The epidemiology of systemic sclerosis (scleroderma) among male U.S. veterans

J Chron Dis Vol. 31, pp. 7385

0021-9681/78/0201-0073$02.00/O

0 Pergamon Press Ltd. 1978. Printed in Great Britain

THE

EPIDEMIOLOGY OF SYSTEMIC SCLEROSIS (SCLERODERMA) AMONG MALE U.S. VETERANS THOMAS A. MEDSGER, JR., and ALFONSE T. MASI *University of Pittsburgh, Pittsburgh, PA, U.S.A. tuniversity of Tennessee, Memphis, TN, U.S.A. (Received

in revised form May 1977)

Abstract-A

comprehensive VA hospital survey of U.S. male veterans diagnosed scleroderma during 1963-1968 was completed and led to the following conclusions: (1) The average annual incidence rate of cases newly diagnosed in a VA hospital was 2.3 per million male veterans. (2) Incidence rates increased with age, peaked in the 45-54yr age group for both Whites and Non-Whites and plateaued thereafter. The pattern of mortality rates closely paralleled the incidence rates and peaked in the 5564 and 65 + age groups for Whites and Non-Whites, respectively. (3) Without adjusting for hospital utilization, the Non-White incidence and mortality rates were significantly greater than those of Whites by age, region and in total. However, when adjustments were made for VA hospital utilization, using a 0.1% sample of patients with other diagnoses, no significant difference was found by race in relative proportions of scleroderma patient discharges compared to all other patient discharges. (4) The highest scleroderma incidence and mortality was found in the East South Central and South Atlantic regions. After adjustment for hospital utilization, or control patient deaths, a significantly higher relative frequency of White male scleroderma cases, but not deaths, was observed. (5) Scleroderma cases did not differ from hospitalized VA control patient samples in regard to urban or rural residence location, smoking habits, or frequency of simultaneously diagnosed malignancy. Patients were significantly more often married, heavier alcohol consumers, and employed as laborers or other lessskilled occupations. The importance of these personal findings is uncertain at present. Considering these results, scleroderma appears to be a disease of increasing incidence and mortality with age, and of relatively uniform incidence and mortality by race throughout the major geographic regions of U.S.A., with the possible exception of the southeast section of the country. The observed incidence and mortality rates in male veterans were comparable to frequencies in males as reported in several published community studies. The consistent age-specific patterns of incidence and mortality, as well as likeness of race and residence, suggest the importance of host rather than geographic environmental factors in scleroderma pathogenesis. Predisposition to, or acquisition of, this disease may be modified by certain personal factors related to marital status, alcohol use and occupation, but the differences found and explanation of their biologic significance require further study.

INTRODUCTION

Few epidemiologic studies of the rare connective tissue diseases, including systemic lupus erythematosus, systemic sclerosis (scleroderma), polymyositisdermatomyositis or polyarteritis syndromes, have been reported from this country and these were conducted in limited geographical areas [l-6]. Except for Cobb’s summary of mortality from connective tissue diseases for 1959-1961, no nationwide assessment of incidence or mortality From the Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA and the Department of Medicine, University of Tennessee College of Medicine, Memphis, TN. Dr. Medsger was a Research Associate in the VA Career Development Program and was located at the Memphis VA Hospital during the data collection phase of this study. Requests for reprints should be addressed to: Thomas A. Medsger, jr., M.D., Department of Medicine, 985 Scaife Hall. Universitv of Pittsburgh School of Medicine. Pittsburgh. I PA 15261. Current titles and addresses: *Associate Professor of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A. tProfessor of Medicine and Director, Division of Connective Tissue Diseases, University of Tennessee College of Medicine, Memphis, TN, U.S.A. 73

Thomas

A. Medsger

and Alfonse

T. Masi

TABLE ~.SCORING SYSTEMFOR RETROSPECTIVE CLINICAL CLASSIFICATIONOF PATIENTS WITH SYSTEMIC SCLEROSIS (SCLERODERMA)

3 Points

each:

Acrosclerosis Gastrointestinal involvement* Pulmonary, cardiac or renal involvement* Sclerodactyly alone Sclerodermatous skin changes on trunk Raynaud’s phenomenon Articular or muscular involvement*

2 Points each: 1 Point each:

Patient’s classification

Required points

Definite

7+

Probable

5 or 6

Possible

3 or 4

*Involvements

typical

of scleroderma

Example

of involvements

Point score I

Acrosclerosis, gastrointestinal and Raynaud’s and Acrosclerosis, pulmonary Raynaud’s and Pulmonary, sclerodactyly Raynaud’s and not attributable

to other

6 4

diseases.

has been reported for these disorders in U.S.A. [7]. The purpose of this study is to describe epidemiologic features of scleroderma among male U.S. veterans diagnosed within the Veterans Administration (VA) hospital system in order to provide a national perspective of this disorder which would not be evident from single community studies. Furthermore, it is our intent to compare the epidemiologic patterns of occurrence observed among veterans with those previously reported for scleroderma [3,4].

