Category: Rheumatology

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CAR T Cell Therapy for Rheumatoid Arthritis Highly Effective in First Patients

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Patients own immune cells genetically modified in the laboratory, track down the disease driving B cells, even deep within tissues. Inflammatory foci such as those seen here around the knee joints of a study participant (magenta) are no longer detectable even several months after CD19-CAR T-cell therapy (right in the PET-MRI image). Swelling and pain have subsided, with improved mobility. © Charité | David Simon

Immunotherapies such as CAR T cell therapy are used primarily to treat cancer. In the future, these patient-specific therapies, manufactured from patients’ own immune cells, could also help cure autoimmune diseases. Six patients with particularly severe rheumatoid arthritis have now received this treatment at Charité – Universitätsmedizin Berlin. In Nature Medicine, the researchers report the results from the world’s first clinical trial of its kind: Disease activity decreased substantially in all participants. By the end of the observation period, three of the patients no longer required any medication for rheumatoid arthritis.

Rheumatoid arthritis is a chronic disease in which the immune system mistakenly attacks the body’s own joints. This causes recurrent inflammation and joint swelling and, as the disease progresses, can lead to joint damage. Currently available treatments can usually keep the inflammation under control, but do not cure the disease. Patients therefore require lifelong medication, including anti-inflammatory drugs and medications that suppress the immune system, with all the associated side effects.

In some patients, even several of the newer treatments fail to produce an adequate response. Doctors then call the disease treatment-refractory. For those affected, this means persistent pain, restricted mobility and a substantial impact on quality of life. “One reason could be disease driving B cells – memory cells of the adaptive immune system that may survive in the lymph nodes, bone marrow or joint tissue after an infection, where they produce harmful antibodies directed against the body’s own tissues and repeatedly reignite the inflammation,” explains Prof David Simon, who designed the trial for this patient group together with Prof Gerhard Krönke at Charité’s Department of Rheumatology and Clinical Immunology.

The researchers hope that CAR T cells, patients’ own immune cells genetically modified in the laboratory, could selectively track down the disease driving B cells, even deep within tissues, reset the pathological B-cell memory as fully as possible and thereby effectively give the B-cell system a fresh start.

Cell therapy resets the immune system

Originally developed for cancer treatment, CAR T cells are now being used more widely. In cancer treatment, patients’ immune cells are given a kind of “training” to specifically recognise and eliminate tumour cells; in autoimmune diseases, the aim is instead to direct immune cells toward disease driving memory cells. “The identifying marker on many B cells, both abnormal B cells in cancers of the blood or lymphatic system and disease driving B cells in rheumatoid arthritis, is the surface molecule CD19. You could think of it as a kind of ‘name tag’” explains David Simon. “To enable CAR T cells to detect and eliminate the disease-causing cells, we equip patients’ own immune cells with a receptor that acts like a search sensor for CD19.”

For this type of CD19 CAR T-cell therapy, T cells are first collected from the patient’s blood. These are immune cells that normally recognize and eliminate infected or abnormal cells. In the laboratory, the cells are genetically modified and equipped with the key recognition feature: a chimeric, or artificial, antigen receptor, known as a CAR, that binds specifically to the CD19 molecule. Before the modified immune cells can be returned to the patient in a single infusion, a short course of preparatory chemotherapy is required to create space in the immune system. This temporarily reduces the number of certain immune cells so that the CAR T cells can then multiply effectively and carry out their function. Once returned to the body, the modified immune cells begin searching for the CD19 marker and specifically attack cells that carry it. In doing so, they temporarily eliminate all CD19-positive B cells, allowing the immune system to reset and helping to eliminate even long-lived disease-driving B cells in the joints that would otherwise be difficult to reach.

Will the approach work in difficult-to-treat rheumatoid arthritis?

For the world’s first clinical trial to evaluate the safety and efficacy of a CD19 CAR T-cell therapy in rheumatoid arthritis, the research team at Charité initially enrolled six patients with particularly severe disease. The three women and three men, aged 31 to 69, had received up to eight targeted or biologic therapies over the previous ten years, none of which had been sufficiently effective.

