Table 1.

Characteristics of the included studies

References	Diagnosis and patient number	RA therapies	Findings
Rodríguez-Carrio J. (2015) [19]	114 RA** 33 HC 72 CV risk	None or NSAIDs: 10.5%; GC: 53.5%; MTX: 70.1%; TNFi: 39.4%; TCZ: 10.5%	Total MPs: RA 4.21 vs. HC 2.1 (p < 0.0001) vs. CV risk 3.14 × 106/ml (p = 0.001) CD146+, CD66+, CD3CD31+ MPs were increased in RA vs. HC (p = 0.029, p = 0.001, p < 0.001) RA total MPs were associated with traditional CV risk factors and with the number of CV risk factors CD146+ was associated with disease duration (p = 0.005); CD66b+ with DAS28 (p = 0.032), ESR (p = 0.022), age at diagnosis (p = 0.021); CD3+CD31+ with DAS28 (p = 0.007), TJC (p = 0.026), SJC (p = 0.003); CD14+ with RF (p = 0.041) Patients in TCZ: lower CD3+CD31+ and CD66b+ (p = 0.005; p = 0.011) Patients in MTX: lower CD3+DC31+ (p = 0.033) TNFα correlated with CD3+CD31+ (p = 0.097) if no traditional CV risk factors (p < 0.0001). At multivariate regression model including CV risk factors, TNFα was associated with CD3+CD31+ (p = 0.012) MPs from RA had a dose-dependant anti-angiogenic effect (CD14+ and CD41+ MPs) and endothelial activation (CD62E, CD144, VEGFR)
Arntz O.J. (2018) [20]	41 RA** 24 HC	DMARDs: 75%; GC: 53.7%; bDMARDs: 19.5%	No difference in size, protein content concentration, concentration plasmatic EVs in RA vs. HC No difference in size, content, concentration plasmatic EVs in RF+ vs. RF- (no difference between disease parameters apart from ESR higher in RF+, p < 0.05) In RF+: 13/28 were found to have IgM-RF in EVs. Patients with IgM-RF on EVs had higher VAS, CRP, DAS28 and ESR (p < 0.001, p < 0.01, p < 0.05, p < 0.01), no difference for TJC and SJC
Skriner K. (2006) [21]	5 RA* 5 ReA 5 OA	–	Similar amount of exosomes in all patients Citrullinated and non-citrullinated proteins present in all samples Fibronectin/IgG immune complex only in RA exosomes
Atehortùa L. (2019) [22]	9 RA** 9 SLE 6 HC	–	Endothelial cells internalized MPs and MPs-IC Macrovascular HUVEC + MPs/MPs-IC ➔ increase ICAM-1, ICAM-2, IL-6 and IL-8 (dose dependant for ICAM-1, IL-6 and IL-8) Microvascular HMVEC-L + MPs-IC ➔ increase in ICAM-1 Microvascular HMVEC-L + MPs ➔ increase in CCL2 Microvascular HMVEC-L + MPs/MPs-IC ➔ increase in CCL5 No effect of MPs/MPs-IC on HMVEC-D HUVEC + MPs/MPs-IC ➔ increase of adhesion of classical monocytes HUVEC + MPs ➔ increase of adhesion of non-classical monocytes (not for MPs-IC) HMVEC-L + MPs/MPs-IC ➔ decrease of adhesion of classical monocytes MPs and more MPs-IC altered endothelial monolayers (micro- and macrovasculature) with increased permeability of macrovascular endothelial cells
Barbati C. (2018) [23]	20 (+10) RA** 20 HC	ETN 50 mg SC weekly + csDMARDS: 20; csDMARDs: 10	Total MPs and endothelial MPs higher at baseline in RA vs. HC (p < 0.0001) (no difference for platelet and leucocyte MPs) After ETN: total MPs and endothelial MPs decreased from baseline (p < 0.0001 and p = 0.03) At baseline TNFα was more expressed on MPs in RA than HC (p = 0.0009) with a decrease after 4 months of ETN (p = 0.0002) (no change for patients treated only with csDMARDs) In vitro experiment: MPs-TNFα decreased dose-dependently after incubation with ETN Significant correlation between MPs-TNFα and DAS28, TJC, SJC, CDAI, and HAQ RA-MPs increased dose-dependently apoptosis and autophagy with respect to untreated cell (p = 0.005 and p = 0.02)
