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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Service de Rhumatologie, Hôpital de
Bicêtre (Assistance publique-Hôpitaux de Paris [AP-HP]),
Le Kremlin Bicêtre, France; Service d'Anatomo-pathologie,
Hôpital Beaujon (AP-HP), Paris, France; Service
d'Epidémiologie, Hôpital de Bicêtre (AP-HP), Le
Kremlin Bicêtre, France; Fédération de Rhumatologie,
Hôpital Lariboisière (AP-HP), Paris, France; Service de
Rhumatologie, Centre Hospitalier Lyon-Sud, Lyon, France; and the
Service de Rhumatologie, Hôpital de Hautepierre, Strasbourg,
France. CRI (Club Rhumatismes et Inflammation): the practitioners who
referred patients are listed in an Appendix.
A national prospective study was designed to collect all cases of
lymphoma appearing in patients with rheumatoid arthritis (RA) treated
with methotrexate (MTX) throughout France over a period of 3 years. A
total of 25 cases of lymphoma were recorded, 18 cases of non-Hodgkin
lymphoma (NHL), 3 of which were associated with the presence of
Epstein-Barr virus (EBV) in lymphoma cells, and 7 cases of Hodgkin
disease (HD), 5 of them associated with EBV. Among the 8 patients who
were treated by MTX withdrawal alone, 3 underwent remission, but 2 of
them had a relapse, the third patient with clonal EBV-associated large
granular lymphocytes T-cell NHL remaining alive in complete remission.
The estimated annual incidence rate of NHL in RA patients treated with
MTX was 33.3.10 Several studies have suggested an increased risk of
lymphoma in patients with rheumatoid arthritis (RA).1-3
Recently, it was shown that RA patients treated with methotrexate (MTX)
can develop lymphoproliferative disorders that share characteristics with the lymphomas occurring in immunosuppressed patients; the Epstein-Barr virus (EBV) genome was present in lymphoma cells and
spontaneous regression was possible after withdrawal of the drug
alone.4-8 MTX, now the most common disease-modifying
antirheumatic drug (DMARD) used in RA, was, however, introduced 20 years ago and no excessive risk of lymphoma has been observed in one
retrospective study9 and in several longitudinal studies
of patients receiving MTX, even after long-term
follow-up.10-13 However, these studies included only
several hundred patients, which might not be enough to detect an
excessive risk of a rare event, which is the occurrence of
lymphoma. A truly longitudinal study of thousands of patients treated
with MTX during a long period was impossible. Therefore, we decided to
design a national prospective study, through an organization linking
the 61 French departments of rheumatology, to collect all new cases of
lymphoma appearing in French patients with RA treated with MTX over a
period of 3 years. The objectives were to characterize these lymphomas,
to assess their outcome after several years, and to estimate their
incidence as compared to the general population.
Study design
Histology
Histologic analyses.
A paraffin-embedded fixed specimen from each case was collected and
reviewed by one pathologist (D.C.-H.). The aims of this review were to
confirm the diagnosis of lymphoma and to classify non-Hodgkin lymphoma
(NHL) according to the Revised European and American Lymphoma
(REAL) classification15 and Hodgkin disease (HD)
according to the Rye system.16 Histologic samples had been fixed in formalin and were analyzed after hematoxylin and eosin, Giemsa, and periodic-acid-Schiff staining and Gordon-Sweet
impregnation. In all cases, the immunohistochemistry was determined by
means of a 3-step indirect immunoperoxidase method followed by the
diaminobenzidine (DAB) reaction, using a panel of primary antibodies
against CD3, CD20/L26, Detection of EBV.
The presence of the EBV genome was systematically investigated by
conventional RNA in situ hybridization methods17 using fluorescein-conjugated EBV oligonucleotides (EBER1 and EBER2, Dako,
Glostrup, Denmark), and by immunohistochemistry against LMP-1 (EBV
latent membrane protein, clone CS1-4, Dako). In one case of leukemic
T-cell lymphoma, polymerase chain reaction (PCR) amplification of the
EBNA1 region was used to detect EBV.
Detection of clonality.
Clonality was assessed by immunohistochemistry against Epidemiology and statistical analyses
Comparison of patients with NHL and
HD.
