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

New, non-invasive test for bowel diseases

1st July 2019

A new study proposes a novel, non-invasive test for assessing gut function that may help screen and monitor treatment of gut diseases using only a small sample (1ml) of blood and stool. 
 
How well your gut functions is determined by the gut-blood barrier , a complex multi-layer system. In those with IBD, and other intestinal diseases, the gut-blood barrier is impaired. Here the intestinal wall is more like a ripped sieve, allowing more bacterial products to pass from the gut into the blood. This is commonly referred to as a leaky gut.
 
This test measures the concentration of gut bacterial products (produced by bacteria during metabolism) in the patient’s blood and stool. The authors believe that with further research this assessment of gut leakage will be very important in the diagnosis and treatment of IBD and other intestinal diseases.
 
The usual strategy for diagnosing and monitoring IBD is based on a colonoscopy, which is invasive, often requires anaesthesia, and assesses structural lesions, rather than gut malfunction. Gut disorders can happen before there are visible structural changes, so diagnosing based on functional tests evaluating gut leakage could allow clinicians to detect the disease earlier. While there is no cure for IBD, it is controllable. Early diagnosis would enable patients to control symptoms before they became severe, improving their quality of life.
 
This new research provides a non-invasive, simple test that could not only be useful for diagnosing IBD, but also other gut disorders, such as coeliac disease and food allergies. It is also helpful for detecting diseases that result in a leaky gut, such as heart failure, high blood pressure and liver ailments.
 
Marcin Ufnal, senior author on the study said: “This may be a very important tool for diagnosis and treatment of gut and other diseases, using the leaky gut as a marker for disease, as well as a potential target for treatment. “
 
Reference
  1. Jaworska K et al. Inflammatory bowel disease associates with increased gut-to-blood penetration of SCFA: A new, noninvasive marker of a functional intestinal lesion. Experimental Physiology 2019;DOI: 10.1113/EP087773

New data demonstrate impact of emapalumab in patients with macrophage activation syndrome

20th June 2019

SOBI has announced that new research demonstrating the effects of emapalumab in patients with macrophage activation syndrome (MAS), a form of secondary haemophagocytic lymphohistiocytosis (HLH) complicating systemic juvenile idiopathic arthritis (sJIA), was presented at the EULAR/Paediatric Rheumatology European Society (PReS) Scientific Congress in Madrid.  
 
The study showed that treatment with emapalumab led to rapid neutralisation of interferon gamma (IFNγ) and a complete response in all patients who participated in the study. Furthermore, emapalumab demonstrated a favourable safety profile. Emapalumab has previously been shown to induce rapid and sustained responses in patients with primary HLH.
 
Emapalumab is FDA-approved for paediatric (newborn and older) and adult patients with primary HLH with refractory, recurrent or progressive disease or intolerance to conventional HLH therapy.
 
The data was also recognised with the Gold PReS KOURIR Award during the conference.
 
MAS is a rare, life-threatening condition characterised by uncontrolled hyperinflammation which may develop on a background of rheumatic diseases such as sJIA. It is classified as a secondary form of HLH and is caused by excessive activation and expansion of T cells and macrophages. A vast body of evidence has been accumulated which points to uncontrolled overproduction of IFNγ as a major driver of hyperinflammation and hypercytokinaemia in diseases such as MAS and HLH.
 
“It is extremely encouraging to see a complete response in the first six patients treated with emapalumab, particularly considering that MAS is a serious and potentially fatal complication, and that all of these patients had failed other treatments,” said Dr. Fabrizio De Benedetti, Head of the Division of Paediatric Rheumatology and Head of the Laboratory of ImmunoRheumatology, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
 
The new data represents the results of an on-going international pilot study, in which six MAS patients with a background of sJIA and inadequate response to high-dose intravenous glucocorticoids received emapalumab according to the prescribed dose regimen required per protocol.
 
Emapalumab is a monoclonal antibody that neutralises interferon gamma (IFNγ), a key cytokine which contributes to the inflammation and tissue damage seen in MAS. The purpose of the study is to assess the drug’s pharmacokinetics, efficacy and safety for treatment of MAS and to confirm the proposed dose regimen.

First lung map uncovers new insights into asthma

For the first time, researchers have mapped the building blocks of the human lungs and airways, in both asthma patients and those without asthma. 
 
