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15th June 2023
The impact of apremilast on inflammatory and structural changes in psoriatic arthritis (PsA) can be better understood through magnetic resonance imaging (MRI), according to a recent study presented at the European Congress of Rheumatology (EULAR) 2023.
The data came from the MOSAIC phase 4, multicentre, single-arm, open-label study, in which the researchers used MRI to examine the effect of the oral immunomodulating phosphodiesterase-4 inhibitor apremilast on inflammation in patients with active PsA.
MOSAIC was the first trial to use MRI to assess inflammation in peripheral joints and entheses instead of traditional X-ray methods. Participants received oral apremilast 30 mg daily, either as monotherapy or in combination with stable methotrexate. Treatment continued for 48 weeks and individuals had an MRI scan of the hand performed at baseline and at Weeks 24 and 48.
Researchers set the primary endpoint as the change from baseline in the composite score of hand bone marrow oedema, synovitis and tenosynovitis in fingers two to five, assessed by the PsA MRI Score (PsAMRIS) at Week 24, and for which a negative change reflects disease improvements.
In addition, a total inflammation score, which comprised of bone marrow oedema, synovitis, tenosynovitis and periarticular inflammation in fingers, was also assessed. The team also considered disease activity with the clinical disease activity index for psoriatic arthritis (cDAPSA), which is lowered as disease activity reduces.
MOSAIC enrolled 122 patients who received apremilast. The mean age was 47 years (55% women) and the mean duration of PsA was 1.9 years. Some 98 patients provided evaluable data for the primary endpoint.
The least-squares mean change from baseline in the composite inflammation score of bone marrow oedema, synovitis, and tenosynovitis assessed by PsAMRIS was -2.32 at Week 24 and -2.91 at Week 48.
Significant improvements from baseline were also seen in total inflammation scores for those taking apremilast, together with a reduction in cDAPSA score. In addition, no significant structural progression was observed.
The researchers suggested their findings highlighted the value of using MRI and PsAMRIS as measures of disease activity change following PsA treatments.
An acute coronary syndrome (ACS) risk stratification tool failed to improve either adherence to treatment guidelines or reduce the incidence of adverse cardiovascular outcomes compared to standard care, according to a recent cluster randomised controlled trial.
Non-ST segment elevation ACS (NSTEACS), which comprises non-ST elevation myocardial infarction (MI) and unstable angina, is a leading cause of disability, hospital admission and death. The Global Registry of Acute Coronary Events (GRACE) risk score (GRS) is designed to stratify risk in patients with ACS and provides an excellent ability to assess the risk for death.
In fact, optimal use of guideline-indicated care for non-ST-elevation myocardial infarction has previously been associated with greater survival gains. However, whether in practice using GRS leads to greater adherence to NSTEACS treatment guidelines and reduces the level of adverse cardiovascular sequalae was uncertain.
In the current study, published in the BMJ, researchers sought to determine if risk stratification using the GRS in patients presenting to hospital with suspected NSTEACS, enhanced the adoption of guideline-recommended therapy and reduced adverse cardiovascular outcomes.
Hospitals were randomised equally to patient management by either standard care or according to the GRS. The primary outcomes of interest were use of guideline recommended management and the time to a composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospital admission, and readmission for a cardiovascular event.
A total of 3,050 participants with a mean age of 65.7 years (69% female) were recruited and 1,440 were randomised to GRS care.
The uptake of guideline-recommended processes was not significantly different between the GRS and standard care groups (odds ratio, OR = 1.16, 95% CI 0.70 – 1.92, p = 0.56). In addition, the time to the first composite cardiac event was not significantly improved by the use of the GRS (hazard ratio, HR = 0.89, 95% CI 0.68 – 1.16, p = 0.37).
Secondary outcomes of interest included the EQ-5D-5L quality of life measure and the mean duration of the hospital admission for NSTEACS. As with the primary outcome, these metrics were not significantly different between the two groups.
