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Take a look at a selection of our recent media coverage:

Scientists recognised for transformative lupus research projects

21st December 2018

The Lupus Research Alliance has announced the 2018 recipients of the Dr. William E. Paul Distinguished Innovator Award in Lupus and Autoimmunity: namely, Nir Hacohen, PhD and Vijay Kuchroo, DVM, PhD.

Dr. Hacohen is seeking better ways to treat lupus kidney disease, the major cause of illness and death among patients with lupus. Dr. Kuchroo is looking at ways to harness regulatory T and B cells as a new approach to lupus treatment. Both projects have the potential to stimulate innovative strategies for prevention, treatment, and cure of lupus.

Dr. Hacohen serves as Director of the Center for Cell Circuits and Center for Cancer Immunology, Massachusetts General Hospital and Broad Institute, and Professor of Medicine at Harvard Medical School. Dr. Kuchroo is a Professor of Neurology at Harvard Medical School and Brigham and Women’s Hospital. 

The immune response in lupus nephritis

Lupus nephritis (inflammation of the kidneys) is a major cause of illness and death among patients with lupus. The failure to stop the harmful effects caused by lupus nephritis is thought by many researchers to be due to an incomplete understanding of the immune system. 

Dr. Hacohen is seeking to understand why the immune response (to tumors, bacteria or self) varies so dramatically across individuals. According to Dr. Hacohen, “The results of these studies will generate new hypotheses for how immune cells work together to cause tissue damage in lupus nephritis patient kidneys, lead to new drug targets and better predictors of disease, and guide researchers in the improvement of mouse models to understand human lupus nephritis.”

The role proteins play in regulating the body’s immune system in lupus

“T cells and B cells are the primary types of lymphocytes (a subtype of white blood cells) that determine the body’s immune response to foreign substances in the body,” noted Dr. Kuchroo. “Once activated to mount an immune response, T and B cells need to be turned off by another class of regulatory cells. In patients with lupus, these regulatory cells are not able to properly function. This study will examine how to induce and promote the function of these regulatory T and B cells for treating lupus.”

How does diet during pregnancy impact allergies in offspring?

17th December 2018

Pregnant women routinely swear off alcohol and tobacco to boost their chances of having a healthy baby. What about common food allergens like nuts and milk?
 
There are scant data that describe how often pregnant women deliberately stop eating a specific food item in order to prevent future food allergies in their newborns. As a first step toward addressing this data gap, a research team led by Karen Robbins, MD, an allergist at Children’s National Health System, pored through a longitudinal study conducted by the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention.
 
About 4900 pregnant women completed the Infant Feeding Practices Study II prenatal questionnaire from May 2005 to June 2007. The study tracked 2000 pregnant women from the third trimester of pregnancy and their infants through the first year of life. A small percentage of women said they had consumed fewer allergens during pregnancy to stave off food allergies in their newborns, according to a poster Dr Robbins presented during the American College of Asthma Allergy and Immunology 2018 Annual Scientific Meeting. While their numbers were small, most of these women reported giving up major allergens such as nuts, milk or eggs during pregnancy, including:
  • 144 (2.9%) reported restricting their diet in some way to prevent future food allergies in their offspring
  • 84 women (1.7%) ate fewer nuts
  • 15 women (0.3%) ate fewer eggs and
  • 2 women (0.04%) ate/drank consumed less dairy/milk.
“At the time the survey was conducted, few pregnant women in this large data set said they gave up certain foods with the express aim of avoiding a food allergy in their babies,” Dr Robbins says. “However, mothers who had an older child with a food allergy or who had food allergies themselves had significantly higher odds of trying this food avoidance strategy.”
 
Despite the diet changes, infants born to these expectant mothers were twice as likely to experience problems with food at age 4 months – though not at age 9 months or 12 months. And these infants were no more likely to be diagnosed with a food allergy.
 
According to the FDA, millions of Americans suffer a food allergy each year. Reactions can range from mild to life-threatening and can begin soon after eating a problematic food item or an ingredient from that food. Among the most common allergenic foods are milk, eggs, fish, shellfish, tree nuts, peanuts, wheat and soybeans.
 
“We really need to know more about how often targeted food avoidance occurs among US pregnant women who have a family history of food allergies,” Dr Robbins adds. “We hope to learn what factors into these women’s decision-making as well as why many of them settled on food avoidance as a potential strategy to try to prevent food allergy in their infants.”
 
