Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019;59(4):145-155.
doi: 10.3960/jslrt.19028.

Immune response in LPD during methotrexate administration (MTX-LPD) in rheumatoid arthritis patients

Shuntaro Saito, Tsutomu Takeuchi
Review

Immune response in LPD during methotrexate administration (MTX-LPD) in rheumatoid arthritis patients

Shuntaro Saito et al. J Clin Exp Hematop. 2019.

Abstract

Methotrexate (MTX) is known as a first-line synthetic disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Although the risk of LPD development increases by RA inflammation itself, observation of spontaneous regression of LPD after MTX discontinuation lead to the theory of lymphomagenic role of MTX. In this review, we focused on the several immune response involved in LPD that developed under MTX administration in RA patients.

Keywords: Epstein-Barr virus; Immune response; Lymphoproliferative disorder; Methotrexate; Rheumatoid arthritis.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST: SS has received speaking fees from Chugai Pharmaceutical, Eisai, Bristol–Myers K.K, Asahikasei Pharma Corp, Pfizer Japan, and consultant fees from Asahikasei Pharma Corp. TT has received research grants from Astellas Pharma Inc, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Taisho Toyama Pharmaceutical Co., Ltd., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, speaking fees from AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co,. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., and Astellas Pharma Inc, and Daichi Sankyo Co., Ltd, and consultant fees from Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbvie GK, Nipponkayaku Co., Ltd, Janssen Pharmaceutical K.K., Astellas Pharma Inc.

Figures

Fig. 1
Fig. 1
Changes in lymphocyte counts in regressive and persistent MTX-LPD Changes in lymphocyte counts in the regressive and persistent LPD. † control vs regressive, p < 0.05; regressive vs persistent, p < 0.05 ‡ control vs regressive, p < 0.05; regressive vs persistent, p < 0.05; control vs persistent, p < 0.05 *p < 0.05 for the comparison with the value at week 0 in each group MTX, methotrexate.
Fig. 2
Fig. 2
Changes in each peripheral blood cell subset in regressive and persistent MTX-LPD Changes in the proportion of each lymphocyte subset after MTX cessation. Changes in the proportion of (A) Th1, (B) Th2, (C) EMCD8+ T cells, and (D) EBV-specific CD8+ T cells among CD8+ T cells after MTX cessation.† regressive vs. control, P < 0.05 ‡ regressive vs. control, P < 0.05; regressive vs. persistent, P < 0.05 *P < 0.05 for comparison with the value at week 0 in each group Th1/2, T helper 1/2; EM, effector memory; EBV, Epstein–Barr virus.
Fig. 3
Fig. 3
Hypothetical immunological mechanism for the development and regression of MTX-LPD in RA patients Hypothesis of the pathological and regression mechanism of ‘regressive LPD’ as a narrow sense of ‘MTX-associated LPD’. MTX, methotrexate; LPD, lymphoproliferative disorder; Th1, T helper 1; EBV, Epstein–Barr virus
See this image and copyright information in PMC

References

    1. Baecklund E, Iliadou A, Askling J, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum. 2006; 54: 692-701. 10.1002/art.21675 - DOI - PubMed
    1. Hashimoto A, Chiba N, Tsuno H, et al. Incidence of malignancy and the risk of lymphoma in Japanese patients with rheumatoid arthritis compared to the general population. J Rheumatol. 2015; 42: 564-571. 10.3899/jrheum.140533 - DOI - PubMed
    1. Kameda T, Dobashi H, Miyatake N, et al. Association of higher methotrexate dose with lymphoproliferative disease onset in rheumatoid arthritis patients. Arthritis Care Res. 2014; 66: 1302-1309. 10.1002/acr.22306 - DOI - PubMed
    1. Singh JA, Saag KG, Bridges SL, Jr, et al. 2015 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016; 68: 1-26. 10.1002/art.39480 - DOI - PubMed
    1. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017; 76: 960-977. 10.1136/annrheumdis-2016-210715 - DOI - PubMed

MeSH terms