tbuckley/cabot-search huggingface dataset:
SAT0054 Risk factors for acute exacerbation of rheumatoid arthritis-associated interstitial pneumonia
Authors: A Yashima, H Yamashita, R Kamei, K Suga, M Nakano, S Yamada, Y Takahashi, H Kaneko
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Acute exacerbation (AE) is recently recognized as deterioration of respiratory status in idiopathic pulmonary fibrosis. It is reported that AE also occurs in other interstitial lung diseases (ILD) such as collagen vascular diseases associated ILD (CVD-ILD). However, the characteristics and risk factors of AE in CVD-ILD are not clearly identified. <h3>Objectives</h3> To clarify the characteristics of patients with rheumatoid arthritis-associated interstitial pneumonia (RA-IP) and to investigate the risk factors associated with AE and its survival of RA-IP. <h3>Methods</h3> We examined the clinical features of 60 RA-IP patients admitted to our hospital between July 2010 and September 2016. We compared the characteristics between patients who developed AE (AE group) and those who didn9t (non-AE group), and between patients who survived after AE (alive group) and those who died after AE (dead group), and identified variables significantly associated with AE occurrence and survival using Cox hazards analyses. <h3>Results</h3> Thirty-six (60%) were female. Twenty-two (36.7%) developed AE and seven of them (11.7%) died with the mean follow-up period of 2.7 years. The mean age at RA diagnosis was 61.1±16.3 years in AE group and 61.5±13.1 years in non-AE group. Sex, smoking habit and high-resolution computed tomography (HRCT) pattern were not significantly different between two groups. Although there was no significant difference, more patients in AE group received methotrexate (MTX) treatment than those in non-AE group (40.9% vs. 18.9%, <i>p</i>=0.08), and MTX use was significantly associated with occurrence of AE in a Cox hazard analysis (Hazard ratio [HR] 1.09, 95% confidence interval [CI] 1.01–1.18). Further, age (median 70 vs. 82 years, <i>p</i>=0.002) and matrix metalloproteinase-3 (MMP-3) level (median 84.8 vs. 205.6 ng/mL, <i>p</i>=0.03) on admission were significantly higher in dead group than in alive group. Univariate analyses revealed that age ≧ 75 years (HR 10.53, 95% CI 1.26–88.15), MMP-3 ≧ 200 ng/mL (HR 15.58, 95% CI 1.38–175.8), and 3L or more oxygen use (HR 8.46, 95% CI 1.02–70.49) on admission were associated with death (Table 1). <h3>Conclusions</h3> Our data suggest that MTX use relates to the occurrence of AE, and age, MMP-3 level, and oxygen volume on admission relate to AE survival in patients with RA-IP. <h3>References</h3> Hozumi H, Nakamura Y, Johkoh T, et al. BMJ Open 2013; 3: e003132. Suda T, Kaida Y, Nakamura Y, et al. Respiratory Medicine 2009; 103: 846–853. <h3>Disclosure of Interest</h3> None declared
AB0247 Evaluation of rheumatoid arthritis cases with high anti-ccp antibody level
Authors: K Suzuki, M Minami, Y Nishio, N Hara, S Nakamura
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Anti-cyclic citrullinated peptide antibodies (Anti-CCP Ab) are well-established serological markers that show high sensitivity and specificity in diagnosing early rheumatoid arthritis (RA). Furthermore, Anti-CCP Ab is reported to be associated with bone erosions of RA. Therefore, Anti-CCP Ab positive RA patient can be a candidate for intensive treatment. <h3>Objectives</h3> Upper measurement limit of Anti-CCP Ab increased recently up to 1200 units. High level of Anti-CCP Ab may be a predictor of the profound therapy for RA. To understand the importance of Anti-CCP Ab level, we evaluated RA patients with high titer Anti-CCP Ab in relationship to the other activity markers of RA and the intensity of the treatment for