The term lupus érythémateaux was used for the first time by Cazénave (Cazénave 1851) in 1851 to distinguish the noninfectious forms of lupus from cutaneous tuber- culosis (lupus vulgaris). Cazénave referred in his original paper to Biett’s earlier report on this disease, which was termed erytheme centrifuge, as being a very good description of what nowadays would be called discoid lupus erythematosus (DLE).
Also, in 1845, Hebra (Hebra 1845) precisely described systemic manifestations of LE that occurred in patients who had the classic “butterfly erythema,” which he named
“seborrhea congestive”. Since the earlier descriptions had always discussed LE in the context of cutaneous tuberculosis, it is very much Cazénave’s achievement to have clearly separated LE from an infectious disease, thus clearing the way for further studies on this complex disease following other hypotheses and directions.
Based on Hebra’s work, further clinical and histopathologic studies on the relation of cutaneous lesions and systemic manifestations of LE were performed. Kaposi (Kaposi 1869, 1872, 1880) recognized the relationship of DLE and systemic LE (SLE) and extensively described the butterfly erythema as a facial cutaneous sign of SLE.
Accordingly, through his continuous efforts, which are reflected in several publica- tions between 1869 and 1880, Kaposi is nowadays recognized as the first describer of SLE. In 1872, Kaposi described SLE as an acute febrile eruption with pronounced painful joint involvement and a characteristic facial erythema that he termed
“erysipelas perstans faciei” (Fig. 4.1).
The most extensive description on the systemic manifestations of LE at that time must be referred to Osler in 1895 (Osler 1895) in his work titled “On the visceral com- plications of erythema exsudativum multiforme”. Although he had not adopted the term “lupus erythematosus” from his European colleagues, he based his studies on their work, and, thus, the investigations dealing with this fascinating and complex disease reached the New World by the end of the 19th century.
In an article published by the Journal of the American Medical Association in 1923, Goeckerman (Goeckerman 1923) pointed again in depth to the systemic nature of LE (“lupus erythematosus as a systemic disease”). In Europe, Hutchinson (Hutchinson 1888) emphasized at the end of the 19th century the multisystem nature of LE and the different expressions and variations of the disease with respect to cutaneous and sys- temic manifestations in different patients.
In summary, the complex disease LE was first recognized and evaluated by its vis- ible cutaneous manifestations before the analysis and study of its systemic manifes- tations established the multisystem nature of LE.
Historical Background
of Cutaneous Lupus Erythematosus
Percy Lehmann
4
Clinical and Histologic Classifications of Lupus Erythematosus
On establishing the unifying concept that LE comprised a common disease with hete- rogenous expressions, attempts were undertaken to develop a clinical classification of the different forms of LE.
In 1921, Brocq (Brocq 1921) subdivided LE into three different forms: DLE, dis- seminated DLE, and SLE. In 1934, O’Leary (O’Leary 1934) further developed the clas- sification, trying to connect the cutaneous manifestations to certain systemic involve- ments. He stressed that disseminated DLE represented the transition from a localized cutaneous disease to a multisystem systemic illness, namely, SLE. At that time, no serologic markers had been identified, which later helped better characterize the dif- ferent subsets in the LE spectrum. The concept of a disease spectrum was, finally, emphasized by Dubois and Tuffanelli (Dubois and Tuffanelli 1964). They extensively described 520 consecutive patients with SLE, with precise characterization of the var- ious cutaneous and systemic disease expressions, therefore demonstrating the dis- ease continuum from the relatively benign forms of limited skin disease such as local- ized DLE to the potentially fatal fully expressed SLE. Between these two poles a spectrum of characteristic disease manifestations was recognized in which clinical, histopathologic, serologic, immunologic, and photobiologic features composed the fundamentals for the specific diagnosis of an LE subset with a well-established prog- nostic value.
The modern and generally accepted classification of LE is based mostly on the work of Gilliam, Sontheimer, and their coworkers (Gilliam and Sontheimer 1981a, b, 1982, 1983). Based on the spectrum concept of Dubois, they concentrated on the rela- tionships that exist between the various cutaneous and systemic manifestations of LE. Clinical, histopathologic, photobiologic, immunologic, and genetic studies led
Fig. 4.1. Historical drawing of cutaneous lupus erythematosus (from Kaposi’s Handatlas der Hautkrankheiten [Kaposi 1898])
Gilliam and Sontheimer to the extensive in-depth description of the immunogeneti- cally homogeneous LE subset, namely, subacute cutaneous LE (SCLE). This work led to the modern classification of LE and has been widely agreed on. This progress had been made possible by the rapid developments in biochemistry, immunology, and molecular biology that were integrated into clinical science and helped investigate the various phenomenologic expressions of LE. Examples include the discovery of the LE cell factor by Hargraves et al. (Hargraves et al. 1948) in 1948 and the development of the antinuclear antibody assay in 1957 by Friou (Friou 1957). These laboratory inves- tigations prompted the era of intense research on clinical-serologic correlations.
The discovery and characterization of numerous antibodies led to a better under- standing of the various expressions of LE sometimes assuming a marker function for the disease.
