Contortionist Scarlet Checkers pulls at her facial skin, showing off its hyper-elastic tendency to over a million YouTube viewers. She may be a circus performer, but there’s no smoke and mirrors here — this is genuinely just what Checkers’ skin does naturally. She makes the most of her other anatomical deviations by performing the splits, dislocations and impressive backbending to delighted audiences.  

Checkers, from Philadelphia, was born with a form of Ehlers-Danlos syndrome (EDS), a genetic condition that affects collagen (the main component of connective tissue). Her extreme flexibility may have its benefits for her line of work, but it also comes with many disadvantages including chronic pain, exhaustion and frequent injury. 

The Ehlers-Danlos syndromes, of which there are 13, have historically been considered rare diseases — thought to affect just one in 5,000. But recently, doctors have learned that while 12 of the subtypes are genuinely uncommon, hypermobile EDS (hEDS) — also known as hypermobility spectrum disorder (HDS) — may affect far more people than first realised and cause seemingly unconnected problems besides joint hypermobility and stretchy, fragile skin.

“We use the acronym ‘Just GAPE’ which stands for problems with joints (and other soft tissues), gut disorders, allergy (and atopic disease and autoimmune disorders). The E stands for exhaustion because fatigue is increasingly recognised as a key characteristic of EDS,” says GP Dr Emma Reinhold, clinical champion for Ehlers-Danlos syndromes, explaining the wide range of symptoms now associated with the hypermobile form of the disorder. 

No presentation of EDS is the same. For some, the condition is relatively mild, while others have more severe symptoms that lead to profound disability. Recently, scientists have learnt that hEDS is associated with other serious events for some patients, including autonomic dysfunction, and the immunological condition mast cell activation syndrome (MCAS), which can result in anaphylaxis. 

“The analogy we use is that it’s like a smouldering fire. If you allow it to stay smouldering, it could spread to other parts of the body and burn out of control. But identify it early and get on top of it, and you may be able to prevent the very severe end of MCAS,” Reinhold explains. 

Unfortunately for EDS patients, early identification doesn’t happen very often — the median time to diagnosis is ten years from the first onset of symptoms. This is in part due to there being no definitive test to confirm someone has the condition. Instead it’s based on medical history and a physical examination. Reinhold, who has hEDS herself, was involved in developing a toolkit for the Royal College of GPs to increase awareness of the condition and help improve diagnosis rates in primary care. 

“Until you’ve actually got the label, so much is closed off to you,” she explains. “Often people get misdiagnosed with things like conversion disorder or anxiety instead.”

A recent report by Healthwatch England (a statutory body that addresses the needs of people who use health and social care services) confirmed patients with hypermobility-related disorders face huge difficulties getting a diagnosis and appropriate advice. 

While there’s currently no cure for EDS, there are options that can alleviate symptoms and prevent injury. From specialist physiotherapy and nutritional advice, to simple adjustments during routine medical procedures, outcomes for EDS patients are better if they’re given that label as early as possible.  

“Some of us end up using having to use a wheelchair, either because we're so knackered or because we have so many issues with our knees, hips and ankles by the time we’re diagnosed. But if you could identify EDS in childhood, different approaches could be taken that would prevent that long-term disability,” points out Reinhold.

The catch-22 is that if doctors think something is rare, they’re less likely to identify it. Medical students are taught ‘when you hear the sound of hooves, think horses, not zebras’. The ‘zebra’ represents a rare disease (defined as one affecting fewer than one in 2000 people). EDS charities around the world use a zebra logo to promote the idea that sometimes it really is that ‘rare’ condition. 

“It's a massively undiagnosed condition so it's stayed rare because people think it's rare. It becomes self-perpetuating,” Reinhold reveals. 

Her work in developing the GP toolkit did not go unnoticed though. Shortly after it was published, she received a personal message on Twitter from Dr Joanne Demmler, senior data analyst in the National Centre for Population Health and Wellbeing Research, based at Swansea University. Demmler was using statistical methods to try to determine the true prevalence of (and symptoms associated with) EDS, but needed Reinhold’s help with clinical definitions.

“When I saw the paper’s raw data I just thought 'oh my gosh, that is so exciting’. I knew I needed to help this work to get out there and be published,” Reinhold reveals.

