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Can Pentraxin-3 be a candidate marker in the follow-up of the patients with Behcet's disease?

Behget's disease (BD) is a chronic, relapsing multisystemic disease characterized with nonspecific vasculitis that affects various sizes of vessels. The highest prevalence was reported in the Eastern Mediterranean and in Asia. [1,2] Inherited and adaptive immunity accompanied with bacterial and viral infections, activations of neutrophils, natural killers, and cytotoxic T cells were found to be responsible in the etiology. [3-5] BD's association with human leukocyte antigen-B51 (HLA-B51) gene is well known, however there is no certain laboratory parameter for the diagnosis or follow-up of BD. Pentraxins (PTXs) are acute phase proteins that affect humoral arm of congenital immunity. [6] They are divided into two groups as short and long PTXs. [7,8] C-reactive protein (CRP) is the prototype of the short PTX family mainly produced in the liver in response to inflammatory signals and PTX-3 is the prototype of the long PTX family. [9,10] While CRP is produced by hepatocytes, PTX-3 is produced by different cell types and functions locally. Different from classic PTXs, PTX-3 is secreted as a response to interleukin-1 beta and tumor necrosis factor alpha. PTX-3 plays a complex role in vivo, recognizing a diverse range of pathogens modulating complement activity by binding C1q and facilitating pathogen recognition by macrophages and dendritic cells. Because of this extrahepatic synthesis in contrast to CRP, PTX-3 levels are believed to be a more reliable indicator of disease activity produced at sites of inflammation. [11] Increased levels of PTX-3 have been observed in some autoimmune disorders. [11,12] In small vessel vasculitis, PTX-3 levels correlate with clinical activity of the disease and represent a candidate marker for monitoring the disease. [11] Nevertheless, there is only one recent report investigating PTX-3 association in patients with BD and BD's activity. Therefore, in this study, we aimed to assess the level of PTX-3 as an inflammatory marker and compare it with CRP levels in patients with BD.

PATIENTS AND METHODS

Forty-two BD patients (15 males, 27 females; mean age 39.7 [+ or -] 8.6 years; range 20 to 64 years), who attended Rheumatology Clinic at the Department of Internal Medicine, Medeniyet University Goztepe Training and Research Hospital between January 2011 and June 2011 and were diagnosed according to the International Study Group of BD, 13 and 42 healthy controls (14 males, 28 females; mean age 40.8 [+ or -] 8.2 year; range 25 to 60 years) were included. Exclusion criteria were disorders and habits that may affect inflammatory state (i.e. diabetes mellitus, dyslipidemia, malignancy, other rheumatologic or inflammatory disease, alcohol consumption, smoking, drug use). The present study was approved by the Ethical Board (01.04.2011 dated, decision no: 11/C) and written informed consent was obtained from all patients. The study was conducted in accordance with the principles of the Declaration of Helsinki. Morning blood samples were taken after an overnight fasting. Blood samples were centrifuged at 1,500 g for 10 minutes at room temperature within two hours after collection. Serum CRP was measured by nephelometric method (Immage[R] Immunochemistry System, Beckman Coulter, USA) as a part of daily clinical practice. Plasma (ethylenediaminetetraacetic acid-anticoagulated) samples were stored at -200 [degrees]C until analysis. Plasma PTX-3 concentration was measured by using the commercially available enzyme-linked immunosorbent assay kit (Quantikine Human Pentraxin 3/TSG-14 Immunoassay, R&D Systems, Minneapolis, USA). The analytic sensitivity of the test was 0.025 ng/mL, and the intra-assay variation coefficient (CV %) for the three separate concentrations were 3.8 (mean value: 2.61 [+ or -] 0.01, n=20), 3.7 (mean value: 7.72 [+ or -] 0.28, n=20), and 4.4 (mean value: 14.1 [+ or -] 0.62, n=20)

Statistical analysis

The data were expressed as mean [+ or -] standard deviation (SD) or mean [+ or -] standard error of the mean (SEM). Statistical analysis was performed using SPSS version 16.0 for Windows (SPSS Inc., Chicago, IL, USA). Comparison between the groups were made with unpaired t-test and Mann-Whitney U test, as appropriate. Correlations were performed by the Spearman rank test. The clinical performance of CRP and PTX-3 were assessed using receiver operating characteristics curves and calculated likelihood ratios for two cut-points with either high sensitivity or high specificity. A p value of <0.05 was considered to be statistically significant.