Differences in clinical characteristics between patients with NHL and
patients with HD were assessed by the Wilcoxon rank sum test (for
continuous variables) or the Comparison of NHL and HD incidence
rates with the French national incidence rates.
We could assume to have collected most if not all the cases of lymphoma
occurring in RA patients treated with MTX in France over the study
period. However, no direct data were available for the total number of
RA patients treated by MTX in France during the study period. We used
several sources of data to estimate this number.
Characteristics of the patients During the 3 years of the study, 25 new cases of lymphoma were recorded among RA patients treated with MTX in France. At the time of lymphoma diagnosis, the mean age of the patients was 63 years (range, 39-82 years), the mean duration of RA was 16.2 years (range, 25-49 years) and the mean duration of MTX treatment was 5.2 years (range, 1.4-13 years) with a mean cumulative dose of 2.2 g (range, 0.5-5.2 g). RA was erosive and rheumatoid factor positive in 24 of the 25 patients, whereas secondary Sjögren syndrome was present in only 2. There was no concomitant DMARD except in 4 cases (cyclosporine, azathioprine, hydroxychloroquine, and tiopronine, respectively). No patient had hepatitis C or human immunodeficiency virus infection (tested in all patients). As seen in Table 1, extranodal locations of lymphoma were frequent and observed in 13 patients (52%; 12 of 18 NHL and 1 of 7 HD). A comparison between patients with NHL and patients with HD is given in Table 2.
Pathology The 25 new cases of lymphoma comprised 18 NHL and 7 HD (Table 1). The 18 NHL cases consisted of 2 T-cell NHL (one pleomorphic small and medium T-cell lymphoma and one large granular lymphocyte [LGL] T-cell lymphoma) and 16 B-cell NHL (12 diffuse large B-cell lymphomas, 3 marginal zone B-cell lymphomas [MZLs] and one lymphocytic B-cell lymphoma).Clonality, assessed in 8 of the 16 B-cell NHL by immunohistochemistry
or in situ hybridization, revealed in all studied cases a restrictive
expression of In NHL, EBV was detected by immunohistochemistry with anti-LMP antibodies and in situ hybridization with the EBER probes in 2 of the 12 diffuse large B-cell NHLs, whereas no low-grade B-cell NHL expressed EBV. PCR amplification of the EBNA1 gene of EBV was strongly positive in peripheral blood lymphocytes of the patient with LGL T-cell lymphoma. The 7 cases of HD were subclassified as follows: 2 of the nodular sclerosis type, 4 of the mixed cellularity type, and 1 unclassified case due to extranodal involvement (liver). Hodgkin cells expressed CD30 in all cases, CD15 in 6 of 7 cases, and CD20 in 1 case, whereas EBV was detected in 5 of the 7 patients. Outcome The outcome for the patients is shown in Figure 1. MTX therapy was stopped in all patients but one. In 8 patients (5 with NHL, 3 with HD), MTX was withdrawn without any specific treatment of the lymphoma for at least 6 months. Four cases remained stable (2 HD, 1 large B-cell NHL, and 1 lymphocytic lymphoma), 1 patient with HD worsened, and all 5 subsequently received chemotherapy. Among 3 patients who achieved initial spontaneous remission, 2 had relapse at 12 and 14 months and were given further chemotherapy (1 large B-cell NHL and 1 MZL, respectively). The third patient with LGL T-cell NHL is still alive in complete remission (CR) at 41 months of follow-up. Two of these 3 lymphomas were EBV+ (1 large B-cell NHL and the LGL T-cell NHL), and all of them were monoclonal.
One patient with mediastinal HD died before starting chemotherapy. One with Helicobacter pylori-associated gastric mucosa-associated lymphoid tissue (MALT) lymphoma (extranodal MZL) was successfully treated with antibiotics and is still alive in CR. The remaining patients received chemotherapy or radiotherapy or both. The median follow-up of surviving patients was 34 months (range, 25-54 months). The death-free survival rate was plotted for NHL and HD
(Figure 2). The 2 survival curves did not
significantly differ (P = .42, log-rank test) with an
estimated hazard ratio of 1.6 (95% CI, 0.5-5.6). In patients with HD,
the median survival was 27 months. Eleven of the 25 patients died (4 of
7 HD, 1 of 2 T-cell NHL, 0 of 4 low-grade malignancy B-cell NHL, and 6 of 12 large B-cell NHL). Among the 14 patients still alive, 10 are in
CR and 4 in partial remission (PR).
