Key Points
Question
What are the prevalence and risk factors of having concurrent autoimmune diseases in patients with cutaneous lupus erythematosus?
Findings
In this cross-sectional study that included 129 participants, 17.8% had a coexisting autoimmune condition, with the most common being autoimmune thyroid disease. White race, nonsmoking, family history of autoimmunity, and positive antinuclear antibody test result were risk factors associated with coexisting autoimmune conditions.
Meaning
Patients with cutaneous lupus erythematosus have an increased prevalence of coexisting autoimmune conditions compared with the general population and should be monitored closely.
This cross-sectional study examines the prevalence and risk factors of having coexisting autoimmune conditions in patients with cutaneous lupus erythematosus.
Abstract
Importance
Increased rates of autoimmune conditions have been reported in association with systemic lupus erythematosus (SLE). Little is known about coexisting autoimmune conditions in patients with cutaneous lupus erythematosus (CLE) without SLE.
Objective
To determine the prevalence and risk factors of having coexisting autoimmune conditions in patients with CLE.
Design, Setting, and Participants
This cross-sectional study was performed from November 2008 to February 2017 at the
University of Texas Southwestern Medical Center (UTSW) and Parkland Health and Hospital System, Dallas, Texas.
Participants were identified through the UTSW Cutaneous Lupus Registry. All participants had a dermatologist-confirmed diagnosis of CLE using clinicopathological correlation. Exclusion criteria included age younger than 18 years, and meeting at least 4 American College of Rheumatology diagnostic criteria for SLE.
Participants with CLE and without concomitant autoimmune diseases were compared by demographic and disease characteristics.
Main Outcomes and Measures
The primary and secondary outcomes were presence of coexisting autoimmune condition(s) and individual autoimmune diseases, respectively. Predictor variables significantly associated with coexisting autoimmune diseases were identified by univariate and multivariable logistic regression analyses.
Results
Among the 285 participants initially screened, 129 participants with CLE were included (102 [79.1%] female; median age, 49 years [interquartile range, 38.3-57.1 years]). Coexisting autoimmune conditions were found in 23 (17.8%). Autoimmune thyroid disease had the highest frequency at 4.7% (n = 6). Multivariable logistic regression analyses showed that patients with CLE who were white (odds ratio [OR], 2.88; 95% CI, 1.00-8.29; P = .0498), never smokers (OR, 3.28; 95% CI, 1.14-9.39; P = .03), had family history of autoimmune disease (OR, 3.54; 95% CI, 1.21-10.39; P = .02), and history of positive antinuclear antibody test result (OR, 4.87; 95% CI, 1.69-14.03; P = .003) had a significant association with having coexisting autoimmune conditions.
Conclusions and Relevance
This study suggests that patients with CLE without concurrent SLE can have increased rates of coexisting autoimmune conditions. Collecting a thorough review of systems can prompt clinicians to pursue further testing and evaluation by other specialists. Future studies investigating development of coexisting autoimmune conditions over time in the CLE population are necessary to confirm these findings.
Introduction
Cutaneous lupus erythematosus (CLE) is characterized by a variety of photosensitive skin findings that appear in the presence or absence of systemic lupus erythematosus (SLE). Both CLE and SLE are autoimmune disorders as defined by the modified Witebsky postulates.1 Among patients with SLE, 6% to 30% have a coexisting autoimmune condition, including Sjögren syndrome, autoimmune thyroid disease, rheumatoid arthritis (RA), and immune thrombocytopenia.2,3 Because little is known about autoimmune diseases in patients who have CLE without concurrent SLE (CLE-only), we investigated the prevalence and risk factors of having coexisting autoimmune conditions in patients with CLE-only.
Methods
A cross-sectional study was conducted among patients with CLE. Participants were recruited from outpatient dermatology clinics at University of Texas Southwestern (UTSW) Medical Center and Parkland Health and Hospital System in Dallas, Texas, from November 2008 to February 2017. All participants had diagnoses of CLE confirmed by a dermatologist (B.F.C.) using clinicopathological correlation. Exclusion criteria included age younger than 18 years, and having met at least 4 American College of Rheumatology criteria for SLE. Autoimmune diagnoses were collected by patient history and medical record review. A 6-month period from the patient’s study visit allowed time for participants to be evaluated by other subspecialties to confirm diagnoses of autoimmune diseases. This study was approved by the UTSW Institutional Review Board. All participants provided written informed consent.
