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The natural history of pediatric-onset discoid lupus erythematosus
ORIGINAL
ARTICLE
The natural history of pediatric-onset discoid lupus erythematosus Lisa M. Arkin, MD,a Leah Ansell, MD,a Alfred Rademaker, PhD,b Megan L. Curran, MD,d Michael L. Miller, MD,d Annette Wagner, MD,c Brandi M. Kenner-Bell, MD,c Sarah L. Chamlin, MD,c Anthony J. Mancini, MD,c Marisa Klein-Gitelman, MD, MPH,d and Amy S. Paller, MS, MDa,c Chicago, Illinois Background: Pediatric discoid lupus erythematosus (DLE) is rare. The risk of progression to systemic lupus erythematosus (SLE) is uncertain. Objective: We sought to determine the risk of progression of pediatric DLE to SLE and to characterize its phenotype. Methods: This was a retrospective review of 40 patients with DLE. Results: Six (15%) of 40 patients presented with DLE as a manifestation of concurrent SLE. Of the remaining 34, 9 (26%) eventually met SLE criteria and 15 (44%) developed laboratory abnormalities without meeting SLE criteria. Only 10 (29%) maintained skin-limited disease. The average age at progression to SLE was 11 years, with greatest risk in the first year after DLE diagnosis. Most (89%) patients with SLE met diagnostic criteria with mucocutaneous disease (discoid lesions, malar rash, oral and nasal ulcers, photosensitivity), positive antibodies, and/or cytopenia without developing end-organ damage over 5 years of median follow-up. Limitations: The study was retrospective. Conclusions: In pediatric patients, DLE carries a significant risk of progression to SLE but may predict a milder phenotype of systemic disease. All patients require careful monitoring for SLE, particularly within the first year of diagnosis. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.12.028.) Key words: autoimmune disease; discoid lupus; pediatric dermatology; systemic lupus erythematosus.
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verall, 20% of systemic lupus erythematosus (SLE) cases present during the first 2 decades of life.1,2 Pediatric SLE tends to be more severe than adult SLE, with an aggressive clinical course, a higher frequency of end-organ involvement at onset, a requirement for sustained immunosuppression, and increased mortality. Renal, neurologic, cardiac, and pulmonary involvement occurs more frequently in children.1,3-6 Prognosis in pediatric SLE is related to disease severity at presentation. Delay in diagnosis and treatment initiation may increase morbidity and mortality.
From the Department of Dermatology,a Department of Preventive Medicine,b and Divisions of Dermatologyc and Rheumatology,d Department of Pediatrics, Northwestern University Feinberg School of Medicine. Dr Arkin is now at Rush University Medical Center, Chicago. Dr Ansell is now at New York Presbyterian Hospital of Columbia University. Drs Klein-Gitelman and Paller contributed equally to this article as senior authors. Supported by Society for Pediatric Dermatology Pilot Project Grant 2012.
Abbreviations used: ACR: CLE: DLE: SLE:
American College of Rheumatology cutaneous lupus erythematosus discoid lupus erythematosus systemic lupus erythematosus
Specific subtypes of cutaneous lupus erythematosus (CLE) include acute CLE, subacute CLE, and chronic CLE.7,8 Chronic CLE, the most common subtype described in adults, includes discoid lupus erythematosus (DLE), lupus panniculitis, chilblain Conflicts of interest: None declared. Accepted for publication December 21, 2014. Reprint requests: Lisa M. Arkin, MD, Departments of Dermatology and Pediatrics, Rush University Medical Center, 707 S Wood St, Suite 220, Annex Bldg, Chicago, IL 60612. E-mail: Lisa.Arkin@ gmail.com. Published online January 29, 2015. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.12.028
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lupus, hypertrophic lupus, and possibly tumid lupus. Rheumatology and/or Dermatology at the Ann and DLE is most prevalent and is characterized by Robert H. Lurie Children’s Hospital of Chicago, IL. At atrophy, follicular plugging, telangiectasia, dyspigleast 2 health encounters were required. Patients with mentation, and discoid scarring.7-10 neonatal lupus, subacute CLE, acute CLE, tumid lupus, In adults, the frequency of progression of DLE to and lupus panniculitis were excluded. SLE is reported to range from 0% to 28%, with an Data were analyzed for concurrence of or interval between onset of DLE and SLE ranging from progression to SLE. Diagnosis was based on months to decades.10-14 fulfillment of 4 or more of Lesions are further classified the 1982 SLE American CAPSULE SUMMARY as localized (confined to the College of Rheumatology head and neck) or general(ACR) criteria.24 Criteria Pediatric discoid lupus erythematosus ized (involving the entire for confirmation of DLE may be associated with systemic disease. body); this distinction may included a specific diagnosis Almost 40% of children with discoid be clinically significant, as from a board-certified pedilupus erythematosus in our study were some studies in both adults atric dermatologist or rheugiven the diagnosis of systemic lupus and children have demonmatologist and support from erythematosus (15% concurrently and strated a higher risk of SLE 1 of the following: (1) a 26% eventually met diagnostic criteria), with generalized DLE.15-18 clinical description consiswith greatest risk of progression in the tent with DLE; or (2) histoNephropathy, arthralgias, first year. pathologic confirmation of and elevated antinuclear DLE. antibody titers may also preChildren with discoid lupus The following data were dict transformation to SLE in erythematosus require monitoring for collected for all patients adults.18 However, adults systemic disease. when available: age at diagwith DLE who develop SLE nosis of DLE, age at diagnosis often have mild clinical disof SLE if relevant, race/ethnicity, follow-up duration, ease with infrequent neurologic and renal involvedistribution of lesions, and family history of autoimment.14,19,20 Wieczorek et al11 found that most mune disease. Clinical data reported by the clinician patients with DLE were given the diagnosis of SLE included all ACR classification criteria for SLE.24,25 by meeting mucocutaneous and laboratory criteria without development of end-organ damage. Patients were subsequently stratified into 4 Fewer than 3% of patients develop DLE before 10 subgroups: (1) DLE with concurrent diagnosis of years of age.15,21 The natural history in children SLE; (2) DLE with progression to SLE; (3) DLE with laboratory abnormalities but not satisfying 1982 ACR remains poorly understood. Small studies have