1462
DIMINISHED INCIDENCE OF SEVERE RHEUMATOID ARTHRITIS ASSOCIATED WITH ORAL CONTRACEPTIVE USE DERKJEN V A N ZEBEN, JOHANNA M. W. HAZES, JAN P. VANDENBROUCKE, BEN A. C. DIJKMANS, and ARNOLD CATS It has been suggested that the negative association between rheumatoid arthritis (RA) and oral contraceptive (OC) use might be limited to the more severe forms of RA. To investigate this further, we studied 121 consecutive female patients with definite RA, 52 female patients with probable RA, and 378 female controls. All patients had RA symptoms of recent onset. After a mean followup period of 6 years, patients with definite RA were classified as having either a severe disease course (n = 76) or a mild disease course (n = 45). The negative association between OC use prior to the onset of RA symptoms and the development of RA was limited to those patients with definite RA who had a severe disease course. We therefore conclude that OC use prior to the onset of RA symptoms is only associated with a reduction in the incidence of severe RA. This may explain the divergent results of previous studies. Conflicting findings about the negative association of oral contraceptive (OC) use and the development of rheumatoid arthritis (RA) have been published (1-10). In April 1989, an international roundtable conference was organized t o discuss these conflicting results (11). In a metaanalysis, the reduction in the incidence of RA associated with OC use was restricted mainly to hospital-based studies, whereas populationFrom the Departments of Rheumatology and Clinical Epidemiology, University Hospital, Leiden, The Netherlands. Derkjen van Zeben, MD: Department of Rheumatology; Johanna M. W. Hazes, MD: Department of Rheumatology: Jan P. Vandenbroucke, MD: Department of Clinical Epidemiology; Ben A. C. Dijkmans, MD: Department of Rheumatology; Arnold Cats, MD: Department of Rheumatology. Address reprint requests to Derkjen van Zeben, MD, University Hospital, Department of Rheumatology, Building I , C2-Q, PO Box 9600, Leiden 2300 RC, The Netherlands. Submitted for publication November 21, 1989; accepted in revised form April 11, 1990. Arthritis and Rheumatism, Vol. 33, No. 10 (October 1990)
based studies showed no such protective effect of OC (12). In general, the latter studies dealt with milder forms of RA. It was therefore suggested that OC use might only protect against more severe forms of RA. In a previous case-control study, the preventive effect of OC on the incidence of RA was assessed (10). Subsequently, we enrolled the patients from that study into a followup study extending over the next 6 years. This enabled us to subdivide the patient groups according to the 6-year outcome of their RA. The aim of the present investigation was to investigate whether the negative association between OC use and RA was different in mild and severe forms of the disease.
PATIENTS AND METHODS The present investigation was started as a casecontrol study to determine the preventive effect of OC use on the incidence of R A (10). The study was started in 1984 at the Department of Rheumatology , Leiden University Hospital in The Netherlands, which is the only referral clinic for rheumatic disorders in the area. All consecutive women who attended the outpatient clinic for the first time between 1982 and 1986, who had recent onset of symptoms of RA (12.5 IU by latex fixation and/or >25 IU by the Rose-Waaler test. HLA-DR tissue typing was performed in 97% of all women, according to the double fluorescence technique (17). Outcome assessment. In the fall of 1989, we started to analyze our data. Since the patients entered the study between 1982 and 1986, the duration of followup varied. For the present study, where outcome was evaluated, only patients with a followup of 3 or more years were selected; 12 patients who developed symptoms of RA late in 1986 were excluded because the followup time was too short, and 2 patients had refused to cooperate. Thirty-five patients who were originally classified as having possible RA were excluded because a different diagnosis was ultimately made. At the end of the followup period, patients with RA were divided into 2 groups according to disease severity. Patients were classified as having severe RA if 1 of the following characteri$ics was present: a disability score 21.25, erosion score 230, mean number of persistently swollen joints 2 4 , use of 2 or more disease-modifying drugs, or the presence of nodules and other extraarticular manifestations. If none of these characteristics was present, patients were classified as having mild RA. Statistical analysis. OC exposure was defined both for patients and controls as any use of OC prior to the onset of RA. Crude odds ratios, as estimates of the relative risk (RR), were calculated, with 95% confidence intervals (CI) accord-
1463
Characteristics of controls, patients with probable rheumatoid arthritis (RA), and patients with definite or classic RA
Table 1.
