http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(5): 763–765 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.878016
ORIGINAL ARTICLE
Clinical characteristics and incidence of methotrexate-related lymphoproliferative disorders of patients with rheumatoid arthritis Yuji Yoshida1, Yuko Takahashi2, Hiroyuki Yamashita2, Toshikazu Kano2, Hiroshi Kaneko2, and Akio Mimori2
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1Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan and 2Division of Rheumatic Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan
Abstract
Keywords
Objective. To investigate the incidence and clinical features of methotrexate (MTX)-related lymphoproliferative disorders (MTX-LPDs) in patients with rheumatoid arthritis (RA). Patients. In total, 589 RA outpatients were examined at the National Center for Global Health and Medicine in the period from January 1990 to October 2010. Results. MTX was used in 403 cases, and the duration of follow-up was 2379 person-years. Four patients developed MTX-LPDs; the incidence of MTX-LPDs was calculated as 0.00168/personyear and the standardized incidence as 8.21 (95% CI: 0.16–24.30). The mean total dosage of MTX was 1142 ⫾ 871 mg, and the dosage at LPD onset was 7.4 ⫾ 1.9 mg/week. The patients who developed MTX-LPDs had significantly shorter disease duration of RA compared with the patients who had not received MTX, but who had not progressed to LPDs (3.1 years vs. 12.5 years; P ⫽ 0.01). The following LPD subtypes were observed: diffuse large B-cell lymphoma (N ⫽ 2); Hodgkin’s lymphoma (N ⫽ 1); and T-cell lymphoma (N ⫽ 1). After withdrawal of MTX, two of these patients showed spontaneous regression of the tumor, one did not have a recurrence, while the other patient relapsed and required chemotherapy. Conclusion. Our study revealed that MTX-LPDs are not rare complications of RA outpatients. The MTX-LPDs were associated with a relatively shorter RA duration, and half of them showed tumor regression after MTX withdrawal, which suggested an association with MTX. It is important to consider the possibility of MTX-LPD in RA patients who have received MTX.
Rheumatoid arthritis, Lymphoproliferative disorder, Incidence, Methotrexate
Introduction Lymphoproliferative disorders (LPDs) may develop in patients who are immunodeficient. In the 4th edition of the WHO classification, immunodeficiency-associated LPDs are classified in four subcategories: LPDs with primary immune disorders, lymphomas associated with HIV infections, post-transplant LPDs, and other iatrogenic immunodeficiency-associated LPDs (OIIA-LPDs) [1]. OIIA-LPDs occur in patients with autoimmune diseases under immunosuppressive medication, and methotrexate (MTX) is reported to be one of the most LPD-inducing drugs. OIIA-LPDs associated with MTX are specifically named MTX-associated LPDs (MTX-LPDs). MTX is an inhibitor of dihydrofolate reductase, and is administered to patients with autoimmune diseases, such as rheumatoid arthritis (RA), psoriasis, dermatomyositis, and Crohn’s disease. In RA, MTX is an anchor drug that is the most widely used. Despite its efficacy, MTX is a potential risk factor for MTX-LPDs in RA patients, and it has been reported that 85% of patients with MTX-LPDs have RA [2]. Recently, Tokuhira et al. indicated that LPDs in RA patients could be categorized into three groups: MTX-regressive LPDs,
History Received 30 May 2013 Accepted 15 November 2013 Published online 4 February 2014
MTX-persistent LPDs, and other-drug-mediated LPDs, and each has a different prognosis [3]. However, MTX-LPDs in RA have not been studied extensively, and the incidence and characteristics of the disease remain unclear. Therefore, we conducted a retrospective cohort study in our hospital, to estimate the incidence and characteristics of MTX-LPDs.
