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To update estimates of cancer risk in SLE relative to the general population.
A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers.
Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin’s lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61–0.88), endometrial (SIR 0.44, 95% CI 0.23–0.77), and possibly ovarian cancers (0.64, 95% CI 0.34–1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23).
These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.
Systemic lupus erythematosus (SLE) is one of the most common systemic autoimmune rheumatic diseases, often affecting young and middle-aged people. Females are particularly affected (female:male ratio of 9:1). Although survival in SLE has improved, morbidity related to the disease and its treatment remains considerable. One important consideration is cancer risk.
The immune system’s role in cancer risk is a topic of increasing interest, and accordingly, the association between autoimmunity and cancer has been under study for over a decade. Suggested pathways linking SLE and cancer include possible links with medication exposures, or even interactions between medications and viral exposures. Also potentially pertinent are clinical characteristics, such as co-existing Sjogren’s syndrome or other overlap syndromes that may occur in SLE. Some have hypothesized that an increased prevalence of traditional “lifestyle” cancer risk factors may influence malignancy incidence in SLE. Additionally, inherent immune system abnormalities have been suggested as mediators of a potentially increased cancer risk in SLE.
To date, varying estimates of cancer risk in SLE have been generated, most with fairly wide confidence intervals (CIs). The standardized incidence ratio (SIR) estimates for over-all cancer in these studies ranged from 1.1 (95% CI 0.7–1.6) to 2.6 (95% CI 1.5–4.4). These studies do not represent optimal estimates of cancer risk in SLE, due to small sample sizes and possibly non-representative sampling. In 2005 we published a large multi-centre study (23 centres, 9, 547 SLE patients) that clarified cancer risk in SLE, particularly with respect to a nearly 4 fold increase of non-Hodgkin lymphoma (NHL). Our current goal was to conduct in-depth, updated analyses of cancer risk in SLE, compared to the general population.
We assembled a multisite (30 centers) international cohort of patients diagnosed with SLE. These consisted of clinically confirmed SLE patients in follow up, the vast majority of who fulfill American College of Rheumatology (ACR) criteria (one cohort, in Scotland, was assembled using administrative data). Patients were linked to regional tumor registries to determine cancer occurrence. Information was available on birth-date, sex, lupus diagnosis and cohort entry dates, and date of death, if applicable. The person-years of follow-up were calculated from the date of SLE cohort entry to the last date seen in clinic, end of the cancer registry information, or death (whichever occurred earliest). All new-onset observed cancers during the person-years of follow-up were included.
Standardized incidence ratios, SIRs, were calculated as the ratio of observed to expected cancers. Cancers expected were determined by multiplying person-years in the cohort by the geographically matched age, sex, and calendar year–specific cancer rates, and summing over all person-years. We calculated 95% CIs, assuming that the observed number of malignancies followed a Poisson distribution. As well, we present analyses evaluating stratified rates of over-all cancers, and hematological cancers specifically, for groups characterized by demographics and SLE duration.
In total 16,409 patients were studied (Table 1); 7,700 of these originated from the United States, 3,689 from Canada, 4,250 from Europe and 770 from Asia (Korea). Ninety percent were female. The patients provided a total of 121,283 person-years of follow-up (mean 7.4 years) spanning the calendar period 1958–2009, although most of the person-years came from the 1970’s onward.
Within the observation interval, 644 cancers occurred (Table 2). The data confirmed an increased risk of cancer among patients with SLE, particularly for specific cancer subtypes. For all cancers combined, the SIR estimate was 1.14 (95% CI 1.05–1.23). For all hematologic malignancies, it was 3.02 (95% CI 2.48–3.63). Regarding specific types of hematological malignancies, increased risk was demonstrated for all lymphomas (SIR 4.07, 95% CI 3.24–5.04) as well as for non-Hodgkin lymphoma (NHL) specifically, and leukemia. We also demonstrated an increased risk of cancers of the vulva, lung, and thyroid, and a suggestion of possible increased risk for hepatic cancer. Meanwhile, a substantial decreased risk was seen for breast and endometrial cancer, and possibly ovarian cancer.
When SIR estimates were stratified by age, SLE patients in the youngest age group (<40 years) appeared to have a particularly high relative cancer risk (compared to sex and age-appropriate general population rates). In contrast, an increase in over-all cancer risk, compared to the sex and age-matched general population, was not apparent for SLE patients aged ≥60 years (although the increased risk of hematological malignancies remained). Regarding trends over SLE duration, our stratified results previously suggested that an increased risk of cancer detection early in SLE, was followed by trends for somewhat lower SIRs, although the confidence intervals for some of the SLE duration-specific estimates overlapped.
Our study results more precisely define cancer risk in SLE versus the general population, highlighting a dichotomy. On one hand, there is an increased risk of NHL, leukemia and cancers of the vulva, lung, thyroid, and possibly liver. Conversely, there is a decreased risk of breast, endometrial, and possibly ovarian cancer. Hence, the over-all cancer risk in SLE is only slightly increased, compared to the general population.
