83 Lupus Erythematosus

Lupus erythematosus (LE) is a clinical syndrome that has multiple, but largely unknown causes. It exhibits an extremely broad spectrum of symptoms, and it can range in severity from being potentially fatal within a few weeks to eliciting minor indolent symptoms which, prior to immunologic testing, are virtually undiagnosable.

History

Medical use of the term lupus has been traced to the fifteenth century, when it designated a variety of cancer. The term was reintroduced by London physi­cian Robert Willan in 1808 to designate cutaneous tuberculosis, particularly when it affected the face. Cutaneous tuberculosis eventually received the syn­onym lupus vulgaris. In 1851 P. L. Alph6e Cazenave of Paris used the term lupus erythemateaux to de­scribe the condition that came to be called discoid lupus erythematosus (DLE) by Vienna’s Moriz Kaposi in 1872 (Jarcho 1957). During 1866-70, Kaposi diagnosed this disease in 22 patients and concluded that it was more common and more severe in women. All 3 deaths occurred among his 15 fe­male patients. Although one of these had pulmonary tuberculosis, and cutaneous tuberculosis was com­mon, Kaposi believed that DLE is not related to tuberculosis. Such a causal relationship, however, came to be advocated, particularly by French derma­tologists, and remained under discussion until the 1930s. During the 5 years in which Kaposi saw 22 cases of DLE, 279 cases of lupus vulgaris were seen in the same department (Kaposi 1872). One genera­tion later, among 30,000 dermatologic patients seen in Manchester, England, between 1893 and 1913, a diagnosis of DLE was made in 142 instances (0.47 percent), and lupus vulgaris in 1.5 percent.

Kaposi (1872) used the term disseminated lupus erythematosus, but referred thereby to cases with widespread skin lesions rather than visceral involve­ment. Nevertheless, he described some cases having fever, pleuropneumonia, arthralgia, and arthritis. Recognition developed slowly that various visceral manifestations are attributes of the systemic disease rather than coincidences. From 1894 to 1903, Wil­liam Osler saw 29 patients (17 aged 3-15 years; 12 aged 18-57 years), who had an “erythema with vis­ceral lesions.” He is credited with having provided the first clear descriptions of systemic lupus eryth­ematosus (SLE) although, by modern criteria, the diagnosis that resulted from those descriptions does not fit all of the cases.

Osler (1904) added involvement of the kidneys and central nervous system to the description of Kaposi, whereas Alfred Kraus and Carl Bohac (1908-9) recognized that pneumonia belongs to the syndrome. Before the 1940s, most publications on lupus erythematosus were written by dermatolo­gists, and consequently, skin lesions were consid­ered essential to satisfy the diagnosis. Emanual Libman and Benjamin Sacks (1923) described four cases of noninfectious endocarditis (heart inflamma­tion) of which three had the skin lesions of LE. A review of 11 cases of Libman-Sacks endocarditis in 1932 found that 5 lacked the skin eruption. George Belote and H. S. Ratner (1936) concluded that this form of heart disease nevertheless is a manifesta­tion of SLE. Leukopenia and sensitivity to sunlight were convincingly related to SLE in 1939, but it was only in the 1940s that it became accepted that a skin eruption is not a necessary component of SLE. Recent data indicate that even with the current longer life expectancy of SLE patients, only about 40 percent ever have the “butterfly” facial rash, and that an eruption occurs somewhere on the body in about 75 percent of the cases.

SLE was perceived to be rare and uniformly fatal because only the most severe cases identified by their rash were being diagnosed. For example, at the University Hospital in Prague there were just eight cases from 1897 to 1908. At the Johns Hopkins Hospi­tal, only three cases were diagnosed between 1919 and 1923. In fact among 7,500 autopsies of cases above 13 years of age reviewed at the same hospital in 1936, there were just five instances of SLE. Five cases were diagnosed at the Mayo Clinic between 1918 and 1921 (Goeckerman 1923), but, as the dis­ease became more familiar, 132 cases were recog­nized during the decade 1938 to 1947 (Montgomery and McCreight 1949).

In 1948, Malcolm Hargraves, a hematologist at the Mayo Clinic, reported a discovery, which he said “has been called an L.E. cell in our laboratory be­cause of its frequent appearance in the bone marrow in cases of acute disseminated L.E.” (Hargraves 1969). In the next 4 years, numerous modifications of Hargrave’s procedure were devised in various labo­ratories to make demonstration of the LE cell easier and more reliable.