Birò E. (2007) [24]	10 RA* (8 for SF, 9 for plasma) 10 HC	–	Complement activator products (C4b/c and C3b/c) in RA SF were higher than RA plasma and HC (p < 0.05, p < 0.01, p < 0.01, p < 0.01); no difference between RA plasma and HC SAP and IgG in RA SF were lower than RA plasma and HC (p < 0.001, p < 0.001, p < 0.01, p < 0.01); no difference between RA plasma and HC CRP was higher in RA plasma than HC (p < 0.001); no difference between SF and plasma IgM showed no difference between all groups MPs were higher in RA SF than HC plasma (p < 0.05); no difference between RA plasma and HC or RA SF and RA plasma MPs with C1q, C4, and C3 were higher in RA SF than RA plasma and HC plasma (p < 0.01; p < 0.05); no difference between RA plasma and HC plasma MPs with CRP and SAP showed no difference between groups MPs with IgM and IgG were higher in RA SF than RA and HC plasma (p < 0.05, p < 0.01, p < 0.01, p < 0.01)
Boilard E. (2010) [25]	20 RA 20 OA 6 JIA 19 PsA 14 Gout	–	Platelet MPs are abundant in inflammatory SF (no statistical significance provided)
Burbano C. (2018) [26]	60 RA** anti-CCP−RF− = 6 anti-CCP+RF+/− = 26 anti-CCPhiRFhi = 28 40 HC	No bDMARDs	Plasma EV count: statistically different between HC anti-CCP+RF+/− (no difference for seronegative and anti-CCPhiRFhi) EV size distribution: anti-CCP+RF+/− and anti-CCP−RF− had decreased proportions of 0.1–1 μm and elevated proportions of 1–3 μm and 3–6 μm EV as compared with HC Cellular source: seropositives had more CD41a+ EVs and seronegatives had elevated CD105+ EVs EV components: EV-ICs and EV-CPs were significantly elevated in seropositives as compared with HC. Anti-CCP+RF+/− had higher C1q EVs and HMGB1 than other groups. EVs of seronegative patients were similar to HC. EV-ICs, EV-CPs, EV-C1q, and EV-HMGB1 derived from platelets and leukocytes (more from platelets in seropositives). EVs from seropostives had higher frequencies and wider distribution of EV-IgM+ and EV-IgG+ (on 5 patients for group) EVs positive for IgG, IgM, CD41a, and citrulline were associated with systemic inflammation in seropositive patients EVs from seropositive patients could activate mononuclear phagocytes and induce pro-inflammatory cytokines (TNFα, IL-6, and IL-1beta)
Burbano C. (2019) [27]	34 RA** (according to DAS28: 28 in remission and 18 in moderate activity) 34 SLE 14 HC	No bDMARDs	MP-ICs promote MDM differentiation to a pro-inflammatory profile (M1-like) more evident in SLE and RA than HC. MDM differentiated with MP-ICs from RA patients were resistant to repolarization to M2-like after IL4- treatment. MDM differentiated with MP-ICs from RA patients enhanced T cell proliferation, B cell activation markers, and B cell death prevention (not found for IFNγ, TNFα, and other B cells parameters)
Berckmans R.J. (2002) [28]	10 RA* 10 non-RA arthritis 20 HC	RA: number of DMARDs 2.6 (0–5); non-RA: number of DMARDs 1.5 (1–3)	MPs from RA plasma, but not from SF, strongly bound annexin V Similar results for non-RA MPs from platelets were absent in SF but were the most abundant in plasma (p < 0.0001). The opposite was for granulocytes and monocytes (p = 0.0001, p < 0.0001). In SF, MPs from CD4+, CD8+, B cells and erythrocytes were low (p = 0.0001, p = 0.0002, 0=0.041, p = 0.0001). No difference for RA and non-RA. Thrombin-generating capacity (factor VIIa) for SF MPs was higher than patients’ and HC plasma TF was absent on SF MPs despite they initiated TF-mediated thrombin generation Patients’ plasma vs HC: prothrombin fragment F1+2 and thrombin-antithrombin were increased (p < 0.0001, p = 0.0003). No difference for RA and non-RA SF (p = 0.16 and 0.26). Higher levels in SF as compared with patients’ plasma (p < 0.0001, p < 0.0001). Higher levels in RA plasma than non-RA plasma (p = 0.004, p = 0.0003)
