Glaucoma may be an autoimmune disease

Glaucoma, a disease that afflicts nearly 70 million people worldwide, is something of a mystery despite its prevalence. Little is known about the origins of the disease, which damages the retina and optic nerve and can lead to blindness.

A new study from MIT and Massachusetts Eye and Ear has found that glaucoma may in fact be an autoimmune disorder. In a study of mice, the researchers showed that the body’s own T cells are responsible for the progressive retinal degeneration seen in glaucoma. Furthermore, these T cells appear to be primed to attack retinal neurons as the result of previous interactions with bacteria that normally live in our body.

The discovery suggests that it could be possible to develop new treatments for glaucoma by blocking this autoimmune activity, the researchers say.

“This opens a new approach to prevent and treat glaucoma,” says Jianzhu Chen, an MIT professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study, which appears in Nature Communications on Aug. 10.

Dong Feng Chen, an associate professor of ophthalmology at Harvard Medical School and the Schepens Eye Research Institute of Massachusetts Eye and Ear, is also a senior author of the study. The paper’s lead authors are Massachusetts Eye and Ear researchers Huihui Chen, Kin-Sang Cho, and T.H. Khanh Vu.

Genesis of glaucoma

One of the biggest risk factors for glaucoma is elevated pressure in the eye, which often occurs as people age and the ducts that allow fluid to drain from the eye become blocked. The disease often goes undetected at first; patients may not realize they have the disease until half of their retinal ganglion cells have been lost.

Most treatments focus on lowering pressure in the eye (also known as intraocular pressure). However, in many patients, the disease worsens even after intraocular pressure returns to normal. In studies in mice, Dong Feng Chen found the same effect.

“That led us to the thought that this pressure change must be triggering something progressive, and the first thing that came to mind is that it has to be an immune response,” she says.

To test that hypothesis, the researchers looked for immune cells in the retinas of these mice and found that indeed, T cells were there. This is unusual because T cells are normally blocked from entering the retina, by a tight layer of cells called the blood-retina barrier, to suppress inflammation of the eye. The researchers found that when intraocular pressure goes up, T cells are somehow able to get through this barrier and into the retina.

The Mass Eye and Ear team then enlisted Jianzhu Chen, an immunologist, to further investigate what role these T cells might be playing in glaucoma. The researchers generated high intraocular pressure in mice that lack T cells and found that while this pressure induced only a small amount of damage to the retina, the disease did not progress any further after eye pressure returned to normal.

Further studies revealed that the glaucoma-linked T cells target proteins called heat shock proteins, which help cells respond to stress or injury. Normally, T cells should not target proteins produced by the host, but the researchers suspected that these T cells had been previously exposed to bacterial heat shock proteins. Because heat shock proteins from different species are very similar, the resulting T cells can cross-react with mouse and human heat shock proteins.

To test this hypothesis, the team brought in James Fox, a professor in MIT’s Department of Biological Engineering and Division of Comparative Medicine, whose team maintains mice with no bacteria. The researchers found that when they tried to induce glaucoma in these germ-free mice, the mice did not develop the disease.

Human connection

The researchers then turned to human patients with glaucoma and found that these patients had five times the normal level of T cells specific to heat shock proteins, suggesting that the same phenomenon may also contribute to the disease in humans. The researchers’ studies thus far suggest that the effect is not specific to a particular strain of bacteria; rather, exposure to a combination of bacteria can generate T cells that target heat shock proteins.

One question the researchers plan to study further is whether other components of the immune system may be involved in the autoimmune process that gives rise to glaucoma. They are also investigating the possibility that this phenomenon may underlie other neurodegenerative disorders, and looking for ways to treat such disorders by blocking the autoimmune response.

“What we learn from the eye can be applied to the brain diseases, and may eventually help develop new methods of treatment and diagnosis,” Dong Feng Chen says.

The research was funded by the National Institutes of Health, the Lion’s Foundation, the Miriam and Sheldon Adelson Medical Research Foundation, the National Nature Science Foundation of China, the Ivan R. Cottrell Professorship and Research Fund, the Koch Institute Support (core) Grant from the National Cancer Institute, and the National Eye Institute Core Grant for Vision Research.

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Story Source:

Materials provided by Massachusetts Institute of Technology. Note: Content may be edited for style and length.

