Blood levels of MIF protein may predict brain atrophy with PPMS

Higher blood levels of macrophage migration inhibitory factor (MIF), a molecule involved in inflammation, may predict a faster rate of brain shrinkage, or atrophy, in people with primary progressive multiple sclerosis (PPMS).

That’s according to a new analysis of data from the SPRINT-MS Phase 2 trial (NCT01982942) that investigated ibudilast, an experimental oral MS therapy aiming to reduce inflammation in people with progressive forms of multiple sclerosis (MS).

While previous trial data showed that ibudilast significantly slowed brain atrophy, the treatment had no effect on MIF levels over its two years. However, “we cannot exclude a functional effect,” the researchers wrote.

The study, “Serum macrophage migration inhibitory factor levels predict brain atrophy in people with primary progressive multiple sclerosis,” was published in the Multiple Sclerosis Journal.

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People with MS have higher than normal levels of MIF in their blood and spinal fluid. This small protein, used by immune cells to communicate with each other, seems to be linked with inflammation and higher disease activity, suggesting that inhibiting it may help in treating MS.

Ibudilast, being developed by MediciNova, aims to ease inflammation by targeting three inflammatory molecules: interleukin-1, tumor necrosis factor-alpha, and interleukin-6. Research, however, has shown it can also inhibit MIF.

Scientist at the Johns Hopkins University School of Medicine set out to examine whether MIF levels are associated with clinical outcomes in people with MS, and how ibudilast affected levels of this protein.

They used data from the completed SPRINT-MS trial, which enrolled 255 people with PPMS and secondary progressive MS (SPMS), and tested up to 100 mg of ibudilast versus a placebo for about two years, both given daily.

Earlier results showed that ibudilast significantly slowed brain volume loss by 48%, and its use also slowed atrophy in retina, a light-sensitive layer of the eye whose thinning indicates neuronal loss in the brain.

“Interestingly, the effect of ibudilast on brain and retinal atrophy in the SPRINT-MS trial was only observed in those with primary progressive multiple sclerosis (PPMS), and not in secondary progressive multiple sclerosis (SPMS),” the researchers wrote.

Their analysis examined how the reported rates of brain atrophy might link with MIF levels in patients’ blood and cerebrospinal fluid (CSF, the liquid surrounding the brain and spinal cord).

Overall, 223 trial participants had available blood measures of MIF, and 68 had CSF assessments. Serial measurements of MIF were available for 205 patients in the blood, and for 34 patients in the CSF.

Significant link between MIF blood levels, brain atrophy in MS patient group

Generally, men tended to have higher MIF blood levels at the start of the trial (baseline measure) than women. This sex difference was not significant for the whole group or among SPMS patients, but it was for people with PPMS. Higher baseline MIF levels in the CSF also were seen in male PPMS patients relative to female patients, but not among those with SPMS.

MIF blood levels significantly associated with the rate of brain atrophy only in PPMS patients, the researchers showed. In this group, every standard deviation increase in baseline MIF blood levels linked with a 0.113% reduction in brain volume.

Results here remained significant after adjusting by factors such as age, use of immunomodulatory MS treatments, and disease duration.

In turn, MIF levels in the CSF at baseline did not predict brain atrophy in either patient group.

Examining MIF levels over time, the researchers found that people with decreasing MIF levels tended to have slower brain atrophy during the trial. However, changes in this protein’s levels over time did not significantly differ between ibudilast or placebo patients with either disease subtype.

A finding that ibudilast did not effect MIF levels in PPMS or SPMS patients “does not exclude the possibility of functional inhibition of MIF-CD74 [an MIF receptor] signaling. Ibudilast may act as an allosteric inhibitor [affecting only the protein’s activity] and thus may not alter levels of MIF,” the researchers wrote.

Further studies in larger patient groups and in tests measuring MIF activity are needed to validate the utility of MIF in predicting likely patient outcomes, and to clarify whether ibudilast effects are partly based on MIF inhibition.