The key question was whether CAR T cells can track down the disease-driving B cells in the joints and whether the treatment is not only effective but also safe. For the researchers, the results from the first part of the COMPARE trial are highly encouraging: “Disease activity decreased markedly in all six patients. During follow-up of up to one year, three patients were in sustained remission without any medication for rheumatoid arthritis,” reports Gerhard Krönke, who leads the joint Clinical Rheumatology research group at Charité and the German Rheumatology Research Center (DRFZ), a Leibniz Institute. “This is particularly remarkable given that none of the established treatments had previously been able to relieve their symptoms adequately.”

The cell therapy appears to have done more than temporarily curb inflammation in the joints: the modified immune cells also tracked down and eliminated disease-promoting B cells in deeper reservoirs such as the bone marrow, lymph nodes and joint tissue. At regular follow-up visits over the subsequent twelve months, the research team found that levels of the autoantibodies characteristic of rheumatoid arthritis had declined sharply.

David Simon adds: “When the B-cell system later recovered, predominantly naïve B cells that had not yet been shaped by the disease returned. In contrast, the B cells directed against the body’s own tissues that had been present before treatment were no longer detectable in almost all patients, an indication that the treatment may indeed be able to reset the pathological immune memory.” Protective antibodies from previous vaccinations, for example against chickenpox or tetanus, remained detectable. Despite the profound depletion of B cells, protective antibody memory appears to be largely preserved. However, any longer-term effects of the therapy on the immune system still need to be investigated.

Early successes, but still some way to go

The trial shows that, in some patients, a single CAR T-cell treatment can lead to a sustained symptom-free period without medication – a state of disease inactivity known as remission. For selected patients with rheumatoid arthritis who have not responded adequately to treatment, it may in the future be possible to reset the pathological immune memory in a targeted way and thereby stop the persistent inflammation, instead of having to suppress it continuously with drugs.

Nevertheless, CAR T-cell therapy for autoimmune diseases, and for rheumatoid arthritis in particular, remains experimental. There is not yet any long-term experience with this treatment. In addition, responses to the therapy varied among patients in the current trial: some did not achieve a complete response, and in one case the disease returned after an initial medication-free period of remission. In contrast, the researchers consider the safety data obtained thus far to be encouraging. “After the participants received the CD19 CAR T cells, we observed only a temporary, mild-to-moderate cytokine release syndrome (CRS) in all participants, which was readily manageable. There were no severe neurological complications or other serious adverse events, and infections were rare,” explains Dr Marie Luise Hütter-Krönke, Medical Director of the Hematology Early Clinical Trial Unit at Charité’s Department of Hematology, Oncology and Cancer Immunology.

In a second phase of the trial involving ten additional patients, the researchers will compare the new treatment approach with a drug already approved for rheumatoid arthritis that also targets B cells. In this way, they aim to determine whether CAR T cells have a stronger and longer-lasting effect and whether they can indeed reset immune memory. If the new concept is confirmed in this and other, larger trials, it could ultimately become an alternative for patients whose lives are severely affected and for whom no adequate treatment is currently available.

Source: Charité – Universitätsmedizin Berlin

Categories : Pain Management RheumatologyTags :

Exercise Helps Hip Arthritis Pain, but Perhaps Less than We Thought

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Photo by RDNE Stock project


A new Cochrane review finds that exercise may improve pain and function, but the benefits may fall short of what patients would notice in daily life.

Hip osteoarthritis is a condition affecting millions of people worldwide and a leading cause of chronic pain and disability. Exercise is widely recommended as a first-line treatment for managing hip arthritis pain.

Led by researchers from University of Sydney and University of Melbourne, the findings show exercise produces small improvements in pain and physical function for people with hip osteoarthritis, but those improvements may not be large enough to make a meaningful difference to patients.

The review included 18 clinical trials involving 1368 people. Participants were mostly women (63%) and were aged between 53 and 74 years, meaning findings may not apply to younger people. Exercise programmes in the included studies varied widely, lasting between two and 52 weeks and covering a range of types including strengthening, aerobic, and mind-body approaches.

Compared with no treatment or usual care, exercise probably reduces pain by around 7 points on a 100-point scale. However, experts generally consider an improvement of at least 12 points necessary for patients to notice a meaningful difference in daily life. Physical function showed a similar pattern. The authors note, however, that these thresholds were derived largely from knee and mixed osteoarthritis populations, and may not entirely reflect the hip osteoarthritis experience.

Quality of life, arguably the outcome patients care about most, showed little to no improvement with exercise regardless of the comparison used.
 

