suPAR in Autoimmune Rheumatic Diseases: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Maria Infantino.

The soluble urokinase plasminogen activator receptor (suPAR) is the bioactive form of urokinase plasminogen activator receptor (uPAR), a membrane-bound glycoprotein, and it is primarily expressed on the surface of immunologically active cells. Mirroring local inflammation and immune activation, suPAR has gained interest as a potential prognostic biomarker in several inflammatory diseases. Mirroring immune system activation, suPAR has been associated with many autoimmune rheumatic diseases.

  • suPAR
  • rheumatoid arthritis
  • autoimmune diseases

1. Rheumatoid Arthritis (RA)

RA is a chronic inflammatory disease characterized by leukocyte infiltration in synovial fluid and the surrounding synovial tissue [20,21][1][2]. However, various cells of the myeloid and leukocyte lineage, including monocytes/macrophages, neutrophils, B lymphocytes, mast cells, and subsets of T helper cells, mediate the intrinsic chain of events. Leukocytes are recruited to the inflamed area by chemokines and other chemo-attractants. Numerous growth factors, cytokines, and chemokines interact to regulate joint physiology, causing cartilage and bone degeneration. In 2010, Pliyev et al. conducted a comparative analysis of neutrophils isolated from the paired samples of synovial fluid (SF) and peripheral blood (PB) of RA patients. The blood concentration of suPAR was found to be significantly lower than in SF. Neutrophils are the predominant leucocytes accumulating in SF during the acute RA phase and represent the major cellular source of suPAR in SF. The authors demonstrated that SF neutrophils release the chemotactically active cleaved D2-D3 form of suPAR, which results in a prolonged inflammatory response [22][3]. Furthermore, Pliyev et al. [22][3] objectified the association of suPAR with the number of swollen joints [22][3]. The link between suPAR and disease activity in early RA was examined in a study by Enocsson et al. (2021). The authors evaluated suPAR levels at the disease onset and after 3 and 36 months in 252 Swedish patients affected by early RA. The authors demonstrated that suPAR levels were higher in RA patients at all-time points (baseline, 3 and 36 months) compared to healthy controls. Moreover, baseline suPAR levels were significantly associated with baseline disease activity, whereas suPAR levels correlated with joint damage (Larsen score > 5) at 36 months [23][4]. Recent research has already shown that suPAR is much more effective than CRP and ESR in identifying low-grade inflammation in RA. Toldi et al. analyzed the association of suPAR levels with DAS28 scores in RA patients. It emerged that suPAR levels in the subgroup with DAS28 < 2.6 (disease remission) were lower than in the subgroup with DAS28 > 2.6 (active disease) but still higher than in healthy controls (HC). The authors further demonstrated that suPAR values were significantly higher in patients with 4 tender and/or swollen joints than in patients with 2–3 or 0–1 tender and/or swollen joints. SuPAR may therefore be especially helpful in identifying inflammatory activity in patients who have clinical symptoms affecting joints but are in remission according to DAS28 scores [24][5]. Slot et al. evaluated the importance of suPAR in RA and other autoimmune diseases such as Reactive Arthritis (ReA) and Primary Sjogren’s Syndrome (pSS). The median suPAR value in RA was 1.47 μg/L (range 0.65–6.62), 0.68 μg/L in ReA (range 0.52–1.48), and 1.12 μg/L in pSS (range 0.76–1.92). SuPAR in RA also showed a positive correlation with CRP, ESR, and the number of swollen joints. The ReA group, on the other hand, had the lowest plasma suPAR concentrations while also having the highest CRP values of any group. The authors hypothesized that the higher suPAR concentrations in RA compared to ReA may be due to the relationship between suPAR and erosive activity [25][6].
Overall, these studies show that the uPA/uPAR interaction, in conjunction with the surrounding microenvironment and extracellular signals from various cell types, mediates RA pathogenesis. However, its role is in its early stages and will require further investigation in the near future.

