Rheumatoid Arthritis-associated Lymphoproliferative Disorders: A Multi-center Analysis of Clinical Outcomes and Evaluation of Anti-rheumatic Drugs After LPD Onset

YOSHIHIKO HOSHIDA¹, Atsuko Tsujii², SHIRO OHSHIMA³, YUKIHIKO SAEKI³, MASATO YAGITA⁴, TOMOYA MIYAMURA⁵, Masao Katayama⁶, TOMONORI KAWASAKI⁷, YASUSHI HIRAMATSU⁸, Hisaji Oshima⁹, TOSHIHIKO MURAYAMA¹⁰, SHINJI HIGA¹¹, KAZUYA KURAOKA¹², FUMINORI HIRANO¹³, KENJI ICHIKAWA¹⁴, MITSUTOSHI KUROSAWA¹⁵, HIROAKI SUZUKI¹⁵, NORIYUKI CHIBA¹⁶, TAKAO SUGIYAMA¹⁷, YUKO MINAMI¹⁸, HITOSHI NIINO¹⁹, ATSUSHI IHATA²⁰, IKUO SAITO²¹, AKIKO MITSUO²², TOSHITAKA MAEJIMA²³, ATSUHIRO KAWASHIMA²⁴, HIROSHI TSUTANI²⁵, KOICHIRO TAKAHI²⁶, TAKAHIKO KASAI²⁷, YOKO SHINNO²⁸, YOSHIRO TACHIYAMA²⁹, NORIHIRO TERAMOTO³⁰, KENICHI TAGUCHI³¹, SHINJI NAITO³², SHIGERU YOSHIZAWA³³, MASAHIRO ITO³⁴, YASUO SUENAGA³⁵, Shunsuke Mori³⁶, SHOICHI NAGAKURA³⁷, NORIE YOSHIKAWA³⁸, MITSUHARU NOMOTO³⁹, ATSUHISA UEDA⁴⁰, SHOUHEI NAGAOKA⁴¹, YUKIO TSUURA⁴², KEIGO SETOGUCHI⁴³, SHOJI SUGII⁴⁴, Asami Abe⁴⁵, TOSHIAKI SUGAYA⁴⁶, HIROYUKI SUGAHARA⁴⁷, MASAHIRO KOSETO⁴⁸, YASUO KUNUGIZA², NORISHIGE IIZUKA³, RYOSUKE YOSHIHARA⁴, HIROKI YABE⁵, TOMOAKI FUJISAKI⁶, EIICHI MORII⁷, MORISHIGE TAKESHITA⁸, MASAKAZU SATO⁹, KAZUYOSHI SAITO¹⁰, Kiyoshi Matsui¹¹, YASUHIKO TOMITA¹², HIROSHI FURUKAWA¹³ and Shigeto Tohma¹⁴, ¹National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Japan, ²Osaka Minami Medical Center, Kawachinagano City, Japan, ³National Hospital Organization (NHO), Osaka Minami Medical Center, Kawachinagano, Japan, ⁴Medical Research Institute KITANO HOSPITAL, PIIF Tazuke-kofukai, Osaka, Japan, ⁵NHO Kyushu Medical Center, Fukuoka, Japan, ⁶National Hospital Organization, Nagoya Medical Center, Nagoya, JP, Nagoya, Japan, ⁷NHO Nagoya Medical Center, Nagoya, Japan, ⁸Japanese Red Cross Society Himeji Hospital, Himeji, Japan, ⁹National Tokyo Medical Center, Tokyo, Japan, ¹⁰NHO Kumamoto Medical Center, Kumamoto, Japan, ¹¹Daini Osaka Police Hospital, Osaka, Japan, ¹²NHO Kure Medical Center /Chugoku Cancer Center, Kure, Japan, ¹³NHO Asahikawa Medical Center, Asahikawa, Japan, ¹⁴Nissei hospital, Sapporo, Japan, ¹⁵NHO Hokkaido Cancer Center, Sapporo, Japan, ¹⁶NHO Morioka Medical Center, Morioka, Japan, ¹⁷NHO Shimoshizu Hospital, Yotsukaido, Japan, ¹⁸NHO