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Take a look at a selection of our recent media coverage:
5th February 2025
Paroxysmal nocturnal haemoglobinuria is an ultra-rare disease that imposes significant medical and psychological burdens on patients. Mainstay treatment with complement inhibitors has improved patient outcomes but unmet needs remain. Dr João Gonçalves PhD explains how the treatment landscape is evolving to encompass different therapeutic targets and modalities, including danicopan, to provide a personalised, person-centred approach to management.
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening haematologic disorder characterised by complement-mediated haemolysis of red blood cells. The disease results from a somatic mutation in the phosphatidyl inositol glycan A (PIG-A) gene, leading to the absence of glycosylphosphatidylinositol-anchored proteins, particularly CD55 and CD59, on the surface of erythrocytes.
The loss of these regulatory proteins results in uncontrolled activation of the complement system, particularly the terminal pathway, which drives intravascular haemolysis and promotes a prothrombotic state.1–3
PNH presents with a characteristic triad of haemolytic anaemia, cytopaenia and thrombosis. Haemolysis leads to symptoms such as fatigue, haemoglobinuria and abdominal pain. Additionally, the haemolysis-related iron loss can exacerbate anaemia, further reducing patients’ quality of life. Cytopaenia in PNH patients is often due to associated bone marrow failure, which might coexist with aplastic anaemia or myelodysplastic syndromes.4,5
Thrombosis is a significant cause of morbidity and mortality in PNH, with patients exhibiting an increased risk of life-threatening thromboembolic events such as stroke, deep vein thrombosis and pulmonary embolism. The underlying mechanisms involve complement activation-induced platelet dysfunction, haemolysis-driven nitric oxide depletion and endothelial damage.6,7
The chronic nature of PNH significantly affects patients’ quality of life and health outcomes. Frequent medical interventions, including blood transfusions, anticoagulation therapy and hospitalisation for thromboembolic events, contribute to a substantial burden on healthcare systems.7,8
Additionally, the psychological impact of PNH, including increased anxiety and depression, complicates clinical management and highlights the need for effective, long-term therapeutic strategies.6
The advent of complement inhibitors, such as the monoclonal antibodies eculizumab and ravulizumab, has revolutionised PNH treatment by significantly reducing intravascular haemolysis and improving survival rates.
These drugs target C5 in the complement cascade, preventing the formation of the membrane attack complex and mitigating erythrocyte destruction.9,10 However, despite their efficacy, 11–27% of patients continue to experience breakthrough haemolysis, primarily attributed to extravascular haemolysis mediated by the alternative complement pathway.11–13
While C5 inhibitors have successfully addressed intravascular haemolysis, they do not entirely prevent C3-mediated extravascular haemolysis, which remains a significant challenge for some patients.
The persistence of anaemia in patients treated with ravulizumab or eculizumab underscores the need for targeting upstream mechanisms of complement activation. This has driven the development of next-generation therapies that address the alternative complement pathway, offering a more comprehensive treatment strategy.12,13
A promising addition to the PNH therapeutic landscape is danicopan, an oral complement factor D inhibitor that selectively targets the alternative complement pathway and is approved in the European Union as an add-on to ravulizumab or eculizumab for a subset of patients with PNH.
Unlike C5 inhibitors, danicopan acts upstream in the complement cascade, preventing C3-mediated extravascular haemolysis while preserving the efficacy of C5 blockade.14,15 This dual mechanism of action is particularly relevant for patients experiencing persistent anaemia or breakthrough haemolysis despite treatment with eculizumab or ravulizumab.13,14,16
Clinical studies have demonstrated that danicopan effectively reduces haemolysis and improves haemoglobin levels in patients with PNH inadequately controlled on C5 inhibitors.9,14 Oral administration provides a significant advantage over intravenous therapies, enhancing patient adherence and convenience.13,14
Given that frequent infusions pose a barrier to optimal management in PNH, oral administration could transform the treatment experience, reducing healthcare burden and improving patient satisfaction.7,8
The introduction of factor D inhibitors signals a shift towards personalised, multi-targeted complement inhibition strategies. Future research may explore combination therapies that further refine complement regulation, addressing both intravascular and extravascular haemolysis more effectively.
Additionally, gene therapies and haematopoietic stem cell transplantation remain areas of interest, particularly for patients with severe bone marrow failure syndromes.9
PNH is a complex and debilitating disorder that imposes significant clinical and psychological burdens on patients. Although C5 inhibitors have dramatically improved outcomes, breakthrough haemolysis and extravascular haemolysis remain challenges for some individuals.
The introduction of danicopan as an add-on therapy, targeting an alternative complement pathway to provide a more comprehensive therapeutic approach, represents a significant advance in treating PNH.
With its oral formulation, danicopan has the potential to enhance patient adherence, reduce treatment burden and improve overall quality of life. Future innovations in complement inhibition and emerging gene therapies will refine PNH management, offering new hope for patients suffering from this rare and potentially life-threatening disease.
João Gonçalves PharmD PhD
Faculty of Pharmacy, University of Lisbon, Portugal
1 Graf M, Gallicchio V. History, etiology, and treatment of paroxysmal nocturnal hemoglobinuria. Trends Int Med 2022;2(1):1–8.
2 Graciaa S et al. Risk of disseminated gonococcal infections with terminal complement blockade. J Pediatr Hematol Oncol 2021;44(2):e493–e495.