The primary outcome was presence of at least 1 coexisting autoimmune condition(s) defined by the modified Witebsky postulates and included in the updated list by Hayter and Cook.1 The Witebsky postulates are based on the presence of autoantibodies or autoreactive T cells and identification of an immune response toward affected tissue, ability to reproduce the condition in animal models or through transfer by autoreactive T cells and/or autoantibodies in healthy individuals, and clinical improvement after immunosuppression.1 Patient demographic and clinical characteristics were compared to identify risk factors associated with concomitant autoimmune disease(s).
Sample size was not calculated for this pilot study. We performed univariate and multivariable logistic regression analyses to identify risk factors associated with autoimmune diseases in patients with CLE. For univariate analyses, we used the Mann-Whitney U test for continuous variables and χ2 or Fisher exact tests for categorical variables. Two-sided P < .05 was considered significant. Predictors in the logistic regression model included variables significant at P < .05 from the univariate analyses. All statistical analyses were performed using SPSS, version 25.
Results
Of the 285 patients initially screened, 129 patients with CLE-only were included. Twenty-three (17.8%) patients with CLE-only had at least 1 coexisting autoimmune condition (Table 1). Thirteen distinct autoimmune diagnoses were reported. Autoimmune diseases found in the highest frequencies were autoimmune thyroid disease (6 [4.7%]), Sjögren syndrome (4 [3.1%]), RA (3 [2.3%]), and alopecia areata (3 [2.3%]).
Table 1. Coexisting Autoimmune Conditions in 129 Patients With Cutaneous Lupus Erythematosus Without Systemic Lupus Erythematosusa.
| Autoimmune Disease | No. (%) |
|---|---|
| Autoimmune thyroid diseaseb | 6 (4.7) |
| Sjögren syndrome | 4 (3.1) |
| Rheumatoid arthritis | 3 (2.3) |
| Alopecia areata | 3 (2.3) |
| Morphea | 2 (1.6) |
| Addison’s disease | 1 (0.8) |
| Chronic inflammatory demyelinating polyneuropathy | 1 (0.8) |
| Guillain-Barré syndrome | 1 (0.8) |
| Immune thrombocytopenic purpura | 1 (0.8) |
| Microscopic polyangiitis | 1 (0.8) |
| Multiple sclerosis | 1 (0.8) |
| Pernicious anemia | 1 (0.8) |
| Ulcerative colitis | 1 (0.8) |
One participant had rheumatoid arthritis, Sjögren syndrome, and microscopic polyangiitis, and another had Sjögren syndrome and Guillain-Barré syndrome.
Autoimmune thyroid disease includes Graves disease and Hashimoto thyroiditis.
Demographic and clinical characteristics are summarized in Table 2. Univariate analyses showed that those with at least 1 coexisting autoimmune condition(s) were less likely to have high school level of education (3 [14%] vs 34 [36%]; P = .02), and more likely to be white (15 [65%] vs 42 [40%]; P = .03) and to have nonsmoking history (15 [65%] vs 37 [35%]; P = .01), positive family history for autoimmunity (11 [48%] vs 21 [19%]; P = .003), history of positive antinuclear antibody (ANA) test result (16 [70%] vs 31 [29%]; P < .001), and CLE below the neck (13 [57%] vs 34 [32%]; P = .03).
Table 2. Univariate Analysis of Demographic and Clinical Features of Patients With Cutaneous Lupus Erythematosus (CLE) Without Systemic Lupus Erythematosus With and Without Coexisting Autoimmune Conditions.