The analysis, published in BMJ Open, showed roughly ten cases in 5,000 patients, significant because it pushes the disease out of the ‘rare’ category. And EDS was not only associated with musculoskeletal diagnoses but other diverse conditions too, including those affecting the nervous and digestive systems, and even mental health problems. 

“I got thinking: ‘well this is quite amazing’. It’s clearly a multisystemic disorder — it’s not just about muscles and having bruises and dislocating things. It's about a lot of different things,” reveals Demmler. 

The researchers also noticed a pronounced gender difference in the mean age of diagnosis. Men were diagnosed eight and a half years earlier on average than women. Women are naturally more hypermobile, which could contribute to the disorder being more frequently missed. And hormones do play a part in how the condition manifests. But Reinhold believes it is yet more evidence that women’s pain is less likely to be taken seriously by doctors. 

“Women are often dismissed by doctors, labelled as anxious or overdoing things. We really hope this work inspires people to come and ask a lot more questions and delve deeper,” she says. 

Crucially, hEDS losing its ‘rare’ status could trigger more funding to determine better methods of diagnosis and more effective treatment options for the condition. It will hopefully also galvanise research into the pathophysiology of the disease and why it causes such wide-reaching symptoms in the body. 

“Fingers crossed, this paper will open so many doors that would have been closed before,” says Reinhold.

Two billion of the world’s population living in low and middle income countries still do not have access to modern medicine. This is because “big pharma invariably lives in the first world” and “first tier countries still offer the lion’s share of their revenue stream,” CEO and founder of Masters Speciality Pharma Zulf Masters explains. Leveraging his own experience selling drugs in Latin America, Masters Speciality Pharma facilitates the supply of high-quality medicines to patients in need in the developing world.

Although it is clear that broadening access to medicine in poorer countries is not purely the responsibility of pharma companies, tangible progress cannot be achieved without them.

Compared to governments and supranational bodies, the pharma industry contains the only stakeholders who can develop and bring urgently needed new medicines to market on a large scale. This is because of their research and development (R&D) expertise and capability. It is simply not feasible for poorer countries to be able to develop and manufacture innovative products themselves on the necessary scale.

The Amsterdam-based Access to Medicine Foundation was founded in 2008 to build a consensus on the expectations on pharma companies regarding broadening access to medicine, as the not-for-profit’s research programme manager Danny Edwards explains. “Companies should be developing the right products for global health and then ensuring their availability and affordability in poorer countries.”

A decade after the creation of its index, the foundation performed a review of progress regarding access to medicine, concluding: “Compared with ten years ago, pharmaceutical companies are taking seriously the problems people face in low- and middle-income countries when accessing healthcare,” in the words of Access to Medicine Foundation executive director Jayasree K Iyer.

However, she cautioned: “The situation is still fragile – a retreat by one company, or a drop in healthcare investments, will jeopardise the progress made so far.”

Based on analysing the 20 largest research-focused pharma companies’ performance in 106 low and middle-income countries, the report found that pharma companies are changing how they do business to allow them to reach people in low-income countries.

There are now 17 companies setting goals and targets related to access to medicine, compared to eight in 2008, as well as seven more companies disconnecting bonuses from sales incentives to a total of nine.

Moreover, R&D pipelines have grown significantly in certain disease areas. Edwards highlights neglected tropical diseases as an example of a success story. “This is an area where we would have seen very little research 15 years ago, because there is no commercial incentive for pharma companies to engage,” he says. But over the past decades the number of projects has grown from 38 to 90; other examples are malaria, HIV/ADIS and tuberculosis – all of which are high-burden and priority diseases.

Edwards singles out Sanofi and Johnson and Johnson (J&J) for their work in R&D for neglected areas. Sanofi recently secured approval for fexinidazole for sleeping sickness, while J&J is developing a paediatric version of drug-resistant tuberculosis focused bedaquiline.

The review also identified that the three primary methods for furthering access – equitable pricing, voluntary licensing and drug donations – were being employed more frequently and with a heightened focus on access.

Gilead is a prime example of success in voluntary licensing. “They are particularly effective at engaging with generic manufacturers to boost scale, reach and coverage of their products,” says Edwards. They agree licensing terms for patented products so that they can be supplied more cost-effectively by other manufacturers. Edwards focuses on Gilead’s work on HIV, but Masters focuses on the company’s impressive record in Hepatitis C.