The research from the Wellcome Sanger Institute, University Medical Center Groningen, Open Targets, GSK and collaborators revealed the identity of each cell type, creating the first draft Human Cell Atlas of the lung. They also discovered an entirely new cell state that produces mucus in asthma patients.
 
The maps reveal the differences between asthmatic and normal airways and identify how cells in the lung communicate with each other. Understanding the cells and their signals could lead to finding new drug targets for treating asthma.
 
While it is often manageable with medication, asthma can cause ongoing problems and there is the risk of severe, life-threatening asthma attacks. A better understanding of healthy lung cells and the differences with asthmatic lungs is required to develop new effective medications.
 
To explore cell types within normal lungs and upper airways, researchers used single cell technology to study samples from 17 people. They analysed more than 36,000 individual cells from the nasal area and from three different areas of the lung. This allowed researchers to see exactly which genes were active in each cell and identify the specific cell type.
 
The researchers then detected the different cell types and activities in lung samples from six asthma patients, comparing them to normal lungs. They discovered there were clear differences between the cells in normal and asthmatic lungs. One symptom of asthma is an overproduction of mucus. However, not all the cells responsible for this were known. The researchers discovered a new mucus-creating cell state – the muco-cilliated state – in asthmatic lungs, that had not been seen before.
 
Dr Felipe Vieira Braga, a first author on the paper from the Wellcome Sanger Institute and Open Targets, said: “We have generated a detailed anatomical map of the respiratory airways, producing the first draft human lung cell atlas from both normal and asthmatic people. This has given us a better definition of the cell types in asthmatic lungs, and allowed us to discover an entirely new cell state in asthmatic patients that produces mucus.”
 
The study revealed large differences between normal and asthmatic lungs, in the cells and how they communicated with each other. The asthmatic lungs had many more inflammatory Th2 cells, which sent the vast majority of cellular signals in asthma, compared with a broad range of cell communications in normal lungs.
 
Dr Martijn Nawijn, a senior author from University Medical Center Groningen, said: “We already knew that inflammatory Th2 cells played a role in asthma, but only now do we see how great that influence is. In normal people, all kinds of cells communicate with each other in order to keep the airways functioning well. But in asthma patients, almost all of those interactions are lost. Instead of a network of interactions, in asthma the inflammatory cells seem to completely dominate the communication in the airways.”
 
Knowing the types of cells in asthmatic lungs and how they communicate, could help researchers seek new drug targets that could prevent the cells from responding to the inflammatory signals and help restore normal lung function.
 
The atlases also revealed that location was important for the lung cells. The study showed that cells in different areas of the lung had very different cellular activities. This has further implications for studying drug targets and designing drug trials.
 
Dr Sarah Teichmann, a senior author from the Wellcome Sanger Institute, University of Cambridge and Open Targets, and co-chair of the Human Cell Atlas Organising Committee, said: “As part of the Human Cell Atlas initiative, we have created the first comprehensive cellular map of the lungs. Our large-scale, open access data reveals the activity of different cells, their communication pathways and locations. The lung cell atlas will provide a great resource for further lung research and we hope that it will enable the identification of potential new therapeutic targets for asthma relief.”

Distinguishing helpful and harmful gut immune cells offers new view on inflammatory diseases

A type of immune cell that contributes to inflammatory bowel disease exists in two forms, ‘good’ and ‘bad’, and a new study from the Francis Crick Institute in London has characterised these distinct populations, which could help scientists to develop treatments targeting inflammation while preserving healthy gut function.
 
These two populations are akin to worker and soldier ants, playing different roles depending on their context.
 
The ‘worker ant’ population of immune cells is found naturally in the gut and helps keep the lining of the intestines healthy. The other population is triggered in response to infection by a pathogen. Similar to soldier ants, these immune cells are called in to help fight infection, travelling from lymph nodes – where they are produced – to the gut and other parts of the body to attack the invading pathogens. Although they are necessary to fight infection, these cells can cause excessive inflammation.
 
By studying the differences between these two cell populations in mice, a multidisciplinary research team has revealed potential ways to target the cells associated with immune-inflammatory diseases, while sparing the ones that help keep the gut healthy.
 