Methods and patients A retrospective cohort study was conducted with a total of 589 patients with RA who received treatment at the National Center for Global Health and Medicine between 1990 and 2010. Patients were diagnosed as suffering from RA based on the 1987 American Rheumatism Association criteria [4], and LPDs were diagnosed through examinations of pathologic tissues. Patients who were referred to the clinic because of LPDs were excluded from the study. The Ethics Review Committee of our hospital approved this retrospective study. The following parameters were recorded for each patient: age; sex; usage of biologic agents; duration of MTX treatment; dosage of MTX; and duration of RA. Statistical analysis
Correspondence to: Yuji Yoshida, Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel: ⫹ 81-66879-3833. Fax: ⫹ 81-6-6879-3839. E-mail: [email protected]. osaka-u.ac.jp
Fisher’s exact probability test or the Student’s unpaired t-test was used. All data were analyzed using the JMP version 8.0.1 software. Statistical significance was set at a level of P ⫽ 0.05. Confidence intervals (CIs) were determined at 95%.
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Table 1. Characteristics of the patients. Age (mean, years) Sex (male: female) RA duration (years) Biologics use (%) Infliximab (%) Etanercept (%) Adalimumab (%) Tocilizumab (%)
MTX(⫺)RA
MTX(⫹)RA
P-value
67.5 ⫾ 12.6 0.24 12.5 ⫾ 13.2 11.2 0 9.1 1.6 0.5
64.2 ⫾ 12.9 0.28 11.9 ⫾ 12.1 33.3 17.9 11.2 2.2 2.0
⬍ 0.001 0.45 0.045 ⬍ 0.001
Results
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Patients’ demographics Table 1 shows the patients’ demographics. In total, 403 patients had received MTX. The patients treated with MTX had a mean age of 64.2 ⫾ 12.9 years, 78% were female, and the mean RA duration was 11.9 ⫾ 12.1 years, which was similar to the patients who did not receive MTX treatment. However, the proportions of patients who had received biologic agents differed between the groups (MTXtreated vs. no MTX treatment, respectively) as follows: infliximab, 17.9% vs. 0%; etanercept, 11.2% vs. 9.1%; adalimumab, 2.2% vs. 1.6%; and tocilizumab, 2.0% vs. 0.5%. Secondary Sjögren’s syndrome coexisted in 56 patients, (9.5%), of whom 41 patients (73%) took MTX while 15 (27%) did not. Disease activity was not determined in the unified methods, including DAS28, HAQ, and SDAI. Therefore, we were unable to analyze the disease activity of RA in this study. Incidence of MTX-LPDs Four cases of MTX-LPDs were observed among the patients with RA in a total of 2379 observation periods. The incidence of MTXLPDs was calculated as 168 per 100,000 person-years (Table 2). Based on the national population [5], the standardized incidence was calculated as 8.21 (95% CI: 0.16–24.3). Characteristics of the patients with MTX-LPDs The patients’ characteristics are described in Table 3. The patients had a mean age of 68.5 (range, 54–77) years, mean RA duration of 6.3 (range, 0.8–6.7) years, mean total dosage of MTX was 1142 (range, 155–1970) mg, and mean duration of MTX administration was 3.1 (range, 0.5–5.3) years. The received mean dosage of MTX at the onset of LPDs was 7.4 ⫾ 1.9 mg/week. The patients who developed MTX-LPDs had significantly shorter disease duration of RA compared with the patients who had not received MTX but who had not progressed to LPDs (3.1 vs. 12.5 years; P ⫽ 0.01). Two of the four patients received biological agents (etanercept and tocilizumab) and Sjögren’s syndrome coexisted in Patient 2. With the exception of RA duration, no significant trend was noted for these factors. Pathology and clinical course of MTX-LPDs The patients’ pathologies and characteristics are described in Table 3. The LPD pathologies included diffuse large B-cell lymphoma (DLBCL; N ⫽ 2); Hodgkin’s lymphoma (HL; N ⫽ 1);
