Minor differences in efficacy between biologics for rheumatoid arthritis

21st July 2020

In patients with rheumatoid arthritis who have failed to achieve sufficient control with methotrexate, there are few important differences between second-line biologic treatments.

This is according to a systematic review and meta-analysis by a team from Cologne, Germany.

The researchers included a network meta-analysis that allowed for comparison of treatments that were not studied directly in head-to-head trials and also contacted market authorisation holders for unpublished studies and any additional but unpublished data from studies.

This provided a huge amount of information for analysis at the individual patient level. Data was analysed only from randomised controlled trials in adults who were treated with methotrexate combined with a biologic agent for at least 24 weeks.

A total of 38 trials were included in the final analysis although only 34 trials (with nearly 11,000 patients) covering eight different biologics provided data on clinical remission. The authors reported that overall, the analysis revealed few statistically significant differences in terms of benefits and harms between the biologics. However, some differences were detected, for instance, anakinra was the least effective biologic and certolizumab showed the most harm.

Commenting on their findings, the authors noted that though biologics have been available for many years, there was a lack of both comparative studies and long-term data such that they could only derive conclusions of low certainty.

Reference
Janke K et al. Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic review and network meta-analysis including aggregate results from re-analaysed individual patient data. BMJ 2020;370:m2288 http://dx.doi.org/10.1136 bmj.m2288.

Statistics on COVID-19-related deaths are likely to have been over-reported

Statisticians from the Centre for Evidence-based Medicine (CEBM) have noted an anomaly with the way that COVID-19-related deaths are reported by Public Health England (PHE).

This might indicate that in reality, fewer people have actually died after becoming infected.

Each day figures for hospital-related deaths in England are released and then later updated later to include community-related deaths. However, the daily death toll in England varies considerably; for instance it was 16 on 6 July but 152 the following day and some days there are no reported deaths in Scotland or Wales.

According to statisticians from the CEBM, the most likely explanation for this variation is the way in which the community data is collected. By checking the NHS central register of deaths each day and matching this to the PHE register of positive tests, it means that when someone dies who has also tested positive for the virus, this is counted as a COVID-19-related death irrespective of how they actually died.

For example, an individual who tested positive in March but was killed in a car crash in June is still counted as a community-related COVID-19 death. Until this issue is resolved, the daily death toll is no longer being reported by PHE and it is entirely possible that the true figure will never be known.

Reference
Centre for Evidence-based Medicine. www.cebm.net/covid-19/why-no-one-can-ever-recover-from-covid-19-in-england-a-statistical-anomaly/

Oxford vaccine shows boost to antibody response

The results from a Phase I/II trial of a vaccine produced by a team from the Jenner Institute, Oxford, indicate that the vaccine appears to be safe and able to generate spike-specific antibodies after 28 days.

The single-dose vaccine is based on a chimpanzee adenovirus and directed at the spike protein of the coronavirus which facilitates receptor binding and entry to host cells. The study enrolled 1077 healthy adults (median age 35 years) who were randomised to receive either the test vaccine (543) or a meningococcal conjugate vaccine which acted as a control. A sub-group of 10 patients from the COVID-19 vaccine group received a booster dose on day 28.

In the test vaccine group, spike-specific antibodies peaked by day 28 and remained elevated to day 56. Neutralising antibodies were initially detected in only 32 patients after a single dose of the test vaccine but in the sub-group of 10 patients, neutralising antibodies were detected in all 10 patients by day 42. Systemic adverse effects reported in the test vaccine group included fatigue (70%), headache (68%), muscle ache (60%), malaise (61%) and chills (56%). A protocol amendment allowed participants to have access to prophylactic paracetamol which reduced the proportion of those reporting systemic effects.

The authors concluded that these preliminary results indicate that the COVID-19 vaccine is safe and that reactogenicity was reduced by paracetamol. Phase II and III trials that will include a wider group of patients are currently in progress.

Reference
Folegatti PM et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 : a preliminary report of a phase ½, single-blind, randomised controlled trial. Lancet. 2020; (published online July 20). https://doi.org/10.1016/S0140-6736(20)31604-4

Skin rashes help to identify cases of COVID-19

17th July 2020

Using data collected as part of the COVID symptom app study, a team from Kings College, London have suggested that the occurrence of skin rashes in conjunction with other COVID-19 symptoms are predictive of a positive swab test for the virus.

Between 7 May and 22 June, of the 336,847 UK users who registered with the app, 6403 reported that they had skin symptoms. Among those who had tested positive for COVID-19, 8.8% reported skin-related changes and these individuals were generally older (mean age 50.2 years) and slightly more likely to be women.

