M. Izumikawa

Association of Higher Methotrexate Dose With Lymphoproliferative Disease Onset in Rheumatoid Arthritis Patients

Methotrexate (MTX) is used as an anchor drug for rheumatoid arthritis (RA). Lymphoproliferative disease (LPD) occasionally develops in patients treated with MTX, and is known as MTX‐associated LPD (MTX‐LPD). Although MTX‐LPD occurs mainly in RA patients, it has not been established if MTX administration is an independent risk factor for LPD in RA patients. We examined the clinical characteristics of MTX‐LPD in Japanese RA patients and attempted to determine the risk factors for MTX‐LPD development.

Primary central nervous system lymphoma in a rheumatoid arthritis patient treated with methotrexate: a case report

BackgroundRheumatoid arthritis is a systemic inflammatory disease characterized by synovitis and the destruction of articular structures in multiple joints. Methotrexate is recommended as an anchor drug for rheumatoid arthritis treatment to achieve the therapeutic goal of reducing damage to joints and improving clinical score. However, several studies have shown that methotrexate has been associated with the development of lymphoproliferative disorders, namely methotrexate-associated lymphoproliferative disorders. On the other hand, primary central nervous system lymphoma is an aggressive disease with poor prognosis. Both methotrexate-associated lymphoproliferative disorders and primary central nervous system lymphoma are reported to be associated with Epstein-Barr virus.Case presentationA Japanese female patient of between 60 and 70 years of age with rheumatoid arthritis was admitted to our hospital because of sudden convulsion and impaired consciousness. Just before admission, she was treated with adalimumab and methotrexate. Contrast-enhanced computed tomography scan showed a densely stained mass with surrounding edema in both frontal lobes and the left nucleus basalis, and enlarged lymph nodes in the right supraclavicular fossa. We performed a biopsy of the right cervical lymph node, but could not establish a histopathological diagnosis. In situ hybridization showed the presence of Epstein Barr virus, therefore we diagnosed this case as methotrexate-associated lymphoproliferative disorders mediated by Epstein Barr virus after considering the drug history of the patient. After we discontinued methotrexate, patient symptoms gradually improved. The masses at both frontal lobes and the left nucleus basalis were gradually regressed.ConclusionSince the frequency of methotrexate use and the maximum dosage has been increasing, particular attention should be paid to the development of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients who are treated with methotrexate.

A case of catastrophic antiphospholipid syndrome, which presented an acute interstitial pneumonia-like image on chest CT scan

We report the case of catastrophic antiphospholipid syndrome (CAPS) complicated with mixed connective tissue disease (MCTD). A female patient was diagnosed with acute interstitial pneumonia (AIP) with MCTD by chest CT scan. Corticosteroid therapy was refractory for lung involvement, and she died due to acute respiratory failure. The autopsy revealed that AIP was compatible with lung involvement of CAPS. We therefore suggest that chest CT might reveal AIP-like findings in CAPS patients whose condition is complicated with pulmonary manifestations.

THU0209 Lymphocyte subsets in biopsy specimen are associated with spontaneous regression of lymphoproliferative disorders in rheumatoid arthritis patients treated with methotrexate