The researchers concluded that use of the GRS score failed to improve guideline recommended management for NSTEACS or reduce a composite of adverse cardiovascular outcomes.
Using capnography breath data, a machine learning algorithm diagnosed chronic obstructive pulmonary disease (COPD) with an accuracy of 91%.
In the study, published in Respiratory Research, UK researchers used the N-Tidal device and applied machine learning techniques to capnography data to help distinguish the CO2 recordings (i.e. capnograms) of patients with and without COPD.
The team utilised capnography data from four clinical studies and developed machine learning algorithms to discriminate COPD from non-COPD, which comprised a group of patients who were either healthy or who had other conditions including asthma, heart failure, pneumonia, breathing pattern disorder and motor neurone disease.
The team developed three machine learning models and the predictability for COPD was assessed using receiver operator characteristic (ROC) curves and the subsequent estimates of sensitivity, specificity negative and positive predictive values.
A total of 88,186 capnograms were collected from 295 patients, with each patient providing an average of 299 capnograms over 179 days.
The highest accuracy (91.3%) was provided by an XGBoost model with a corresponding sensitivity of 91.5% and a specificity of 91.4% for the diagnosis of COPD. Even on an unseen test data set, the XGBoost model still had an accuracy of 90%.
According to the manufacturer of the N-Tidal device, TidalSense, it takes under five minutes from the start of the breath test to diagnosis.
Based on the findings of the current study, the researchers concluded that the ability of the N-Tidal capnography device to accurately diagnose COPD in near-real-time lends support to its future use in a clinical setting.
COPD led to 3.23 million deaths in 2019 and was the third leading cause of global deaths. Spirometry is generally considered to the be gold standard diagnostic tool for COPD, and its use is on the rise, yet it is also one of the major causes for misdiagnosis. Capnography is a widely used technique that could be used to diagnose COPD.
Oseltamivir use does not lower the risk of hospitalisation among older and high-risk patients with influzena, according to the findings of a recent systematic review and meta-analysis.
Published in JAMA Internal Medicine, researchers examined whether oseltamivir use in adult and adolescent outpatients with influenza reduced the risk of hospitalisation. They searched for randomised controlled trials that compared oseltamivir against placebo or nonactive controls in outpatients with a confirmed influenza infection. They set the primary outcome of interest as the first hospitalisation but excluded readmissions. In addition, the team also examined a primary safety outcome which was the rate of any adverse event, regardless of grade.
A total of 15 eligible trials with 6,295 individuals, of whom 3,443 were assigned to oseltamivir, were included in the final analysis. The participants had a mean age of 45.3 years (53.6% female). Of the 15 studies, 60% were sponsored by Roche, the manufacturer of oseltamivir.
Overall, oseltamivir was not associated with reduced risk of first hospitalisation (Risk Ratio, RR = 0.77, 95% CI 0.47 – 1.27). In addition, the drug failed to reduce hospitalisations among those aged 65 years and older (RR = 0.99, 95% CI 0.19 – 5.13) and in patients considered at greater risk of hospitalisation (RR = 0.90, 95% CI 0.37 – 2.17).
In terms of the primary safety outcome, patients given oseltamivir experienced significantly more nausea (RR = 1.43, 95% CI 1.13 – 1.82), vomiting (RR = 1.83, 95% CI 1.28 – 2.63) and a composite of gastrointestinal symptoms (RR = 1.21 95% CI 1.02 – 1.45).
The researchers concluded that oseltamivir use did not reduce the risk of hospitalisation but did lead to an increased risk of adverse gastrointestinal effects. They called for more studies to identify high-risk patients who might benefit from the drug.
Oseltamivir is an anti-viral agent used in the management of influenza. However, the benefits of the drug remain unclear. Some evidence demonstrates a clear advantage, whereas another review concluded that the evidence for a clinically significant effects on complications and viral transmission is limited because of a rarity of such events and problems with study design.
