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1. Patient-reported preferences for subcutaneous or intravenous administration of parenteral drug treatments in adults with immune disorders: a systematic review and meta-analysis

Author

Vera Bril, Johannes Lampe, Nichola Cooper, Peter Kiessling, and Ann Gardulf

Subjects
administration route, intravenous, meta-analysis, patient preference, quality of life, subcutaneous, systematic literature review, treatment satisfaction, Public aspects of medicine, RA1-1270
Abstract

Aim: Several studies have found subcutaneous (SC) and intravenous (IV) administration of similar drugs for long-lasting immunological and autoimmune diseases to have similar clinical effectiveness, meaning that what patients report they prefer is, or should be, a major factor in treatment choices. Therefore, it is important to systematically compile evidence regarding patient preferences, treatment satisfaction and health-related quality of life (HRQL) using SC or IV administration of the same drug. Materials & methods: PubMed database searches were run on 15 October 2021. Studies involving patients with experience of both home-based SC and hospital-based IV administration of immunoglobulins or biological therapies for the treatment of any autoimmune disease or primary immunodeficiencies (PIDs) were included. The outcomes assessed were patient preferences, treatment satisfaction and HRQL. Preference data were meta-analyzed using a random-effects model. Results: In total, 3504 citations were screened, and 46 publications describing 37 studies were included in the review. There was a strong overall preference for SC over IV administration, with similar results seen for PIDs and autoimmune diseases: PID, 80% (95% confidence interval [CI], 64–94%) preferred SC; autoimmune diseases, 83% (95% CI: 73–92%); overall, 82% (95% CI: 75–89%). The meta-analysis also found that 84% (95% CI: 75–92%) of patients preferred administration at home to treatment in hospital. Analysis of treatment satisfaction using the life quality index found consistently better treatment interference and treatment setting scores with SC administration than with IV administration. Conclusion: Compared with IV infusions in hospital, patients tend to prefer, to be more satisfied with and to report better HRQL with SC administration of the same drug at home, primarily due to the greater convenience. This study contributes to evidence-based care of patients with autoimmune diseases or PIDs.

Published
2024
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2. Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19

Author

Allison K. Maher, Katie L. Burnham, Emma M. Jones, Michelle M. H. Tan, Rocel C. Saputil, Laury Baillon, Claudia Selck, Nicolas Giang, Rafael Argüello, Clio Pillay, Emma Thorley, Charlotte-Eve Short, Rachael Quinlan, Wendy S. Barclay, Nichola Cooper, Graham P. Taylor, Emma E. Davenport, and Margarita Dominguez-Villar

Subjects
Science
Abstract

Although myeloid cell dysfunction has been observed in COVID-19, the underlying mechanisms remain incompletely understood. Here, the authors demonstrate that monocytes from patients with mild to moderate COVID-19 show a blunted innate immune response and a pro-thrombotic signature following secondary SARS-CoV-2 challenge.

Published
2022
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3. Rilzabrutinib placebo in adults and adolescents with persistent or chronic immune thrombocytopenia: LUNA 3 phase III study

Author

David J. Kuter, James B. Bussel, Waleed Ghanima, Nichola Cooper, Terry Gernsheimer, Michele P. Lambert, Howard A. Liebman, Michael D. Tarantino, Michelle Lee, Hailing Guo, and Ahmed Daak

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background: Immune thrombocytopenia (ITP) is characterized by primarily autoantibody-mediated platelet destruction and impaired platelet production resulting in thrombocytopenia and an increased risk of bleeding. Other manifestations include increased risk of thrombosis and diminished quality of life. Current treatment approaches are directed toward lowering the rate of platelet destruction or stimulating platelet production to prevent bleeding. Rilzabrutinib is an oral, reversible, potent Bruton tyrosine kinase inhibitor that was specifically designed to treat immune-mediated diseases and mediates its therapeutic effect through a dual mechanism of action: (1) inhibiting B-cell activation and (2) interrupting antibody-coated cell phagocytosis by Fc gamma receptor in spleen and liver. A 24-week dose-finding phase I/II study of rilzabrutinib in patients with ITP showed a 40% platelet response (⩾2 consecutive platelet counts of ⩾50 × 10 9 /L and increase from baseline ⩾20 × 10 9 /L without rescue medication use) and a well-tolerated safety profile with only grade 1/2 transient adverse events across dose levels. Objectives: Assess the efficacy and safety of oral rilzabrutinib in adult and adolescent patients with persistent or chronic ITP. Design: Rilzabrutinib 400 mg BID is being evaluated in the ongoing LUNA 3 multicenter, double-blind, placebo-controlled phase III study. Methods and analysis: The primary endpoint is durable platelet response, defined as achieving platelet counts of ⩾50 × 10 9 /L for at least two-thirds of ⩾8 available weekly scheduled platelet measurements during the last 12 weeks (including ⩾2 available measurements within the last 6 weeks) of the 24-week blinded treatment period in the absence of rescue therapy. Ethics: Ethical guidelines and informed consent are followed. Discussion: The LUNA 3 trial will further investigate rilzabrutinib’s safety and efficacy in adult and adolescent patients, with the primary goal of addressing a major objective in treating patients with ITP: durability of platelet response. Trail Registration: ClinicalTrials.gov NCT04562766: https://clinicaltrials.gov/ct2/show/NCT04562766 ; EU Clinical Trials Register EudraCT 2020-002063-60: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-002063-60 .

Published
2023
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4. Third primary SARS-CoV-2 mRNA vaccines enhance antibody responses in most patients with haematological malignancies

Author

Lucy B. Cook, Gillian O’Dell, Eleni Vourvou, Renuka Palanicawandar, Sasha Marks, Dragana Milojkovic, Jane F. Apperley, Sandra Loaiza, Simone Claudiani, Marco Bua, Catherine Hockings, Donald Macdonald, Aris Chaidos, Jiri Pavlu, Nichola Cooper, Sarah Fidler, Paul Randell, and Andrew J. Innes

Subjects
Science
Abstract

SARS-CoV-2 vaccination has shown reduced efficacy in patients with haematological malignancies. Here, the authors show that a third vaccine is able to enhance SARS-CoV-2 antibody responses in most cases in a cohort of 381 patients with haematological malignancies.

Published
2022
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6. PB2625: VAYHIT2: A RANDOMIZED, DOUBLE-BLIND, PHASE III TRIAL OF IANALUMAB VS PLACEBO IN ADDITION TO ELTROMBOPAG IN PATIENTS WITH PRIMARY IMMUNE THROMBOCYTOPENIA (ITP) WHO FAILED FIRST-LINE STEROID TREATMENT

Author

Francesco Zaja, Hanny Al-Samkari, Marc Michel, Waleed Ghanima, Nichola Cooper, Raymond Wong, Wilma Barcellini, Fengkui Zhang, Emerenziana Marturano, Severine Peyrard, and Adam Cuker

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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7. P1589: PATIENT (PT) AND PHYSICIAN (MD) PERCEPTIONS OF THE BURDEN OF IMMUNE THROMBOCYTOPENIA (ITP) AND ITS MANAGEMENT: RESULTS FROM THE ITP WORLD IMPACT SURVEY (I-WISH) 2.0

Author

Nichola Cooper, Caroline Kruse, Waleed Ghanima, Drew Provan, Yoshiaka Tomiyama, Ming Hou, Donald Arnold, Cristina Santoro, Francesco Zaja, Barbara Lovrencic, Mervyn Morgan, Leron Lahav, Michal Winograd, Tom Bailey, Jens Haenig, Mahnouch Georget, and James Bussel

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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8. PB2552: VAYHIA: A RANDOMIZED, DOUBLE-BLIND, PHASE III TRIAL TO ASSESS THE EFFICACY AND SAFETY OF IANALUMAB VS PLACEBO IN PATIENTS WITH WARM AUTOIMMUNE HEMOLYTIC ANEMIA THAT FAILED ≥1 LINE OF TREATMENT

Author

Wilma Barcellini, Marc Michel, Adam Cuker, Nichola Cooper, Waleed Ghanima, Raymond Wong, Francesco Zaja, Fengkui Zhang, Vladimir Bezlyak, Thu Thuy Nguyen, and Hanny Al-Samkari

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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11. European Delphi panel to build consensus on tapering and discontinuing thrombopoietin receptor agonists in immune thrombocytopenia

Author

Adele Barlassina, Tomás José González-López, Nichola Cooper, and Francesco Zaja

Subjects
expert consensus, immune thrombocytopenia, sustained response off treatment, thrombopoietin receptor agonists, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

To establish pan-European consensus on tapering and discontinuing thrombopoietin receptor agonists (TPO-RAs) in patients with immune thrombocytopenia (ITP), we applied a three-step Delphi technique consisting of a one-to-one interview round and two online survey rounds. Three healthcare professionals (HCPs) from Italy, Spain, and the United Kingdom formed the Steering Committee (SC), which advised on study design, panelist selection, and survey development. A literature review also informed the development of the consensus statements. Likert scales were used to collect quantitative data on panelists’ level of agreement. Twelve hematologists representing nine European countries assessed 121 statements spanning three categories: (1) patient selection; (2) tapering and discontinuation strategies; (3) post-discontinuation management. Consensus was reached on approximately half of the statements in each category (32.2%; 44.6%; 66%). Panelists agreed on patients’ main selection criteria, patients’ involvement in decision-making, tapering strategies, and follow-up criteria. Areas not reaching consensus were risk factors and predictors of successful discontinuation, monitoring intervals, and rates of successful discontinuation or relapse. This lack of consensus signals knowledge and practice gaps among European countries and suggests the need for the development of clinical practice guidelines that outline a pan-European, evidence-based approach to tapering and discontinuing TPO-RAs.

Published
2023
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12. Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib

Author

Nichola Cooper, Waleed Ghanima, Quentin A Hill, Phillip LR Nicolson, Vadim Markovtsov, and Craig Kessler

Subjects
cevidoplenib, entospletinib, fostamatinib, hmpl-523, spleen tyrosine kinase, syk, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors.