Definite/classic RA
Probable Controls RA Mild Severe (n = 378) (n = 52) (n = 45) (n = 76) Mean age at symptom onset (years) Mean age at first visit (years) Mean time between symptom onset and first visit (years) Mean followup from symptom onset (years) % seropositive % HLA-DR4 positive
36.2
36.5
35.4
36.7
37.8
37.7
37.7
38.5
I .6
1.3
I .5
1.8
4.6
5.8
6.1
28.8 27.3
41.3 34.8
76.3 60.5
-2.0 2.6 25.4
ing to the method of Woolf (18). Mantel-Haenszel summary odds ratios were computed to adjust for year of birth (19). A 95% CI excluding unity was considered statistically significant at the 5% level. Since controlling for other potential confounders (age at symptom onset, marital status, age at menarche, menopausal state, parity, history of smoking and drinking) had not yielded material differences in our previous study, this procedure was omitted in the present study.
RESULTS After 6 years, 52 patients were diagnosed as having either possible or probable RA. These patients had oligoarthritis, polyarthritis, or arthralgias, sometimes with positive rheumatoid factor or a single erosive joint lesion, and they did not fulfill the criteria for definite or classic RA, or for a seronegative spondylarthropathy (20,21). None of these patients fulfilled any of the severity criteria. One hundred twenty-one patients had definite or classic RA. The percentages of all patients with definite RA fulfilling each severity criterion were 23% for disability score 21.25, 39.7% for erosion score 230, 43% for mean number of persistently swollen joints 2 4 , 24.8% for use of 2 2 disease-modifying drugs, and 14.9% for the presence of nodules and other extraarticular manifestations. According to our definition, 76 patients had a severe disease course, and 45 patients had a mild disease course. All patients and controls were comparable with respect to age at symptom onset and age at first visit to the outpatient clinic (Table 1). The mean duration of followup from symptom onset was comparable in patients with definite RA who had a severe or mild disease course, and slightly lower in patients with probable RA (Table I). The percent-
VAN ZEBEN ET AL
1464
Table 2. Relative risk (RR) estimates for oral contraceptive (OC) use before onset of symptoms in controls, patients with probable rheumatoid arthritis (RA), and patients with definite or classic RA Definiteklassic RA Probable Controls RA Mild Severe (n = 378) (n = 52) (n = 45) (n = 76)
OC use* 323 (85.4) 42 (80.7) 37 (82.2) 50 (65.8) RR 1 0.72 0.79 0.33 95% confidence interval 0.27-1.89 0.21-2.79 0 . 1 9 4 5 7
* Values are the number (%) of individuals who had ever used OC prior to the onset of RA symptoms.
ages of seropositivity and HLA-DR4 positivity were highest in patients with severe definite RA and lowest in the control group, as had been expected (Table I). The risk of severe RA among women who had used oral contraceptives prior to the onset of symptoms (RR = 0.33) was less than half that among women who had never used oral contraceptives; the 95% CI excluded unity (0.19-0.57) (Table 2). This negative association was not found in patients who had definite RA with a mild disease course or in patients with probable RA. When patients with a short followup period were also included, the risk of severe RA relative to the control group was 0.29 (95% CI 0.17O S O ) , and the risk of mild RA relative to the control group was 0.76 (95% CI 0.24-2.38). Adjustment for age in the various subgroups yielded no material difference (data not shown).