“Exercise is recommended as a primary treatment for hip osteoarthritis, and this review doesn’t overturn that, but it does suggest we should be honest with patients that the average benefit may be modest, and that we need better-designed trials to understand who benefits most and from which type of exercise.”

— Michelle Hall, co-lead author from the University of Sydney. 


This update analysed results differently from its 2014 predecessor, which pooled all available data together and found high-quality evidence that exercise slightly reduced pain. The new review separated trials according to what exercise was being compared against.

When exercise was tested against a placebo or sham treatment, the evidence for pain relief weakened considerably. And adding exercise on top of another treatment made little difference either. While no single type of exercise came out on top, the authors caution that the evidence to answer that question properly simply isn’t there yet.

Not a recommendation away from exercise

The review stops short of saying exercise is ineffective or should be abandoned as a recommendation. Exercise carries broad health benefits beyond arthritis, is low-cost, and is unlikely to cause harm. 

Most studies included in this review were small and unblinded, which may have influenced outcomes. Because pain and function were largely self-reported, and participants knew whether they were exercising, exercise may appear more effective than it truly is.

The authors call for larger, better-designed trials to give patients and clinicians a clearer picture of what exercise can realistically achieve for hip osteoarthritis specifically.
 

“There just isn’t a huge body of evidence out there. For some people struggling with hip pain, exercise can really be their only hope, but I also don’t want to give patients false hope. It’s important future research is done with larger, better-quality trials, examining what types of exercise work specifically for different people.” 

— Belinda Lawford, co-lead author from the University of Melbourne. 

Read the review

By Mia Parkinson

Source: Cochrane

Categories : RheumatologyTags :

Drug Reduces the Risk of Developing Rheumatoid Arthritis, Clinical Trial Finds

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Rheumatoid arthritis. Credit: Scientific Animations CC4.0

A clinical trial led by researchers from Hospital Clínic de Barcelona, the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and The Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) has compared the effectiveness of abatacept and hydroxychloroquine in preventing the development of rheumatoid arthritis in patients with palindromic rheumatism, an autoimmune disease that progresses to arthritis in approximately half of all patients. The trial was conducted over two years across 14 hospitals throughout Spain and involved 70 patients with palindromic rheumatism. The findings, published in Nature Medicine, indicate that abatacept is significantly more effective than hydroxychloroquine in preventing the onset of arthritis.

Palindromic rheumatism is characterised by intermittent episodes of joint inflammation, with acute flare-ups lasting a few days and resolving spontaneously. However, around half of patients eventually develop rheumatoid arthritis, a chronic disease that causes irreversible joint damage. This risk is particularly high in individuals with biomarkers such as rheumatoid factor and anti-citrullinated peptide antibodies. The presence of these two autoantibodies – proteins of the immune system that mistakenly attack the body’s own organs and tissues – is used in the diagnosis of the disease.

Until now, in the absence of clinical trial evidence, the standard approach has been to treat patients with palindromic rheumatism using hydroxychloroquine, a drug with anti-inflammatory and immunosuppressive properties aimed at improving disease symptoms. In this context, the team led by Raimon Sanmartí, head of the Inflammatory Arthropathies Research Group at IDIBAPS, conducted a two-year clinical trial involving 70 patients with palindromic rheumatism. The objective was to compare the effectiveness of hydroxychloroquine with abatacept, a lymphocyte inhibitor – a type of white blood cell that attacks the joints after mistakenly identifying them as a threat – in reducing progression from palindromic rheumatism to rheumatoid arthritis

The results show that treatment with abatacept significantly reduces progression to rheumatoid arthritis. Only 20% of patients receiving abatacept developed arthritis, compared with 50% of those treated with hydroxychloroquine. Furthermore, patients treated with abatacept not only avoided progression to rheumatoid arthritis in most cases, but also experienced a significant improvement in palindromic rheumatism symptoms. “The study shows that patients treated with abatacept are more likely to achieve complete remission of attacks associated with acute pain and joint swelling, and that their inflammatory episodes are less severe,” explains Isabel Haro, Head of the Peptide Synthesis and Biomedical Applications Unit at IQAC-CSIC. The research team also highlights that both drugs proved safe and well tolerated throughout the trial.