Background Patients with rheumatoid arthritis (RA) have a high risk for lymphoproliferative disorders (LPDs). An LPD in a patient treated with methotrexate (MTX) is known as MTX-associated LPD (MTX-LPD), which is classified among immunodeficiency-associated lymphoproliferative disorders (ID-LPD) as “other iatrogenic ID-LPD” in the 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (1). We previously reported that MTX is an independent risk factor for LPD onset in Japanese patients with RA (2). In MTX-LPD, MTX withdrawal can result in spontaneous regression of LPD. In addition, limited evidence indicates that Epstein–Barr virus infection is related to spontaneous regression of MTX-LPD. No biomarker has been identified that predicts spontaneous regression of MTX-LPD. Objectives To identify a biomarker that predicts spontaneous regression of MTX-LPD in RA patients. Methods We enrolled RA patients from Kagawa Prefecture, Japan, who developed MTX-LPD during the period from June 2010 through December 2016. RA was diagnosed in accordance with the American College of Rheumatology 1987 classification criteria and was treated with disease-modifying antirheumatic drugs, including MTX. The patients were divided into two groups: those followed-up after discontinuation of MTX alone (MTX withdrawal group) and those who received chemotherapy at 1 month or later after MTX discontinuation (chemotherapy group). The following variables were compared between groups: change in peripheral lymphocyte subsets after MTX discontinuation, serum soluble interleukin-2 receptor, and lymphocyte subsets and Epstein–Barr virus–encoded RNAs in a biopsy specimen from a lesion. Results We enrolled 43 MTX-LPD patients (29 in the withdrawal group and 14 in the chemotherapy group). From among these groups, we selected 32 patients for analysis of changes in peripheral lymphocyte subsets (23 in the withdrawal group and 9 in the chemotherapy group) and 22 for analysis of lymphocyte subsets in a lesion specimen (11 each in the withdrawal group and chemotherapy group). Peripheral lymphocyte counts were significantly higher after MTX discontinuation in the withdrawal group. Analysis of lymphocyte subsets from lesion specimens revealed significantly higher CD8-positive lymphocyte counts in the chemotherapy group than in the withdrawal group. Conclusions Lymphocyte count differed before and after MTX discontinuation, and a higher CD8-positive lymphocyte count in a lesion specimen was associated with spontaneous regression of MTX-LPD. These findings may help identify a predictive marker for MTX-LPD treatment and management. References Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, 2008. Association of higher methotrexate dose with lymphoproliferative disorders onset in rheumatoid arthritis patients. Kameda T, Dobashi H, Miyatake N, Inoo M, Onishi I, Kurata N, Mitsunaka H, Kawakami K, Fukumoto T, Susaki K, Izumikawa M, Nakashima S, Shimada H, Takeuchi Y, Haba R, Mano S, Onishi H, Imataki O, Matsunaga T. Arthritis Care Res (Hoboken). 2014 Sep;66(9):1302–9. Disclosure of Interest None declared

FRI0609 Usefulness of FDG-PET/CT imaging and serological biomarkers to predict relapse in IGG4-related disease

Background IgG4-RD shows relapses frequently. It is important to search to the factors to predict relapse. Recent research has shown the usefulness of FDG-PET/CT for IgG4-RD because it is more sensitive than conventional imaging to detect organ involvement of the disease. It has been suggested that FDG-PET/CT is also useful for monitoring therapeutic response of IgG4-RD. Objectives We investigate the usefulness of FDG-PET/CT imaging and serological biomarkers to predict relapse in IgG4-RD. Methods We analyzed 24 patients with IgG4-RD treated for more than 1 year between 2008 and 2016 in our facility. The diagnosis for IgG4-RD was based on comprehensive diagnostic criteria for IgG4-RD. All cases underwent FDG-PET/CT at least once, and laboratory data were collected from their medical records retrospectively. Levels of serum C-reactive protein (CRP), eosinophil/leukocyte ratio, serum IgG, IgG4, IgA, IgM, IgE, sIL2-R and serum compliment were investigated. Results The patients had a mean age of 67.9 years (range: 50–87 years). In the cases with high FDG uptake on FDG-PET/CT, they had a greater number of organ involvements, higher serum IgG and sIL-2R levels. Eight patients experienced relapses following treatment. Higher serum IgG predicted relapses of IgG4-RD. FDG-PET/CT findings at baseline were not associated with relapse. FDG-PET/CT was performed in 13 patients after initiation of treatment and 4 patients had a relapse. There were no significant reduction of abnormal FDG uptake in 6 patients, and 4 of 6 patients relapsed. Conclusions In this study, we examined the factors to predict relapse in IgG4-RD. Patients with higher serum IgG were regarded as a risk of relapse, but FDG-PET/CT findings at baseline were not associated with relapse. FDG-PET/CT reexamined after initiation of treatment is useful to predict relapse of IgG4-RD. References Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012 Feb;22(1):21–30. Nakatani K. Utility of FDG PET/CT in IgG4-related systemic disease Clin Radiol. 2012 Apr;67(4):297–305. Zhang J, Chen H, Ma Y, et al. Characterizing IgG4-related disease with 18F-FDG PET/CT: a prospective cohort study. Eur J. Nucl Med Mol Imaging. 2014;41:1624–1634. Disclosure of Interest None declared

