Table 1.
Changed metabolites in rheumatoid arthritis (RA). Biomarker category highlighted in bold: Corresponding metabolites listed in column “Results”.
| Reference | Matrix | Instruments | Disease Activity and/or Severity |
Patients Treated? |
Biomarker Categories * |
Results | |
|---|---|---|---|---|---|---|---|
| Rantapää-Dahlqvist 1991 [50] | Plasma | ELISA and radioimmunoassay kit |
Median | Yes | D | ↑ | lipoprotein (a) |
| ↓ | cholesterol, HDL | ||||||
| Lauridsen 2010 [44] |
Plasma | 1H-NMR | Mixed: DAS28 active (5.0), in remission (2.6) |
N/A | D, M | ↑ | cholesterol C-21, lactate, acetylated glycoprotein, unsaturated lipid |
| ↓ | HDL | ||||||
| Chandrasekharan 2018 [36] | Plasma | LC–MS | DAS28 (2.7) | Yes (mixed) | D, Ri | ↑ | L-ornithine, ADMA, SDMA |
| ↓ | L-citrulline | ||||||
| Sasaki 2019 [32] | Plasma | CE–Q-TOF-MS | Mixed: DAS28-ESR active (>3.2), inactive (<3.2) |
No biologicals | D, M | ↑ | N,N-dimethylglycine, urea |
| ↓ | guanidoacetic acid, histidine, homoarginine or N6,N6,N6-trimethyllysine | ||||||
| Kishikawa 2021 [60] | Plasma | CE–TOF-MS | N/A | N/A | D | ↑ | ethanolamine phosphate, ATP, GDP, ADP, 6-aminohexanoic acid, taurine |
| ↓ | xanthine | ||||||
| Liu 2021 [33] | Plasma | UPLC–LTQ/Orbitrap- MS | N/A | No (rat model) | D | ↑ | glutamic acid, arginine, methionine |
| ↓ | proline, valine, tyrosine, phenylalanine, leucine, glycine, tryptophan, histidine, threonine | ||||||
| He 2021 [28] | Plasma | GC–Q-TOF-MS | Mixed: medium, high | N/A | D | ↓ | glutamine, cysteine, citric acid |
| Krähenbühl 1999 [46] | Plasma, Urine | Radioenzymatic assay and HPLC | DAS (4.35) | N/A | D | ↑ | in plasma: long-chain acylcarnitine |
| ↓ | in urine: carnitine | ||||||
| Madsen 2011 [34] | Serum | GC–TOF-MS and UPLC–MS |
Mixed: DAS28 (4.06) | Yes (mixed) | D | ↑ | glyceric acid, D-ribofuranose, hypoxanthine |
| ↓ | histidine, threonic acid, methionine, cholesterol, asparagine, threonine | ||||||
| Ouyang 2011 [29] | Serum | 1H-NMR | N/A | Yes (mixed) | D | ↑ | lactic acid |
| ↓ | glucose, creatinine, pyruvate, citrate, proteinogenic AAs, glycerides, phosphocholine | ||||||
| Young 2013 [43] | Serum | 1H-NMR | N/A | Naive for DMARDs | D, M | ↑ | 3-hydroxybutyrate, lactate, acetylglycine, taurine, glucose |
| ↓ | LDL-CH3, LDL-CH2, alanine, methylguanidine, lipids | ||||||
| Jiang 2013 [26] | Serum | GC–TOF-MS and UPLC–QTOF-MS |
Mixed: active, mild, or moderate | N/A | D, M | ↑ | homoserine, glyceraldehyde, lactic acid, dihydroxyfumaric acid, aspartic acid |
| ↓ | 4,8-dimethylnonanoyl carnitine | ||||||
| Zabek 2016 [37] | Serum | 1H-NMR | DAS28 (6.84) |
Yes (no TNFi) | D, M | ↑ | 3-hydroxyisobutyrate, acetate, NAC, acetoacetate, acetone |
| ↓ | valine, isoleucine, lactate, alanine, creatinine, GPC APC, histidine | ||||||
| Zhou 2016 [49] | Serum | GC–MS | N/A | N/A | D | ↑ | fatty acids, cholesterol, carbohydrates |
| ↓ | amino acids, glucose, 1,5-anhydrosorbitol, urate, 2-ketoisocaproate | ||||||
| Li 2018 [54] | Serum | UPLC–HRMS | DAS28 (median 6.40) |
N/A | D | ↑ | 4-methoxyphenylacetic acid, glutamic acid, leucine, phenylalanine, tryptophan, proline, glyceraldehyde, fumaric acid, cholesterol |
| ↓ | capric acid, argininosuccinic acid, bilirubin | ||||||
| Dubey 2019 [30] | Serum | 1H-NMR | N/A | No DMARDs | D | ↓ | compared to reactive arthritis: leucine, valine, phenylalanine, arginine/lysine |