Published
2023
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13. Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial

Author

Nikhil Vergis, Rachel Phillips, Victoria Cornelius, Alexia Katsarou, Taryn Youngstein, Lucy Cook, Michelle Willicombe, Clio Pilay, Tina Shturova, Melanie Almonte, Asad Charania, Richard Turner, Onn Min Kon, Graham Cooke, Mark Thursz, Svetlana Cherlin, James Wason, Dragana Milojkovic, Andew J. Innes, and Nichola Cooper

Subjects
COVID-19, coronavirus, randomised controlled trial, protocol, pneumonia, fostamatinib, Medicine (General), R5-920
Abstract

Abstract Objectives The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. Trial design A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. Participants Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease CRP ≥ 30mg/L at any time point Informed consent from patient or personal or professional representative Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug. EXCLUSION: Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission but before baseline, not related to a pre-existing condition (e.g., obstructive sleep apnoea) Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, i.e. SpO2 < 90% on ≥ 60% inspired oxygen by facemask at baseline; non-invasive ventilation; or invasive mechanical ventilation In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy Known severe allergic reactions to the investigational agents Child-Pugh B or C grade hepatic dysfunction Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics Pregnant or breastfeeding Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects’ safety or compliance with study procedures. Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Non-English speakers will be able to join the study. If participants are unable to understand verbal or written information in English, then hospital translation services will be requested at the participating site for the participant where possible. Intervention and comparator RUXOLITINIB (RUX) (14 days): An oral selective and potent inhibitor of Janus Associated Kinases (JAK1 and JAK2) and cell proliferation (Verstovek, 2010). It is approved for the treatment of disease-related splenomegaly or constitutional symptoms in myelofibrosis, polycythaemia vera and graft-versus-host-disease. RUX will be administered orally 10mg bd Day 1-7 and 5mg bd Day 8-14. FOSTAMATINIB (FOS) (14 days): An oral spleen tyrosine kinase inhibitor approved for the treatment of thrombocytopenia in adult participants with chronic immune thrombocytopenia. FOS will be administered orally 150mg bd Day 1-7 and 100mg bd Day 8-14. Please see protocol for recommended dose modifications where required. COMPARATOR (Standard of Care, SOC): experimental arms will be compared to participants receiving standard of care. It is accepted that SOC may change during a rapidly evolving pandemic. Co-enrolment to other trials and rescue therapy, either pre- or post-randomisation, is permitted and will be accounted for in the statistical analysis. Main outcomes Pairwise comparison (RUX vs SOC and FOS vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a score ≥ 5 on a modified WHO COVID-19 Ordinal Scale, comprising the following indicators of disease severity: Death OR Requirement for invasive ventilation OR Requirement for non-invasive ventilation including CPAP or high flow oxygen OR O2 saturation < 90% on ≥60% inspired oxygen Randomisation Participants will be allocated to interventions using a central web-based randomisation service that generates random sequences using random permuted blocks (1:1:1), with stratification by age (

Published
2021
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14. Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA)

Author

Ivan O. Rosas, Norbert Bräu, Michael Waters, Ronaldo C. Go, Atul Malhotra, Bradley D. Hunter, Sanjay Bhagani, Daniel Skiest, Sinisa Savic, Ivor S. Douglas, Julia Garcia-Diaz, Mariam S. Aziz, Nichola Cooper, Taryn Youngstein, Lorenzo Del Sorbo, David J. De La Zerda, Andrew Ustianowski, Antonio Cubillo Gracian, Kevin G. Blyth, Jordi Carratalà, Bruno François, Thomas Benfield, Derrick Haslem, Paolo Bonfanti, Cor H. van der Leest, Nidhi Rohatgi, Lothar Wiese, Charles Edouard Luyt, Rebecca N. Bauer, Fang Cai, Ivan T. Lee, Balpreet Matharu, Louis Metcalf, Steffen Wildum, Emily Graham, Larry Tsai, and Min Bao

Subjects
Coronavirus disease 2019, Interleukin-6, Randomised controlled trial, Tocilizumab, Severe acute respiratory syndrome coronavirus-2, Viral load, Medicine (General), R5-920
Abstract

Summary: Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

Published
2022
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16. Distorted TCR repertoires define multisystem inflammatory syndrome in children.

Author

Amna Malik, Eszter N Tóth, Michelle S Teng, Jacob Hurst, Eleanor Watt, Lauren Wise, Natalie Kent, Jack Bartram, Louis Grandjean, Margarita Dominguez-Villar, Stuart Adams, and Nichola Cooper

Subjects
Medicine, Science
Abstract

While the majority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) display mild or no symptoms, rare individuals develop severe disease presenting with multisystem inflammatory syndrome (MIS-C). The reason for variable clinical manifestations is not understood. Here, we carried out TCR sequencing and conducted comparative analyses of TCR repertoires between children with MIS-C (n = 12) and mild (n = 8) COVID-19. We compared these repertoires with unexposed individuals (samples collected pre-COVID-19 pandemic: n = 8) and with the Adaptive Biotechnologies MIRA dataset, which includes over 135,000 high-confidence SARS-CoV-2-specific TCRs. We show that the repertoires of children with MIS-C are characterised by the expansion of TRBV11-2 chains with high junctional and CDR3 diversity. Moreover, the CDR3 sequences of TRBV11-2 clones shift away from SARS-CoV-2 specific T cell clones, resulting in distorted TCR repertoires. In conclusion, our study reports that CDR3-independent expansion of TRBV11-2+ cells, lacking SARS-CoV-2 specificity, defines MIS-C in children.

Published
2022
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17. American Society of Hematology 2019 guidelines for immune thrombocytopenia

Author

Cindy Neunert, Deirdra R. Terrell, Donald M. Arnold, George Buchanan, Douglas B. Cines, Nichola Cooper, Adam Cuker, Jenny M. Despotovic, James N. George, Rachael F. Grace, Thomas Kühne, David J. Kuter, Wendy Lim, Keith R. McCrae, Barbara Pruitt, Hayley Shimanek, and Sara K. Vesely

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Background: Despite an increase in the number of therapies available to treat patients with immune thrombocytopenia (ITP), there are minimal data from randomized trials to assist physicians with the management of patients.Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the management of ITP.Methods: In 2015, ASH formed a multidisciplinary guideline panel that included 8 adult clinical experts, 5 pediatric clinical experts, 2 methodologists with expertise in ITP, and 2 patient representatives. The panel was balanced to minimize potential bias from conflicts of interest. The panel reviewed the ASH 2011 guideline recommendations and prioritized questions. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence (up to May 2017) and formulate recommendations.Results: The panel agreed on 21 recommendations covering management of ITP in adults and children with newly diagnosed, persistent, and chronic disease refractory to first-line therapy who have non–life-threatening bleeding. Management approaches included: observation, corticosteroids, IV immunoglobulin, anti-D immunoglobulin, rituximab, splenectomy, and thrombopoietin receptor agonists.Conclusions: There was a lack of evidence to support strong recommendations for various management approaches. In general, strategies that avoided medication side effects were favored. A large focus was placed on shared decision-making, especially with regard to second-line therapy. Future research should apply standard corticosteroid-dosing regimens, report patient-reported outcomes, and include cost-analysis evaluations.

Published
2019
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18. Updated international consensus report on the investigation and management of primary immune thrombocytopenia

Author

Drew Provan, Donald M. Arnold, James B. Bussel, Beng H. Chong, Nichola Cooper, Terry Gernsheimer, Waleed Ghanima, Bertrand Godeau, Tomás José González-López, John Grainger, Ming Hou, Caroline Kruse, Vickie McDonald, Marc Michel, Adrian C. Newland, Sue Pavord, Francesco Rodeghiero, Marie Scully, Yoshiaki Tomiyama, Raymond S. Wong, Francesco Zaja, and David J. Kuter

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

Published
2019
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19. Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib

Author

Nichola Cooper, Ivy Altomare, Mark R. Thomas, Phillip L. R. Nicolson, Steve P. Watson, Vadim Markovtsov, Leslie K. Todd, Esteban Masuda, and James B. Bussel

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background: Patients with immune thrombocytopenia (ITP) are at risk of bleeding and, paradoxically, thromboembolic events (TEEs), irrespective of thrombocytopenia. The risk of thrombosis is increased by advanced age, obesity, and prothrombotic comorbidities: cancer, hyperlipidemia, diabetes, hypertension, coronary artery disease, and chronic kidney disease, among others. Certain ITP treatments further increase the risk of TEE, especially splenectomy and thrombopoietin receptor agonists. Spleen tyrosine kinase (SYK) is a key signaling molecule common to thromboembolic and hemostatic (in addition to inflammatory) pathways. Fostamatinib is an orally administered SYK inhibitor approved in the USA and Europe for treatment of chronic ITP in adults. Methods: The phase III and extension studies included heavily pretreated patients with long-standing ITP, many of whom had risk factors for thrombosis prior to initiating fostamatinib. This report describes long-term safety and efficacy of fostamatinib in 146 patients with up to 5 years of treatment, a total of 229 patient-years, and assesses the incidence of thromboembolic events (by standardized MedDRA query). Results: Platelet counts ⩾50,000/µL were achieved in 54% of patients and the safety profile was as described in the phase III clinical studies with no new toxicities observed over the 5 years of follow-up. The only TEE occurred in one patient (0.7%, or 0.44/100 patient-years), who experienced a mild transient ischemic attack. This is a much lower rate than might be expected in ITP patients. Conclusion: This report demonstrates durable efficacy and a very low incidence of TEE in patients receiving long-term treatment of ITP with the SYK inhibitor fostamatinib. ClinicalTrials.gov identifiers: NCT02076399, NCT02076412, and NCT02077192.

Published
2021
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21. Thrombopoietin receptor agonists: ten years later

Author

Waleed Ghanima, Nichola Cooper, Francesco Rodeghiero, Bertrand Godeau, and James B. Bussel

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

The two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, were licensed in the US for treatment of immune thrombocytopenia (ITP) in 2008 and, since then, their use has progressively increased around the world; they are currently used in more than 100 countries. The six largest randomized controlled trials conducted in ITP have used one of these two agents. All studies have demonstrated a platelet response rate between 50-90%, depending on the criteria used, with good safety and tolerability. TPO-RA were shown to be effective in reducing bleeding and the need for concomitant or rescue medication. Many other investigations of their mechanism of effect, prospective and retrospective trials, and studies focusing on toxicity have been performed widening our knowledge of these two agents. Initial concerns on issues such as myelofibrosis have not been confirmed. Only a small number of patients develop moderate-severe reticulin fibrosis and/or collagen fibrosis; however, these are usually reversed after discontinuation of TPO-RA. Studies indicate, however, that TPO-RA may increase the risk of venous thromboembolism. Both TPO-RA are currently approved in patients with chronic ITP aged >1-year who are refractory to at least one other treatment. Eltrombopag has acquired two additional indications: severe aplastic anemia refractory to first-line treatment and hepatitis C patients undergoing treatment with interferon-ribavirin. Despite these wide-ranging studies, important questions still need to be answered. This summary review on TPO-RA will summarize what is known regarding efficacy in ITP, evaluate safety concerns in more depth, and focus on the questions that remain.

Published
2019
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22. Immune Thrombocytopenia (ITP): Current Limitations in Patient Management

Author

Deirdra R. Terrell, Cindy E. Neunert, Nichola Cooper, Katja M. Heitink-Pollé, Caroline Kruse, Paul Imbach, Thomas Kühne, and Waleed Ghanima

Subjects
immune thrombocytopenia (ITP), quality of life, treatment, refractory, Medicine (General), R5-920
Abstract

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia caused by increased platelet destruction and impaired platelet production. First-line therapies include corticosteroids, intravenous immunoglobulin, and anti-D immunoglobulin. For patients who are refractory to these therapies, those who become corticosteroid dependent, or relapse following treatment with corticosteroid, options include splenectomy, rituximab, and thrombopoietin-receptor agonists, alongside a variety of additional immunosuppressive and experimental therapies. Despite recent advances in the management of ITP, many areas need further research. Although it is recognized that an assessment of patient-reported outcomes in ITP is valuable to understand and guide treatment, these measures are not routinely measured in the clinical setting. Consequently, although corticosteroids are first-line therapies for both children and adults, there are no data to suggest that corticosteroids improve health-related quality of life or other patient-related outcomes in either children or adults. In fact, long courses of corticosteroids, in either children or adults, may have a negative impact on a patient’s health-related quality of life, secondary to the impact on sleep disturbance, weight gain, and mental health. In adults, additional therapies may be needed to treat overt hemorrhage, but unfortunately the results are transient for the majority of patients. Therefore, there is a need to recognize the limitations of current existing therapies and evaluate new approaches, such as individualized treatment based on the probability of response and the size of effect on the patient’s most bothersome symptoms and risk of adverse effects or complications. Finally, a validated screening tool that identifies clinically significant patient-reported outcomes in routine clinical practice would help both patients and physicians to effectively follow a patient’s health beyond simply treating the laboratory findings and physical symptoms of ITP. The goal of this narrative review is to discuss management of newly diagnosed and refractory patients with ITP, with a focus on the limitations of current therapies from the patient’s perspective.

