27 November 2019

Referring severe asthma in the era of biologics

Research Respiratory

Just how much GPs are up to speed on the value of biologics in severe asthma was a key theme of series of Allergy and Asthma GP clinics held around Australia by the global not-for-profit group, Optimum Patient Care (OPC) last month.1

If you were to have listened at of these each workshops, held in Brisbane, Sydney and Melbourne, there appears to be a way to go yet before GPs recognise the who, when and how of biologics in asthma.

But perhaps that’s not all that surprising.

Uncontrollable, asthma-like symptoms, which may indicate severe asthma can also occur in people with non-severe asthma or non-asthma conditions such as  bronchitis, bronchiectasis, obesity, rhinitis. And then there are patients who appear to have uncontrollable symptoms, but rather than having severe disease are actually failing to follow to their prescribed management, and/or have poor inhaler technique.2 So sometimes identifying patients who have severe asthma who may be eligible for biologics may not be as simple as the eligibility criteria suggests – poor symptom control, frequent severe exacerbations, serious exacerbations including at least one hospitalisation in the past year, and airflow limitation (FEV1 ,80% predicted).3

In addition to all these complications, the drug treatment landscape for severe asthma is changing rapidly, with multiple new therapies recently becoming available in Australia, and more on the way next year.

Where is GP awareness on biologics?

OPC CEO Professor David Price has an opinion similar to that reflected in the workshops. He believes awareness of what biologics are and how they fit into clinical practices is still relatively low among Australian GPs.

“I don’t think they have clear pathways in their minds , or their best practice protocols yet,” he told The Medical Republic. He also thinks there is an issue with the categorisation of the severity of asthma, what constitutes control and who is at risk. He notes that “20% of asthma deaths occur in patients with ‘mild’ disease”.

Professor Pete Smith, from Griffith University and Bond University and a keynote at the OPC clinics, said: “While all patients are at risk, those patients receiving two or more courses of oral steroids for asthma flare-ups should be considered for [specialist] referral for two reasons: to reduce the risk of severe asthma exacerbations and to reduce the risk of oral corticosteroid (OCS) related side effects.”

According to Dr Greg King, a respiratory physician with the Woolcock Institute of Medical Research, identifying uncontrolled symptoms is key.

“Symptoms and bronchodilator-use [that occurs] more than weekly, or a history of exacerbations requiring prednisone once a year or more, despite regular use of ICS/LABA,” this represents poor control.

He concedes, it remains a challenge to differentiate poor control from poor treatment adherence, poor device technique or indeed whether the described symptoms are actually due to asthma. But experienced clinicians can usually discern, through history and examination if these other factors are contributing to the patient’s symptoms.

With regard GPs’ understanding  of the significance of the new biologics in treating severe asthma, Dr King is more positive.

“I believe GPs, in my area (the North Shore of Sydney) are very much aware of the value of biologics and severe asthma,” he tells The Medical Republic.

“In fact, I think biologics have changed or, in fact, made us think more about severe asthma, where previously, we had mostly been happy to keep with the status quo.

“This applies to GPs and specialists. [The advent of biologics for asthma treatment] has made us reassess the value of doing the ‘basics’ well and thoroughly. I believe that even in the age of biologics and high tech therapy, that the basics are very important, perhaps even more important than before.”

Dr Joy Lee, a respiratory physician from Melbourne believes the degree of GP understanding tends to vary depending on patient populations.

“Many of our GPs are looking after our severe asthma patients. They see them on a regular monthly, sometimes fortnightly basis to administer or supervise their biologics,” she tells The Medical Republic.

“Unlike in other health networks (e.g. UK) where the majority of biologics are given in the hospitals, many asthma centres (here in Victoria at least) are trying as a priority to involve the GPs in the ongoing treatment of our patients in a shared care model.

“Once a severe asthma patient is stabilised on regular biologic therapy, they may only need to attend the hospital severe asthma clinic every six months for review.  In saying this, GPs who have not had any exposure/or patients treated with biologics may not have much knowledge with regards to who may qualify and who should be referred.

Dr Lee estimates that up to only half of GPs are suitably up to speed today on biologics and the latest trends in severe asthma treatment.

