ARTHRITIS & RHEUMATISM Vol. 40, No. 9, Septembcr 1997, pp 1580-1586 0 1997, American College of Rheumatology 1580 RHEUMATOID ARTHRITIS AND THE RISK OF MALIGNANCY JOLANDA CIBERE, JOHN SIBLEY, and MAY HAGA Objective. To determine the relative risks of malignancy and of site-specific malignancies in patients with rheumatoid arthritis (RA). Methods. In a prospective cohort study, 862 patients with RA (96% white) were enrolled from 1966 to 1974 and were followed up for up to 35 years (mean 17.4 years) at the University of Saskatchewan Rheumatic Disease Unit. All diagnoses of cancer were crossreferenced with the Provincial Cancer Registry. Expected cancer incidence rates were determined based on province of Saskatchewan population statistics matched to each study patient for age, sex, and calendar year. Standardized incidence ratios (SIRS) of the observedto-expected cancer incidence and 95% confidence intervals (95% CI) were then calculated. Results. A total of 136 cases of cancer were observed compared with 168 expected (SIR 0.80, P = 0.011 [95%CI 0.67-0.951). The relative risk of colorectal malignancy was significantly reduced in the RA study population (SIR 0.52, P = 0.037 [95%CI 0.25-0.961). A significant excess of leukemia was found (SIR 2.47, P = 0.026 [95% CI 1.12-4.69]), whereas the incidence rates for Hodgkin’s disease and non-Hodgkin’s lymphoma and all other site-specific malignancies were not found to be significantly different from general population rates. Conclusion. In our cohort of RA patients, colorectal cancer was detected in only half the expected number of patients. This risk reduction may be related to long-term nonsteroidal antiinflammatory d ru g (NSAID) use in RA, as has been suggested in several other studies of long-term NSAID use. An increased risk of leukemia was confirmed. This may be due to the persistent immune stimulation associated with RA itSupported by NIH grant AM-21393 to the Arthritis, Rheumatism and Aging Medical Information System. Jolanda Cibere, MD, John Sibley, MD, May Haga, B A University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Address reprint requests to John Sibley, MD, Royal University Hospital, Saskatoon, SK S7N OW& Canada. Submitted for publication December 16, 1996; accepted in revised form April 11, 1997. self, since other potential explanatory factors for increased leukemia were not apparent. Despite the excess of hemopoietic malignancy and despite treatment of RA with potentially oncogenic agents, the overall risk of malignancy was reduced in this RA cohort. Several authors have investigated an association between rheumatoid arthritis (RA) and malignancy (16). This information is summarized in Table 1. In 1978, a large cohort study by Isomaki et a1 (1) demonstrated an increased risk of leukemia, lymphoma, and multiple myeloma as well as a significantly increased risk of cancer of the respiratory organs in men, and a decreased risk of stomach and rectal cancer in women. Subsequent studies (2-5), with the exception of one (6), have generally confirmed the higher incidence of lymphoproliferative and myeloproliferative malignancies in RA. However, there is disagreement regarding what subtypes of hemopoietic cancers are increased in RA. An increased incidence of non-Hodgkin’s lymphoma was confirmed in a study by Prior et a1 (2) and in a large Swedish study by Gridley et a1 ( 5 ) , although, in the latter study, non-Hodgkin’s lymphoma was significantly increased in women only. Other studies have found an increased risk of multiple myeloma (3,4). An excess of leukemia has not been reported since the study by Isomaki et a1 (1) in 1978. Similarly, differences in the rates of solid tumors in RA have not been widely confirmed in the literature with the exception of the study by Gridley et a1 ( 5 ) ,which found a reduced risk of colon cancer in women. Also germane to any examination of RA and malignancy is the cancer-sparing or cancer-promoting potential of RA therapies. Animal studies have shown that various nonsteroidal antiinflammatory drugs (NSAIDs) can prevent colon carcinogenesis in rats (7-9). Recently, several large studies of human cohorts (10-13) have shown a reduced risk of colorectal cancer in association with regular, long-term aspirin use. In addition, Schreinemachers and Everson ( 3 3) reported reduced rates of lung and breast cancer in women who took aspirin regularly. This is of particular interest in RISK OF MALIGNANCY IN RA 1581 Table 1. Published