criteria for SLE; and (4) DLE with skin-limited disease demonstrated a significantly higher early rate of through follow-up. Patients with both DLE and SLE progression to SLE (up to 25%) during a variable were also stratified to evaluate for phenotypic follow-up duration of months to years,15,21-23 differences between those with SLE at onset and suggesting that age of onset may modify the disease those who subsequently progressed to meet criteria severity, pattern of organ involvement, and serologic for SLE. findings. The interval from diagnosis of DLE to SLE Finally, to investigate associations between DLE has not been well studied because of the small and other SLE manifestations, a retrospective chart number of studies and limited follow-up. The review was performed for all patients with SLE but primary objective of this investigation was to not DLE followed up through 2012. The same clinical describe the clinical and serologic characteristics of and serologic data noted above were collected for pediatric DLE and to determine the inherent risk for this cohort within 6 months of diagnosis. SLE. Secondary analyses aimed to investigate the clinical phenotype in affected patients who met diagnostic criteria for SLE. Statistical analysis Progression to SLE was measured as a dichotomous variable on the basis of fulfillment of the ACR METHODS criteria. Groups 1, 2, 3, and 4 were evaluated Hospital admissions, outpatient clinic visits, and for differences in age at presentation, gender, laboratory studies were reviewed after approval by the race/ethnicity, family history of SLE and other Northwestern University Feinberg School of Medicine autoimmune diseases, histopathologic confirmation, Investigation Review Board for all patients given the lesion distribution, and follow-up duration. Duration diagnosis of DLE before the age of 16 years and seen of follow-up was calculated from the date of the between 1995 and 2012 by faculty of the Divisions of d
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Table I. Patient demographics
Total, n (%) Female, n (%) Race White, n (%) Black, n (%) Hispanic, n (%) Asian, n (%)
DLE with progression to SLE
DLE with laboratory abnormalities without SLE
Skin-limited DLE
9 (26) 8 (89)
15 (44) 11 (73)
10 (29) 5 (50)
4 (44) 4 (44) 1 (11) 0
5 6 3 1
(35) (35) (24) (6)
P values
Total followed up for progression to SLE
34 .22 .56
2 (33) 3 (25) 5 (42) 0
DLE with concurrent SLE at diagnosis
SLE cohort without DLE
6 (15) 5 (83)
93 76 (82)
1 2 2 1
34 19 32 8
(14) (29) (43) (14)
P values
.99 .49
(37) (20) (34) (9)
DLE, Discoid lupus erythematosus; SLE, systemic lupus erythematosus.
Table II. Disease characteristics
Total, n (%) Age at presentation of DLE, y, mean (SD) Length of follow-up, y, mean (SD) Biopsy confirmed diagnosis, n (%) Lesional distribution, n (%) Head/neck Generalized Family history of SLE, n (%) Family history of other autoimmune disease, n (%)
DLE with progression to SLE
DLE with laboratory abnormalities without SLE
Skin-limited DLE
9 (26) 10.6 (4.2)
15 (44) 8.6 (3.3)
10 (29) 7.1 (3.4)
5.3 (3.1) 5 (56)
4.5 (2.6) 6 (40)
3.8 (2.1) 8 (80)
4 5 2 1
(44) (56) (22) (11)
9 6 2 4
(60) (40) (13) (27)
7 3 2 4
(70) (30) (20) (40)
Total followed up for progression to SLE
DLE with concurrent diagnosis of SLE
P values across 4 groups
34
6 13.2 (3.5)
.03*
4.5 (1.6) 1 (17)
.82 .08
4 (67) 2 (33) 0 1 (17)
.73 .76 .60
DLE, Discoid lupus erythematosus; SLE, systemic lupus erythematosus. *Statistically significant.
primary diagnosis to the date of the last follow-up or death. Secondary analyses compared the groups by age of onset of DLE, age of progression to SLE (defined as the age when the patient fulfilled $4 of the ACR criteria for diagnosis), distribution of cutaneous lesions, family history of autoimmune disease, and clinical and laboratory features at diagnosis of SLE. Variables were compared descriptively between groups using frequencies and percentages for categorical variables and means and SD for quantitative variables. Categorical variables were compared among groups using Fisher exact test. Qualitative variables were compared using the Wilcoxon rank sum test. All calculated P values were 2-sided with less than .05 considered statistically significant.
RESULTS Demographics A total of 40 patients 16 years of age or younger at diagnosis of DLE were included in the study. Six
patients presented with DLE as a manifestation of concurrent SLE and were compared with the remaining 34, with skin-limited disease, who were analyzed for progression to SLE. In all, 93 patients with rheumatologist-confirmed SLE without DLE were identified to better elucidate the modifying effect of DLE in those who developed SLE. Patients in all groups were overwhelmingly female, but no statistically significant differences were found in race or ethnicity (Table I). Risk of progression to SLE Six patients (15%) were concurrently given the diagnosis of SLE (group 1). Of the 34 remaining, 9 (26%) eventually met 1982 ACR criteria for SLE (group 2). Fifteen (44%) developed laboratory abnormalities without meeting SLE criteria (group 3), and 10 patients (29%) maintained skin-limited DLE (group 4) over 5 years of median follow-up (range 1-11 years) (group 4) (Table II). The age at diagnosis of DLE was higher in patients with concurrent SLE (median, 13.2 years) or progression
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to SLE (median, 10.6 years) than in those who never met criteria for SLE (8.6 years for laboratory abnormalities without SLE and 7.1 years for skin-limited disease; P \ .03). There were no statistically significant differences in age at DLE diagnosis, length of follow-up duration, family history of SLE or autoimmunity, gender, and race/ethnicity between those with concurrence of or progression to SLE (Table II). Lesion distribution and risk of SLE In contrast to the data reported in adults, progression to SLE was not seen more in children with generalized DLE (Table II) (P = .73). SLE criteria met by patients with DLE who progressed to systemic disease The average age at progression to diagnosis of SLE was 11 years, with greatest risk in the first year after DLE diagnosis. Of patients, 67% progressed to meet criteria for SLE within 1 year, 78% within 2 years, and all patients within 3 years of diagnosis (data not shown). ACR diagnostic criteria for patients with progression to SLE are listed in Table III. Of patients, 89% met criteria with mucocutaneous-limited disease (discoid lesions, malar rash, photosensitivity, or oral ulcers) and laboratory involvement (either antibodies or cytopenia), but none met criteria without positive autoantibodies. Most