Relationship Between Rheumatoid Arthritis and Malignancy — Published Studies
This section will review published studies, prospective and retrospective, pertaining to the relationship between certain malignancies and rheumatoid arthritis.
Gadalla, et al., 2009
The risk of breast cancer in elderly women with systemic autoimmune rheumatic diseases (SARD), including RA, was evaluated in a population-based, case-control study of 84,778 women diagnosed with incident breast cancer and an equal number of cancer-free controls.12024 Females aged 67–99 that were diagnosed in 1993–2002 with incident primary invasive adenocarcinoma of the breast were identified using the Surveilence, Epidemiology, and End Results (SEER)-Medicare linked database. Controls were frequency matched in a 1:1 ratio for the calendar year of breast cancer diagnosis and age in 3 categories (67–74, 74–84, and 85+). Breast cancer patients were considered to have SARDs if they had 1 inpatient or 2 outpatient claims for various rheumatic diseases, including RA. The association of breast cancer risk and SARD, overall and by estrogen-receptor status, was calculated using unconditional logistic regression. Additional breast cancer risk, including obesity and parity, as well as, SARD severity, duration, and treatment history were not controlled for in this study. Of the cases with known estrogen receptor (ER) status (78.2%), most were ER-positive (84.9%). Four percent of study participants were identified as having at least 1 SARD condition (n=3033 in breast cancer cases, n=3396 in controls). Of those with more than 1 SARD condition, 84.6% had RA. Females with RA were found to have reduced risk for breast cancer (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82–0.92). This decreased risk was associated with ER-positive and ER-negative tumor status (OR 0.83, 95% CI 0.78–0.89 and OR 0.90, 95% CI 0.80–1.03, respectively).
Anderson, et al., 2009
The risk of myeloid malignancies in patients with certain autoimmune conditions was evaluated in a large population-based case-control study. 12052 A total of 13,486 patients with a diagnosis of myeloid malignancy were identified from the US Surveillance Epidemiology and End Results (SEER)-Medicare database; these were frequency matched to 160,086 population-based controls by hematopoietic malignancy by calendar year and age range. While many autoimmune diseases were analyzed in the report, only results for RA, UC, and CD are summarized here. In general, autoimmune disease was associated with an increased risk of acute myeloid leukemia (AML) (OR 1.29, 95% CI 1.20–1.39) and myelodysplastic syndrome (MDS) (OR 1.50, 95% CI 1.35–1.66). Acute myeloid leukemia was found to be positively associated with RA and ulcerative colitis (OR 1.28, 95% CI 1.11–1.47 and OR 1.72, 95% CI 1.28-2.31, respectively) and MDS was associated with RA (OR 1.52, 95% CI 1.27–1.81). In comparison, Crohn’s disease was found to be associated with chronic myeloproliferative disorder (OR 2.18, 95% CI 1.01–4.71). Overall, autoimmune conditions were not associated with an increased risk of chronic myeloid leukemia or chronic myeloproliferative disorder (OR 1.09, 95% CI 0.94–1.27 and OR 1.15, 95% CI 0.97–1.37, respectively).
