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Figure.
Standardized incidence rate (SIR) estimates of development of non-Hodgkin lymphoma with the corresponding 95% confidence intervals of studies included in the meta-analysis for systemic lupus erythematosus (SLE) (A), rheumatoid arthritis (RA) (B), and primary Sjögren syndrome (pSS) (C). The random-effects (RE) pooled SIRs are shown. The horizontal axis is plotted on a logarithmic scale. BA indicates biological agent; CT, conventional antirheumatic treatment; and IS, cytotoxic treatment.

Standardized incidence rate (SIR) estimates of development of non-Hodgkin lymphoma with the corresponding 95% confidence intervals of studies included in the meta-analysis for systemic lupus erythematosus (SLE) (A), rheumatoid arthritis (RA) (B), and primary Sjögren syndrome (pSS) (C). The random-effects (RE) pooled SIRs are shown. The horizontal axis is plotted on a logarithmic scale. BA indicates biological agent; CT, conventional antirheumatic treatment; and IS, cytotoxic treatment.

Table 1. 
Characteristics of the SLE Cohort Studies Considered in the Meta-analysis
Characteristics of the SLE Cohort Studies Considered in the Meta-analysis
Table 2. 
Characteristics of the RA Cohort Studies Considered in the Meta-analysis
Characteristics of the RA Cohort Studies Considered in the Meta-analysis
Table 3. 
Characteristics of the pSS Cohort Studies Considered in the Meta-analysis
Characteristics of the pSS Cohort Studies Considered in the Meta-analysis
1.
Pettersson  TPukkala  ETeppo  LFriman  C Increased risk of cancer in patients with systemic lupus erythematosus. Ann Rheum Dis 1992;51437- 439
PubMedArticle
2.
Prior  P Cancer and rheumatoid arthritis: epidemiologic considerations. Am J Med 1985;78 ((suppl 1)) (1) 15- 21
PubMedArticle
3.
Kassan  SSThomas  TLMoutsopoulos  HM  et al.  Increased risk of lymphoma in sicca syndrome. Ann Intern Med 1978;89888- 892
PubMedArticle
4.
Cibere  JSibley  JHaga  M Systemic lupus erythematosus and the risk of malignancy. Lupus 2001;10394- 400
PubMedArticle
5.
Kauppi  MPukkala  EIsomaki  H Elevated incidence of hematologic malignancies in patients with Sjögren’s syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control 1997;8201- 204
PubMedArticle
6.
Sweeney  DMManzi  SJanosky  J  et al.  Risk of malignancy in women with systemic lupus erythematosus. J Rheumatol 1995;221478- 1482
PubMed
7.
Rothman  KJGreenland  S Modern Epidemiology. 2nd ed. Philadelphia, Pa Lippincott Williams & Wilkins1998;
8.
Metintas  SMetintas  MUcgun  IOner  U Malignant mesothelioma due to environmental exposure to asbestos: follow-up of a Turkish cohort living in a rural area. Chest 2002;1222224- 2229
PubMedArticle
9.
Freedman  LSBarchana  MAl-Kayed  S  et al.  A comparison of population-based cancer incidence rates in Israel and Jordan. Eur J Cancer Prev 2003;12359- 365
PubMedArticle
10.
Whitehead  A Meta-Analysis of Controlled Clinical Trials.  New York, NY John Wiley & Sons2002;
11.
Cochran  WG The combination of estimates from different experiments. Biometrics 1954;10101- 129Article
12.
Higgins  JPThompson  SG Quantifying heterogeneity in a meta-analysis. Stat Med 2002;211539- 1558
PubMedArticle
13.
Lau  JAntman  EMJimenez-Silva  JKupelnick  BMosteller  FChalmers  TC Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 1992;327248- 254
PubMedArticle
14.
Egger  MDavey Smith  GSchneider  MMinder  C Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315629- 634
PubMedArticle
15.
Begg  CBMazumdar  M Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;501088- 1101
PubMedArticle
16.
Zintzaras  EStefanidis  I Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis. J Hum Genet 2005;5084- 91
PubMedArticle
17.
Abu-Shakra  MGladman  DDUrowitz  MB Malignancy in systemic lupus erythematosus. Arthritis Rheum 1996;391050- 1054
PubMedArticle
18.
Mellemkjaer  LAndersen  VLinet  MSGridley  GHoover  ROlsen  JH Non-Hodgkin’s lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus. Arthritis Rheum 1997;40761- 768
PubMedArticle
19.
Bjornadal  LLofstrom  BYin  LLundberg  IEEkbom  A Increased cancer incidence in a Swedish cohort of patients with systemic lupus erythematosus. Scand J Rheumatol 2002;3166- 71
PubMedArticle
20.
Hakulinen  TIsomaki  HKnekt  P Rheumatoid arthritis and cancer studies based on linking nationwide registries in Finland. Am J Med 1985;78 ((suppl 1)) (1) 29- 32
PubMedArticle
21.
Gridley  GMcLaughlin  JKEkbom  A  et al.  Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993;85307- 311
PubMedArticle
22.
Mellemkjaer  LLinet  MSGridley  GFrisch  MMoller  HOlsen  JH Rheumatoid arthritis and cancer risk. Eur J Cancer 1996;32A1753- 1757
PubMedArticle
23.
Silman  AJPetrie  JHazleman  BEvans  SJ Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 1988;47988- 992
PubMedArticle
24.
Mariette  XCazals-Hatem  DWarszawki  JLiote  FBalandraud  NSibilia  JInvestigators of the Club Rhumatismes et Inflammation, Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002;993909- 3915
PubMedArticle
25.
Geborek  PBladstrom  ATuresson  C  et al.  Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005;64699- 703
PubMedArticle
26.
Kinlen  LJ Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 1985;7844- 49
PubMedArticle
27.
Davidson  BKKelly  CAGriffiths  ID Primary Sjögren’s syndrome in the North East of England: a long-term follow-up study. Rheumatology (Oxford) 1999;38245- 253