This is in fact quite similar to the profile seen in another autoimmune rheumatic disease, rheumatoid arthritis (RA). A meta-analysis has demonstrated that in RA, the SIR for overall malignancy is 1.05 (95% CI 1.01,1.09), with an increase in lymphoma risk (SIR 2.08, 95% CI 1.80, 2.39) and lung cancer (SIR 1.63, 95% CI 1.43, 1.87) but a decreased risk of breast cancer (SIR 0.84, 95% CI 0.79, 0.90).
There are various possible explanations for a link between lymphoma and SLE. It is known that translocations involving the juxtaposition of an oncogene beside a gene important for immune cell function may favor the emergence of a lymphoma. Since the chances of a translocation are proportional to the rate of lymphocyte proliferation, possibly upregulated lymphocyte proliferation (related to autoimmunity) might explain some of the excess lymphoma risk in autoimmune diseases like SLE. Certainly in a related condition, primary Sjogren’s syndrome, authors have implicated chronic antigenic stimulation of lymphocytes. However, immunosurveillance is also a normal part of cancer defense, so a very active immune system might also be able to delete abnormal (precancerous) cells more efficiently. Detailed case-cohort analyses are currently underway, assessing both drugs and cumulative disease activity as potential mediators of lymphoma risk in SLE.
It has been shown that the most common NHL subtype among cases that arise in SLE is diffuse large B cell (DLBC) lymphoma. In our multi-centre international cohort data, DLBC was the most common NHL histological subtype[12;13]. This NHL subtype arises from activated lymphocytes, again suggesting that chronic inflammation might heighten lymphoma risk in autoimmune diseases like SLE.
A PRoliferating-Inducing Ligand (APRIL) is a cytokine highly expressed in DLBC lymphomas in the general population. High concentrations of APRIL have been implicated as possible risk factors related to RA and SLE disease onset. Intriguingly, one study of APRIL expression in the SLE DLBC lymphoma tissues reported a strong association in SLE, but not in the RA. The authors noted that the high expression of APRIL in DLBC lymphomas in some patients might indicate APRIL mediates lymphoma development in these disease subsets. However, the conclusions are by no means definitive. We are currently conducting a similar histology review on the DLBC lymphoma cases in our sample, to determine if the findings confirm high expression of APRIL and/or a role for other agents, such as Epstein Barr virus.
With respect to lung cancer risk, we have previously demonstrated that most SLE patients who develop this are smokers, emphasizing yet another reason to counsel SLE patients in smoking cessation. Interestingly, only the minority of the SLE patients with lung cancer had been previously exposed to immunosuppressive drugs.
Regarding the higher risk of vulvar cancers in SLE, one important factor is the possibility of altered clearance of viruses, particularly human papillomavirus, HPV, which is linked to this malignancy, as well as to cervical cancer. In young patients prior to initiation of sexual activity, vaccination against HPV may be useful ,. Altered viral clearance can also predispose to hepatic cancer, and our group has noted at least one case of a hepatitis-positive SLE patient developing a hepatic malignancy (unpublished communication).
The higher risk of thyroid cancer in SLE has been suggested by some authors but few concerted efforts have attempted to determine why this might be so. Associations between SLE and thyroid autoimmunity have been well-documented and thyroid autoimmunity itself increases thyroid cancer risk. One case-control study noted an increased risk of papillary thyroid cancer in SLE, particularly for patients with thyroid autoimmunity.
SLE patients appear to have considerable decreased risk for certain hormone-sensitive cancers, as has been shown in this paper as well as in a recent meta-analysis, where decreased risk was seen in SLE for breast cancer (SIR 0.74, 95% CI 0.61–0.89), endometrial cancer (SIR 0.44, 95% CI 0.23–0.77) and ovarian cancer (SIR 0.64, 95% CI 0.49–0.90). The fact that women with SLE have decreased risk of several hormone-sensitive cancers suggests the possibility of alterations in estrogen metabolism and/or other hormones. Interestingly, results stratifying our female subjects according to age (<50 years, mainly premenopausal, and >=50 years, mainly postmenopausal) showed decreased breast cancer risk in SLE (relative to the general population) for both age groups (data not shown).
It remains a possibility that medications may influence cancer risk in SLE, such as aspirin and non-steroidal anti-inflammatory drugs [22–24] and corticosteroids , and anti-malarial drugs . Oncologists have proposed that antimalarials have potential applications in cancer treatment  possibly through a cell death process called autophagy. These drugs will be further evaluated in ongoing analyses by our group.
It is an interesting potential hypothesis that the lower risk for certain cancers in SLE may be related to specific genetic factors that place individuals at risk for SLE, but protect against breast cancer. Though this hypothesis remains to be fully tested, our initial work thus far has failed to explain breast cancer risk in SLE on the basis of genetic factors.