Ibarakihigashi Hospital, Ibaraki, Japan, ¹⁹NHO Yokohama Medical Center, Yokohama, Japan, ²⁰National Hospital Organization Yokohama Medical Center, Yokohama, Japan, ²¹NHO Sagamihara Hospital, Sagamihara, Japan, ²²NHO Disaster Medical Center, Tachikawa, Japan, ²³NHO Shinshu Ueda Medical Center, Ueda, Japan, ²⁴NHO Kanazawa Medical Center, Kanazawa, Japan, ²⁵NHO Awara Hospital, Awara, Japan, ²⁶NHO Osaka Toneyama Medical Center, Toyonaka, Japan, ²⁷Japan Red Cross Society Tokushima Hospital, Komatsushima, Japan, ²⁸NHO Okayama Medical Center, Okayama, Japan, ²⁹NHO Hiroshima Nishi Medical Center, Otake, Japan, ³⁰NHO Shikoku Cancer Center, Matsuyama, Japan, ³¹NHO Kyushu Cancer Center, Fukuoka, Japan, ³²NHO Ureshino Medical Center, Ureshino, Japan, ³³NHO Fukuoka Hospital, Fukuoka, Japan, ³⁴NHO Nagasaki Medical Center, Omura, Japan, ³⁵NHO Beppu Medical Center, Beppu, Japan, ³⁶NHO Kumamoto Saishun Medical Center, Koshi, Japan, ³⁷NHO Kumamoto Minami Hospital, Uki, Japan, ³⁸NHO Miyakonojo Medical Center, Miyakonojo, Japan, ³⁹NHO Kagoshima Medical Center, Kagoshima, Japan, ⁴⁰Yokohama City University Medical Center, Yokohama, Japan, ⁴¹Yokohama Minami Kyosai Hospital, Yokohama, Japan, ⁴²Department of Pathology Yokosuka Kyosai Hospital, Yokosuka, Japan, ⁴³Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital / Tokyo Metropolitan Komagome Hospital, Tokyo, Japan, ⁴⁴Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan, ⁴⁵Niigata Rheumatic Center, Shibata, Japan, ⁴⁶Fuchu Hospital, Izumi, Japan, ⁴⁷Sumitomo Hospital, Osaka, Japan, ⁴⁸Nippon Life Hospital, Osaka, Japan, ⁴⁹JCHO Hoshigaoka Medical Center, Hirakata, Japan, ⁵⁰Kishiwada City Hospital, Kishiwada, Japan, ⁵¹Hyogo Prefectural Kakogawa Hospital, Kakogawa, Japan, ⁵²Ako Central Hospital, Ako, Japan, ⁵³Matsuyama Red Cross Hospital, Matsuyama, Japan, ⁵⁴Osaka University, Suita, Japan, ⁵⁵Fukuoka University, Fukuoka, Japan, ⁵⁶Kurashiki University of Science and the Arts, Kurashiki, Japan, ⁵⁷University of Occupational and Environmental Health, Kitakyushu, Japan, ⁵⁸Hyogo Medical University, Nishinomiya, Japan, ⁵⁹International University of Health and Welfare, Otawara City, Japan, ⁶⁰NHO Tokyo National Hospital, Kiyose, Japan, ⁶¹NHO Tokyo National Hospital, Dallas, TX