Michael B.N.R. (2019) [29]	40 RA** 33 seropositive 7 seronegative 35 young-onset 15 extra-articular manifestations 30 OA 33 HC	No therapy, GC included	SF from RA vs. OA: more annexin V, leucocyte-derived, monocyte-derived, granulocyte-derived MPs CD4+ and CD8+ MPs (p < 0.001, p < 0.001, p < 0.001, p < 0.001), B cell–derived not detectable in both Granulocyte-derived MPs were more elevated in established RA SF than early RA (p = 0.03), annexin V MPs and platelet-derived MPs were increased in RA SF with extra-articular manifestations (p = 0.02, p < 0.011), ACPA positive RA patients had more SF granulocyte MPs than ACPA negative (p = 0.02). There was a weak correlation between ACPA titer, CD4 MPs and granulocyte-derived MPs Plasma annexin V and leucocyte-derived MPs were different in RA, OA and HC (p < 0.001, p < 0.001). RA plasma had more annexin V, leucocyte-derived, platelet-derived MPs, and CD61 as compared with OA and HC (p < 0.01, p < 0.001, p < 0.01, p < 0.001, p < 0.001, p = 0.02, p < 0.001). OA plasma had more annexin V, CD61 MPs vs. HC (p = 0.002, p = 0.01). Leucocyte-derived MP sub-populations (CD20, CD4, CD8, CD14, CD66b) were not detectable in plasma No difference emerged for plasma MP profile among clinical and serological RA phenotypes
Chen Z. (2018) [30]	11 RA** 11 OA	–	MMP14 and VEGF expression were higher in RA than OA in serum (p < 0.001) and synovial tissue (p < 0.001) MMP14 and VEGF were higher in RA than OA in FLS (p < 0.001) miR-150-5p expression was lower in RA than OA in serum, synovial tissue, and FLS (p < 0.001) Exo150 downregulated MMP14 and VEGF expression in RA FLS and inhibited migration and angiogenesis in vitro (p < 0.001)
Wang L. (2018) [31]	25 RA** 25 HC	No therapy	Treg frequency was decreased in RA vs. HC and inhibited by RA-exosomes RA exosomes resulted in a decreased Treg ratio vs. HC exosomes miR-17, miR-19b, and miR-121 were overexpressed in RA miR-17 had a negative correlation with Treg miR-17 inhibited expression of TGFBRII and Treg induction
Van Eijk I.C. (2009) [32]	24 RA* (9 re-evaluated after 8 weeks) 15 HC	No therapy at baseline (NSAIDs admitted) Treated for 8 weeks with SSZ, MTX and GC: 9	Total MPs were similar in RA and HC MPs exposing C1q, CRP, and SAP were higher in RA vs. HC (p < 0.001) At baseline, ESR and CRP correlated with MPs exposing C1q, CRP, and SAP (p = 0.02; p < 0.001; p = 0.003; p = 0.02; p = 0.001; p = 0.02) After treatment, ESR, DAS28, and CRP decreased, whereas total circulating MPs and MPs exposing complement components or activator molecules were unaffected
Cloutier N. (2012) [33]	23 RA 18 PsA	–	MPs in RA were heterogeneous in size (mostly 100–300 and 700–3000 nm) Annexin V MPs in RA were higher than PsA (p = 0.0004) In RA there were more MP-ICs and CD41+ MP-ICs than PsA (p < 0.0001; p = 0.0006) Blockade of CD32a did not impede mpIC formation Platelet MPs contained citrullinated epitopes and were recognized by ACPA (vimentin and fibrinogen) MPs and MP-ICs stimulated leukotriene production by neutrophils
Knijff-Dutmer E.A.J. (2002) [34]	19 RA* 9 active 10 inactive 10 HC	No anticoagulants and/or GC allowed; MTX: 6; SSZ: 5; gold: 2; HCQ: 4; LFN: 1; NSAIDs	Platelet count was normal in all 3 groups PMPs were higher in RA than in HC (p = 0.05), with no difference between active and inactive disease PMPs correlated with DAS28 in active RA patients (p = 0.05), but not with CRP or ESR