Resource
 
Robbins K et al. Prenatal food allergen avoidance practices for food allergy prevention. American College of Asthma Allergy and Immunology 2018 Annual Scientific Meeting presentation.

Most accurate tool yet developed to predict asthma in young children

Scientists at Cincinnati Children’s Hospital Medical Center in the US have created and tested a decision tool that appears to be the most accurate, non-invasive method yet developed to predict asthma in young children.
 
The researchers hope the Pediatric Asthma Risk Score (PARS) will become the most common tool used by medical practitioners to predict asthma and help prevent the common airway disease from developing.
 
“PARS is superior to the Asthma Predictive Index (API) in its ability to predict asthma in children with mild to moderate asthma risk, with an 11% increase in sensitivity,” says Gurjit Khurana Hershey, MD, PhD, director of Asthma Research at Cincinnati Children’s and senior author of the study. “Children with mild to moderate risk may be the most likely asthma patients to respond favourably to prevention strategies.”
 
The study, published online in the Journal of Allergy and Clinical Immunology, found that the API missed 43% of asthmatic children identified by PARS as mild to moderate risk. PARS and the API equally predicted asthma risk for children with the most risk factors.
 
The API has been seen as the gold standard to which other predictive models have been compared. While useful for predicting which children will not develop asthma, it “leaves much room for improvement in terms of identifying children who will,” says Jocelyn Biagini Myers, PhD, a researcher in the division of Asthma Research and lead author of the study. A notable achievement of the PARS over the API is that it delivers a personalised asthma risk score to the patient, she says.
 
The PARS tool included new and less invasive criteria than previous tools. Additions included demographic data and clinical factors routinely collected during an asthma or allergy assessment in a doctor’s office.
 
Dr Khurana Hershey and her colleagues devised the tool using data from the Cincinnati Childhood Allergy and Air Pollution study – a group of 762 infants born between 2001 and 2003 in Cincinnati and northern Kentucky. These were children of parents who had at least one allergy symptom. The children were examined annually at the ages of 1, 2, 3, 4 and 7 for the development of allergic disease. They were skin tested for 15 airborne and food allergens including cat, dog, cockroach, dust mites, trees, mould, weeds, grass, cow’s milk and hen’s egg.
 
Of the 762 infants, 589 were evaluated for asthma development at the age of 7 using objective measures of lung function. Sixteen percent had asthma. The researchers also queried parents for numerous factors that contribute to asthma risk.
 
The children with asthma at age 7 were more likely to have at least one parent with asthma, two or more positive skin tests to airborne or food allergens, eczema at a young age, wheezing apart from colds, frequent wheezing at a young age, a diagnosis of allergic rhinitis in the first three years of life, and to be African-American.
 
The researchers compared the PARS model to the original API and found it to be 11% more sensitive than the API.
 
“Our PARS model either outperforms and/or is less invasive than 30 existing models intended to predict asthma development,” says Dr Hershey. “The PARS also may be more clinically useful and applicable in an office setting.”
 
To facilitate easy implementation of PARS in clinical and research settings, the study contains a PARS scoring sheet that includes the decision tool and clinical interpretations. A PARS web application, which provides fast and easy calculation, is accessible at https://pars.research.cchmc.org. Smartphone apps are being developed for the iPhone and for android phones.
 
Reference
  1. Biagini Myers J et al. A Pediatric Asthma Risk Score to better predict asthma development in young children. J Allergy Clin Immune 2018;DOI: 10.1016/j.jaci.2018.09.037.

Prevention and treatment of ICU-acquired delirium requires a personalised approach

A population heath study from the Regenstrief Institute and Indiana University Center for Aging Research has determined that haloperidol, the drug most commonly used to treat delirium in hospital medical and surgical intensive care units (ICUs), did not benefit elective thoracic surgery ICU patients when given prophylactically, with the possible exception of those who have had surgery to remove their oesophagus.
 
The study results indicate the need for a personalised approach to delirium in the ICU.
 
The work is the first to evaluate the use of the antipsychotic drug haloperidol to reduce post-operative delirium in elderly patients undergoing elective non-cardiac thoracic surgery.
 
Researchers found no differences in delirium incidence or severity between haloperidol and placebo in patients who had undergone elective non-cardiac thoracic surgery except in the small number of study participants who were admitted to the ICU after removal of the oesophagus, a procedure known as oesophagectomy. Removal of this organ is a treatment for oesophageal cancer.
 