RA. <h3>Methods</h3> Total of 186 RA patients with Anti-CCP Ab higher than 30 units was included in this study. Baseline markers such as CRP, MMP-3, RF and anti-CCP Ab were measured at the entry of the study. Relationship among these markers ware evaluated and examined using statistical significance for the single-factor ANOVA and the multiple comparisons. Among those cases 131 cases were treated conservatively with biologics and/or DMARDs and were followed up more than one year. We graded them from I to IV by the intensity of the treatment. Grade I: Biological agent. Grade II: Methotrexate (MTX) more than 12mg or combination with more than 3 DMARDS Grade III: MTX 6–11mg or combination with two recommended DMARDS Grade IV: single use of DMARDS including MTX less than 5mg. <h3>Results</h3> There was no relationship between titers of Anti-CCP Ab and titers of RF. We found significant statistical correlation between anti-CCP antibody titers and inflammatory markers such as CRP and MMP-3. There was significant statistical correlation between CRP and MMP-3. In terms of treatment intensity, strong intensity group showed high titer of anti-CCP Ab and CRP. Titer of RF and MMP-3 level did not have any relationship with the treatment intensity. In cases treated with biologics, anti-CCP Ab and CRP were significantly higher compared to non-biologic case group. In 80% of cases treated with biologics titer of anti-CCP was more than 200 units. However, non-biologic treatment was continued in more than 50% of cases with anti-CCP Ab higher than 200 units. <h3>Conclusions</h3> Even though we treated cases based on the severity of the symptoms of the patient and response in laboratory data, high anti-CCP Ab titers and CRP at the base line were most associated with the treatment intensity after 1 year. The results of our study suggest that the titer of anti-CCP Ab can be better a predictor of the treatment intensity than MMP-3 and RF. <h3>Disclosure of Interest</h3> None declared
Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma
Authors: Jaeryung Kim, Dae-Young Park, Hosung Bae, Do Young Park, Dongkyu Kim, Choong-Kun Lee, Sukhyun Song, Tae-Young Chung, Dong Hui Lim, Yoshiaki Kubota, Young-Kwon Hong, Yulong He, Hellmut G Augustin, Guillermo Oliver, Gou Young Koh
Journal: Journal of Clinical Investigation (2017)

Primary open-angle glaucoma (POAG) is often caused by elevated intraocular pressure (IOP), which arises due to increased resistance to aqueous humor outflow (AHO). Aqueous humor flows through Schlemm's canal (SC), a lymphatic-like vessel encircling the cornea, and via intercellular spaces of ciliary muscle cells. However, the mechanisms underlying increased AHO resistance are poorly understood. Here, we demonstrate that signaling between angiopoietin (Angpt) and the Angpt receptor Tie2, which is critical for SC formation, is also indispensable for maintaining SC integrity during adulthood. Deletion of Angpt1/Angpt2 or Tie2 in adult mice severely impaired SC integrity and transcytosis, leading to elevated IOP, retinal neuron damage, and impairment of retinal ganglion cell function, all hallmarks of POAG in humans. We found that SC integrity is maintained by interconnected and coordinated functions of Angpt-Tie2 signaling, AHO, and Prox1 activity. These functions diminish in the SC during aging, leading to impaired integrity and transcytosis. Intriguingly, Tie2 reactivation using a Tie2 agonistic antibody rescued the POAG phenotype in Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged mice. These results indicate that the Angpt-Tie2 system is essential for SC integrity. The impairment of this system underlies POAG-associated pathogenesis, supporting the possibility that Tie2 agonists could be a therapeutic option for glaucoma.
