0RESEARCH ARTICLE
Open Access
High mobility group box 1 levels in large vessel vasculitis are not associated with disease activity but are influenced by age and statins
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6 Alexandre W. S. de Souza1,2*, Kornelis S. M. van der Geest1, Elisabeth Brouwer1, Frederico A. G. Pinheiro2,
7 Ana Cecilia Diniz Oliveira2, Emilia Inoue Sato2, Luis Eduardo C. Andrade2, Marc Bijl3, Johanna Westra1
and Cees G. M. Kallenberg
Abstract
Introduction: Takayasu arteritis (TA) and giant cell arteritis (GCA) are large vessel vasculitides (LVV) that usually present as granulomatous inflammation in arterial walls. High mobility group box 1 (HMGB1) is a nuclear protein that acts as an alarmin when released by dying or activated cells. This study aims to evaluate whether serum HMGB1 can be used as a biomarker in LVV.
Methods: Twenty-nine consecutive TA patients with 29 healthy controls (HC) were evaluated in a cross-sectional study. Eighteen consecutive GCA patients with 16 HC were evaluated at the onset of disease and some of them during follow-up. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay.
Results: In GCA patients at disease onset mean serum HMGB1 levels did not differ from HC (5.74 ±4.19 ng/ml vs. 4.17 ± 3.14 ng/ml; p = 0.230). No differences in HMGB1 levels were found between GCA patients with and without polymyalgia rheumatica (p = 0.167), ischemic manifestations (p = 0.873), systemic manifestations (p = 0.474) or relapsing disease (p = 0.608). During follow-up, no significant fluctuations on serum HMGB1 levels were observed from baseline to 3 months (n =13) (p = 0.075), 12 months (n = 6) (p = 0.093) and at the first relapse (n = 4) (p = 0.202). Serum HMGB1 levels did not differ between TA patients and HC [1.19 (0.45-2.10) ng/ml vs. 1.46 (0.89-3.34) ng/ml; p = 0.181] and no difference was found between TA patients with active disease and in remission [1.31 (0.63-2.16) ng/ml vs. 0.75 (0.39-2.05) ng/ml; p = 0.281]. HMGB1 levels were significantly lower in 16 TA patients on statins compared with 13 patients without statins [0.59 (0.29-1.46) ng/ml vs. 1.93 (0.88-3.34) ng/ml; p = 0.019]. Age was independently associated with higher HMGB1 levels regardless of LVV or control status. Conclusions: Patients with TA and GCA present similar serum HMGB1 levels compared with HC. Serum HMGB1 is not useful to discriminate between active disease and remission. In TA, use of statins was associated with lower HMGB1 levels. HMGB1 is not a biomarker for LVV.
* Correspondence: alexandre_wagner@uol.com.br department of Rheumatology and Clinicallmmunology, University of Groningen, University MedicalCenter Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands
2Rheumatology Division, Universidade Federalde Sao Paulo - Escola Paulista de Medicina, R. Botucatu, 720, 04023 900 Sao Paulo, SP, Brazil Fulllist of author information is available at the end of the article
O© 2015 de Souza et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution BnlVled CBntf3l License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
33 Introduction
34 Takayasu arteritis (TA) and giant cell arteritis (GCA) are
35 large vessel vasculitides (LVV) characterized by granu-
36 lomatous inflammation of the vessel wall [1]. Although
37 both diseases present significant overlap in features and
38 some similarities in the distribution of angiographic le-
39 sions [2], TA predominantly affects young females and
40 involves the aorta and its main branches whereas GCA
41 affects predominantly branches of carotid and vertebral
42 arteries in individuals older than 50 years [1].