Hemminki, et al., 2008
The risk of malignancy in rheumatoid arthritis (RA) was evaluated in a nationwide population of RA patients in Sweden. An RA database was constructed by linking several nationwide Swedish registries.12066 Cancer diagnoses were identified in the RA population by linking this database to the Swedish Cancer Registry. Of the 50,354 RA patients, 42,262 were hospitalized for the first time during the period 1980 to 2004 and were included in the analyses. Of these, 4366 patients developed cancer subsequent to being hospitalized for RA (overall standardized incidence ratio [SIR] 1.23, 95% CI 1.19–1.27); 3947 developed a malignancy later than 1 year after hospitalization for RA (SIR 1.17, 95% CI 1.13–1.20). The highest risk for all cancers was seen in the year following the first hospitalization for RA; however, the risk over time of developing most cancers was not different when calculated over the follow-up period. RA patients were found to be at highest risk for Hodgkin’s lymphoma (SIR 4.05, 95% CI 2.82–5.63), followed by non-Hodgkin’s lymphoma (SIR 2.34, 95% CI 2.07–2.63), squamous cell skin cancer (SIR 1.89, 95% CI 1.68–2.12), and lung cancer (SIR 1.73, 95% CI 1.57–1.89). The risk of other cancers was also increased in the study populations (see Table/figure). In contrast, the overall risk for many cancers was significantly decreased, including, colon (SIR 0.77, 95% CI .068–0.88), rectal (SIR 0.68, 95% CI 0.56–0.82), and endometrial cancers (SIR 0.73, 95% CI 0.55–0.79). Further, RA diagnosed in patients less than 50 years of age was a risk factor for certain cancers, including breast (SIR 1.21, 95% CI 1.04–1.39), squamous cell cancer of the skin (SIR 2.37, 95% CI 1.46–3.62), non-Hodgkin’s lymphoma (SIR 2.45, 95% CI 1.72–2.83), and leukemia (SIR 1.81, 95% CI 1.09–2.83). For most other sites, increased age at RA diagnosis correlated with a higher risk of malignant diagnosis.
Figure 3250 – SIR for Subsequent Cancer of Patients With RA by Follow-Up Time
Hemminki K. Cancer risk in hospitalized rheumatoid arthritis patients. Rheumatology 2008;47. Table 1 page 699 is used by Permission of The British Society of Rheumatology.
Some figures may not display clearly when rendered as a PDF or printed.
Khurana, et al., 2008
The risk of developing lung cancer was evaluated in a large case control study of US military veteran patients with RA. Of the 483,721 patients in the study population (91.7% male), 8768 (1.81%) had a diagnosis of RA and 7280 (1.5%) had a diagnosis of lung cancer.12026 Of the 7,280 patients with lung cancer, 247 (3.4%) had RA, compared with 8521 (1.8%) in the control population (those without a diagnosis of lung cancer, n=476,441). For those patients with available smoking data (72.6% total), 3623 cases (72.6%) and 180,894 controls (59.2%) had a history of smoking. After controlling for age, gender, tobacco, and asbestos exposure, the risk for lung cancer was found to be significantly increased in patients with RA (adjusted odds ratio [aOR] 1.43; 95% CI 1.23–1.65) compared to those without RA. Further, the risk for lung cancer in patients with RA increased with age with the risk was highest in patients older than 75 (aOR 1.61, 95% CI 1.27–2.05). However, the risk of developing lung cancer was not significantly elevated in patients younger than 55 years (aOR 1.59; 95% CI 0.95–2.67).
Smitten, et al., 2008
The risk of 4 malignancies, including lymphoma, lung, colorectal, and breast cancers, was evaluated in patients with RA.12053 The authors reported the results of a meta-analysis using 21 studies of population and community-based RA cohorts, which were published between January 1990 and December 2007. Of the 21 studies, 13 reported the standardized incidence ratio (SIR) for overall malignancy, 12 for lung cancer, 10 for colorectal cancer, 9 for breast cancer, and 14 for lymphoma. Compared to the general population, patients with RA were not at an increased risk for overall malignancies (SIR 1.05, 95% CI 1.01–1.09). However, RA patients were found to be at an increased risk lymphoma (SIR 2.08, 95% CI 1.80–2.39) with a higher risk for Hodgkin’s lymphoma observed than non-Hodgkin’s lymphoma (SIR 3.29, 95% CI 2.56–4.22 and SIR 1.95, 95% CI 1.70–2.24, respectively). Rheumatoid arthritis patients also had an increased risk of lung cancer with an estimated SIR of 1.63 (95% CI 1.43–1.87). In contrast, patients with RA were found to be at a decreased risk for colorectal and breast cancers (SIR 0.77, 95% CI 0.65–0.90 and SIR 0.84, 95% CI 0.79–0.90, respectively).
