Survivorship and Death in Rheumatoid Arthritis Jarnal Uddin, Arthur S. Kraus and H. Garfield Kelly Data are presented on survivorship and causes of death of 475 patients with rheumatoid arthritis first seen between 1954 and 1966. The observed cumulative survival rate was lower than expected i n each sex at each year of follow-up, particularly in the later years. The adjusted rate was generally lower in males than in females. Eighteen of the 86 deaths due t o known causes were attributed to infection, a significantly excessive proportion. A number of studies are available on the course and prognosis of patients with rheumatoid arthritis, which deal particularly with factors affecting functional capacity and disability.1-6 Little has been written on longevity and causes of death. Both Duthie et a17 and VanDam et aP have compared death rates per thousand patient years of observation by sex and age without regard to the trend in mortality, year by year, following initial contact. Cobb et UP have graphed cumulative survival rates of a group of patients with both rheumatoid arthritis and ankylosing spondylitis from the time of onset of disease. This study presents data on survivorship and causes of death of 475 patients with probable, definite or classic rheumatoid arthritis (RA) , according to American Rheumatism Association criteria,lO from the time of their entry in the Queen’s University Rheumatic Diseases registry, between 1954 and 1966. Approximately one third of all patients required no hospital care during this period of time. The analysis of survivorship takes into consideration not only death rates per thousand patient years of observation, but also the cumulative survival rate from time of entry in the registry through each successive year of follow-up during the total period of observation. METHODS From the Departments of Medicine, Community Health and Epidemiology, and the Rheumatic Diseases Unit, Queen’s University, Kingston, Ontario. JAMAL UDDIN,MD, FRCP (C) : Assistant Resident in Medicine (Rheumatology) , Kingston Hospital and Queen’s University. ARTHUR S. KRAUS, ScD, FAPHA: Associate Professor of Biostatistics, Queen’s University. H. GARFIELD KELLY, MD, CM. FRCP(C), FACP: Professor of Medicine, Queen’s University. Reprint requests should be addressed to Dr. H. Garfield Kelly, Etherington Hall, Queen’s University, Kingston, Ontario, Canada. Submitted for publication Aug 5, 1969; accepted, Sept 8, 1969. To calculate survivorship, it was necessary to determine the number of patients alive, dead or lost to follow-up in each successive year of the study period by correspondence or interview with patients, relatives, physicians or other interested persons. Thirty- four patients (7%) were lost to follow-up, and 94 patients (20%) died during the study period. Survivorship for all patients was calculated from data which included sex, date of birth, date of entry in the rheumatic diseases registry and date of death or loss from follow-up, by the life-table method applied by Merrell and Shulman to a survivorship study of chronic disease in general and systemic lupus erythematosus (SLE) in particularP The cumulative survival rate for all patients with RA was calculated and compared with the expected survival rate for a general population sample which Mhritis and Rheumatism, Vol. 13, No. 2 (March-April 1970) 125 UDDIN R A 1 would match the patient group with respect to age and sex distribution. The expected survival rate was based on age-sex-specific death rates in Ontario in 1961.'* The statistical significance of differences, when indicated, was determined 'by the method of Greenwood, using the standard error of the life-table survival rate.I5 An analysis of cause of death was based on the underlying cause of death listed on the death certificate and verified by autopsy when available. RESULTS Survivorship T h e observed cumulative survival rate for RA patients was lower in each sex a t each year of follow-up than the expected survival rate for the general population, with a more pronounced difference in the later years of follow-up. Through the fifth year of follow-up in males and the seventh year of follow-up in females (in which years there remained 50 person-years of follow-up in each sex), the difference was statistically significant (p < 0.01) (Tables 1 and 2, Fig 1). T h e relationship between observed and expected survival rates can be expressed: adjusted cumulative survival rate = observed cumulative survival rate expected cumulative survival rate Adjusted survival rates in the early years of follow-up, which were above 90% in each sex, gradually fell below BOY0 in later years. Adjusted survival rates for males were always appreciably lower than those for females, except during the last 2 years of follow-up when the small numbers remaining in the series could easily have produced, by chance, an apparent reversal of this relationship (Table 3). Causes of Death Of the 94 patients who died, causes of death were determined from death certificates in 86 and confirmed by autopsy in 28 (Table 4 ) . T h e most frequent cause of death was cardiovascular disease of all varie126 Table 1. Life-Table Analysis Showing Observed and Expected Cumulative Survival