PubMedArticle
28.
Valesini  GPriori  RBavoillot  D  et al.  Differential risk of non-Hodgkin’s lymphoma in Italian patients with primary Sjögren’s syndrome. J Rheumatol 1997;242376- 2380
PubMed
29.
Pertovaara  MPukkala  ELaippala  PMiettinen  APasternack  A A longitudinal cohort study of Finnish patients with primary Sjögren’s syndrome: clinical, immunological, and epidemiological aspects. Ann Rheum Dis 2001;60467- 472
PubMedArticle
30.
World Health Organization, International Classification of Diseases, Seventh Revision (ICD-7).  Geneva, Switzerland World Health Organization1955;
31.
World Health Organization, International Classification of Diseases, Eighth Revision (ICD-8).  Geneva, Switzerland World Health Organization1965;
32.
World Health Organization, International Classification of Diseases, Ninth Revision (ICD-9).  Geneva, Switzerland World Health Organization1977;
33.
Zintzaras  EChatzoulis  DZKarabatsas  CHStefanidis  I The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis. J Hum Genet 2005;50267- 275
PubMedArticle
34.
Sterne  JAEgger  MSmith  GD Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. BMJ 2001;323101- 105
PubMedArticle
35.
Prior  PSymmons  DPHawkins  CFScott  DLBrown  R Cancer morbidity in rheumatoid arthritis. Ann Rheum Dis 1984;43128- 131
PubMedArticle
36.
Thomas  EBrewster  DHBlack  RJMacfarlane  GJ Risk of malignancy among patients with rheumatic conditions. Int J Cancer 2000;88497- 502
PubMedArticle
37.
Asten  PBarrett  JSymmons  D Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol 1999;261705- 1714
PubMed
38.
Georgescu  LQuinn  GCSchwartzman  SPaget  SA Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment. Semin Arthritis Rheum 1997;26794- 804
PubMedArticle
39.
Georgescu  LPaget  SA Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate? Drug Saf 1999;20475- 487
PubMedArticle
40.
Kamel  OWvan de Rijn  MWeiss  LM  et al.  Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1993;3281317- 1321
PubMedArticle
41.
Salloum  ECooper  DLHowe  G  et al.  Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 1996;141943- 1949
PubMed
42.
Baecklund  ESundstrom  CEkbom  A  et al.  Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 2003;481543- 1550
PubMedArticle
43.
Voulgarelis  MDafni  UGIsenberg  DAMoutsopoulos  HM Malignant lymphoma in primary Sjögren’s syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren’s Syndrome. Arthritis Rheum 1999;421765- 1772
PubMedArticle
44.
Knowles  DM Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol 1999;12200- 217
PubMed
45.
Wahl  SMWilder  RLKatona  IM  et al.  Leukapheresis in rheumatoid arthritis: association of clinical improvement with reversal of anergy. Arthritis Rheum 1983;261076- 1084
PubMedArticle
46.
Malone  DGWahl  SMTsokos  MCattell  HDecker  JLWilder  RL Immune function in severe, active rheumatoid arthritis: a relationship between peripheral blood mononuclear cell proliferation to soluble antigens and synovial tissue immunohistologic characteristics. J Clin Invest 1984;741173- 1185
PubMedArticle
47.
Yocum  DEWilder  RLDougherty  SKlippel  JHPillemer  SWahl  S Immunologic parameters of response in patients with rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 1990;331310- 1316
PubMedArticle
48.
Wolfe  FMichaud  K Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18 572 patients. Arthritis Rheum 2004;501740- 1751
PubMedArticle
49.
Varoczy  LGergely  LZeher  MSzegedi  GIlles  A Malignant lymphoma-associated autoimmune diseases: a descriptive epidemiological study. Rheumatol Int 2002;22233- 237
PubMedArticle
50.
Ioannidis  JPVassiliou  VAMoutsopoulos  HM Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheum 2002;46741- 747
PubMedArticle
51.
Lewis  PHazleman  BLHanka  RRoberts  S Cause of death in patients with rheumatoid arthritis with particular reference to azathioprine. Ann Rheum Dis 1980;39457- 461
PubMedArticle
52.
Tennis  PBombardier  CMalcolm  EDowney  W Validity of rheumatoid arthritis diagnoses listed in the Saskatchewan Hospital Separations Database. J Clin Epidemiol 1993;46675- 683
PubMedArticle
53.
Cheema  GSRoschke  VHilbert  DMStohl  W Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 2001;441313- 1319
PubMedArticle
54.
Groom  JKalled  SLCutler  AH  et al.  Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome. J Clin Invest 2002;10959- 68
PubMedArticle
55.
Jacobi  AMOdendahl  MReiter  K  et al.  Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 2003;481332- 1342
PubMedArticle
56.
Bohnhorst  JOThoen  JENatvig  JBThompson  KM Significantly depressed percentage of CD27+ (memory) B cells among peripheral blood B cells in patients with primary Sjögren’s syndrome. Scand J Immunol 2001;54421- 427
PubMedArticle
57.
Hansen  AOdendahl  MReiter  K  et al.  Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum 2002;462160- 2171
PubMedArticle
58.
Tzioufas  AGBoumba  DSSkopouli  FNMoutsopoulos  HM Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren’s syndrome. Arthritis Rheum 1996;39767- 772
PubMedArticle
59.
Skopouli  FNDafni  UIoannidis  JPAMoutsopoulos  HM Clinical evolution, and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum 2000;29296- 304
PubMedArticle
60.
Harris  NLJaffe  ESStein  H  et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;841361- 1392
PubMed
Review Article
November 14, 2005

