This talk was given by Dr. Grant Schulert Cincinnati Children's Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.
This talk was given by Dr. Jennifer Huggins of Cincinnati Childrens Hospital, at the Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day, on July 22nd, 2017.
This talk was given by Dr. Daniel Lovell of Cincinnati Children's Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.
Rare Pulmonary Diseases in Systemic JIA. This presentation tracks the increased use of biologics to treat SJIA and observes the trends in rare pulmonary diseases.
What is SJIA - How is it different than other diseases - Dr. Hermine BrunnerSystemic JIA Foundation
This talk was given by Dr. Hermine Brunner of Cincinnati Childrens Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.
This document discusses systemic juvenile idiopathic arthritis (S-JIA), including its clinical presentation, course, treatment and pulmonary complications. S-JIA is characterized by quotidian fever, evanescent rash, arthritis, lymphadenopathy, hepatosplenomegaly and serositis. It can follow a variable course from monophasic to persistent. Complications include macrophage activation syndrome (MAS), growth failure, joint damage and amyloidosis. New targeted biologics like anti-IL-1 and anti-IL-6 agents are the current recommended treatment approaches. The document also notes several reported cases of pulmonary hypertension and interstitial lung disease in S-JIA patients and questions what disease
Benjamin Korman, MD discusses the genetics of scleroderma and the genomic era. Genetics and genomics are complicated, and getting more so every day. Every patient is genetically unique, but new technology will make it easier to understand individuals’ genetic susceptibility to disease and response to therapy.
This document summarizes research on the immunomodulatory effects of antimalarial drugs (AMs) such as hydroxychloroquine (HCQ). It finds that in addition to their antimicrobial properties, AMs have multiple immunomodulatory mechanisms of action including inhibiting T and B cell signaling and cytokine production. Studies show HCQ is associated with improved glycemic control and a reduced risk of developing diabetes in patients with autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis. The document concludes that AMs have diverse metabolic, cardiovascular and antithrombotic effects beyond their traditional antimalarial use, helping to explain their benefits in treating certain autoimmune conditions.
This talk was given by Dr. Jennifer Huggins of Cincinnati Childrens Hospital, at the Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day, on July 22nd, 2017.
This talk was given by Dr. Daniel Lovell of Cincinnati Children's Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.
Rare Pulmonary Diseases in Systemic JIA. This presentation tracks the increased use of biologics to treat SJIA and observes the trends in rare pulmonary diseases.
What is SJIA - How is it different than other diseases - Dr. Hermine BrunnerSystemic JIA Foundation
This talk was given by Dr. Hermine Brunner of Cincinnati Childrens Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.
This document discusses systemic juvenile idiopathic arthritis (S-JIA), including its clinical presentation, course, treatment and pulmonary complications. S-JIA is characterized by quotidian fever, evanescent rash, arthritis, lymphadenopathy, hepatosplenomegaly and serositis. It can follow a variable course from monophasic to persistent. Complications include macrophage activation syndrome (MAS), growth failure, joint damage and amyloidosis. New targeted biologics like anti-IL-1 and anti-IL-6 agents are the current recommended treatment approaches. The document also notes several reported cases of pulmonary hypertension and interstitial lung disease in S-JIA patients and questions what disease
Benjamin Korman, MD discusses the genetics of scleroderma and the genomic era. Genetics and genomics are complicated, and getting more so every day. Every patient is genetically unique, but new technology will make it easier to understand individuals’ genetic susceptibility to disease and response to therapy.
This document summarizes research on the immunomodulatory effects of antimalarial drugs (AMs) such as hydroxychloroquine (HCQ). It finds that in addition to their antimicrobial properties, AMs have multiple immunomodulatory mechanisms of action including inhibiting T and B cell signaling and cytokine production. Studies show HCQ is associated with improved glycemic control and a reduced risk of developing diabetes in patients with autoimmune diseases like systemic lupus erythematosus and rheumatoid arthritis. The document concludes that AMs have diverse metabolic, cardiovascular and antithrombotic effects beyond their traditional antimalarial use, helping to explain their benefits in treating certain autoimmune conditions.
This document discusses hypothyroidism. It defines hypothyroidism as a hormonal deficiency caused by dysfunction of the thyroid gland that interrupts the synthesis and secretion of T4 and TSH. It discusses the epidemiology, risk factors, classifications, clinical manifestations, diagnosis, screening, and treatment of hypothyroidism. It notes that the prevalence is estimated to be 1-7% of the population and is more common in women and older adults. Diagnosis is based on elevated TSH and low free T4 levels. Treatment goals are to normalize TSH levels and improve symptoms.
The Role of Extracorporeal Photopheresis in Scleroderma is presented by
Jaehyuk Choi
Assistant Professor in the Department of Dermatology
Director of the Extracorporeal Photopherisis Unit
Dr Trevor Pickersgill - Diagnosing a RelapseMS Trust
1) Diagnosing relapses in multiple sclerosis (MS) patients can be complex, as relapses can mimic other conditions and symptoms are not always clearly MS-related.
2) It is important to properly diagnose relapses to determine the MS disease course, guide treatment decisions, and understand the patient's prognosis.
3) In addition to traditional relapses, atypical presentations must be considered, such as relapses related to MS treatments, infections, neurological conditions mimicking MS, and non-neurological or functional issues. A thorough examination is needed.