RESULTS

All the patients with BD were under treatment and their clinical data can be seen in Table 1. Both CRP and PTX-3 levels were significantly higher among patients with BD than healthy controls (0.71 [+ or -] 0.13 vs 0.27 [+ or -] 0.03, p<0.001 for CRP and 1.33 [+ or -] 0.29 vs 0.85 [+ or -] 0.12, p<0.05 for PTX-3; respectively) (Table 2). Nevertheless, increases in PTX-3 and CRP levels were similar (area under the curve: 0.633 [+ or -] 0.062 vs 0.729 [+ or -] 0.05; respectively) (Figure 1). Subgroup analyses were performed according to clinical features of BD. Mean PTX-3 and CRP levels were 1.1 vs 1.5, p=0.5; 0.5 vs 0.9, p=0.5; respectively, in patients with mucocutaneous involvement alone and with other involvements; whereas they were 0.9 vs 1.6, p=0.1; 0.5 vs 0.8, p=0.3; respectively, in patients with and without peripheral arthritis; and 1.7 vs 0.9, p=0.06; 1.0 vs 0.5, p=0.07; respectively, in patients with and without uveitis (Table 3).

DISCUSSION

In the present study, we determined that PTXs, both CRP and PTX-3, which are inflammation markers, were significantly higher in patients with BD. Nevertheless, specificity and sensitivity of PTX-3, which is a novel long PTX, were similar to those of CRP. In previous studies, it was hypothesized that PTX-3, unlike CRP, may be a rapid marker for primary local activation of innate immunity and inflammation and an indicator of disease activity while in other studies, correlation between levels of PTX-3 and CRP was found to be weak. [14-17] In this study, PTX-3, similar to CRP, was found to be associated with BD but did not show any superiority when compared to CRP. There are limited number of studies investigating PTX-3 levels in rheumatologic diseases. In a study investigating whether PTX-3 is an indicator of small vessel vasculitis activity [11] in patients with Churg-Strauss syndrome, Wegener's granulomatosis, and microscopic polyangiitis, systemic lupus erythematosus, rheumatoid arthritis, and CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia), PTX-3 levels were higher in patients with untreated vasculitis and lower in patients who underwent immunosuppressive treatments (p<0.005). Different from our study, PTX-3 levels did not correlate with CRP levels in patients with vasculitis. [11]

In another study conducted on patients with rheumatoid arthritis, it was shown that PTX-3, unlike CRP, contributed to the complement-mediated mechanism causing inflammation and tissue damage. Increased levels of PTX-3 protein was obtained in synovial fluids from patients with rheumatoid arthritis. In contrast to other acute phase reactants, the majority of PTX-3 synthesis is extrahepatic and in that study the main source of PTX-3 was the synovial pannus. [12]

A study in patients with psoriatic arthritis showed a positive correlation between PTX-3 and disease activity of psoriasis. A strong PTX-3 staining in fibroblasts, endothelial cells and monocytes/macrophages was detected in severe psoriatic skin lesions. [18]

Recently, in a Turkish cohort of BD patients similar to our study group, [19] it was determined that PTX-3 levels did not correlate with CRP or with any domains of BD's current activity form in contrast to our present study. In our study, PTX-3 levels were found to be significantly higher in patients with BD. Since most of the patients of our cohort were in remission, we tried to find out the difference of PTX-3 levels according to BD's site-specific involvement, rather than disease activity. PTX-3 levels did not show any difference according to involvement. We only observed a slight increase in patients who had uveitis. However, this increase was not statistically significant. Our study indicates that PTX-3 can be an alternative parameter to CRP in the follow-up of BD. However, we need further studies to determine the relationship between PTX-3 and severity of BD.

doi: 10.5606/ArchRheumatol.2017.6129

Declaration of conflicting interests

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding

The authors received no financial support for the research and/or authorship of this article.

REFERENCES

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[2.] O'duffy JD. Summary of International Symposium on Behqet's Disease. Istanbul, September 29-30, 1977. J Rheumatol 1978; 5:229-33.

[3.] Yazici H, Fresko I, Yurdakul S. Behqet's syndrome: disease manifestations, management, and advances in treatment. Nat Clin Pract Rheumatol 2007; 3:148-55.

[4.] Zierhut M, Mizuki N, Ohno S, Inoko H, Gul A, Onoe K, et al. Immunology and functional genomics of Behget's disease. Cell Mol Life Sci 2003; 60:1903-22.

[5.] Tuzun B, Tuzun Y, Yurdakul S, Hamuryudan V, Yazici H, Ozyazgan Y. Neutrophil chemotaxis in Behget's syndrome. Ann Rheum Dis 1999; 58:658.

