Clinicopathological characteristics and rituximab addition to cytotoxic therapies in patients with rheumatoid arthritis and methotrexate‐associated large B lymphoproliferative disorders

Yamada, K; Oshiro, Yumi; Okamura, Seiichi; Fujisaki, Tomoaki; Kondo, Seiji; Nakayama, Yoshihito; Suematsu, Eiichi; Tamura, Kazuo; Takeshita, Morishige

doi:10.1111/his.12627

Cited by 25 publications

(21 citation statements)

References 26 publications

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“…Some of immunosuppressant, other than MTX, are also known to increase the risk of LPD when they are used. Previous report has shown that 25% of OIIA‐LPD is associated with non‐MTX drugs . Furthermore, longstanding chronic inflammation is one of the risk for LPD .…”

Section: Discussionmentioning

confidence: 98%

Three different CT and FDG PET/CT findings of pulmonary involvement in methotrexate‐associated lymphoproliferative disease

Matsubayashi

Suzuki

Sakamoto

et al. 2020

Respirology Case Reports

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Lymphoproliferative disease (LPD) is one of the complications of methotrexate (MTX) therapy. In MTX-associated LPD (MTX-LPD), LPD lesions limited to the lungs are rare and show various types of opacity. A 75-yearold woman with rheumatoid arthritis (RA) presented with myalgia. She had been taking MTX for 11 years. Chest computed tomography (CT) scans showed a nodule in the left lower lobe that had grown significantly and a new nodule in the right lower lobe. 18 F-fluorodeoxyglucose (FDG)/positron emission tomography (PET)/CT revealed significant FDG uptake in these nodules. Transbronchial biopsy specimen showed diffusely distributed CD20-positive lymphoid cells, and we made a diagnosis of MTX-LPD. All lung lesions disappeared within months after the immediate discontinuation of MTX. We also had two other patients with MTX-LPD lung lesions that had high FDG uptake. FDG PET/CT might be a useful diagnostic tool as it may reflect disease progression and help identify separate lesions.

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Section: Discussionmentioning

confidence: 98%

Three different CT and FDG PET/CT findings of pulmonary involvement in methotrexate‐associated lymphoproliferative disease

Matsubayashi

Suzuki

Sakamoto

et al. 2020

Respirology Case Reports

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“…Differences in selection criteria make comparisons with other studies less informative. Published studies almost always focus only on specific drugs [6,53], autoimmune diseases [60,61], malignancies [10][11][12], and/ or specific combinations [62], such as methotrexateassociated lymphoproliferative disorders in rheumatoid arthritis patients [7,8,[63][64][65].…”

Section: Discussionmentioning

confidence: 99%

Other immunomodulatory agent-related lymphoproliferative diseases: a single-center series of 72 biopsy-confirmed cases

et al. 2018

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Ongoing development of new drugs, as well as novel indications in the treatment of autoimmune diseases leads to the increasing use of immunomodulatory and immunosuppressive drugs. Immunomodulatory agent-related lymphoproliferative disorders are a known and potentially life threatening complication of chronic administration of these drugs, but are less well characterized compared with post-transplant lymphoproliferative disorders. The heterogeneous drug targets, various underlying disease indications, different drug combinations used and relatively low incidence render data collection and interpretation difficult. In this retrospective paper, we describe the clinicopathological characteristics of a larger single-center series of 72 immunomodulatory agent-related lymphoproliferative disorder cases. We divided the cases according to the therapy, administered in the year preceding diagnosis of a lymphoproliferative disorder, in an immunosuppressive drug, an immunomodulatory drug and a combination of immunosuppressive and immunomodulatory drugs group. We observed differences in "time to lymphoproliferative disorder development" with a shorter time for all the immunomodulatory drug-related cases combined (immunomodulatory and immunomodulatory + immunosuppressive = immunomodulatory-all) vs immunosuppressive-only (p = 0.0031). The proportion of malignant cases in patients receiving immunomodulatory therapy was, however, also significantly lower when compared with the immunosuppressive treated cases (43 vs 88%; p = 0.0184). The immunomodulatory/suppressive agent-related lymphoproliferative disorders were less often associated with the Epstein-Barr virus (EBV) (31 vs 66%; p = 1.829e-05) and the lymphoproliferative disorders incidence in the first year after immunomodulatory/immunosuppressive therapy initiation was lower (18 vs 41%; p = 0.04151)-compared with a published series of 140 post-transplant lymphoproliferative disorder cases from the same center. However, a similar histopathological spectrum from nondestructive, to polymorphic and monomorphic lesions as in post-transplant lymphoproliferative disorders is observed. With increasing use of immunosuppressive and especially immunomodulatory therapy, a higher incidence of immunomodulatory/suppressive agent-related lymphoproliferative disorders is to be expected. Life-long awareness for development of immunomodulatory/suppressive agent-related lymphoproliferative disorders with clinical follow-up and timely biopsies of suspicious lesions is required since these lymphoproliferative disorders arise both early after therapy initiation and many years later. Histopathological confirmation and correct classification is necessary to guide therapy and EBV ISH should be a part of routine pathological diagnostics.

