Axial spondyloarthritis (AxSpA), a painful and debilitating form of arthritis that affects almost 1% of people worldwide, causing inflammation of the spine, joints, eyes, gut and skin. Currently there is a very limited drug arsenal against this devastating disease, which has a serious impact on the quality of life. Although several treatments, including biotherapies, have been approved for AxSpA, nearly 50% of patients do not respond to any treatment and develop severe pain and bone deformities. But it is not just the disease itself that these patients face. Compared to the average population, they may also have a 30% increase in cardiovascular events or mental illnesses such as depression; and a 60% increase in the likelihood of stroke. Hence, there is a desperate need to find new treatments that are effective and cover all clinical symptoms. In an article published today in the journal Science Translational Medicine, researchers from the Schroeder Arthritis Institute, part of the University Health Network of Toronto, they made a discovery that could lead to new treatments for this condition.
The study focuses on the role of the macrophage migration inhibitory factor (MIF), which works as a protein that induces an inflammatory or immune response in the body. It is well known for its pro-inflammatory effects and is recognized as a negative regulator of the immunosuppressive actions of glucocorticoids. In line with this, MIF has been implicated in the development of many acute inflammatory and autoimmune diseases, as well as chronic inflammatory metabolic disorders. MIF can act via its CD74 receptor and controls the recruitment of inflammatory cells through the chemokine receptors CXCR2 and CXCR4. Furthermore, MIF can exert proinflammatory effects through its enzymatic activities, one being an oxido-reductase and the other a structure “tautomerase”. Several experimental evidences provide indications that MIF, in addition to regulating inflammation, may also be linked to energy metabolism, also controlling inflammatory and metabolic processes including insulin resistance. Until now, however, the role that MIF plays in the progression of the disease of SpA was unknown.
In their 2017 publication, the researchers found that the concentration or expression of MIF substantially increased in the blood, joint fluids, and intestinal tissues of AxSpA patients, compared with those of a different type of arthritis patients or healthy volunteers. In the same paper, they also showed that MIF could be involved in promoting the development of new bone formation. These recent findings have helped to consolidate those findings and further understanding of MIF’s role in aXSpA. In this study, the researchers observed that the expression of MIF and its CD74 receptor increased in the blood and tissues of preclinical models; and that patient neutrophils secrete higher concentrations of MIF than healthy individuals.The specific blocker of MIF, called MIF098, successfully prevented and limited the onset of the disease and its development in the preclinical model. The team will now focus on testing the potential of other MIF-targeted therapies, which could lead to finding a new treatment.
This, in turn, prompts the system to cause more inflammation. With these new notions, the researchers hope to test the efficacy of MIF blockers in patients with SpA through clinical trials, in which they would seek to determine the optimal concentration and frequency of administration of MIF-targeted drugs for humans, as well as to study potential side effects, to ensure safety. Currently available drugs do not work for half of all patients with AxSpA. Therapy with NSAIDs and steroids is not always effective and serious complications may appear over time. Interestingly, one of the first MIF inhibitors discovered by chance is NAPQ, which is a redox metabolite of paracetamol, the common Tylenol. The fact that often patients not responsive to steroids or NSAIDs can find relief with paracetamol doses of 1-2 gr/day, suggests that this drug can also act by interfering on the MIF. There are also natural molecules that interfere with the enzymatic activity of MIF: among these some polyphenols from licorice, the soy isoflavones and ellagic acid.
This polyphenol is well represented in foods such as strawberries, pomewgranate, grape seeds, walnuts, pecans, cranberries and goji berries. These are all foods rapresented in the so called Auto-Immune Protocol diet (AIP), engineered few years ago to possibily treat autoimmunities like rheumatoid arthritis and LES. There are no known studies indicating that these substances affect the clinical progression or symptom management of spondylopathies. However, introducing these foods with a regulated lifestyle and in the context of an anti-inflammatory diet, may contribute to conditioning the pain which is one of the major frustrating symptoms of this pathology.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Advised in this website
Nakamura A et al. Sci Translat Med 2021; 13(616):eabg1210.
Hernández-Palma LA et al. Cytokine. 2019 Mar; 115:89-96.
Trivedi-Parmar V et al. J Med Chem. 2018; 61(18):8104-19.
Kim KW, Kim HR. Korean J Intern Med. 2016; 31(4):634-42.
Morrison MC, Kleemann R. Front Immunol. 2015 Jun; 6:308.
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