Published
2020
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23. Evidence for B Cell Exhaustion in Chronic Graft-versus-Host Disease

Author

Ahmad Khoder, Abdullah Alsuliman, Rafet Basar, Catherine Sobieski, Kayo Kondo, Amin Majid Alousi, Richard Szydlo, Muharrem Muftuoglu, Hila Shaim, Jane F. Apperley, Elif Gokdemir, Nichola Cooper, Rohtesh S. Mehta, David Marin, Richard Champlin, Elizabeth Shpall, and Katayoun Rezvani

Subjects
chronic graft-versus-host disease, CD19+CD21−CD27−CD10− cells, exhausted B cells, stem cell transplantation, CD21– B cells correlate with cGVHD severity, Immunologic diseases. Allergy, RC581-607
Abstract

Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). A number of studies support a role for B cells in the pathogenesis of cGvHD. In this study, we report the presence of an expanded population of CD19+CD21− B cells with features of exhaustion in the peripheral blood of patients with cGvHD. CD21− B cells were significantly increased in patients with active cGvHD compared to patients without cGvHD and healthy controls (median 12.2 versus 2.12 versus 3%, respectively; p

Published
2018
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24. Eltrombopag – a novel approach for the treatment of chronic immune thrombocytopenic purpura: review and safety considerations

Author

Lucy Cook and Nichola Cooper

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Lucy Cook, Nichola CooperDepartment of Haematology, Imperial Health Care NHS Trust, Hammersmith Hospital, London, UKAbstract: Eltrombopag is one of a number of novel agents recently developed for use in the treatment of patients with immune thrombocytopenia (ITP). Rather than preventing destruction of platelets, these agents increase the production of platelets, presumably overwhelming the immune system resulting in normal platelet counts in individuals refractory to or dependent on other therapies. These treatments are well tolerated and in randomized controlled trials show an improvement in platelet counts and a reduction in bleeding in refractory patients. This article summarizes the development of this new class of drug and evaluates the safety and efficacy of eltrombopag in patients with ITP.Keywords: eltrombopag, immune thrombocytopenic purpura, thrombopoietin

Published
2010

25. Natural Killer Cells Improve Hematopoietic Stem Cell Engraftment by Increasing Stem Cell Clonogenicity In Vitro and in a Humanized Mouse Model.

Author

Michelle Escobedo-Cousin, Nicola Jackson, Raquel Laza-Briviesca, Linda Ariza-McNaughton, Martha Luevano, Sophie Derniame, Sergio Querol, Michael Blundell, Adrian Thrasher, Bernat Soria, Nichola Cooper, Dominique Bonnet, Alejandro Madrigal, and Aurore Saudemont

Subjects
Medicine, Science
Abstract

Cord blood (CB) is increasingly used as a source of hematopoietic stem cells (HSC) for transplantation. Low incidence and severity of graft-versus-host disease (GvHD) and a robust graft-versus-leukemia (GvL) effect are observed following CB transplantation (CBT). However, its main disadvantages are a limited number of HSC per unit, delayed immune reconstitution and a higher incidence of infection. Unmanipulated grafts contain accessory cells that may facilitate HSC engraftment. Therefore, the effects of accessory cells, particularly natural killer (NK) cells, on human CB HSC (CBSC) functions were assessed in vitro and in vivo. CBSC cultured with autologous CB NK cells showed higher levels of CXCR4 expression, a higher migration index and a higher number of colony forming units (CFU) after short-term and long-term cultures. We found that CBSC secreted CXCL9 following interaction with CB NK cells. In addition, recombinant CXCL9 increased CBSC clonogenicity, recapitulating the effect observed of CB NK cells on CBSC. Moreover, the co-infusion of CBSC with CB NK cells led to a higher level of CBSC engraftment in NSG mouse model. The results presented in this work offer the basis for an alternative approach to enhance HSC engraftment that could improve the outcome of CBT.

Published
2015
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26. Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host

Author

Hugues de Lavallade, Paula Garland, Takuya Sekine, Katja Hoschler, David Marin, Kate Stringaris, Eva Loucaides, Katherine Howe, Richard Szydlo, Ed Kanfer, Donald Macdonald, Peter Kelleher, Nichola Cooper, Ahmad Khoder, Ian H. Gabriel, Dragana Milojkovic, Jiri Pavlu, John M. Goldman, Jane F. Apperley, and Katayoun Rezvani

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background In 2009 the declaration by the World Health Organization of a global pandemic of influenza-H1N1 virus led to a vaccination campaign to ensure protection for immunocompromised patients. The goal of this study was to determine the efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies.Design and Methods We evaluated humoral and cellular immune responses to 2009 H1N1 vaccine in 97 adults with hematologic malignancies and compared these responses with those in 25 adult controls. Patients received two injections of vaccine 21 days apart and the controls received one dose. Antibody titers were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. Cellular immune responses to H1N1 were determined on days 0 and 49.Results By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (P

Published
2011
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27. Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia

Author

David J. Kuter, Merlin Efraim, Jiri Mayer, Marek Trněný, Vickie McDonald, Robert Bird, Thomas Regenbogen, Mamta Garg, Zane Kaplan, Nikolay Tzvetkov, Philip Y. Choi, A.J. Gerard Jansen, Milan Kostal, Ross Baker, Jaromir Gumulec, Eun-Ju Lee, Ilona Cunningham, Isaac Goncalves, Margaret Warner, Ralph Boccia, Terry Gernsheimer, Waleed Ghanima, Olga Bandman, Regan Burns, Ann Neale, Dolca Thomas, Puneet Arora, Beiyao Zheng, Nichola Cooper, and Hematology

Subjects
Purpura, Thrombocytopenic, Idiopathic, Treatment Outcome, Platelet Count, Agammaglobulinaemia Tyrosine Kinase, Administration, Oral, Humans, General Medicine, Protein Kinase Inhibitors
Abstract

BACKGROUND Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment.

Published
2022
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28. Iron status influences the response of cord blood megakaryocyte progenitors to eltrombopag in vitro

Author

James B. Bussel, Henry A. Feldman, Haley E. Ramsey, E Vlachodimtropoulou Koumoutsea, Emoke Deschmann, Bethan Psaila, Nichola Cooper, Michael K. Georgieff, Liu Z-J., Martha Sola-Visner, and John B. Porter

Subjects
medicine.medical_specialty, Iron, Eltrombopag, Stimulation, Benzoates, chemistry.chemical_compound, Megakaryocyte, Internal medicine, medicine, Progenitor cell, Thrombopoietin, Megakaryopoiesis, Megakaryocyte Progenitor Cells, Chemistry, Cell Differentiation, Hematology, Iron deficiency, medicine.disease, Platelets and Thrombopoiesis, Fetal Blood, Endocrinology, medicine.anatomical_structure, Hydrazines, Apoptosis, Pyrazoles
Abstract

Key Points High concentrations of eltrombopag suppress cord blood MK differentiation and proliferation in vitro.These effects are mediated by the iron-chelating effects of eltrombopag and are modulated by the iron status of the MK progenitors., Visual Abstract, Eltrombopag (ELT) is a thrombopoietic agent approved for immune thrombocytopenia and also a potent iron chelator. Here we found that ELT exhibited dose-dependent opposing effects on in vitro megakaryopoiesis: low concentrations (≤6 µM, ELT6) stimulated megakaryopoiesis, but high concentrations (30 µM, ELT30) suppressed megakaryocyte (MK) differentiation and proliferation. The suppressive effects of ELT30 were reproduced by other iron chelators, supporting iron chelation as a likely mechanism. During MK differentiation, committed MK progenitors (CD34+/CD41+ and CD34−/CD41+ cells) were significantly more sensitive than undifferentiated progenitors (CD34+/CD41− cells) to the suppressive effects of ELT30, which resulted from both decreased proliferation and increased apoptosis. The antiproliferative effects of ELT30 were reversed by increased iron in the culture, as were the proapoptotic effects when exposure to ELT30 was short. Because committed MK progenitors exhibited the highest proliferative rate and the highest sensitivity to iron chelation, we tested whether their iron status influenced their response to ELT during rapid cell expansion. In these studies, iron deficiency reduced the proliferation of CD41+ cells in response to all ELT concentrations. Severe iron deficiency also reduced the number of MKs generated in response to high thrombopoietin concentrations by ∼50%, compared with iron-replete cultures. Our findings support the hypothesis that although iron deficiency can stimulate certain cells and steps in megakaryopoiesis, it can also limit the proliferation of committed MK progenitors, with severity of iron deficiency and degree of thrombopoietic stimulation influencing the ultimate output. Further studies are needed to clarify how megakaryopoiesis, iron deficiency, and ELT stimulation are clinically interrelated.

Published
2021

29. Autocrine Vitamin D-signaling switches off pro-inflammatory programs of Th1 cells

Author

Alexandra F. Freeman, Majid Kazemian, Jack A. Bibby, Daniel Chauss, Daniel S. Chertow, Michail S. Lionakis, Reuben McGregor, Tilo Freiwald, Nehal N. Mehta, Heather L. Teague, Luopin Wang, Audrey Kelly, Behdad Afzali, Estefania Nova-Lamperti, Kevin M. Vannella, Amna Malik, Daniella M. Schwartz, Bingyu Yan, Claudia Kemper, Didier Portilla, Giovanna Lombardi, Marcos J Ramos-Benitez, Susan D. John, Nichola Cooper, Arian Laurence, Paul Lavender, Erin E. West, Zonghao Zhang, and Dhaneshwar Kumar

Subjects
T-Lymphocytes, Immunology, Cell, Complement, BACH2, Article, STAT3, 03 medical and health sciences, 0302 clinical medicine, Vitamin D and neurology, medicine, Immunology and Allergy, Humans, Epigenetics, Vitamin D, Receptor, Autocrine signalling, Transcription factor, 030304 developmental biology, Inflammation, 0303 health sciences, biology, Chemistry, c-JUN, COVID-19, Cell biology, single cell RNA-sequencing, medicine.anatomical_structure, 030220 oncology & carcinogenesis, SARS-CoV2, biology.protein, Homeostasis
Abstract

The molecular mechanisms governing orderly shutdown and retraction of CD4+ type 1 helper T (TH1) cell responses remain poorly understood. Here we show that complement triggers contraction of TH1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ+ TH1 cells to suppressive interleukin-10+ cells. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4+ T cells of patients with COVID-19 were TH1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system. During homeostasis TH1 cells activate a cell-intrinsic inflammatory shutdown program and shift to IL-10 production. Chauss et al. find that this TH1 homeostatic program is dependent on vitamin D signaling and is disrupted in severe COVID-19.