“Our findings may help ensure that future therapies for inflammatory diseases that target these cells do not inadvertently damage the resident intestinal population important for gut health,” says Gitta Stockinger, Francis Crick Institute group leader and senior author of the paper.
 
The results might also explain why attempts to target molecules released by these cells have been successful in inflammatory conditions affecting the skin (such as psoriasis) and nervous system (such as multiple sclerosis) but have failed in gut-specific conditions like Crohn’s disease.
 
T helper 17 (Th17) cells have a known role in inflammatory disorders, but also help to keep the gut lining healthy. Previous studies attempting to distinguish between these two functions have studied Th17 cells in isolation in culture dishes, failing to mimic the complex biology of the immune system and microbiome inside the body.
 
In this study, researchers at the Crick and King’s College London investigated Th17 cells in mice activated by either harmless microbes normally present in the gut (gut flora), or an intestinal pathogen equivalent to a type of E.coli in humans. They used genetically modified mice in which activated Th17 cells are fluorescently labelled, marking them for further analysis.
 
The gut flora-activated Th17 cells kept their function as a protective barrier and did not cause inflammation. By contrast, the pathogen-activated Th17 cells vigorously released pro-inflammatory signals and caused widespread inflammation.
 
To show that the two populations are distinct in the gut, the team infected gut-flora activated Th17 mice with the pathogen and used a drug to block any new Th17 cells from moving to the gut. The Th17 cells analysed were non-inflammatory, confirming that the resident Th17 are distinct from pathogen-activated Th17 cells and have a different role in the body. However, blocking the invasion of the fighter Th17 cells into the gut prevented the mice from successfully fighting off the infection.
 
“Th17 cells clearly have many roles in the body – and we need them to fight off infection and keep our intestines healthy,” says Gitta. “Any treatment for inflammatory disease would need to dampen the abnormal attack of Th17 cells on healthy tissues, without causing digestive complications or an inability to fight off germs.”
 
Computer analysis by Saeed Shoaie’s group at King’s College London, combined with cell biology analysis by Max Gutierrez’s group at the Crick, revealed that the two cell populations metabolised nutrients differently too. The flora-activated Th17 cells had minimal metabolic activity, similar to that of immune cells that stay dormant until they need to respond. In contrast, the pathogen-activated Th17 cells were very metabolically active, displaying a metabolic profile typical of cells that cause inflammation.
 
“The differences that we detected in the metabolism of these two cell populations give us a new opportunity to selectively target the pathogenic cells, while leaving the gut-resident ones intact,” says Sara Omenetti, Crick postdoc and first author of the paper. “This could form the basis of more successful treatments for Crohn’s and other conditions, where targeting Th17 cells in the gut can actually worsen symptoms.”

New standards raise the bar for IBD care

IBD UK, a partnership of 17 professional and patient organisations chaired by Crohn’s & Colitis UK, believe that people with IBD should receive safe, consistent, high-quality and personalised care, wherever they live and whatever their age, from diagnosis to treatment and ongoing monitoring, but unfortunately this is not currently the case.
 
Standards launching today (20 June 2019) aim to drastically improve how we care for people with IBD across the UK. Announced today at the British Society of Gastroenterology annual conference, these 59 statements set out what good care and treatment looks like for patients with the conditions, with the aim that every IBD service in the UK will work to meet these.
 
This work builds on previous IBD Standards, created in 2009, and updated in 2013, which underpin the 2015 NICE quality standard on IBD and were an integral component of the IBD Quality Improvement Programme in the UK supported by the Royal College of Physicians until 2015. Whilst significant improvements have been made, there is still much to be done to reduce variation.
 
Few services are able to offer their patients psychological support, there are a lack of IBD Nurse Specialists and half of patients wait over a year for their diagnosis.1 Not only this, the way we care for people with IBD has changed in the intervening years, with new therapy options, and a shift to self-management and personalised care and support.
 
The 2019 IBD Standards have been supported by active involvement from healthcare professionals representing organisations including the British Society of Gastroenterology, the Royal College of Nursing and the Royal College of General Practitioners,2 alongside input from another 150 through an online survey. As well as this, almost 700 patients were surveyed through Crohn’s & Colitis UK, CICRA and IA,3 about what is important to them regarding the care they receive.
 
