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Not Just Skin Deep: Systemic Disease Involvement in Patients With Cutaneous Lupus
REVIEW
Not Just Skin Deep: Systemic Disease Involvement in Patients With Cutaneous Lupus Jack C. O’Brien1 and Benjamin F. Chong1 Cutaneous lupus erythematosus, specifically discoid lupus erythematosus, disproportionately affects those with skin of color and may result in greater dyspigmentation and scarring in darker skin types. In this article, we review investigations relevant to cutaneous lupus patients with skin of color at University of Texas Southwestern Medical Center, associations and risk of progression to systemic lupus, and recommendations for monitoring for systemic disease spread. Between 5% and 25% of patients with cutaneous lupus can develop systemic lupus. If they progress to systemic disease, patients often develop mild systemic disease with primarily mucocutaneous and musculoskeletal manifestations. Patients with cutaneous lupus should be followed up closely to monitor for systemic disease involvement. The University of Texas Southwestern Cutaneous Lupus Erythematosus Registry, of which almost two thirds of participants are those with skin of color, is a part of an ongoing effort to better understand the pathophysiologic mechanisms of CLE and to identify prognostic indicators of risk of progression to systemic lupus. Journal of Investigative Dermatology Symposium Proceedings (2017) 18, S69eS74; doi:10.1016/j.jisp.2016.09.001
INTRODUCTION Cutaneous lupus erythematosus (CLE) is a photosensitive cutaneous autoimmune disease with three main subtypes: acute, subacute, and chronic. Acute CLE is characterized by the classic “butterfly rash” and can persist for weeks to months (Werth, 2005). Subacute CLE was initially described by Sontheimer et al. (1979) and manifests as either erythematous annular plaques coalescing into polycyclic plaques or as papulosquamous psoriasiform lesions (Sontheimer, 2005). Chronic CLE has the largest number of subtypes, including discoid lupus erythematous (DLE), lupus erythematosus tumidus, Chilblain’s lupus, and lupus 1
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Publication of this article was supported by the National Institutes of Health. Correspondence: Benjamin F. Chong, 5323 Harry Hines Boulevard, Dallas, Texas 75309-9069, USA. E-mail: [email protected] Abbreviations: ANA, anti-nuclear antibody; CLE, cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; OR, odds ratio; SLE, systemic lupus erythematosus Received 25 August 2016; accepted 2 September 2016
panniculitis. The most common type of chronic CLE, DLE (Cardinali et al., 2000; Durosaro et al., 2009), is characterized by erythematous to violaceous scaly papules and plaques in a photosensitive distribution that later develop peripheral hyperpigmentation central atrophy, scarring, and hypopigmentation (Tebbe and Orfanos, 1997). These pigmentary changes can be especially pronounced in patients with skin of color. THE CLE EXPERIENCE AT UNIVERSITY OF TEXAS SOUTHWESTERN The University of Texas Southwestern Medical Center’s Cutaneous Lupus Erythematosus Registry was established in 2009 with a stated goal of prospectively following CLE patients over time to characterize CLE disease course, identify risk factors for progression to systemic lupus erythematosus (SLE), improve how clinicians diagnose and treat CLE, and predict their prognoses. Participants in the CLE Registry are recruited from outpatient dermatology clinics at University of Texas Southwestern Medical Center and Parkland Memorial Hospital. Almost two thirds of the participants in the registry are those with skin of color, and the most common subtype of CLE represented is chronic CLE. More specifically, two thirds of the registry is composed of participants diagnosed with DLE. About half of the participants meet American College of Rheumatology criteria (Tan et al., 1982) for SLE (Table 1). Studies investigating quality of life-specific measures in CLE indicate that CLE can have profound effects on quality of life, especially in patients with skin of color (Vasquez et al., 2013). In a multicenter cross-sectional study at University of Texas Southwestern and University of Pennsylvania with inclusion of substantial numbers of patients with skin of color, CLE had a negative effect on quality of life. Female sex, low socioeconomic status, systemic disease, and worse skin disease activity were associated with poor quality of life (Vasquez et al., 2013). In a study of 223 CLE patients at the University of Pennsylvania, African Americans initially presented with greater measures of disease damage than white patients and had higher measures of disease damage at follow-up (Verma et al., 2014). PROGRESSION OF CLE TO SLE Although CLE can present in the setting of SLE, it can also occur independently of internal organ involvement (Durosaro et al., 2009). A European database analysis of 1,002 CLE patients showed that 40% of patients with CLE met criteria for SLE, with the most common criteria being a positive test result for anti-nuclear antibody (ANA) and mucocutaneous manifestations, such as photosensitivity and DLE
ª 2016 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
www.jidsponline.org
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JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus
Table 1. University of Texas Southwestern CLE Registry participant demographic and clinical characteristics (N [ 244) Characteristic
n
%
Race/ethnicity African American/African
116
48
White
88
36
Hispanic
21
9
Asian
9
4
Other
10
4
204
84
40
16
Sex Female Male Predominant CLE subtype CCLE1
190
78
SCLE
35
14
ACLE
19
8
Yes
120
49
No
124
51
Concomitant SLE diagnosis2
Number of SLE criteria, mean and SD2
4
2.3
SLE criteria2 Photosensitivity
179
73
Discoid rash
175
72
Positive ANA
158
65
Immunologic disorder
90
37
Hematologic disorder
89
36
Arthritis
75
31
Malar rash
65
27
Oral ulcers
64
26
Renal disorder
38
16
Serositis
23
9
3
1
Neurologic disorder
Abbreviations: ACLE, acute cutaneous lupus erythematosus; ANA, anti-nuclear antibody; CCLE, chronic cutaneous lupus erythematosus; CLE, cutaneous lupus erythematosus; SD, standard deviation; SLE, systemic lupus erythematosus. 1 DLE is the predominant CCLE subtype, accounting for 87% of the CCLE group (165 participants with DLE). Other CCLE subtypes include lupus erythematosus tumidus, Chilblain’s lupus, bullous SLE, and lupus panniculitis. 2 Information refers to data collected at initial visit.