2. Systemic Lupus Erythematosus (SLE)

SLE is a potentially severe autoimmune condition characterized by inflammation with a fluctuating clinical course of flares that may lead to permanent organ damage and quiescent periods, and it is associated with reduced quality of life, increased mortality, and accumulating irreversible organ damage [26][7].
Since the current information provided by CRP and ESR is constrained by their low sensitivity and low specificity, as well as by a number of preanalytical factors that can interfere with results, such as the diurnal cycle, sampling method, or even physical activity, there is a critical need to identify novel inflammation’s parameters [27][8].
Various studies have considered suPAR as a predictor of disease activity and organ damage in SLE. Enocsson et al. found that levels of suPAR were significantly higher in a group of 198 SLE patients compared to HC; however, no significant association with disease activity, neither defined as SLE disease activity index-2000 (SLEDAI-2K) nor as the physician’s global assessment (PGA), was found. Moreover, they found that the levels appeared to reflect irreversible organ damage, especially in the renal, ocular, and neuropsychiatric domains of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Of all the organ systems considered, renal damage had the most pronounced impact on suPAR levels [28][9].
In Toldi et al.’s study, 89 SLE patients were enrolled at various stages of disease duration and activity. suPAR plasma levels were elevated in SLE patients compared to HC patients and were revealed to be higher in SLE patients with vasculitis than in patients without vasculitis. Interestingly, in contrast with CRP and ESR, suPAR enabled the differentiation between patients with high disease activity (SLEDAI > 8) and those with moderate disease activity or in remission (SLEDAI ≤ 8) [29][10].
Another study conducted by Enocsson et al. in 2019 on 344 SLE patients demonstrated that suPAR levels at baseline were associated with global organ damage after 5 years of follow-up. In line with previous observations [28][9], there was no correlation with disease activity (SLEDAI-2K) at baseline, and no association with the presence of autoantibodies included in the ‘immunological disorder criterion’ of the ACR classification (of which anti-dsDNA antibody levels often parallel the disease activity). suPAR serum concentrations were found to correlate with musculoskeletal damage in SLE patients, which was responsible for the second-most frequent type of organ damage in the study cohort [30][11]. This is in line with the observations of Pliyev et al. [22][3] in a RA cohort objectifying the association of suPAR with the number of swollen joints, originating from synovial neutrophils, thereby recruiting leukocytes in the joints and promoting joint inflammation and subsequent damage.
Up to 60% of SLE patients have renal involvement, and lupus nephritis continues to be the leading source of morbidity and mortality over the disease’s progression. In the cohort of 202 patients with renal biopsy-proven lupus nephritis studied by Qin et al., active lupus nephritis had suPAR levels that were considerably greater than those of the SLE group without renal involvement and of healthy controls. Moreover, the patients with nephrotic syndrome, non-infectious leukocyturia, acute renal failure, and higher SLEDAI scores presented significantly higher baseline suPAR levels [31][12]. In addition, suPAR levels decreased significantly during remission, and the level of suPAR was found to be a risk factor for long-term renal outcomes [31][12].
Finally, in children with lupus nephritis, the increased amount of circulating suPAR has been associated with both multi-organ involvement and systemic inflammation [32][13].
SuPAR’s role in the pathogenesis of SLE is unknown, but its effects on leukocyte recruitment, phagocytic uptake of dying cells (efferocytosis), and complement regulation suggest that suPAR may have a central role in the pathogenesis of the disease.

3. Systemic Sclerosis (SSc)

Several biomarkers reflecting disease activity and severity in SSc have been described, but their role has not been completely clarified [33,34][14][15].
In a study by Legany et al. published in 2015, high levels of suPAR were found in SSc patients compared with HC patients, and higher levels were found in patients with anti-Scl-70 autoantibodies. Higher suPAR levels were found in patients with a diffuse cutaneous sclerosis variant compared with a limited cutaneous variant. suPAR levels also correlated with pulmonary involvement. suPAR levels correlated with a severe decrease in Diffusing Lung Capacity for Carbon monOxide (DLCO) and Forced Vital Capacity (FVC) values and increased levels were found in pulmonary fibrosis and pulmonary arterial hypertension within interstitial lung diseases. Higher suPAR levels were associated with vascular abnormalities (digital ulcers, Raynaud phenomenon, and pathological nailfold capillaroscopy) and with joint manifestations suggesting that this biomarker could become very important for early diagnosis and assessment of disease severity [35][16].
The association between suPAR levels and the severity of pulmonary involvement and the inverse correlation with DLCO in a recent study on 121 SSc patients was not confirmed. However, its levels were associated with the extent of skin involvement, autoantibody positivity, and vascular features (the presence of pulmonary arterial hypertension, telangiectasias, and present or past history of digital ulcers) [36][17].