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Journal Reference:

1. Huihui Chen, Kin-Sang Cho, T. H. Khanh Vu, Ching-Hung Shen, Mandeep Kaur, Guochun Chen, Rose Mathew, M. Lisa McHam, Ahad Fazelat, Kameran Lashkari, Ngan Pan Bennett AU, Joyce Ka Yu TSE, Yingqian Li, Honghua Yu, Lanbo Yang, Joan Stein-Streilein, Chi Him Eddie Ma, Clifford J. Woolf, Mark T. Whary, Martine J. Jager, James G. Fox, Jianzhu Chen, Dong F. Chen. Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma. Nature Communications, 2018; 9 (1) DOI: 10.1038/s41467-018-05681-9

https://bit.ly/2MDX2OG

Small firm workers in high-deductibles get less help with out-of-pocket costs

• Employees in small companies with high-deductible health plans are at a disadvantage compared to people who work for larger companies, according to a new report in Health Affairs.
• The study by Agency for Healthcare Research and Quality researchers found that more than three-fourths of HDHP enrollees in small companies didn’t have an employer-funded account that helps them pay for out-of-pocket costs. Slightly more than two-thirds of those at large companies have such accounts.
• The common HDHP traits of lower healthcare use and higher financial burdens are more of a concern for people working for small companies, the authors said.

HDHPs have become a standard benefit design for employers and payers. They made up only 11% of employer-sponsored members in 2006, but that percentage jumped to more than 46% in 2016. The plans have successfully contained health costs by shifting more costs onto members, but they haven’t pushed people to become better healthcare consumers.

HDHPs have helped bend the health insurance cost curve. A recent Mercer survey found that employer-sponsored health insurance costs have increased about 3% annually since 2012. That’s compared to yearly increases of at least double that the previous decade.

But the cost shift has left patients with larger healthcare bills. It’s only a matter of time before health coverage becomes unaffordable on that path. With that in mind, Mercer said employers are eyeing other cost-saving strategies over the next five years, including monitoring and managing high-cost claimants, better managing cost for specialty pharmacy and focusing on creating a culture of health.

The new study, which used the Medical Expenditure Panel Survey – Insurance Component data from 2006 to 2016, found that HDHP enrollees in the biggest companies have “significant advantages” compared to people in small companies. These advantages included employer-funded accounts, alternative plan options, deductible levels and choice of providers.

The researchers found that employer contributions to health savings accounts (HSAs) and health reimbursement arrangements (HRAs), which members use to pay for shouldering more healthcare costs, are lacking for small employers. In 2006, small companies were more likely to provide an HSA or HRA than a large company, but now large companies that have at least 1,000 employees are much more likely to offer one of those savings accounts.

Overall, the study found that an HDHP covered 23% of employer-sponsored enrollees in 2016 that had an employer-funded account. Most of those were HSAs, which allow the employee to take the money with them when they leave. With HRAs, however, the companies own account and the employee loses the money when they leave the job.

Large companies with HDHPs also had much lower deductibles for individual plans than smaller companies ($2,154 mean deductible for large companies and between $2,717 to $2,801 for smaller companies). Family coverage was much of the same — $4,280 for large companies and $5,173 to $5,873 for smaller businesses.

The report also found that larger companies have a higher percentage of employees in preferred provider organization (PPO) plans. Plus, employees in small companies are more likely to have only an HDHP option. That leaves no choice for consumers.

“Consistent with other studies, we also found that the percentage of enrollees in PPOs generally increased with firm size for all non-HDHP and HDHP enrollees, including those with and without employer-funded accounts. And we found that within each firm size category, non-HDHP enrollees were less likely than HDHP enrollees to be in a PPO,” the researchers added.

https://bit.ly/2nnveTX

Boston Children’s expands gene sequencing of patients with epilepsy, IBD

• Boston Children’s Hospital is set to sequence the DNA of 3,000 people to better understand epilepsy and inflammatory bowel disease (IBD).
• The initiative aims to generate insights into disease pathways and find novel drug targets, while also improving the care of the sequenced patients.
• Boston Children’s is working with GeneDx and WuXi NextCODE to sequence the DNA and interpret the resulting data.

Understanding of the genetic drivers of epilepsy and IBD has advanced apace over the past decade. Through genetic sequencing initiatives, researchers have linked mutations in the protein coding gene ADCY7 to IBD, identified PRRT2 as a factor in the benign familial infantile form of epilepsy and made many other discoveries.

These advances have started to influence patient care. Yet, knowledge of disease pathways remains incomplete and the translation of scientific advances into breakthrough treatments is just starting to gather pace. To take epilepsy as an example, more research into the mechanistic links between genes and seizures is needed, as are efforts to classify variants and translate findings into clinical care.

Boston Children’s wants to contribute to these efforts. Having set up an epilepsy genetics program at the start of the decade, Boston Children’s is now expanding the initiative to accelerate the pace of scientific progress and step up its interest in IBD.