(Biazar et al., 2013). The incidence of CLE is similar to that of SLE, which both have an incidence of approximately 3 per 100,000 (Durosaro et al., 2009). In 1872, Kaposi was the first to identify progression of DLE to SLE. Subsequent studies investigating this disease progression estimated the incidence to be between 5% and 10% (Millard and Rowell, 1979; Healy et al., 1995). The highest risk of developing SLE appears to be within the first year of diagnosis (Gronhagen et al., 2011), but it has been reported to occur up to 15 years later (Callen, 1985). A recent population-based study from Sweden indicated that progression to SLE can occur in as many as 18% of patients with CLE (Gronhagen et al., 2011). In that study, patients with DLE had a 9.8% probability of being diagnosed with SLE within the first year of diagnosis of CLE, which increased to 16.7% after 3 years. The risk of progression within 3 years of diagnosis was greater in women than men (20.7% vs. 10.4%). In a S70
study of 156 CLE patients in Rochester, MN, 12% of patients developed SLE. The mean time to progression was 8.2 years, and the cumulative incidence of SLE was 5% at 5 years and 23% at 25 years (Durosaro et al., 2009). In addition, children with DLE can develop SLE. In a retrospective review of 40 pediatric patients with discoid lupus, 26% were later diagnosed with SLE, all within 3 years. The average age at progression to SLE was 11 years. However, those who progressed generally had mild disease, with 89% having disease limited to abnormal laboratory test results and mucocutaneous involvement (Arkin et al., 2015). To further define disease progression to SLE in CLE patients, researchers at the University of Pennsylvania prospectively followed 77 patients with CLE to assess disease severity and determine which new SLE criteria were met. Of these, 17% developed SLE, with a mean time to diagnosis of SLE of 8.03 years. Most CLE patients who progressed to SLE had mild systemic disease and gained mucocutaneous or immunologic criteria or developed inflammatory arthritis (Wieczorek et al., 2014). Multiple risk factors have been identified as predictors of systemic spread in CLE (Chong et al., 2012). These include clinical findings such as discoid lesions below the head and neck (generalized DLE) (Callen, 1982; Callen, 1985; Cardinali et al., 2000; Healy et al., 1995; Ng et al., 2000; Scott and Rees, 1959; Vera-Recabarren et al., 2010), periungual telangiectasias, and arthritis. The association between periungual telangiectasias in CLE patients with SLE compared with CLE patients without SLE was first shown when Callen et al. (1982) noted that 76% of SLE patients with DLE showed periungual telangiectasias, whereas 0% of those with DLE but not SLE had them (Callen, 1982). A later study in an Italian cohort comparing 19 DLE patients with SLE versus 166 DLE patients without SLE showed similar results; nailfold abnormalities were present in 76% of 19 patients with DLE and SLE and in no patients with skin-limited disease (Cardinali et al., 2000). Laboratory abnormalities, including high titer ANAs, hematologic abnormalities (leukopenia, anemia), and persistently elevated erythrocyte sedimentation rate, have also been identified as risk factors for systemic spread in DLE (Callen, 1982; Healy et al., 1995; Millard and Rowell, 1979). There are limited data available on how to delay the onset of SLE in CLE patients. Some evidence exists that prednisone and antimalarials may slow progression. In a retrospective analysis of 130 United States military personnel who developed SLE, the 26 patients who were treated with hydroxychloroquine before SLE diagnosis had a longer duration from first symptom to SLE diagnosis (1.08 vs. 0.29 years) than those who did not receive hydroxychloroquine (James et al., 2007). They also showed lower autoantibody levels over time. However, randomized controlled trials need to be designed to definitively determine whether these medications are effective in preventing or slowing disease progression. DISCOID LESIONS AS A BENIGN PROGNOSTIC INDICATOR Discoid lesions have been postulated to portend a benign prognosis in SLE patients. This is based on two studies showing low rates of renal disease in patients with DLE
Journal of Investigative Dermatology Symposium Proceedings (2017), Volume 18
JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus Figure 1. Approach to a newly diagnosed patient with cutaneous lupus. The evaluation of a patient with cutaneous lupus begins with assessment of ongoing or prior extracutaneous manifestations. Laboratory investigation and referrals to other specialists (e.g., rheumatology or nephrology) are guided by the history, physical examination, and clinical test results. ANA, anti-nuclear antibody; CBC, complete blood count; CLE, cutaneous lupus erythematosus; CRP, C-reactive protein; ENA, extractable nuclear antigen; dsDNA, double-stranded DNA; ESR, erythrocyte sedimentation rate; SLE, systemic lupus erythematosus.
