Morris Siegel

The epidemiology of systemic lupus erythematosus

Abstract The present review has focused on the methods and results of epidemiological studies of SLE for clues to its etiology based on reports of the occurrence of SLE in the general population and on the conditions under which it is likely to occur. The review covers the period from 1950 to 1972, and is limited to idiopathic SLE. Reports of population studies on SLE were published from four widely scattered regions, namely, New York City; Jefferson County, Alabama; Rochester, Minnesota; and Malmo, Sweden. Geographic variations in the prevalence of the disorder were observed, which were largely attributed to regional differences in completeness of case finding. The reported crude rates were highest in Rochester, lowest in Jefferson County, and at an intermediate level in Malmo and New York City where the findings were similar. In New York City, the annual incidence of newly occurring cases of idiopathic SLE from 1956 to 1965 appeared to be stabilized at a level of about 2.5/100,000 general population, while the prevalence of existing cases rose progressively from 4.1 to 15.5 per 100,000 during the same 10-yr period. The even level in incidence trend indicated that the occurrence of SLE was not appreciably influenced by changes in host or environmental conditions during the study period. The steady increase in prevalence was attributed to earlier recognition of the disease and to longer survival because of improved therapy. The annual mortality was roughly half the incidence in the decade 1956–1965. The specific incidence of the disease by age and sex was usually highest at 15–44 yr of age, while its prevalence was maximal at 45–64 yr. The respective incidence and prevalence rates at these ages were 14.0 and 90.9/100,000 for black females and 3.8 and 27.6 for white females in New York City. The rates among Puerto Ricans appeared to be intermediate between those for blacks and whites. However, some of the evidence on age and SLE pointed to an earlier age-distribution of cases among Puerto Ricans than among blacks or whites. The risk of SLE was higher for black females than whites in both New York City and Jefferson County, Alabama, according to cooperative studies there. In males, however, the comparative results on ethnic differences in the occurrence of SLE were conflicting and inconclusive because of the small number of cases in each area. The higher rates of SLE for blacks and Puerto Ricans could not be related to more complete case finding or to unfavorable environmental conditions in low socioeconomic groups. On the other hand, the results appeared to be related to underlying ethnic differences in immune mechanism, according to studies on serum gamma globulin level and Mantoux reaction to BCG in normal subjects. Familial studies revealed some evidence of an increase in serum gamma globulin, and possibly in antinuclear factor and other SLE-related immunological and clinical abnormalities among first-degree relatives of SLE cases. The findings were indicative of a demonstrable familial or a genetic influence in the occurrence of the disorder. The abnormalities were mainly concentrated in selected families, and environmental factors could not be excluded. However, the occurrence of the disease was found to be independent of birth order, an indication that it represents a random event consistent with genetic factors and unrelated to change with time in parity, parental age, and related environmental influences. More direct evidence for genetically determined host factors in the predisposition to SLE has been sought in studies on the relationship of the disorder to the histocompatibility (HL-A) antigens which may be closely linked to the activity of the immune mechanism. Thus far, different specific HL-A antigens, viz., A5, A7, A8, A13, W5, W15, and an X type, were observed by various investigators in association with SLE and the risk of developing the disease. Whether these diverse findings have biological significance or are artifacts attributable to chance and other factors unrelated to SLE is still not known. In the predisposed subject, each of the three broad groups of environmental agents, namely, physical, chemical, and biologic, has been associated with SLE. The relationship of the disorder to physical agents such as ultraviolet radiation and trauma has been well documented in past clinical experiences. The association of SLE and chemical agents described in early clinical reports on inducing factors has been strengthened by many studies on procainamide, hydralazine, and other drugs responsible for an increased frequency of drug-induced SLE. Interest in the role of biological agents has been renewed by reports on increased antibody levels for paramyxovirus and other viral antigens in affected patients, and the detection of cellular inclusions resembling paramyxoviruses in cases of SLE and other disorders. Whether these widespread findings in man are coincidental manifestations of SLE or evidence of persistent virus infections that may be responsible for the disease has not yet been ascertained. In animals, however, support for the role of viral and genetic factors in the pathogenesis of SLE has been well documented in the susceptibility of inbred NZB/NZW mice to SLE-like disorders, and the identification of a virus-like agent in the affected NZB mice. In susceptible dogs, also, SLE-like manifestations appear to be due to genetic and nongenetic factors, presumably of viral origin.