The Risk of Lymphoma Development in Autoimmune DiseasesA Meta-analysis

Author Affiliations

Author Affiliations: Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece (Dr Zintzaras); and Department of Pathophysiology, National University of Athens School of Medicine, Athens, Greece (Drs Voulgarelis and Moutsopoulos).

Arch Intern Med. 2005;165(20):2337-2344. doi:10.1001/archinte.165.20.2337
Abstract

Background  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.

Methods  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.

Results  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<.01; I2>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.

Conclusions  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.

The association of malignancy with autoimmune rheumatic diseases has been a subject of investigation for years. It has been shown that there is increased risk of malignancies, mainly non-Hodgkin lymphoma (NHL), in patients with rheumatoid arthritis (RA), primary Sjögren syndrome (pSS), and systemic lupus erythematosus (SLE). The findings were based mainly on case reports and a few cohort studies, but with disparate estimates. Therefore, there is inadequate conclusive evidence confirming the risk of NHL in these patients. The mechanism of lymphomagenesis is unclear in autoimmune disease. Observational studies have indicated that lymphoma can develop in individuals with immune dysregulation, those who are receiving immunosuppressive drugs, or those who have been exposed to unknown environmental factors. A number of recent cohort studies indicate a high risk of lymphoma development in some autoimmune rheumatic diseases. Some studies suggested that the risk factor of lymphoma development is high,13 others reported moderate risk,4,5 and one did not find any association.6 To provide an estimate of lymphoma development risk in autoimmune rheumatic disorders, we conducted a meta-analysis of all available cohort studies relating SLE, RA, and pSS to the risk of NHL development. In the meta-analysis, we calculated a pooled estimate of this risk that is expressed as a standardized incidence rate (SIR). In addition, the heterogeneity among studies and the existence of bias have been investigated. We also discuss the pathogenetic aspects of lymphomagenesis in these classic autoimmune disorders.

METHODS
SEARCH STRATEGY

We searched PubMed (1974 through April 2005) for English-language articles using the following criteria: systemic lupus erythematosus, SLE, rheumatoid arthritis, RA, Sjögren’s syndrome, or SS; non-Hodgkin lymphoma; and relative risk, RR, standardized incidence rate, or SIR. All data were then studied to assess their appropriateness for inclusion in the meta-analysis. All references cited in the retrieved articles were also reviewed to identify additional published work not indexed by PubMed, and the we reached consensus. Abstracts, case reports, editorials, and review articles were excluded.

DATA EXTRACTION

We included cohort studies that used established diagnostic criteria for SLE, RA, and pSS; that included histologic confirmation of NHL; and that provided SIRs and 95% confidence intervals (CIs) or enough data to allow us to calculate these numbers. In the latter case, the SIR was defined as the ratio of the number of observed cases with NHL divided by the number of expected cases in the general population. The 95% CI was calculated using the standard error of the natural logarithm of the SIR, that is, ln(SIR), which was estimated by the inverse of the square root of the observed number of cases.79 In addition to the SIR and 95% CI, we extracted information on data origin, diagnosis criteria used, cohort duration, cohort size, number of cases, and treatment with immunosuppressive agents. We excluded studies that provided SIRs for lymphomas or malignancies without specifying the NHL SIRs and studies that did not provide the expected number of NHL cases from registries or surveys. Lymphomas will hereafter be referred to as NHL.