Analysis of relapses During the mean follow-up of 34 months, 5 relapses were observed after an initial remission: 2 in patients treated by withdrawal of MTX alone and 3 in patients given chemotherapy. In all cases, the histologic pattern was similar at relapse and diagnosis: 4 cases of large B-cell NHL and 1 case of MZL B-cell NHL. Clonality was demonstrated in the 5 B-cell NHLs at both diagnosis and relapse, while in the patient with EBV+ large B-cell NHL who relapsed, EBV was also detected at relapse.Epidemiology In the present study, we observed 18 new cases of NHL in 3 years (6 every year): 12 in women and 6 in men. Thus, the observed annual incidence of NHL in RA women and men treated with MTX was 4/24 000 = 16.7 × 10 5 (95% CI, 0-33.3)
and 2/6000 = 33.3 × 105 (95% CI, 0-80.5),
respectively, using the highest estimation of RA patients treated
with MTX (n = 30 000; Table 3). This
observed annual incidence of NHL did not significantly exceed the
annual incidence of NHL in France23 after adjustment for
age and sex: SMR = 1.07 (0.6-1.7).
On the other hand, we observed 7 new cases of HD in 3 years (2 in 1996, 3 in 1997, and 2 in 1998), 2 in women and 5 in men. Thus, the observed
annual incidence of HD in RA women and men treated with MTX was
0.67/24 000 = 2.8 × 10 Using a male-female ratio of 1:12 among RA patients treated with MTX instead of 1:4 did not change conclusions with SMRs, adjusted for age and sex, equal to 1.0 (95% CI, 0.6-1.5) and 6.5 (95% CI, 2.6-13.4) for NHL and HD, respectively. Using the lowest estimation of the number of RA patients (n = 27 000) also led to similar conclusions (Table 3).
This 3-year prospective study is the first prospective study of the literature recording all the cases of lymphomas occurring in RA patients treated with MTX in a whole country. This enabled us to define the characteristics of the 25 collected lymphomas, their outcome, and, because we could assume to have collected most if not all the cases in France over the study period, to estimate the incidence of this complication in RA patients treated with MTX. In addition, the 3-year follow-up of the patients gives precious indications on the long-term prognosis of such lymphomas. The histologic patterns of the observed lymphomas were heterogeneous: 18 NHL (16 B-cell NHL and 2 T-cell NHL) and 7 HD. All the NHL that could be studied were monoclonal (tested in 9 of 18). Extranodal locations of NHL were frequent (12 of 18, 67%) and several marginal zone-type NHLs were observed (3 cases), as in the lymphomas occurring in patients with Sjögren syndrome25 or chronic hepatitis C virus infection.26 Interestingly, in both these diseases, a chronic autoantigenic stimulation has been suspected to play a role in the etiology of lymphoma.27 However, the frequency of secondary Sjögren syndrome was not increased in the present RA patients with lymphoma and this complication was found in none of the 3 patients with MALT lymphoma. Thus, whether treated or not with MTX, RA could represent another disease in which a chronic autoantigenic stimulation might lead to an increased risk of lymphoma. It has been known since 1993 that some lymphoproliferative disorders appearing in patients treated with MTX were associated with EBV and might spontaneously resolve after withdrawal of the drug, like the lymphoproliferations occurring in immunosuppressed patients.4 These results are particularly interesting, because EBV is frequently found in the synovium of RA patients28 and these patients could have impaired immunologic control of EBV.29 As compared to populations with no immunodeficiency, an association with EBV could be slightly more frequent in our patients: EBV was detected in 5 of 7 HD patients, in 2 of 12 with diffuse large B-cell NHL, and in 1 with LGL T-cell NHL. This latter patient is of particular interest because LGL T-cell NHL, which can be associated with untreated RA, has recently been described in immunosuppressed renal allograft patients,30 but has only very rarely been associated with EBV.30-32 Moreover, this patient with monoclonal LGL T-cell NHL is the only patient in stable remission more than 3 years after MTX withdrawal without other treatment. Two other patients with monoclonal B-cell NHL experienced remission after MTX withdrawal alone, but had a relapse 12 to 14 months later. Among our patients with NHL, EBV was detected in lymphoma cells in 2 of 3 patients who experienced remission after MTX withdrawal alone, but