43 Despite clinical symptoms, acute phase reactants and
44 vascular imaging help to assess disease activity in LVV,
45 there is a need for novel biomarkers for diagnosis, progno-
46 sis and to distinguish active disease from damage or infec-
47 tion. In TA, active disease is associated with higher serum
48 levels of pentraxin-3, matrix metalloproteinase 9 (MMP-9),
49 interleukin (IL)-6, IL-8, IL-18, B cell-activating factor
50 (BAFF), monocyte chemoattractant protein-1 (MCP-1)
51 and regulated on activation, normal T cell expressed and
52 secreted (RANTES) [3-9]. In GCA, high serum levels of
53 tumor necrosis factor alpha (TNF-a), IL-6, IL-10, che-
54 mokine (C-X-C motif) ligand 9 (CXCL9) and BAFF are
55 associated with active disease while serum levels of CC
56 chemokines CCL2 and CCL11 are decreased at disease on-
57 set [10-14]. Moreover, adaptive immunity is triggered dur-
58 ing GCA pathogenesis manifested by T helper (Th)1 and
Th17 responses with the production of interferon (IFN)-y 59
and IL-17A, which enhance arterial inflammation [15, 16]. 60
High mobility group box 1 (HMGB1) is a nuclear non- 61
histone protein that acts as an alarmin when released 62 into the extracellular milieu either by cellular death or 63
upon activation of inflammatory cells, e.g. macrophages 64 by lipopolysaccharide (LPS) or IFN-y [17, 18]. High 65
serum HMGB1 levels have been observed in infectious 66
diseases, atherosclerosis, mechanical trauma, cancer, and 67
in systemic autoimmune diseases such as systemic lupus 68 erythematosus (SLE) [19-23]. In systemic vasculitis, high 69
serum HMGB1 levels were observed in Kawasaki dis- 70
ease, immunoglobulin (Ig)A vasculitis, and in patients 71
with antineutrophil cytoplasmic antibody (ANCA)- 72 associated vasculitis, especially in granulomatosis with 73
polyangiitis (GPA) with granulomatous manifestations 74
[24-27]. Serum HMGB1 levels have not been evalu- 75
ated in patients with LVV. This study aims to evaluate 76
serum HMGB1 levels as a surrogate marker of disease 77
activity in patients with LVV and associations between 78
serum HMGB1 and acute phase reactants, disease 79
manifestations and therapy in patients with TA and 80
GCA. Due to epidemiological differences in the preva- 81 lence of both diseases, patients with TA were recruited 82
from Brazil whereas GCA patients were recruited 83
from The Netherlands. 84
t1 1 Table 1 Demographic, disease features and therapy of patients with giant cell arteritis at disease onset and Takayasu arteritis
t1 2 Variables GCA HC P Variables TA HC P
t1 3 (n = 18) (n =16) (n = 29) (n = 29)
t1 4 Demographic features
t1 5 Age, years 72.0 (63.7-75.0) 68.5 (63.0-72.0) 0.643 Age, years 38.0 (34.5-48.5) 38.0 (27.5-48.5) 0.392
t1 6 Females, n (%) 14 (77.8) 11 (68.8) 0.551 Females, n (%) 28 (96.6) 27 (93.1) 0.553
t1 7 Disease features and therapy
t1 8 GCA Results TA Results
t1 9 Headache, n (%) 12 (66.7) Disease duration, months 108 (60-186)
t1 10 Constitutional symptoms, n (%) 8 (44.4) Angiographic type V, n (%) 16 (55.2)
t1 t1 11 12 Cranialischemic manifestations, n (%) 8 (44.4) Previous ischemic events, n (%) 11 (37.9)
t1 13 Jaw claudication, n (%) 6 (33.3) Active disease, n (%) 11 (37.9)
t1 14 Visual symptoms, n (%) 4 (22.2) Remission, n (%) 18 (62.1)
t1 15 Polymyalgia rheumatica, n (%) 4 (22.2) Statins, n (%) 16 (55.2)
t1 16 Headache, n (%) 12 (66.7) Prednisone, n (%) 16 (55.2)
t1 17 ESR, mm/1st hour 69.6 ± 28.7 Prednisone daily dose, mg 8.7 (5.0-28.7)
t1 18 CRP, mg/l 40.0 (20.2-84.2) Immunosuppressive agents, n (%) 19 (65.5)
t1 19 Positive TAB, n/total 8/11 Biologicalagents, n (%) 9 (31.0)
t1 20 Positive PET-CT scan, n/total 13/15
