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  • Standardizing Care and Fostering Systemic Autoinflammatory Disease (SAID) Research Through the CARRA Autoinflammatory Disease Network Schulert, G., Cherian, J., Muskardin, T., Twilt, M., Akoghlanian, S., Amarilyo, G., Dissanayake, D., Durrant, K., Ferguson, P., Gutierrez, M., Harel, L., Hausmann, J., Bekenstein, M., Laxer, R., Lenert, A., Li, S., Licameli, G., Lionetti, G., Michelow, I., Moorthy, L., Propst, E., Saper, V., Srinivasalu, H., Stepanovskiy, Y., Thatayatikom, A., Tucker, L., Wright, P., Yildirim-Toruner, C., Dedeoglu, F., Lapidus, S., CARRA Investigators WILEY. 2020: 153–55
  • Response to: 'Successful treatment of plasma exchange for refractory systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome and severe lung disease' by Sato et al. Annals of the rheumatic diseases Saper, V. E., Chen, G., Guillerman, R. P., Khatri, P., Cron, R. Q., Mellins, E. D. 2020

    View details for DOI 10.1136/annrheumdis-2020-217426

    View details for PubMedID 32317313

  • Drug Reaction and High Fatality Lung Disease in Systemic Onset Juvenile Idiopathic Arthritis (sJIA) Saper, V., Mellins, E., Kwong, B. MOSBY-ELSEVIER. 2020: AB95
  • Response to: 'Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease: case report' by Bader-Meunier et al. Annals of the rheumatic diseases Saper, V. E., Chen, G., Khatri, P., Mellins, E. D. 2020

    View details for DOI 10.1136/annrheumdis-2020-217000

    View details for PubMedID 32054603

  • Multiplex Serum Analysis Identifies Potential Biomarkers of Systemic Juvenile Idiopathic Arthritis, Macrophage Activation Syndrome, and Associated Pulmonary Alveolar Proteinosis: Evidence for Independently-regulated Hyperinflammatory and Eosinophilic Inflammation Chen, G., Schulert, G., De Jesus, A., Saper, V., Schneider, C., Trapnell, B., Grom, A. A., Goldbach-Mansky, R., Mellins, E., Khatri, P., Canna, S. WILEY. 2019
  • Emergent high fatality lung disease in systemic juvenile arthritis. Annals of the rheumatic diseases Saper, V. E., Chen, G., Deutsch, G. H., Guillerman, R. P., Birgmeier, J., Jagadeesh, K., Canna, S., Schulert, G., Deterding, R., Xu, J., Leung, A. N., Bouzoubaa, L., Abulaban, K., Baszis, K., Behrens, E. M., Birmingham, J., Casey, A., Cidon, M., Cron, R. Q., De, A., De Benedetti, F., Ferguson, I., Fishman, M. P., Goodman, S. I., Graham, T. B., Grom, A. A., Haines, K., Hazen, M., Henderson, L. A., Ho, A., Ibarra, M., Inman, C. J., Jerath, R., Khawaja, K., Kingsbury, D. J., Klein-Gitelman, M., Lai, K., Lapidus, S., Lin, C., Lin, J., Liptzin, D. R., Milojevic, D., Mombourquette, J., Onel, K., Ozen, S., Perez, M., Phillippi, K., Prahalad, S., Radhakrishna, S., Reinhardt, A., Riskalla, M., Rosenwasser, N., Roth, J., Schneider, R., Schonenberg-Meinema, D., Shenoi, S., Smith, J. A., Sönmez, H. E., Stoll, M. L., Towe, C., Vargas, S. O., Vehe, R. K., Young, L. R., Yang, J., Desai, T., Balise, R., Lu, Y., Tian, L., Bejerano, G., Davis, M. M., Khatri, P., Mellins, E. D. 2019

    Abstract

    To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

    View details for DOI 10.1136/annrheumdis-2019-216040

    View details for PubMedID 31562126

  • The 14th International Workshops on Opportunistic Protists (IWOP 14) Cushion, M. T., Limper, A. H., Porollo, A., Saper, V. E., Sinai, A. P., Weiss, L. M. WILEY. 2018: 934–39

    View details for DOI 10.1111/jeu.12631

    View details for Web of Science ID 000451783600018

  • The 14th International Workshops on Opportunistic Protists (IWOP 14). The Journal of eukaryotic microbiology Cushion, M. T., Limper, A. H., Porollo, A., Saper, V. E., Sinai, A. P., Weiss, L. M. 2018

