Specialist Forum September 2021

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Vol. 21 • No. 9 • September 2021

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Psychiatry

ADHD | Depression | Insomnia | Stereotyping

BILOCOR 5, 10. Each tablet contains 5, 10 mg bisoprolol fumarate respectively. S3 A38/5.2/0053, 0051. NAM NS2 06/5.2/0061, 0062. For full prescribing information, refer to the professional information approved by SAHPRA, 23 July 2010. BILOCOR CO 2,5/6,25, 5/6,25, 10/6,25. Each tablet contains 2,5, 5, 10 mg bisoprolol fumarate respectively and 6,25 mg hydrochlorothiazide. S3 A44/7.1.3/1010, 1011, 1012. NAM NS2 13/7.1.3/0260, 0261, 0262. For full prescribing information, refer to the professional information approved by SAHPRA, 06 May 2019. BRE711/04/2021.

CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za

SF | CONTENTS

September 2021 | Vol. 21 No. 9 www.medicalacademic.co.za

INSIDE this issue

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MEDICAL ETHICS

Informed patient, revered doctor

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ENDOCRINOLOGY

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Semaglutide improves CVD outcomes beyond traditional risk factor control

9 12 17

Reducing complexities in T2DM management

Obesity 101

28 PSYCHIATRY

CPD: The cost of untreated ADHD

CPD: Insomnia: A predictor of suicidal ideation

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CPD: The progressive nature of depression

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CPD: Covid-19: The great mental health equaliser

45 CRITICAL CARE

CPD: Tackling harmful chemicals in medical devices

48 CARDIOLOGY

51 53

BP-lowering pharmacotherapy should be the foundation of risk prevention

20 key messages from the new ESC HF management guideline Recognising rare diseases: Access and action

Expert opinion: Patient selection for premixed insulin in diabetes

20 DERMATOLOGY 23 27

How to recognise atopic dermatitis

Skin infections in AD may lead to life-threatening complication

Painful skin conditions

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This article was independently sourced by Specialist Forum.

Informed patient, revered doctor A patient’s right to be informed of all information relevant to his or her condition and available treatment options, for the purposes of being able to provide informed consent to receive medical treatment, flows from various legislations and guidelines within South Africa.

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patient must be provided with sufficient information to enable him or her to make an informed decision, in relation to the medical treatment proposed by their healthcare practitioner.

Informed consent must be obtained from every patient before prescribing any form of treatment – or performing any form of surgical

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procedure – on the patient. It is imperative that a copy of the informed consent form completed by the medical practitioner and signed by the patient is placed in the patient’s file.

These are the words of Natasha Naidoo, senior associate in Norton Rose Fulbright’s Insurance Litigation Team in Johannesburg, who spoke at a recent medical ethics seminar. Her

advice, further, was that medical practitioners must ensure that they complete an informed consent form in respect of every patient and that the form is signed by both parties. “This form serves as evidence that all requirements, for all intents and purposes of obtaining informed consent, have been met,” she enthused.

Naidoo stated further that practitioners

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are often faced with large amounts of timeconsuming paperwork and admin. One of the reasons provided by healthcare practitioners for not keeping contemporaneous patient records is that there simply is not sufficient time. They are faced with large amounts of paperwork and admin on a daily basis and are required to attend to their patients simultaneously. Their main focus is obviously their patients. Some healthcare practitioners are of the view that they are unlikely to receive a complaint or have a medical malpractice claim instituted against them. It is therefore important to look at the case law which deals with patient recordkeeping.

The case law #1 In ARB v IVF Hammersmith and R, an England Appeal Court held that a father’s claim against a clinic for breach of contract relating to damages suffered as a result of raising his child – who was born by IVF to his estranged wife without his consent – were not recoverable due to legal policy.

The child was conceived via IVF from embryos (created with the gametes of the separated couple), which were stored at the clinic. The father instituted action against the clinic on the basis that the mother had forged his signature on the consent forms, resulting in the clinic staff implanting a frozen egg into her.

He claimed that the procedure was carried out without his written informed consent.

The court considered various factors – including fraudulent misrepresentation of the father’s signature, the contract entered into between the parties and the father’s failure to inform the clinic of the changes in his relationship with the mother, which had resulted in him being contributorily negligent. The court also took into consideration public and legal policy issues surrounding the father’s claim.

It was held that the clinic was subject to strict liability, and that it had breached its obligations towards the father by performing a procedure without obtaining his written informed consent.

The father’s appeal against the court’s decision, for damages resulting from the birth of the child without his consent, however failed. This, despite the court’s satisfaction with his evidence that he had no intention of procreating with the mother of the child.

The court applied principles concerning legal policy, which illustrate the difficulty involved in attempting to measure the loss suffered, the unwillingness on the part of the parent to regard the child as a financial liability, the refusal to offset the benefits derived from parenthood from its financial-liability obligation, and the moral and ethical considerations associated with allowing such a claim.

The judgment is a stark reminder to healthcare professionals and establishments to ensure that the identity of the patient is confirmed and the informed consent of the

patient obtained in writing before any procedure is undertaken. Healthcare professionals and establishments should also ensure that terms and conditions of admission to a healthcare establishment, or for the rendering of services, exclude any liability arising due to dishonesty of a patient (in this case the mother). Naidoo states in her article that South African courts have, in general, been more accommodating of wrongful birth claims than the English courts.

The case law #2 In a second instance, North West surgeon Dr Samuel Smith’s detailed motivation to a patient’s medical scheme for keyhole surgery, instead of the riskier open surgery finally tipped the legal scales in his favour after two years of litigation. The Supreme Court of Appeal dismissed a negligence claim that there had not been informed consent and that Smith had not explained the risks of the procedure. Naidoo said that the lesson for doctors was for them to keep notes proving how they explained the risks to the patient, which was likely to reduce the probability of lengthy legal battles.

The patient, Rabia Beukes, had a laparoscopy to repair a hernia after she sought help for abdominal pain. Mrs Beukes alleged that during the surgery her colon was perforated and she developed sepsis, which resulted in her being hospitalised for two months for further treatment. She alleged that this was due to the doctor’s negligence and that she would have chosen a different procedure if he informed her of the risks associated with keyhole surgery.

According to Beukes, the doctor did not provide her with any information relating to the options available to her; nor did not inform her of the risks and benefits associated with each option.

However, both the High and Supreme Courts held in favour of Dr Smith. It was held that the doctor must have explained the risks to Mrs Beukes, which was evident from the detailed letter he wrote to her medical aid motivating the funding of her keyhole surgery instead of the riskier open surgery. Dr Smith was fortunate that despite not keeping contemporaneous medical records which could prove that informed consent was in fact obtained, the court held in his favour by taking into consideration the letter he had penned to Mrs Beukes’ medical aid. “This judgment highlights the importance of keeping clearly and accurately written medical records [within each patient’s folder],” says Naidoo. “Medical records serve as evidence of professional competence and ignorance, in cases where it is the patient’s word against the healthcare practitioner’s.”

Informed consent guidelines What do HPCSA Guidelines state with reference to informed consent and the manner in which it must be obtained from a patient? These include: » An actual discussion being held in consultation

with the patient, during which he or she is provided with information relating to their condition. The amount of information provided is dependent upon the nature of the condition, the complexity of the treatment or procedure being recommended, the risks associated with the recommended treatment or procedure, while also taking into consideration the patient’s wishes » The patient being informed of the treatment options available. For example, whether medication is recommended to manage a condition and what the different options are; or if surgery is recommended, whether there is an alternative for the patient’s specific condition, plus the possible benefits and side-effects associated with the recommended medication and/or surgical procedure » The healthcare practitioner recommending which medication or form of treatment, in his/her opinion, would benefit the patient most – taking into consideration the patient’s condition, medical history and the outcome to be achieved » An assessment of the costs associated with the recommended treatment, medication or procedure concerned » That the patient is provided with the opportunity to ask any questions.

During the webinar, Naidoo made it clear that the practitioner is required to inform the patient of the risks and adverse side effects of each option (surgery, other treatments, medication); along with the benefits of each. Her take is that withholding information is not helpful when faced with a situation where the patient may not be able to afford a particular option. This may be due to a lack of available funds or the fact that their medical scheme may not provide cover for a particular option. However, it is the patient who is required to make the decision as to which of the options available to them seems preferable, so it remains the healthcare practitioner’s duty to inform the patient of all possible options. It may still be possible for the patient to, for example, source the required funds from a friend or relative.

“All of the above information provided to the patient will then place him or her in the position to make an informed decision and, in doing so, to provide informed consent to the healthcare practitioner. An informed consent form must record the discussion between the healthcare practitioner and the patient, it must be signed by both parties, and a copy of the signed form should be placed in the patient file as it forms an integral component By Vanessa Rogers on behalf of Natmed of the patient’s Medical Defence records.” SF

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Semaglutide improves CVD outcomes beyond traditional risk factor control

Novo Nordisk hosted a glucagon-like peptide-1 receptor agonist (GLP-1RA) virtual summit on 26 June 2021. One of the keynote speakers was Prof Mpiko Ntsekhe, Head of the Cardiology Division at the University of Cape Town. Prof Ntsekhe discussed diabetes as a cardiometabolic disease and looked at the role of semaglutide, a GLP-1RA, in preventing and managing cardiovascular diseases (CVDs) in patients with type 2 diabetes (T2DM).

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iewed through the narrow traditional lens, diabetes is a metabolic disease and the primary goal of care is glycaemic control. However, an alternative view, which is more patientcentred, is that diabetes is a cardiometabolic disease associated with a high rate of CVD – often independent of glycaemic control. If we view diabetes in this way, the primary goal is to manage micro- and macrovascular complications, said Prof Ntsekhe.

Atherosclerotic CVD (ASCVD) – in particularly stroke, myocardial infarction (MI), peripheral vascular disease and HF – is the main cause of morbidity and disability adjusted life years in patients with T2DM. 9 T2DM doubles, and in some cases triples, the risk of MI and stroke, relative to age and gender matched controls. The absolute risks of ASCVD in patients with T2DM depends on multiple variables:10 » Age » Gender » Hypertension » Lipid profile » Smoking » Duration of diabetes

» Presence of microvascular complications » Use of specific risk lowering medications (eg statins).

A review of data from 2007-2017 by Einarson et al, which included data from more than 4.5 million participants with T2DM, found that globally, overall CVD affects about 32.2% of all persons with T2DM. CVD is a major cause of mortality among people with T2DM, accounting for approximately half of all deaths over the study period. Coronary artery disease and stroke were the major contributors.1

What is the predominant manifestation of CVD in patients with T2DM? Shah et al looked at the associations between T2DM and 12 initial manifestations of cardiovascular disease. Data from more than 1.8 million participants were analysed of which 1.8% (34 198) had T2DM. Follow-up period was 5.5 years and during this time, the researchers observed 113 638 first presentations of CVD. A total of 17.9% of participants with T2DM had a first CV presentation, the most common of which were peripheral arterial disease (PAD) (16.2%) and heart failure (HF) (14.1%).

T2DM was positively associated with PAD, ischaemic stroke, stable angina, HF, and non-fatal myocardial infarction (MI), but was inversely associated with abdominal aortic aneurysm and subarachnoid haemorrhage, and not associated with arrhythmia or sudden cardiac death. 2 The aim of the 2020 International Survey of the Occurrence of Cardiovascular Disease Among Patients With T2DM (CAPTURE) was to estimate the contemporary (2019) prevalence of established CVD in people with T2DM across 13 countries from five continents. In total, 9823 adults with T2DM managed in primary as well as specialist care, participated. Overall CVD prevalence was 34.8%, with most (85.8%) categorised as ASCVD (31.8%). Overall coronary heart disease prevalence was 17.7%, carotid artery disease was 8.4%, and cerebrovascular disease was 7.2%. The overall prevalence of HF was 2.4%, driven by a relatively low prevalence in China (0.2%). Prevalence estimates were similar across primary and specialist care settings. The researchers concluded that in 2019, about one in three adults with T2DM attending a primary or specialist healthcare visit, had established CVD.3

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In the CAPTURE study patients were treated with GLP-1RAs such as semaglutide, and sodium-glucose cotransporter-2 inhibitors (SGLT-2is). The majority of guidelines now recommend early introduction of these agents as second-line therapy in combination with metformin in patients who are at high risk or have established CVD, noted Prof Ntsekhe.

The role of semaglutide in reduction of CVD in T2DM Semaglutide has an extended half-life of about seven days, allowing for one weekly dosing.

Its efficacy and safety have been shown in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6).

Patients (n=3297) with T2DM who were on a standard-care regimen, were randomised to receive once-weekly semaglutide (0.5mg or 1mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of CV death, non-fatal MI, or non-fatal stroke. At baseline, 83% of participants had established CVD, chronic kidney disease (CKD), or both.

The primary outcome occurred in 6.6% in the semaglutide group and 8.9% of those in the placebo group. Non-fatal MI occurred in 2.9% of the participants receiving semaglutide and in 3.9% of those receiving placebo. Non-fatal stroke occurred in 1.6% of participants in the semaglutide group and 2.7% in the placebo group. Rates of death from CV causes were similar in the two groups. The team concluded that in patients with T2DM who were at high CV risk, the rate of CV death, non-fatal MI, or non-fatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo.4 Prof Ntsekhe noted that the majority of patients in the study had established CVD – either past MI or stroke. But what are the implications for patients who were considered high risk, but did not have a history of CVD? In a post-hoc analysis of SUSTAIN-6, Leiter et al grouped participants according to gender, age (50-65 years and > 65 years), and CV risk profile at baseline (prior MI or stroke versus no prior MI or stroke, and established CVD versus CV risk factors alone, including participants with CKD). Time to major adverse cardiovascular events (MACE) and its individual components (CV death, nonfatal MI, nonfatal stroke), hospitalisation for unstable angina or HF, and revascularisation (coronary and peripheral) were analysed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA1c and body weight, as well as tolerability. A total of 41.5% of participants had a history of MI or stroke and 76.8% had established CVD. Compared with placebo, semaglutide reduced the risk of

the first occurrence of MACE and each MACE component consistently across all subgroups (gender, age, and baseline CV risk profile).

Revascularisations, HbA1c and body weight were also reduced consistently across all subgroups compared with placebo. 5 In this post-hoc analysis of SUSTAIN 6, once-weekly semaglutide versus placebo reduced the risk of MACE in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile, stressed Prof Ntsekhe.

The findings of this study have important implications. Fang et al showed that even in developed countries such as the United States, diabetes care – specifically the effective management of CVD risk factors and reductions – needs to improve. Newer agents like semaglutide offer major opportunities for better patient care and outcomes, said Prof Ntsekhe.

pressure and plateaued for those with poor glycaemic control.6

Take home messages

1 2 3 4

The burden of diabetes is high and growing – particularly in geographical regions such as sub-Saharan Africa.

The burden of CVD in patients with T2DM is high with ASCVD predominating as the main manifestation.

It is important to view diabetes as a cardiometabolic disease rather than a disorder of dysglycaemia.

Early use of once-weekly semaglutide provides opportunity to improve CVD outcomes beyond traditional risk factor control.

References 1. Einarson TR, Acs A, Ludwig C, et al. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence

h s wit

t adul M8 f o D -95% e T2 v a 90% h w i ll tes s e t l b u a 7 d di ion a y 2045 l l i 693 m betes b dia have

from across the world in 2007-2017. Cardiovasc Diabetol, 2018.

2. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol, 2015.

3. Alguwaihes A, Arenas Leon JL, Bayram F, et al. CAPTURE: a cross-sectional study of the contemporary (2019) prevalence of cardiovascular disease in adults with type 2 diabetes across 13 countries. https://www.easd.org/virtualmeeting/ home.html#!resources/capture-a-cross-sectional-

Fang et al evaluated trends in diabetes treatment and control in American adults (1999-2018). Data from the National Health and Nutrition Examination Survey (NHANES) were analysed. Diabetes control improved from 1999 to the early 2010s among participants but subsequently stalled and declined.

Between the 2007-2010, and 2015-2018, the percentage of adult NHANES participants with diabetes in whom glycaemic control (<7%) was achieved declined from 57.4% to 50.5%.

After major improvements in lipid control (non–high-density lipoprotein cholesterol level, <2.8mmol/L) in the early 2000s, minimal improvement was seen from 2007-2010 (52.3%) to 2015-2018 (55.7%). From 2011-2014 to 20152018, the percentage of participants in whom blood-pressure control (<140/90mmHg) was achieved decreased from 74.2% to 70.4%.

The percentage of participants in whom all three targets were simultaneously achieved plateaued after 2010 and was 22.2% in 20152018. The percentages of participants who used any glucose-lowering medication or any blood-pressure-lowering medication were unchanged after 2010, and the percentage who used statins plateaued after 2014. After 2010, the use of combination therapy declined in participants with uncontrolled blood

study-of-the-contemporary-2019-prevalence-ofcardiovascular-disease-in-adults-with-type-2diabetes-across-13-countries-6443597c-6a85-4a9e8895-8e97f8f0c390 4. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM, 2016.

5. Leiter LA, Bain SC, Hramiak I, et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovasc Diabetol, 2019.

6. Fang M, Wang D, Coresh J, et al. Trends in Diabetes Treatment and Control in U.S. Adults, 1999–2018.

NEJM, 2021.

7. Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract, 2018.

8. Centres for Disease Control and Prevention.

Diabetes Fast Facts. https://www.cdc.gov/diabetes/ basics/quick-facts.html 9. Wang CC, Hess CN, Hiatt WR, et al. Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes – Mechanisms, Management, and Clinical Considerations. Circulation, 2016.

10. American Diabetes Association. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes. Diabetes Care, 2019. SF

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Reducing complexities in T2DM management

This article is based on a presentation by Dr Julien Trokis, a diabetologist based in the Western Cape. Dr Trokis was one of the keynote speakers at the recent South African launch of iGlarLixi, a once-daily titratable fixed-ratio formulation that combines basal insulin glargine 100 units/mL and the glucagon-like peptide-1 receptor agonist (GLP-1RA), lixisenatide.

The combination offers a once-weekly, single-injection option for treatment intensification.

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his year marks the 100th anniversary of the discovery of insulin. According to the 9 th edition of the International Diabetes Foundation (2019), an estimated 463 million people globally have diabetes (type 1 and type 2 combined).1,2 T2DM accounts for the vast majority (around 90%) of cases (416 million). About 65 million people with T2DM need insulin, but only 50%

OADs was 8.7%, 9.1%, and 9.7%. In patients taking one, two, or three OADs, median time from treatment initiation to intensification with an OAD or insulin exceeded the maximum follow-up time of 7.2 years. The probability of patients with poor glycaemic control taking one, two, or three OADs, intensifying at end of follow-up with an OAD, was 21.1%–43.6% and with insulin 5.1%–12.0%.13

are able to access treatment. Apart from limited access to treatment, Dr Trokis discussed some of the other challenges that complicate the effective management of patients with T2DM.1,2,3

In a follow-up study (2016), Khunti et al found that 36.5% of patients had their treatment intensified during the study period (three years). Of these, the treatment of 50%, 42.5% and 7.4% was intensified with bolus or premix insulin or GLP-1RAs, respectively. The median time from initiation of basal insulin to treatment intensification was 4.3 years. Among patients clinically eligible for treatment intensification (HbA1c ≥7.5%), 30.9% had their treatment regimen intensified. The median time to intensification in this group was 3.7 years.14 In a cohort of 105 477 patients, Paul et al showed that mean HbA1c was 8.1% at diagnosis, 11% had a history of cardiovascular disease, and 7.1% experienced at least one macrovascular event during 5.3 years of median follow-up. In patients with HbA1c consistently >7% and 7.5% two years post-diagnosis, 26% and 22% never

The problem of clinical inertia Khunti et al (2013) showed that in people with HbA1c ≥7%, ≥7.5%, or ≥8%, median time from above HbA1c cut-off to intensification with an additional oral anti-diabetic (OAD) agent was 2.9, 1.9, or 1.6 years, respectively, for those taking one oral antidiabetic agent (OAD) and >7.2, >7.2, and >6.9 years for those taking two OADs. Median time to intensification with insulin was >7.1, >6.1, or 6 years for those taking one, two, or three OADs.13 Mean HbA1c at intensification with an OAD or insulin for people taking one, two, or three

received any treatment intensification.15 Compared to patients with HbA1c <7%, in patients with HbA1c ≥7%, a one year delay in receiving treatment intensification was associated with significantly increased risk of MI, stroke, heart failure and composite macrovascular events by 67%, 64% and 62% respectively. One year delay in treatment intensification in interaction with HbA1c above

7.5% was also associated with similar increased risk of macrovascular events.15 According to Khuni et al, clinicians’ inertia may be driven by:14 » Lack of knowledge about the current opinion that aggressive control early on following diagnosis leads to significant benefit in appropriate patients » The assumption that the management of patients with T2DM and multiple comorbidities is challenging and require specialist training » Worries about potential adverse side effects such as hypoglycaemia » Concerns about patient adherence (patients might be unable or unwilling to adapt to the increasingly complex regimen) » Lack of time available to primary care physicians to adequately tackle concerns.

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Patient-level inertia maybe the result of: Misperceptions about insulin therapy such as: » The belief that insulin therapy is not efficacious » Their quality of life will drop considerably » They will not be able to adhere to increasingly complex regimens » Fears of unwanted side effects such as weight gain, hypoglycaemia, and injection pain.

Intervening earlier Unfortunately, many patients do not achieve recommended glycaemic targets. In Canada 49.9%, in the United States 44% and in Europe only 37.4%, and in South Africa, the International Diabetes Management Practices Study survey showed that 36% of patients achieve their recommended targets. 8,9,10,23 Guidelines support individualised glycaemic targets based on patient preference, as well as treatment efficacy, and safety profiles. Although individualised targets are advocated, guidelines recommend a target HbA1c of <7% for most non-pregnant adults with T2DM. In patients who do not achieve individualised targets, a stepwise introduction of pharmacotherapy is recommended. 5,6 The 2020 American Association of Clinical Endocrinologists and American College of Endocrinology and ADA guidelines recommend early combination therapy in patients with HbA1c >9% or 1.5%-2% above target, respectively, as the effectiveness of most OADs rarely exceeds a 1% HbA1c reduction. 5,22 The importance of early initiation of pharmacotherapy was shown in the landmark United Kingdom Prospective Diabetes Study (UKPDS). The study showed that by the time HbA1c levels reach >7.5%, the risk of microvascular complications increases 2.5-5-fold.4,5,6 Every 1% reduction of HbA1c was associated with reductions in the risk of: » 21% of any endpoint related to diabetes » 21% for deaths related on diabetes » 14% for myocardial infarction » 37% for microvascular complications.

Weight gain: A consequence of intensification According to Dr Trokis, studies show that the majority of patients with T2DM are already overweight or obese by the time they are diagnosed. In addition, a sub-study of UKPDS showed that patients started on OADs gain an average of eight kilogrammes over a ten-year period. 3,12 The fear of gaining further weight is physiologically and psychologically undesirable for patients who already struggle with their weight – a concern shared by clinicians, added Dr Trokis. These concerns negatively impact treatment adherence and treatment intensification, he added. 3

Controlling both FPG and PPG According to guidelines, the primary purpose of treating glycaemia in patients with T2DM is to reduce blood glucose sufficiently to relieve any symptoms of hyperglycaemia to prevent or delay the onset of microvascular and macrovascular complications. 5,6 Monnier et al showed that HbA1c levels are determined by a combination of both FPG and postprandial hyperglycaemia (PPG) and Riddle et al demonstrated that PPG accounted for 66% of total hyperglycaemia in patients taking basal insulin. Thus, both PPG and FPG need to be addressed to achieve sustained glycaemic control.16,17 Raccah et al found that between 24% to 54% of patients with T2DM globally had residual hyperglycaemia with HbA1c not at target, despite achieving FPG control on a basal insulin, indicating a significant unmet need for PPG control.18

Options after basal failure There are various options for intensification after basal failure:7 Adding rapid-acting insulin progressively to an existing basal insulin regimen Switching to multiple daily premix insulin doses (basal and prandial insulin co-formulation) Adding a daily or weekly GLP-1RA to an existing basal insulin regimen Switching to a once-daily fixed-ratio combination (FRC) of basal insulin and GLP-1RA.

