Biomarkers Differentiating RRMS and SPMS in Multiple Sclerosis—A Systematic Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Selection
2.2. Selected Studies
2.3. Data Extraction and Quality Assessment
3. Results
3.1. Neurofilament Light Chain (NfL)
3.2. YKL-40/CHI3L1
3.3. Glial Fibrillary Acidic Protein (GFAP)
3.4. Brain-Derived Neurotrophic Factor (BDNF)
3.5. Immunological Cytokines
3.6. Monocyte Chemoattractant Protein-1 (MCP-1/CCL2)
3.7. Tau-Protein
3.8. Neurofilament Heavy Chain (NfH)
3.9. MMP-2
3.10. Galectin-9
3.11. N-Acetylaspartate (NAA)
3.12. CD86
3.13. Osteopontin
3.14. TIMP-1, MMP-9, and MMP-9/TIMP-1
4. Discussion
4.1. Neurofilament Light Chain (NfL)
4.2. Glial Fibrillary Protein (GFAP)
4.3. Chitinase-3-like Protein 1 (CHI3L1/YKL-40)
4.4. IL-1β
4.5. N-Acetylaspartate (NAA)
4.6. Galectin-9
4.7. Neurofilament Heavy Chain (NfH)
4.8. Monocyte Chemoattractant Protein-1 (MCP-1/CCL2)
4.9. IFN-γ
4.10. Osteopontin
4.11. Main Findings and Perspectives
4.12. Strengths and Limitations
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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First Author, Year of Publication, Country | Diagnostic Criteria | Study Design | Total Number of Participants | Sex (Female/Male) | Age | Biomarker(s) | p-Value | Mean/ Median Difference | Risk of Bias |
---|---|---|---|---|---|---|---|---|---|
Talaat, 2023, Egypt [17] | McDonald 2017 | Case–control study | RRMS (n = 30) SPMS (n = 16) PPMS (n = 6) | RRMS (24/6) SPMS (12/4) PPMS (4/2) | (Mean) RRMS 28.23 SPMS 32.31 PPMS 34.21 | CSF-CHI3L1 (ng/mL) | RRMS vs. PMS p ≤ 0.001 | 127% | Fair |
Loonstra, 2023, The Netherlands [18] | McDonald 2017 | Cross-sectional study | RRMS (n = 171) SPMS (n = 79) | RRMS (140/31) SPMS (47/32) | (Mean) RRMS 52.88 SPMS 52.9 | s-NfL (pg/mL) s-GFAP (pg/mL) | RRMS vs. SPMS p = 0.009 RRMS vs. SPMS p = 0.043 | 17% 19% | Good |
Dias de Sousa, 2022, Brazil [19] | McDonald 2010 | Cross-sectional study | RRMS (n = 21) SPMS (n = 6) | RRMS (17/4) SPMS (5/1) | (Mean) F-RRMS 40.1 M-RRMS 32.8 F-SPMS 52.2 M-SPMS 60 | p-IL-2 (pg/mL) p-IL-8 (pg/mL) p-IL-1β (pg/mL) p-IL-6 (pg/mL) p-IL-12 (pg/mL) p-TNF-α (pg/mL) p-IFN-γ (pg/mL) p-IL-4 (pg/mL) p-IL-10 (pg/mL) p-BDNF (pg/mL) Cultures of PBMC IL-4 (pg/mL) IFN-γ (pg/mL) IL-10 (pg/mL) IL-17 (pg/mL) TNF-α (pg/mL) IL-6 (pg/mL) | RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS p < 0.05 RRMS vs. SPMS p < 0.05 RRMS vs. SPMS ns RRMS vs. SPMS p < 0.05 RRMS vs. SPMS ns RRMS vs. SPMS ns | ND | Poor |
Lamancová, 2022, Slovakia [20] | Lublin 2013 | Cohort study | RRMS (n = 40) SPMS (n = 25) | RRMS (24/16) SPMS (10/15) | (Mean) RRMS 39 SPMS 49 | s-CXCL13 (pg/mL) s-CHI3L1 (pg/mL) s-NfL (pg/mL) s-MCP-1 (pg/mL) s-MMP-2 (pg/mL) s-MMP-9 (pg/mL) | RRMS vs. SPMS p < 0.001 RRMS vs. SPMS p < 0.01 RRMS vs. SPMS p < 0.001 RRMS vs. SPMS p < 0.01 RRMS vs. SPMS p < 0.001 RRMS vs. SPMS ns | 75% 81% 85% 31% Decrease Decrease | Poor/fair |