The pediatric hospital already performs genetic tests, such as chromosomal arrays and gene panels, on patients who are suffering from seizures. In some cases, these efforts fail to yield a diagnosis. The expanded sequencing initiative is focused on this subset of patients. With the initial screening effort failing to make a diagnosis, Boston Children’s will perform a broader analysis of the patient’s DNA.

Boston Children’s has two ambitions for the program. The main goal is to improve understanding of the genetic causes of epilepsy and IBD and identify possible ways to improve treatment. However, as the work will take place at a CLIA-certified lab, the results will also inform the care of the patient who undergoes sequencing.

The initiative will leverage Boston Children’s ties to the industry and existing genomics infrastructure. The hospital has operated a genomics platform built on WuXi NextCODE’s technology since 2016, and will use the service provider’s tools to interpret variants and perform other analyses in its latest initiative. Long-running genetic testing company GeneDx will perform the sequencing.

https://bit.ly/2KFDTKv

FDA found problems a year ago at China plant now recalling tainted valsartan

An FDA inspection of the Zhejiang Huahai Pharmaceutical plant a year ahead of its global recall of tainted heart drug valsartan found a plant with little regard for quality control and which blamed out-of-specification test results on “ghost peaks,” lab errors and environmental pollution.

The plant repeatedly reanalyzed API batches to achieve passing results, even when tests showed a “large differential,” then shipped them to the U.S. without ever investigating why the out-of-spec results occurred in the first place. The problems were laid out in a highly redacted FDA Form 483 just posted by the FDA which stemmed from a May 15, 2017, inspection.

In July, the European Medicines Agency announced that Huahai had informed it had identified N-nitrosodimethylamine (NDMA), a chemical that might lead to cancer, in the valsartan provided to the European market.

The drugmaker instigated a voluntary recall in Europe and Asia of affected API batches as did drugmakers like Teva’s Actavis, Stada and Dexcel Pharma, which has used the ingredient in their finished products. It said the impurity appeared to be the result of a manufacturing change.

Since then the the FDA has identified more than a dozen products in the U.S. with the impurity that are being recalled. It updated the list today, adding Hetero Labs, labeled as Camber Pharmaceuticals. In a previous update, the FDA said its investigation into the situation found the tainted ingredient may have been on the market for years.

“Based on records from the manufacturer of the recalled valsartan, some levels of the impurity may have been in the valsartan-containing products for as long as four years,” the agency said.

But it also pointed out that FDA scientists estimate that if 8,000 people took the highest valsartan dose (320 mg) from the recalled batches every day for the full four years, there may be one additional case of cancer over the lifetimes of those 8,000 people. “This assessment led to FDA’s decision to have these batches recalled,” the agency said.

Among other issues reported in the Form 483, the FDA said that the Chinese company was not consistently quantifying or documenting impurities found in analytical testing. It also said equipment was not thoroughly cleaned, with paint pieces found on some.

https://bit.ly/2vDZCOu

Lundbeck brings third Parkinson’s drug into clinic

Denmark’s Lundbeck is bringing a third potential drug for Parkinson’s disease to the clinic – a human antibody that the company hopes will tackle the underlying cause of the condition.

The compound known as Lu AF82422 was invented by Lundbeck in collaboration with Genmab, the company that also developed Janssen’s blood cancer drug Darzalex (daratumumab).

According to Lundbeck Lu AF82422 is a human antibody targeting the toxic proteins causing the death of the dopamine-producing brain cells that leads to Parkinson’s disease.

The compound is thought to work like the body’s natural antibodies when the immune system works to remove harmful proteins.

As it targets the underlying biology of the disease, Lu AF82422 may potentially not only treat its symptoms, but might also slow or stop its progression.

The first ever antibody that Lundbeck has brought into clinical development, in the phase 1 study it will be studied in both healthy volunteers and patients with Parkinson’s disease.

Lundbeck has already added two other potential Parkinson’s drugs to its pipeline this year: Lu AF28996 and foliglurax. The Danish pharma also began developing Lu AF764323 for schizophrenia and Alzheimer’s disease this year.

There is a desperate need for new drugs for Parkinson’s – with only a handful of drugs being approved in the last decade.

Sunovion’s under-the-tongue film APL-130277 is close to the market, after hitting its target in a late-stage trial by improving motor function compared with placebo.

The FDA last year approved Newron’s Xadago (safinamide) as an add-on treatment for patients taking levodopa/carbidopa and are experiencing “off” episodes, following a five-year battle with the regulator. Xadago was approved in Europe in 2015.

Acadia’s Nuplazid, which treats hallucinations and delusions caused by the disease, was FDA-approved in 2016 but there are concerns about its safety.