DISCUSSION The results of the present study indicate that the negative association between oral contraceptive use and the incidence of rheumatoid arthritis is limited to the more severe forms of the disease. In this prospective study, we were able to evaluate outcome in a group of consecutive RA patients followed, from the start of the disease, for a mean duration of 6 years, a period during which disability and erosive joint lesions become prominent (22-24). The negative association between OC use and the more severe forms of RA could explain the divergent results of previous studies (1-11). In hospitalbased studies, the more severe forms of RA will be encountered. This clarifies the finding of a reduced incidence of RA among OC users, as opposed to the lack of association with OC use in population-based studies, where the milder forms of RA predominate, and where the effect of OC use is possibly diluted. Because most European studies have been hospital based and the US studies have been population
based, our findings could also bridge the “transatlantic divide” described by Vandenbroucke et al, who only found a protective effect of OC use on one side of the ocean (25). The novelty of our approach lies in the examination of the association of RA and OC use in terms of the outcome of the disease. In the past, only the ARA diagnostic criteria have been used as an approximation of disease severity (5). No difference in the effect of OC exposure could be found between probable, definite, or classic RA subgroups. Separate analyses of seropositive and seronegative RA patients showed only a slightly stronger effect of OC use in seropositive patients in 2 studies (2,lO) and no difference in a third (5). Likewise, the effect of OC exposure did not differ markedly between HLA-DR4 positive and HLA-DR4 negative women (10). Although rheumatoid factor and HLA-DR4 are associated with an unfavorable course of RA (26,27), when used independently as parameters for disease outcome, they are obviously not sufficiently predictive to show the negative association of OC use on the occurrence of severe RA. The frequency of HLA-DR4 in patients with definite RA and a mild disease course was lower than that found in a cross-sectional study done in our outpatient clinic (27) and was comparable with the HLA-DR4 frequency in RA patients in an open Dutch population (28). In view of the fact that we prospectively studied incident cases, some of which would escape detection in a cross-sectional study, our results and the results of these other studies are not discordant. Since it appears that the negative association between OC use and RA is found mainly in the severe forms of the disease, the next question is whether OC use prevents the onset of the disease or ameliorates its course. The nature of the present study does not allow this question to be answered. According to earlier data on this patient group (lo), the negative association between OC use and RA was independent of OC dose, duration, and past or current use, which is consistent with most other studies. The only exception is a case-control study in which OC were associated with a reduced incidence of RA only after 12 months of use (9). These findings support an effect that prevents the development of the disease, rather than a diseasemodifying effect. The epidemiologic questions not addressed in this small study are many. There may be other factors associated with RA and the use of OC, such as socioeconomic factors, marriage, and parity. These are addressed in further reports of the original casecontrol study and other relevant literature (29-3 1).
ORAL CONTRACEPTIVES IN THE RISK OF SEVERE RA ACKNOWLEDGMENTS The authors thank c*Braakman-van Wijk for technical assistance with data processing and J. Ravensbergen for secretarial assistance.
REFERENCES 1. Wingrave SJ, Kay CR: Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Lancet I:569-571, 1978 2. Vandenbroucke JP, Boersma JW, Festen JJM, Valkenburg HA, Cats A, Huber-Bruning 0, Rasker JJ: Oral contraceptives and rheumatoid arthritis: further evidence for a preventive effect. Lancet IM39-842, 1982 3. Linos A, O’Fallon WM, Worthington JW, Kurland LT: Case-control study of rheumatoid arthritis and prior use of oral contraceptives. Lancet I: 1299-1300, 1983 4. Vandenbroucke JP, Witteman JCM, Valkenburg HA, Boersma JW, Cats A, Festen JJM, Hartman AP, HuberBruning 0, Rasker JJ, Weber J: Noncontraceptive hormones and rheumatoid arthritis in perimenopausal and postmenopausal women. JAMA 255: 1299-1303, 1986 5 . Del Junco DJ, Annegers JF, Luthra HS, Coulam CB, Kurland LT: Do oral contraceptives prevent rheumatoid arthritis? JAMA 254: 1938-1941, 1985 6. Alebeck P, Ahlbom A, Ljungstrom K, Allander E: Do oral contraceptives reduce the incidence of rheumatoid arthritis? Scand J Rheumatol 13: 140-146, 1984 7. Vessey MP, Villard-Mackintosh L, Yeates D: Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception 35:457-464, 1987 8. Hernandez-Avila M, Liang M, Willett WC, Stampfer MJ, Colditz G, Rosner B, Hennekens CH. Speizer FE: Oral contraceptives and postmenopausal hormone use and the risk of rheumatoid arthritis (abstract). Arthritis Rheum 31 (suppl4):S36, 1988 9. Spector T, Silman A, Roman E: Protective effect of prior oral contraceptive use for rheumatoid arthritis (abstract). Arthritis Rheum 31 (suppl 4):S58, 1988 10. 