3 Bravo-Perez C. Paroxysmal nocturnal hemoglobinuria: biology and treatment. Medicina 2023;59(9):1612.
4 Ahsan M, Ishtiaq R, Ishtiaq D. Ischemic stroke presenting as the first symptom in a setting of paroxysmal nocturnal hemoglobinuria. Cureus 2017;9(7):e1439.
5 Di Matteo S et al. Cost-utility analysis comparing pegcetacoplan to anti-c5 monoclonal antibodies in the treatment of paroxysmal nocturnal hemoglobinuria. ClinicoEconomics and Outcomes Res 2024;16:225–32.
6 Panse J et al. The burden of illness of patients with paroxysmal nocturnal haemoglobinuria receiving c5 inhibitors in France, Germany and the United Kingdom: patient‐reported insights on symptoms and quality of life. Eur J Haematol 2022;109(4):351–63.
7 Dingli D et al. The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the c5-inhibitors eculizumab or ravulizumab: results from a us patient survey. Ann Hematol 2022;101(2):251–63.
8 Griffin M, Kelly R, Pike A. A review of the treatment landscape in paroxysmal nocturnal haemoglobinuria: where are we now and where are we going? Ther Adv Rare Dis 2020;Oct 22.
9 Brodsky RA et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica 2020;106(1):230–7.
10 Kelly R et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011;117(25):6786–92.
11 Latyshev V. Hematological response in patients with paroxysmal nocturnal hemoglobinuria treated with c5-inhibitor. Oncohematology 2024;19(1):83–91.
12 Versino F, Fattizzo B. Complement inhibition in paroxysmal nocturnal hemoglobinuria: from biology to therapy. Int J Lab Hematol 2024;46(S1):43–54.
13 Risitano A, Perna F, Selleri C. Achievements and limitations of complement inhibition by eculizumab in paroxysmal nocturnal hemoglobinuria: the role of complement component 3. Mini Rev Med Chem 2011;11(6):528–35.
14 Risitano A et al. Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica 2020;106(12):3188–97.
15 Yuan X et al. Small-molecule factor d inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica 2016;102(3):466–75.
16 Kulasekararaj A et al. Phase 2 study of danicopan in patients with paroxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab. Blood 2021;138(20):1928–38.
27th November 2024
Personalised treatment innovations in the field of rheumatology are transforming patient care and outcomes, driven by significant advances in understanding the origins of rheumatological diseases. Professor Xenofon Baraliakos, president-elect of EULAR, speaks to Helen Quinn about the biggest challenges and opportunities in the field and where he sees rheumatology advancing to next.
Scientific advancements in rheumatology are shifting treatment from a one-size-fits-all approach towards more patient-centred care. Inflammation can show up differently across individuals, arising from a variety of causes. Targeted therapies now offer more effective and individualised options for patients, marking the beginning of a new era in rheumatologic care.
Within this exciting landscape of research innovation and clinical advancement, Professor Xenofon Baraliakos will take over the European Alliance of Associations for Rheumatology (EULAR) presidency in June 2025, having recently been voted as the Alliance’s president-elect.
Professor Baraliakos is a world-leading expert in rheumatology and is currently seeing out his term as president of the Assessment of Spondyloarthritis International Society alongside his roles as medical director at Rheumazentrum Ruhrgebiet in Herne, Germany, and full professor of internal medicine and rheumatology at Ruhr-University Bochum, Germany.
‘We are at a pretty advanced stage when it comes to now being able to have the right techniques to understand where diseases come from,’ Professor Baraliakos explains. ‘In the last 20 to 25 years, we have seen a huge development with biologics, which was a revolution.’
Indeed, biologics have transformed the treatment of inflammation, offering a safer and more effective options compared to traditional medications such as prednisone and cortisone, which reduce inflammation but can have unwanted side effects.
The rise of personalised therapies means there has been a step away from broad treatment options like TNF blockers, IL-6 blockers and IL-17 blockers, which treat everything rather than specific cytokines. Alongside this, advancements have also been made in tissue and blood analysis, allowing researchers to gain further insights into the causes of inflammation and select treatments based on an individual’s needs.
‘We understand better why one [patient] is getting a response and one is not and what this means. We understand better how diseases occur and how they develop over time. Now that means we also have a big unmet need: to translate that basic science back to clinical outcomes,’ Professor Baraliakos says. ‘Before, we just didn’t know where the disease came from. I think now we are in a very good position in terms of developing the field further – even faster.’
It is hoped that this additional knowledge will lead to fewer treatment failures for patients, as clinicians can identify the most effective treatment for each individual. In addition, Professor Baraliakos explains that by borrowing treatments from fields such as oncology and haematology and developing them further for their own needs in rheumatology, certain treatments may even be able to give the hope of a cure.
‘We are now also in the position to speak about possibilities to cure rheumatological diseases,’ he says. ‘This of course may take time, but curing is now, I believe, in reach, as compared to not being an option 10 years ago.’
Professor Baraliakos has contributed extensively to imaging research in rheumatology, and he says the first 10 years of this century saw the MRI and ultrasound becoming standard tools for diagnosing rheumatic diseases. But the biggest changes have come through recent improvements in image quality, with clinicians now able to get much greater detail of information from the images, allowing them to read and understand the progression of the disease more accurately.
‘We’ve learned how to interpret the images better in the clinical context. Something showing as ‘positive’ on imaging does not always mean the presence of a disease. We’ve learned to make that differentiation: that signal of inflammation may not be rheumatological, the inflammation may be something else. [It’s a] distinction between pathology and a coincidental finding,’ he explains.