Xu D. (2018) [35]	76 RA 20 HC	–	20 miRNAs were aberrantly expressed in serum exosomes from 3 RA (2 statistically significant: miR-548a-3p and miR-6891-3p) miR-6089 was decreased in serum of RA vs. HC (p < 0.001) miR-6089 was reduced in PBMCs in RA vs. HC (p < 0.001) miR-6089 was negatively correlated with CRP, RF, and ESR (p < 0.001)
Marton N. (2017) [36]	20 RA** 15 PsA 19 HC	DMARDs: 96%; bDMARDs: 35%	MVs from RA and PsA could not impair osteoclastogenesis Presence of exosomes inhibited the ability of CD14+ monocytes to differentiate into TRAP+ multinucleated cells in RA and HC (p < 0.01), PsA-derived exosomes enhanced osteoclastogenesis (p < 0.05) RA and HC derived exosomes expressed higher levels of RANK than PsA (p < 0.05) In RA, exosomes were mostly platelet-derived (CD42b+), while MVs were more B cell (CD19+) and T cells (CD3+)
Gitz E. (2014) [37]	10 RA* 10 HC	–	CD41+ MPs were higher in RA than HC (p < 0.01). CLEC-2 on CD41+ was similar. GPVI on CD41+ was lower in RA than HC (p < 0.01, p < 0.01). Soluble GPVI was higher in RA than HC (p < 0.01)
Greisen S.R. (2017) [38]	5 RA* 5 HC	Treatment according to ACR 2015 guidelines	EVs were present in plasma and SF RA: they could be isolated from PBMC and SFMC. EV size distribution did not differ between RA and HC cell cultures. PD-1 is present in RA patients both in soluble form and in association with EVs RA vs. HC PBMC: 12 miRNA, linked to PD-1/PD-ligands, were found different (p < 0.05) miRNA content in EVs from RA SFMC, RA, and HC PBMC was different: a minor number of PD-1, PD-L1, and PD-L2 related miRNA changed in EVs generated from stimulation of RA SFMC Data suggested that EVs transfer the co-inhibitory receptor PD-1 to cells in the microenvironment Lymphocytes co-cultured with EVs had an increased PD-1 expression (p < 0.05) The number of lymphocytes co-cultured with EVs from RA PBMCs was higher than those co-cultured with HC PBMCs (p < 0.05)
Gyorgy B. (2012) [39]	Plasma: 12 RA** 9 OA SF: 8 RA** 8 OA 10 oligoarticular JIA	–	Data on 3 patients per group. In SF pellets, there were other particles besides MVs (proteins, immunecomplexes). Besides canonical MV proteins, many plasma proteins (albumin, transferrin, fibrinogen, prothrombin, haptoglobin) and immunocomplex related proteins (complement, immunoglobins) were present. No difference in the 3 groups. Data on 8 patients for RA group. Annexin A MVs were not signifincatly elevated in RA vs. OA. Most MVs derived from B and T cells in RA e OA SF, lower monocyte and platelet MVs were present. CD3+ MVs were higher in RA than OA SF (p = 0.027). CD8+ MVs were higher in RA than OA SF (p = 0.009). B cell–derived MVs were lower in JIA than OA and RA SF (p = 0.009, p = 0.004). CD3 and CD8 MVs were undetectable in RA and OA plasma (p < 0.001), indicating local production. RANK and RANK-L associated MVs were found in all 3 groups. T and B cell-derived MVs correlated to RF (p = 0.002, p = 0.001). T and B cell–derived MV count correlated (p < 0.001). CD41 EVs correlated with disease duration (p = 0.008). SF cell number showed weak association with CD3 and CD8 MV counts (p = 0.039, p = 0.017)
