2007: Rheumatoid Arthritis Associated Lymphoproliferative Disorders: Current Features and It’s Changing Pattern Due to the Influence of Anti-rheumatic Drugs

Yoshihiko Hoshida¹, Atsuko Tsujii², Shiro Ohshima², Yukihiko Saeki², Masato Yagita³, Tomoya Miyamura⁴, Masao Katayama⁵, Yasushi Hiramatsu⁶, Hisaji Oshima⁷, Toshihiko Murayama⁸, Shinji Higa⁹, Fuminori Hirano¹⁰, Kenji Ichikawa¹¹, Noriyuki Chiba¹², Takao Sugiyama¹³, Atsushi Ihata¹⁴, Akiko Mitsuo¹⁵, Hiroshi Tsutani¹⁶, Koichiro Takahi¹⁷, Akira Okamoto¹⁸, Shigeru Yoshizawa¹⁹, Yasuo Suenaga²⁰, Shunsuke Mori²¹, Shoichi Nagakura²², Norie Yoshikawa²³, Atsuhisa Ueda²⁴, Shouhei Nagaoka²⁵, Keigo Setoguchi²⁶, Shoji Sugii²⁷, Asami Abe²⁸, Toshiaki Sugaya²⁹, Masahiro Koseto³⁰, Yasuo Kunugiza³¹, Norishige Iizuka³², Ryosuke Yoshihara³³, Tomoaki Fujisaki³⁴, Hiroyuki Sugahara³⁵, Ikuo Saito³⁶, Kazuya Kuraoka³⁷, Norihiro Teramoto³⁸, Masahiro Ito³⁹, Kenichi Taguchi⁴⁰, Yuko Minami⁴¹, Shinji Naito⁴², Mitsuharu Nomoto⁴³, Kazuyoshi Saito⁴⁴, Kiyoshi Matsui⁴⁵, Yasuhiko Tomita⁴⁶, Hiroshi Furukawa⁴⁷ and Shigeto Tohma⁴⁸, ¹Department of Pathology, NHO Osaka Minami Medical Center, Kawachinagano, Japan, ²Department of Rheumatology, NHO Osaka Minami Medical Center, Kawachinagano, Japan, ³Division of Inflammation and Immunity, Tazuke-Kofukai Medical Research Institute Kitano Hospital, Osaka, Osaka, Japan, ⁴Department of Rheumatology, NHO Kyushu Medical Center, Fukuoka, Japan, ⁵Department of Rheumatology, NHO Nagoya Medical Center, Nagoya, Japan, ⁶Department of Hematology and Oncology, Japanese Red Cross Society Himeji Hospital, Himeji, Japan, ⁷National Hospital Organization Tokyo Medical Center, Meguroku, Japan, ⁸Department of Pathology, NHO Kumamoto Medical Center, Kumamoto, Kumamoto, Japan, ⁹Division of Rheumatology, Daini Osaka Police Hospital, Osaka, Osaka, Japan, ¹⁰Department of Rheumatology, NHO Asahikawa Medical Center, Asahikawa, Hokkaido, Japan, ¹¹Department of Rheumatology, NHO Hokkaido Medical Center, Sapporo, Japan, ¹²epartment of Rheumatology, NHO Morioka Medical Center, Morioka, Japan, ¹³Department of Rheumatology, NHO Shimoshizu Hospital, SIkaido, Chiba, Japan, ¹⁴Department of Rheumatology, NHO Yokohama Medical Center, Yokohama, Japan, ¹⁵Department of Rheumatology, NHO Disaster Medical Center, Tachikawa, Japan, ¹⁶Department of Rheumatology, NHO Awara Hospital, Awara, Fukui, Japan, ¹⁷Department of Rheumatology, NHO Osaka Toneyama Medical