studies of rheumatoid arthritis and the risk ratios for malignancy 0bserved:expected risk of malignancy Study (ref. no.) Isomaki et al, 1978 (1) No. of patients 11,483 men, 34,618 women Prior et al, 1984 (2) 448 Katusic et al, 1985 (3) 521 Gridley et al, 1993 (5) 3,750 men, 7,933 women Moritomo et al, 1995 (6) 665 Hemopoietic Non-llodgkin’s Hodgkin’s Multiple Colorectal Colon Rectal Lung cancer Leukemia lymphoma disease myeloma cancer cancer cancer cancer 2.7* 2.78 23.0$ 3.2 1.8 1.9t 2.2 3.18 7.1 2.1.12.2$ - - 1.2 - 4.6t 0.9 5.01 1.8 0.8 - - 2.5* 1.4 4.9 1.9 1.9 0.8 1.3 - - - - 1.7 - 8.0$ - - - 1.1 0.8 ~ 1.2 0.7 O.ht ~ 0.6 0.6t - 0.5 0.7 0.7 - 1.3* 1.3 0.8 1.4 1.2 1.5 0 * P < 0.01. t P < 0.05. $ P < 0.001. RA, since most R A patients are long-term users of aspirin or other NSAIDs. Indeed, it is somewhat surprising that RA studies have generally not reported a lower-than-expected incidence of colorectal cancer. In 1985, Fries et a1 (14) assessed the effects of gold or prednisone therapy on mortality and found a trend of reduced deaths due to malignancy in R A patients who were treated with either of these 2 drugs. Conversely, several studies have investigated the possibility of an increased risk of malignancy in RA patients treated with disease-modifying antirheumatic drugs (DMARDs) (15-19). Azathioprine has been reported to be associated with an 8-10-fold increased risk of lymphoproliferative malignancies in RA patients (16,17). Cyclophosphamide therapy is well known to increase the risk of lymphoproliferative malignancy (20,21), and this trend has been found in patients with RA as well (15,18). Methotrexate may also be associated with hemopoietic malignancies, although the literature consists predominantly of case reports (22-26). In a recent case-control study, Williams et a1 (19) found that R A patients with leukemia or lymphoma showed a trend toward increased prior methotrexate or azathioprine use compared with matched RA controls without leukemia or lymphoma. In our institution, we have a large R A cohort that has been followed up prospectively since 1966. This has given us the opportunity to further evaluate the longterm risk of malignancy in RA. PATIENTS AND METHODS Patients. During the study enrollment period, our university-based Rheumatic Disease Unit (RDU) was the sole referral center for the northern half of the province of Saskatchewan, serving a population of -450,000 with a racial composition of -96% white and 4% North American Indian. All consecutive new patients with a clinical diagnosis of RA in whom symptoms started after age 16 and who were seen between 1966 and 1974 (n = 1,191) were assessed by a rheumatologist and enrolled into a long-term prospective study of outcome in RA (27). More than 90% were first seen as outpatients. Prospective data collection began in 1966. Patients who had been seen in the RDU between 3955 and 1965 and who were still being followed up after 1966 were also entered into the study (n = 285). For these patients, the 195.5-1965 data were retrospectively abstracted from all available clinic and hospital records. Our study population does not represent an inception cohort. We could not account for those patients with RA for whom cancer may have preempted their eventual referral to our RDU. Thus, we excluded from our analysis all patients who had a diagnosis of cancer made prior to their first visit to the RDU (n = 26). In addition, patients who developed cancer within the first year of followup (n = 5) were excluded in order to reduce the possibility of recruitment bias due to inadvertent inclusion of patients who had rheumatologic manifestations due to an underlying malignancy (28,29). Study closure was January 1 , 1995. Evaluation. After the initial comprehensive examination, patients were seen once yearly or more frequently as clinically indicated. Standard clinical data (30) were gathered throughout the study course. Since 1981, followup also consisted of a semi-annual mailing of the Stanford Health Assessment Questionnaire (HAQ) (31). The HAQ inquires into a broad spectrum of health concerns, including comorbid diagnoses. All diagnoses of cancer were confirmed and crossreferenced with the Provincial Cancer Registry. This registry is a record of all premorbid diagnoses of cancer in our province since 195.5. Prior to 1988, diagnoses of cancer that were established only on the death certificate or at autopsy were not recorded in the Cancer Registry. Therefore, in order to