Mellemkjaer, et al., 2008
The risk of non-Hodgkin’s lymphoma (NHL) associated with a personal or family history of autoimmune disease was evaluated in a large, population-based case-control study.12054 This study included 24,728 NHL patients in Denmark (years 1977–1997) and Sweden (years 1964–1998) and 55,632 controls matched for age, sex, and country of residence. In total, 872 NHL patients and 1258 controls had autoimmune disease. Of the NHL patients and controls with autoimmune disease, 92.5% and 92.9% had 1 condition, 6.8% and 6.6% had 2 conditions, and 0.7% and 0.5% had 3 conditions, respectively. Results showed that a personal history of systemic autoimmune disease with the presence of autoantibodies was associated with an increased risk for NHL. Specifically, patients with RA were found to have an increased risk for NHL (OR 1.6, 95% CI 1.4–1.9), with an even greater risk observed for high-grade lymphoma (OR 2.0, 95% CI 1.2–3.4). Patients with nonsystemic autoimmune diseases, including Crohn’s disease and psoriasis, had an increased risk of NHL (OR 2.1, 95% CI 1.3–3.2 and OR 1.7, 95% CI 1.2–2.4, respectively). This risk remained elevated for over 5 years after initial hospitalization for the respective autoimmune disease. In contrast, a familiar history of autoimmune disease was not associated with an increased risk of NHL.
Baecklund, et al., 1998, 2003, 2006, 2008
Baecklund, et al. (1998), performed a nested
case-control study to evaluate the risk of lymphoma in a RA population
in the Uppsala health care region of Sweden.2318 To
identify an association between disease activity and the risk of developing
lymphoma, RA patients were linked to a Swedish cancer registry. In
total, 42 cases of lymphoma were identified in 11,683 patients with
RA admitted to the hospital between 1965 and 1983. Cases were individually
matched to 3 controls from the same RA cohort. Determination of the
inflammatory activity of disease (high, medium, low) was estimated
through a scoring method based on erythrocyte sedimentation rates
(ESR), number of tender and swollen joints, physician’s global
assessment, and length of disease duration. Results showed a strong
association between disease severity and lymphoma development. Rheumatoid
arthritis patients with high inflammatory activity were found to have
higher risk for lymphoma (odds ratio
To further explore the relationship between RA disease severity and development of lymphoma, Baecklund, et al, performed a matched case-control study of 378 consecutive RA patients who had been diagnosed with lymphoma between 1964 and 1995.2304 Patients were identified from a population-based cohort of 74,651 RA patients entered in the Swedish Inpatient Registry. Controls were matched for age, gender, RA discharge date, and county of residence. In addition, each control was free of lymphoma at the time of diagnosis of their corresponding case. Individuals in both cohorts met American College of Rheumatology criteria for disease and disease activity was determined through review of medical history, including swollen and tender joint counts, ESR, and physician’s global assessment. Disease activity was scored at each visit and characterized as mild, moderate, or severe. History of RA treatment, including DMARDs, corticosteroids, and nonsteroidal anti-inflammatory drugs, was obtained. The authors evaluated the association between Epstein-Barr virus (EBV) and lymphomas.