Rate in Males With Rheumatoid Arthritis Cumulative Patients Survival rate (96) No. of living at Person _yr. of beginning years of EXfollow up of year* follow-upt Observed pectedz 1 2 3 4 5 6 7 8 9 10 151 108 93 76 60 51 36 26 19 3 135.0 104.0 86.5 71.0 56.0 46.0 32.0 23.5 11.0 1.5 91.9 85.7 81.8 74.8 73.5 65.4 61.3 56.1 56.1 56.1 96.9 94.1 91.0 87.4 83.8 80.0 77.0 74.2 71.5 67.4 * For year 1 = no. entering study group. For subsequent years = no. alive at the beginning of previousyear - (deaths lossto follow up no. alive when they reached the end of the observation period) during the previous year. t Person years of follow-up = no. alive at the beginning of the year - M (no. lost to follow-up +no. alive when they reached the end of the observation period) during the year. 3 Based on general population sample. + + ties (51 patients), but the proportionate mortality for this cause group was lower than expected. Of special interest was the high incidence of death from infection (18 patients), which was much higher than the expected incidence of death from this cause in the general population sample (Table 5). Relatively small numbers of patients died Irom neoplastic disease, renal failure, respiratory insufficiency and gastrointestinal disease. I n eight instances, the cause of deatli could not be determined. DISCUSSION Three previous studies have documented decreased survival of patients with T h e first of these by Cobb et U P presented Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970) SURVIVORSHIP AND DEATH IN RA Table 2. Life-Table Analysis Showing Observed and Expected Cumulative Survival Rate in Females With RA Table 3. Cum u Iat ive Survival Rate (I) Patients No. of living at Person EXyr. of beginning years of follow up of year* follow-uptobserved pectedl 1 2 3 4 5 6 7 8 9 10 324 260 217 175 146 113 88 56 41 26 299.0 241.5 199.0 164.5 132.5 102.0 74.5 49.5 35.5 13.5 95.3 92.9 90.1 85.7 81.8 79.4 74.1 71.1 63.1 58.4 97.9 95.6 93.4 91.2 89.5 87.3 84.0 82.1 80.2 78.5 q + 4 0 . , 2 . . . . . . . . 4 6 8 1 YEARS Of FOLLOW-UP 1 2 3 4 5 6 7 8 9 10 Males Female 94.8 91.1 89.9 85.6 87.7 81.8 79.6 75.6 78.5 83.2 99.9 97.2 96.5 94.0 91.4 91.0 88.2 86.6 78.7 74.4 observed cumulative survival rate expected cumulative survival rate - 40 No. of yr. of follow-up * Adjusted cumulative survival rate = * For year 1 = no. entering the study group; for subsequent years = no. alive at the beginning of loss to follow-up previous year - (deaths no. alive when they reached the end of the observation period) during the previous year. t Person years of follow-up = no. alive at the beginning of the year - % (no. lost to follow-up +no. alive when they reached the end of the observation period) during the year. $ Based on general population sample. + Adjusted Cumulative Survival Rate* (96) in Males and Females With RA 0 Fig 1. Observed and expected cumulative surviva1 rate in males and females with RA. Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970) . Table 4. Cause of Death of 94 RA Patients Cardiovascular Cardiac Cerebrovascular Pulmonary emboli &/or infarction Mesenteric th rombosis Ruptured abdominal aneurysm Postoperative shock Total Infectious Pulmonary Septicemia and pyemia Postgastrectorny peritonitis Total Respiratory (Chronic Pulmonary Disease) Neoplastic Renal Amyloidosis Necrotizing papillitis HeDatorenal failure Total Gastrointestinal GI hemorrhage Chronic pancreatitis Total Unknown Total all causes 4 ( 3)1 1 2 ( 01- a ( 0) 94 (28) * Number in parentheses indicates no. confirmed by autopsy. 127 UDDlN E l AL Table 5. Comparison of Observed Leading Causes of Death of Male and Female RA Patients With Those Expected in a General Population of the Same Age-Group Male Cause of death Cardiac Infectious Throm boem bol ic Neoplastic Female % Observed % Expected % Observed % Expected 35.30 26.47 8.82 8.82 48.61 2.62 12.09 12.39 38.50 19.23 26.92 7.69 41.65 2.53 20.60 6.36 data on 583 patients with RA and ankylosing spondylitis who were hospitalized and subsequently followed for an average period of 9.6 years. Observed death rates for males and females under 50 years of age were, respectively, 20.6 and 10.7/ 1000 patient years of observation, in contrast to expected death rates for males and females of 3.9 and 2.9, respectively. Over the age of 50, observed and expected death rates did not differ significantly for either sex. The higher mortality for younger males could not be correlated with the presence or absence of spondylitis. Duthie et al? have reported findings on the course and prognosis of 307 patients with RA severe enough to require hospital admission. At the time of final assessment, after an average follow-up period of 9 years, 75 patients were dead and 32 were lost to follow-up. Death rates per thousand years of observation by age and sex revealed the observed death rate to be higher than the expected rate in all three age groups: under 50, from 50-59, and over 60 in both sexes. The report by VanDam et U P was based on a follow-up of 1214 patients with R A over a period of 11 years, during which period of time 229 patients died. The observed death rate was approximately 60% higher than the expected rate in both sexes. When the disease began before 50 