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Author: Louise Stanley

New drug treatment regimen shows promise for patients with lupus

Written by Louise Stanley on . Posted in Clinical trials, Inflammation and chronic disease.

The results of a randomised controlled trial, published in Annals of Internal Medicine, found that a new drug treatment regimen – using belimumab soon after rituximab – reduced a disease-related autoantibody and severe disease flares in lupus patients.

Systemic lupus erythematosus (SLE or lupus) is a long-term autoimmune condition, causing a variety of problems including joint pain, skin rashes, kidney disease and tiredness. While there is no known cure for this debilitating disease, the BEAT-Lupus clinical trial found that the combination of belimumab and rituximab shows promising results; reducing severe lupus flares by 3-fold for patients who had persistent, severe lupus disease requiring rituximab therapy at the beginning of the study.

Senior author Professor Caroline Gordon, Emeritus Professor of Rheumatology and member of the Institute of Inflammation and Ageing’s Rheumatology Research Group, together with colleagues from University College London conducted a phase 2 randomised trial involving 52 patients with SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy. Patients were treated with rituximab and then randomly assigned four to eight weeks later to receive intravenous belimumab or placebo for 52 weeks.

The researchers found that IgG anti-dsDNA antibody levels were lower in belimumab-treated patients at 52 weeks compared with placebo-treated patients (geometric mean, 47 versus 103 IU/mL; 70% greater reduction from baseline). The risk for severe flare was reduced significantly with belimumab versus placebo (hazard ratio, 0.27), with three and 10 severe flares in the belimumab and placebo groups, respectively. There was no increase seen in the incidence of serious adverse events in the belimumab group.

Professor Michael Ehrenstein, Chief Investigator of the BEAT-Lupus trial, said: “Thanks to the dedication of the lupus teams at participating hospitals we are delighted to not only have completed recruitment, but also to provide preliminary evidence for a clinical benefit of the combination of rituximab and belimumab, compared to patients treated with rituximab alone.”

“These findings support further exploration of belimumab after rituximab as the first combination biologic therapy for patients with SLE, at least in those whose disease is refractory to conventional therapy and/or requires high corticosteroid dosages,” the authors write.

Professor Gordon previously pioneered the methodology for assessing lupus disease activity and flares using the BILAG-2004 index. The main secondary clinical outcome of reduction of severe lupus flare in the BEAT-Lupus trial was based on this work, and flare was defined using this index.

She explained: “We were delighted to find that this treatment regimen not only reduced disease causing autoantibodies but also reduced severe flares which cause very distressing symptoms and disruption to patients’ lives. This study offers the hope that this combination of drugs will be useful in the future if the results are confirmed in a larger trial.”

The study was funded primarily by Versus Arthritis; GlaxoSmithKline provided belimumab free of charge, as well as some additional funding.

Contraceptive pill can reduce type 2 diabetes risk in women with polycystic ovary syndrome

Written by Louise Stanley on . Posted in Inflammation and chronic disease.

A study led by BHP founder-member the University of Birmingham has revealed for the first time that the contraceptive pill can reduce the risk of type 2 diabetes by over a quarter in women with polycystic ovary syndrome (PCOS).

The research findings also show that women with PCOS have twice the risk of developing type 2 diabetes or pre-diabetes (dysglycemia) – highlighting the urgent need to find treatments to reduce this risk.

In addition to the risk of type 2 diabetes, PCOS – which affects 10% of women world-wide – is also associated with a number of other conditions in the long-term, such as endometrial cancer, cardiovascular disease, and non-alcohol related fatty liver disease (NAFLD).

Symptoms of PCOS include irregular periods or no periods at all, which can lead to fertility issues, and many suffer from unwanted hair growth (known as ‘hirsutism’) on the face or body, hair loss on the scalp, and oily skin or acne. These symptoms are caused by high levels of hormones called androgens in the blood of women with PCOS.

Women with PCOS also often struggle with weight gain and the cells in their body are often less responsive to insulin – the hormone that allows the body to absorb glucose (blood sugar) into the cells for energy. This reduced response to insulin can lead to elevated blood glucose levels and can cause the body to make more insulin, which in turn causes the body to make more androgens. The androgens further increase insulin levels – driving a vicious circle.