FRI0408 Neopterin as a serological marker of disease activity in patients with anti-melanoma differentiation-associated gene 5 antibody positive clinically amyopathic dermatomyositis
Authors: S Tsunoda, A Nishioka, T Abe, M Kitano, K Matsui, H Sano
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Anti-melanoma differentiation-associated gene 5 (MDA5) antibody in clinically amyopathic dermatomyositis (CADM) is associated with rapidly progressive interstitial lung disease (RPILD). RPILD is a rare disorder with a bad outcome, and therefore the intensive treatment with combinational immunosuppressive drugs in addition to steroid need to be initiated. However until now, good serological markers to evaluate disease activity in CADM have not been established. Activated alveolar macrophage is one of the possible candidates worsening the condition of RPILD. <h3>Objectives</h3> To investigate new serological markers of disease activity in anti-MDA5 antibody positive CADM for therapeutic indication. <h3>Methods</h3> Thirteen anti-MDA5 antibody positive CADM patients were enrolled. We serially measured serum anti-MDA5 antibody, and neopterin and IL-18 as markers of activated macrophage by serum enzyme-linked immunosorbent assay. We tracked them at three points in each patients: before treatment, soon after a series of intravenous cyclophosphamide pulse therapy (about 3months later after onset) and the remission status (about one year later after onset). <h3>Results</h3> Four patients died soon after the initial treatment because of the deterioration of RPILD. At onset of the disease, the levels of serum anti-MDA5 antibody and neopterin were extremely high (169.75±24.3 index and 27.6±24.1 nmol/l) in all patients. However serum IL-18 level was almost normal (479.3±301.4 pg/ml). Among the 9 surviving patients, it took about one year for anti-MDA5 antibody level to decrease to the normal range. On the other hand, neopterin level decreased quickly after the initial treatment. The level of anti-MDA5 antibody transitioned from 169.75±24.3 index to 93.1±50.1 index, and then to 44.8±45.4 index (P=0.003). Neopterin level transitioned from 27.6±24.1 nmol/l to 9.1±6.5 nmol/l, and then to 6.4±5.0 nmol/l (P=0.006). IL-18 level transitioned from 479.3±301.4 pg/ml to 246.0±175.8 pg/ml, and then to 233.3±180.1 pg/ml (P=0.02). The level of anti-MDA5 didn9t correlate with the level of ferritin (r=0.28), neopterin (r=0.16), IL-18 (r=0.06) and soluble IL-2 receptor (r=0.27), but the level of neopterin was well correlated with the level of ferritin (r=0.95), IL-18 (r=0.77) and soluble IL-2 receptor (r=0.75). <h3>Conclusions</h3> Anti-MDA5 antibody titer is useful if the patients could reach and maintain the remission or not. Serum neopterin level is useful to predict the clinical status at present for therapeutic indication. <h3>References</h3> Matsushita, et al. Br J Dermatol. 2016 Jul 25. doi: 10.1111/bjd.14882. Xu Y, et al. Clin Rheumatol. 2016, 35: 113–6. Enomoto Y et al. Arthritis Res Ther. 2017,19:9. doi:10.1186/s13075-016-1214-8. <h3>Disclosure of Interest</h3> None declared
THU0419 Risk of total hip and knee replacement in gout patients prior to and following diagnosis: a national population study in taiwan
Authors: C-F Kuo, J-S Chen, K-H Yu, S-F Luo
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Total joint replacement (TJR) is a major surgical procedure aiming to replace damaged natural joints with artificial prosthesis to restore function and alleviate pain. Total knee replacement (TKR) and total hip replacement (THR) are two common replacement procedures, mainly as a result of osteoarthritis, rheumatoid arthritis, trauma, fracture and infection. Whether gout associates with a greater risk of TJR independent of these primary risk factors is controversial, despite tophaceous or chronic deforming gouty arthritis may lead to joint destruction and