Posted on Rheumatoid arthritis

Common workplace fumes and dusts may heighten rheumatoid arthritis risk

Breathing in common workplace dusts and fumes from agents such as vapours, gases, and solvents, may heighten the risk of developing rheumatoid arthritis, suggests research published online in the Annals of the Rheumatic Diseases.

What’s more, they seem to boost the detrimental impact of smoking and genetic susceptibility to the disease, the findings indicate.

Rheumatoid arthritis (RA) is a chronic autoimmune joint disorder characterised by painful and disabling inflammation. It affects up to 1% of the world’s population.

While it’s known that cigarette smoking increases the risk of developing rheumatoid arthritis, it isn’t known what impact breathing in workplace dusts and fumes might have.

In a bid to find out, the researchers drew on data from the Swedish Epidemiological Investigation of RA. This comprises 4033 people newly diagnosed between 1996 and 2017 and 6485 others matched for age and sex, but free of the disease (comparison group). 

Personal job histories were provided and used to estimate the amount of individual exposure to 32 airborne workplace agents, using a validated technique. 

Each participant was assigned a Genetic Risk Score (GRS), according to whether they carried genes that could increase their chances of developing rheumatoid arthritis.

Rheumatoid arthritis is characterised by the presence or absence of anti-citrullinated protein antibodies or ACPA for short. ACPA positivity denotes a worse prognosis with higher rates of erosive joint damage.

Nearly three quarters of those with rheumatoid arthritis testing positive (73%) and negative (72%) for ACPA had been exposed to at least one workplace dust or fume compared with around two thirds (67%) of people in the comparison group.

Analysis of the data showed that exposure to workplace agents was not only associated with a heightened risk of developing rheumatoid arthritis, but also seemed to boost that risk further by interacting with smoking and genetic susceptibility.

Exposure to any workplace agent was associated with a 25% heightened risk of developing  ACPA positive rheumatoid arthritis, overall. And this risk increased to 40% in men.

Specifically, 17 out of 32 agents, including quartz, asbestos, diesel fumes, gasoline fumes, carbon monoxide, and fungicides, were strongly associated with an increased risk of developing ACPA positive disease. Only a few agents—quartz dust (silica), asbestos, and detergents—were strongly associated with ACPA negative disease.

The risk increased in tandem with the number of agents and duration of exposure, with the strongest associations seen for exposures lasting around 8–15 years. Men tended to have been exposed to more agents, and for longer, than women. 

‘Triple exposure’ to a workplace agent, plus smoking, plus a high GRS, was associated with a very high risk of ACPA positive disease, ranging from 16 to 68 times higher, compared with ‘triple non-exposure’. 

In particular, the risk of developing ACPA positive rheumatoid arthritis for the triple exposed was 45 times higher for gasoline engine exhaust fumes, 28 times for diesel exhaust, 68 times higher for insecticides and 32 times higher for quartz dust (silica). The corresponding range for ACPA negative disease wasn’t significant.

This is an observational study, and as such, can’t establish cause. The researchers also acknowledge several limitations to their findings: the study relied on personal recall; and while the exposure estimates were derived using a validated method, the results can be relatively crude.

And given that there are often several workplace agents in the air at any one time, it is difficult to pinpoint which ones might be the potential triggers.

Nevertheless, the researchers conclude:“Occupational inhalable agents could act as important environmental triggers in RA development and interact with smoking and RA-risk genes, leading to excessive risk for ACPA-positive RA.” 

They add: “Our study emphasises the importance of occupational respiratory protections, particularly for individuals who are genetically predisposed to RA.” 

The study findings have several important implications for disease development and prevention, notes Dr Jeffrey Sparks, of Brigham and Women’s Hospital, Boston, USA, in a linked editorial. 

“First, each occupational inhalable agent had a unique profile of the way it interacted with RA risk genes and with smoking….These unique interactions suggest that if the relationship between inhalable agents and RA is indeed causal, they may do so via distinct pathways.”

Alluding to the stronger associations found for ACPA positivity, Dr Sparks comments that the findings further support the growing belief that ACPA positive disease may be very different from ACPA negative rheumatoid arthritis.

Greater public health efforts are needed to curb the risk of developing rheumatoid arthritis, he concludes.

