New technology could lead to quicker diagnoses of infectious diseases

15th January 2019

Could the gut microbiome help prevent the development of cow’s milk allergy?

Scientists at the University of Chicago have found that gut microbes from healthy human infant donors transplanted into mice protected animals exposed to milk from experiencing allergic reactions, while gut microbes transplanted from infants allergic to milk did not.

The study, published in the journal Nature Medicine, was supported in part by NIH’s National Institute of Allergy and Infectious Diseases.

Researchers transplanted gut microbes from each of eight infant donors into groups of mice raised in a sterile environment and sensitised to milk protein — meaning the animals’ immune systems created allergic antibodies to milk.

When later exposed to milk, mice receiving no microbes or microbes from milk-allergic children produced allergic antibodies and experienced anaphylaxis. Mice receiving gut microbes from non-allergic infants had no reactions.

Investigators then analysed microbes in infant stool samples, finding many differences between the stool of infants who were allergic to milk and those who were not.

Mice transplanted with microbes from non-allergic infants also harboured a family of microbes previously found to protect against developing food allergies. Further experiments identified one microbe, Anaerostipes caccae, that prevented the development of milk allergy when transplanted alone into groups of mice.

Researchers then sampled cells along the mice’s gut linings — where food allergies in mice and humans begin to develop. They found that mice that received microbes from non-allergic infants expressed different genes compared to those that did not, suggesting that microbes residing in the gut impact the host’s immune system.

The researchers conclude that intestinal microbes play a critical role in regulating allergic responses to food and suggest that further research could lead to microbiome-modifying therapies to prevent or treat food allergy.

Fulfilling a promise to Mosul with point-of-care ultrasound

8th January 2019

Dr Henryk Pich spent time travelling in the Middle East as a young man. Not surprisingly, he feels a personal connection to the region and, after seeing the devastation caused by years of war to cities such as Mosul, wanted to offer whatever help he could.

He contacted CADUS, an independent German aid organisation building mobile clinics for areas with significant need and, once the fighting had ended, joined a highly skilled, inter-disciplinary team of paramedics, nurses, doctors, technicians and project managers working in Mosul.

His first trip centred on a refugee camp outside of Mosul providing primary healthcare to the hundreds of thousands of refugees displaced from their homes, from where the team visited the specialist women and children’s teaching hospital in Mosul, the Al Khansaa Hospital.

The experience formed a lasting impact on Dr Pich: “The Al Khansaa used to be one of the biggest hospitals in Northern Iraq – with 300 beds for women and children’s services and a high quality reputation in the wider region – yet 85 % of the hospital and its resources had been destroyed or stolen. The staff are very well trained, but there is a lack of equipment. There is a lot of improvisation and many things have to run at a rudimentary level. I naturally expressed my concern and desire to help as much as I could and pledged to return.”

Dr Pich is passionate about ultrasound, particularly in the specialties of regional anaesthesia and emergency medicine, and uses his skills to educate others whenever possible. He explained: “Point-of-care ultrasound is a vital resource for intensivists and emergency physicians around the world. It enables a quick and accurate diagnosis, guides life-saving interventions, and operates as the ‘eyes and hands’ of modern-day doctors. The reliability, durability and portability of some ultrasound systems make them ideally suited to use in war-torn destinations, and it made sense to me to return with an appropriate ultrasound machine and training resources.”

The potential impact of a new point-of-care ultrasound system in the Mosul hospital could be far-reaching, and so Dr Pich approached FUJIFILM SonoSite for support for his return mission and a SonoSite M-Turbo system was donated. Dr Pich explained: “I know this machine well and was very happy to take it to Mosul. It is small, light and easy to carry in one hand. It has excellent probes of various types that are resilient and reliable, and the whole system is intuitive to use and easy to teach to others. In a critical care setting, time is of the essence and this ultrasound machine boots up within a few seconds and is ready for use straightaway.”

With the ultrasound system arranged, Dr Pich had clear objectives for his next visit – to hand over the machine and, alongside an Arabic translator, deliver a training course in regional anaesthesia and emergency ultrasound. “In Germany I carry out a lot of FAST (focused assessment with sonography for trauma) scans, and planned to teach this technique to my Iraqi colleagues, as well as lung scans and guidance for nerve blocks.”

Dr Pich was eager to see how life had changed for the people of Mosul since his visit the previous year: “There is some life on the streets again, security has greatly improved and, although there is still a lack of basic materials in the hospital, staff continue to work there with enthusiasm and dedication. It was a pleasure to hand over the M-Turbo and deliver the training course to surgeons and radiologists. I talked about regional anaesthesia, guiding needle insertion, and how to interpret views of structures and identify nerves; I had a practice pad and needles with me, so they could each experience a simulated exercise. Then one radiologist on the course was very keen to use it to guide her in taking biopsies of breast tissue, which was an application of the device that I hadn’t foreseen. As soon as the course was over, the Iraqi attendees took the M-Turbo to the emergency room to assess a woman with a hernia in the abdominal wall – it was very satisfying to see it being used immediately and effectively to raise the level of care they could provide.”