This document provides information on ANCA-Associated Vasculitis (AAV). It discusses the classification, epidemiology, clinical features, diagnosis and treatment of AAV. Key points include: AAV includes GPA, MPA, RLV and EGPA which are associated with ANCA antibodies; clinical manifestations can include ENT, lung, kidney, and skin involvement; diagnosis involves labs like ANCA testing and biopsies; and treatment involves immunosuppressive drugs like cyclophosphamide and rituximab for induction of remission.
dialogue between immune cells and stem cells in treating Kawasaki diseaseHNatasha1
This document discusses Kawasaki disease, a condition that causes inflammation in blood vessels. It first provides background on Kawasaki disease and stem cells. It then discusses the etiology, pathophysiology, and immunopathogenesis of Kawasaki disease. The document outlines how intravenous immunoglobulin is used to treat Kawasaki disease but is not always effective. It proposes that induced pluripotent stem cells could be used to model Kawasaki disease and investigate treatment approaches, including stem cell transplantation. In conclusion, induced pluripotent stem cells show potential as an alternative treatment for Kawasaki disease.
1) Plasma exchange (PE) significantly improves outcomes for patients with Guillain-Barré syndrome compared to supportive care alone based on data from multiple randomized controlled trials. PE results in greater improvement in disability and faster recovery.
2) Intravenous immunoglobulin (IVIg) is as effective as PE based on trials comparing the two treatments, with no significant differences in outcomes.
3) Combining PE and IVIg does not provide additional benefit over either treatment alone.
Can brain atrophy measurement help us in monitoring MS progression in routine...MS Trust
This presentation by Dana Horáková, Department of Neurology and Centre of Clinical Neuroscience at the Charles University in Prague, looks at why and how we should measure brain atrophy.
It was presented at the MS Trust Annual Conference in November 2014.
This presentation by Gavin Giovannoni looks at the new treatment paradigm for MS. It includes: arguments for early treatment in multiple sclerosis, the effect of MS on quality of life and whether highly-effective treatments stabilise MS.
It was presented at the MS Trust Annual Conference in November 2013.
An epileptic seizure that occurs despite antiepileptic drugs that had previously prevented seizures is called a breakthrough seizure. Breakthrough seizures can increase morbidity, mortality, and economic burden. Their causes include insufficient dosing, missed doses, provoking factors like stress or drugs, or ongoing epileptic processes. Management involves identifying the etiology, adjusting antiepileptic drug treatment, using newer drugs, and treating the underlying seizures.
This document discusses new and emerging drugs for progressive multiple sclerosis. It provides an overview of the current treatment landscape and explores potential reasons for past clinical trial failures. It also examines the underlying pathological mechanisms of progressive disease and proposes that trials may have targeted the wrong outcomes, patient populations, or stages of disease progression. Ongoing trials of drugs like ocrelizumab and natalizumab aim to address some of these challenges by exploring therapies in earlier progressive phases and assessing disability outcomes over longer periods of time.
This document summarizes the London experience with autologous hematopoietic stem cell transplantation (AHSCT) for multiple sclerosis (MS). It provides data on 54 patients who underwent AHSCT, with a median follow up time of 23 months. Complications included admissions to the intensive care unit and re-admissions post-transplant, with no treatment related deaths in this group. Outcomes included low rates of relapses, disability progression, and new MRI lesions post-transplant. The results were consistent with prior studies and support further investigation of AHSCT as a treatment for highly active relapsing MS and progressive MS with disease activity. Ongoing trials are exploring whether AHSCT may be superior to
This document discusses treatment options for patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have progressed on initial endocrine therapy. It considers fulvestrant monotherapy or the combination of everolimus and exemestane as potential second-line hormonal therapies. Trial data is presented showing that fulvestrant 500mg improves median overall survival by 4.1 months compared to 250mg. The TAMRAD trial found the combination of tamoxifen and everolimus increased clinical benefit rate over tamoxifen alone. The BOLERO-2 trial demonstrated that adding everolimus to exemestane significantly prolonged progression-free survival compared to exemestane alone. Subgroup analyses from
Neurological Manifestation of Anti Phospholipid Syndrome Ade Wijaya
The document discusses neurological manifestations of antiphospholipid syndrome (APS). APS is an autoimmune disorder defined by blood clots and pregnancy problems associated with persistent antiphospholipid antibodies. It can cause neurological issues like stroke in young patients even without other risk factors. APS has a thrombotic and immune-mediated pathogenesis. Treatment involves anticoagulation with warfarin to prevent blood clots.
This presentation discusses the graft versus tumour effect (GVT) in hematopoietic stem cell transplantation (HSCT). It provides laboratory and clinical evidence that the immune cells from the donor (graft) can induce remissions in hematological malignancies (tumour) after transplant. However, these same graft cells can also cause graft-versus-host disease (GvHD). Recent research aims to separate these effects by using regulatory T-cells to suppress GvHD while preserving the GVT effect.
Watch the video of the presentation on Youtube: https://www.youtube.com/watch?v=WRegqg5yvRs
El Dr Welte té nombroses publicacions en àrees diverses relacionades amb el malalt crític. Particularment interessants són els seus estudis en relació al trasplantament pulmonar, així com els seus estudis sobre pneumònia i sèpsia. Així mateix, participa activament en la xarxa alemanya Capnetz, emprada per a l'elaboració d'estudis multicèntrics relacionats amb la pneumònia adquirida a la comunitat.