Fan W. (2017) [40]	34 RA** 33 OA 42 HC	–	CD4 MPs were higher in RA than OA and HC (p < 0.0052, p < 0.0007). In CD4 MPs: CD161/CD39 MPs were higher in RA than OA and HC (p < 0.0045, p < 0.0013), CD73/CD39 MPs were higher in RA than OA and HC (p < 0.0312, p < 0.0065) CD161/CD39 MPs were positively correlated with DAS28, SJC and RF (p = 0.007, p = 0.003, p = 0.011). CD73/CD39 MPs were negatively correlated with DAS28, SJC, and RF (p = 0.004, p = 0.018, p = 0.014) In RA FLSs culture, CD161/CD39 MPs increased CCL20 production (p < 0.002), CD73/CD39 MPs increased CCL17 and CCL22 production (p < 0.0018, p < 0.0022). No effects for HC MPs In RA PBMCs culture CD161/CD39 MPs increased IL-17 production (p < 0.0045), CD39/CD73 MPs inhibited IL-17 production and increased IL-10 production (p < 0.0217, p < 0.0156). No effects for HC MPs
Umekita K. (2009) [41]	20 RA* (6 received LCAP) 10 HC	PDN: 12 (mean dosage 6.4 mg/die); MTX: 8; SSZ: 5; bucillamine: 4; tacrolimus: 3; LFN: 1	Mean CD61 and CD42a were higher in RA than HC (p < 0.0001, p < 0.0001). No difference for CD66b and CD16 MPs in RA and HC CD61 MPs correlated with CRP, ESR, DAS28 (p = 0.02, p = 0.002, p = 0.0126). CD42a correlated with ESR (p = 0.01) After the first section of LCAP: CD61 and CD42a MPs decreased (p < 0.05), CD66b and CD16 MPs increased (p < 0.01) After 8 weeks of follow-up (5 LCAP): DAS28 and DAS28-CRP decreased significantly, mean numbers of CD61 and CD42a MPs decreased (p = 0.004, p = 0.005), mean numbers of CD66b and CD16 MPs did not change.
Messer L. (2009) [42]	7 RA* 5 OA 3 microcrystalline arthritis 5 ReA	PDN: 100%; MTX: 100%; IFX: 14%	MPs from SF were higher in RA and microcrystalline arthritis than OA and ReA (p < 0.05, p < 0.05) The ability of RA FLS to induce BAFF, IL-6, and IL-8 after stimulation of MPs is independent from MP origin (OA or RA) RA FLS released TSLP protein and SLPI after MPs exposure (not only derived from RA SF)
Jüngel A. (2007) [43]	9 RA* 7 OA	–	RA and OA synovial fibroblasts, incubated with MPs, produced PGE2 dose-dependently (p < 0.005). PGE2 was not present in MPs. No difference according to MPs origin Incubation of RA and OA synovial fibroblasts with MPs did not increase phospholipase A2 release. MPs dose-dependently induced COX-2 and mPGES-1 mRNA in RA and OA synovial fibroblasts (p < 0.05, p < 0.05), not COX-1, mPGES-2, and cytosolic PGES. No difference according to MPs origin Upregulation of PGE2 was mainly mediated via COX-2 (p < 0.05) MPs activated NF-kB and AP-1 signaling in synovial fibroblasts. There was a significant reduction of the induction of mPGES-1 by MPs in RA synovial fibroblasts, when NF-kB and AP-1 were inhibited (p < 0.05, p < 0.05) MPs increased p38 and JNK, but only the inhibition of JNK caused a significant reduction in PGE2 production MPs transferred arachidonic acid into sinovial fibroblasts
Wang Y. (2017) [44]	76 RA 20 HC	–	RA miR-548-3p was downregulated in serum and PBMCs exosomes vs. HC (p < 0.001) Low levels of miR-548a-3p were associated with higher levels of CRP, RF, and ESR (p < 0.001) miR-548a-3p was involved in TLRs-mediated response (in particular TLR4 and NF-kB)
Szabó-Taylor K.É. (2017) [45]	71 RA** 54 HC	–	Exofacial thiol EV levels decreased upon LPS stimulation of U397 cells (p < 0.05). Monocytes from RA (n = 6) released EVs with lower exofacial thiol content vs. HC (p < 0.001) Plasma-derived EV esofacial thiols did not show any difference between RA and HC (CD9, CD41a, annexin V), while total plasma thiol levels were lower in RA vs. HC (p < 0.0001) Higher number of plasma exofacial peroxiredoxin-1 positive EVs in RA (n = 16) vs. HC (p < 0.05)
Headland S.E. (2015) [46]	7 RA (blood+SF) 22 RA (SF) HC	No treatment: 2; GC: 3; DMARDs: 3; bDMARDs: 3 No treatment: 0; GC: 3; DMARDs: 13; bDMARDs: 0	There were more total, CD66b, CD14, and CD3 MVs in SF than in plasma (p = 0.005, p = 0.016, p = 0.022, p = 0.008). SF MVs had more annexin A1 than plasma MVs, with more annexin A1 MV of neutrophil origin. In SF, there were more neutrophil MVs than monocyte or T cell MVs (p < 0.001, p = 0.001), with more annexin A1 (p < 0.001 for both)