In terms of pricing, Edwards provides the example of Novartis Access where they offer a basket of 15 on and off-patent medicines targeting key non-communicable diseases; 14 of these are on the WHO’s list of essential medicines. The medicines are priced at $1 per treatment a month, and the approach is currently being rolled out across sub-Saharan African, Southeast Asia, Central America and Central and Eastern Europe.

The most progress is seen where multiple stakeholders are working in synergy, which Edwards notes is a particularly interesting finding of the review. He states that governments can contribute to the effort by setting research priorities and supporting the funding of research to create a “de-risking mechanism [which] tends to bring companies to the table”.

The Sanofi case study Edwards provides is a good example of multi-stakeholder efforts leading to success as the company worked the drugs for neglected diseases initiative on fexinidazole.

The need for a multiple actor approach is the central premise of Masters Speciality Pharma. Company CEO Zulf Masters explains the company provides a regulatory compliant and trustworthy partner; since it knows the corridors of power, it can facilitate relationships between companies and national governments and supranational bodies.

Other drivers noted by Edwards include “a marked shift in interest in [corporate social responsibility] from the investment community. It is not enough for companies to be interested only in commercial outcomes, they also need to be interested in social outcomes, such as sustainability and access to medicine. Companies are, of course, guided by the investment community”.

Further to this, “companies today find it really challenging to recruit talent unless they can tell a very compelling story about their engagement with these types of social outcomes”.

However, Masters thinks most companies are only paying lip service to corporate social responsibility, and instead pharma companies have moved towards a heightened focus on access to medicine because they have realised the enormous alternative revenue stream developing countries can bring. This is primarily due to the “sheer volume of people who are going to consume the products” so it will make up for a significant price reduction. The Access to Medicine Foundation records that 83% of the global population – around 6 billion people - live in low and middle-income countries.

Unfortunately, Edwards emphasised that “one of the interesting findings is that we do progress, but it is limited and concentrated.” Not only is the progress concentrated on certain disease areas, it also clustered in certain regions and five companies are carrying out almost two-thirds of the work; GSK, Johnson and Johnson, the German-based Merck group, Novartis and Sanofi.

This creates fragility because if “one of those companies decides to change direction, this would cause a huge dent in R&D, which is so badly needed for global health”.

This concentrated situation means “only a fraction of the people in need are benefitting from solutions for improving access – even though effective treatments and vaccines now exist,” Iyer wrote in a LinkedIn article.

However, this is not the only concern about the results of the not-for-profit’s ten-year review. Edwards notes that “on the whole registration performance is poor; [this] is the first key step to access. You can develop and new product and register with the Food and Drug Administration in the US or the European Medicines Agency, but if you’re not registering it in low and middle-income countries… there is [essentially] no access”.

This situation can largely be explained by continuing barriers to access – particularly in areas like Sub-Saharan Africa – which country governments and supranational bodies need to focus on rectifying if they want to encourage companies to do business there.

An example of a barrier to access is import taxes on drugs; Masters notes that this is the norm in some countries in Latin America – for example, Brazil and Colombia This creates a more complex access situation than in the first world. Where there is no VAT on medicines. Corruption and political instability are other problems, and these issues have actually caused “pharma to wholesale deregister products from certain geographies”.

Iyer notes: “Going forward, the big challenge for all of us working on access is to match the scale of action to the scale of the problem.”

“We see the success stories…the challenge [now is] to take the lessons we’ve learned [from] where it’s worked and scale that across other disease and into other countries,” Edwards explains.

Although Edwards notes more work needs to be done to ensure better access to poorer countries, such as Sub-Saharan Africa, resolving the access problem is much complicated than this; it is also necessary to focus on the poorer people in the richer middle-income countries.

“When we talk about the two billion [without access to medicines], it’s very easy to assume we mean Sub-Saharan Africa, but, a significant proportion, are in the wealthier middle income countries, such as Brazil, China, India, Pakistan, Nigeria and South Africa,” Edwards adds.

“I think in our next round of analysis…we’ll be taking a closer look at what access means to the poorest people in those middle income countries.”

Masters concludes pharma needs to continue to re-focus itself towards patients and the need to provide the same, high quality drugs in the developing world as in the first world.