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      Systemic Lupus Erythematous and Malignancy Risk: A Meta-Analysis

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          Abstract

          Background

          Pilot studies have estimated cancer incidence in patients with systemic lupus erythematous (SLE). However, the results have been inconclusive. To ascertain the correlation between SLE and malignancy more comprehensively and precisely, we conducted a meta-analysis.

          Methods

          PubMed, the Cochrane Library and Embase databases through June 2014, were searched to identify observational studies evaluating the association between SLE and malignancy. The outcomes from these studies were measured as relative risks (RRs). A random or fixed effects model was chosen to calculate the pooled RR according to heterogeneity test. Between-study heterogeneity was assessed by estimating I 2 index. Publication bias was assessed by Egger’s test.

          Results

          A total of 16 papers, including 59,662 SLE patients, were suitable for the meta-analysis. Of these papers, 15 reported RRs for overall malignancy, 12 for non-Hodgkin lymphoma (NHL) and lung cancer, 7 for bladder cancer, 6 for Hodgkin lymphoma (HL) and leukemia, 5 for skin melanoma, and liver and thyroid cancers, 4 for multiple myeloma (MM), and esophageal and vaginal/vulvar cancers and 3 for laryngeal and non-melanoma skin cancers. The pooled RRs were 1.28 (95% CI, 1.17–1.41) for overall cancer, 5.40 (95% CI, 3.75–7.77) for NHL, 3.26(95% CI, 2.17–4.88) for HL, 2.01(95% CI, 1.61–2.52) for leukemia, 1.45(95% CI, 1.04–2.03) for MM, 4.19(95% CI, 1.98–8.87) for laryngeal cancer, 1.59 (95% CI, 1.44–1.76) for lung cancer, 1.86(95% CI, 1.21–2.88) for esophageal cancer, 3.21(95% CI, 1.70–6.05) for liver cancer, 3.67(95% CI, 2.80–4.81) for vaginal/vulvar cancer, 2.11(95% CI, 1.12–3.99) for bladder cancer, 1.51(95% CI, 1.12–2.03) for non-melanoma skin cancer, 1.78(95% CI, 1.35–2.33) for thyroid cancer, and 0.65(95% CI, 0.50–0.85) for skin melanoma. Only the meta-analyses of overall malignancy, NHL, and liver and bladder cancers produced substantial heterogeneity (I 2, 57.6% vs 74.3% vs 67.7% vs 82.3%). No apparent publication bias was detected except for NHL studies.

          Conclusions

          Our data support an association between SLE and malignancy, not only demonstrating an increased risk for NHL, HL, leukemia, and some non-hematologic malignancies, including laryngeal, lung, liver, vaginal/vulvar, and thyroid malignancies, but also a reduced risk for skin melanoma. Although an increased risk of MM, and esophageal, bladder and non-melanoma skin cancers was identified from the accumulated data in these studies, this observation requires confirmation.

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          Most cited references43

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

          The risk of development of non-Hodgkin lymphoma (NHL) in autoimmune patients has been investigated in several cohort studies. These studies revealed inconclusive results. To shed some light on this controversy, we conducted a meta-analysis of all available cohort studies linking systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren syndrome (pSS) to the risk of NHL development. We searched the PubMed database (1974 to April 2005) for English-language cohort studies using the key words systemic lupus erythematosus, SLE, rheumatoid arthritis, RA, Sjögren syndrome, or SS; non-Hodgkin lymphoma; and relative risk, RR, standardized incidence rate, or SIR. All cohort studies that used established diagnostic criteria for SLE, RA, and pSS; had histologic confirmation of NHL; and provided standardized incidence rates (SIRs) were included in the meta-analysis. The 20 studies chosen for the analysis included 6 for SLE, 9 for RA, and 5 for pSS. Overall, the meta-analysis suggested extreme heterogeneity among the studies (P 70%), high risk of NHL development for pSS (random effects SIR, 18.8; 95% confidence interval [CI], 9.5-37.3); moderate risk for SLE (random effects SIR, 7.4; 95% CI, 3.3-17.0); and lower risk for RA (random effects SIR, 3.9; 95% CI, 2.5-5.9). In RA, the random effects SIRs of NHL with conventional antirheumatic treatment, cytotoxic treatment, and treatment with a biological agent were 2.5 (95% CI, 0.7-9.0), 5.1 (95% CI, 0.9-28.6), and 11.5 (95% CI, 3.7-26.9), respectively. Rheumatic disease may present a potential risk factor for development of NHL. In this regard, we focused on the underlying pathophysiologic mechanisms related to lymphomagenesis in pSS, SLE, and RA, to justify the varying potential for and background of NHL development.
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            A note on graphical presentation of estimated odds ratios from several clinical trials.