“Our work suggests that just as you can’t lump all cancer patients together for treatment, you can’t put all delirium patients in the same bucket,” said Regenstrief Institute investigator Babar A Khan, MD, MS, who led the new study published in the Journal of the American Geriatrics Society.1 “We need a personalised approach to delirium, focusing on people at higher risk of developing this complication.”
 
He notes that while elective surgery patients typically are healthier than other ICU patients, they are very much at risk of delirium. He counsels those considering elective surgery to consult with their primary care clinicians and their surgeon to weigh the significant risks of delirium with the benefits of the proposed procedure.
 
Dr Khan is also a co-author of the groundbreaking October 2018 New England Journal of Medicinestudy that reported that haloperidol did not significantly alter the duration of delirium in ICU patients.
 
“Because we now know that haloperidol, the most commonly used drug to treat ICU delirium doesn’t, with possibly few exceptions, work, we need to focus on nonpharmacological therapies and vigilantly curtail administration of drugs that are harmful to the brain, especially the ageing brain,” said Dr Khan.
 
Approximately five million Americans are admitted to a surgical or medical ICU annually. Delirium, a sudden and serious change in brain function causing confusion, occurs in as many as three quarters of those treated in the ICU. Causes include sepsis, metabolic problems such as liver and kidney disease as well as drugs that injure the brain.
 
Individuals who experience delirium are more likely to have longer hospital stays and hospital-associated complications. They also have a greater likelihood of dying in the hospital for up to a year after their hospital stay than ICU patients who did not experience delirium. They are also more likely to lose physical functioning and experience cognitive impairment.
 
“This landmark study represents a first attempt to reduce the incidence and morbidity of delirium in the postoperative patient,” said thoracic surgeon Kenneth Kesler, MD, Harris B Shumacker, Professor of Surgery at IU School of Medicine, senior author of the JAGS study. “Although unfortunately an overall negative study, it does move us forward by identifying both a subset of patients who may benefit from haloperidol prophylaxis and those patients who are at risk for delirium following large surgical procedures.”
 
Reference
  1. Khan B et al. Preventing Post-operative Delirium after Major Non-Cardiac Thoracic Surgery – A Randomized Clinical Trial. J Am Geriatric Soc 2018;66:2289-97.

Expert analysis: Challenges in diagnosing connective tissue diseases

 

Connective tissue diseases (CTD) are a group of disorders involving the protein-rich tissue that supports organs and other parts of the body. However, more commonly the acronym CTD identifies systemic autoimmune rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and SLE-like diseases, Sjogren syndrome (SS), scleroderma (SSc), inflammatory autoimmune myopathies (AM), systemic autoimmune vasculitides (AV), mixed or undifferentiated connective tissue disease (MCTD/UCTD), and anti-phospholipid syndrome (APS).

All these disorders are also defined as systemic autoimmune rheumatic diseases (SARD) and are characterised by an autoimmune response against self-antigens that ends in chronic inflammation and irreversible tissue damage if untreated, with high direct and indirect costs for the social/health systems. SARD can affect several organs and tissues of the body; as a consequence, different specialists may see these patients but ultimately, rheumatologists or clinical immunologists are the main physicians providing care for SARD.

Classification and diagnosis 

The classification and the diagnosis of SARD are based on clinical signs and symptoms, however laboratory and instrumental parameters are also required.1 These tools improved our classification/diagnostic power; this is the case, for example, for RA with the new anti-citrullinated peptide antibodies and joint magnetic resonance and/or ultrasound Doppler evaluation.2 In addition, the histology or immune-phenotyping of the damaged tissues help in diagnosis but, unfortunately, are not always feasible or specific because of overlapping pathogenic pathways.3

Although each disease displays peculiar clinical pictures, some manifestations are not specific at all (such as thrombosis in APS) or frequently overlapping among different diseases (for example, inflammatory arthritis). Moreover, the clinical manifestations are non-specific particularly at the beginning of the clinical history making difficult the correct diagnosis. Consequently, biological biomarkers play a crucial role in directing physicians towards the right diagnosis. In particular, autoantibodies are offering the most reliable tools nowadays (Table 1). Additional tools, such as cytokines or genetic biomarkers (including non-coding RNA/DNA) are quite promising but not useful in practice at the moment.