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3 4

Fixed-ratio combinations According to Blonde et al, adding a GLP-1RA to a basal insulin has been associated with improved overall glycaemic control, addressing the need for PPG control. The newer titratable FRCs combine basal insulin with GLP-1RA in one combination, offering less complex dosing schedules leading to improved treatment adherence.20 The clinical trial programme of iGlarLixi showed that:24,25,26 » LixiLan O: Evaluated the efficacy and safety of iGlarLixi compared with both components, iGlar and Lixi, given separately in T2DM patients inadequately controlled on metformin, with or without a second oral glucose-lowering drug. Greater reductions in HbA1c from baseline (8.1%) were achieved with iGlarLixi compared with iGlar and Lixi (−1.6%, −1.3%, −0.9%, respectively), reaching mean final HbA1c levels of 6.5% for iGlarLixi versus 6.8% and 7.3% for iGlar and Lixi, respectively. More patients reached target HbA1c <7% with iGlarLixi (74%) versus iGlar (59%) or Lixi (33%). Mean body weight decreased with iGlarLixi (−0.3kg) and Lixi (−2.3kg) and increased with iGlar (+1.1kg, difference 1.4kg). Documented symptomatic

hypoglycaemia (≤70mg/dL) was similar with iGlarLixi and iGlar (1.4 and 1.2 events/patientyear) and lower with Lixi (0.3 events/patientyear). iGlarLixi improved PGG control versus iGlar and demonstrated considerably fewer nausea (9.6%) and vomiting (3.2%) events than Lixi (24% and 6.4%, respectively). 24 » LixiLan L: Evaluated the efficacy and safety of iGlarLixi, and lixisenatide, compared with iGlar in patients with T2DM inadequately controlled on basal insulin with or without up to two oral glucose-lowering agents.

HbA1c decreased from 8.5% to 8.1% during the run-in period. After randomisation, iGlarLixi showed greater reductions in HbA1c from baseline compared with iGlar (–1.1% vs. –0.6%), reaching a mean final HbA1c of 6.9% compared with 7.5% for iGlar. HbA1c <7% was achieved in 55% of iGlarLixi patients compared with 30% on iGlar. Mean body weight decreased by 0.7kg with iGlarLixi and increased by 0.7kg with iGlar (1.4kg difference). Documented symptomatic hypoglycaemia (≤3.9mmol/L) was comparable between groups. Mild gastrointestinal (GI) side effects were very low but more frequent with iGlarLixi.

Slow titration of FRCs has been shown to reduce the occurrence and severity of GI side effects. 25 » Solimix: The first head-to-head clinical trial comparing the safety and efficacy of iGlarLixi versus premix insulin in adults with insufficiently controlled T2DM on basal insulin plus one or two OAD agents. The SoliMix trial found that when managing T2DM, the once-daily iGlarLixi edged out the twice-daily premix insulin analogue BIAsp 30. The key results of the SoliMix study are that in comparison with the fixed mixture, BIAsp 30, the fixed-ratio combination iGlarLixi demonstrated non-inferiority and, in fact, superiority in terms of HbA1c reduction importantly, it did so without causing significant body weight change – this was increased with the BIAsp 30 but reduced with iGlarLixi. The number of patients who achieved HbA1c target without weight gain and without significant hypoglycaemia was increased with the iGlarLixi. 26 SF

Scan the QR code for a list of references used in this article.

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This article was independently sourced by Specialist Forum.

Obesity 101

Novo Nordisk hosted an Obesity Summit on 10 July that looked at some key challenges in the management of this chronic disease. This article highlights some of the presentations made at the summit.1

A

ccording to World Health Organization (WHO) data, about 650 million people worldwide are obese.

Women (41%) are more affected compared to men (31%). 2

Obesity, is it a chronic disease?

Dr Sundeep Ruder,

endocrinologist based at Life Fourways Hospital and a lecturer at the University of the Witwatersrand French physiologist, Dr Claude Bernard coined the term homeostasis (milieu interieur) in the late 1800s to describe the importance of maintaining the body’s internal balance in a close and wise relationship with nature, so that

or trouble. Distress is at the root of obesity. In its causality it is driven by feelings of distress that leaves a void, leading to indulging behaviours such as overeating and being sedentary.1 “Our ancestors had a wise and close relationship with nature where eating was done with gratitude. Through the ages however, our relationship with nature has changed, leading to an amplification of hedonistic desires. Although we know that certain excesses are not good for us, we are often unable to change our behaviour.”1 The fast food industry stokes our hedonistic desires by producing food to ‘gratify the tongue’ aimed at increasing their profit margins, without taking the health and well-being of individuals into consideration.1 The marketing of these products, which we don’t need, is one of the drivers of the obesity pandemic. When a person is incited to consume products that are not good for them, he/she may become unable to regulate his/ her behaviour. In addition, as a result of our modern way of working (eg technology), we are increasingly becoming sedentary. This is the perfect melting pot for an obesity pandemic.1 As a result of unhealthy eating habits and sedentary lifestyles, the body’s homeostasis is disrupted and we become psychologically unbalanced. This in turn has pathophysiological implications. The mind becomes unregulated and the intellect (logical discourse or executive

Photo credit: Shutterstock.com

functioning) remains undeveloped and not strong enough to manage the mind.1

its equilibrium results from a continuous and delicate compensation. If we live out of balance of nature’s laws, diseases such as obesity and type 2 diabetes (T2DM) develop, said Dr Ruder.1 Obesity is a disease of disproportionate fat accumulation due to excessive eating.

Disease is defined as discomfort, inconvenience, distress,

Patients with obesity should be treated in a holistic and not mechanistic manner. This means that we need to take the mind, intellect, and body into consideration in order to develop effective management strategies.1

Classification of obesity According to the WHO, obesity is defined as abnormal or excessive fat accumulation that may impair health. 2 There are different ways to assess and measure obesity, but the most common measure is the body mass index (BMI), which is an inexpensive and easy assessable tool.1

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male's risk of oesophageal cancer by 52% and for colon cancer by 24%, and in women, endometrial cancer by 59%, gall bladder cancer by 59%, and postmenopausal breast cancer by 12%. Excess bodyweight also contributes to non-fatal but costly or disabling disorders such as osteoarthritis. 8 Furthermore, evidence suggests that excess bodyweight is linked to many additional disorders, including benign prostate hypertrophy, infertility, asthma, and sleep apnoea.8 Wang et al demonstrated that a 1% reduction in BMI is equivalent to a weight loss of roughly 1kg for an adult of average weight. This change might sound small but could have a substantial effect on consequent health burdens. 8 They calculated that a 1% BMI reduction could avoid more than two million incident cases of diabetes in the United States, more than one million CVDs, and 73 000–127 000 cases of cancer, with a gain of about 16 million quality-adjusted life years. 8

Obesity is a chronic and multifactorial disease In the past, obesity was explained in simple terms of energy intake that exceeds energy expenditure. Today the focus is more on what influences energy intake and expenditure, said Dr Ruder.1 In obese patients, homeostasis is disrupted as a result of hedonistic input (increased palatability or pleasure) and environmental factors (inactive lifestyle, smoking cessation, psychosocial factors).1 New research suggests that obesity is the result of dysfunction in the sub-cortical structures of the brain. Subcortical structures are a group of diverse neural formations deep within the brain and include the hypothalamus, area postrema and nucleus tractus solitarius.6 They are involved in complex activities such as regulation of body temperature, thirst, rate of breathing, hunger, and satiety. They act as information hubs of the nervous system, relaying and modulating information that passes to different areas of the brain.6 The sub-cortical areas of the brain are linked to the periphery (enteric nerves, vagal nerves, pancreas, stomach, small and large intestine, and adipose tissue).6 Gut hormones access the brain through multiple neurological pathways such as the arcuate nucleus and the suprachiasmatic nucleus.

The arcuate nucleus, situated at the base of the hypothalamus, plays a role in many physiological functions such as feeding and metabolism.6 The suprachiasmatic nucleus is a bilateral structure located in the anterior part of the hypothalamus and is the central pacemaker of the circadian timing system. The hypothalamus is considered the most important. 6

Badman and Flier explain that some peripheral signals can act directly on NPY/ AgRP and pro-opiomelanocortin (POMC)/ cocaine- and amphetamine-regulated transcript (CART) neurons to promote particular appetite sensations via their effects on second-order neurons.7 For instance, ghrelin – the hunger hormone – can activate the hunger-promoting NPY/ AgRP neurons to induce feelings of hunger.

Conversely, glucagon-like peptide 1 (GLP-1) promotes satiety by activating CART/POMC neurons to promote feelings of satiety, while at the same time inhibiting the hunger-promoting NPY/AgRP neurons.7 Hypothalamic neurons are also influenced by anorexic and/or orexigenic signals from the nucleus tractus solitarius and the area postrema of the hindbrain, which in turn is influenced by peripheral signals acting on vagal afferents.7 The net result of this is a change in appetite and feeding behaviour, as well as other effectors of energy regulation, such as the metabolic rate and energy storage.7

Obesity associated with increased mortality and morbidity Obesity is not only associated with increased mortality, but also with significantly increased morbidity, which can affect almost every organ system, warned Dr Ruder. The organs affected by obesity can be broadly grouped into three classes: metabolic, mechanical, and mental (eg depression and anxiety).1 According to Wang et al, the health burden from obesity is largely driven by an increased risk of T2DM, cardiovascular diseases (CVDs), and several forms of cancer. For instance, every additional 5kg/m2 in BMI increases a

In the United Kingdom it would avoid more than 200 000 incident cases of diabetes, 122 000 CVDs, and more than 30 000 incident cases of cancer, with a gain of about three million quality-adjusted life years over 20 years.8

Why is obesity not treated as a chronic disease?

Dr Nasreen Alfaris,

endocrinologist based at the King Fahad Medical Centre in (Saudi Arabia) High BMI accounted for four million deaths globally. More than 60% of deaths related to high BMI were due to CVDs. The disease burden related to high BMI has increased since 1990. 9 Over the last 25 years, the prevalence of obesity has doubled in more than 70 of the 195 countries included in an analysis that assessed overweight and obesity trends between 1980 and 2015 among children and adults. The study showed that the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. 9 Despite the fact that obesity is increasing globally, it is still an undiagnosed and untreated disease, said Dr Alfaris, who specialises in obesity medicine.1 Caterson et al found that about 50% of people with obesity wait on average six years from when their weight struggle starts (mean age of 33-years), before they consult a healthcare professional. Yaemsiri et al found that 74% of overweight, and 29% of obese individuals (16 720) included in their analysis, never had a diagnosis of overweight/obesity.10,11 Although the majority of overweight/obese individuals (74% women, 60% men) pursued at least one weight management strategy,

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fewer (39% women, 32% men) pursued both dietary change and physical activity.

Among overweight/obese adults, those with a diagnosis of overweight/obesity were more likely to diet (74% versus 52%), exercise (44% versus 34%), or pursue both (41% versus 30%) than those who remained undiagnosed.11 Saxon et al found that weight-loss medications are rarely prescribed to eligible patients. Phentermine accounted for >75% of all medication days, with a majority of patients filling it for more than four months. Less than 25% of prescribing providers accounted for approximately 90% of all prescriptions.12 This would be unacceptable in the management of any other chronic disease, said Dr Alfaris. According to her the main reason for this, is the lack of training in obesity management across the continuum of care.1

Why do we need pharmacotherapy in obesity management?

Dr Sean Wharton,

Co-chair of the 2020 Canadian Obesity Guidelines According to Dr Wharton all diets lead to short-term weight loss, but eventually, the majority of patients will regain weight. A metaanalysis of 29 long-term weight loss studies found that more than 50% of lost weight was regained within two years, and by five years more than 80% of lost weight was regained.13 Dr Wharton explained that the reason why people regain weight is as a result of so-called metabolic adaptation. Metabolic adaptation refers to the slowing down of one’s metabolic rate (metabolism) after long-term undereating and substantial fat loss, in an attempt to conserve energy.1 Studies show that for each kilogramme of lost weight, calorie expenditure decreases by

about 20–30kcal/d whereas appetite increases by about 100kcal/d above the baseline level prior to weight loss. Despite these predictable physiologic phenomena, the typical response of the patient is to blame themselves as lazy or lacking in willpower, sentiments that are often reinforced by healthcare providers, state Hall and Kahan.13 Metabolic adaptation persists over time and is likely a proportional, but incomplete, response to contemporaneous efforts to reduce body weight, write Fothergill et al.

The team measured long-term changes in resting metabolic rate (RMR) and body composition in participants of The Biggest Loser competition. RMR was determined at the end of the 30-week competition and six years later.14 Of the 16 competitors, 14 participated in this study. Weight loss at the end of the competition was 58.3±24.9kg, and RMR decreased by 610±483 kcal/day. After six years, 41.0±31.3kg of the lost weight was regained, while RMR was 704±427 kcal/day below baseline and metabolic adaptation was -499±207kcal/day.

Weight regain was not significantly correlated with metabolic adaptation at the competition’s end, but participants who maintained greater weight loss at six years also experienced greater concurrent metabolic slowing.14

Role of hormones This means that hunger intensity does not go away when a patient loses weight, explained Dr Wharton. Hunger intensity is dictated by hormones and neurochemicals in the brain.1 Sumithran et al found that one year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss, do not revert to the levels recorded before weight loss.15 They enrolled 50 overweight or obese patients without diabetes in a 10-week weightloss programme for whom a very-low-energy

diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, they examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.15 Weight loss (mean 13.5±0.5kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin, and amylin and to increases in levels of ghrelin, gastric inhibitory polypeptide, and pancreatic polypeptide.

There was also a significant increase in subjective appetite.15 One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin, peptide YY, cholecystokinin, insulin, ghrelin, gastric inhibitory polypeptide, and pancreatic polypeptide, as well as hunger.15 In addition, said Dr Wharton, dieting depresses mitochondria functioning and gene expression. Mitochondria are important organelles for the adaptation to energy demand that play a central role in bioenergetics metabolism. Its disruption markedly affects energy homeostasis. As mentioned by Dr Ruder, the brain, more specifically the hypothalamus, is the main hub that controls energy homeostasis.1 Van der Kolk et al found that differentially regulated subcutaneous adipose tissue in mitochondria-related gene expressions may lead to alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.16 Chen et al investigated the potential of SHC517, a mitochondrial uncoupler, to reduce obesity. Mitochondrial uncouplers decrease caloric efficiency. They found that SHC517 reversed obesity without altering food intake or compromising lean mass.17 Obesity should be managed using evidencebased chronic disease management principles.

Dr Wharton is one of the co-authors of the 2020 Canadian Adult Obesity Clinical Practice Guidelines: Pharmacotherapy in Obesity Management.18 The guideline recommends that all people living with obesity should have access to evidence-informed interventions. The three pillars of intervention include:18 Pillar 1: Implement multicomponent behaviour modification that includes management of sleep time and stress. Cognitive behavioural therapy and/or acceptance and commitment therapy are recommended.18 Pillar 2: According to the Canadian guideline, if a patient meets the criteria (BMI ≥30kg/m2 or BMI ≥27kg/m2 with obesity-related comorbidities (eg T2DM), pharmacotherapy can be initiated.18 There are several factors to be taken into

Liraglutide 3 mg is the only GLP-1 approved in South Africa for weight management1-7

NEW

I ha󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧 to 󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷 f󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶󰇶 But I 󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷󰇷 to 󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰󰇰 an󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧󰈧

liraglutide injection 3mg

SARAH, consultant; Age: 43; BMI: 37 Patient portrayal.

Your patients with obesity have the will. You can offer them the way.

Obesity is a chronic disease, and most patients want your help.8 #

Liraglutide 3 mg is 97 % similar to natural GLP-11

Liraglutide 3 mg works in the hypothalamus in the brain9

HUNGER

SATIETY

Liraglutide 3 mg is similar to natural GLP-1, working in the brain to decrease appetite and thereby reduce food intake1

Where it increases feelings of satiety and decreases hunger1

As a result, patients taking Liraglutide 3 mg feel satisfied and eat less food, leading to weight loss1

BMI=body mass index; GLP-1=glucagon-like peptide-1 #

Shown in animal models. The exact mechanism of action is unknown.

References: 1. Saxenda® Professional Information. 2. Victoza® Professional Information. 3. Xultophy® Professional Information. 4. TRULICITY Professional Information. 5. BYETTA Professional Information. 6. South African Health Products Regulatory Authority (SAHPRA). Registered Health Products [online 2020][cited 2020 October 09]; Available from URL: https://www.sahpra.org.za/registered-health-products/. 7. IMS May 2020. 8. Bray GA, Kim KK, Wilding JPH; on behalf of the World Obesity Federation. Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obes Rev. 2017;18(7):715-723. 9. Secher A, Jelsing J, Baquero AF, et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124(10):4473-4488.

Abbreviated professional information Proprietary Name: Saxenda® Scheduling Status: S4 Composition: One ml of solution contains 6 mg of liraglutide and phenol 0,55 % m/v as the preservative.Indications: Saxenda® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for medically supervised chronic weight management programme in adult patients with an initial Body Mass Index (BMI) of: • ≥ 30 kg/m2 (obese), or • ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight related comorbidity such as dysglycaemia (pre-diabetes and type 2 diabetes mellitus), hypertension, dyslipidaemia, or obstructive sleep apnoea. Contra-Indications: • Hypersensitivity to liraglutide or to any of the excipients listed under Composition. • Pregnancy and lactation. Warnings & Special Precautions: Saxenda® must not be used as a substitute for insulin. There is limited experience in patients with congestive heart failure New York Heart Association (NYHA) class I - II and Saxenda® should therefore be used with caution. There is no experience in patients with congestive heart failure NYHA class III - IV and Saxenda® is therefore not recommended in these patients. The safety and efficacy of Saxenda® have not been established in the following patients, viz: • Treated with other products for weight management, • With obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain, • With severe renal impairment, • With severe hepatic impairment, • With inflammatory bowel disease and diabetic gastroparesis. Use in these patients is not recommended.Use of Saxenda® has been associated with the risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Saxenda® should be discontinued; if acute pancreatitis is confirmed, Saxenda® should not be restarted. In clinical trials, a higher rate of cholelithiasis and cholecystitis was observed in patients treated with Saxenda® than in patients on placebo. Patients should be informed of the characteristic symptoms of cholelithiasis and cholecystitis.

In clinical trials in type 2 diabetes, thyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in patients with pre-existing thyroid disease. Saxenda® should therefore be used with caution in patients with thyroid disease. An increase in heart rate was observed in clinical trials. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should be informed of the symptoms of increased heart rate (palpitations or feelings of a racing heartbeat while at rest). For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with Saxenda® should be discontinued. Patients treated with Saxenda® should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion. Patients with type 2 diabetes receiving Saxenda® in combination with a sulphonylurea have an increased risk of hypoglycaemia. Pregnancy and lactation: Saxenda® should not be used during pregnancy and lactation. Dosage and Directions for Use: The starting dose is 0,6 mg once daily. The dose should be increased to 3.0 mg once daily in increments of 0,6 mg with at least one week intervals to improve gastro-intestinal tolerability. If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Daily doses higher than 3,0 mg are not recommended. Saxenda® is for subcutaneous use only. It must not be administered intravenously or intramuscularly. Saxenda® is administered once daily at any time, independent of meals. However, it is preferable that Saxenda® is injected around the same time of the day. It should be injected in the abdomen, thigh or upper arm. Saxenda® should not be used in combination with another GLP-1 receptor agonist. When initiating Saxenda®, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia Saxenda® is not recommended for use in children below 18 years of age due to lack of data. Side Effects: Gastrointestinal reactions were the most frequently reported adverse reactions during treatment with Saxenda®. Very common side effects are nausea, vomiting diarrhoea, constipation. Common side effects include: Hypoglycaemia, insomnia, dizziness, dysgeusia, dry mouth, dyspepsia, gastritis, gastro-oesophageal reflux disease, abdominal pain upper, flatulence, eructation, abdominal distension, cholelithiasis, injection site reactions, asthenia & fatigue. Uncommon side effects include: dehydration, tachycardia, pancreatitis, cholecystitis, urticaria & malaise. Rare side effects include: anaphylactic reaction, acute renal failure & renal impairment. Overdosage With overdose, the patients reported severe nausea, vomiting and diarrhoea, but recovered without complications. None of the patients reported severe hypoglycaemia. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. Reg. No.: 50/21.13/1091.

For full prescribing information, refer to the Professional Information approved by the Regulatory Authority.

NEW Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 150 Rivonia Road, 10 Marion Street Office Park, Building C1, Sandton, Johannesburg, 2196, South Africa. Tel: (011) 202 0500. Fax: (011) 807 7989. www.novonordisk.com.

17671T. ZA21SX00017 July 2021.

liraglutide injection 3mg

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consideration in determining the appropriate choice of pharmacotherapy for patients with overweight or obese.18 The mechanism of action, adverse side effects, safety, and tolerability of each agent must be considered in the context of each patient’s comorbidities and existing medications.18 The cost of medications as well as the mode (oral versus subcutaneous) and frequency of administration can be a barrier to patient adherence. It is important to assess concomitant medications that a patient is taking as possible contributors to weight gain and to consider alternatives where appropriate.18 Dr Wharton explained that in diabetes, prediabetes, hypertension, obstructive sleep apnoea, and polycystic ovarian syndrome, GLP1RAs are recommended as first-line therapy.1 In Canada, liraglutide is considered the first choice for diabetes and prediabetes patients, naltrexone/ bupropion is the second choice and orlistat the third choice. Combination naltrexone/bupropion is not registered in South Africa for weight management.18 Liraglutide is a daily, subcutaneously administered, GLP-1 receptor analogue, which acts centrally on the POMC/CART neurons, resulting in improved satiation and satiety and reduction in hunger, with a transient effect to decrease gastric emptying.18 Liraglutide increases insulin release and suppresses glucagon during times of glucose elevation. Liraglutide is approved in Canada for the management of T2DM at a dose of 1.2mg or 1.8mg daily, with near maximal therapeutic efficacy for HbA1C lowering at the 1.8mg dose.18 Liraglutide was approved in Canada in 2015 for chronic obesity management at a dose of 3mg daily, in people with or without T2DM. The recommended starting dose of liraglutide is 0.6mg daily, with up-titration by 0.6mg each week until the 3mg target dose is achieved.18 Among people with normoglycemia or prediabetes, liraglutide 3mg with health behaviour modification resulted in an 8% weight loss at one year, compared to 2.6% on placebo (health behaviour) modification alone).18 In terms of categorical weight loss, 63.2% of patients on liraglutide lost ≥5% body weight at one year, compared with 27.1% of patients in the placebo group, 33.1% and 10.6% of participants lost more than 10% of their body weight on liraglutide 3mg and placebo, respectively.18 Patients with prediabetes were followed to three years, with sustained weight loss of -6.1% in the liraglutide group vs -1.9% in placebo. Following a -6% weight loss with a low-calorie diet, liraglutide 3mg plus health behaviour counselling reduced weight by a further -6.2% at one year compared with -0.2% in the placebo group (ongoing health behaviour counselling alone).18 More patients on liraglutide 3mg were

able to maintain the ≥5% run-in weight loss (81.4%) compared with those receiving placebo (48.9%). Fewer patients on liraglutide 3mg regained ≥5% body weight (1.9%) compared to placebo (17.5%).18 Assess the patient after three months on the therapeutic dose, based on whether they have been successful in preventing any of the aspects that are concerning, such as diabetes, prediabetes, and cravings. If these things have improved, continue treatment. If there are no or limited improvements, look at adding a second medication or stopping the first medication.18 Obesity management should be individualised and can either comprise one of the pillars mentioned above, or a combination of all three pillars, concluded Dr Wharton.1

attend/9042421427299782923 2. WHO. Obesity & Overweight. 2020. Available from https://www.who.int/news-room/fact-sheets/detail/ obesity-and-overweight 3. Misra A, Chowbey P, Makker BM, et al. Consensus statement for diagnosis of obesity, abdominal obesity and the metabolic syndrome for Asian Indians and recommendations for physical activity, medical and surgical management. J Assoc Physicians India, 2009.

4. Stegenga H, Haines A, Jones K, et al. Identification, assessment, and management of overweight and obesity: summary of updated NICE guidance. BMJ, 2014.

5. Nakata Y, Okada M, Hashimoto K, et al. Weight Loss Maintenance for 2 Years after a 6-Month Randomised Controlled Trial Comparing EducationOnly and Group-Based Support in Japanese Adults.

Obes Facts, 2014.