            To display a number of estimates of a parameter obtained from different studies it is common practice to plot a sequence of confidence intervals. This can be useful but is often unsatisfactory. An alternative display is suggested which represents intervals as points on a bivariate graph, and which has advantages. When the data are estimates of odds ratios from studies with a binary response, it is argued that for either type of plot, a log scale should be used rather than a linear scale.
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              Increased risk of lymphoma in sicca syndrome.

              The risk of cancer was ascertained in 136 women with sicca syndrome followed at the National Institutes of Health (NIH). Seven patients developed non-Hodgkin's lymphoma from 6 months to 13 years after their first admission to NIH. This was 43.8 times (P less than 0.01) the incidence expected from the rates of cancer prevailing among women of the same age range in the general population during this time. In addition, three cases of Waldenström's macroglobulinemia occurred in this study group. Eight patients developed cancers other than lymphoma, similar to the number expected based on the rates prevailing in the general population. Patients with a history of parotid enlargement, splenomegaly, and lymphadenopahy had an increased risk of lymphoma. These clinical conditions did not appear to be early manifestations of undiagnosed lymphoma but rather seemed to identify a subgroup of patients with sicca syndrome with marked lymphoid reactivity, who had a particularly high risk of subsequently developing lymphoma.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 April 2015
                2015
                : 10
                : 4
                : e0122964
                Affiliations
                [1 ]Department of Hematology, the First Affiliated Hospital of Zhejiang University, Hangzhou, People’s Republic of China
                [2 ]Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
                [3 ]School of Population Health, the University of Western Australia, Perth, Australia
                [4 ]Department of Hematology, the Second Affiliated Hospital of Zhejiang University, Hangzhou, People’s Republic of China
                [5 ]Department of Hematology, the Affiliated Children’s Hospital of Zhejiang University, Hangzhou, People’s Republic of China
                Baylor College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LHC HYT JJ. Performed the experiments: LHC HYT GXX JJ. Analyzed the data: LHC HYT GXX JJ. Contributed reagents/materials/analysis tools: LHC HYT GXX PL JHW JJ. Wrote the paper: LHC HYT JJ. Designed the software used in analysis: XYZ YMT. Performed statistical work: HTM.

                ‡ These authors share first authorship on this work.

                Article
                PONE-D-14-36332
                10.1371/journal.pone.0122964
                4401738
                25885411
                b27d057c-cb0d-489b-867d-277f0cdf4b70
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 19 August 2014
                : 16 February 2015
                Page count
                Figures: 7, Tables: 4, Pages: 21
                Funding
                This work was supported by the Program for Zhejiang Leading Team of S&T Innovation (grant number 2011R50015, http://www.zjkjt.gov.cn/html/node05/detail150408/2010/15040802_18629.html.) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All files included in our article are available from the PubMed database (accession numbers: 1586239, 7473469, 8651970,9125261, 9676054, 11035137, 11434573, 11480849, 12109649, 14514131, 16175938, 17893972, 18386139, 20041274, 21953088, 23410586).

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