Early intervention

“The results of this study indicate that we can intervene at an early stage to modify the natural course of the disease and reduce the risk of patients developing more severe and irreversible conditions,” says Sanmartí. “This opens the door to a paradigm shift in the treatment of these patients.”

The study, which involved several national research centres, also analysed the evolution of a number of biomarkers (autoantibodies) developed by the CSIC research group during patient follow-up. “Although no significant differences were observed between abatacept and hydroxychloroquine in terms of autoantibody responses, this work demonstrates the value of immunomodulatory approaches in the early stages of disease, when it is still possible to prevent progression to more severe and chronic forms,” notes Haro.

Rheumatoid arthritis is a disease that significantly affects patients’ quality of life and places a considerable burden on healthcare systems. Preventing its development in a substantial proportion of cases represents an important advance in the management of rheumatic diseases.

Source: Institute for Advanced Chemistry of Catalonia

Categories : RheumatologyTags :

Abatacept Trumps Hydroxychloroquine in Cutting Risk of Rheumatoid Arthritis

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Rheumatoid arthritis. Credit: Scientific Animations CC4.0

A clinical trial led by researchers from Hospital Clínic de Barcelona, the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and the Institute of Advanced Chemistry of Catalonia (IQAC-CSIC) has compared the effectiveness of abatacept and hydroxychloroquine in preventing the development of rheumatoid arthritis in patients with palindromic rheumatism, an autoimmune disease that progresses to arthritis in approximately half of all patients. The trial was conducted over two years across 14 hospitals throughout Spain and involved 70 patients with palindromic rheumatism. The findings, published in Nature Medicine, indicate that abatacept is significantly more effective than hydroxychloroquine in preventing the onset of arthritis.

Palindromic rheumatism is characterised by intermittent episodes of joint inflammation, with acute flare-ups lasting a few days and resolving spontaneously. However, around half of patients eventually develop rheumatoid arthritis, a chronic disease that causes irreversible joint damage. This risk is particularly high in individuals with biomarkers such as rheumatoid factor and anti-citrullinated peptide antibodies. The presence of these two autoantibodies is used in the diagnosis of the disease.

Until now, in the absence of clinical trial evidence, the standard approach has been to treat patients with palindromic rheumatism using hydroxychloroquine, a drug with anti-inflammatory and immunosuppressive properties aimed at improving disease symptoms. In this context, the team led by Raimon Sanmartí, head of the Inflammatory Arthropathies Research Group at IDIBAPS, conducted a two-year clinical trial involving 70 patients with palindromic rheumatism. The objective was to compare the effectiveness of hydroxychloroquine with abatacept, a lymphocyte inhibitor – a type of white blood cell that attacks the joints after mistakenly identifying them as a threat – in reducing progression from palindromic rheumatism to rheumatoid arthritis

The results show that treatment with abatacept significantly reduces progression to rheumatoid arthritis. Only 20% of patients receiving abatacept developed arthritis, compared with 50% of those treated with hydroxychloroquine. Furthermore, patients treated with abatacept not only avoided progression to rheumatoid arthritis in most cases, but also experienced a significant improvement in palindromic rheumatism symptoms. “The study shows that patients treated with abatacept are more likely to achieve complete remission of attacks associated with acute pain and joint swelling, and that their inflammatory episodes are less severe,” explains Isabel Haro, Head of the Peptide Synthesis and Biomedical Applications Unit at IQAC-CSIC. The research team also highlights that both drugs proved safe and well tolerated throughout the trial.

Early intervention

“The results of this study indicate that we can intervene at an early stage to modify the natural course of the disease and reduce the risk of patients developing more severe and irreversible conditions,” says Sanmartí. “This opens the door to a paradigm shift in the treatment of these patients.”

The study, which involved several national research centres, also analysed the evolution of a number of biomarkers (autoantibodies) developed by the CSIC research group during patient follow-up. “Although no significant differences were observed between abatacept and hydroxychloroquine in terms of autoantibody responses, this work demonstrates the value of immunomodulatory approaches in the early stages of disease, when it is still possible to prevent progression to more severe and chronic forms,” notes Haro.

Source: Spanish National Research Council 

Categories : Neurology RheumatologyTags :

Study Links OTC Joint Pain Supplement to Accelerating Dementia

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New research has found an association between taking glucosamine, a popular over-the-counter supplement used for joint pain, and a higher likelihood of progressing from mild cognitive impairment to Alzheimer’s disease.