Photobiology
Of the different external factors that have detrimental effects on disease activity, the sun’s radiation has been best studied. Already in Cazénave’s original description (Cazénave 1881) it was mentioned that outdoor workers were predisposed to the dis- order and that exacerbations of the disease were related to environmental factors.
Hutchinson (Hutchinson 1888) reported in his Harveian Lectures on Lupus, pub- lished in 1888, that patients with LE did not tolerate exposure to the sun. In 1915, Pusey (Pusey 1915) described a young lady with LE that first appeared after some days of extensive golfing in the summertime. The lesions disappeared after strict avoidance of the sun, only to reexacerbate the next summer after a golf tournament.
Freund (Freund 1929) evaluated in a study from 1920 to 1927 the admission of patients with LE to the Department of Dermatology in Berlin. He demonstrated an increased prevalence of new LE cases in May and June and concluded that climatic factors were responsible for this climax in the number of new patients with LE.
Shortly after these observations it became clear that artificial light sources were also able to induce LE.Jesionek (Jesionek 1916), a German pioneer of phototherapy,warned clinicians in 1916 not to apply phototherapy in patients with LE. He described two cases in which phototherapy had caused dramatic exacerbation of the disease with induction of systemic multiorgan involvement for previously limited DLE. In 1929, Fuhs (Fuhs 1929) reported a patient with exacerbated “lupus erythematosus subacu- tus” after irradiation with an artificial light source. Possibly, this is the first description of the exquisite light sensitivity of the SCLE subset. The author unsuccessfully tried to determine the action spectra and dosages that led to disease induction.
Epstein (Epstein et al. 1965) was the first investigator to introduce the repeated exposure technique, which enabled him and his coworkers to induce LE lesions in 5 of 25 patients. Baer and Harber (Baer and Harber 1965) also tested a limited number of patients, and Freeman et al. (Freeman et al. 1969) as well as Cripps and Rankin (Cripps and Rankin 1973) performed for the first time studies with monochromatic radiation, because of these studies, the action spectrum of LE was ascribed to the ultraviolet (UV) B range. In 1990, our group (Lehmann et al. 1990) demonstrated that the action spectrum of LE reaches into the long-wave UVA region. In the original study, 128 patients with LE had been tested using a standardized phototest protocol.
This study was extended, and over the ensuing 15 years 405 patients with LE were phototested (Kuhn et al. 2001). Other groups confirmed the published results (Leenu- taphon and Boonchai 1999, Nived et al. 1993, Walchner et al. 1997, Wolska et al. 1989).
During these studies, a rare subset of cutaneous LE, namely LE tumidus (LET), turned out to be even more photosensitive than SCLE (Kuhn et al. 2001). LET was first men- tioned by Gougerot and Burnier (Gourgerot and Burnier 1930) in 1930, but since then LET has been documented rarely in the literature.
In 1981, Provost and coworkers (Provost 1983, Provost and Reichlin 1981, Provost et al. 1983, 1985) described the anti-Ro/SSA autoantibody as a serologic marker for neonatal LE and the association of these autoantibodies with a group of patients with LE and exquisite photosensitivity. Subsequently, Norris and colleagues demonstrated that UV irradiation modulates the expression of Ro/SSA antigens by epidermal ker- atinocytes (LeFeber et al. 1984, Norris and Lee 1985). For the first time, a molecular explanation for photosensitivity of patients with LE was presented. Ten years later, in 1994, Casciola-Rosen et al. (Casciola-Rosen et al. 1994) studied UV-induced apopto- sis of keratinocytes of patients with LE. They demonstrated the compartmentaliza- tion of specific nucleosome constituents to the cytoplasmatic cell surface blebs of apoptotic keratinocytes. This was hypothesized to be a possible first step in the cas- cade that finally leads to an autoimmune disease.
References
O’Leary PA (1934) Disseminated lupus erythematosus. Minn Med 17:637–644
Baer RL, Harber LC (1965) Photobiology of lupus erythematosus. Arch Dermatol 92:124–128 Brocq L (1921) Précis-atlas de pratique dermatologique. G Doin, Paris, pp 468–477
Casciola-Rosen LA, Anhalt G, Rosen A (1994) Autoantigens targeted in systemic lupus erythe- matosus are clustered in two populations of surface structures on apoptotic keratinocytes. J Exp Med 179:1317–1330
Cazénave PLA (1851) Lupus érythémateux (érythéme centrifuge). Ann Mal Peau Syph 3:297–299 Cripps DJ, Rankin J (1973) Action spectra of lupus erythematosus and experimental
immunoflourescence. Arch Dermatol 107:563–567
Dubois EL, Tuffanelli DL (1964) Clinical manifestations of systemic lupus erythematosus. JAMA 190:104–111
Epstein JH, Tuffanelli DL, Dubois EL (1965) Light sensitivity and lupus erythematosus. Arch Dermatol 91:483–485
Freeman RG, Knox JM, Owens DW (1969) Cutaneous lesions of lupus erythematosus induced by monochromatic light. Arch Dermatol 100:677–682
Freund H (1929) Inwieweit ist der Lupus erythematodes von allgemeinen Faktoren abhängig?