t1 t1 t1 21 22 23 Continuous variables are presented as mean ± standard deviation or as median and interquartile range CRP C-reactive protein, ESR erythrocyte sedimentation rate, GCA giant cell arteritis, HC healthy controls, n number of patients, PET-CT positron emission com tomography, TA Takayasu arteritis, TAB temporal artery biopsy puted
Methods
Study population
The study comprised 18 GCA patients with 16 healthy controls (HC), both from the University Medical Center Groningen (UMCG), The Netherlands (Table 1), and 29 consecutive TA patients from Universidade Federal de Sao Paulo (UNIFESP), Brazil with 29 HC from the same region (Table 1). Inclusion criterion for TA patients was the fulfillment of the 1990 American College of Rheumatology (ACR) classification criteria [28] while the exclusion criteria were current chronic infectious disease, malignancy, and pregnancy. GCA patients were included if they fulfilled the 1990 ACR criteria [29] or when presenting compatible manifestations associated with an enhanced 18F-fluorodeoxyglucose uptake in large vessels by positron emission computed tomography (18FDG-PET/CT). Exclusion criteria for GCA included current chronic infectious disease and malignancy. The study was approved by the Ethics Committee on Research from UNIFESP and by the Medical Ethical Committee of UMCG and complied with the Declaration of Helsinki. All necessary consent was provided from all participants involved in this study.
Active disease in GCA was considered if patients presented manifestations of active disease (e.g. temporal headache, optic neuritis, jaw claudication) not attributable to other causes and/or polymyalgia rheumatica (PMR) symptoms with an increase in ESR > 30 mm/hour whereas remission was considered in the absence of GCA manifestations with normal ESR [30]. Kerr's criteria and the Indian Takayasu activity score 2010 (ITAS2010) with acute phase response (ITAS.A) using ESR or CRP were employed to ascertain disease activity in TA [31, 32].
In the 18 GCA patients, blood samples were collected at disease onset prior to glucocorticoid therapy and follow-up samples were obtained from 13 patients at 3 months and from six patients at 12 months. Blood samples were collected from 29 TA patients as a cross-sectional evaluation.
Serum HMGB1
Serum HMGB1 levels were determined by enzyme-linked immunosorbent assay (ELISA) using a commercial kit (Shino Test Corp., Sagamihara, Kanagawa, Japan) according to the manufacturer's instructions. Results were expressed in nanograms per milliliter.
Statistical analysis
Statistical analysis was performed using IBM SPSS software for Windows version 20.0 (IBM Corp, Armonk, NY, USA) and graphs were created with GraphPad Prism version 3.02 (GraphPad Software, La Jolla, CA, USA). Mean ± standard deviation or median and interquartile range were used to present normally distributed and nonnormally distributed continuous variables, respectively. Categorical variables were presented as total number and percentage.
Comparisons between groups were performed using Student's t test or Mann-Whitney U test for continuous data or using chi-square test or Fisher's exact test for categorical variables. Correlations between numerical data were performed with Spearman's correlation coefficient. A linear regression model was built to analyze whether age and the diagnosis of LVV were independently associated with serum HMGB1 levels. Receiver operating characteristic (ROC) analysis was performed to find out the HMGB1 cutoff with the best sensitivity and specificity to differentiate GCA from TA. The cutoff value was chosen from the maximized sum of sensitivity and specificity. Paired t test or Wilcoxon's test were used to analyze longitudinal data. The significance level accepted was 5 % (p < 0.05).