Table 1. Autoantibodies in SARD

Antibody/abbreviation Disease
Rheumatoid factor (RF)

Anti-citrullinated protein antibodies (ACPA)

 Rheumatoid arthritis
Anti-nuclear antibodies (ANA)

Anti-double stranded DNA antibodies (anti-dsDNA)

Anti-Sm antibodies (anti-Sm)

Lupus anticoagulant (LA)

Anti-cardiolipin antibodies (anti-CL)

 Systemic lupus erythematosus
ANA

Anti-topoisomerase I

Anti-centromere A,B,C (anti-CENP A,B,C)

Anti-RNA polymerase III

 Systemic sclerosis
Anti-SSA/Ro

Anti-SSB/La

RF

ANA

 Sjogren’s syndrome
Anti-U1 ribonucleoprotein (anti-U1 RNP) Mixed connective tissue disease
ANA Undifferentiated connective tissue disease
LA

Anti-CL

Anti-beta2-glycoprotein I antibodies (anti-b2GPI)

 Antiphospholipid syndrome
ANCA

Proteinase 3 (PR3)

Myeloperoxidase (MPO)

 ANCA-associated vasculitides

 

Autoantibodies represent well-accepted classification criteria and, in some cases, they are also entry classification criteria; the most recent examples are represented by anti-phospholipid antibodies (aPL) for APS and anti-nuclear antibodies detectable by indirect immunofluorescence or equivalent solid phase assays for SLE.4,5 From this point of view, they represent mandatory inclusion criteria for clinical trials.

Autoantibodies in diagnosis                    

SARD are chronically evolving disorders characterised by the production of autoantibodies, even years before the appearance of the clinical manifestations. Because of the non-specific clinical symptoms at the beginning of the SARD, the detection of autoantibodies is a useful diagnostic tool. By contrast, early diagnosis is mandatory in order to start treatment before irreversible tissue damage takes place. This approach results in a better prognosis (that is, less organ damage) and in the reduction of the costs of the disease. The most common approach is the use of screening assays (for example, ANA detection) for supporting the suspect of the autoimmune origin of the disease and then the request for autoantibody profiles for identifying autoantibodies associated to SLE-, SSc-, SS- or AM-like disorders6 (Table 2).

Table 2. Autoantibodies and their associations with clinical manifestations in SARD

Autoantibody Disease association Clinical manifestations
anti-topoisomerase I SSc ILD, digital ulcers, diffuse skin involvement, heart involvement
anti-CENP A, B, C SSc PAH, bowel involvement, digital ulcers, limited skin involvement
anti-RNA polymerase III SSc SRC, tendon friction rubs, severe diffuse skin involvement
anti-U3 RNP SSc PAH, myositis, heart involvement, diffuse skin involvement
anti-U1 RNP SSc, SSc/PM overlap, SLE, MCTD Myositis, PAH, arthritis, limited skin involvement
anti-PM-Scl PM/DM, SSc/myositis overlap, SSc Myositis, limited skin involvement
anti-Th/To SSc PAH, ILD, bowel involvement, limited skin involvement
anti-U11/U12 SSc ILD
anti-mitochondria PBC/lcSSc and PBC/SS overlap Cholestatic liver disease
anti-Ku SLE, SSc, SLE/PM/SSc and PM/SSc overlap Myositis, arthritis
anti-dsDNA SLE Nephritis, disease activity
anti-Ro/SSA SLE, SS, SCLE Haematologic disorder, photosensitivity, neonatal lupus, C2 deficiency
anti-aminoacyl-tRNA synthetases

(anti-Jo1, -PL7,

-PL12, -EJ,  -OJ,

-KS, -Zo, -YRS)

 PM/DM Myositis, ILD, mechanic’s hands
anti-ribosomal P protein SLE Neuropsychiatric manifestations
anti-histones SLE Drug-induced lupus
anti-nucleosomes SLE, APS Drug-induced lupus, nephritis, disease activity
anti-C1q SLE Active renal disease
anti-citrullinated proteins RA Severe disease
LA, anti-CL, anti-b2GPI APS Thrombosis, miscarriages
 
ILD, interstitial lung disease; SRC, scleroderma renal crisis; PAH, pulmonary arterial hypertension; PM, polymyositis; DM, dermatomyositis; lcSSc, limited cutaneous systemic sclerosis; SCLE, sub-acute cutaneous lupus erythematosus
 