“First, environmental health initiatives should reduce public exposure to ambient pollutants, including carbon monoxide and gasoline exhaust. Second, occupational health initiatives should mitigate occupational hazards, including detergents and asbestos. Third, public health initiatives should continue to reduce cigarette smoking,” he writes.

Posted on Multiple Sclerosis

Immunotherapy eliminates disease-causing cells in mice with MS-like disease

The cancer therapy known as CAR-T has revolutionized treatment of some blood cancers since it was introduced in 2017. The therapy uses genetically altered immune cells to home in on cancer cells and destroy them.

Now, studying mice with an autoimmune disease similar to multiple sclerosis (MS), researchers at Washington University School of Medicine in St. Louis have shown that the same approach can be used to eliminate unwanted cells that cause autoimmunity. The findings, available online in Science Immunology, extend the powerful tool of immunotherapy to a class of diseases that are often debilitating and difficult to treat.

“We were able to use CAR-T cells to eliminate just the immune cells that are causing the autoimmunity and not other immune cells you might need to protect against viruses or other infection,” said co-senior author Chyi-Song Hsieh, MD, PhD, the Alan A. and Edith L. Wolff Professor of Rheumatology and a professor of medicine and of pathology & immunology. “Our CAR-T cells were very effective at treating mice that have an MS-like disease.”

At the heart of CAR-T therapy are the immune system’s T cells, crucial elements of the body’s defense force. T cells respond to threats such as bacteria, viruses and cancerous cells by coordinating an immune assault and killing foreign organisms and infected or cancerous cells.

But every once in a while, T cells mistake healthy cells for infected cells and turn their weapons on the body’s own cells and tissues, triggering an autoimmune disease. MS is marked by rogue T cells that trigger the destruction of myelin, the protective covering over nerves. As myelin is eaten away, communication between the brain and spinal cord and the rest of the body becomes unreliable, and people begin experiencing symptoms such as fatigue, pain, tingling, vision problems and loss of coordination. Immunosuppressive drugs can quash the self-destructive activity of rogue T cells, but such drugs also suppress helpful T cells and put people at risk of severe infections.

In CAR-T cancer therapies, doctors take a patient’s own T cells, modify them to recognize and vigorously attack his or her specific cancer, and then put them back in the body on a seek-and-destroy mission. Inspired by this approach, the researchers set out to create CAR-T cells equipped to seek out and destroy the rogue T cells that cause MS. The idea was to make CAR-T cells that would function akin to a police department’s internal affairs office, rooting out the bad apples in the T cells defense force while leaving good T cells in place to protect the body.

“Having MS can really erode your quality of life, and while current therapies slow down the course of the disease, they don’t cure it and they have side effects,” said co-senior author Gregory F. Wu, MD, PhD, an associate professor of neurology and of pathology & immunology. “I believe that this is a fully treatable disease, and CAR-T cells may be the way toward much better therapeutics.”

Along with Hsieh and Wu, the research team included co-authors Nathan Singh, MD, an assistant professor of medicine, and Takeshi Egawa, MD, PhD, an associate professor of pathology & immunology.

First, the researchers made some bait. They designed a molecule by combining a fragment of a protein found in myelin with a protein that activates T cells. Only T cells that target myelin — the bad apples, so to speak — would respond to this hybrid molecule. Then, they loaded the bait molecule onto a kind of T cell known as killer T cells. Any rogue T cells that took the bait would be eliminated by the killer T cells.

That was the idea, at least. To see whether it worked, the researchers turned to mice with an MS-like condition. Treating such mice with the engineered CAR-T cells prevented disease in those that had yet to develop problems, and reduced signs of disease in those that were already showing neurological effects.

“We’re working on improving the CAR-T cells, to get them to kill more efficiently and last longer so that we can get better treatment outcomes,” Hsieh said. “Right now, there’s no way to tell who is going to get MS or when, so preventing disease in people isn’t realistic, but we could treat it, and I think the CAR-T approach looks very promising.”

The beauty of the CAR-T approach is that by swapping out the protein fragment in the bait molecule, killer T cells can be redirected toward different rogue immune cells to treat different diseases.