“Many are perhaps too accepting or complacent of patients with asthma having treatment with several courses of oral corticosteroids per year or emergency department presentations for exacerbations,” she says.

Somewhere between 3% and 11% of asthma sufferers will suffer from severe asthma, although these are international estimates. Australian rates are still not well known.

The Australian Asthma Handbook4 defines severe asthma as “asthma that remains uncontrolled despite maximal standard treatment, or which can only be controlled with such treatment.”

But, as mentioned earlier assessment needs to also include an assessment for possible confounding factors such as adherence, inhaler techniques and exposure to environmental factors such as cigarette smoke.4

Up to date information is widely available

While it seems GP understanding  of this issue still has a way to go, the problem is not a lack of available information. Australian peak organisations have been diligent on providing important, timely and comprehensive updates on the use of biologics in severe asthma.

The National Asthma Council published a comprehensive information paper earlier this year5, the Centre for Excellence in Severe Asthma has just celebrated the first anniversary of its comprehensive and globally-used Severe Asthma Toolkit, with a series of updates2, the RACGP has recently published a comprehensive review of the topic in its Australian Journal of General Practice6 and the MJA published on the topic in July last year.7

There is plenty of up-to-date information available. What’s needed is for that information to be absorbed and put into GP clinical practice. Says Professor Price: “Where once the need to defer to a specialist may have been seen as a failure of treatment by the GP, now it should probably be viewed as a measure of effectiveness in diagnosis.”

Where the ‘wild ones’ are?

Another issue highlighted at the OPC seminars was the need to identify patients with supposedly “mild” asthma who self-treat using over-the-counter relievers to manage their condition. They simply increase their inhaler use when symptoms occur more frequently or more severely and don’t even see a doctor. Professor Price says such patients are literally “out in the wild”.

“As a GP, how am I meant to find these at-risk patients? Am I meant to be recalling all my ‘milds’?”, says Professor Price.

Professor Price says GPs need to be alert for patients with a history of asthma, even if these patients are presenting with a comorbid condition. There is also a role for pharmacy and more public education.

Clinical audits can also help. Professor Price points to the OPC asthma audit tool for GPs8 as an example of practical tool that can help educate both the GP and assist with better patient health outcomes.

In this case OPC installs a data collation tool to identify asthma patients within a practice, and notes their current management.  The de-identified, privacy-compliant data is analysed, and a report is generated. This report provides feedback to GPs on key aspects of asthma management in the practice.

In addition, Dr Lee suggested, an alert system built into GP patient software could be of use in identifying some of these “wild ones”, by alerting the doctor, prior to the consultation, which patients have ever had a diagnosis of asthma.

“Pharmacies could also assist by recommending all patients  who purchase Ventolin inhalers OTC see their GP to discuss their asthma control,” she says.

‘Killer blue inhalers’

On the issue of OTC preventers, Professor Smith, who hails from the UK where preventers are still restricted medicine, says Australia is one of the few countries where a SABA can be bought directly at a pharmacy.

While the reasoning behind the move was sound, namely to provide ready access to urgent rescue therapy,  it has unfortunately evolved into a “perpetual bad habit” in some patients.

“SABAs alone can be dangerous”, he says, pointing to the internationally-recognised GINA guidelines that now say that to reduce the risk of serious exacerbations, all adults and adolescents with asthma should  be treated with inhaled corticosteroid (ICS)-containing treatment either when symptoms occur (as in mild asthma) or on a daily basis (for more severe asthma).9 Budesonide-formoterol (Symbicort) recently received TGA and PBS approval for use in mild asthma in Australia.

Not long after the GINA guidelines were published, Ventolin was given the tag “killer blue inhaler” in an opinion piece by a UK expert in The Lancet.10 The controversy has continued, increasing the pressure on authorities to reduce accessibility to SABAs.

Dr Lee suggests SABAs may need to be rescheduled in Australia to reduce their availability.

“The OTC availability of Ventolin means that is not regulated, and patients can go to any chemist, multiple times a week or month to purchase multiple inhalers frequently without it ever being flagged that the patient’s asthma management control should be checked,” Dr Lee says.