The finding by researchers at University of Florida’s McKnight Brain Institute is based on a large retrospective analysis of patients’ records as well as supporting data from advanced imaging technology used to scan human brain specimens and Alzheimer’s disease mouse models.

While the results are preliminary and require validation in a human clinical trial, they provide yet another piece of a much bigger mechanistic picture involving metabolic dysregulation and neurodegeneration, according to the study published in Nature Metabolism.

“In the United States, there are about 7 million people living with Alzheimer’s and millions more with related dementias such as Lewy body or frontotemporal dementia,” said senior author Ramon Sun, PhD, director of the Center for Advanced Spatial Biomolecule Research and associate director for innovation of UF’s McKnight Brain Institute. “A lot of these people actively take an over-the-counter supplement that could be making their disease progression worse.”

The team used artificial intelligence to comb deidentified UF Health records from 2012 to 2024 for patients diagnosed with either ADRD or mild cognitive impairment, or MCI. They found that a significant proportion (8%) of both types of patients reported taking glucosamine: 1896 with ADRD and 2750 with MCI.

After controlling for age, sex and demographics, the analysis showed that glucosamine use was associated with a 25% higher likelihood of progression from mild cognitive impairment to dementia.

In addition, researchers found that taking glucosamine was associated with a 25% increase in mortality risk, or the likelihood of death within a specified time frame, among ADRD patients. For the MCI group, there was no such impact, suggesting the impact of glucosamine may be greater in patients with established dementia.

Notably, said Sun, researchers revealed that a metabolic process in which a protein and sugar-tagging pathway is overactive in Alzheimer’s could be a new target for intervention.

“Our results suggest that altered metabolism is a significant contributor to Alzheimer’s progression and, in addition, addressing the metabolic defect could be an important complement to approaches focused on Alzheimer’s plaques and tangles,” Sun said.

By Michelle Jaffee

Source: McKnight Brain Institute, University of Florida

Categories : RheumatologyTags :

Not All Rheumatoid Arthritis Drugs Are Equal for Quality of Life

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Photo by Towfiqu barbhuiya

A study published in Rheumatology & Autoimmunity challenges the assumption that achieving clinical remission in rheumatoid arthritis is sufficient, showing that patient-reported outcomes vary significantly by drug class even when disease activity is comparable.

Investigators found that patients taking TNF inhibitors reported better energy levels, mood, and emotional wellbeing than those taking older conventional drugs, while IL-6 and JAK inhibitors showed particular advantages for patients’ physical functioning. These differences persisted even after accounting for how well the underlying inflammation was controlled.

The study provides real-world evidence that different drug classes offer distinct advantages across quality-of-life domains, supporting a more nuanced, patient-centred approach to treatment selection rather than a one-size-fits-all strategy.

“Despite achieving clinical remission, patients with rheumatoid arthritis may still experience symptoms such as fatigue, sleep disturbances, and mental or communication issues compared with healthy individuals, highlighting the importance of evaluating patient-reported outcomes as a composite measure of treatment efficacy,” the authors wrote.

They noted that the study arrives at a moment when regulators are pushing for patient-reported outcomes to be formally incorporated into drug approvals and reimbursement decisions, and when artificial intelligence–based tools are beginning to use multiple data streams to match the right drug to the right patient.

Source: Wiley

Categories : RheumatologyTags :

Study Finds Common Medication Brings Little Relief in Osteoarthritis

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The University of Tasmania’s Menzies Institute for Medical Research has found that commonly prescribed medication, Diacerein, does not improve knee osteoarthritis symptoms, following a national study.

Diacerein, a medication derived from plants such as rhubarb and aloe vera, has long been recognised for its anti-inflammatory properties and is commonly used to treat osteoarthritis in Europe and Asia.

Led by Associate Professor Dawn Aitken, head of the Musculoskeletal Research Group at Menzies, the DICKENS trial is the largest study globally to investigate Diacerein’s ability to reduce pain in people with knee osteoarthritis who also have inflammation within the joint (effusion synovitis).

“We designed this large trial to test Diacerein in a group of osteoarthritis patients who we thought would have the best chance at benefiting from the drug and found that it did not improve pain or function or decrease local knee inflammation.