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“…demonstrated differences in the phenotype and genetic characteristics of MTX-LPD-DLBCL and de novo DLBCL such as a genomic profile with 3q and 12 gains, 13q loss, different expression levels of relevant pathogenic biomarkers, and a microenvironment with high numbers of cytotoxic T lymphocytes and M2 macrophages 21 . In other studies, most MTX-DLBCL cases had an activated-B-cell immunophenotype, especially Epstein-Barr virus (EBV) - positive cases, and MTX-EBV+DLBCL commonly expressed CD30 22 , 23 . Ejima-Yamada et al .…”

Section: Lpd Regression After Isd Withdrawalmentioning

confidence: 98%

“…In P-G, de novo LDP and irreversible MTX-LPD due to ISDs are involved, although it is difficult to discriminate between them. Regarding this point, the differences between de novo LPD and MTX-LPD have been investigated in several studies 20 - 23 . Carreras et al .…”

Section: Lpd Regression After Isd Withdrawalmentioning

confidence: 99%

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Clinical management for other iatrogenic immunodeficiency-associated lymphoproliferative disorders

Tokuhira¹,

Tamaru²,

Kizaki³

2019

J Clin Exp Hematopathol

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Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD), a category of immunodeficiency-associated LPD according to the World Health Organization classification, is associated with immunosuppressive drugs (ISDs). Several factors, including autoimmune disease (AID) activity, Epstein-Barr virus (EBV) infection, ISD usage, and aging, influence the development of OIIA-LPD, resulting in complicated clinical courses and outcomes. Most OIIA-LPD develops in patients with rheumatoid arthritis using methotrexate (MTX-LPD). The management of MTX-LPD is based on the clinical course, i.e., with/without regression, with/without relapse/regrowth event (RRE), LPD subtype, and ISDs for AIDs after LPD development. There are three clinical courses after ISD withdrawal: regressive LPD without relapse/regrowth (R-G), regressive LPD with RRE (R/R-G), and persistent LPD (P-G). The majority of EBV+ diffuse large B-cell lymphomas are classified in R-G, whereas classic Hodgkin lymphoma is generally classified in R/R-G. Polymorphic LPD (P-LPD) in MTX-LPD develops with heterogeneous pathological features similar to monomorphic LPD. Chemotherapy for MTX-LPD is selected according to that for de novo LPD, although the strategy for aggressive P-LPD and non-specific LPD is not well established. The absolute lymphocyte count in the peripheral blood has been suggested as a candidate marker for MTX-LPD development and RRE. Several clinical issues, including correct diagnosis among overlapping clinicopathological features in MTX-LPD and clinical management of LPD by ISDs other than MTX, require further investigation.

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Clinicopathological characteristics and rituximab addition to cytotoxic therapies in patients with rheumatoid arthritis and methotrexate‐associated large B lymphoproliferative disorders

Abstract: In RA patients with MTX-BLPD, immunosuppression by MTX, EBV infection and low BCL2 expression in tumour cells may play roles in tumorigenesis and tumour regression. R+ cytotoxic therapies as well as MTX withdrawal were highly effective in these patients.

Cited by 25 publications

References 26 publications

Three different CT and FDG PET/CT findings of pulmonary involvement in methotrexate‐associated lymphoproliferative disease

Three different CT and FDG PET/CT findings of pulmonary involvement in methotrexate‐associated lymphoproliferative disease

Other immunomodulatory agent-related lymphoproliferative diseases: a single-center series of 72 biopsy-confirmed cases

Clinical management for other iatrogenic immunodeficiency-associated lymphoproliferative disorders

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