As new guidelines suggest a move away from Ventolin-only treatment of asthma and move toward greater use of a reliever and ICS combination treatment, there exists an inconsistency to Ventolin but not ICS readily available over the counter.

Timing and if ‘the price is right’

It’s no secret that biologics aren’t a cheap treatment option. And as biologics in respiratory medicine have only been around a short amount of time, biosimilars aren’t even due to be in play for a few years.

The cost issue brings into play some other important dynamics around referral.  Can patients afford them and even if they can, given that they aren’t disease modifying, they are for control, are they going to be worth such a long-term investment?

The  PBS conditions around prescribing biologics are restrictive. The government wants to make certain that there is no waste. Before being eligible for a PBS subsidy a patient must have either been treated by the same specialist for the last six months, or less than six months if have been diagnosed by a multidisciplinary asthma clinic team which must include a respiratory specialist.11

Patients who attempt to self-fund can be up for costs of between $450 and more than $1600 per month depending on which biologic they are prescribed.1

Says Professor Smith: “We need to consider pretty carefully patients we put on biologics in terms of cost, effectiveness, and importantly, long-term ability to comply
and pay.”

Once a patient has been assessed at the specialist level and started on one of the three available biologics in Australia (benralizumab, mepolizumab and omalizumab) it is important that the patient’s GP is involved.

After the initial three doses, treatment can be returned to the GP care setting but to remain eligible for continuing PBS biologic access a patient must be reviewed the specialist every five to six months.6

Patients on monoclonal therapy require the usual asthma care from their GP, and need to keep taking their ICS regularly. They should also be made aware that flare ups can still occur while on biologic therapy.5

Still some black holes

Most experts will attest to how  the biologics have changed the lives of patients suffering from severe asthma. And the repercussions of their effectiveness in these highly atopic individuals is extending.  Nasal polyps, often associated with severe allergic asthma, are dramatically responding to these new treatments.

“Professor Simon Carney, an ENT Surgeon from Flinders University in Adelaide feels that biologics have a very real role in patients with nasal polyps and asthma. In patients who continue to struggle with polyps and their asthma, despite adequate sinus surgery, biologics do represent the “holy grail” for these patients who would otherwise need to be on long-term oral steroids.”

But big issues remain in that they are not universally appropriate of effective.

Current biologics are targeted at eosinophilic asthma which only applies to about half of all asthma sufferers.2

“There remains a huge black hole in our treatments for the other half of patients whose disease is driven by non-allergic mechanisms”,  Dr King says.

New biologics on the horizon which may also be effective in non-type 2 immune response asthma.
“Clearly, more research is needed in this area. There are going to be more biologics and other non-ICS based therapies coming out and I think it is very important that GPs improve the knowledge about these newer treatments. In doing so, I believe that the general knowledge around managing asthma and most importantly, assessing asthma, will improve,” Dr King says.

References:

OPC Asthma and Allergy Seminar Series, Sydney, Melb, Brisbane, Sept-October 2019.

Severe Asthma Toolkit, updated 2019 https://toolkit.severeasthma.org.au/, ‘Diagnosis & Assessment’

Chung FK, et al, International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma, European Respiratory Journal 2014 43: 343-37

The Australian Asthma Handbook, https://www.asthmahandbook.org.au/

Katelaris, C, Mcdonald V, et al, 2019 , Monoclonal antibody therapy for Severe Asthma, Information paper for HCPs, National Asthma Council Australia

Meyers J, Yoo J, Reddel H, Difficult to treat and severe asthma in adults: Towards a new treatment paradigm, AJGP, 48 (4), 2019

Upham JW & Ping Chung L, Optimising treatment for severe asthma, MJA, 2018: 209 (2) s22-s27

https://optimumpatientcare.org.au/quality-improvement/asthma-clinical-review/

GINA Guidelines, 2019, https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf

Bush, A. Preventing asthma deaths: above all, do no harm. Lancet Respiratory Medicine, June 25 http://dx.doi.org/10.106/s2213-2600(19)30197-3

PBS Schedule, Aust Govt Dept of Health, March 2018