In 1954 it was discovered that the formation of LE cells results from a reaction between a factor in the serum and leukocyte nuclei. This led in 1957 to the development of a quantifiable test of this antigen­antibody reaction. The determination of antinuclear antibodies (ANA) has gradually replaced the LE cell as the principal diagnostic test for SLE. These tests have greatly increased case finding and thereby have led to the recognition that SLE exhibits a broad range of severity. Nevertheless, the ANA test may cause confusion because many circumstances induce ANA reactions, at least in low titer. In North Amer­ica and Europe, “false positive” reactions are most often due either to a drug or to another connective tissue disease, whereas in tropical Africa they have been related to endemic malaria.

The next advance was the standardization of crite­ria for the diagnosis of SLE. For this purpose, a committee OfAmerican rheumatologists in 1971 pub­lished a battery of clinical and laboratory findings of which a specified number had to be present for the diagnosis to be probable. This schema was well re­ceived, and a modification prepared in 1982 has been adopted in many countries (Tan et al. 1982).

Drug-Induced SLE

A syndrome that was indistinguishable from SLE was recognized at the Cleveland Clinic in 1954 in patients who were taking the antihypertensive drug hydralazine. Since then, many drugs have been sus­pected or have been proven potentially to have such an effect. By far the most consistent SLE-inducing agent is procainamide; this drug, used to treat car­diac arrhythmias, was first reported to induce SLE in 1962. After 6 months of therapy, ANA develop in at least half of these cases; and after 1 year, a quar­ter of the cases may exhibit symptoms of SLE. In patient populations in which potentially lupus­inducing drugs, such as procainamide, hydralazine, phenytoin, and isoniazid are widely used, about 10 percent of the cases of SLE are drug-induced (Lee, Rivero, and Siegel 1966). Drug-induced SLE is rela­tively benign. The female preponderance is dimin­ished and its most frequent symptoms are pleurisy and arthralgia. Fever, leukopenia, and skin lesions occur about half as frequently as in idiopathic SLE; renal involvement and pericarditis are rare, and cen­tral nervous system involvement does not occur. Only the development of ANA warrants close obser­vation. If it is possible to discontinue the inciting drug after symptoms have developed, those symp­toms will disappear within several weeks.

Treatment and Mortality

In the 1940s it was generally acknowledged that there was no effective treatment for either DLE or SLE. The initial breakthrough occurred in 1949, with the discovery that the corticosteroids cortisone and corticotropin can exert a dramatic suppression of most symptoms of SLE.

Modem therapy has not only improved the quality of life of the SLE patient but has also greatly pro­longed his or her survival. Before the advent of corti­costeroids, one-half of these patients died within 2 to 3 years of being diagnosed. Now the mean survival of 15 years after diagnosis has reached 75 percent. Two factors in addition to the therapeutic agents cited above help to account for this improvement: (1) better antibiotic therapy for potentially fatal bacte­rial infections; and (2) recognition of much milder cases for which a more benign course is likely even with minimal therapy.

Mortality is influenced by race and sex. According to U.S. data for 1968 to 1976, the annual mortality rate, relative to 1.0 for white males, was 1.6 for black males; 3.7 for white females; and 10.5 for black females (Gordon, Stolley, and Schinar 1981).

Epidemiology, Distribution, and Incidence Reviews of the proportion of cases of DLE in the clientele of dermatology clinics began to be reported at the beginning of this century. An incidence of between 0.25 percent and 0.75 percent has been con­sistently found in various parts of the world (Gahan 1942).

The only epidemiological conclusion about SLE reached until the 1950s was that the disease occurs predominantly in young women. In 1952 an ethnic predisposition was postulated, based on the observa­tion of the often deleterious effect of sun exposure: Redheaded, freckled persons with an inability to tan were deemed most susceptible (Brunsting 1952). This conclusion was contradicted, however, by M. Siegel and his colleagues (1964), whose epidemio­logical data indicated that SLE is actually more common among blacks. Studies in San Francisco (Fessel 1974) and Baltimore (Hochberg 1987) sub­stantiated this increased susceptibility of blacks, par­ticularly among black women. National data from Veterans Administration hospitals have confirmed the racial difference among men as well (Siegel and Lee 1973). Unlike infectious diseases such as rheu­matic fever or tuberculosis, the occurrence of SLE appears not to be related to socioeconomic factors. In terms of total population, the annual incidence of SLE in the United States has been estimated at about 5 per 100,000, with black females about three times more susceptible and black males two times more susceptible than their white COimterparts. The mean age of onset is 28 to 30 years, but the prepon­derance of female patients varies with age. About twice as many females as males suffer from the dis­ease during the first decade of life and from the sev­enth decade on. But between ages 20 and 40, there are 8 female patients for every male.