In addition to advancements in imaging and the understanding of pathology, Professor Baraliakos emphasises the critical role of artificial intelligence (AI) in driving the future of rheumatology. Screening for diseases using AI is enabling early and accurate diagnosis, reducing the risk of misdiagnosis and unnecessary treatment while also ensuring patients are directed to the right clinician without losing time.
‘AI will change everything,’ he says. ‘It will make us aware of things we’re not really seeing that much. AI will be much more sensitive to [pathological] change, so the sensitivity of image interpretation will be improved beyond the human eye and human understanding.’
Coupled with AI’s ability to identify images with greater speed and accuracy, Professor Baraliakos believes these advancements will play an essential role in enhancing patient-centred treatment models. ‘I would see AI as a tool and not as a threat,’ he says.
Professor Baraliakos hopes to use his platform as the future president of EULAR to expand the Alliance’s global outreach and education initiatives, leveraging recent scientific advancements and enhancing interdisciplinary collaboration to ensure optimal treatment for all patients no matter where they live.
‘I think EULAR is on a very good track,’ he says. ‘We are already the number one global rheumatology organisation worldwide. But of course, we need to develop and go with the science of the times. We need to invest in improving the patients’ situation because there are big differences between countries and continents.’
To this end, Professor Baraliakos hopes to extend the EULAR’s reach ‘to provide research, but also educational activities that are for everyone,’ whether they are based in Europe or further afield.
One of his first tasks as president will be to oversee the Alliance’s annual Congress and he is keen to make it ‘the place to be’ in the rheumatology calendar and ‘where you really see the most recent rheumatological status, what is moving the field, and where the field will be moving towards’.
While the focuses of next year’s Congress remain safely under wraps for the time being, Professor Baraliakos is resolute that it will cover the most recent research and innovations in the field at a time of such exciting progress. He believes that being flexible in the structure and forward-looking in the content is the key to achieving this goal.
‘We are trying new formats to attract people and implement their ideas where possible. Content wise, we’re concentrating on what’s hot and what’s important. I think that makes it attractive for everyone, and also really exciting, but suited to the times we’re living in,’ he says.
Reflecting on his work and plans for the future, Professor Baraliakos says that at the heart of his ambitions is a strong desire to understand rheumatological diseases even better and to champion translational research and bring it back to the patient.
‘The most rewarding part of my work is to really see ideas coming into life,’ he says. ‘I feel the responsibility, but I’m also looking forward to really applying my plans to reach the goal, to improve patients’ lives and improve outreach overall.’
25th November 2024
Professor Antonio Almeida has been at the forefront of clinical haematology for more than 20 years and last year he became president of the European Hematology Association (EHA). Speaking to Julie Penfold, he shares his plans for his second year as EHA president, key takeaways from June’s EHA Congress and his insights into the future of clinical haematology.
There’s never a dull moment when specialising in the field of haematology, with near-constant clinical developments emerging and an abundance of reasons to be optimistic for the future of patient care and outcomes.
‘Haematology is a very exciting specialty,’ explains Professor António Almeida, head of department at Hospital da Luz in Lisbon, founding dean of Portugal’s Catolica Medical School, and president of the European Hematalogy Association (EHA).
‘I think we are certainly a specialty in which scientific innovation hits the clinical ground very, very fast. And even now, when we know so much about genetic mutations, new treatments and targeted treatments, we’re always discovering new pathways for patients and promising treatment options.’
He adds: ‘Not only are we now targeting the genetic landscape but we’re also targeting all the immunological and all the microenvironments that surround the diseases. It really makes haematology a crest-of-the-wave type of specialty.’
One of Professor Almeida’s main aims when he took up the role of EHA president in 2023 was to foster greater recognition of haematologists throughout Europe. As such, the EHA has been working hard to promote the specialty within the European Union and with national authorities and societies.
‘Haematology is a very diverse subject, and we range from a huge variety of diseases from coagulation to benign to malignant, and from a huge range of activities from clinical to laboratory to research,’ Professor Almeida explains. ‘That’s why it’s really important with this diversity that people are recognised for their specialty.’
To reflect this diversity and demonstrate how the field is evolving, EHA shared a new vision statement at its 2024 congress, alongside the rollout of a new brand identity. The previous iteration of the vision statement, ‘Towards a cure for all blood diseases’, has been adapted and now reads: ‘Towards prevention, cure and quality of life for all patients with blood disorders’.
Professor Almeida explains that it was important for the vision statement to be updated as ‘many of our diseases are becoming chronic and not necessarily cured’. In addition, there was an agreement within the association for it to evolve to reflect ‘what our members would identify with’ in their day-to-day practice when supporting a variety of patients with differing needs and outcomes.
‘We really want to cater for the whole population including those who have chronic disease and the burden of chronic disease. We want to make sure that they really have their needs addressed and that we can look at preventing certain diseases too,’ Professor Almeida says.
‘For example, how can we improve screening, and how can we improve the quality of life of patients [who] are on chronic therapies and have side effects but want to continue living a normal life? How can we ensure their symptoms are mitigated? I think this is how the vision statement really translates into clinical practice. It’s fundamentally addressing the day-to-day needs that haematologists and patients have.’
Two other key aims for Professor Almeida’s presidency are to increase EHA members’ involvement in the association and for the EHA to become more active in promoting research. Both of these ambitions have progressed well, Professor Almeida says.
For example, at the EHA Congress in June 2024, more than 18,000 people attended – the biggest number yet for this annual event. ‘What we have seen with the greater participation of members at Congress is really the way forward that we’re working towards – that is to have members more involved and to be able to support them with new research grants and more educational offers, so they feel that the EHA is helping both their careers and practice in haematology,’ Professor Almeida says.