Center, Toyonaka, Japan, ¹⁸Department of Rheumatology, NHO Himeji Medical Center, Himeji, Japan, ¹⁹Department of Rheumatology, NHO Fukuoka Hospital, Fukuoka, Japan, ²⁰Department of Rheumatology, NHO Beppu Medical Center, Beppu, Oita, Japan, ²¹Department of Rheumatology, NHO Kumamoto Saishun Medical Center, Goshi, Japan, ²²Department of Hematology, NHO Kumamoto Minami Hospital, Ushiro, Japan, ²³Department of Rheumatology, NHO Miyakonojo Medical Center, Miyakonojo, Japan, ²⁴Department of Rheumatology, Yokohama City University, Yokohama, Japan, ²⁵Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama, Japan, ²⁶Department of Systemic immunological diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan, ²⁷Department of Internal Medicine, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan, ²⁸Department of Rheumatology, Niigata Rheumatic Center, Shibata, Japan, ²⁹Department of Rheumatology, Fuchu Hospital, Izumi, Japan, ³⁰Department of Laboratory Medicine and Internal Medicine (Clinical Immunology), Nippon Life Hospital, Osaka, Osaka, Japan, ³¹Department of Orthopedics, JCHO Hoshigaoka Medical Center, Hirakata, Japan, ³²Department of Pathology, Kishiwada City Hospital, Kishiwada, Japan, ³³Department of Rheumatology, Hyogo Prefectural Kakogawa Hospital, Kakogawa, Japan, ³⁴Department of Hematology, Matsuyama Red Cross Hospital, Matsuyama, Japan, ³⁵Department of Hematology, Sumitomo Hospital, Osaka, Osaka, Japan, ³⁶Department of Pathology, NHO Sagamihara Hospital, Sagamihara, Kanagawa, Japan, ³⁷Department of Diagnostic Pathology, NHO Kure Medical Center /Chugoku Cancer Center, Kure, Hiroshima, Japan, ³⁸Department of Pathology, NHO Shikoku Cancer Center, Matsuyama, Japan, ³⁹Department of Pathology, NHO Nagasaki Medical Center, Nagasaki, Japan, ⁴⁰Department of Pathology, NHO Kyushu Cancer Center, Fukuoka, Japan, ⁴¹Department of Pathology, NHO Ibarakihigashi Hospital, Nakagun, Japan, ⁴²Department of Pathology, NHO Ureshino Medical Center, Ureshino, Japan, ⁴³Department of Pathology, NHO, Kagoshima Medical Center, Kagoshima, Japan, ⁴⁴First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyusyu Fukuoka, Japan, ⁴⁵Hyogo College of Medicine, Nishinomiya, Japan, ⁴⁶Department of Pathology, International University of Health and Welfare, Narita, Japan, ⁴⁷Department of Rheumatology, NHO Tokyo National Hospital, Tokyo, Japan, ⁴⁸National Hospital Organization Tokyo National Hospital, Dallas, TX