Results suggested an association between more
active disease and lymphoma development.2304 Most
lymphomas (48%) were diagnosed as diffuse large B-cell lymphomas (DLBCLs)
and EBV was present in 12% of all lymphoma cases. Patients with medium
and high disease activity based on Steinbrocker functional classification
had an elevated risk for developing lymphoma (crude
In another analysis reviewing the pathology of 35 cases of lymphoma in RA patients, Baecklund, et al. (2003), determined that the predominant type of lymphoma in RA patients was DLBCLs.2326 Additionally, in a separate study, 139 lymphomas were further classified as expressing genetic characteristics of normal GC B cells or expressing genetic characteristics associated with activated peripheral B lymphocytes (non-GC). The findings demonstrated that 70% of DLBCLs were of the non-GC subtype, which were more prevalent in patients with long-standing and highly active RA. Further, patients who presented with the non-GC DLBCLs had more advanced lymphoma at diagnosis and a poorer prognosis, compared to patients in the GC DLBCL group. 2327
In a follow-up study of the same population, the authors examined a new germinal center (GC) marker, human germinal-center-associated lymphoma protein (HGAL) in RA-associated DLBCL. Of the 111 cases of RA-associated DLBCL, 38 (34%) were positive for HGAL by immunohistochemical staining. Human germinal-center–associated lymphoma protein was associated with less disseminated lymphoma disease at initial presentation with extra nodal involvement and more advanced disease being less common in HGAL-positive cases compared with HGAL-negative cases (P=0.02 and P=0.003, respectively). Further, the mean survival time for HGAL-positive lymphomas was longer (13 months, range 1–119 months) than for HGAL negative lymphomas (7 months, range 0–75 months). While these results did not reach significance, authors noted that HGAL as a GC marker may be associated with a better clinical outcome in RA patients with DLBCL.12027
Kumar, et al., 2007
Kumar, et al., assessed the differences in causes
of death, including malignancies, in patients with RA, compared with
their siblings and a control group of patients with lower-limb osteoarthritis
(OA).8086 Two
hundred and fifty-seven RA patients were identified from an RA cohort
established in 1992. Same-sexed siblings (n=371) were identified as
a comparator population as these individuals have shared genetic material.
Osteoarthritis patients (n=485) were used as a second control population
as these individuals share similar disabilities and some treatment
options with RA patients. Causes of death were obtained from records
collected through the Office of National Statistics. In total, 398
deaths were reported. Mortality among RA patients was significantly
higher compared to same-sex siblings
Llorca, et al., 2007
To evaluate the incidence of cancer and cancer-related
mortality in RA, Llorca, et al., studied 182 consecutive RA patients
from the rheumatology outpatient clinic of the Hospital Xeral-Calde,
in Lugo, Spain. 8084 All
patients were enrolled between March and
Ekstrom, et al., 2003
Ekstrom, et al., assessed the risk of malignant
lymphoma in 76,527 rheumatoid arthritis (RA) patients and 70,290 first-degree
relatives of a subset of all RA patients.2313 Rheumatoid
arthritis patients were identified from the population-based Swedish
Hospital Discharge Registry; the cohort included patients over 16
years of age who were discharged with a diagnosis of RA from 1964
to 1999. First-degree relatives of the patients were identified through
the nationwide Multi-Generation Register. To determine incidence of
lymphoma and death statistics, both cohorts were linked to 5 additional
nationwide, population-based registers, including the Cancer Register
and the Cause of Death Register. In total, 8898 cancers were diagnosed
among the RA patients during 731,206 patient-years of follow-up. The
standardized incidence ratio (SIR) for all cancer was 1.07 (95% CI:
Cibere, et al., 1997
To determine the relative risks of malignancy and of site-specific malignancy in RA patients, Cibere, et al., conducted a prospective cohort study of patients from the Rheumatic Disease Unit in Saskatchewan, Canada.11082 In total, 862 patients diagnosed with RA between the years 1966 and 1974 were followed for up to 35 years (mean: 17.4 years), accumulating 14,998 patient-years of follow-up. Patients with cancer at baseline or who had developed cancer within the first year of follow-up were excluded. Expected cancer incidence ratios were based on data from the Provincial Cancer Registry in Saskatchewan. The authors noted that there were insufficient numbers of patients on disease-modifying antirheumatic drugs (DMARDs) or cytotoxic therapies to assess for an association of those drugs with malignancy.