The University of Birmingham-led team of scientists carried out two studies to firstly identify the risk of developing type 2 diabetes and pre-diabetes in women with PCOS, and secondly to investigate the impact of the use of combined oral contraceptives, often referred to as ‘the pill’, on the risk of type 2 diabetes and pre-diabetes in women with PCOS. The pill is often given to women with PCOS to improve the regularity of menstrual bleeds.

Using UK patient GP records of 64,051 women with PCOS and 123,545 matched control women without PCOS, they first carried out a large population-based cohort study to analyse the risk of type 2 diabetes and pre-diabetes. They found that women with PCOS were twice at risk of type 2 diabetes or pre-diabetes, compared to those without PCOS. They also identified hirsutism (excessive hair growth) – a clinical sign of high androgen levels – as a significant risk factor for type 2 diabetes and pre-diabetes among women with PCOS.

To investigate the impact of the pill on type 2 diabetes or pre-diabetes, the researchers, including experts at the RCSI University of Medicine and Health Sciences, then carried out a further nested case control study of 4,814 women with PCOS. The scientists found that use of combined oral contraceptives reduced the odds of developing type 2 diabetes and pre-diabetes in women with PCOS by 26%.

The researchers behind the study, published in Diabetes Care, are now planning to carry out a clinical trial to further evidence their findings in the hope it will lead to changes in global healthcare policy.

Co-senior author Professor Wiebke Arlt, Director of the University of Birmingham’s Institute of Metabolism and Systems Research, said: “We knew from previous, smaller studies, that women with PCOS have an increased risk of type 2 diabetes. However, what is important about our research is that we have been able to provide new evidence from a very large population-based study to show for the very first time that we have a potential treatment option – combined oral contraceptives – to prevent this very serious health risk.”

Joint first author Dr Michael O’Reilly, Health Research Board Emerging Clinician Scientist and Clinical Associate Professor at RCSI University of Medicine and Health Sciences, added: “We hypothesise that the pill reduces the risk of diabetes by dampening the action of androgens. How does this work? The pill contains oestrogens which increase a protein in the blood called sex hormone-binding globin (SHBG). SHBG binds androgens and, thereby, renders them inactive. Thus, if the pill is taken, SHBG increases. This decreases the amount of unbound, active androgens, lowering their impact on insulin and diabetes risk.”

Joint first author Anuradhaa Subramanian, also of the University of Birmingham, added: “With one in 10 women living with PCOS, which is a life-long metabolic disorder, it is incredibly important that we find ways of reducing its associated health risks.”

Co-senior author Krish Nirantharakumar, Professor in Health Data Science and Public Health at the University of Birmingham’s Institute of Applied Health Research, added: “Importantly, our data highlight that normal weight women with PCOS were also at increased risk of type 2 diabetes and pre-diabetes. This parallels our previous finding of increased NAFLD risk in normal weight women with PCOS, further challenging the notion that PCOS-related metabolic complications are only relevant in the context of obesity. These data suggest that, rather than obesity in isolation, PCOS-specific factors, including androgen excess, underpin the increased metabolic risk.”

The study was supported by funding from Health Data Research UK, Wellcome Trust, the Health Research Board, and the National Institute for Health Research Birmingham Biomedical Research Centre which is based at BHP founding members the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust.

The research was also carried out in collaboration with the University of Colombo in Sri Lanka, and McGill University in Canada.

Specific cell population plays key role in effect of arthritis and people’s pain

Written by Louise Stanley on . Posted in Inflammation and chronic disease.

Research led by scientists at BHP founder-member the University of Birmingham has identified a new specific population of cells that plays a key role in the affect arthritis has on the body and the subsequent pain felt by patients.

The research team, led by scientists from the University ’s Institute of Inflammation and Ageing, conducted a clinical trial involving 52 patients with osteoarthritis – the most common type of arthritis in the UK – which causes joints to become painful and stiff.

All of the patients had osteoarthritis in their knee and were aged between 35 and 85. Of these patients, 29 had early stage disease, while 22 had end-stage disease.

The team, including experts from the University of Bath and Birmingham’s Royal Orthopaedic Hospital, measured levels of inflammation of the lining of the knee joint at different anatomical sites using MRI scans.

Patient-reported pain severity and pain location was recorded using a knee map, where patients marked the anatomical location of where they felt most pain and where they felt least pain or no pain. The researchers then collected joint lining tissue biopsies from parts of the knee where patients reported feeling pain, as well as areas where patients felt no pain.