“We were hoping that if the drug was effective, it could be included on the Australian Register of Therapeutic Goods (ARTG) as an approved treatment for osteoarthritis in Australia,” Associate Professor Aitken said. “Unfortunately, it’s back to the drawing board to find more effective drug therapies.”

Osteoarthritis is the most common form of arthritis, affecting one in five Australians over the age of 45 and is a major cause of pain, disability, and joint replacement surgery. Despite its widespread burden, very few effective drug treatments exist.

Associate Professor Aitken said the publication of the trial in JAMA Internal Medicine – one of the world’s most prestigious medical journals – highlighted both the significance and rigour of the work.

“While the findings weren’t what we expected or hoped for, publishing this work in JAMA Internal Medicine reinforces the global importance of high-quality research, and we are proud that Menzies is contributing to the global effort to better understand and treat osteoarthritis.”

Associate Professor Aitken is hopeful that other promising drugs in the development stage will become available to bring relief to those suffering chronic pain, but highlighted that non-drug therapies are available.

“Chronic pain has a huge impact on the lives of those who live with it, and the lack of effective drug treatments is frustrating.

“While we currently lack drug treatments for chronic pain, we know that the most effective therapies include education, exercise, weight management and psychological support.”

Despite these findings, patients should not stop taking Diacerein without talking to their treating doctor first.

Source: University of Tasmania

Categories : Metabolic Disorders RheumatologyTags :

Can GLP-1 Agonists ‘Change the Weather’ for Osteoarthritis?

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For GPs, solutions for treating osteoarthritis are frustratingly limited – it’s like the weather, everyone talks about it but nobody does anything about it. While standard care can relieve symptoms, there is currently no way to regenerate the actual lost cartilage in the joints. Some experimental treatments have proven successful in animal models and in petri dishes, but those are still many years away from being approved and available on the market.

But what if there was a currently available drug that could be repurposed? Since overweight and obesity worsen osteoarthritis symptoms by placing excess strain on weight-bearing joints, GLP-1 agonists such as semaglutide have proven that they can help by promoting rapid weight loss, as demonstrated by the STEP-9 trial.

Research into GLP-1s has now revealed that they may offer a whole constellation of other benefits, such as a potential reduction in stroke risk. Now, it appears that GLP-1 agonists may have a direct effect on osteoarthritis independent of weight loss. In our podcast, we look at a recently published article in Cell Metabolism that suggests that GLP-1 agonists might go beyond just the weight loss – promote actual cartilage regrowth by jumpstarting the joint cells’ energy processing pathways. We also explore some of the caveats of potentially using GLP-1 agonists in this way, such as a lack of understanding of the long term effects, as well as the well-documented occurrence of muscle loss.

Categories : Ageing RheumatologyTags :

Scientists Regenerate Joint Cartilage in Mice by Blocking an Ageing Protein

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The knee joint of a young mouse (left), aged mouse (middle) and treated aged mouse (right). The red indicates cartilage. Credit: Nidhi Bhutani

An injection that blocks the activity of a protein involved in ageing reverses naturally occurring cartilage loss in the knee joints of old mice, a Stanford Medicine-led study has found. The treatment also prevented the development of arthritis after knee injuries mirroring the ACL tears often experienced by athletes or recreational exercisers. An oral version of the treatment is already in clinical trials with the goal of treating age-related muscle weakness.

Samples of human tissue from knee replacement surgeries – which include both the extracellular scaffolding, or matrix, in the joint as well as cartilage-generating chondrocyte cells – also responded to the treatment by making new, functional cartilage.

The study results suggest it may be possible to regenerate cartilage lost to ageing or arthritis with an oral drug or local injection, rendering knee and hip replacement unnecessary.

The treatment directly targets the cause of osteoarthritis, a disease for which no drug can slow down or reverse its progress; the primary treatments for osteoarthritis are pain control and surgical replacement of the affected joints.

The protein, 15-PGDH – termed a gerozyme due to its increase in prevalence as the body ages – is a master regulator of ageing. Gerozymes, identified by the same researchers in 2023, also drive the loss of tissue function. They are a major force behind age-related loss of muscle strength in mice. Blocking the function of 15-PGDH with a small molecule results in an increase in old animals’ muscle mass and endurance. Conversely, expressing15-PGDH in young mice causes their muscles to shrink and weaken. The gerozyme has also been implicated in the regeneration of bone, nerve and blood cells.