In addition to the launch of the new IBD Standards, this year for the first time, IBD services will be benchmarked, measuring how their services meets the set of statements. From today IBD Services can register for the IBD Benchmarking Tool, and from 1st October they will be able to complete the self-assessment, involving gathering evidence and answering questions as a multidisciplinary team and with patients. Reports released in Q1 of 2020 will showcase these results, providing an opportunity to push through real change, support with business cases and shine a light on what services are doing well and areas they could improve.
 
Alongside the IBD Benchmarking Tool, IBD UK, supported by Crohn’s & Colitis UK, will be launching the first UK-wide IBD Patient Survey on 8 July to allow people with Crohn’s and Colitis to feedback anonymously on their service and care. The IBD Standards provide an opportunity to lead to real changes in the way care in the NHS is delivered to patients with Crohn’s and Colitis, creating a significant impact and influencing decision making.
 
Rukshana Kapasi, Chair of IBD UK says, “This is an exciting and groundbreaking opportunity for services and patients to work collaboratively leading to the shared priority of improving the lives of people with Crohn’s and Colitis. This version of the IBD Standards gives us the tools to drive up the quality of IBD Services and with that, the care for people with IBD. These comprehensive guidelines have included patient involvement throughout and have been endorsed by key professional organisations.”
 
References
  1. Crohn’s & Colitis UK survey, 2018
  2. Crohn’s & Colitis UK hosted online survey of 151 healthcare professionals, 2018
  3. Crohn’s & Colitis UK hosted online survey of 689 patients, 2018

Repurposing drugs or combining therapies could help in treating autoimmune disease

19th June 2019

Funded by Versus Arthitis, research led by the University of Birmingham’s Institute of Inflammation and Ageing and Institute of Cardiovascular Sciences has been published in Proceedings of the National Academy of Sciences.1
 
The research, a collaboration with the University of Oxford, University of Cambridge, University of York, Université Rennes in France, and the University of Lausanne in Switzerland, was supported by the National Institute for Health Research Birmingham Biomedical Research Centre.
 
Dr Saba Nayar, of the University of Birmingham, explained: “In this study, we found for the first time that fibroblasts – cells that play a critical role in healing – also play a key role in the process of the formation of tertiary lymphoid structures, which are small clusters of blood and tissue cells found at the sites of chronic inflammation.
 
“Inflammation is the body’s process of fighting against things that harm it, such as infections, injuries, and toxins, in an attempt to heal itself. When something damages cells, our bodies releases chemicals that trigger a response from our immune system.
 
“This response usually lasts for a few hours or days in the case of acute inflammation, however in chronic inflammation the response lingers, leaving your body in a constant state of alert. Chronic inflammation occurs in a range of conditions from cancer to arthritis and autoimmune conditions – illnesses or disorders that occur when healthy cells get destroyed by the body’s own immune system.”
 
Dr Joana Campos, also of the University of Birmingham, added: “Tertiary lymphoid structures are believed to play a key role in the progression of autoimmune conditions such as Sjögren’s Syndrome – a condition that affects parts of the body that produce fluids like tears and spit.
 
“Previously research has not identified the role fibroblasts play in the formation and maintenance of tertiary lymphoid structures.
 
“We proved that fibroblasts expand and acquire immunological features in a process that is dependent on two cytokines – substances which are secreted by cells including fibroblasts in the immune system.”
 
Dr Francesca Barone, also of the University of Birmingham, said: “Our research has led us to conclude that, by re-purposing already existing drugs or combining therapies, we could use these medications to directly target immune cells and fibroblasts to attack these cytokines in patients who have difficult to treat autoimmune diseases in which the formation of tertiary lymphoid structures plays a critical role.
 
“Our findings were surprising and unexpected and have addressed functional questions that the science community has been trying to address since tertiary lymphoid structures were first discovered.”
 
Reference
  1. Nayar S et al Immuno-fibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. PNAS 2019.

Expert view: JAK inhibitors in ulcerative colitis – raising an alert

18th June 2019

Cytokines are key drivers of immune-mediated diseases altering cell behaviour through reversible protein kinases mediate protein phosphorylation, a fundamental component of cell signalling. This function is executed within the cell and activates or deactivates pathways that change gene expression controlling most signal transduction cascades from cell growth and proliferation to the initiation and regulation of immunological responses.
 
