Regression Of Lymphoproliferative Disorders Research Articles

Usefulness of Sarilumab in Patients with Rheumatoid Arthritis after Regression of Lymphoproliferative Disorders

Lymphoproliferative disorders (LPDs) are serious complications associated with rheumatoid arthritis (RA) treatment that mostly occur during methotrexate (MTX) treatment. Cessation of MTX may induce regression of LPDs but is often followed by a flare of RA. Here, we describe two patients with RA flares after the discontinuation of MTX due to LPDs and sarilumab was useful for the treatment of RA without a relapse of LPDs. Patient 1 was an 84-year-old woman, who developed an LPD in the pharyngeal region after 7 years of MTX treatment. Discontinuation of MTX induced regression of LPD but RA flared within 6 months. Administration of sarilumab, in addition to salazosulfapyridine and prednisolone, reduced the RA activity without LPD relapse. Patient 2 was a 76-year-old man, who developed LPD in the pharyngeal region after 5 years of MTX treatment. Discontinuation of MTX induced regression of LPD, but soon RA flared. Although treatment with tocilizumab (TCZ) was effective in controlling RA, it flared again after 2 years. TCZ was switched to sarilumab and RA was in remission. LPD did not recur during these periods.

Response to Dr Urata's Letter to the Editor of Modern Rheumatology regarding a study of "Treatment of rheumatoid arthritis after regression of lymphoproliferative disorders".

In Response: We greatly appreciate Dr Yukitomo Urata’s thoughtful comments in the letter to the Editor [1] on the statistical issue in our study [2]. Persistent-type LPD developed in RA patients undergoing treatment had ... a low relapse rate for 6 years after LPD treatment. However, after that, it reversed and the relapse rate was higher than that of the regressive-type (Figure 1). This is a crucial point clinically. The total number at risk in Figure 2(b) did not match the number in Figure 2(a), which was a simple miscalculation. The numbers have been corrected as shown in Figure 1. Kazuhisa Nakano has received research grants from Mitsubishi-Tanabe, Eisai, and Eli Lilly. This work was supported by a research grant from the Ministry of Health, Labour, and Welfare of Japan (H30-menneki-shitei-002).

Treatment of rheumatoid arthritis after regression of lymphoproliferative disorders in patients treated with methotrexate: a retrospective, multi-center descriptive study.

To identify the optimal treatment for rheumatoid arthritis (RA) after the regression of lymphoproliferative disorders (LPDs). The subjects were 232 patients with RA who developed LPD between 2000 and 2017 at seven hospitals participating in the LPD-WG study. Kaplan-Meier and Cox proportional regression analyses were performed to determine the factors associated with the rate of LPD relapse and the retention of biological disease-modifying antirheumatic drugs (bDMARDs). Treatment for RA was resumed in 138 patients after spontaneous regression of LPD after the discontinuation of methotrexate and in 52 patients after chemotherapy for LPD (persistent-LPD). LPD relapses occurred in 23 patients. Not DMARDs use but Hodgkin's lymphoma was identified as a risk factor for LPD relapse. In 88 RA patients treated with bDMARDs [tocilizumab, 39 patients; abatacept 20 patients; tumor necrosis factor inhibitor, 29 patients], the one-year retention rate was 67.8%. The risk factors for discontinuation of bDMARDs were persistent-LPD, non-diffuse large B-cell lymphomas (non-DLBCL), and a high clinical disease activity index (CDAI). Tocilizumab showed the highest retention rate among bDMARDs, particularly in DLBCL. Although any bDMARD could be used in patients after LPD regression, effectiveness and risk for relapse should be carefully assessed for each LPD subtype.

Association of Epstein-Barr virus with regression after withdrawal of immunosuppressive drugs and subsequent progression of iatrogenic immunodeficiency-associated lymphoproliferative disorders in patients with autoimmune diseases.

Patients with autoimmune diseases (AIDs) may develop lymphoproliferative disorders (LPDs) during treatment with immunosuppressive agents (IS) such as methotrexate (MTX), biological agents, or tacrolimus. Some LPDs in patients with AIDs (AID-LPDs) regress after withdrawal of IS, and a high incidence of Epstein-Barr virus (EBV) positivity in such patients has been reported. To identify characteristics and factors predictive of the response to treatment and disease progression, we retrospectively analyzed clinical and histopathological data for 81 patients with AID-LPDs. Almost all of them (96%) had been treated with MTX. Diffuse large B cell lymphoma was the most common LPD type (61%) and seven patients (9%) had classical Hodgkin lymphoma (CHL). EBV was detected by in situ hybridization with an EBV-encoded small RNA (EBER) probe in 43% of the examined cases. In 59 patients, IS was discontinued as the initial treatment, resulting in regression of LPDs in 69% of them, and multivariate analysis showed that EBER positivity was an independent factor predictive of such regression (p = 0.022). Two-year progression-free survival (PFS) and overall survival for the patients overall were 63% and 83%, respectively. Poor PFS was associated with advanced stage (p = 0.024), worse performance status (PS, p = 0.031), CHL histology (p = 0.013), and reactivation of EBV-related antibodies (p = 0.029). In conclusion, EBV positivity demonstrated using an EBER probe is useful for prediction of successful regression after withdrawal of IS in patients with AID-LPDs. Patients with advanced stage disease, worse PS, CHL histology, or reactivation of EBV-related antibodies should be closely monitored after initial treatment.