Sağir, 2021, Turkey [21] | McDonald 2017 | Cross-sectional study | RRMS (n = 12) SPMS (n = 7) | RRMS (9/3) SPMS (5/2) | (Mean) RRMS 44.0 SPMS 50.4 | s-BDNF (pg/mL) | RRMS vs. SPMS p < 0.05 | Decrease | Poor |
Uphaus, 2021, Germany [22] | McDonald 2017 | Cohort study | RRMS (n = 169) SPMS (n = 27) | RRMS (116/53) SPMS (21/6) | (Median) Follow-up: RRMS 39.1 SPMS 51.1 | s-NfL (pg/mL) | Follow-up: RRMS vs. SPMS p < 0.001 | 51% | Fair/good |
Eslami, 2020, Iran [23] | McDonald 2017 | Cross-sectional study | RRMS (n = 51) SPMS (n = 25) | RRMS (41/10) SPMS (13/12) | (Mean) RRMS 33.7 SPMS 37.6 | s-IL-6 (pg/mL) s-IL-8 (pg/mL) | RRMS vs. SPMS p = 0.008 RRMS vs. SPMS ns | 92% 12% | Poor |
Ferraro, 2020, Italy [24] | McDonald 2010 | Cohort study | RRMS (n = 21) SPMS (n = 43) PPMS (n = 27) | RRMS (15/6) PMS (49/21) | (Median) RRMS 40 PMS 60 | p-NfL (pg/mL) | RRMS vs. PMS p = 0.007 | 32% | Poor |
Högel, 2020, Finland [25] | ND | Cross-sectional study | RRMS (n = 46) SPMS (n = 33) | RRMS (36/10) SPMS (20/13) | (Median) RRMS 46.32 SPMS 56.12 | s-GFAP (pg/mL) s-NfL (pg/mL) | RRMS vs. SPMS p < 0.001 RRMS vs. SPMS p < 0.001 | 83% 71% | Fair |
Naegelin, 2020, Switzerland [26] | McDonald 2001 | Cohort study | RRMS (n = 178) SPMS (n = 56) | RRMS (138/40) SPMS (29/27) | (Mean) RRMS 41.74 SPMS 53.77 | s-BDNF (ng/mL) | RRMS vs. SPMS p = 0.004 | −6% | Good |
Gencer, 2019, Turkey [27] | McDonald 2010 | Cross-sectional study | RRMS (n = 25) SPMS (n = 15) | RRMS (19/6) SPMS (10/5) | (Median) RRMS 35 SPMS 45 | s-BDNF (ng/mL) | RRMS vs. SPMS p = 0.065 | Decrease | Poor |
Gil-Perotin, 2019, Spain [28] | McDonald 2017 | Cohort study | RRMS (n = 99) SPMS (n = 35) PPMS (n = 23) | RRMS (79/20) SPMS (21/14) PPMS (10/13) | (Median) RRMS 35 SPMS 45 PPMS 51 | CSF-NfL (pg/mL) CSF-CHI3L1 (ng/mL) | RRMS vs. PMS ns RRMS vs. SPMS ns | −10% 17% | Fair |
Ribeiro, 2019, Switzerland [29] | McDonald 2010 | Cross-sectional study | RRMS (n = 147) SPMS (n = 17) PPMS (n = 4) | All MS (119/49) | (Mean) All MS 42.02 | s-TNF-α (pg/mL) | RRMS vs. PMS p = 0.802 | No difference | Poor |
Barro, 2018, Switzerland [30] | Lublin 1996, McDonald 2001 and 2005 | Cohort study | RRMS + CIS (n = 189) SPMS (n = 54) PPMS (n = 14) | All MS (179/78) | (Median) All MS 44.0 | s-NFL (pg/mL) | RRMS + CIS vs. PMS < 0.001 | 41% | Good |
Herman, 2018, Sweden [31] | McDonald 2005 | Cohort study | RRMS (n = 30) SPMS (n = 16) | RRMS (21/9) SPMS (10/6) | (Mean) RRMS 39 SPMS 58 | CSF-Galectin-9 (pg/mL) CSF-MCP-1 (pg/mL) CSF-TNF-α (pg/mL) | RRMS vs. SPMS p = 0.007 RRMS vs. SPMS p = 0.006 RRMS vs. SPMS p = 0.08 | 30% 35% 42% | Fair/good |