(Merola et al., 2011; Prystowsky and Gilliam, 1975). However, larger-scale retrospective studies have been equivocal on whether DLE is a marker of benign prognosis (Merola et al., 2013). In 1,043 patients with SLE, 117 of whom had concomitant DLE, those with DLE were more likely to have photosensitivity (odds ratio [OR] ¼ 1.63), leukopenia
(OR ¼1.55), and anti-Smith antibodies (OR ¼ 2.41) but were less likely to have arthritis (OR ¼ 0.49) or pleuritis (OR ¼ 0.56). No association was seen with lupus nephritis or endstage renal disease (Merola et al., 2013). A similar study was done in the PROFILE cohort, which is a multisite group of 2,228 prospectively followed SLE patients, of whom www.jidsponline.org
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JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus Figure 2. Approach to a follow-up patient with cutaneous lupus. The follow-up evaluation centers on determining if the patient’s disease is stable or has progressed. Laboratory investigation should be focused on prior laboratory test result abnormalities and screening for occult systemic involvement. ANA, antinuclear antibody; CBC, complete blood count; CLE, cutaneous lupus erythematosus; CRP, C-reactive protein; dsDNA, double-stranded DNA; ESR, erythrocyte sedimentation rate; SLE, systemic lupus erythematosus.
17.6% have DLE (Alarcon et al., 2002). Multivariate analysis comparing SLE patients with and without DLE showed that features associated with DLE included African American race, other American College of Rheumatology skin criteria, leukopenia, vasculitis, chronic seizures, and smoking (Santiago-Casas et al., 2012). SLE patients without DLE were more likely to be Hispanic or have criteria of arthritis, have positive results for ANA and antiedouble-stranded DNA antibodies, and have positive results for antiphospholipid antibodies. End-stage renal disease was more prevalent in SLE patients without DLE in the PROFILE cohort. However, this study was limited by lack of dermatologists involved, biopsies not being used to determine criteria, no assessment of disease activity, and limited information available on medications (Santiago-Casas et al., 2012). S72
Comparison of autoantibody profiles in subsets of DLE and SLE patients suggest that DLE could reduce disease burden in patients with SLE. Patients with DLE have lower rates of positive autoantibodies, including antibodies to nuclear antigens (e.g., double-stranded DNA) (Prystowsky and Gilliam, 1975; Vila et al., 2006). We have shown that protein arrays show lower autoantibody concentrations against several nuclear antigens in SLE patients with DLE compared with SLE patients without DLE, including those against double-stranded DNA (double-stranded DNA), singlestranded DNA, histones H2A and H2B, and the SS-A (52kDa) antigen (Chong et al., 2012). We previously compared ANAs from different Ig classes measured by ELISA and indirect immunofluorescence including IgM, IgG, and IgA in 35 SLE patients, 23 DLE patients without SLE, and 22 healthy
Journal of Investigative Dermatology Symposium Proceedings (2017), Volume 18
JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus
control subjects. SLE patients expressed the highest amounts of IgG, IgM, and IgA ANA, followed by DLE-only patients and healthy control subjects (Jost et al., 2014). The increased IgG/ IgM ratio in SLE patients is suggestive of a possible protective effect of IgM ANAs. Mechanistically, IgM autoantibodies could decrease IgG autoantibody production by autoreactive B cells, diminish dendritic cell activation, or act as competitive inhibitors with IgG ANAs by binding to the same circulating nuclear antigens (Witte, 2008; Witte et al., 1998; Villalta et al., 2013). SCREENING RECOMMENDATIONS FOR SLE IN CLE PATIENTS Because up to 18% of patients with CLE may eventually develop SLE, patients with CLE should be screened for internal organ involvement. Initial evaluation includes a thorough history and physical examination, including assessment of clinical American College of Rheumatology criteria. Providers can assess for new CLE skin lesions and look for symptoms such as photosensitivity, small joint pains (e.g., hands, wrists), and oral ulcers lasting for more than 2 weeks. We recommend that the initial laboratory investigation include a complete blood count with differential to screen for hematologic abnormalities, blood urea nitrogen level, and creatinine level; urinalysis to assess for renal disease; and an ANA test to check for immunologic abnormalities. If the ANA test result is positive at 1:160 titer or higher, providers can order antiedouble-stranded DNA antibodies, an extractable nuclear antigen panel containing antieSS-A (Ro), antieSS-B (La), antieScl-70, antieJo-1, anti-Smith, and other inflammatory markers including erythrocyte sedimentation rate, C-reactive protein, and complement levels (Figure 1). In the setting of new systemic complaints for