in only 1 of the 15 others. Hence, like others,4-8 we suggest an association between the presence of EBV in lymphoma cells and spontaneous regression after withdrawal of the drug. Therefore, among lymphomas occurring in RA patients treated with MTX, there is probably a minor subset that can spontaneously resolve after withdrawal of the drug. Close monitoring of these patients is, however, mandatory because recurrence is frequent during follow-up. Overall, our findings are in accordance with a recent 6-year case-control study by Kamel et al (49 patients with NHL and RA), who found that the majority of NHL occurring in RA patients did not share characteristics with the lymphomas of immunosuppressed patients.33 Whether or not RA patients treated with MTX have an increased risk of
developing lymphoma remains a matter of controversy. No excessive risk
of lymphoma has been observed in several groups of patients receiving
MTX, even after long-term follow-up.9-12 In a recent
survey13 and in another smaller
study,34 it was suggested that treatment with MTX did not
have any effect on the occurrence of lymphoma, which was
associated with a persistent inflammatory activity of the disease. In
addition, it was recently demonstrated that a response to MTX was
related to reduced mortality in patients with severe RA.35
Because we could assume we had collected most of the cases of lymphoma
appearing in RA patients treated with MTX in France, we estimated the
annual incidence of NHL in these patients (16.7 × 10 Lastly, our study points to a high incidence of HD in RA patients treated with MTX. Interestingly, 5 of 7 patients had HD associated with EBV, whereas this association is usually present in only 40% of those with HD.36 These were typical cases of HD with a CD30+CD15+ phenotype and not lymphoproliferative disorders resembling HD, as previously described in some RA patients treated with MTX.37 Typical HD has, however, also been described in RA patients receiving MTX.37-40 It is noteworthy that in 2 cases in the literature the lymphoproliferation, which decreased after MTX withdrawal perhaps only because steroids were increased to control the activity of RA, recurred several months later.39,40 Among our 3 patients with HD who were treated with MTX withdrawal alone without any chemotherapy for at least 6 months, none of them experienced spontaneous remission. In our study, the annual incidences of HD in RA patients treated with
MTX were estimated to be 2.8 × 10 Several reasons argue for the consistency of our conclusions, concerning comparisons of NHL and HD incidence with French incidences. (1) The numbers of new cases of NHL and HD were not likely to have been overestimated because all cases were reviewed by the same pathologist. Moreover, the number of annual new cases were similar during the 3-year study. (2) Although the number of RA patients treated with MTX was not directly available, very similar estimations of number of persons-years (between 27 000 and 30 000) were obtained from multiple and independent sources. (3) The conclusions were similar by using the lowest and the highest of these estimations. (4) The conclusions were similar by using a male-female ratio of 1:4 women corresponding to the sex ratio of RA patients treated with MTX in France22 as well as using a male-female ratio of 1:12 corresponding to the lowest sex ratio of RA in the literature. In conclusion, this 3-year prospective study in France indicates that the overall risk of NHL is not increased in RA patients treated with MTX. However, a minor subset of NHL occurring in these patients is probably linked to MTX treatment and may resolve after withdrawal of the drug alone. When possible, it might therefore be advisable to wait for 2 to 3 months after MTX withdrawal before starting chemotherapy. Close monitoring of these patients is nevertheless mandatory because recurrence is frequent during short-term follow-up. Finally, EBV-associated HD not resolving after withdrawal of MTX and requiring classical chemoradiotherapy could be more common in RA patients treated with MTX.
We are indebted to Prof J. P. Daurès for providing the sex and age distribution of French RA patients treated with MTX, to Prof A. Saraux, Pr J. Sany, and Dr B. Decot for valuable advice and comments in epidemiology and statistics, to Prof F. Stoll-Keller and Dr C. Pallier for EBV PCR, to Dr E. Guérin for PCR to detect T-cell clonality, and to S. Vo for technical assistance.
