Introduction
Materials and Methods
Systematic Review Protocol and PEO
Search Strategy and Algorithm
Inclusion and Exclusion Criteria
Outcomes of Interest
Quality of Studies
Data Extraction
Data Synthesis
Results
Search Results
Studies Characteristics
Study Design and Origin
Biological Fluids
Samples
Bazzichi [39] | Ciregia [38] | Fineschi [37] | Han [46] | Hsu [45•] | Khoonsari [41] | Khoonsari [42] | Ramirez-Tejero [40] | Ruggiero [43] | Wahlen [44] | ||
---|---|---|---|---|---|---|---|---|---|---|---|
Year | 2009 | 2018 | 2022 | 2020 | 2021 | 2018 | 2018 | 2018 | 2014 | 2020 | |
Οrigin | Italy | Italy | Sweden | Taiwan | Taiwan | Sweden | Sweden | Spain | Italy | Sweden | |
Funding | NR | Yes | Yes | Yes | Yes | Yes | NR | Yes | No | Yes | |
Biological fluid used | Saliva | Saliva | Serum | Serum | Serum, urine | CSF | CSF | Plasma | Serum | Plasma | |
Recruitment site | NR | Rheumatology Unit | Health Care Center, Pain Clinic | University Hospital | Outpatient Clinics | FMS Association | Outpatient Dept of Rehabilitation | FMS Association | NR | Part of RCT | |
Patients (n) | 22 | 30a | 30 | 20 | 30 | 39 | 13 | 12 | 16 | 30 | |
Controls (n) | 26 HC | 30 RA, 30 MG, 30 HCa | 24 HCb | 20 HC | 25 HC | 38 HC | 11 RA, 8 OND | 12 HC | 12 HC | 31 HC | |
Age (years) | Patients | 43.4 ± 13.2 | 49.9 ± 12.5 | 48.8 ± 10.9 | 52.9 ± 9.6 | 52.1 ± 2.0 | 47.2 ± 9.2 | 47 (25–60)f | 50.6 ± 6.3 | 52 ± 12 | 54 (13)e |
Controls | 38.8 ± 11.5 | 45.4 ± 13.2 RA, 46.4 ± 14.3 MG, 42.6 ± 6.2 HC | 50.0 ± 11.5 | 47.5 ± 7.5 | 51.2 ± 1.8 | 47.9 ± 14.4 | 52 (39–59)f RA, 53 (45–60)f OND | 47.6 ± 7.9 | 48 ± 13 | 57 (9)e | |
Sex (n) | Patients | F | 51 F, 9 M | - | F | 29 F, 1 M | F | F | F | F | F |
Controls | F | 52 F, 8 M RA | - | F | 24 F, 1 M | 5 F, 33 M | F | F | F | F | |
46 F, 14 M MG 40 F, 20 M HC | |||||||||||
ACR criteria used | 1990 | NR | 2009, 2016 | 2010 | 2011 | 1990 | 1990 | 1990 | 2010 | 1990 | |
Duration of diagnosis | - | 5.2 ± 4.3 yrs | - | 9.1 ± 8.9 yrs | - | - | - | - | 6.3 ± 4.5 mo | 12 (14)e yrs | |
BMI (kg/m2) | - | - | - | 22.8 ± 4.0 | - | 25.8 ± 8.4 | - | - | 27 ± 5 | 26 (6)e | |
VAS | 7.9 ± 1.9 | 6.5 ± 2.5 P | - | 5.0 ± 2.2 | 5.3 ± 0.4 | - | 6.7 FM | 5.6 ± 2.8 | 5.7 ± 3.1c | 5.0 (3.6)c,e | |
7.7 ± 2.5 Fa | 2.5 RA | ||||||||||
4.5 ± 3.1 An | |||||||||||
PPT (kPa) | - | - | - | 230.5 ± 102 | - | - | - | - | - | 175 (88)e | |
Tender points (n) | 14 ± 3 | 16 ± 4 | - | - | - | - | - | - | - | 16 (2)e | |
WPI | - | - | 12.8 ± 2.6 | 7.4 ± 4.8 | 8 ± 1 | - | - | - | - | - | |
FIQ | 66.8 ± 14.4 | 61 ± 15 | - | 43.5 ± 12.7 | - | - | - | 52.4 ± 17.1 | 61.8 ± 21.9 | 58 (24)e | |
FACIT | - | 23 ± 10 | - | - | - | - | - | - | - | - | |
PCS-12 | - | 47 ± 24d | - | - | - | - | - | 33.5 ± 9.2 | - | - | |
MCS-12 | - | 48 ± 19d | - | - | - | - | - | 38.5 ± 14 | - | - | |
SSS | - | - | - | 5.1 ± 2.5 | - | - | - | - | - | - | |
PSQI | - | 13.0 ± 3.1 | - | 10.4 ± 3.0 | - | - | - | - | - | - | |
BAI | - | - | - | 13.9 ± 8.8 | - | - | - | - | - | - | |
BDI | - | - | - | 14.0 ± 9.8 | - | - | - | - | - | - | |
HADS | - | - | - | - | - | - | - | - | - | 13 (14)e | |