4. Behcet’s Syndrome

Behcet’s syndrome is a chronic relapsing vasculitis characterized by multiple manifestations such as mucocutaneous lesions (oral and genital ulcers, erythema nodosum, and papulopustular lesions), arthritis, uveitis, neurological, gastrointestinal, and vessels involvements [37][18]. A study published by Saylam Kurtipek et al. in 2016 showed a statistically significant increase in suPAR levels in 30 patients with Behcet’s syndrome compared to 41 HC. They found a statistically significant difference between the two groups for CRP and suPAR levels but not for suPAR levels related to disease activity, even if the study has been conducted in a low number of patients and with early treatment with colchicine [38][19].

5. Psoriasis

Psoriasis is a chronic, immune-mediated inflammatory skin condition that has been associated with cardiovascular, metabolic, psychiatric, and arthritic comorbidities [39][20]. In a 2015 study, suPAR levels were analyzed in 65 Psoriasis patients versus a 50 HC cohort. There were no statistically significant differences in suPAR levels between the two groups [40][21]. These findings were confirmed in a more recent study. Moreover, suPAR levels were not associated with Psoriasis Area and Severity Index (PASI) scores, duration of disease, type of Psoriasis, treatment performed, and presence of arthralgias [41][22]. Both studies showed no utility of suPAR as a biomarker for Psoriasis, but studies in cohorts of patients with severe disease characterized by higher PASI scores have not yet been conducted.

6. Ankylosing Spondylitis (AS)

AS is an immune-mediated rheumatic disease characterized by chronic inflammation. The axial and sacroiliac joints are the main targets of the autoimmune reaction in AS. Spondylitis, a persistent inflammation of the spine, eventually results in the fusing of the vertebrae as the disease advances and extra bone is formed (ankylosis). Systemic autoimmune reactions can cause significant target organ damage in the later stages of the disease, causing enthesitis, peripheral arthritis, and extra-articular manifestations such as the gastrointestinal tract, eye inflammation, and heart inflammation [42][23]. As a result, early and reliable detection and monitoring of inflammation are critical in the management of AS.
In a 2013 study by Toldi et al. in a cohort of 33 AS patients at various stages of disease duration and activity and 29 HC, the CRP and ESR values were higher in AS patients than in healthy individuals, while suPAR values were comparable. There was a correlation found between BASDAI scores and CRP and ESR values in AS patients, but not with suPAR levels. So, these results do not support its usefulness in the assessment of inflammation in AS. For this reason, plasma suPAR levels are not used for monitoring the disease activity in AS such as ESR and CPR values [43][24].

7. ANCA-Associated Vasculitis (AAV)

AAV is characterized by pauci-immune necrotizing inflammation of the small blood vessels. AAV involves multiple organ systems including Granulomatosis with PolyAngiitis (GPA), Microscopic PolyAngiitis (MPA), and Eosinophilic Granulomatosis with Polyangitis (EGPA). The disease frequently presents as a pauci-immune focal segmental necrotizing glomerulonephritis with a very rapid decline in renal function. The kidney is the most organ susceptible to the disease. MyeloPeroxidase (MPO) and PRoteinase 3 (PR3) are the two most significant target antigens of ANCAs, which are the serologic markers of AAV [44][25]. SuPAR is linked to kidney disorders and has been used to predict the progression of renal function loss. The objective of Fei Huang et al.’s study was to determine whether suPAR levels were associated with ANCA-AAV disease activity. SuPAR levels in 90 AAV patients were assessed, and it was found that they were significantly higher than in HC patients. Additionally, suPAR was found to be significantly higher in AAV patients who were in active stages of the disease compared to those who were in partial remission, indicating a link between disease activity and a poor prognosis [45][26]. Similar findings were found in another study by Rowaiye et al. where 60 patients with renal involvement and AAV have been followed up for a median period of 12 months with higher levels of suPAR in patients with relapse compared with patients with inactive AAV. These findings suggest that plasma suPAR levels are a predictive biomarker for renal AAV patients’ mortality risk categorization. Notably, higher baseline suPAR levels were found in non-survivors than in survivors. In 2021, Zabinska et al. observed a statistically significant correlation between suPAR levels and kidney function in AAV with renal involvement associated with the immune activation state. So, the observed correlation between suPAR and the reported clinical characteristics may suggest that suPAR has the capacity to indicate renal involvement and disease severity [44][25].