Table 2. Incidence of LPD for patients with RA. Person-years Onset Incidence
MTX(⫹) 2379 4 168/100,000
MTX(⫺) 2463 0 0/100,000
and T-cell lymphoma TCL (N ⫽ 1). Half of the patients were positive for Epstein–Barr virus-encoded RNA (EBER), which suggests an association with Epstein–Barr virus (EBV) infection. The LPDs regressed shortly after MTX discontinuation in two patients (Patients 1 and 2). Patient 1 developed a nodule on his neck and was diagnosed as having DLBCL. He rapidly achieved complete remission after discontinuation of MTX and did not relapse. Patient 2 developed a persistent fever and an abdominal nodule and was diagnosed as having HL using computed tomography (CT)-guided needle biopsy. Spontaneous regression after discontinuation of MTX was also observed in Patient 2, although after 2 months this patient relapsed and was treated with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone). After two courses of treatment, she achieved complete remission, but unfortunately died of pneumonia, which was a complication of the treatment. Patient 3 developed TCL while Patient 4 developed DLBCL. These two patients did not display tumor regression after MTX discontinuation and, therefore, Patient 3 received operative treatment while Patient 4 required chemotherapy. After their respective treatments, both patients achieved complete remission and did not relapse. Tokuhira et al. [3] reported that MTX-Regressive LPDs showed relatively lower serum lactate dehydrogenase (LDH), C-reactive protein (CRP), and soluble interleukin-2 receptor (sIL-2R) levels compared to MTX-Persistent LPDs. In our study, at the onset of LPDs, the levels of LDH, CRP, and sIL-2R were higher in Patient 2 (559 U/L, 21.5 mg/dl, and 1765 U/ml, respectively) than in Patient 1 (328 U/L, 1.75 mg/dl, and 473 U/ml), Patient 3 (229 U/L, 0.53 mg/dl, and 426 U/ml), and Patient 4 (347 U/L, 11.4 mg/dl, and 4248 U/ml). No significant trend was found between the MTX-Regressive LPD and MTX-Persistent LPD groups.
Discussion Recent studies highlighted drug-mediated LPDs, especially in RA patients. There are many case reports of MTX-LPDs [6–9], with a certain percentage showing tumor reduction when MTX is discontinued. Regression of drug-induced LPDs after drug withdrawal was specifically reported for MTX, but not for other anti-RA drugs. Therefore, it has been suggested that a significant proportion of malignant lymphomas are induced by MTX in RA patients. However, previous large-scale clinical studies have shown no evidence of increased risk of malignant lymphoma [10–14]. Bernatsky et al. [10] reported the relative risk of malignant lymphomas in patients who took MTX as 1.18 (0.99–1.40) in their case-controlled study, while Wolfe and Michaud [11] reported the odds ratio for malignant lymphoma as 1.3 (0.7–2.4) in their total of 89710 person-years of observation. It was reported that MTX-LPDs had specific clinical features. The frequency of an extranodal occurrence of MTXinduced LPD is relatively high, at approximately 40% [15]. In our study, two of four patients experienced an extranodal occurrence. Moreover, approximately 40% of LPDs in MTX-treated RA patients are EBV positive [1]. Latent EBV infection may be involved in the development of EBV-associated B-cell LPDs. In our study, two of four patients were EBER positive and developed DLBCL. Although our data support previous reports, the number of cases was too small to analyze these trends. Hoshida et al. [16] compared MTX-LPDs and LPDs not associated with MTX (non-MTX-LPDs) in RA patients, and reported that MTX-LPDs and non-MTX-LPDs patients had similar clinical findings with respect to age, sex, primary site, and stage of LPDs, whereas the duration of RA was significantly shorter in patients who received MTX treatment (132 months vs. 240 months; P ⬍ 0.05).