Cadth 2015 c1 coles canada cadth presentationCADTH Symposium
This document discusses the treatment of a 19-year-old female law student and marathon runner with multiple sclerosis who had an inadequate response to interferon beta. It considers evidence from real-world databases and indirect treatment comparisons to help guide switching to alternative treatments like fingolimod or natalizumab. It also describes the patient's choice and good response to the more aggressive therapy alemtuzumab, which was later approved for use in the UK based on evidence of greater effectiveness and lower costs compared to other treatments.
This document provides an overview of chronic spontaneous urticaria (CSU), including its epidemiology, pathophysiology, clinical presentation, investigations, and management. It discusses the diagnosis and classification of urticaria and focuses on the diagnosis and investigation of CSU. Routine diagnostic measures for CSU include CBC, ESR or CRP, and eliminating possible causes such as medications or foods. Extended diagnostic testing may include allergy testing, infections screening, autoantibody testing such as the autologous serum skin test, and screening for underlying conditions. The gold standard treatment for CSU is non-sedating H1 antihistamines as monotherapy or in increased doses. Refractory cases may require the addition
1. Klaus Schmierer presents disclosures related to research funding and speaking engagements from various pharmaceutical companies involved in multiple sclerosis treatment.
2. He discusses two important lessons about MS treatment - that the disease is progressive from the start, and patients have a better chance of avoiding disability if treated early.
3. Selective immune reconstitution therapy (SIRT) and treatments like alemtuzumab and cladribine that deplete memory B cells have been shown to be highly effective at controlling disease activity, with alemtuzumab demonstrating similar efficacy to cladribine but with different adverse effect profiles.
The 'omics' revolution: How will it improve our understanding of infections a...WAidid
This slideset explains the ‘Omics’ technology and its role in the study of infections and vaccination. It is a revolution as it offers powerful tools to interrogate the animal / human immune response to vaccines and infections.
The views expressed in the presentations are that of the author and do not necessarily reflect the views of the Government of Canada. Presentations are shared in the original format received from the presenter.
Presentations given at the Conference to Develop a Federal Framework on Lyme Disease are the property of the author, unless otherwise cited. If you reference the author's work, you must give the author credit by naming the author and their work as well as the place and date it was presented.
For more information, contact the Lyme Disease Conference Secretariat at maladie_lyme_disease@phac-aspc.gc.ca
This document discusses hypothyroidism. It defines hypothyroidism as a hormonal deficiency caused by dysfunction of the thyroid gland that interrupts the synthesis and secretion of T4 and TSH. It discusses the epidemiology, risk factors, classifications, clinical manifestations, diagnosis, screening, and treatment of hypothyroidism. It notes that the prevalence is estimated to be 1-7% of the population and is more common in women and older adults. Diagnosis is based on elevated TSH and low free T4 levels. Treatment goals are to normalize TSH levels and improve symptoms.
The Role of Extracorporeal Photopheresis in Scleroderma is presented by
Jaehyuk Choi
Assistant Professor in the Department of Dermatology
Director of the Extracorporeal Photopherisis Unit
Dr Trevor Pickersgill - Diagnosing a RelapseMS Trust
1) Diagnosing relapses in multiple sclerosis (MS) patients can be complex, as relapses can mimic other conditions and symptoms are not always clearly MS-related.
2) It is important to properly diagnose relapses to determine the MS disease course, guide treatment decisions, and understand the patient's prognosis.
3) In addition to traditional relapses, atypical presentations must be considered, such as relapses related to MS treatments, infections, neurological conditions mimicking MS, and non-neurological or functional issues. A thorough examination is needed.
This document provides information on ANCA-Associated Vasculitis (AAV). It discusses the classification, epidemiology, clinical features, diagnosis and treatment of AAV. Key points include: AAV includes GPA, MPA, RLV and EGPA which are associated with ANCA antibodies; clinical manifestations can include ENT, lung, kidney, and skin involvement; diagnosis involves labs like ANCA testing and biopsies; and treatment involves immunosuppressive drugs like cyclophosphamide and rituximab for induction of remission.
dialogue between immune cells and stem cells in treating Kawasaki diseaseHNatasha1
This document discusses Kawasaki disease, a condition that causes inflammation in blood vessels. It first provides background on Kawasaki disease and stem cells. It then discusses the etiology, pathophysiology, and immunopathogenesis of Kawasaki disease. The document outlines how intravenous immunoglobulin is used to treat Kawasaki disease but is not always effective. It proposes that induced pluripotent stem cells could be used to model Kawasaki disease and investigate treatment approaches, including stem cell transplantation. In conclusion, induced pluripotent stem cells show potential as an alternative treatment for Kawasaki disease.
1) Plasma exchange (PE) significantly improves outcomes for patients with Guillain-Barré syndrome compared to supportive care alone based on data from multiple randomized controlled trials. PE results in greater improvement in disability and faster recovery.
2) Intravenous immunoglobulin (IVIg) is as effective as PE based on trials comparing the two treatments, with no significant differences in outcomes.
3) Combining PE and IVIg does not provide additional benefit over either treatment alone.