Iacobaeus, 2018, Sweden [32] | McDonald 2010 | Cross-sectional study | RRMS (n = 47) SPMS (n = 29) | RRMS (31/16) SPMS (20/9) | (Mean) RRMS 34 SPMS 60 | p-CD86 p-IL-10 p-IL-17 p-TGF-beta1 | RRMS-rem vs. SPMS p < 0.01 RRMS vs. SPMS p < 0.05 RRMS vs. SPMS ns RRMS vs. SPMS ns | Decrease Decrease Decrease Increase | Poor |
Stein, 2018, USA [33] | McDonald 2010 | Cross-sectional study | RRMS (n = 26) SPMS (n = 24) | RRMS (15/11) SPMS (12/12) PPMS (9/20) | (Median) RRMS 38 SPMS 50 PPMS 53 | CSF-IL-1β (pg/mL) CSF-IL-6 (pg/mL) CSF-TNF-α (pg/mL) CSF-IL-10 (pg/mL) | RRMS vs. SPMS p = 0.0377 RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns | 65% 33% 63% 87% | Fair |
Kallaur, 2017, Brazil [34] | McDonald 2010 | Cohort study | RRMS (n = 126) SPMS (n = 25) PPMS (n = 9) | All MS (99/59) | (Median) RRMS 44 PMS 53 | s-IL-1β (pg/mL) s-IL-6 (pg/mL) s-TNF-α (pg/mL) s-IFN-γ (pg/mL) s-IL-12 (pg/mL) s-IL-17 (pg/mL) s-IL-4 (pg/mL) s-IL-10 (pg/mL) | RRMS vs. PMS p = 0.0168 RRMS vs. PMS p = 0.6041 RRMS vs. PMS p = 0.8734 RRMS vs. PMS p = 0.0309 RRMS vs. PMS p = 0.0003 RRMS vs. PMS p = 0.9081 RRMS vs. PMS p = 0.0509 RRMS vs. PMS p = 0.2557 | 125% 17% 0% 21% 0% 0% 0% 12% | Good/fair |
Burman, 2016, Sweden [35] | McDonald 2010 | Cross-sectional study | Cohort A: RRMS-rem (n = 18) SPMS (n = 20) Cohort B RRMS-rem (n = 11) SPMS (n = 15) | Cohort A RRMS-rem (12/6) SPMS (11/9) | (Median) Cohort A RRMS-rem 39 SPMS 59 | CSF-YKL-40 (ng/mL) | Cohort A + B SPMS vs. RRMS-rem ns | Increase | Poor |
Burman, 2016, Sweden [36] | McDonald 2010 | Cross-sectional study | Cohort A RRMS (n = 25) SPMS (n = 22) Cohort B RRMS (n = 31) SPMS (n = 16) | Cohort A RRMS (18/7) SPMS (15/7) Cohort B RRMS (21/10) SPMS (9/7) | (Median) RRMS (A:36)(B:39) SPMS (A:59)(B:58.5) | CSF-Galectin-9 (pg/mL) | A: RRMS vs. SPMS p < 0.01 B: RRMS vs. SPMS p < 0.05 A+B: RRMS vs. SPMS p < 0.001 | 31% 24% 27% | Fair |
Salehi, 2016, Iran [37] | McDonald 2010 | Cross-sectional study | RRMS-rem (n = 14) SPMS (n = 10) | RRMS-rem (13/1) SPMS (8/2) | (Mean) RRMS-rem 35.07 SPMS 35.50 | s-CD8: IFN-γ s-CD8: IL-17 s-CD8: TNF-α | RRMS-rem vs. SPMS ns RRMS-rem vs. SPMS ns RRMS-rem vs. SPMS ns | 9% −28% −3% | Poor/fair |
Mañé-Martínez, 2016, Spain [38] | Poser, McDonald 2001 and 2005 | Cross-sectional study | RRMS (n = 192) SPMS (n = 6) | RRMS (121/71) SPMS (4/6) | (Mean) RRMS 34.8 SPMS 43.5 | CSF-NfL (ng/L) CSF-GFAP (ng/L) CSF-YKL-40 (ng/mL) CSF-MCP-1 (pg/mL) CSF-t-tau (pg/mL) CSF-p-tau (pg/mL) | RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns | −51% 47% −11% 5% 47% 33% | Fair |