Interestingly, in patients with classic COVID-19 symptoms not tested, a similar proportion (8.2%) also reported a rash. In an attempt to better understand the nature of the skin problems, the team collected photographs from patients. The rashes were categorised as erythemato-papular, erythemato-vesicular types, urticarial and acral. The rashes appeared as the same time as other COVID-19 symptoms in most patients (47%), afterwards in over a third (35%) whereas in 17%, the rash appeared prior to the onset of symptoms. Furthermore, in 21% of those testing positive, the rash was the only symptom.

The authors concluded that their study strongly supports the inclusion of skin rashes in the list of suspicious COVID-19 symptoms to help identify cases of the infection.

Reference
Bataillie V et al. Diagnostic value of skin manifestations of SARS-CoV-2 infection. medRxiv 2020.07. https://doi.org/10.1101/2020.07.10.20150656

Phase I results for mRNA-1273 show promise as COVID-19 vaccine

Data released on 14 July shows that a new COVID-19 vaccine was able to generate a satisfactory immune response.

As with most trials, the vaccine, mRNA-1273, encodes the SARS-CoV-2 spike glycoprotein which mediates host cell attachment and is needed for the virus to enter cells. The Phase I study included 45 healthy volunteers (aged 18 to 55 years) who were split into three groups, with each group receiving either a 25, 100 or 250mcg dose of the vaccine which was administered on days 1 and 29.

The results which cover a period of 43 days after the second vaccination showed that after the first dose, antibody responses were greatest for the two higher strengths and increased further after the second vaccination. In addition, although neutralising antibodies were detected after the first vaccination in less than half of the participants, all had detectable antibodies after the second dose. The vaccine was well tolerated were participants reporting mild-to-moderate severity arthralgia, fatigue and headache with localised mild injection site pain.

The authors report that their findings support the advancement of the vaccine for a Phase II trial (which began in May) and hopefully a Phase III trial starting in July 2020.

Reference
Jackson LA et al. An mRNA vaccine against SARS-CoV-2 – Preliminary report. N Engl J Med 2020; July 14: DOI: 10.1056/NEJMoa2022483

Study suggests that neutralising antibodies to COVID-19 decline over time

A team from the Department of Infectious Diseases, Kings’ College London, found that while neutralising antibodies to COVID-19 appear after an average of 14 days post-onset of symptoms (POS), levels subsequently declined over the next two to three months.

The researchers examined a cohort of 59 patients and 6 healthcare workers (77% male) with a mean age of 55 years (range 23 to 95 years) with a wide range of disease severity. Sequential serum samples were collected between 1 and 94 days POS. The team found that patients developed either a low, medium or high neutralising antibody titre (ABT) and that the titre level achieved depended on disease severity and was highest among those with more severe disease though the time to reach peak levels did not differ between the groups. However, ABT declined for all levels of disease severity and interestingly among patients with the least severe disease, antibodies became undetectable 34 days POS.

The authors were unable to determine the level of antibody titre required to provide protection against re-infection and called for further studies to understand the ability of ABT to offer protection from
the risk of renewed infection.

Reference
Seow Jet al. Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection. medRxiv 2020. doi: https://doi.org/10.1101/2020.07.09.20148429

Should saturated fat be back on the menu?

15th July 2020

The 1950s diet-heart hypothesis linked saturated fat to the development of coronary heart disease. But does more recent evidence suggest otherwise? Rod Tucker finds out more.

Developed during the 1950s, the diet-heart hypothesis suggested that greater consumption of fat raised cholesterol levels and led to the development of coronary heart disease (CHD). As such, the recommendation to reduce consumption of fat, particularly saturated fat was subsequently adopted by the select committee on nutrition and human needs¹ and incorporated into international nutritional guidelines.

Fast forward to 2017, and the American Heart Association concluded in an advisory paper that ‘lowering intake of saturated fat and replacing it with unsaturated fat, especially polyunsaturated fats, will lower the incidence of CVD’.² In the UK, advice from the NHS suggests that eating ‘too much saturated fats… will raise “bad” LDL cholesterol in your blood’.³

While now a cornerstone of dietary advice as a means to minimise the risk of developing CHD, closer inspection of the literature on the relationship between saturated fat and heart disease reveals that there is little objective evidence to support this premise. So, is it time to stop vilifying saturated fat and dispense with years of dietary dogma that has created a fear of fats and advocated that we embrace ‘low fat’ foods?