DOI 10.3109/14397595.2013.878016
Methotrexate-related lymphoproliferative disorders of patients with rheumatoid arthritis 765
Table 3. Characteristics of the patients with MTX-LPDs. Patient no. 1 2 3 4
Sex M F F F
Age 77 54 72 71
RA duration (years) 6.6 6.0 5.5 0.8
MTX duration (years) 5.3 4.3 2.4 0.5
Total dosage of MTX (mg) 1772 1970 671 155
Biologics None ETN Non TCZ
Pathology status DLBCL HL T-cell DLBCL
EBER ⫺ ⫹ ⫹ ⫺
Prognosis CR PR→CT No change→OP No change→CT
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CR, complete remission; PR, partial remission; CT, chemotherapy; OP, operation; EBER, Epstein-Barr virus-encoded RNA; ETN, etanercept; TCZ, tocilizumab
In general, the effect of the drug on the tumor was accumulative. Therefore, a longitudinal study rather than a cross-sectional study was required to evaluate the risk of MTX-LPDs. We observed 589 patients with RA, including 403 patients who had received MTX continuously over a long period (median follow-up period, 5.9 years) from the first medical examination, and four such patients developed MTX-LPDs. Our data were based on medical records, as this approach was considered more reliable than other methods, including physician billings and patient questionnaires. We analyzed four MTX-LPD patients’ backgrounds and found that they showed a lesser relationship with total dose and MTX treatment duration, and the condition occurred after a relatively short RA duration and shorter duration of MTX treatment. Cumulative disease activity is strongly associated with LPDs in RA patients [17], and carcinogenic drugs usually exhibit time and dose dependency. Therefore, it was suggested that MTX-LPDs occurred independently of drug toxicity and inflammation, unlike allergic or immunodeficiency-mediated mechanisms, such as EBV activation. Moreover, half of MTX-LPDs patients showed disease regression after ceasing MTX, which suggests a strong association with MTX. Our data supports the previous report of Tokuhira et al. that MTX-LPDs appeared to have a better prognosis than other more common types of lymphoma [3]. The incidence of MTX-associated LPD in patients with RA was 168/100,000 person-years, and the standardized incidence ratio was calculated as 8.21 (95% CI 0.16–24.3). In contrast, no LPDs were observed in the patients with RA who did not take MTX (a total of 2463 person-years). Although our study did not include sufficient RA patients with MTX-LPD, it is the first report on the incidence of MTX-LPDs in a Japanese RA cohort, and it suggests that MTX increases the incidence of LPDs in patients with RA. The limitations of our study were that the number of patients is too low to analyze this rare disease and that several confounding factors, such as RA severity, are not explored. A further study that includes a larger patient population and that carefully assesses the confounding factors is needed.
Acknowledgments We thank Toru Hirano and Shimbo Takuro for assistance with the analysis of the data.
Conflicts of interest None.
References 1. Gaulard P, Swerdlow SH, Harris NL, Jaffe ES, Sundstrom C. Other iatrogenic immunodeficiency associated lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW (eds.). WHO Classification of Tumors of the Haematopoietic and Lymphoid Tissues. 4th ed. Lyon: International Agency for Research on Cancer, 2008. pp. 350–1.