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 33:173-179, 1990 11. Female sex hormones and rheumatoid arthritis. Br J Rheumatol 28 (suppl 1):1-72, 1989 12. Spector TD, Hochberg MC: The protective effect of the oral contraceptive pill on rheumatoid arthritis: an overview of the analytical epidemiological studies using meta-analysis. Br J Rheumatol 28 (suppl 1): 11-12, 1989 13. 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 14. Siegert CEH, Vleming LJ, Vandenbroucke JP, Cats A: Measurement of disability in Dutch rheumatoid arthritis patients. Clin Rheumatol 3:305-309, 1984 15. Fries JF, Spitz P, Kraines RG, Holman HR: Measure-
1465
ment of patient outcome in arthritis. Arthritis Rheum 23:137-145, 1980 16. The Epidemiology of Chronic Rheumatism: Atlas of Standard Radiographs of Arthritis. Vol 2. Edited by JH Kellgren, MR Jeffrey, J Ball. Oxford, Blackwell, 1963 17. Vankood JJ, van Leeuwen A, Ploem JS: Simultaneous detection of two cell populations by two-colour fluorescence and application to the recognition of B-cell determinants. Nature 262:795-797, 1976 18. Woolf B: On estimating the relation between bloodgroup and disease. Ann Hum Genet 19:251-253, 1955 19. Mantel N , Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. JNCI 22:719-748, 1959 20. Cats A, van der Linden S, Goei The HS, Khan MA: Proposals for diagnostic criteria of ankylosing spondylitis and allied disorders. Clin Exp Rheumatol 5:167-171, 1987 21. Calin A. Porta J, Fries JF, Schurman DJ: Clinical history as a screening test for ankylosing spondylitis. JAMA 237:2613-2614, 1977 22. Sherrer YS, Bloch DA, Mitchell DM, Young DY, Fries JF: The development of disability in rheumatoid arthritis. Arthritis Rheum 29:494-500, 1986 23. Brook A, Corbett M: Radiographic changes in early rheumatoid disease. Ann Rheum Dis 36:71-73, 1977 24. Brook A, Fleming A, Corbett M: Relationship of radiological change to clinical outcome in rheumatoid arthritis. Ann Rheum Dis 36:274-275, 1977 25. Vandenbroucke JP, Hazes JMW, Dijkmans BAC, Cats A: Oral contraceptives and the risk of rheumatoid arthritis: the great transatlantic divide? Br J Rheumatol 28 (SUPPI 1):1-3, 1989 26. Cats A, Hazevoet HM: Significance of positive tests for rheumatoid factor in the prognosis of rheumatoid arthritis. Ann Rheum Dis 29:254-260, 1970 27. Westedt ML, Breedveld FC, Schreuder GMTh, D’Amaro J, Cats A, de Vries RRP: Immunogenetic heterogeneity of rheumatoid arthritis. Ann Rheum Dis 45: 534-538, 1986 28. De Jongh BM, van Romunde LKJ, Valkenburg HA, de Lange GG, van Rood JJ: Epidemiological study of HLA and GM in rheumatoid arthritis and related symptoms in an open Dutch population. Ann Rheum Dis 43:613-619, 1984 29. Hazes JMW, Dijkmans BAC, Vandenbroucke JP, de Vries RRP, Cats A: Pregnancy experience associated with the risk of rheumatoid arthritis (abstract). Br J Rheumatol 28 (suppl 2):87, 1989 30. Hazes JMW, Dijkmans BAC, Vandenbroucke JP, de Vries RRP, Cats A: Cigarette smoking and the onset of rheumatoid arthritis (abstract). Br J Rheumatol28 (suppl 2):95, 1989 31. Spector TD, Roman E, Silman AJ: The pill, parity, and rheumatoid arthritis. Arthritis Rheum 33:782-789, 1990
DIMINISHED INCIDENCE OF SEVERE RHEUMATOID ARTHRITIS ASSOCIATED WITH ORAL CONTRACEPTIVE USE DERKJEN V A N ZEBEN, JOHANNA M. W. HAZES, JAN P. VANDENBROUCKE, BEN A. C. DIJKMANS, and ARNOLD CATS It has been suggested that the negative association between rheumatoid arthritis (RA) and oral contraceptive (OC) use might be limited to the more severe forms of RA. To investigate this further, we studied 121 consecutive female patients with definite RA, 52 female patients with probable RA, and 378 female controls. All patients had RA symptoms of recent onset. After a mean followup period of 6 years, patients with definite RA were classified as having either a severe disease course (n = 76) or a mild disease course (n = 45). The negative association between OC use prior to the onset of RA symptoms and the development of RA was limited to those patients with definite RA who had a severe disease course. We therefore conclude that OC use prior to the onset of RA symptoms is only associated with a reduction in the incidence of severe RA. This may