| Souto-Carneiro 2020 [61] | Serum | 1H-single-pulse NMR and CPMG NMR |
DAS28-CRP (2.3) | Yes |
D (RA/PsA) |
↑ | phenylalanine |
| ↓ | alanine, threonine, leucine, valine, acetate, creatine, lactate, choline, lipid ratios | ||||||
| Luan 2021 [35] | Serum | LC–HRMS | Mixed: low, moderate, high | N/A | D | ↑ | CAR 20:3, aspartyl-phenylalanine, pipecolic acid, PE (18:1), LPE (20:3) |
| ↓ | histidine, phosphatidic acid (28:0) | ||||||
| Koh 2022 [59] | Serum, SF | UPLC–Q-TOF-MS | Mixed: low, high | No lipid modulators | D, M | ↑ | LPC, PC, EtherPC, PE, SM subclasses |
| Liao 2013 [52] | Blood | N/A | N/A | Yes | D | ↓ | total cholesterol, LDL |
| Yang 2015 [45] | SF | GC–TOF-MS | Mixed: DAS28 inactive (<3.2), active (>3.2) | N/A | D | ↑ | lactic acid, carnitine, pipecolinic acid, diglycerol, beta-mannosylglycerate |
| ↓ | valine, citric acid, gluconic lactone, glucose, G-1-P, mannose, ribitol, 5-methoxytryptamine | ||||||
| Alonso 2016 [41] | Urine | 1H-NMR | Mixed: DAS28 very low (1.7), very high (5.5) | Yes | D, M | ↑ | tyrosine |
| ↓ | N-acetyl amino acids, citrate, alanine, carnitine | ||||||
| Sasaki 2019 [32] | Urine | CE–Q-TOF-MS | Mixed: DAS28-ESR active (>3.2), inactive (<3.2) |
No biologicals | D, M | ↑ | 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 2-quinolinecarboxylic acid, gibberellic acid, hypotaurine, N-acetylglucosamine 1-phosphate, riboflavin |
| Hur 2021 [62] | Plasma | UPLC–MS | Mixed: DAS28-CRP (3.0) | Yes | M, D | ↑ | glucuronate |
| ↓ | 6-bromotryptophan, bilirubin, biliverdin, N-acetyltryptophan, N-acetyltyrosine, serine, trigonelline | ||||||
| Priori 2015 [39] | Serum | 1H-NMR | DAS28-CRP responders (median 4.56), non-res. (median 4.65) |
Yes (etanercept plus DMARDs and/or GC) | Pre | ↑ | isoleucine, leucine, valine, alanine, glutamine, tyrosine, glucose |
| ↓ | 3-hydroxybutyrate | ||||||
| Cuppen 2016 [63] | Serum | LC–MS | DAS28 (4.5) | No biologicals | Pre, M | ↑ | in good responders: sn1-LPC (15:0), lysine |
| ↓ | in good responders: sn1-LPC (18:3-ω3/ω6), ethanolamine | ||||||
| Takahashi 2019 [40] | Serum | CE–TOF-MS | Mixed: moderate, high | Yes (TNFi or abatacept) | Pre | ↑ | TNFi responders: betonicine; ABT responders: citric acid, quinic acid |
| ↓ | TNFi res.: glycerol 3-phosphate, N-acetylalanine, hexanoic acid, taurine; ABT res.: 3-aminobutyric acid | ||||||
| Kapoor 2013 [42] | Urine | 1D-NMR | Severe | Yes | Pre | ↑ | histamine, glutamine, xanthurenic acid |
| ↓ | ethanolamine | ||||||
| Surowiec 2016 [64] | Plasma | LC–MS | None | No | Pro | ↑ | kynurenine, LPC (16:0), hypoxanthine, LPC (14:0), 3-indolelactic acid, PLs, SM |
| ↓ | oleic acid, β-hydroxypalmitic acid, fatty acids, acylcarnitines | ||||||
| Chu 2020 [47] | Plasma | UHPLC–HRMS | Healthy | No | Pro | ↓ | acylcarnitine, cholesterol ester, polyamine |
| van Halm 2007 [53] | Serum | ELISA, immunoturbidimetric method | Healthy | N/A | Pro | ↑ | total cholesterol, triglycerides, apo B |
| ↓ | HDLc | ||||||
| Myasoedova 2010 [51] | Blood | N/A | N/A | N/A | Pro | ↓ | total cholesterol, LDL |
| Jonsson 2001 [58] | Serum | Dry chemistry, ELISA | Early | Yes (mixed) | Ri | ↑ | cholesterol, LDL, LDL/HDL ratio |
* D, diagnostic; M, monitoring; Pre, predictive; Pro, prognostic; Re, response; Ri, risk; S, safety.