2. Salloum R, Cooper DL, Howe G, Lacy J, Tallini G, Crouch J, et al. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrezate for Rheumatoid Arthritis and other rheumatic diseases. J Clin Oncol. 1996;14(6):1943–9. 3. Tokuhira M, Watanabe R, Nemoto T, Sagawa M, Tomikawa T, Tamaru J, et al. Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis. Leuk Lymphoma. 2012:53(4):616–23. 4. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–324. 5. Matsuda T, Marugame T, Kamo KI, Katanoda K, Ajiki W, Sobue T; Japan Cancer Surveillance Research Group . Cancer incidence and incidence rates in Japan in 2005: Based on data from 12 populationbased cancer registries in the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2011;41(1):139–47. 6. Kingsmore SF, Hall BD, Allen NB, Rice JR, Caldwell DS. Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review. J Rheumatol 1992;19(9):1462–5. 7. 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(2):325–9. 8. Niitsu N, Okamoto M, Nakamine H, Hirano M. Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate. Cancer Sci 2010;101(5): 1309–13. 9. Rizzi R, Curci P, Delia M, Rinaldi E, Chiefa A, Specchia G, Liso V. Spontaneous remission of “methotrexate-associated lymphoproliferative disorders” after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature. Med Oncol. 2009;26(1):1–9. 10. Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in Rheumatoid Arthritis. Arch Intern Med. 2008;168(4):378–81. 11. Wolfe F, Michaud K. Lymphoma in Rheumatoid Arthritis. Arthritis Rheum. 2004;50(6):1740–51. 12. Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2010;54(3):692–701. 13. Asten P, Barrett J, Symmons D. Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol. 1999; 26(8):1705–14. 14. Askling J, Fored CM, Baecklund E, Brandt L, Backlin C, Ekbom A, et al. Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis 2005;64(10):1414–20. 15. Salloum E, Cooper DL, Howe G, Lacy J, Tallini G, Crouch J, 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. 16. Hoshida Y, Xu JX, Fujita S, Nakamichi I, Ikeda J, Tomita Y, et al. Lymphoproliferative disorders in Rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication. J Rheumatol. 2007;34: 322–40. 17. Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006:54:692–701.
ORIGINAL ARTICLE
Clinical characteristics and incidence of methotrexate-related lymphoproliferative disorders of patients with rheumatoid arthritis Yuji Yoshida1, Yuko Takahashi2, Hiroyuki Yamashita2, Toshikazu Kano2, Hiroshi Kaneko2, and Akio Mimori2
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1Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan and 2Division of Rheumatic Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan
Abstract
Keywords
Objective. To investigate the incidence and clinical features of methotrexate (MTX)-related lymphoproliferative disorders (MTX-LPDs) in patients with rheumatoid arthritis (RA). Patients. In total, 589 RA outpatients were examined at the National Center for Global Health and Medicine in the period from January 1990 to October 2010. Results. MTX was used in 403 cases, and the duration of follow-up was 2379 person-years. Four patients developed MTX-LPDs; the incidence of MTX-LPDs was calculated as 0.00168/personyear and the standardized incidence as 8.21 (95% CI: 0.16–24.30). The mean total dosage of MTX was 1142 ⫾ 871 mg, and the dosage at LPD onset was 7.4 ⫾ 1.9 mg/week. The patients who developed MTX-LPDs had significantly shorter disease duration of RA compared with the patients who had not received MTX, but who had not progressed to LPDs (3.1 years vs. 12.5 years; P ⫽ 0.01). The following LPD subtypes were observed: diffuse large B-cell lymphoma (N ⫽ 2); Hodgkin’s lymphoma (N ⫽ 1); and T-cell lymphoma (N ⫽ 1). After withdrawal of MTX, two of these patients showed spontaneous regression of the tumor, one did not have a recurrence, while the other patient relapsed and required chemotherapy. Conclusion. Our study revealed that MTX-LPDs are not rare complications of RA outpatients. The MTX-LPDs were associated with a relatively shorter RA duration, and half of them showed tumor regression after MTX withdrawal, which suggested an association with MTX. It is important to consider the possibility of MTX-LPD in RA patients who have received MTX.
