Rheumatoid arthritis

Posted on autoimmune conditions, Cancer, Rheumatoid arthritis

Rogue immune cells linked to leukaemia are a key driver of autoimmune diseases like RA

Killer T Cell

A killer T cell (centre) hunting a target cell. Credit: NIH Image Gallery CREDIT NIH Image Gallery

Gene variants associated with leukaemia can produce ‘rogue’ immune cells that drive autoimmune diseases, according to a new study from the Garvan Institute of Medical Research.

Scientists had previously noticed that leukaemia patients were also likely to develop an autoimmune disease, such as rheumatoid arthritis or aplastic anaemia. Research into this link revealed that immune cells called killer T cells – responsible for destroying harmful cells and pathogens – were a key player.

This new research provides insight into the role these killer T cells play in leukaemia and autoimmune disease. Gene variations affecting a protein that controls the growth of killer T cells can turn them rogue, the researchers found.

“We showed that these rogue killer T cells are driving the autoimmunity. They’re probably one of the cell types most directly contributing to autoimmune disease,” says Dr Etienne Masle-Farquhar, a postdoctoral researcher in the Immunogenomics and Genomic Medicine Labs at Garvan.

“Our research also narrows down a few pathways that might be helpful in targeting these cells for future treatments,” he says.

The findings are published in the journal, Immunity.

Cancers can grow when tumour cells are not identified or destroyed by the immune system. Autoimmune diseases occur when the immune system attacks the body’s own cells, mistaking them for harmful or foreign cells.

“We knew that people with various autoimmune diseases acquire these rogue killer T cells over time, but also that inflammation can cause immune cells to proliferate and develop mutations. We set out to discover whether the rogue T cells were causing these autoimmune conditions, or simply associated with them,” says Dr Masle-Farquhar.

The researchers used new high-resolution screening methods to look at blood from children with rare inherited autoimmune diseases.

They then used a technique called CRISPR/Cas9, a genome editing tool, in mouse models, to find out what happens when the protein STAT3 is genetically altered.

STAT3 is found throughout the body and is critical for various cell functions, including controlling the immune system’s B cells and T cells.

The team found that if these proteins are altered, they can cause rogue killer T cells to grow unchecked, resulting in enlarged cells that bypass immune checkpoints to attack the body’s own cells.

In addition, even just 1-2% of a person’s T cells going rogue could cause autoimmune disease.

“It’s never been clear what the connection between leukaemia and autoimmune disease is – whether the altered STAT3 protein is driving disease, or whether leukaemic cells are dividing and acquiring this mutation just as a by-product. It’s a real chicken-and-egg question, which Dr Masle-Farquhar’s work has been able to solve,” says Professor Chris Goodnow, Head of the Immunogenomics Lab and Chair of The Bill and Patricia Ritchie Foundation at Garvan.

“This gives some really good cracks in the coalface of where we might do better in terms of stopping these diseases, which are sometimes life threatening,” he says.

Future applications could include better targeting of medication, like already TGA-approved JAK inhibitors, based on the presence of these mutations. “We can now go and look for T cells with STAT3 variations. That’s a big step forward in defining who’s the bad guy,” says Professor Goodnow.

The study also identified two specific receptor systems – ways for cells to talk to one another – that are linked to stress.

“Part of what’s driving these rogue cells to expand as killer T cells is the stress-sensing pathways. There is a lot of correlation between stress, damage and ageing. Now we have tangible evidence of how that’s connected to autoimmunity,” Professor Goodnow says.

The team’s research may help develop screening technologies that clinicians could use to sequence the complete genome of every cell in a blood sample, to identify which cells might turn rogue and cause disease.

Further study is needed to determine whether rogue killer T cells are involved in all autoimmune diseases, and what proportion of people with rheumatoid arthritis and other autoimmune conditions have rogue cells and STAT3 variations.

Posted on Rheumatoid arthritis

RA Treatment Recommendations


Since their first publication in 2010, the EULAR recommendations for the use of disease-modifying anti-rheumatic treatments (DMARDs) in people with RA have become a most important publication in the field. Their updates are relied upon by many healthcare professionals, professional organisations and other stakeholders to offer an up-to-date and robust analysis on an optimal approach to the application of available treatment options in clinical practice. The recommendations were last updated in 2019, and there have been no new drug classes released since then; however, two key factors warranted revisiting this fifth version of the document

Firstly, in early 2022 a randomised, controlled clinical trial in RA patients selected for various risk factors showed a higher rate of major cardiovascular events and malignancies in those receiving tofacitinib, a Janus kinase inhibitor (JAKi) compared to tumour necrosis factor inhibitors; indeed, already in 2021 the United States Food and Drug Administration (FDA) released a warning on these risks. In addition, the 2021 update of the RA management guidelines from the American College of Rheumatology (ACR), discouraged the use of glucocorticoids, reasoning that the toxicity outweighs the benefits.