The prevalence, sex ratio, and mortality rates for SLE in northern Europe resemble those of U.S. white populations (Helve 1985; Hochberg 1987). In other parts of the world, as recognition of the disease has increased, more cases are being diagnosed. For example, SLE was rarely diagnosed in India before 1970, but from 1974 to 1985, 181 cases were seen in one hospital in New Delhi (Malaviya et al. 1987). Studies in Hawaii (Serdula and Rhoads 1979) and Malaysia (Frank 1980) indicate greater susceptibil­ity of Chinese than other ethnic groups, and the death rate due to SLE for Oriental women in the United States (nearly three times that of white women) is similar to that of black women (Kaslow 1982). The prevalence of SLE among Polynesians also exceeds that of Caucasians (Serdula and Rhoads 1979; Hart, Grigor, and Caughey 1983).

In the predominantly black population of Jamaica, SLE constitutes a remarkably large proportion of treated rheumatic diseases. Indeed, 22 percent of all outpatients and 37 percent of inpatients with rheu­matic disease suffer from SLE (Wilson and Hughes 1979). In view of the prevalence of SLE among non­white populations elsewhere, the apparent rarity of the disease among African blacks has been perplex­ing. The first case was reported from Senegal in 1960. Between 1967 and 1978, only 21 cases were recorded in Kampala, Uganda. A 5-year prospective analysis of cases of polyarthritis in Zimbabwe re­ported in 1969 found no case of SLE, whereas an­other study during 1979-84 discovered 31 cases (30 female, ages 13 to 46 years) (Taylor and Stein 1986). The possibility of differences in susceptibility of vari­ous African ethnic groups must be considered. Dur­ing 1960-72, for example, 130 cases of SLE were admitted to two hospitals in Cape Town, South Af­rica. These included 86 “coloureds” (mainly Indian), 36 whites, and only 8 “Bantu.” In terms of each 1,000 female admissions, this meant a rate of 4.9 “coloured,” 3.8 “Bantu,” and 2.3 white (Jessop and Meyers 1973). The data from much of the world remain inadequate to draw firm conclusions about ethnic and other possible variables related to SLE.

Thomas G. Benedek

Bibliography

Beck, J. S. 1969. Antinuclear antibodies: Methods of detec­tion and significance. Mayo Clinic Proceedings 44: 600-19.

Belote, G. H., and H. S. Ratner. 1936. The so-called Libman-Sacks syndrome: Its relation to dermatology. Archives of Dermatology and Syphilology 33: 642—64.

Brunsting, L. A. 1952. Disseminated (systemic) lupus erythematosus. Proceedings of the Staff of the Mayo Clinic 27: 410-12.

Fessel₁ W. J. 1974. Systemic lupus erythematosus in the community. Incidence, prevalence, outcome and first symptoms; the high prevalence in black women. Ar­chives of Internal Medicine 134: 1027—35.

Findlay, G. H., and J. G. Lups. 1967. The incidence and pathogenesis of chronic discoid lupus erythematosus: An analysis of 191 consecutive cases from the Trans­vaal. South African Medical Journal 41: 694-8.

Frank, A. O. 1980. Apparent predisposition to systemic lupus erythematosus in Chinese patients in West Ma­laysia. Annals of the Rheumatic Diseases 39: 266-9.

Gahan, E. 1942. Geographic distribution of lupus erythe­matosus. Archives OfDermatology and Syphilology 45: 1133-7.

Goeckerman, W. H. 1923. Lupus erythematosus as a sys­temic disease. Journal of the American Medical Asso­ciation 80: 542—7.

Gordon, M. F., P. D. Stolley, and R. Schinar. 1981. Trends in recent systemic lupus erythematosus mortality rates. Arthritis and Rheumatism 24: 762-76.

Greenwood, B. M., E. M. Herrick, and E. J. Holbrow. 1970. Speckled antinuclear factor in African sera. Clinical and Experimental Immunology 7: 75—83.