Rheumatoid arthritis, Lymphoproliferative disorder, Incidence, Methotrexate
Introduction Lymphoproliferative disorders (LPDs) may develop in patients who are immunodeficient. In the 4th edition of the WHO classification, immunodeficiency-associated LPDs are classified in four subcategories: LPDs with primary immune disorders, lymphomas associated with HIV infections, post-transplant LPDs, and other iatrogenic immunodeficiency-associated LPDs (OIIA-LPDs) [1]. OIIA-LPDs occur in patients with autoimmune diseases under immunosuppressive medication, and methotrexate (MTX) is reported to be one of the most LPD-inducing drugs. OIIA-LPDs associated with MTX are specifically named MTX-associated LPDs (MTX-LPDs). MTX is an inhibitor of dihydrofolate reductase, and is administered to patients with autoimmune diseases, such as rheumatoid arthritis (RA), psoriasis, dermatomyositis, and Crohn’s disease. In RA, MTX is an anchor drug that is the most widely used. Despite its efficacy, MTX is a potential risk factor for MTX-LPDs in RA patients, and it has been reported that 85% of patients with MTX-LPDs have RA [2]. Recently, Tokuhira et al. indicated that LPDs in RA patients could be categorized into three groups: MTX-regressive LPDs,
History Received 30 May 2013 Accepted 15 November 2013 Published online 4 February 2014
MTX-persistent LPDs, and other-drug-mediated LPDs, and each has a different prognosis [3]. However, MTX-LPDs in RA have not been studied extensively, and the incidence and characteristics of the disease remain unclear. Therefore, we conducted a retrospective cohort study in our hospital, to estimate the incidence and characteristics of MTX-LPDs.
Methods and patients A retrospective cohort study was conducted with a total of 589 patients with RA who received treatment at the National Center for Global Health and Medicine between 1990 and 2010. Patients were diagnosed as suffering from RA based on the 1987 American Rheumatism Association criteria [4], and LPDs were diagnosed through examinations of pathologic tissues. Patients who were referred to the clinic because of LPDs were excluded from the study. The Ethics Review Committee of our hospital approved this retrospective study. The following parameters were recorded for each patient: age; sex; usage of biologic agents; duration of MTX treatment; dosage of MTX; and duration of RA. Statistical analysis
Correspondence to: Yuji Yoshida, Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel: ⫹ 81-66879-3833. Fax: ⫹ 81-6-6879-3839. E-mail: [email protected]. osaka-u.ac.jp
Fisher’s exact probability test or the Student’s unpaired t-test was used. All data were analyzed using the JMP version 8.0.1 software. Statistical significance was set at a level of P ⫽ 0.05. Confidence intervals (CIs) were determined at 95%.
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Table 1. Characteristics of the patients. Age (mean, years) Sex (male: female) RA duration (years) Biologics use (%) Infliximab (%) Etanercept (%) Adalimumab (%) Tocilizumab (%)
MTX(⫺)RA
MTX(⫹)RA
P-value
67.5 ⫾ 12.6 0.24 12.5 ⫾ 13.2 11.2 0 9.1 1.6 0.5
64.2 ⫾ 12.9 0.28 11.9 ⫾ 12.1 33.3 17.9 11.2 2.2 2.0
⬍ 0.001 0.45 0.045 ⬍ 0.001
Results