Autoantibodies are also widely used for disease subgrouping. For example, SSc patients sub grouped according to the presence of anti-topoisomerase or anti-centromere autoantibodies display different clinical picture and evolution.7,8 The same is also the case for the autoantibodies detectable in a different AM.9

The presence of different autoantibody profiles is useful for risk stratification in some diseases. The best example is represented by APS, in which the number of tests positive for aPL (that is, lupus anticoagulant, anti-cardiolipin, anti-b2 glycoprotein) or the aPL titres are risk factors. In other words, the higher the number of positive tests (triple or double versus single positivity) or the antibody titres, the higher the risk for thrombosis or miscarriages.10

SARD subgrouping and risk profiling allow a better disease characterisation and ultimately the best treatment approach according to precision (or personalised) medicine.

In addition to their defined role in the diagnosis of AID, a number of autoantibodies represent biomarkers for damage or involvement of particular tissues or organs, making them important in defining relevant comorbidities. This is the case for anti-C1q antibodies closely associated with active renal disease in SLE11 (Table 2).

The presence of an autoantibody might be the determining factor for starting primary prophylactic therapy, even in the absence of overt clinical signs, in order to reduce the risk of the clinical manifestations. Anti-phospholipid antibodies are the most popular example, justifying antiplatelet therapy even in asymptomatic aPL-positive carriers or low-dose aspirin and heparin in pregnant women at high risk for miscarriages.10

Conclusions                     

Nowadays, autoantibody detection is performed by automated assays in high-throughput routine service laboratories. The availability of the new assays has uncovered many problems, including quality control, quality assurance, standardisation, analytical sensitivity/specificity, within and between laboratory reproducibility and clinical sensitivity. These aspects are all relevant to the overall clinical interpretation of the tests and several international standardisation initiatives are currently ongoing.12,13

References

  1. Meroni PL et al. Standardization of autoantibody testing: a paradigm for serology in rheumatic diseases. Nat Rev Rheumatol 2014;10(1):35–43.
  2. Aletaha D et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62(9):2569–81.
  3.  Barturen G et al. Moving towards a molecular taxonomy of autoimmune rheumatic diseases. Nat Rev Rheumatol 2018;14(3):180.
  4. Miyakis S et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4(2):295–306.
  5. Aringer M et al. Classification criteria for systemic lupus erythematosus (in press).
  6. Meroni PL, Borghi MO. Diagnostic laboratory tests for systemic autoimmune rheumatic diseases: unmet needs towards harmonization. Clin Chem Lab Med 2018;56(10):1743–8.
  7. Didier K et al. Autoantibodies associated with connective tissue diseases: What meaning for clinicians? Front Immunol 2018;9:541.
  8. Choi MY, Fritzler MJ. Progress in understanding the diagnostic and pathogenic  role of autoantibodies associated with systemic sclerosis. Curr Opin Rheumatol 2016;28(6):586–94.
  9. Palterer B et al. Bench to bedside review of myositis autoantibodies. Clin Mol Allergy 2018;16:5.
  10. Chighizola CB et al. The treatment of anti-phospholipid syndrome: A comprehensive clinical approach. J Autoimmun 2018;90:1–27.
  11. Gensous N et al; FHU ACRONIM. Predictive biological markers of systemic lupus erythematosus flares: a systematic literature review. Arthritis Res Ther 2017;19(1):238.
  12. Monogioudi E et al. Standardization of autoimmune testing – is it feasible? Clin Chem Lab Med 2018;56(10):1734–42.
  13. Conrad K et al. From autoantibody research to standardized diagnostic assays in the management of human diseases – report of the 12th Dresden Symposium on Autoantibodies. Lupus 2016;25(8):787–96.

European Commission approval for self-administration of Xolair® across all indications

Novartis has announced that the European Commission (EC) has approved Xolair® (omalizumab) prefilled syringe (PFS) for self-administration, allowing patients with severe allergic asthma (SAA) and chronic spontaneous urticaria (CSU) to administer their own treatment.
 
With this approval, Xolair is the first and only biologic to offer the option of self-administration for SAA and CSU.
 