6. Bosman R. SCALE-ing obesity. Specialist Forum, 2021.

d be l u o e h ity s evidenc s e b g O usin disease d e g a c man d chroni inciples base ment pr age man

7. Badman MK and Flier JS. The gut and energy balance: visceral allies in the obesity wars. Science, 2005.

8. Wang YC, McPherson K, Marsh T, et al. Health and economic burden of the projected obesity trends in the USA and the UK. The Lancet, 2011.

9. The GBD 2015 Obesity Collaborators. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. NEJM, 2017.

10. Caterson ID, Alfadda AA, Auerbach P, et al. Gaps to bridge: Misalignment between perception, reality and actions in obesity. Diabetes Obes Metab, 2019.

Pillar 3: Recommended surgical interventions include sleeve gastrectomy, gastric bypass, or duodenal switch. Bariatric surgery can be considered:18 » For people with BMI ≥40kg/m2 or BMI ≥35kg/m2 with at least one obesity-related disease to reduce long term overall mortality, to induce control and possibly remission of T2DM, to improve many obesityrelated diseases (eg cholesterol issues, hypertension, fatty liver), to induce long term weight loss, and to improve quality of life. » In patients with poorly controlled T2DM despite optimal clinical management and Class I obesity (BMI between 30 and 35kg/m2). » For weight loss and/or to control obesityassociated diseases in patients with Class 1 Obesity (BMI 30-35), for whom optimal medical and behavioural management have been insufficient to produce significant weight loss.

These interventions should be supported by medical nutrition therapy (eg nutrition assessment, diagnostics, therapy, and counselling) and physical activity (30-60 minutes of aerobic activity on most days of the week at moderate to vigorous intensity), recommended Dr Wharton.1,18

11. Yaemsiri S, Slining MM, Agarwal SK, et al. Perceived weight status, overweight diagnosis, and weight control among US adults: the NHANES 2003-2008 Study. Int J Obes (Lond), 2011.

12. Saxon DR, Iwamoto SJ, Mettenbrink CJ, et al. AntiObesity Medication Use in 2.2 Million Adults Across 8 Large Healthcare Organizations: 2009-2015.

Obesity (Silver Spring), 2019.

13. Hall K and Kahan S. Maintenance of lost weight and long-term management of obesity. Med Clin North Am, 2018.

14. Fothergill E, Guo J, Howard L, et al. Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity, 2016.

15. Sumithran P, Prendergast LA, Delbridge E, et al.

Long-term persistence of hormonal adaptations to weight loss. NEJM, 2011.

16. Van der Kolk BW, Muniandy M, Kaminska D, et al. Differential Mitochondrial Gene Expression in Adipose Tissue Following Weight Loss Induced by Diet or Bariatric Surgery. J Clin Endocrinol Metab, 2021.

17. Chen S-Y, Beretta M, Alexopoulos SJ, et al.

Mitochondrial uncoupler SHC517 reverses obesity in mice without affecting food intake. J Metabol, 2021.

18. Pedersen SD, Manjoo P, Wharton S, et al. Canadian Adult Obesity Clinical Practice Guidelines: Pharmacotherapy in Obesity Management. https:// obesitycanada.ca/guidelines/pharmacotherapy.

19. Pedersen S. From Pre- to Post-Bariatric Surgery:

References

2020 Canadian Adult Obesity Clinical Practice

1. Novo Nordisk Obesity Summit. https://

Guidelines. https://drsue.ca/2020/10/from-pre-to-

app.gotowebinar.com/unified/index.

post-bariatric-surgery-2020-canadian-adult-obesity-

html#/webinar/3063148551862069518/

clinical-practice-guidelines/. SF

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This is a sum m a the artic le entitle ry of opin d: E premixe ion: Patient sele xpert d insulin ction fo r formula care. To t io ns in dia r e a d t he full a be t es www.m rticle, g edicalac o to ademic.c on t he S o.za pecialis t Forum and click t he bo t t logo at om o f t h e p a g e.

This article was independently sourced by Specialist Forum.

EXPERT OPINION:

Patient selection for PREMIXED PREMIXED INSULIN INSULIN in diabetes

Authors: Sanjay Kalra, Leszek Czupryniak, Gary Kilov, et al.

Diabetes is a huge and growing global public health problem with an enormous economic burden. According to the International Diabetes Federation (IDF), the number of adults living with diabetes in 2017 is projected to increase from 425 to 629 million in 2045 (a 48% rise).

T

Originally published in: Diabetes Ther (2018) 9:2185–2199. https://doi.org/10.1007/ s13300-018-0521-2

he loss of the first phase of insulin is the initial pathophysiologic defect in type 2 diabetes mellitus (T2DM).

Insulin, alone or along with other pharmacologic and nonpharmacologic measures of treatment, is widely used in the management of diabetes. Insulin enables adequate glycaemic control thus significantly reducing the vascular complications of diabetes.

Early insulin use has been associated with reversal of diabetes. To tackle the epidemic of diabetes, various countries are scaling up equitable and affordable access to insulin for improved care.

Multiple regimens, formulations, and delivery devices of insulin are increasingly being used to individualise treatment and attain the best possible glycaemic control in people with diabetes.

Available subcutaneous insulins differ in onset, peak, and duration of action and in safety profiles, ranging from ultra-short-acting to ultralong-acting preparations.

Guidelines for the non-pharmacologic and pharmacologic management of diabetes have been formulated by the IDF, American Diabetes Association (ADA), and American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE).

The approach to insulin therapy has been described in multiple guidelines for diabetes.

The ADA has described an algorithm for the

motivation, presence of complications, overall health status, and cost of formulations.

In these guidelines, the key disease characteristics influencing the choice for initiation and continuation of therapy include the duration and severity of diabetes. Though these guidelines provide elaborate algorithms for insulin therapy, criteria for regimen and formulation selection are inadequately addressed. The guidelines, which largely focused on basal and rapid-acting insulins, do not include directions for use of all available formulations.

The guidelines of the Society for Endocrinology, Metabolism and Diabetes of South Africa and others have explained practical aspects of insulin regimens in detail, providing a patient-centred approach to initiation and intensification of therapy.

In this article, we identify the gaps in current practices and build an objective, rational approach to patient selection for premixed insulins.

Premixed insulins are fixed component formulations of rapid or short-acting and intermediate- or long-acting insulins for both fasting and postprandial glycaemic control.

These formulations include the conventional premixed formulations with human insulin, premixed analogue formulations, and a premixed coformulation of rapid-acting and

Premixed insulin analogues have efficacy and safety outcomes similar to those of basal or basal-bolus insulin. In a review comparing premixed and basal plus regimens, Downie et al reported similar efficacy and safety with both regimens for both insulin initiation in insulinnaive patients and intensification in patients who have failed on basal insulin.

In a meta-analysis of 13 randomised controlled

initiation of insulin therapy with basal insulin and the stepwise inclusion of rapid-acting and premixed insulins.

The IDF and AACE/ACE have also described a comprehensive algorithm for adding or intensifying insulin in persons with T2DM. The AACE/ACE explores factors that should be considered when selecting a formulation for insulin initiation, including age, life expectancy,

ultra-long-acting basal insulin analogues.

Premixed insulins can be dosed once, twice, or thrice daily, depending upon patient requirements. The premixed insulins have pharmacokinetics that favour both 24-hour efficacy and patient convenience. This explains the high adherence rates and better glycaemic control with premixed insulins.

The conventional premixed biphasic human

trials (16-60 weeks, n=5255), comparing the premixed and basal-bolus regimens there were no significant differences in HbA1c levels, rate of hypoglycaemia, weight change, or daily insulin dose with the two regimens despite the greater complexity and number of injections associated with basal-bolus insulin.

Better overall glycaemic control is also reported with premixed insulins (insulin lispro 25/27,

Premixed insulin: formulations and pharmacokinetics

insulin is a combination of regular human insulin and neutral protamine Hagedorn (NPH) in ratios of 30/70 or 50/50. These are administered 30 min prior to meals, and the action lasts for about 10-16 hours. The analogue premixed formulations (Lispro 25/75, Lispro 50/50, BIAsp 30/70, BIAsp 50/50) have a quicker onset of action and can be administered up to 15 min prior to meals. When compared with conventional premixed formulations, the analogue formulations are longer acting with duration of action ranging from 12- to 24-hours.

IDegAsp (70/30) is a combination of the ultra-long-acting insulin degludec (IDeg) and rapid-acting analogue insulin aspart (IAsp) that provides safe and well-tolerated control of both fasting and prandial hyperglycaemia. IDegAsp 70/30 offers advantages of mealtime flexibility with quicker onset (10- to 20 minutes) and longer duration of action (24-hours).

Premixed insulin: initiation and intensification

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BIAsp 70/30) than with the basal insulins (insulin glargine) in insulin-naive as well as pretreated patients. Some researchers report a higher risk of minor nocturnal hypoglycaemia with premixed insulin than with basal insulin regimen.

The Indian National Consensus Group (INCG) has provided guidance for initiation and intensification of therapy with premixed insulin in the management of diabetes in primary care.

According to INCG, premixed insulins, preferably analogue formulations, offer a simple, safe, and easy option for the initiation of treatment in diabetes and should be considered for the management of all stages of diabetes.

The Royal Australian College of General Practitioners (RACGP) and RSSDI has provided guidance for the initiation, titration, and intensification of therapy with premixed insulin.

According to these guidelines, premixed insulin may be an appropriate and simple option for glycaemic control when fasting and postprandial glucose levels are consistently elevated.

Patients may be switched to premixed insulin if target HbA1c levels are not achieved with basal insulin alone or therapy intensified to basal plus or basal bolus. It is important to emphasise appropriate nutrition and physical activity at all stages of treatment initiation and intensification.

Treatment with premixed insulin (10 U or 0.1– 0.2 U/kg/day immediately before or soon after the largest meal, usually the evening meal) can be started in insulin-naive persons with diabetes.

The dose is then titrated once or twice a week depending upon the lowest blood glucose levels (fasting/prandial) over the last three days.

Some clinicians use the criteria of 50 U/day or 0.5 U/kg/day to guide the twice daily dosing of premixed insulin. Twice daily dosing can again be titrated to achieve the target fasting and prandial glycaemic control.

A practical approach commonly used for high-mix insulin is to distribute the dose of premixed insulin as two-thirds in the morning and one-third in the evening when the oncedaily insulin dose exceeds 20 or 30 U.

Factors influencing choice of premixed formulations Patient-centred factors Patient-centred factors include the physical and cognitive capability to administer multiple injections and monitor blood glucose several times a day, support of the family and treating physician, patient preferences, meal patterns, and activity routine. The key patient characteristics that influence the choice of therapy with premixed insulin include duration and symptoms of hyperglycaemia, overall health and other medical conditions, past and ongoing treatment, lifestyle, and patient preferences.

Initial and continued therapy with premixed insulin should be guided by patient attributes and tailored to patient needs instead of trying

to find a ‘one-size-fits-all’ regimen. Initiation of a small dose of insulin (2 IU) in the clinic helps to overcome needle phobia.

of an individual’s glycaemic levels, motivation level, psychosocial limitations, ease of use, and acceptance of insulin, premixed insulin can be used once, twice, or thrice daily.

Dietary factors Dietary patterns and preferences influence glycaemic control and are an important factor to be considered in the selection of insulin formulations for treatment. Premixed insulins are best used in persons who consume meals of balanced and uniform dietary composition.

Regularity in meals is key in the achievement of glycaemic goals. However, dietary patterns may vary according to professional lifestyles and religious practices. Cultural practices such as Ramadan influence the glycaemic control and use of insulin in people with diabetes. IDegAsp may be considered as the preferred premixed insulin for people with diabetes who fast during Ramadan. Persons with erratic dietary patterns may benefit from IDeg Asp as it does not need to be injected at the same meal-time(s) each day.

Patient preferences Premixed insulin is the best option in patients who are unwilling or unable to adhere to the increased injections and monitoring required with basal plus/basal-bolus regimens.

Patient satisfaction and convenience With fewer injections required, flexibility in time of administration, and reduction of the injection-meal time gap, IDegAsp insulin offers more convenience to patients. Twice daily premixed insulin regimens protect the privacy of a patient and allow freedom of choice in selfdisclosure of medical status. The flexibility in timing of administration makes this premixed co-formulation a preferred choice, particularly for people with busy lifestyles and variable meal patterns.

Lifestyle In patients with busy/stressful lifestyles and erratic meal patterns, the flexibility to match insulin administration with the major meal of the day offers convenience and improves compliance. According to a multinational consensus group, IDegAsp is a good preparation for initiation of insulin therapy in the following: drug-naive patients with symptoms of hyperglycaemia, patients on a high carbohydrate diet, patients with high HbA1c levels, and postprandial excursions. It can also be used to initiate therapy following failure of (single, dual, or triple) oral anti-diabetic agents.

Overall health status The overall health of the patient is a key determinant for the choice of insulin formulation. Analogues have an advantage over human insulins due to the lower risk of hypoglycaemia associated with their use.

Metabolic health Another important determinant of glycaemic goals and control is the metabolic health of the patient. This includes non-glycaemic parameters related to renal, hepatic, endocrine, and metabolic parameters. The Metabolic Quartet, HbA1c, blood pressure, weight, and lipids, describes the four vasculo-metabolic targets in diabetic patients.

The pathology of postprandial hyperglycaemia may include impaired glucagon suppression in addition to reduced secretion of insulin.

Number of injections per day The number-based insulin taxonomic model assigns a code based on the frequency of injections and simplifies the classification of regimens used for insulin therapy including the premixed insulins. Based upon the patterns

Insulin distress Defined as the emotional response to the suggestion of insulin use, insulin distress is a common deterrent in attainment of glycaemic control. Premixed insulins having a lower index of intrusion and flexibility help to reduce insulin distress. Patient distress, apprehension, and anxiety associated with insulin use are reduced if such formulations are used. The pharmacokinetics of premixed insulin allow a more patient-friendly approach to initiation and continuation of therapy.

Laws of Parsimony According to the Law of Therapeutic Parsimony in diabetes care, the least number, quantity, and frequency of administration of a drug should be prescribed to achieve desired therapeutic outcomes without compromising the safety and well-being of patients. With control of both fasting and prandial glucose levels and HbA1c, premixed insulins are an appropriate choice for achieving glycaemic targets and reducing complications in persons with diabetes. The use of premixed formulations has allowed a reduction in numbers of required injections. The flexibility offered by premixed analogues is associated with reduction in injection-meal time gaps and improved compliance. These formulations have reduced the requirement for frequent glucose monitoring.

Conclusion Premixed insulins are an important tool for glycaemic control in persons with diabetes.

Equally important in diabetes care is the selection of the most appropriate insulin regimen for a particular individual at a specific time. Management of diabetes has evolved from a ‘glucocentric’ approach to a ‘patientcentred’ approach. SF

NovoMix® 30

• Oral anti-diabetic therapies: Highlighting the limitation in potency and reduction in HbA1c

NovoMix® 30

Mean change fom baseline HbA1c (%)

DPP-4 (Sita) 100 mg

GLP-1 (Lira) 1,2 mg

GLP-1 (Lira) 1,8 mg

SGLT2 (Dapa) 10 mg

SGLT2 (Empa) 25 mg

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- 0,5

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- 1,0

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- 1,18 %

- 1,5

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* With changes in HbA1c as a primary end point

Just a 1 % reduction in HbA1c could have a significant positive impact on your patients5

I n s u l i n e ff e c t

Risk reduction5

Myocardial infarction

Microvascular complications

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It is simple to start patients on NovoMix® 30 NovoMix® 30 Twice-daily Addressing fasting and postprandial glucose Insulin effect

I n s u l i n e ff e c t

START with 12 UNITS once daily Addressing fasting and postprandial glucose

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Breakfast Adapted from Garber AJ et al. 20066

Start NovoMix® 30 OD. 12 units / day at supper / dinner.6 Titrate as required.6 When 30 units / day has been reached and glycaemic targets have not been met, or further titration is limited by hypoglycaemia, split the NovoMix® 30 dose 50:50 prebreakfast and predinner.7,8

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Start NovoMix® 30 BD. 12 units / day, split into 6 units before breakfast and 6 units before dinner. Titrate as required.9

Adapted from Raskin P, et al. 20059

30G x 8mm 32G x 4mm

32G x 5mm

References: 1. The Society for Endocrinology, Metabolism and Diabetes of South Africa Type 2 Diabetes Guidelines Expert Committee. The 2017 SEMDSA Guideline for the Management of Type 2 Diabetes Guideline Committee. JEMDSA 2017;22(1)(Supplement 1):S1-S192. 2. Lorenzi M, et al. Liraglutide Versus SGLT-2 Inhibitors in People with Type 2 Diabetes: A Network Meta-Analysis. Diabetes Ther 2017;8:85-99. 3. Valensi P, et al. Initiating insulin therapy with, or switching existing insulin therapy to, biphasic insulin aspart 30⁄70 (NovoMix® 30) in routine care: safety and effectiveness in patients with type 2 diabetes in the IMPROVE™ observational study. J Clin Pract 2009;63(3):522-531. 4. IMS September 2020. 5. Stratton IM, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-412. 6. Garber AJ, et al. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The 1-2-3 study). Diabetes Obes Metab 2006;8:58–66. 7. NovoMix® approved package insert Nov 2014. 8. Unnikrishnan A, et al. Practical guidance on intensification of insulin therapy with BIAsp 30: a consensus statement. Int J Clin Pract 2009;63(11):1571–1577. 9. Raskin P et al. Initiating Insulin Therapy in Type 2 Diabetes. A comparison of biphasic and basal insulin analogs. Diab Care 2005;28(2);260-265.

Insulin effect

Proprietary Name: NovoMix® 30. Scheduling Status: S3 Composition: soluble insulin aspart/protamine-crystallised insulin aspart 100 U/ml in the ratio of 30/70. Indications: Treatment of insulin requiring patients with diabetes mellitus. Contra-Indications: Hypoglycaemia, hypersensitivity to insulin aspart or to any of the excipients, intravenous injection. Warnings & Special Precautions: When using insulin in combination with pioglitazone, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any signs of cardiac function deterioration occur. Insulin antibodies-Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyperglycaemia or hypoglycaemia. Patients, whose blood glucose control is greatly improved, e.g. by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia, and should be advised accordingly. Inadequate dosing or discontinuation of treatment, especially in Type 1 diabetes (insulin-dependent diabetes mellitus) may lead to hyperglycaemia and diabetic ketoacidosis. Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. NovoMix® 30 can be used in children and adolescents aged 10 years and above when premixed insulin is preferred. Limited clinical data exists for children aged 6 to 9 years. Before travelling between different time zones the patient should seek the doctor’s advice since this may mean that the patient has to take the insulin and meals at different times. Renal or hepatic impairment may reduce the patient’s insulin requirements. Patients should be advised to take precautions in order to avoid hypoglycaemia while driving. Pregnancy and lactation: Intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. There are no restrictions on treatment with NovoMix® 30 during lactation or for women breastfeeding their infants. Dosage and Directions for Use: Dosage of NovoMix® 30 is individual and determined on the basis of the physician’s advice in accordance with the needs of the patient The individual insulin requirement is usually between 0.5 and 1Units/kg/day. When using NovoMix® 30 once daily, it is generally recommended to move to twice-daily subcutaneous injections when reaching 30 units by splitting the dose into equal breakfast and dinner doses. Dose titration should continue as needed.

A NovoMix® 30 thrice-daily regimen can be safely initiated from a twice-daily regimen by splitting the morning dose into equal morning and lunch doses. NovoMix® 30 is administered subcutaneously in the thigh or in the abdominal wall. If convenient, the gluteal or deltoid region may be used. Injection sites should be rotated within the same region. In patients with type 2 diabetes, NovoMix® 30 can be given as monotherapy if oral antidiabetic medicines cannot be tolerated or are contraindicated or in combination with oral antidiabetic medicines, when the blood glucose is inadequately controlled with oral antidiabetic medicines alone. NovoMix® 30 should never be administered Side oedema refraction of 0 intravenously.

2 4 Effects:6Hypoglycaemia, 8 10 and12 14anomalies 16may occur 18upon institution 20 22insulin therapy 24 hrs and are usually of transitory nature. Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur during treatment with insulin. These reactions are usually transitory and normally disappear during continued treatment. Intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy. Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection site within an area. Anaphylactic reactions are reported as very rare but can potentially be life-threatening. Peripheral neuropathy is reported as rare. Reg. No.: 35/21.1/0031. For full prescribing information refer to package insert approved by the medicines regulatory authority.

Breakfast

Lunch

Evening Meal

Novo Nordisk (Pty) Ltd. Reg. No.: 1959/000833/07. 150 Rivonia Road, 10 Marion Street Office Park, Building C1, Sandton, Johannesburg, 2196, South Africa. Tel: (011) 202 0500. Fax: (011) 807 7989. www.novonordisk.com. 17896T. ZA21NM3000029 July 2021.

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Photo credit: Shutterstock.com

This article was independently sourced by Specialist Forum.

How to recognise ATOPIC ATOPIC dermatitis Atopic dermatitis (AD) is a common itchy skin condition that tends to run in families.

Individuals with AD show a genetic predisposition to allergic conditions such as asthma, allergic rhinitis, allergic conjunctivitis, and food allergy. AD is a potentially debilitating disease and can lead to serious lifethreatening complications.1,2,3

I

n our article on page 19 we discuss some of the life-threatening complications associated with AD, which include sepsis, endocarditis and bone and joint infections.

Prevalence of AD in South Africa Although AD predominantly presents in early childhood (see box 1 for diagnostic criteria), adult onset AD (late onset) is also common. Studies have also shown that the prevalence of AD differs significantly between ethnic groups. In the United States for example, AD prevalence was higher in children from African descent compared to Caucasians. 2 Numerous studies suggest that the prevalence of AD is increasing in South Africa. From 1995 to 2002, increases were reported for adolescents (13- to 14-years) in Cape Town for self-identified symptoms of AD (15.5%26.2%) and physician-diagnosed AD (9.6%-16.7%).3 AD is more common in urban than rural settings in South Africa. For example, in Cape Town, a prevalence of 23.5% was reported in children between one- to three-years, compared to 1.8% in the rural Eastern Cape.3

Impact on quality of life While many cases of AD are mild, and can be

managed with simple topical treatment, up to 50% of AD cases are moderate–severe, which negatively impact patients quality of life (QoL) as a result of constant itching, loss of sleep, pain, and social isolation due to low self-esteem.1 AD has been shown to be associated with psychiatric disorders (depression and anxiety) and suicidality as a result of constant itching and discomfort, disfigurement, and perceived social-stigmatisation. In addition, poor sleep related to AD may increase the risk of psychiatric disorders.4 Schonmann et al found that among the 526 808 patients with AD included in their study, AD was associated with increased incidence of new depression (14%) and anxiety (17%). They observed a stronger effect of AD on depression with increasing severity compared with no AD: mild (10%), moderate (19%) and severe (26%).4 In addition, they found that AD was more strongly associated with depression and anxiety in those aged 40 to 59 years (compared with younger and older age groups) and were more prevalent in men than in women.4

Presentation and diagnosis of AD The cardinal symptom of AD is itching, which can be debilitating. Clinical findings are characterised by ill-defined, papular erythema and fine scale.

Chronic eczema results in thickening and increased scaling of the skin (lichenification).1 Generalised dry skin (xerosis and/ or ichthyosis vulgaris) is typical in more extensive cases. Depending on the severity and chronicity of disease, skin findings may also include exudate, vesicles, fissures, lichenification and excoriations.1

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Silverberg et al found that AD lesion distribution differed based on ethnicity and age. In patients with dark skin, the erythema is often not visible. Instead the scaling or thickening from lichenification may be more prominent with hyper- or hypopigmentation.1,5 The most common sites of skin lesions include the popliteal fossae, lower legs, dorsal feet, and antecubital fossae, but in patients with darker skin, lesions on the trunk were significantly more common. 5 Age ≥60 years was associated with significantly lower proportions of active lesions on the face and scalp, and significantly higher proportion of lesions on the buttocks or genitals.5 Although AD is associated with allergic conditions, it is not an allergy per se. Rather, AD inflammation is mediated by T cell activation in the skin where the antigenic targets for activation are likely to be numerous in any one individual.1 IgE is considered to play little in the role of mediating the skin inflammation, yet, in

Managing AD

individuals with AD, IgE allergies are more common and account for the association with allergic rhinitis, food allergy and asthma.1 Induction of IgE responses in AD is thought to be a consequence of increased allergen exposure through broken skin in the setting of a cutaneous drive towards the initiation of Th2 responses (which subsequently induce B cell class switching to IgE production).1 Therefore demonstration of allergic responses (measurement of specific immunoglobulin [Ig] E) are not required to make a diagnosis, according to Plant and Ardern-Jones.1

once daily during treatment of an inflammatory episode, or TCS used for two consecutive days a week (sometimes referred to as ‘weekend therapy’) as a strategy to prevent flares.6 TCIs are known as steroid-sparing options and were approved in the early 2000s for the treatment of AD. TCIs such as tacrolimus ointment (0.03% and 0.1%) and pimecrolimus cream (1%), are recommended treatment options in conte mporary management guidelines.1 The 2020 South African algorithm for the treatment of AD in paediatric patients recommends:3 TCIs as first-line treatment for patients with AD in sensitive body areas, patients with steroid-induced atrophy and patients who have current long-term uninterrupted TCS use.

