Elsevier

Journal of Autoimmunity

Volume 42, May 2013, Pages 130-135
Journal of Autoimmunity

Short communication
Cancer risk in systemic lupus: An updated international multi-centre cohort study

https://doi.org/10.1016/j.jaut.2012.12.009Get rights and content

Abstract

Objective

To update estimates of cancer risk in SLE relative to the general population.

Methods

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.

Results

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).

Conclusion

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.

Highlights

► We studied 16,409 SLE patients, finding a slight increase in over-all cancer risk versus the general population. ► For non-Hodgkin's lymphoma, NHL the SIR was 4.39. 95% CI 3.46, 5.49). ► However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61–0.88) and endometrial (SIR 0.44, 95% CI 0.23–0.77) cancer.

Introduction

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 [1]. 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 [2]. Some have hypothesized that an increased prevalence of traditional “lifestyle” cancer risk factors may influence malignancy incidence in SLE [3]. Additionally, inherent immune system abnormalities have been suggested as mediators of a potentially increased cancer risk in SLE [4].

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) [5] to 2.6 (95% CI 1.5–4.4) [6]. 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, 9547 SLE patients) that clarified cancer risk in SLE, particularly with respect to a nearly 4 fold increase of non-Hodgkin lymphoma (NHL) [7]. Our current goal was to conduct in-depth, updated analyses of cancer risk in SLE, compared to the general population.

Section snippets

Materials and methods

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

Results

In total 16,409 patients were studied (Table 1); 7700 of these originated from the United States, 3689 from Canada, 4250 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

Discussion

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

Conclusion

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

Potential conflicts of interest

None.

Grant support

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

Acknowledgments

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.

References (35)

  • J. Bin et al.

    Lung cancer in systemic lupus erythematosus

    Lung Cancer

    (2007)
  • A. Antonelli et al.

    Prevalence of thyroid dysfunctions in systemic lupus erythematosus

    Metabolism

    (2010)
  • G. Azizi et al.

    Autoimmune thyroid disease: a risk factor for thyroid cancer

    Endocr Pract

    (2011)
  • E. Zintzaras et al.

    The risk of lymphoma development in autoimmune diseases: a meta-analysis

    Arch Intern Med

    (2005)
  • S.S. Kassan et al.

    Increased risk of lymphoma in sicca syndrome

    Ann Intern Med

    (1978)
  • S. Bernatsky et al.

    The prevalence of factors influencing cancer risk in lupus: social habits reproductive issues and obesity

    J Rheumatol

    (2002)
  • B. Lofstrom et al.

    Expression of APRIL in diffuse large B cell lymphomas from patients with systemic lupus erythematosus and rheumatoid arthritis

    J Rheumatol

    (2011)
  • M. Abu-Shakra et al.

    Malignancy in systemic lupus erythematosus

    Arthritis Rheum

    (1996)
  • T. Pettersson et al.

    Increased risk of cancer in patients with systemic lupus erythematosus

    Ann Rheum Dis

    (1992)
  • S. Bernatsky et al.

    An international cohort study of cancer in systemic lupus erythematosus

    Arthritis Rheum

    (2005)
  • A.L. Smitten et al.

    A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis

    Arthritis Res Ther

    (2008)
  • G. Ott et al.

    Molecular pathogenesis of follicular lymphoma

    Haematologica

    (2008)
  • M. Voulgarelis et al.

    Clinical, immunologic, and molecular factors predicting lymphoma development in Sjogren's syndrome patients

    Clin Rev Allergy Immunol

    (2007)
  • C. Dias et al.

    Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma

    Nat Rev Rheumatol

    (2011)
  • S. Bernatsky et al.

    Non-Hodgkin's lymphoma in systemic lupus erythematosus

    Ann Rheum Dis

    (2005)
  • S. Bernatsky et al.

    Histology, prognostic factors, treatment, and outcome in SLE patients with non-Hodgkins lymphoma [Abstract]

    Arthritis Rheum

    (2009)
  • S. Bernatsky et al.

    The relationship between cancer and medication exposures in systemic lupus erythematosus: a case-cohort study

    Ann Rheum Dis

    (2008)
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