ensure like comparisons, cancers within our study cohort that were diagnosed only at death prior to 1988 were excluded. Prevalence rates in relation to the risk factors of smoking and obesity were determined from HAQs completed between 1984 and 1986. Obesity was defined as a body mass index >27.8 for men and >27.3 for women (32). Sjogren’s syndrome was diagnosed clinically if there CIBERE ET AL 1582 was believed to be substantial dryness of the eyes or mouth for no other apparent reason. Many, but not all, patients diagnosed with Sjogren's syndrome were referred to ophthalmologists for diagnostic confirmation and therapy. Vasculitis was also diagnosed clinically. Biopsies for Sjogren's syndrome and vasculitis were done if hclieved to be clinically warranted, but were not required as part of this study. RA functional class was defined in accordance with the classification system of Steinbrocker et a1 (33). Statistical analysis. Provincial cancer statistics were used to calculate the expected cancer incidence rates for each study patient, corrected for age, sex, and calendar year. The relative risks of any cancer and of each site-specific cancer for the study cohort were then calculated as standardized incidence ratios (SIRS), that is, the ratio of observed-to-expectcd cancers, along with the corresponding 95% confidence intervals (95% CI) (34). The first year of followup was censored for each patient. The last year of followup was censored for each patient, unless a malignancy of interest was diagnosed in that year, or unless followup was known to extend beyond study closure. All data after the diagnosis of cancer were excluded. For those patients lost t o followup at study closure, all data up to the loss of followup were included. Rates for smoking and obesity in the general population were derived from Canadian epidemiology studies conducted during the 1980s (35,36), and were compared with the rates found in the study group, using the chi-square test. Statistical significance was defined as P < 0.05. RESULTS Of the original 1,191 patients enrolled with a clinical diagnosis of RA, 893 were found to have definite or classic RA (37). Of these, 26 patients had cancer diagnosed prior to study enrollment (i.e., prior to first contact at our RDU) and 5 developed cancer within the first year of followup. These 31 patients were excluded from further analysis. The 5 malignancies excluded during the first year of followup were 1 lymphosarcoma, 1 colorectal, 1 lung, 1 prostate, and 1 skin cancer. Inclusion of these patients in the analysis did not change the significance of our results. The study population of interest thus consisted of 862 patients. At study closure, their status was as follows: 330 (38%) were still under observation, 466 (54%) had died, 26 (3%) had refused to participate, and 40 (5%) were lost to followup. Our findings are based on 14,998 patient-years of followup. A summary of the demographic and clinical features, as well as the medication use, of the study cohort is shown in Table 2. As expected, almost all the patients had been receiving NSAID therapy, most of them on a long-term basis. Azathioprine, methotrexate, and cyclophosphamide were used by 7 % , 7 % , and 2% of patients, respectively. Any 1 of these 3 cytotoxic agents was used in 12% of the patients. Table 2. Characteristics of the rheumatoid arthritis (RA) study patients" RA patients (n = 862) Feature Demographic Sex, 5% female Race, % white Mean followup (range), years Mean age (range) at onset of RA, years Clinical Rheumatoid factor positive Subcutaneous nodules Joint erosions RA functional class 2-3 Vasculitis Sjogren's syndrome Drug use All NSAIDs Aspirin Prednisone Parenteral gold Hydroxychloroquine Penicillamine Azathioprine Methotrexate Cyclophosphamide 67 96 17.4 (0.6-35) 43 (16-82) 91 57 89 13 10 32 97 95 63 50 29 23 7 7 2 Except where otherwise indicated, values are the percentage of patients. NSAIDs = nonsteroidal antiinflammatory drugs. Potential lifestyle risk factors for cancer in our patients and in the general population are compared in Table 3. The proportion of current smokers was greater in the study patients than in the general population (36% versus 29%; P > 0.05), particularly in women, where the difference reached statistical significance (44% versus 28%; P < 0.001). The prevalence of obesity in the study cohort was similar to that in the general population (35% versus 31%), with a slight predominance in both male (42% versus 