DATA SYNTHESIS

In the meta-analysis, we calculated the pooled ln(SIR) using as a weighted factor the inverse of the square root of the observed number of cases.10 We then calculated the 95% CI of the pooled SIR, by taking the exponential of the 95% limits of the ln(SIR). The pooled ln(SIR) was estimated using fixed-effects and random-effects (RE) models (DerSimonian-Laird). Random-effects modeling assumes a genuine diversity in the results of various studies, and it incorporates into the calculations a between-study variance. Therefore, when there is heterogeneity between studies, the pooled ln(SIR) is estimated using the RE model.10 The heterogeneity between studies was tested using the Q statistic, which is a weighted sum of squares of the deviations of individual-study ln(SIR) estimates from the overall estimate.11 If P<.10, then the heterogeneity was considered statistically significant. Heterogeneity was also quantified with the I2 metric, which is independent of the number of studies in the meta-analysis.12 We performed a cumulative meta-analysis to evaluate the trend of pooled ln(SIR) over time.13 We also performed subgroup analyses for each sex and according to type of treatment, when the data were available. In addition, sensitivity analyses were carried out by excluding specific studies. The publication bias was tested using the Egger regression test for funnel plot asymmetry14 and the Begg-Mazumdar test, which is based on the Kendall tau.15 Analyses were performed using SAS routines (SAS Institute Inc, Cary, NC),10 StatsDirect (StatsDirect Ltd, Cheshire, England), and Compaq Visual Fortran (Hewlett Packard, Avondale, Pa) with the Institute of Museum and Library Sciences library, Washington, DC.16

RESULTS

The literature review identified 84 titles in PubMed that met the search criteria. We reviewed the abstracts of these articles and judged 26 articles to be potentially relevant. We read the full articles of the selected studies to assess their appropriateness for meta-analysis and assessed their references. We then selected 20 studies for the analysis, including 6 for SLE,1,4,6,1719 9 for RA,2,5,2026 and 5 for pSS3,5,2729 (Tables 1, 2, and 3). All studies were published between 1978 and 2005.

In 6 studies,2,3,20,23,26,27 the SIRs or the 95% CIs of SIRs were calculated from data provided in the articles. Two studies2,22 included only female patients. In 3 studies,3,5,20 the cohort consisted of cases with a mixture of rheumatic diseases. Only 3 RA studies2,20,21 reported SIR results by sex. Seven studies2,5,1922,27 did not report the type of treatment before NHL diagnosis, and 4 studies4,6,17,28 reported no use of immunosuppressive therapy in documented NHL cases. Four RA studies reported the use of therapy before NHL diagnosis,2326 and 2 of those studies23,25 compared a group treated with a cytotoxic or a biological agent with a group of patients with RA who received conventional antirheumatic treatment. In more detail, 3 studies23,24,26 reported the use of cytotoxic therapy such as methotrexate,24 azathioprine sodium,23,26 or cyclophosphamide,26 and 1 study25 used a biological agent (anti–tumor necrosis factor, ie, etanercept or infliximab). In the azathioprine study,23 patients with RA not treated with azathioprine were used as control subjects. In the study assessing the efficacy of biological agents,25 patients with RA exposed to etanercept or infliximab were compared with a cohort of patients with RA who were never exposed to any type of biological drug. In our meta-analysis, the controls of both studies underwent evaluation for the risk of NHL development as a separate group (conventionally treated patients). In 2 studies,5,27 it was not specified whether NHL appeared before or after diagnosis of the autoimmune disease. In 4 studies,2,17,20,22 the NHL development before the diagnosis of the autoimmune disease was not excluded. The duration of cohorts ranged from 11 to 24, 7 to 24, and 1 to 25 years for SLE, RA, and pSS, respectively. The median follow-up times for pSS, SLE, and RA were 22, 20.5, and 9.5 years, respectively. The median age at NHL diagnosis and the median time from autoimmune disease diagnosis to NHL development were reported in only 4 studies referring to SLE patients,4,6,17,18 and the interval between SLE diagnosis and NHL diagnosis was estimated to be 7.5 years.

In total, the studies included 8700 cases with SLE, 95 104 cases with RA, and 1300 cases with pSS. The SIR of NHL in patients with SLE in the 6 cohort studies ranged from 5.2 to 44.4; in patients with RA, from 1.9 to 24.0; and in patients with pSS, from 8.7 to 44.4. A significant heterogeneity (P<.01; I2>70%) was found for SLE, RA, and pSS studies. The RE pooled SIRs for NHL were 7.4 (95% CI, 3.3-17.0), 3.9 (95% CI, 2.5-5.9), and 18.8 (95% CI, 9.5-37.3) for SLE, RA, and pSS, respectively (Figure). Therefore, there was a high risk of NHL development in pSS, a lower risk in SLE, and an even lower risk in RA. However, the 95% CIs for SLE and RA overlapped, indicating lack of a real difference between the 2 diseases.