Chen X.M. (2020) [47]	15 RA** 30 PsA 15 psoriasis 15 gout 15 HC	No therapy in the previous 4 weeks	198 and 31 microRNAs were up- and downregulated, respectively, in RA vs. HC 36 commonly expressed microRNAs were identified (29 up- and 7 downregulated) vs. HC 5 microRNAs (hsa-miR-151a-3p, hsa-miR-199a-5p, hsa-miR-370-3p, hsa-miR-589-5p, and hsa-miR-769-5p) were considered to be connected with the common pathogenesis of PsA, psoriasis, RA, and gout
Oba R. (2019) [48]	20 RA 20 OA 13 EBV 10 atopic dermatitis 20 HC	–	CD3 and CD4 were included in both Th1 and Th2 derived EVs Alpha and beta chains of HLA-DR were dominant in Th1 derived EV vs. Th2 derived EVs CD3+ HLA-DR+ EVs were higher in Th1 than Th2 (no diffeernce for CD3/CD4+ and CD3/CD63+) CD3+HLA-DR+ EVs were similar in RA and OA vs. HC CD3+CD4+ EVs were higher in all four diseases vs. HC (RA vs. HC: p < 0.05) CD3+CD8+ EVs were higher in EBV infection and lower in RA (p < 0.01)
Villar-Vesga J. (2019) [49]	18 RA** All positive for ACPA and/or RF 41 HC	No biologics	Platelets were a frequent source of MPs (50% in RA and 40% in HC) with platelet activation markers (CD62P, CD154, annexin V, and DIOC6). RA had more citrullinated peptides and IgG MPs than HC (p ≤ 0.05; p ≤ 0.01) Platelets from HC produced MPs when stimulated with collagen type IV, similarly to RA
Reich N. (2011) [50]	12 RA* 9 for RA synovial fibroblasts 3 for SF	MTX: 8; GC: 7; ADA: 4; ETN: 1; RTX: 2; LFN 1; IFX: 1	Expression of chemokines in RA synovial fibroblasts co-incubated with MPs from Jurkat T cells, U937 monocytes, and SF was increased (CXCL1, CXCL2, CXCL3x, CXCL5, and CXCL6) Supernatants from RA synovial fibroblasts co-incubated with MPs induced migration of ECs in transwell chamber assays vs. supernatants without MPs (p = 0.01) and neutralizing antibodies reduced the stimulatory effect Supernatants did not affect proliferation or viability of ECs (number of apoptotic or necrotic cells unchanged)
Michael B.N.R. (2018) [51]	23 RA** 17 OA 22 HC	No DMARDs	SF MPs were higher in RA than OA (p < 0.0001), SF PMPs were higher in RA than OA (p = 0.0472), SF non-PMPs were also higher (p < 0.0001) Plasma MPs were higher in RA (p < 0.0001) and OA (p < 0.01) vs. HC, plasma PMPs were higher in RA (p < 0.0001) and OA (p < 0.01) vs. HC, plasma non-PMPs were higher in RA (p < 0.0001) and OA (p < 0.01) vs. HC
Liao T. L. (2018) [52]	40 RA** with active disease (DAS28 > 3.2) after csDMARDs 20 with cronic HCV 20 without HCV	csDMARDs, ADA, ETN, GOL, RTX	miR-155 was increased in PBMCs in RA patients with HCV vs. patients without HCV (p < 0.001) and it suppressed HCV replication (p < 0.01) RA patients with HCV had higher exo-miR-155 levels vs. HCV negative (p < 0.01), RA patients with HCV treated with RTX had decreased exo-miR-155 expression vs. TNFi or csDMARDs (p < 0.05)
Rodríguez-Carrio J. (2015) [53]	13 RA 33 HC	TNFi naive; GOL: 11 or ETN: for 3 months; all on MTX; GC: 10	Tang and EPC increased after treatment, Tang reached levels similar to HC (p = 0.522) DAS28 decreased (p < 0.001) and paralleled Tang increased (p = 0.011) Tang increase was greater in good responders (p = 0.03), only good responders displayed parallel increase of Tang and EPCs (p = 0.037); treatment was associated with decreasing VEGF (p = 0.002), leptin (p = 0.014), SDF1a (p = 0.002) in the whole group, IL-8 and TNFα in good responders (p = 0.045) Tang-MP shedding was decreased after treatment (p = 0.021), especially in good responders (p = 0.006)