Pimecrolimus and tacrolimus are indicated for the treatment of mild-to-moderate and moderate-to-severe AD, respectively.

For mild–acute AD flares in paediatric patients, we recommend low or moderate potency TCSs once daily or pimecrolimus twice daily until clear.

For moderate AE flares, patients may use an appropriate strength TCSs, either once or twice daily or a TCI twice daily.

If a TCI is selected as first-line therapy and the acute flare is not controlled, a short (7–14 days) course of TCS may achieve control, which can then be gradually reduced or switched to a TCI to maintain results.

A TCI twice daily for mild-to-moderate AD flares is recommended in children and sensitive body areas. In the European AD guidelines, pimecrolimus is recommended as the treatment of choice for facial lesions and children. The treatment should be applied twice daily from the first

Box 1: Management of all patients with AD Step 1: For all patients Avoid irritants » Avoid soaps/shower gels/bubble baths » Use emollients to wash Repair barrier » Emollients regularly applied even when AD control is good » For more active disease use ointment formulations Treat inflammation (itch) » Topical CSs: Ladder of potency use least potent possible » Topical CIs: Use as steroid-sparing agents and prevention

Step 2: If all topical treatment fails Phototherapy Systemic immunosuppression (methotrexate, ciclosporin, azathioprine, mycophenolate mofetil)

Step 3: If classical immunosuppressant treatment fails Dupilumab

The overall goals of treatment for AD are to reduce the signs and symptoms of disease, induce disease remission and improve the quality of life of both patients and their caregivers.3 Regular application of topical emollients alongside treatment with topical corticosteroids (TCSs) or calcineurin inhibitors (TCIs) forms the foundation of treatment of all AD. Concerns regarding the safety of TCSs as first-line therapy for treating AD flares have led to poor treatment adherence, and subsequent worsening of disease control and quality of life.1,6 Safety concerns include skin thinning and retardation of growth and development. These concerns are thought to mainly originate from what is now considered to be inappropriate use, such as using potent TCS on the face or continual long-term use.6 Strategies recommended to minimise exposure to TCS, and hence the risk of adverse events, include reducing frequency of application to

Box 2: Diagnostic criteria of AD in children In order to qualify as a case of AD, the child must have: » An itchy skin condition (or parental report of scratching or rubbing in a child) Plus three or more of the following: » Onset <2-years (not used if child is <4-years) » History of skin crease involvement (including cheeks in children 10-years) » History of a generally dry skin » Personal history of other atopic disease (or history of any atopic disease in a firstdegree relative in children <4-years) » Visible flexural dermatitis (or dermatitis of cheeks/forehead and outer limbs in children <4-years).

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appearance of signs and symptoms until complete resolution.

For the management of severe disease flares, moderate or potent TCSs are recommended.

In the European AD guidelines, pimecrolimus is recommended for facial lesions and for children, and both pimecrolimus and tacrolimus for long-term maintenance treatment.

For patients with four or more acute flares per year, proactive maintenance treatment.

This is a combination of long-term, lowdose anti-inflammatory treatment (TCIs or TCSs of the appropriate strength) two and three times weekly, applied to areas of skin previously affected by AD, together with the liberal use of emollients over the entire body.

Alternatively, intermittent therapy with TCI may be recommended, which involves the resumption of treatment at the very first signs of a new flare, that is, pruritus.

The duration of maintenance therapy is determined on an individual basis.

Discontinuation may be attempted by slowly decreasing the frequency of application and closely monitoring the results.

References available on request. SF

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SF | DERMATOLOGY This article was independently sourced by Specialist Forum.

Skin infections in AD may lead to life-threatening complication

Patients with atopic dermatitis (AD), have an increased risk of recurrent bacterial skin infections, which may become systemic and lead to life-threatening complications including sepsis, endocarditis and bone and joint infections.1

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bout 20% of children with AD hospitalised for infectious complications had invasive bacterial infections. Bacterial infections are easily recognised by the appearance of weeping lesions, honey-coloured crusts and pustules.1,3

A brief overview of AD AD, also referred to as atopic eczema, is one of the most common non-communicable skin diseases, affecting up to 20% of children and 2%–8% of adults in most countries of the world. AD is characterised primarily by scaly, pruritic, erythematous lesions located on flexural surfaces. 2 In many instances, AD begins in childhood, while severe cases may persist in adulthood.

About 30% of adult cases develop in adulthood. AD is often the first step in the development of other atopic diseases, such as allergic rhinoconjunctivitis or asthma and food allergy. 2 Most AD cases can be regarded as mild, whereas less than 10% of patients suffer from severe eczematous skin lesions. The percentage of severe cases seems to be higher in the adult AD population. 2

Skin infections in AD Despite AD patients’ increased risk of recurrent bacterial skin infections, which may lead to life-threatening complications, there is a lack of consensus on how to define and treat associated bacterial colonisation and infection. This is according to a consensus statement recently issued by a panel of experts from the International Eczema Council Skin Infection Group, published in the British Journal of Dermatology.1 The panel conceded that it is challenging to diagnose skin infections – especially in darkskinned individuals. Increases in erythema in dark-skinned individuals are more difficult to distinguish.1 In dark-skinned individuals, perifollicular accentuation is often present and erythema appears violaceous and often muted. This can lead to poor recognition of inflammation, underestimation of disease severity and inadequate intervention. Patients with AD of African descent often have extensor disease rather than the characteristic flexural lesions.1 In addition, skin infections are associated with concomitant AD flares, and erythema, oozing and crusting and increased cutaneous warmth, which are all clinical features of AD.1

Clinical features of skin infections Staphylococcus aureus is the most common infectious organism, although beta-haemolytic streptococci may also be involved. A recent meta-analysis found that the pooled prevalence of S. aureus colonisation of lesional AD skin

September 2021 | Vol. 21 No. 9 www.medicalacademic.co.za

is 70%, non-lesional AD skin 39% and of the nares 62%.1 The typical signs of S. aureus infection include weeping, honey-coloured crusts, and pustules, both interfollicular and follicular based (folliculitis). By contrast, beta-haemolytic streptococcal infection may present with well-defined, bright red erythema, thickwalled pustules, and heavy crusting. In severe cases, cutaneous bacterial infection may cause abscesses – especially with methicillinresistant S. aureus (MRSA) infection – fever and lymphadenopathy.1 Several non-bacterial infections can occur concomitantly with bacterial skin infection and can resemble bacterial infections, including eczema herpeticum (EH), which is caused by the local spread of herpes simplex virus (HSV).

HSV favours AD lesional skin and is commonly observed in the context of AD.1 Early in the course of EH the characteristic skin lesions are superficial clusters of dome-

Prevention of infections in AD patients

shaped vesicles and/or small, round, punchedout erosions. As the disease progresses, lesions may become superficially infected with S. aureus and may develop an impetiginised scale.1 EH typically arises in involved AD skin, most frequently on the face, neck, upper trunk, and antecubital/popliteal areas with AD, and is often accompanied by fever, malaise and lymphadenopathy.1 Moderate-to-severe AD, filaggrin loss-offunction mutation, a history of S. aureus skin infection, greater allergen sensitisation and type 2 immunity are important risk factors for EH. Staphylococcal α-toxin and reductions in the tight junction protein claudin-1 result in greater epidermal spread of herpes simplex virus in vitro. This infection can spread rapidly and, in severe cases, may lead to keratoconjunctivitis and encephalitis.1 Fungal colonisation can also complicate the clinical picture of AD. For instance, Malassezia colonisation is thought to drive inflammation in AD in a subset of patients who typically have dermatitis in areas with a high density of sebaceous glands (eg head, neck, and upper chest and back).1 This seborrhoeic distribution overlaps with, but is distinct from, the distribution of allergic contact dermatitis or airborne allergy, which typically involve the upper face, eyelids and periorbital regions, anterior neck, postauricular area and exposed areas on the arms. Malassezia is a commensal yeast. Although it is not more abundant on AD skin, patients with AD are more frequently sensitised to Malassezia.1 In some patients, sensitisation to yeast antigens induces autoreactivity to human proteins via molecular mimicry, leading to sustained skin inflammation. Cross-reactivity between Malassezia-specific IgE and Candida albicans has also been shown.1

corticosteroids (TCS) and topical calcineurin inhibitors (TCI), have been reported to improve skin barrier functions based on transepidermal water loss. 3 A number of antibacterial/steroid topical combinations are commercially available. These include combinations with 1% hydrocortisone or with a potent TCS such as betamethasone valerate 0.1%.4 Fusidic acid has major advantages over other available topical antimicrobial agents. It shows very good penetration into the skin. High in vitro skin permeability to both the fusidic acid and betamethasone valerate components of the combination product formulation has also been documented.4 Furthermore, fusidic acid has high antistaphylococcal activity even against MRSA. Unlike neomycin and gentamicin, it has a very low potential to sensitise and induce contact allergic dermatitis. It also has very good cosmetic acceptability, unlike clioquinol and chlortetracycline, which can mark clothes and bedding.4 TCS and TCI have been reported to decrease S. aureus colonisation in AD lesions. Topical anti-inflammatory treatments have been associated with increased microbial diversity in AD lesions. 3 Although multiple case reports have found an association between EH and the use of anti-inflammatory medications in AD, this was not supported by a recent multicentre study, which reviewed more than 200 cases of EH. The authors found that the use of TCS, TCI, systemic CS or cyclosporine was not associated with the onset of EH. 3 Uncontrolled AD inflammation is likely the primary risk factor for EH (or bacterial infections), rather than the anti-inflammatory treatment. Therefore, in the absence of an

The approach in preventing infections in AD is based on addressing the predisposing factors for infections. Daily skin hydration and moisturisation are recommended for patients with AD to maintain skin barrier function. 3 Patients with AD should take a daily warm shower or bath, followed by gentle drying and application of a moisturiser or a prescribed topical medication. The choice of moisturiser should be based on the patient’s or parent’s preference and experience. 3 In general, a thick or ointment-based moisturiser (eg petrolatum) is better than cream in retaining moisture in the skin.

Application of petrolatum has been indicated to up-regulate antimicrobial peptides and induce key barrier differentiation markers such as filaggrin and involucrin, in patients with AD. 3 The use of standard topical antiinflammatory medications, including topical

IT TAKES

2

TO TACKLE INFECTED

ECZEMA WHEN A MILD STEROID IS APPROPRIATE 1,2

WHEN A MORE POTENT STEROID IS REQUIRED1,2

• Staphylococcus Aureus colonises skin lesions in at least 90 % of patients with eczema3 • Fucidin® H and Fucibet® effectively break the itch-scratch-infection cycle at two points4,5,6

FUSIDIC ACID is highly effective against S. aureus7

Corticosteroid targets inflammation8,9

References: 1. Ference JD, Last AR. Choosing Topical Corticosteroids. Am Fam Physician 2009;79(2):135-140. 2. Green C, Colquitt JL, Kirby J et al. Clinical and cost-effectiveness of once daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation. Technology assessment report commissioned by the HTA Programme on behalf of The National Institute for Clinical Excellence. [Online] 2003 Nov. [cited 23 June 2021]; Available from URL: https://www.nice.org.uk/guidance/ta81/documents/ta81-atopic-dermatitiseczema-topical-steroids-assessment-report-2. 3. Chu AC. Antibacterial/steroid combination therapy in infected eczema. Acta Derm Venereol 2008;Suppl 216:28-34. 4. Ramsay CA, Savoie JM, Gilbert M, et al. The treatment of atopic dermatitis with topical fusidic acid and hydrocortisone acetate.

J Eur Acad Dermatol Venereol 1996;7(Suppl 1):S15-S22. 5. Leung DYM. The role of Staphylococcus aureus in atopic eczema. Acta Derm Venereol 2008; Suppl 216: 21–27. 6. Strategos J. Fusidic acid-betamathasone combination in infected eczema: an open, randomized comparison with gentamicinbetamethasone combination. Pharmatherapeutica 1986;4:601-606. 7. Wilkinson JD. Fusidic acid in dermatology. Br J Dermatol 1998;139:37-40. 8. FUCIDIN H® cream approved package insert, 5 June 2014. 9. FUCIBET® cream approved package insert, 5 June 2014.

FUCIDIN® H CREAM. Each gram of cream contains fusidic acid anhydrous 20 mg, hydrocortisone acetate 10 mg. Reg. No. 45/13.4.1/0568. FUCIBET® CREAM. Each 1 g of cream contains fusidic acid anhydrous 20 mg and betamethasone (as valerate) 1 mg. Reg. No. 45/13.4.1/0678. Under license from LEO Pharmaceutical Products, Ballerup, Denmark. For full prescribing information refer to the package insert approved by the medicines regulatory authority. 2021061510131587.

Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Telephone + 27 11 635 0000. www.adcock.com.

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active infection, anti-inflammatory treatment should confer protection against infections in patients with AD. 3 Because of the current Covid-19 pandemic there has been some concern about whether systemic anti-inflammatory medications for AD may increase the risk of patients with AD for this viral infection. 3 Case series, mainly from Italy, thus far, have not supported an increased risk of SARSCoV-2 infection in patients with AD treated with systemic anti-inflammatory medications. 3

Management of infection complications in AD For patients with AD who have signs and symptoms of systemic illness, hospitalisation and empirical intravenous antibiotics are recommended. The empirical antibiotic regimen should provide coverage against S. aureus. 5 For critically ill patients, coverage for both MRSA and MSSA with vancomycin and an anti-staphylococcal beta-lactam is appropriate because vancomycin is inferior to nafcillin or first-generation cephalosporins for the treatment of serious MSSA infections. 5 For severe but non–life-threatening infections, vancomycin may be used alone as empirical therapy, pending culture results.

Clindamycin can also be considered if there is no concern for an endovascular infection and the local prevalence of clindamycin resistance is less than 15%. 5 Bacteraemia because of S. aureus requires the use of a bactericidal intravenous agent initially. For MRSA, vancomycin is the drug of choice. For MSSA, cefazolin and nafcillin are both acceptable first-line agents, though nafcillin can cause venous irritation and phlebitis when administered peripherally. 5 As long as there are no concerns for ongoing bacteraemia or an endovascular focus, completion of therapy with an oral agent to which the isolate is susceptible is appropriate in children with S.aureus bacteraemia. 5 Duration of therapy should be determined by the clinical response, but typically seven to 14 days is recommended. Infective endocarditis is a rare complication of AD. Careful auscultation for a heart murmur is recommended. 5 For patients with AD with uncomplicated, non-purulent skin infection, a beta-lactam antibiotic that covers both S. aureus and β-hemolytic streptococci (eg, cefazolin or cephalexin) may be sufficient pending clinical response or culture, considering local epidemiology and resistance patterns. 5 In contrast, for patients with AD with a skin abscess, history of MRSA colonisation, close contacts with a history of skin infections, or recent hospitalisation, coverage for MRSA should be considered. 5

Clindamycin, doxycycline, trimethoprimsulfamethoxazole, and linezolid are all acceptable oral options for MRSA skin infections in both children and adults, assuming the isolate is susceptible in-vitro. 5 Patients with AD with minor, localised skin infections such as impetigo may be treated with topical mupirocin ointment. The duration of therapy typically ranges from five to 10 days depending on clinical response. 5 HSV testing should be done, but treatment with systemic antiviral should not be withheld pending the results. Coinfection of EH with S. aureus is also common and concurrent treatment with an anti–S. aureus antibiotic should be considered. 5

D in A n o i t infec causes l a i r e d Bact mon an idity b m r o o c is ant m c fi i sign There are no formal guidelines regarding the preferred route of administration of antivirals or indications for hospitalisation in patients with EH. For patients with extensive skin involvement, signs of systemic illness, and those less than a year old, parenteral acyclovir should be considered initially. Fever and mild systemic symptoms often accompany mucocutaneous HSV infections, particularly with the initial episode. 5 Once clinical improvement is reported, a transition to an oral agent to complete the course of therapy is appropriate. For mild cases, oral acyclovir can be considered and was associated with faster healing and resolution of pain in a randomised, placebocontrolled trial of 60 adults and adolescents with EH. 5 Valacyclovir, the L-valyl ester prodrug of acyclovir, has a three to five-fold greater bioavailability than oral acyclovir, which can be dosed less frequently, and with plasma concentrations are comparable with parenteral acyclovir. 5 Topical antivirals do not have an appreciable benefit in HSV mucocutaneous disease and do not have a role in the treatment of EH. Patients with herpetic lesions on or around the eye should be emergently evaluated by an ophthalmologist. 5 Rarely, EH can be complicated by HSV meningoencephalitis, which should be treated with a prolonged course of intravenous acyclovir and managed in conjunction with a neurologist and infectious disease specialist. 5 Patients with AD with recurrent EH may

benefit from long-term suppressive therapy, though this has not been studied. The need for ongoing therapy should be reassessed after six to 12 months. The development of resistance to acyclovir is rare in EH but may be suspected in cases of recalcitrant EH or frequent recurrences of EH despite suppressive therapy and good adherence to long-term therapy. 5

Conclusions Bacterial infection in AD is common and causes significant morbidity. Overt bacterial infection is easily recognised. However, less overt manifestation of infection may be more difficult to diagnose, especially given the greater risk of infection with flares (themselves associated with increased erythema and oozing).

The prevention of infection in AD should emphasise skin barrier repair and maintenance anti-inflammatory medications without relying on antibiotics. The need for antibiotics in patients with severe AD exacerbations remains controversial.

This is because some of the signs and symptoms associated with severe AD exacerbation resemble that of bacterial skin infections. It is possible that there is a threshold at which S. aureus levels and the extent of host tissue damage evolve into an infection.

Studies are needed to investigate the biomarkers that assist in determining this threshold. Acute-phase response markers such as C-reactive protein and erythrocyte sedimentation rate may be helpful in determining the need for antibiotics in patients with severe AD exacerbation who are suspected of having infections.

Future studies should also address whether anti-inflammatory treatments, especially those that specifically target type 2 inflammation, may benefit patients with AD with active infection.

This is based on the premise that suppressing type 2 inflammation may lead to the improvement of immunity against microbial pathogens.

References 1. Alexander H, Paller AS, Traidl-Hoffman C, et al. The role of bacterial skin infections in atopic dermatitis: expert statement and review from the International Eczema Council Skin Infection Group. British Journal of Dermatology, 2018.

2. Wollenberg A, Barbarot S, Bieber T, et al. Consensusbased European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. JEAVD, 2018.

3. Boguniewicz J, Boguniewicz M, Ong PY, et al. The infectious complications of atopic dermatitis. Ann Allergy Asthma Immunol, 2021.

4. Chu AC. Antibacterial/steroid combination therapy in infected eczema. Acta Derm Venereol, 2008.

5. Wang V, Boguniewicz J, Boguniewicz M and Ong PY. The infectious complications of atopic dermatitis.

CME Review, 2020. SF

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www.medicalacademic.co.za

This article was independently sourced by Specialist Forum.

Painful skin conditions Some dermatological or skin conditions such as pyoderma gangrenosum and postherpetic neuralgia are often associated with severe pain. Conditions associated with mild pain include bullous and pruriginous diseases, atopic dermatitis, psoriasis vulgaris, and erysipelas.

D

ermatologists should be willing to treat pain as they are the experts in the progression of these diseases and understand when affected patients should show improvements such as reductions in pain, says Prof Robert Micheletti, chief of dermatology, at the Hospital of the University of Pennsylvania (United States).

However, it is important to know your limitations. If you do not feel comfortable prescribing pain medication, or if a patient starts exhibiting behaviours that might be indicative of addiction, refer him/her to a specialist experienced in pain management, he stresses.

Pain associated with skin diseases Pain associated with skin diseases is mostly neuropathic and can be triggered by mechanical, thermal, and/or chemical noxious stimuli. Neuropathic pain is caused by damage to the peripheral or central nervous system. This kind of burning, stabbing, and/ or lancinating pain is diagnosed in conditions such as pyoderma gangrenosum and postherpetic neuralgia.

What is pyoderma gangrenosum?

Pyoderma gangrenosum ranks among the most painful skin disorders. A neutrophilic dermatosis, pyoderma gangrenosum is part of the group of autoinflammatory skin disorders and is one of the differential diagnoses in lower leg ulcers.

The characteristic clinical presentation of an ulcer with distinctly erythematous, undermined borders is often preceded by only minimal local trauma (pathergy phenomenon). Subsequently, one or more, slowly progressive ulcers develop, partly with a moth-eaten appearance. Most commonly affected areas include the lower legs, forearms, and sometimes shoulders, abdomen, and chest.

Pyoderma gangrenosum treatment Apart from wound management, pyoderma gangrenosum treatment involves topical

measures, sometimes also antibiotic and immunosuppressive agents, primarily corticosteroids and cyclosporine. Pain management focuses in particular on opioids and an additional agent such as an anticonvulsant. Topical application of 0.1% morphine gel – as adjunct to systemic therapies – has been reported to reduce severe neuropathic pain.

What is postherpetic neuralgia?

Herpes zoster is triggered by reactivation of the latent varicella zoster virus. The lifetime prevalence of herpes zoster is approximately 30%-50% in patients older than 85 years.

About 10%-50 % of herpes zoster patients develop postherpetic neuralgia. Postherpetic neuralgia is defined as pain persisting for 90 days after the acute onset. In about 15% of patients, the pain persists for up to two years.

The hallmark of acute herpes zoster is stabbing, episodic or continuous pain, usually appearing one to two days – but also up to a week – prior to initial skin lesions.

Patients experience pain in the head and genital region as extremely severe and burdensome. Besides aseptic meningitis, paralysis, ocular involvement, ear involvement including deafness, postherpetic neuralgia persisting over months to years represents the primary complication. It must be distinguished from transverse myelitis with the involvement of vertebral ganglia, which may result in paraparesis and loss of sensation.

Clinical experience has shown that neuralgia often develops in cases of inadequate initial pain management and thus also increased pain intensity. Immunocompromised patients and elderly individuals are at an increased risk of postherpetic neuralgia.

Postherpetic neuralgia treatment In addition to antiviral medication, pain management is paramount at the onset of the disease. Antivirals are credited with pain

reduction and possible complete relief of acute pain. Likewise, pain reduction is assumed to be achieved by a short course of corticosteroids at the onset of the disease. However, the development of postherpetic neuralgia is not completely prevented by antivirals or corticosteroids.

In the acute phase, NSAIDs and/or acetaminophen are recommended for mild to moderate pain. For more severe pain, opioids are indicated. Following titration with immediaterelease tramadol, the patient may be switched to sustained-release tramadol at a dose of 50mg twice a day (maximum 600mg every day).

In case of excruciating pain, immediaterelease oxycodone 5mg may be given every four hours, with a possible further increase by additional 5mg every four hours – as tolerated – every other day.

If prolonged use is indicated, switching the patient to the corresponding sustainedrelease form (administration every 12 hours) is recommended. The anticonvulsants gabapentin or pregabalin are further options besides opioids.

Amitriptyline, an antidepressant, may be integrated into the long-term treatment of postherpetic neuralgia, eg in combination with anticonvulsants or opioids.

Available topical therapies include lidocaine and capsaicin patches. In a small group of patients, topical application of a cannabinoid receptor agonist resulted in pain reduction by more than 80%.

References Dotinga R. VIDEO: Painful skin conditions need pain management by dermatologists. Dermatology News, 2018. https://www.mdedge.com/dermatology/ article/158881/medical-dermatology/video-painfulskin-conditions-need-pain-management Beiteke U, Bigge S, Reichenberger C, and Gralow I. Pain and pain management in dermatology. JDDG, 2015.