Meeting: ACR Convergence 2023

Keywords: Cohort Study, Disease-Modifying Antirheumatic Drugs (Dmards), Drug toxicity, rheumatoid arthritis, Tumor necrosis factor (TNF)

Session Information

Date: Monday, November 13, 2023

Title: (1308–1344) RA – Treatments Poster II

Session Type: Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: The largest multi-center collaborative study on lymphoproliferative disorders (LPD) in rheumatoid arthritis (RA) (RA-LPD) in Japan was conducted to characterize its clinical outcomes and identify suitable treatments.

Methods: Patients with RA who developed LPD between January 1999 and March 2021 were retrospectively analyzed in a multicenter collaborative study across 48 hospitals in Japan. Significant differences were evaluated using Fisher’s exact test, the Mann-Whitney U-test, the Log-rank test, and a multivariate analysis with the Cox proportional hazard model. Significance was set at p < 0.05.

Results: Clinical outcomes of RA-LPD A total of 752 RA-LPD patients were enrolled. Their clinicopathological characteristics were presented at the ACR Convergence 2022. As shown in Figure 1, among 438 patients, 81.4% spontaneously regressed after the withdrawal of immunosuppressive agents, while 32.0% showed regrowth after a median of 12 months (range: 1-92). Among the 439 patients treated with first-line therapy, 365 (77.8%) achieved a complete or partial response to first-line therapy. The 5-year overall survival (OS) rate was 86.3%. The multivariate analysis identified an advanced clinical stage, Hodgkin lymphoma as independent regrowth after spontaneous regression, an older age ( >70 years), the T cell phenotype, and a sIL-2R level >1300 U/mL as independent unfavorable prognostic factors. Necessity for re-biopsy in patients with regrowth or relapse Eight patients with RA-LPD developed different histological subtypes after the regression or remission of RA-LPD. Among them, 6 patients (5.7%) showed regrowth after temporary tumor regression following the withdrawal of methotrexate (MTX), and 2 (2.2%) relapsed during temporary remission after chemotherapy. The tumor-related death rate was significantly higher in these patients (62.5%) than in those who developed LPD with the same histology (24.6%) (p=0.030) (Table 1). Therefore, re-biopsy is required for patients with regrowth or relapse. Recommended anti-rheumatic drug regimens after LPD onset The effects of antirheumatic drugs administered after the onset of LPD on the clinical outcomes of RA-LPD were examined in 393 patients with the relevant information available. The trastuzumab (TCZ) only group maintained a significantly higher rate of spontaneous regression than the none, MTX only, and TCZ plus tacrolimus (TAC) groups (Figure 2a). The prognosis of patients after the onset of LPD was better in the TAC only and TCZ only groups than in the none group, which included patients who had never been treated with MTX, TAC, TCZ, tumor necrosis factor inhibitors, abatacept, or a Janus-activating kinase inhibitor (Figure 2b).

Conclusion: The present study showed the clinical outcomes of RA-LPD and identified independent factors associated with post-spontaneous regression (SR)-free survival (PSRFS) and overall survival. Based on the results obtained, TCZ only regimens are recommended after the onset of LPD and re-biopsy is required for patients with regrowth or relapse.

Figure 1. The clinical course of RA-LPD.
Among 752 patients with RA-LPD, 68.5% spontaneously regressed after the withdrawal of immunosuppressive agents. Among them, 81.4% showed tumor regression, while 32.0% showed regrowth with a median of 12 months (range: 1-92).

Figure 2.
Kaplan-Meier curves of RA-LPD according to antirheumatic drugs administrated after the onset of LPD.
a). PSRFS curve of RA-LPD. The rate of spontaneous regression was significantly higher in the TCZ only group than in the none, MTX only, and TCZ plus TAC groups.
b) OS curve of RA-LPD. The prognosis of patients after the onset of LPD was better in the TAC only and TCZ only groups than in the none group.

Table 1. Summary of eight patients who developed different histological subtypes after the regression or remission of RA-LPD.