follow-up patients, providers can check complete blood count, blood urea nitrogen and creatinine levels, urinalysis, and ANA test (if the results were not already positive). For follow-up patients with a history of positive ANA test results, we recommend rechecking antiedouble-stranded DNA antibodies, extractable nuclear antigen antibodies (if antieSS-A, eSS-B, and -Smith antibody test results are not previously positive), erythrocyte sedimentation rate, C-reactive protein, and complement levels (Figure 2). Patients with CLE warrant close follow-up. Patients with unstable, active disease should be followed up at biweekly to monthly intervals, whereas those with stable disease can be seen every 3e6 months. In our experience, patients with CLE tend to do better with tapering medications during fall and winter. In those with concomitant SLE, we recommend that they have appropriate referrals as directed by disease manifestations (e.g. rheumatology, nephrology, hematology, neurology). In summary, up to 20% of patients with CLE can progress to developing SLE. Fortunately, those who progress often have mild systemic disease. Risk factors for systemic spread include generalized DLE, periungual telangiectasias, arthritis, and persistent laboratory result abnormalities. Therefore, it is important to carefully screen patients with a thorough history and physical examination and selected laboratory testing. CONFLICT OF INTEREST BFC is an investigator for Daavlin Corporation and Biogen Incorporated.
ACKNOWLEDGMENTS We are indebted to Rose Ann Cannon for assisting in the manuscript preparation.
REFERENCES Alarcon GS, McGwin G Jr, Petri M, Reveille JD, Ramsey-Goldman R, Kimberly RP. Baseline characteristics of a multiethnic lupus cohort: PROFILE. Lupus 2002;11:95e101. Arkin LM, Ansell L, Rademaker A, Curran ML, Miller ML, Wagner A, Kenner-Bell BM, Chamlin SL, Mancini AJ, Klein-Gitelman M, Paller AS. The natural history of pediatric-onset discoid lupus erythematosus. J Am Acad Dermatol 2015;72:628e33. Biazar C, Sigges J, Patsinakidis JM, Ruland V, Amler S, Bonsmann G, Kuhn A. Cutaneous lupus erythematosus: first multicenter database analysis of 1002 patients from the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Autoimmun Rev 2013;12:444e54. Callen JP. Chronic cutaneous lupus erythematosus. Clinical, laboratory, therapeutic, and prognostic examination of 62 patients. Arch Dermatol 1982;118:412e6. 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;12:278e88. Cardinali C, Caproni M, Bernacchi E, LAmato L, Fabbri P. The spectrum of cutaneous manifestations in lupus erythematosus—the Italian experience. Lupus 2000;9:417e23. Chong BF, Song J, Olsen NJ. Determining risk factors for developing systemic lupus erythematosus in patients with discoid lupus erythematosus. Br J Dermatol 2012;166:29e35. Chong BF, Tseng LC, Lee T, Vasquez R, Li QZ, Zhang S, Karp DR, Olsen NJ, Mohan C. IgG and IgM autoantibody differences in discoid and systemic lupus patients. J Invest Dermatol 2012;132:2770e9. Durosaro O, Davis MD, Reed KB, Rohlinger AL. Incidence of cutaneous lupus erythematosus, 1965-2005: a population-based study. Arch Dermatol 2009;145:249e53. 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;164:1335e41. Healy E, Kieran E, Rogers S. Cutaneous lupus erythematosusea study of clinical and laboratory prognostic factors in 65 patients. Ir J Med Sci 1995;164:113e5. James JA, Kim-Howard XR, Bruner BF, Jonsson MK, McClain MT, Arbuckle MR, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus 2007;16:401e9. Jost SA, Tseng LC, Matthews LA, Vasquez R, Zhang S, Yancey KB, Chong BF. IgG, IgM, and IgA antinuclear antibodies in discoid and systemic lupus erythematosus patients. ScientificWorldJournal 2014;2014:171028. 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;10:1413e20. Merola JF, Prystowsky SD, Iversen C, Gomez-Puerta JA, Norton T, Tsao P, Massarotti E, Schur P, Bermas B, Costenbader KH. Association of discoid lupus erythematosus with other clinical manifestations among patients with systemic lupus erythematosus. J Am Acad Dermatol 2013;69: 19e24. Millard LG, Rowell NR. Abnormal laboratory test results and their relationship to prognosis in discoid lupus erythematosus. A long-term follow-up study of 92 patients. Arch Dermatol 1979;115:1055e8. Ng PP, Tan SH, Koh ET, Tan T. Epidemiology of cutaneous lupus erythematosus in a tertiary referral centre in Singapore. Australas J Dermatol 2000;41:229e33. Prystowsky SD, Gilliam JN. Discoid lupus erythematosus as part of a larger disease spectrum. Correlation of clinical features with laboratory findings in lupus erythematosus. Arch Dermatol 1975;111:1448e52. Santiago-Casas Y, Vila LM, McGwin G Jr, Cantor RS, Petri M, RamseyGoldman R, Reveille JD, Kimberly RP, Alarcon GS, Brown EE. Association of discoid lupus erythematosus with clinical manifestations and damage accrual in a multiethnic lupus cohort. Arthritis Care Res (Hoboken) 2012;64:704e12.