The epidemiology of systemic lupus erythematosus: Preliminary results in New York City

Abstract 1. 1. The present report describes the preliminary results of a long-term epidemiological investigation on the extent and trend of systemic lupus erythematosus (SLE) in the general population and on the abnormalities in family members of affected individuals. 2. 2. According to the data obtained in a defined area of New York City from 1951 to 1959, inclusive, there was no evidence of an increase in the incidence of the disease in recent years. However, there was evidence of an increase in prevalence which was attributable to better recognition of the disease and improved medical care. 3. 3. Racial differences were observed in the occurrence of systemic lupus erythematosus which are of epidemiological significance. Morbidity and mortality rates were highest in non-white females from 15 to 54 years of age. 4. 4. Certain serological and physical abnormalities related to systemic lupus erythematosus appeared to be more frequent in family members of patients with systemic lupus erythematosus than in matched relatives of patients with non-collagen diseases. The relation of these differences to genetic and environmental factors is under investigation.

ANTIBODY PRODUCTION IN RHEUMATIC DISEASES. THE EFFECT OF BRUCELLA ANTIGEN

The possibility that a disordered immune response is related to the development of the rheumatic diseases has been an attractive hypothesis for investigation for years. Several investigators have attempted to demonstrate quantitative differences in the immune response between patients with these diseases and control subjects when they were inoculated with various antigens. Rantz, Creger and Choy (1) challenged patients with rheumatic fever and rheumatoid arthritis by injecting isologous red blood cells intravenously, and by the inoculation of influenza A and B vaccine. The patients with rheumatic fever responded with an increased titer of isohemagglutinins and in increased titer of antibodies to influenza virus compared with the control groups. There was no difference in the immune response to these two antigens between the rheumatoid arthritic patients and control subjects. In a prospective study, Rejholec (2) administered brucella vaccine subcutaneously to a group of 900 children. A small group developed very high titers of brucella antibody, measured by the indirect Coombs technique. All the children were followed clinically and a very high percentage of the hyper-reactors were shown subsequently to develop rheumatic fever; indeed, the only cases of rheumatic fever appeared in this hyper-reactor group. Miller, Kibrick, and Massel (3), by using influenza virus and typhoid. 0 and H antigens, were unable to show hyperreactivity in a group of patients with rheumatic

Poliomyelitis in Pregnancy: Effect on Fetus and Newborn Infant.

Summary 1. A prospective study was made of the outcome of gestation following the occurrence of poliomyelitis in New York City from 1949 to 1953, inclusive. During this period eighty-seven pregnancies, which resulted in eighty-eight products of gestation, were investigated. Sixty-five fetuses were associated with paralytic poliomyelitis during gestation and twenty-three with nonparalytic poliomyelitis. 2. There was no evidence of an increase in congenital defects, and inconclusive evidence of an increase in prematurity. 3. Fetal deaths were observed in from 35 to 46 per cent of the pregnancies complicated by the onset of poliomyelitis in the first trimester of gestation. Most of these fetal deaths were delivered within two weeks of the onset of clinical infection, and appeared to be directly related to the occurrence of poliomyelitis in the mother. 4. An increase in the incidence of neonatal poliomyelitis was observed which was associated with paralytic maternal infection shortly before delivery. 5. An increase in the neonatal mortality rate was noted which was related to neonatal poliomyelitis and to anoxemia following post-mortem cesarean section in women dying of bulbar poliomyelitis.