This is particularly important as Professor Almeida notes significant variations in funding for haematology research across Europe. ‘It’s very, very important that we recognise that most of the research grants and most of the research happens in the top five countries and the rest ends up not having much access,’ he explains. ‘Promoting research and facilitating access to research is a big flagship that we’re going to move forward with.’
As part of these efforts, over 3,000 abstracts were submitted for this year’s Congress, which was another record high, and this is something that Professor Almeida is particularly proud of. ‘This meant we had top quality work being presented and the haematology communities are now really looking at EHA Congress as one where they want to present their work,’ he explains. ‘We had presentations of trials that really are changing practice both in malignant oncology and also in benign oncology.’
For Professor Almeida, one of his personal highlights at the Congress was the scope of the presidential sessions. ‘Not only did we have oncology, coagulation and red cell diseases, but we also had a lot of innovation and translational science touching clinical, which was particularly exciting,’ he explains.
Another highlight was a talk on sickle cell disease, looking at how the landscape has changed with new emerging therapies such as anti-sickling agents and antibodies. He recalls: ‘It’s really changing the outlook for patients with sickle cell disease and helping us decide where we should be treating, who we should be treating, and who we should be aiming to change therapies in.’
A session on coagulation looked at how pregnant women can be treated with anticoagulants and what the evidence is, which Professor Almeida found both interesting and helpful. ‘In general haematology, we get lots of referrals about this area so it could make a difference for these patients,’ he says.
While the EHA Congress highlighted significant progress and innovations that have the potential to revolutionise the care of blood disorders, it also underlined the ongoing challenge of managing haematology patient needs as their conditions change and, at times, worsen.
‘How we deal with patients that have relapsed multiple times, and how we deal with patients with chronic disease is now really becoming a big challenge,’ says Professor Almeida. ‘The way that we’re tackling this is really by reducing side effects and by trying more and more to reduce toxicity. For example, stopping certain treatments, if that’s an option; looking at ways of reducing doses; and improving combinations so that patients experience [fewer] side effects from their treatments.’
In chronic myeloid leukaemia, for example, many treatments are available, and each have different side effect profiles. Professor Almeida says clinicians are increasingly tailoring these treatment choices to optimise patients’ care. ‘We can choose which treatment to use based on what the disease presents but also what the patient is most likely to have as a side effect profile and [we can] avoid this to minimise the toxicity,’ he says.
Targeting treatments to specific mutations in certain diseases is also becoming a reality. Professor Almeida says: ‘With this, we are moving more and more towards personalised medicine in which patients can be treated not only for their disease specificities, but also for their own specificities.’
This personalisation of care is only set to improve as the use of technology in haematology is anticipated to really take off. Professor Almeida believes this will include the escalation of using artificial intelligence within clinical trials and using registry and synthetic data to determine the best treatment aims for patients.
‘I think we will also see the advent of new therapies to look at and modulate the immune system to treat all sorts of blood disorders,’ Professor Almeida suggests. ‘We’ve seen this very effectively in CAR T-cells in lymphomas, and I’m sure we will see this in other haematological diseases, and it’ll certainly make a huge difference for patients.’
14th August 2024
Heart failure with preserved ejection fraction disproportionately affects women. Dr Pankaj Garg, lead author of a recent study published in the European Heart Journal Open, discusses the necessity of sex-specific approaches in cardiovascular diagnostics and treatment to address this disparity, and summarises how this research paves the way for future studies and clinical guidelines to embrace personalised medicine.
Despite known differences in cardiac structure and function between the sexes, there are no validated sex-specific diagnostic tools for heart failure.
Specifically focusing on heart failure with preserved ejection fraction (HFpEF), which has a higher prevalence in women versus men, our recent research investigated whether sex influences the assessment of left ventricular filling pressure (LVFP) using cardiac magnetic resonance (CMR), which is crucial for diagnosing heart failure regardless of ejection fraction.
Our study’s motivation lay in enhancing diagnostic accuracy and enabling personalised treatment strategies by considering sex-specific physiological variations.
In the derivation cohort of 835 patients (60% female), participants were suspected of having pulmonary hypertension and heart failure. Each patient underwent invasive right heart catheterisation and CMR within a 24-hour period.
We utilised multivariable regression to develop a sex-specific CMR model for estimating LVFP, measured by pulmonary capillary wedge pressure (PCWP). This model included left atrial volume (LAV) and left ventricular mass (LVM) to account for the structural differences between sexes.
The study further validated the model using a cohort of 454 patients with confirmed heart failure, of which 36% were female. This validation assessed primary endpoints, including heart failure hospitalisation and major adverse cardiovascular events (MACE).
The derivation cohort was meticulously selected, and the close timing between the invasive right heart catheterisation and CMR ensured accuracy in correlating the two measurements.
Multivariable regression allowed for incorporating relevant cardiac parameters that differ between sexes, such as LAV and LVM. These parameters are crucial as they reflect the anatomical and functional differences in the cardiac structure between men and women.
The validation cohort provided a robust testing ground for the model, ensuring its applicability in a real-world clinical setting. The primary endpoints of heart failure hospitalisation and MACE are clinically relevant, reflecting the model’s potential to predict significant adverse outcomes.
The findings that the sex-specific CMR-derived PCWP was significantly associated with these endpoints over a considerable follow-up period underline the model’s prognostic value.