Croitoru D, Naderi-Azad, Sachdeva M, et al.

A Wound Care Specialist’s Approach to Pyoderma Gangrenosum. Advances in Wound Care, 2020. SF

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SF | CPD: ADHD

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Photo credit: Shutterstock.com

This article was independently sourced by Specialist Forum.

The cost of untreated ADHD ADHD

A

n estimated 8.4% of children and 2.5% of adults have ADHD. ADHD is often first identified in school-aged children when it leads to disruption in the classroom or problems with schoolwork.

It is more common among boys than girls.1 ADHD is diagnosed according to the following criteria established by the Diagnostic and Statistical Manual of Mental Disorder-fifth edition (DSM-5):2

Inattention » Often cannot give close attention to details or makes careless mistakes in schoolwork at work, or with other activities » Often has trouble holding attention on tasks or play activities » Often does not seem to listen when spoken to directly » Often does not follow through on instructions and does not finish schoolwork, chores, or duties in the workplace (eg loses focus or is side-tracked) » Often has trouble organising tasks and activities » Often avoids, dislikes, or is reluctant to do tasks that require mental effort over a long period of time (such as schoolwork or homework) » Often loses things necessary for tasks and activities (eg school materials, pencils, books, tools, wallets, keys, paperwork, eyeglasses, and mobile telephones) » Is often easily distracted » Is often forgetful in daily activities.

Hyperactivity and impulsivity » Often fidgets with or taps hands or feet, or squirms in seat » Often leaves seat in situations when remaining seated is expected » Often runs about or climbs in situations where it is not appropriate (adolescents or adults might be limited to feeling restless » Often unable to play or take part in leisure activities quietly » Is often ‘on the go’ or acting as if ‘driven by a motor’ » Often talks excessively » Often blurts out an answer before a question has been completed » Often has trouble waiting their turn » Often interrupts or intrudes on others (eg conversations or games).

Risk factors Kim and colleagues recently published the findings of an extensive review aimed identifying and evaluating the evidence of environmental factors and peripheral biomarkers associated with a diagnosis of ADHD.3 Included meta-analyses were classified by the strength of the evidence of potential environmental risk factors, environmental protective factors, and peripheral biomarkers for ADHD. The five classes were convincing (class I), highly suggestive (class II), suggestive (class III), weak (class IV) and not significant (NS). 3

There were 35 eligible articles, out of the original 1829 identified articles, which provided 63 unique meta-analyses (40 potential environmental factors and 23 peripheral biomarkers).

There were five environmental risk factors graded as class I (convincing):3 » Pre-pregnancy obesity (defined as body mass index [BMI] ≥30 kg/m2) » Childhood eczema » Hypertensive disorders during pregnancy (chronic hypertension, gestational hypertension, and pre-eclampsia » Maternal acetaminophen exposure during pregnancy.

Class II (highly suggestive) environmental risk factors included:3 » Maternal smoking during pregnancy » Childhood asthma » Pre-pregnancy overweight (defined as BMI 25–29.9 kg/m2).

Class III (suggestive) evidence included some perinatal hypoxic conditions:3 » 5-minute Apgar score <7 » Breech or transverse presentation » Preterm birth.

The highest class for parenting environmental risk factors was Class IV (weak):3 » Low education level of father and mother » Single parent family.

Breast-feeding was determined to be the only statistically significant (class IV) environmental protective factor against ADHD. 3

SF | CPD: ADHD

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To com plete the quiz , go t o w w w . medicala cademic .c o.za and clic k on t h e CPD ta b

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects children, adolescents and adults. ADHD involves problems with attention, concentration and/or increased activity levels, resulting in problems with school, work, and social situations. Individuals with ADHD also often experience trouble with impulse control.1 Furthermore, lower concentration of serum vitamin D in individuals with ADHD was the only biomarker graded as a high level of evidence (class II [highly suggestive]. Class III [suggestive] biomarkers included higher blood lead and lower blood magnesium in patients with ADHD. 3 Overall, this review revealed that within the 63 identified environmental factors and biomarkers, only pre-pregnancy obesity and overweight, maternal smoking and maternal acetaminophen exposure during pregnancy retained high level of evidence as risk factors for ADHD. However, the associations are possibly not causative and so the authors suggest that high-quality primary studies are required to confirm the results of this systematic review. 3

Multimodal approach to ADHD Current practice guidelines recommend a multimodal approach in the treatment of ADHD that includes educational, behavioural, mental health interventions, and pharmacological management.1,4,5 Psychostimulants are the medications with the highest established efficacy in treating individuals with ADHD and are recommended as first-line treatment options. Methylphenidate is the most commonly prescribed and studied drug. It is known to be effective in treating all three core ADHD symptoms: carelessness, hyperactivity, and impulsivity.4

How safe is long-term therapy?

While the efficacy of stimulants is wellestablished, optimal duration of treatment is not always clear. What is clear, however, is that discontinuation of therapy can have long-term implications.4 Matthijssen et al looked at the effect of discontinuation of methylphenidate in patients with ADHD who were continuously treated for at least two years. The participants had to be on a stable regimen of either 36mg or 54mg of extended-release methylphenidate for the past four weeks. 5 They then entered a blinded study in which they were randomly assigned either to remain on this dosage for seven weeks or to undergo a three-week taper to placebo followed by four weeks on placebo. Teacher, parent, and clinician assessments (all blind to study group) were performed at baseline and at seven weeks.5 At the end of the seven-week trial, 40.4% of the patients in the discontinuation group worsened, and only 15.9% of those who continued medication worsened. 5 Furthermore, the authors found that the effect of continuing methylphenidate was significant in younger participants (below the median age of 13.8 years). 5 Patients in the discontinuation group had worse scores on the ADHD Rating Scale, as rated by both parents and teachers. It is of note that 16% of the participants who remained on their stable medication regimen worsened,

which is likely due to the nocebo effect of believing that one might be on a placebo.

Clearly, this study demonstrates that stimulant administration remains generally effective over two years of treatment. 5 Fredriksen et al performed a systematic review to look at the effects of long-term stimulant treatment in adults. Their review included 15 studies. They concluded that stimulant therapy of ADHD has long-term beneficial effects and is well tolerated. 5 Numerous studies using large national or insurance databases are beginning to establish the long-term benefit of psychopharmacological treatment of ADHD. Relative to periods off medication, ADHD patients on medication have fewer motor vehicle accidents, have a lower risk of traumatic brain injury, are less likely to engage in criminal activity, have lower rates of suicidal behaviour, and have lower rates of substance abuse.7,8,9,10,11 According to Schoeman and Liebenberg, untreated ADHD has a significant impact on the quality of life (QoL) of patients and their families. The burden of disease is significant, with the disability-adjusted life years (DALYs) calculated as 424 per 100 000.12 Significant comorbidity, estimated at more than 50% with ADHD, contributes to the burden of disease and reduced QoL of patients with ADHD. Adults with ADHD are more likely to suffer from comorbid medical disorders (eg asthma, unplanned pregnancies, and sexually

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transmitted diseases), as well as psychiatric disorders (eg mood disorders, anxiety disorder, substance abuse disorders and behavioural disorders).12 Untreated ADHD also impairs educational attainment and employment status, impairs work performance (reduced productivity and increased absenteeism), adversely affects interpersonal relationships (irritability and low frustration tolerance) and adds to significant societal costs (because of substance abuse and accidents).12 In a South African study, adult ADHD more than doubled the healthcare costs of medical scheme beneficiaries. However, the costs attributable to direct costs of ADHD formed only 0.56% of the total value of claims.

Of this, medication was the largest expense (5.47% of total costs and 38.48% of direct costs), whereas psychiatric services formed only 3.27% of the direct costs. This correlates with international findings where the cost of medication for treatment of ADHD amounted to 7% of all direct and indirect costs.12 It is clear that stimulant treatment is effective, offer long-term benefit, and that untreated ADHD negatively affect patients’ and their caregivers’ QoL. In addition, found Schoeman and de Klerk, pharmacological treatment of ADHD is cost-effective.13 According to Schoeman and de Klerk, lack of clinical knowledge and financial support for ADHD are major barriers to treatment and diagnosis. In South Africa, funding for treatment for children with ADHD is private, either via medical schemes or via the state sector (limited).13 Adults with ADHD, however, have less access to care. Some medical schemes that cover for childhood ADHD often do not provide benefits for the treatment of adult ADHD, and patients can often not afford private treatment in addition to their monthly contributions to these funds.13 This affects early diagnosis and optimal treatment, thereby escalating long-term costs. Improved outcomes are possible if patients with ADHD receive timely and accurate diagnosis and receive chronic and comprehensive care.13 Schoeman proposed that schemes should recognise adult ADHD as a chronic disorder, which needs chronic treatment and, therefore, remunerate for services and medication from chronic benefits.13

Are there more cost-effective options available?

According to the 11th annual edition of the Association for Accessible Medicine 2019 Access & Savings Report, the health system in the United States has saved $2 trillion in the last 10 years due to low-cost generics.

In 2018, cost savings were $293 billion thanks to generic drugs.14 While most doctors are familiar with generics, studies show that many are not aware of what pseudo-generics or clones are. To recap, generics are equivalent to the originator in terms of key strength and active ingredient, dosage form, route of administration, therapeutic effectiveness, and quality, but can only be produced once the patent protection of an originator drug expires.15 Pseudo-generics or clones are also referred to as authorised generics. In many instances, the product is produced on the same production line as the originator but marketed at a lower price. As part of the registration process, the innovator must motivate why the further application is required.16

https://www.psychiatry.org/patients-families/adhd/ what-is-adhd 2. AAFP National Research. DSM-5 diagnostic criteria for ADHD. https://www.aafp.org/dam/AAFP/documents/ patient_care/adhd_toolkit/adhd19-assessment-table1. pdf 3. Kim JH, Kim JY, Lee J, et al. Environmental risk factors, protective factors, and peripheral biomarkers for ADHD: an umbrella review. Lancet Psychiatry,2020.

4. Lohr WD, Wanta JW, Baker M, et al. Intentional Discontinuation of Psychostimulants Used to Treat ADHD in Youth: A Review and Analysis. Front Psychiatry, 2021.

5. Matthijssen AM, Dietrich A, Bierens M, et al.

Continued benefits of methylphenidate in ADHD after 2 years in clinical practice: a randomized placebocontrolled discontinuation study. Am J Psychiatry, 2019.

6. Fredriksen M, Halmoy A, Faraone SV, et al. Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: A review of controlled and

ons icati d e ant m to treat l u m d Sti n use HD for e e b have of AD than s m r pto onge l , sym s r a cs 80 ye antibioti r e v o n5 se of o u i t e c h t fe at in e r t to

naturalistic studies. European Neuropsychopharmacology, 2013.

7. Chang Z, Quinn PD, Hur K, et al. Association between medication use for attention-deficit/hyperactivity disorder and risk of motor vehicle crashes. JAMA Psychiatry, 2017.

8. Liao Y-T, Yang Y-H, Kuo T-Y, et al. Dosage of methylphenidate and traumatic brain injury in ADHD: a population-based study in Taiwan. Eur Child Adolesc Psychiatry, 2018.

9. Lichtenstein P, Halldner L, Zetterqvist J, et al.

Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med, 2012.

10. Liang SH, Yang YH, Kuo TY, et al. Suicide risk reduction in youths with attention-deficit/

Conclusions ADHD is a neurodevelopment disorder typically diagnosed in childhood. However, more than 30% of children diagnosed with ADHD retain the diagnosis into adulthood. Untreated ADHD has long-term implications, negatively impact QoL of both patient and caregiver/s. Significant comorbidity, estimated at more than 50% with ADHD, contributes to the burden of disease and reduced QoL of patients with ADHD. Adolescents and adults on ADHD medication have fewer motor vehicle accidents, have a lower risk of traumatic brain injury, are less likely to engage in criminal activity, have lower rates of suicidal behaviour, and have lower rates of substance abuse. While some medical schemes cover medication for children, adults are not covered and often have to pay for medication on top of their medical scheme fees. As a result, many opt for no treatment. However, a number of clones or authorised generics have come to market over the past few years. A clone only differs from the original drug in terms of price, packaging, and branding.

References 1. American Psychiatric Association. What is ADHD?

hyperactivity disorder prescribed methylphenidate: a Taiwan nationwide population-based cohort study. Res Dev Disabil, 2018.

11. Quinn PD, Chang Z, Hur K, et al. ADHD medication and substance-related problems. Am J Psychiatry, 2017.

12. Schoeman R and Liebenberg R. The South African Society of Psychiatrists/Psychiatry Management Group management guidelines for adult attentiondeficit/hyperactivity disorder. South African Journal of Psychiatry, 2017.

13. Schoeman R and de Klerk M. Adult attention-deficit hyperactivity disorder: A database analysis of South African private health insurance. South African Journal of Psychiatry, 2017.

14. AAM Report. Generic savings totaled $293 billion in 2018. APhA. https://www.pharmacist.com/article/aamreport-generic-savings-totaled-293-billion-2018?is_sso_ called=1. Published May 21, 2019 15. Hebbar K, Sahana GK, Nalini P, Deepak GN, et al.

Assessment of awareness on generic drugs among health care professionals and laypersons. International Journal of Basic & Clinical Pharmacology, 2017.

16. Medical Academic. Rise of the clones. https://www. medicalacademic.co.za/courses/rise-of-the-clones/ 17. Barbaresi WJ, Colligan RC, Weaver AL, et al.

Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study.

Pediatrics, 2013. SF

OROS® engineered for full patient benefits1

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Effective1

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Affordable2

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*Not actual size References: 1. Coghill D, Seth S. Osmotic, controlled-release methylphenidate for the treatment of ADHD. Expert Opinion Pharmacotherapy 2006;7(15):2119-2138. 2. Data on File.

S6 NEUCON® OROS® 18 mg, 27 mg, 36 mg or 54 mg extended-release tablets containing 18 mg, 27 mg, 36 mg, 54 mg of methylphenidate hydrochloride, respectively. Reg. No’s.: 46/1.2/0380; 46/1.2/0381;46/1.2/0382; 46/1.2/0383.

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LICENCE HOLDER: Janssen Pharmaceutica, Reg. No.: 1980/011122/07, No. 2, Medical Street, Halfway House, Midrand, 1685. Tel: (011) 518 7000. www.janssen.co.za Marketed by sanofi-aventis south africa (pty) ltd, reg. no.: 1996/010381/07. 2 Bond Street, Grand Central Ext. 1, Midrand, 1685, South Africa. Tel: (011) 256 3700.

Fax: (011) 256 3707. www.sanofi.com. CP-97720

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Insomnia – a predictor of SUICIDAL SUICIDAL ideation

Insomnia is a common symptom in individuals with depression and anxiety and vice versa. Although depression is the main cause of suicide, new studies show that insomnia is also an important predictor of suicidal ideation.1,2

S

everal theories have been proposed to explain the association between sleep disturbances and suicidality.

According to these theories, sleep disturbances lead to emotion dysregulation, thwarted belongingness, disgust with the world, and impulsivity, thereby increasing suicidality.1 Studies investigating this bidirectional relationship between insomnia and suicidal ideation suggest that each contribute to the development and are a consequence of one another, while others propose the existence of two distinct cause-effect associations (anxiety predicts a sleep disturbance and a sleep disturbance predicts depression). 2

What is insomnia?

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, insomnia is defined as the subjective experience of difficulty initiating sleep, maintaining sleep and/or early morning awakening, occurring for at least three nights a week for a duration of >3 months. A further criterion is clinically significant distress or impairment in important areas (eg social, occupational, educational) of functioning.3

Episodes of acute or transient insomnia each year affect >80% of adults. Chronic insomnia (>three months in duration) includes difficulty falling asleep, insufficient sleep, or perceived nonrestorative sleep producing daytime complaints of somnolence, fatigue, irritability, or difficulty concentrating and performing everyday tasks, and has a population prevalence of about 14%.4

How much sleep do we need?

One of the fallacies about getting a good night’s rest is that you need eight hours of sleep to function ‘normally’. Eight hours is just an average, anything between four and nine hours is within the ‘normal’ range. The number of hours we need to sleep is genetically programmed, according to South African sleep expert, Dr Alison Bentley. 5 There are four things that you need to be able to fall asleep:5 1. Feeling sleepy 2. Feeling safe 3. Getting comfortable 4. Letting go.

It is hugely important for patients to understand the biology of sleep. The minority

of people can sleep whenever or wherever they want. Most people – particularly the elderly – have to ‘manage’ their sleep within fairly strict parameters. 5

How we fall asleep is determined by:5 » The duration of time spent awake (homeostatic force): Comparing it to a credit card, Dr Bentley explained that when you wake up in the morning you start ‘spending’ and continue to do so the entire day. When you go to bed, you have to pay for your ‘spending’. But unlike our credit cards, she said, you actually need to pay it off completely so that when you wake up the next morning, you are at zero again. If you don’t pay it off, you start off with a sleep debt and you get sleepier as the day go on. » The hours slept in the last episode: If you haven’t slept enough, you have an increased chance of falling asleep. » How long since you woke up: For about 30 to 60 minutes after you have woken up, you have sleep inertia. That is why sticking to a schedule (showering, having breakfast) is

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extremely important because it allows your brain to kick into gear. If you wake up and hit the road, your brain may not function at the level it is supposed to function. Sleep inertia is further influenced by the sleep stage you wake up in. The deeper your state of sleep, the greater the impact of sleep inertia. » The biological time of day (circadian force): Every living organism has a circadian rhythm. A circadian rhythm is the period of the day where there is a definite biological ‘downtime’, which is not necessarily sleep but occurs at the same time every day. Circadian rhythms are all about the production of melatonin, noted Dr Bentley.

The secretion of melatonin has a very specific clock time, which means it doesn’t occur all day. The secretion of melatonin is controlled by exposure to light through the retina. When we are exposed to light, the secretion of melatonin is switched off. During the day, we have no melatonin production, but as soon as it gets dark and the pathway between the retina and hypothalamus is inhibited, we start to produce melatonin.

Dr Bentley pointed out that people who

are on electronic devices at night will have trouble falling asleep because the light emitted by these devices stop the secretion of melatonin. Melatonin will only be secreted when it is dark enough, she stressed. Dim light melatonin onset has a definitive point when secretion starts.

Once melatonin secretion starts, it causes a drop-in body temperature (up to half to one degree in some people). It is during this drop that you feel most sleepy, which is the easiest time in the 24 hours for us to fall asleep. It is critical that when we want to fall asleep as a set time that we know when this is happening.

If you try to fall asleep while your body temperature is high, it is going to be extremely difficult. Your body temperature will stay low for the rest of the night and will start to rise when the melatonin secretion is finished.

Your natural wake up time is when your body temperature starts to rise.

Insomnia as a chronic disorder According to Morin et al (2020), chronic insomnia has serious consequences such

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References: 1. Nakajima T, Sasaki T, Nakagome K, Takazawa S, Ikebuche E, Ito Y. 2000. Comparison of the effects of zolpidem and zopiclone on nocturnal sleep and sleep latency in the morning. A cross-over study in healthy young volunteers.

Life Sciences; 67:81-90. 2. Drover DR. Comparative Pharmacokinetics and Pharmacodynamics of Short-Acting Hypnosedatives. Zaleplon, Zolpidem and Zopiclone. Clin Pharmacokinet. 2004;43(4):227-238.

S5 ZOLNOXS 10 mg Tablets. Reg. No.: 36/2.2/0328. Each film-coated tablet contains 10 mg zolpidem tartrate. For full prescribing information refer to the professional information approved by the medicines regulatory authority (11/2004).

Trademarks are owned by or licensed to the Aspen Group of companies. © 2021 Aspen Group of companies or its licensor. All rights reserved. Pharmacare Limited.

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CAN’T FALL ASLEEP 1,2

Aspen

as fatigue, poor cognitive function, mood disturbance, and distress or interference with personal functioning.6 It is therefore imperative that healthcare professionals improve their knowledge about insomnia trajectories to identify at-risk individuals, to evaluate long-term prognosis, and to design effective prevention programmes to reduce morbidity and mortality.6 About 29% of the participants in their study had substantial levels of psychological distress (mood and anxiety symptoms lasting >1 day in the past two weeks). Only about 13% of participated indicated that they were prescribed medication to help them sleep.6 Overall, 41.6% of the participants had insomnia that persisted over the entire five-year follow-up period. Individuals with more severe insomnia were at greater risk of persistent sleep disturbances, with 62.9% of that subgroup versus 30.3% of the subsyndromal group reporting insomnia at each annual

The team concluded that insomnia is modifiable and as a risk factor for suicidal ideation deserves additional research to establish the mechanism of this association.1 Morin et al urged healthcare practitioners to intervene early with evidence-based interventions rather than assume that insomnia will remit spontaneously.6

follow-up assessment.6 Morin et al noted that their findings suggest that insomnia is often a persistent condition, particularly once it reaches disorder status.

Although insomnia is not always taken seriously in the medical community, there is increasing evidence that acute insomnia is a risk factor for future episodes of insomnia, that the presence of an insomnia disorder is associated with a greater risk for a persistent course, and that persistent insomnia is associated with increased risks for medical (eg hypertension), psychiatric (eg depression), and occupational (eg absenteeism), morbidity and mortality.6

as increasing sleep efficiency. 9 However, CBT has limitations. Only a about 30% of patients with insomnia experience full remission and a significant proportion experience residual sleepiness following CBT. Faced with these scenarios, a variety of pharmacological agents can be used to treat this insomnia. The choice of pharmacotherapy will depend on the specific insomnia symptoms, their severity and duration, the drug efficacy and safety, as well as comorbid disorders.9 According to the 2019 European Guideline for the Diagnosis and Management of Insomnia, patients with chronic insomnia often suffer from a co-morbid psychiatric disorder, and medical conditions. Psychiatric comorbidities, include depression, bipolar, general anxiety, panic, and post-traumatic stress disorders.7 Insomnia has also been linked to a number of medical conditions such as chronic

Insomnia and suicidal ideation According to Simmons et al (2020) both short and long sleep duration have been linked to suicidal ideation. They found that insomnia symptoms but not sleep duration are associated with frequency of suicidal ideation in adults.1

rest • restore • revive

References: 1. Nakajima T, Sasaki T, Nakagome K, Takazawa S, Ikebuche E, Ito Y. 2000. Comparison of the effects of zolpidem and zopiclone on nocturnal sleep and sleep latency in the morning. A cross-over study in healthy young volunteers.

Life Sciences; 67:81-90. 2. Drover DR. Comparative Pharmacokinetics and Pharmacodynamics of Short-Acting Hypnosedatives. Zaleplon, Zolpidem and Zopiclone. Clin Pharmacokinet. 2004;43(4):227-238.

S5 ZOLNOXS 10 mg Tablets. Reg. No.: 36/2.2/0328. Each film-coated tablet contains 10 mg zolpidem tartrate. For full prescribing information refer to the professional information approved by the medicines regulatory authority (11/2004).

Trademarks are owned by or licensed to the Aspen Group of companies. © 2021 Aspen Group of companies or its licensor. All rights reserved. Pharmacare Limited.

Co. Reg. No.: 1898/000252/06. Healthcare Park, Woodlands Drive, Woodmead, 2191. ZAR-ZOD-09-21-00001 09/2021

Photo credit: Shutterstock.com

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How to manage insomnia International guidelines recommend cognitive behavioural therapy (CBT) as first-line treatment. If CBT is not effective, unavailable or if the patient is unwilling to undergo therapy, pharmacological therapy is warranted.

According to the 2019 British Association for Psychopharmacology the goal of treatment is to lessen suffering and improve daytime function.7,8 Hassinger et al write meta-analyses have shown that CBT is an efficacious treatment for reducing sleep latency, wake time after sleep onset, and early morning awakenings, as well

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Save the Date

September is World Suicide Awareness Month obstructive pulmonary disease, diabetes, and chronic kidney diseases. It also has important neurological implications and has been associated with neurodegenerative disease and fatal familial insomnia.