AB0294 Lymphocyte Recovery after Methotrexate Discontinuation Relate To Spontaneous Regression of Mtx-Lpd in Ra Patients

Background Rheumatoid arthritis (RA) patients have a high risk of onset of lymphoproliferative disorders (LPD). Especially, LPD develop in patients treated with methotrexate (MTX) is known as MTX-associated LPD (MTX-LPD). MTX-LPD is classified among the “immunodeficiency-associated lymphoproliferative disorders (ID-LPD)” as an “other iatrogenic ID-LPD” in the 2008 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (1). We previously reported that MTX is an independent risk factor for LPD onset in Japanese RA patients (2). Characteristic of MTX-LPD is that MTX withdrawal possibly results in spontaneous regression of the LPD. Furthermore, there are some reports that the Epstein-Barr virus (EBV) infection is related to spontaneous regression of MTX-LPD. However, enough evidence about the relation with EBV infection and spontaneous regression of MTX-LPD is not presented. In addition, biomarker predicting a spontaneous regression of MTX-LPD has not been clarified. Objectives We examined the clinical characteristics of MTX-LPD in Japanese RA patients and attempted to determine the predictive marker for spontaneous regression of MTX-LPD. Methods We enrolled 33 RA patients who developed MTX-LPD from Kagawa Prefecture, Japan between June 2010 and December 2015. Patients were diagnosed according to American College of Rheumatology 1987 classification criteria, and treated with disease modifying antirheumatic drugs (DMARDs) including MTX. We divided into patients who were followed-up after the discontinuation of MTX alone (MTX withdrawal group) and patients who were performed chemotherapy after one month or more of the MTX discontinuation (chemotherapy group). The following differences between the two groups were examined: 1) serum LDH; 2) serum CRP; 3) sIL-2 receptor; 4) lymphocyte counts before and after MTX discontinuation; 5) hemoglobin; 6) histological findings related to LPD; 7) EBV association; 8) number of LPD lesions and 9) outcome. Results There were 28 patients in the MTX withdrawal group and 5 patients in the chemotherapy group. Laboratory data such as LDH, CRP, sIL-2R, lymphocyte counts and hemoglobin showed no significant difference in two groups. Furthermore, there is no difference between two groups about EBV infection and number of LPD lesions. However, significant differences were found in the change ratio of lymphocyte between the two groups. Conclusions We revealed that the change of lymphocyte before and after the MTX discontinuation relate to spontaneous regression of the MTX-LPD. This data suggest that the recover of lymphocyte after the MTX discontinuation may become a predictive marker for MTX-LPD treatment strategy. References Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, 2008. Association of higher methotrexate dose with lymphoproliferative disorders onset in rheumatoid arthritis patients. Kameda T, Dobashi H, Miyatake N, Inoo M, Onishi I, Kurata N, Mitsunaka H, Kawakami K, Fukumoto T, Susaki K, Izumikawa M, Nakashima S, Shimada H, Takeuchi Y, Haba R, Mano S, Onishi H, Imataki O, Matsunaga T. Arthritis Care Res (Hoboken). 2014 Sep;66(9):1302–9. Disclosure of Interest None declared