In each of these tissues, regeneration is due to increases in the proliferation and specialisation of tissue-specific stem cells. However, chondrocytes change their patterns of gene expression to assume a more youthful state without the involvement of stem cells. 

“This is a new way of regenerating adult tissue, and it has significant clinical promise for treating arthritis due to ageing or injury,” said Helen Blau, PhD, professor of microbiology and immunology. “We were looking for stem cells, but they are clearly not involved. It’s very exciting.”

Blau, who directs the Baxter Laboratory for Stem Cell Biology and Nidhi Bhutani, PhD, associate professor of orthopaedic surgery, are the senior authors of the research, which was published online in Science.

‘Dramatic regeneration’

“Millions of people suffer from joint pain and swelling as they age,” Bhutani said. “It is a huge unmet medical need. Until now, there has been no drug that directly treats the cause of cartilage loss. But this gerozyme inhibitor causes a dramatic regeneration of cartilage beyond that reported in response to any other drug or intervention.”

There are three main types of cartilage in the human body. One, elastic cartilage, is soft and flexible and forms structures like the outer ear. A second, fibrocartilage, is dense and tough, absorbing shock in areas such as between the spinal vertebrae. The third, hyaline cartilage, is smooth and glossy, providing a low-friction surface for lubrication and flexibility in joints like the ankles, hips, shoulders and parts of the knee. Hyaline cartilage, also known as articular cartilage, is the cartilage most commonly affected by osteoarthritis.

Osteoarthritis occurs when a joint is stressed by ageing, injury or obesity. The chondrocytes begin to release pro-inflammatory molecules and to break down collagen, which is the primary structural protein of cartilage. When collagen is lost, the cartilage thins and softens; the accompanying inflammation causes the joint swelling and pain that are hallmarks of the disease. Under normal circumstances, articular cartilage rarely regenerates. Although some populations of putative stem or progenitor cells capable of generating cartilage have been identified in bone, attempts to identify similar populations of cells in the articular cartilage have been unsuccessful.

Previous research from Blau’s lab has shown that a molecule called prostaglandin E2 is essential to muscle stem cell function. 15-PGDH degrades prostaglandin E2. Inhibiting 15-PGDH activity, or increasing levels of prostaglandin E2, supports the regeneration of damaged muscle, nerve, bone, colon, liver and blood cells in young mice.

Blau, Bhutani and their colleagues wondered if 15-PGDH might also play a role in ageing cartilage and joints. They wanted to find out if a similar pathway contributes to cartilage loss from ageing or in response to injury. When they compared the amount of 15-PGDH in the knee cartilage in young versus old mice, they saw that, as in other tissues, levels of the gerozyme increased about two-fold with age.

They next experimented with injecting old animals with a small molecule drug that inhibits 15-PGDH activity – first into the abdomen, which affects the entire body, then directly into the joint. In each case, the knee cartilage, which was markedly thinner and less functional in older animals as compared with younger mice, thickened across the joint surface. Further experiments confirmed that the chondrocytes in the joint were generating hyaline, or articular, cartilage, rather than less-functional fibrocartilage.

“Cartilage regeneration to such an extent in aged mice took us by surprise,” Bhutani said. “The effect was remarkable.”

Addressing ACL tears

Similar results were observed in animals with knee injuries like the ACL tears that frequently occur in people participating in sports such as soccer, basketball and skiing that require sudden pivoting, stopping or jumping. While the tears can be surgically repaired, about 50% of people develop osteoarthritis in the injured joint within about 15 years.

The researchers found that a series of injections twice a week for four weeks of the gerozyme inhibitor after injury dramatically reduced the chance that osteoarthritis develops in the mice. Animals treated with a control drug had levels of 15-PGDH that were twice as high as in their uninjured peers, and they developed osteoarthritis within four weeks.

The animals treated with the gerozyme inhibitor also moved more typically and put more weight on the paw of the affected leg than did untreated animals.

“Interestingly, prostaglandin E2 has been implicated in inflammation and pain,” Blau said. “But this research shows that, at normal biological levels, small increases in prostaglandin E2 can promote regeneration.”

A closer investigation of the chondrocytes in the joints of old mice and young mice showed that old chondrocytes expressed more detrimental genes involved in inflammation and the conversion of hyaline cartilage to unwanted bone, and fewer genes involved in cartilage development.