Can brain atrophy measurement help us in monitoring MS progression in routine...MS Trust
This presentation by Dana Horáková, Department of Neurology and Centre of Clinical Neuroscience at the Charles University in Prague, looks at why and how we should measure brain atrophy.
It was presented at the MS Trust Annual Conference in November 2014.
This presentation by Gavin Giovannoni looks at the new treatment paradigm for MS. It includes: arguments for early treatment in multiple sclerosis, the effect of MS on quality of life and whether highly-effective treatments stabilise MS.
It was presented at the MS Trust Annual Conference in November 2013.
An epileptic seizure that occurs despite antiepileptic drugs that had previously prevented seizures is called a breakthrough seizure. Breakthrough seizures can increase morbidity, mortality, and economic burden. Their causes include insufficient dosing, missed doses, provoking factors like stress or drugs, or ongoing epileptic processes. Management involves identifying the etiology, adjusting antiepileptic drug treatment, using newer drugs, and treating the underlying seizures.
This document discusses new and emerging drugs for progressive multiple sclerosis. It provides an overview of the current treatment landscape and explores potential reasons for past clinical trial failures. It also examines the underlying pathological mechanisms of progressive disease and proposes that trials may have targeted the wrong outcomes, patient populations, or stages of disease progression. Ongoing trials of drugs like ocrelizumab and natalizumab aim to address some of these challenges by exploring therapies in earlier progressive phases and assessing disability outcomes over longer periods of time.
This document summarizes the London experience with autologous hematopoietic stem cell transplantation (AHSCT) for multiple sclerosis (MS). It provides data on 54 patients who underwent AHSCT, with a median follow up time of 23 months. Complications included admissions to the intensive care unit and re-admissions post-transplant, with no treatment related deaths in this group. Outcomes included low rates of relapses, disability progression, and new MRI lesions post-transplant. The results were consistent with prior studies and support further investigation of AHSCT as a treatment for highly active relapsing MS and progressive MS with disease activity. Ongoing trials are exploring whether AHSCT may be superior to
This document discusses treatment options for patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have progressed on initial endocrine therapy. It considers fulvestrant monotherapy or the combination of everolimus and exemestane as potential second-line hormonal therapies. Trial data is presented showing that fulvestrant 500mg improves median overall survival by 4.1 months compared to 250mg. The TAMRAD trial found the combination of tamoxifen and everolimus increased clinical benefit rate over tamoxifen alone. The BOLERO-2 trial demonstrated that adding everolimus to exemestane significantly prolonged progression-free survival compared to exemestane alone. Subgroup analyses from
Neurological Manifestation of Anti Phospholipid Syndrome Ade Wijaya
The document discusses neurological manifestations of antiphospholipid syndrome (APS). APS is an autoimmune disorder defined by blood clots and pregnancy problems associated with persistent antiphospholipid antibodies. It can cause neurological issues like stroke in young patients even without other risk factors. APS has a thrombotic and immune-mediated pathogenesis. Treatment involves anticoagulation with warfarin to prevent blood clots.
This presentation discusses the graft versus tumour effect (GVT) in hematopoietic stem cell transplantation (HSCT). It provides laboratory and clinical evidence that the immune cells from the donor (graft) can induce remissions in hematological malignancies (tumour) after transplant. However, these same graft cells can also cause graft-versus-host disease (GvHD). Recent research aims to separate these effects by using regulatory T-cells to suppress GvHD while preserving the GVT effect.
Watch the video of the presentation on Youtube: https://www.youtube.com/watch?v=WRegqg5yvRs
El Dr Welte té nombroses publicacions en àrees diverses relacionades amb el malalt crític. Particularment interessants són els seus estudis en relació al trasplantament pulmonar, així com els seus estudis sobre pneumònia i sèpsia. Així mateix, participa activament en la xarxa alemanya Capnetz, emprada per a l'elaboració d'estudis multicèntrics relacionats amb la pneumònia adquirida a la comunitat.
Cadth 2015 c1 coles canada cadth presentationCADTH Symposium
This document discusses the treatment of a 19-year-old female law student and marathon runner with multiple sclerosis who had an inadequate response to interferon beta. It considers evidence from real-world databases and indirect treatment comparisons to help guide switching to alternative treatments like fingolimod or natalizumab. It also describes the patient's choice and good response to the more aggressive therapy alemtuzumab, which was later approved for use in the UK based on evidence of greater effectiveness and lower costs compared to other treatments.
This document provides an overview of chronic spontaneous urticaria (CSU), including its epidemiology, pathophysiology, clinical presentation, investigations, and management. It discusses the diagnosis and classification of urticaria and focuses on the diagnosis and investigation of CSU. Routine diagnostic measures for CSU include CBC, ESR or CRP, and eliminating possible causes such as medications or foods. Extended diagnostic testing may include allergy testing, infections screening, autoantibody testing such as the autologous serum skin test, and screening for underlying conditions. The gold standard treatment for CSU is non-sedating H1 antihistamines as monotherapy or in increased doses. Refractory cases may require the addition
1. Klaus Schmierer presents disclosures related to research funding and speaking engagements from various pharmaceutical companies involved in multiple sclerosis treatment.
2. He discusses two important lessons about MS treatment - that the disease is progressive from the start, and patients have a better chance of avoiding disability if treated early.
