studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 369A
nosed at younger age. Conclusions: Based on our findings, the
activating KIR gene KIR2DS1 is highly expressed in patients
with autoimmune hepatitis, suggesting its potential involvement
in pathogenesis of type I AIH. However further studies are
needed to fully understand the role of KIR2DS1 as marker for
AIH.
Disclosures:
Teresa Zolfino - Board Membership: Abvie; Grant/Research Support: Bayer;
Speaking and Teaching: Bristol
Luchino Chessa - Board Membership: Abbvie; Speaking and Teaching: BMS,
Jannsen
The following authors have nothing to disclose: Simona Onali, Roberto Littera,
Carlo Carcassi, Luca Secci, Sara Lai, Rita Porcella, Sara Cappellini, Claudia
Salustro, Cinzia Balestrieri, Giancarlo Serra, Maria Conti, Francesco Figorilli,
Michele Casale, Stefania Casu, Maria Cristina Pasetto, Laura Matta, Rosetta
Scioscia, Lucia Barca
310
Possible involvement of activating follicular helper T
cells in autoimmune hepatitis
Naruhiro Kimura, Satoshi Yamagiwa, Hiroki Honda, Toru Setsu,
Kentaro Tominaga, Hiroteru Kamimura, Masaaki Takamura,
Shuji Terai; gastroenterology and hepatology, Niigata university,
Niigata, Japan
BACKGROUND: There is an increasing interest in the role of
follicular helper T (Tfh) cells in autoimmunity from the perspective
of both their role in breaking tolerance and their effects on
disease progression. Dysregulated Tfh cells have been shown
to be responsible for the induction of fatal autoimmune hepatitis
(AIH) in mice that are unable to produce natural regulatory T
cells after neonatal thymectomy and that are genetically devoid
of the programmed cell death 1 (PD-1)-mediated signaling.
However, the involvement of Tfh cells in the immune pathogenesis
of AIH has not been fully characterized. AIM: To evaluate
the numbers of different subsets of circulating Tfh and B cells
and their potential role in the pathogenesis of AIH. METHODS:
Heparinized peripheral blood was collected from 18 patients
with AIH, 22 patients with chronic hepatitis B (CHB) and 21
healthy volunteers (HC). Mononuclear cells were separated
using the Ficoll gradient, and various surface markers were
then investigated using flow cytometry. Cytokine production
was investigated using peripheral blood Tfh cells after stimulation
with phorbol myristate acetate (PMA) and ionomycin. We
also investigated the distribution of CXCR5 + CD4 + cells in the
liver using immunohistochemical staining. RESULTS: CXCR5 +
CD4 + Tfh cells comprised 8.3% (median) (range 2.7-18.3),
7.8% (4.1-13.5), and 8.1% (3.1-13.5) of the total T cells in the
blood of patients with AIH, CHB, and HC, respectively. The Tfh
cells were then classified into several subsets according to their
expression of PD-1, inducible co-stimulator (ICOS) and CXCR3.
We found a significant increase in the proportion of activated
ICOS + Tfh cells in the blood (19.4%) and livers (24.3%) of
patients with AIH compared with the proportion in the blood
of the same patients after prednisolone (PSL) treatment (1.6%).
The frequency of ICOS + Tfh cells was significantly decreased
in the PSL-treated patients (median 22.6%, range 15.2-34.5)
compared with the patients who were not treated with PSL
(median 35.7%, range 26.0-56.2), although the levels of alanine
aminotransferase (ALT) were decreased after treatments
in both groups (17 ± 30.2 IU/l in PSL-treated and 15 ± 14.7
IU/l in non-PSL-treated patients). CXCR5 + cells were detected
among infiltrated lymphocytes in the portal area of the liver
of patients with AIH. Furthermore, we confirmed that Tfh cells
secreted IL-21 and IL-17 and expressed PD-1 after stimulation
with PMA and ionomycin. CONCLUSIONS: Previous studies
have reported that an increase in Tfh cells is associated with
the activity of autoimmune diseases. Our results suggest that
ICOS + Tfh cells may be associated with the disease activity of
AIH.
Disclosures:
Shuji Terai - Speaking and Teaching: Otsuka Pharma.
The following authors have nothing to disclose: Naruhiro Kimura, Satoshi
Yamagiwa, Hiroki Honda, Toru Setsu, Kentaro Tominaga, Hiroteru Kamimura,
Masaaki Takamura
311
Methotrexate therapy for Autoimmune Hepatitis
James Haridy 1 , Amanda J. Nicoll 1,2 , Siddharth Sood 1 ; 1 Department
of Gastroenterology and Hepatology, Royal Melbourne
Hospital, Melbourne, VIC, Australia; 2 Department of Gastroenterology,
Eastern Health, Melbourne, VIC, Australia
Background: Autoimmune hepatitis (AIH) is characterised by
typically diverse phenotypical manifestation and response to
treatment. Corticosteroids and azathioprine are standard firstline
therapies. There are limited options in patients who display
poor response or intolerance to these medications. Methotrexate
(MTX) is readily available, often employed in other autoimmune
conditions, and has therefore been postulated as a
possible second-line therapy. Evidence of efficacy has been
limited to a small number of case-reports, despite more widespread
anecdotal use. Aim: To assess the response to MTX in
AIH. Method: A retrospective case-series was conducted using
subjects located through the gastroenterology liver database of
a tertiary referral centre. Subjects with a diagnosis of AIH were
identified and diagnosis confirmed using the International Autoimmune
Hepatitis Group criteria. Medical records were examined
to determine medication history. Patients were included
if they had prior treatment exposure to methotrexate (MTX) for
their AIH. Baseline and follow-up data was collected to determine
response to MTX over the initial 12-months of therapy. Follow-up
was collected up to 3-years following initiation of MTX
if available. Results: 11 patients (age 24 – 72 years; mean,
56 years) were identified with confirmed AIH and MTX use.
10/11 (90.9%) were female and 4/11 (36.4%) had biopsy
or imaging evidence of cirrhosis prior to initiation of MTX. The
most common indication for MTX was incomplete response
to thiopurines (5/11, 45.5%). The median dose of prednisolone
prior to initiating MTX was 8.0mg (range 0-15mg). 5/11
(45.5%) of subjects ceased MTX within twelve months due to
an adverse event, most commonly deterioration in liver function
(range 1-12 months). 5/11 (45.5%) achieved or maintained
complete remission at 12-months on MTX. These patients experienced
a median decrease in prednisolone dosage of 5.3 mg,
with a median dose of 3 mg (range 0 – 5mg) at 12-months.
1/11 (9%) achieved a partial response at 12-months but
later achieved complete remission on MTX monotherapy by
36-months. 1/6 (16.7%) patients continuing MTX at 12-months
were steroid free. Conclusion: Prior use of MTX in AIH has been
limited to three individual case reports, however it is mentioned
in guidelines as a possible alternative second-line therapy. In
our case series, we show that MTX is safe, and that over 50%
of patients are able to be maintained on it with good effect on
liver function and minimal steroid use. MTX may have a role in
treatment of AIH in a subset of patients who are refractory or
intolerant of first-line therapies.
Disclosures:
Amanda J. Nicoll - Grant/Research Support: MSD; Speaking and Teaching:
Bayer
Siddharth Sood - Grant/Research Support: Qiagen USA
The following authors have nothing to disclose: James Haridy