Disclosures: Y. HOSHIDA: None; A. Tsujii: None; S. OHSHIMA: None; Y. SAEKI: None; M. YAGITA: Medical & Biological Laboratories, CO., Ltd, 9, ONK therapeutics, 9; T. MIYAMURA: None; M. Katayama: None; T. KAWASAKI: None; Y. HIRAMATSU: None; H. Oshima: None; T. MURAYAMA: None; S. HIGA: None; K. KURAOKA: None; F. HIRANO: None; K. ICHIKAWA: None; M. KUROSAWA: None; H. SUZUKI: None; N. CHIBA: None; T. SUGIYAMA: None; Y. MINAMI: None; H. NIINO: None; A. IHATA: None; I. SAITO: None; A. MITSUO: None; T. MAEJIMA: None; A. KAWASHIMA: None; H. TSUTANI: None; K. TAKAHI: None; T. KASAI: None; Y. SHINNO: None; Y. TACHIYAMA: None; N. TERAMOTO: None; K. TAGUCHI: None; S. NAITO: None; S. YOSHIZAWA: None; M. ITO: None; Y. SUENAGA: None; S. Mori: AbbVie GK, 5, 6, Asahikasei Pharma Corp,, 5, Boehringer Ingelheim Japan, 6, Chugai Pharmaceutical Co. Ltd., 6, Chugai Pharmaceutical Co., Ltd., 5, Eli Lilly Japan K.K., 6, Janssen Pharmaceutical K.K., 6, Pfizer Japan Inc., 6, Taisho Pharma Co., Ltd., 6; S. NAGAKURA: None; N. YOSHIKAWA: None; M. NOMOTO: None; A. UEDA: None; S. NAGAOKA: None; Y. TSUURA: None; K. SETOGUCHI: None; S. SUGII: Eisai CO., Ltd., 6, MOCHIDA PHARMACEUTICAL CO>, 6; A. Abe: AbbVie/Abbott, 6, Asahi Kasei Pharma Corporation, 6, Bristol-Myers Squibb(BMS), 6, Chugai Pharmaceutical, 6, Janssen Pharma, 6, UCB Japan, 6; T. SUGAYA: None; H. SUGAHARA: None; M. KOSETO: None; Y. KUNUGIZA: None; N. IIZUKA: None; R. YOSHIHARA: None; H. YABE: None; T. FUJISAKI: None; E. MORII: None; M. TAKESHITA: None; M. SATO: None; K. SAITO: None; K. Matsui: None; Y. TOMITA: None; H. FURUKAWA: None; S. Tohma: AbbVie/Abbott, 5, AsahiKASEI Co., Ltd., 6, Chudai Pharmaceutical Co., Ltd., 5, Mitsubishi Tanabe Pharma Corporation, 5, Pfizer Japan Inc., 6.

To cite this abstract in AMA style:

HOSHIDA Y, Tsujii A, OHSHIMA S, SAEKI Y, YAGITA M, MIYAMURA T, Katayama M, KAWASAKI T, HIRAMATSU Y, Oshima H, MURAYAMA T, HIGA S, KURAOKA K, HIRANO F, ICHIKAWA K, KUROSAWA M, SUZUKI H, CHIBA N, SUGIYAMA T, MINAMI Y, NIINO H, IHATA A, SAITO I, MITSUO A, MAEJIMA T, KAWASHIMA A, TSUTANI H, TAKAHI K, KASAI T, SHINNO Y, TACHIYAMA Y, TERAMOTO N, TAGUCHI K, NAITO S, YOSHIZAWA S, ITO M, SUENAGA Y, Mori S, NAGAKURA S, YOSHIKAWA N, NOMOTO M, UEDA A, NAGAOKA S, TSUURA Y, SETOGUCHI K, SUGII S, Abe A, SUGAYA T, SUGAHARA H, KOSETO M, KUNUGIZA Y, IIZUKA N, YOSHIHARA R, YABE H, FUJISAKI T, MORII E, TAKESHITA M, SATO M, SAITO K, Matsui K, TOMITA Y, FURUKAWA H, Tohma S. Rheumatoid Arthritis-associated Lymphoproliferative Disorders: A Multi-center Analysis of Clinical Outcomes and Evaluation of Anti-rheumatic Drugs After LPD Onset [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/rheumatoid-arthritis-associated-lymphoproliferative-disorders-a-multi-center-analysis-of-clinical-outcomes-and-evaluation-of-anti-rheumatic-drugs-after-lpd-onset/. Accessed .

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