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1st July 2020
The guideline sought to address the medical management of adult outpatients as well as those who are hospitalised with the condition. There are 11 recommendations and for each one there is an estimate of the strength of the recommendation (that is, strong, conditional or no recommendation) and the quality of the associated evidence (for example, high/moderate/low/very low/or evidence gap). Interestingly, only one recommendation was deemed as “strong” and based on moderate quality evidence. In contrast the majority of recommendations were associated with low or very low-quality evidence.
The best evidence was for the use of a biologic such as infliximab, adalimumab etc for treatment in an outpatient setting for those with moderate to severe disease. This was based on evidence from 16 randomised trials indicating that a biologic can induce disease remission within 6-8 weeks compared to placebo. In contrast the guideline does not recommend the use of methotrexate to induce remission or as a maintenance therapy although this is based on very low-quality evidence.
Despite the desire for high-quality, evidence-based guidelines, there are still too many unknowns in the management of patients with moderate to severe ulcerative colitis.
Reference
Feuerstein JD et al. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology 2020;158:1450-61.
The primary research questions posed by the review are:
Background
The majority of vitamin D is produced by the action of sunlight on the skin and the main circulating metabolite is 25-hydroxyvitamin D (25(OH)D) which is used to provide a measure of vitamin D status. In 2016, the Scientific Advisory Committee on Nutrition (SACN) produced a report on vitamin D1 and defined a vitamin D level of less than 25nmol/l as being associated with an increased risk of poor musculoskeletal health outcomes, for example, rickets or osteomalacia (that is, soft bones). The SACN report recommended that serum vitamin D should not fall below 25nmol/l throughout the year and advice from the NHS2 suggests that during the autumn and winter, adults and children over 5 years should take a supplement containing 10mcg vitamin D. Interestingly, the SACN report in 2016 also reviewed the evidence on vitamin D and the risk of infections and concluded that it did not generally show a beneficial effect. More recently, SACN has reviewed the evidence since 2016 and once again concluded that the evidence does not support recommending vitamin D supplementation3 to prevent acute respiratory infections in the general UK population.
Clinical studies reviewed
NICE identified a total of five studies which examined the potential relationship between vitamin D status and COVID-19. All of the studies were observational in nature.
None of these studies were able to provide sufficient evidence to answer the first and second research questions.
In relation to the third question, three studies sought to examine the relationship between vitamin D status and COVID-19. The study by D’Avolio et al4 examined differences in vitamin D levels among those testing positive vs negative for COVID-19. The results showed that that patients testing positive for COVID-19 had a significantly lower vitamin D level compared to those testing negative (27.75 nmol/l vs 61.5 nmol/l, p = 0.004). However, the study was subject on selection bias, that is, it is unclear how the patients were identified and recruited and only those who were symptomatic were included. In addition, other potential confounders which are known to be important in COVID-19 such as body mass index, ethnicity, smoking status were not recorded.
The second study5 used logistic regression models to examine the relationship between vitamin D levels and ethnicity for the development of COVID-19. The study included positive COVID-19 tests from 1474 individuals and then compared these with serum 25(OH)D levels contained in a large UK Biobank. The results of the modelling (which was adjusted for recognised confounders such as smoking status, weight and several other factors) found no significant relationship between baseline 25(OH)D levels and the development of COVID-19 infection. In addition, there was also no relationship between ethnicity and COVID-19 infection. A limitation of the study was the vitamin D levels were recorded historically and may have changed at the time of participant assessment.
The third study6 examined the association between vitamin D levels and the number of deaths in 20 European countries. The study observed a moderate degree of negative correlation (r = -0.44, p = 0.05) between serum 25(OH)D levels and the number of cases of COVID-19 per 1 million population. However, reported vitamin D levels for this study were taken from a single earlier study and in some cases, the data was over 15 years old. Furthermore, other factors which might have influenced the association were not considered.
The final observational study7 also examined vitamin D levels and deaths from COVID-19 this time across 12 European countries. The authors reviewed published vitamin D levels in older adults in these countries which they correlated with the reported number of COVID-19-related deaths. The concluded that low 25(OH)D levels were correlated with increased mortality from COVID-19 although the correlation coefficient is not reported. As with the previous European study, historical vitamin D levels were used and there was no consideration of potential confounders.
One other included study was a case-controlled telephone survey of 1,486 people with Parkinson’s disease8 designed to explore whether such patients were more at risk from COVID-19. The results showed no significant increased risk but those with Parkinson’s disease were statistically less likely to be taking vitamin D supplements. Again, limitations include no adjustment was made for confounders and COVID-19 status was self-reported.
Summary
The NICE evidence review has concluded that to date, there is no good evidence for either a preventative or protective role of vitamin D in relation to COVID-19. Nevertheless, given the importance of vitamin D for bone and muscle health, NICE recommends that individuals continue to follow the advice advocated by SACN.
The review is available online at www.nice.org.uk/advice/es28/chapter/Key-messages.
References
30th June 2020
But could having a healthy gut microbiome profile influence how we respond to infection with COVID-19?