MATERIALS

AND

METHODS

(a) Scleroderma case detection. The VA inpatient discharge data system (IDDS) was used to identify all patients discharged during the study period of 1963-1968 with a diagnosis of scleroderma, diffuse scleroderma, systemic sclerosis or progressive systemic sclerosis in the rubric 710.0 of the 7th revision of the International Classification of Diseases, Adapted (ICDA). All available hospital medical records of scleroderma patients discharged from VA hospitals in the continental U.S. during this time interval were reviewed and only those individuals who met specified criteria for disease were included for analysis. (b) Diagnostic classijication. Eight organ system involvements of scleroderma, detectable ante-mortem, were considered in the diagnostic classification as described in our previous community study [3]. Using combinations of organ system involvements, we developed a scoring system and minimal criteria for classifying patients as definite, probable, or possible scleroderma (Table 1). Because of their relative specificity for the diagnosis of scleroderma, the classical findings of acrosclerosis (i.e. sclerodermatous skin changes extending proximally beyond the digits onto the limbs) and typical gastrointestinal involvement (e.g. abnormal distal esophageal peristalsis) each received the most points in this scoring system. Clinical and laboratory abnormalities were attributed to scleroderma only if the specified changes occurred in the absence of other possible contributing diseases or mechanisms. Regardless of classification, in all cases accepted in the study, scleroderma was considered by the investigators as the most likely clinical diagnosis. Patients were excluded if they had: (1) one of the other connective tissue diseases as the primary diagnosis even though criteria for scleroderma were met, (2) sclerodactyly (sclerodermatous skin change limited to digits) and Raynaud’s phenomenon only, or (3) morphea or other localized forms of scleroderma only. The clinical records of all accepted patients were abstracted on detailed pre-coded forms, including all VA admissions related to scleroderma or its complications.

The Epidemiology of Systemic Sclerosis

75

(c) Veteran population denominators. Publications of the VA Research Statistics Service [S] and special tabulations allow the estimation of total numbers of male veterans (combined Whites and Non-Whites) in civil life eligible for VA hospital benefits, by age and state of residence for each year of the study. However, no data are available on the race- and age-specific distribution of male veterans by state except in the U.S. Decennial Censuses. VA estimates of total living veterans in the U.S. varied slightly and within 3% from 1960 to June 30, 1965 (21.9million). However, within the next year (June 30, 1966), the veteran population increased by 16% (to 25.4 million), but then changed less than 2% through 1970. The sharp increment occurred exactly during the middle 12 months of the study period. Since age- and race-specific veteran population data are available by individual states only in the U.S. Decennial Censuses [9], instead of the VA estimates we used these sources to derive veteran denominators. Although the interval mid-point of the 1960 and 1970 Decennial Censuses (4/l/65) is not the exact mid-point of the study interval (l/1/66), the abrupt non-linear increase of veterans during the study interval did actually center within the middle 12 months of the study period (from 7/l/65 to 6/30/66). Thus, mid-point male veteran population denominators were derived by linear extrapolation (i.e. by averaging the 1960 and 1970 Census data) by age, race, state, region and U.S. total. Person-year denominators for the 19631968 study interval were derived by multiplying the latter averages by 6, i.e. the number of years in the study interval. (d) Incidence and mortality rates by age, race and geographical areas. The entry date of a patient into study was the time that scleroderma was Jirst diagnosed on discharge from a VA hospital, although the diagnosis may have been made earlier in another setting. Using only patients so diagnosed within the study period (19631968), average annual incidence rates of VA hospital diagnosed scleroderma were computed per million male veterans. For total cases, as well as for Whites and Non-Whites separately, age-specific rates were calculated for: the total U.S., each state according to residence of patients at the time of entry to study; and 9 standard geographical regions. In a fashion similar to incidence, average annual mortality rates with scleroderma were computed as deaths per million veterans. For these calculations, the numerator was deaths (either within or outside VA hospitals) among all patients ever diagnosed scleroderma (alive or deceased) in a VA hospital during 1963-1968. (e) VA hospitalized control patient sample. In order to evaluate possible differences in VA hospital utilization by race and state or region of residence, a 0.1% random sample of all 1963-1968 male VA dhospital discharges, excluding scleroderma, was obtained. Available information on patients in the control sample included race, yr of birth, date of discharge from hospital, location of residence, marital status, bed section, and both primary and secondary diagnoses. This sample included a total of 3354 discharges, of which only males discharged from medical bed sections were analyzed further since the great majority of scleroderma patients were also discharged from these sections. In order to match the patient group, controls residing outside of the continental U.S. were excluded. The 1763 male discharges from medical bed sections were contributed by 1259 veterans; 962 had a single VA discharge and 297 had multiple discharges during the study period. All male scleroderma cases discharged from medical bed sections during the same interval were compared with. this 0.1% control sample of VA patients discharged with other diagnoses. (f) Statistical methods. The person-years method was used to calculate total male, race- and age-specific average annual scleroderma incidence (i.e. the average annual rate of Jirst VA hospital discharge diagnosis of scleroderma) and mortality rates per million male veterans in civil life for the U.S. and its geographic regions during the study interval. Differences between observed and expected numbers of patients by age, race, or geographical areas were tested using the Chi-square method with Yates’ correction when applicable. Two-tailed probability levels of statistical significance were used in testing the null hypothesis.

76

Thomas

A. Medsger

and Alfonse

T. Masi

TABLE 2. SCLERODERMA CASES AND AVERAGE ANNUAL INCIDENCE RATES PER MILLION MALE VETERANS BY RACE AND AGE AT TIME OF FIRST VA HOSPITAL DIAGNOSIS, 1963-1968