3. Selective immune reconstitution therapy (SIRT) and treatments like alemtuzumab and cladribine that deplete memory B cells have been shown to be highly effective at controlling disease activity, with alemtuzumab demonstrating similar efficacy to cladribine but with different adverse effect profiles.
The 'omics' revolution: How will it improve our understanding of infections a...WAidid
This slideset explains the ‘Omics’ technology and its role in the study of infections and vaccination. It is a revolution as it offers powerful tools to interrogate the animal / human immune response to vaccines and infections.
The views expressed in the presentations are that of the author and do not necessarily reflect the views of the Government of Canada. Presentations are shared in the original format received from the presenter.
Presentations given at the Conference to Develop a Federal Framework on Lyme Disease are the property of the author, unless otherwise cited. If you reference the author's work, you must give the author credit by naming the author and their work as well as the place and date it was presented.
For more information, contact the Lyme Disease Conference Secretariat at maladie_lyme_disease@phac-aspc.gc.ca
Salon b 18 kasim 2011 11.30 11.50 benan bayrakcityfngnc
1. Hemophagocytosis frequently occurs during systemic inflammation and is associated with increased heme oxygenase-1 (HO-1) expression.
2. Within bone marrow of sepsis patients, macrophages constitute the principal source of HO-1 expression, which reflects heme breakdown.
3. Very high serum ferritin levels in pediatric patients with systemic inflammation are associated with increased risk of critical care and death.
Genetics play an important role in infectious diseases. Host genetic factors determine susceptibility and disease progression for many infections like tuberculosis, malaria, and HIV/AIDS. Specific genes influence disease outcomes, like sickle-cell trait providing protection against malaria. Understanding host genetics provides insights into disease pathways and targets for prevention and treatment. Future applications include personalized medicine, genetic counseling, and gene therapy.
Open Source Pharma /Genomics and clinical practice / Prof Hosur opensourcepharmafound
Genomics is increasingly being used in clinical practice to inform diagnosis and treatment. The document discusses several examples where genomics has identified disease-causing genes and mutations, leading to new treatments. It also describes methods for genome sequencing and variant calling. The author's studies on epilepsy found variants in genes related to brain function in drug-resistant epilepsy patients. A large number of variants were in the 3' UTR, suggesting expression level variations in these genes may cause epilepsy.
1) Manuel L. Gonzalez-Garay presented research projects at UTHealth from 2009-2015 investigating rare genetic disorders using next-generation sequencing and metabolomics.
2) An experimental design involved whole exome sequencing of 81 healthy volunteers from the Young Presidents' Organization to explore the practical value and challenges of genomic information for healthy individuals.
3) Analysis of the sequencing data and metabolomics profiles identified several disease-causing variants and metabolic deficiencies, demonstrating the potential for precision medicine approaches in volunteers of normal health.
This study examined the role of genetic and autoimmune factors in premature ovarian failure (POF) in 78 women. The women were divided into 3 groups based on the number of CGG repeats in the FMR1 gene: less than 28 repeats, 28-36 repeats, and more than 36 repeats. The study found that women with 28-36 repeats were most strongly associated with the presence of anti-ovarian antibodies, suggesting an autoimmune cause of POF. Women with autoimmune-driven POF had significantly higher anti-Mullerian hormone levels than those without an autoimmune cause. The presence of anti-ovarian antibodies above 10 IU/mL was associated with a normal CGG repeat number and better preservation
Immunological Aspects of Myasthenia Gravis Ade Wijaya
MG is an antibody-mediated neuromuscular junction disease caused by IgG antibodies against acetylcholine receptors or the muscle-specific kinase in some cases. The thymus often exhibits structural changes like tumors or follicular hyperplasia and plays an important role in the pathogenesis by impairing regulatory T cells and conventional T cells, creating a pro-inflammatory environment. Understanding the immunological mechanisms involved helps manage patients.
This research article investigated associations between polymorphisms in the NRAMP1 and VDR genes and susceptibility to tuberculosis infection and disease progression in a Venezuelan population. The results showed that variants in the NRAMP1 3'UTR region were associated with susceptibility to M. tuberculosis infection, as seen in comparisons between tuberculosis-infected and uninfected controls, and with progression to active tuberculosis disease, as shown in comparisons between tuberculosis patients and infected controls. In contrast, no associations were found between variants in the VDR gene and tuberculosis susceptibility. This study confirms that NRAMP1 3'UTR polymorphisms are associated with M. tuberculosis infection and disease progression in this Venezuelan population.
Genomic sequencing is expected to have the most impact in stratifying cancer patients for treatment, diagnosing genetic diseases to enable prevention, and providing information to reduce adverse drug reactions. However, diagnosing rare diseases using genomics faces many challenges, including a lack of expertise, infrastructure, and reimbursement for interpretation. Additionally, databases of genetic variants are often inaccurate, with around 27% of entries being wrong in their clinical implications. This leads to difficulties in diagnosis and determining treatment relevance. New interdisciplinary diagnostic concepts and centers are needed to help address these hurdles.