UK biotech e-Therapeutics this year began working with genomics firm C4X Discovery to develop new therapies for Parkinson’s.

https://bit.ly/2vE8rYr

US start-up launches bilingual healthcare app

HoyHealth, an innovative health-tech start-up has launched HoyDoc, smartphone application that connects patients to medical providers through a bilingual telemedicine platform.

HoyDoc has been developed for patients seeking remote and affordable healthcare access in their own language. The medical advice is currently available to registered users in English and Spanish.

The mobile app allows direct connection between patients and healthcare providers from anywhere in the US and additionally will allow users to store their health records securely in their smart devices.

Mario Anglada, chief executive officer at Hoy Health, said: “The HoyDOC mobile app gets us one step closer to providing a complete primary health bilingual ecosystem and one step closer to fulfilling our mission of providing accessible and affordable healthcare to everyone, everywhere.”

HoyDOC mobile application can be downloaded for iOS and Android devices and is powered by the PrognoCIS patient portal, offering secure service compliant with the heath data acts and guidance in the US.

The company did not reveal if medics will be able to issue prescriptions over the phone and how the referral will be sent to the second-level specialist care work.

It is not yet certain what services will be available for patients aside the fact that the application users will be able to speak directly with doctors, nurses, psychologists and a variety of other healthcare related professionals.

But the New Jersey digital healthcare start-up said in a statement that the app should allow to resolve more than 80% of the common problems that are seen at a clinic.

According to the American Well 2015 Telehealth Survey, 64% of the US population favour an appointment via video connection over more traditional clinic visits.

Telemedicine and remote patient monitoring continue to expand significantly. In the US the market value is estimated to hit $36.2 billion by 2020, which is more than double of the 2014 estimation.

The popularity of “virtual doctors” spreads around the world in a record time. Just last year England’s national healthcare provider trialled GPatHand mobile application, which quickly gained thousands of NHS patients in London.

Despite inquiries and uncertainties about the application in the UK, the developer, Babylon Health, is already operating its services in Rwanda and signed commercial agreements with e-commerce giant in China and global insurance company.

https://bit.ly/2M9xk8B

Online pharmacies putting profit before patients – BBC documentary

A BBC programme “Online Doctors Uncovered” revealed online pharmacy “sites putting profit before patient care” and highlighted the ease with which patients can obtain prescription-only medicines from “very dangerous” websites.

The programme and investigation led by Dr. Faye Kirkland, a GP and journalist, exposed a number of online prescribing sites which the BBC claimed are taking advantage of a regulatory loophole by using companies based outside of the UK to employ doctors.

As part of the programme, two volunteers obtained prescription only co-codamol and slimming pill Xenical (orlistat) – which the BBC claimed their GPs would be “highly unlikely” to prescribe.

Both volunteers were able to buy the medicines online by submitting false medical histories on sites online forms and finalising the purchase through a Romanian-based payment system.

Steve Field, chief inspector of General Practice at the Care Quality Commission (CQC), told BBC that websites that it does not regulate can be “very dangerous”.

However, the CQC currently has no jurisdiction over organisations registered outside England, and Field called for a “change in the law” to crack down on “services that offer care into England but are based abroad – and the risks that this can pose”.

A online pharmacy, based in Nottingham, UK Meds, also came under fire after a former opiate addict was able to order 100 dihydrocodeine tablets, while another ordered the highest strength of pregabalin – a drug the BBC claimed is becoming “increasingly abused”.

The BBC discovered that “UK Meds cannot be regulated by the CQC because it hires doctors to do consultations and prescriptions through its sister company EU General Practitioners in Romania.”

In its response, UK Meds said it complies with all regulations from the Medicines and Healthcare products Regulatory Agency and General Pharmaceutical Council (GPhC), but “the company is not required to be registered by the CQC”.

Duncan Rudkin, chief executive of the GPhC,commented in a statement released after the programme was aired: “We are playing our part, along with other regulators in strengthening the safeguards in place for patients and the public through our regulation of pharmacies and pharmacy professionals in Great Britain.”

“We are currently seeking views about the actions that online pharmacy owners in Great Britain would be expected to take to make sure people obtain medicines safely online. This is a rapidly changing area and we want to make sure we are addressing all the issues, so we would encourage people to respond to our consultation.”

A CQC report on England-based online primary care services published earlier this year found that while there had been strong improvement in many aspects of service provision since the previous round of inspections, 435 were still not providing a satisfactory level of care with inappropriate prescribing of medicines quoted as a particular cause for concern.

https://bit.ly/2vyaixY