In RA, the subgroup analysis on sex produced large heterogeneity (P<.01; I2>70%) for both sexes, and the RE pooled SIRs were 3.8 (95% CI, 1.7-8.8) and 5.0 (95% CI, 1.3-19.1) for female and male patients, respectively, which did not deviate substantially from the overall estimate (Figure). The subgroup analysis for the studies not reporting the type of treatment produced an RE pooled SIR of 3.3 (95% CI, 2.0-5.3). The subgroup analyses for the studies using cytotoxic drugs (methotrexate, azathioprine, and cyclophosphamide) and those using conventional antirheumatic treatment produced RE pooled SIRs of 5.1 (95% CI, 0.9-28.6) and 2.5 (95% CI, 0.7-9.0), respectively. The study25 that used a biological agent produced an SIR of 11.5 (95% CI, 3.7-26.9). In a sensitivity analysis, when the study with the biological agent25 was excluded, the RE pooled SIR was 3.48 (95% CI, 2.28-5.32), similar to the overall SIR. Because the studies on SLE and pSS do not specify or report the treatment of each cohort (Tables 1 and 3), it is not possible to perform the subgroup analysis performed in RA. However, in a sensitivity analysis when the SLE studies with NHL cases that had not received any immunosuppressive treatment4,6,17 were excluded, the RE pooled SIR was 8.1 (95% CI, 2.1-32.0), a bit larger than the overall SIR. In addition, the subgroup analysis for these studies4,6,17 produced an SIR of 6.6 (95% CI, 3.3-13.3). In pSS, when the study with NHL cases that did not receive immunosuppressive therapy was excluded, the SIR was 15.7 (95% CI, 7.4-33.2).

In cumulative meta-analysis, the RE pooled SIR in SLE declined from 44.4 in 1992 to 27.10 in 1995 and to 7.42 in 2001. In RA, the SIR declined from 9.3 in 1985 to 5.3 in 1993 and to 3.2 in 2005. In pSS, the SIR declined from 44.4 in 1978 to 22.5 in 1997 and to 20.3 in 1999. In all diseases, there has been a monotonic decrease since the first study. However, the values of SIRs were not correlated with the duration of follow-up; the Spearman rank correlation coefficients for SLE, RA, and pSS were −0.43 (P = .31), 0.20 (P = .56), and 0.31 (P = .61), respectively. In addition, there was no clear pattern that the magnitude of SIR was related to patient selection (clinic or hospital) in all autoimmune diseases.

There was no evidence of publication bias in SLE and pSS (P>.10 for the Egger and Begg-Mazumdar tests). In RA, there was marginal significance (P = .08 and P = .09 for the Egger and Begg-Mazumdar tests, respectively), indicating the existence of a differential magnitude of effect in large vs small studies.33 However, this result might not be reliable, because the number of studies is relatively small.34 Some studies had a selection bias because patients were hospitalized (data were obtained from hospital discharge registries), and therefore the more severe cases were considered.

COMMENT

The meta-analysis results showed that NHL is more common in patients with autoimmune diseases than in the general population, especially in patients with pSS and SLE. Because the follow-up time in the RA group was shorter than those for pSS and SLE, the possibility of overlooking RA-associated NHL cases that developed later in the disease process cannot be excluded. The fact that certain studies in RA did not show an increase in SIR is probably owing to the short duration of the follow-up.24 In several studies, particularly RA studies, the use of cytotoxic agents (eg, methotrexate, azathioprine, and cyclophosphamide) before NHL development is not reported. In the RA studies in which the treatment is reported, the risk of NHL with cytotoxic or biological agents is greater than the risk with conventional antirheumatic treatment. In the assessment of the impact of treatment on lymphomagenesis in RA, only 1 study used biological agents. Although the comparison of etanercept and infliximab with other treatment modalities in this group of patients does not seem fair, these drugs have a high likelihood of being associated with NHL development. However, the information on the role of these cytotoxic or immunomodulatory agents in lymphomagenesis in RA is rather limited, and any inferences cannot be taken for granted. In addition, these phenomena need to be considered against the background that the occurrence of NHL in patients with RA might be associated with disease activity or severity. In this regard, cytotoxic or biological therapy may be indicative of a specific group of patients with RA who have more severe disease and a high predisposition for NHL development. For several decades, it has been known that patients with RA have an increased risk of NHL development.2022,35,36 The reason is still not fully understood, and controversy remains as to whether the risk is a consequence of immunosuppressive therapy.23,24,3741 Recent data suggest that high and long-standing inflammatory activity in RA may itself contribute to the development of lymphomas, which are preferentially of the aggressive, diffuse, extranodal, large B-cell type.42 Because indolent extranodal marginal-zone B-cell lymphoma of the mucosa-associated lymphoid tissue is the most common type of lymphoma in pSS,43 this dissimilarity indicates different mechanisms underlying lymphoma development in these 2 diseases. The specific diffuse, extranodal, large B-cell lymphoma subtype in RA implies an underlying immunodeficiency status.44 Peripheral mononuclear cells from patients with RA who were not receiving cytotoxic or long-acting antirheumatic drugs were found to be hypoproliferative in vitro to a battery of soluble recall antigens.4547 Therefore, an impaired T-cell function could be relevant to an impairment of immune responses toward emerging malignant B cells.