During the Covid-19 pandemic, cases of influenza decreased, although it is anticipated that the virus will re-emerge as normalcy returns following the pandemic. Consequently, there is a need to re-evaluate the available treatments for influenza.
Selinexor triple therapy with bortezomib and dexamethasone, provides a clinically meaningful improvement in overall survival in lenalidomide-refractory patients with multiple myeloma, according to a study presented at the 2023 European Haematology Association (EHA) Congress.
Among newly diagnosed adults with multiple myeloma, first-line treatment options is lenalidomide. One potential treatment option if patients become lenalidomide-refractory is the use of selinexor. The drug is a potent, orally administered exportin 1 inhibitor, the action of which blocks nuclear export of tumour suppressor, growth regulatory and anti-inflammatory proteins. This leads to accumulation of these proteins in the nucleus, enhancing their anti-cancer activity in the cell.
The BOSTON trial in 2020 demonstrated how selinexor triple therapy (with bortezomib, and dexamethasone) was effective in patients with multiple myeloma who had received one to three previous lines of therapy.
For the study presented at the EHA Congress 2023, researchers undertook a subgroup analysis of data from the BOSTON trial. They focused on the impact being lenalidomide-refractory and how this affected the effectiveness and safety of either selinexor triple therapy (SVd) – comprising selinexor 100 mg, bortezomib and dexamethasone – or standard therapy (Vd) of bortezomib and dexamethasone only. The outcomes of interest were both progression-free survival (PFS) and overall survival (OS), but researchers also examined the objective response rate (ORR) and the very good partial response (VGPR).
Among a total of 402 patients, 106 were classified as lenalidomide-refractory and equally distributed between the two therapy arms, with 53 in each.
The median PFS was significantly longer for the SVd group (10.2 vs 7.1 months, hazard ratio, HR = 0.52, 95% CI 0.31 – 0.88, p = 0.012). In addition, the median OS was also statistically significant, representing clinically meaningful improvement for the SVd group (HR = 0.53, 95% CI 0.30 – 0.95, p = 0.03).
Patients assigned to selinexor also had a higher ORR (67.9% vs 47.2%) and a higher VGPR or better (35.8% vs 24.5%).
The most common treatment-emergent adverse events, defined as affecting more than a quarter of patients, with SVd and Vd, were thrombocytopenia (71.7% vs 40.4%), nausea (50.9% vs 11.5%), fatigue (45.3% vs 21.1%), diarrhoea (43.4% vs 19.2%), anaemia (39.6% vs 25.0%), and peripheral neuropathy (30.2% vs 38.5%).
Commenting on these findings at EHA, the presenting author, Professor Maria-Victoria Mateos said ‘The data presented emphasise the synergy between selinexor and bortezomib, highlighting the importance of a double mode of action switch. These results are particularly relevant considering the increased use of the daratumumab lenalidomide dexamethasone combination in clinical practice today,
‘These findings further support the use of selinexor in combination with bortezomib in proteasome inhibitor/bortezomib-naïve or lenalidomide-refractory relapsed refractory multiple myeloma patients, as well as for patients at first relapse.’
Dystrophic epidermolysis bullosa is caused by a gene mutation, and the recent FDA approval of the corrective gene therapy VYJUVEK represents the first specific treatment to become available. Rod Tucker finds out more.
Dystrophic epidermolysis bullosa (DEB) is a rare genetic, blistering skin disorder that is usually present from birth. In addition to blistering, open wounds develop together with extra-cutaneous manifestations, affecting the eyes, oral cavity and many internal organ systems. Moreover, the disease places a huge burden on sufferers, caregivers and their families.
DEB occurs as a result of mutations in COL7A1, a gene encoding the alpha-1 chain of collagen type VII (C7) which form the anchoring fibrils of the skin and mucous membranes. Individuals with the disease have been referred to as ‘butterfly children’ due to the mechanical fragility of their skin which is analogous to that of a butterfly’s wings.