EPIDEMIOLOGY OF SYSTEMIC LUPUS ERYTHEMATOSUS: TIME TREND AND RACIAL DIFFERENCES

DESPITE extensive clinical and immunological investigations in recent years, there is still little known about the etiology of systemic lupus erythematosus (SLE) .1,2 Clinical studies have revealed the strong predilection of the disease for females of childbearing age, the exacerbation of symptoms following excessive exposure to sun and use of chemotherapy, and the development of lupus-like syndromes after long-continued administration of such drugs as hydralazine, diphenylhydantoin, and isoniazid.23 Numerous other environmental conditions have been implicated from time to time, such as bacterial and viral infections, but the supportive data have been inconclusive.3 Evidence on the possible role of genetic factors has also been inadequate. Thus far the data have been limited to the occasional report of multiple cases in the same family, the random distribution of cases by birth order, the increased frequency of abnormal immunological reactions in patients and some of their family members, and the occurrence of the disease in agammaglobulinemia, a genetically determined condition.4-7 Our limited knowledge of the nature of systemic lupus erythematosus and its associated conditions has been obtained by clinical and laboratory studies largely based on the patient alone and, in some instances, on his family members. Such studies have been restricted by lack of knowledge of the general population of which the patient is part. The current investigation was, therefore, undertaken to see what additional information on causation could be obtained by a population study. The present report will describe the data thus far obtained on two aspects of the epidemiology of the disease: (1) the trend of morbidity and mortality rates from 1951 to 1960, inclusive, and (2) racial differences in occurrence during this ten-year period. The investigation was carried out in a defined area of Manhattan, east of Fifth Avenue, with a heterogeneous population of 725,000 and excellent medical facilities. Data on the residents in the area were obtained from census counts in 1950 and 1960. The intercensal population from 1951 to 1960 was estimated by arithmetic interpolation. The mid-period

Fetal mortality in maternal rubella

Abstract An increase in early fetal deaths and perinatal mortality was observed in a prospective study of 763 cases of maternal rubella in New York City from 1957 to 1964, inclusive. The increase appeared to be limited to cases with onset in the first trimester. Spontaneous fetal deaths accounted for 18.3 per cent of the total fetal loss following rubella. An additional 81.7 per cent were due to artificial termination of labor for therapeutic reasons. The combined fetal loss from spontaneous deaths and induced abortions was 73.6 per cent of cases reported in the first three months of gestation. There was no evidence of an increase in virulence of infection in the extensive epidemic of rubella in 1964 as measured by fetal mortality following maternal disease in recent years.

The changing pattern of rheumatic heart disease; the experience in New York City Department of Health cardiac consultation clinics, 1943 to 1953.

Summary 1. An analysis was made of the clinical diagnoses of 65,044 examinations by the Cardiac Consultation Service Clinics of the New York City Health Department from 1943 to 1953, inclusive, in order to determine whether there has been a change in the relative frequency of organic heart disease following rheumatic fever. 2. The relative frequency of detectable heart disease following a history of rheumatic fever in children referred to the consultation service decreased from about 60 per cent in 1943 to about 30 per cent in 1948. The 30 per cent frequency level has been maintained since 1948. 3. The foregoing findings are consistent with the decrease in prevalence of rheumatic heart disease reported from other source material by various investigators.

Unresolved issues in the first five years of the rubella immunization program

Despite extensive use of atttenuated rubella vaccine during the past five years, the degree of fetal risk in susceptible women inoculated early in pregnancy is still an unresolved issue. Although there is considerable evidence of chronic vaccine virus infection of the products of gestation in aborted fetuses, congenital defects have not yet been reported in the newborn infants of susceptible vaccinated pregnant women. The normal findings in the newborn infant can be misleading with respect to the safety of the vaccines in early pregnancy, because they represent only a small selected group of reported cases. The immediate need is for more complete reporting of all relevant cases wherever they occur in order to determine without many more years of delay whether the fetal risk has public health significance or is so low as to be of negligible importance.

Variations in Age Distribution of Poliomyelitis. Comparative Ratios of Younger and Older Age Groups.

Summary 1. The seasonal fluctuation in cases of poliomyelitis in New York City for those under 10 years of age and those over 10 years was examined from 1944 to 1952, inclusive. 2. Annual variations were observed in the seasonal occurrence of cases. The two age groups examined tended to conform to the pattern of incidence that prevailed in any given year. 3. The trend in the percentage distributionof cases by age and week of onset revealed differences between the two age groups considered. In the younger age group it decreased to a low point in the thirty-fifth week and then increased. In the older age group the reverse trend was noted. 4. The use of a decrease in reported cases of poliomyelitis in young age groups following administration of gamma globulin as a gauge of its effectiveness should be made with caution.