Age at first VA diagnosis <2s 25-34 35-44 45-54 55-64 65+ Total

Whites Cases Rates 2 20 68 105 41 31 213

0.2 0.6 1.6 3.5 3.2 3.5 1.9

Non-Whites Cases Rates 0 5 32 30 8 9 84

0.0 1.8 8.6 11.5 8.4 10.8 7.1

Totals Cases Rates 2 25 100 135 49 46 351

0.2 0.7 2.1 4.1 3.6 4.1 2.3

RESULTS

(a) Morbidity Scleroderma cases and incidence by age and race. During 1963-1968, 593 males were discharged from a VA hospital with a diagnosis of scleroderma, diffuse scleroderma, systemic sclerosis or progressive systemic sclerosis. Using the specified diagnostic classification, 504 (85%) were accepted for study. Of the 89 excluded, 45 did not meet the diagnostic criteria, 23 had localized scleroderma, 11 were felt to have scleredema, 3 had scleroderma associated with porphyria, and 7 had miscellaneous unrelated disorders. No attempt was made to search for cases of scleroderma that may have been discharged with other diagnoses. Among the 504 scleroderma patients, 357 were diagnosed for the first time in a VA hospital during the study interval (1963-1968), and only this group was used for incidence analyses. The number of new cases diagnosed each yr was relatively constant over the study period. At the time of entry of these 357 patients, 188 were classified dejinite, 83 probable, and 86 possible. At last clinical evaluation in 1970, after a mean followup or survivorship of 2.6 yr, the last or only (entry) classification was 224 definite, 75 probable, and 58 possible cases. In no case did a rehospitalized patient show regression of &ssihcation to a less definite class. Although in a few instances, the severity of Raynaud’s phenomenon, cutaneous or articular involvement was noted to be diminished, no patient had objective evidence of improvement in gastrointestinal, pulmonary (except pleuritis), cardiac (except pericarditis) or renal manifestations once these involvements were documented. The median interval from onset of first symptoms attributable to scleroderma until the initial VA diagnosis was 18 months, ranging from 1 month to over 15 yr. The very long intervals were usually seen in patients whose Raynaud’s phenomenon antedated other clinical findings. The distribution of these intervals did not differ significantly by diagnostic classification, age or race subgroups. Additional clinical features noted in these cases first diagnosed in the study interval and their influence on survival are described elsewhere [ 133. The age and race distribution of the 357 VA scleroderma patients at the time of entry to study is given in Table 2. The age distribution is unimodal, reaching 135 total patients between ages 45-54. Non-Whites had an earlier median entry age (46.7 yr) than Whites (49.6 yr), but the difference is not significant. Only two (0.6%) had scleroderma diagnosed before age 25 and the decade 25-34 yr had only 25 (7.0%) cases. Whites (273) predominated over Non-Whites (84) in a ratio of 3.25:1. Included among the Non-Whites were 79 Blacks, 4 American Indians, and 1 Filipino. The total average annual incidence of VA hospital diagnosed scleroderma cases was 2.3 per million male veterans (Table 2). The rate increased with age, reached its highest in the 45-54yr age group and plateaued thereafter. At all ages, Non-Whites had almost 3-fold or greater rates than Whites; the overall difference by race was statistically significant (P < 0.01). A distinct paucity of scleroderma cases was diagnosed before age 35,

77

The Epidemiology of Systemic Sclerosis TAEILE3.

SCLERODERMA CASES AND AVERAGR+NNUAL INCIDENCE RATES* PER MILLION MALE VETERANS BY REGION OF RESIDENCE AND RACE, 19621968

Geographic region of residence at entry New England Middle Atlantic East North Central West North Central East South Central South Atlantic West South Central Mountain Pacific Total

Whites Cases Rates* 16 36 41 22 34 65 22 13 24 273

1.7 1.3 1.4 1.8 4.7 3.6 1.8 2.2 1.2 1.9

Non-Whites Cases Rates* 1 8 19 4 8 22 10 0 12 84

4.9 3.5 8.6 9.1 1.6 7.8 7.5 9.4 7.1

Totals Cases Rates* :: 60 26 42 87 32 13 36 357

1.8 1.4 2.0 2.1 5.0 4.1 2.4 2.2 1.8 2.3

*Regional incidence rates age-adjusted to total U.S. Veterans, 1960 and 1970 Census mid-point population.

which applied to both Whites and Non-Whites; the difference is highly significant (P < 0.001) when compared with all other ages combined. Scleroderma cases and incidence by region and race. The VA hospital average annual incidence rates, i.e. discharge rates of newly diagnosed scleroderma cases, were highest for residents of Arkansas (9.6), District of Columbia (7.8), North Carolina (7.3), Mississippi (6.2), Virginia (5.3), and Tennessee (4.5). When the cases were grouped according to residence by standard geographical regions, significant (P < 0.001) heterogeneity was found in rates for Whites and total cases, but not for Non-Whites (Table 3). The East South Central and South Atlantic states showed the highest rates due to their relative excess of White cases. When compared with all other areas, these two regions combined showed a considerably higher rate (P < 0.001); this difference was statistically significant for total cases and especially for Whites, but not for Non-Whites. Age-adjustment resulted in minimal changes due to the similarity in age distributions of Whites and Non-Whites within and between regions. However, since these data may be influenced by differential rates of VA hospital utilization between regions and by race, relative frequencies of scleroderma case admissions were also calculated. The denominator for these calculations was control patients discharged from medical bed sections in the 0.1% random sample and the numerator was scleroderma patients discharged from medical bed sections. Relative frequency of scleroderma to other VA hospital patients by region. Since it was not known which of the control sample patients had a first as opposed to readmission diagnosis within the study interval, all 1259 control patients were compared with all scleroderma patients discharged from medical bed sections during the same study period. Thus, scleroderma patients first diagnosed before 1963 in a VA hospital but readmitted and discharged from a medical bed section during 1963-1968 (113) were added to the scleroderma patients first diagnosed and discharged from a medical bed section during the study interval (320). This total of 433 scleroderma patients provided the case (numerator) data for comparison on age, race, and region of residence with the 1259 control (denominator) patients from the 0.1% sample described above. As a control measure of VA hospital utilization, the 6 yr interval rate of patients discharged from a medical bed section with any diagnosis, excluding scleroderma, was determined by region for Whites and Non-Whites, separately and combined (Table 4). During 1963-1968, the average national VA hospital utilization by Non-Whites (117.2 patients per 1000 veterans) was 2.7 times as high as the utilization by Whites (43.6). Also, utilization by Non-Whites (P < 0.05) and especially by Whites (P < 0.001) differed significantly over all regions. Thus, it was necessary to consider VA hospital utilization by race and region in comparing racial and regional scleroderma frequencies. The overall ratio of scleroderma cases per 10,000 other patients discharged from VA hospitals during the study interval did not differ significantly for Whites (3.27)