This document summarizes research on the role of NFAT5 deficiency in immunodeficiency and autoimmune enterocolopathy. The researchers identified a deletion of the NFAT5 gene in a patient with unexplained infections and chronic intestinal inflammation. Further analysis showed NFAT5 deficiency resulted in reduced natural killer cells and impaired T cell function and cytokine production. Studies in human cells and mouse models confirmed the link between immune cell dysfunction and NFAT5 deficiency. The research demonstrates how genetic analysis can help clinical diagnosis and provide novel insights into disease mechanisms.
The document summarizes a study assessing whether anti-nucleosome antibodies (anti-NCS) increase the risk of renal relapse in patients with clinically inactive systemic lupus erythematosus (SLE). The study followed 115 inactive SLE patients for 12 months. At baseline, 18 patients (16%) were anti-NCS positive. Anti-NCS positive patients had a higher incidence of renal relapse compared to anti-NCS negative patients at 12-month follow up (38.9% vs 13.4%). A Cox regression analysis determined anti-NCS positivity at baseline increased the risk of renal relapse after adjusting for confounding factors, with a hazard ratio of 5.31. The results indicate anti-N
The document discusses the immune system's role in menopause, infertility, and pregnancy. It covers how sex hormones like estrogen and progesterone impact the immune system and conditions like autoimmune disorders. The document also addresses topics like recurrent pregnancy loss, endometriosis, sperm antibodies, and evaluating medical research studies.
Professor Michael Levin's presentation at Meningitis Research Foundation's 2013 conference Meningitis & Septicaemia in Children & Adults www.meningitis.org/conference2013
This document provides an overview of connective tissue diseases, including systemic lupus erythematosus (SLE) and systemic sclerosis. It discusses diagnostic criteria and biomarkers for SLE such as anti-nuclear antibodies (ANA) and disease-specific autoantibodies. Treatment options for SLE and lupus nephritis are reviewed, including hydroxychloroquine, belimumab, and the Aspreva Lupus Management Study comparing mycophenolate mofetil to intravenous cyclophosphamide. The roles of BAFF/APRIL in SLE pathogenesis and as therapeutic targets are also summarized. Finally, the document distinguishes between diffuse and limited subtypes of systemic sclerosis.
Induced pluripotent stem cells (iPSCs) derived from patients with alpha-1 antitrypsin deficiency (AATD) due to mutations in the SERPINA1 gene were differentiated into hepatic cells. The PiZZ iPSC-derived hepatic cells displayed intracellular accumulation of mutant alpha-1 antitrypsin (AAT) protein compared to controls, resulting from decreased AAT protein flux and secretion. Microarray analysis identified 135 genes that distinguished PiZZ iPSC-hepatic cells from controls, providing insights into AATD liver disease pathogenesis. The disease-specific cells also exhibited increased autophagic flux and responses to drugs that could augment or adversely affect autophagy, supporting the utility of
Leading Quality Improvements in Pediatric Rheumatology Care - Dr. Esi MorganSystemic JIA Foundation
This talk was given by Dr. Esi Morgan of Cincinnati Childrens Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.
Macrophage Activation Syndrome (MAS) is caused by excessive activation and multiplication of macrophages and cytotoxic T cells, leading to massive inflammation. In MAS, these immune cells overproduce cytokines that cause a "cytokine storm" and the macrophages begin destroying normal blood cells. This can cause a sudden drop in blood cell counts and become life-threatening. MAS shares similarities to hemophagocytic lymphohistiocytosis, a genetic disease where cytotoxic cells cannot properly kill infected cells. MAS most commonly occurs in systemic juvenile idiopathic arthritis and is diagnosed based on signs of infection, low blood cell counts, high ferritin levels, and liver dysfunction. Treatment involves high-dose corticosteroids,
COPA mutations impair Golgi-ER transport causing hereditary autoimmune-mediat...Systemic JIA Foundation
Mutations in the COPA gene, which encodes a subunit of the COPI vesicle coat complex important for retrograde Golgi-ER transport, were found to cause a rare inherited autoimmune disease characterized by inflammatory lung disease and arthritis. The identified mutations impaired COPA's ability to bind cargo proteins for transport. Patient cells exhibited elevated endoplasmic reticulum (ER) stress and the expression of pro-inflammatory cytokines that promote a T helper 17 cell response. It is proposed that mutant COPA causes ER stress, which leads to immune activation and generation of Th17 cells driving the autoimmune phenotype. This identifies the first example of a vesicular trafficking defect causing autoimmunity and provides insights into molecular links between ER stress and
This document provides an overview of Children's Interstitial Lung Disease (ChILD). It discusses that ChILD is a heterogeneous group of rare lung disorders that cause damage to the alveolar walls. The prevalence and specific entities of ChILD differ from adult interstitial lung disease. ChILD can be difficult to diagnose due to its diversity and is associated with significant morbidity and mortality. Over time, diagnostic tools and understanding of ChILD have improved, leading to identification of genetic causes and targeted treatments. However, more research is still needed.
1) ILD is a common manifestation of many connective tissue diseases (CTDs) that can be an early or only sign of CTD. It has various presentations and outcomes depend on the presentation. The mechanisms driving ILD in CTDs are likely different than those in childhood ILD and are more linked to environmental exposures.
2) The frequency of ILD varies across different CTDs and detection methods. For example, ILD occurs in 23-40% of scleroderma patients detected by high-resolution CT but 70-80% detected by lung biopsy.
