PEPITEM ‘replacement therapy’ shows potential for early-stage inflammatory arthritis

Scientists investigating the naturally occurring immunopeptide PEPITEM have shown reductions in arthritic joint swelling to a degree comparable to the current standard of care, and reduce the inflammatory changes that cause joint damage.

PEPITEM (Peptide Inhibitor of Trans-Endothelial Migration) was first discovered by researchers at the University of Birmingham, who characterized the Adiponectin-PEPITEM pathway.

This tightly orchestrated process regulates immune function and immune cell trafficking between different parts of the body, providing a natural homeostasis (balance) between immune activation and suppression.

New study explores arthritis pathway

In the most recent study, led by Professor Helen McGettrick from the University of Birmingham, UK with collaborators from the University of Federico III, Naples, Italy, researchers investigated how this pathway is dysregulated in inflammatory arthritis, and the efficacy of PEPITEM in pre-clinical animal models.

Inflammatory arthritis is a group of diseases including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), where the immune system attacks the joints, causing severe joint damage, pain, and disability.

Under normal conditions, adiponectin in the bloodstream stimulates white blood cells to produce PEPITEM, which in turn reduces white blood cell migration in the tissues, so preventing an unregulated inflammatory response. However, in inflammatory arthritis, white blood cells fail to respond to adiponectin, and secrete less PEPITEM in the joint. The natural “brake” that prevents white cell migration into the joint cavity is lost, and the inflammatory response becomes unregulated.

Preclinical results show strong potential

The researchers examined the effect of PEPITEM in human and animal studies, and the results, published in Arthritis and Rheumatology, show promise.

Professor Helen McGettrick 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.

“There could be significant benefits over existing therapies, which are immunosuppressive in otherwise healthy populations, the risk of toxicity from natural peptide is extremely low, and administration in early disease could reduce reliance on steroids in the earliest phases of rheumatoid arthritis and psoriatic arthritis.”

Human samples reveal reduced response

The initial study of peripheral blood mononuclear (PBMCs, white blood cells) harvested from treatment naïve human donors with suspected inflammatory arthritis, showed a reduced capacity to respond to adiponectin, which could be restored by the addition of PEPITEM.

Further examination of whole blood indicated a lower bioavailability of PEPITEM in patients with early RA, leading the researchers to hypothesize that supplementation with PEPITEM could restore immune regulation, and reduce the inflammatory changes seen in early-stage disease.

Animal models highlight therapeutic effects

Their work in animal (mouse) models of inflammatory arthritis conducted in Birmingham and gouty arthritis conducted by collaborators in Naples, showed that injection of synthetic PEPITEM, could prevent the onset of inflammatory arthritis, with significant reductions in disease incidence. In addition, joint swelling was reduced by PEPITEM when compared with infliximab—the current standard of care.

Tissue studies confirmed that these changes were mirrored in synovial tissue (tissue inside the joints), with significantly less joint inflammation, cartilage damage and bone erosion observed in PEPITEM treated mice, and significantly fewer leukocytes (white blood cells) infiltrating the joints.

Molecular findings and wider implications

Molecular studies showed significant down-regulation of inflammatory mediators (NF-kB and COX2 protein) within the synovial tissue in PEPITEM-treated mice compared to controls, and a significant increase in the foxp3 transcript, which is crucial for the development of a type of white blood cell that suppresses the immune response, to prevent excessive inflammation and autoimmune disease.

Professor 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. Even when inflammation is therapeutically well controlled, existing Disease-Modifying Anti-Rheumatic Drugs (DMARDs) do not reverse joint damage.”