Results
Disease features and therapy of GCA and TA patients
Disease features and therapy of GCA and TA patients are described in Table 1. After the first evaluation, all GCA patients were treated with high-dose prednisolone (60 mg/day) with slow tapering after improvement of disease symptoms and laboratory abnormalities. Disease relapse was observed in four (22.2 %) GCA patients and the median time to the first relapse after diagnosis was 6.0 months (6.0-15.0). Methotrexate 10-15 mg per week was added to two patients (11.1 %) after the first relapse during steroid tapering. Five GCA patients (27.8 %) were on statins at disease onset.
Previous ischemic events in TA included unstable angina (four patients), stroke (three patients), acute myo-cardial infarction (two patients), transient ischemic attacks and mesenteric ischemia in one patient each. Two TA patients were treated only with prednisone whereas the remainder used either an immunosuppres-sive drug or a biologic agent. ESR, ITAS.A ESR and ITAS.A C-reactive protein (CRP) values were significantly higher in TA patients with active disease than in those in remission, whereas there was a trend for higher serum CRP levels in patients with active disease. No significant differences could be found between patients with active disease and remission regarding therapy (Table 2).
HMGB1 levels in giant cell arteritis
In GCA patients with active disease at onset and prior to therapy mean serum HMGB1 levels did not differ between patients and HC (5.74 ± 4.19 ng/ml vs. 4.17 ± 3.14 ng/ml; p = 0.230) (Fig. 1). Furthermore, among GCA patients mean serum HMGB1 levels at onset were not higher in patients with or without PMR [1.25 (0.21-10.50) ng/ml vs. 5.42 (2.94-8.92) ng/ml; p = 0.167], cranial ischemic manifestations (5.56 ± 3.31 ng/ml vs. 5.89 ±4.95 ng/ml; p = 0.873), constitutional symptoms (4.92 ± 3.90 ng/ml vs.
t2 .1 Table 2 Comparison between patients with Takayasu arteritis with active disease and in remission
t2 . 2 Variables Active disease (n = 11) Remission (n = 18) P
t2 . 3 HMGB1, ng/ml 1.31 (0.63-2.16) 0.75 (0.39-2.05) 0.281
t2 . 4 ESR, mm/1st hour 39.0 (25.0-68.0) 17.5 (8.0-25.5) 0.017
t2 . 5 CRP, mg/l 6.0 (4.4-24.9) 2.0 (0.1-10.7) 0.053
t2 .6 ITAS2010 3.0 (2.2-5.2) - -
t2 . 7 ITAS.A ESR 3.5 (2.0-6.2) 1.0 (1.0-1.7) 0.001
t2 . 8 ITAS.A CRP 5.1 ±2.5 2.1 ±0.9 0.012
t2 . 9 Statins, n (%) 7 (63.6) 9 (50.0) 0.702
t2 .10 Prednisone, n (%) 6 (54.5) 10 (55.6) 0.958
t2 .11 Prednisone daily dose, mg 20.0 (7.5-45.0) 5.0 (2.5-13.7) 0.055
t2 12 Immunosuppressive agents, n (%) 7 (63.6) 12 (66.7) 0.868
t2 13 Biological agents, n (%) 3 (27.3) 6 (33.3) 0.732
t2.14 Continuous variables are presented as median and interquartile range or as mean ± standard deviation
t2.15 CRP C-reactive protein, ESR erythrocyte sedimentation rate, ITAS Indian Takayasu activity score, ITAS.A Indian Takayasu activity score with acute phase response, t2.16 HMGB1 high mobility group box 1, n number of patients
200 201 202
6.40 ± 4.50 ng/ml; p = 0.474) or relapsing disease (4.75 ± 3.31 ng/ml vs. 6.02 ± 4.47 ng/ml; p = 0.608), respectively.