Published
2021

30. A Review of Romiplostim Mechanism of Action and Clinical Applicability

Author

Adriana Balduzzi, Gerald A. Soff, James B. Bussel, Tatiana Lawrence, Nichola Cooper, John W. Semple, Bussel, J, Soff, G, Balduzzi, A, Cooper, N, Lawrence, T, and Semple, J

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Recombinant Fusion Proteins, Pharmacokinetic, Pharmaceutical Science, Review, Receptors, Fc, thrombopoietin receptor agonist, 03 medical and health sciences, 0302 clinical medicine, Megakaryocyte, Internal medicine, hemic and lymphatic diseases, Drug Discovery, medicine, pharmacodynamics, media_common.cataloged_instance, Humans, structure, European union, Aplastic anemia, Thrombopoietin, media_common, Pharmacology, Chemotherapy, Clinical Trials as Topic, Purpura, Thrombocytopenic, Idiopathic, Pharmacodynamic, Hematology, Romiplostim, business.industry, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, immune thrombocytopenia, 030220 oncology & carcinogenesis, Immunology, Bone marrow, business, pharmacokinetics, medicine.drug
Abstract

Thrombocytopenia results from a variety of conditions, including radiation, chemotherapy, autoimmune disease, bone marrow disorders, pathologic conditions associated with surgical procedures, hematopoietic stem cell transplant (HSCT), and hematologic disorders associated with severe aplastic anemia. Immune thrombocytopenia (ITP) is caused by immune reactions that accelerate destruction and reduce production of platelets. Thrombopoietin (TPO) is a critical component of platelet production pathways, and TPO receptor agonists (TPO-RAs) are important for the management of ITP by increasing platelet production and reducing the need for other treatments. Romiplostim is a TPO-RA approved for use in patients with ITP in the United States, European Union, Australia, and several countries in Africa and Asia, as well as for use in patients with refractory aplastic anemia in Japan and Korea. Romiplostim binds to and activates the TPO receptor on megakaryocyte precursors, thus promoting cell proliferation and viability, resulting in increased platelet production. Through this mechanism, romiplostim reduces the need for other treatments and decreases bleeding events in patients with thrombocytopenia. In addition to its efficacy in ITP, studies have shown that romiplostim is effective in improving platelet counts in various settings, thereby highlighting the versatility of romiplostim. The efficacy of romiplostim in such disorders is currently under investigation. Here, we review the structure, mechanism, pharmacokinetics, and pharmacodynamics of romiplostim. We also summarize the clinical evidence supporting its use in ITP and other disorders that involve thrombocytopenia, including chemotherapy-induced thrombocytopenia, aplastic anemia, acute radiation syndrome, perisurgical thrombocytopenia, post-HSCT thrombocytopenia, and liver disease.

Published
2021

31. Fostamatinib is an effective second‐line therapy in patients with immune thrombocytopenia

Author

James B. Bussel, Quentin A. Hill, Michelle Sholzberg, Nichola Cooper, Michael D. Tarantino, Sandra Tong, Leslie Todd, Ralph V. Boccia, Michael Boxer, and Waleed Ghanima

Subjects
Adult, Male, medicine.medical_specialty, Pyridines, Morpholines, Short Report, Aminopyridines, Fostamatinib, Gastroenterology, 03 medical and health sciences, spleen tyrosine kinase, 0302 clinical medicine, Short Reports, Internal medicine, Oxazines, Post-hoc analysis, medicine, Humans, SYK, Platelet, In patient, Aged, Aged, 80 and over, platelet, Purpura, Thrombocytopenic, Idiopathic, Second-line therapy, biology, Platelet Count, business.industry, autoimmune, Hematology, Middle Aged, Immune thrombocytopenia, Safety profile, Pyrimidines, idiopathic thrombocytopenic purpura, 030220 oncology & carcinogenesis, biology.protein, Female, Antibody, business, 030215 immunology, medicine.drug, Platelets Haemostasis and Thrombosis
Abstract

Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received fostamatinib as second‐line therapy (after steroids ± immunoglobulins) versus third‐or‐later‐line therapy (after ≥2 prior lines of therapy including a second‐line agent). Platelet responses ≥50 000/µl were observed in 25/32 (78%) second‐line and 54/113 (48%) third‐or‐later‐line patients. Bleeding events were less frequent in second‐line (28%) versus third‐or‐later‐line (45%) patients. Responses once achieved tended to be durable in both groups. The safety profile was similar in both groups. In this post hoc analysis, fostamatinib was more effective as second‐line than third‐or‐later‐line therapy for ITP.

Published
2020

32. Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets

Author

Neline Kriek, Willianne Hoepel, Jonathan M. Gibbins, Tanya Sage, Marit J. van Gils, Joanne L. Mitchell, Sophie M. Jegouic, Jeroen den Dunnen, Steven W. de Taeye, Silvia Loureiro, Ian M. Jones, Nichola Cooper, Jan Nouta, Manfred Wuhrer, Alexander P. Bye, Gestur Vidarsson, Clinical Immunology and Rheumatology, AII - Inflammatory diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Landsteiner Laboratory, Medical Microbiology and Infection Prevention, and Infectious diseases

Subjects
Glycosylation, Immunology, Syk, Fostamatinib, medicine.disease_cause, Biochemistry, Viral/blood, Immunoglobulin G, Antibodies, SARS-CoV-2/immunology, P2Y12, Antibodies, Viral/blood, Von Willebrand factor, Antigen-Antibody Complex/immunology, Spike Glycoprotein, Coronavirus/metabolism, medicine, Humans, Thrombosis/immunology, Hypoglycemic Agents, Insulin, Platelet, Platelet activation, Platelet Activation/immunology, Blood Platelets/immunology, Immunoglobulin G/immunology, Coronavirus, biology, business.industry, Coronavirus/metabolism, Regular Article, Cell Biology, Hematology, Spike Glycoprotein, von Willebrand Factor/genetics, biology.protein, COVID-19/complications, business, Sugars, medicine.drug
Abstract

A subset of patients with coronavirus disease 2019 (COVID-19) become critically ill, suffering from severe respiratory problems and also increased rates of thrombosis. The causes of thrombosis in severely ill patients with COVID-19 are still emerging, but the coincidence of critical illness with the timing of the onset of adaptive immunity could implicate an excessive immune response. We hypothesized that platelets might be susceptible to activation by anti–severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies and might contribute to thrombosis. We found that immune complexes containing recombinant SARS-CoV-2 spike protein and anti-spike immunoglobulin G enhanced platelet-mediated thrombosis on von Willebrand factor in vitro, but only when the glycosylation state of the Fc domain was modified to correspond with the aberrant glycosylation previously identified in patients with severe COVID-19. Furthermore, we found that activation was dependent on FcγRIIA, and we provide in vitro evidence that this pathogenic platelet activation can be counteracted by the therapeutic small molecules R406 (fostamatinib) and ibrutinib, which inhibit tyrosine kinases Syk and Btk, respectively, or by the P2Y12 antagonist cangrelor.

Published
2021
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33. Tapering and Discontinuation of Thrombopoietin Receptor Agonist Therapy in Patients With Immune Thrombocytopenia:Results From a Modified Delphi Panel

Author

Nicholas Ramscar, John-Paul Westwood, Drew Provan, Charlotte Bradbury, Jecko Thachil, Nichola Cooper, Quentin A. Hill, Anuja Roy, and John D. Grainger

Subjects
Agonist, Pediatrics, medicine.medical_specialty, medicine.drug_class, Recombinant Fusion Proteins, Eltrombopag, Tapering, Receptors, Fc, Benzoates, Medication Adherence, chemistry.chemical_compound, Recurrence, Physicians, Surveys and Questionnaires, Humans, Medicine, In patient, Thrombopoietin receptor, Purpura, Thrombocytopenic, Idiopathic, Original Paper, Romiplostim, Platelet Count, business.industry, Remission Induction, Hematology, General Medicine, romiplostim, Immune thrombocytopenia, Discontinuation, treatment discontinuation, Hydrazines, Thrombopoietin, chemistry, immune thrombocytopenia, Retreatment, Pyrazoles, thrombopoietin receptor agonists, Self Report, business, eltrombopag, Receptors, Thrombopoietin, medicine.drug
Abstract

Background: Recent evidence suggests that in patients with immune thrombocytopenia (ITP) with a stable response on thrombopoietin receptor agonists, treatment may be tapered and/or discontinued. Objectives: The objective of this study was to provide a guide for tapering and discontinuation of TPO-RA therapy in patients with ITP, based on hematologist survey results, existing evidence, and expert consensus. Patients/Methods: UK hematologists completed a survey to characterize self-reported practice patterns related to TPO-RA tapering and discontinuation in patients with ITP. Using a modified Delphi panel approach, ITP experts developed consensus statements regarding the use of TPO-RA tapering and discontinuation. Results: Survey respondents estimated that 30–34% of their patients were suitable for tapering or discontinuation and that 29–35% of these patients required treatment re-initiation after an average treatment-free interval of 86–106 days. No clear predictors of patient suitability or response to tapering or discontinuation were identified. The ITP expert consensus was that approximately 30% of patients are eligible for tapering and discontinuation, which may be considered after 6–12 months for patients demonstrating an adequate treatment response (platelet count >50,000/µL at ≥75% of assessments in the preceding 6 months). Treatment re-initiation may be considered if the platelet count decreases or if the patient becomes symptomatic. Individual differences need to be taken into account when considering TPO-RA tapering or discontinuation. Conclusions: Tapering and discontinuation of TPO-RA therapy may be considered for certain patients with ITP. Further study is needed to better predict patients likely to achieve sustained off-treatment responses after tapering and discontinuation.

