Study Highlights Potential Metabolic Targets in Autoimmune Disease

Though significant advances have been made in the treatment of diseases like rheumatoid arthritis (RA) in recent years, there remain considerable gaps in therapies for patients with autoimmune diseases.

Metabolic pathways have long been understood to play a role in the immune system, and so a better understanding of metabolic responses could be helpful in understanding and treating autoimmune diseases, according to corresponding author Andras Perl, MD, of the State University of New York, Syracuse.

“Various disease-specific derangements in metabolic pathways are identified in lymphocytes derived from systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients,” Perl notes. “With consideration to immune cells, the metabolic signature is known to change depending on stages of development and pathological conditions, whether they are in quiescent, activated, or, memory state.”

Perl and colleagues write in the journal Immunometabolism about some of the most recent findings related to the metabolic signatures of various autoimmune diseases, and the team suggests pathways and specific metabolites that they believe could be fruitful targets for new therapies.

The authors begin with a discussion of RA, noting that the development of new disease-modifying antirheumatic drugs (DMARDS) has greatly improved outcomes in patients with the disease. The authors note that many of these drugs come with a high cost, though, and thus have raised the overall cost of healthcare.

At the same time, Perl and colleagues note that other autoimmune conditions, such as SLE and scleroderma, have not seen the same number of new treatments. The good news, they say, is that there are a number of interesting targets.

Perl and colleagues write that several future potential targets worthy of exploration include the mechanistic target of rapamycin (mTOR), general control nonderepressible 2 (GCN2), Indoleamine-2,3-dioxygenase 1 (IDO1), Arginase 1 (ARG1), and others.

Among them, the authors say the mTOR pathway in particular has considerable potential.

“The mechanistic target of rapamycin (mTOR) pathway is increasingly recognized as one of the key drivers of proinflammatory responses in autoimmune diseases,” the authors write.

In patients with SLE, Perl and colleagues say therapeutic options include sirolimus, N-acetyl cysteine, metformin, and halofuginone hydrobromide, but they also note that some patients with SLE appear to have improved after taking fish oil.

The authors say research in metabolomics has made a clear impact in developing therapeutics and targets in a number of autoimmune disorders.

“Targeting glycolysis via mTOR with sirolimus has clearly been shown in both humans and mice to ameliorate both surrogate markers (such as anti dsDNA) as well as composite validated disease measures such as [SLE Disease Activity Index] and [British Isles Lupus Activity Group scores],” they write. “While balancing energy production between [oxidative phosphorylation] and glycolysis has been studied extensively, maintenance of a reducing environment by the [pentose phosphate pathway] and other antioxidant pathways is far less understood.”

Going forward, Perl and colleagues suggest that continued research into cell-type activation of mTOR complexes and the introduction of mTORC2 or dual mTORC1/mTORC2 complex inhibitors could provide potential new therapeutic options for patients with SLE.

Reference

Piranavan P, Bhamra M, Perl A. Metabolic targets for treatment of autoimmune diseases. Immunometabolism. 2020;2(2):e200012. doi: 10.20900/immunometab20200012