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RHEUMATOID ARTHRITIS IN WOMEN Incidence Rates in Group Health Cooperative, Seattle, Washington, 1987-1 989 CARIN E. DUGOWSON, THOMAS D. KOEPSELL, LYNDA F. VOIGT, LINDA BLEY, J. LEE NELSON, and JANET R. DALING As part of a prospective case-control study of newly diagnosed rheumatoid arthritis (RA) in women, we identified all cases of probable, definite, or classic RA diagnosed in 1987-1989 in 18-64-year-old women who were members of a health maintenance organization based in the Seattle, Washington area. Using both the 1958 and the 1987 American Rheumatism Association criteria for the diagnosis of RA and enrollment data from the health maintenance organization, we calculated the incidence by age and diagnostic class. Rates of RA incidence in women increased steadily with age. The incidence of probable, definite, or classic RA ranged from 13.1 per 100,000 person-years at risk for 18-29From the Department of Epidemiology, and the Department of Health Services. the School of Public Health and Community Medicine, the Division of Rheumatology, the Department of Medicine, the University of Washington, and the Division of Clinical Research, the Fred Hutchinson Cancer Research Center, Seattle, Washington. Supported by contract NO1 HD-62914 from the National Institute of Child Health and Human Development. Carin E. Dugowson, MD, MPH: Department of Epidemiology, School of Public Health and Community Medicine, and Division of Rheumatology, Department of Medicine, University of Washington; Thomas D. Koepsell, MD, MPH: Department of Epidemiology and Department of Health Services, School of Public Health and Community Medicine, University of Washington; Lynda F. Voigt, PhD: Department of Epidemiology, School of Public Health and Community Medicine, University of Washington; Linda Bley. MS: Department of Epidemiology, School of Public Health and Community Medicine, University of Washington; J. Lee Nelson, MD: Division of Clinical Research, Fred Hutchinson Cancer Research Center; Janet R. Daling, PhD: Department of Epidemiology, School of Public Health and Community Medicine, University of Washington. Address reprint requests to Carin E. Dugowson, MD, MPH, Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, 1124 Columbia Street, MP381, Seattle, WA 98104. Submitted for publication March 21, 1991; accepted in revised form July 24, 1991. Arthritis and Rheumatism, Vol. 34, No. 12 (December 1991)

year-old women to 82.1 per 100,000 person-years for 60-64-year-old women. The overall incidence rate, age= adjusted to the 1980 US female population, was 27.91 100,000 person-years. The overall incidence rate for definitdclassic RA, age-adjusted to the 1980 US female population, was 23.9 per 100,000 person-years. When compared with adjusted rates of incidence of definite RA in Rochester, Minnesota, in 1950-1974, the incidence rates we found were 44.7% lower. Methodologic differences, changes in diagnostic criteria, and a declining incidence of RA among women over time may all be partial explanations for these results. The possible effects of reproductive factors, including oral contraceptives use, are discussed.

Although rheumatoid arthritis (RA) is one of the most common of the inflammatory arthritides, there is little available information on incidence rates to help clarify the epidemiology of the disease. Table 1 shows a list of all articles from 1950 to the present that are indexed in Medline with the key words “rheumatoid arthritis” and “incidence” and that provide population incidence data (1-13). The most complete data for the US are from a study by Linos et a1 (l), who calculated incidence rates in Rochester, Minnesota during the years 195g1974, by a retrospective review of medical records at the Mayo Clinic. Their data demonstrated a 41% decline in the incidence of RA in women over that period, from 68 per 100,000 to 40 per 100,000, while the incidence in men remained stable. They were also the first to observe that the increasing rate of oral contraceptive use paralleled the decline of RA incidence in women (1). Using data from surveys conducted by the Royal College of General Practitioners (RCGP), Hoch-

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RA INCIDENCE IN WOMEN Table 1. Summary of published reports, since 1950, on the incidence of rheumatoid arthritis (RA)* RA Age incidence Year(s) Inclusion range per 100,OOO Author(s) (ref.) studied Location criteria included person-years