patients remained without end-organ damage through the end of study follow-up: no patient had neurologic disease, 1 had renal involvement, and arthritis and serositis were present in the same patient. Association of DLE with other clinical manifestations of SLE Patients with both DLE and SLE were significantly younger at diagnosis than the 93 patients with SLE without DLE (13.1 vs 11.2 years, respectively; P = .04). Patients in the DLE-SLE cohort were more likely to be photosensitive (P \.0001) and less likely to develop arthritis (P \ .03), than those with SLE without DLE (data not shown). The risk of having other ACR criteria did not differ between the 2 groups, although this may have been limited by small sample size. Characteristics of patients with DLE who developed laboratory abnormalities without meeting criteria for SLE Abnormal laboratory values for patients who never met ACR SLE criteria are shown in Table IV. Seven (47%) had 1 laboratory abnormality, 4 (27%) had 2, 3 (20%) had 3, and 1 (7%) had 4 abnormalities. In comparison with patients with DLE
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Table III. 1982 American College of Rheumatology criteria in patients with discoid lupus erythematosus who progressed to systemic lupus erythematosus 1982 ACR criteria
Photosensitivity Malar rash Discoid lesions Oral or nasal ulcers Arthritis Serositis Renal Neurologic ANA Immunologic* Hematologicy Mucocutaneous disease 1 immunologic 6 hematologic criteriaz Isolated mucocutaneous diseasex
n (%) (n = 9)
9 4 9 1 1 1 1 9 9 6 8
(100) (44) (100) (11) (11) (11) (11) 0 (100) (100) (67) (89) 0
ACR, American College of Rheumatology; ANA, antinuclear antibody. *Anti-Smith, antidouble-stranded deoxyribonucleic acid, anticardiolipin, lupus anticoagulant, or b-2 glycoprotein antibodies. y Leukopenia (white blood cell count\4) or lymphopenia (absolute lymphocytes \1500/L); thrombocytopenia (platelets \100,000); hemolytic anemia with reticulocytosis. z Photosensitivity, malar rash, discoid lesions, oral or nasal ulcers, ANA, anti-Smith, antidouble stranded deoxyribonucleic acid (dsDNA), anticardiolipin, lupus anticoagulant, or b-2 glycoprotein antibodies. x Photosensitivity, malar rash, discoid lesions, oral or nasal ulcers.
and concurrent SLE or progression to SLE, children with DLE and laboratory-limited abnormalities were less likely to have leukopenia (P \ .04), anti-Smith antibodies (P \ .01), and anti-U1 ribonucleoprotein antibodies (P \.01) at presentation.
DISCUSSION To our knowledge, this is the largest study to investigate the natural history of pediatric-onset DLE.15,21-23,26 Overall, 38% of patients developed SLE, 15% of whom were given the diagnosis of DLE as a manifestation of concurrent SLE and 26% of whom developed progression to SLE, consistent with the up to 25% rate of progression noted in prior pediatric studies of DLE.15,23,27 Patients with SLE progression were at greatest risk within the first year after diagnosis, although mean follow-up duration was limited to 5.0 years. There were no statistically significant differences in follow-up between those with concurrence or progression to SLE, laboratory abnormalities, or skin-limited disease (P = .82), although there was a trend to longer follow-up duration in those with SLE. Patients with SLE were also older at diagnosis relative to those who never
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Table IV. Patients with laboratory abnormalities who did not meet American College of Rheumatology criteria for systemic lupus erythematosus Laboratory abnormalities
Positive ANA Leukopenia Antiphospholipid antibodies Anti-Smith antibodies Anti-U1-RNP antibodies Anti-Ro/SSA or Anti-La/SSB antibodies
n (%) (n = 15)
12 4 3 1 3 4
(80) (27) (20) (7) (20) (27)
Leukopenia (white blood cell count\4); antiphospholipid antibodies (anticardiolipin, lupus anticoagulant or b-2 glycoprotein antibodies). ANA, Antinuclear antibody; RNP, ribonucleoprotein.
met SLE criteria (P \ .03). Prospective studies with more patients and long-term follow-up are necessary to determine whether those with youngest-onset DLE are at lower risk for progression to SLE. Impact on SLE phenotype Pediatric SLE remains a heterogeneous disease and it has long been speculated that subtypes with variable clinical phenotypes can have differing prognoses. Several studies in adults suggest that DLE predicts a more benign course if SLE develops, including a lower risk of nephritis, arthritis, and pleuritis.9,19,28,29 A recent study in adults found that DLE in SLE was significantly associated with photosensitivity, leukopenia, and anti-Smith antibodies, and a reduced risk of arthritis and pleuritis.19 Although our data demonstrated increased photosensitivity and a decreased association of arthritis with SLE, failure to demonstrate other significant clinical or serologic features may be because of the small sample size. Most patients (89%) who developed SLE during the study period had isolated mucocutaneous disease and supportive laboratory studies but no end-organ damage. This suggests that pediatric patients with DLE who develop SLE may have mild systemic disease. Larger multicenter studies are needed to evaluate definitive phenotypic subsets of SLE among pediatric patients with DLE. A significant proportion of children (44%) developed laboratory abnormalities without meeting 1982 ACR criteria for SLE. In 2012, the ACR released revised classification criteria for SLE diagnosis, which adds greater weight to immunologic findings.25 Although these revised criteria are predominantly used for the purposes of research, review of the 4 patients with 3 or more laboratory abnormalities suggests that at least 2 might have met the new criteria, increasing the percentage who met criteria for progression to SLE to 28%. Notably, all of these