78

Thomas

A. Medsger

and Alfonse

T. Masi

TABLE 4. REGIONAL AND RACIAL FREQUENCIES OF MALE VA SCLERODERMA CASES AND CONTROL PATIENTS jxsCHARGED FROM A VA HOSPITAL MEDICAL SECTION BED (1963-1968),CONTROL PATIENT DISCHARGE RATES AND RATIO OF SCLERODERMA TO 10,~o CONTROL PATIENTS"

Whites Regions N England M Atlantic EN Central WN Central ES Central S Atlantic WS Central Mountain Pacific Total

Cases

Controls*

22 46 52 26 43 79 24 15 29 336

73 (45.9) 146 (31.5) 145 (30.4) 1 I1 (55.5) 7X (63.2) 135 (44.1) 132 (65.3) 75 (75.4) 132 (41.2) 1027 (43.6)

Totals

Non-Whites Ratiot 3.0 3.2 3.6 2.3 5.5 5.9 1.8 2.0 2.2 3.3

Cases 1 9 23 5 I2 23 11 0 13 97

Controls* 7 (197.4) 26 (68.7) 42 (110.8) 9 (120.1) 22 (133.1) 66 (143.8) 43 (188.3) 2 (61.4) 15 (66.5) 232 (117.2)

*Number of control patients in 0.1% sample and control 196331968 (shown in parentheses). tRatio of scleroderma cases to 10,000 patients discharged

patient

Ratio?

Cases

1.4 3.5 5.5 5.6 5.5 3.5 2.6

23 55 75 31 55 102 35 15 42 433

8.7 4.2 discharge

rates

Controls* 80 172 187 120 100 201 175 77 147 1259

(49.1) (34.1) (36.4) (57.8) (71.6) (57.1) (77.8) (74.9) (42.8) (49.3)

per 1000 veterans

Ratio 2.9 3.2 4.0 2.6 5.5 5.1 2.0 1.9 2.9 3.2 during

with other diagnoses.

and Non-Whites (4.18) (Table 4) as contrasted with the previously described scleroderma incidence rates (Table 3) for Whites (1.9) and Non-Whites (7.1). Furthermore, the ratios of scleroderma to control patients between Whites and Non-Whites were not different in any region except for a highly significant(P < 0.001) excess of Non-White scleroderma cases in the Pacific region (13 observed vs 4.4 expected). The reason for this unusual concentration of Non-White cases was not evident after detailed scrutiny. In the East South Central and South Atlantic regions, a significantly greater number (P < 0.001) of White cases was observed (122) compared to expected (70.3) based on the distribution of White scleroderma and control patients nationally. The ratio of scleroderma to 10,000 control patients in these two regions was 5.5 and 5.9 respectively among Whites as compared to 2.6 in all other regions combined. Whether this impressive difference represents a truly higher scleroderma occurrence among White males in these regions or a preferential utilization of VA hospitals by white scleroderma patients is not known. Relative frequency of scleroderma to other VA hospital patients by age. In analyzing VA hospital utilization for control diagnoses by age, in a manner analogous to region of residence at entry, both Whites and Non-Whites showed increasing utilization with age (Table 5). In each age group, Non-Whites again showed greater utilization than Whites. The ratios of scleroderma to 10,000 other (control) patients were rather similar by age groups for Whites and Non-Whites with no significant differences found. From

TABLE 5. AGE AND RACE FREQUENCIES OF MALE VA SCLERODERMA CASES AND CONTROL PATIENTS DISCHARGED FROM A VA HOSPITAL MEDICAL BED SECTION (1963-1968),CONTROL PATIENT DISCHARGE RATES AND RATIO OF SCLERODERMA TO lo,o()oCONTROL PATIENTS

Whites

Age

Totals

Non-Whites

Groups

Cases

Controls*

Ratio?

Cases

<25 25-34 3544 45-54 55-64 65+ Total

2: 92 134 45 42 336

17 (10.1) 41 (7.1) 188 (26.3) 279 (54.8) 133 (62.9) 369 (209.1) 1027 (43.6)

0.6 5.4 4.9 4.8 3.4 1.1 3.3

0 7 39 32 8 11 97

Controls* 6 19 62 60 29 56 232

*Number of control patients in 0.1% sample and control 1963-1968 shown in parentheses. tRatio of scleroderma cases to 10,000 patients discharged

(39.5) (40.1) (99.9) (138.3) (183.5) (402.9) (117.2) patient

Ratio?

Cases

Controls*

Ratio?

3.7 6.3 5.3 2.8 2.0 4.2

1 29 131 166 53 53 433

23 (12.5) 60 (9.7) 250 (32.2) 339 (61.4) 162 (71.3) 425 (223.1) 1259 (49.3)