Proteomics methodology | 2-DE/MALDI-TOF/TOF | 2-DE/SELDI-TOF MS | Olink proteomics | LC–MS/MS | NanoLC-MS/MS, QTOF | NanoLC-MS/MS | LC–MS/MS | NanoLC-MS/MS | 2-DE/MS MS, MALDI-TOF/TOF | 2-DE/MS | |
Database used | UniProt | - | - | UniProt | UniProt | UniProt | UniProt | UniProt | NCBI | UniProt | |
Identified proteins (n) | 13 | 467 | 94 | 375 | 8 | 299 | 1422 | 266 | 3 | 381 | |
Different proteins (n) | 11 | 17 | 19 | 22 | 8 | 4 | 10 | 33 | 3 | 18 |
FMS Diagnostic Criteria
Medications
Pain and Quality of Life Scales
Proteomic Methodology and Database
Quality of Included Studies
Proteins Identified
Proteins Identified in Saliva and Their Role
Identified proteins | UniProt ID | Difference compared to controls | Role(s) | Studies reporting difference |
---|---|---|---|---|
TALDO | P37837 | ↑ | Pentose Pathway and NADPH [113] | |
PGAM1 | P18669 | ↑ | Glycolysis [55] | |
S100-A8 S100-A12 | P05109 P80511 | ↑ ↑ | S100 proteins, OS [114] | |
PSMA2 | P25787 | ↑ | Ubiquitin-dependent abnormal protein degradation | Bazzichi [39] |
RhoGDI2 | P52566 | ↑ | Metastasis inhibitor | Bazzichi [39] |
HPR | P00739 | ↑ | Innate immunity | Bazzichi [39] |
CFL1 | P23528 | ↑ | Cytoskeleton [143] | Bazzichi [39] |
CyPA | P62937 | ↑ | Cyclosporine receptor, role in protein folding [144] | Bazzichi [39] |
PFN1 | P07737 | ↑ | Cytoskeleton [73] | Bazzichi [39] |
AMY1A | P04745 | ↑a | Digestion of starch in the oral cavity | Ciregia [38] |
ΕΝΟ1 | P06733 | ↑ | Glycolysis, anti-ENO1 antibodies in NSI | Ciregia [38] |
GSTP | P09211 | ↑a | Reduced glutathione conjugation, link to PGA2 | Ciregia [38] |
IgKC, Iglc2 | P01834 P0CG05 | ↑ ↑ | Constant region of immunoglobulin light chains | Ciregia [38] |
pIgR | P01833 | ↓a | IgA and IgM transcytosis in mucosal epithelial cells | Ciregia [38] |
Albumin | P02768 | ↑b | Plasma protein | Ciregia [38] |
TRFE | P02787 | ↑ | Main iron-binding protein [82] | Ciregia [38] |
CYS | P01037 | ↓ | Cell cycle | Ciregia [38] |
Proteins Identified in the CSF and Their Role
Identified proteins | UniProt ID | Difference compared to controls | Role(s) | Studies reporting difference |
---|---|---|---|---|
L1CAM | P32004 | ↑ | Neuronal structure–function, synaptic plasticity [145] | Khoonsari [42] |
C4-A | P0C0L4 | ↑ | Classical complement pathway [146] | Khoonsari [42] |
LYSC | P61626 | ↑ | Bacteriolytic | Khoonsari [42] |
PTPRz | P23471 | ↑ | Differentiation into mature, fully myelinated oligodendrocytes, protection from apoptosis [147] | Khoonsari [42] |
ApoD | P05090 | ↓ | Component of HDL | Khoonsari [41] |
α1ACT | P01011 | ↓ | Unclear | Khoonsari [42] |
PGRN | P28799 | ↑ | Regulator of lysosomal function and growth factor involved in inflammation and cell proliferation [148] | Khoonsari [42] |
LRP1 | Q07954 | ↓a | Phagocytosis of apoptotic cells [149] | Khoonsari [42] |
ApoC3 | P02656 | ↑ | Atherogenic protein [57] | Khoonsari [41] |
LG3BP | Q08380 | ↑ | Cell-to-cell adhesion, pro-inflammatory signaling | Khoonsari [41] |
PCSK1 | P29120 | ↑ | Neuropeptides [150] | Khoonsari [41] |
MDH | P40925 | ↓ | Gluconeogenesis [60] | Khoonsari [41] |
CAMKIIα | Unknown | ↓a | Many cascades, learning and memory | Khoonsari [42] |
cKIT | A0A0U2N547 | ↑b | Stem cell growth factor receptor | Khoonsari [42] |
