). Data are extensive in patients with isolated DLE; however, studies assessing the clinical characteristics of SLE patients with DLE are limited. In the present study, we found that SLE patients with DLE were more likely to have malar rash, photosensitivity, oral ulcers, leukopenia, vasculitis, and more damage accrual, including individual components of the SDI such as chronic seizures, scarring alopecia, extensive scarring of the skin, and skin ulcerations. Conversely, arthritis, ESRD, and immunologic abnormalities such as ANAs, anti-dsDNA antibodies, and antiphospholipid antibodies were less common in patients with DLE.

Lupus is a heterogeneous disease characterized by a wide spectrum of clinical manifestations, including discoid rash, which may occur with or without systemic involvement. There is evidence that genetic and environmental factors are involved in the pathogenesis of this complex disease (11–16). Genetic associations have been reported in patients with CLE, including polymorphisms of genes encoding HLA, tumor necrosis factor α, and complement molecules (12–15). Also, ethnicity has been shown to contribute to the heterogeneity of the clinical manifestations observed in SLE. For instance, the prevalence of DLE has been noted to vary among different ethnic populations (17, 18). The overall frequency of DLE in our cohort of SLE patients was nearly 18%. This prevalence is comparable with data from previous large cohort studies of DLE in SLE patients reporting an overall prevalence of approximately 14% in Latin American, African American, and white American populations (18). Conversely, al-Attia reported a prevalence of discoid rash of 3% in a population of Arab patients with SLE (11), whereas Kapadia and Haroon found it to be present in 57.5% of SLE patients from Pakistan (19), highlighting the broad range of frequencies of DLE among different ethnic groups. Furthermore, in our multiethnic cohort, African Americans more commonly had DLE, as previously reported by other authors (20). Interestingly, our population of Hispanics from Texas was less likely to have DLE when compared to other ethnic groups, including Hispanics from Puerto Rico and whites. This is a novel finding that contrasts a previous study assessing the clinical manifestations of SLE in Hispanic populations that shows similar rates of DLE among Mestizos and whites (21). However, SLE patients in this previous study included patients from different Latin American countries, including Mexico, Guatemala, and Peru, whereas our study included Hispanics mainly of Mexican ancestry. Taken together, these findings support the evidence that genetic factors contribute to the variability in the clinical expression of SLE.

In addition, the association of DLE with cigarette smoking, which has been widely recognized, was supported by our data (22). This finding underscores the important role of this environmental trigger in the pathogenesis of DLE as an independently associated factor, particularly among genetically predisposed individuals (22–25). Smoking has been previously linked to a shorter time to integument damage occurrence (26) and a significantly reduced clinical response in patients receiving antimalarials (27). It has been suggested that smoking may interfere with the accumulation of antimalarials within lysosomes, as well as with their metabolism through enhancement of their elimination via the cytochrome P450 enzyme complex (28). However, in contrast to this observation, recent studies have not shown a direct effect of cigarette smoking on response to antimalarials and suggest that other factors have a greater impact. Wahie et al studied DLE patients treated with hydroxychloroquine and found that cigarette smoking did not have any significant influence on the response to this medication (29). Instead, they found that disseminated skin involvement and concomitant systemic disease were significantly associated with the lack of response to hydroxychloroquine. In addition, Leroux and colleagues found that cigarette smoking did not affect plasma levels of hydroxychloroquine in a population of SLE patients (30).

We, like other investigators, have found a high frequency of mucocutaneous involvement in patients with DLE. Ng et al studied patients from a dermatologic center in Singapore and found that the majority of SLE patients with DLE had oral ulcers, malar rash, and photosensitivity, whereas only 20% had serious organ involvement (renal or central nervous system) (31). However, previous studies have shown an association of oral ulcers and photosensitivity with higher disease activity in patients with DLE, suggesting that these manifestations must not be overlooked because they may herald a worse prognosis in patients with limited cutaneous involvement (32). Our cohort of SLE patients with DLE presented more damage accrual compared to those without DLE as measured by the SDI. The assessment of the individual components of the SDI revealed that the higher scores were mainly attributed to the skin damage caused by DLE.

We found a lower frequency of arthritis among patients with DLE. These findings concur with previous studies that report a lower occurrence of arthralgias and arthritis in patients with chronic CLE (1, 33). Of note, Tebbe et al showed that the presence of arthralgias was significantly associated with systemic disease among patients with CLE (34). However, the latter study included patients from Germany and Austria, for which ethnic disparities must be taken into account when evaluating these findings. Furthermore, these patients were evaluated for the presence of arthralgias, whereas in our study an assessment was made for arthritis.

We found that SLE patients with DLE had a lower frequency of ANAs, anti-dsDNA antibodies, and antiphospholipid antibodies compared to patients without discoid rash. This observation has been reported by other authors who have suggested that DLE appears to be associated with a lower frequency of immunologic markers of disease activity (4). However, the prevalence of anti-dsDNA antibodies in our patients with discoid rash (49.6%) was higher than that found in previous large cohorts of SLE patients with chronic CLE (30%) (1). Anti-dsDNA antibodies are usually regarded as a marker of systemic involvement (1) and have been related to widespread cutaneous disease and a higher prevalence of nephropathy and hemolytic anemia (35). Isotypes of anti-dsDNA antibodies have been associated with variable clinical expression in SLE; for example, Förger et al reported significant associations of the IgG isotype with lupus nephritis and the IgM isotype with cutaneous manifestations (36). Our data showed that DLE was associated with less ESRD and with a higher frequency of mucocutaneous manifestations and vasculitis. However, the isotypes of anti-dsDNA antibodies were not assessed in our cohort of lupus patients. Although our cohort of patients with DLE had a lower prevalence of antiphospholipid antibodies, there were no significant differences in the prevalence of thromboembolic events when compared to SLE patients without discoid rash. Our data also revealed an association of DLE with leukopenia, which contrasts with previous reports of lower frequencies of leukopenia in SLE patients with chronic CLE (1). This laboratory parameter is particularly important for patients with limited discoid rash because it has been identified as a marker of progression toward widespread disease and systemic involvement (5).