The updated EULAR recommendations were developed by a multidisciplinary task force of rheumatologists, other health professionals, and patient research partners, including infectious disease and epidemiology specialists. The information is based on evidence collected from three systematic reviews across efficacy and safety of both DMARDs and glucocorticoids.

The recommendations were already presented at the EULAR Congress in June 2022 (in Copenhagen) and the full paper which includes all details of the discussion process for every item is now being published in the Annals of the Rheumatic Diseases online on November… 2022. The recommendations include 5 overarching principles and 11 recommendations on the use of DMARDs, including conventional synthetic, biologic, and targeted synthetic agents, as well as glucocorticoids. Guidance on monotherapy, combination therapy, treat-to-target, and tapering strategies is also provided. The general principles say that treatment of RA patients should aim at the best care and must be based on a shared decision between the patient and the rheumatologist – who is the person who should primarily care for people with RA. Treatment decisions are based on disease activity, safety issues and other patient factors, such as comorbidities and progression of structural damage. But RA also incurs high individual, medical and societal costs, all of which should be considered in its management. The principles also highlight that patients require access to multiple drugs with different modes of action to address the heterogeneity of their disease, and they may require multiple successive therapies throughout life.

The individual recommendations outline that DMARD treatment should be started as soon as possible after the RA diagnosis is made, with an aim of reaching sustained remission or low disease activity. The core recommendation for initial treatment with methotrexate plus glucocorticoids is retained from earlier versions. For people who have an insufficient response to this therapy within 3 (significant improvement) to 6 (target attainment) months, further lines of treatment should be based on stratification according to individual risk factors. This requires sufficiently frequent monitoring, which should be performed at least every 3 months in people with active disease. Importantly, for people who achieve sustained remission, DMARDs may be tapered but should not be stopped.

One minor change to the previous version is that, in line with the respective SLR results, the group continues to recommend the consideration of the addition of short-term glucocorticoids when initiating or changing csDMARDs, but emphasizes more strongly that they should be tapered and discontinued as quickly as possible. A newly amended recommendation also outlines that only after glucocorticoids have been discontinued and a patient is in sustained remission, dose reduction of DMARDs may be considered, whether they are conventional synthetic, biologic, or targeted synthetic agents.

Posted on Rheumatoid arthritis

Primary care provider training program improves RA care on Navajo Nation


Research presented this week at ACR Convergence 2022, the American College of Rheumatology’s annual meeting, described a novel program that offers rheumatoid arthritis (RA) training to primary care providers in the Navajo Nation, the largest American Indian reservation in the United States. Despite the high prevalence of RA and associated morbidity and mortality in this vulnerable community, the Navajo Nation has a single rheumatologist serving 250,000 tribal members. As a result, most RA care has shifted to primary care providers on the reservation, who do not feel confident prescribing RA medications or managing the disease (

In addition to developing the RA training program, known as the Rheumatology Access Expansion Initiative, researchers wanted to understand how the program affected provider knowledge and self-reported confidence in RA diagnosis and management.

“The United States faces a critical shortage of rheumatology providers, and this deficit is expected to worsen dramatically over the next decade. In addition, racial and ethnic minorities, particularly Black, Latinx, and Indigenous people, often face longer delays in diagnosis and treatment and [have] less access to rheumatology care,” explains Jennifer Mandal, MD, an assistant professor at the University of California, San Francisco (UCSF), director of the RAE Initiative and the study’s lead author.

Dr. Mandal says for many patients, the physical distance from the nearest rheumatologist is an insurmountable barrier. Meanwhile, many primary care providers have no choice but to attempt to diagnose and treat rheumatologic diseases with little or no specialist guidance.

The 12-week training program was designed by a team of rheumatologists, pharmacists, and Navajo cultural interpreters. It is based on an established educational model, Project ECHO (Extension for Community Healthcare Outcomes), which uses videoconferencing to conduct seminars with community providers. The RA Navajo Nation curriculum included weekly interactive seminars consisting of a didactic followed by case discussion. Participants included 15 physicians plus a nurse practitioner, physician assistant, and community health worker.