8. Key Messages

In RA, most of the studies suggest many advantages of suPAR in detecting low-grade inflammation and agree with the association of suPAR with the number of swollen joints [22][3] and disease activity [23,24][4][5].
Various studies have considered suPAR as a predictor of disease activity and organ damage in SLE [29][10]; however, in other research, no significant association with disease activity was found [28][9]. suPAR correlates with musculoskeletal damage in SLE [30][11], as well as autoantibody positivity, skin involvement, and vascular features [36][17]. SuPAR is able to discriminate between SLE patients with high disease activity and those with less active disease or those in remission [29][10]. Regarding Behcet’s syndrome, Psoriasis, and AS, the number of current studies is not yet sufficient to draw conclusions on the effectiveness of suPAR. On the contrary, in AAV, suPAR levels are valuable predictive biomarkers for renal involvement and disease severity [44][25].

References

  1. Pillinger, M.H.; Abramson, S.B. The neutrophil in rheumatoid arthritis. Rheum. Dis. Clin. N. Am. 1995, 21, 691–714.
  2. Edwards, S.W.; Hallett, M.B. Seeing the wood for the trees: The forgotten role of neutrophils in rheumatoid arthritis. Immunol. Today 1997, 18, 320–324.
  3. Pliyev, B.K.; Menshikov, M.Y. Release of the soluble urokinase-type plasminogen activator receptor (suPAR) by activated neutrophils in rheumatoid arthritis. Inflammation 2010, 33, 1–9.
  4. Enocsson, H.; Lukic, T.; Ziegelasch, M.; Kastbom, A. Serum levels of the soluble urokinase plasminogen activator receptor (suPAR) correlates with disease activity in early rheumatoid arthritis and reflects joint damage over time. Transl. Res. 2021, 232, 142–149.
  5. Toldi, G.; Beko, G.; Kadar, G.; Macsai, E.; Kovacs, L.; Vasarhelyi, B.; Balog, A. Soluble urokinase plasminogen activator receptor (suPAR) in the assessment of inflammatory activity of rheumatoid arthritis patients in remission. Clin. Chem. Lab. Med. 2013, 51, 327–332.
  6. Slot, O.; Brunner, N.; Locht, H.; Oxholm, P.; Stephens, R.W. Soluble urokinase plasminogen activator receptor in plasma of patients with inflammatory rheumatic disorders: Increased concentrations in rheumatoid arthritis. Ann. Rheum. Dis. 1999, 58, 488–492.
  7. Ugarte-Gil, M.F.; Gonzalez, L.A.; Alarcon, G.S. Lupus: The new epidemic. Lupus 2019, 28, 1031–1050.
  8. Burcsar, S.; Toldi, G.; Kovacs, L.; Szalay, B.; Vasarhelyi, B.; Balog, A. Urine soluble urokinase plasminogen activator receptor as a potential biomarker of lupus nephritis activity. Biomarkers 2021, 26, 443–449.
  9. Enocsson, H.; Wettero, J.; Skogh, T.; Sjowall, C. Soluble urokinase plasminogen activator receptor levels reflect organ damage in systemic lupus erythematosus. Transl. Res. 2013, 162, 287–296.
  10. Toldi, G.; Szalay, B.; Beko, G.; Bocskai, M.; Deak, M.; Kovacs, L.; Vasarhelyi, B.; Balog, A. Plasma soluble urokinase plasminogen activator receptor (suPAR) levels in systemic lupus erythematosus. Biomarkers 2012, 17, 758–763.
  11. Enocsson, H.; Wirestam, L.; Dahle, C.; Padyukov, L.; Jonsen, A.; Urowitz, M.B.; Gladman, D.D.; Romero-Diaz, J.; Bae, S.C.; Fortin, P.R.; et al. Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus. J. Autoimmun. 2020, 106, 102340.