Proteins Identified in Plasma and Their Role
Identified proteins | UniProt ID | Difference compared to controls | Role(s) | Studies reporting difference | ||
---|---|---|---|---|---|---|
Complement | C1Qc C9 C2 CFAΗ C1S C7 C1r C3B CFI C4B | P02747 P02748 P06681 P08603 P09871 P10643 P00736 P01024 P05156 P0C0L5 | ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↔ ↔ ↔ | Apart from CFAH (an inhibitory protein of the alternative pathway), the remaining are involved in forming the membrane attack complex. This pathway is triggered by IgM/IgG-immunocomplexes, leading to chemotaxis and plasma protein secretion, facilitating opsonization. C3B acts as an opsonin [146] | Ramirez-Tejero [40] Wahlen [44] | |
Coagulation | IX, Χ, FGA, FGB, FGG, protein S, ZPI, PLG, KNG1, B2GP, α2AP | P00740 P00742 P02671 P02675 P02679 P07225 Q9UK55 P00747 P01042 P02749 P08697 | ↑ ↑ ↓ ↑ ↑ ↓ ↑ ↓ ↓ ↑ ↔ | The complement cascade can be activated by coagulation proteins. FGA, FGB, and FGG form fibrin. IX and X are activators of the complement cascade. ZPI is an anticoagulant protein that inhibits the activity of clotting factors. PLG is converted to plasmin, while B2GP is associated with the APS [151] | Ramirez-Tejero [40] Wahlen [44] | |
Lipid metabolism: | ApoL1, ApoC2, ApoC3, FETUB | O14791 P02655 P02656 Q9UGM5 | ↑ ↑ ↓ ↓ | ApoL1 is part of HDL; ApoC2 and ApoC3 regulate triglyceride metabolism. Relationship of FETUB to atherosclerosis [152] | Ramirez-Tejero [40] Wahlen [44] | |
Ig structure | IgHM, IgAC, IgKC | P01871 P01876 P01834 | ↑ ↑ ↓ | Parts of Igs, each with specific roles in the immune response | Ramirez-Tejero [40] Wahlen [44] | |
Acute phase reactants | SAP, SAA4 A1AGP1, A1AGP2, Hp, HRG, PZP | P02743 P35542 P02763 P19652 P00738 P04196 P20742 | ↑ ↑ ↑ ↑ ↑ ↓ ↑ | Inflammation and tissue damage response. Concentration increases in acute phase reactions. HRG is a negative inflammation marker, with levels decreasing in the acute phase [153] | Ramirez-Tejero [40] Wahlen [44] | |
Hormone-related | TBG, CBG, AGT | P05543 P08185 P01019 | ↓ ↓ ↓ | TBG and CBG are thyroxine and corticosteroid transporters, respectively AGT is linked to the RAAS | Ramirez-Tejero [40] | |
Transferrin (TRFE) | P02787 | ↑ | Iron-binding protein [68] | Ramirez-Tejero [40] Wahlen [44] | ||
A2M | P01023 | ↔ | Protease inhibitor, immune response (trapping proteases), coagulation, inflammation, autoimmunity [135] | |||
CA | P00915 | ↓ | Acid–base balance | Ramirez-Tejero [40] | ||
CD14 | P08571 | ↓ | Recognizes bacterial components, immune response [154] | Ramirez-Tejero [40] | ||
Structural | GSN, Aktin cytoplasmic 1 | P06396 P60709 | ↑ ↑ | Cytoskeleton | Ramirez-Tejero [40] Wahlen [44] | |
THBS1 | P07996 | ↑ | Angiogenesis inhibition, coagulation cascade [79] | Ramirez-Tejero [40] | ||
A1BG | P04217 | ↓ | Unknown [155] | Wahlen [44] |
Proteins Identified in the Serum and Their Role
Identified proteins | UniProt ID | Difference compared to controls | Role(s) | Studies reporting difference | |
---|---|---|---|---|---|
Complement | C4A, C1qC | P0C0L4 P02747 | ↑ ↑ | Han [46] Hsu [45•] | |