subsequent TJR <h3>Objectives</h3> We carried out a case control study using the National Health Insurance (NHI) database with full coverage of the general population of Taiwan to investigate the burden of TJR in gout patients at diagnosis compared to matched controls. We further followed incident gout patients and their matched controls after diagnosis to compare their subsequent risk for TJR. <h3>Methods</h3> The Taiwan National Health Insurance database was used to identify 74,729 new diagnosis gout patients in 2005. These were matched 1:1 to 74,729 controls by birth year and sex with people who did not have gout diagnosis or urate-lowering treatment prescription. Odds ratios (ORs) of total hip or knee replacement (THR or TJR) at diagnosis and hazards ratios (HRs) after diagnosis were estimated adjusted for gender, age at diagnosis, comorbidities, co-medications, place of residence, income and occupation. <h3>Results</h3> Gout was associated with adjusted ORs (95% CIs) of 0.87 (0.54 to 1.40), 1.01 (0.57 to 1.79), 0.93 (0.64 to 1.35) for the THR, TKR and TJR at diagnosis, respectively. The incidence rate of THR or TKR in the patients with gout was 1.60 and 1.76 (per 1,000 person-years) which was higher than matched controls (0.99 and 0.98, respectively). Gout was also associated with an adjusted HR (95% CI) of 1.41 (1.19 to 1.68), 1.37 (1.16 to 1.61) and 1.37 (1.22 to 1.56) for developing THR, TKR and TJR. <h3>Conclusions</h3> Compared to matched controls people with gout did not have an increased risk of TJR at diagnosis but the risk increased substantially after diagnosis. Whether adequate urate-lowering treatment reduces the risk requires further study. <h3>References</h3> Kuo CF, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nature reviews. Rheumatology 2015;11:649–62. Roddy E, Zhang W, Doherty M. Are joints affected by gout also affected by osteoarthritis? Ann Rheum Dis 2007;66:1374–7. <h3>Disclosure of Interest</h3> None declared
AB0899 Depression and anxiety correlate with disease-related characteristics and quality of life in chinese patients with gout: a cross-sectional study
Authors: T Fu, H Cao, R Yin, L Zhang, Q Zhang, L Li, X Feng, Z Gu
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Depression and anxiety are common worldwide and may lead to disease aggravation and decreased health-related quality of life (HRQoL). The increasing prevalence of depression and anxiety in gout patients is associated with demographic and gout characteristics. However, there are currently no known reported studies related to the association between HRQoL and depression/anxiety. <h3>Objectives</h3> This cross-sectional study aims to evaluate the prevalence of depression and anxiety and investigate the potential risk factors for depression and anxiety in Chinese gout patients. <h3>Methods</h3> A self-report survey was administered to 193 gout patients and 208 healthy individuals from September 2015 to September 2016. Patients were asked to complete a set of standardized self-report questionnaires [Visual Analog Scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD-7) questionnaire, Short Form 36 health survey (SF-36)]. Independent samples t-tests, χ<sup>2</sup> analyses, and logistic regression were used to analyze the data. <h3>Results</h3> We found 15% of gout patients had depression, and 5.2% had anxiety, which were significantly higher than the healthy controls (1.4 and 1.0%, respectively). There were significant correlations among education, pain, disease duration, stage of gout, disability, number of tophi, presence of tender joints, HRQoL, and psychological status. Meanwhile, logistic regression analysis identified number of tophi, HAQ-DI, and MH scale as predictors of depression in gout patients. Education, GH, and VT domains were significantly accounted for anxiety. <h3>Conclusions</h3> The prevalence of depressive and anxious