Submitted June 6, 2001; accepted January 25, 2002.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Xavier Mariette, Service de Rhumatologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France; e-mail: xavier.mariette{at}bct.ap-hop-paris.fr.
1.
Lea AJ.
An association between the rheumatic diseases and the reticuloses.
Ann Rheum Dis.
1964;23:480-484 2. Banks PM, Witrak GA, Conn DLM. Lymphoid neoplasia developing after connective tissue disease. Mayo Clin Proc. 1979;54:104-108[Medline] [Order article via Infotrieve]. 3. Hakulinen T, Isomaki H, Knekt P. Rheumatoid arthritis and cancer studies based on linking nationwide registries in Finland. Am J Med. 1985;78:29-32[Medline] [Order article via Infotrieve].
4.
Kamel OW, Van de Rijn M, Weiss LM, et al.
Reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis.
N Engl J Med.
1993;328:1317-1321
5.
Salloum E, Cooper DL, Howe G, et al.
Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases.
J Clin Oncol.
1996;14:1943-1949 6. Georgescu L, Quinn GC, Schwartzman S, Paget SA. Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment. Semin Arthritis Rheum. 1997;26:794-804[CrossRef][Medline] [Order article via Infotrieve]. 7. Kamel OW, Van de Rijn M, Hanasono MM, Warnke RA. Immunosuppression-associated lymphoproliferative disorders in rheumatic patients. Leuk Lymphoma. 1995;16:363-368[Medline] [Order article via Infotrieve]. 8. Bachman TR, Sawitzke AD, Perkins SL, Ward JH, Cannon GW. Methotrexate-associated lymphoma in patients with rheumatoid arthritis: report of two cases. Arthritis Rheum. 1996;39:325-329[Medline] [Order article via Infotrieve]. 9. Moder KG, Tefferi A, Cohen MD, Menke DM, Luthra HS. Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study. Am J Med. 1995;99:276-281[CrossRef][Medline] [Order article via Infotrieve].
10.
Bologna C, Picot MC, Jorgensen C, Viu P, Verdier R, Sany J.
Study of eight cases of cancer in 426 rheumatoid patients treated with methotrexate.
Ann Rheum Dis.
1997;56:97-102 11. Kremer JM. Safety, efficacy and mortality in a long-term cohort of patients with rheumatoid arthritis taking methotrexate: follow-up after a mean of 13.3 years. Arthritis Rheum. 1997;40:984-985[Medline] [Order article via Infotrieve]. 12. Weinblatt ME, Maier AL, Fraser PA, Coblyn JS. Long-term prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy. J Rheumatol. 1998;25:238-242[Medline] [Order article via Infotrieve]. 13. Wolfe F. Inflammatory activity, but not methotrexate or prednisone use predicts non-Hodgkin's lymphoma in rheumatoid arthritis: a 25-year study of 1,767 RA patients. Arthritis Rheum. 1998;41:S188. 14. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315-324[Medline] [Order article via Infotrieve].
15.
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML.
A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group.
Blood.
1994;84:1361-1392
16.
Lukes RJ, Butler JJ.
The pathology and nomenclature of Hodgkin's disease.
Cancer Res.
1966;26:1063-1083 17. Chang KL, Chen YY, Shibata D, Weiss LM. Description of an in situ hybridization methodology for detection of Epstein-Barr virus RNA in paraffin-embedded tissues, with a survey of normal and neoplastic tissues. Diagn Mol Pathol. 1992;1:246-255[Medline] [Order article via Infotrieve]. 18. Bregeon C, Rolland D, Canonne F, Renier JC. Estimation de la prévalence de la polyarthrite rhumatoïde à partir d'une étude en milieu rhumatologique dans l'arrondissement d'Angers. [Prevalence estimate of rheumatoid arthritis based on a rheumatological study in Angers] Rev Rheum. 1986;53:83-90. 19. Louvot J, Flipo RM, Le Dantec L, et al. Estimation de la prévalence de la polyarthrite rhumatoïde en France: etude au sein de la communauté urbaine de Lille. [Prevalence estimate of rheumatoid arthritis in France: study in the city of Lille] Rev Rhum. 1996;10:824. 20. Saraux A, Guedes C, Allain J, et al. Prevalence or rheumatoid arthritis and spondyloarthropathy in Brittany, France. J Rheumatol. 1999;26:2622-2627[Medline] [Order article via Infotrieve]. 21. Le Dantec L, Flipo RM, Louvot J, Coquerelle P, Duquesnoy B, Delcambre B. Prise en charge thérapeutique de la polyarthrite rhumatoïde dans une importante cohorte de malades ambulatoires. [Treatment of rheumatoid arthritis in a large cohort of outpatients] Rev Rhum. 1996;63:823. 22. Sany J, Dropsy R, Daurès JP. Cross-sectional epidemiological survey of rheumatoid arthritis patients seen in private practice in France: descriptive results (1629 cases). Rev Rhum Eng Ed. 1998;65:462-470. 23. Ménégoz F, Chérié-Challine L, Grosclaude P, Jougla E. Le cancer en France: incidence et mortalité: situation en 1995: evolution entre 1975 et 1995. Edition DGS et réseau FRANCIM.: La Documentation Française; 1998.