Remrts of rates amongfemales Linos et a1 (I) Wood et al (2) Bachman (3) Kato et a1 (4) Hochberg ( 5 ) Gran et al (6) Hochberg ( 5 ) Hernandez-Avila et a1 (7) Del Puente et aI (8) Boyer et al (9) Reports of rates among females and males combined# O’Sullivan and Cathcart (10) Oen et al (1 1) Isomaki (12) Silman (14) Silman (14)

1950-74 1958-64 I963 1965-66

1970-72 1969-8I 1981-82 1976-82 1967-86 I97042

1968 1972-82 1973-75 1980** 1985**

Rochester, MN Japan Oregon Japan RCGP (UK) Norway RCGP (UK)

us

Arizona Alaska

us

Alaska Finland RCGP (UK) RCGP (UK)

DIC DIC NA PIDIC NA DIC NA DIC D/C D/C

D PIDIC D NA NA

All

> I4 50-59 >I4 15-64

All 15-64

30-55 >20 NA

> 14 > I5 NA NA

37t 130 I50 110 320$ 17

260$ 248 5188 57

290 123 42 136 74

* D = definite RA; C = classic RA; P = probable RA (all by the American Rheumatism Association 1958 criteria [16]). RCGP = Royal College of General Practitioners; NA = information not available.

t Age-adjusted to US population, 1960 Census. $ Age-adjusted to 1981 Census of Great Britain.

5 Includes 102 cases of “unditTerentiated polyarthritis.” 1 Age-adjusted to US population, 1980 Census. # Separate rates for males and females were not provided. ** Data from ref. 13.

berg (5) found a 20% decline in the incidence of RA among women in the United Kingdom between the periods 1970-1972 and 1981-1982 (329 per 100,000 to 260 per 100,000). Using the same data source (131, Silman (14) reported a decline between 1980 and 1985 in the number of “new episodes” of RA in men and women combined: from 136 per 100,000 to 74 per 100,000. However, the RCGP studies did not include accurate denominator data; in addition, neither diagnostic criteria nor confirmation of the diagnosis of RA by Physical examination were part of those studies. For these reasons, Silman later suggested that the apparent decline in the incidence of RA was, at least in Part, an artifact of study methodology and reporting (15). This may help to explain the order of magnitude differencein the 1970s rates reported by Linos et a1 and by Hochberg. However, such discrepancies make discussion of a temporal decline somewhat problematic. Calculation of R A incidence rates in a prospectively studied, population-based cohort has not PreViOUSly been reported. This information is of importance for both clinical care and basic science research and

would assist in the assessment of the reported secular trends in the incidence of RA in women. In the present study, we calculated the incidence of RA in women who are members of a large prepaid health plan in the Seattle, Washington area, using techniques designed to maximize accurate ascertainment of new cases.

METHODS A population-based case-control study on the effects of reproductive factors on the incidence of RA is currently being conducted. One part of the study utilizes the mernbership of Group Health Cooperative of Puget Sound (GHC), which is a large health maintenance organization serving much of western Washington state. Approximately 15% of the area’s population belongs to GHC. Seventy-five percent of its members are enrolled in employer-sponsored health plans, but there are also a large number of Medicare and Medicaid recipients among the membership. In the case-control study, we are attempting to include all newly diagnosed cases of rheumatoid arthritis in women who are age 18-64 at diagnosis. It is GHC policy that all patients with newly diagnosed RA are seen in consulta-

DUGOWSON ET AL

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Table 2. Age-specific incidence of rheumatoid arthritis (RA) in women: cases identified at Group Health Cooperative. 1987-1989 All RA Age

Average annual Person-years No. of enrollment at risk cases

11

18-29 3&39 4049 5&59 60-64

28,067 34,388 26,746 15,410 8,120

84,201 103,164 80,238 46,230 24,360

19 24 21 20

Total

1 l2,73 1

338,193

95

Definite RA Rate per 100,000 per year

No. of cases

Rate per 100,000 per year

13.1 18.4 29.9 45.4 82.1

11 17 21 17

13.1 16.5 26.2 36.8 61.6

28.1 (95% CI 22.3-33.9).