Published
2021
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34. Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension

Author

Emilia M. Swietlik, Daniel Greene, Na Zhu, Karyn Megy, Marcella Cogliano, Smitha Rajaram, Divya Pandya, Tobias Tilly, Katie A. Lutz, Carrie C.L. Welch, Michael W. Pauciulo, Laura Southgate, Jennifer M. Martin, Carmen M. Treacy, Christopher J. Penkett, Jonathan C. Stephens, Harm J. Bogaard, Colin Church, Gerry Coghlan, Anna W. Coleman, Robin Condliffe, Christina A. Eichstaedt, Mélanie Eyries, Henning Gall, Stefano Ghio, Barbara Girerd, Ekkehard Grünig, Simon Holden, Luke Howard, Marc Humbert, David G. Kiely, Gabor Kovacs, Jim Lordan, Rajiv D. Machado, Robert V. MacKenzie Ross, Colm McCabe, Shahin Moledina, David Montani, Horst Olschewski, Joanna Pepke-Zaba, Laura Price, Christopher J. Rhodes, Werner Seeger, Florent Soubrier, Jay Suntharalingam, Mark R. Toshner, Anton Vonk Noordegraaf, John Wharton, James M. Wild, Stephen John Wort, Allan Lawrie, Martin R. Wilkins, Richard C. Trembath, Yufeng Shen, Wendy K. Chung, Andrew J. Swift, William C. Nichols, Nicholas W. Morrell, Stefan Gräf, Stephen Abbs, Lara Abulhoul, Julian Adlard, Munaza Ahmed, Timothy J. Aitman, Hana Alachkar, David J. Allsup, Philip Ancliff, Richard Antrobus, Ruth Armstrong, Gavin Arno, Sofie Ashford, William J. Astle, Anthony Attwood, Paul Aurora, Christian Babbs, Chiara Bacchelli, Tamam Bakchoul, Siddharth Banka, Tadbir Bariana, Julian Barwell, Joana Batista, Helen E. Baxendale, Phil L. Beales, David L. Bennett, Agnieszka Bierzynska, Tina Biss, Maria A.K. Bitner-Glindzicz, Graeme C. Black, Marta Bleda, Iulia Blesneac, Detlef Bockenhauer, Sara Boyce, John R. Bradley, Gerome Breen, Paul Brennan, Carole Brewer, Matthew Brown, Andrew C. Browning, Michael J. Browning, Rachel J. Buchan, Matthew S. Buckland, Teofila Bueser, Carmen Bugarin Diz, John Burn, Siobhan O. Burns, Oliver S. Burren, Nigel Burrows, Carolyn Campbell, Gerald Carr-White, Keren Carss, Ruth Casey, Mark J. Caulfield, Jenny Chambers, John Chambers, Melanie M.Y. Chan, Floria Cheng, Patrick F. Chinnery, Manali Chitre, Martin T. Christian, Jill Clayton-Smith, Maureen Cleary, Naomi Clements Brod, Elizabeth Colby, Trevor R.P. Cole, Janine Collins, Peter W. Collins, Cecilia J. Compton, H. Terence Cook, Stuart Cook, Nichola Cooper, Paul A. Corris, Nicola S. Curry, Matthew J. Daniels, Mehul Dattani, Louise C. Daugherty, John Davis, Anthony De Soyza, Sri V.V. Deevi, Timothy Dent, Charu Deshpande, Eleanor F. Dewhurst, Peter H. Dixon, Sofia Douzgou, Kate Downes, Anna M. Drazyk, Elizabeth Drewe, Daniel Duarte, Tina Dutt, J. David M. Edgar, Karen Edwards, William Egner, Melanie N. Ekani, Perry Elliott, Wendy N. Erber, Marie Erwood, Maria C. Estiu, Dafydd Gareth Evans, Gillian Evans, Tamara Everington, Hiva Fassihi, Remi Favier, Debra Fletcher, Frances A. Flinter, R. Andres Floto, Tom Fowler, James Fox, Amy J. Frary, Courtney E. French, Kathleen Freson, Mattia Frontini, Abigail Furnell, Daniel P. Gale, Vijeya Ganesan, Michael Gattens, Hossein-Ardeschir Ghofrani, J. Simon R. Gibbs, Kate Gibson, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Keith Gomez, Pavels Gordins, David Gosal, Jodie Graham, Luigi Grassi, Lynn Greenhalgh, Andreas Greinacher, Paolo Gresele, Philip Griffiths, Sofia Grigoriadou, Detelina Grozeva, Mark Gurnell, Scott Hackett, Charaka Hadinnapola, Rosie Hague, William M. Hague, Matthias Haimel, Matthew Hall, Helen L. Hanson, Eshika Haque, Kirsty Harkness, Andrew R. Harper, Claire L. Harris, Daniel Hart, Ahamad Hassan, Grant Hayman, Alex Henderson, Archana Herwadkar, Jonathan Hoffman, Rita Horvath, Henry Houlden, Arjan C. Houweling, Fengyuan Hu, Gavin Hudson, Aarnoud P. Huissoon, Matthew Hurles, Melita Irving, Louise Izatt, Roger James, Sally A. Johnson, Stephen Jolles, Jennifer Jolley, Dragana Josifova, Neringa Jurkute, Mary A. Kasanicki, Hanadi Kazkaz, Rashid Kazmi, Peter Kelleher, Anne M Kelly, Wilf Kelsall, Carly Kempster, Nathalie Kingston, Nils Koelling, Myrto Kostadima, Ania Koziell, Roman Kreuzhuber, Taco W. Kuijpers, Ajith Kumar, Dinakantha Kumararatne, Manju A. Kurian, Michael A. Laffan, Fiona Lalloo, Michele Lambert, Hana Lango Allen, D. Mark Layton, Claire Lentaigne, Tracy Lester, Adam P. Levine, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Eleni Louka, Paul A. Lyons, Bella Madan, Eamonn R. Maher, Jesmeen Maimaris, Samantha Malka, Sarah Mangles, Rutendo Mapeta, Kevin J. Marchbank, Stephen Marks, Hugh S. Markus, Hanns-Ulrich Marschall, Andrew Marshall, Mary Mathias, Emma Matthews, Heather Maxwell, Paul McAlinden, Mark I. McCarthy, Harriet McKinney, Stuart Meacham, Adam J. Mead, Sarju G. Mehta, Michel Michaelides, Carolyn Millar, Shehla N. Mohammed, Anthony T. Moore, Monika Mozere, Keith W. Muir, Andrew D. Mumford, Andrea H. Nemeth, William G. Newman, Michael Newnham, Sadia Noorani, Paquita Nurden, Jennifer O’Sullivan, Samya Obaji, Chris Odhams, Steven Okoli, Andrea Olschewski, Kai Ren Ong, S. Helen Oram, Elizabeth Ormondroyd, Willem H. Ouwehand, Claire Palles, Sofia Papadia, Soo-Mi Park, David Parry, Smita Patel, Joan Paterson, Andrew Peacock, Simon H. Pearce, Kathelijne Peerlinck, Romina Petersen, Clarissa Pilkington, Kenneth E.S. Poole, Bethan Psaila, Angela Pyle, Richard Quinton, Shamima Rahman, Anupama Rao, F. Lucy Raymond, Paula J. Rayner-Matthews, Augusto Rendon, Tara Renton, Andrew S.C. Rice, Alex Richter, Leema Robert, Irene Roberts, Sarah J. Rose, Robert Ross-Russell, Catherine Roughley, Noemi B.A. Roy, Deborah M. Ruddy, Omid Sadeghi-Alavijeh, Moin A. Saleem, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Robert N. Sarkany, Simon Satchell, Sinisa Savic, Genevieve Sayer, John A. Sayer, Laura Scelsi, Andrew M. Schaefer, Sol Schulman, Richard Scott, Marie Scully, Claire Searle, Arjune Sen, W.A. Carrock Sewell, Denis Seyres, Neil Shah, Olga Shamardina, Susan E. Shapiro, Adam C. Shaw, Keith Sibson, Lucy Side, Ilenia Simeoni, Michael A. Simpson, Matthew C. Sims, Suthesh Sivapalaratnam, Damian Smedley, Katherine R. Smith, Kenneth G.C. Smith, Katie Snape, Nicole Soranzo, Olivera Spasic-Boskovic, Simon Staines, Emily Staples, Hannah Stark, Kathleen E. Stirrups, Alex Stuckey, Petros Syrris, R. Campbell Tait, Kate Talks, Rhea Y.Y. Tan, Jenny C. Taylor, John M. Taylor, James E. Thaventhiran, Andreas C. Themistocleous, David Thomas, Ellen Thomas, Moira J. Thomas, Patrick Thomas, Kate Thomson, Adrian J. Thrasher, Chantal Thys, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Ian P. Tomlinson, Matthew Traylor, Paul Treadaway, Salih Tuna, Ernest Turro, Philip Twiss, Tom Vale, Chris Van Geet, Natalie van Zuydam, Anthony M Vandersteen, Marta Vazquez-Lopez, Julie von Ziegenweidt, Annette Wagner, Quinten Waisfisz, Neil Walker, Suellen M. Walker, James S. Ware, Hugh Watkins, Christopher Watt, Andrew R. Webster, Lucy Wedderburn, Wei Wei, Steven B. Welch, Julie Wessels, Sarah K. Westbury, John-Paul Westwood, Deborah Whitehorn, James Whitworth, Andrew O.M. Wilkie, Catherine Williamson, Brian T. Wilson, Edwin K.S. Wong, Nicholas Wood, Yvette Wood, Christopher Geoffrey Woods, Emma R. Woodward, Austen Worth, Michael Wright, Katherine Yates, Patrick F.K. Yong, Timothy Young, Ping Yu, Patrick Yu-Wai-Man, Eliska Zlamalova, Russel Hirsch, R. James White, Marc Simon, David Badesch, Erika Rosenzweig, Charles Burger, Murali Chakinala, Thenappan Thenappan, Greg Elliott, Robert Simms, Harrison Farber, Robert Frantz, Jean Elwing, Nicholas Hill, Dunbar Ivy, James Klinger, Steven Nathan, Ronald Oudiz, Ivan Robbins, Robert Schilz, Terry Fortin, Jeffrey Wilt, Delphine Yung, Eric Austin, Ferhaan Ahmad, Nitin Bhatt, Tim Lahm, Adaani Frost, Zeenat Safdar, Zia Rehman, Robert Walter, Fernando Torres, Sahil Bakshi, Stephen Archer, Rahul Argula, Christopher Barnett, Raymond Benza, Ankit Desai, Veeranna Maddipati, University of Cambridge [UK] (CAM), Columbia University [New York], University of Sheffield [Sheffield], University of Cincinnati (UC), St George's, University of London, Vrije Universiteit Amsterdam [Amsterdam] (VU), Golden Jubilee National Hospital, Glasgow, Royal Free Hospital [London, UK], Heidelberg University Hospital [Heidelberg], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen] (THM), Fondazione IRCCS Policlinico San Matteo, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Universität Heidelberg [Heidelberg], Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Imperial College London, Royal Hallamshire Hospital, University of Graz, Freeman Hospital, Royal United Hospitals Bath (RUH), Great Ormond Street Hospital for Children [London] (GOSH), Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., King‘s College London, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität [Graz, Autriche], Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Swietlik, Emilia [0000-0002-4095-8489], Megy, Karyn [0000-0002-2826-3879], Tilly, Tobias [0000-0002-6762-5342], Stephens, Jonathan [0000-0003-2020-9330], Toshner, Mark [0000-0002-3969-6143], Morrell, Nicholas [0000-0001-5700-9792], Graf, Stefan [0000-0002-1315-8873], Apollo - University of Cambridge Repository, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karl-Franzens-Universität Graz, HAL-SU, Gestionnaire, British Heart Foundation, and The Academy of Medical Sciences

