A naturally occurring peptide could reduce arthritic joint swelling as effectively as current medications, without suppressing the immune system.
In the body, a peptide called PEPITEM is naturally produced. It acts as a brake on the immune system by telling white blood cells to stop migrating into healthy tissues and causing inflammation.
Under normal conditions, this keeps the immune system active enough to fight infection but restrained enough to avoid attacking one’s own body.
But in the more than 53 million Americans with arthritis, white blood cells in the joints stop responding to the hormone that normally triggers PEPITEM production. As a result of the lack of PEPITEM, widespread inflammation occurs.
Now, researchers in the UK and Italy have shown that replacing the missing PEPITEM can reduce painful joint swelling and prevent the bone damage that current therapies fail to reverse or repair.
In animal studies, PEPITEM was as effective as the standard-of-care prescription drug infliximab at reducing arthritis-related inflammation.
PEPITEM was also able to treat patients without broadly suppressing the immune system, something standard medications do, creating risks of opportunistic infections, cardiotoxicity, and malignancy
Additionally, the risk of toxicity is extremely low because PEPITEM is already naturally present in the body.
Over 53 million Americans suffer from some type of inflammatory arthritis, including rheumatoid arthritis (RA), psoriatic arthritis, gout and ankylosing spondylitis (stock)
If confirmed in human trials, PEPITEM could offer a new approach for early-stage arthritis, reducing reliance on steroids and potentially reversing joint damage rather than just managing symptoms.
Dr Helen McGettrick, study author and expert in inflammation and aging at the University of Birmingham in the UK, said: ‘We have shown observable reversal of clinical disease manifestation, and PEPITEM has the potential to provide an alternative therapy to limit disease severity and progression in early-stage inflammatory arthritis.’
Researchers took blood samples from adults with suspected inflammatory arthritis, which includes rheumatoid arthritis, gout and psoriatic arthritis, who had not started any medication yet.
They compared those samples to the blood of healthy volunteers of the same age. Then, using genetic analysis, they measured how well the patients’ white blood cells responded to adiponectin, the hormone that normally triggers PEPITEM production.
They also measured PEPITEM levels in both blood and joint fluid.
In patients with early arthritis, white blood cells had significantly fewer adiponectin receptors and lower levels of the signaling protein that triggers PEPITEM production.
Next, researchers moved to animal studies in which they caused three different types of inflammatory arthritis in groups of mice: one mimicking rheumatoid arthritis, the second mimicking psoriatic arthritis and a third mimicking acute gouty arthritis.
In some mice, they injected PEPITEM before symptoms appeared. In others, they waited for the first signs of joint swelling before starting treatment, which is also typical in humans.
PEPITEM significantly prevents the onset and reduces the severity of arthritis in a mouse model of rheumatoid arthritis. Mice treated with a vehicle control (placebo, shown in black) developed severe arthritis over time, with their clinical scores rising sharply. In contrast, mice treated with PEPITEM (shown in red) barely developed arthritis at all
They compared these mice to control groups that received either a placebo or infliximab, a standard biologic drug for arthritis.
To measure the effects, the researchers tracked daily joint swelling using a precision measuring instrument called a caliper, scored the severity of arthritis on a clinical scale and analyzed the animals’ joints under microscopes.
They also performed single-cell genetic sequencing on immune cells from the joints to see exactly how PEPITEM changed the cells’ behavior at a molecular level.
In people with early-stage inflammatory arthritis, researchers found that, although PEPITEM was very low in the joints, it was normal or even elevated in the blood, suggesting that it was being blocked from reaching its target.
In the animal studies, PEPITEM prevented arthritis from developing altogether in most mice when given before symptoms appeared.
In mice treated after joint swelling had already begun, PEPITEM reduced disease severity, decreased ankle thickness and lowered the number of immune cells infiltrating the joint.
The peptide worked as well as infliximab. Perhaps the greatest benefit of the experimental peptide infusion, researchers said, was that it did not suppress the immune system, unlike standard autoimmune disease medications.
The gold-standard drug infliximab blocks a key inflammation protein called TNF-alpha.
This figure shows what happened inside the joints of mice with arthritis after treatment with PEPITEM. Researchers took joint tissue and bone samples from mice that received either a placebo or PEPITEM before arthritis symptoms appeared, then examined the samples under microscopes and with 3D bone scans
In people with arthritis, the body makes too much of this protein, causing the immune system to attack its own joints. By stopping that attack, infliximab reduces pain and swelling.
Because the drug shuts down part of the immune system, though, it makes the body far more vulnerable to infections, some of which can be life-threatening, such as tuberculosis, fungal infections, pneumonia, and sepsis.
But PEPITEM did not broadly suppress the immune system. It reduced harmful inflammation while increasing the migration of regulatory T cells, specialized immune cells that act as brakes for an overzealous immune response, into the joints.
Mice treated with PEPITEM also showed less cartilage damage and bone erosion compared to untreated mice with arthritis.
The researchers concluded in their report, published by the journal Arthritis and Rheumatology, that replacing missing PEPITEM could restore the body’s natural brake on inflammation, offering a potential alternative to existing therapies that leave patients vulnerable to infections.
McGettrick added: ‘Previous work has shown PEPITEM has promise as a new therapeutic agent for bone repair, enhancing bone mineralization, formation, and strength, while reversing bone loss.’
Inflammatory arthritis can be debilitating. For most people, it feels like a deep, aching, throbbing pain inside the joint.
The pain is typically worse in the morning or after long periods of sitting, a phenomenon known as gelling. It can take 30 minutes or more of moving around before the joints loosen up.
Top arthritis drugs, including infliximab, are excellent at calming inflammation and preventing additional joint destruction. But once cartilage breaks down or bone wears away, these medications do not repair it (stock)
Many patients also experience intense stiffness, as if the joint were rusted shut. Bending fingers, climbing stairs or something as simple as opening a jar becomes a struggle.
Some describe a burning sensation around the joint, while others feel sudden, sharp, stabbing pains with certain movements.
The pain can be unpredictable, flaring up for no clear reason and disappearing in the same way.
Chronic pain caused by arthritis disrupts sleep night after night, leading to deep, unrelenting fatigue.
Many patients also describe the disease’s emotional weight and the frustration of not having a body that works as well as it once did, and the anxiety that it will only get worse.