According to this recent and speculative review by researchers from the Rajiv Gandhi Cancer Institute, New Delhi, the answer is quite possibly.
While there is currently no specific evidence of a connection between the gut microbiome and COVID-19, the authors consider that since the virus has been detected in stool samples and that infection is associated with diarrhoea in some patients, it is entirely possible that a gut-lung axis exists.
In support of their argument, the authors cite evidence that changes in the gut microbiome or “dysbiosis” are linked to disorders such as type 2 diabetes, depression and cardiovascular disease and how respiratory infections alter the range of organisms present in the gut. They speculate that since elderly patients have a less diverse gut microbiome, this could account for why these patients are more susceptible to problems when infected with the virus.
Finally, the authors contend that improving gut microbiome diversity through the use of pre- and probiotics could enhance the immune system and thus an individual’s ability to fight infection with COVID-19.
Reference
Dhar D, Mohanty A. Gut microbiota and covid-19 – possible link and implications Virus Res 2020;285;198018.
This was a large trial including 3904 adults recruited from 359 practices in five European countries (including the UK) who were randomised to either the electronic decision support tool (intervention group) or usual care. The aim was to determine if the support tool could help facilitate deprescribing of potentially inappropriate and non-evidence-based drugs to elderly patients in an effort to improve patient outcomes over a 24-month period.
The primary outcomes were a composite of unplanned hospital admission or death from any cause. The researchers looked at self-reported falls, adverse drug reactions (in terms of symptoms) and quality of life. After 24 months, 44.6% of patients in the intervention group had either an unplanned hospital admission or died compared to 48.4% in the control group and this difference was not significant. There were also no differences in any other measures apart from a reduction in the number of medicines prescribed to those randomised to the intervention group.
The authors concluded that the decision support tool should still be implemented as it reduced prescribing without detriment to any of the patient outcomes.
Reference
Rieckert A et al. Use of an electronic decision support tool to reduce polypharmacy in elderly people with chornic diseases: cluster randomised controlled trial. BMJ 2020;369:m1822.
The study included 530 type 1 diabetic patients (mean age 51 years) who had the condition for an average of 34.6 years. All patients had early-to-moderate diabetic kidney disease and a serum urate level of at least 270micromol/litre and were randomised to allopurinol 100mg daily or placebo for a period of 3 years with an additional 2-month wash-out period at the end of the study.
In addition, during a 9-week run-in period, patients received the equivalent of 10mg ramipril or 300mg Irbesartan to achieve a blood pressure of no higher than 140/90 mmHg. The primary outcome was the change in glomerular filtration rate (GFR) after 3 years plus the 2-month wash-out period at the end of the trial.
Mean serum urate levels decreased from 6.2 to 3.1mg/decilitre in the allopurinol group but remained unchanged in the placebo group and there was a non-significant mean change in GFR levels of -3ml with allopurinol and -2.5ml in the placebo group.
The authors reported no differences in adverse effects between the two groups.
Reference
Doria A et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med 2020;382(26):2493-503.
While it is recognised that these drugs should not be used in the longer-term due to toxicity, corticosteroids are often continued as maintenance therapy in order to prevent a disease release.
For this new study, a French team of researchers examined whether withdrawal of corticosteroids in patients with quiescent disease would lead to a disease flare. They randomised 123 patients to either maintenance therapy (prednisolone 5mg/daily) or stopping the drug for a period of 12 months.
Included patients had clinically stable disease over the preceding year and prednisolone 5mg/day as part of their treatment regime. The primary outcome was the proportion of patients experiencing a flare at 52 weeks. The results showed that the proportion of patients experiencing a disease flare was significantly less in the maintenance group compared to the withdrawal group (7% vs 27%). When looking at the severity of flares, it was also clear that those in the maintenance group experienced a significantly lower proportion of moderate/severe flares. Interestingly there were no differences in adverse events between the two groups.
The authors called for further studies in larger patient cohorts to validate their preliminary findings.
Reference
Mathian A et al. Withdrawal of low-dose prednisolone in SLE patients with clinically quiescent disease for more than 1 year: a randomised clinical trial. Ann Rheum Dis 2020;79:339-46.
Consequently, CLE has become an ill-defined disease according to a recent review of the condition by a group from Duke University, Durham, USA.
The article considers the difficulty in making a diagnosis as there are at least four subtypes with an additional barrier being that the precise pathophysiology remains unclear which therefore hinders the develop a specific and effective treatment. Despite this, the authors describe how over the years, a wide range of therapies have been used including topical agents for example, corticosteroids and calcineurin inhibitors and systemic agents such as antimalarials, immunosuppressants, retinoids and thalidomide. In recent years, attention has focused on the use treatment with biologics, in particular belimumab and rituximab although ustekinumab has also been tried. Other biologics include anifrolumab, which targets the type 1 interferon receptor.
The results to date indicate that the biologics show some promise for patients suffering from moderate-to-severe CLE or even systemic lupus erythematosus (SLE) which cutaneous involvement. However, currently none of these treatments are specially licensed for CLE. The authors finish by describing how current studies are underway to target the immune cells and inflammatory pathways involved in the pathogenesis in an effort to develop more targeted treatments in the future.