24.
Samuels SJ, Beaumont JJ, Breslow NE.
Power and detectable risk or seven tests for standardized mortality ratios.
Am J Epidemiol.
1991;133:1191-1197
25.
Royer B, Cazals-Hatem D, Sibilia J, et al.
Lymphomas in patients with Sjögren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses.
Blood.
1997;90:766-775
26.
De Vita S, Sacco C, Sansonno D, et al.
Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection.
Blood.
1997;90:776-782 27. Mariette X. Lymphomas in patients with Sjögren's syndrome: review of the literature and physiopathologic hypothesis. Leuk Lymphoma. 1999;33:93-99[Medline] [Order article via Infotrieve]. 28. Takeda T, Mizugaki Y, Matsubara L, Imai S, Koike T, Takada K. Lytic Epstein-Barr virus infection in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 2000;43:1218-1225[CrossRef][Medline] [Order article via Infotrieve].
29.
Toussirot E, Wendling D, Tiberghien P, Luka J, Roudier J.
Decreased T cell precursor frequencies to Epstein-Barr virus glycoprotein gp 110 in peripheral blood correlate with disease activity and severity in patients with rheumatoid arthritis.
Ann Rheum Dis.
2000;59:533-538 30. Gentile TC, Hadlock KG, Uner AH, et al. Large granular lymphocyte leukaemia occurring after renal transplantation. Br J Haematol. 1998;101:507-512[CrossRef][Medline] [Order article via Infotrieve].
31.
Loughran TP Jr, Zambello R, Ashley R, et al.
Failure to detect Epstein-Barr virus DNA in peripheral blood mononuclear cells of most patients with large granular lymphocyte leukemia.
Blood.
1993;81:2723-2726 32. Pellenz M, Zambello R, Semenzato G, Loughran TP Jr. Detection of Epstein-Barr virus by PCR analyses in lymphoproliferative disease of granular lymphocytes. Leuk Lymphoma. 1996;23:371-374[Medline] [Order article via Infotrieve]. 33. Kamel OW, Holly EA, Van de Rijn M, Lele C, Sah A. A population based, case control study of non-Hodgkin's lymphoma in patients with rheumatoid arthritis. J Rheumatol. 1999;26:1676-1680[Medline] [Order article via Infotrieve].
34.
Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L.
Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study.
Br Med J.
1998;317:180-181 35. Krause D, Schleusser B, Herborn G, Rau R. Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum. 2000;43:14-21[CrossRef][Medline] [Order article via Infotrieve].
36.
Knecht H, Odermatt BF, Bachmann E, et al.
Frequent detection of Epstein-Barr virus DNA by the polymerase chain reaction in lymph node biopsies from patients with Hodgkin's disease without evidence of B or T cell clonality.
Blood.