[6.] Garlanda C, Bottazzi B, Bastone A, Mantovani A. Pentraxins at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility. Annu Rev Immunol 2005; 23:337-66.

[7.] Norata GD, Marchesi P, Pulakazhi Venu VK, Pasqualini F, Anselmo A, Moalli F, et al. Deficiency of the long pentraxin PTX3 promotes vascular inflammation and atherosclerosis. Circulation 2009; 120:699-708.

[8.] Doni A, Michela M, Bottazzi B, Peri G, Valentino S, Polentarutti N, et al. Regulation of PTX3, a key component of humoral innate immunity in human dendritic cells: stimulation by IL-10 and inhibition by IFN-gamma. J Leukoc Biol 2006; 79:797-802.

[9.] Reid MS, Blobel CP. Apexin, an acrosomal pentaxin. J Biol Chem 1994; 269:32615-20.

[10.] Noland TD, Friday BB, Maulit MT, Gerton GL. The sperm acrosomal matrix contains a novel member of the pentaxin family of calcium-dependent binding proteins. J Biol Chem 1994; 269:32607-14.

[11.] Fazzini F, Peri G, Doni A, Dell'Antonio G, Dal Cin E, Bozzolo E, et al. PTX3 in small-vessel vasculitides: an independent indicator of disease activity produced at sites of inflammation. Arthritis Rheum 2001; 44:2841-50.

[12.] Luchetti MM, Piccinini G, Mantovani A, Peri G, Matteucci C, Pomponio G, et al. Expression and production of the long pentraxin PTX3 in rheumatoid arthritis (RA). Clin Exp Immunol 2000; 119:196-202.

[13.] Criteria for diagnosis of Behqet's disease. International Study Group for Behqet's Disease. Lancet 1990; 335:1078-80.

[14.] Peri G, Introna M, Corradi D, Iacuitti G, Signorini S, Avanzini F, et al. PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans. Circulation 2000; 102:636-41.

[15.] Muller B, Peri G, Doni A, Torri V, Landmann R, Bottazzi B, et al. Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients. Crit Care Med 2001; 29:1404-7.

[16.] Hess AP, Hamilton AE, Talbi S, Dosiou C, Nyegaard M, Nayak N, et al. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol Reprod 2007; 76:102-17.

[17.] Tong M, Anderstam B, Sjoberg B, Alvestrand A. Circulating levels of long pentraxin 3 (PTX3) are elevated in hemodialysis patients and increase acutely after a single HD session. J Am Soc Nephrol 2006; 17:735A. [Abstract]

[18.] Bevelacqua V, Libra M, Mazzarino MC, Gangemi P, Nicotra G, Curatolo S, et al. Long pentraxin 3: a marker of inflammation in untreated psoriatic patients. Int J Mol Med 2006; 18:415-23.

[19.] Yazmalar L, Batmaz I, Sula B, Alpayci M, Aydin F, Turkqu F, et al. Serum levels of alpha-1 acid glycoprotein and pentraxin 3 in patients with Behqet's disease and relationship with disease activity. Int J Dermatol 2015; 54:394-400.

Banu ALPASLAN MESCI, (1) Banu ISBILEN BASOK, (2) Hatice GUL SAGUN, (1) Gokhan GONENLI, (1) Mukaddes KAVALA, (3) Esen KASAPOGLU GUNAL, (4) Esra EKIZ, (5) Ferruh ISMAN, (2) Aytekin OGUZ (1)

(1) Department of Internal Medicine, Medeniyet University Goztepe Training and Research Hospital, Istanbul, Turkey

(2) Department of Biochemistry, Medeniyet University Goztepe Training and Research Hospital, Istanbul, Turkey

(3) Department of Dermatology, Medeniyet University Goztepe Training and Research Hospital, Istanbul, Turkey

(4) Department of Rheumatology, Medeniyet University Goztepe Training and Research Hospital, Istanbul, Turkey

(5) Department of Internal Medicine, Esenler Women's & Children Hospital, Istanbul, Turkey

Received: July 04, 2016 Accepted: August 01, 2016 Published online: December 15, 2016

Correspondence: Esra Ekiz, MD. Esenler Kadin Dogum ve Cocuk Hastaliklari Hastanesi, lc Hastaliklari Klinigi, 34230 Esenler, Istanbul, Turkey.