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JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus Scott A, Rees EG. The relationship of systemic lupus erythematosus and discoid lupus erythematosus: A clinical and hematological study. AMA. Arch Dermatol 1959;79:422e35. Sontheimer RD. Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings. Autoimmun Rev 2005;4:253e63. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 1979;115:1409e15. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25: 1271e7. Tebbe B, Orfanos CE. Epidemiology and socioeconomic impact of skin disease in lupus erythematosus. Lupus 1997;6:96e104. Vasquez R, Wang D, Tran QP, Adams-Huet B, Chren MM, Costner MI, JCohen JB, Werth VP, Chong BF. A multicentre, cross-sectional study on quality of life in patients with cutaneous lupus erythematosus. Br J Dermatol 2013;168:145e53. Vera-Recabarren MA, Garcia-Carrasco M, Ramos-Casals M, Herrero C. Comparative analysis of subacute cutaneous lupus erythematosus and
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chronic cutaneous lupus erythematosus: clinical and immunological study of 270 patients. Br J Dermatol 2010;162:91e101. Verma SM, Okawa J, Propert KJ, Werth VP. The impact of skin damage due to cutaneous lupus on quality of life. Br J Dermatol 2014;170:315e21. Vila LM, Molina MJ, Mayor AM, Peredo RA, Santaella ML, Vila S. Clinical and prognostic value of autoantibodies in puerto Ricans with systemic lupus erythematosus. Lupus 2006;15:892e8. Villalta D, Bizzaro N, Bassi N, Zen M, Gatto M, Ghirardello A, Iaccarino L, Punzi L, Doria A. Anti-dsDNA antibody isotypes in systemic lupus erythematosus: IgA in addition to IgG anti-dsDNA help to identify glomerulonephritis and active disease. PLoS One 2013;8:e71458. Werth VP. Clinical manifestations of cutaneous lupus erythematosus. Autoimmun Rev 2005;4:296e302. Wieczorek IT, Propert KJ, Okawa J, Werth VP. Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. JAMA Dermatol 2014;150:291e6. Witte T. IgM antibodies against dsDNA in SLE. Clin Rev Allergy Immunol 2008;34:345e7. Witte T, Hartung K, Sachse C, Matthias T, Fricke M, Deicher H, Kalden JR, Lakomek HJ, Peter HH, Schmidt RE. IgM anti-dsDNA antibodies in systemic lupus erythematosus: negative association with nephritis. SLE Study Group. Rheumatol Int 1998;18:85e91.
Journal of Investigative Dermatology Symposium Proceedings (2017), Volume 18
Not Just Skin Deep: Systemic Disease Involvement in Patients With Cutaneous Lupus Jack C. O’Brien1 and Benjamin F. Chong1 Cutaneous lupus erythematosus, specifically discoid lupus erythematosus, disproportionately affects those with skin of color and may result in greater dyspigmentation and scarring in darker skin types. In this article, we review investigations relevant to cutaneous lupus patients with skin of color at University of Texas Southwestern Medical Center, associations and risk of progression to systemic lupus, and recommendations for monitoring for systemic disease spread. Between 5% and 25% of patients with cutaneous lupus can develop systemic lupus. If they progress to systemic disease, patients often develop mild systemic disease with primarily mucocutaneous and musculoskeletal manifestations. Patients with cutaneous lupus should be followed up closely to monitor for systemic disease involvement. The University of Texas Southwestern Cutaneous Lupus Erythematosus Registry, of which almost two thirds of participants are those with skin of color, is a part of an ongoing effort to better understand the pathophysiologic mechanisms of CLE and to identify prognostic indicators of risk of progression to systemic lupus. Journal of Investigative Dermatology Symposium Proceedings (2017) 18, S69eS74; doi:10.1016/j.jisp.2016.09.001
INTRODUCTION Cutaneous lupus erythematosus (CLE) is a photosensitive cutaneous autoimmune disease with three main subtypes: acute, subacute, and chronic. Acute CLE is characterized by the classic “butterfly rash” and can persist for weeks to months (Werth, 2005). Subacute CLE was initially described by Sontheimer et al. (1979) and manifests as either erythematous annular plaques coalescing into polycyclic plaques or as papulosquamous psoriasiform lesions (Sontheimer, 2005). Chronic CLE has the largest number of subtypes, including discoid lupus erythematous (DLE), lupus erythematosus tumidus, Chilblain’s lupus, and lupus 1