Coagulation | FGA, FGB, FGG, Prothrombin, GPV, GP1BA | P02671 P02675 P02679 P00734 P40197 P07359 | ↓ ↓ ↓ ↓ ↓ ↓ | FGA, FGB, and FGG polymerize and create fibrin. Platelet glycoproteins allow platelets to adhere to damaged vessel walls [151] | Han [46] Hsu [45•] |
Retinoid transporters: | TTR, RBP4 | P02766 P02753 | ↑ ↑ | The increase might be due to hypovitaminosis A [43] | Ruggiero [43] |
Ig form: | GLV3-25, HG3, GHV1OR15-1 IGLC2 | P01717 P01743 P23083 P0CG05 | ↓ ↓ ↓ ↓ | Parts of Igs, each with a specific role in immune response | Han [46] |
Acute phase | SAP, SAA4 | P02743 P35542 | ↑ ↓ | Inflammation response, tissue damage. Levels increase in acute phase reactions [153] | Han [46] |
Cell signaling, cytokines, receptors | IL1RAP, CD16B, CD16A, IL-18R1, CD40, IL-10RB, TNFRSF9, IL-8, TNF, TNFSF14, CD5, CCL3 | Q9NPH3 O75015 P08637 Q13478 P25942 Q08334 Q07011 P10145 P01375 O43557 P06127 P10147 | ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ | Inflammatory: IL1RAP, IL-8, TNF, TNFSF14, CCL3 Anti-inflammatory: IL-10RB Regulatory: IL-18R1, CD5 Pro-inflammatory, depending on signaling: TNFRSF9 | Fineschi [37] Han [46] |
Growth factors | FGF-21, FGF-19, FGF-23, CSF-1 | Q9NSA1 O95750 Q9GZV9 P09603 | ↑ ↑ ↑ ↑ | FGF/FGFR pathways participate in the development of most organs, angiogenesis and lymphangiogenesis [159] | Fineschi [37] |
KRT80, PFN1 | Q6KB66 P07737 | ↑ ↓ | Cytoskeleton. PFN1 interacts with autophagy proteins [72] | Han [46] | |
Enzymes | SIRT2, SULT1A1, MMP10, HMT1 | Q8IXJ6 P50225 P09238 O95568 | ↑ ↑ ↑ ↑ | SIRT2, a cell-cycle regulator, deacetylates target proteins. SULT1A1 transfers a sulfur group. MMP10 degrades extracellular substance components, HMT1 is a methyltransferase | Fineschi [37] Han [46] |
Protease inhibitors | AAT, SEPRINB3 | P01009 P29508 | ↑ ↓ | Protease inhibition, tissue protection. AAT protects lungs from neutrophil elastase [160] | Hsu [45•] Ruggiero [43] |
S100 | S100-A7, S100-A12 | P31151 P80511 | ↓ ↑ | Fineschi [37] Hsu [45•] | |
THBS1 THBS2 | P07996 P35442 | ↓ ↓ | Inhibition of angiogenesis, coagulation [79] | Han [46] | |
Skin | LYVE1, Gal-7, hornerin | Q9Y5Y7 P47929 Q86YZ3 | ↑ ↓ ↑ | Skin role, LYVE1 is the most specific lymphedema marker [162] | Han [46] Hsu [45•] |
STAMBP, Axin-1, TMPRSS13 | O95630 O15169 Q9BYE2 | ↑ ↑ ↑ | Transport | Fineschi [37] Han [46] |
Proteins Identified in Several Biological Fluids
Identified proteins | Uniprot ID | Levels in FMS biological fluids compared to controls | Studies reporting difference (n) | |||
---|---|---|---|---|---|---|
Serum | Plasma | Saliva | CSF | |||
FGA | P02671 | ↓a | ↓a | |||
FGB | P02675 | ↓ | ↑ | |||
PFN1 | P07737 | ↓ | ↑ | |||
TRFE | P02787 | ↑ | ↑ | |||
Α2Μ | P01023 | ↑b | ||||
ApoC3 | P02656 | ↓ | ↑ | |||
Complement C4A | P0C0L4 | ↑ | ↑ | |||
Complement C1qC | P02747 | ↑ | ↑ | |||
FGG | P02679 | ↓ | ↑ | |||
Hp | P00738 | ↑ | ||||
Ig λ-2 chain C regions | P0CG05 | ↓ | ↑ | |||
Ig kappa chain C region | P01834 | ↓ | ↑ | |||
Ig α-1 chain C region | P01876 | ↑ | ↑ | |||
PGAM1 | P18669 | ↑ | ||||
SAA4 | P35542 | ↓ | ↑ | |||
SAP | P02743 | ↑ | ↑ | |||
S100-A12 | P80511 | ↑ | ↑ | |||
S100-A8 | P05109 | ↑ | ||||
TALDO | P37837 | ↑ | ||||
THBS1 | P07996 | ↓ | ↑ |