0.4 4.8 5.2 4.9 3.3 1.2 3.4

discharge

with other

rates

diagnoses,

per 1000 veterans

during

The Epidemiology of Systemic Sclerosis

19

age 25 to 54 approximately 5 scleroderma patients in each race were discharged per 10,000 control patients discharged’during the study interval. The ratio decreased significantly in older ages; it is not known whether this decrease reflects a lesser scleroderma occurrence or a relatively greater increase in other disorders causing hospitalization in the older ages. Malignancies diagnosed in scleroderma and control patients. Including all 504 scleroderma cases identified in this survey, 18 (3.6%) had malignant neoplasms diagnosed in VA hospitals during the 1963-1968 study interval. Of the 433 scleroderma patients diagnosed on a medical bed section, 12 (2.8%) were simultaneously diagnosed during their initial admission as having a malignancy. In comparison, 61 (4.8%) of the 1259 controls from the 0.1% sample had a malignancy as the primary diagnosis during their earliest medical bed section admission in the study interval. This difference is not statistically significant. The distribution of primary malignancy sites in scleroderma showed no impressive difference between cases and controls. Included among the scleroderma associated malignancies were adenocarcinoma of the prostate (4 cases), multiple myeloma (2 cases) and single instances of Hodgkin’s disease, malignant lymphoma, basal cell carcinoma of the skin, and adenocarcinoma of the tongue, larynx and lung. In 10 of 12 (83%) of the cases, symptoms of scleroderma began more than 1 yr prior to the clinical features of the tumor, while in the remaining 2, the disorders occurred within 1 yr of each other. Personal and environmental factors related to scleroderma cases Urban-rural residence. Medical bed section scleroderma patients and controls were divided into urban or rural geographic location of residence at the time of their earliest VA diagnosis within the study period, All patients living within a standard metropolitan area (SMA) according to the 1960 and 1970 U.S. Censuses were considered to have an urban residence, while all others were considered to reside in rural areas [9]; 164 (37.9%) of the 433 scleroderma patients were considered rural compared with 449 (35.7%) of 1259 medical bed section controls. This difference between patients and controls is not significant. Marital status. Marital status at the earliest medical bed section admission during the study interval was available for all 433 scleroderma patients and for 1258 controls. These distributions were also compared in Table 6 with another male VA hospital national control sample previously published [lo]. Significantly more scleroderma patients were married than either control group (P < O.Ol), which was due to significantly (P < 0.001) fewer scleroderma patients in the widowers group. These marital differences were found primarily in Whites between ages 35-54, and were not attributed to age differences between scleroderma patients and controls, since the scleroderma TABLE 6. PER CENT FREQUENCY OF MARITAL STATUS OF MALE VA SCLERODERMA* AND CONTROL PAYIENTSt DISCHARGED FROM A MEDICAL BED SECTION (1963-1968) AND OF A MALE VA HOSPITAL CONTROLS SAMPLE (1959-1961) MATCHED TO CANCER PATIENTS

Marital status Single Married Separated Divorced Widowed Total

Random controls

Whites Scleroderma

Cancer controls

Random controls

Non-Whites ScleroCancer derma controls

Random controls

Totals Scleroderma

Cancer controls

(N = 1026) (N = 338) (N = 622) (N = 232) (A’= 95) (N = 84) (N = 1258) (N = 433)(N = 706) 13.8 14.8 12.7 15.0 11.3 11.9 14.0 14.5 12.6 62.2 74.1 67.7 57.9 67.3 63.1 61.6 72.4 67.1 3.1 2.4 1.9 6.9 7.8 3.6 3.8 3.3 2.1 7.9 7.5 8.4 9.0 8.7 6.0 8.0 7.8 8.1 13.0 1.2 9.3 11.2 4.9 15.4 12.6 2.0 10.1 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0

*Scleroderma patient marital status frequencies were age-adjusted by race group to the random controls. tRandom 0.1% VA hospitalized control patient sample. SNational sample of VA hospital controls, matched to cancer patients, from reference 10.

80

Thomas A. Medsger and Alfonse T. Masi

TABLET.PERCENTDISTREWTIONBYOCCUPATIONAL AND OF A MALE VA HOSPITAL CONTROL Occupational categories

Professional and managerial Clerical Sales Crafts Operations Service Labor Farm Unemployed Not specified

Whites Controls Scleroderma

CATEGORIESOFMALE VA SCLERODERMAPATIENTS (1963-1968) SAMPLE (1959-1961) MATCHED TO CANCER PATIENTS*

Non-Whites Controls Scleroderma

Totals Controls Scleroderma

(N = 382)

(N = 622)

(N = 107)

(N = 84)

(N = 489)

(N = 706)

5.2 3.1 5.2 11.3 9.2 9.9 38.7 11.0 2.1 4.2

10.9 5.5 6.1 27.0 13.7 12.7 10.1 4.5 4.2 5.3

2.8 0.0 1.0 8.4 10.3 16.8 43.9 7.5 1.9 7.8

8.3 2.4 0.0 11.9 14.3 20.2 22.6 8.3 9.5 2.4

4.7 2.5 4.3 10.6 9.4 11.5 39.9 10.2 2.0 4.9

10.6 5.1 5.4 25.2 13.7 13.6 11.6 5.0 4.8 5.0

*Keller, A. Z., reference 10.

distributions are age-adjusted to the random control population. For example, in the 45-54 year group, only 1 (0.75%) of 133 cases was widowed compared to 50 (17.9%) of 279 controls. Younger (< 55 years) White scleroderma patients had a higher proportion of divorces than controls, whereas older (65+ yr) cases had a lower proportion of divorces. Among cases no significant racial difference was detected in marital status. Smoking habits. Scleroderma cases were compared to a VA control patient sample on their recorded smoking and alcohol consumption habits. Control data were obtained from New York City VA hospital patients in two independent studies by Keller [ll, 121. Among patients with specified smoking histories, no difference was found between cases and controls in the proportion of non-smokers or of smokers of varying quantities, among all ages combined. Alcohol consumption. Significant differences were found in alcohol consumption between scleroderma patients and Keller’s control samples. Scleroderma patients had a higher proportion of moderate (1+ ounces whiskey/day) consumption (54%) than controls (44%), and a higher proportion of heavy (4 + ounces whiskey/day) consumption (29%) than controls (22%) (P < 0.001 and P < 0.05, respectively). Because the control group was limited to veterans hospitalized in New York City, we compared it also to all scleroderma patients with urban residence location and found an identical significant excess of heavier alcohol consumption (4+ ounces whiskey/day) among our scleroderma patients. Unfortunately, no national control data were available describing the smoking and drinking habits of hospitalized male veterans. Occupation. Comparisons were made between the occupations of all scleroderma patients and a national sample of VA controls published by Keller [lo]. As in our study, occupation was determined by careful review of the medical records. In this analysis (Table 7) the case number is 489 (433 medical bed section scleroderma patients plus 56 scleroderma patients first diagnosed on other bed sections). Significant case-control differences were found in the distribution of occupations among Whites (P -C 0,001) and Non-Whites (P < 0.02). More White and Non-White laborers were found among scleroderma cases than controls (P < 0.001) and this difference persisted when analysis was done excluding the East South Central and South Atlantic regions which were over-represented in the scleroderma series. Except for an increased proportion of farmers in the East South Central and South Atlantic regions, no significant difference in distribution of occupations was found among scleroderma cases in comparing these two geographical regions with all others combined. Among Whites, craftsmen (P < 0.001) and professional-managerial workers (P < 0.005) were more frequent among control than among scleroderma patients. The reasons for these findings are not known at present, but male VA scleroderma patients seem to belong to a less-skilled work group.