Immunological responses are activated through pathogens or injury activating pro-inflammatory cytokine genes but in the absence of pathogens or continuation of activation  after resolution of injury can cause chronic inflammation. Several hundred protein kinases have been identified and associated with pro- and anti-inflammatory processes.1
 
The protein kinases can be targeted by small molecules inhibiting phosphorylation of proteins thereby preventing activation.  These small molecule inhibitors can interfere with kinase activity by either: (i) blocking adenosine triphosphate (ATP)-kinase binding, (ii) interfering with kinase–protein interactions or (iii) down-regulating kinase gene expression levels through the use of RNA interference strategies.2 Many kinase inhibitors have been successfully used in cancer therapy since the turn of the century. 
 
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, has been intensely researched and novel drugs are now in the final stages of development or have been introduced for the treatment of autoimmune disorders including rheumatoid arthritis, psoriasis and inflammatory bowel disease. JAKs are tyrosine kinases, transferring phosphate from ATP to tyrosine on other proteins including STATs, a family of DNA binding proteins driving gene transcription, a pathway not used by TNF-alpha, IL-1, IL17 or other cytokines introducing a different target in inflammatory diseases.
 
JAK inhibitors 
The JAK family comprises four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Tofacitinib, a first generation JAK inhibitor, is non-selective and was approved for rheumatoid arthritis initially by the US Food and Drug Administration in 2012, and then the European Medicines Agency (EMA) in 2017, after reviewing long-term data and efficacy at a dose of 5mg twice a day. In 2018, the EMA approved tofacitinib for ulcerative colitis (UC) with a loading dose of 10mg twice a day for 8–16 weeks with maintenance dose of 5mg twice a day. 
 
Adverse reactions (ADRs) are predictable based on the cytokines inhibited. It is yet to be seen if selectivity reduces the incidence of ADRs in the long term. 
 
Are JAKS safe?
Infection is a concern but it seems to be similar to other biologics. Increased risk of viral infections such as herpes zoster are associated with tofacitinib due to JAK inhibitory effects on the host defence system, which needs further investigations. Varicella Zoster Immunoglobulin status may inform prescribers about the need for vaccination prior to starting; however, tofacitinib does not affect the response to influenza vaccinations. 
 
Neutropaenia and anaemia are common with higher doses of tofacitinib, and need to be monitored carefully. 
 
Cardiovascular disease is a high risk for patients with autoimmune diseases but long-term data are needed to determine if JAK inhibition prevents, ameliorates, or exacerbates cardiovascular risk. Non-selective JAKs increase serum concentrations of low density lipoproteins and high density lipoproteins but it needs to be determined if this affects the cardiovascular risk of patients due to IL-6 inhibition.
 
The IL-6 blockade also raised concerns about gastrointestinal perforation but may also be due to the inhibition of other GI specific cytokines inhibited. This further highlghts the complex role JAK-dependent cytokines play in the host.
 
There do not seem to be signs of increased risk of haematological or solid organ malignancy linked to JAK inhibition, but long-term data are needed for confirmation.
 
On 20 March 2019, the EMA issued a safety alert for tofacitinib.3 Early results from an ongoing study in patients with rheumatoid arthritis (study A3921133) showed an increased risk of blood clots in the lungs and death when the normal dose of 5mg twice daily was doubled. The aim of the study was to look at the risks of heart and circulatory problems with tofacitinib in patients 50 years of age or older who were already at higher risk of these, and to compare its safety with a TNF inhibitor. It is not clear how this is translatable to the IBD community as 10mg BD is licensed as a loading dose in UC. The EMA recommends that patients receiving tofacitinib, irrespective of indication, should be monitored for the signs and symptoms of pulmonary embolism, and be advised to seek medical attention immediately if they experience them.
 
The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)4 is recommending that clinicians do not prescribe the 10mg twice daily dose of tofacitinib in patients with UC who have a history of blood clots, clotting disorders, or have had heart failure, cancer, or are taking combined hormonal contraceptives or hormone replacement therapy. The new advice means that, because 10mg is the only recommended starting dose for ulcerative colitis, patients with this condition who are at high risk of blood clots must not be started on Xeljanz. 
 
