ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 3142

Tocilizumab Enhances Regulatory T-Cell Activation and Proliferation in Giant Cell Arteritis

Chie Miyabe1, Klemen Strle2, Yoshishige Miyabe1, John H. Stone1,3, Andrew D. Luster1,4 and Sebastian Unizony1,5, 1Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 2Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 3Rheumatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 4Massachusetts General Hospital, Charlestown, MA, 5Rheumatology, Massachusetts General Hospital, Boston, MA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: , , ,

Session Information

Date: Tuesday, November 10, 2015

Title: Vasculitis III

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose :
CD4+
T
helper (Th) 17 cells, Th1 cells, and regulatory T-cells (Treg) contribute to
the pathogenesis of giant cell arteritis (GCA). Interleukin (IL)-6, a key
mediator in the differentiation of both Th17 and Treg cells, is up-regulated in
this disease. Preliminary use of the IL-6 receptor antagonist tocilizumab (TCZ)
has shown encouraging results in patients with GCA. However, the mechanism of
action of TCZ in this disorder is unknown. We aimed to characterize the
effector and regulatory CD4+ T-cell compartments in the peripheral blood of patients
with GCA treated with TCZ

Methods: We
evaluated 39 patients with GCA classified into one of three categories (Table
1): 1) active disease (aGCA, n=11); 2) disease remission on corticosteroid
(CS) monotherapy (rGCA-CS, n=17); and 3) disease remission on TCZ therapy (rGCA-TCZ,
n=11). Thirteen healthy controls (HC) were also included. Using flow cytometry,
we determined the percentages (%) of IFNg+IL-17- (Th1), IL-17+IFNg- (Th17), IL21+,
CD25high (Treg), and CD45RA-Foxp3high (activated Treg, aTreg) cells within the CD4+
T-cell population. In addition, we determined the % of Foxp3+ cells expressing the
proliferation marker Ki67, and the activation markers CCR4 and CTLA4. We assessed
Treg function in suppression assays. Serum levels of IL-12, IFNg, IL-6,
IL-1β, IL-23, IL-21, TNF-α, CCL20, IL-17A, and IL-10 were measured by
Luminex. Univariate and multivariate analyses were completed.

Results: The
frequency (mean %) of Treg cells was equivalent across groups. However, the frequency
of aTregs was significantly higher in rGCA-TCZ patients (1.3%) compared to
rGCA-CS patients (0.6%; p<0.01) (Figure 1). The significant
difference in aTregs persisted in age-, sex-, and CS-dose-adjusted analysis. Moreover,
the number of Ki67+ Tregs was significantly higher in rGCA-TCZ patients (31.7%)
as opposed to rGCA-CS patients (16.4%; p<0.01) and aGCA patients (15.5%;
p<0.01). Multivariate analyses demonstrated that compared to rGCA-CS patients,
Tregs from rGCA-TCZ patients expressed CCR4 and CTLA4 significantly more often
(Figure 1). Tregs were functional in all groups. The frequency of Th1 cells
was equivalent across groups. The frequency of CD21+CD4+ T-cells was
significantly higher in aGCA patients compared to patients with GCA in
remission. The frequency of Th17 cells was significantly higher in GCA patients
compared to HC. IL-10 levels were significantly increased in the serum of aGCA
patients

Conclusion: The
therapeutic effects of TCZ in GCA could be mediated by changes in the
activation and proliferative potential of Tregs

 

Table 1. Baseline characteristics of GCA patients and healthy controls

rGCA-CS

(n= 17)

rGCA-TCZ

(n = 11)

aGCA

(n =11)

P-value

Controls*

(n = 13)

P-value

  Age, years: mean (SD)

74 (10)

69 (8)

72 (10)

0.77

50 (14)

<0.01

  Sex: % females

65

82

82

0.48

46

0.09

  Ethnicity/Race: % White

88

91

100

0.26

77

0.16

  Relapsing disease: number (%)

10 (59)

11 (100)

8 (73)

0.05

–

–

  Biopsy-proven GCA: number (%)

10 (59)

5 (45.5)

7 (63.5)

0.77

–

–

  Positive vascular imaging¥: number (%)

1 (6)

4 (36)

3 (27)

0.14

  Disease duration, months: median (IQR)

27 (6; 54)

29.5 (19.5; 67)

24 (0; 54)

0.40

–

–

  Duration of CS treatment, months: median (IQR)

33 (9; 56)

28 (10; 68)

26 (4; 57)

0.61

–

–

  Duration of TCZ treatment, months: median (IQR)

–

21 (14; 29)

–

–

–

–

  Prior MTX use: number (%)

6 (35)

4 (36.4)

3 (30)

0.95

–

–

 CS dose at time of sampling, mg/day: mean (SD)

15.5 (19.4)

0.2  (0.4)

8.0 (6.8)

<0.01#

–

–

GCA = giant cell arteritis; CS = corticosteroids (prednisone); TCZ = tocilizumab; MTX = methotrexate; rGCA-CS = GCA in remission on CS; rGCA-TCZ = GCA in remission on TCZ without or without CS; aGCA = active GCA; SD = standard deviation; IQR = interquartile range; ¥ MRA, CTA or PET/CT; Analysis: ANOVA, Student’s t-test, and Fisher’s exact test;  *compared to all GCA patients; # rGCA-CS versus rGCA-TCZ

 

 

Figure 1. Regulatory T-cell frequencies
and phenotypes

 

Disclosure: C. Miyabe, None; K. Strle, NIH K (K01AR062098), 2,Arthritis Foundation, 2; Y. Miyabe, None; J. H. Stone, None; A. D. Luster, None; S. Unizony, None.

To cite this abstract in AMA style:

Miyabe C, Strle K, Miyabe Y, Stone JH, Luster AD, Unizony S. Tocilizumab Enhances Regulatory T-Cell Activation and Proliferation in Giant Cell Arteritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/tocilizumab-enhances-regulatory-t-cell-activation-and-proliferation-in-giant-cell-arteritis/. Accessed .

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