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Patients’ demographics Table 1 shows the patients’ demographics. In total, 403 patients had received MTX. The patients treated with MTX had a mean age of 64.2 ⫾ 12.9 years, 78% were female, and the mean RA duration was 11.9 ⫾ 12.1 years, which was similar to the patients who did not receive MTX treatment. However, the proportions of patients who had received biologic agents differed between the groups (MTXtreated vs. no MTX treatment, respectively) as follows: infliximab, 17.9% vs. 0%; etanercept, 11.2% vs. 9.1%; adalimumab, 2.2% vs. 1.6%; and tocilizumab, 2.0% vs. 0.5%. Secondary Sjögren’s syndrome coexisted in 56 patients, (9.5%), of whom 41 patients (73%) took MTX while 15 (27%) did not. Disease activity was not determined in the unified methods, including DAS28, HAQ, and SDAI. Therefore, we were unable to analyze the disease activity of RA in this study. Incidence of MTX-LPDs Four cases of MTX-LPDs were observed among the patients with RA in a total of 2379 observation periods. The incidence of MTXLPDs was calculated as 168 per 100,000 person-years (Table 2). Based on the national population [5], the standardized incidence was calculated as 8.21 (95% CI: 0.16–24.3). Characteristics of the patients with MTX-LPDs The patients’ characteristics are described in Table 3. The patients had a mean age of 68.5 (range, 54–77) years, mean RA duration of 6.3 (range, 0.8–6.7) years, mean total dosage of MTX was 1142 (range, 155–1970) mg, and mean duration of MTX administration was 3.1 (range, 0.5–5.3) years. The received mean dosage of MTX at the onset of LPDs was 7.4 ⫾ 1.9 mg/week. The patients who developed MTX-LPDs had significantly shorter disease duration of RA compared with the patients who had not received MTX but who had not progressed to LPDs (3.1 vs. 12.5 years; P ⫽ 0.01). Two of the four patients received biological agents (etanercept and tocilizumab) and Sjögren’s syndrome coexisted in Patient 2. With the exception of RA duration, no significant trend was noted for these factors. Pathology and clinical course of MTX-LPDs The patients’ pathologies and characteristics are described in Table 3. The LPD pathologies included diffuse large B-cell lymphoma (DLBCL; N ⫽ 2); Hodgkin’s lymphoma (HL; N ⫽ 1);
Table 2. Incidence of LPD for patients with RA. Person-years Onset Incidence
MTX(⫹) 2379 4 168/100,000
MTX(⫺) 2463 0 0/100,000
and T-cell lymphoma TCL (N ⫽ 1). Half of the patients were positive for Epstein–Barr virus-encoded RNA (EBER), which suggests an association with Epstein–Barr virus (EBV) infection. The LPDs regressed shortly after MTX discontinuation in two patients (Patients 1 and 2). Patient 1 developed a nodule on his neck and was diagnosed as having DLBCL. He rapidly achieved complete remission after discontinuation of MTX and did not relapse. Patient 2 developed a persistent fever and an abdominal nodule and was diagnosed as having HL using computed tomography (CT)-guided needle biopsy. Spontaneous regression after discontinuation of MTX was also observed in Patient 2, although after 2 months this patient relapsed and was treated with R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone). After two courses of treatment, she achieved complete remission, but unfortunately died of pneumonia, which was a complication of the treatment. Patient 3 developed TCL while Patient 4 developed DLBCL. These two patients did not display tumor regression after MTX discontinuation and, therefore, Patient 3 received operative treatment while Patient 4 required chemotherapy. After their respective treatments, both patients achieved complete remission and did not relapse. Tokuhira et al. [3] reported that MTX-Regressive LPDs showed relatively lower serum lactate dehydrogenase (LDH), C-reactive protein (CRP), and soluble interleukin-2 receptor (sIL-2R) levels compared to MTX-Persistent LPDs. In our study, at the onset of LPDs, the levels of LDH, CRP, and sIL-2R were higher in Patient 2 (559 U/L, 21.5 mg/dl, and 1765 U/ml, respectively) than in Patient 1 (328 U/L, 1.75 mg/dl, and 473 U/ml), Patient 3 (229 U/L, 0.53 mg/dl, and 426 U/ml), and Patient 4 (347 U/L, 11.4 mg/dl, and 4248 U/ml). No significant trend was found between the MTX-Regressive LPD and MTX-Persistent LPD groups.