The Epidemiology of Systemic Sclerosis

81

TABLE 8. DEATHS AMONG VA HOSPITAL DIAGNOSED MALE SCLERODERMA PATIENTSAND AVERAGE ANNUALMORTALITYRATESPERMILLION VETERANS

(1963-1968)

BY AGE AND RACE AND U.S. MALE MORTALITY PROM SCLBRO-

(19591961)*

DERMA

Age <25 2534 3544 4>54 55-64 65+ All ages

Whites Deaths Rates 1 9 33 61 34 37 175

0.3 0.4 0.7 1.8 3.7 3.0 1.4

Non-Whites Deaths Rates 0 1 15 20 6 8 50

0.0 0.5 3.7 6.8 8.3 8.6 4.6

Totals Deaths Rates 1 10 48 81 40 45 22.5

0.3 0.4 0.9 2.1 4.0 3.4 1.6

U.S.* Rates 0.0 0.3 1.4 2.6 3.3 3.0 1.6t

*Reference 7. tAl1 ages U.S. male rate age-adjusted to veterans population distribution.

(b) Mortality Scleroderma deaths and mortality rates by age and race. Among all 504 male patients with a VA hospital discharge diagnosis (alive or deceased) of scleroderma during 1963-1968, 225 (45%) had died during that same time interval, either within or outside of VA hospitals. As shown in Table 8, deaths among these cases occurred in a White (175) to Non-White (50) ratio of 3.1:1 which is quite similar to the previously determined 3.3:1 incidence ratio of newly diagnosed cases (Table 3). The greatest number of deaths occurred between ages 45 and 54. The frequencies among veterans were not adjusted for hospital utilization. The all-ages average annual mortality with scleroderma was 1.6 per million male veterans. Similar to incidence, mortality increased with age, peaked at ages 55-64 and declined slightly thereafter. The rate for Non-Whites was significantly greater than for Whites (P -L O.Ol), exactly paralleling the relative differences in incidence rates by race. Table 8 also shows that the overall age pattern of mortality of male veterans with scleroderma is similar to that published by Cobb for all U.S. males during the yr 1959-1961 [7]. Scleroderma case deaths and mortality rates by region. Table 9 shows the distribution of the 225 deceased male veteran scleroderma patients and mortality rates by geographic regions. No significant discrepancies in pattern were found between these mortality rates and the previously calculated incidence rates (Table 3). The East South Central and South Atlantic States again show the highest rates per million male veterans, due mainly to the relatively increased mortality among Whites. Using the life table method, survival did not differ significantly according to region among the male veteran patients first diagnosed in a VA hospital during the study interval [13]. Regional scleroderma mortality rates derived by Cobb [7] for 1959-1961 TABLE 9. DEATHS AMONG VA HOSPITAL DIAGNOSED MALE SCLERODERMA PATIENTS AND AVERAGE ANNUAL MORTALITY RATES PER MILLION VETERANS (1963-1968) BY GEOGRAPHIC REGlONS AND RACE

Regions New England Middle Atlantic East North Central West North Central East South Central South Atlantic West South Central Mountain Pacific Total

Whites Deaths Rates 7 22 31 15 23 39 15 9 14 175

0.8 0.8 1.1 1.4 3.5 2.4 1.4 1.7 0.8 1.3

Non-Whites Deaths Rates 1 5 11 2 5 15 6 0 5 50

5.3 2.8 6.2 5.6 4.3 5.1 4.2 0.0 4.8 4.6

Totals Rates Deaths 8 27 42 17 28 54 21 9 19 225

0.9 0.9 1.5 1.5 3.6 2.8 1.7 1.6 1.0 1.6

82

Thomas A. Medsger and Alfonse T. Masi

were not published separately regional variation in mortality.

for males, but the combined

sex rates showed little

Comparison of scleroderma and control deaths by age, race, and geographic

regions.

Of the 225 scleroderma deaths, 166 (64%) occurred in a VA hospital. These patients were compared with 26% control sample patients who died in VA hospitals during 1963-1968. A significantly greater proportion of scleroderma patients (60%) died below age 65 than controls (24%), a difference (P < 0.001) found for both Whites and NonWhites. Among Whites, a relatively greater number of cases than controls resided in the South Atlantic region, while relatively more Non-White scleroderma cases than controls had been residents of the East North Central states but neither difference was significant. These findings would tend to suggest that the previously described incidence differences by region reflect VA hospital utilization. As was found with the incidence of newly diagnosed scleroderma cases, the significant difference in mortality between Whites and Non-Whites disappeared when adjustment was made using control patient mortality, i.e. a measure of VA hospital utilization.