Although this meta-analysis provided a more precise estimate of the relative risk of NHL in relation to autoimmune diseases than did the individual studies, because it has used a vast amount of patients, its major limitation is the large heterogeneity between studies. The heterogeneity might be owing to different baseline risk populations, study designs, and data sources. Therefore, the results should be interpreted with caution. The meta-analysis was restricted to NHL because adequate studies established strong associations between B-cell lymphoproliferation and autoimmunity. Studies that investigated the incidence rate of lymphomas (NHL or Hodgkin disease) without specifying the rates separately were not included.37,48 In addition, studies that did not provide information about the expected number of NHL cases in the general population were omitted from the analysis.42,4952 However, exclusion of such studies may have biased the results. Moreover, 4 studies included cases with NHL that developed before the diagnosis of the autoimmune diseases. The inclusion of these cases in the cohort studies may obscure the interpretation of the autoimmunity-NHL association. Regardless of these limitations, the meta-analysis showed that autoimmune diseases are associated with an increased risk of NHL. Assuming that the expected cases (E) of NHL can be estimated by the weighted mean of the expected cases provided by the included studies in the meta-analysis, and using the number of patients as weights, then E = 17. Thus, the RE pooled SIR for RA of 3.9 means that there is a 3.9-times increase in the incidence, or (SIR × E)/100 000 = 66 cases per 100 000 patient-years, and the RE pooled SIR for SLE of 7.4 means that there is a 7.4-times increase in the incidence or 126 cases per 100 000 patient-years, and the RE pooled SIR for pSS of 18.8 means that there is an 18.8-times increase in the incidence or 320 cases per 100 000 patient-years. In this setting, the association of NHL with autoimmune diseases generates increasing interest because it may concern the mechanisms of lymphomagenesis in general.

The B-cell disorder seen in patients with pSS is particularly severe compared with the B-cell dysfunction seen in other autoimmune diseases such as SLE. It has been shown that patients with pSS have higher incidence and higher serum levels of B-cell activating factor compared with patients with SLE.53,54 Furthermore, patients with active SLE have decreased numbers of CD19+/CD27 naive B cells and increased numbers of CD19+/CD27+ memory B cells,55 in contrast to patients with pSS who are characterized by a significant reduction in the number of the peripheral CD27+ memory B cells.56,57 Given the vigor with which immunoglobulin genes are modified during immune responses, it is plausible to hypothesize that some of the critical transforming events are the product of an intense ectopic germinal center reaction in pSS. In this regard, patients with pSS with an increased risk of NHL are characterized by splenomegaly, lymphadenopathy, mixed monoclonal cryoglobulinemia, and parotid swelling, all indicators of an extensive lymphoproliferation.3,58,59 This could possibly explain why lymphoid malignancies are more common in pSS than in SLE. In the diseases studied, the risk of NHL development since the first study was reduced and may be attributed to revised and/or more accurate classification of NHL during this period or to more effective treatment of the underlying B-cell dysregulation of autoimmune diseases.60

Despite the limitations of this meta-analysis, it provides new and sustained evidence establishing differences of NHL development risk in various autoimmune disorders. 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. Further studies are warranted to correlate our epidemiologic data with the underlying disease mechanisms. In addition, the risk of NHL in patients receiving immunosuppressive drugs must be investigated.

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Article Information

Correspondence: Haralampos M. Moutsopoulos, MD, FACP, FRCP, Department of Pathophysiology, National University of Athens School of Medicine, Mikras Asias 75, Athens 11527, Greece (hmoutsop@med.uoa.gr).

Accepted for Publication: July 11, 2005.

Financial Disclosure: None.

Acknowledgment: We thank John Stefanidis, MD, and Betina Haidich, MD, for comments.