Pasquali, 2015, Italy [39] | McDonald 2010 | Cross-sectional study | RRMS (n = 30) SPMS (n = 30) | RRMS (21/9) SPMS (19/11) | (Mean) RRMS 40.8 SPMS 56.4 | s-IL-17 s-IFN-γ s-TGF-beta1 s-IL-2 s-IL-4 s-IL-6 s-IL-8 s-IL-10 s-IL-12 s-TNF-alfa | RRMS vs. SPMS p = 0.003 RRMS vs. SPMS p = 0.013 RRMS vs. SPMS p = 0.029 RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns RRMS vs. SPMS ns | −69% −37% 42% 22% 6% −42% 49% −17% 17% 40% | Good |
Acar, 2014, Turkey [40] | McDonald 2010 | Cross-sectional study | RRMS (n = 58) SPMS (n = 21) PPMS (n = 4) PRMS (n = 6) | RRMS (40/18) PMS (19/12) | (Mean) RRMS 34.5 PMS 40.4 | s-TIMP1 (ng/mL) s-MMP9/TIMP1 | RRMS vs. PMS ns RRMS vs. PMS ns | 14% −28% | Fair |
Gresle, 2014, Australia [41] | ND | Cohort study | RRMS (n = 81) SPMS (n = 13) | RRMS (55/26) SPMS (10/3) | (Median) RRMS 44.5 SPMS 55 | s-pNfH (ng/mL) | RRMS vs. SPMS p = 0.048 | Δ0.18 ng/mL | Fair |
Huber, 2014, USA [42] | McDonald 2010 | Cohort study | RRMS (n = 12) SPMS (n = 26) | RRMS (5/7) SPMS (11/15) | (Mean) RRMS 46.3 SPMS 53.8 | Cultures of PBMC p-IL-17 (pg/mL) p-IFN-γ (pg/mL) | RRMS vs. SPMS p = 0.114 RRMS vs. SPMS p = 0.792 | Increase Decrease | Good |
Shimizu, 2013, Japan [43] | ND | Cross-sectional study | RRMS (n = 11) SPMS (n = 6) | All MS (6/11) | (Mean) All MS 38.3 | s-osteopontin (ng/mL) | RRMS vs. SPMS p < 0.05 | 75% | Poor |
Jaworski, 2012, Poland [44] | McDonald 2001 | Cross-sectional study | RRMS (n = 34) SPMS (n = 14) | RRMS (22/12) SPMS (5/9) | (Mean) RRMS 32.8 SPMS 44.5 | CSF t-tau (pg/mL) CSF p-tau (pg/mL) s-p-tau (pg/mL) | RRMS vs. SPMS p = 0.01 RRMS vs. SPMS ns RRMS vs. SPMS ns | −38% −21% 24% | Poor |
Axelsson, 2011, Sweden [45] | McDonald 2001 | Cohort study | Baseline: RRMS (n = 15) SPMS (n = 10) 8–10 years follow-up: RRMS (n = 10) SPMS (n = 15) | RRMS (3/12) SPMS (6/4) | (Mean) RRMS 40 SPMS 43 | CSF-GFAP (ng/L) CSF-NfL (ng/L) | Follow up: RRMS vs. SPMS ns RRMS vs. SPMS ns | 16% −1% | Fair |
Ragheb, 2011, USA [46] | McDonald 2001 or 2005 | Case–control study | RRMS (n = 42) SPMS (n = 8) | All MS (39/11) | (Mean) All MS 43.9 | CSF-CXCL13 (pg/mL) | RRMS vs. SPMS ns | −77% | Poor/fair |
Correale, 2010, Argentina [47] | Poser and McDonald 2001 | Cross-sectional study | RRMS (n = 24) SPMS (n = 24) | RRMS (16/8) SPMS (16/8) | (Mean) RRMS 37.3 SPMS 38.5 | CSF-CHI3L1 (ng/mL) s-CHI3L1 (ng/mL) | RRMS vs. SPMS p < 0.01 RRMS vs. SPMS ns | −26% Equal | Fair |
Benešová, 2009, Czech Republic [48] | McDonald 2001 | Cross-sectional study | RRMS (n = 40) SPMS (n = 20) | RRMS (29/11) SPMS (14/6) | (Mean) RRMS 32.2 SPMS 47.5 | s-MMP-9 (ng/mL) s-MMP-2 (ng/mL) s-MMP-9/TIMP-1 s-TIMP-1 (ng/mL) | RRMS vs. SPMS ns RRMS vs. SPMS p < 0.002 RRMS vs. SPMS ns RRMS vs. SPMS ns | 7% 26% 4% −6% | Fair |
