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Alterations in tryptophan metabolism are common among patients with rheumatoid arthritis (RA), researchers found, and preclinical studies suggest that correcting them is a viable treatment strategy.

Participants in France's so-called of individuals with early, as-yet-untreated RA showed marked differences in levels of several tryptophan metabolites relative to healthy controls, including increases in some and decreases in others, according to Harry Sokol, MD, PhD, of Sorbonne Université in Paris, and colleagues.

Specifically, two players in tryptophan's kynurenine metabolic pathway -- kynurenic acid (KA) and xanthurenic acid (XA) -- were downregulated in the RA patients, while quinolinic acid was upregulated, the researchers .

And when mice were treated with an enzyme that raises KA and XA production, they resisted development of collagen antibody-induced arthritis, a standard lab model of RA.

All of which suggests that RA might be treated without messing with immune system components, with improved safety and the possibility of layering with existing anti-rheumatic drugs.

Tying tryptophan metabolism to RA isn't new, Sokol's group observed. This amino acid is important in many body functions, including generation of serotonin. Researchers had found that RA patients displayed alterations in some of the same metabolites analyzed in the new study, suggestive of a causative (or at least contributory) role. However, efforts to translate those findings into therapies never took off.

Sokol and colleagues, however, believed that this avenue deserved another look with modern techniques: in particular, "quantitative metabolomics to provide a global and accurate overview of [tryptophan] metabolism alterations in a large cohort of early untreated patients with RA and relevant RA experimental models."

To start, the group performed metabolomic testing on stored samples from ESPOIR, a 574-person cohort assembled about 20 years ago, and on 98 serum samples from healthy local blood donors. A replication cohort of 69 RA patients, drawn from a previous pharmacodynamic study of adalimumab (Humira), was also analyzed.

Not only did levels of KA and XA differ between patients and controls, but the levels in RA correlated quantitatively with clinical parameters such as swollen joint counts and morning stiffness, and also with multiple interleukin species and other inflammation-related biomarkers. This was seen in both the ESPOIR and adalimumab study cohorts.

For the animal model studies, Sokol and colleagues used recombinant aminoadipate aminotransferase (AADAT) to boost KA and XA release. This enzyme is broadly active in mammals, catalyzing a number of biologically important transformations that can involve lysine, methionine, and glutamate as well as tryptophan. Previous research had shown that its activity is suppressed in animals as they develop artificially induced arthritis, rebounding as the condition resolves with time.

Notably, this body of research indicates that "decreased AADAT level is a consequence of inflammation rather [than] RA specific," Sokol and colleagues wrote. Moreover, they argued, "it is still unknown how [tryptophan] metabolism impacts RA pathogenesis, but we can suggest that these metabolites may modulate the cellular energy of targeted cells." As a treatment approach, therefore, targeting this pathway should be completely independent of the mechanisms underlying current RA drugs, which mainly seek to deactivate particular immune system components -- and thus, at least in theory, raising the possibility of combination therapies that don't further increase infection risks beyond those with conventional treatments.

Sokol's group emphasized that more research is needed before human studies could be considered. There is the possibility of off-target effects from AADAT, given its wide range of normal substrates. Just as important, the full spectrum of activity involving KA, XA, and other tryptophan metabolites is not understood; "dedicated studies" in this direction are needed, the researchers wrote.

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