References
1.
Pettersson  TPukkala  ETeppo  LFriman  C Increased risk of cancer in patients with systemic lupus erythematosus. Ann Rheum Dis 1992;51437- 439
PubMedArticle
2.
Prior  P Cancer and rheumatoid arthritis: epidemiologic considerations. Am J Med 1985;78 ((suppl 1)) (1) 15- 21
PubMedArticle
3.
Kassan  SSThomas  TLMoutsopoulos  HM  et al.  Increased risk of lymphoma in sicca syndrome. Ann Intern Med 1978;89888- 892
PubMedArticle
4.
Cibere  JSibley  JHaga  M Systemic lupus erythematosus and the risk of malignancy. Lupus 2001;10394- 400
PubMedArticle
5.
Kauppi  MPukkala  EIsomaki  H Elevated incidence of hematologic malignancies in patients with Sjögren’s syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control 1997;8201- 204
PubMedArticle
6.
Sweeney  DMManzi  SJanosky  J  et al.  Risk of malignancy in women with systemic lupus erythematosus. J Rheumatol 1995;221478- 1482
PubMed
7.
Rothman  KJGreenland  S Modern Epidemiology. 2nd ed. Philadelphia, Pa Lippincott Williams & Wilkins1998;
8.
Metintas  SMetintas  MUcgun  IOner  U Malignant mesothelioma due to environmental exposure to asbestos: follow-up of a Turkish cohort living in a rural area. Chest 2002;1222224- 2229
PubMedArticle
9.
Freedman  LSBarchana  MAl-Kayed  S  et al.  A comparison of population-based cancer incidence rates in Israel and Jordan. Eur J Cancer Prev 2003;12359- 365
PubMedArticle
10.
Whitehead  A Meta-Analysis of Controlled Clinical Trials.  New York, NY John Wiley & Sons2002;
11.
Cochran  WG The combination of estimates from different experiments. Biometrics 1954;10101- 129Article
12.
Higgins  JPThompson  SG Quantifying heterogeneity in a meta-analysis. Stat Med 2002;211539- 1558
PubMedArticle
13.
Lau  JAntman  EMJimenez-Silva  JKupelnick  BMosteller  FChalmers  TC Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 1992;327248- 254
PubMedArticle
14.
Egger  MDavey Smith  GSchneider  MMinder  C Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315629- 634
PubMedArticle
15.
Begg  CBMazumdar  M Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;501088- 1101
PubMedArticle
16.
Zintzaras  EStefanidis  I Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: a meta-analysis. J Hum Genet 2005;5084- 91
PubMedArticle
17.
Abu-Shakra  MGladman  DDUrowitz  MB Malignancy in systemic lupus erythematosus. Arthritis Rheum 1996;391050- 1054
PubMedArticle
18.
Mellemkjaer  LAndersen  VLinet  MSGridley  GHoover  ROlsen  JH Non-Hodgkin’s lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus. Arthritis Rheum 1997;40761- 768
PubMedArticle
19.
Bjornadal  LLofstrom  BYin  LLundberg  IEEkbom  A Increased cancer incidence in a Swedish cohort of patients with systemic lupus erythematosus. Scand J Rheumatol 2002;3166- 71
PubMedArticle
20.
Hakulinen  TIsomaki  HKnekt  P Rheumatoid arthritis and cancer studies based on linking nationwide registries in Finland. Am J Med 1985;78 ((suppl 1)) (1) 29- 32
PubMedArticle
21.
Gridley  GMcLaughlin  JKEkbom  A  et al.  Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993;85307- 311
PubMedArticle
22.
Mellemkjaer  LLinet  MSGridley  GFrisch  MMoller  HOlsen  JH Rheumatoid arthritis and cancer risk. Eur J Cancer 1996;32A1753- 1757
PubMedArticle
23.
Silman  AJPetrie  JHazleman  BEvans  SJ Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 1988;47988- 992
PubMedArticle
24.
Mariette  XCazals-Hatem  DWarszawki  JLiote  FBalandraud  NSibilia  JInvestigators of the Club Rhumatismes et Inflammation, Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002;993909- 3915
PubMedArticle
25.
Geborek  PBladstrom  ATuresson  C  et al.  Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005;64699- 703
PubMedArticle
26.
Kinlen  LJ Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 1985;7844- 49
PubMedArticle
27.
Davidson  BKKelly  CAGriffiths  ID Primary Sjögren’s syndrome in the North East of England: a long-term follow-up study. Rheumatology (Oxford) 1999;38245- 253
PubMedArticle
28.
Valesini  GPriori  RBavoillot  D  et al.  Differential risk of non-Hodgkin’s lymphoma in Italian patients with primary Sjögren’s syndrome. J Rheumatol 1997;242376- 2380
PubMed
29.
Pertovaara  MPukkala  ELaippala  PMiettinen  APasternack  A A longitudinal cohort study of Finnish patients with primary Sjögren’s syndrome: clinical, immunological, and epidemiological aspects. Ann Rheum Dis 2001;60467- 472
PubMedArticle
30.
World Health Organization, International Classification of Diseases, Seventh Revision (ICD-7).  Geneva, Switzerland World Health Organization1955;
31.
World Health Organization, International Classification of Diseases, Eighth Revision (ICD-8).  Geneva, Switzerland World Health Organization1965;
32.