explain the divergent results of previous studies. Conflicting findings about the negative association of oral contraceptive (OC) use and the development of rheumatoid arthritis (RA) have been published (1-10). In April 1989, an international roundtable conference was organized t o discuss these conflicting results (11). In a metaanalysis, the reduction in the incidence of RA associated with OC use was restricted mainly to hospital-based studies, whereas populationFrom the Departments of Rheumatology and Clinical Epidemiology, University Hospital, Leiden, The Netherlands. Derkjen van Zeben, MD: Department of Rheumatology; Johanna M. W. Hazes, MD: Department of Rheumatology: Jan P. Vandenbroucke, MD: Department of Clinical Epidemiology; Ben A. C. Dijkmans, MD: Department of Rheumatology; Arnold Cats, MD: Department of Rheumatology. Address reprint requests to Derkjen van Zeben, MD, University Hospital, Department of Rheumatology, Building I , C2-Q, PO Box 9600, Leiden 2300 RC, The Netherlands. Submitted for publication November 21, 1989; accepted in revised form April 11, 1990. Arthritis and Rheumatism, Vol. 33, No. 10 (October 1990)
based studies showed no such protective effect of OC (12). In general, the latter studies dealt with milder forms of RA. It was therefore suggested that OC use might only protect against more severe forms of RA. In a previous case-control study, the preventive effect of OC on the incidence of RA was assessed (10). Subsequently, we enrolled the patients from that study into a followup study extending over the next 6 years. This enabled us to subdivide the patient groups according to the 6-year outcome of their RA. The aim of the present investigation was to investigate whether the negative association between OC use and RA was different in mild and severe forms of the disease.
PATIENTS AND METHODS The present investigation was started as a casecontrol study to determine the preventive effect of OC use on the incidence of R A (10). The study was started in 1984 at the Department of Rheumatology , Leiden University Hospital in The Netherlands, which is the only referral clinic for rheumatic disorders in the area. All consecutive women who attended the outpatient clinic for the first time between 1982 and 1986, who had recent onset of symptoms of RA (12.5 IU by latex fixation and/or >25 IU by the Rose-Waaler test. HLA-DR tissue typing was performed in 97% of all women, according to the double fluorescence technique (17). Outcome assessment. In the fall of 1989, we started to analyze our data. Since the patients entered the study between 1982 and 1986, the duration of followup varied. For the present study, where outcome was evaluated, only patients with a followup of 3 or more years were selected; 12 patients who developed symptoms of RA late in 1986 were excluded because the followup time was too short, and 2 patients had refused to cooperate. Thirty-five patients who were originally classified as having possible RA were excluded because a different diagnosis was ultimately made. At the end of the followup period, patients with RA were divided into 2 groups according to disease severity. Patients were classified as having severe RA if 1 of the following characteri$ics was present: a disability score 21.25, erosion score 230, mean number of persistently swollen joints 2 4 , use of 2 or more disease-modifying drugs, or the presence of nodules and other extraarticular manifestations. If none of these characteristics was present, patients were classified as having mild RA. Statistical analysis. OC exposure was defined both for patients and controls as any use of OC prior to the onset of RA. Crude odds ratios, as estimates of the relative risk (RR), were calculated, with 95% confidence intervals (CI) accord-
1463
Characteristics of controls, patients with probable rheumatoid arthritis (RA), and patients with definite or classic RA
Table 1.
Definite/classic RA
Probable Controls RA Mild Severe (n = 378) (n = 52) (n = 45) (n = 76) Mean age at symptom onset (years) Mean age at first visit (years) Mean time between symptom onset and first visit (years) Mean followup from symptom onset (years) % seropositive % HLA-DR4 positive
36.2
36.5
35.4
36.7
37.8
37.7
37.7
38.5
I .6
1.3
I .5
1.8
4.6
5.8
6.1
28.8 27.3
41.3 34.8
76.3 60.5
-2.0 2.6 25.4
ing to the method of Woolf (18). Mantel-Haenszel summary odds ratios were computed to adjust for year of birth (19). A 95% CI excluding unity was considered statistically significant at the 5% level. Since controlling for other potential confounders (age at symptom onset, marital status, age at menarche, menopausal state, parity, history of smoking and drinking) had not yielded material differences in our previous study, this procedure was omitted in the present study.