The comparison between the generic and sex-specific CMR-derived PCWP models revealed significant differences in LVFP estimates between males and females when using the generic model (14.7 ± 4 vs. 13 ± 3.0 mmHg, P < 0.001). These differences were absent when using the sex-specific model (14.1 ± 3 vs. 13.8 mmHg, P = 0.3), underscoring the importance of a tailored approach.
Unlike the generic model, the sex-specific CMR-derived PCWP demonstrated a significant association with heart failure hospitalisation (hazard ratio (HR) 3.9, P = 0.0002) and MACE (HR 2.5, P = 0.001) over a mean follow-up period of 2.4 ± 1.2 years.
This indicates that accounting for sex improves the precision and prognostic performance of CMR biomarkers for heart failure.
Our study emphasises the substantial differences in cardiac structure and function between men and women. Women typically have smaller cardiac dimensions, higher heart rates and distinct patterns of cardiac remodelling compared with men.
These differences are crucial as they affect the interpretation of diagnostic tests and the effectiveness of subsequent treatments. HFpEF, which is more prevalent in women, is characterised by a stiffer left ventricle, leading to increased LVFP and LAV. In contrast, men are more prone to heart failure with reduced ejection fraction (HFrEF), which follows different pathophysiological mechanisms.
Using generic models for estimating LVFP often leads to misdiagnosis or underestimation of disease severity in women, resulting in inadequate treatment. The sex-specific models developed in this study offer a more accurate assessment of cardiac function, enhancing risk stratification and enabling personalised treatment plans.
Indeed, our study demonstrated that the sex-specific CMR model is more effective than traditional diagnostics in predicting heart failure hospitalisation and MACE, highlighting the necessity of tailored diagnostic tools. Improved diagnostic accuracy facilitates timely and appropriate interventions, ultimately enhancing clinical outcomes for both men and women.
Recognising and addressing sex differences in cardiovascular diseases is essential for developing clinical guidelines that incorporate sex-specific diagnostic and treatment approaches.
Our research underscores the importance of considering sex differences in cardiovascular physiological models and the need for more studies focused on these differences to enhance the overall quality of care and reduce health disparities between men and women.
By developing and validating a sex-specific CMR model for assessing LVFP, we have shown that accounting for sex-specific factors significantly improves diagnostic accuracy and prognostic performance in heart failure patients.
Incorporating these factors into clinical practice can refine heart failure diagnosis and treatment, leading to better health outcomes and personalised patient care. The findings advocate for integrating sex-specific approaches in clinical guidelines and practices, ensuring that both men and women receive optimal and tailored cardiovascular care.
This approach enhances diagnostic precision and facilitates better management of heart failure, having profound implications for clinical practice and potentially reducing the burden of this condition globally.
Furthermore, our study highlights the necessity of personalised medicine and advocates for a paradigm shift in how heart failure is diagnosed and treated. The significant differences found in LVFP estimates between males and females using the generic but not the sex-specific model illustrate the potential for misdiagnosis and inappropriate management if sex differences are not accounted for.
Our findings are a call to action for the healthcare community to prioritise research on sex differences in cardiovascular diseases. This will lead to developing diagnostic tools and treatment protocols that reflect sex-specific physiological differences, ultimately improving patient outcomes.
Dr Pankaj Garg MD MRCP PhD
Associate professor in cardiovascular medicine, University of East Anglia, and honorary consultant cardiologist, Norfolk and Norwich University Hospitals Foundation Trust, UK
24th May 2024
While methotrexate is currently the first-line drug given for juvenile idiopathic arthritis, its effectiveness and tolerability are in fact limited in some patients. With the development of stratified medicine their top priority, Dr Stephanie Shoop-Worrall PhD, Professor Lucy Wedderburn and the CLUSTER consortium set out to discover whether machine learning could transform treatment pathways for children with this debilitating condition.
Children with a diagnosis of juvenile idiopathic arthritis (JIA) often face a long journey to get the right medications, leading to unnecessary pain, uncontrolled symptoms and risking joint damage. Currently, methotrexate is the first-line drug given for JIA, but it is only effective or tolerated in just under half of the children who are treated with it.
In a complex and varied disease like JIA, what does ‘effective’ mean? With signs and symptoms ranging from swollen joints to skin rashes, debilitating pain to symptomless, sight-risking eye inflammation, what does ‘response to treatment’ look like? And how can it mean the same thing for every child?
Researchers have started to look beyond a response versus non-response paradigm and are seeking to understand whether different elements of disease change in different ways following a new treatment, and so require different approaches to disease management. These kinds of investigations are only made possible using new methods of machine learning.
By studying large data sets from thousands of children with JIA, it is hoped that machine learning can facilitate stratified treatment, ultimately reducing pain and suffering in children, aiding clinicians with treatment pathway decisions, and saving money for the NHS and other health systems around the world.
Professor Wedderburn is a professor of paediatric rheumatology based at Great Ormond Street Hospital and University College London (UCL). Mixing clinical and research work, she leads the large UK consortium CLUSTER – a multidisciplinary group of researchers working in JIA who have come together to find ways to improve treatment.
She describes the approach in paediatric rheumatology as ‘holistic’, bringing expertise from psychology, nursing, physiotherapy, occupational therapy and many more specialities.
‘Paediatric rheumatology is an incredibly collaborative field. We do a lot of work with the patients and families. We’re relatively small compared to the adult RA [rheumatoid arthritis] research community, but we’re very linked up, and I think that is a huge benefit,’ Professor Wedderburn says.