Reference
Petty AJ et al. Cutaneous lupus erythematosus: progress and challenges. Curr Allergy Asthma R. 2020;20:12-22
In a new, small observational study, a French team followed the progress of patients with SLE who became infected with COVID-19. Data were collected for 17 patients, admitted between 29 March and the 6 April and who had used HCQ for a mean of 7.5 years (range 0.5 to 29.8 years). At the time of admission, all patients (except one) had clinically quiescent SLE.
In addition, 12 patients were also receiving prednisolone at doses below 10mg/day and 7 an immunosuppressant. All patients had the classic clinical signs of COVID-19 except for a higher rate of dyspnoea, headache and diarrhoea. When admitted, both HCQ and prednisolone were maintained but immunosuppressants were discontinued. In total, 7 patients required intensive care and 11 needed oxygen therapy.
At the time of writing (7 April) 5 had been discharged, 7 remained in hospital and two died. A single patient developed acute tenosynovitis after COVID-19 infection, but none of the others experienced a worsening of SLE during their admission.
While based on a small sample, the authors concluded that taking HCQ for SLE does not affect the course of infection with COVID-19.
Reference
Mathian A et al. Clinical course of coronavirus disease 2019 (CODI-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine. Ann Rheum Dis [letter] 2020;79:837-9.
In a recent survey of 609 French patients, 63% stated that their disease had worsened during confinement and 28% had experienced a considerable deterioration of their disease. Moreover, 43% reported that confinement had led to them changing their treatment, mainly the use of NSAIDs, which are the reference treatment for SpA. In total, 39% had modified their intake of NSAIDs, 28% had completely stopped while 11% reduced their intake. This discontinuation of NSAIDs had occurred in the majority of cases without patients informing their physician and largely was as a result of warning about the use of these drugs in the context of COVID-19 which was highlighted in the media. In addition, NSAIDs were often discontinued when patients experienced a disease flare. Fortunately, only 11% of patients discontinued their DMARDS.
Although it was unclear from the survey whether treatment discontinuation led to a worsening of symptoms, another contributory factor was lack of physical activity which is known to reduce disease activity and is incorporated into patient treatment plans.
The authors recommended that patients be provided with evidence on NSAIDs and how to undertake physical activity at home, especially if further lockdown measures are introduced at a later date.
Reference
Roux CH et al. Impact of home confinement during the COVID-19 pandemic on medication use and disease activity in Spondyloarthritis patients. Arthritis Rheumatol [letter] 2020; June 17 doi.org/10.1002/art.41397.
26th June 2020
However, what is more alarming is the notion that infection with COVID-19 might actually lead to the development of diabetes as had been reported recently in the media.2,3 But what is the evidence to support this premise and should patients without diabetes be unduly concerned?
The origins of the media stories are a letter written by a group of experts in the New England Journal of Medicine.4 The authors suggest that there is a bidirectional relationship between COVID-19 and diabetes. This is based firstly on the observation that having diabetes increases a patient’s risk of mortality (see reference 1) and secondly, the evidence that severe diabetic complications such as diabetic ketoacidosis and hyperosmolarity, requiring high dose of insulin, have been observed in patients infected with COVID-19.5-7 Although this would suggest that COVID-19 might cause diabetes, closer examination of the references cited by the authors reveals a very different picture.
The first reference5 relates to a newly diagnosed diabetic patient who developed diabetic ketoacidosis after infection with COVID-19. The authors concluded that it was possible for COVID-19 to aggravate pancreatic beta cell function and cause diabetic ketoacidosis, that is, infection might worsen a problem that is likely to be experienced by someone with existing diabetes. Both the second6 and third references7 include patients with existing diabetes although in reference 6, there were 42 patients developed ketosis, 27 of whom did not have diabetes. Ketosis refers to the production of ketones in the liver, leading to elevated levels of ketone bodies in the blood and is not necessarily related to diabetes.
In contrast, ketoacidosis is a severe metabolic disorder which is mostly seen in those with diabetes, although it can be induced in patients without diabetes such as those who have been fasting.8,9 Ketoacidosis occurred in 5 of the study patients, of which two did not have diabetes and the authors suggested that COVID-19 might accelerate fat breakdown and induce ketosis and subsequently ketoacidosis but called for further research to explore this association. In the final study,7 the authors explored the association between the triglyceride and glucose index (TyG) and mortality in 151 patients of whom 25.8% were diabetic. While the results showed that the TyG was significantly associated with an increased risk of severe infection (with COVID-19) and mortality, there is no specific mention of diabetes and the authors simply concluded that the TyG index was higher in those with more severe infection and among those who died.
In summary, although media speculation implies that infection with COVID-19 is able to trigger diabetes, there is little currently no convincing evidence to support this claim. Nevertheless, an international group of diabetic researchers have established the CoviDiab registry10 project to try and establish the extent and characteristics of new-onset COVID-19-related diabetes and to determine its pathogenesis, management and outcomes. Hopefully over time as the data contained in the registry is expanded, researchers will have a much clearer idea of whether there is an association between COVID-19 and the development of diabetes.
References
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