Subjects
0301 basic medicine, Candidate gene, Cardiac & Cardiovascular Systems, genetic association studies, 030204 cardiovascular system & hematology, Biology, Bayesian inference, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, pulmonary hypertension, medicine, Family history, Gene, Genetics & Heredity, Genetics, family history, Science & Technology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Kinase insert domain receptor, computed tomography, General Medicine, Original Articles, medicine.disease, Pulmonary hypertension, Phenotype, 3. Good health, 030104 developmental biology, Cardiovascular System & Cardiology, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Life Sciences & Biomedicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, vascular endothelial growth factor receptor
Abstract

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Published
2020
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35. Identification of occult cerebral microbleeds in adults with immune thrombocytopenia

Author

Deena Paul, Thomas Young, James B. Bussel, Camelia Vladescu, Asad Luqmani, Adam D. Waldman, Melanie A. Morrison, Alice C. J. Hart, David J. Sharp, Nichola Cooper, Maria Atta, Amna Malik, National Institute for Health Research, Imperial College Healthcare NHS Trust- BRC Funding, and Imperial Health Charity

Subjects
Adult, Male, medicine.medical_specialty, PURPURA, Immunology, Neuroimaging, 030204 cardiovascular system & hematology, Biochemistry, Gastroenterology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, medicine, Humans, Platelet, Prospective Studies, Poisson regression, Adverse effect, Prospective cohort study, 1102 Cardiorespiratory Medicine and Haematology, Aged, Cerebral Hemorrhage, Aged, 80 and over, Purpura, Thrombocytopenic, Idiopathic, Hematology, Science & Technology, medicine.diagnostic_test, Platelet Count, business.industry, Magnetic resonance imaging, 1103 Clinical Sciences, Cell Biology, Middle Aged, Magnetic Resonance Imaging, Occult, PREVALENCE, Natural history, BLEEDING SCORE, Cross-Sectional Studies, symbols, RISK-FACTORS, 1114 Paediatrics and Reproductive Medicine, Female, business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, MRI
Abstract

Management of symptoms and prevention of life-threatening haemorrhage in Immune thrombocytopenia (ITP) must be balanced against adverse effects of available therapies. Since current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for improved treatment stratification. In this cross-sectional, prospective study of 49 patients with ITP and lowest recorded (nadir) platelet counts below 30 x 109/L, we used Susceptibility-Weighted Magnetic Resonance Imaging (SWI) to detect cerebral microbleeds (CMBs) as a marker of occult haemorrhage. CMBs were detected using a semi-automated method and correlated with clinical metadata using multivariate Poisson regression analysis. Lobar CMBs were identified in 43% (21/49); prevalence increased with decreasing nadir platelet count (15/25 15x109/L), and was associated with longer disease duration (p=7x10-6), lower nadir platelet count (p=0.005), lower platelet count at time of MRI (p=0.029), and higher organ bleeding scores (p=0.028). Mucosal and skin bleeding scores, number of previous treatments, age and sex were not associated with CMBs. Occult cerebral microhaemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Although associated, neither low platelet count or bleeding scores predict CMBs. SWI could therefore provide an additional non-invasive biomarker of haemorrhagic phenotype, and potential adjunct for treatment stratification. Further longitudinal studies in children and adults will allow greater understanding of the natural history, and clinical and prognostic significance of CMBs.

Published
2020
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36. Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals with 56 Distinct Heterozygous NFKB1 Mutations

Author

Tiziana Lorenzini, Manfred Fliegauf, Nils Klammer, Natalie Frede, Michele Proietti, Alla Bulashevska, Nadezhda Camacho-Ordonez, Markku Varjosalo, Matias Kinnunen, Esther de Vries, Jos W.M. van der Meer, Rohan Ameratunga, Chaim M. Roifman, Yael D. Schejter, Robin Kobbe, Timo Hautala, Faranaz Atschekzei, Reinhold E. Schmidt, Claudia Schröder, Polina Stepensky, Bella Shadur, Luis A. Pedroza, Michiel van der Flier, Mónica Martínez-Gallo, Luis Ignacio Gonzalez-Granado, Luis M. Allende, Anna Shcherbina, Natalia Kuzmenko, Victoria Zakharova, João Farela Neves, Peter Svec, Ute Fischer, Winnie Ip, Oliver Bartsch, Safa Barış, Christoph Klein, Raif Geha, Janet Chou, Mohammed Alosaimi, Lauren Weintraub, Kaan Boztug, Tatjana Hirschmugl, Maria Marluce Dos Santos Vilela, Dirk Holzinger, Maximilian Seidl, Vassilios Lougaris, Alessandro Plebani, Laia Alsina, Monica Piquer-Gibert, Angela Deyà-Martínez, Charlotte A. Slade, Asghar Aghamohammadi, Hassan Abolhassani, Lennart Hammarström, Outi Kuismin, Merja Helminen, Hana Lango Allen, James E. Thaventhiran, Alexandra F. Freeman, Matthew Cook, Shahrzad Bakhtiar, Mette Christiansen, Charlotte Cunningham-Rundles, Niraj C. Patel, William Rae, Tim Niehues, Nina Brauer, Jaana Syrjänen, Mikko R.J. Seppänen, Siobhan O. Burns, Paul Tuijnenburg, Taco W. Kuijpers, Klaus Warnatz, Bodo Grimbacher, Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William J. Astle, Anthony Attwood, Chiara Bacchelli, Joana Batista, Helen E. Baxendale, Claire Bethune, Shahnaz Bibi, Marta Bleda, Barbara Boardman, Claire Booth, John R. Bradley, Gerome Breen, Matthew Brown, Michael J. Browning, Mary Brownlie, Matthew S. Buckland, Oliver S. Burren, Keren Carss, John Chambers, Anita Chandra, Naomi Clements Brod, Hayley Clifford, Nichola Cooper, Louise C. Daugherty, E.G. Davies, Sophie Davies, John Davis, Sarah Deacock, Sri V.V. Deevi, John Dempster, Lisa A. Devlin, Eleanor F. Dewhurst, Kate Downes, Elizabeth Drewe, Daniel Duarte, J. David M. Edgar, Karen Edwards, William Egner, Tariq El-Shanawany, Marie Erwood, Debra Fletcher, James Fox, Amy J. Frary, Mattia Frontini, Abigail Furnell, H. Bobby Gaspar, Rohit Ghurye, Kimberly C. Gilmour, Nicholas S. Gleadall, Sarah Goddard, Pavels Gordins, Stefan Gräf, Luigi Grassi, Daniel Greene, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Matthias Haimel, Lorraine Harper, Grant Hayman, Archana Herwadkar, Fengyuan Hu, Stephen Hughes, Aarnoud P. Huissoon, Roger James, Stephen Jolles, Jennifer Jolley, Julie Jones, Yousuf Karim, Mary A. Kasanicki, Peter Kelleher, Carly Kempster, Sorena Kiani, Nathalie Kingston, Nigel Klein, Myrto Kostadima, Roman Kreuzhuber, Dinakantha Kumararatne, James Laffan, Sara E. Lear, Rachel Linger, Hilary Longhurst, Lorena E. Lorenzo, Paul A. Lyons, Jesmeen Maimaris, Ania Manson, Rutendo Mapeta, Jennifer Martin, Mark I. McCarthy, Elizabeth M. McDermott, Harriet McKinney, Stuart Meacham, Karyn Megy, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai H.K. Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Christopher J. Penkett, Romina Petersen, Mark J. Ponsford, Waseem Qasim, Ellen Quinn, Isabella Quinti, F. Lucy Raymond, Paula J. Rayner-Matthews, Alex Richter, Nilesh Samani, Crina Samarghitean, Alba Sanchis-Juan, Ravishankar B. Sargur, Sinisa Savic, Suranjith L. Seneviratne, W.A. Carrock Sewell, Denis Seyres, Fiona Shackley, Olga Shamardina, Ilenia Simeoni, Michael A. Simpson, Kenneth G.C. Smith, Simon Staines, Emily Staples, Hannah Stark, Hans Stauss, Cathal L. Steele, Jonathan Stephens, Kathleen E. Stirrups, David Thomas, Moira J. Thomas, Patrick Thomas, Adrian J. Thrasher, Tobias Tilly, Catherine Titterton, Paul Treadaway, Salih Tuna, Ernest Turro, Rafal Urniaz, Julie von Ziegenweidt, Neil Walker, Christopher Watt, Steven B. Welch, Deborah Whitehorn, Lisa Willcocks, Nicholas Wood, Yvette Wood, Sarita Workman, Austen Worth, Katherine Yates, Nigel Yeatman, Patrick F.K. Yong, Timothy Young, Ping Yu, Eliska Zlamalova, Tranzo, Scientific center for care and wellbeing, Huisarts & Ziekenhuis, Lorenzini, Tiziana, Fliegauf, Manfred, Klammer, Nils, Frede, Natalie, Proietti, Michele, Bulashevska, Alla, Camacho-Ordonez, Nadezhda, Varjosalo, Markku, Kinnunen, Matias, de Vries, Esther, van der Meer, Jos W. M., Ameratunga, Rohan, Roifman, Chaim M., Schejter, Yael D., Kobbe, Robin, Hautala, Timo, Atschekzei, Faranaz, Schmidt, Reinhold E., Schroeder, Claudia, Stepensky, Polina, Shadur, Bella, Pedroza, Luis A., van der Flier, Michiel, Martinez-Gallo, Monica, Ignacio Gonzalez-Granado, Luis, Allende, Luis M., Shcherbina, Anna, Kuzmenko, Natalia, Zakharova, Victoria, Neves, Joao Farela, Svec, Peter, Fischer, Ute, Ip, Winnie, Bartsch, Oliver, Baris, Safa, Klein, Christoph, Geha, Raif, Chou, Janet, Alosaimi, Mohammed, Weintraub, Lauren, Boztug, Kaan, Hirschmugl, Tatjana, Dos Santos Vilela, Maria Marluce, Holzinger, Dirk, Seidl, Maximilian, Lougaris, Vassilios, Plebani, Alessandro, Alsina, Laia, Piquer-Gibert, Monica, Deya-Martinez, Angela, Slade, Charlotte A., Aghamohammadi, Asghar, Abolhassani, Hassan, Hammarstrom, Lennart, Kuismin, Outi, Helminen, Merja, Allen, Hana Lango, Thaventhiran, James E., Freeman, Alexandra F., Cook, Matthew, Bakhtiar, Shahrzad, Christiansen, Mette, Cunningham-Rundles, Charlotte, Patel, Niraj C., Rae, William, Niehues, Tim, Brauer, Nina, Syrjanen, Jaana, Seppanen, Mikko R. J., Burns, Siobhan O., Tuijnenburg, Paul, Kuijpers, Taco W., Warnatz, Klaus, Grimbacher, Bodo, Experimental Immunology, Graduate School, AII - Inflammatory diseases, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Molecular Systems Biology, Institute of Biotechnology, University of Helsinki, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, and Pediatric surgery