“I see patients in the clinic who have a rare disease known as myelin oligodendrocyte glycoprotein (MOG) antibody disease that is very similar to MS,” Wu said. “Unlike MS, which is complicated, we know exactly what the target is in MOG antibody disease. I wish I could just get rid of these self-reactive cells for my patients, but we’ve had no way to do that. Now, we are working toward using the patient’s own immune cells to create CAR-T cells that would eliminate those self-reactive T cells.”

Posted on Rheumatoid arthritis

Trial compares therapies for reducing cardiovascular risk among people with rheumatoid arthritis

People with rheumatoid arthritis are at increased risk of cardiovascular (CV) disease, with studies indicating an approximate 50 percent increase in risk of CV events such as heart attack and stroke. Some immunomodulators—drugs that decrease inflammation—have been shown to reduce CV risk in the general population. Researchers from Brigham and Women’s Hospital led a consortium that conducted a randomized clinical trial among people with rheumatoid arthritis to assess the impact of two anti-inflammatory strategies. All 115 patients in the trial had moderate or high disease activity despite being on low-dose methotrexate. Participants continued to take methotrexate and were randomized to additionally receive a TNF inhibitor (TNFi) or hydroxychloroquine and sulfasalazine (triple therapy). Both groups had statistically significant reductions in disease activity and in arterial inflammation, with no differences noted between the groups.

“Our results highlight the importance of conducting clinical trials specifically among patients with RA rather than the general population,” said corresponding author Daniel H. Solomon of the Division of Rheumatology, Inflammation and Immunology. “Prior trials in the general population have shown differential effects on CV risk between different immunomodulators, but in our trial, two different immunomodulator treatment strategies produced similar reductions in CV risk.”

Posted on Autism

Trial to test whether a drug that targets gut bacteria can improve irritability in autistic teens

A new trial will test whether a medication that targets gut bacteria can also improve irritability in teenagers with autism spectrum disorder.

The Tapestry study, a collaboration between the Murdoch Children’s Research Institute, Queensland Children’s Hospital, University of Sydney, Southern Adelaide Local Health Network and Flinders University is recruiting adolescents, aged 13-17, in Australia, the US and New Zealand with moderate to severe autism and who experience irritability such as aggression, self-harm and severe tantrums.

The trial medication, AB-2004, is designed to soak up certain toxins produced by bacteria in the gut to prevent them from entering the bloodstream and reaching the brain. Scientific studies have shown there may be a link between changes and irregularities in gut bacteria and the brain, which could contribute to certain neurological conditions, including irritability in children with autism. Gut bacteria are influenced by anxiety, poor diet and an unsettled sleep and stomach.

Murdoch Children’s Professor David Amor, who is leading the randomised-controlled trial in Melbourne alongside Dr Catherine Marraffa, said the study would test whether lowering levels of certain substances produced by gut bacteria could be a potential treatment for irritability in teenagers with autism spectrum disorder. 

“There is a significant difference in the gut bacteria of children with autism compared to those who are not on the spectrum,” he said. This difference may lead to higher levels of certain substances that are produced by bacteria in the gut.

“The therapy we are trialling is designed to absorb the substances associated with some autism characteristics in the gut to reduce their entry into the brain via the bloodstream. We hope this will improve traits of irritability and anxiety, offering families an alternative to anti-psychotic treatments.”

The medication is designed to act in the gut only and does not enter other bodily tissues, lessening the potential for side effects across other parts of the body. AB-2004 was shown to be safe and well tolerated in a previous study involving adolescents on the spectrum.

Murdoch Children’s Dr Kylie Crompton said the severity of daily challenges faced by some children with autism, combined with the lack of safe and effective treatment options, had resulted in a significant unmet need for innovative medical interventions. 

“Children with autism need better options formanaging anxiety and irritability or distress,” she said. This trial offers potential hope for children who too often struggle with anxiety and irritability in all aspects of their daily life.”

The trial, sponsored by Axial Therapeutics, across 25 hospital sites in Australia, the US and New Zealand, is seeking 140 participants. Axial is a pharmaceutical company dedicated to improving the lives of people with neurological conditions.

Dr Crompton said the trial was possible with the backing of The Lorenzo and Pamela Galli Charitable Trust, administered by the University of Melbourne, which supports researchers across the Parkville medical precinct in the areas of cancer and developmental disorders.