3) Multiple histopathologies can occur in CTD-ILD including NSIP and UIP patterns, and different patterns have varying impacts
Epigenetics and cell fate in JIA and pulmonary fibrosis by Jim HagoodSystemic JIA Foundation
This document discusses the potential role of epigenetic mechanisms in idiopathic pulmonary fibrosis (IPF) and juvenile idiopathic arthritis (JIA). It outlines how epigenetic changes like DNA methylation and histone modifications can alter gene expression and cell phenotypes, contributing to diseases like IPF that involve remodeling of lung tissue. Studies have found differential methylation and expression of genes in IPF lung tissue. Epigenetic therapies targeting mechanisms like DNA methylation and histone acetylation may one day help treat IPF and other diseases. The document also discusses how epigenetics may contribute to autoimmunity and JIA, noting differences in T cell methylation profiles between JIA patients and controls.
This document summarizes the immune mechanisms involved in systemic juvenile idiopathic arthritis (sJIA). It discusses how sJIA is characterized by excessive inflammation driven by cytokines like interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-18 (IL-18). These cytokines promote inflammation by recruiting and activating immune cells. While the triggers for overproduction of these cytokines in sJIA are unknown, they lead to systemic symptoms and joint damage. The document also reviews efforts to understand disease heterogeneity and developing anti-inflammatory treatments targeting these cytokines.
Describing and Interpreting an Immersive Learning Case with the Immersion Cub...Leonel Morgado
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Research Updates in SJIA & MAS - Grant Schulert
1. Research update on
SJIA and MAS
SJIA Family Education Day
July 22, 2017
Grant Schulert, MD PhD
Assistant Professor of Pediatrics
Cincinnati Children’s Hospital Medical Center
2. Key Questions
• What is the cause of systemic JIA?
• What happens during MAS, and why do
only some patients get MAS?
3. Autoimmune
Disease (1900s)
Adaptive immunity
High-titer autoantibodies
and/or autoreactive,
antigen-specific T cells
Destructive immune
response to self
antigens
Lupus, rheumatoid
arthritis
Autoinflammatory
Disease (late 1990s)
Innate immunity
NO high-titer autoantibodies
or autoreactive, antigen-
specific T cells
Episodes of seemingly
unprovoked inflammation
that sometimes results in
tissue destruction
Periodic fever syndromes
(FMF, TRAPs, etc);
Systemic JIA?
5. Genetics and systemic JIA
• Systemic JIA is rarely
familial* although
twins/siblings with
disease have been
described
• Higher incidence in some
ethnic groups (Asia,
Northern vs Southern
Europe) suggests shared
genetic risk
6. DNA Sequence Variation in the
Human Genome
• In general, each human’s
genome is >99.5% identical to
any other humans
• But, that means up to 10-20
million bases of differences
– Mostly single nucleotide
changes
• Nomenclature:
– Single nucleotide polymorphism
(SNP) – change present in at
least 1% of population
– Rare variant – present in less
than 1% of population
7. SNPs and genome-wide
association studies (GWAS)
• GWAS are large-scale studies to
identify associations between SNPs
and phenotypes (diseases)
• Compare SNP prevalence between
thousands of patients and controls
• SNPs that are associated with disease
are considered to mark genomic
regions that may influence risk of
disease
• Results: Manhattan plots, where height
of peak reflects strength of association
8. GWAS in (non-systemic) JIA
• Examined 2816
patients with JIA
oligoarticular or RF-
negative polyarticular
JIA (poligos) compared
to 13000 controls
• Used Immunochip –
123,000 SNPs with
minor allele frequency
>1%
Nature Genetics 45, 664–669 (2013)
10. GWAS in (non-systemic) JIA
• Highest single SNP in
HLA-DQB1 region, 2%
in controls vs. 12% in
patients (OR=6.01,
p=3.14x10-174)
• Other identified genes
with known functions in
immunity and roles in
other autoimmune
diseases
11. GWAS in systemic JIA
• Large, multinational collaborative led by Dr.
Michael Ombrello at NIH
• Examined 982 children with systemic JIA
compared to ~9000 controls
– 770 SJIA patients stratified into 9 geographically
defined, ancestrally matched case-control collections
• 27-35K SNPs in the MHC region, overall 4-6million
genotypes or imputed SNPs
Proc Natl Acad Sci USA (2015) 112: 15970
12. GWAS in systemic JIA
Proc Natl Acad Sci USA (2015) 112: 15970
Ann Rheum Dis (2016)
13. GWAS in systemic JIA
• Clearly identified the
MHC locus as a
significant (if weaker)
bona fide susceptibility
region for systemic JIA
in multiple populations
• Top SNP: HLA-
DRB1*11, OR 2.6
(p=2.8x10-17)
Proc Natl Acad Sci USA (2015) 112: 15970
14. GWAS in systemic JIA
• In addition, 24 genetic
regions with suggestive
association with systemic
JIA
• None previously associated
with any rheumatic
diseases
• No evidence for shared
genetic architecture
between systemic JIA and
other JIA subtypes
Ann Rheum Dis (2016)
15. Key Questions
• What is the cause of systemic JIA?
• What happens during MAS, and why do
only some patients get MAS?