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Publication of this article was supported by the National Institutes of Health. Correspondence: Benjamin F. Chong, 5323 Harry Hines Boulevard, Dallas, Texas 75309-9069, USA. E-mail: [email protected] Abbreviations: ANA, anti-nuclear antibody; CLE, cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; OR, odds ratio; SLE, systemic lupus erythematosus Received 25 August 2016; accepted 2 September 2016
panniculitis. The most common type of chronic CLE, DLE (Cardinali et al., 2000; Durosaro et al., 2009), is characterized by erythematous to violaceous scaly papules and plaques in a photosensitive distribution that later develop peripheral hyperpigmentation central atrophy, scarring, and hypopigmentation (Tebbe and Orfanos, 1997). These pigmentary changes can be especially pronounced in patients with skin of color. THE CLE EXPERIENCE AT UNIVERSITY OF TEXAS SOUTHWESTERN The University of Texas Southwestern Medical Center’s Cutaneous Lupus Erythematosus Registry was established in 2009 with a stated goal of prospectively following CLE patients over time to characterize CLE disease course, identify risk factors for progression to systemic lupus erythematosus (SLE), improve how clinicians diagnose and treat CLE, and predict their prognoses. Participants in the CLE Registry are recruited from outpatient dermatology clinics at University of Texas Southwestern Medical Center and Parkland Memorial Hospital. Almost two thirds of the participants in the registry are those with skin of color, and the most common subtype of CLE represented is chronic CLE. More specifically, two thirds of the registry is composed of participants diagnosed with DLE. About half of the participants meet American College of Rheumatology criteria (Tan et al., 1982) for SLE (Table 1). Studies investigating quality of life-specific measures in CLE indicate that CLE can have profound effects on quality of life, especially in patients with skin of color (Vasquez et al., 2013). In a multicenter cross-sectional study at University of Texas Southwestern and University of Pennsylvania with inclusion of substantial numbers of patients with skin of color, CLE had a negative effect on quality of life. Female sex, low socioeconomic status, systemic disease, and worse skin disease activity were associated with poor quality of life (Vasquez et al., 2013). In a study of 223 CLE patients at the University of Pennsylvania, African Americans initially presented with greater measures of disease damage than white patients and had higher measures of disease damage at follow-up (Verma et al., 2014). PROGRESSION OF CLE TO SLE Although CLE can present in the setting of SLE, it can also occur independently of internal organ involvement (Durosaro et al., 2009). A European database analysis of 1,002 CLE patients showed that 40% of patients with CLE met criteria for SLE, with the most common criteria being a positive test result for anti-nuclear antibody (ANA) and mucocutaneous manifestations, such as photosensitivity and DLE
ª 2016 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
www.jidsponline.org
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JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus
Table 1. University of Texas Southwestern CLE Registry participant demographic and clinical characteristics (N [ 244) Characteristic
n
%
Race/ethnicity African American/African
116
48
White
88
36
Hispanic
21
9
Asian
9
4
Other
10
4
204
84
40
16
Sex Female Male Predominant CLE subtype CCLE1
190
78
SCLE
35
14
ACLE
19
8
Yes
120
49
No
124
51
Concomitant SLE diagnosis2
Number of SLE criteria, mean and SD2
4
2.3
SLE criteria2 Photosensitivity
179
73
Discoid rash
175
72
Positive ANA
158
65
Immunologic disorder
90
37
Hematologic disorder
89
36
Arthritis
75
31
Malar rash
65
27
Oral ulcers
64
26
Renal disorder
38
16
Serositis
23
9
3
1
Neurologic disorder
Abbreviations: ACLE, acute cutaneous lupus erythematosus; ANA, anti-nuclear antibody; CCLE, chronic cutaneous lupus erythematosus; CLE, cutaneous lupus erythematosus; SD, standard deviation; SLE, systemic lupus erythematosus. 1 DLE is the predominant CCLE subtype, accounting for 87% of the CCLE group (165 participants with DLE). Other CCLE subtypes include lupus erythematosus tumidus, Chilblain’s lupus, bullous SLE, and lupus panniculitis. 2 Information refers to data collected at initial visit.