The researchers were also able to pinpoint subcategories of old chondrocytes that change their patterns of gene expression after treatment. One, which expresses 15-PGDH and genes involved in cartilage degradation, decreased in prevalence from 8% to 3% after treatment. Another, which does not express 15-PGDH but does express genes involved in the production of fibrocartilage, also decreased in prevalence: from 16% to 8% after treatment. A third population, which does not make 15-PGDH and which expresses genes involved in hyaline cartilage formation and the maintenance of the extracellular matrix necessary for its function, increased in prevalence after treatment from 22% to 42%. The findings indicate an overall shift in gene expression after treatment to a more youthful cartilage composition – without the involvement of stem or progenitor cells.

Finally, the researchers studied human cartilage tissue removed from patients with osteoarthritis undergoing total knee replacements. Tissue treated with the 15-PGDH inhibitor for one week exhibited lower levels of 15-PGDH-expressing chondrocytes and lowered cartilage degradation and fibrocartilage genes than control tissue and began to regenerate articular cartilage.

“The mechanism is quite striking and really shifted our perspective about how tissue regeneration can occur,” Bhutani said. “It’s clear that a large pool of already existing cells in cartilage are changing their gene expression patterns. And by targeting these cells for regeneration, we may have an opportunity to have a bigger overall impact clinically.”

Blau added, “Phase 1 clinical trials of a 15-PGDH inhibitor for muscle weakness have shown that it is safe and active in healthy volunteers. Our hope is that a similar trial will be launched soon to test its effect in cartilage regeneration. We are very excited about this potential breakthrough. Imagine regrowing existing cartilage and avoiding joint replacement.”

Source: Stanford University

Categories : RheumatologyTags :

Study Finds People on Colchicine Less Likely to Need Joint Replacement

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Photo by Towfiqu barbhuiya: https://www.pexels.com/photo/person-feeling-pain-in-the-knee-11349880/

Gout is the most common form of inflammatory arthritis, with worldwide prevalence of approximately 4%.  The accumulation of monosodium urate crystals in gout leads to the clinical manifestations of the disease and if left inadequately treated, leads to chronic arthritis with joint damage. Due to its anti-inflammatory properties, colchicine, an alkaloid drug derived from the autumn crocus plant, is commonly used in the management of gout for both prophylaxis and treatment of gout flares.

A recent study on colchicine’s potential benefit for cardiovascular disease noted that participants who were taking the drug had fewer joint replacements than those taking a placebo. Since colchicine is commonly used in gout, researchers wondered if colchicine would lower risk of joint replacement in those with gout as well. Further, because osteoarthritis is the most common reason for joint replacement, and because osteoarthritis and gout can occur together, researchers wondered if colchicine could lower the risk of joint replacement in those with both gout and osteoarthritis. 

A new study from Boston University Chobanian & Avedisian School of Medicine has found that people with gout who were prescribed colchicine had a modest 12% risk of joint replacement compared to those who did not receive the drug. Additionally, those with both gout and osteoarthritis who took colchicine had a 23% lower risk of needing joint replacement. 

While it would have been ideal for a clinical trial to address the question of whether colchicine reduces the need for joint replacement in gout, it was not readily feasible to conduct such a trial of adequate sample size and duration. Therefore, the researchers used real-world evidence from a UK population-based database in which they identified people with gout, and then divided that pool into those who were newly prescribed colchicine and those who were not. They then assessed the frequency of knee and hip replacement in both groups. 

According to the researchers, these findings suggest that colchicine may have benefits beyond symptom relief alone. “This observation could have broad implications for duration of colchicine use in gout, which is often limited to just the first six months of getting started on a urate-lowering therapy or limited to treatment of flares,” explains corresponding author Tuhina Neogi, MD, PhD, Professor of Rheumatology and professor of medicine at the school. 

Additionally, Neogi believes these findings have implications for potential benefits of colchicine for osteoarthritis irrespective of gout, which is the most common form of arthritis and a leading reason for joint replacement surgery. “Prior trials of colchicine in osteoarthritis have been largely negative, but they likely have been too small and had too short a duration to detect potential effects,” adds Neogi who also is chief of rheumatology at Boston Medical Center.

These findings appear online in the journal Arthritis & Rheumatology.

Source: Boston University