Other potential risk factors should also be taken into consideration before prescribing, says the EMA.
 
In view of the hypercoagulable state of IBD patients,5 the young female cohort likely to be on hormonal contraception and the ageing patient population newly diagnosed with IBD, this concerns raised in this alert should be discussed with the multidisciplinary team managing IBD patients.
 
References
  1. Patterson H, et al. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin Exp Immunol 2014;176:1–10
  2. Melnikova I, Golden J. Targeting protein kinases. Nat Rev Drug Discov 2004;3:993–4.
  3. European Medicines Agency. EMA alert 20/03/2019. Increased risk of blood clots in lungs and death with higher dose of Xeljanz (tofacitinib) for rheumatoid arthritis. www.ema.europa.eu/en/news/increased-risk-blood-clots-lungs-death-higher-… (accessed June 2019).
  4. European Medicines Agency. EMA press release 17/05/2019. Restrictions in use of Xeljanz while EMA reviews risk of blood clots in lungs. www.ema.europa.eu/en/documents/referral/xeljanz-article-20-procedure-res… (accessed June 2019).
  5. Owczarek D. Inflammatory bowel disease: Epidemiology, pathology and risk factors for hypercoagulability. World J Gastroenterol 2014;20(1):53–63.

Immuno-PET precisely diagnoses IBD inflammation without invasive procedures

Inflammation in inflammatory bowel disease (IBD) can be quickly and precisely diagnosed using a new type of nuclear medicine scan, according to research published in the June issue of The Journal of Nuclear Medicine.
 
Using immuno-positron emission tomography (immuno-PET) to image monoclonal antibodies directed against specific innate immune cell markers, investigators were able to effectively assess IBD in murine models. In addition, immuno-PET has high potential for theranostic diagnosis and precision treatment of IBD and other inflammatory diseases.
 
“The diagnosis and maintenance of IBD is heavily reliant on endoscopy, which is invasive and does not provide real-time information regarding the role of specific mediators and drug targets,” said Patrick A Hughes, PhD, head of the Gastrointestinal Neuro-immune Interactions Group, Centre for Nutrition and Gastrointestinal Disease at the University of Adelaide in Australia. “There is a need to develop less invasive tools that provide quick diagnostic information for IBD. This is particularly relevant when the area of inflammation is beyond the reach of the endoscope, such as difficult-to-access regions of the small intestine, and in patient populations that have increased risk in endoscopy, including paediatrics and haemophiliacs.”
 
Activation of the innate immune system is intimately linked to inflammation in IBD. Innate immune cells are marked by the cell surface receptor CD11b, and they secrete IL-1β to generate immune responses. In the study, the authors compared the ability of immuno-PET with 89Zr-conjugated antibodies against IL-1β and CD11b versus the ability of 18F-FDG PET and magnetic resonance imaging (MRI) to detect inflammation in colitic mice.
 
To evaluate the imaging methods, mice with ulcerative colitis were assessed daily for signs of acute colitis. Healthy mice were age- and weight-matched to the colitic mice, and comparisons were made regarding body weight loss, colon shortening and epithelial barrier permeability. Researchers then measured the levels of IL-1β and CD11b concentration, determining that the colitic mice had increases in these innate immune mediators.
 
Immuno-PET imaging revealed that in colitic mice, distal colonic uptake of 89Z-α-IL-1β was increased by approximately three-fold, uptake of 89Z-α-CD11b was increased by approximately five-fold and uptake of 18F-FDG was increased approximately 3.5 fold. MRI analysis showed an approximately two-fold increase in the T2 signal intensity ratio in colitic mice. A robust positive correlation was observed between colonic uptake of 18F-FDG and percentage body weight loss, with a strong trend toward a similar effect observed for 89Z-α-IL-1β, but not for 89Z-α-CD11b. MRI analysis of inflammation, however, did not correlate with percentage weight loss.
 
In addition, an ex vivo analysis indicated that the uptake of 89Z-α-IL-1β and 89Z-α-CD11b was increased throughout the entire gastrointestinal tract in colitic mice as compared to control mice. 89Z-α-IL-1β was distributed mainly in the gastrointestinal tract, while 89Z-α-CD11b was distributed to more tissue types. Furthermore, 89Z-α-IL-1β correlated with colitis severity, whereas 89Z-α-CD11b did not.
 