The providers completed a pre- and post-training knowledge test covering RA diagnosis and management. They also completed pre- and post-training surveys about their confidence in three areas: RA diagnosis, treatment with conventional disease-modifying anti-rheumatic drugs (cDMARDs), and treatment with biologics. Participants were also asked to rate the usefulness of each session, using a scale ranging from one (not useful) to five (extremely useful).

Among those who completed the knowledge and confidence surveys, performance on the knowledge test improved 22%. Confidence ratings rose significantly, with the greatest increase in management with biologics. The mean session usefulness rating was 4.52 out of 5 (17 of 18 participants).

“We successfully designed and implemented a 12-week RA training program for Navajo Nation primary care providers. The curriculum, now in its third cohort, has been very well received and has improved the providers’ knowledge of evidence-based RA guidelines and their confidence in disease management,” Dr. Mandal says.

Future plans include expanding the program to other Native American communities and potentially developing a new course on spondyloarthritis. The researchers also intend to look at patient outcome data, but “given the history of medical exploitation of American Indians, it is important to us to establish a solid track record of trust and reliability in the Navajo community for several years before we ask permission to review patient health records.” 

For now, Dr. Mandal says, “This model is cost-effective, logistically feasible, even in very rural communities, and easily scalable. We hope our work can serve as a blueprint for other rheumatology providers who may be interested in launching similar remote training programs in other underserved communities across the United States and beyond. By providing high-quality rheumatology training and mentoring to front-line primary care providers in vulnerable communities, this program could have a positive impact on many thousands of patients suffering from rheumatic diseases.”

Posted on Rheumatoid arthritis

New guideline introduces recommendations for an integrative approach to RA treatment

Family holidays
Family holidays

 

The American College of Rheumatology (ACR) released a summary of its new guideline for Exercise, Rehabilitation, Diet and Additional Integrative Interventions for Rheumatoid Arthritis. This is the first ACR guideline about an Integrative Approach to Rheumatoid Arthritis (RA) and is considered complementary to the ACR’s 2021 Guideline for the Treatment of RA, which covers pharmacologic therapies.

“Together with pharmacologic treatment options, exercise, rehabilitation, diet, and additional integrative interventions are considered as potential adjunctive treatments for RA. Patients and clinicians often seek evidence-based insight into these treatment options,” said Benjamin J. Smith, DMSc, PA-C, DFAAPA, Interim Program Director and Associate Dean at the Florida State University College of Medicine and co-principal investigator of the guideline. “Recognizing the need to support patients and clinicians when considering treatments to complement their pharmacologic regimen, the ACR developed this guideline.”

The guideline includes 28 recommendations; only one recommendation was strong. Out of the 27 conditional recommendations, four were about exercise, 13 about rehabilitation, three about diet, and seven about additional integrative interventions.

The one strong recommendation states that consistent engagement in exercise is advised over no exercise. The type of exercise, frequency, intensity, and duration is not formally defined, but the guideline emphasizes “moving regularly.” The specific elements of an exercise intervention should be tailored to each patient at the given time in their disease trajectory, considering their capabilities, access, and other health conditions.

Importantly, the guideline recommendations relate to RA-specific outcomes. For example, the guideline recommends adherence to a Mediterranean-style diet over no formally defined diet. The Mediterranean-style diet emphasizes the intake of vegetables, fruits, whole grains, nuts, seeds, and olive oil; moderate amounts of low-fat dairy and fish; and limits added sugars, sodium, highly processed foods, refined carbohydrates, and saturated fats.

“The conditional recommendation for adhering to a Mediterranean-style diet but not other formally defined diets, to improve RA-specific outcomes, may be surprising to some clinicians,” said Bryant R. England, MD, PhD, Associate Professor of Rheumatology and Immunology at the University of Nebraska Medical Center and one of the guideline’s co-principal investigators. “The Voting Panel acknowledged, however, that other health indications may exist for alternative diet and dietary supplements, which makes it crucial for clinicians and patients to engage in shared decision-making.”

The Patient Panel, which provided input into the guideline recommendations, emphasized that rheumatology clinicians are often the first contact for therapeutic decisions. It’s important to patients that their clinicians be knowledgeable about integrative therapies and help guide patients to other members of the interprofessional care team with relevant expertise (such as occupational therapists, physical therapists, dietitians, etc.).

“Being able to include the diverse integrative interventions in the management of persons with RA throughout their disease course, as an interdisciplinary team, is essential. This guideline highlights the vital role expert members of interprofessional healthcare teams serve in providing optimal care to people with RA,” said Dr. Smith.