Xolair, which targets immunoglobulin E (IgE), is the first and only biologic to be approved in the European Union, Iceland, Norway, and Liechtenstein for self-administration (or administration by a trained caregiver) for the treatment of SAA in patients 6 years of age and older that have difficulty in controlling their asthma symptoms and for CSU in patients 12 years of age and older who continue to have hives that are not controlled by H1 antihistamines. Studies in severe allergic asthma and chronic spontaneous urticaria have shown that appropriately trained patients can effectively self-administer Xolair at home.1-3
 
The efficacy of Xolair has been demonstrated in large-scale clinical trials and real world studies. Xolair has been shown to reduce severe exacerbations and corticosteroid use in SAA1, as well as rapidly reduce symptoms in CSU.4
 
The EC approval will allow patients with no known history of anaphylaxis to self-inject Xolair PFS, or be injected by a trained lay-caregiver, from the fourth dose onwards, if a physician determines that this is appropriate.5 The patient or the caregiver must have been trained in the correct sub-cutaneous injection technique and the recognition of the early signs and symptoms of serious allergic reactions.5
 
“Today’s positive news is a big step forward for patients living with immunoglobulin E- mediated asthma and chronic spontaneous urticaria. Decreasing the number of regular clinic visits allows patients the flexibility to fit their treatment around their lives and helps to reduce the burden of these diseases. It also allows physicians a greater capacity for patients who need extra care, which is important” said Professor Dr Karl-Christian Bergmann, Allergy Center Charité, Berlin.
 
Administered via injection every two or four weeks, Xolair is widely used and well tolerated.6 With 13 years of physician experience in Europe and one million patient years of exposure, use of Xolair in SAA and CSU is supported by a wealth of evidence from randomised clinical trials and real-world studies.1-3 Anaphylactic reactions were rare in clinical trials (≥ 1/10,000 to < 1/1000)5 and via post-marketing reports (approximately 0.2%).5
 
References
  1. Liebhaber M, Dyer Z. J Asthma 2007;44(3):195-196.
  2. Ghazanfar M,Thomsen S. J Dermatolog Treat 2018;29(2):196.
  3. Denman S et al. Br J Dermatol 2016;175(6):1405-1407.
  4. Maurer M et al. N Engl J Med 2013;368(10):924-935.
  5. Xolair® Summary of Product Characteristics. Novartis Europharm Limited. Last accessed: December 2018.
  6. Humbert M et al. Allergy 2005;60(3):309-316.

The role of NGS in myeloid leukaemia: Part 1

13th December 2018

Myeloid malignancies are complex clonal diseases arising in haematopoietic stem or progenitor cells. These heterogenous disorders comprise many different subtypes such as myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and acute myeloid leukaemia (AML).
 
There is a growing need for molecular profiling of these blood and bone marrow disorders to provide better definition and classification to inform diagnosis, prognosis and the development of novel therapies.
 
Next generation sequencing (NGS) offers the promise of being able to detect rare and subclonal mutations, profiling the cancer genomics, enabling the high-throughput determination of DNA mutations, facilitating precision medicine and more.1 High-throughput, massively parallel sequencing makes it possible to detect somatic and germline mutations – even though these typically present at only a low level. NGS is different from traditional sequencing methodologies with respect to its precision and scale: case in point, NGS can detect multiple mutations in 19,000 genes – simultaneously.2
 
NGS: An abbreviated history 
The story of NGS can be traced back to 1977 with the debut of the Sanger Sequencing method. Around a decade later, the $3B Human Genome Project began and the first draft sequence assembly was eventually published in 2001 as a result of a yeoman’s effort by hundreds of scientists and terrific advances in sequencing technology. Along the way, George Church spurred the development of multi-plexing.3 Fast-forward to today and the exciting era of NGS-enabled $1K whole genome sequencing capabilities that can be executed by an individual in only one day.4
 
NGS provides coverage of up to 98% of the targeted sequence regions2 and hence has the enormous potential to accelerate the discovery of genetic disorders and pharmacogenetic markers for personalised medicine treatments. The application of NGS testing of clonal myeloid malignancies is expanding with broad utility across major clinical utility categories including diagnostics and prognostics. There are numerous factors to consider before deciding which NGS strategy will best meet your research and/or clinical diagnostic needs.
 
Variants have high utility across multiple applications
NGS provides clinicians with a powerful diagnostic tool when patients present with unusual clinical outcomes and/or complex phenotypes. Until recently, NGS was an expensive, time-consuming and daunting approach. The resultant data volumes alone were troublesome and spawned a whole new field of science – bioinformatics.
 