Tel: +90 212-440 39 00 e-mail: dr.esra@gmail.com

Caption: Figure 1. Sensitivities of C-reactive protein and Pentraxin-3.
Table 1. Laboratory findings of patients with Behget's disease

                                      Values         Normal range

Hemoglobin (g/dL)                      10.7            11.7-15.5
Hematocrit (%)                         32.4              37-44
Leukocyte count (mcrL)                 9.24          3.800-11.000
Platelet (mcrL)                      291.000        150.000-350.000
Erythrocyte sedimentation rate          9                0-20
  (mm/h)
C-reactive protein (mg/L)              0.72               0-6
Urea (g/dL)                            119               13-43
Creatinine (mg/dL)                     1.48             0.7-1.3
Rheumatoid factor (IU/mL)              14.0              0-18
Anti-CCP (unit/mL)                     0.6               0-2.5
ANA                              1:>1000 granular      Negative
                                     pattern
Anti-SSA                           ++ Positive         Negative
Anti-SSB                           +++ Positive        Negative
Ro-52 (52 Kda)                     +++ Positive        Negative
ANCA                                 Negative          Negative
Anticardiolipin IgM/IgG              Negative          Negative
Venereal disease research-RPR        Negative          Negative
  test
Complement component 4 (C4)            22.9              15-50
  (mg/dL)
Double-stranded DNA (dsDNA)          Negative          Negative
  antibody
Direct Coombs test (IgG)          ++++ Positive        Negative

Anti-CCP: Anti-cyclic citrullinated peptide; ANA: Antinuclear
antibody; Anti-SSA: Anti Sjogren syndrome A; Anti-SSB: Anti Sjogren
syndrome A; ANCA: Anti-neutrophil cytoplasmic antibody; RPR: Rapid
plasma regain; dsDNA: Double stranded Deoxyribonucleic acid; IgG:
Immunoglobulin G.

Table 2. Comparison of inflammatory markers between two study groups

                            Healthy controls (n=42)

                       n    Mean [+ or -] SD     Mean [+ or -] SEM
Gender
  Males                14
  Females              28
C-reactive protein          0.27 [+ or -] 0.03
  (mg/dL)
Erythrocyte                                      20.1 [+ or -] 11.0
  sedimentation rate
  (mm/hr)
Pentraxin-3 (ng/mL)                              0.85 [+ or -] 0.12

                            Patients with BD (42)

                       n     Mean [+ or -] SD    Mean [+ or -] SEM
Gender
  Males                15
  Females              27
C-reactive protein                               0.71 [+ or -] 0.13
  (mg/dL)
Erythrocyte                 24.3 [+ or -] 16.5
  sedimentation rate
  (mm/hr)
Pentraxin-3 (ng/mL)                              1.33 [+ or -] 0.29

                         P
Gender
  Males
  Females
C-reactive protein     <0.001
  (mg/dL)
Erythrocyte            >0.05
  sedimentation rate
  (mm/hr)
Pentraxin-3 (ng/mL)    <0.05

SD: Standard deviation; SEM: Standard error of mean.

Table 3. Comparison of pentraxin-3, C-reactive protein and
erythrocyte sedimentation rate levels with regards to sites of
involvement in patient group

                                      Pentraxin-3    P

With only mucocutaneus (n=18) vs       1 vs 1.5     0.5
with other involvement (n=26)

With uveitis (n=18) vs without        1.7 vs 0.9    0.06
uveitis (n=21)

With peripheral arthritis (n=15) vs   0.9 vs 1.6    0.1
without peripheral arthritis (n=22)

                                         CRP        P

With only mucocutaneus (n=18) vs      0.5 vs 0.9   0.59
with other involvement (n=26)

With uveitis (n=18) vs without        1.0 vs 0.5   0.07
uveitis (n=21)

With peripheral arthritis (n=15) vs   0.5 vs 0.8   0.3
without peripheral arthritis (n=22)

                                        ESR       P

With only mucocutaneus (n=18) vs      20 vs 27   0.5
with other involvement (n=26)

With uveitis (n=18) vs without        29 vs 19   0.07
uveitis (n=21)

With peripheral arthritis (n=15) vs   24 vs 25   0.3
without peripheral arthritis (n=22)

CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate.
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Title Annotation:ORIGINAL ARTICLE
Author:Mesci, Banu Alpaslan; Basok, Banu Isbilen; Sagun, Hatice Gul; Gonenli, Gokhan; Kavala, Mukaddes; Gun
Publication:Turkish Journal of Rheumatology
Date:Jun 1, 2017
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