Hargraves, M. M. 1969. Discovery of the LE cell and its morphology. Mayo Clinic Proceedings 44: 579—99.

Hart, H. H., R. R. Grigor, and D. E. Caughey 1983. Ethnic difference in the- prevalence of systemic lupus ery­thematosus. Annals of the Rheumatic Diseases 42: 529-32.

Helve, T. 1985. Prevalence and mortality rates of systemic lupus erythematosus and causes of death in SLE pa­tients in Finland. Scandinavian Journal of Rheuma­tology 14: 43—6.

Hench, P. S., et al. 1950. Effects of cortisone acetate and ' pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Archives of Inter­nal Medicine 85: 545—666.

Hochberg, M. C. 1985. The incidence of systemic lupus erythematosus in Baltimore, Maryland, 1970-1977. Arthritis and Rheumatism 28: 80—6.

1987. Mortality from systemic lupus erythematosus in England and Wales, 1974—1983. British Journal of Rheumatism 26: 437—41.

Jarcho, S. 1957. Notes on the early modem history of lupus erythematosus. Journal of the Mount Sinai Hospital 24: 939-44.

Jessop S., and O. L. Meyers. 1973. Systemic lupus erythe­matosus. South African Medical Journal 47: 222—5.

Kaposi, M. 1872. Neue Beitrage zur Kenntniss des Lupus erythematosus. Archiv fur Dermatologie und Syphilis 4: 18-41.

Kaslow, R. A. 1982. High rate of death caused by systemic lupus erythematosus among U.S. residents of Asian descent. Arthritis and Rheumatism 2: 414—18.

Keil, H. 1937. Conception of lupus erythematosus and variants. Archives OfDermatology and Syphilology 36: 729-57.

Kraus, A., and C. Bohac. 1908. Bericht uber acht Falle von Lupus erythematodes acutus. Archiu fiir Derma­tologic und Syphilis 43: 117—56.

Lee, S. L., I. Rivero, and M. Siegel. 1966. Activation of systemic lupus erythematosus by drugs. Archives of Internal Medicine 117: 620—6.

Libman, E., and B. Sacks. 1924. A hitherto undescribed form of valvular and mural endocarditis. Transac­tions of the Association of American Physicians 38: 46-61.

MacLeod, J. M. 1913. Discussion on the nature, varieties, causes and treatment of lupus erythematosus. British Medical Journal 2: 313—19.

Malaviya, A. N., et al. 1987. Systemic connective tissue diseases in India - IX. Survival in systemic lupus erythematosus. Journal of the Association of Physi­cians of India 36: 509—11.

Montgomery, H., and W. G. McCreight. 1949. Dissemi­nated lupus erythematosus. Archives of Dermatology and Syphilology 60: 356—72.

Osler, W. 1904. On the visceral manifestations of the erythema group of skin diseases. American Journal of the Medical Sciences 127: 1-23, 751—4.

Page, F. 1951. Treatment of lupus erythematosus with mepacrine. Lancet 2: 755—8.

Rose, E., and D. M. Pillsbury. 1939. Acute disseminated lupus erythematosus — a systemic disease. Annals of Internal Medicine 12: 951—63.

Rothfield, N. F., et al. 1963. Chronic discoid lupus erythematosus: A study of 65 patients and 65 controls. New England Journal of Medicine 269:1155-61.

Serdula, M. K., and G. G. Rhoads. 1979. Frequency of systemic lupus erythematosus in different ethnic groups in Hawaii. Arthritis and Rheumatism 22: 328-33.

Siegel, M., and S. L. Lee. 1973. The epidemiology of sys­temic erythematosus. Seminars in Arthritis andRheu- matism 3: 1—54.

Tan, E. M., et al. 1982. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthri­tis and Rheumatism 25: 1271—7.

Taylor, H. G., and C. M. Stein. 1986. Systemic lupus erythematosus. Annals of the Rheumatic Diseases 45: 645-8.

Urman, J. D., and N. F. Rothfield. 1977. Corticosteroid treatment in systemic lupus erythematosus: Survival studies. Journal of the American Medical Association 238: 2272-6.

Wagner, L. 1976. Immunosuppressive agents in lupus ne­phritis: A critical analysis. Medicine 55: 239-50.

Wilson, W. A., and G. R. Hughes. 1979. Rheumatic disease in Jamaica. Annals of the Rheumatic Diseases 38: 320-5.