The FDA approval of VYJUVEK – also known as beremagene geperpavec or B-VEC – provides the first novel topical gene therapy. The treatment contains two copies of the COL7A1 coding sequence, encapsulated in a modified herpes simplex virus (HSV) type 1.
The delivery of the functional genes within B-VEC is achieved after outer shell viral proteins interact with proteins on the surface of skin cells to facilitate viral nucleocapsid entry. Once within the cell, the viral DNA is transcribed and translated into C7 and secreted into the extracellular space to assemble into anchoring fibrils.
Although yet to be officially approved by the European Medicines Agency (EMA), in 2018 the organisation granted B-VEC orphan drug designation, which will hopefully simplify the approval process. In addition, the UK’s National Institute for Health and Care Excellence is currently appraising the treatment.
But how effective is this novel topical therapy?
In an abstract abstract presented at the World Congress on Epidermolysis Bullosa in 2020, researchers described the use of B-VEC applied the wounds of two patients with recessive DEB in a phase 1 trial. It also detailed the findings of a phase 2 trial in which a total of 10 patients received the treatment. Overall, seven out of eight wounds treated with B-VEC closed completely within a median of 20.14 days.
Based on these early and positive findings, a phase 3, randomised, double-blind, placebo-controlled trial was initiated and published in the New England Journal of Medicine. The trial enrolled 31 patients, including children and adults, with DEB.
The trial used an intra-patient control design in which for each patient, the site investigator selected two wounds of similar size, anatomical region, and appearance. The wounds within each pair were then randomly assigned in a 1:1 ratio to receive either a weekly application of B-VEC or placebo for 26 weeks. The primary endpoint was complete wound healing at six months, whereas a secondary endpoint was complete wound healing after three months.
The results were remarkable. After six months, 67% of wounds treated with B-VEC were completely healed, compared to 22% of placebo-treated wounds (p = 0.002). Furthermore, complete healing of wounds after only three months occurred in 71% of those using B-VEC and 20% of placebo-treated wounds (p < 0.001). The researchers also examined the durability of the wound response in terms of sustained complete healing at both three and six months. This was seen in 50% of wounds treated with B-VEC but only 7% of placebo-treated wounds.
These positive findings in the phase 3 trial formed the basis of the FDA approval. But the results were important for a number of other reasons. Firstly, the successful use of a topical gene therapy over time bode well for not just DEB, but potentially for other genetic skin disorders. Secondly, the trial demonstrated the successful use a replication-defective HSV vector.
Thirdly, since B-VEC is formulated as a methylcellulose gel, it enables the patient or carer to apply the product themselves to existing wounds. Finally, because patients with epidermolysis bullosa are at an increased risk of squamous cell carcinoma (SCC), which can develop within chronic wounds, B-VEC may ultimately lower the risk of SCC.
But B-VEC is not the only therapeutic modality under investigation and there at least three other approaches being trialled. The first involves tautologous keratinocyte sheets containing full-length C7 using a retroviral vector and transplanted onto wound sites. In a phase 1/2 trial using this technique, researchers observed how wound healing exceeding 50% occurred in 95% of treated wounds compared to 0% in untreated control wounds.
The second approach makes use of recombinant human collagen 7 replacement therapy, which is given intravenously. Results from a phase 2 open-label study showed that after 120 days, 69.2% of treated wounds achieved a pre-specified response of a >2-point improvement on a wound-specific assessment scale.
For the third approach, work with topical or intra-dermal gentamicin was seen to induce type VII collagen and anchoring fibril production at the dermal-epidermal junction of erosion sites in five patients with recessive dystrophic epidermolysis bullosa.
While the findings to date are promising, B-VEC is not a panacea. For instance, because the treatment does not penetrate through the skin, it is only able to treat existing wounds rather than preventing new ones from forming. Furthermore, it is likely to require life-long dosing and has no effect on the systemic disease manifestations.
The EMA estimates that epidermolysis bullosa affects up to 36,000 people across Europe and, despite its limitations, B-VEC has the potential to provide relief for the cutaneous symptoms of this burdensome disease, which will be welcomed by sufferers and carers alike.