Mean serum HMGB1 levels in GCA patients were 5.74 ±4.19 ng/ml at baseline, 5.18 ± 3.98 ng/ml at 3 months, 8.19 ± 6.80 ng/ml at 12 months, and 6.23 ± 2.48 ng/ml at the first relapse. During follow-up, no significant fluctuations on serum HMGB1 levels were observed from baseline levels to 3 and 12 months (Fig. 2). Moreover, serum HMGB1 levels in relapsing patients were not different from their levels at disease onset (p = 0.825), at 3 months (p = 0.629), at 12 months (p = 0.601) and from HC (p = 0.170) (Table 3). In GCA patients no correlation was present between HMGB1 and ESR (rho = -0.220; p = 0.380) or between HMGB1 and CRP levels (rho = -0.258; p = 0.301).
Serum HMGB1 in Takayasu arteritis 203
As depicted in Fig. 3, serum HMGB1 levels did not differ 204
between TA patients with active disease [1.31 (0.63-2.16) 205
ng/ml], patients in remission [0.75 (0.39-2.05) ng/ml] and 206
HC [1.46 (0.89-3.34) ng/ml] (p = 0.220). Similar median 207
serum HMGB1 levels were found in TA patients with and 208
without previous ischemic events [1.53 (0.42-3.34) ng/ml 209
vs. 0.97 (0.50-1.93) ng/ml; p = 0.486]. There was no dif- 210
ference in serum HMGB1 levels in TA patients under 211
prednisone therapy compared with those not receiving 212
prednisone [1.13 (0.45-2.34) ng/ml vs. 1.31 (0.36-1.94) 213
ng/ml; p = 0.676] or between TA patients receiving im- 214
munosuppressive agents compared with those on bio- 215
logical agents [1.59 (0.43-2.45) ng/ml vs. 0.59 (0.42-0.96); 216
p = 0.140]. However, serum HMGB1 levels were signifi- 217
cantly lower in TA patients on statins compared with 218
GCA patients
Fig. 1 Serum high mobility group box 1 (HMGB1) levels in patients with giant cellarteritis (GCA) and healthy controls (HC). GCA patients at disease onset present similar serum HMGB1 levels compared to HC
0 3 months 6 months 12 months
Fig. 2 Longitudinallevels of serum high mobility group box 1 (HMGB1) in patients with giant cellarteritis (GCA). Serum HMGB1 in individualGCA patients along follow-up and during relapses (red dots)
t3.1 Table 3 Longitudinal data on disease activity and serum HMGB1 levels in patients with giant cell arteritis
t3.2 Variables Baseline (n = 18) 3 months (n =13) 12 months (n = 6) Relapse (n =4)
t3.3 HMGB1, ng/ml 5.74 ±4.19 5.18 ±3.98 8.19 ± 6.80 6.23 ± 2.48
t3.4 ESR, mm/1st hour 69.6 ± 28.7 15.1 ±6.6 21.0 ±4.9 57.5 ± 24.2
t3.5 CRP, mg/l 40.0 (20.2-84.2) 2.5 (2.5-7.0) 8.0 (5.1-14.7) 38.5 (12.0-82.2)
t3.6 Prednisolone, mg/day - 20.0 (18.7-27.5) 18.7 (3.7-30.0) 6.2 (1.2-9.3)
t3.7 Continuous variables are presented as median and interquartile range or as mean ± standard deviation t3.8 CRP C-reactive protein, ESR erythrocyte sedimentation rate, HMGB1 high mobility group box 1
219 patients not receiving these agents [0.59 (0.29-1.46) ng/ml
F4 220 vs. 1.93 (0.88-3.34) ng/ml; p = 0.019] (Fig. 4).
221 No correlation could be observed between serum
222 HMGB1 levels and ESR (rho = 0.104; p = 0.590), CRP
223 (rho = 0.090; p = 0.642), ITAS2010 (rho = 0.230; p = 0.231),
224 ITAS.A ESR (rho = 0.216; p = 0.261) or ITAS.A CRP
225 (rho = 0.070; p = 0.720).