Discussion Recent studies highlighted drug-mediated LPDs, especially in RA patients. There are many case reports of MTX-LPDs [6–9], with a certain percentage showing tumor reduction when MTX is discontinued. Regression of drug-induced LPDs after drug withdrawal was specifically reported for MTX, but not for other anti-RA drugs. Therefore, it has been suggested that a significant proportion of malignant lymphomas are induced by MTX in RA patients. However, previous large-scale clinical studies have shown no evidence of increased risk of malignant lymphoma [10–14]. Bernatsky et al. [10] reported the relative risk of malignant lymphomas in patients who took MTX as 1.18 (0.99–1.40) in their case-controlled study, while Wolfe and Michaud [11] reported the odds ratio for malignant lymphoma as 1.3 (0.7–2.4) in their total of 89710 person-years of observation. It was reported that MTX-LPDs had specific clinical features. The frequency of an extranodal occurrence of MTXinduced LPD is relatively high, at approximately 40% [15]. In our study, two of four patients experienced an extranodal occurrence. Moreover, approximately 40% of LPDs in MTX-treated RA patients are EBV positive [1]. Latent EBV infection may be involved in the development of EBV-associated B-cell LPDs. In our study, two of four patients were EBER positive and developed DLBCL. Although our data support previous reports, the number of cases was too small to analyze these trends. Hoshida et al. [16] compared MTX-LPDs and LPDs not associated with MTX (non-MTX-LPDs) in RA patients, and reported that MTX-LPDs and non-MTX-LPDs patients had similar clinical findings with respect to age, sex, primary site, and stage of LPDs, whereas the duration of RA was significantly shorter in patients who received MTX treatment (132 months vs. 240 months; P ⬍ 0.05).
DOI 10.3109/14397595.2013.878016
Methotrexate-related lymphoproliferative disorders of patients with rheumatoid arthritis 765
Table 3. Characteristics of the patients with MTX-LPDs. Patient no. 1 2 3 4
Sex M F F F
Age 77 54 72 71
RA duration (years) 6.6 6.0 5.5 0.8
MTX duration (years) 5.3 4.3 2.4 0.5
Total dosage of MTX (mg) 1772 1970 671 155
Biologics None ETN Non TCZ
Pathology status DLBCL HL T-cell DLBCL
EBER ⫺ ⫹ ⫹ ⫺
Prognosis CR PR→CT No change→OP No change→CT
Mod Rheumatol Downloaded from informahealthcare.com by Korea University on 01/05/15 For personal use only.
CR, complete remission; PR, partial remission; CT, chemotherapy; OP, operation; EBER, Epstein-Barr virus-encoded RNA; ETN, etanercept; TCZ, tocilizumab
In general, the effect of the drug on the tumor was accumulative. Therefore, a longitudinal study rather than a cross-sectional study was required to evaluate the risk of MTX-LPDs. We observed 589 patients with RA, including 403 patients who had received MTX continuously over a long period (median follow-up period, 5.9 years) from the first medical examination, and four such patients developed MTX-LPDs. Our data were based on medical records, as this approach was considered more reliable than other methods, including physician billings and patient questionnaires. We analyzed four MTX-LPD patients’ backgrounds and found that they showed a lesser relationship with total dose and MTX treatment duration, and the condition occurred after a relatively short RA duration and shorter duration of MTX treatment. Cumulative disease activity is strongly associated with LPDs in RA patients [17], and carcinogenic drugs usually exhibit time and dose dependency. Therefore, it was suggested that MTX-LPDs occurred independently of drug toxicity and inflammation, unlike allergic or immunodeficiency-mediated mechanisms, such as EBV activation. Moreover, half of MTX-LPDs patients showed disease regression after ceasing MTX, which suggests a strong association with MTX. Our data supports the previous report of Tokuhira et al. that MTX-LPDs appeared to have a better prognosis than other more common types of lymphoma [3]. The incidence of MTX-associated LPD in patients with RA was 168/100,000 person-years, and the standardized incidence ratio was calculated as 8.21 (95% CI 0.16–24.3). In contrast, no LPDs were observed in the patients with RA who did not take MTX (a total of 2463 person-years). Although our study did not include sufficient RA patients with MTX-LPD, it is the first report on the incidence of MTX-LPDs in a Japanese RA cohort, and it suggests that MTX increases the incidence of LPDs in patients with RA. The limitations of our study were that the number of patients is too low to analyze this rare disease and that several confounding factors, such as RA severity, are not explored. A further study that includes a larger patient population and that carefully assesses the confounding factors is needed.
Acknowledgments We thank Toru Hirano and Shimbo Takuro for assistance with the analysis of the data.
Conflicts of interest None.
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