However, Professor Wedderburn remains ‘frustrated’ by drug treatments available for children with JIA. Despite the increase in the number of medications available, the drugs are licensed without guidance on when and how to use them in children. What’s more, with a rare and complex disease such as JIA, a child’s predicted response to drugs such as methotrexate varies significantly across different disease features.
As such, the researchers want to move away from a one-size-fits-all system and provide a scientific and biological basis for medication pathways based on the predicted outcomes shown in their data.
Professor Wedderburn says: ‘That’s really what CLUSTER is all about. How can we move to a point where you have true precision medicine or stratified medicine? Many of my patients are in these studies, if they’re willing, and most people want to be involved because we explain it’s the way to get real-world data. This consortium brought together childhood data from huge cohorts – absolutely fabulous for such a rare disease.’
Professor Wedderburn’s colleague and the lead author of their recent publication, Dr Stephanie Shoop-Worrall PhD, is a research fellow at the University of Manchester. She specialises in epidemiology and data science and analyses the CLUSTER data using machine learning.
CLUSTER represents about 5,000 families, which make up approximately half the number of cases of JIA in the UK. Looking at four cohorts of these children who began their treatment before January 2018, Dr Shoop-Worrall and the team were able to find patterns in treatment outcomes which determined how effective methotrexate was on different elements of JIA for groups of children.
‘We’ve got this window of opportunity; we need to treat early on to get better outcomes,’ Dr Shoop-Worrall says. ‘This trial-and-error approach [to medicines] is just wasting people’s time and could lead to much worse outcomes, prolonging chronic pain in children, the potential for disability in the longer term, and massively impacting their lives. So, we really do need to get the right drug first.’
When a child is diagnosed with JIA, they will be diagnosed with one of seven types of the disease. Some diagnoses mirror those seen in adults, while others are unique to children. Describing the current approach as ‘a bit contentious’, Dr Shoop-Worrall has shown through machine learning that the traditional diagnosis groups do not necessarily predict how effective methotrexate will be.
The research team analysed data from when the children started taking methotrexate and followed them over the next year, looking at four outcomes: active joint count, both clinician and patient progress scores, and blood biomarker data. The aim was to capture a spectrum of objective clinical and patient-reported measurements to give an overview of the disease and determine which parts of JIA might be affected by methotrexate.
Dr Shoop-Worrall identified six different groups of children, each describing a different response to methotrexate. The first group, known as the ‘fast responders’, comprised about one in 10 children, all of whose disease responded well to the medication. By six months, this group had no swollen joints, normal bloodwork, and both looked better clinically and felt completely better. The next group, termed ‘slow improvers’, was made up of children who took about a year to achieve the same outcome.
Two more groups showed only partial improvement of JIA with methotrexate. In approximately 8% of children, their joints got better, and the children felt better, but the clinicians reported evidence of JIA, and the children remained on methotrexate. Another 13% of children showed partial improvement and looked better clinically in terms of having no swollen joints and normal blood work, but their symptoms, including pain, persisted.
A small group of about 7% of children, known as the ‘improve-relapse’ group, showed improved symptoms after six months, followed by a relapse. And in the final group of about 44% of children, methotrexate did not impact most of their disease. Small improvements in swollen joints were observed in some cases as the drug is designed to tackle inflammation, but the overall clinical picture did not improve.
Dr Shoop-Worrall says: ‘Once we’d found the clusters, we looked to see if existing subtypes of JIA match up with the patterns. And the answer is no.’
Professor Wedderburn adds: ‘It’s a rather depressing message for families to discover that the name of the condition doesn’t help us know whether they’re going to get better on methotrexate or what the next drug should be. It really isn’t a stratifier. It’s just a label based on what we see in the first few months in the clinic – a nice descriptor.’
Their findings also challenge the traditional binary classification of patients into ‘responders’ and ‘non-responders’ seen in standard clinical trials. For Professor Wedderburn, the groups described by machine learning resonate strongly with what she sees in clinic. She adds: ‘[It’s] really important to get that message across to our community that just dichotomising response doesn’t bring the real lived experience out the way this dissecting of the response can start to do.’
Machine learning has opened the door to the possibility of predicting which aspects of a child’s disease would be helped by methotrexate and which children should start other therapies either alongside, or instead of, methotrexate as first line.
‘We want to get kids into remission quickly; that’s the overall aim of stratified medicine in this disease,’ Dr Shoop-Worrall says. ‘This paper is the first step towards that. If we can figure out who should be on this drug and what kind of response they’ll get, that really pushes forward the aim of stratified treatment.’
The next steps will see the researchers bringing more biological data, such as gene expression and protein data, into their analyses and integrating their findings across different disciplines. They will also investigate the impact of the sociological and psychological elements of the illness, in both cases, working with global cohorts of JIA patients.
Dr Shoop-Worrall concludes: ‘Being able to get a panel of biomarkers or a prediction model that we can integrate into practice to say, right, okay, now we know the different types of response, and this is exactly the group you fit into. That would be a huge step forward for drug selection right from diagnosis.’
The researchers believe machine learning will play an essential role in improving understanding of treatment outcomes, minimising children’s exposure to unnecessary treatments, optimising treatment selection and ultimately improving the quality of care for children with JIA.
20th May 2024
With the potential of personalised medicine becoming ever clearer, clinicians are increasingly turning their attention to the various ways in which this can be realised, and genomics is a prime example of where huge progress can be made. Consultant in medical oncology Dr Nirupa Murugaesu discusses how the 100,000 Genomes Project has supported both research and service delivery in the UK and how whole genome sequencing can be harnessed to transform cancer care.