1991;78:760-767 37. Kamel OW, Weiss LM, Van de Rijn M, Colby TV, Kingma DW, Jaffe ES. Hodgkin's disease and lymphoproliferations resembling Hodgkin's disease in patients receiving long-term low-dose methotrexate therapy. Am J Surg Pathol. 1996;20:1279-1287[CrossRef][Medline] [Order article via Infotrieve]. 38. Padeh S, Sharon N, Schiby G, Rechavi G, Passwell JH. Hodgkin's lymphoma in systemic onset juvenile rheumatoid arthritis after treatment with low-dose methotrexate. J Rheumatol. 1997;24:2035-2037[Medline] [Order article via Infotrieve]. 39. Chevrel G, Berger F, Miossec P, et al. Hodgkin's disease and B cell lymphoproliferation in rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum. 1999;42:1773-1776[CrossRef][Medline] [Order article via Infotrieve]. 40. Moseley AC, Lindsley HB, Skikne BS, Tawfik O. Reversible methotrexate associated lymphoproliferative disease evolving into Hodgkin's disease. J Rheumatol. 2000;27:810-813[Medline] [Order article via Infotrieve].
41.
Devesa SS, Blot WJ, Stone BJ, Miller BA, Tarone RE, Fraumeni JF Jr.
Recent cancer trends in the United States.
J Natl Cancer Inst.
1995;87:175-182 42. Medeiros LJ, Greiner TC. Hodgkin's disease. Cancer. 1995;75:357-369[CrossRef][Medline] [Order article via Infotrieve]. 43. Hessol NA, Katz MH, Liu JY, Buchbinder SP, Rubino CJ, Holmberg SD. Increased incidence of Hodgkin's disease in homosexual men with HIV infection. Ann Intern Med. 1992;117:309-311[CrossRef][Medline] [Order article via Infotrieve].
The practitioners of the CRI who referred patients were J. M. Berthelot (Nantes), P. Bertin (Limoges), M. Blanc (Chambéry), A. Cantagrel (Toulouse), D. Clerc (Le Kremlin-Bicêtre), B. Combe (Montpellier), M. Dougados (Paris), J. P. Eschard (Reims), J. P. Larbre (Lyon), P. Le Blay (Lorient), P. Le Goff (Brest), J. L. Le Quintrec (Paris), V. Lucas (La Roche sur Yon), P. Miossec (Lyon), X. Puéchal (Le Mans), H. Roux (Marseille), A. Saraux (Brest), J. Tebib (Lyon), E. Veillard (Rennes), and J. M. Ziza (Paris).
© 2002 by The American Society of Hematology.
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  T A Simon, A L Smitten, J Franklin, J Askling, D Lacaille, F Wolfe, M C Hochberg, K Qi, and S Suissa Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment Ann Rheum Dis, December 1, 2009; 68(12): 1819 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Kristinsson, L. R. Goldin, M. Bjorkholm, J. Koshiol, I. Turesson, and O. Landgren Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies Haematologica, November 1, 2009; 94(11): 1581 - 1589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Sokol and L Beaugerie Inflammatory bowel disease and lymphoproliferative disorders: the dust is starting to settle Gut, October 1, 2009; 58(10): 1427 - 1436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Visser, W Katchamart, E Loza, J A Martinez-Lopez, C Salliot, J Trudeau, C Bombardier, L Carmona, D van der Heijde, J W J Bijlsma, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative Ann Rheum Dis, July 1, 2009; 68(7): 1086 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Askling, E Baecklund, F Granath, P Geborek, M Fored, C Backlin, L Bertilsson, L Coster, L T Jacobsson, S Lindblad, et al. Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register Ann Rheum Dis, May 1, 2009; 68(5): 648 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S Bernatsky, L Joseph, J-F Boivin, C Gordon, M Urowitz, D Gladman, P R Fortin, E Ginzler, S-C Bae, S Barr, et al. The relationship between cancer and medication exposures in systemic lupus erythaematosus: a case-cohort study Ann Rheum Dis, January 1, 2008; 67(1): 74 - 79. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 T. Mikuls The treatment of lymphoma complicating autoimmune disease: two birds with one stone? Ann. Onc., April 1, 2007; 18(4): 615 - 618. [Full Text] [PDF]
|
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A S Russell, G V Wallenstein, T Li, M C Martin, R Maclean, B Blaisdell, K Gajria, J C Cole, J-C Becker, and P Emery Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment Ann Rheum Dis, February 1, 2007; 66(2): 189 - 194. [Abstract] [Full Text] [PDF]