Background/Purpose: The effect of antirheumatic drugs on the development of lymphoproliferative disorders (LPDs) in rheumatoid arthritis (RA) patients remains unclear. The current study aimed to characterize the clinicopathological features of LPDs in RA patients (RA-LPD) based on the recent advancement in antirheumatic drugs.

Methods: In this multicenter collaborative study across 48 hospitals in Japan, RA patients who also developed LPDs and visited the hospitals between January 1999 and March 2021 were retrospectively analyzed. The study also enrolled consecutive non-RA patients who developed LPDs (sporadic LPD) for comparative analysis. Significant differences were evaluated using Fisher's exact test, Mann-Whitney U-test, and log-rank test, and multivariate analysis was performed using logistic regression analysis and Cox-proportional hazard's models. Statistical significance was set up at p< 0.05.

Results: A total of 752 RA-LPD patients and 770 sporadic-LPD patients were included. We observed statistically significant differences between the clinicopathological features (such as female dominance, increase CRP and LDH levels, and increased EBER-1 positivity) of RA-LPD and sporadic LPD patients. Subtype analysis of the primary sites or histology indicated that the frequencies of LPD-associated immunosuppressive conditions, such as Hodgkin lymphoma (HL), polymorphic LPD (P-LPD), significantly increased. Furthermore, RA-LPD patients were analyzed based on the antirheumatic drug administered before the onset of LPD, and the clinicopathological characteristics differed between the naïve and methotrexate (MTX)-only groups , the MTX-only and MTX plus tacrolimus (TAC) groups, the MTX-only and the monoclonaltumor necrosis factor inhibitor (mTNFi) groups, and the MTX-only and soluble TNFi (sTNFi) groups, respectively (Figure 1, Table 1), as follows.

1) Naïve group vs MTX-only group: The MTX-only group showed significantly higher EBER-1 positivity, increased oral cavity origin, and decreased orbit origin, stomach origins and MALToma histologic subtype.

2) MTX-only vs MTX plus TAC group: The MTX plus TAC group showed a significant increase in the frequency of pharynx origin and ALCL histologic subtype and a decrease in the frequency of of lung origin.

3) MTX-only vs MTX plus mTNFi group: The MTX plus mTNFi group showed a significantly higher frequency of EBER-1 positivity. A high frequency of HL-like lesion was observed in both groups.

4) MTX-only vs MTX plus sTNFi group: Higher frequencies of submandibular gland origin, MALToma and HL-like lesion were observed in the MTX plus sTNF (ETN) group.

When the clinicopathological features of RA-LPD patients were compared between the 1999 to 2009 and 2010 to 2021 periods, immunosuppressive markers such as P-LPD and EBER-1 positivity rates showed an increase in the 2010 to 2021 period (Figure 2). Thus, the clinicopathological characteristics of RA-LPD appear to change over time.

Conclusion: In conclusion, the recent advancement of antirheumatic drugs have influenced the clinicopathological features of RA-LPD. The disease appears to shift from being disease-related to therapy-related.
Table 1: Characteristics of RA-LPD subtypes
RA-LPD, lymphoproliferative disorders in rheumatoid arthritis

Figure 1: Clinicopathological difference in RA-LPD based on the antirheumatic drugs used
RA-LPD, lymphoproliferative disorders in rheumatoid arthritis

Figure 2: Comparison of the clinicopathological difference in RA-LPD between the 2000s and the 2010s.
RA-LPD, lymphoproliferative disorders in rheumatoid arthritis
Disclosures: Y. Hoshida, None; A. Tsujii, None; S. Ohshima, None; Y. Saeki, None; M. Yagita, None; T. Miyamura, None; M. Katayama, None; Y. Hiramatsu, None; H. Oshima, None; T. Murayama, None; S. Higa, None; F. Hirano, None; K. Ichikawa, None; N. Chiba, None; T. Sugiyama, None; A. Ihata, None; A. Mitsuo, None; H. Tsutani, None; K. Takahi, None; A. Okamoto, None; S. Yoshizawa, None; Y. Suenaga, None; S. Mori, None; S. Nagakura, None; N. Yoshikawa, None; A. Ueda, None; S. Nagaoka, None; K. Setoguchi, None; S. Sugii, None; A. Abe, None; T. Sugaya, None; M. Koseto, None; Y. Kunugiza, None; N. Iizuka, None; R. Yoshihara, None; T. Fujisaki, None; H. Sugahara, None; I. Saito, None; K. Kuraoka, None; N. Teramoto, None; M. Ito, None; K. Taguchi, None; Y. Minami, None; S. Naito, None; M. Nomoto, None; K. Saito, None; K. Matsui, None; Y. Tomita, None; H. Furukawa, None; S. Tohma, Pfizer, Mitsubishi-Tanabe Pharma, Daiichi Sankyo, Chugai Pharmaceutical, AbbVie/Abbott, Ono Pharmaceutical, Takeda Pharmaceutical, Astellas Pharm, Ayumi Pharmaceutical, QIAGEN K.K, Asahi Kasei Pharma.