Saturated fat and heart disease

The relationship between intake of saturated fats and heart disease has been extensively explored in studies including more than 75,000 people and in recent years, reviews have failed to find convincing evidence for its harmful effects. For example, a systematic review and meta-analysis in 2015 which included data from 12 prospective studies concluded that intake of saturated fat is not associated with all-cause mortality, cardiovascular disease, coronary heart disease, ischaemic stroke or type 2 diabetes.⁴

However, cohort studies lack vigour and more robust evidence from randomised trials is required to more clearly define this relationship. In the late 1960s, the Minnesota Coronary Experiment (MCE), a randomised trial in over 9,000 people, was designed to test whether replacement of saturated fat with vegetable oil rich in linoleic acid reduced heart disease.

The study was conducted within state mental health hospitals and a nursing home to allow for a tight control of diet. Over a period of 4.5 years, researchers compared two diets containing either 18% saturated fat (the control diet) and 9% (the intervention diet). When reported, the authors found no difference in cardiovascular events, cardiovascular deaths or even total mortality.⁵

The study was not published until 1989, but in 2015, researchers uncovered further and unreported data from the MCE study and re-analysed the data. They concluded that while reducing saturated fat did reduce serum cholesterol by up to 13%, this was not associated with any benefit in terms of either myocardial infarction or mortality.⁶

Further evidence that saturated fats have no real effect on CHD comes from a 2020 Cochrane systematic review. This found that reducing saturated fat had little or no effect on cardiovascular mortality, all-cause mortality, non-fatal myocardial infarction or CHD mortality.⁷ In contrast to the recent reviews, earlier analyses have reported beneficial effects in terms of CHD events from replacing saturated fat with polyunsaturated fatty acids.⁸

Other recent data even suggests that a higher intake of carbohydrate (as recommended in dietary guidelines) increases the risk of heart disease. In the prospective urban rural epidemiological (PURE) study which included 125,287 participants from 18 countries who were followed for 10 years, it was found that replacing saturated fat with carbohydrate had an adverse effect on blood lipids.

As the authors concluded, ‘high carbohydrate intake has the most adverse impact on cardiovascular disease risk factors, whereas monounsaturated fatty acids seem to be beneficial and saturated fatty acids are not harmful’.⁹ In a further analysis of total mortality and major cardiovascular events, the same group reported that ‘higher saturated fat intake was associated with a lower risk of stroke’.¹⁰

Although saturated fat is known to increase low density lipoprotein (LDL) cholesterol levels, LDL itself actually comprises several sub fractions of differing size. The smaller and more dense LDL particles are associated with a higher CHD risk¹¹ than the larger LDL particles and studies suggest that saturated fat increases the concentration of larger LDL particles.¹² In addition, saturated fats increase high density lipoprotein levels (HDL) which are considered to be protective against heart disease.¹³

In summary, although saturated fats have been demonised over the years with a cultural shift towards eating low fat foods, this does not mean that saturated fat is without harm. In a recent study of 195,658 participants followed for 10 years, it was found that saturated fat intake was significantly associated with all-cause mortality but only where it represented 20% or more of total calorie intake.¹⁴

An unintended consequence of the shift to low fat foods, has been the recommendation to limit many foods including dairy products, eggs, unprocessed meats, all of which have been shown to reduce the risk of CHD.¹⁵ Individuals should therefore not seek to avoid eating these healthy foods simply because of a fear that they contain saturated fat.

References

1. Dietary goals for the United States. United States. Congress. Senate. Select Committee on Nutrition and Human Needs. Washington: U.S. Govt. Print. Off, 1977:92.
2. Sacks FM et al. American Heart Association. Dietary fats and cardiovascular disease: A Presidential advisory from the American Heart Association. Circulation 2017;136(3):e1-e23
3. NHS. Fat: the facts.
4. De Souza RJ et al. Intake of saturated and trans unsaturated fatty acids and risk of all-cause mortality, cardiovascular disease and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 2015;351:h3978
5. Frantz ID et al. Test of effect of lipid lowering by diet on cardiovascular disease risk. The Minnesota Coronary Survey. Arteriosclerosis 1989;9(1):129–35
6. Ramsden CE et al. Re-evaluation of the traditional diet- heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968–73). BMJ 2016;353:i1246.
7. Hooper L et al. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev 2020;5:CD011737.
8. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomised controlled trials. PLoS Med 2010:7(3):e1000252.
9. Mente A et al. Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study. Lancet Diabetes Endocrinol 2017;5:774–87.
10. Dehghan M et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet 2017;390:2050–62.
11. Krauss RM. Lipoprotein sub fractions and cardiovascular risk. Curr Opin Lipidol 2010;21(4):305 –11.
12. Dreon DM et al. Change in dietary saturated fat intake is correlated with change in mass of large low-density-lipoprotein particles in men. Am J Clin Nutr 1998;67:828–36.
13. Gordon DJ et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79(1):8 -15.
14. Ho FK et al. Associations of fat and carbohydrate intake with cardiovascular disease and mortality: prospective cohort study of UK Biobank participants. BMJ 2020;368:m688.
15. Astrup A et al. Saturated fats and health: a reassessment and proposal for food-based recommendations. J Am Col Cardiol 2020;June 16: doi: 10.1016/j.jacc.2020.05.077.