Sellam J. (2009) [54]	24 RA* 43 pSS 20 SLE 44 HC	GC less than 10 mg; MTX: 16; anti-TNF: 5; LFN: 2	Patients with pSS (p < 0.0001), SLE (p = 0.0004) and RA (p = 0.004) showed increased plasma levels of total MPs vs HC. No difference between pSS, RA and SLE All showed increased levels of platelet MPs (p < 0.0001), pSS also increased leukocyte MPs (<0.0001) and higher vs. RA (p = 0.015) and SLE (p = 0.003) Leukocytes MPs and DAS28 showed negative correlation in RA (p = 0.005) Total and platelet MPs were inversely correlated with sPLA2 activity in all groups (p = 0.0007 and p = 0.002)
Berckmans R. J. (2005) [55]	8 RA* 3 UA	DMARDs 4.5 in RA	MPs numbers in UA and RA were similar SF from RA and UA contained MPs of monocytic (CD14) and granulocytic (CD66e) origin and low levels of MPs from platelets and erythrocytes; MPs from B cells were present in 2 RA patients; MPs from CD8+ T cells SF MPs + FLS: increase in MCP-1 (p = 0.01), sICAM-1 (p = 0.01), IL-8 (p = 0.008), IL-6 (p = 0.042), VEGF (p = 0.001), RANTES (p = 0.031), and decrease in GM-CSF (p = 0.002). Total number and granulocyte-derived MPs of SF MPs and plasma MPs correlated with IL-8 (p < 0.0001) and MCP-1 (p < 0.0001); monocytes-derived MPs did not
Tsuno H. (2018) [56]	12 active RA* (DAS28 > 2.7) 11 inactive RA* (DAS28 < 2.3) 10 OA 10 HC	Active: DMARDs: 75%; MTX: 50%; bDMARDs: 8%; PDN: 41.7%) Inactive: DMARDs: 90.9%; MTX: 81.8%; bDMARDs: 18.1%	204 protein spots were detected on the gel In RA 28/204 protein spots had different intensity (p < 0.05), in particular 7 of these In active RA 24 spots showed ≥ 1.3-fold intensity differences vs. HC, in inactive RA 5 spots (only 2 overlapped with active RA) Six protein spots were identified, among which TLR3 showed 6-fold higher intensity in active RA group vs. the others The band intensity of TLR3 fragments (17-18 kDa) was higher in RA vs. HC
Viñuela-Berni V. (2015) [57]	55 RA* 6 remission 6 LDA 22 MDA 21 HDA 14 SLE 20 HC	DMARDS (MTX, SSZ), PDN: 31; no treatment: 20 For the 8 patients prospectically followed: MTX, SSZ, and PDN	Levels of Annexin V+ MPs derived from monocytes (CD14+), platelets (CD41a+), EC (CD62E+) and B cells (CD19+) were enhanced in HDA RA vs. HC (p < 0.001); no difference for LDA and HC MDA RA had enhanced levels of CD14+ and CD62E+ MPs (p < 0.05) Differences in urine levels of CD14+ and CD19+ between LDA and HDA Correlation between plasma and urine levels of MPs and DAS28 (p < 0.05) No difference in MPs levels between treated and untreated patients Decrease in plasma levels of all MPs after 4 weeks of therapy (p < 0.05) and urine MPs levels of CD14+, CD41+ and CD3+ MPs (p < 0.05) Mononuclear cells from HDA stimulated with MPs induced release of IL-1, IL-17, and TNFα, and an association between release of IL1 and TNFα and DAS28 was observed (p < 0.05)
Yoo J. (2017) [58]	60 RA** 30 CR (DAS28ESR ≤ 2.6) 30 non-CR (DAS28 > 2.6)	MTX for at least 6 months for all patients; GC: 4 in CR, 29 in non-CR	Six candidate proteins identified Serum and exosomal AA protein levels were higher in non-CR vs. CR (p = 0.001), serum and exosomal AA levels correlated (p = 0.001) Serum CRP correlated with serum AA in CR (p = 0.001) and in non-CR (p < 0.001) Serum CRP correlated with exosomal AA in non-CR (p < 0.001), but not in CR Exosomal levels of LYVE-1 were lower in non-CR vs. CR (p = 0.01), no difference between serum LYVE-1 levels in CR and non-CR; there was a weak correlation between serum and exosomal LYVE-1 There was a positive correlation between serum and exosomal LYVE-1 and CRP in non-CR (p = 0.04, p = 0.002) and a negative correlation between anti-CCP titer and exosomal LYVE-1 in non-CR (p = 0.014)