81

15

23.9 (95% CI 18.5-29.3)*

* Rates are age-adjusted to the 1980 US female population;crude rates were 28.1 and 24.0 per 100,OOO person-years for all RA and definite RA, respectively. 95% C1 = 95% confidence interval. tion by one of the organization’s rheumatologists. The majority of case referralsto the larger study havebeen from these rheumatologists, with more than 75% of all new RA cases at GHC being identified in this manner. Additional referrals are obtained from GHC internists and family physicians. All GHC rheumatologists, internists, and family physicians are sent reminders every 2 months about the study and its criteria for referral of RA cases. In the early phases of the study, surveillance of laboratory records to identify all patients who underwent rheumatoid factor testing and review of all test results (negative or positive) reported in medical records provided a check on the thoroughness of our referral networks in identifying cases. Only 1 case of RA was identified solely through surveillance of laboratory records. Case ascertainment began in November 1986. Calculation of incidence rates for the present analyses is based on cases identified from January 1, 1987 through December 3 1, 1989. The date when study personnel were contacted by the referring physician was used to determine whether a case fell within the study period. The median time from onset of symptoms to date of referral was 16 months. Women who consented to participate in the study were examined by a board-certified study rheumatologist and classified according to the American Rheumatism Association (ARA) 1958 and 1987 criteria for the diagnosis of RA (16,17). If a discrepancy was found between the patient’s clinical status at her identification date and her status at study examination, the medical record was abstracted to determine whether additional signs or symptoms had been present at the time of diagnosis (identificationdate) but were attenuated by therapy prior to the study examination. This additional information was then used to help determine her diagnostic classification. Ten women who were referred as possibly eligible RA cases refused to participate in the casecontrol study; subsequent review of their medical records showed that 9 were eligible for inclusion, and they have been included in the analysis reported here. Of these 9 women, 5 were classified as having probable RA and 4 as having definite RA according to the 1958 criteria, using medical record data only.

GHC routinely maintains age- and sex-stratified membership counts. These data were used to provide current and accurate denominator information for incidence rates. Information on diagnosis was not available for the membership as a whole; therefore, we were unable to exclude prevalent RA cases from the denominator. Assuming a prevalence rate of 2% in women, this change in denominator does not appreciably change the calculated incidence rates. All analyses were performed using both the ARA 1958 criteria and the ARA 1987 criteria for the diagnosis of RA. Rates for probable RA by the 1958 criteria are also reported. To maximize comparability with other published incidence data, the rates reported here are based on the 1958 criteria.

RESULTS During the years 1987-1989, the average annual number of females in the eligible age range enrolled at GHC was 112,731. There were 338,193 person-years at risk. In this period, a total of 95 women 18-64 years of age presented to GHC physicians with newly occurring RA. Of those 95, 81 fulfilled the ARA criteria for definite or classic RA and 14 fulfilled criteria for probable RA. The racial distribution of the RA patients reflected the racial makeup of GHC,with 88.5% white, 4.3% black, 3.2% Asian, 1.0% Native American, and 3% other racial groups. Age-specific rates of RA incidence among women in the study population are shown in Table 2. Annual incidence rates increased with age, from 13.1 per 100,000 women in the 18-29-year age category to 82.1 per 100,000 in the 60-64-year age group. The overall annual rate of incidence of classic, definite, or probable RA in women 18-64 years of age in 19871989, age-adjusted to the 1980 US female population, was 28.1 per 100,000 women.

RA INCIDENCE IN WOMEN

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Table 3. Comparison of the rates of incidence of definite rheumatoid arthritis in women in the study in Rochester, Minnesota (1950-74; ref. 1) versus those in the present study

Rochester, MN, Age 18-29 30-39 4049 50-59 60-64

Overall

1950-74

Present study

Difference (%)

13.1 38.3 48.5 88.4 81.9 43.2*

13.1 16.5 26.2 36.8 61.6 23.9*

0 -56.9 -46.0 -58.4 -24.8 -44.7

* Age-adjusted to 1980 US female population ages 18-64.