226 Comparison between Takayasu arteritis and giant cell
227 arteritis regarding serum HMGB1 levels
228 GCA patients at disease onset presented significantly
229 higher median serum HMGB1 levels compared with TA
230 patients with active disease [4.70 (2.55-8.92) ng/ml vs. F5 231 1.31 (0.63-2.16) ng/ml; p = 0.0075] (Fig. 5). Even when
232 GCA and TA patients without statins were analyzed sep-
233 arately, serum HMGB1 levels were significantly higher
234 in GCA patients compared to TA patients [5.06 (2.86235 10.0) ng/ml vs. 1.80 (0.63-3.34); p = 0.015].
236 Higher serum HMGB1 levels observed in GCA com-
237 pared with TA seems to be an effect of aging, since
238 serum HMGB1 levels were also higher in GCA controls
239 than in TA controls [2.98 (1.70-6.23) ng/ml vs. 1.46
240 (0.89-3.34) ng/ml; p = 0.019]. A weak correlation was
241 found between serum HMGB1 levels and age in all study
242 participants (rho = 0.244; p = 0.019) while in a linear re-
243 gression model, age was independently associated with
serum HMGB1 levels (P = 0.056; p = 0.003; R2 = 0.099), 244
regardless of the diagnosis of LVV or control status. 245
ROC analysis of GCA and TA patients showed that the 246
best HMGB1 cutoff value for differentiating GCA from 247
TA is 2.17 ng/ml with 83.3 % sensitivity and 79.3 % 248
specificity. 249
Discussion 250
In this study, we observed that patients with active LVV 251
present similar serum HMGB1 levels compared with pa- 252
tients in remission and HC. TA patients in remission 253
and those with relapsing disease were already under 254
therapy and the use of statins was associated with lower 255
serum HMGB1 levels. Furthermore, in GCA patients 256
with active disease prior to therapy, serum HMGB1 257
levels were not different from HC but were higher than 258
HMGB1 levels found in TA patients with active disease. 259
The need for reliable biomarkers for disease activity is 260
an issue of utmost importance in TA. The evaluation of 261
disease activity is a challenge; since the disease course is 262
protracted and silent relapses are common, occurring in 263
up to 96 % of patients who attained remission. It is not 264
easy to define when the disease is actually in remission 265
and most patients develop new angiographic lesions over 266
time usually without clear manifestations of disease 267
Active TA TA in remission Controls
Fig. 3 Serum high mobility group box 1 (HMGB1) levels in patients with Takayasu arteritis (TA) and healthy controls (HC). TA patients with active disease and in remission present similar serum HMGB1 levels compared with HC
Statins No statins
Fig. 4 Influence of statins use on serum high mobility group box 1 (HMGB1) levels in patients with Takayasu arteritis (TA). Statins use was associated with significantly lower serum HMGB1 levels in TA patients
Fig. 5 Serum high mobility group box 1 (HMGB1) levels in patients with giant cellarteritis (GCA) and Takayasu arteritis (TA) with active disease. GCA patients at disease onset and prior to any therapy present higher serum HMGB1 levels than TA patients with active disease but already on treatment with prednisone and immunosuppressive or biologicalagents
268 activity [33]. In this context, a novel biomarker would
269 help medical decisions for TA.
270 Granulomatous inflammation and vessel wall necrosis
271 are well-known features of LVV [34]. Either necrosis or in-
272 filtrating macrophages are important sources of HMGB1
273 release into the extracellular milieu that in turn activate
274 innate and adaptive immunity [35]. Patients with GPA and
275 predominant granulomatous inflammation present higher
276 serum HMGB1 levels compared with GPA patients with
277 predominantly vasculitic manifestations [25]. Thus, we
278 evaluated associations between disease activity in LVV and
279 serum HMGB1 levels. Unfortunately, no difference could
280 be found between patients with active disease and remis-
281 sion or between patients with LVV and HC.