Vasculitis was more commonly seen among our patients with DLE. It has been reported that approximately 10–20% of lupus patients present with some form of vasculitis (37). However, our data contrast with previous studies reporting a lower frequency of this manifestation in SLE patients with chronic CLE (1). Of interest, Zecević et al found that SLE patients with nonspecific cutaneous manifestations had significantly increased disease activity compared to those with only lupus erythematosus–specific lesions (38). Cutaneous vasculitis represents one of the lupus erythematosus–nonspecific skin manifestations and it has been shown to be the most frequent type of vasculitis in patients with SLE; it has also been associated with lupus activity and a worse prognosis (39–41). Callen and Kingman reported a link between cutaneous vasculitis and the progression of disease as manifested by renal and central nervous system involvement (41). The association of DLE with visceral vasculitis has been previously described in case reports. Nguyen et al reported a case of severe mesenteric and coronary vasculitis in a patient with chronic DLE without other evidence of systemic involvement (42).

In agreement with other studies, we found that severe renal involvement, particularly ESRD, was less frequent in patients with DLE (1, 4). A plausible explanation for this finding is that our SLE patients with DLE had a lower frequency of anti-dsDNA antibodies as compared to those without discoid rash. Anti-dsDNA antibodies bind glomerular collagen with high affinity and have been implicated in the pathogenesis of lupus nephritis (43); however, the exact mechanism remains controversial. Recent data suggest that immune complexes of chromatin fragments with anti-dsDNA antibodies and their subsequent binding to the glomerular basement membrane may represent a key event in the development of nephritis (44). However, no association was found between discoid rash and overall renal involvement among our cohort of patients with SLE. On the other hand, although less frequently, DLE patients with isolated disease may also present with renal involvement as shown in previous studies, mainly when having hypocomplementemia and disseminated cutaneous lesions, for which periodic monitoring is highly recommended for these patients (31–45).

Even though more skin damage was noted in our DLE patients, thus accounting for higher SDI scores, these patients also presented other features leading to more damage accrual, such as a higher frequency of chronic seizures. Neurologic manifestations have been described in patients with DLE. Koskenmies et al reported neurologic involvement in 7.3% of patients with DLE as compared to 3.6% in subacute CLE; the majority of patients presented with epilepsy (33). Feinglass et al described an association of vasculitis with neuropsychiatric involvement (46). This observation was further supported by Karassa et al, who reported a significant correlation of cutaneous vasculitic lesions with central nervous system involvement in SLE (47). Vasculitis of the brain vessels has been described in 7–15% of patients with neuropsychiatric lupus at autopsy; however, Johnson and Richardson reported that neuropathologic findings in these patients consist predominantly of changes related to small blood vessels, characterized by a noninflammatory proliferative vasculopathy (48). In the study by Karassa et al, a negative correlation between neuropsychiatric manifestations and discoid lesions was established, which contrasts with data from our study (47). Nonetheless, our findings together with other studies highlight the importance of cutaneous vasculitis as a possible marker of a worse prognosis in patients with discoid rash, perhaps placing them at an increased risk for developing neurologic complications such as seizures.

Some limitations of the present study should be addressed. First, an assessment of disease activity in this multiethnic cohort of SLE patients was not possible because the instruments used to measure this parameter were not homogenous throughout the study centers, and even though the instruments used at the different centers are reliable, their scores cannot be converted. In addition, these data were not available for all of the study patients. Second, the assessment of the medication profile in our cohort is limited, since information on the starting date of therapy of the individual medications and treatment duration was not available for all of the patients. This information is relevant for data analysis because early treatment certainly impacts the progression of disease. For example, antimalarials have been associated with a decrease in disease flares (49) and integument injury (26), less damage accrual (50, 51), and improved survival (52) among lupus patients. Third, antibodies were done locally when clinically indicated and not per protocol. Finally, we were not able to document the extension of skin involvement among patients with DLE. The pattern of cutaneous involvement in DLE is particularly meaningful in terms of prognostic value. Widespread DLE has been associated with a higher frequency of laboratory abnormalities such as anemia, elevated erythrocyte sedimentation rate, high ANA titers, and anti-dsDNA antibodies. In addition, widespread disease has been related to a higher prevalence of photosensitivity, panniculitis, and systemic involvement (1, 31).

In summary, we found that DLE was associated with a higher frequency of mucocutaneous manifestations (other than DLE), integument damage, leukopenia, vasculitis, and chronic seizures, and a lower frequency of arthritis, ESRD, and immunologic abnormalities. We also corroborated the association of DLE with smoking and African American ethnicity while describing for the first time, to our knowledge, a decreased risk of DLE among Texan Hispanics. This is the largest study examining the clinical associations of discoid rash in patients with SLE. Our findings highlight the importance of surveillance of this population of SLE patients, particularly because of the association with serious manifestations such as vasculitis and chronic seizures.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Vilá had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Santiago-Casas, Vilá, Petri, Ramsey-Goldman, Reveille, Kimberly, Alarcón, Brown.

Acquisition of data. Santiago-Casas, Vilá, Petri, Ramsey-Goldman, Reveille, Kimberly, Alarcón, Brown.

Analysis and interpretation of data. Santiago-Casas, Vilá, McGwin, Cantor, Petri, Ramsey-Goldman, Reveille, Kimberly, Alarcón, Brown.

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