DISCUSSION

The many advantages of VA data for epidemiologic purposes have been previously noted [lO-161. However, by no means do all qualified veterans use VA hospitals for their inpatient needs, and certain selection factors, such. as income, residence location, and type or convenience of VA facility might influence utilization. Unfortunately, no estimate is available of the proportion of veterans admitted to a VA hospital at any time during their life. Based on our 0.1% control sample, approximately 2,500,OOOdifferent male veterans (or 11% of the total veteran population) were discharged from a VA hospital during the 6 yr period. Other potentials and limitations of hospital-acquired data for epidemiologic studies are recognized [17]. This study seems justified since no data have been reported on detailed national incidence patterns of scleroderma, a disease of unknown etiology which may have important epidemiologic features. In this study, scleroderma cases were classified as to reliability of diagnosis using a system similar to the one employed in a previous community survey of this disease [S]. The primary purpose of the diagnostic classification system is to allow consistency of diagnosis for such retrospective medical record analyses. More sensitive and specific criteria for clinical purposes may be developed using more specialized testing (e.g. pulmonary diffusing capacity) than is usually performed in general hospital evaluation. Using all male veterans as a denominator, the average annual incidence of scleroderma cases diagnosed for the first time in VA hospitals was 2.3 per million for the 1963-1968 period. In our community survey of hospital-diagnosed scleroderma patients in Shelby County, Tennessee, we found a nearly identical annual incidence of 2.4 new cases per million males during the same time period, although the latter data are based on a small number of patients [3]. Also, the age-specific scleroderma incidence in this male veteran population. parallels closely the incidence pattern observed in Shelby County males. In the latter population, a low incidence in the younger ages (< 35) and a generally increasing frequency with age was found, peaking in the 55-64 yr age group and declining somewhat thereafter [3]. Among male veterans, incidence peaked in an earlier decade (age 45-54) and remained stable thereafter. At age 65 or older, the incidence may either remain constant, for reasons unknown, or underdiagnosis may contribute to the slightly lower’ rates observed. Cobb’s age-specific national mortality rates for scleroderma in males parallel closely the observed veteran mortality rates [7]. However, it should be noted that the methods for ascertaining mortality rates in the two studies are entirely different. Cobb’s figures are based on death certificate diagnoses, which in our experience with scleroderma results primarily in underreporting (patients diagnosed during life but not so listed on death certificate) but does include some overreporting (incorrect diagnoses). Similarly,

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83

our method of basing diagnosis on clinical case analysis has limitations, especially underreporting (legitimate cases may fail to meet retrospective criteria). More importantly, many veterans utilize non-VA hospitals. Despite these reservations regarding their accuracy and comparability, we believe that the age-specific patterns of mortality are representative of the disease. The pattern of increasing scleroderma incidence with age is even more evident for females, and especially White females, who in Shelby County showed a continual increase through the 65+ age group [3]. In older patients with limited skin involvement from scleroderma, the diagnosis may be missed and systemic manifestations may be attributed to chronic disease processes other than scleroderma, e.g. idiopathic pulmonary fibrosis, congestive heart failure, etc., which increase with age. Despite the likelihood of missed diagnoses with aging, the incidence and mortality from scleroderma increased with age in this and several other population studies, a phenomenon of possible pathogenetic significance [3,4,7]. We have previously reiterated the importance of blood vessels as a target tissue in scleroderma, based partly on age-specific incidence patterns similar to those observed in certain degenerative vascular diseases [l&23]. In addition, the significant sparing of younger males and the marked female to male incidence ratio of approximately 1O:l during the childbearing yr may suggest that endocrine factors, either interacting with the vascular system, or separately, may also contribute to the disease process [3]. Although the ratio of scleroderma cases per 10,000 control VA discharges decreased in the older ages in this study, this trend is probably due to a greater relative increase with age of control diseases compared with scleroderma, and the relatively early death of scleroderma patients. The ratio of White to Non-White veteran scleroderma cases was 3.3: 1 which is significantly less than the 12: 1 ratio in the total male veteran population. On the surface, this finding and the race-specific incidence and mortality rates presented might indicate a greater predisposition to scleroderma of Non-Whites than Whites. However, if consideration is given to the significantly greater utilization of VA hospitals by Non-Whites within all but one geographic region, then the relative frequency of White to Non-White scleroderma cases is not different from expected. We used a VA 0.1% control patient sample as an indicator of hospital utilization in adjusting scleroderma incidence and mortality patterns by age, race and geographic region. With such adjustments, alternate interpretations of the frequency findings are possible. On the one hand, Non-Whites may have significantly greater morbidity and mortality than Whites from all causes, including scleroderma, to explain their higher VA hospital utilization and higher scleroderma incidence. On the other hand, NonWhites may not have significantly higher morbidity or mortality, but may utilize VA hospitals more frequently for all conditions, including scleroderma, because of socioeconomic or hospital availability reasons. Both circumstances may be true to some extent, and these possibilities have not yet been adequately explored. The available community studies on male scleroderma incidence suggest no difference by race, but the numbers of cases are small [3,4]. If scleroderma incidence is truly higher in Non-White than White males, the relative excess is probably of a low magnitude and further investigation will be needed to clarify this question. Similarly, the question of an increased relative frequency of scleroderma in White males residing in the East South Central and South Atlantic regions requires additional study because of the significant differences found in both incidence and ratio of scleroderma to control patients in these regions compared to all other regions in U.S.A. combined. VA mortality of White and Non-White males combined agree closely with age-specific national data reported by Cobb. The latter data were not specified separately by age and race, but for all ages showed a higher mortality for Non-White than White males, 2.1 vs 1.0 scleroderma deaths per million population, respectively, in 1959-1961. However, studies in Baltimore showed a slightly higher male mortality in Whites (1.3) than