Considering only those patients who presented with definite or classic RA, the highest annual incidence rates were again seen in the oldest age group (60-641, with 61.6 cases per 100,OOO. The lowest rate was seen in the 18-29-year age group: 13.1 per 100,000. The annual rate of incidence of definite or classic RA in women 18-64 years of age, age-adjusted to the 1980 US female population, was 23.9 per 100,000. The small number of cases of probable RA made it impossible to derive meaningful age-specific rate calculations for that group alone. Classification of cases using the 1987 revised criteria for RA did not alter the eligibility of any of the Patients with definite RA, and the incidence rates were therefore unchanged. No patients with probable RA by the 1958 criteria would have been classified as having RA by the 1987 criteria. For comparison of our results with other reported rates of RA incidence in the US, we used data from Linos and colleagues' study in Rochester, Minnesota (1). Linos et al's estimates were also based on a defined population and used the 1958 ARA criteria for case definition. The two sets of rates are shown in Table 3. Differences in age-specific incidence rates ranged from a minimum difference of 0% among 18-29-year-old women to a maximum difference of 58.4% in the 50-59-year age group. Overall, the ageadjusted incidence of RA among the GHC women was 44.7% lower than the corresponding rate from Linos et d ' s study.

DISCUSSION Any study of RA incidence has inherent difficulties due to methodoIogic considerations. First, the OPeratiOnal definition of RA is itself a significant problem. Lacking an etiologic agent or unique clinical Or laboratory feature, the diagnosis of RA has been

based on combinations of clinical and laboratory features which are themselves subject to measurement error. The diagnostic criteria have been revised several times, most recently in 1987, to reflect an evolving clinical definition. Diagnostic consistency over time and among physicians remains a problem. Previous studies may have overestimated incidence rates by including patients with conditions that were thought to be RA but are now distinguished from it. In particular, psoriatic arthritis and the HLA-B27associated syndromes are diagnosed with increasing frequency. Furthermore, the concept that women are uncommonly affected by these illnesses is now believed to be incorrect (18). The increased incidence, or at least reporting, of these diseases corresponds temporally to the lower reported rates of RA incidence. Silman (19) has reported a decline over time in the severity of RA, with rheumatoid factor positivity, subcutaneous nodules, erosive arthritis, and extraarticular disease occurring less frequently. These first 3 features are included in the criteria for the diagnosis of RA. If RA is now occurring, or initially presenting, in a milder form, the absence of these features would lead to an apparent decline in the incidence of the disease. Identification of cases in defined populations, by standardized protocols, has been difficult to achieve. Because RA is a disease of high prevalence but relatively low incidence, a large study population is required to precisely measure incidence. Case identification and surveillance is difficult in part because hospitalization or death from RA is uncommon. Referral and recruitment bias remains a concern. Finally, the verification of case eligibility is difficult.Medical records are often insufficient for this. They are generally incomplete with respect to diagnostic criteria, and include data that has not been collected in a standardized manner. Few studies have independently examined incident cases. Taken together, these problems present significant obstacles to calculation of accurate incidence rates and may account for some of the wide variability in reported incidence rates, as seen in Table 1. In the present study, adverse selection into a prepaid health plan, by which patients with established illness would choose a medical plan that provides complete coverage, might theoretically lead to a higher prevalence of RA among the membership of such plans, but would not be expected to affect incidence rates. The use of a prepaid health plan as a study base had the advantage of enrollees' ready access to care, which would pro-