Corresponding author Dr Simon Jones, of the Institute of Inflammation and Ageing, said: “Inflammation of the joint lining membrane is a known characteristic feature of osteoarthritis. However, its association with joint pain has previously not been clear because both the amount and specific location of inflammation and the location and severity of pain varies among patients.

“Our findings showed that in patients with osteoarthritis of the knee, inflammation of the joint lining membrane tissue was associated with both the location and severity of patient reported joint pain.

“Critically, for the first time we were able to demonstrate that joint lining tissue at the site of patient-reported pain contained a different gene signature, with specific populations of cells – called synovial fibroblasts – that promoted joint inflammation and the growth and survival of nerve cells.”

A gene signature contains information about the activity of a specific group of genes in a cell or tissue. Gene signatures can show how likely certain diseases of conditions can develop or spread and can be used to help diagnose disease, make a prognosis and plan treatment.

Dr Jones added: “Current pain relief medications for patients with knee osteoarthritis are limited in their effectiveness and can cause adverse side effects. Our data provides the rationale to develop therapeutic drugs that are designed to control the activity of specific joint lining cells in order to alleviate joint pain in osteoarthritis patients.”

The research, funded by Versus Arthritis, was carried out over a period of almost four years and is published in the journal EBioMedicine.

Triple-drug combo could prove key weapon in fight against cancer

Written by Louise Stanley on . Posted in Cancer outcomes, Clinical trials, Experimental medicine.

Combining three existing drugs – a commonly-used anti-epileptic, a contraceptive steroid and a cholesterol-lowering agent – could form an effective and non-toxic treatment for a range of aggressive blood cancers, a new study reveals.

The discovery by University of Birmingham scientists has led to a £1 million funding award from Blood Cancer UK to run a randomised clinical trial to test the new drug combo against another experimental agent (Danazol) in patients living with Myelodysplastic Syndromes (MDS).

Over 7,000 people in the UK have MDS and many patients die because their disease transforms into acute myeloid leukaemia (AML) – an even more aggressive blood cancer. The general outlook for AML is poor, but when AML arises from MDS it is worse.

Left untreated, AML kills patients quickly by crippling production of normal blood cells. AML is most prevalent in elderly people – many of whom cannot tolerate ‘traditional’ treatment of intensive chemotherapy because of their age and frailty.

Scientists at the University of Birmingham had already discovered that mixing bezafibrate (BEZ – cholesterol-lowering) with medroxyprogesterone acetate (MPA – contraceptive steroid) eased a range of blood cancers including AML, chronic lymphocytic leukaemia (CLL) and non-Hodgkins lymphoma.

Now clinical trials show that adding valproic acid to a low-dose combination of the other two drugs offers enhanced killing of AML cells – giving the low-dose triple-drug combo (VBaP) a cancer-busting impact similar to a high dose of BEZ and MPA (BaP).

Researchers from the University of Birmingham have published their findings in British Journal of Cancer.

Co-author Professor Chris Bunce, commented: Using existing drugs to treat conditions outside of their approved indications is a proven approach to generate effective low-toxicity therapies. We believe that treating patients earlier with low toxicity therapies is the most effective clinical strategy for improving patient outcomes.”

Earlier clinical trials had shown that low-doses of BaP given to patients who could not have chemotherapy produced no toxic side effects and helped patients to boost their production of blood cells.

However high doses of the dual combo were not well tolerated, due to the frail nature of the patients caused by their age, poor kidney function, disease and, in some cases, prior chemotherapy treatments.

Co-author Dr Farhat Khanim commented: “A major challenge in our previous BaP trials has been the focus on elderly patients for whom more intensive therapies were not option.

“For many of these patients there are very few treatment options other than regular transfusions to combat life-threatening deficits in red cells and platelets and antibiotic control of frequent life threatening infections.

“It is therefore an attractive option to consider testing VBaP in MDS patients. As the drug combination may have profound impact on quality of life and survival of these patients.”

Artificial Intelligence project aims to improve diversity and equality in AI systems

Written by Louise Stanley on . Posted in Health inequalities.

A new project has been launched across BHP members, aiming to address racial and ethical health inequalities using artificial intelligence (AI).

STANDING Together, being led by BHP founding member University Hospitals Birmingham NHS Foundation Trust (UHB), aims to develop standards for datasets that AI systems use, to ensure they are diverse, inclusive and work across all demographic groups. The resulting standards will help regulators, commissioners, policymakers and health data institutions assess whether AI systems are underpinned by datasets that represent everyone, and don’t leave underrepresented or minority groups behind.