World Health Organization, International Classification of Diseases, Ninth Revision (ICD-9).  Geneva, Switzerland World Health Organization1977;
33.
Zintzaras  EChatzoulis  DZKarabatsas  CHStefanidis  I The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis. J Hum Genet 2005;50267- 275
PubMedArticle
34.
Sterne  JAEgger  MSmith  GD Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. BMJ 2001;323101- 105
PubMedArticle
35.
Prior  PSymmons  DPHawkins  CFScott  DLBrown  R Cancer morbidity in rheumatoid arthritis. Ann Rheum Dis 1984;43128- 131
PubMedArticle
36.
Thomas  EBrewster  DHBlack  RJMacfarlane  GJ Risk of malignancy among patients with rheumatic conditions. Int J Cancer 2000;88497- 502
PubMedArticle
37.
Asten  PBarrett  JSymmons  D Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol 1999;261705- 1714
PubMed
38.
Georgescu  LQuinn  GCSchwartzman  SPaget  SA Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment. Semin Arthritis Rheum 1997;26794- 804
PubMedArticle
39.
Georgescu  LPaget  SA Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate? Drug Saf 1999;20475- 487
PubMedArticle
40.
Kamel  OWvan de Rijn  MWeiss  LM  et al.  Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1993;3281317- 1321
PubMedArticle
41.
Salloum  ECooper  DLHowe  G  et al.  Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 1996;141943- 1949
PubMed
42.
Baecklund  ESundstrom  CEkbom  A  et al.  Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 2003;481543- 1550
PubMedArticle
43.
Voulgarelis  MDafni  UGIsenberg  DAMoutsopoulos  HM Malignant lymphoma in primary Sjögren’s syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren’s Syndrome. Arthritis Rheum 1999;421765- 1772
PubMedArticle
44.
Knowles  DM Immunodeficiency-associated lymphoproliferative disorders. Mod Pathol 1999;12200- 217
PubMed
45.
Wahl  SMWilder  RLKatona  IM  et al.  Leukapheresis in rheumatoid arthritis: association of clinical improvement with reversal of anergy. Arthritis Rheum 1983;261076- 1084
PubMedArticle
46.
Malone  DGWahl  SMTsokos  MCattell  HDecker  JLWilder  RL Immune function in severe, active rheumatoid arthritis: a relationship between peripheral blood mononuclear cell proliferation to soluble antigens and synovial tissue immunohistologic characteristics. J Clin Invest 1984;741173- 1185
PubMedArticle
47.
Yocum  DEWilder  RLDougherty  SKlippel  JHPillemer  SWahl  S Immunologic parameters of response in patients with rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 1990;331310- 1316
PubMedArticle
48.
Wolfe  FMichaud  K Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18 572 patients. Arthritis Rheum 2004;501740- 1751
PubMedArticle
49.
Varoczy  LGergely  LZeher  MSzegedi  GIlles  A Malignant lymphoma-associated autoimmune diseases: a descriptive epidemiological study. Rheumatol Int 2002;22233- 237
PubMedArticle
50.
Ioannidis  JPVassiliou  VAMoutsopoulos  HM Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheum 2002;46741- 747
PubMedArticle
51.
Lewis  PHazleman  BLHanka  RRoberts  S Cause of death in patients with rheumatoid arthritis with particular reference to azathioprine. Ann Rheum Dis 1980;39457- 461
PubMedArticle
52.
Tennis  PBombardier  CMalcolm  EDowney  W Validity of rheumatoid arthritis diagnoses listed in the Saskatchewan Hospital Separations Database. J Clin Epidemiol 1993;46675- 683
PubMedArticle
53.
Cheema  GSRoschke  VHilbert  DMStohl  W Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 2001;441313- 1319
PubMedArticle
54.
Groom  JKalled  SLCutler  AH  et al.  Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome. J Clin Invest 2002;10959- 68
PubMedArticle
55.
Jacobi  AMOdendahl  MReiter  K  et al.  Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum 2003;481332- 1342
PubMedArticle
56.
Bohnhorst  JOThoen  JENatvig  JBThompson  KM Significantly depressed percentage of CD27+ (memory) B cells among peripheral blood B cells in patients with primary Sjögren’s syndrome. Scand J Immunol 2001;54421- 427
PubMedArticle
57.
Hansen  AOdendahl  MReiter  K  et al.  Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum 2002;462160- 2171
PubMedArticle
58.
Tzioufas  AGBoumba  DSSkopouli  FNMoutsopoulos  HM Mixed monoclonal cryoglobulinemia and monoclonal rheumatoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjögren’s syndrome. Arthritis Rheum 1996;39767- 772
PubMedArticle
59.
Skopouli  FNDafni  UIoannidis  JPAMoutsopoulos  HM Clinical evolution, and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum 2000;29296- 304
PubMedArticle
60.
Harris  NLJaffe  ESStein  H  et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;841361- 1392
PubMed
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