symptoms among gout patients was higher than healthy individuals. Education, disability, tophi and HRQoL were important risk factors linked to this disorder in Chinese gout population. These findings suggested medical personnel should pay more attention to the psychological health of gout patients and make objective interventions to relieve their depression and anxiety, especially those with low education level, more than two tophi, severe disability, and poor HRQoL. <h3>Acknowledgements</h3> This study was supported by Grants from the Chinese National Natural Science Foundation (no. 81671616 and 81471603). <h3>Disclosure of Interest</h3> None declared
THU0688 Disease flares, damage accrual and survival in anca-associated vasculitis
Authors: S Paramalingam, G Dogra, A Mclean-Tooke, J Nossent
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> ANCA- associated vasculitis (AAV) is a potentially life threatening condition requiring careful monitoring and balancing of treatment options to minimize morbidity and mortality. <h3>Objectives</h3> To investigate the influence of baseline disease characteristics and induction therapy on the disease course and outcome in ANCA- associated vasculitis. <h3>Methods</h3> Single centre longitudinal cohort study of all adult patients with an EMEA algorithm based diagnosis of AAV followed up to August 2016. Clinical data including disease activity (BVAS), ANCA type and level, treatment, relapses (BVAS &gt;3) and organ damage (VDI) and other complications (e.g. infections) during the disease course were recorded. Predictors for ESRD, death, cancer and damage accrual were analysed by multivariate logistic regression presented as Odds Ratios (OR). <h3>Results</h3> A total of 63 patients (59% male) (mean age at diagnosis 57 years, 59% with GPA, 24% MPA and 16% EGPA) were included. Fluorescence ANCA was positive in 92%, while 47% had MPO-ANCA and 43% PR3-ANCA. Induction therapy included corticosteroids (92%), Cyclophosphamide (57%), Rituximab (35%) and Plasmapheresis (6%). During 46 months of follow-up 34 patients (54%) experienced 71 relapses (rate 2.5/100 months) and 55 serious complications occurred (rate 2/100 months). Mean VDI at last follow-up was 2.1 with only 11 patients (17.4%) not developing organ damage. Averaged BVAS correlated with last VDI scores (Rs 0.25,p=0.012). Overall, 4 patients (6.3%) died, 19 (27%) developed renal insufficiency of which 2 (3.1%) required chronic dialysis, while 6 (9.5%) developed a new cancer. Age was an independent predictor (OR 1.09, p=0.05) for patient survival (95% and 91% at 1 and 5 years), but no effect was seen for baseline BVAS, gender, AAV or ANCA subtype (all p&gt;0.1). <h3>Conclusions</h3> While current treatment reduces the risk of death, AAV is still associated with a high rate of disease relapse, organ damage accrual and serious complications. <h3>Disclosure of Interest</h3> None declared
14-3-3ζ binds the proteasome, limits proteolytic function and enhances sensitivity to proteasome inhibitors
Authors: Y Gu, K Xu, C Torre, M Samur, B G Barwick, M Rupji, J Arora, P Neri, J Kaufman, A Nooka, L Bernal-Mizrachi, P Vertino, S-Y Sun, J Chen, N Munshi, H Fu, J Kowalski, L H Boise, S Lonial
Journal: Leukemia (2017)
Validation of the hematopoietic cell transplantation-specific comorbidity index in non-myeloablative allogeneic stem cell transplantation.
Authors: Muthu Veeraputhiran, Sally Arai, Robert Lowsky, David Bernard Miklos, Everett Meyer, Lori S. Muffly, Robert Negrin, Andrew R. Rezvani, Judith Shizuru, Wen-Kai Weng, Laura J. Johnston
Journal: Journal of Clinical Oncology (2016)