patients initiated oral hydroxychloroquine at first evidence of laboratory involvement (data not shown), raising the possibility that this intervention may have modified disease progression. Hydroxychloroquine is an immunomodulatory drug that is thought to antagonize toll-like receptors 7 and 9. Although commonly prescribed for SLE and CLE, the only Food and Drug Administrationeapproved indication for pediatric patients remains malaria. In adults with SLE, hydroxychloroquine has been shown to delay disease onset, prevent flares, retard renal damage, and reduce autoantibody accumulation.30,31 In the pediatric population, most providers introduce it for treatment of CLE because of its good safety profile and anecdotal evidence of efficacy for at least some affected children. Prospective randomized controlled trials of hydroxychloroquine administration for DLE are necessary to evaluate its potential systemic disease-modifying effects in this disease. Our study was limited by the retrospective nature of data collection with its intrinsic risk for incomplete results. The study was based at a tertiary referral center and the prevalence of concurrent SLE may have been overestimated through capture of patients with more severe disease at onset, although this should not have impacted our rate of SLE progression. It was also limited in its ability to evaluate for severity of disease at presentation, as disease activity scores were not documented. The greatest limitation, however, may be the average 5 years of follow-up duration in our study, as several recent adult studies have documented mean progression to SLE over 8 to 10 years.11,12 Studies at pediatric hospitals are likely to share this limitation, as most patients are transitioned to adult providers by age 21 years. Therefore we may have failed to capture adolescent patients with DLE who progressed to SLE many years after their initial diagnosis. On the other hand, our data demonstrating greatest incidence of SLE diagnosis within the first year after DLE onset could highlight a key difference between pediatric and adult DLE, as pediatric patients may present with rapid early progression to SLE rather than greater total frequency of systemic disease. Future long-term prospective studies of DLE with transition from pediatric to adult providers are necessary to validate these data and fully understand the natural history of this disease in children. REFERENCES 1. Papadimitraki ED, Isenberg DA. Childhood- and adult-onset lupus: an update of similarities and differences. Expert Rev Clin Immunol. 2009;5:391-403. 2. Gutierrez-Suarez R, Ruperto N, Gastaldi R, et al. A proposal for a pediatric version of the Systemic Lupus International
J AM ACAD DERMATOL
6 Arkin et al
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Collaborating Clinics/American College of Rheumatology Damage Index based on the analysis of 1,015 patients with juvenile-onset systemic lupus erythematosus. Arthritis Rheum. 2006;54:2989-2996. Font J, Cervera R, Espinosa G, et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis. 1998;57: 456-459. Tucker LB, Uribe AG, Fernandez M, et al. Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII). Lupus. 2008; 17:314-322. Watson L, Leone V, Pilkington C, et al. Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort. Arthritis Rheum. 2012;64:2356-2365. Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED. Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr. 2008;152:550-556. Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of systemic lupus erythematosus. Br J Dermatol. 1996;135: 355-362. Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol. 1981;4:471-475. Callen JP. Chronic cutaneous lupus erythematosus: clinical, laboratory, therapeutic, and prognostic examination of 62 patients. Arch Dermatol. 1982;118:412-416. Gronhagen CM, Fored CM, Granath F, Nyberg F. Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden. Br J Dermatol. 2011;164:1335-1341. Wieczorek IT, Propert KJ, Okawa J, Werth VP. Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. JAMA Dermatol. 2014;150:291-296. Durosaro O, Davis MD, Reed KB, Rohlinger AL. Incidence of cutaneous lupus erythematosus, 1965-2005: a populationbased study. Arch Dermatol. 2009;145:249-253. Healy E, Kieran E, Rogers S. Cutaneous lupus erythematosusea study of clinical and laboratory prognostic factors in 65 patients. Ir J Med Sci. 1995;164:113-115. Chong BF, Song J, Olsen NJ. Determining risk factors for developing systemic lupus erythematosus in patients with discoid lupus erythematosus. Br J Dermatol. 2012;166:29-35. Sampaio MC, de Oliveira ZN, Machado MC, dos Reis VM, Vilela MA. Discoid lupus erythematosus in childrenea retrospective study of 34 patients. Pediatr Dermatol. 2008;25: 163-167. Cardinali C, Caproni M, Bernacchi E, Amato L, Fabbri P. The spectrum of cutaneous manifestations in lupus erythematosusethe Italian experience. Lupus. 2000;9:417-423. Vera-Recabarren MA, Garcia-Carrasco M, Ramos-Casals M, Herrero C. Comparative analysis of subacute cutaneous lupus
n 2015
18.
19.
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
erythematosus and chronic cutaneous lupus erythematosus: clinical and immunological study of 270 patients. Br J Dermatol. 2010;162:91-101. Tebbe B, Mansmann U, Wollina U, et al. Markers in cutaneous lupus erythematosus indicating systemic involvement: a multicenter study on 296 patients. Acta Derm Venereol. 1997; 77:305-308. Merola JF, Prystowsky SD, Iversen C, et al. Association of discoid lupus erythematosus with other clinical manifestations among patients with systemic lupus erythematosus. J Am Acad Dermatol. 2013;69:19-24. Merola JF, Chang CA, Sanchez MR, Prystowsky SD. Is chronic cutaneous discoid lupus protective against severe renal disease in patients with systemic lupus erythematosus? J Drugs Dermatol 2011;10:1413-1420. George PM, Tunnessen WW Jr. Childhood discoid lupus erythematosus. Arch Dermatol. 1993;129:613-617. Cherif F, Mebazaa A, Mokni M, El Euch D, Azaiz MI, Dhahri AB. Childhood discoid lupus erythematosus: a Tunisian retrospective study of 16 cases. Pediatr Dermatol. 2003;20: 295-298. Moises-Alfaro C, Berron-Perez R, Carrasco-Daza D, Gutierrez-Castrellon P, Ruiz-Maldonado R. Discoid lupus erythematosus in children: clinical, histopathologic, and follow-up features in 27 cases. Pediatr Dermatol. 2003;20: 103-107. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271-1277. Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677-2686. Dickey BZ, Holland KE, Drolet BA, et al. Demographic and clinical characteristics of cutaneous lupus erythematosus at a pediatric dermatology referral center. Br J Dermatol. 2013;169: 428-433. Callen JP. Systemic lupus erythematosus in patients with chronic cutaneous (discoid) lupus erythematosus: clinical and laboratory findings in seventeen patients. J Am Acad Dermatol. 1985;12:278-288. Jacobsen S, Petersen J, Ullman S, et al. A multicenter study of 513 Danish patients with systemic lupus erythematosus, I: disease manifestations and analyses of clinical subsets. Clin Rheumatol. 1998;17:468-477. To CH, Mok CC, Tang SS, Ying SK, Wong RW, Lau CS. Prognostically distinct clinical patterns of systemic lupus erythematosus identified by cluster analysis. Lupus. 2009;18: 1267-1275. Olsen NJ, Schleich MA, Karp DR. Multifaceted effects of hydroxychloroquine in human disease. Semin Arthritis Rheum. 2013;43:264-272. James JA, Kim-Howard XR, Bruner BF, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16:401-409.