Dermatol Wochenschr 89:1939–1946
Friou GJ (1957) Clinical application of lupus serum: nucleoprotein reaction using fluorescent antibody technique. J Clin Invest 36:890
Fuhs E (1929) Lupus erythematosus subacutus mit ausgesprochener Überempfindlichkeit gegen Quarzlicht. Z Hautkr 30:308–309
Gilliam JN, Sontheimer RD (1981a) Distinctive cutaneous subsets in the spectrum of lupus ery- thematosus. J Am Acad Dermatol 4:471–475
Gilliam JN, Sontheimer RD (1981b) Skin manifestations of SLE. Clin Rheum Dis 8:207–218 Gilliam JN, Sontheimer RD (1982) Subacute cutaneous lupus erythematosus. Clin Rheum Dis
8:343–352
Gilliam JN, Sontheimer RD (1983) Clinically and immunologically defined subsets of lupus ery- thematosus. Dermatol Clin 2:147–165
Goeckerman WH (1923) Lupus erythematosus as a systemic disease. JAMA 80:542–547 Gourgerot H, Burnier R (1930) Lupus érythémateux tumidus. Bull Soc Fr Dermatol Syphil
37:1291–1292
Hargraves MM, Richmond H, Morton R (1948) Presentation of two bone marrow elements: The
“tart” cell and the “LE” cell. Mayo Clin Proc 23:25–28
Hebra F (1845) Bericht über die Leistungen in der Dermatologie. In: Jahresbericht über die Fortschritte der gesamten Medizin in allen Ländern. Enke Verlag, Erlangen, pp 226–227 Hutchinson J (1888) Harveian lectures on lupus. Lecture III. On the various forms of lupus vul-
garis and erythematosus. Br Med J 1:113–118
Jesionek A (1916) Richtlinien der modernen Lichttherapie. Strahlentherapie 7:41–65
Kaposi M (1869) Zum Wesen und zur Therapie des Lupus erythematodes. Arch Dermatol Syph 1:18–41
Kaposi M (1872) Neue Beiträge zur Kenntnis des Lupus erythematodes. Arch Dermatol Syph 1:36–78
Kaposi M (1880) Pathologie und Therapie der Hautkrankheiten. In: Vorlesungen für praktische Ärzte und Studierende (2nd ed). Urban & Schwarzenberg, Vienna, pp 608–615
Kaposi, M (1898–1900) Handatlas der Hautkrankheiten fur Studierende und Ärzte. Wilheld Braumüller, Vienna
Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed M, Lehmann P (2000) Lupus erythe- matosus tumidus, a neglected subset of cutaneous lupus erythematosus: report of 40 cases.
Arch Dermatol 136:1033–1040
Kuhn A, Sonntag M, Richter-Hintz D, Oslislo C, Megahed M, Ruzicka T, Lehmann P (2001) Pho- totesting in lupus erythematosus: a 15-year experience. J Am Acad Dermatol 45:86–95 Leenutaphong V, Boonchai W (1999) Phototesting in oriental patients with lupus erythemato-
sus. Photodermatol Photoimmunol Photomed 15:7–12
LeFeber WP, Norris DA, Ran SR, Lee LA, Huff JC, Kubo M, Boyce ST, Kotzin BL, Weston WL (1984) Ultraviolet light induces binding of antibodies to selected nuclear antigens on cul- tures of human keratinocytes. J Clin Invest 74:1545
Lehmann P, Holzle E, Kind P, Goerz G, Plewig G (1990) Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation. J Am Acad Dermatol 22:181–187 Nived O, Johansen PB, Sturfelt G (1993) Standardized ultraviolet-A exposure provokes skin reac-
tion in systemic lupus erythematosus. Lupus 2:247–250
Norris DA, Lee LA (1985) Antibody-dependent cellular cytotoxicity and skin disease. J Invest Dermatol 85:165S-175S
Osler W (1895) On the visceral complications of erythema exsudativum multiforme. Am J Med Sci 110:629–646
Provost TT (1983) Neonatal lupus erythematosus. Arch Dermatol 119:619–622
Provost TT, Reichlin M (1981) Antinuclear antibody-negative systemic lupus erythematosus. J Am Acad Dermatol 4:84–89
Provost TT, Arnett TC, Reichlin M (1983) Homozygous C2 deficiency, lupus erythematosus, and anti-Ro(SS-A) antibodies. Arthritis Rheum 26:1279–1281
Provost TT, Herrera-Esparza R, Diaz LA (1985) Nucleoprotein autoantibodies in lupus eryth- matosus. J Invest Dermatol 85:133–139
Pusey WA (1915) Attacks of lupus erythematosus following exposure to sunlight or other weather factors. Arch Dermatol Syph 34:388
Walchner M, Messer G, Kind P (1997) Phototesting and photoprotection in LE. Lupus 6:167–174 Wolska H, Blazczyk M, Jablonska S (1989) Phototests in patients with various forms of lupus ery-
thematosus. Int J Dermatol 28:98–103