years of age, the adjusted death rate was about 50% higher than when it began after the age of 50. Our data indicate decreased survival of RA patients in all age and sex groups (Table 6 ) . It might appear that the recent study by Burch14 on Pima Indians is at variance with this finding and those previously cited. Although Burch did not find a higher mortality among Indians with probable or definite RA than “in all others,” his “all others” classification included an appreciable number of patients with a positive test for rheumatoid factor who. were shown to have an excessive mortality rate. Therefore, Burch’s data are not comparable with and do not contradict those of the previously noted authors. Our data also demonstrate that in a given population of patients with RA of all grades of severity, the difference between observed and expected survival rates becomes statistically significant during later years of follow-up in both sexes (Table 1 and 2, Fig 1). Adjusted survival rates for males were almost always appreciably below those for females. As noted in Fig 1, the trend of the observed cumulative survival rate for males is essentially linear in its downward course during the first 8 years; whereas, for females, it appears to decrease less sharply in the first few years of follow-up than later on. This trend is in contrast to that of many other chronic diseases, particularly those that are obviously life-threatening. For example, in SLE15-17 and cancer of the 128 Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970) SURVIVORSHIP AND DEATH IN RA breast,ls the decrease in survival was rela- death, or the type and duration of treattively greater in the first few years of follow- ment. The majority of patients who died from infection were receiving steroid, but UP. The distribution of causes of death in so were those who died from cardiac, our group of patients did not differ signifi- thromboembolic and neoplastic disorders. cantly from those in other reports, all of It is difficult to evaluate the specific role of which show a relatively high incidence of steroid in increasing the incidence of inEecdeath from infection (Table 7). In our tion in the presence of so many compliseries, the observed incidence of death from cating factors-the debilitating nature of infection was about ten times higher than the disease, the presence of coexisting disexpected in males and about seven times ease, and the possible adverse effects of the higher than that expected in females, both other forms of treatment. differences being statistically significant (p T h e infectious cause group was the only < .001) (Table 5). one which showed a pronounced relative It has not been possible to correlate the excess (Table 5 ) . However, only 18 deaths incidence of infection with the duration were attributed to infection; whereas, total and severity of disease, the mean age of observed deaths (94) exceeded total ex- Table 6. Observed and Expected Death Rates per 1000 Patient Years of Observation by Age and Sex Male Age (yrs) < 50 5059 60 and > Observed Expected* Patient yrs death rate death rate Patient yrs 159.0 138.5 272.0 * Based on general Table 7. Female 6.3 43.3 117.6 3.8 13.3 63.6 389.5 304.0 622.0 Observed Expected* death rate death rate 10.3 19.7 72.3 2.1 8.9 43.2 population sample. Comparison of Causes of Death of RA Patients in Different Series Studies VanDam Cobb Cause of Death Distribution Card iovascutar* Infection Cancer Renal disease Gastrointestinal disease Respiratory disease Miscellaneous Unknown Uddin Duthie 137 patients 229 patients 94 patients 75 patients (20) (28) (4011 35.0 23.4 10.9 12.4 5.8 45.3 14.7 13.3 17.3 8.0 38.5 12.6 15.2 7.8 6.5 7.3 5.1 1.3 16.9 2.2 - - - - (96) 51.0 19.1 7.4 4.2 2.1 4.2 3.2 8.5 * Includes all deaths from heart and vascular diseases. t Number in parentheses indicates no. of autopsies. Arthritis and Rheumatism, Vol. 13, No. 2 (March-April 1970) 123 UDDIN ET A 1 pected deaths (60) by 34, making it appare n t that causes other than infection also contributed to increased mortality. Hopefully, therapeutic measures will soon become available which will increase longevity a n d narrow the g a p between the observed mortality rate for RA patients and the expected mortality rate for the general population. 1961. Vol. 1. Relazioni. Minerva Medica. Torino, Italy, 1961, p. 161. 9. COUB,S., ANDERSON, F. and BAUER,W. Length of life and cause of death in rheumatoid arthritis. New Eng J Med 249:553, 1953. G. A., Conu, S., 10. ROPES,M. W., BENNETT, JACOX,R. and JESSAR,R. A. 1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175, 1958. 11. MERRELL, M. and SHULMAN, L. E. Determination of prognosis in chronic disease, illustrated by systemic lupus erythematosus. REFERENCES J Chron Dis 1:12, 1955. I. RACAN,C. and FARRINGTON, E. The 12. Vital Statistics, 1961. Dominion Bureau clinical features of rheumatoid arthritis. Prog- of Statistics, Health and Welfare Division, Vital nostic indices. JAMA 181:663, 1962. Statistics Section, Ottawa, Canada. 2. SHARP,J. T., CALKINS, E., COHEN,A. S., 13. GREENWOOD, M. A report on the natural SCHUBART, A. F. and CALABRO, J. J. Observa- duration of cancer. Appendix I. 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