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mote complete case identification and avoid a bias toward lower rates. Furthermore, GHC policy mandates referral of all patients with suspected RA to a rheumatologist for diagnosis and management guidance. The enthusiastic cooperation of the 3 rheumatologists served to promote recruitment into this study. Laboratory-based surveillance suggested that few cases that proved to be RA were missed. Thus, although incomplete ascertainment is always a concern, it is unlikely to be entirely responsible for the low incidence rates we found, given the multiple case identification techniques employed and the identification of only 1 additional case in 2 years by laboratory surveillance. The data that provide the best comparison with the present results are from the study in Rochester, Minnesota by Linos et al (1). Seattle and Minnesota each have a largely Caucasian population (88.5% and 98.1%, respectively, in the 1980 Census) with many residents of Scandinavian origin, providing a comparison between two groups that are ethnically similar. Both studies used the 1958 ARA criteria for diagnosis of cases, although ascertainment methods were very different between Linos et al's study and ours. Nonetheless, Linos and colleagues demonstrated a similar pattern of decreasing incidence of RA in women over time. The current study demonstrates incidence rates that are consistently lower than those reported by Linos et al. All RA patients in the current study were examined by a study rheumatologist, whereas Linos used retrospective chart review. Based on the study examination, 5 women referred by GHC physicians (5.7%) were found not to qualify for inclusion. This examination also enabled identification of referred patients who in fact had rheumatic conditions distinct from RA. Another potential explanation for the differences between Linos' findings and ours is geographic variation in incidence rates. Although the ethnic mix of the study populations and the geographic latitude lines of the areas studied are similar, unidentified geographic variables could be of importance. There were no age restrictions in the study by Linos, whereas our study was limited to women age 18-64. However, overall rates were age adjusted using the age limits of the current study. Comparison by agedecade also shows marked differences in incidence rates (Table 3). Our results could represent a continued secular decline in the incidence of RA among women. This trend was first noted by Linos et al and was confirmed in Great Britain by Silman (14.15) and

DUGOWSON ET AL by Hochberg (5). The mechanisms for such a sexspecific decline, if any, are not known. The greatest difference between the two studies in the RA incidence observed is in the 30-59-year age group, with no difference in the youngest group and a smaller difference at older ages. It is possible that changes in contraceptive use could play a role. Oral contraceptive use has been shown in some studies to decrease the risk of RA (20,21). Women age 60-64 spent relatively few of their reproductive years during the time when oral contraceptive use was most prevalent, perhaps accounting in part for the greater decline in RA incidence rates among younger women. However, oral contraceptive use has declined sharply among married women between 1973 and 1988, compared with an increased use of condoms and sterilization (22). If oral contraceptive use were a strong determinant of RA incidence, this change should increase the risk of RA, whereas the greatest difference in rates between our study and that by Linos et al was seen in the 30-59-year-old group. Reproductive factors distinct from contraceptive practices may also be important in terms of the risk of developing RA. We and others have recently demonstrated that nulliparity increases a woman's risk for subsequent development of RA (23-25). Changes in parity and in contraceptive practice would be changes in risk factors specific to women. Other factors that might affect women more than men remain to be elucidated. We note that calculation of incidence rates using the ARA 1987 revised criteria for the diagnosis of RA did not produce any difference in the results when cases of probable RA by the 1958 ARA criteria were excluded. However, in a larger sample of women with newly diagnosed RA, we have shown a discrepancy of 14%, with fewer diagnoses of RA made using the new criteria (26). It will be important in the future to obtain information using both sets of criteria, when changes in incidence rates over time are addressed.

REFERENCES 1. Linos A, Worthington JW, O'Fallon WM, Kurland LT:

The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence and mortality. Am J Epidemiol 11 1:87-98, 1980 2. Wood JW. Kato H, Johnson KG. Uda Y, Russell WJ, Duff IF: Rheumatoid arthritis in Hiroshima and Na-