AB0922 FDG-PET/CT Is A Valuable Tool for Relapsing Polychondritis

Background Relapsing polychondritis (RP) is a comparatively rare inflammatory disorder t in which recurrent episodes of inflammation occur in the external ear, nose, and joints. Although the pathogenesis of RP is unclear, it is believed to involve autoimmune mechanism such as autoantibody to type II collagen. Clinically, diagnosis in early stages of RP is difficult because of few typical physical findings. Furthermore, airway involvement is the most important complication of RP, and is associated with significant morbidity and mortality. Therefore it is important to diagnosis and treat RP in early stages. On the other hand, fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been an established in a field of oncology. Recently, FDG-PET/CT is used as diagnostic tool for inflammatory disorder such as infection or collagen vascular disease. Objectives We investigate the features and the usefulness of FDG-PET/CT in the diagnosis of RP. Methods We enrolled the five RP patients (M/F: 1/4) who fulfilled the RP criteria by Damiani and Levine, and treated in our facility between 2005 and 2015. All patients had undergone FDG-PET/CT before treatment. Inflammatory lesion was evaluated by using the maximum standardized uptake value (SUV max). Furthermore, we performed follow-up FDG-PET/CT due to evaluate the efficacy of treatment for RP. Results FDG-PET/CT findings revealed abnormal FDG accumulation in the cartilages for all five patients. The lesions of abnormal FDG accumulation were tracheal/bronchial in 3 cases, auricular cartilage in 2 cases. The mean SUV max in tracheal/bronchial was 4.84 and in auricular cartilage was 2.53. All RP patients received glucocorticoid (GC) treatment. 3 patients were performed methylprednisolone-pulse therapy. All RP patients had well responce to initial GC treatment. However three patients were refractory for GC treatment. In these patients, one treated with methotrexate combined with GC and another 2 cases cyclophosphamide. The follow-up FDG-PET/CT was undergone in 2 patients. These findings revealed that FDG accumulation was significantly decreased or disappeared. Conclusions In RP patients, FDG-PET/CT is useful for the early diagnosis. Additionally, we suggest that FDG-PET/CT is valuable for monitoring response to treatment. References Jinlin Wang et al. Ann Nucl. Med. (2014)28:276–284 Yamashita H et al. Rheumatology 2014 Aug;53(8):1482–90 Disclosure of Interest None declared

THU0286 The Efficacy and The Long-Term Prognosis of Rituximab for Refractory Thrombotic Microangiopathy Associated with Connective Tissue Diseases

Background Recently, it has been described in many reports that B cell has important roles in connective tissue disease (CTD). Rituximab (RTX), anti-CD20 monoclonal antibody is widely known as effective for patients with several autoimmune hematological disorders including thrombotic microangiopathy (TMA) through not only B cell depletion but reducing antigen-presenting cell function, complement hyperactivation, release of inflammatory cytokines and abnormal auto-reactive T cell response through co-stimulatory signals.1) TMA is developed in CTD occasionally. CTD-TMA especially with normal activity of von Willebrand factor cleaving protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member-13 (ADAMTS-13) is often resistant for plasma exchange (PE) conducted for thrombotic thrombocytopenic purpura with ADAMTS-13 inhibitor and lack of ADAMTS-13 activity as a first-line treatment.2) It has been reported that the autoantibodies other than ADAMTS-13 inhibitor, complement hyperactivation, and excessive inflammatory cytokines production associated with refractory TMA.3) Objectives We investigate the efficacy and the long-term prognosis of RTX treatment for refractory TMA associated with CTD. Methods We enrolled 7 CTD-TMA patients (SLE; 3, SS; 2, MCTD; 1, DM; 1) with refractory to PE treatment between 2006 and 2015. We examined the ADAMTS-13 activity, its inhibitor and ultra-large von Willebrand factor multimers (UL-VWFMs) at TMA onset. RTX was given 375mg/m2 per a dose. We defined complete response (CR) as platelet counts >150×109/l for more than 3 consecutive days, with normal levels of serum LDH and an absence of TMA-related symptoms. We considered CR continued more than 30 days after RTX treatment as remission. In addition, we investigated as follow subjects; duration from initial RTX treatment to CR, duration of sustained CR, relapse and adverse events. Results No abnormality of ADAMTS-13 activity was observed 6 patients. The thrombocytopenia was improved immediately within 2–3 weeks after the initiation of RTX and hemolytic anemia and neuropsychiatric manifestations were improved following after the recovery of thrombocytopenia, respectively. 6 patients could achieve CR. They who achieved CR all have sustained long-term remission by only 1 or 2 doses of RTX administration and there was no relapse. RTX was partial response for 1 patient with insufficient recovery of thrombocytopenia but detectable serum haptoglobin and she was reported with controllable bacterial pneumonia. Conclusions We suggest that RTX treatment has efficacy with high response rate and long-term remission for the refractory CTD-TMA patients. Moreover, RTX treatment can be the first-line treatment for CTD-TMA. References Roberto Stasi. Rituximab in autoimmune hematologic disease: not just a matter of B cells. Semin Hematol. 2010; 47: 170–179. Tomomi Matsuyama, Masataka Kuwana, Masanori Matsumoto, et.al. Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases. Thromb Haemost. 2009; 102: 371–378. Marina Noris, Federica Mescia, Giuseppe Remuzzi. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat. Rev. Nephrol. 2012; 8: 622–633. Disclosure of Interest None declared