  12. Qin, D.D.; Song, D.; Huang, J.; Yu, F.; Zhao, M.H. Plasma-soluble urokinase-type plasminogen activator receptor levels are associated with clinical and pathological activities in lupus nephritis: A large cohort study from China. Lupus 2015, 24, 546–557.
  13. Soltysiak, J.; Zachwieja, J.; Benedyk, A.; Lewandowska-Stachowiak, M.; Nowicki, M.; Ostalska-Nowicka, D. Circulating suPAR as a biomarker of disease severity in children with proteinuric glomerulonephritis. Minerva Pediatr. 2019, 71, 4–11.
  14. Manetti, M. Emerging biomarkers in systemic sclerosis. Curr. Opin. Rheumatol. 2016, 28, 606–612.
  15. Muangchan, C.; Harding, S.; Khimdas, S.; Bonner, A.; Canadian Scleroderma Research Group; Baron, M.; Pope, J. Association of C-reactive protein with high disease activity in systemic sclerosis: Results from the Canadian Scleroderma Research Group. Arthritis Care Res. 2012, 64, 1405–1414.
  16. Legany, N.; Toldi, G.; Distler, J.H.; Beyer, C.; Szalay, B.; Kovacs, L.; Vasarhelyi, B.; Balog, A. Increased plasma soluble urokinase plasminogen activator receptor levels in systemic sclerosis: Possible association with microvascular abnormalities and extent of fibrosis. Clin. Chem. Lab. Med. 2015, 53, 1799–1805.
  17. Butt, S.; Jeppesen, J.L.; Iversen, L.V.; Fenger, M.; Eugen-Olsen, J.; Andersson, C.; Jacobsen, S. Association of soluble urokinase plasminogen activator receptor levels with fibrotic and vascular manifestations in systemic sclerosis. PLoS ONE 2021, 16, e0247256.
  18. Karadag, O.; Bolek, E.C. Management of Behcet’s syndrome. Rheumatology 2020, 59, iii108–iii117.
  19. Saylam Kurtipek, G.; Kesli, R.; Tuncez Akyurek, F.; Akyurek, F.; Ataseven, A.; Terzi, Y. Plasma-soluble urokinase plasminogen activator receptor (suPAR) levels in Behcet’s disease and correlation with disease activity. Int. J. Rheum. Dis. 2018, 21, 866–870.
  20. Parisi, R.; Iskandar, I.Y.K.; Kontopantelis, E.; Augustin, M.; Griffiths, C.E.M.; Ashcroft, D.M.; Global Psoriasis, A. National, regional, and worldwide epidemiology of psoriasis: Systematic analysis and modelling study. BMJ 2020, 369, m1590.
  21. Kurtipek, G.S.; Kesli, R.; Tuncez Akyurek, F.; Akyuret, F.; Terzi, Y. Plasma-soluble urokinase plasminogen activator receptor (suPAR) levels in psoriasis patients and correlation with disease severity. Acta Dermatovenerol. Alp. Pannonica Adriat. 2015, 24, 73–75.
  22. Hamie, L.; Eid, E.; Abbas, O.; Safi, R.; Nammour, T.; Tamim, H.; Makki, M.; Stephan, C.; Hasbani, D.; Wehbe, H.; et al. SuPAR, a potential inflammatory mediator in psoriasis pathogenesis. Clin. Exp. Pharmacol. Physiol. 2020, 47, 1705–1712.
  23. Braun, J.; Sieper, J. Ankylosing spondylitis. Lancet 2007, 369, 1379–1390.
  24. Toldi, G.; Szalay, B.; Beko, G.; Kovacs, L.; Vasarhelyi, B.; Balog, A. Plasma soluble urokinase plasminogen activator receptor (suPAR) levels in ankylosing spondylitis. Jt. Bone Spine 2013, 80, 96–98.
  25. Zabinska, M.; Koscielska-Kasprzak, K.; Krajewska, J.; Bartoszek, D.; Augustyniak-Bartosik, H.; Krajewska, M. Immune Cells Profiling in ANCA-Associated Vasculitis Patients-Relation to Disease Activity. Cells 2021, 10, 1773.
  26. Huang, F.; Li, Y.; Xu, R.; Cheng, A.; Lv, Y.; Liu, Q. The Plasma Soluble Urokinase Plasminogen Activator Receptor Is Related to Disease Activity of Patients with ANCA-Associated Vasculitis. Mediat. Inflamm. 2020, 2020, 7850179.
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