Dr Pich continues to be involved with CADUS and is now working with them to plan ongoing support for Al Khansaa in the future: “It is very important for us to keep the connection with our colleagues in Mosul, not only to encourage more donations but also to transfer knowledge and skills. I am very grateful to SonoSite for its generosity and think the M-Turbo was just the right piece of equipment they needed. I felt a large sense of responsibility transporting this valuable machine to a war-stricken country, for people who really needed it, but I am very pleased with what we were able to accomplish. The most satisfying aspect of this experience is knowing that I fulfilled my promise to the dedicated staff at Al Khansaa, to bring resources and education that could help them deliver, and raise, the quality of care the women and children in Mosul so desperately need.”

New plan for NHS tackling ‘major killer conditions’ to save up to 500,000 lives

The NHS Long Term Plan, published today (7 January) outlines how over three million people will be treated from new stroke, respiratory and cardiac services over the next decade.

The measures, supported by £4.5bn in new service model funding, will help prevent over 150,000 heart attacks, strokes and cases of dementia, according to the plan.

Measures in the plan will also help over three million people through improved stroke, respiratory and cardiac services over the next 10 years, it said.

Around 30,000 people with dangerously high inherited cholesterol levels will be genetically tested –around a quarter of those affected.

Roughly 80,000 hospital admissions could be avoided through investing in earlier detection and better treatment of respiratory conditions. Smart inhalers will also be piloted, allowing patients to monitor their condition at all times.

Every hospital with a major A&E department will offer same day emergency care, meaning that patents will be treated and discharged in the same day, avoiding the need for overnight stays.

NOVESA Phase IIa trial in patients with systemic sclerosis initiated

7th January 2019

Janssen seeks EMA approval of Stelara for adults with ulcerative colitis

Janssen has announced the submission of a Group Type II Variation Application to the European Medicines Agency (EMA) seeking approval of Stelara^® (ustekinumab) for the treatment of adults with moderately to severely active ulcerative colitis (UC).

Ustekinumab is a human monoclonal antibody that targets the interleukin (IL)-12 and IL-23 cytokines, which are believed to play an important role in the immune and inflammatory responses seen in immune-mediated diseases, such as UC and Crohn’s disease.¹

This submission follows a supplemental Biologics License Application (sBLA) made to the United States’ Food and Drug Administration (FDA) on December 20, 2018, which also seeks approval of ustekinumab for the treatment of adults with moderately to severely active UC.

“Ulcerative colitis (UC) is a chronic, painful and debilitating condition that has a significant impact on quality of life. UC affects up to one million people across Europe, and some of these patients struggle to achieve and maintain high levels of clinical response with currently available therapies. This submission for ustekinumab in UC brings us one step closer to providing a new treatment option to help address this important unmet need,” said Jaime Oliver, MD, Janssen Therapeutic Area Lead, Immunology, Europe, Middle East & Africa, Cilag GmbH International. “We look forward to working with the European Medicines Agency (EMA) as the application process progresses.”

This submission is based on data from the Phase III UNIFI global clinical development programme, which includes two studies (one induction and one maintenance study) evaluating the efficacy and safety of ustekinumab for the treatment of moderately to severely active UC in adults. Data from the Phase III induction study were recently presented at the 2018 American College of Gastroenterology (ACG) and United European Gastroenterology Week (UEGW) annual meetings, indicating that treatment with a single intravenous (IV) dose of ustekinumab induces clinical remission and response in adults with moderately to severely active UC who previously experienced an inadequate response or intolerance to conventional or biologic therapies.² Results from the Phase III maintenance study will be presented at future scientific meetings.

“We’re excited to bring this innovative therapy, with a proven track record in Crohn’s and other immune diseases, one step closer to being available for people living with ulcerative colitis,” said Scott E Plevy, MD, Gastroenterology Disease Area and IL-23 Pathway Leader, Janssen Research & Development, LLC. “This submission builds upon our 20-year legacy of research and development to address unmet needs of people living with inflammatory bowel diseases.”

The common (in ≥1% of patients) adverse reactions reported in controlled periods of the adult psoriasis, psoriatic arthritis and Crohn’s disease clinical studies with ustekinumab as well as in the post-marketing experience are: arthralgia, back pain, diarrhoea, dizziness, fatigue, headache, injection site erythema, infection site pain, myalgia, nasopharyngitis, nausea, oropharyngeal pain, pruritus, upper respiratory tract infection and vomiting.³

References

1. Croxford A et al. IL-23 and IL-23 in health and disease. Cytokine Growth Factor Rev. 2014;25(4):415–21.
2. Sands B et al. Safety and efficacy of ustekinumab induction therapy in patients with moderate to severe ulcerative colitis: results from the Phase 3 UNIFI study. United Europe Gastroenterology Week (UEGW) 2018, Vienna, Austria. 20–24 Oct 2018: LB01.
3. European Medicines Agency. Ustekinumab Summary of Product Characteristics. https://www.ema.europa.eu/en/medicines/human/EPAR/stelara. Last updated December 2018; last accessed December 2018.

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.”

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

17th December 2018

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5. Xolair^® Summary of Product Characteristics. Novartis Europharm Limited. Last accessed: December 2018.
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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

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

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.

Most accurate tool yet developed to predict asthma in young children

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.