SAT0010 ANTI-CD30 IMMUNOTHERAPY AMELIORATES BONE AND CARTILAGE DESTRUCTION IN EXPERIMENTAL MODEL OF RHEUMATOID ARTHRITIS IN MICE

Background:CD30 is a member of the TNF-receptor family and commonly expressed on lymphocytes of Hodgkin lymphoma and anaplastic large cell lymphoma. It has been reported that levels of soluble CD30 in serum and joint fluid is significantly elevated in rheumatoid arthritis (RA). Although RA patients may develop lymphoproliferative disorders (LPD) as a result of immunosuppression by MTX or bDMARDs, safety medications after the regression of LPD for RA have not yet been established.Objectives:To explore the potential of CD30 targeting therapy for RA.Methods:(1) Immuno-histological staining of CD30 was performed for fresh synovial tissues of RA and osteoarthritis (OA). In addition, double immunofluorescence staining of CD30 with CD3, CD20, CD68, CD138 were performed on RA synovial tissue. (2) Brentuximab vedotin (BV) is an anti-CD30 antibody conjugated with monomethyl auristatin E, designed to induce apoptosis of CD30 expressing cells. A multiple myeloma cell line (RPMI8226) was used as a non-lymphoma cell line and plasma cell-like cell line. Immuno-cytological staining for CD30 was performed on RPMI8226. Cells were cultured and harvested on days 0, 1, and 3 to evaluate the effects of BV (50 μl / ml per well). Cytospin specimens were stained by May-Grunwald-Giemsa (MGG) staining for cell counting and by FIFC-terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining for detection of apoptosis. (3) Collagen antibody induced arthritis (CAIA) was induced in DBA/1 mice by arthritogenic cocktail of monoclonal antibodies against type II collagen. BV was administered to the treatment groups (30mg/kg and 70mg/kg n=4 each) and evaluated clinical score, histological findings and levels of SAA, IL-6, and TNFα in serum by ELISA. Student’st-test (two-tailed) was used to determine statistical significance for analysis of synovial tissues and cell line assay. Two way ANOVA with Dunnett’s post hoc analysis was used for multiple comparisons of mice model.Results:(1) The number of CD30-positive cells was significantly higher in RA synovial tissue than in OA synovial tissue (p<0.01) (Fig. 1). CD30-positive cells were detected around the lymphoid follicles. Double immunofluorescence showed CD30 and CD138 double-positive cells in the synovial tissue of RA, suggesting CD30 is predominantly expressed by plasma cells. (2) RPMI8226 cells expressed CD30. BV caused apoptosis of RPMI8226 cells, and the number of cells treated with BV decreased to 95% compared to controls. (3) All control mice (n=4) developed severe arthritis, and their scores reached a peak (score: 13.3) on day 10. In the mice of treatment group of 30 mg/kg, paw swelling was slightly decreased, their clinical score reached a peak (score: 9.3) on day 10. In contrast, paw swelling was significantly reduced in the 70 mg/kg treatment group. The peak of the clinical score was 4.3 on day 10 (Fig.2). Histological score evaluated synovitis with infiltration of inflammatory cells, pannus formation, and erosion of bone and cartilage. Histological score of hind paws were 3.0 ± 0.8 for the control group, 2.7 ± 1.0 for 30 mg/kg group, and 0.7 ± 1.1 for 70 mg/kg group (p<0.01), respectively. The serum levels of SAA and IL-6 of treatment group were lower than those of no treatment group (p<0.01).Conclusion:We showed the expression of CD30 on synovial tissue of RA and the expression of CD30 on plasma cells. In addition, the current study provides the first evidence that BV depletion of CD30-positive cells suppressed arthritis and osteochondral destruction in CAIA mice. Our results may provide an important clue for the development of an effective treatment for RA with iatrogenic immunodeficiency-related LPD.Disclosure of Interests:Minami Matsuhashi: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Yoshihisa Nasu: None declared, Ryuichi Nakahara: None declared, Masahito Watanabe: None declared, Yoshifumi Hotta: None declared, Toshifumi Ozaki: None declared

Clinical aspects in patients with rheumatoid arthritis complicated with lymphoproliferative disorders without regression after methotrexate withdrawal and treatment for arthritis after regression of lymphoproliferative disorders