12th June 2023
The safety of Covid-19 mRNA vaccines when used in children under five years of age has been reassured following a recent analysis of nearly a quarter of million doses.
Published in the journal Pediatrics, US researchers analysed information contained within the Vaccine Safety Datalink (VSD) on the use of mRNA vaccines in children aged five years of age and younger.
The VSD is a collaborative effort between the Centers for Disease Control and Prevention and eight data-contributing health systems. It maintains comprehensive electronic medical records for members, including Covid-19 vaccination data from retail pharmacies and state immunisation registries.
The researchers examined a total of 23 pre-specified safety outcomes including myocarditis, pericarditis and seizures. The primary analyses compared the incidence of these safety outcomes during a pre-specified risk interval (one to 21 days post-vaccination) with outcomes among primary series vaccinated comparators who were less recently vaccinated at 22-42 days post-vaccination.
In total, 135,005 doses of the Pfizer-BioNTech Covid-19 vaccine and 112,006 doses of the Moderna Covid-19 vaccine (i.e. mRNA vaccines) were given to children aged six months to five years in the VSD population. The risk ratios were not elevated for any of the pre-specified safety outcomes following any dose of either mRNA vaccine. As an example, the risk ratios for convulsions and seizures in zero to seven days post-vaccination were 0.64 (95% CI 0.25 – 1.51, p = 0.89) for Pfizer-BioNTech and 0.85 (95% CI, 0.27 – 2.32, p = .70) after Moderna.
The researchers concluded that these ongoing surveillance data should provide reassurance to clinicians, parents and policymakers.
A previous interim analysis concluded that the incidence of selected serious outcomes was not significantly higher one to 21 days post-vaccination compared with 22-42 days post-vaccination for mRNA Covid-19 vaccines. Moreover, a further analysis indicated a low incidence of myocarditis and pericarditis among individuals persons aged five to 39 years. While these data are reassuring, further safety monitoring data are needed for mRNA doses, particularly when administered to children aged six months to five years of age, hence the current study.
UVB phototherapy (UVBP) for the treatment of atopic eczema in adults does not increase the risk of cutaneous cancers, according to a retrospective analysis.
Published in the Journal of the American Academy of Dermatology, Taiwanese researchers retrospectively assessed whether UVBP use in adults with atopic eczema elevated the risk of cutaneous cancers.
The team undertook a nationwide, population-based cohort study from 2001-18 to estimate the risk of developing both non-melanoma skin cancer and melanoma. They excluded patients under 20 years of age, those with a prior diagnosis of skin cancer and individuals who had received PUVA therapy. The cohort of patients who had received UVBP were then matched 4:1 to a group of atopic eczema patients who had not received phototherapy.
The researchers calculated the number of UVBP sessions for each patient and adjusted their analysis for a number of covariates including immunosuppressant therapy.
After exclusion, a total of 1,241 patients in the UVBP group were matched to 4,964 patients in the non-UVBP group. For the entire cohort, mean age was 42.4 years and 65.8% were men.
Compared to those not receiving UVBP, there was no overall and significant increased risk of skin cancer in the phototherapy group (adjusted Hazard ratio, aHR = 0.91, 95% CI 0.35 – 2.35). Similarly, there was no increased risk of either non-melanoma skin cancer (aHR = 0.80, 95% CI 0.29 – 2.26) or cutaneous melanoma (aHR = 0.80, 95% CI 0.08 – 7.64).
In addition, the risk of either form of cutaneous cancer was not increased when analysed based on the number of UVBP sessions.
UVBP is a recommended second-line treatment following failure of first-line treatment in patients with atopic eczema. While the existing literature suggests that longer-term use of UVBP does not increase the risk of cancer, this evidence is derived from patients with psoriasis. Consequently, whether this treatment modality is also safe in the longer term among those with atopic eczema remains uncertain.