Higher rates of substance abuse have also been reported among people with insomnia.7 In the presence of comorbidities, clinical judgement should decide whether the insomnia or the co-morbid condition is treated first, or whether both are treated at the same time.7 Once the decision is made to institute pharmacotherapy, it is desirable to select a hypnotic agent that displays rapid onset of action, optimal duration of action, and preservation of sleep architecture, while at the same time is devoid of morning residual sleepiness and/or memory loss and does not interact additively or synergistically with other medicines to produce untoward side effects. 9 There is a general consensus that pharmacotherapy should be initiated at the lowest effective dose and for a short-term duration eg four weeks or less. However, in reality, this short duration may not be effective or acceptable to patients. Longer course of treatment may be warranted for those who demonstrate sustained response in the absence of adverse events and have a regular follow-up visit with their healthcare providers. 9 In primary insomnia (sleep-onset insomnia, sleep-maintenance insomnia, or insomnia associated early morning awakening), pairing short-term use of pharmacotherapy with some form of CBT can be effective, especially in patients with a low-likelihood of CBT-response.9 Long-term use of medications for chronic insomnia should be as an intermittent dosing ‘as needed’ in the setting of maintenance CBT, when possible. Comorbid insomnia should be treated with pharmacotherapy providing dual benefit. 9

Conclusions It is important to keep in mind that not everyone needs eight hours of sleep a night to function normally. According to Dr Bentley, four to nine hours of sleep is within the normal range for some people. However, if a patient’s

daily functioning is impaired because of the number of hours he/she sleeps a night, it might be indicative that he/she suffers from insomnia. Chronic insomnia has long-term health consequences and has been identified as the foremost cause of suicidality and warrants early and effective intervention.

CBT is recommended as first-line treatment.

However, if CBT is not effective, unavailable or if the patient is unwilling to undergo therapy, pharmacological therapy is warranted. Despite its high prevalence and burden, insomnia often remains unrecognised and untreated.

References 1. Simmons Z, Erickson LD, Hedges D and Kay DB. Insomnia Is Associated With Frequency of Suicidal Ideation Independent of Depression: A Replication and Extension of Findings From the National Health and Nutrition Examination Survey. Front Psychiatry, 2020.

2. Alvaro PK, Roberts RM, Harris JK, et al. A Systematic Review Assessing Bidirectionality between Sleep Disturbances Anxiety, and Depression. SLEEP, 2013.

3. Bjorøy I, Jørgensen VA, Pallensen S, et al. The Prevalence of Insomnia Subtypes in Relation to Demographic Characteristics, Anxiety, Depression, Alcohol Consumption and Use of Hypnotics. Front Psychol, 2020.

4. Pagel JF, Pandi-Perumal SR and Monti JM. Treating insomnia with medications. Sleep Science and Practice, 2018.

5. Bosman R. What is a circadian rhythm sleep disorder? https://www.medicalacademic.co.za/ course-tag/dr-alison-bentley/ 6. Morin CM, Jarrin DC, Ivers H, et al. Incidence, Persistence, and Remission Rates of Insomnia Over 5 Years. JAMA Network Open, 2020.

7. Riemann, Baglioni, Bassetti. European guideline for the diagnosis and treatment of insomnia. https://

Time to reach peak plasma concentration is 84 minutes and elimination half-life is 2,5 hours, therefore suited to the person who

CAN’T FALL ASLEEP 1,2

www.guidelines.co.uk/sleep-disorders/insomniaguideline/454893.article.

8. Wilson S, Anderson K, Baldwin D, et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia,

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parasomnias and circadian rhythm disorders: An update. Journal of Psychopharmacology, 2019.

9. Hassinger AB, Bletnisky N, Dudekula R, et al. Selecting a pharmacotherapy regimen for patients with chronic insomnia. Expert Opin Pharmacother, 2020. SF

To com plete the quiz , go t o w w w . medicala cademic .c o.za and clic k on t h e CPD ta b

References: 1. Nakajima T, Sasaki T, Nakagome K, Takazawa S, Ikebuche E, Ito Y. 2000. Comparison of the effects of zolpidem and zopiclone on nocturnal sleep and sleep latency in the morning. A cross-over study in healthy young volunteers.

Life Sciences; 67:81-90. 2. Drover DR. Comparative Pharmacokinetics and Pharmacodynamics of Short-Acting Hypnosedatives. Zaleplon, Zolpidem and Zopiclone. Clin Pharmacokinet. 2004;43(4):227-238.

S5 ZOLNOXS 10 mg Tablets. Reg. No.: 36/2.2/0328. Each film-coated tablet contains 10 mg zolpidem tartrate. For full prescribing information refer to the professional information approved by the medicines regulatory authority (11/2004).

Trademarks are owned by or licensed to the Aspen Group of companies. © 2021 Aspen Group of companies or its licensor. All rights reserved. Pharmacare Limited.

Co. Reg. No.: 1898/000252/06. Healthcare Park, Woodlands Drive, Woodmead, 2191. ZAR-ZOD-09-21-00001 09/2021

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This article was independently sourced by Specialist Forum.

The progressive nature of DEPRESSION DEPRESSION

Globally, major depressive disorder (MDD) is one of the most severe and common psychiatric disorders. It is characterised by sadness, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, feelings of tiredness, and poor concentration. In its most severe form, depression can lead to suicide.1,2

A

2018 meta-analysis evaluated the aggregate prevalence of depression in communities from 30 countries between 1994-2014. A total of 90 studies were identified and met the inclusion criteria (n =1 112 573 adults).1 Among continents, South America had the highest aggregate prevalence at 20.6%.

This was followed by Asia at 16.7%, North America at 13.4%, Europe at 11.9%, and Africa at 11.5%. Australia had the lowest prevalence of depression at 7.3%. The prevalence of depression was significantly higher in women 14.4%).1 Numerous studies have shown an increase in psychiatric conditions such as MDD and anxiety since the outbreak of the Covid-19 pandemic. MDD disproportionately affects women and Covid-19 is likely to have far-reaching consequences for women’s mental health. 3 GlobalData Healthcare estimates that the

is twice as high in women (10.4%) compared to men (5.5%). Women have suffered the majority of pandemic-related economic and job losses globally. For example, in the United States, women account for 53.8% of overall net job loss since the start of the pandemic, report GlobalData. 3 In some people, MDD runs a chronic course and substantially impairs their occupational potential and quality of life. The World Health Organization (WHO) predicted that by 2020, MDD will rank second in the global disease burden rankings and by 2030 it will be the leading cause of disability. The reason for this is because of MDDs progressive nature, which is associated with poor prognosis, loss of working ability and impaired social functioning. 2

Abnormal brain structural and functional alterations indicated in MDD

considered mainly due to abnormalities in neurotransmitters, especially serotonin, norepinephrine, and dopamine. This has been evidenced by the use of different antidepressants such as selective serotonin receptor inhibitors, serotonin-norepinephrine receptor inhibitors, dopamine-norepinephrine receptor inhibitors in the treatment of depression.4 However, in recent years, advanced brain imaging techniques such as ultra-high definition magnetic resonance imaging (MRI), has allowed scientists an unprecedented insight into how brain dysfunctions lead to MDD. 5 Based on these insights, scientists now belief that MDD is caused by abnormal alterations in brain structure and functionality.

Negative correlations were found between a greater number of prior depressive episodes and a reduction in the hippocampal and amygdala volume, as well as the thinning of

12-month total prevalence of MDD for this year

Previously, the cause of MDD was

the medial prefrontal cortex (PFC). It was also

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found that illness duration was correlated with volume reduction in the hippocampus, putamen, insula and medial PFC. 2 Liu et al (2017) explains that the hippocampus, the most commonly studied brain region in depression research, is part of the limbic system and develops nerve fibre connectivity with emotion-related brain regions, for instance, the PFC and amygdala.

The hippocampus contains high levels of glucocorticoid receptors and glutamate and regulates the hypothalamus-pituitary-adrenal (HPA) axis, which makes it more susceptible to stress and depression.6 The PFC regulates thinking and behaviour in the brain. This nerve centre is divided into two subregions: ventromedial prefrontal cortex (vmPFC) and dorsolateral sectors (dlPFC).

VmPFC involves the regulation of affection, including the generation of negative emotion, and dlPFC mediates cognitive functions, such as intention formation, goal-directed action, and attentional control. The two sectors have both been shown to have significant roles in depression. 6 In a stress-induced depressive model, the PFC in depression showed a significant reduction of glutamate in the GABAergic pathway, which may contribute to depression.

Activation of metabotropic glutamate receptor 3, which plays a significant role in regulating the function and cognition of the PFC, can result in long-term depression in the medial PFC. 6 The amygdala plays a significant role in affective modulation and memory encoding.

The amygdala is also a critical site of neuronal

plasticity for fear conditioning. Morphological and functional changes of the amygdala associated with depression have been verified in many studies.6 Depression disrupts glutamate signalling at the N-Methyl-D-aspartate receptor in the amygdala in humans. Amygdalar functional connectivity differs in late-life depression phenotypes, and this discrepancy may be a criterion to distinguish phenotypes of late-life depression and evaluate the severity.6

f the o % DD ut 60 Abo ls with M cide, idua i v u i s d in plate o 15% m e t t con 10% 4 t u o e ab uicid and s t i m com

In addition, the volume of the amygdala varied with the severity of the depression.

Interestingly, a study showed that larger grey matter volume in the bilateral amygdala was found in first-degree relatives of depressed patients. 6 Furthermore, amygdala perturbations caused by negative stimuli, which elicit greater amygdala activation, might be an early and subtle risk marker for depression. Recent

Photo credit: Shutterstock.com

Limbic system

evidence suggests that postpartum depression can increase amygdalar response to infant stimuli and decrease bilateral amygdala-right insular cortex connectivity. The latter may have a stimulative effect on depression and anxiety.6 In a clinical study of early-childhood-onset depression, functional connectivity was reduced in the bilateral amygdala. Abnormal amygdala functional connectivity is also found in late-onset depressed patients. Hence, a distributed neuronal network including cortical and limbic regions rather than a discrete brain region contributes to depression.6

The neuroprogressive nature of MDD Liu et al (2021) examined the relationship between the course of illness and brain functional alterations to explain the progressive nature of depression. MDD. Using functional MRI imaging, the team constructed large-scale intrinsic functional connectivity networks to map large-scale intrinsic connectivity networks in the ‘resting’ brain. 2 Participants included 95 medicationfree MDD patients and 111 matched healthy controls. Follow-up was six months. After six months of treatment with a selective serotonin reuptake inhibitor, 56 patients achieved clinical remission and finished their second scan. 2 The results revealed that, compared with healthy controls, patients with first-episode depression exhibited hypoconnectivity in the somatomotor, default mode and dorsal attention networks, and those with recurrent depression exhibited hyperconnectivity in the somatomotor, salience, executive control, default mode and dorsal attention networks, as well as within and between salience and executive control networks. 2 Moreover, the disrupted components in patients with current MDD did not change significantly when the patients achieved remission after treatment, and subhyperconnectivity. Sub-hypoconnectivity were still found in those with remitted recurrent MDD. Additionally, the hypoconnectivity in first-episode depression and hyperconnectivity in recurrent depression were associated with the number of episodes and total illness duration. 2 The authors concluded that their results provide new evidence supporting the progressive nature of intrinsic functional connectivity abnormalities across the course of depression. The results also provided moderate evidence supporting the coexistence of progressive, trait-like, and temporary adaptive functional connectivity alterations in MDD. These findings enable scientists to gain insight into the underlying mechanisms of the progressive nature of MDD that calls for full course management. 2

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Individualising management of MDD The two studies above shows that abnormal brain structural and functional alterations cause MDD and that functional connectivity abnormalities play a role in the progression of the disorder. 2,6 As a result of the progressive nature of the disorder, some patients are at higher risk of suicide than others. Studies show that about 60% of the individuals with MDD contemplate suicide, and about 10% to 15% commit suicide.4 So, can using the findings from neuroscientific studies, predict which patients are at higher risk of suicide? After suffering a personal loss as a result of suicide, Prof Leanne Williams, a clinical neuroscientist at Stanford University (United States) and founder of the Stanford Centre for Precision Mental Health and Wellness, has devoted her life to find a way to translate the findings from neuroscience into actionable clinical tools in psychiatry, which she believes may be useful in identifying patients at high risk of suicide. Thus enabling clinicians to intervene timeously and individualising treatment.7,8 Using biotyping (functional MRI imaging scans to monitor changes in the brain), Prof Williams and her team have identified six types of neural circuit dysfunctions involved in MDD and anxiety, and eight subtypes.7 Their research has shown that certain neural circuit dysfunctions lead to for example unrelenting negative thoughts, or dampening of the reward networks, thus robbing a person of the ability to feel pleasure (anhedonia).

Those two subtypes, along with a third called cognitive control, which orchestrates attention, planning, and impulse control, often respond poorly to depression treatments, elevating the risk of suicide, according to Prof Williams. 8 The six neural circuit dysfunctions and eight biotypes in MDD and anxiety are:7 Default mode (rumination biotype): The brain is ‘idling’ and struggling to engage. In this mode we tend to selfreflect. We need default mode to switch from one brain state to the other. If your brain can switch between these brain states easily, and focus, that is optimal. However, some patients with MDD get ‘stuck’ in default mode. This leads to functional overactivation and hyperconnectivity of the default mode circuit. In MDD, hyperfunctioning of the default mode circuit has been associated with higher levels of maladaptive rumination about depressive thoughts.

Salience perception (anxious avoidance): Responds to important cues or signals such as pain or hunger and picks up cues in the environment, which guide the brain to move into a

1

2

3

4

different state. Hypoconnectivity within the salience circuit has been noted in depression, social anxiety disorder, and panic disorder and has been inversely associated with symptom severity.

These salience circuit dysfunctions might contribute to so-called anxious avoidance biotypes characterised by difficulty distinguishing relevant salient cues and an avoidance of situations that could generate interoceptive or environmental stimulus overload.

Negative affect (negative bias and threat dysregulation biotypes): This is also referred to as ‘fight or flight’ mode, which is switched on automatically if you perceive a threat or stressor. It can also be switched on consciously to regulate stress. However, if a person experiences trauma, these circuits can stay in alarm mode, resulting in hyper-alertness/vigilance, which may result in symptoms similar to posttraumatic stress disorder. Amygdala hyperactivation during non-conscious threat processing has been reported in current MDD, generalised anxiety disorder, generalised social phobia– anxiety disorder, specific phobia, and panic disorder.

Positive affect (anhedonia and context insensitivity biotypes): Also referred to as the reward circuit, which is triggered when we experience something positive like pleasure, social connectedness, or anything that motivates us to make positive changes in our lives. These circuits are under stress when our social interaction is limited. Hypoactivation in some people with MDD suggest a distinct loss of sensitivity to reward stimuli that characterises an anhedonia biotype. Striatal hypoactivation in these patients is apparent in response to socially rewarding stimuli (such as happy faces) and during rewardmotivated decision making. Anatomically, a loss of striatal grey matter might contribute to a functional anhedonia biotype. Anhedonia has also been associated with greater activation of the orbitofrontal cortex during the processing of happy faces and reward outcomes, which might reflect compensation for striatal hypoactivation.

Anhedonia might encompass negative-affect-circuit dysfunction as suggested by reports of amygdala hypoactivation to happy faces in unmedicated MDD, generalised anxiety disorder, and panic disorder. In remitted MDD, overactivation of the anterior cingulate and midfrontal region has

5

6

been observed during the anticipation of primary rewards. These findings suggest a context-insensitivity biotype of neural dysfunction, in which there is a heightened anticipation of reward without sensitivity to the surrounding context or the capacity to differentiate emotional context. This dysfunction can persist even during remission.

Attention circuit (inattention biotype): Involved in maintaining our focus and attention. When default mode is engaged, and we are relaxed, the attention circuit is supressed. When we need to focus, the attention circuit becomes engaged. The frontoparietal attention circuit is defined by nodes in the medial superior frontal cortices, anterior insula, anterior inferior parietal lobule, and praecuneus. It is implicated in alertness, sustained attention, and the support of recollection. A close interplay between the attention and default mode circuits could be important to configuration of the switching between resting and task-context processing. Hypoconnectivity within the frontoparietal attention circuit has been noted in MDD and in social anxiety and suggests the presence of an inattention biotype. In anxiety, frontoparietal circuit hypoconnectivity has been correlated with a specific behavioural profile of false alarm errors consistent with disruption to sustained attention.

Cognitive control circuit (cognitive dyscontrol biotype): The cognitive control circuit comprises the dorsolateral PFC, anterior cingulate cortex (ACC), dorsal parietal cortex, and precentral gyrus. Together these regions and their interconnectivity are implicated in the support of higher cognitive functions, such as working memory and selective attention. Under task-specific demands the cognitive control circuit is implicated in cognitive flexibility. Dysfunction of the cognitive control circuit during effortful selective processing of relevant

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0,25 mg / 0,5 mg / 1,0 mg

5 mg / 10 mg / 15 mg / 20 mg orodispersible tablets 2,5 mg / 5 mg / 10 mg film-coated tablets IM powder for solution for injection

ALCHERA. Reg. No.: 33/2.2/0029. Each tablet contains 7,5 mg of zopiclone. S5 ATIVAN SL 1 mg. Reg. No.: R/2.6/319. Each sublingual tablet contains 1 mg of lorazepam. S5 ATIVAN SL 2 mg. Reg. No.: R/2.6/320. Each sublingual tablet contains 2 mg of lorazepam.

ATIVAN 1 mg. Reg. No.: D/2.6/126. Each tablet contains 1 mg of lorazepam. S5 ATIVAN 2,5 mg. Reg. No.: D/2.6/128. Each tablet contains 2,5 mg of lorazepam. S5 ATIVAN Injection. Reg. No.: JX/2.6/295. Each 1 ml solution contains 4 mg of lorazepam.

AZOR-0,25 (tablet). Reg. No.: 29/2.6/0180. Each tablet contains 0,25 mg of alprazolam. S5 AZOR-0,5 (tablet). Reg. No.: 29/2.6/0181. Each tablet contains 0,5 mg of alprazolam. S5 AZOR-1,0 (tablet). Reg. No.: 29/2.6/0182. Each tablet contains 1 mg of alprazolam.

CARBILEV 25/250. Reg. No.: 30/5.4.1/0269. Each tablet contains 25 mg carbidopa and 250 mg of levodopa. S4 CARBILEV 25/100. Reg. No.: 30/5.4.1/0271. Each tablet contains 25 mg carbidopa and 100 mg of levodopa. S3 DEGRANOL tablets. Reg. No.: G/2.5/220. Each tablet contains 200 mg of carbamazepine. S5 ESPIRIDE (capsule ). Reg. No .: Y /2 .5 /386. Each capsule contains 50 mg of sulpiride. S5 ETHIPRAMINE 10 mg Tablets. Ref. No .: B695 (Act 101 /1965). Each tablet contains 10 mg of imipramine hydrochloride. S5 ETHIPRAMINE 25 mg Tablets. Ref. No .: B694 (Act 101 /1965). Each tablet contains 25 mg of imipramine hydrochloride. S5 NORMISON 10 mg. Reg. No.: L/2.2/125. Each soft gelatin capsule contains 10 mg of temazepam. S5 NORMISON 20 mg.

Reg. No.: M/2.2/205. Each soft gelatin capsule contains 20 mg of temazepam. S3 Phenytoin Sodium 100 mg Tablet. Reg. No.: B884 (Act 101/1965). Each tablet contains 100 mg of phenytoin sodium. S3 Phenytoin Sodium Capsules. Reg. No.: B885 (Act 101/1965).

Each capsule contains 100 mg of phenytoin sodium. S5 PREXOLAN 2,5 (film-coated tablet). Reg. No.: 43/2.6.5/0908. Each film-coated tablet contains 2,5 mg of olanzapine. S5 PREXOLAN 5 (film-coated tablet). Reg. No.: 43/2.6.5/0909. Each film-coated tablet contains 5 mg of olanzapine. S5 PREXOLAN 10 (film-coated tablet). Reg. No.: 43/2.6.5/0910. Each film-coated tablet contains 10 mg of olanzapine. S5 PREXOLAN IM (powder for solution for injection). Reg. No.: 43/2.6.5/0911. Each vial contains 10 mg of olanzapine.

S5 PREXOLAN ODT 5. Reg. No.: 44/2.6.5/0915. Each orodispersible tablet contains 5 mg of olanzapine. S5 PREXOLAN ODT 10. Reg. No.: 44/2.6.5/0916. Each orodispersible tablet contains 10 mg of olanzapine S5 PREXOLAN ODT 15. Reg. No.: 44/2.6.5/0917.

Each orodispersible tablet contains 15 mg of olanzapine. S5 PREXOLAN ODT 20. Reg. No.: 44/2.6.5/0918. Each orodispersible tablet contains 20 mg of olanzapine. S5 TRANQIPAM - 1. Reg. No.: U/2.6/38. Each tablet contains 1 mg of lorazepam. S5 TRANQIPAM - 2,5. Reg. No.: U/2.6/39. Each tablet contains 2,5 mg of lorazepam. S5 TREPILINE 10. Reg. No.: J/1.2/219. Each tablet contains 10 mg of amitriptyline hydrochloride. S5 TREPILINE 25. Reg. No.: J/1.2/220. Each tablet contains 25 mg of amitriptyline hydrochloride.

S5 ZOLNOXS 10 mg Tablets. Reg. No.: 36/2.2/0328. Each film-coated tablet contains 10 mg zolpidem tartrate. For full prescribing information refer to the professional information approved by the medicines regulatory authority (ALCHERA 10/2000; ATIVAN SL 1 mg and 2 mg 06/1999; ATIVAN 1 mg and 2,5 mg 07/2012; ATIVAN Injection 03/2015; AZOR-0,5 06/1996; AZOR 0,25 04/1996; AZOR-1,0 04/1996; CARBILEV 09/1996; DEGRANOL 03/1985; ESPIRIDE 04/1998; ETHIPRAMINE 11/1969; NORMISON 12/1989; Phenytoin Sodium 11/1969; PREXOLAN film-coated tablets & IM 03/2014; PREXOLAN ODT 03/2013; TRANQIPAM 02/1990; TREPILINE 07/2017; ZOLNOXS 10 mg 11/2004). Trademarks are owned by or licensed to the Aspen Group of companies. © 2021 Aspen Group of companies or its licensor. All rights reserved. Marketed by Aspen Pharmacare. Co. Reg. No.: 1898/000252/06. Healthcare Park, Woodlands Drive, Woodmead, 2191. ZAR-COR-01-21-00004 03/2021.

S5 S5 S5 S4

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stimuli while inhibiting irrelevant stimuli suggests a cognitive dyscontrol biotype.

Hypoactivation of the dorsolateral PFC and dorsal ACC has been observed in MDD. Such hypoactivation persists with later-life depression, suggesting that a cognitive dyscontrol biotype might have a trait-like status. ACC and dorsolateral PFC hypoactivation during an inhibition task has been associated with slowing of the time to inhibit responses for people with higher anxiety. Problems with selective inhibition in depression could also be suggested by problems suppressing default mode rumination,

and a profile of positive correlation (rather than anticorrelation) between dorsal prefrontal cognitive control regions and posterior cingulate default mode regions.

Use of neural circuit dysfunction to guide treatment According to Prof Williams, it is essential to understand how neural-circuit-based biotypes relate to interventions. Currently, the choice of pharmacotherapy is based on clinical interview, and typically only around 30% of patients recover with the first drug they are prescribed.

Prof Williams recommends the following

potential interventions based on biotyping, which she beliefs is the future of psychiatry:

Conclusions MDD is one of the main causes of suicide.

Neuroscience has expanded our knowledge of brain abnormalities that are present in people with MDD. Biotyping is being investigated as a way to predict which patients are at higher risk of suicide, allowing clinicians to intervene timeously and more effectively. Prof Williams acknowledges that biotyping is not the only way to understand depression. Self-reporting, genomics, physiology, and behavioural factors all play a role. Biotyping is just a way to build on clinical expertise, she says. Scientists are now working the development of biomarkers, similar to those used in breast cancer and cardiovascular disease, which can be used to guide treatment decisions. 9

References 1. Lim GY, Tam WW, Lu Y, et al. Prevalence of Depression in the Community from 30 Countries between 1994 and 2014. Scientific Reports, 2018.

2. Liu J, Fan Y, Zeng L-L, et al. The neuroprogressive nature of major depressive disorder: evidence from an intrinsic connectome analysis. Translation Psychiatry, 2021.

3. GlobalData Healthcare. Major depressive disorder:why does it affect women more? Pharmaceutical Technology, 2021. https://www.pharmaceutical-technology.com/ comment/major-depressive-disorder-women/ 4. Bains N and Abdijadid S. Major Depressive Disorder.