Xiao Liu, Clinical Researcher in Artificial Intelligence and Digital Healthcare at the University of Birmingham and UHB, and STANDING Together project co-leader, said: “We’re looking forward to starting work on our project, and developing standards that we hope will improve the use of AI both in the UK and around the world. We believe AI has enormous potential to improve patient care, but through our earlier work on producing AI guidelines, we also know that there is still lots of work to do to make sure AI is a success stories for all patients. Through the STANDING Together project, we will work to ensure AI benefits all patients and not just the majority.”

NHSX’ NHS AI Lab, the NIHR, and the Health Foundation have awarded in total £1.4m to four projects, including STANDING Together. The other organisations working with BHP on STANDING Together are the Massachusetts Institute of Technology, Health Data Research UK, Oxford University Hospitals NHS Foundation Trust, and The Hospital for Sick Children (Sickkids, Toronto).

The NHS AI Lab introduced the AI Ethics Initiative to support research and practical interventions that complement existing efforts to validate, evaluate and regulate AI-driven technologies in health and care, with a focus on countering health inequalities. Today’s announcement is the result of the Initiative’s partnership with The Health Foundation on a research competition, enabled by NIHR, to understand and enable opportunities to use AI to address inequalities and to optimise datasets and improve AI development, testing and deployment.

Brhmie Balaram, Head of AI Research and Ethics at NHSX, said: “We’re excited to support innovative projects that demonstrate the power of applying AI to address some of our most pressing challenges; in this case, we’re keen to prove that AI can potentially be used to close gaps in minority ethnic health outcomes. Artificial intelligence has the potential to revolutionise care for patients, and we are committed to ensuring that this potential is realised for all patients by accounting for the health needs of diverse communities.”

Dr Indra Joshi, Director of the NHS AI Lab at NHSX, added: “As we strive to ensure NHS patients are amongst the first in the world to benefit from leading AI, we also have a responsibility to ensure those technologies don’t exacerbate existing health inequalities. These projects will ensure the NHS can deploy safe and ethical Artificial Intelligence tools that meet the needs of minority communities and help our workforce deliver patient-centred and inclusive care to all.”

The STANDING Together team can be contacted at contact@datadiversity.org

Birmingham leads the way in delivery of a new advanced therapy in uveal melanoma

Written by Louise Stanley on . Posted in Cancer outcomes, Experimental medicine.

BHP founder-member University Hospitals Birmingham is the first site in the UK to treat a uveal melanoma patient with the new therapy Tebentafusp outside a clinical trial. Uveal melanoma is a rare cancer situated within the eye. This initiative is being led by Dr Leila Khoja, Immunotherapy lead for the Birmingham Experimental Cancer Medicine Centre (ECMC) and senior clinical lecturer at another of BHP’s founder members, the University of Birmingham.

Developed by Immunocore PLC, Tebentafusp is a bispecific immunotherapy drug, a type of advanced therapy. Immunotherapies harness the body’s immune system to fight cancer, helping it to attack it and to prevent tumours from growing. However, in some tumours the immune response is inadequate to control the tumour and, even in tumours that respond, resistance to treatment can develop. Tebentafusp’s mechanism of action enables it to attach to the tumour and simultaneously to T-cell immune cells. This means that it is able to pull in and activate tumour specific T-cells in hard to treat tumours.

Birmingham participated in the phase II study of Tebentafusp, and the results were published in Clinical Cancer Research. This led to a phase III trial, where it was shown to offer patients better outcomes in terms of survival, when compared with standard drugs offered by their clinical teams.  It is the first drug of this type for a solid tumour that has been proven to offer this benefit to patients. Regulatory approval for Tebentafusp is in process, but the drug is currently available through a compassionate use programme.

Transferring Tebentafusp into standard clinical care for patients with solid tumours is challenging, as specialist pharmacy, nursing and junior doctor skills are required. Hospitals also need to have sufficient capacity to deliver infusions of the drug on an inpatient basis, as the dose is increased over a three week period, before it can be provided on an outpatient basis. The development of this programme will create a model for similar therapies in the future, and Birmingham ECMC is currently facilitating the setup of clinical trials in this field.

These initiatives underline the importance of the Birmingham ECMC and Midlands Wales Advanced Therapy Treatment Centre (MW-ATTC) networks in supporting the delivery of the innovative therapies of the future, training staff and providing the infrastructure required.