In October 1990, some of the best scientific brains in the world began working on an international programme to sequence an entire human genome. It took 10 years to complete an initial sequence and cost billions of US dollars.
Fast forward to today, and the picture is vastly different. ‘Because of next-generation sequencing and advances in technology we are now able to sequence a genome comprising around 20,000 genes in less than a week, at a fraction of the cost,’ says Dr Nirupa Murugaesu, consultant in medical oncology and cancer genomics lead at London’s Guy’s and St Thomas’ NHS Foundation Trust.
‘We can now see how routine sequencing to understand the mutational landscape of cancers has helped in terms of understanding more how the cancer is likely to behave, and also determining the best treatment approaches for patients.’
Dr Murugaesu is also principal clinician in cancer genomics and clinical studies at Genomics England. The organisation has been collaborating with NHS England, Queen Mary University of London and the University of Westminster on research into how whole genome sequencing can be combined with clinical data from patients to identify changes in in their cancer’s DNA.
The study, published earlier this year in the journal Nature Medicine, involved more than 13,000 participants with solid mass tumours, and examined clinicopathological data – their type of cancer, histological subtype, the behaviour of their tumour, the types of treatment and survival – over a five-year period.
By combining that information with genomic data, the researchers could pinpoint the cancer’s genetic changes and mutations that resulted in different outcomes. Crucially, this can improve precision cancer care, meaning therapies can be better targeted and individualised to each patient.
Participants were recruited as part of the UK’s 100,000 Genomes Project, which has also collected and analysed data on a number of rare diseases. The solid cancer study found that, through whole genome sequencing, clinicians can use a single test to uncover genetic changes in a tumour.
What sets this study apart from other research in genomics is that, for the first time, the information collected could be applied in real-world settings and in real time, Dr Murugaesu explains.
‘The unique selling point was to have a research study that is embedded within a healthcare system. After the genomes were sequenced, the results were in fact returned to the respective hospital trusts and treating clinicians,’ she says.
‘Normally when research is carried out, the results are not necessarily fed back. We have clinical trials and outcomes that do not always reflect what we end up seeing in practice. But here, we have that real-world clinical information linked with patients’ genomic data, so if there were relevant findings that could be acted upon, this could be undertaken by the treating clinical team.’
Currently, this can be applied in healthcare settings and influence how cancer patients are treated. In particular, it may be helpful in knowing which treatments are less likely to work, or which may not be necessary. ‘If we know from the data that a person’s tumour is likely to be less aggressive, we can decide to not overtreat them, and we can give less-toxic therapies,’ Dr Murugaesu says.
In addition, clinicians can provide patients with more information about how their cancer is likely to behave and what their prognosis may be. In the future, as more data are accumulated and genomics research progresses further, they may be used to develop new and improved therapies as well.
Having laid the groundwork for genomic testing in England, the 100,000 Genomes Project has led to a Genomic Medicine Service being developed and rolled out nationwide.
As a result, Dr Murugaesu says there are criteria for ensuring that minimum standards are met for testing different cancer types, and, importantly, that testing is provided equitably across the country, rather than only at larger cancer centres.
Enormous progress has been made from the early shoots of genomics, when sequencing took years and had a hefty price tag, to becoming embedded into routine care. Now, however, training and education must keep pace with the science, Dr Murugaesu explains.
‘It is now about upskilling the workforce – not just oncologists, but the whole multidisciplinary team – so they understand the role of genomics, and that there is a Genomic Medicine Service available to their patients,’ she says.
In addition, infrastructure and pathways must be set up efficiently to ensure that when a patient undergoes genomic sequencing, their results are returned to their treating team in a timely manner. If genomic testing is performed alongside a biopsy to confirm a cancer diagnosis, and taking that as Day 1, the goal is to have the results back by Day 14, Dr Murugaesu says.
‘That is a challenge that’s not consistently being met, but work is ongoing and one of the main focuses over the next year will be to try and understand the bottlenecks so we can streamline these pathways,’ she adds.
Other technology will have a role in supporting enhanced learning about the genomics of cancer, too. A case in point is liquid biopsies, whereby a blood sample can enable the extraction of circulating tumour DNA – which is shed by tumours, especially those that are more advanced – and sequencing of that DNA can then be undertaken, just as you would for a genomic panel. ‘The repertoire is expanding for what is available and possible to fully molecularly profile tumours,’ Dr Murugaesu says.
Again, performed as soon as there is radiological suspicion of cancer, a simple blood sample can enable genomic sequencing of the tumour’s circulating DNA. If successful, this testing can potentially circumvent problems associated with tissue biopsies, such as not getting enough tissue to yield meaningful results. This has implications for patients – needing to go through the upheaval of a repeat biopsy, for example – and places resource and time pressures on healthcare systems.
A pilot exploring this technology in non-small cell lung cancer is currently under way and has demonstrated promising results in the initial phase.
‘The next phase has now launched and there will be 10,000 tests made available across England for patients with suspected lung cancer, which is exciting because there’s a real opportunity to expand our circulating tumour DNA testing,’ Dr Murugaesu says. ‘There is more and more emerging data about what the role of circulating DNA may be, including screening and earlier detection of cancers.’
There is interesting work in genomic testing across Europe, too. For example, scientists at The Hartwig Medical Foundation in Amsterdam found clinically relevant data from almost 5,000 metastatic solid tumour samples, and supported recruitment to a large-scale trial in the Netherlands – the Drug Rediscovery Protocol (DRUP) trial.