| Feature | No. (%) | P Valuea | ||
|---|---|---|---|---|
| All CLE-Only Patients (N = 129) | No Coexisting Autoimmune Condition (n = 106) | ≥1 Coexisting Autoimmune Condition(s) (n = 23) | ||
| Sex | ||||
| Male | 27 (21) | 23 (22) | 4 (17) | .65 |
| Female | 102 (79) | 83 (78) | 19 (83) | |
| Age, median (IQR), y | ||||
| At study visit | 49 (38-57) | 48 (38-56) | 51 (45-60) | .11 |
| At CLE onset | 39 (31-51) | 38 (31-48) | 44 (33-57) | .18 |
| CLE duration, median (IQR), y | 4 (1-12) | 5 (1-13) | 2 (1-8) | .26 |
| Race | ||||
| White | 57 (44) | 42 (40) | 15 (65) | .03b |
| African American | 66 (51) | 58 (55) | 8 (35) | |
| Asian | 2 (2) | 2 (2) | 0 | |
| Other | 4 (3) | 4 (4) | 0 | |
| Ethnicity | ||||
| Non-Hispanic | 120 (93) | 98 (92) | 22 (96) | .59 |
| Hispanic | 9 (7) | 8 (8) | 1 (4) | |
| Education | ||||
| No. | 94 | 22 | ||
| Less than high school | 14 (11) | 13 (14) | 1 (5) | .02 |
| High school graduate | 37 (29) | 34 (36) | 3 (14) | |
| College | 48 (37) | 37 (39) | 11 (50) | |
| Graduate school | 17 (13) | 10 (11) | 7 (32) | |
| Smoking status | ||||
| No. | 105 | 23 | ||
| Never | 52 (40) | 37 (35) | 15 (65) | .01 |
| Ever | 76 (59) | 68 (65) | 8 (35) | |
| Family history of autoimmunity | 31 (24) | 21 (19) | 11 (48) | .003 |
| Predominant CLE subtype | ||||
| Chronic | 108 (84) | 92 (87) | 16 (70) | .06 |
| Subacute | 21 (16) | 14 (13) | 7 (30) | |
| CLE lesions below the neck | 47 (36) | 34 (32) | 13 (57) | .03 |
| ACR diagnostic criteria | ||||
| Discoid rash | 95 (74) | 81 (76) | 14 (61) | .13 |
| Photosensitivity | 71 (55) | 61 (58) | 10 (43) | .22 |
| Positive ANA test resultc | 47 (36) | 31 (29) | 16 (70) | <.001 |
| Blood disorder | 15 (12) | 12 (11) | 3 (13) | .73 |
| Oral ulcers | 7 (5) | 6 (6) | 1 (4) | .80 |
| Arthritis | 7 (5) | 6 (6) | 1 (4) | .80 |
| Malar rash | 5 (4) | 4 (4) | 1 (4) | >.99 |
| Immunologic disorder | 6 (5) | 3 (3) | 3 (13) | .07 |
| No. of criteria, median (IQR) | 2 (1-3) | 2 (1-2) | 2 (2-3) | .28 |
| CLASI scores, median (IQR) | ||||
| CLASI activity | 3 (2-8) | 4 (2-8) | 3 (1-13) | .85 |
| CLASI damage | 5 (1-10) | 6 (1-10) | 3 (1-7) | .12 |
Abbreviations: ACR, American College of Rheumatology; ANA, antinuclear antibody; CLASI, cutaneous lupus erythematosus disease area and severity index; IQR, interquartile range.
P value determined by χ2, Fisher exact, or Mann-Whitney U test to compare groups with and without coexisting autoimmune conditions.
Whites vs nonwhites.
Positive ANA test result was defined as having a titer of 1:160 or greater.
Multivariable analyses showed that white race was more frequently present in CLE-only patients with at least 1 coexisting autoimmune condition(s) (odds ratio [OR], 2.88; 95% CI, 1.00-8.29; P = .0498). Additionally, CLE-only patients who never smoked (OR, 3.28; 95% CI, 1.14-9.39; P = .03), had positive family history for autoimmunity (OR, 3.54; 95% CI, 1.21-10.39; P = .02), and had positive ANA test results (OR, 4.87; 95% CI, 1.69-14.03; P = .003) were more likely to have 1 or more coexisting autoimmune condition(s) (Table 3).
Table 3. Multivariable Logistic Regression Analysis of Clinical and Demographic Factors Associated With Patients With Cutaneous Lupus Erythematosus Without Systemic Lupus Erythematosus but With Coexisting Autoimmune Condition(s).
| Factor | OR (95% CI) | P Valuea |
|---|---|---|
| Race (white vs nonwhite) | 2.88 (1.00-8.29) | .0498 |
| Smoking status (never vs ever) | 3.28 (1.14-9.39) | .03 |
| Family history of autoimmunity | 3.54 (1.21-10.39) | .02 |
| Positive ANA test result | 4.87 (1.69-14.03) | .003 |
Abbreviations: ANA, antinuclear antibody; OR, odds ratio.
Hosmer and Lemeshow coefficient = 0.97, providing excellent fit of the model to the data.