Teunissen, 2009, The Netherlands [49] | McDonald 2001 | Cross-sectional study | RRMS (n = 42) SPMS (n = 28) | RRMS (26/16) SPMS (17/11) | (Mean) RRMS 37 SPMS 54 | CSF-NAA (mmol/L) CSF-NfH (Unit/mL) CSF-NfL (ng/L) CSF-t-Tau (ng/L) | RRMS vs. SPMS p < 0.05 RRMS vs. SPMS p < 0.05 RRMS vs. SPMS ns RRMS vs. SPMS ns | Decrease Increase Decrease Decrease | Fair |
Jasperse, 2007, The Netherlands [50] | Poser | Cross-sectional study | RRMS (n = 26) SPMS (n = 12) | RRMS (17/9) SPMS (5/7) | (Median) RRMS 43.5 SPMS 49.6 | CSF-NAA (μmol/L) | RRMS vs. SPMS p = 0.015 | Decrease | Fair |
Comabella, 2004, Spain [51] | Lublin 1996 | Cross-sectional study | RRMS (n = 46) SPMS (n = 35) | RRMS (29/17) SPMS (28/7) | (Mean) RRMS 35.6 SPMS 47.5 | p-osteopontin (ng/mL) | RRMS-rem vs. SPMS p < 0.0005 | Increase | Fair |
Filion, 2003, Canada [52] | Poser | Cross-sectional study | RRMS − therapy (n = 23) RRMS + therapy (n = 23) SPMS (n = 29) | RRMS − therapy (13/10) RRMS +therapy (15/8) SPMS (18/11) | (Median) RRMS − therapy 38 RRMS +therapy 40 SPMS 50 | s-CD86 (MFI) s-IL-1β (pg/mL) s-IL-6 (pg/mL) s-IL-10 (pg/mL) s-IL-12 (pg/mL) s-TNF-α (pg/mL) | RRMS− vs. SPMS p < 0.05 RRMS+ vs. SPMS ns RRMS− vs. SPMS ns RRMS+ vs. SPMS p < 0.05 RRMS− vs. SPMS ns RRMS+ vs. SPMS ns RRMS− vs. SPMS ns RRMS+ vs. SPMS ns RRMS− vs. SPMS p < 0.001 RRMS+ vs. SPMS p < 0.001 RRMS− vs. SPMS p < 0.05 RRMS+ vs. SPMS p < 0.001 | Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase Increase | Fair |
Karni, 2002, USA [53] | ND | Cross-sectional study | RRMS (n = 39) SPMS (n = 18) | RRMS (34/5) SPMS (13/5) | (Mean) RRMS 36.7 SPMS 56.5 | s-IFN-γ (pg/mL) | RRMS vs. SPMS p = 0.028 | 55% | Poor |
Sarchielli, 2002, Italy [54] | Poser | Cross-sectional study | RRMS (n = 20) SPMS (n = 15) | RRMS (13/7) SPMS (10/5) | (Mean) RRMS 33.5 SPMS 38.4 | CSF-BDNF (pg/mL) | RRMS vs. SPMS ns | −6% | Fair |
Semra, 2002, England [55] | Poser | Cross-sectional study | RRMS (n = 16) SPMS (n = 13) PPMS (n = 6) | RRMS (9/7) SPMS (8/5) PMS (2/4) | (Mean) RRMS 32.6 SPMS 45.3 PPMS 41.2 | CSF-NfL (Unit/mg) | RRMS vs. PMS p = 0.14 | Increase | Poor |
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Toftegaard, C.; Severinsen, C.M.; Jensen, H.B. Biomarkers Differentiating RRMS and SPMS in Multiple Sclerosis—A Systematic Review. Sclerosis 2024, 2, 166-185. https://doi.org/10.3390/sclerosis2030012
Toftegaard C, Severinsen CM, Jensen HB. Biomarkers Differentiating RRMS and SPMS in Multiple Sclerosis—A Systematic Review. Sclerosis. 2024; 2(3):166-185. https://doi.org/10.3390/sclerosis2030012
Chicago/Turabian StyleToftegaard, Camilla, Charlotte Marie Severinsen, and Henrik Boye Jensen. 2024. "Biomarkers Differentiating RRMS and SPMS in Multiple Sclerosis—A Systematic Review" Sclerosis 2, no. 3: 166-185. https://doi.org/10.3390/sclerosis2030012