Subjects
0301 basic medicine, Male, NF-KAPPA-B, Medizin, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Fluorescent Antibody Technique, Autoimmunity, Disease, NUCLEAR-FACTOR, Kaplan-Meier Estimate, medicine.disease_cause, Hypogammaglobulinemia, 0302 clinical medicine, NFKB1 variants and mutations, autosomal dominant inheritance, common variable immunodeficiency, reduced penetrance, variable expressivity, HDE PED, Immunology and Allergy, variants and mutations, NF-κB1-related phenotype, Immunodeficiency, IMMUNODEFICIENCY, NF-?B1-related phenotype, 1184 Genetics, developmental biology, physiology, Disease Management, Middle Aged, NF-kappa B1-related phenotype, Prognosis, Penetrance, Immunohistochemistry, Magnetic Resonance Imaging, 3. Good health, Phenotype, NFKB1 variant, Female, Haploinsufficiency, NFKB1 mutation, Adult, Heterozygote, Immunology, HAPLOINSUFFICIENCY, Article, 03 medical and health sciences, autosomal dominant, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, business.industry, Common variable immunodeficiency, NF-kappa B p50 Subunit, NF-KAPPA-B1, Immune dysregulation, medicine.disease, 030104 developmental biology, Biological Variation, Population, CELLS, Mutation, Primary immunodeficiency, 3111 Biomedicine, business, Tomography, X-Ray Computed, Biomarkers, 030215 immunology
Abstract

Contains fulltext : 229571.pdf (Publisher’s version ) (Closed access) BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

Published
2020
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37. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders

Author

Minka J A Vries, Alexander Tolios, Johanna Gebhart, Ilenia Simeoni, Will Thomas, Stefanie Hofer, Matthias Haimel, Sofia Papadia, Keith Gomez, Daniel Greene, Rutendo Mapeta, Christopher J. Penkett, Willem H. Ouwehand, Michael Laffan, Kate Downes, Ernest Turro, Suthesh Sivapalaratnam, Louise C. Daugherty, Yvonne M. C. Henskens, Karyn Megy, Nick Gleadall, Howard Martin, Ingrid Pabinger, Martin Besser, Stephen Abbs, Andrew D Mumford, Daniel Duarte, Jonathan Stephens, Shoshana Revel-Vilk, Namir Al Hasso, Salih Tuna, Olga Shamardina, Sri V V Deevi, Chantal Thys, Emily Symington, Kathleen Freson, Nichola Cooper, Imperial College Healthcare NHS Trust- BRC Funding, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, RS: CARIM - R1 - Thrombosis and haemostasis, Promovendi CD, Biochemie, Faculteit FHML Centraal, MUMC+: DA CDL Algemeen (9), and RS: Carim - B04 Clinical thrombosis and Haemostasis

Subjects
Male, 0301 basic medicine, Platelet disorder, Immunology, Gene Dosage, Hemorrhage, Context (language use), VARIANTS, 030204 cardiovascular system & hematology, BIOBANK, Bioinformatics, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Copy-number variation, Hemostatic function, 1102 Cardiorespiratory Medicine and Haematology, MUTATION, GENETIC DIAGNOSIS, Blood Platelet Disorders, INHERITED THROMBOCYTOPENIA, Hemostasis, business.industry, High-Throughput Nucleotide Sequencing, 1103 Clinical Sciences, Thrombosis, Oligogenic Inheritance, NIHR BioResource, Cell Biology, Hematology, medicine.disease, DYSFUNCTION, Bleeding diathesis, 030104 developmental biology, 1114 Paediatrics and Reproductive Medicine, Female, business
Abstract

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD. ispartof: BLOOD vol:134 issue:23 pages:2082-2091 ispartof: location:United States status: published

Published
2019
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38. A HaemSTAR-led, UK-wide ‘flash-mob’ audit of intravenous immunoglobulin use in immune thrombocytopenia

Author

Arunodaya Mohan, Mairi Walker, Luke Carter-Brzezinski, Chris Peet, Yezenash Ayalew, Israa Kaddam, Rita Perry, David Tucker, Mac Macheta, Hayder Hussein, Suriya Kirkpatrick, Julia Wolf, Cristina Crossette-Thambiah, Sarah Wharin, Dianne Plews, Melek Akay, Graham McIlroy, Alexandros Rampotas, Lydia Wilson, Sarah Davis, Jesca Boot, Regina Nolan, Akila Danga, Dan Mei Xu, Tina T. Biss, Dominique Chan-Lam, Jennifer Swieton, Tanya Freeman, Claire Burney, Keir Pickard, Sheila Jen, Chloe Knott, Alvin Katumba, Sam Ackroyd, Edward Blacker, Beena Salhan, Richard Buka, Duncan Murray, Charlotte Bradbury, Sally Chown, Quentin A. Hill, Mohd Sharin Mohd Noh, Chira Mustafa, Nicola Crosbie, Surenthini Suntharalingam, Katja Kimberger, Rory McCulloch, Thomas Skinner, Naoimh Herlihy, Daire Quinn, Abbas Zaidi, Haroon Miah, Louise Garth, Eleana Loizou, Robert Dunk, Dan Halperin, Michael J R Desborough, Nithya Prasannan, Rupert Hipkins, Holly Gibson, Christopher McDermott, Amelia Fisher, Yogesh Upadhye, Sarah Wexler, Hina Peter, Sarah Jaafar, Sine Janum, Andrew J. Doyle, John Willan, Sree Sreedhara, Han Wang, Jonathan Kerr, Laura Aiken, Tom Bull, Seda Cakmak, Jennifer Darlow, Martin Besser, Michael Joffe, Benjamin Bailiff, Susan Robinson, Charlotte Wilding, Atiqa Miah, Jorge Cartier, Ryan Mullally, Miroslab Kmonicek, Samuel Harrison, Marquita Camillieri, Vickie MacDonald, Jane Graham, Ayesha Ejaz, Ipek Cakmak, Upekha Badaguma, Michelle Melly, Christopher Bailey, Belen Sevillano, Francesca Crolla, Frances Seymour, Indrani Venkatadasari, Laura Magill, Claire Lentaigne, Pamela Oshinyemi, Katherine Leighton, Maipelo Kgologolo, Zara Sayar, Elissa K. Dhillon, Lindsay McLeod-Kennedy, Sophie Hanina, Alice Thorpe, David Wright, Andrew Hastings, Caroline Shrubsole, Gillian C. Lowe, Nichola Cooper, Shivali Walia, Gulnaz Shah, Abi Martin, David Sharpe, Anna Dillon, Georgina Talbot, Imogen Swart-Rimmer, Phillip L R Nicolson, Paul Greaves, Olivia Kreze, Gemma Scott, Amir Shenouda, Edmund Watson, Shereef Elmoamly, Roochi Trikha, Wayne Thomas, Rebecca Pryor, Hafiz Qureshi, Laura Batey, Abigail Atkin, Dimitris Tsitsikas, Suthesh Sivapalaratnam, and Hajer Oun

Subjects
Response rate (survey), biology, business.industry, Research, General Medicine, 030204 cardiovascular system & hematology, Immune thrombocytopenia, 03 medical and health sciences, Flash (photography), 0302 clinical medicine, hemic and lymphatic diseases, Immunology, biology.protein, Medicine, 030212 general & internal medicine, Antibody, business
Abstract

Intravenous immunoglobulin (IVIg) is a common therapy for patients with immune thrombocytopenia (ITP). The initial response rate for IVIg is 80%[1][1] and is typically rapid, with some patients responding in 24 hours, although usually in 2–4 days.[2][2] When IVIg is used alone, the response is

Published
2019

39. Blockchain Technology for Global Social Change

Author

Jane Thomason, Sonja Bernhardt, Tia Kansara, Nichola Cooper, Jane Thomason, Sonja Bernhardt, Tia Kansara, and Nichola Cooper

Subjects
Digital currency--Social aspects, Digital currency--Economic aspects, Blockchains (Databases)--Social aspects, Blockchains (Databases)--Economic aspects
Abstract

Emerging technologies continue to affect a variety of industries, making processes more effective and efficient. However, they also impact society by promoting opportunities to encourage social change and socioeconomic advancement. Blockchain is one that is already influencing third world countries and disrupting the globe. Blockchain Technology for Global Social Change is an essential research publication that provides insight into advancements being made in blockchain and some potential applications of the technology that can improve the lives of individuals in emerging markets. This publication covers a range of topics such as digital government, health systems, and urbanization and is ideal for policymakers, academicians, researchers, sociologists, government officials, economists, and financial experts seeking current and relevant research on evolving blockchain technologies.

Published
2020

40. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Author

Keren J. Carss, Gavin Arno, Marie Erwood, Jonathan Stephens, Alba Sanchis-Juan, Sarah Hull, Karyn Megy, Detelina Grozeva, Eleanor Dewhurst, Samantha Malka, Vincent Plagnol, Christopher Penkett, Kathleen Stirrups, Roberta Rizzo, Genevieve Wright, Dragana Josifova, Maria Bitner-Glindzicz, Richard H. Scott, Emma Clement, Louise Allen, Ruth Armstrong, Angela F. Brady, Jenny Carmichael, Manali Chitre, Robert H.H. Henderson, Jane Hurst, Robert E. MacLaren, Elaine Murphy, Joan Paterson, Elisabeth Rosser, Dorothy A. Thompson, Emma Wakeling, Willem H. Ouwehand, Michel Michaelides, Anthony T. Moore, Andrew R. Webster, F. Lucy Raymond, Timothy Aitman, Hana Alachkar, Sonia Ali, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Natalie Canham, Keren Carss, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Colin Church, Naomi Clements-Brod, Virginia Clowes, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Charu Deshpande, Lisa Devlin, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, Frances Flinter, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Neeti Ghali, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Simon Holden, Muriel Holder, Susan Holder, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Melissa Lees, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Sarju Mehta, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Sofia Papadia, Soo-Mi Park, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Julia Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Richard Sandford, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Richard Scott, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Marc Tischkowitz, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie Vogt, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Evangeline Wassmer, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Pediatric surgery, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, APH - Quality of Care, Amsterdam Reproduction & Development (AR&D), Rue-Albrecht, K, RS: CARIM - R1.04 - Clinical thrombosis and haemostasis, MUMC+: DA CDL Algemeen (9), Med Microbiol, Infect Dis & Infect Prev, RS: CARIM - R1.03 - Cell biochemistry of thrombosis and haemostasis, Biochemie, Raymond, Lucy [0000-0003-2652-3355], Apollo - University of Cambridge Repository, Vascular Medicine, and Paediatric Infectious Diseases / Rheumatology / Immunology

Subjects
0301 basic medicine, Male, DNA Mutational Analysis, EXOME, PROTEIN, Eye, whole-genome sequence, NIHR-BioResource Rare Diseases Consortium, Medical and Health Sciences, Choroideremia, ACTIVATION, 0302 clinical medicine, Ethnicity, 2.1 Biological and endogenous factors, Exome, rare sequence variant, Copy-number variation, Aetiology, MUTATION, Genetics (clinical), Exome sequencing, Genetics & Heredity, Genetics, Genome, Adaptor Proteins, Biological Sciences, DYSTROPHY, copy-number variants, Female, Human, Common disease-common variant, LEBER CONGENITAL AMAUROSIS, Ethnic Groups, Genes, Recessive, Biology, DIAGNOSIS, Article, 03 medical and health sciences, Rare Diseases, Retinal Diseases, STARGARDT DISEASE, Clinical Research, REVEALS, Journal Article, medicine, Recessive, Humans, retinal dystrophy, Eye Disease and Disorders of Vision, Alleles, Adaptor Proteins, Signal Transducing, Whole genome sequencing, Base Sequence, Genome, Human, Human Genome, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, GENE, Introns, Stargardt disease, Good Health and Well Being, 030104 developmental biology, Genes, Mutation, 030221 ophthalmology & optometry, Human genome
Abstract

