Elevated circulatory Glycine to Histidine ratio in Preclinical models of Rheumatoid Arthritis: A Targeted NMR-based metabolomics study

Description: Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes joint inflammation, bone and cartilage destruction, and sometimes disability. The pathophysiology of RA, on the other hand, is multifactorial and, to a significant extent, unknown. Abnormal glycine metabolism is well established pathophysiological feature in RA [1] and the circulatory levels of glycine are largely reported to be elevated in RA [2].  Further, various clinical studies report the decreased circulatory levels of histidine in RA Patients. The low free serum histidine levels have also been found to be associated with disease activity in RA [3]. Other studies reported higher levels of free histidine in the synovial fluid (SF) compared to that in the patient serum samples of RA (considered to be an inflammatory arthritis condition) but SF histidine levels were significantly lower than corresponding results in patients with osteoarthritis (OA, considered to a non-inflammatory arthritis condition) [4]. Therefore, we hypothesized and demonstrated that the circulatory glycine to histidine ratio (GHR) is significantly elevated in RA compared to NC (with p-value <0.0001). For this, fifty (N= 50) serum samples obtained from thirty (N=30) normal control rats and twenty (N=20) rat models of rheumatoid arthritis (RA, induced using Complete Freund's adjuvant (CFA) treatment) were analyzed using high-resolution 800 MHz NMR spectrometer. The serum metabolic profiles were measured using standard 1D-¹H-CPMG NMR experiments and the concentration levels of selected metabolites (glycine and histidine) were estimated using NMR suite of commercial software CHENOMX following the procedure as described previously from our research group [5].   The mean values (±standard deviation) of circulatory GHR levels in the serum samples of RA and NC rats were found to be 6.65 ± 2.29 and 3.46 ± 0.93, respectively. We further performed the receiver operating characteristic (ROC) curve analysis and the resulted area under ROC curve value of 0.97 (with 95% confidence interval 0.92-1.0 and p-value <0.0001) suggested that the circulatory GHR levels have significant potential to serve as a better preclinical indicator of disease activity in RA and may be a reliable clinical biomarker for monitoring the treatment response in such preclinical models.

References:

[1] Lemon, H.M., Chasen, W.H. and Looney, J.M., 1952. Abnormal glycine metabolism in rheumatoid arthritis. The Journal of clinical investigation, 31(11), pp.993-999.

[2] Trang, L.E., Fürst, P., Odeback, A.C. and Lövgren, O., 1985. Plasma amino acids in rheumatoid arthritis. Scandinavian journal of rheumatology, 14(4), pp.393-402.

[3] Gerber, D.A., 1975. Low free serum histidine concentration in rheumatoid arthritis. A measure of disease activity. The Journal of clinical investigation, 55(6), pp.1164-1173.

[4] Sitton, N. G., Dixon, J. S., Bird, H. A., & Wright, V. (1986). Serum and synovial fluid histidine: a comparison in rheumatoid arthritis and osteoarthritis. Rheumatology international, 6(6), 251-254.

[5] Umesh Kumar, Abhai Kumar, Smita Singh, Payal Arya, Sandeep Kumar Singh, Rameshwar Nath Chaurasia, Anup Singh, and Dinesh Kumar, “An elaborative NMR based plasma metabolomics study revealed metabolic derangements in patients with Mild Cognitive Impairment: A study on North Indian Population” Metabolic Brain Disease (2021) 36, 957–968. (DOI: 10.1007/s11011-021-00700-z)