(Biazar et al., 2013). The incidence of CLE is similar to that of SLE, which both have an incidence of approximately 3 per 100,000 (Durosaro et al., 2009). In 1872, Kaposi was the first to identify progression of DLE to SLE. Subsequent studies investigating this disease progression estimated the incidence to be between 5% and 10% (Millard and Rowell, 1979; Healy et al., 1995). The highest risk of developing SLE appears to be within the first year of diagnosis (Gronhagen et al., 2011), but it has been reported to occur up to 15 years later (Callen, 1985). A recent population-based study from Sweden indicated that progression to SLE can occur in as many as 18% of patients with CLE (Gronhagen et al., 2011). In that study, patients with DLE had a 9.8% probability of being diagnosed with SLE within the first year of diagnosis of CLE, which increased to 16.7% after 3 years. The risk of progression within 3 years of diagnosis was greater in women than men (20.7% vs. 10.4%). In a S70
study of 156 CLE patients in Rochester, MN, 12% of patients developed SLE. The mean time to progression was 8.2 years, and the cumulative incidence of SLE was 5% at 5 years and 23% at 25 years (Durosaro et al., 2009). In addition, children with DLE can develop SLE. In a retrospective review of 40 pediatric patients with discoid lupus, 26% were later diagnosed with SLE, all within 3 years. The average age at progression to SLE was 11 years. However, those who progressed generally had mild disease, with 89% having disease limited to abnormal laboratory test results and mucocutaneous involvement (Arkin et al., 2015). To further define disease progression to SLE in CLE patients, researchers at the University of Pennsylvania prospectively followed 77 patients with CLE to assess disease severity and determine which new SLE criteria were met. Of these, 17% developed SLE, with a mean time to diagnosis of SLE of 8.03 years. Most CLE patients who progressed to SLE had mild systemic disease and gained mucocutaneous or immunologic criteria or developed inflammatory arthritis (Wieczorek et al., 2014). Multiple risk factors have been identified as predictors of systemic spread in CLE (Chong et al., 2012). These include clinical findings such as discoid lesions below the head and neck (generalized DLE) (Callen, 1982; Callen, 1985; Cardinali et al., 2000; Healy et al., 1995; Ng et al., 2000; Scott and Rees, 1959; Vera-Recabarren et al., 2010), periungual telangiectasias, and arthritis. The association between periungual telangiectasias in CLE patients with SLE compared with CLE patients without SLE was first shown when Callen et al. (1982) noted that 76% of SLE patients with DLE showed periungual telangiectasias, whereas 0% of those with DLE but not SLE had them (Callen, 1982). A later study in an Italian cohort comparing 19 DLE patients with SLE versus 166 DLE patients without SLE showed similar results; nailfold abnormalities were present in 76% of 19 patients with DLE and SLE and in no patients with skin-limited disease (Cardinali et al., 2000). Laboratory abnormalities, including high titer ANAs, hematologic abnormalities (leukopenia, anemia), and persistently elevated erythrocyte sedimentation rate, have also been identified as risk factors for systemic spread in DLE (Callen, 1982; Healy et al., 1995; Millard and Rowell, 1979). There are limited data available on how to delay the onset of SLE in CLE patients. Some evidence exists that prednisone and antimalarials may slow progression. In a retrospective analysis of 130 United States military personnel who developed SLE, the 26 patients who were treated with hydroxychloroquine before SLE diagnosis had a longer duration from first symptom to SLE diagnosis (1.08 vs. 0.29 years) than those who did not receive hydroxychloroquine (James et al., 2007). They also showed lower autoantibody levels over time. However, randomized controlled trials need to be designed to definitively determine whether these medications are effective in preventing or slowing disease progression. DISCOID LESIONS AS A BENIGN PROGNOSTIC INDICATOR Discoid lesions have been postulated to portend a benign prognosis in SLE patients. This is based on two studies showing low rates of renal disease in patients with DLE
Journal of Investigative Dermatology Symposium Proceedings (2017), Volume 18
JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus Figure 1. Approach to a newly diagnosed patient with cutaneous lupus. The evaluation of a patient with cutaneous lupus begins with assessment of ongoing or prior extracutaneous manifestations. Laboratory investigation and referrals to other specialists (e.g., rheumatology or nephrology) are guided by the history, physical examination, and clinical test results. ANA, anti-nuclear antibody; CBC, complete blood count; CLE, cutaneous lupus erythematosus; CRP, C-reactive protein; ENA, extractable nuclear antigen; dsDNA, double-stranded DNA; ESR, erythrocyte sedimentation rate; SLE, systemic lupus erythematosus.
(Merola et al., 2011; Prystowsky and Gilliam, 1975). However, larger-scale retrospective studies have been equivocal on whether DLE is a marker of benign prognosis (Merola et al., 2013). In 1,043 patients with SLE, 117 of whom had concomitant DLE, those with DLE were more likely to have photosensitivity (odds ratio [OR] ¼ 1.63), leukopenia
(OR ¼1.55), and anti-Smith antibodies (OR ¼ 2.41) but were less likely to have arthritis (OR ¼ 0.49) or pleuritis (OR ¼ 0.56). No association was seen with lupus nephritis or endstage renal disease (Merola et al., 2013). A similar study was done in the PROFILE cohort, which is a multisite group of 2,228 prospectively followed SLE patients, of whom www.jidsponline.org
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JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus Figure 2. Approach to a follow-up patient with cutaneous lupus. The follow-up evaluation centers on determining if the patient’s disease is stable or has progressed. Laboratory investigation should be focused on prior laboratory test result abnormalities and screening for occult systemic involvement. ANA, antinuclear antibody; CBC, complete blood count; CLE, cutaneous lupus erythematosus; CRP, C-reactive protein; dsDNA, double-stranded DNA; ESR, erythrocyte sedimentation rate; SLE, systemic lupus erythematosus.