ARTICLE
The natural history of pediatric-onset discoid lupus erythematosus Lisa M. Arkin, MD,a Leah Ansell, MD,a Alfred Rademaker, PhD,b Megan L. Curran, MD,d Michael L. Miller, MD,d Annette Wagner, MD,c Brandi M. Kenner-Bell, MD,c Sarah L. Chamlin, MD,c Anthony J. Mancini, MD,c Marisa Klein-Gitelman, MD, MPH,d and Amy S. Paller, MS, MDa,c Chicago, Illinois Background: Pediatric discoid lupus erythematosus (DLE) is rare. The risk of progression to systemic lupus erythematosus (SLE) is uncertain. Objective: We sought to determine the risk of progression of pediatric DLE to SLE and to characterize its phenotype. Methods: This was a retrospective review of 40 patients with DLE. Results: Six (15%) of 40 patients presented with DLE as a manifestation of concurrent SLE. Of the remaining 34, 9 (26%) eventually met SLE criteria and 15 (44%) developed laboratory abnormalities without meeting SLE criteria. Only 10 (29%) maintained skin-limited disease. The average age at progression to SLE was 11 years, with greatest risk in the first year after DLE diagnosis. Most (89%) patients with SLE met diagnostic criteria with mucocutaneous disease (discoid lesions, malar rash, oral and nasal ulcers, photosensitivity), positive antibodies, and/or cytopenia without developing end-organ damage over 5 years of median follow-up. Limitations: The study was retrospective. Conclusions: In pediatric patients, DLE carries a significant risk of progression to SLE but may predict a milder phenotype of systemic disease. All patients require careful monitoring for SLE, particularly within the first year of diagnosis. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2014.12.028.) Key words: autoimmune disease; discoid lupus; pediatric dermatology; systemic lupus erythematosus.
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verall, 20% of systemic lupus erythematosus (SLE) cases present during the first 2 decades of life.1,2 Pediatric SLE tends to be more severe than adult SLE, with an aggressive clinical course, a higher frequency of end-organ involvement at onset, a requirement for sustained immunosuppression, and increased mortality. Renal, neurologic, cardiac, and pulmonary involvement occurs more frequently in children.1,3-6 Prognosis in pediatric SLE is related to disease severity at presentation. Delay in diagnosis and treatment initiation may increase morbidity and mortality.
From the Department of Dermatology,a Department of Preventive Medicine,b and Divisions of Dermatologyc and Rheumatology,d Department of Pediatrics, Northwestern University Feinberg School of Medicine. Dr Arkin is now at Rush University Medical Center, Chicago. Dr Ansell is now at New York Presbyterian Hospital of Columbia University. Drs Klein-Gitelman and Paller contributed equally to this article as senior authors. Supported by Society for Pediatric Dermatology Pilot Project Grant 2012.
Abbreviations used: ACR: CLE: DLE: SLE:
American College of Rheumatology cutaneous lupus erythematosus discoid lupus erythematosus systemic lupus erythematosus
Specific subtypes of cutaneous lupus erythematosus (CLE) include acute CLE, subacute CLE, and chronic CLE.7,8 Chronic CLE, the most common subtype described in adults, includes discoid lupus erythematosus (DLE), lupus panniculitis, chilblain Conflicts of interest: None declared. Accepted for publication December 21, 2014. Reprint requests: Lisa M. Arkin, MD, Departments of Dermatology and Pediatrics, Rush University Medical Center, 707 S Wood St, Suite 220, Annex Bldg, Chicago, IL 60612. E-mail: Lisa.Arkin@ gmail.com. Published online January 29, 2015. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.12.028
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lupus, hypertrophic lupus, and possibly tumid lupus. Rheumatology and/or Dermatology at the Ann and DLE is most prevalent and is characterized by Robert H. Lurie Children’s Hospital of Chicago, IL. At atrophy, follicular plugging, telangiectasia, dyspigleast 2 health encounters were required. Patients with mentation, and discoid scarring.7-10 neonatal lupus, subacute CLE, acute CLE, tumid lupus, In adults, the frequency of progression of DLE to and lupus panniculitis were excluded. SLE is reported to range from 0% to 28%, with an Data were analyzed for concurrence of or interval between onset of DLE and SLE ranging from progression to SLE. Diagnosis was based on months to decades.10-14 fulfillment of 4 or more of Lesions are further classified the 1982 SLE American CAPSULE SUMMARY as localized (confined to the College of Rheumatology head and neck) or general(ACR) criteria.24 Criteria Pediatric discoid lupus erythematosus ized (involving the entire for confirmation of DLE may be associated with systemic disease. body); this distinction may included a specific diagnosis Almost 40% of children with discoid be clinically significant, as from a board-certified pedilupus erythematosus in our study were some studies in both adults atric dermatologist or rheugiven the diagnosis of systemic lupus and children have demonmatologist and support from erythematosus (15% concurrently and strated a higher risk of SLE 1 of the following: (1) a 26% eventually met diagnostic criteria), with generalized DLE.15-18 clinical description consiswith greatest risk of progression in the tent with DLE; or (2) histoNephropathy, arthralgias, first year. pathologic confirmation of and elevated antinuclear DLE. antibody titers may also preChildren with discoid lupus The following data were dict transformation to SLE in erythematosus require monitoring for collected for all patients adults.18 However, adults systemic disease. when available: age at diagwith DLE who develop SLE nosis of DLE, age at diagnosis often have mild clinical disof SLE if relevant, race/ethnicity, follow-up duration, ease with infrequent neurologic and renal involvedistribution of lesions, and family history of autoimment.14,19,20 Wieczorek et al11 found that most mune disease. Clinical data reported by the clinician patients with DLE were given the diagnosis of SLE included all ACR classification criteria for SLE.24,25 by meeting mucocutaneous and laboratory criteria without development of end-organ damage. Patients were subsequently stratified into 4 Fewer than 3% of patients develop DLE before 10 subgroups: (1) DLE with concurrent diagnosis of years of age.15,21 The natural history in children SLE; (2) DLE with progression to SLE; (3) DLE with laboratory abnormalities but not satisfying 1982 ACR remains poorly understood. Small studies have criteria for SLE; and (4) DLE with skin-limited disease demonstrated a significantly higher early rate of through follow-up. Patients with both