AB0197 Evaluation of Serum IL-10 and IP-10 Levels Is Useful as Prognostic Biomarkers for Selection of IL-6R Antibody (TCZ) Prior To Tumor Necrosis Factor (TNF) Inhibitor in Rheumatoid Arthritis Treatment

Background Biomarkers of response to treatment in rheumatoid arthritis (RA) are sorely needed given the large inter-individual variability in efficacy of the available drugs. However, there is few reported to distinguish between responses to the different biologics (Bio) 1). Some authors think it will be difficult to obtain good predictive biomarkers for the efficacy of Bio before administration. Consequently, it is important that we identify the novel biomarker to predict the efficacy of these agents before the administration of Bio. Objectives To identify a serum biomarker for prediction of the response to Bio in patients with RA, we investigated whether serum cytokine level before treatment with Bio may represent useful prognostic biomarkers for TNF inhibitor (GLM) or IL-6R antibody (TCZ) treatment in bio-naïve RA. Methods To identify a serum biomarker for prediction of the response to Bio in patients with RA, we performed serum cytokines analysis in RA patients before and after Bio treatment with TCZ and GLM. At the first, we enrolled 10 responder and 10 poor-responder RA patients treated with Bio. 29 cytokines levels before treatment were measured using MILLIPLEX MAP Human Cytokine/Chemokine®. According to analysis of these 29 cytokines, IL-17, IL-6, IL-10 and IP-10 were eliminated as candidates for novel biomarker to predict the effectiveness of RA treatment. Then we enrolled 41 bio-naïve RA patients before administration of TCZ (n=27) or GLM (n=14). We measured these four serum cytokines before and after treatment with each Bio using ELISA. At baseline and 24 weeks after Bio-therapy with TCZ or GLM, we assessed DAS28 and measured serum levels of IL-17, IL-6, IL-10 and IP-10 using commercial ELISA kits. Responders and non-responders were defined as patients who had clinical remission (CR; DAS28 <2.6) and non-CR (DAS28 >2.6) at 24 week after administration of Bio. Wilcoxon two samples test was performed to compare cytokine levels. Results Mean age was 57.6±15.9, 70.6±14.7 years old and mean disease duration was 77.1±86.2, 114.0±142.6 months in TCZ and GLM patients, respectively. Disease activity of RA was 4.78±0.98 and 4.23±0.76 with DAS28 in TCZ and GLM patients, respectively. In CR group of TCZ (n=19), the serum IP-10 and IL-10 levels decreased compared with non-CR group by ELISA, significantly (P<0.05). As for RA patients treated with TCZ, IP-10 levels were significantly higher in responders. As for RA patients treated with GLM, responders showed a trend toward higher levels of baseline IL-10 compared to non- responders, while IP-10, IL-17 and IL-6 differences did not reach statistical significance. Conclusions In our study, the serum levels of IP-10 and IL-10 before Bio administration appeared to be associated with favorable responses to TCZ. Furthermore, these cytokines including IP-10 were not associated to response of GLM treatment. It is suggested that bio-naïve RA with low serum IP-10 levels might be treated with TCZ better than TNFi (GLM). References Gibbons LJ, Hyrich KL. Biologic therapy for rheumatoid arthritis: clinical efficacy and predictors of response. BioDrugs. 2009; 23(2): 111–24. Acknowledgement None. Disclosure of Interest None declared