“With the support of the Galli Trust we can generate new evidence about the causes of neurodevelopmental disability and determine whether new and existing therapies are effective in improving outcomes and quality of life for these children and their families,” she said.

The 16-week trial includes taking the medication for eight weeks, six in-clinic visits and three telehealth appointments and the collection of blood, urine and stool samples as well as completing questionnaires.

The medication, a powder taken by mouth three times per day, is tasteless and odorless and is mixed with any soft food.

To see if your child is eligible for the study a pre-screening questionnaire can be accessed by visiting www.theautismstudy.com

Posted on Infectious Diseases

Where did Omicron come from?

Laboratory of Viral Hemorrhagic Fever in Benin


Prof. Jan Felix Drexler (left) and co-author Dr. Anges Yadouleton (center) in the Laboratory of Viral Hemorrhagic Fever (LFHB) in Benin © Charité | Anna-Lena Sander

First discovered a year ago in South Africa, the SARS-CoV-2 variant later dubbed “Omicron” spread across the globe at incredible speed. It is still unclear exactly how, when and where this virus originated. Now, a study published in the journal Science* by researchers from Charité – Universitätsmedizin Berlin and a network of African institutions shows that Omicron’s predecessors existed on the African continent long before cases were first identified, suggesting that Omicron emerged gradually over several months in different countries across Africa.

Since the beginning of the pandemic, the coronavirus has been constantly changing. The biggest leap seen in the evolution of SARS-CoV-2 to date was observed by researchers a year ago, when a variant was discovered that differed from the genome of the original virus by more than 50 mutations. First detected in a patient in South Africa in mid-November 2021, the variant later named Omicron BA.1 spread to 87 countries around the world within just a few weeks. By the end of December, it had replaced the previously dominant Delta variant worldwide.

Since then, speculations about the origin of this highly transmissible variant have centered around two main theories: Either the coronavirus jumped from a human to an animal where it evolved before infecting a human again as Omicron, or the virus survived in a person with a compromised immune system for a longer period of time and that’s where the mutations occurred. A new analysis of COVID-19 samples collected in Africa before the first detection of Omicron now casts doubt on both these hypotheses.

The analysis was carried out by an international research team led by Prof. Jan Felix Drexler, a scientist at the Institute of Virology at Charité and the German Center for Infection Research (DZIF). Other key partners in the European-African network included Stellenbosch University in South Africa and the Laboratory of Viral Hemorrhagic Fever (LFHB) in Benin. The scientists started by developing a special PCR test to specifically detect the Omicron variant BA.1. They then tested more than 13,000 respiratory samples from COVID-19 patients that had been taken in 22 African countries between mid-2021 and early 2022. In doing so, the research team found viruses with Omicron-specific mutations in 25 people from six different countries who contracted COVID-19 in August and September 2021 – two months before the variant was first detected in South Africa.

To learn more about Omicron’s origins, the researchers also decoded, or “sequenced,” the viral genome of some 670 samples. Such sequencing makes it possible to detect new mutations and identify novel viral lineages. The team discovered several viruses that showed varying degrees of similarity to Omicron, but they were not identical. “Our data show that Omicron had different ancestors that interacted with each other and circulated in Africa, sometimes concurrently, for months,” explains Prof. Drexler. “This suggests that the BA.1 Omicron variant evolved gradually, during which time the virus increasingly adapted to existing human immunity.” In addition, the PCR data led the researchers to conclude that although Omicron did not originate solely in South Africa, it first dominated infection rates there before spreading from south to north across the African continent within only a few weeks.

“This means Omicron’s sudden rise cannot be attributed to a jump from the animal kingdom or the emergence in a single immunocompromised person, although these two scenarios may have also played a role in the evolution of the virus,” says Prof. Drexler. “The fact that Omicron caught us by surprise is instead due to the diagnostic blind spot that exists in large parts of Africa, where presumably only a small fraction of SARS-CoV-2 infections are even recorded. Omicron’s gradual evolution was therefore simply overlooked. So it is important that we now significantly strengthen diagnostic surveillance systems on the African continent and in comparable regions of the Global South, while also facilitating global data sharing. Only good data can prevent policymakers from implementing potentially effective containment measures, such as travel restrictions, at the wrong time, which can end up causing more economic and social harm than good.”