DLE and SLE progression to SLE (up to 25%) during a variable were also stratified to evaluate for phenotypic follow-up duration of months to years,15,21-23 differences between those with SLE at onset and suggesting that age of onset may modify the disease those who subsequently progressed to meet criteria severity, pattern of organ involvement, and serologic for SLE. findings. The interval from diagnosis of DLE to SLE Finally, to investigate associations between DLE has not been well studied because of the small and other SLE manifestations, a retrospective chart number of studies and limited follow-up. The review was performed for all patients with SLE but primary objective of this investigation was to not DLE followed up through 2012. The same clinical describe the clinical and serologic characteristics of and serologic data noted above were collected for pediatric DLE and to determine the inherent risk for this cohort within 6 months of diagnosis. SLE. Secondary analyses aimed to investigate the clinical phenotype in affected patients who met diagnostic criteria for SLE. Statistical analysis Progression to SLE was measured as a dichotomous variable on the basis of fulfillment of the ACR METHODS criteria. Groups 1, 2, 3, and 4 were evaluated Hospital admissions, outpatient clinic visits, and for differences in age at presentation, gender, laboratory studies were reviewed after approval by the race/ethnicity, family history of SLE and other Northwestern University Feinberg School of Medicine autoimmune diseases, histopathologic confirmation, Investigation Review Board for all patients given the lesion distribution, and follow-up duration. Duration diagnosis of DLE before the age of 16 years and seen of follow-up was calculated from the date of the between 1995 and 2012 by faculty of the Divisions of d
d
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Table I. Patient demographics
Total, n (%) Female, n (%) Race White, n (%) Black, n (%) Hispanic, n (%) Asian, n (%)
DLE with progression to SLE
DLE with laboratory abnormalities without SLE
Skin-limited DLE
9 (26) 8 (89)
15 (44) 11 (73)
10 (29) 5 (50)
4 (44) 4 (44) 1 (11) 0
5 6 3 1
(35) (35) (24) (6)
P values
Total followed up for progression to SLE
34 .22 .56
2 (33) 3 (25) 5 (42) 0
DLE with concurrent SLE at diagnosis
SLE cohort without DLE
6 (15) 5 (83)
93 76 (82)
1 2 2 1
34 19 32 8
(14) (29) (43) (14)
P values
.99 .49
(37) (20) (34) (9)
DLE, Discoid lupus erythematosus; SLE, systemic lupus erythematosus.
Table II. Disease characteristics
Total, n (%) Age at presentation of DLE, y, mean (SD) Length of follow-up, y, mean (SD) Biopsy confirmed diagnosis, n (%) Lesional distribution, n (%) Head/neck Generalized Family history of SLE, n (%) Family history of other autoimmune disease, n (%)
DLE with progression to SLE
DLE with laboratory abnormalities without SLE
Skin-limited DLE
9 (26) 10.6 (4.2)
15 (44) 8.6 (3.3)
10 (29) 7.1 (3.4)
5.3 (3.1) 5 (56)
4.5 (2.6) 6 (40)
3.8 (2.1) 8 (80)
4 5 2 1
(44) (56) (22) (11)
9 6 2 4
(60) (40) (13) (27)
7 3 2 4
(70) (30) (20) (40)
Total followed up for progression to SLE
DLE with concurrent diagnosis of SLE
P values across 4 groups
34
6 13.2 (3.5)
.03*
4.5 (1.6) 1 (17)
.82 .08
4 (67) 2 (33) 0 1 (17)
.73 .76 .60
DLE, Discoid lupus erythematosus; SLE, systemic lupus erythematosus. *Statistically significant.
primary diagnosis to the date of the last follow-up or death. Secondary analyses compared the groups by age of onset of DLE, age of progression to SLE (defined as the age when the patient fulfilled $4 of the ACR criteria for diagnosis), distribution of cutaneous lesions, family history of autoimmune disease, and clinical and laboratory features at diagnosis of SLE. Variables were compared descriptively between groups using frequencies and percentages for categorical variables and means and SD for quantitative variables. Categorical variables were compared among groups using Fisher exact test. Qualitative variables were compared using the Wilcoxon rank sum test. All calculated P values were 2-sided with less than .05 considered statistically significant.
RESULTS Demographics A total of 40 patients 16 years of age or younger at diagnosis of DLE were included in the study. Six
patients presented with DLE as a manifestation of concurrent SLE and were compared with the remaining 34, with skin-limited disease, who were analyzed for progression to SLE. In all, 93 patients with rheumatologist-confirmed SLE without DLE were identified to better elucidate the modifying effect of DLE in those who developed SLE. Patients in all groups were overwhelmingly female, but no statistically significant differences were found in race or ethnicity (Table I). Risk of progression to SLE Six patients (15%) were concurrently given the diagnosis of SLE (group 1). Of the 34 remaining, 9 (26%) eventually met 1982 ACR criteria for SLE (group 2). Fifteen (44%) developed laboratory abnormalities without meeting SLE criteria (group 3), and 10 patients (29%) maintained skin-limited DLE (group 4) over 5 years of median follow-up (range 1-11 years) (group 4) (Table II). The age at diagnosis of DLE was higher in patients with concurrent SLE (median, 13.2 years) or progression
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to SLE (median, 10.6 years) than in those who never met criteria for SLE (8.6 years for laboratory abnormalities without SLE and 7.1 years for skin-limited disease; P \ .03). There were no statistically significant differences in age at DLE diagnosis, length of follow-up duration, family history of SLE or autoimmunity, gender, and race/ethnicity between those with concurrence of or progression to SLE (Table II). Lesion distribution and risk of SLE In contrast to the data reported in adults, progression to SLE was not seen more in children with generalized DLE (Table II) (P = .73). SLE criteria met by patients with DLE who progressed to systemic disease The average age at progression to diagnosis of SLE was 11 years, with greatest risk in the first year after DLE diagnosis. Of patients, 67% progressed to meet criteria for SLE within 1 year, 78% within 2 years, and all patients within 3 years of diagnosis (data not shown). ACR diagnostic criteria for patients with progression to SLE are listed in Table III. Of patients, 89% met criteria with mucocutaneous-limited disease (discoid lesions, malar rash, photosensitivity, or oral ulcers) and laboratory involvement (either antibodies or cytopenia), but none met criteria without positive autoantibodies. Most patients remained without end-organ damage through the end of study follow-up: no patient had neurologic disease, 1 had renal involvement, and arthritis and serositis were present in the same patient. Association of DLE with other clinical manifestations of SLE Patients with both DLE and SLE were significantly younger at diagnosis than the 93 patients with SLE without DLE (13.1 vs 11.2 years, respectively; P = .04). Patients in the DLE-SLE cohort were more likely to be photosensitive (P \.0001) and less likely to develop arthritis (P \ .03), than those with SLE without DLE (data not shown). The risk of having other ACR criteria did not differ between the 2 groups, although this may have been limited by small sample size. Characteristics of patients with DLE who developed laboratory abnormalities without meeting criteria for SLE Abnormal laboratory values for patients who never met ACR SLE criteria are shown in Table IV. Seven (47%) had 1 laboratory abnormality, 4 (27%) had 2, 3 (20%) had 3, and 1 (7%) had 4 abnormalities. In comparison with patients with DLE