282 On the other hand, GCA patients at disease onset and
283 prior to therapy presented serum HMGB1 levels that
284 were similar to those of HC, and no association could be
285 found between HMGB1 and acute phase reactants, dis-
286 ease manifestations or disease relapse. Moreover, during
287 follow-up no significant fluctuations in serum HMGB1
288 levels were observed in GCA patients. Novel biomarkers
289 in GCA would help to recognize active disease in pa-
290 tients with signs and symptoms of GCA but normal
291 acute phase reactants. However, serum HMGB1 levels
292 were not increased in patients with active disease.
293 Serum HMGB1 levels were significantly higher in
294 GCA patients than in TA patients, and even though the
295 ROC analysis showed that a cutoff value of 2.17 ng/ml
296 in HMGB1 levels would help to differentiate GCA from
297 TA, we believe that it is unlikely that in clinical practice
298 it would replace the 50-year-old cutoff point used to dif-
299 ferentiate both entities [1]. Furthermore, GCA controls
300 had higher serum HMGB1 than TA controls. These
301 findings indicate that serum HMGB1 levels increase dur-
302 ing aging and may be influenced by the burden of
atherosclerosis in older individuals. In mice, the age- 303
dependent DNA double-strand break is associated with 304
a reduction of nuclear HMGB1 in neurons leading to an 305
increased release of extracellular HMGB1 [36]. However, 306
in a population study performed in Japan with 626 sub- 307
jects, aging did not seem to affect serum HMGB1 levels 308
in healthy subjects [37]. In the present study, although 309
only a weak correlation was found between age and 310
serum HMGB1 levels, age was independently associated 311
with serum HMGB1 levels regardless of the diagnosis of 312
LVV or control status. 313
We found a strong association between statins and 314
lower serum HMGB1 levels in 16 patients with TA (55.2 315
%). Recently, lower HMGB1 levels were observed in 316
hyperlipidemic patients and in GPA patients in remis- 317
sion both on statin therapy [38, 39]. Moreover, atorva- 318
statin was able to reduce in vitro the release of HMGB1 319
in stimulated human umbilical vein endothelial cell 320
(HUVEC) cultures. This indicates that the inhibition of 321
HMGB1 release by activated cells is one of the pleio- 322
tropic effects of statins [39]. Other drugs may also influ- 323
ence HMGB1 release from cells such as dexamethasone 324
and metformin [40, 41]. These findings may explain in 325
part why TA patients already under treatment presented 326
serum HMGB1 levels similar to HC. 327
The role of statins in GCA has still to be determined. 328
No impact on relapse rate or on the prevention of severe 329
ischemic events was observed in retrospective studies. 330
However, conflicting results were found regarding the 331
influence of statins on acute phase reactants and daily 332
glucocorticoid dose in GCA patients using statins [42-44]. 333
In TA patients, a retrospective study could not find any 334
difference in ischemic events between patients with and 335
without statins but associations with disease activity were 336
not analyzed [45]. In the present study, more TA patients 337
used statins than GCA patients at diagnosis although this 338
difference was not statistically significant (data not shown). 339
This could be due to the long disease course of our TA pa- 340
tients in comparison with the GCA patients who were eval- 341
uated at disease onset. 342
Limitations of this study are its mainly cross-sectional 343
nature and the inclusion of patients already on therapy 344
for TA, whereas the low number of patients and the 345
short-term follow-up period are limitations for the GCA 346
patients. Nevertheless, the data seem robust enough to 347
conclude that HMGB1 is not a suitable biomarker in 348
LVV in contrast to SLE [23]. 349
Conclusions 350
Serum HMGB1 levels were neither different between pa- 351
tients with LVV and HC, nor between patients with ac- 352
tive disease and those in remission. Therefore, serum 353
HMGB1 is not a useful biomarker for LVV. Moreover, 354
serum HMGB1 levels were not associated with any 355
356 disease phenotypes in LVV. In long-standing TA, ther-
357 apy with statins seems to lead to lower serum HMGB1
358 levels.