17.6% have DLE (Alarcon et al., 2002). Multivariate analysis comparing SLE patients with and without DLE showed that features associated with DLE included African American race, other American College of Rheumatology skin criteria, leukopenia, vasculitis, chronic seizures, and smoking (Santiago-Casas et al., 2012). SLE patients without DLE were more likely to be Hispanic or have criteria of arthritis, have positive results for ANA and antiedouble-stranded DNA antibodies, and have positive results for antiphospholipid antibodies. End-stage renal disease was more prevalent in SLE patients without DLE in the PROFILE cohort. However, this study was limited by lack of dermatologists involved, biopsies not being used to determine criteria, no assessment of disease activity, and limited information available on medications (Santiago-Casas et al., 2012). S72
Comparison of autoantibody profiles in subsets of DLE and SLE patients suggest that DLE could reduce disease burden in patients with SLE. Patients with DLE have lower rates of positive autoantibodies, including antibodies to nuclear antigens (e.g., double-stranded DNA) (Prystowsky and Gilliam, 1975; Vila et al., 2006). We have shown that protein arrays show lower autoantibody concentrations against several nuclear antigens in SLE patients with DLE compared with SLE patients without DLE, including those against double-stranded DNA (double-stranded DNA), singlestranded DNA, histones H2A and H2B, and the SS-A (52kDa) antigen (Chong et al., 2012). We previously compared ANAs from different Ig classes measured by ELISA and indirect immunofluorescence including IgM, IgG, and IgA in 35 SLE patients, 23 DLE patients without SLE, and 22 healthy
Journal of Investigative Dermatology Symposium Proceedings (2017), Volume 18
JC O’Brien and BF Chong Systemic Disease Spread in Cutaneous Lupus
control subjects. SLE patients expressed the highest amounts of IgG, IgM, and IgA ANA, followed by DLE-only patients and healthy control subjects (Jost et al., 2014). The increased IgG/ IgM ratio in SLE patients is suggestive of a possible protective effect of IgM ANAs. Mechanistically, IgM autoantibodies could decrease IgG autoantibody production by autoreactive B cells, diminish dendritic cell activation, or act as competitive inhibitors with IgG ANAs by binding to the same circulating nuclear antigens (Witte, 2008; Witte et al., 1998; Villalta et al., 2013). SCREENING RECOMMENDATIONS FOR SLE IN CLE PATIENTS Because up to 18% of patients with CLE may eventually develop SLE, patients with CLE should be screened for internal organ involvement. Initial evaluation includes a thorough history and physical examination, including assessment of clinical American College of Rheumatology criteria. Providers can assess for new CLE skin lesions and look for symptoms such as photosensitivity, small joint pains (e.g., hands, wrists), and oral ulcers lasting for more than 2 weeks. We recommend that the initial laboratory investigation include a complete blood count with differential to screen for hematologic abnormalities, blood urea nitrogen level, and creatinine level; urinalysis to assess for renal disease; and an ANA test to check for immunologic abnormalities. If the ANA test result is positive at 1:160 titer or higher, providers can order antiedouble-stranded DNA antibodies, an extractable nuclear antigen panel containing antieSS-A (Ro), antieSS-B (La), antieScl-70, antieJo-1, anti-Smith, and other inflammatory markers including erythrocyte sedimentation rate, C-reactive protein, and complement levels (Figure 1). In the setting of new systemic complaints for follow-up patients, providers can check complete blood count, blood urea nitrogen and creatinine levels, urinalysis, and ANA test (if the results were not already positive). For follow-up patients with a history of positive ANA test results, we recommend rechecking antiedouble-stranded DNA antibodies, extractable nuclear antigen antibodies (if antieSS-A, eSS-B, and -Smith antibody test results are not previously positive), erythrocyte sedimentation rate, C-reactive protein, and complement levels (Figure 2). Patients with CLE warrant close follow-up. Patients with unstable, active disease should be followed up at biweekly to monthly intervals, whereas those with stable disease can be seen every 3e6 months. In our experience, patients with CLE tend to do better with tapering medications during fall and winter. In those with concomitant SLE, we recommend that they have appropriate referrals as directed by disease manifestations (e.g. rheumatology, nephrology, hematology, neurology). In summary, up to 20% of patients with CLE can progress to developing SLE. Fortunately, those who progress often have mild systemic disease. Risk factors for systemic spread include generalized DLE, periungual telangiectasias, arthritis, and persistent laboratory result abnormalities. Therefore, it is important to carefully screen patients with a thorough history and physical examination and selected laboratory testing. CONFLICT OF INTEREST BFC is an investigator for Daavlin Corporation and Biogen Incorporated.
ACKNOWLEDGMENTS We are indebted to Rose Ann Cannon for assisting in the manuscript preparation.
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