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Table III. 1982 American College of Rheumatology criteria in patients with discoid lupus erythematosus who progressed to systemic lupus erythematosus 1982 ACR criteria
Photosensitivity Malar rash Discoid lesions Oral or nasal ulcers Arthritis Serositis Renal Neurologic ANA Immunologic* Hematologicy Mucocutaneous disease 1 immunologic 6 hematologic criteriaz Isolated mucocutaneous diseasex
n (%) (n = 9)
9 4 9 1 1 1 1 9 9 6 8
(100) (44) (100) (11) (11) (11) (11) 0 (100) (100) (67) (89) 0
ACR, American College of Rheumatology; ANA, antinuclear antibody. *Anti-Smith, antidouble-stranded deoxyribonucleic acid, anticardiolipin, lupus anticoagulant, or b-2 glycoprotein antibodies. y Leukopenia (white blood cell count\4) or lymphopenia (absolute lymphocytes \1500/L); thrombocytopenia (platelets \100,000); hemolytic anemia with reticulocytosis. z Photosensitivity, malar rash, discoid lesions, oral or nasal ulcers, ANA, anti-Smith, antidouble stranded deoxyribonucleic acid (dsDNA), anticardiolipin, lupus anticoagulant, or b-2 glycoprotein antibodies. x Photosensitivity, malar rash, discoid lesions, oral or nasal ulcers.
and concurrent SLE or progression to SLE, children with DLE and laboratory-limited abnormalities were less likely to have leukopenia (P \ .04), anti-Smith antibodies (P \ .01), and anti-U1 ribonucleoprotein antibodies (P \.01) at presentation.
DISCUSSION To our knowledge, this is the largest study to investigate the natural history of pediatric-onset DLE.15,21-23,26 Overall, 38% of patients developed SLE, 15% of whom were given the diagnosis of DLE as a manifestation of concurrent SLE and 26% of whom developed progression to SLE, consistent with the up to 25% rate of progression noted in prior pediatric studies of DLE.15,23,27 Patients with SLE progression were at greatest risk within the first year after diagnosis, although mean follow-up duration was limited to 5.0 years. There were no statistically significant differences in follow-up between those with concurrence or progression to SLE, laboratory abnormalities, or skin-limited disease (P = .82), although there was a trend to longer follow-up duration in those with SLE. Patients with SLE were also older at diagnosis relative to those who never
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Table IV. Patients with laboratory abnormalities who did not meet American College of Rheumatology criteria for systemic lupus erythematosus Laboratory abnormalities
Positive ANA Leukopenia Antiphospholipid antibodies Anti-Smith antibodies Anti-U1-RNP antibodies Anti-Ro/SSA or Anti-La/SSB antibodies
n (%) (n = 15)
12 4 3 1 3 4
(80) (27) (20) (7) (20) (27)
Leukopenia (white blood cell count\4); antiphospholipid antibodies (anticardiolipin, lupus anticoagulant or b-2 glycoprotein antibodies). ANA, Antinuclear antibody; RNP, ribonucleoprotein.
met SLE criteria (P \ .03). Prospective studies with more patients and long-term follow-up are necessary to determine whether those with youngest-onset DLE are at lower risk for progression to SLE. Impact on SLE phenotype Pediatric SLE remains a heterogeneous disease and it has long been speculated that subtypes with variable clinical phenotypes can have differing prognoses. Several studies in adults suggest that DLE predicts a more benign course if SLE develops, including a lower risk of nephritis, arthritis, and pleuritis.9,19,28,29 A recent study in adults found that DLE in SLE was significantly associated with photosensitivity, leukopenia, and anti-Smith antibodies, and a reduced risk of arthritis and pleuritis.19 Although our data demonstrated increased photosensitivity and a decreased association of arthritis with SLE, failure to demonstrate other significant clinical or serologic features may be because of the small sample size. Most patients (89%) who developed SLE during the study period had isolated mucocutaneous disease and supportive laboratory studies but no end-organ damage. This suggests that pediatric patients with DLE who develop SLE may have mild systemic disease. Larger multicenter studies are needed to evaluate definitive phenotypic subsets of SLE among pediatric patients with DLE. A significant proportion of children (44%) developed laboratory abnormalities without meeting 1982 ACR criteria for SLE. In 2012, the ACR released revised classification criteria for SLE diagnosis, which adds greater weight to immunologic findings.25 Although these revised criteria are predominantly used for the purposes of research, review of the 4 patients with 3 or more laboratory abnormalities suggests that at least 2 might have met the new criteria, increasing the percentage who met criteria for progression to SLE to 28%. Notably, all of these
patients initiated oral hydroxychloroquine at first evidence of laboratory involvement (data not shown), raising the possibility that this intervention may have modified disease progression. Hydroxychloroquine is an immunomodulatory drug that is thought to antagonize toll-like receptors 7 and 9. Although commonly prescribed for SLE and CLE, the only Food and Drug Administrationeapproved indication for pediatric patients remains malaria. In adults with SLE, hydroxychloroquine has been shown to delay disease onset, prevent flares, retard renal damage, and reduce autoantibody accumulation.30,31 In the pediatric population, most providers introduce it for treatment of CLE because of its good safety profile and anecdotal evidence of efficacy for at least some affected children. Prospective randomized controlled trials of hydroxychloroquine administration for DLE are necessary to evaluate its potential systemic disease-modifying effects in this disease. Our study was limited by the retrospective nature of data