COVID-19 symptoms persist after acute infection

13th July 2020

A new observational study suggests that COVID-19 symptoms can persist for at least two months after the initial infection.

Italian doctors established a post-acute outpatient services for patients discharged from hospital and who had been infected with COVID-19. The analysis included 143 patients (37% female) with a mean age of 56.5 years (ranging from 18 to 84). During hospitalisation, 72% of patients had evidence of interstitial pneumonia and the mean duration of their hospital stay was 13.5 days. In addition, all patients had at least two negative test results for COVID-19, 24 hours apart.

At enrolment, all patients completed a standardised questionnaire on current symptoms as well as an assessment of their quality of life. Patients were assessed 60 days after the onset of their first COVID-19 symptoms.

After 60 days, only 18 (12.6%) were completely symptom-free whereas 32% still had one or two symptoms and more than half (55%) had three or more symptoms. The main symptoms reported were fatigue (53%), dyspnoea (43%), joint pain (27%) and chest pain (21%). Furthermore, 44% actually reported a worsening of their quality of life.

Although this study had a small sample size and was limited to a single hospital, the authors suggested that clinicians need to focus not only on the acute symptoms but should continue to monitor patients after discharge.

Reference
Carfi A et al. Persistent symptoms in patients after acute COVID-19. JAMA 2020; Jul 9 doi:10.1001/jama.2020.12603.

Both tacrolimus and beclomethasone equally effective in refractory ulcerative proctitis

Ulcerative proctitis (UP) is a form of ulcerative colitis (UC) that is limited to the rectum and considered by many to be the initial manifestation of UC.

Satisfactory induction therapy for UP may therefore help to delay disease progression. The usual treatment for UP is 5-aminosalicylic acid (5-ASA) and where this is ineffective, corticosteroids are added but this only induces remission in around 46% of cases and is associated with several side-effects.

In this randomised, double-blind trial by a Dutch and Flemish team, 85 patients (aged 18 years and over) and with endoscopically proven UP, refractory to 5-ASA were given either topical tacrolimus (2mg suppositories) or beclomethasone (3mg suppositories) once daily for 4 weeks.

A clinical response was defined as a ≥ 3-point change in the Mayo score (which ranges from 0 to 12) with higher scores representing more severe disease. At the study end, there was no significant difference in clinical response between tacrolimus or beclomethasone (63% vs 59%, p = 0.812). In addition, the proportion of patients in remission was also not significantly different (46% vs 38%, p = 0.638).

The authors concluded that either treatment represents a viable treatment option for patients refractory to 5-ASA that should be offered before other therapies.

Reference
Lie MRKL et al. No superiority of tacrolimus suppositories vs beclomethasone suppositories in a randomised trial of patients with refractory ulcerative proctitis. Clin Gastroenterol Hepatol 2020;18(9):1777-84.

Study reviews and offers management advice for the effect of COVID-19 on different organ systems

Although COVID-19 causes substantial respiratory problems including pneumonia and acute respiratory distress syndrome, the virus leads to widespread organ-specific manifestations that are now being increasingly appreciated.

This is according to a new review by a team from the division of Cardiology, University Irvine Medical Centre, New York.

The wide range of effects that occur secondary to infection with COVID-19 include direct viral toxicity, endothelial cell damage, thrombo-inflammation, dysregulation of the immune system and even dysregulation of the renin-angiotensin-aldosterone system. However, the importance of these secondary effects in the pathophysiological response of COVID-19 it is still not entirely clear.

As an example, as the virus gains entry to cells via the ACE2 receptor which is present on arterial and venous endothelial cells of various organs, the subsequent infection-mediated endothelial injury leads to elevation of von Willebrand factor which can result in excessive thrombin production that inhibits fibrinolysis and ultimately cause microthrombi deposition and microvascular dysfunction. The authors provide a comprehensive review of the clinical manifestations of COVID-19 infection in each organ systems and offer advice on appropriate management options.

They conclude by discussing the importance of clinicians around the globe being able to recognise the organ-specific presentations of the virus and have an understanding of management considerations to provide the best possible care for patients.

Reference
Gupta A et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020; https://doi.org/10.1038/s41591-020-0968-3.