One hundred thirty-six patients were diagnosed
with malignancies compared to an expected incidence of 168 cases (standardized
incidence ratio [SIR]: 0.80, 95%
Mellemkjaer, et al., 1996
To examine the incidence of cancer within an
RA population, Mellemkjaer, et al., conducted a follow-up study of
a cohort of 20,699 patients recorded in the Danish Hospital Discharge
Register from 1977 to 1987.2312 Patients
with RA were identified by a discharge diagnosis according to the
8th International Classification of Diseases (ICD-8). Per inclusion
criteria for the RA cohort, each patient had 1 or more hospitalizations
with RA as a discharge diagnosis. To determine death and cancer occurrences,
their records were linked to the Danish Cancer Registry. Patients
were followed-up at 1 year and again through
Moritomo, et al., 1995
The incidence of malignant neoplasms was evaluated
in 655 consecutive RA patients treated at the Center for Adult Diseases
in Osaka, Japan, between the years 1980 and 1989. Patients were followed
for
Gridley, et al., 1993
The risk of developing cancer in RA was evaluated
in a population-based cohort study, which included a total of 11,683
patients with RA identified from the Swedish Hospital Inpatient Register
from 1965 to 1983. Patient records were linked to the National Swedish
Cancer Registry allowing investigators to identify the incidence of
malignancies in this RA population. The cohort had a follow-up of
20 years with a total of 101,000 patient-years. The overall cancer
incidence for the RA patients was similar to that expected for both
males and females (standardized incidence ratio
Eriksson, et al., 1993
Eriksson, et al., conducted a population-based,
case-control study to evaluate the risk of developing multiple myeloma
(MM) in patients with RA.2323 Utilizing
the Swedish Cancer Register, 275 patients with verified MM were matched
for age, gender, and county to control subjects. Cases were recruited
from 1982 to 1986. The study utilized a comprehensive questionnaire
that went to living subjects or to next of kin for deceased subjects.
Data reported included treatment (medications and radiotherapy) and
history of medical illness and rheumatic disease, among other things.
In total, 239 MM patients and 220 controls were included in the analysis.
Study findings demonstrated an increased risk of MM; however, this
increase was not significant (odds ratio [OR]: 1.86, 95% CI:
Katusic, et al., 1985
Medical records of patients with RA diagnosed between 1950 and 1975 at Mayo Clinic in Rochester, Minn., were reviewed to determine the number and type of malignancies. Follow-up averaged 14 years, and 98% of the outcomes were evaluable. Overall, the authors reported on 521 patients who were followed for a total of 7389 patient-years. The follow-up period varied from 1 year to 34.3 years. In total, 112 malignancies were observed in the RA population. Of those, 28 were nonmelanoma skin cancers and, without baseline rates in Rochester for skin cancer, these data were not included. Malignancies diagnosed after RA diagnosis (n=67 in 64 patients) were compared to the expected incidence in Rochester and to the Iowa Surveillance, Epidemiology, and End Results Program database. Fig.5452321
Figure 545 – Observed and Expected Number of Malignancies, All Sites (Excluding Skin), Subsequent to the Diagnosis of Rheumatoid Arthritis (RA) in the RA Cohort, Rochester, MN, 1950-1974
Katusic S, Beard CM, Kurland LT, et al. Occurrence of malignant neoplasms in the Rochester, Minnesota, rheumatoid arthritis cohort. Am J Med. 1985;78(1A):50-55 is used with permission of Elsevier Inc. All rights reserved.
Some figures may not display clearly when rendered as a PDF or printed.
The results failed to detect an increased risk of cancer in the RA patient population studied compared to the general population. However, the authors did observe a significantly increased incidence of MM but noted that this increase was based on small numbers of patients that resulted in a wide confidence interval.2321
Prior, et al., 1984 and 1985
Retrospective data was obtained from 489 consecutive
patients with RAs seen at the Queen Elizabeth Medical Center in the
United Kingdom between 1964 and 1978 to determine their cancer morbidity.2315 The
patients were followed through 1981, and the follow-up was extended
to 1983 on the reanalysisResults were reanalyzed using a cohort method
for cancer morbidity.2320 The
Cancer Registry in Birmingham was used to determine expected rates
of cancer. Overall, 42 neoplasms were observed, which represents a
significant increase of cancers in the RA population compared to the
general population (
Isomaki, et al., 1978
The incidence of malignancy in RA patients was
reviewed using 2 national registries: 1) Social Insurance Institution’s
Population Data Register from 1965 and 2) the Finnish Cancer Registry
from 1952. From the former registry, a total of 11,483 male and 34,618
female RA patients were identified and matched against the Cancer
Registry. Rheumatoid arthritis patients were followed for neoplasms
from
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