NGS was adopted quickly by the scientific community largely because of its highly parallel approach to sequencing. However, the adoption rate was also driven in part by its inherent synergy with more conventional molecular technologies such as qPCR. In balancing time-to-results, multi-target testing and standardization, both are complementary. Specifically, qPCR is highly standardised, offers fast results, is commonly utilised in all labs but is limited with respect to target-plexing. Comparatively, NGS has high target-plexing, the data interpretation is more complicated and standardisation is in progress but not yet fully defined. That said, NGS has forever altered how clinicians and researchers alike approach the discovery and application of new treatments. And, NGS could potentially relieve some of the healthcare deficit, protect millions of people from adverse drug reactions and identify health issues if applied in the screening of the five most common health disorders in the USA (cardiovascular, stroke, cancer, COPD and diabetes).3
 
There are multiple clonal disorders of haematopoietic stem cells including AML, myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia (CMML), among others that can also be screened for using NGS. There is a growing need for molecular characterisation of these heterogenous blood and bone marrow disorders. The massively parallel nature of NGS affords clinical researchers with unprecedented insights into the genetic drivers of myeloid malignancies.
 
A number of key genes have been identified as oncogenic and many can now be readily detected and used to classify these disorders via NGS.5 For example, targeted gene sequencing with a focus on the most critical mutations (for example, SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2) can detect gene abnormalities in nearly 90% of MDS patients. Numerous molecular markers have been identified which enable the stratification of AML patients which, in turn, informs treatment decisions through a prognostic utility.6 The WHO classification of myeloid neoplasms and acute leukaemia was heavily revised in 2016 in response to the multitude of biomarkers and other molecular markers that have been identified since the guidelines were first institutionalised in 2008.7 Diagnosis (which myeloid malignancy) and prognosis (risk ranges from low and favorable to high and adverse) are affected by which variants are expressed.
 
Therapeutic utility is also afforded via NGS and the identification of genes and/or groups of genes which have been targeted in the development of treatments. The target specificity of such treatments, which includes approved drugs as well as those currently involved in clinical trials, allows for a precision medicine approach where the therapeutic treatment is tailored to the genetic variant(s) identified.8 Despite the large number of variants, a well-designed NGS assay can effectively capture all the variants in a single experiment and an integrated data analytics solution can greatly aid interpretation.
 
References
  1. https://www.nature.com/collections/jmgqdxpvsk/content/content
  2. http://pediatrics.aappublications.org/content/137/Supplement_1/S3
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437232/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633438/
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807384/
  6. https://www.ncbi.nlm.nih.gov/pubmed/27276561
  7. https://www.ncbi.nlm.nih.gov/pubmed/27069254
  8. http://www.hematology.org/Thehematologist/Mini-Review/5496.aspx

Collaborative discovery of microbiome-based biomarkers for IBD

BiomX Ltd, a microbiome company developing customised phage therapies,  has entered into a collaboration with Janssen Research & Development to utilise BiomX’s XMarker microbiome-based biomarker discovery platform. The XMarker platform will be used to stratify responders and non-responders to inflammatory bowel disease (IBD) therapeutics.
 
The collaboration was facilitated by Johnson & Johnson Innovation Limited.
 
“The XMarker platform was created for BiomX’s microbial target discovery, based on the advanced algorithms developed by our scientific founders and our internal computational team,” stated Jonathan Solomon, CEO of BiomX. “Beyond target discovery, we believe that our microbiome analytics holds great promise for the development of a new class of biomarkers in major disease areas such as liver disease, cancer and IBD.”
 
There is growing evidence that the composition of the microbiome is a promising predictive tool for disease and for patient response to therapy in conditions such as IBD, cancer and liver disease. BiomX’s novel XMarker platform applies a unique metagenomics-based approach to decipher full microbial genomic signatures that can be further developed into predictive biomarkers. The platform combines ultra-high-resolution DNA analysis, machine-learning techniques and high-scale cloud computing resources to build classifiers of high sensitivity and specificity.

England’s chief pharmacist appointed to probe ‘problematic’ overprescribing in NHS

12th December 2018

The Government has chosen England’s chief pharmacist to look into “problematic” overprescribing in the NHS, it has announced.

Health and Social care secretary Matt Hancock revealed last week (8 December) that the Government will look into overprescribing to address “problematic polypharmacy” and ensure patients receive the treatment they need.