RESULTS After 6 years, 52 patients were diagnosed as having either possible or probable RA. These patients had oligoarthritis, polyarthritis, or arthralgias, sometimes with positive rheumatoid factor or a single erosive joint lesion, and they did not fulfill the criteria for definite or classic RA, or for a seronegative spondylarthropathy (20,21). None of these patients fulfilled any of the severity criteria. One hundred twenty-one patients had definite or classic RA. The percentages of all patients with definite RA fulfilling each severity criterion were 23% for disability score 21.25, 39.7% for erosion score 230, 43% for mean number of persistently swollen joints 2 4 , 24.8% for use of 2 2 disease-modifying drugs, and 14.9% for the presence of nodules and other extraarticular manifestations. According to our definition, 76 patients had a severe disease course, and 45 patients had a mild disease course. All patients and controls were comparable with respect to age at symptom onset and age at first visit to the outpatient clinic (Table 1). The mean duration of followup from symptom onset was comparable in patients with definite RA who had a severe or mild disease course, and slightly lower in patients with probable RA (Table I). The percent-
VAN ZEBEN ET AL
1464
Table 2. Relative risk (RR) estimates for oral contraceptive (OC) use before onset of symptoms in controls, patients with probable rheumatoid arthritis (RA), and patients with definite or classic RA Definiteklassic RA Probable Controls RA Mild Severe (n = 378) (n = 52) (n = 45) (n = 76)
OC use* 323 (85.4) 42 (80.7) 37 (82.2) 50 (65.8) RR 1 0.72 0.79 0.33 95% confidence interval 0.27-1.89 0.21-2.79 0 . 1 9 4 5 7
* Values are the number (%) of individuals who had ever used OC prior to the onset of RA symptoms.
ages of seropositivity and HLA-DR4 positivity were highest in patients with severe definite RA and lowest in the control group, as had been expected (Table I). The risk of severe RA among women who had used oral contraceptives prior to the onset of symptoms (RR = 0.33) was less than half that among women who had never used oral contraceptives; the 95% CI excluded unity (0.19-0.57) (Table 2). This negative association was not found in patients who had definite RA with a mild disease course or in patients with probable RA. When patients with a short followup period were also included, the risk of severe RA relative to the control group was 0.29 (95% CI 0.17O S O ) , and the risk of mild RA relative to the control group was 0.76 (95% CI 0.24-2.38). Adjustment for age in the various subgroups yielded no material difference (data not shown).
DISCUSSION The results of the present study indicate that the negative association between oral contraceptive use and the incidence of rheumatoid arthritis is limited to the more severe forms of the disease. In this prospective study, we were able to evaluate outcome in a group of consecutive RA patients followed, from the start of the disease, for a mean duration of 6 years, a period during which disability and erosive joint lesions become prominent (22-24). The negative association between OC use and the more severe forms of RA could explain the divergent results of previous studies (1-11). In hospitalbased studies, the more severe forms of RA will be encountered. This clarifies the finding of a reduced incidence of RA among OC users, as opposed to the lack of association with OC use in population-based studies, where the milder forms of RA predominate, and where the effect of OC use is possibly diluted. Because most European studies have been hospital based and the US studies have been population
based, our findings could also bridge the “transatlantic divide” described by Vandenbroucke et al, who only found a protective effect of OC use on one side of the ocean (25). The novelty of our approach lies in the examination of the association of RA and OC use in terms of the outcome of the disease. In the past, only the ARA diagnostic criteria have been used as an approximation of disease severity (5). No difference in the effect of OC exposure could be found between probable, definite, or classic RA subgroups. Separate analyses of seropositive and seronegative RA patients showed only a slightly stronger effect of OC use in seropositive patients in 2 studies (2,lO) and no difference in a third (5). Likewise, the