35%) and female (32% versus 27%) RA patients, although these differences Table 3. Incidence rates of cancer risk factors in rheumatoid arthritis (RA) patients and the general population" Prevalence, % Risk factor Smoker Total Male Female Obesity Total Male Female " NS = RA patients (1984-1986) General population (1986-1990) P 36 28 44 29 30 28 NS NS <:0.001 35 42 32 31 35 27 NS NS NS not signficant (P> 0.05). RISK OF MALIGNANCY IN RA 1583 Table 4. lncidence of site-specific cancers in rheumatoid arthritis patients* Cancer site All Bladder Breast Colorectal Gynecologic Ovary Uterus Cervix Kidney Liverigallbladder Lung Female Male Hemopoie tic Leukemia Non-Hodgkin’s lymphoma Hodgkin’s disease Oropharynx Pancreas Prostate Skin Stomachiesophagus Observed: expected incidence 136:167.5 2:5.4 18:22.8 10:19.0 10:12.71 5:5.6 4:6.4 112.0 5r3.1 512.6 16:14.8 516.0 11:8.8 12:9.6 913.6 3:5.5 0:0.43 3:1.00 5:3.9 12:12.0 45151.6 415.6 SIR 95% CI P 0.80 0.36 0.90 0.52 0.78 0.89 0.62 0.49 1.62 1.93 1.08 0.84 1.24 1.25 2.47 0.55 0.00 3.00 1.27 1.00 0.83 0.71 0.67-0.95 0.04-1.33 0.46-1.24 0.25-0.96 0.36-1.44 0.28-2.09 0.16-1.60 0.06-2.76 0.52-3.78 0.62-4.50 0.61-1.75 0.27-1.96 0.62-2.22 0.64-2.18 1.12-4.69 0.11-1.60 0.00-8.53 0.60-8.76 0.41-2.96 0.51-1.74 0.63-1.16 0.19-1.84 0.01 1 NS NS 0.037 NS NS NS NS NS NS NS NS NS NS 0.026 NS NS NS NS NS NS NS *SIR = standardized incidence ratio; 95% CI interval; NS = not signficant (P > 0.05). = 95% confidence were not statistically significant. Data on other risk factors for malignancy, such as hormone therapy, dietary factors, and family history, were not available. By 35 years of followup, 136 of the 862 RA patients were identified as having malignancies, whereas 168 were expected (SIR 0.80, P = 0.011 [95% CI 0.67-0.951) (Table 4). Colorectal cancer risk was reduced by nearly half, with 10 cases observed compared with 19 expected (SIR 0.52, P = 0.037 [95% CI 0.250.961). There was a trend toward a reduced risk for breast cancer in women, although the apparent reduction was not statistically significant. The overall risk of hemopoietic malignancy was only slightly increased (SIR 1.25, P > 0.05 [95% CI 0.64-2.181). However, subanalysis showed that leukemia was significantly overrepresented (SIR 2.47, P = 0.026 [95% CI 1.12-4.691). No cases of Hodgkin’s disease were identified, and only 3 patients developed non-Hodgkin’s lymphoma (SIR 0.55, P > 0.05 [95% CT 0.11-1.601). Lung cancer was more frequent than expected, but not significantly so. Because of the significant differences in smoking rates observed in our cohort, lung cancer was analyzed separately for men and women, but the results showed no difference from expected rates for either subgroup. There was no difference in observed and expected rates of prostate cancer. No other statistically significant differences were found, although the number of cases of each of the other site-specific malignancies was small. DISCUSSION In our cohort of RA patients, we found a reduced risk of colorectal cancer. This has not been a universal finding in other studies. Isomaki et a1 (1) and Gridley et al ( 5 ) did report reduced rates of colorectal cancer in their series of RA patients. In contrast, several studies (2,3,6) found trends toward an increased risk for colorectal cancer, although these series involved small numbers of malignancies and the excess occurrences were not statistically significant. Our results are consistent with reports of reduced colorectal malignancy among patients who are regular users of aspirin (10-13). In those studies, it was noted that long-term aspirin use was associated with a progressive decrease in risk. However, this risk reduction does not become apparent until after at least 10 years of aspirin use on a regular basis. Most of our patients had been on a long-term regimen of NSAIDs, and our followup was sufficient to be able to confirm a reduced risk of colorectal cancer. Factors other than NSAID use that may have contributed to the reduced occurrence of colorectal cancer observed in our cohort are not apparent. Corticosteroids also inhibit prostaglandin synthesis, and 65% of our study cohort received corticosteroids at some time. Although we had an insufficient number of patients to assess for any cancer-sparing effect of corticosteroids independent of NSAIDs, we did not observe any enhanced reduction of colorectal cancer in those patients who received corticosteroids (unpublished observations). It is conceivable that