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

Published
2017
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41. Human retinoic acid-regulated CD161(+) regulatory T cells support wound repair in intestinal mucosa

Author

Estefania Nova-Lamperti, Mehdi Pirooznia, Eirini Pantazi, Marco Romano, Claudia Kemper, David J. Cousins, Hong-Wei Sun, Daniel Chauss, Han-Yu Shih, Behdad Afzali, Dominic A. Boardman, Polychronis Pavlidis, Majid Kazemian, Reuben McGregor, Giovanni A M Povoleri, Arian Laurence, Pablo D. Becker, Nichola Cooper, Nick Powell, Benedetta Costantini, Giorgia Fanelli, Cristiano Scottà, Shahram Kordasti, Yun-Ching Chen, and Giovanna Lombardi

Subjects
0301 basic medicine, EXPRESSION, HOMEOSTASIS, SUBSETS, Population, Immunology, Retinoic acid, Inflammation, chemical and pharmacologic phenomena, Tretinoin, INNATE, Biology, T-Lymphocytes, Regulatory, Article, 03 medical and health sciences, chemistry.chemical_compound, HUMAN NKR-P1A, Intestinal mucosa, Crohn Disease, RAR-related orphan receptor gamma, T-Lymphocyte Subsets, hemic and lymphatic diseases, medicine, Immunology and Allergy, FOXP3 GENE, Humans, Intestinal Mucosa, education, education.field_of_study, Wound Healing, Science & Technology, INDUCTION, SIGNATURE, hemic and immune systems, FOSL2, IN-VITRO, EXPANSION, 030104 developmental biology, chemistry, 1107 Immunology, Cancer research, medicine.symptom, Wound healing, Life Sciences & Biomedicine, medicine.drug, NK Cell Lectin-Like Receptor Subfamily B
Abstract

Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn's disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn's disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.

Published
2018
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42. Evidence for B cell exhaustion in chronic graft-versus-host disease

Author

Abdullah Alsuliman, Elif Gokdemir, Jane F. Apperley, Richard E. Champlin, Muharrem Muftuoglu, Richard Szydlo, Amin M. Alousi, Catherine Sobieski, Ahmad Khoder, Kayo Kondo, Nichola Cooper, Katayoun Rezvani, David Marin, Rafet Basar, Hila Shaim, Rohtesh S. Mehta, and Elizabeth J. Shpall

Subjects
0301 basic medicine, medicine.medical_treatment, C-C chemokine receptor type 7, Hematopoietic stem cell transplantation, CXCR3, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Immunology and Allergy, CD19+CD21-CD27-CD10-cells, Original Research, education.field_of_study, biology, IGM MEMORY, hemic and immune systems, medicine.anatomical_structure, exhausted B cells, CD21-B cells correlate with cGVHD severity, SURVIVAL, Life Sciences & Biomedicine, lcsh:Immunologic diseases. Allergy, EXPRESSION, chronic graft-versus-host disease, Population, Immunology, CD11c, chemical and pharmacologic phenomena, stem cell transplantation, CHRONIC GVHD, CD19, 03 medical and health sciences, BRONCHIOLITIS OBLITERANS, medicine, CD19+CD21−CD27−CD10− cells, MARROW-TRANSPLANTATION, education, B cell, CLONAL EXPANSION, Science & Technology, business.industry, medicine.disease, MIXED CRYOGLOBULINEMIA, CD21– B cells correlate with cGVHD severity, 030104 developmental biology, Graft-versus-host disease, RECONSTITUTION, biology.protein, T-CELLS, lcsh:RC581-607, business, 030215 immunology
Abstract

Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). A number of studies support a role for B cells in the pathogenesis of cGvHD. In this study, we report the presence of an expanded population of CD19+CD21− B cells with features of exhaustion in the peripheral blood of patients with cGvHD. CD21− B cells were significantly increased in patients with active cGvHD compared to patients without cGvHD and healthy controls (median 12.2 versus 2.12 versus 3%, respectively; p

Published
2017

43. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency

Author

Mohammed F Sadiyah, Ira Palmer, Anwar A. Sayed, Ahmad Khoder, Joshua Kaufman, Warren Strober, Alejandro V. Villarino, Paul T. Wingfield, Michael Mueller, Majid Kazemian, Joshua McElwee, Ahmed N. Hegazy, Behdad Afzali, Fred P. Davis, Julia Keith, Jason D. Hughes, Hong-Wei Sun, Charlotte O'Brien, Holm H. Uhlig, Michelle A. Linterman, Yu Zhang, Arian Laurence, Nichola Cooper, John J. O'Shea, Ine Vanderleyden, Dalia Kasperaviciute, Timothy J. Aitman, Rahul Roychoudhuri, Olena Kamenyeva, Juha Grönholm, Kim Montgomery-Recht, Ivan J. Fuss, Nicholas P. Restifo, Norman R. Watts, Peter Kelleher, Jana Vandrovcova, Michael J. Lenardo, Westminster Medical School Research Trust, Imperial College Healthcare NHS Trust- BRC Funding, Leuka, Zhang, Yu [0000-0002-6904-0372], Villarino, Alejandro V [0000-0001-8068-2176], Roychoudhuri, Rahul [0000-0002-5392-1853], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Pancytopenia, AUTOIMMUNITY, Genome-wide association study, CELL DIFFERENTIATION, Haploinsufficiency, Adrenal Cortex Hormones, Recurrence, Plasma cell differentiation, Immunology and Allergy, Respiratory Tract Infections, Immunodeficiency, Genetics, Lymphocyte differentiation, Syndrome, Middle Aged, Colitis, 3. Good health, Pedigree, TRANSCRIPTION FACTORS, Basic-Leucine Zipper Transcription Factors, PLASMA-CELL-DIFFERENTIATION, 1107 Immunology, B-CELLS, Female, FUNCTIONAL PREDICTIONS, Life Sciences & Biomedicine, Adult, Heterozygote, SUSCEPTIBILITY LOCI, SEQUENCING DATA, Fever, DATABASE, Immunology, COMMON VARIABLE IMMUNODEFICIENCY, Polymorphism, Single Nucleotide, Article, CLASSIFICATION, Autoimmune Diseases, 03 medical and health sciences, Young Adult, Lymphopenia, Journal Article, medicine, Humans, GENOME-WIDE ASSOCIATION, Gene, METAANALYSIS, Science & Technology, IDENTIFICATION, business.industry, Common variable immunodeficiency, Immunologic Deficiency Syndromes, medicine.disease, RISK LOCI, 030104 developmental biology, Mutation, Splenomegaly, Primary immunodeficiency, T-CELLS, business, Tomography, X-Ray Computed
Abstract

The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.

Published
2017
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44. Haemophagocytic lymphohistiocytosis associated with Mycobacterium tuberculosis infection

Author

Yee Man Tracy Hui, Toby Pillinger, Nichola Cooper, and Asad Luqmani

Subjects
Adult, Male, endocrine system, Tuberculosis, Early initiation, Article, Lymphohistiocytosis, Hemophagocytic, Mycobacterium tuberculosis, Chemoimmunotherapy, Bone Marrow, hemic and lymphatic diseases, medicine, Humans, In patient, Mycobacterium Infections, biology, medicine.diagnostic_test, business.industry, fungi, General Medicine, medicine.disease, biology.organism_classification, musculoskeletal system, Bronchoalveolar lavage, medicine.anatomical_structure, Granuloma, Immunology, Bone marrow, Lymph Nodes, business, hormones, hormone substitutes, and hormone antagonists
Abstract

Haemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal condition that can be primary or secondary. Secondary HLH can occur in association with infections, most commonly viral infections, but has also been reported in association with Mycobacterium tuberculosis (TB). Prompt identification of the underlying cause of HLH is important as it guides treatment decisions. Early initiation of appropriate treatment (eg, anti-TB treatment) reduces morbidity and mortality. We present a case of HLH associated with TB infection. Initial TB investigations were negative and standard combination chemoimmunotherapy for HLH resulted in a limited clinical response. On apparent relapse of HLH, further investigation revealed TB with changes on CT chest, granuloma on bone marrow and eventual positive TB culture on bronchoalveolar lavage. Subsequent treatment with quadruple anti-TB treatment resulted in rapid clinical response and disease remission. We advocate continued monitoring for TB infection in patients with HLH, and prophylaxis or full treatment for those at high risk.

Published
2015

45. The Importance of Age, Fludarabine, and Total Body Irradiation in the Incidence and Severity of Chronic Renal Failure after Allogeneic Hematopoietic Cell Transplantation

Author

Michael Jarmulowicz, Karl S. Peggs, Rafael F. Duarte, Kirsty Thomson, Nichola Cooper, Panagiotis D. Kottaridis, Stephen Mackinnon, Anna Cassoni, and Julio Delgado

Subjects
Adult, Male, medicine.medical_specialty, Renal failure, Transplantation Conditioning, Adolescent, Gastroenterology, Fludarabine, Internal medicine, Total body irradiation, medicine, Humans, Transplantation, Homologous, Cumulative incidence, Child, Retrospective Studies, Preparative Regimen, Transplantation, Hematopoietic cell transplantation, business.industry, Incidence, Incidence (epidemiology), Age Factors, Hematopoietic Stem Cell Transplantation, Dose-Response Relationship, Radiation, Retrospective cohort study, Hematology, Middle Aged, Surgery, Child, Preschool, Hematologic Neoplasms, Toxicity, Kidney Failure, Chronic, Female, business, Vidarabine, Whole-Body Irradiation, medicine.drug
Abstract

Nonmalignant late effects, including chronic renal failure (CRF), impair the quality of life of long-term survivors after allogeneic hematopoietic cell transplantation. One of the major risk factors is the use of total body irradiation (TBI) in the preparative regimen; TBI is currently fractionated in an attempt to reduce toxicity. We analyzed 241 patients who had TBI-based preparative regimens for allogeneic hematopoietic cell transplantation. TBI was delivered as a single fraction of 7.5 Gy (7.5S group), 12 Gy in 6 fractions (12F group), or 14.4 Gy in 8 fractions (14.4F group). The cumulative incidence of CRF at 2 years was 12%. Statistical analysis revealed that older age (P < .001) and fludarabine administration (P = .016) had a significant effect on the incidence of CRF. Furthermore, single-fraction TBI was also significantly associated with CRF severity, because 7 (6.3%) of 111 patients in the 7.5S group developed severe CRF, as opposed to 1 (0.8%) of 130 patients in the 12F and 14.4F groups combined (P = .044). However, these conclusions should be regarded as preliminary in view of the retrospective and nonrandomized nature of this study.

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