THU0410 The Efficacy of Rituximab for Refractory Thrombotic Microangiopathy (TMA) Associated with Connective Tissue Diseases Regardless of Adamts-13 Activity Levels

Background Thrombotic microangiopathy (TMA) is characterized by microvascular thrombosis with thrombocytopenia, haemolytic anemia, and red blood cell fragmentation. TMA is often reported to develop under various clinical conditions such as malignant hypertension, stem cell transplantation, pregnancy, drug-induced, and connective tissue diseases (CTD). TMA is associated with deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member-13 (ADAMTS-13) induced by its inhibitor. Excessive production of ultra-large von Willebrand factor multimers (UL-VWFMs) also induced TMA. Plasma exchange (PE) is the standard treatment for TMA patients, and PE treatment can reduce mortality from 90% to less than 20% 1). However, some cases without the deficiency of ADAMTS-13 activity are resistant to PE treatment in TMA associated with CTD (CTD-TMA) 2). Recently, rituximab (RTX), anti-CD20 monoclonal antibody, is known as effective treatment for patients with refractory CTD-TMA. RTX is considered to affect on immune response by not only depleting B cells but modulating antigen-presenting cell function and release of inflammatory or immunomodulatory cytokines, and normalizing the abnormal auto-reactive T-cell response through co-stimulatory signals 3). Objectives We investigate the efficacy and safety of RTX treatment (two doses of RTX, 375 mg/m2 once per week) for CTD-TMA with refractory to PE treatment. Methods We enrolled six CTD-TMA patients with refractory to PE treatment. We examined the ADAMTS-13 activity, its inhibitor and UL-VWFMs at TMA onset.In addition, we investigated as follow subjects; efficacy of RTX treatment, duration from initial RTX treatment to complete remission (CR), duration of sustained CR, relapse and adverse events. Results Five patients were female and one was male with average age of 41.5 years. CTD included three systemic lupus erythematosus, two Sjögrens syndrome and one mixed connective tissue disease. No abnormality of ADAMTS-13 activity was observed in five patients. ADAMTS-13 inhibitor was also not detected these five patients. UL-VWFMs were detected with two patients with neither deficiency of ADAMTS-13 activity nor presence of its inhibitor. In all patients, the cytopenia such as anemia and thrombocytopenia was improved immediately after the initial RTX administration. In addition, five of six patients could achieve CR within two weeks, and they have sustained in CR for at least 24 weeks. After 24 weeks, one of five patients who achieved CR relapsed, but she could achieve 2nd-CR after RTX re-treatment.Refractory CTD-TMA was controlled with RTX treatment, and serious complications were not occurred. Conclusions We suggest that RTX treatment could be expected the efficacy and safety for the refractory CTD-TMA patients regardless of ADAMTS-13 activity levels. It is possible that RTX treatment might be first line treatment strategy for CTD-TMA patients. References Sadler JE. Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Blood 2008; 112(1): 11-18. T Matsuyama. Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases. Thromb Haemost 2009; 102: 371-378. Stasi R. Rituximab in autoimmune hematologic disease:not just a matter of B cells. Semin Hematol 2010; 47: 170-179. Disclosure of Interest None declared