increased frequency of gastrointestinal (GI) symptoms or GI bleeding could lead to increased investigations and therefore early detection of precancerous lesions in NSAID users. However, this is unlikely to account for the large risk reduction found in our cohort. Generally, the concern about GI blood loss in NSAID users is focused on bleeding in the upper GI area. We did not have a screening program for occult GI bleeding. We do have coding for bowel polypectomy, but we had no information that any of our patients underwent benign polypectomy despite our followup with a semi-annual HAQ. Furthermore, our study patients were not subjected to additional surveillance with fecal occult blood testing or sigmoidoscopy other than the routine surveillance that applies to the general population. The risk reduction in colorectal cancer could 1584 have been conceivably due, in part, to RA itself, although to date no such pathogenetic mechanism has been established or suggested. Furthermore, the degree of risk reduction for colorectal cancer that we observed (52%) is similar to that reported in non-RA NSAID users (10-13). Premature mortality is a feature in patients with RA, including our cohort (38). However, that should not have been a confounding factor in our results, since our controls were matched for age, as well as sex and calendar years of followup. Dietary factors appear to play a role in colorectal cancer, with obesity being associated with an increased risk of cancer (32). The prevalence of obesity in our study patients was slightly higher than in the general population. Thus, if anything, one would have expected more, not less, colorectal cancer in our study cohort, thereby adding to the significance of our results. Our data showed a trend toward an increased risk of lymphoproliferative malignancies. A similar trend has been observed in some studies (3,14), while other studies found not only a trend, but a significant excess of hemopoietic malignancies (1,2,5). In our subanalysis, leukemia was significantly overrepresented. This has not been consistently observed in the literature. In studies where subanalyses were done, only some (1,2,5) showed an excess of leukemia. In 2 of those studies (1,5), results were significant only for men, while in a third study (2), only women had an increased risk of leukemia. Similar inconsistencies have been noted for lymphoma, and are likely due to small numbers of observed malignancies. Nevertheless, there is a persistent overrepresentation of hematologic malignancies in previously published studies. This excess risk of hemopoietic malignancy was confirmed in our study. Although several factors have been proposed to account for the increased risk of lymphoproliferative malignancy in RA, those factors are not evident in our cohort. Cytotoxic medications, in particular azathioprine and cyclophosphamide, have been associated with an increased risk of hemopoietic malignancy (15-19). However, of our 12 patients with hemopoietic malignancy, only 2 had received cytotoxic agents. One had been receiving cyclophosphamide, while the other had received both cyclophosphamide and azathioprine. Thus, cytotoxic agents do not account for the increased leukemia seen in our cohort. Sjogren’s syndrome is also associated with an increased risk of lymphoproliferative malignancy, but this is an unlikely factor in this study. We diagnosed Sjogren’s syndrome on clinical grounds, not requiring biopsy or ophthalmology confirmation. Yet, despite CIBERE ET AL these less stringent diagnostic criteria, only 3 of our 12 patients with hemopoietic malignancies had Sjogren’s syndrome. Two of these 3 patients with Sjogren’s syndrome had received cytotoxic agents. Viruses, in particular Epstein-Barr virus, and other infectious agents have been investigated as causative agents in the pathogenesis of both lymphoma and RA (39,40), although to date no clear link has been established. Thus, it may well be that increased lymphoproliferative malignancy is a consequence of RA itself. RA is characterized by persistent immune stimulation. This chronic immune stimulation and polyclonal lymphocyte proliferation could conceivably increase the potential for malignant transformation, predisposing to an increased risk of hemopoietic malignancy. A trend toward increased lung cancer in RA has been reported (1,3,5), and in a large Finnish study (l), the difference reached statistical significance in men. The incidence of lung cancer in