Metformin use by overweight or obese patients reduces the risk of developing long Covid by around 41%, according to the findings of a recent randomised, placebo-controlled trial.
Published in The Lancet Infectious Diseases, the study followed up on previous research which sought to determine whether the use of metformin, ivermectin or fluvoxamine prevented the primary outcome. These were the occurrence of hypoxemia, an emergency department visit, hospitalisation, or death associated with Covid-19. The researchers concluded that none of three drugs reduced the primary outcome.
For the follow-up study, the same researchers followed a subgroup of patients for 300 days to assess if any of the drugs would prevent long Covid. The participants were adults aged 30-85 years with overweight or obesity and with Covid symptoms for less than seven days. In the original trial, metformin was titrated up to a dose of 1,500 mg daily and the subsequent development of long Covid was physician diagnosed. The design of the original trial enabled a comparison of metformin use with a matching placebo and the findings of the current study largely relate to metformin.
A total of 1,126 participants, 564 assigned to metformin and the remainder to matched placebo were included in the analysis. Overall, 8.3% of the cohort had developed long Covid by day 300.
The cumulative incidence of long Covid was 6.3% in the metformin group, but 10.4% (7.8-12.9) in those who received placebo (Hazard ratio, HR = 0.59, 95% CI 0.39 – 0.89 p = 0.012). In practice therefore, use of metformin reduced the absolute risk of developing long Covid by 4.1%. In other words, 24 people would need to take metformin to prevent one case of long Covid.
In the subgroup there were some interesting observations. The reduction in the risk of developing long Covid from using metformin was only significant if given less than three days from symptom onset (HR = 0.37, 95% CI 0.15 – 0.95). Similarly, the effect was also only significant in patients under 45 years of age, women and those with a body mass index greater than 30. Furthermore, metformin had no significant effect among those vaccinated against Covid-19.
Despite the positive findings, the researchers do acknowledge some limitations. Firstly, it is unclear if their findings would be generalisable to adults of a normal weight. Secondly, with a largely white population, whether metformin would still be effective for different ethnicities is unclear.
9th June 2023
A cilta-cel infusion lowers the risk of disease progression or death compared to standard care in lenalidomide-refractory patients with multiple myeloma, according to the findings of a recent randomised trial.
Multiple myeloma represents a malignant disease of plasma cells with a worldwide incidence of 6-7 cases per 100 000 persons per year. Lenalidomide is an immunomodulatory drug for maintenance treatment in newly diagnosed multiple myeloma which improves progression-free survival (PFS). But when patients fail to respond to lenalidomide, what is the most appropriate therapy?
This was the question addressed in a recent study published in the New England Journal of Medicine. Researchers undertook a randomised trial of cilta-cel – a B-cell maturation antigen-directed CAR-T cell therapy – in patients with lenalidomide-refractory disease.
All participants had received one to three prior therapies and were equally randomised to either cilta-cel or the physician’s choice of effective standard care. The physician’s standard care was pomalidomide, bortezomib and dexamethasone, or daratumumab, pomalidomide and dexamethasone. Researchers set the primary outcome as PFS, defined as the time from randomisation to the first documentation of disease progression or death.
In total, 419 patients underwent randomisation, with 208 (mean age 61.5 years, 55.8% male) receiving cilta-cel.
Cilta-cel treatment gave rise to a a significantly lower risk of disease progression or death compared to standard care (hazard ratio, HR = 0.26, 95% CI 0.18 – 0.38, p < 0.001).
After 12 months, PFS was 75.9% (95% CI 69.4 – 81.1) in the cilta-cel group and 48.6% (95% CI 41.5 – 55.3) in the standard care group. In addition, a higher proportion of patients in the cilta-cel group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%) and an absence of minimal residual disease (60.6% vs. 15.6%).
In terms of safety, Grade 3 or 4 adverse events occurred in a similar proportion of participants in the two groups (96.6% vs 94.2%, cilta-cel vs standard care).
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