    Abstract

    The 14th International Workshops on Opportunistic Protists (IWOP-14) was held August 10-12, 2017 in Cincinnati, OH, USA. The IWOP meetings focus on opportunistic protists (OIs); for example, free-living amoebae, Pneumocystis spp., Cryptosporidium spp., Toxoplasma, the Microsporidia, and kinetoplastid flagellates. The highlights of Pneumocystis spp. research included the reports of primary homothallism for mating; a potential requirement for sexual replication in its life cycle; a new antigen on the surface of small asci; roles for CLRs, Dectin-1, and Mincle in host responses; and identification of MSG families and mechanisms used for surface variation. Studies of Cryptosporidia spp. included comparative genomics, a new cryopreservation method; the role of mucin in attachment and invasion, and epidemiological surveys illustrating species diversity in animals. One of the five identified proteins in the polar tube of Microsporidia, PTP4, was shown to play a role in host infection. Zebrafish were used as a low cost vertebrate animal model for an evaluation of potential anti-toxoplasma drugs. Folk medicine compounds with anti-toxoplasma activity were presented, and reports on the chronic toxoplasma infection provided evidence for increased tractability for the study of this difficult life cycle stage. Escape from the parasitophorus vacuole and cell cycle regulation were the topics of the study in the acute phase.

    View details for PubMedID 29722096

  • Altered signaling in systemic juvenile idiopathic arthritis monocytes CLINICAL IMMUNOLOGY Macaubas, C., Wong, E., Zhang, Y., Nguyen, K. D., Lee, J., Milojevic, D., Shenoi, S., Stevens, A. M., Ilowite, N., Saper, V., Lee, T., Mellins, E. D. 2016; 163: 66-74

    Abstract

    Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNα) and type II (IFNγ) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002 and 2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011 and 2014), monocytes of patients with recent disease onset were IFNγ hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNγ. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology.

    View details for DOI 10.1016/j.clim.2015.12.011

    View details for Web of Science ID 000370585600010

    View details for PubMedID 26747737

  • CLINICAL AND IMMUNOLOGICAL STUDIES OF CADAVERIC RENAL-TRANSPLANT RECIPIENTS GIVEN TOTAL-LYMPHOID IRRADIATION AND MAINTAINED ON LOW-DOSE PREDNISONE TRANSPLANTATION Saper, V., Chow, D., ENGLEMAN, E. D., Hoppe, R. T., Levin, B., Collins, G., Strober, S. 1988; 45 (3): 540-546

    Abstract

    Twenty-five recipients of cadaveric renal transplants were given total lymphoid irradiation (TLI), perioperative antithymocyte globulin, and low-dose prednisone as the sole maintenance immunosuppressive drug. Nine patients were diabetic, and follow-up was between 19 and 37 months. One-year graft and patient survival was 76% and 87%, respectively, Serious complications included four deaths from cardiovascular disorders, and two deaths from viral infections. Studies of peripheral blood T cell subsets showed a prolonged reduction in the absolute number of helper (Leu-3+) cells, and a rapid recovery of cytotoxic/suppressor (Leu-2+) cells. Analysis of the latter subset, using the monoclonal antibody 9.3, showed that the ratio of suppressor/cytotoxic cells was approximately 10:1. The normal ratio is 1:1. The mean mixed leukocyte reaction remained below 30% of the pre-TLI value for 6 months, and approached 80% at two years. Similar kinetics were observed in the proliferative response to mitogens. The results show that maintenance immunosuppressive drug therapy can be reduced after TLI as compared with conventional drug regimens that use prednisone in combination with cyclosporine and/or azathioprine.

    View details for Web of Science ID A1988M597000008

    View details for PubMedID 3279577

  • RENAL-TRANSPLANT PATIENTS TREATED WITH TOTAL LYMPHOID IRRADIATION SHOW SPECIFIC UNRESPONSIVENESS TO DONOR ANTIGENS IN THE MIXED LEUKOCYTE REACTION (MLR) JOURNAL OF IMMUNOLOGY Chow, D., Saper, V., Strober, S. 1987; 138 (11): 3746-3750

    Abstract

    A group of 25 cadaveric renal transplant recipients received total lymphoid irradiation (TLI) before transplantation, rabbit anti-thymocyte globulin on alternate days for 10 days after transplantation, and low dose prednisone (5 to 10 mg/day) as the sole maintenance immunosuppressive therapy. Allograft function and the mixed leukocyte reaction (MLR) were monitored serially. After 18 to 30 mo, nine patients were selected on the basis of a return of the MLR such that the mean stimulation index to a panel of normal stimulator cells was greater than or equal to 5, a stable serum creatinine level which was less than or equal to 2 mg/dl, and a history of no more than one rejection episode. The MLR of these patients' post-transplant peripheral blood mononuclear leukocytes (PBML) against cryopreserved donor cells was compared with that against cryopreserved normal third-party cells. In control experiments, the MLR of cryopreserved pre-TLI recipient PBML or fresh normal PBML were tested against the same panel of donor and third-party stimulator cells. Seven of the nine recipients showed a pattern of specific unresponsiveness to the donor cells more than 18 mo after transplantation. Preliminary attempts to identify antigen specific suppressor cells were unsuccessful. The pattern of unresponsiveness may indicate a state of specific immune tolerance to the allogeneic graft.

    View details for Web of Science ID A1987H389200028

    View details for PubMedID 2953791

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