7046 Background: The HCT-CI has been extensively studied in Myeloablative (MA) and reduced intensity conditioning (RIC) regimens. However there is paucity of data about the validity of HCT-CI in NMA allogeneic transplant. We conducted a retrospective study to evaluate the validity of the HCT-CI in predicting non relapse mortality (NRM) and Overall Survival (OS) in Total Lymphoid Irradiation and Anti-thymocyte Globulin (TLI/ATG) NMA transplant. Methods: We identified 305 consecutive patients who underwent the TLI/ATG NMA allogeneic HCT between 2008 and 2015 from Blood and Marrow Transplant (BMT) database and by patient chart review at our institution. Results: The median age of the patients were 61 (range: 22-77) years. Majority of patients had Karnofsky’s score 90 or above (84%). Patients with HCT-CI scores of 0, 1,2,3,4 or > 4 are summarized in Table 1 with 32% of patients having a score of 0. Among the HCT-CI, reduced pulmonary function was the most common (n=89); followed by prior history of malignancy (n=39), psychiatric condition (n=38) and diabetes (n=31). The presence of any co-morbidity increased the hazard of death almost 2 –fold (HR=1.96, p < 0.01). There was a statistically significant difference in OS between three HCT-CI categories: score 0; score 1-5; score >=6 (p< 0.001). Conclusions: HCT-CI is a valid tool for predicting OS and NRM in TLI/ATG allogeneic HCT. HCT-CT scores may be incorporated in planning and predicting NMA transplant outcomes. Patient and disease characteristics. Variable Category N (%) Age at transplantation Median (range) 61 (22-77) Sex Male/ female 177/128 Karnofsky’s Performance status 100 84 (28) 90 173 (57) 80 42 (14) 70 6 (2) Type of disease ALL 5 (< 0.5) AML 112 (37) MDS 58 (19) HL 19 (6) NHL 58 (19) CML 8 (< 0.5) Other 45 (15) Comorbidity scores 0 96 (32) 1 66 (22) 2 56 (18) 3 49 (16) 4 23 (8) 5 6 (2) 6 7 (2) 7 2 (< 0.5) Comorbidity by organ system Arrhythmia 22 Cardiac 24 CVA 5 Diabetes 31 Hepatic (mild/ severe) 9/1 IBD 2 Infection 19 Obesity 12 PUD 1 Psychiatry 38 DLCO66-75 57 DLCO<=65 32 Renal 0 Rheumatic disease 4 Prior malignancy 39 Graft source Donor type MRD-sibling 130 (43) MRD- other relative 1 (< 1%) MUD 120 (39) Mismatch URD 54 (18)
Preclinical activity of DCZ3301, a novel aryl-guanidino compound in the therapy of multiple myeloma
Authors: Minjie Gao, Bo Li, Xi Sun, Yunfei Zhou, Yingcong Wang, Van S. Tompkins, Zhijian Xu, Nekitsing Indima, Houcai Wang, Wenqin Xiao, Lu Gao, Gege Chen, Huiqun Wu, Xiaosong Wu, Yuanyuan Kong, Bingqian Xie, Yiwen Zhang, Gaomei Chang, Liangning Hu, Guang Yang, Bojie Dai, Yi Tao, Weiliang Zhu, Jumei Shi
Journal: Theranostics (2017)

We synthesized a novel aryl-guanidino compound, DCZ3301, and found that it has potent cytotoxicity against multiple human cancer cell lines. The anticancer activity was most potent against multiple myeloma (MM). DCZ3301 induced cytotoxicity in MM cell lines, as well as patient myeloma cells, in part by decreasing mitochondrial membrane potential to induce apoptosis. In contrast, DCZ3301 had no cytotoxic effect on normal cells. DCZ3301 also inhibited cell cycling and caused a G2/M accumulation that corresponded with downregulation of Cdc25C, CDK1, and Cyclin B1. DCZ3301 retained its activity against MM cells in the presence of exogenous cytokines (IL-6 or VEGF) or bone marrow stromal cells (BMSCs) and reduced activity of multiple signaling pathways (STAT3, NFκB, AKT, ERK1/2) in MM but not normal cells. The STAT3 pathway played an important role in modulating DCZ3301-mediated cytotoxicity. Knockdown of STAT3 using siRNA in MM cells enhanced DCZ3301-induced cytotoxicity, whereas overexpression of STAT3 in MM cells partially protected them from apoptosis. In addition, DCZ3301 inhibited VEGF and IL-6 secretion in a dose-dependent fashion in a co-culture of MM cells and BMSCs. Combining DCZ3301 with bortezomib induced synergistic cytotoxicity in MM cell lines and primary MM cells. Finally, in vivo efficacy of DCZ3301 was confirmed in an MM xenograft mouse model. Together, these results provide a rationale for translation of this small-molecule inhibitor, either alone or in combination, to the clinic against MM.