RA INCIDENCE IN WOMEN gasaki, Japan: prevalence, incidence, and clinical characteristics. Arthritis Rheum 10:21-31, 1967 3. Bachman DM: Survey of rheumatoid arthritis in Oregon (abstract). Arthritis Rheum 6:761, 1963 4. Kato H, Duff IF, Russell WJ, Uda Y, Hamilton HB, Kawamoto S, Johnson KG: Rheumatoid arthritis and gout in Hiroshima and Nagasaki, Japan: a prevalence and incidence study. J Chronic Dis 23:65%79, 1971 5. Hochberg MC: Changes in the incidence and prevalence of rheumatoid arthritis in England and Wales, 19701982. Semin Arthritis Rheum 19:294-302, 1990 6. Gran JT, Magnus J, Mikkelsen K, Nygaard H, Brath HK: The incidence of classical and definite rheumatoid arthritis in Lillehammer, Norway. Scand J Rheumatol suppl 15:7, 1986 7. Hernandez-Avila M, Liang MH. Willett WC, Stampfer JM, Colditz GA, Rosner B, Roberts WN, Hennekens CH, Speizer FE: Reproductive factors, smoking, and the risk for rheumatoid arthritis. Epidemiology 1 :285291, 1990 8. Del Puente A, Knowler WC, Pettit DJ, Bennett PH: High incidence and prevalence of rheumatoid arthritis in Pima Indians. Am J Epidemiol 129:117&1178, 1989 9. Boyer GS, Lanier AP, Templin DW, Bulkow L: Spondyloarthropathy and rheumatoid arthritis in Alaskan Yupik Eskimos. J Rheumatol 17:489-496, 1990 10. O’Sullivan JB, Cathcart ES: Follow-up evaluation of the effect of criteria on rates in Sudbury, Massachusetts. Ann Intern Med 76573-577, 1972 1 1 . Oen K, Post1 B, Chalmers IM, Ling N, Schroeder ML, Barager FD, Martin L, Reed M, Major P: Rheumatic diseases in an Inuit population. Arthritis Rheum 296574, 1986 12. Isomaki HA: An epidemiologically based follow-up Study of recent arthritis: incidence, outcome and classification. Clin Rheumatol6(suppl 2153-59, 1987 13. Royal College of General Practitioners: Weekly Returns: Notification of Newly-diagnosed Episodes: 4-weekly Summary (reports) 1980-5. Birmingham, Royal College of General Practitioners Research Unit 14. Silman AJ: Recent trends in rheumatoid arthritis. Br J Rheumatol25:328-329, 1986

1507 15. Silman AJ: Has the incidence of RA declined in the

United Kingdom? Br J Rheumatol 1:77-78, 1988 16. Ropes MW, Bennett GA, Cobb S , Jacox R, Jessar RA: 1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175-176, 1958 17. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA Jr, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315-324, 1988 18. Gran JT, Husby G:Ankylosing spondylitis in women. Semin Arthritis Rheum 19:303-312, 1990 19. Silman A, Davies P: Is the incidence of seropositive rheumatoid arthritis decreasing? (abstract). Ann Rheum Dis 40517-518, 1981 20. Vandenbroucke JP, Valkenburg HA, Boersma JW, Cats A, Festen JJM, Huber-Bruning 0,Rasker JJ: Oral contraceptives and rheumatoid arthritis: further evidence for a protective effect. Lancet II:839-842, 1982 21. Hazes JMW, Dijkmans BAC, Vandenbroucke JP, de Vries RRP, Cats A: Reduction of the risk of rheumatoid arthritis among women who take oral contraceptives. Arthritis Rheum 333173479, 1990 22. Mosher WD, Pratt WF: Contraceptive use in the United States, 1973-1988. Advance Data, No. 192, March 20, 1990 23. Dugowson CE, Nelson JL, Koepsell TD, Voigt L: Is nulliparity a risk factor for rheumatoid arthritis? (abstract). Arthritis Rheum 34 (suppl 5):R19, 1991 24. Del Junco DJ, Annegers JF, Coulam CB, Luthra HS: The relationship between rheumatoid arthritis and reproductive function. Br J Rheumatol 28:42-45, 1989 25. Hazes JMW, Dijkmans BAC. Vandenbroucke JP, de Vries RRP, Cats A: Pregnancy and the risk of developing rheumatoid arthritis. Arthritis Rheum 33: 1770-1775, I990 26. Dugowson CE, Nelson JL, Koepsell TD: Evaluation of the 1987 revised criteria for rheumatoid arthritis in a cohort of newly diagnosed female patients. Arthritis Rheum 33:1042-1046, 1990