17. IFNgamma and MAS/HLH
• IFNg believed to be key
driver of inflammation in
familial HLH
– High levels in patients
– IFNg blockade protective in
mice
– Promising early results in
clinical trial of anti-IFNg
monoclonal antibody
• Does IFNg have similar
central role in MAS?
Hemophagocytic macrophages in MAS
18. 1 Number (percentile); 2 Median (IQR); 3 At least one time during disease course
4 Complete remission of MAS/HLH episode after treatment according to the judgment of the investigator
5 Clinical inactive disease according to Wallace Criteria
PATIENTS
NUMBER OF SAMPLES
ACTIVE
DISEASE
INACTIVE
DISEASE
sec-HLH n=14 11 114
Gender, Female1 5 (36)
Age at disease onset (years)2 8.6 (4.1 – 12.9)
sJIA n=54 48 355
Gender, Female1 26 (48)
Age at disease onset (years)2 7.9 (4.6 – 13.6)
sJIA with MAS3 n=27 20 204
Gender, Female1 13 (48)
Age at disease onset
(years)2
9.4 (4.8 – 13.8)
sJIA without MAS n=27 28 155
Gender, Female1 13 (48)
Age at disease onset
(years)2
7.3 (4.1 – 12.1)
Patients’ samples collected at OPBG in Roma, IGG in Genova, and CCHMC in
Cincinnati
Bracaglia et al (in revision
19. Active sHLH
(n=11)
Active MAS
(n=20)
Active sJIA
No MAS
(n=28)
Inactive sJIA
(n=35)
IL-6 11.4
(3.2-49.3)
22.9
(5.5-45.6)
20.3
(5.9-54.9)
3.2
(3.2-7.9)
TNFa 27.6
(10.8-49.2)
14.7
(7.1-33.1)
10
(5.3-15.0)
9.4
(6.1-18.5)
IFNg 34.7
(23.9-170.1)
15.4
(5.1-52.6)
4.9
(3.2-8.6)
4.2
(3.2-9.3)
CXCL9 33598
(3083-127687)
13392
(2163-35452)
837
(471-2505)
901
(466-1213)
CXCL10 4420
(799-8226)
1612
(425-4309)
307
(199-694)
235
(172-407)
CXCL11 1327
(189-2000)
565
(198-1007)
122
(62-197)
111
(63-187)
*p<0.01 MAS vs Active sJIA
Bracaglia, et al. Ann Rheum Dis 2016
20. Serum IFNγ and IFN-induced
chemokines in MAS versus active SJIA
Bracaglia, et al. Ann Rheum Dis 2016
21. IFNg and IFN-induced chemokines
and laboratory features of MAS
Bracaglia, et al. Ann Rheum Dis 2016
22. IFNg, IL-18 and MAS
• IL-18 is a key
proinflammatory cytokine
– Inflammasome-mediated
production in myeloid cells
– Key driver of IFNg
production by CD8 cells
and NK cells
• IL-18 hypersecretion
recurrent MAS
– NLRC4 gain-of-function
mutations (Canna et al)
Nature Immunology (2012) 13:115–117
23. High IL-18 subset of SJIA patients
develop MAS
• Cytokine levels during
active disease can
define two subsets of
SJIA patients:
– High IL-18/IL-6 – high
risk of MAS (green)
– Low IL-18/IL-6 – older,
more arthritis, no MAS
(n=33)
Clinical Immunology 160 (2015) 277–281
24. Cytolytic Defects in FHLH
Cytolytic cells cause destruction of target cells by
delivering granules that contain proteins such as
perforin and granzymes1
Recognition of target
Polarization of the
cytoskeleton
Movement of cytolytic
granules along MTs to the
site of contact
Degranulation and release
of contents
Delivery of content of
granules to target cell aided
by Perforin
24
Apoptosis
Target Cell
Effector Cell
(NK Cell)
Granzyme B
Fusion
Priming
Docking
Munc13-4
Munc18-2
Syntaxin 11
Rab27a
Nucleus
Cytolytic
Granule
Perforin
MTOC
Cytolytic Pathway1,2
Granzymes
25. HLH mutations associated with MAS
• Several reports have
identified rare mutations in
cytolytic pathway genes in
patients with MAS
– PRF1: Vastert et al (2010),
Unal et al (2013), Schulert et
al (2015)
– UNC13D: Hazen et al
(2008), Zhang et al (2008)
• Could there be a genetic
predisposition to MAS in
some patients with systemic
JIA?
26. Genetics of MAS in systemic JIA
• Trio-based whole exome sequencing performed for 14
patients with SJIA and MAS and unaffected parents
– Comparison: 29 patients with SJIA and no history of MAS
• Primary analysis – variants in HLH-associated genes
– PRF1, MUNC13-4, Syntaxin 11, STXBP2, LYST, Rab27A
• Secondary analysis
– Identification of other candidate genes / rare variants
Kaufman et al (2014) Arthritis Rheum
27. Kaufman et al (2014) Arthritis Rheum
Top IPA category of all identified genes:
“Cellular assembly and organization” (p<3.1 x 10-5)
5/14
36%
29. Some answers, many new
questions …
• How do genetic and environmental factors
interact to cause systemic JIA?
• Can cytokine-targeted therapy treat (anti-
IFNg, anti-IL-18) MAS?
• Can genetic or cytokine testing predict risk for
MAS?