359 Abbreviations
360 18FDG-PET/CT: 18F-fluorodeoxyglucose positron emission computed tomography;
361 ACR: American College of Rheumatology; ANCA: antineutrophil cytoplasmic
362 antibody; BAFF: B cell-activating factor; CRP: C-reactive protein; CXCL9: chemokine
363 (C-X-C motif) ligand 9; ELISA: enzyme-linked immunosorbent assay;
364 ESR: erythrocyte sedimentation rate; GCA: giant cell arteritis; GPA: granulomatosis
365 with polyangiitis; HC: healthy controls; HMGB1: high mobility group box 1;
366 HUVEC: human umbilical vein endothelial cell; IFN: interferon; Ig: immunoglobulin;
367 IL: interleukin; ITAS: Indian Takayasu activity score; ITAS.A: ITAS with acute phase
368 response; LPS: lipopolysaccharide; LVV: large vessel vasculitides; MCP-1: monocyte
369 chemoattractant protein-1; MMP-9: matrix metalloproteinase 9; PMR: polymyalgia
370 rheumatica; RANTES: regulated on activation, normal T cell expressed and
371 secreted; ROC: receiver operating characteristic; SLE: systemic lupus
372 erythematosus; TA: Takayasu arteritis; Th: T helper cell; TNF-a: tumor necrosis
373 factor alpha; UMCG: University Medical Center Groningen; UNIFESP: Universidade
374 Federal de Säo Paulo.
375 Competing interests
376 All authors declare that they have no competing interests.
377 Authors' contributions
378 AWSS contributed to the study design, performed laboratory tests,
379 conducted the statistical analysis, and drafted the manuscript. KSMG
380 contributed to the study design, evaluated the study participants, collected
381 data from medical records, and revised the manuscript. EB contributed to
382 the study design, collected data from patients' medical records, helped with
383 the interpretation of results, and revised the manuscript. FAGP evaluated the
384 study participants, collected data from medical records, helped with the
385 interpretation of data and revised the manuscript. ACDO evaluated the
386 study participants, collected data from medical records, helped with the
387 interpretation of data and revised the manuscript. EIS contributed to the
388 study design, helped with the interpretation of results, and revised the
389 manuscript. LECA contributed to the study design, helped with the
390 interpretation of results, and revised the manuscript. MB contributed to
391 the study design, interpretation of data and revised the manuscript. JW
392 contributed to the study design, performed laboratory tests, helped with
393 the interpretation of data and revised the manuscript. CGMK conceived the
394 study, contributed to the study design, interpretation of data and revised the
395 manuscript. All authors read and approved the manuscript.
396 Acknowledgements
397 Authors would like to thank Natalia Regine de França, Olivia de Fatima Costa
398 Barbosa and Sandro Félix Perazzio for their contribution to the development
399 of this study.
400 Author details
401 department of Rheumatology and Clinical Immunology, University of
402 Groningen, University Medical Center Groningen, Hanzeplein 1, 9700 RB,
403 Groningen, The Netherlands. 2Rheumatology Division, Universidade Federal
404 de Säo Paulo - Escola Paulista de Medicina, R. Botucatu, 720, 04023 900 Säo
405 Paulo, SP, Brazil. 3Department of Internal Medicine and Rheumatology,
406 Martini Hospital, Van Swietenplein 1, 9728 NT, Groningen, The Netherlands.
407 Received: 16 December 2014 Accepted: 2 June 2015
408 Published online: 12 June 2015
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doi:10.1186/s13075-015-0672-8
Cite this article as: de Souza ef ai: High mobility group box 1 levels in large vessel vasculitis are not associated with disease activity but are influenced by age and statins. Arfhr/f/s Research & Therapy 2015 17:.
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