our study cohort was increased, although not significantly so. Whether the increase we observed is related to RA is not clear. Matteson et a1 reported increased lung cancer in RA patients treated with azathioprine (16), but the number of patients who were taking azathioprine or other cytotoxic agents was insufficient to make any inferences. Recent evidence has suggested that smokers are at greater risk of developing RA (41-43). Unfortunately, we had information on smoking history for only 20% of our RA patients (174 of 862), since the importance of smoking was not appreciated during the study enrollment period of 1966-1974, nor during the early followup years. Among those study patients for whom the smoking history was known, smoking rates were higher in RA patients compared with the general population (36% versus 29%; P > 0.05), and this difference was significant for female smokers (44% versus 28%; P < 0.001). This higher-than-expected prevalence of smoking may have contributed to the increased rate of lung cancer in our study population. Of course, RA itself and rheumatoid lung disease may predispose to lung cancer, as suggested by case studies in which malignant cells were found in rheumatoid lung nodules (44). There are several strengths to this study, including the large cohort and, in particular, the communitybased nature of the cohort. This should allow for the generalizability of our results to most white patients with RA. All cancer diagnoses in our province are recorded in the Provincial Cancer Registry, thus ensuring that ascertainment of cancer diagnoses was complete and accurate. Followup rates of the study patients have been good. In addition, the period of followup was sufficiently RISK OF MALIGNANCY IN RA long to allow for observation of differences in malignancy rates. Limitations of this study include the fact that there was an insufficient number of patients taking DMARDs and cytotoxic agents to assess for an association with malignancy. Only 50% of patients received p a r e n t e d gold and only 29% received hydroxychloroquine. Azathioprine, methotrexate, and cyclophosphamide were used in only 7%, 7%, and 2% of patients, respectively, and any 1 of these agents was used in only 12% of the patients. These rates of DMARD and cytotoxic usage are low by today’s standards, but they simply reflect the less aggressive approach taken in the management of RA that was the norm during the era of enrollment and in the early followup period of this study. An association of cytotoxic agents with lymphoproliferative malignancy would have been of particular interest, although in an earlier case-control study, we were unable to confirm an increased risk of lymphoproliferative malignancy in RA patients taking azathioprine, cyclophosphamide, or methotrexate (19). In addition, information on smoking and obesity was not complete, and may have been biased toward collecting such information from individuals at risk for those variables. By study conclusion, 54% of our cohort had died. While this is certainly a sizable portion, it is likely that the rate and distribution of malignancies will differ with continued followup as the survivors age. However, in this large cohort of predominantly white patients with RA, comprising 15,000 patient-years of followup, we found the risk of colorectal malignancy was significantly decreased. This risk reduction may be due, at least in part, to a cancer-protective effect of NSAID therapy. Whether other factors such as RA itself contribute to a cancer-protective effect will need to be determined in future investigations. In addition, a significant excess of leukemia was found, and a trend toward increased hemopoietic malignancy waf confirmed. Our data suggest that this increased risk of leukemia, rather than being related to external factors, may be secondary to persistent immune stimulation from R A itself. For many site-specific cancers, the numbers of cases were too small to assess. Nonetheless, despite an excess of hemopoietic malignancy and despite therapy with potentially oncogenic cytotoxic agents in 12% of our patients, the overall risk of malignancy was reduced in this R A cohort. - ACKNOWLEDGMENTS The authors gratefully recognize the work of Dr. D. M. Mitchell who initiated a long-term observational study of patients with RA in 1966, and followed up this large cohort, from which this study is drawn, until his death in 1988. 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