The review will be conducted by England’s chief pharmaceutical officer Dr Keith Ridge, the Government said.

The review will mainly focus on addressing “problematic polypharmacy”, where needed, and reducing overprescribing, the Government said.

Dr Ridge will be tasked with ensuring pharmacists and doctors receive the support they need to review prescriptions and provide patients with “the most appropriate treatment for their needs”, the Government said. 

He will look in particular at situations where there is a potential overlap of multiple medicines prescribed to treat the same condition and where people are subject to repeat prescriptions without being reviewed.

Mr Hancock said: “Recent advances in medicine have led to fantastic developments in managing and treating certain conditions, but poorly managed prescribing can lead to serious issues for patients such as increased admissions to hospital or antibiotic resistance.

“As we invest an extra £20.5bn a year into our NHS, we want to empower doctors and pharmacists to use the data available to ensure patients get the medicines they need and stop taking those that no longer benefit them.”

According to the Government, NHS spending on medicines has risen by 5% a year between 2010 and 2018, from £13bn to £18.2bn.

Study shows women having a heart attack wait longer than men to get help

11th December 2018

Women are being urged to call an ambulance immediately if they have heart attack symptoms, following research showing they wait longer than men to get help. The study has been published in European Heart Journal: Acute Cardiovascular Care, a publication of the European Society of Cardiology (ESC).1

Ischaemic heart disease is the leading cause of death in women and men. There is a misconception that heart attacks are a ‘man’s problem’ but they are just as common in women. On average, women are about 8-10 years older than men when they have a heart attack and they tend to experience different symptoms. But women benefit equally from fast treatment.

Study author Dr Matthias Meyer, a cardiologist at Triemli Hospital, Zurich, Switzerland, said women may wait longer due to the myth that heart attacks usually occur in men and because pain in the chest and left arm are the best known symptoms. “Women and men have a similar amount of pain during a heart attack, but the location may be different,” he said. “People with pain in the chest and left arm are more likely to think it’s a heart attack, and these are usual symptoms for men. Women often have back, shoulder, or stomach pain.”

In heart attacks caused by acute blockage of an artery supplying blood to the heart, rapid reopening of the vessel by inserting a stent is critical. Faster restoration of blood flow translates into more salvaged heart muscle and less dead tissue, less subsequent heart failure, and a lower risk of death. During the last 10-15 years, multiple strategies have been employed within heart attack treatment networks to reduce the time delay between symptoms and treatment. This study investigated whether delays have reduced in women and men.

The study was a retrospective analysis of all 4360 patients (967 women and 3393 men) with acute ST-segment elevation myocardial infarction (STEMI) treated at Triemli Hospital, the second largest percutaneous coronary intervention (PCI) centre in Switzerland, between 2000 and 2016.

The primary outcomes of interest were changes in patient delay (the time from symptom onset to contact with a hospital, emergency medical service, or general practitioner), and system delay (the subsequent time until reopening of the vessel). The secondary outcome of interest was in-hospital mortality.

During the 16-year period, women and men had equal reductions in system delays. Dr Meyer said: “We found no gender difference in the timely delivery of care by health professionals, with both men and women receiving a stent more quickly after contacting the medical services than they did in the past.”

However, patient delay decreased slightly in men over the 16-year period but did not change in women. Women wait approximately 37 minutes longer than men before contacting medical services. Clinical signs of persistent chest discomfort were associated with shorter patient delays in men but not women. “Women having a heart attack seem to be less likely than men to attribute their symptoms to a condition that requires urgent treatment,” said Dr Meyer.

In-hospital mortality was significantly higher in women (5.9%) than men (4.5%) during the study period. Delays were not associated with in-hospital mortality after correcting for multiple factors. Dr Meyer said: “As expected, the acute complications of a heart attack drive in-hospital mortality rather than delays. But we do know from previous studies that delays predict long-term mortality.”

He concluded: “Every minute counts when you have a heart attack. Look out for moderate to severe discomfort including pain in the chest, throat, neck, back, stomach or shoulders that lasts for more than 15 minutes. It is often accompanied by nausea, cold sweat, weakness, shortness of breath, or fear.”

Reference

  1. Meyer MR et al. Gender differences in patient and system delay for primary percutaneous coronary intervention: current trends in a Swiss ST-segment elevation myocardial infarction population. European Heart Journal: Acute Cardiovascular Care 2018. DOI: 10.1177/2048872618810410.

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