Objectives To identify predictive factors for lymphoproliferative disorders (LPDs) that persist after methotrexate (MTX) withdrawal (Persistent-LPD) and the optimal treatment for rheumatoid arthritis (RA) after LPD regression. Methods Among 3666 patients with RA treated with MTX in our department from 2006 to 2017, 26 cases of LPD that regressed after MTX withdrawal (Regressive-LPD) and 25 cases of Persistent-LPD were compared. Multivariate logistic analysis was performed to identify predictive factors for Persistent-LPD. Retention rates of biological disease-modifying antirheumatic drugs (bDMARDs) were calculated using the Kaplan–Meier Method. Results In Persistent-LPD, the incidence of diffuse large B-cell lymphoma was higher (76%). The overall 2-year survival rate was 83.9%: 95.8% for Regressive-LPD and 71.0% for Persistent-LPD. The International Prognostic Index (IPI) risk classification was useful for predicting Persistent-LPD. bDMARDs were introduced in 38 RA patients after LPD regression. Unadjusted retention rate of bDMARDs in the 51 LPD patients was significantly lower than that in the 1668 non-LPD RA patients in our bDMARD cohort (controls) (p = 0.029). The 1-year retention rates for bDMARDs were 69% and 64% for tocilizumab and abatacept, respectively vs. 46% for TNF-inhibitor (TNFi). Conclusion Risk assessment using IPI predicted Persistent-LPD. After LPD regression, non-TNFi tended to have higher retention rates.

Restoration of Decreased T Helper 1 and CD8+ T Cell Subsets Is Associated With Regression of Lymphoproliferative Disorders Developed During Methotrexate Treatment.

Lymphoproliferative disorder (LPD), including malignant lymphoma, is a relatively rare but life-threatening complication in RA patients under methotrexate (MTX) therapy. Spontaneous regression of LPD after MTX withdrawal is regarded as a distinct characteristic in part of such LPDs. The present study aimed to investigate the immunological difference in regressive LPD and persistent LPD. We studied RA patients who developed LPD during MTX administration (n = 35) and clinically matched controls (n = 35). The time of MTX cessation was defined as week 0, and LPD patients were divided into two groups according to LPD status at week 12: regressive group (n = 22) and persistent group (n = 13). Flow cytometric analysis of whole blood samples and serum cytokine assays were conducted for LPD (n = 10) and control patients (n = 10) at weeks 0, 4, and 12. There was a significant decrease in peripheral lymphocytes and the proportion of T helper 1 cells (Th1 cells), effector memory CD8+ T cells (EMCD8+ T) and Epstein-Barr virus (EBV)-specific CD8+ T cells at the time of LPD diagnosis, and a significant increase after MTX cessation was observed in the regressive group but not in the persistent group. The expansion of Th1 cells and EMCD8+ T cells significantly correlated with an increase in serum interferon (IFN)-γ concentration. Changes in Th1 cells, EMCD8+ T cells and EBV-specific CD8+ T cells, which coincided with an increase in IFN-γ, were significantly different between regressive LPD and persistent LPD after MTX cessation.

Reversible infliximab-related lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis

A 63-year-old woman with active rheumatoid arthritis (RA) had been treated with methotrexate and prednisolone. She developed cervical lymph node swelling 30 months after the initiation of infliximab therapy. A computed tomography revealed cervical and mediastinal lymph node swelling and multiple nodules (up to 13 mm in diameter) in the lungs. A lymph node biopsy showed infiltration of numerous Hodgkin-like and Reed-Sternberg-like cells. Immunohistological studies showed that these cells were positive for CD15, CD30, and Epstein-Barr virus (EBV) latent membrane protein. In site hybridization revealed the presence of EBV RNA in the nuclei of these cells. EBV DNA was detected in the biopsy specimen by southern blot analysis. She was diagnosed as having EBV-associated lymphoproliferative disorder (LPD). Immunodeficiency-associated LPD related with infliximab therapy was considered. Cessation of infliximab therapy only led to dramatic regression of LPD. This case illustrates that EBV-associated LPDs can occur as part of infliximab adverse effects in patients with RA.

Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection

To systematically review the experience of therapeutic studies where alpha-interferon with or without ribavirin was administered to patients with lymphoproliferative disorders, in order to evaluate whether eradication of hepatitis C virus may induce regression of lymphoproliferative disorders. We used bibliographical searches in electronic databases and in the Cochrane Library to determine our results. Sixteen studies where an anti-viral regimen was administered to 65 hepatitis C virus-infected patients with lymphoproliferative disorders were identified. Complete remission of the lymphoproliferative disorder was achieved in 75% of the cases. In contrast, hepatitis C virus-negative subjects did not respond to interferon, indicating that the response in the hepatitis C virus-infected patients is not merely due to the antiproliferative effect of interferon. Remission after HCV eradication was maintained, provided that infection did not reappear. In hepatitis C virus-infected patients with non-Hodgkin's lymphoma treated with corticosteroids/chemotherapy liver function tests deterioration did not occur. The addition of interferon to standard chemotherapy may decrease hepatic side-effects of chemotherapy. Although it is evident that larger therapeutical trials of anti-viral therapy are needed to determine the role of this strategy in hepatitis C virus-infected patients with lymphoproliferative disorders, encouraging data emerge from recent studies showing that interferon (plus ribavirin) is an attractive therapeutic option for some hepatitis C virus-related low-grade lymphomas.