We must acknowledge potential limitations of ours study. It is possible that, in some of the cancer cases that occurred within the first year of SLE diagnosis, the SLE-like manifestations were in fact paraneoplastic phenomena. To explore this, in sensitivity analyses, we calculated the SIRs excluding cancers diagnosed in the first year of SLE. The over-all estimates changed little. Thus, it seems unlikely that the elevated over-all cancer risk in SLE reflects a paraneoplastic process alone. Additionally, the majority of the cancers occurred more than 1 year after SLE had been diagnosed.
The persistence of an elevated cancer risk beyond the first year of SLE diagnosis also rules against the possibility that the observed number of cancers was inflated, due to subclinical malignancies being picked up in SLE patients, who tend to have close medical follow-up. There are additional reasons why we believe that this potential bias does not entirely explain our findings of increased cancer risk in SLE. First, breast cancer is one of cancer type where routine screening is available, yet breast cancer was not increased in SLE, in contrast to the striking increase in lymphoma (where no formal screening strategy exists). Furthermore, we have previously demonstrated that in women with SLE do not necessarily present in earlier stages of cancer, compared to the general population. Moreover, evidence suggests that patients with SLE may undergo cancer screening much less frequently than recommended. Last but not least, it has been shown that cancer mortality (not just incidence) is increased in SLE, which is convincing evidence of a true increased cancer risk in SLE.
We did not analyze risk according to race in the current analyses, since we did not have data on race for all subjects. This could be important because, in the general population, breast cancer is less common in blacks than whites. However, an earlier paper from our group suggested that the decreased risk of breast cancer was fairly homogenous across white and non-white SLE patients. That earlier paper also suggested that lymphoma risk was fairly homogeneous across different race/ethnicity groups in SLE.
Although cancers in general are more common with increasing age, younger SLE patients have a particularly high relative cancer risk (compared to the general population). However, it must be kept in mind that the absolute rate, even in those aged <40 years, is about 1.56 cases per 1,000 person-years for SLE, versus about 1 per 1,000 per person-year in the general population. Patients need to be aware that their risk for other adverse events, such as cardiac disease, may actually be equally (or more) important. For example, the Mayo clinic calculator demonstrates that for a smoker aged <40 years, the risk of a heart attack or death from heart disease is 3 per 1,000 person-years. Smoking cessation, optimizing exercise and optimal weight control are lifestyle factors that most people, including SLE patients, can focus on to improve cancer risk (as well as risk for even more common adverse outcomes) .
Regarding trends over SLE duration, an increased risk of cancer detection was apparent initially, followed by trends for somewhat lower SIRs. This suggests perhaps that not all of the excess cancer risk in SLE is caused by drug exposures. Though there was a trend of highest SIRs earliest in the course of SLE, followed by a trend towards lower cancer risk later on, for hematological cancer, the elevated risk in SLE compared to the general population persists in both terms of increased age and SLE duration (Tables 3–4).
An additional limitation of the current analyses is that we were unable to assess clinical effects such as types of organ involvement or drug use across the cohort, since we did not have this information for all the cohort members. However, we are currently analyzing, in a case-cohort subset of patients, the effects of these variables on lymphoma risk in SLE.
To summarize, our data support an association between SLE and cancer, highlighting the risk for NHL and leukemia, but also demonstrating an increased risk of vulvar, lung, thyroid, and possibly liver cancers. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. On the other hand, women with SLE appear to have a decreased risk of breast, endometrial, and possibly ovarian cancer. The etiology of this phenomenon is also uncertain, though investigations are ongoing.
We acknowledge the assistance of Jennifer Lee, Elizabeth Turnbull and Autumn Neville. Our efforts were made possible through the endorsement and support of the Systemic Lupus International Collaborating Clinics research network. Dr. Criswell would like to acknowledge support from the Alliance for Lupus Research and from a Kirkland Scholar Award.
This research was funded by Canadian Institutes of Health Research/Arthritis Society grant RG06/092 and National Institutes of Health (NIH) grant 1R03CA128052-01. We also acknowledge the grant that supports the Chicago Lupus Database, NIH/NIAMS P60 2 AR30692 and the grants that support the UCSF Lupus Outcomes Study, NIH/NIAMS P60 AR053308 and NIH/NIAMS R01 5R01AR56476-9, the grant that support the Hopkins Lupus Cohort NIH R01 AR43727, and the grant by the Department of Education, Universities and Research of the Basque Government supporting the Lupus-Cruces research project. Support for McGill University Health Centre cohort comes from Singer Family Fund for Lupus Research. Dr. Criswell would like to acknowledge support from the Alliance for Lupus Research and from a Kirkland Scholar Award. Dr. Bae’s work is supported by the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A120404).
Potential Conflicts of Interest: None
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