effect of OC exposure did not differ markedly between HLA-DR4 positive and HLA-DR4 negative women (10). Although rheumatoid factor and HLA-DR4 are associated with an unfavorable course of RA (26,27), when used independently as parameters for disease outcome, they are obviously not sufficiently predictive to show the negative association of OC use on the occurrence of severe RA. The frequency of HLA-DR4 in patients with definite RA and a mild disease course was lower than that found in a cross-sectional study done in our outpatient clinic (27) and was comparable with the HLA-DR4 frequency in RA patients in an open Dutch population (28). In view of the fact that we prospectively studied incident cases, some of which would escape detection in a cross-sectional study, our results and the results of these other studies are not discordant. Since it appears that the negative association between OC use and RA is found mainly in the severe forms of the disease, the next question is whether OC use prevents the onset of the disease or ameliorates its course. The nature of the present study does not allow this question to be answered. According to earlier data on this patient group (lo), the negative association between OC use and RA was independent of OC dose, duration, and past or current use, which is consistent with most other studies. The only exception is a case-control study in which OC were associated with a reduced incidence of RA only after 12 months of use (9). These findings support an effect that prevents the development of the disease, rather than a diseasemodifying effect. The epidemiologic questions not addressed in this small study are many. There may be other factors associated with RA and the use of OC, such as socioeconomic factors, marriage, and parity. These are addressed in further reports of the original casecontrol study and other relevant literature (29-3 1).
ORAL CONTRACEPTIVES IN THE RISK OF SEVERE RA ACKNOWLEDGMENTS The authors thank c*Braakman-van Wijk for technical assistance with data processing and J. Ravensbergen for secretarial assistance.
REFERENCES 1. Wingrave SJ, Kay CR: Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Lancet I:569-571, 1978 2. Vandenbroucke JP, Boersma JW, Festen JJM, Valkenburg HA, Cats A, Huber-Bruning 0, Rasker JJ: Oral contraceptives and rheumatoid arthritis: further evidence for a preventive effect. Lancet IM39-842, 1982 3. Linos A, O’Fallon WM, Worthington JW, Kurland LT: Case-control study of rheumatoid arthritis and prior use of oral contraceptives. Lancet I: 1299-1300, 1983 4. Vandenbroucke JP, Witteman JCM, Valkenburg HA, Boersma JW, Cats A, Festen JJM, Hartman AP, HuberBruning 0, Rasker JJ, Weber J: Noncontraceptive hormones and rheumatoid arthritis in perimenopausal and postmenopausal women. JAMA 255: 1299-1303, 1986 5 . Del Junco DJ, Annegers JF, Luthra HS, Coulam CB, Kurland LT: Do oral contraceptives prevent rheumatoid arthritis? JAMA 254: 1938-1941, 1985 6. Alebeck P, Ahlbom A, Ljungstrom K, Allander E: Do oral contraceptives reduce the incidence of rheumatoid arthritis? Scand J Rheumatol 13: 140-146, 1984 7. Vessey MP, Villard-Mackintosh L, Yeates D: Oral contraceptives, cigarette smoking and other factors in relation to arthritis. Contraception 35:457-464, 1987 8. Hernandez-Avila M, Liang M, Willett WC, Stampfer MJ, Colditz G, Rosner B, Hennekens CH. Speizer FE: Oral contraceptives and postmenopausal hormone use and the risk of rheumatoid arthritis (abstract). Arthritis Rheum 31 (suppl4):S36, 1988 9. Spector T, Silman A, Roman E: Protective effect of prior oral contraceptive use for rheumatoid arthritis (abstract). Arthritis Rheum 31 (suppl 4):S58, 1988 10. 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 33:173-179, 1990 11. Female sex hormones and rheumatoid arthritis. Br J Rheumatol 28 (suppl 1):1-72, 1989 12. Spector TD, Hochberg MC: The protective effect of the oral contraceptive pill on rheumatoid arthritis: an overview of the analytical epidemiological studies using meta-analysis. Br J Rheumatol 28 (suppl 1): 11-12, 1989 13. 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 14. Siegert CEH, Vleming LJ, Vandenbroucke JP, Cats A: Measurement of disability in Dutch rheumatoid arthritis patients. Clin Rheumatol 3:305-309, 1984 15. Fries JF, Spitz P, Kraines RG, Holman HR: Measure-
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