Discussion
A total of 17.8% of our CLE-only patients had at least 1 coexisting autoimmune condition, a rate almost 4-fold higher than the general population (4.5%)1 and similar to that reported for patients with SLE.2,3 Moreover, for patients with CLE, meeting 1 to 3 SLE American College of Rheumatology criteria may not increase the risk of coexisting autoimmune conditions vs meeting 4 or more criteria. Patients with autoimmune conditions are susceptible to developing others, likely due to commonly shared genetic abnormalities. Several genetic polymorphisms have been found in multiple autoimmune diseases including genes for protein tyrosine phosphatase nonreceptor type 22 (PTPN22), tumor necrosis factor–induced protein 3 (TNFAIP3), signal transducer and activator of transcription 4 (STAT4), and cytotoxic T-lymphocyte–associated protein 4 (CTLA4).4 Autoimmune thyroid disease including Graves disease and Hashimoto thyroiditis was the most commonly reported autoimmune condition. This rate could be higher because we excluded 9 cases of hypothyroidism due to inadequate documentation. We recommend checking for symptoms, physical examination findings, and laboratory test abnormalities associated with thyroid disease in patients with CLE, especially those with systemic complaints such as fatigue that may mimic SLE.
Sjögren syndrome and RA were 2 other common autoimmune diseases. McDonagh and Isenberg2 identified that 6% of patients with SLE had concomitant RA. Sjögren syndrome has been reported in 9% to 13% of patients with lupus.2,5 While arthritis is the most common symptom in patients with SLE, our data illustrate that arthritis in CLE-only patients may be due to other disease processes such as RA. Referrals to rheumatologists will be helpful to pinpoint arthritis diagnoses. Patients with Sjögren syndrome and those with subacute CLE commonly share circulating anti–Sjögren syndrome–related antigen A antibodies, which likely explains the increase in Sjögren disease prevalence in our cohort. All 4 CLE-only patients with Sjögren syndrome had predominantly subacute CLE. Thus, asking CLE-only patients for presence of sicca-like symptoms can prompt further evaluation and workup.
White patients with CLE-only were more likely to have coexisting autoimmune conditions compared with nonwhites. This could be due to the predisposition for whites to develop some of the most common autoimmune conditions, including Sjögren syndrome, Hashimoto thyroiditis, and morphea.1,6,7,8 The nonsmoking history associated with increased likelihood of coexisting autoimmune diseases in our CLE-only cohort contradicts previous epidemiologic studies linking smoking with development of several autoimmune conditions.9 However, studies have reported protective effects of smoking in autoimmune diseases such as ulcerative colitis and autoimmune diabetes.9,10 Anti-inflammatory effects of nicotine in vivo have been proposed as a mechanism for its protective effects.11 Larger studies are necessary to verify these associations.
A history of positive ANA test result was another risk factor for CLE-only patients having a coexisting autoimmune condition. Having a positive ANA test result indicates a predisposition to autoimmunity but is nonspecific for diagnosis of many autoimmune diseases.12 This is illustrated by the sensitivities of positive ANA test results in autoimmune thyroid disease (20%-70%), RA (41%), Sjögren syndrome (48%), and SLE (93%).13
Family history of autoimmunity was another significant risk factor. The most common autoimmune conditions of CLE family members included SLE, Hashimoto thyroiditis, and RA, which is similarly found in patients with other autoimmune diseases.14 Shared genetic polymorphisms are likely responsible for these findings.
Of note, 8 participants progressed from CLE-only to SLE, with a median time frame of 4.3 years. One had 1 or more coexisting autoimmune condition(s) and had subacute CLE. Three had histories of positive ANA test results at their initial visits.
Limitations
This study was limited by small sample size, missing data due to unavailable medical records from other facilities, and cross-sectional design. Nonetheless, our CLE cohort is predominantly female, consistent with prior studies,15 and racially diverse, which should make it generalizable to larger populations. To confirm our findings, we are planning larger longitudinal studies.
Conclusions
This study showed that CLE-only patients are at increased risk for coexisting autoimmune condition(s). Those CLE-only patients with white race, nonsmoking history, positive ANA test results, and positive family history of autoimmunity were more likely to have additional autoimmune disorders. We recommend that clinicians collect a thorough history and review of systems and perform appropriate screenings for autoimmune disorders in patients with CLE.
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