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 D. P. M. Symmons Lymphoma and rheumatoid arthritis--again Rheumatology, January 1, 2007; 46(1): 1 - 2. [Full Text] [PDF]
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 R. J. Biggar, E. S. Jaffe, J. J. Goedert, A. Chaturvedi, R. Pfeiffer, E. A. Engels, and for the HIV/AIDS Cancer Match Study Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS Blood, December 1, 2006; 108(12): 3786 - 3791. [Abstract] [Full Text] [PDF]
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 K. E. Smedby, E. Baecklund, and J. Askling Malignant Lymphomas in Autoimmunity and Inflammation: A Review of Risks, Risk Factors, and Lymphoma Characteristics. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2069 - 2077. [Abstract] [Full Text] [PDF]
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 O. Landgren, E. A. Engels, R. M. Pfeiffer, G. Gridley, L. Mellemkjaer, J. H. Olsen, K. F. Kerstann, W. Wheeler, K. Hemminki, M. S. Linet, et al. Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia. J Natl Cancer Inst, September 20, 2006; 98(18): 1321 - 1330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. LaCasce Post-transplant lymphoproliferative disorders. Oncologist, June 1, 2006; 11(6): 674 - 680. [Abstract] [Full Text] [PDF]
|
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J Franklin, M Lunt, D Bunn, D Symmons, and A Silman Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis Ann Rheum Dis, May 1, 2006; 65(5): 617 - 622. [Abstract] [Full Text] [PDF]
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 T. R. Mikuls, J. O. Endo, S. E. Puumala, P. A. Aoun, N. A. Black, J. R. O'Dell, J. A. Stoner, E. C. Boilesen, M. A. Bast, D. A. Bergman, et al. Prospective Study of Survival Outcomes in Non-Hodgkin's Lymphoma Patients With Rheumatoid Arthritis J. Clin. Oncol., April 1, 2006; 24(10): 1597 - 1602. [Abstract] [Full Text] [PDF]
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K. E. Smedby, H. Hjalgrim, J. Askling, E. T. Chang, H. Gregersen, A. Porwit-MacDonald, C. Sundstrom, M. Akerman, M. Melbye, B. Glimelius, et al. Autoimmune and Chronic Inflammatory Disorders and Risk of Non-Hodgkin Lymphoma by Subtype J Natl Cancer Inst, January 4, 2006; 98(1): 51 - 60. [Abstract] [Full Text] [PDF]
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 E. T. Chang, K. E. Smedby, H. Hjalgrim, C. Schollkopf, A. Porwit-MacDonald, C. Sundstrom, E. Tani, F. d'Amore, M. Melbye, H.-O. Adami, et al. Medication Use and Risk of Non-Hodgkin's Lymphoma Am. J. Epidemiol., November 15, 2005; 162(10): 965 - 974. [Abstract] [Full Text] [PDF]
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 E. Zintzaras, M. Voulgarelis, and H. M. Moutsopoulos The Risk of Lymphoma Development in Autoimmune Diseases: A Meta-analysis Arch Intern Med, November 14, 2005; 165(20): 2337 - 2344. [Abstract] [Full Text] [PDF]
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W.-h. Feng, J. I. Cohen, S. Fischer, L. Li, M. Sneller, R. Goldbach-Mansky, N. Raab-Traub, H.-J. Delecluse, and S. C. Kenney Reactivation of Latent Epstein-Barr Virus by Methotrexate: A Potential Contributor to Methotrexate-Associated Lymphomas J Natl Cancer Inst, November 17, 2004; 96(22): 1691 - 1702. [Abstract] [Full Text] [PDF]
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 D. A. Yarilin, J. Valiando, and D. N. Posnett A Mouse Herpesvirus Induces Relapse of Experimental Autoimmune Arthritis by Infection of the Inflammatory Target Tissue J. Immunol., October 15, 2004; 173(8): 5238 - 5246. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
and 
immunoglobulin, CD30 (BerH2), and
CD15 (LeuM1).
rearrangement of the T-cell receptor (TCR)
gene was performed.
2 test corrected by Yates
or Fisher exact test (for categorical variables). Overall survival was
calculated by the Kaplan-Meier method. The statistical significance of
differences in outcome between patients with NHL and patients with HD
was assessed by the log-rank test and all tests of significance were
2-tailed. A hazard ratio was estimated with its 95% CI.