StratPearls (Internet), 2021. https://www.ncbi.nlm.nih. gov/books/NBK559078/ 5. Gattarinussi G, Delvecchio G, Maggioni E, et al. Ultrahigh field imaging in Major Depressive Disorder: a review of structural and functional studies. Journal of Affective Disorders, 2021.

6. Liu W, Ge TT, Leng Y, et al. The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex. Neural Plasticity, 2017.

7. Williams LM. Precision psychiatry: a neural circuit taxonomy for depression and anxiety. Lancet Psychiatry, 2016.

8. Underwood E. Brain scans could help personalize treatment for people who are depressed or suicidal.

Science, 2019.

9. Williams LM. NAMI Santa Clara County October 2020 General Meeting. Video: https://www.youtube.com/ watch?v=DW8KqFBXEUc&t=322s SF

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Covid-19: The great mental health equaliser

People with psychiatric disorders not only have to learn how to manage their illness, but they also have to deal with stereotyping, discrimination, prejudice, and stigmatisation.

The main driver of stigmatisation is the lack of knowledge about psychiatric diseases, perpetuated by the media in some countries, and fear and superstition in others.1,2

I

n an editorial in The Lancet (2016), the author writes that people with psychiatric diseases experience shame, ostracism, and marginalisation due to their diagnosis, and often describe the consequences of stigma as a result of their psychiatric disorder worse than those of the condition itself. 3 Prof Wulf Rössler of the department of Clinical and Social Psychiatry at the University of Zurich (Switzerland) and clinical director at the Psychiatric University Hospital Burghölzli, writes that there is no country, society, or culture where people with mental illness have the same societal value as people without psychiatric disorder. 2 People with psychiatric disorders have been ostracised from society since early times.

During the Middle Ages, psychiatric disorders was seen as a punishment from God. People

living with psychiatric disorders were often thought to be possessed by the devil and were burned at the stake or thrown in penitentiaries and ‘madhouses’ where they were chained to the walls or their beds. 2 In the following decades, knowledge and understanding of psychiatric disorders increased, and patient care improved in some countries, but shockingly, the 2020 Human Rights Watch report revealed that people with psychiatric disorders are still shackled in 60 countries across Asia, Africa, Europe, the Middle East, and the Americas. 2,4 Even in countries were conditions for patients living with psychiatric conditions improved, stigmatisation is still rife. A worldwide study conducted in 229 countries showed that in developed countries such as the United States and Canada, 7% to 8% of respondents believe that people with

psychiatric disorders are prone to violence. 2,5 Corrigan and Watson explain that there are three types of stigmatisations:7 » Public stigma: Negative or discriminatory attitudes that others have » Self-stigma: Negative attitudes, including internalised shame, that people living with psychiatric disorder have about their own condition » Institutional stigma: More systemic, involving policies of government and private organisations that intentionally or unintentionally limit opportunities for people with psychiatric disorders. Examples include lower funding for research into psychiatric disorders or health services relative to other healthcare.

According to Prof Rössler, media coverage perpetuates stigmatisation because of consistent and overwhelmingly negative

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and imprecise portrayal of people living with psychiatric disorders. Entertainment programmes, films, television news and newspapers play a central role in disseminating biased information surrounding psychiatric diseases and strengthen negative stereotypes. 2 One recent example is the Oscar winning movie, Joker. Scarf et al (2020) conducted a study to evaluate the impact of the Joker, on viewers’ perceptions of psychiatric disorders.

The lead character in the movie has a psychiatric disorder and becomes increasingly unstable and violent because he no longer has access to medication.6 The researchers found that following the viewing of the movie, study participants displayed high levels of prejudice towards the character and associated his extreme violence with his psychiatric disorder. They also found that the movie may exacerbate self-stigmatisation for those with a psychiatric disorder, which may lead to delays in help seeking.6 Apart from movies, writes Prof Rössler, news reports sensationalise violence and crimes committed by individuals with psychiatric disorders compared to similar crimes by people without psychiatric disorders, thus perpetuating the notion that people with psychiatric disorders are a threat to society. 2

Why do we stigmatise?

Becker explains that people attach labels to others in order to make it easier to understand the social world around them. We label people as ‘deviant’ based on their specific attributes or behaviours, which we perceive as contrary to society’s acceptable norms.7 Another explanation for stigmatisation comes from the social identity theory. According to this theory, individuals draw heavily from their belongingness to a specific social group, which gives rise to intergroup comparison.7 We attribute positive characteristics to our own group (in-group) and engage in derogatory attitudinal reactions (stigmatisation) against the out-group, which makes us feel superior.7 But it is not only the general public that stigmatise patients living with psychiatric disorders. A South African study by Egbe et al, found that healthcare providers are often guilty of so-called treatment stigma. 8 With the decentralisation of psychiatric care and its integration into primary healthcare in South Africa, write the authors, many general healthcare providers who have not been exposed to patients with psychiatric disorders, now have to provide healthcare services for these patients. 8 This is not unique to South Africa. Studies outside of Africa suggest a high level of stigma and discrimination amongst general healthcare providers as well as mental healthcare providers. 8

Among healthcare professionals, psychiatric healthcare professionals have been found to be less optimistic about the prognosis and the long-term outcomes for people living with psychiatric disorders compared to other healthcare professionals. 8

, ntry u o c o here e is n w r e e r h T cultu tal r o , y t en socie e with m l same e peop h t e ople s hav e s p e n s l a il alue v l lness 2 a l t i e l i a c t so men Rössler a t u o lf with f Wu o r P –

about psychiatric disorders is the main driver of stigmatisation. The American National Academies of Sciences, Engineering, and Medicine developed a four-pronged approach, which they believe may play a valuable role in knowledge about and reducing stigmatisation of people living with psychiatric disorders.10 Education: Anti-stigma interventions that present factual information about the disorder with the goal of correcting misinformation or contradicting negative attitudes and beliefs. They counter inaccurate stereotypes or myths by replacing them with factual information.

An example would be an education campaign to counter the idea that people with a psychiatric disorder are violent murderers by presenting statistics showing that homicide rates are similar among people with psychiatric disorders and the general public.

Mental health literacy campaigns:

1

2

Impact of stigmatisation on people living with psychiatric disorders Stigmatisation has a profound impact on people living with a psychiatric disorder and their families. Patients often shy away from social interaction because of a fear of stigmarelated rejection. Thus, they become isolated, which in turn may lead to job losses, and the loss of other gainful opportunities. Some might even refrain from seeking medical help for their symptoms.1 Family stigma is often applied to the parents, siblings, spouses, children, and other relatives of an individual living with a psychiatric disorder. For example, parents have been accused of creating a pathological environment that could favour the onset of a psychiatric disorder, such as the ‘schizophrenic mother’ who induced schizophrenia in her child due to her dysfunctional communication style, write Corrigan et al.1 As a result, the family becomes socially isolated as well, which impact their physical and mental well-being and may lead to economic difficulties. This in turn negatively impacts the family dynamic. In a Swedish study, which involved family members of individuals living with psychiatric disorders, a sizable number stated that the person would be better off dead and/or they wished that the individual and the relative had never met, or that the patient had never been born.1 According to Corrigan et al, stigma and discrimination are the most significant challenges that people living with chronic diseases such as psychiatric disorders, face.1

Can we reduce stigmatisation?

As mentioned above, lack of knowledge

3

4

There is evidence that some in-school mental health literacy programmes improve knowledge, attitudes, and helpseeking behaviour. There is also some evidence that basic health education to improve mental health literacy may be effective in reducing stigma for school-age children. To improve public attitudes without negatively impacting self-stigma, the curricula need to be recovery focused and developmentally and cognitively tailored to different age groups.

Contact: Across a wide range of stigmatising disorders, people without the stigmatised disorders have little meaningful contact with those who have these conditions. Lack of contact fosters discomfort, distrust, and fear.

Contact interventions aim to overcome this interpersonal divide and facilitate positive interaction and connection between these groups. These strategies are aimed at reducing public stigma on a person-to-person basis but have also been shown to benefit self-stigma by creating a sense of empowerment and boosting self-esteem.

Peer services: One approach to integrating contact-based interventions into day-to-day activities is through the use of peer services. When integrated into service-provision teams, peers can help others to identify problems and suggest effective coping strategies.

We are all in the same boat There is some uncertainty about the origin of the metaphor ‘we are all in the same boat’.

Some say it was used by the Greeks when speaking about the risks that all passengers in

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a small boat at sea had to face together. Others say that it was coined by Thomas Hudson, a 16th century British scholar. The meaning, however, is the same, alluding to the fact that people who are together in a boat share the same fate, whether they choose to or not.11,12 Studies have shown that when we experience shared trauma such as war or a pandemic such as Covid-19, we tend to forget our differences and become more understanding or empathetic. McFarland showed that empathy is negatively correlated with prejudice, or stigma. Empathy is defined as the capacity to understand or feel what another person is experiencing from within their frame of reference, that is, the capacity to place oneself in another’s position.13,14,15 Empathy plays a critical interpersonal and societal role, enabling sharing of experiences, needs, and desires between individuals and providing an emotional bridge that promotes prosocial behaviour. Our capacity to perceive and resonate with others’ suffering allows us to feel and understand their pain. The personal distress experienced by observing others’ pain often motivates us to respond with compassion.13,15 During the pandemic, almost all countries worldwide have reported increases in psychiatric disorders including adjustment disorder, generalised anxiety disorder, depression, and post-traumatic stress.16 A meta-analysis of the prevalence of psychiatric disorders among the general population during the Covid-19 pandemic, report rates of 29.6% for stress, 31.9% for anxiety, and 33.7% for depression.17 This has prompted some academics to pose the question whether Covid-19 can play a role in destigmatisation psychiatric disorders. In an editorial published in Time magazine, Prof Jessica Gold of the department of psychiatry at Washington University (United States), writes that the Covid-19 pandemic may just be an equaliser of sorts.18 “Nearly everyone is self-isolated at home, trying to work while managing a household, and dealing with uncertainty and grief. To some degree, everyone is experiencing what life with anxiety is like. This includes those in management, who are dealing not only with their employees’ stress but also their own.

Though depression is already the number one cause of disability worldwide, this is the first time many employers and managers are thinking and openly talking about mental health in the workplace.” 18 This changing attitude about mental health is becoming more apparent as influencers with psychiatric disorder are finally being more vulnerable about their lived experiences and emotions. They are removing the perfectly curated images, she writes.18

The trend may also be due to fact that Covid-19 calls for people to just be more real. Perhaps this will lead to more social connection, or even a decrease in depression and loneliness.18

4. Human Rights Watch. Living in Chains: Shackling of People with Psychosocial Disabilities Worldwide, 2020.

5. Seeman N, Tang S, Brown DB, et al. World survey of mental illness stigma. Journal of Affective Disorders, 2016.

6. Scarf D, Zimmerman H, Winter T, et al. Association of Viewing the Films Joker or Terminator: Dark Fate With Prejudice Toward Individuals With Mental Illness. JAMA Network Open, 2020.

7. Bhanot D, Singh T, Verma SK and Sharad S. Stigma

Photo credit: Shutterstock.com

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and Discrimination During COVID-19 Pandemic.

Frontiers in Public Health, 2021.

8. Egbe CO, Brooke-Sumner C, Kathree T, et al.

Psychiatric stigma and discrimination in South Africa: perspectives from key stakeholders. BMC Psychiatry, 2014.

9. Corrigan PW, Druss BG and Perlick DA. The Impact of Mental Illness Stigma on Seeking and

“In the United States, almost 50% of all adults will experience a psychiatric disorder during their lifetime. These are rates similar to people who suffer from heart disease. Imagine saying to someone with heart disease that they are weak for having it, or that they cannot get care because their care is less important or valued. That is what we have always done with psychiatric disorders, and hopefully, because of this pandemic, it will finally stop. Let’s say once and for all that having a mental illness is a disease that requires treatment, just like any other illness.”18 Psychologist Dr Cheryl Carmin of The Ohio State University writes that it is very possible that acceptance of mental healthcare becomes part of our new normal.19 “We need to focus and take advantage of this upside of the surging stress and anxiety due to Covid-19. As more people experience emotional difficulties, mental health may become more destigmatised.” 19 As the stigma lifts and the culture changes, the sense of shared trauma and experiences are making it easier for people to talk not just about their own struggles, but to recognise those issues in others.19 Covid-19 is prompting conversations that have been needed long before the pandemic hit, she says. We’re talking about compassion fatigue, anxiety, depression, all those difficult topics. And that’s good to get it all out in the open. In other words, she says, the Covid-19 pandemic may become the great psychological equaliser.19

References 1. Corrigan PW and Watson AC. understanding the impact of stigma on people with mental illness.

World Psychiatry, 2002.

2. Rössler W. The stigma of mental disorders: A millennia-long history of social exclusion and prejudices. EMBO Reports, 2016.

3. Author not listed. The health crisis of mental health stigma. The Lancet, 2016.

Participating in Mental Health Care. Psychological Science in the Public Interest, 2014.

10. National Academies of Sciences, Engineering, and Medicine. Ending Discrimination Against People with Mental and Substance Use Disorders: The Evidence for Stigma Change(2016). The National Academies Press.

11. Genlish. All In The Same Boat.

12. The Phrase Finder. All in the Same Boat.

13. Lesley University. The Psychology of Emotional and Cognitive Empathy. https://lesley.edu/article/ the-psychology-of-emotional-and-cognitive-empathy 14. McFarlane S. Authoritarianism, Social Dominance, and Other Roots of Generalized Prejudice. Political Psychology, 2010.

15. Reiss H. The Science of Empathy. Journal of Patient Experiences, 2017.

16. Dragan M, Grajewski P and Shevlin M. Adjustment disorder, traumatic stress, depression and anxiety in Poland during an early phase of the COVID-19 pandemic. European Journal of Psychotraumatology, 2021.

17. Salari N, Hosseinian-Far A, Jalali R, et al. Prevalence of stress, anxiety, depression among the general population during the COVID-19 pandemic: a systematic review and meta-analysis. Globilization and Health, 2020.

18. Gold J. Could COVID-19 Finally Destigmatize Mental Illness? Time, 2020.

19. Goode H and Shinkle E. Another COVID Benefit: Destigmatizing Mental Illness For Once and For All! Global Teletherapy, 2020. SF

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Tackling harmful chemicals in medical devices

Health Care Without Harm Europe (HCWH-E) is a non-profit network of hospitals, healthcare systems and professional bodies, local authorities, research/academic institutions, and environmental organisations with branches in several countries.

W

CWH-E recently hosted a webinar to make healthcare professionals more aware of the potential danger of harmful chemicals used in medical devices.1

Plastic medical devices: a source of harmful exposure to EDCs Dorota Napieska,

chemicals policy and projects officer, HCWH-E Healthcare professionals rely on medical devices to treat their patients and safeguard their health. Plastic medical equipment and devices can, however, be a significant source of exposure to harmful endocrine disrupting chemicals (EDCs), including phthalates such as di(2- ethylhexyl) phthalate (DEHP) and bisphenol A (BPA).1 Phthalates are often used to make polyvinyl chloride (PVC) flexible, whilst BPA is used to produce certain plastics such as polycarbonates and epoxy resins used in medical devices.

These chemicals can harm patients, not only causing infertility and neurodevelopmental issues, but can also undermine the efficacy of treatment. EDCs can impact the human body at very low concentrations and can combine with other EDCs to produce additive effects.1 In May 2021, the European Union passed legislation that requires medical device manufactures to justify why they want to use oncogenic or EDCs above a certain concentration (0.1% weight by weight) in their production processes. This strict requirement is extremely important, said Napierska, because we know that harmful chemicals – most notably BPA

and DEHP – leak out in medical devices.1 While the role of exposure to EDCs and their harmful impact is well-known in the industrial sector, the role of exposure in the healthcare environment is still under-recognised, she added.1 Over the last few decades, HCWH-E has been involved in several campaigns to raise awareness of the harmful effects of EDCs in medical devices.

Despite difficulties to demonstrate a causal link, some associations between EDC exposure and diseases are apparent. Foetuses, children, pregnant and breastfeeding women, and dialysis patients are particularly vulnerable to the effects of these exposures.1 Many alternative substances and materials have been developed in recent years to replace hazardous chemicals used in medical devices.

Healthcare professionals can now choose between safer alternatives, or continue to ignore the potential danger to patients, she added.1 Exposure to phthalates or BPA can be minimised by adopting a precautionary approach and replacing medical devices with phthalateand BPA-free devices.1

Exposure assessment of infants following cardiac surgery Dr Elizabeth Eckert,

Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, Friedrich-AlexanderUniversität Erlangen-Nürnberg (Germany) Plastic medical devices such as tubing, blood and infusion bags, as well as syringes, contain plastic material, which often ranges from 20% to 40% per weight. About 30% of the plastic material contains plasticisers. Plasticisers are not chemically bound to the plastic matrix

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and therefore, patient exposure due to migration into blood, is possible.1 DEHP is classified as oncogenic and is a known EDC, which has been linked to reproductive toxicity effects. DEHP was banned in the manufacturing of toys and childcare products several years ago, yet it is still used widely in the manufacturing of medical devices widely used in paediatric patients, despite the fact that safer alternatives are available.1 A safer alternative is tri-(2-ethylhexyl) trimellitate (TEHTM) for example. Although there is not as much data available for TEHTM, it has been shown to have a lower rate of acute and chronic toxicity potential compared the DEHP, said Dr Eckert.1 In one of their experiments, Dr Eckert and her team studied the migration behaviour of three different blood tubing sets: PVC material with two different plasticisers (DEHP and TEHTM), and silicone as control material. The tubing sets were attached to a standard heart-lung machine used in cardiopulmonary bypass (CPB) in children.2 They analysed the total plasticiser migration, the parent compounds as well as their primary degradation products in blood. Additionally, the total mass loss of the tubing over perfusion time was examined.2 They found that PVC tubing plasticised with DEHP had the highest mass loss over time and showed a high plasticiser migration rate.

In comparison, the migration of TEHTM and its primary degradation products was found to be distinctly lower (by a factor of about 350).

Moreover, it was observed that the storage time of the tubing affected plasticiser migration rates.2 In conclusion, the DEHP substitute TEHTM

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promises to be an effective alternative plasticiser for PVC medical devices particularly regarding the decreased migration rate during medical procedures. 2 In another study, the team investigated the internal exposure situation of infant patients to TEHTM and DEHP. The study collective included 21 infant patients aged two- to 22-months who underwent CPB surgery. 3 Twenty of the patients received blood products during surgery. A special feature was that the used CPB tubing were exclusively plasticised with the alternative plasticiser TEHTM and were free of the standard plasticiser DEHP. 3 The blood products were stored in DEHP plasticised blood bags. Blood and urine samples of each infant patient were analysed before and after the surgery to determine DEHP and TEHTM levels and their metabolites.

Plasticisers were detected in the post-surgery blood samples only, with TEHTM in low levels

preterm babies are at higher risk of developing cognitive (40%), and motor impairments (10%).1 The impact on neurodevelopmental of preterm neonates may be due to several factors:1 » Gestational age » Birth weight » Gender (boys are at higher risk) » Infections (eg severe lung disease) » Genetical abnormalities » Pain.

Although it is difficult to proof, there seems to be a biological plausible relationship between exposure to phthalates and neurodevelopmental outcomes in preterm neonates as well, according to Dr Graz.1 Information obtained from large administrative databases, shows that phthalates exposure can be statistically linked to an increased risk of autism spectrum disorder or hyperactivity. However, these associations have to be interpreted with caution, she stressed.1

They found several associations with short- and long-term health dangers, mainly subfertility, broncho-pulmonary dysplasia, necrotising enterocolitis, parenteral nutrition associated cholestasis and neurodevelopmental disorders. 5 They caution that clinicians should be aware of the potential risks due to phthalate exposure in the NICU. DEHP containing materials should be identified and alternative devices should be considered.6 The Developmental Orgins of Health and Disease studies follow the first month of an infant, starting in utero. The brain of a newborn infant weighs about 500 grams and it will weigh 1.2kg at the age of two-years, 2kg as an adult, and then it loses weight.1 Between the ages of birth and two-years the brain matures and forms new connections.

During this period the brain has very high lipid content and the blood brain barrier is not very efficient in stopping chemicals from crossing

(median 18.4µg/L) and DEHP in rather elevated levels (median 1046µg/L). 3 With respect to the urine samples, TEHTM metabolites were not detected in any of the samples. Significantly increased DEHP metabolites were found in the post-surgery urine samples of all infants (increase factor 5-26).3 The researchers concluded that the study clearly demonstrates the strong contribution of standard medical procedures to the internal plasticiser burden of patients. The elevated internal levels of this plasticiser and its metabolites in infants following cardiac surgery are alarming. 3

All therapies used in NICUs incorporate chemical products – from medical devices, to nutrition, gloves, dressing, monitoring equipment, drugs (eg antibiotics), cleaning solutions, hand disincentives, diapers, and baby hygiene products.1 In addition, long-term ventilation seems to be one of the biggest risk factors for exposure to phthalates. Some neonates born at 25 weeks with a birth weight of 500 grams will need ventilation for between three and six months.1 A study by Mallow and Fox shows that critically infants are subjected to hepatotoxic and reproductive levels of phthalates that are much higher than acceptable limits.4 Dose-response thresholds for DEHP toxicities were determined from published data, as were the magnitudes of DEHP exposures resulting from neonatal contact with PVC devices.

Standard methods of risk assessment were used to determine safe levels of DEHP exposure in neonates, and hazard quotients were calculated for devices individually and in aggregate.4 Daily intake of DEHP for critically ill preterm infants can reach 16mg/kg per day, which is 4000 and 160 000 times higher than desired to avoid reproductive and hepatic toxicities, respectively.

The non-endocrine toxicities of DEHP are similar to complications experienced by preterm neonates.4 They concluded that DEHP exposures in NICUs are much higher than estimated safe limits and might contribute to common early and chronic complications of prematurity.4 Fischer et al reviewed the evidence of the risks associated with the use of medical devices containing DEHP in hospitalised neonates.

the barrier. This is an extremely vulnerable period in the child’s life during which the formation of new connections can stop. This provides some evidence that phthalates may harm neurodevelopment in these children, said Dr Graz.1

Key messages

1 2 3 4

Migration rate of plasticisers into blood strongly depends on the type of plasticiser The plasticiser TEHTM appears to be a suitable alternative to DEHP due to its low migration rate and presumed low toxicity potential Inner burden of infants with DEHP after cardiac surgery is still critically elevated due to DEHP containing stored blood bags Use of DEHP in medical devices for treatment of sensitive population groups, like infants, should be restricted.

Phthalates in the NICU Dr Graz, Woman-

mother-child Department, Neonatology Service, Centre Hospitalier Universitaire (Switzerland)

About 10% of newborns treated in neonatal intensive care units (NICUs) are born prematurely (<37 weeks of gestation). This equates to about 15 million vulnerable newborns every year. Studies have shown that

Key messages

1 2 3 4

Preterm/critically ill neonates are extremely vulnerable due to increased skin/body weight ratio and immature metabolic pathways They often require long hospitalisation, which increases their risk of exposure to high doses of phthalates, resulting in high toxicity levels This as possible long-term effects on their neurodevelopment, endocrine system, their lungs, and eyes Many neonatal specialists are not aware of these long-term effects as a result of increased exposure to phthalates.

References 1. Health Care Without Harm Europe. Tackling harmful chemicals in medical devices. https://noharm-europe. org/issues/europe/webinar-recording-tacklingharmful-chemicals-medical-devices 2. Eckert E, Munch F, Goen T, et al. Comparative study on the migration of di-2-ethylhexyl phthalate (DEHP) and tri-2-ethylhexyl trimellitate (TOTM) into blood from PVC tubing material of a heart-lung machine. J Chemosphere, 2016.

3. Eckert E, Muller J, Hollerer C, et al. Plasticizer exposure of infants during cardiac surgery. Toxicol Lett, 2020.

4. Mallow EB and Fox MA. Phthalates and critically ill neonates: device-related exposures and nonendocrine toxic risks. J Perinatol, 2014.

5. Fischer CJ, Graz MB, Meuhlethaler V, et al. Phthalates in the NICU: Is it safe? Journal of Paediatrics and Child Health, 2013. SF

Freeflex® • DEHP/PVC Free1 • Latex Free1 • Free of Plasticisers1 Developed with the future in mind Reference: 1) Fresenius Kabi data on file.

