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Arthritis Res Ther. 2012; 14(Suppl 3): A16.
Published online Sep 27, 2012. doi:  10.1186/ar3950
PMCID: PMC3467493
Lymphoma risk in systemic lupus: effects of treatment versus disease activity
AE Clarke,corresponding author1 S Bernatsky,1 KH Costenbader,2 MB Urowitz,3 DD Gladman,3 PR Fortin,4 M Petri,5 S Manzi,6 DA Isenberg,7 A Rahman,7 D Wallace,8 C Gordon,9 C Peschken,10 MA Dooley,11 EM Ginzler,12 C Aranow,13 SM Edworthy,14 O Nived,15 S Jacobsen,16 G Ruiz-Irastorza,17 E Yelin,18 SG Barr,14 L Criswell,18 G Sturfelt,15 L Dreyer,16 I Blanco,19 L Gottesman,12 CH Feldman,2 and R Ramsey-Goldman20
1Research Institute of the McGill University Health Centre, Montreal, QC, Canada
2Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
3Toronto Western Hospital and University of Toronto, Toronto, ON, Canada
4University of Laval, QC, Canada
5Johns Hopkins University School of Medicine, Baltimore, MD, USA
6West Penn Allegheny Health System, Pittsburgh, PA, USA
7University College of London, UK
8Cedars-Sinai/UCLA, Los Angeles, CA, USA
9University of Birmingham, UK
10University of Manitoba, Winnipeg, MB, Canada
11University of North Carolina at Chapel Hill, NC, USA
12SUNY - Downstate Medical Center, Brooklyn, NY, USA
13Feinstein Institute for Medical Research, Manhasset, NY, USA
14The University of Calgary, AB, Canada
15University Hospital - Lund, Sweden
16Copenhagen University Hospital, Copenhagen, Denmark
17Hospital de Cruces, UPV/EHU, Barakaldo, Spain
18University of California San Francisco, CA, USA
19Albert Einstein College of Medicine, Bronx, NY, USA
20Northwestern University Feinberg School of Medicine, Chicago, IL, USA
corresponding authorCorresponding author.
Lupus 2012: New targets, new approaches
Peter E Lipsky, John M Esdaile, Matthew H Liang and Paul R Fortin
Lupus 2012: New targets, new approaches
27-30 September 2012
Whistler, Canada
We recently evaluated the risk of malignancy in SLE by linking a multi-site international SLE cohort with regional tumor registries. Across 28 centers, 15,980 patients were observed for 119,846 (average 7.5) person-years. In total, 641 cancers occurred, for an overall standardized incidence ratio (SIR) of 1.14 (95% CI = 1.06 to 1.24). Hematologic malignancies were substantially increased (SIR = 3.01, 95% CI = 2.47 to 3.62), particularly non-Hodgkin's lymphoma (NHL; SIR = 4.36, 95% CI = 3.43 to 5.47) and leukemia (SIR = 1.76, 95% CI = 1.04 to 2.78) [1]. Yet the relative influence of treatment versus disease activity is unknown. Our objective was to determine the relative importance of drugs versus disease activity in mediating the increased risk of lymphoma.
We performed case-cohort analyses within this multi-site SLE cohort. Adjusted hazard ratios (HRs) for lymphoma were generated in multivariate regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarials, glucocorticoids), disease activity (mean adjusted SLEDAI-2K), demographics, calendar year, Sjögren's syndrome, and SLE duration. Partially adjusted models were also performed, using only covariates whose HR CI excluded the null. Sensitivity analyses were performed, lagging cyclophosphamide exposures by 5 years. Medications were treated both categorically (ever/never) and as cumulative doses.
We studied 64 lymphomas (61 NHL, three Hodgkin's) and 4,739 cancer-free controls. As in the general population, lymphoma risk in SLE was higher in males and with age. Lymphomas occurred a mean of 13.1 years (standard deviation 9.8) after SLE diagnosis. Univariate analyses suggested a decreased lymphoma risk within the highest tertile of disease activity (relative to those with the lowest activity) but in fully adjusted models (using all variables listed above), the CI included the null (Table (Table1).1). Sensitivity analyses, lagging cyclophosphamide exposures, yielded similar results. In a partially adjusted model (retaining age and highest tertile of disease activity), the HR suggested a twofold lymphoma risk after cyclophosphamide. Despite a trend towards greater cyclophosphamide use in cases versus controls, in fully adjusted models, no drug was estimated to be an independent risk factor. Still, due to correlation, it remains difficult to differentiate the effects of medications from disease activity.
Table 1
Table 1
Results of univariate and multivariate models assessing HR of exposures on lymphoma development in SLE patients
We did not definitively demonstrate an increased risk for any medications, despite a trend to greater cyclophosphamide use in the lymphoma cases. If anything, we noted a protective effect for very high SLE disease activity. Further work will focus on genetic profiles that might interact with medication exposures to influence lymphoma risk in SLE.
  • Bernatsky S, Ramsey-Goldman R, Labrecque J, Joseph L, Petri M, Zoma A, Manzi S, Urowitz M, Gladman D, Fortin PR, Ginzler E, Yelin E, Bae SC, Wallace D, Edworthy S, Barr S, Jacobsen S, Gordon C, Dooley MA, Peschken C, Hanly J, Alarcón G, Nived O, Ruiz-Irastorza G, Isenberg D, Rahman A, Witte T, Aranow C, Steinsson K, Sturfelt G, Cancer risk in systemic lupus: an updated international multi-centre cohort study [brief report] 2012 Submitted. [PubMed]
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