The comparison demonstrates the strong potential of immuno-PET of innate immune mediators for diagnosing and monitoring IBD, Hughes explains. “These findings are important for inflammatory diseases in general, as many of the biologics used to treat these diseases are directed against specific immune mediators; however, these drugs are also associated with primary and secondary non-response,” he adds. “Future refinements will lead to theranostic applications where the efficacy of drugs can be rapidly and non-invasively determined, leading to precision treatment not only in IBD, but also in other inflammatory diseases.”
 
Reference

Research highlights possible targets to help tackle Crohn’s disease

There is no precise cure for Crohn’s disease and causes are believed to vary. But one indicator of the condition – an abnormal reaction of the immune system to certain bacteria in the intestines – has had new light shed on it thanks to scientists at the University of Plymouth.1
 
The research has focused on different types of macrophages. In inflammatory diseases, like Crohn’s, macrophages mediate the inflammatory destruction of the gut. Just how the tissue reacts (inflammation or suppression) is dependent on the type of macrophage cell present, and how it is stimulated – and scientists have been trying to get to the bottom of this.
 
The new research has shown how different types of macrophage – one type being pro-inflammatory and the other being anti-inflammatory – exhibit quite different molecular mechanisms involved in switching off their functional behaviour when bacteria are present.
 
And this difference, as study author Dr Andrew Foey explains, highlights the possibility of targeting and selectively suppressing the pro-inflammatory cells that drive diseases such as Crohn’s disease.
 
“This small step in understanding of differential off-signalling of macrophage type may go hand-in-hand with understanding the relapsing/remitting presentation of Crohn’s disease,” he said. “It is suggestive of future research endeavours in targeting macrophage responses in the treatment of inflammatory diseases – and it’s a really positive step.”
 
Reference
  1. Al-Shaghdali K et al. Macrophage subsets exhibit distinct E. coli-LPS tolerisable cytokines associated with the negative regulators, IRAK-M and Tollip. PLOS ONE 2019;14(5):e0214681 DOI: 10.1371/journal.pone.0214681

Lynparza approved for first-line maintenance treatment of BRCA-mutated advanced ovarian cancer

AstraZeneca and MSD have announced that the European Commission (EC) has approved Lynparza (olaparib) as a 1st-line maintenance treatment for women with BRCA-mutated advanced ovarian cancer.
 
The licensed indication is as a maintenance treatment of adult patients with advanced (FIGO stages III and IV) BRCA1/2-mutated (germline and/or somatic) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of 1st-line platinum-based chemotherapy.
 
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “This approval sets the stage for a new standard of care in the EU for women with ovarian cancer and a BRCA mutation. The goals of front-line therapy have always been long-term remission and even cure, yet currently 70% of patients relapse within three years of initial treatment. The progression-free survival benefit of Lynparza observed in SOLO-1 represents a major step forward in our ambition to help transform patient outcomes.”
 
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “In SOLO-1, Lynparza demonstrated clinically-meaningful results with a 70% reduction in the risk of disease progression or death in the first-line maintenance treatment of patients with BRCAm advanced ovarian cancer. Merck and AstraZeneca are committed to improving outcomes for people with cancer and we will work to bring this new option to women in the EU, many of whom have historically poor outcomes, as quickly as possible.”
 
The EC approval was based on data from the pivotal Phase III SOLO-1 trial which tested Lynparza as maintenance monotherapy compared with placebo in patients with BRCAm advanced ovarian cancer following 1st-line platinum-based chemotherapy. Results announced in October 2018 at 40.7 months of follow-up showed the median time of progression for patients treated with Lynparza had not yet been reached vs. 13.8 months for those on placebo (HR 0.30 [95% CI, 0.23-0.41], p<0.001).
 
This is the third indication for Lynparza in the EU. AstraZeneca and MSD are exploring additional trials in ovarian cancer, including the ongoing Phase III PAOLA-1 trial, which is testing Lynparza in combination with bevacizumab as a 1st-line maintenance treatment for women with newly-diagnosed, advanced, stage IIIB-IV high grade serous or endometrioid ovarian cancer, regardless of BRCA status.

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