Fresenius Kabi South Africa (Pty) Ltd, Reg. No.: 1998/006230/07 Stand 7, Growthpoint Business Park 162 Tonetti Street, Halfway House Extension 7, Midrand, Gauteng, 1685 PO Box 4156, Halfway House 1685 Tel: + 27 11 545 0000 Fax: + 27 11 545 0060 www.fresenius-kabi.co.za SSA_10_5_2021_V1

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This article was independently sourced by Specialist Forum.

Photo credit: Shutterstock.com

BP-lowering pharmacotherapy should be the foundation of RISK RISK PREVENTION PREVENTION

Numerous studies have demonstrated a log-linear relationship between elevated blood pressure (BP) and a higher risk of cardiovascular disease (CVD), which increases substantially with age.1

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bout 36.1% of males, 33.2% of females in the age group 45- to 54-years have hypertension and in the age group 55- to 64-years, the figures double to 57.6% and 55.5% respectively.

Patients aged between 65- and 74-years, 63.6% of males and 65.8% of females, and in older patients (>75-years), 73.4% of males and 81.2% of females, have hypertension.1 Hypertension is slightly more common in women and conveys an increased risk of heart failure (3-fold) in comparison to men (2-fold). Women are also more likely to have uncontrolled blood pressure.1

Hypertension and angina Patients with hypertension often present with typical anginal chest pain, caused by functional and structural mechanisms that affect coronary microcirculation. Patients with hypertension and microvascular angina often show slow flow and tortuous coronary arteries, suggestive of small vessel obstruction. 2 Common structural abnormalities implicated in hypertension include capillary rarefaction and left ventricular hypertrophy. Functional abnormalities contributing to microvascular angina, include insulin resistance that leads to endothelial dysfunction, and oestrogen

deficiency in post-menopausal women or women who have undergone a hysterectomy. 2

What is angina?

Angina, or chest pain, is the most common symptom of ischaemic heart disease, a major cause of morbidity and mortality worldwide.

Angina is one of the signs of acute coronary syndrome and can further be subdivided into stable and unstable angina. Stable angina is defined as the occurrence of symptoms with exertion only. Unstable angina or symptoms occurring at rest requires more prompt evaluation and management. 3

ß RESTORE cardiac function CARVEDILOL: • is indicated twice daily for mild to moderate stable symptomatic congestive heart failure • is indicated once daily for essential mild to moderate hypertension • has a positive effect on metabolic parameters.1

CARVEDILOL

6,25 mg 12,5 mg

25 mg

For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Fax +27 21 701 5898 Email info@pharmadynamics.co.za CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za CARVETREND 6,25, 12,5, 25 mg. Each tablet contains 6,25, 12,5, 25 mg carvedilol respectively. S3 A37/7.1.3/0276, 0277, 0278. NAM NS2 08/7.1.3/0105, 0104, 0103. BOT S2 BOT1101790, 1791, 1792. For full prescribing information, refer to the professional information approved by SAHPRA, December 2014. 1) Panagiotis C Stafylas, Pantelis A Sarafidis. Carvedilol in hypertension treatment. Vascular Health and Risk Management 2008;4(1):23-30.

CDA708/02/2021.

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Simply put, angina is the result of an imbalance between the myocardial oxygen supply and the myocardial oxygen demand.

It is important to understand the factors that contribute to each of these measures.4 Endothelial cells line the coronary arteries. These cells are responsible for regulating vascular tone and preventing intravascular thrombosis. Stress, hypertension, hypercholesterolemia, viruses, bacteria, and immune complexes can disrupt these two functions and result in coronary heart disease.4 According to the National Institute of Health Care and Excellence, angina can be defined as:5 Í Typical angina: (requires all three) » Constricting discomfort in the front of the chest or in the neck, shoulders, jaw, or arms » Precipitated by physical exertion » Relieved by rest or sublingual glyceryl trinitrate within about 5 min Í Presence of two of the features is defined as atypical angina. Í Presence of one or none of the features is defined as non-anginal chest pain Í Stable angina may be excluded if pain is non-anginal provided clinical suspicion is not raised based on other aspects of the history and risk factors Í Do not define typical, atypical, and nonanginal chest pain differently in men and women or different ethnic groups.

Other causes of chest pain that should be excluded include: Gastroesophageal reflux disease, lung disease, musculoskeletal causes, and anxiety/panic attacks. 3

How is hypertension treated?

Guidelines recommend that patients with stage 1 hypertension (∼69%) do not qualify for immediate drug therapy (see box 1 for hypertension staging). However, a new study by the Blood Pressure Lowering Treatment Trialists’ Collaboration, shows that a 5mmHg reduction of SBP reduces the risk of major CV events by about 10%, irrespective of previous diagnoses of CVD, and even at normal or high– normal BP values.6,7 According to the study authors, their findings provide evidence against the widely held view that an individual’s BP or previous diagnosis of CVD per se are key factors for selecting or deselecting participants for BP-lowering treatment.7 These findings call for revision of clinical guideline recommendations globally and suggest that anti-hypertensive medications are better viewed as treatment options for prevention of CVD regardless of an individual’s BP level and their previous history of CVD, stress the authors.7 For people at risk of CVD, pharmacological BP-lowering treatment should become a

cornerstone of risk prevention irrespective of CVD status or BP.7 Current guidelines recommend that once an individual with hypertension qualifies for pharmacological treatment (see box 1), including patients with masked hypertension, prescription of anti-hypertensives is recommended from one of the four drug classes (usual first line therapy):7

Thiazide diuretics

1

2

Calcium antagonists

Angiotensin converting enzyme (ACE) inhibitors Angiotensin receptor blockers (ARBs) – unless there is a comorbidity consideration favouring the use of a different drug class.

The number of anti-hypertensive drugs to prescribe in drug naïve patients is guided by how far their BP is above target. In patients with BP >20/10mmHg above target, two-drug therapy, either as a single pill combination or two separate pills, should be initiated.7

3 4

How is angina treated?

The aims of pharmacological management of chronic coronary syndromes (CCS) patients are to reduce angina symptoms and exercise-induced ischaemia, and to prevent cardiovascular events, recommends the 2019 European Society of Cardiology guidelines for the diagnosis and management of CCS. 9 Immediate relief of anginal symptoms, or the prevention of symptoms under circumstances likely to elicit angina, is usually obtained with rapidly acting formulations of nitroglycerin. 9 Anti-ischaemic drugs – but also lifestyle changes, regular exercise training, patient education, and revascularisation – all play a role in minimising or eradicating symptoms over the long-term (long-term prevention). 9 Initial drug therapy usually consists of one

or two anti-anginal drugs, as necessary, plus drugs for secondary prevention of CVD. The initial choice of anti-anginal drug(s) depends on the expected tolerance related to the individual patient’s profile and comorbidities, potential drug interactions with co-administered therapies, the patient’s preferences after being informed of potential adverse effects, and drug availability. 9 Whether combination therapy with two anti-anginal drugs (eg a beta-blocker and a calcium channel blocker [CCB]) is superior to monotherapy with any class of anti-anginal drug in reducing clinical events remains unclear.9 Beta-adrenergic blockers or CCBs are recommended as the first choice, although no randomised controlled trials to date have compared this strategy to an alternative strategy using initial prescription of other antiischaemic drugs, or the combination of a betablocker and a CCB. 9 The results of a network meta-analysis of 46 studies and 71 treatment comparisons supported the initial combination of a betablocker and a CCB. The same meta-analysis suggested that several second-line add-on anti-ischaemic drugs (long-acting nitrates, ranolazine, trimetazidine, and, to a lesser extent, ivabradine) may prove beneficial in combination with a beta-blocker or a CCB. 9 The dose of beta-blockers should be adjusted to limit the heart rate to 55–60 beats per minute at rest. Discontinuation should be tapered and not abrupt. 9

References 1. Tackling G and Borhade MB. Hypertensive Heart Disease. StratPearls [Internet], 2021.

2. Vitale C. Microvascular angina and systemic hypertension. e-Journal of Cardiology Practice, 2016.

3. Hermiz C and Sedhaj YR. Angina. StratPearls [Internet], 2021.

4. Gillen C and Goyal A. Stable Angina. StratPearls [Internet], 2021 5. Ford TJ and Berry C. Angina: contemporary diagnosis and management. Heart, 2018.

6. Flack JM and Adekola B. Blood pressure and the new ACC/AHA hypertension guidelines. Trends in Cardiovascular Medicines, 2020.

7. The Blood Pressure Lowering Treatment Trialists’ Collaboration. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. The Lancet, 2021.

8. South African Hypertensive Society. Hypertension. https://www.hypertension.org.za/pages/about-us 9. Knuuti J, Wijn W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). European Heart Journal, 2019. SF

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This article was independently sourced by Specialist Forum.

Photo credit: Shutterstock.com

key messages from the new ESC HF management guideline

The European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure (HF) was published online in the European Heart Journal on 27 August.

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bout 2% of adults worldwide have HF. Prevalence increases with age, from 1% in those under 55 years to more than 10% in people aged 70 and above. In developed countries, the most common causes are coronary artery disease and high blood pressure.

Patients with HF have a poor prognosis and markedly reduced quality of life. The main symptoms are breathlessness, ankle swelling, and tiredness. After diagnosis, patients are hospitalised once every year on average and more than half die within five years.

Chronic HF is a condition where the heart is unable to pump blood around the body properly. It usually occurs because the heart has become too weak or stiff.

Ejection fraction (eg the percentage of the blood within the ventricles that is ejected during the cardiac cycle), is the most important measurement of cardiac function. When the pumping action of the heart is weak it is referred to as HF with reduced ejection fraction (HFrEF) and when it is stiff and does not relax

properly, it is referred to as HF with preserved ejection fraction (HFpEF).

Acute HF Acute HF is a life-threatening condition requiring urgent evaluation and treatment.

It may be the first manifestation of HF (new onset) or, more frequently, it is due to an acute deterioration of chronic HF. Regarding diagnosis, when there is a suspicion of chronic HF, the guidelines recommend measuring the level of hormones produced by the heart (natriuretic peptides). If levels are normal the patient can be reassured that heart failure is very unlikely. If high, this should prompt referral for an echocardiogram to detect the underlying heart problem.

New definition of HF The HF Society of America, the HF Association of the ESC and the Japanese HF Society recently joined forces to redefine HF: HF is a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac

abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion.

The new definition also includes a new classification and staging system. The classification includes: » HFrEF: HF with left ventricular ejection fraction (LVEF) =40% » HF with mildly reduced ejection fraction (HFmrEF): HF with LVEF 41–49% » HFpEF: HF with LVEF 50% » HF with improved ejection fraction: HF with a baseline LVEF = 40%, a 10 point increase from baseline LVEF, and a second measurement of LVEF >40%.

Non-pharmacological treatments Exercise is recommended for all capable chronic heart patients to improve quality of life and reduce HF hospitalisation. In those with more severe disease, frailty, or comorbidities, a supervised, exercise-based, cardiac rehabilitation programme should be considered.

“The vast majority of drug treatments that

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improve survival and reduce hospitalisations also have beneficial effects on quality of life and symptoms,” said guidelines task force chairperson Prof Theresa McDonagh of King’s College Hospital, London, (United Kingdom).

“There are some interventions that do not impact survival but do improve quality of life and symptoms – for example exercise rehabilitation – that should also be offered to patients with chronic HF.” The guidelines recommend that all patients have access to a multi-professional HF disease management programme to ensure that their HF is correctly diagnosed and managed. These programmes have been associated with better care and improved outcomes.

In addition, patients with HF should be encouraged to be actively involved in managing their condition. Self-care includes adopting healthy habits such as physical activity, avoiding excessive salt intake, maintaining a healthy body weight, avoiding excessive alcohol consumption, and not smoking.

It is also important to avoid drinking large volumes of fluid, recognise sleeping problems, monitor changes in symptoms, and know when to contact a health professional.

Patients with HF are at increased risk of infections, which may worsen symptoms and be a precipitant factor for acute heart failure. The guidelines state that influenza, pneumococcal and Covid-19 vaccination should be considered in patients with HF. Recommendations are also given on how to manage patients with HF who have co-existing conditions such as atrial fibrillation and valvular heart disease.

“It is crucial to treat the underlying causes of heart failure and its comorbidities,” said cochairperson of the guidelines task force Prof Marco Metra of the University of Brescia (Italy).

“Proper treatment of high blood pressure, diabetes and coronary artery disease can prevent the development of HF. Atrial fibrillation, valvular heart disease, diabetes, chronic kidney disease, iron deficiency and other comorbidities frequently co-exist with HF and the adoption of specific treatments may have a major impact on the clinical course of our patients.”

20 key messages

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Patients with HF are classified based on their LVEF. Those with a LVEF between 41% and 49% are defined as HFmrEF. Measurement of natriuretic peptide (NP) and echocardiography have key roles in the diagnosis of HF. Angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptorneprilysin inhibitor (ANRi), beta-blockers, mineralocorticoid receptor antagonist, and sodium-glucose co-transporter 2

4

5

inhibitors (SGLT2is) are recommended as cornerstone therapies for patients with HFrEF. Implantable cardioverter-defibrillators are recommended in selected patients with HFrEF of an ischaemic aetiology and should be considered in those with a non-ischaemic aetiology.

Cardiac resynchronisation therapy with defibrillator is recommended in those patients with HFrEF, in sinus rhythm, with a left bundle branch block (LBBB) ≥150 ms and should be considered in those with a LBBB ≥130–149 ms or nonLBBB ≥150 ms.

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ld be u o h ts s ively t n c e i a t o Pa ged t eir a r u enco ate in th e by m p i m c i a gr part t pro habits n e m treat g healthy ti n adop

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9 10 11 12

Advanced HF strategies (heart transplantation/mechanical circulatory support [MCS]) may be appropriate in selected patients.

ACEi/ARNi, beta-blockers, and MRA may be considered in patients with HFmrEF. The diagnosis of HFpEF requires objective evidence of cardiac structural, or functional abnormalities as well as elevated plasma NP concentrations consistent with the presence of LV diastolic dysfunction and raised LV filling pressures. A diastolic stress test is recommended when these markers are equivocal.

To date, no treatment has been shown to reduce mortality and morbidity in patients with HFpEF. It is recommended that all patients with HF be enrolled in a multidisciplinary HFmanagement programme.

Exercise is recommended for all patients who are able, to improve exercise capacity and quality of life, and reduce HF hospitalisation.

Patients with advanced HF refractory to medical/device therapy and who do not have absolute contraindications should be referred for consideration of heart transplantation. MCS should also be considered as a bridge to

transplantation or destination therapy in selected patients.

Four major clinical presentations of acute HF may occur: » Acutely decompensated HF » Acute pulmonary oedema » RV failure » Cardiogenic shock.

Treatment of acute HF is based on diuretics for congestion, inotropes, and short- term MCS for peripheral hypoperfusion.

Patients hospitalised for HF should be carefully evaluated to exclude persistent signs of congestion. Oral treatment should be optimised before discharge.

In addition to oral anticoagulation, a strategy of rhythm control including catheter ablation should be considered in patients whose symptoms and/or cardiac dysfunction are associated with atrial fibrillation.

aortic valve replacement or 17 Surgical transcatheter aortic valve implantation,

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19 20

as advised by the heart team, are recommended in patients with symptomatic severe aortic valve stenosis.

Patients with isolated significant secondary mitral regurgitation and Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for HF patients with functional mitral regurgitation trial criteria should be considered for percutaneous edgeto-edge repair, whereas those with secondary mitral regurgitation and coronary artery disease, who need revascularisation, should be considered for surgery.

It is recommended that patients with type II diabetes are treated with SGLT2is.

Patients should be periodically screened for anaemia and iron deficiency and intravenous iron supplementation with ferric carboxymaltose should be considered in symptomatic patients with LVEF <45% and iron deficiency, and in patients recently hospitalised for HF and with LVEF ≤50% and iron deficiency.

References McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal, 2021.

European Society of Cardiology. ESC Guidelines on heart failure management launched today. News release, 27 August 2021. https://www.eurekalert.org/newsreleases/926357. SF

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This article was independently sourced by Specialist Forum.

Recognising rare diseases: Access and action

he Rare Diseases Access Initiative (RDAI), in association with Rare Diseases South Africa (RDSA), recently brought together an expert panel to discuss the challenges facing those affected by rare diseases in South Africa and to explore possible solutions. A three-hour webinar, attended by more than 100 stakeholders, ended with a call for a coordinated approach to diagnosis and care, and for increased equity in healthcare, for people living with rare diseases.

A rare disease is defined as a disease that affects less than one in 2000 people.

Approximately 8000 different rare diseases have been described to date, of which 80% have a genetic origin and are therefore considered as congenital disorders. Cumulatively, there are 3.7 million South Africans living with a rare disease, representing a significant 6%-8% of the population.

Keynote speakers included Dr Nicholas Crisp, Deputy Director General National Health Insurance, National Department of Health, Dr Natalie Mayet, Deputy Director at the National Institute for Communicable Diseases and Prof Shahida Moosa, Medical Genetics (Stellenbosch University).

Rare diseases are complex and often affect multiple body systems, requiring specialised and coordinated care that comes at a considerable cost to families and the health system. The panellists and audience alike agreed that regardless of the healthcare sector, the South African health system is not geared to respond to the particular challenges that are common to many different rare diseases. Equitable access across the continuum of care for those impacted by rare diseases will extend and improve their quality of life and will also be of economic benefit to their families and the health system.

Dr Helen Malherbe, Head Researcher, RDSA, emphasised: “There is a cost to not diagnosing and not treating rare disease patients, we just have not quantified that cost.”

The development of a national rare disease framework for South Africa is an opportunity to address current imbalances in the health system and to provide for collaborative care that is appropriate for the individual patient.

The creation of a national rare disease policy can support these goals by improving and

coordinating the medical and accessory support of patients with rare diseases, as well as through legislation, monitoring and improved communication and networking for the rare disease community (Figure 1).

Figure 1. National rare disease policy: Coordinating medical support of patients with rare diseases

Improving access throughout the continuum of care Early, accurate rare disease diagnosis enables the best clinical care, treatment options, access to services and support, increased reproductive confidence and the potential for participation in clinical research. Furthermore, a diagnosis provides a medical explanation and prognosis and informs a management plan that is of physical, psychological, emotional and financial benefit to the patient and their family.

Challenges to correct rare disease diagnosis are numerous. There is limited expertise with very few medical geneticists, genetic counsellors and bio-informaticians in South Africa and six of the nine provinces do not have access to medical genetics clinical services; there is little communication and coordination between specialties. There is no South African guideline for undiagnosed rare diseases that can be used to support clinicians in effective pre- and post-diagnosis management, and many families experience problems moving between clinics or provinces for sometimes multiple appointments in a month. Katryn Fourie, the Witwatersrand/ National Health Laboratory Services Genetic Counselling Manager and lecturer, emphasised the dearth of locally available and appropriate screening and diagnostic tests.

Further, the cost of genetic testing represents a significant barrier to access; these tests are generally self-funded by many patients across the public and private health sectors. Genetic testing using international laboratories that offer a wider range of screening and diagnostic services at a significantly lower cost are not funded by medical schemes.

Professor Moosa explained: “For families with rare diseases, the journey to a diagnosis becomes an odyssey that is punctuated by multiple tests and investigations, some that are painful and invasive and many that are unnecessary, and that despite consultation with numerous specialists, many are still left without a diagnosis or find themselves on a misdiagnosis odyssey.” The transition from disjointed to coordinated care for those with rare diseases can be effectively managed by the creation of ‘centres of excellence’ that offer the comprehensive services of a multidisciplinary team to provide continuity of care, with requisite support from other stakeholders (Figure 2). Centres of excellence enable collaboration between stakeholders to improve the equitable provision of public healthcare and opportunities for research, as well as the development of registries that can inform guidelines, policy and legislation.

Figure 2. Centres of excellence: Providing coordinated care for the management of rare diseases

NHI – rare diseases in context Dr Crisp shared his insights on rare diseases in the context of the national health system.

Despite an 8.5% GDP spend on healthcare, South Africa is among the worst performing in the world in terms of health outcomes.

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Rare diseases are currently treated in the public sector although there are the obvious limitations of capping of care and rationing of services, which do happen even with wealthy countries. The transition of the health system will enable greater efficiencies with the implication that there will then be more money to pay for rare disease care, although there may be a point where it is not cost-effective for the individual or the nation. Technical reference committees that inform decision-making on the most appropriate diagnostic and treatment modalities are currently comprised only of clinicians who interface with the patients, although Dr Crisp agreed that it is not always ideal that patient representatives are not included in these committees.

Figure 3. Rare disease/congenital abnormality data framework

Data collection, monitoring and evaluation Dr Natalie Mayet contextualised existing institutional frameworks and policies relative to rare diseases. The National Public Health

of disease matched to environmental exposure, data that is accessible to the patient and health provider and that can be used for informing

biospecimen repositories, as well as the monitoring, evaluation and sharing of data. The prioritisation of national and provincial rare

Institute of South Africa (NAPHISA) will have the functions of strengthening epidemiology and surveillance, conducting research to inform policy and guideline formulation, monitor and evaluate the impact of policy and system implementation and strengthen advocacy.

Dr Mayet is of the view that these functions can only be achieved through collaborative networks and partnerships with stakeholders.

Of the divisions within NAPHISA, noncommunicable disease and environmental health are relevant to a rare diseases framework.

Dr Mayet specifies these two divisions because “Ideally, we want to come to a point where we map environmental exposure to understand the associations between exposure and the burden of rare diseases.” There are multiple existing policy and regulatory frameworks for health information systems across South Africa and specific elements of these frameworks can be leveraged and strengthened to support a proposed data framework for a rare disease/ congenital abnormality surveillance plan (Figure 3). “This data framework is underpinned by healthcare professional capacity building and a robust communication strategy,” Dr Mayet noted. She describes Utopian outcomes of a rare disease data framework as enabling costeffective maternal and new-born screening, precision public health, clearly mapped burden

action for prevention intervention, and research.

disease research will provide greater access, opportunities and support for patients while allowing for the quantification of the burden of disease and contributing to patient registries aligned with biobanks. Dr Malherbe is of the view that “collaborative research combined with collaborative coordinated care including diagnostics, therapeutics and access, is necessary to ensure that nobody is left behind.”

About the RDAI: The RDAI was formed as a coalition of interested groups, with the aim to promote an environment which is favourable for those with rare diseases. Participants in the RDAI and supporters of the objectives are the Board of Healthcare Funders, the Health Funders Association, the Innovative Pharmaceutical Association South Africa, and Rare Diseases South Africa.

lders o h e stak lation g n i s i li rmu Mob s the fo option rd ad towa ventual disease e and tive rare orm sf ec of eff y to tran s. e polic ents’ liv pati The role of collaborative research in rare disease policy Ideally, research should be embedded into clinical care and should be aimed at solving particular problems. Key guiding principles underpinning collaborative research in rare disease is that it must be multidisciplinary, patient-centric, translational and sustainable.

The generation of statistically robust evidence from the trial setting is challenging in rare disease research due to low patient numbers and the ethical implications of including children in such studies, and this limits the development of treatments. There are few natural history studies of rare diseases and lay expertise is overlooked in the setting where patients, clinicians and scientists are widely dispersed.

Collaborative research on rare diseases can increase awareness, improve accuracy and speed of diagnosis, advance treatments and improve access to treatments, improve the quality of life of affected individuals, and further the understanding of the mechanisms of disease. Research contributes to and develops international patient registries and

Summary and way forward “South Africans living with rare diseases could have extended and improved lives if they are able to freely access appropriate and affordable healthcare services without barriers,” said Kelly du Plessis, on behalf of the RDAI. These presentations and discussions will contribute to the refinement and acceptance of a framework document which calls for action on the part of patients, healthcare practitioners, government, researchers, payers and industry towards a national coordinated and collaborative approach. “Our goal is to put South Africa on par with other countries such as the European Union, United Kingdom, Brazil, Russia, India and China, by having a National Rare Disease Policy. Participants concurred that without a Rare Disease framework and policy, South Africa is falling behind other countries and our chance of achieving universal healthcare is diminished,” she concluded. SF

For further information contact: Sharon Pruss Rare Diseases South Africa (RDSA) Cell: +27 83 292 5506 Office: +27 10 594 3844 Email: support@rarediseases.co.za