CD. 31/Z--8

84

Thomas

A. Medsger

and Alfonse

T. Masi

Non-Whites (1.0) during the period 1949-1963 [4]. As with the incidence analyses, adjustment for hospital utilization using the 0.1% control patient sample eliminated any significant difference in mortality by race and also eliminated any significant mortality difference by region. An attempt was made to evaluate personal characteristics of scleroderma and control patients. Data on urban vs rural residence and marital status at entry to study were available as part of routinely coded VA hospital admission data and therefore could be compared in our scleroderma cases and control sample. Data on occupation, smoking and alcohol consumption habits are available only by review of the medical records as was done for the scleroderma patients. Control data on these variables were obtained from published studies by Keller [l&12], with whom one of the authors (ATM) had worked closely in the development of codes for variables compared. The finding of less widowed scleroderma cases than either set of controls could not be explained by differences in age distribution since this factor was adjusted for in the comparison. No explanation is evident for this marital status difference and further studies are necessary to confirm this observation. The increased use of alcohol by scleroderma patients may reflect differences in social status. The scleroderma patients were employed more frequently as laborers in comparison to published controls. Conceivably, dietary or other social or socio-economic factors may contribute to scleroderma pathogenesis. Again, these associations must be considered tentative and require further study for confirmation. Acknowledgements-We are grateful for the cooperation of the Veterans Administration Central Office Medical Record Section (Miss Margaret Kilduff and staff) for the identification of VA scleroderma patients and the 0.1% control sample. Mr. William Malloy of the VA Research Statistics Service supplied VA Annual Reports and other valuable veteran-specific statistical data used in the study. We appreciate the dedicated technical and secretarial help of Mrs.. Marilyn Jacobs and the assistance in coding-by Mrs. Mary G. Miller and Mrs. Maria Bordelon. Dr. John F. McCov. Southern Research Suooort Center. Little Rock VA Hosoital. performed life-table analyses by compute;.’ William E. Hanna, Jr.‘gnd Mrs. .&ice Truffer of the B&eau of Data Processing and Accounts, Social Security Administration, traced some of the patients we were unable to locate through VA records. Dr. Andrew Z. Keller provided valuable comments on the manuscript and advice regarding published control patient comparisons. This study was supported in part by grants from the RGK Foundation, the Miriam Davis Scleroderma Research Fund, the Western Pennsylvania Chapter of The Arthritis Foundation, the Scleroderma Society of the New York Chapter of The Arthritis Foundation and grants AM-12049 and AM-05055 of the National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland, U.S.A.

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7. 8. 9. 10. 11. 12. 13. 14.

Siegel M, Lee SL: The epidemiology of systemic lupus erythematosus. Semin Arth Rheum 3: l-54, 1973 Siegel M, Halley HL, Lee SL: Epidemiologic studies on systemic lupus erythematosus. Arth Rheum 13:802-811, 1970 Medsger TA Jr, Masi AT: The epidemiology of systemic sclerosis (scleroderma). Ann Intern Med 74: 714-721, 1971 Masi AT, D’Angelo WA: Epidemiology of fatal systemic sclerosis (diffuse scleroderma). Ann Intern Med 66:870-883, 1967 Medsger TA Jr, Dawson WN Jr, Masi AT: Epidemiology of polymyositis. Am J Med 48: 715-723, 1970 Kurland LT, Hauser WA, Ferguson RH, Holley KE: Epidemiologic features of diffuse connective tissue disorders in Rochester, MN 1951-1967, with special reference to systemic lupus erythematosus. Mayo Clin Proc 44:649-663, 1969 Cobb S: The Frequency of the Rheumatic Diseases. American Public Health Association Monograph. Cambridge, Harvard University Press, 1971 Veteran Population (June 1963-1968). Research Statistics Service, Office of the Controller, Vet Admin, Washington, D.C. U.S. Census Bureau Reports, 1960 and 1970 (Veterans) Keller AZ: Survivorship with mouth and pharynx cancers and their association with cirrhosis of the liver, marital status, and residence. Am J Pub Hlth 59: 1139-1153, 1969 Keller AZ: Cirrhosis of the liver, alcoholism and heavy smoking associated with cancer of the mouth and pharynx. Cancer 20: 1015-1022, 1967 Keller AZ, Terris M: The association of alcohol and tobacco with cancer of the mouth and pharynx. Am J Pabl Hlth & Nation’s Hlth 55: 1578-1585, 1965 Medsger TA Jr, Masi AT: Survival with scleroderma-2. A life-table analysis of clinical and demographic factors in 358 male U.S. veteran patients. J Chron Dis 26:647-660, 1973 DeBakey ME, Beebe GW: Medical follow-up studies on veterans. JAMA 182:1103-1109, 1962

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15. Beebe GW, Simon AH: Ascertainment of mortality in the U.S. veteran population. Am J Epidem 89:63M43, 1969 16. Keller AZ: Hypertension, age and residence in survival with subarachnoid hemorrhage. Am J Epidem 91: 139-147, 1970 17. Masi AT: Potential uses and limitations of hospital data in epidemiologic research. Am J Pub1 Hltb 55:658+567, 1965 18. Medsger TA Jr, Masi AT, Rodnan GP, Benedek TG, Robinson H: Survival with systemic sclerosis (scleroderma): A life-table analysis of demographic and clinical factors in 309 patients. Ann Intern Med 75:369-376, 1971 19. Norton WL, Nardo JM: Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med 73 :317-324, 1970 20. Hayner NS, Kjelsberg MO, Epstein FH, Francis T Jr: Carbohydrate tolerance and diabetes in a total community, Tecumseh, MI. Diabetes 14:413-423, 1965 21. Goldner JC, Payne GH, Watson FR, Parrish HM: Prognosis for survival after stroke. Am J Med Sci 253: 129-133, 1967 22. Peterson DR, Thompson DJ, Chinn N: Ischemic heart disease prognosis, a community-wide assessment (19661969). JAMA 219: 1423-1427, 1972 23. LeRoy EC, Campbell PM: Pathogenesis of systemic sclerosis; a vascular hypothesis. Semin Artb Rbeum 4:351-368, 1975