Zhang H. G. (2006) [59]	10 RA* 10 OA	–	Membrane-bound TNFα detected on exosomes was produced by RA synovial fibroblasts but not OA synovial fibroblasts; exosomes expressed only the membrane-bound TNFα but not the soluble form RA synovial fibroblasts exosomal TNFα induced cytotoxicity of L929 cells, not OA synovial fibroblasts; preincubation with a TNF antagonist blocked the effect RA synovial fibroblasts exosomes induced activation of NFkB signaling pathway in RA synovial fibroblasts, not OA synovial fibroblasts exosomes, but RA synovial fibroblasts exosomes induced NFkB in OA synovial fibroblasts; the TNF antagonist neutralized the effect RA synovial fibroblasts exosomes induced MMP-1 in RA synovial fibroblasts, less with TNFi (p < 0.0018), not OA synovial fibroblasts exosomes TNFα stimulated production of RA synovial fibroblasts exosomes (p < 0.0011), slightly for OA synovial fibroblasts exosomes; TNFi reduced the effect Coculture of RA synovial fibroblasts exosomes with CD4+T cells resulted in sustained cell proliferation and induction of IFNγ and IL-2 (not OA synovial fibroblasts exosomes) and TNFi partially reversed the effect In T cells, phosphorylated Akt was induced and NFkB activity increased

*1987 ACR criteria; **2010 EULAR/ACR criteria

AA: amyloid A; ACR: American college of rheumatology; ADA: adalimumab; Anti-CCP: anti–citrullinated protein antibodies; ACPA: anti-citrullinated protein antibodies; CDAI: clinical disease activity index; CP: citrullinated peptides; CR: clinical remission; CRP: C-reactive protein; CV: cardiovascular; DAS28: disease activity score on 28 joints; DMARDs: disease modifying anti-rheumatic drugs (b-: biological; cs-: conventional synthetic); EBV: Epstein-Barr virus; EC: endothelial cell; EPC: endothelial progenitor cell; ESR: erythrocyte sedimentation rate; ETN: etanercept; EVs: extracellular vesicles; FLS: fibroblast-like synoviocytes; GC: glucocorticoid; GOL: golimumab; HAQ: health assessment questionnaire; HC: healthy controls; HCQ: hydroxychloroquine; HCV: hepatitis C virus; HDA: high disease activity; HMGB1: high mobility group box 1; HMVEC: human microvascular endothelial cells (-D: dermal; -L: lung); HUVEC: human umbilical vein endothelial cells; IC: immunocomplexes; IFX: infliximab; JIA: juvenile idiopathic arthritis; LCAP: leukocytapheresis; LDA: low disease activity; LFN: leflunomide; MDA: moderate disease activity; MDM: monocyte-derived macrophages; MPs: microparticles; MTX: methotrexate; MVs: microvesicles; NSAIDs: non-steroidal anti-inflammatory drugs; OA: osteoarthritis; PBMC: peripheral blood mononuclear cells; PDN: prednisone; PMPs: platelet microparticles ; PLA2s: phospholipases A2; PsA: psoriatic arthritis; pSS: primary Sjögren syndrome; RA: rheumatoid arthritis; ReA: reactive arthritis; RF: rheumatoid factor; RTX: rituximab; SAP: serum amyloid protein; SC: subcutaneous; SF: synovial fluid; SFMC: synovial fluid mononuclear cells; SJC: swollen joint count; SLE: systemic lupus erythematous; SLPI: secretory leucocyte protease inhibitor; SSZ: sulfasalazine; Tang: angiogenic T cells; TCZ: tocilizumab; TF: tissue factor; TJC: tender joint count; TNFi: tumor necrosis factor inhibitor; TSLP: thymic stroma lymphopoietin; VAS: visual analog scale; UA: undifferentiated arthritis