collection with its intrinsic risk for incomplete results. The study was based at a tertiary referral center and the prevalence of concurrent SLE may have been overestimated through capture of patients with more severe disease at onset, although this should not have impacted our rate of SLE progression. It was also limited in its ability to evaluate for severity of disease at presentation, as disease activity scores were not documented. The greatest limitation, however, may be the average 5 years of follow-up duration in our study, as several recent adult studies have documented mean progression to SLE over 8 to 10 years.11,12 Studies at pediatric hospitals are likely to share this limitation, as most patients are transitioned to adult providers by age 21 years. Therefore we may have failed to capture adolescent patients with DLE who progressed to SLE many years after their initial diagnosis. On the other hand, our data demonstrating greatest incidence of SLE diagnosis within the first year after DLE onset could highlight a key difference between pediatric and adult DLE, as pediatric patients may present with rapid early progression to SLE rather than greater total frequency of systemic disease. Future long-term prospective studies of DLE with transition from pediatric to adult providers are necessary to validate these data and fully understand the natural history of this disease in children. REFERENCES 1. Papadimitraki ED, Isenberg DA. Childhood- and adult-onset lupus: an update of similarities and differences. Expert Rev Clin Immunol. 2009;5:391-403. 2. Gutierrez-Suarez R, Ruperto N, Gastaldi R, et al. A proposal for a pediatric version of the Systemic Lupus International
J AM ACAD DERMATOL
6 Arkin et al
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Collaborating Clinics/American College of Rheumatology Damage Index based on the analysis of 1,015 patients with juvenile-onset systemic lupus erythematosus. Arthritis Rheum. 2006;54:2989-2996. Font J, Cervera R, Espinosa G, et al. Systemic lupus erythematosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis. 1998;57: 456-459. Tucker LB, Uribe AG, Fernandez M, et al. Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII). Lupus. 2008; 17:314-322. Watson L, Leone V, Pilkington C, et al. Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort. Arthritis Rheum. 2012;64:2356-2365. Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED. Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study. J Pediatr. 2008;152:550-556. Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of systemic lupus erythematosus. Br J Dermatol. 1996;135: 355-362. Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the spectrum of lupus erythematosus. J Am Acad Dermatol. 1981;4:471-475. Callen JP. Chronic cutaneous lupus erythematosus: clinical, laboratory, therapeutic, and prognostic examination of 62 patients. Arch Dermatol. 1982;118:412-416. Gronhagen CM, Fored CM, Granath F, Nyberg F. Cutaneous lupus erythematosus and the association with systemic lupus erythematosus: a population-based cohort of 1088 patients in Sweden. Br J Dermatol. 2011;164:1335-1341. Wieczorek IT, Propert KJ, Okawa J, Werth VP. Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. JAMA Dermatol. 2014;150:291-296. Durosaro O, Davis MD, Reed KB, Rohlinger AL. Incidence of cutaneous lupus erythematosus, 1965-2005: a populationbased study. Arch Dermatol. 2009;145:249-253. Healy E, Kieran E, Rogers S. Cutaneous lupus erythematosusea study of clinical and laboratory prognostic factors in 65 patients. Ir J Med Sci. 1995;164:113-115. Chong BF, Song J, Olsen NJ. Determining risk factors for developing systemic lupus erythematosus in patients with discoid lupus erythematosus. Br J Dermatol. 2012;166:29-35. Sampaio MC, de Oliveira ZN, Machado MC, dos Reis VM, Vilela MA. Discoid lupus erythematosus in childrenea retrospective study of 34 patients. Pediatr Dermatol. 2008;25: 163-167. Cardinali C, Caproni M, Bernacchi E, Amato L, Fabbri P. The spectrum of cutaneous manifestations in lupus erythematosusethe Italian experience. Lupus. 2000;9:417-423. Vera-Recabarren MA, Garcia-Carrasco M, Ramos-Casals M, Herrero C. Comparative analysis of subacute cutaneous lupus
n 2015
18.
19.
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
erythematosus and chronic cutaneous lupus erythematosus: clinical and immunological study of 270 patients. Br J Dermatol. 2010;162:91-101. Tebbe B, Mansmann U, Wollina U, et al. Markers in cutaneous lupus erythematosus indicating systemic involvement: a multicenter study on 296 patients. Acta Derm Venereol. 1997; 77:305-308. Merola JF, Prystowsky SD, Iversen C, et al. Association of discoid lupus erythematosus with other clinical manifestations among patients with systemic lupus erythematosus. J Am Acad Dermatol. 2013;69:19-24. Merola JF, Chang CA, Sanchez MR, Prystowsky SD. Is chronic cutaneous discoid lupus protective against severe renal disease in patients with systemic lupus erythematosus? J Drugs Dermatol 2011;10:1413-1420. George PM, Tunnessen WW Jr. Childhood discoid lupus erythematosus. Arch Dermatol. 1993;129:613-617. Cherif F, Mebazaa A, Mokni M, El Euch D, Azaiz MI, Dhahri AB. Childhood discoid lupus erythematosus: a Tunisian retrospective study of 16 cases. Pediatr Dermatol. 2003;20: 295-298. Moises-Alfaro C, Berron-Perez R, Carrasco-Daza D, Gutierrez-Castrellon P, Ruiz-Maldonado R. Discoid lupus erythematosus in children: clinical, histopathologic, and follow-up features in 27 cases. Pediatr Dermatol. 2003;20: 103-107. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271-1277. Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677-2686. Dickey BZ, Holland KE, Drolet BA, et al. Demographic and clinical characteristics of cutaneous lupus erythematosus at a pediatric dermatology referral center. Br J Dermatol. 2013;169: 428-433. Callen JP. Systemic lupus erythematosus in patients with chronic cutaneous (discoid) lupus erythematosus: clinical and laboratory findings in seventeen patients. J Am Acad Dermatol. 1985;12:278-288. Jacobsen S, Petersen J, Ullman S, et al. A multicenter study of 513 Danish patients with systemic lupus erythematosus, I: disease manifestations and analyses of clinical subsets. Clin Rheumatol. 1998;17:468-477. To CH, Mok CC, Tang SS, Ying SK, Wong RW, Lau CS. Prognostically distinct clinical patterns of systemic lupus erythematosus identified by cluster analysis. Lupus. 2009;18: 1267-1275. Olsen NJ, Schleich MA, Karp DR. Multifaceted effects of hydroxychloroquine in human disease. Semin Arthritis Rheum. 2013;43:264-272. James JA, Kim-Howard XR, Bruner BF, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus. 2007;16:401-409.