The study is collecting information on the off-label use of registered targeted therapies for patients with incurable cancer who have exhausted standard treatment options, based on their tumour’s molecular profile.
This is one way of embedding genomic testing into cancer care. Dr Murugaesu hopes this becomes routine in the future so that not only will whole genome and genomic panel sequencing help predict the best therapies, but also it could identify whether patients are at increased risk of their cancer reoccurring.
There is enormous potential for genomic medicine to take much of the guesswork out of how tumours are treated, and to be truly transformative in cancer care globally.
18th January 2024
Combining routine clinical data with whole genome sequence (WGS) data at scale supports clinicians in the delivery of precision cancer care, according to new landmark research.
Published in the journal Nature Medicine, the study showed that WGS could provide a more comprehensive view of a tumour’s genetic landscape by detecting various genetic changes using a single test.
Led by Genomics England, NHS England, Queen Mary University of London, and the University of Westminster, researchers analysed data covering 33 types of solid tumours collected from 13,880 participants with cancer in the 100,000 Genomes Project.
By looking at the genomic data alongside real-world treatment and outcome data collected from participants over a five-year period, such as hospital visits and the type of treatment they received, they were able to find specific genetic changes in the cancer associated with better or worse survival rates and improved patient outcomes.
For example, over 90% of brain tumours and over 50% of colon and lung cancers showed genetic changes that could affect how patients are treated, guiding decisions about surgery or specific treatments they might need.
In more than 10% of sarcomas, larger structural variants were identified that have the potential to impact clinical care and treatment.
And in over 10% of ovarian cancers, the study pinpointed inherited risks offering crucial insights for clinical care.
The study also found patterns across several cancers and uncovered genetic changes that might explain treatment response or predict possible patient outcomes.
‘Together, the findings show the value of combining genomic and clinical data at scale to help healthcare professionals make the best treatment decisions with their patients,’ the researchers concluded.
Dr Nirupa Murugaesu, principal clinician – cancer genomics and clinical studies at Genomics England, and oncology consultant and cancer genomics lead at Guy’s and St Thomas’ NHS Foundation Trust said: ‘This study is an important milestone in genomic medicine. We are starting to realise the promise of precision oncology that was envisioned 10 years ago when the 100,000 Genomes Project was launched.
‘We are showing how cancer genomics can be incorporated into mainstream cancer care across a national health system and the benefits that can bring patients.
‘By collecting long-term clinical data alongside genomic data, the study has created a first-of-its-kind resource for clinicians to better predict outcomes and tailor treatments, which will allow them to inform, prepare and manage the expectations of patients more effectively.’
Professor Dame Sue Hill, chief scientific officer for NHS England and senior responsible officer for genomics, added: ‘The insights gained in this study, in which genomic patterns or profiles have been mapped out in thousands of patients with different types of cancer, support and inform the NHS Genomic Medicine Service in providing a comprehensive genomic testing service for patients with cancer and signals a promising future for healthcare as we continue to hone and enhance the NHS use of genomics and tailor interventions for improved outcomes.’
8th August 2022
The NHS should offer all cancer patients genetic profiling of their cancers at diagnosis and during treatment to shape care and track how the disease evolves, a consensus group of leading experts has concluded.
Group members said action was needed to ensure use of cancer treatments was routinely guided by information about a patient’s individual cancer.
They called for barriers preventing patients from gaining access to ‘biomarker’ tests to be removed – so genetic information and other tests could routinely be used to select the most suitable precision medicine for each patient.
The consensus group was convened by The Institute of Cancer Research, London, and included nine leading institutions, charities, stakeholder groups and life-science companies, including Cancer Research UK, AbbVie, the Association of British HealthTech Industries, AstraZeneca, Bioclavis, Bristol Myers Squibb, Leukaemia UK and Precision Life and the Association of the British Pharmaceutical Industry.
Biomarker tests look for genetic, protein or imaging ‘markers’ to identify which patients are most likely to respond to treatment.
It is crucial for clinicians to be able to assess biomarkers so they can select patients with particular weaknesses in their cancers and match treatment accordingly. But the consensus group warned that testing is not always done because regulatory processes and resources have not kept pace with the science.
The statements are calling for a series of changes in the way biomarker tests are developed, made available and routinely used in the UK:
Regulatory barriers to biomarker testing and development have a direct impact on patients – potentially denying them more personalised treatment.
Biomarker testing and development is expensive – currently, the costs of developing biomarker tests often outweigh the financial benefits of doing so, discouraging industry and academia from investing in biomarker research.
But targeting therapies to those who are most likely to respond would be more cost-effective for the NHS. And clinical trials that use biomarkers to select patients are much more likely to succeed and result in marketing approval.
The ICR and the rest of the consensus group members hope that the calls to action in the new 13-point set of consensus statements will help speed up development of biomarker tests and widen access to them – so that the best treatments can reach the right patients as quickly as possible.
Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said: “We believe every cancer patient should have the opportunity for their cancer to be molecularly profiled to assess biomarkers that can give vital clues about how their disease should best be treated. Biomarker tests can direct treatment precisely to the patients who will most benefit, which can both improve the lives of patients and increase the cost-effectiveness of treatment for the NHS.
“It’s essential that the regulations that govern clinical trials and the approval of new tests and treatments keep pace with the rapidly moving science. At the moment, it can be hard to get new biomarker tests developed, approved and made available for patients. That can in turn act as a disincentive for companies and academics to develop new biomarkers to guide treatment in the future.”
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