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Comment on: Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease: reply.

01 Jun 2019-Rheumatology (Oxford University Press)-Vol. 58, Iss: 6, pp 1115-1117

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  • Dubash, S, Marzo-Ortega, H and McGonagle, D (2019) Comment on: Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease: reply.
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  • Comment on “Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease” S. Dubash1, 2, H. Marzo-Ortega1, 2, D. McGonagle1, 2 1Department of Rheumatology, NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, also known as Reply.

SIR,

  • The authors read with great interest the letter by Alivernini et al in response to their paper on vedolizumab (VDZ) induced severe SpA related entheseal pathology1,2.
  • This is surprising since this complication was completely unreported in large phase III studies of vedolizumab in IBD.
  • Interestingly, SpA was observed in 8/187 (4.8%) cases post-VDZ treatment for IBD which is higher than the previous reported SpA prevalence in other VDZ treated IBD cohorts1,3.
  • Nevertheless, the evidence for synovitis supports an underlying MADCAM-1 independent process for lymphocyte infiltration into the synovium via other mechanisms including an inflammatory effect from adjacent entheses.

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This is a repository copy of Comment on: Emergence of severe
spondyloarthropathy-related entheseal pathology following successful vedolizumab
therapy for inflammatory bowel disease: reply.
White Rose Research Online URL for this paper:
http://eprints.whiterose.ac.uk/143856/
Version: Accepted Version
Article:
Dubash, S, Marzo-Ortega, H and McGonagle, D (2019) Comment on: Emergence of
severe spondyloarthropathy-related entheseal pathology following successful vedolizumab
therapy for inflammatory bowel disease: reply. Rheumatology. kez053. ISSN 1462-0324
https://doi.org/10.1093/rheumatology/kez053
© The Author(s) 2019. Published by Oxford University Press on behalf of the British
Society for Rheumatology. All rights reserved. This is a pre-copyedited, author-produced
version of an article accepted for publication in Rheumatology following peer review. The
version of record is available online at: https://doi.org/10.1093/rheumatology/kez053.
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Reply: Comment onEmergence of severe spondyloarthropathy-related entheseal
pathology following successful vedolizumab therapy for inflammatory bowel disease”
S. Dubash
1, 2
, H. Marzo-Ortega
1, 2
, D. McGonagle
1, 2
1
Department of Rheumatology, NIHR Leeds Biomedical Research Centre, Leeds Teaching
Hospitals NHS Trust, Leeds, United Kingdom.
2
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds,
United Kingdom.
Word Count: 800
References:
Corresponding author:
Prof. Dennis McGonagle
Leeds Institute for Rheumatic and Musculoskeletal Medicine,
Department of Rheumatology
Second floor,
Chapel Allerton Hospital,
Chapeltown Road,
Leeds LS7 4SA,
United Kingdom.
Telephone: +44 (0) 113 2066071
Fax: +44 (0) 113 3924991
E-mail: D.G.McGonagle@leeds.ac.uk

SIR,
We read with great interest the letter by Alivernini et al in response to our paper on
vedolizumab (VDZ) induced severe SpA related entheseal pathology
1,2
. We note their
agreement with our study demonstrating severe SpA and enthesitis following VDZ treatment
for inflammatory bowel disease (IBD), including either VDZ initiation or withdrawal of prior
TNFi as potential triggers of this complication
1
. We would like to congratulate Alivernini
and colleagues for the provision of novel data on the incidence of SpA under vedolizumab
therapy which is surprisingly high at nearly 5%
1
. This is surprising since this complication
was completely unreported in large phase III studies of vedolizumab in IBD.
All their cases fulfilled ASAS criteria, were HLA-B27 negative, failed at least one previous
TNFi, and had well controlled IBD
1
. Interestingly, SpA was observed in 8/187 (4.8%) cases
post-VDZ treatment for IBD which is higher than the previous reported SpA prevalence in
other VDZ treated IBD cohorts
1,3
. In comparison, the disease severity of their cases appears
lower with a median CRP of 15.9 compared to a much higher mean CRP of 56.7 mg/L in our
study
1,2
.
The synovial biopsy conducted in two cases of knee synovitis by Alivernini et al is also novel
and afforded the first opportunity for immunohistochemistry evaluation of VDZ associated
SpA. Synovial infiltration with CD68+ macrophages, CD138+ and CD20+ indicating B
lineage cells and CD3+ a pan-T-cell marker was reported. It is known that macrophages are
linked to the destruction of synovial tissue through the T-cell mediated release of pro-
inflammatory cytokines
4
. The authors do not report on VDZ relevant protein expression
including anti-47 integrin or MADCAM-1, its corresponding receptor but point to
literature that reported such 47 expression from synovial lymphocytes previously in SpA.
However, previous studies failed to demonstrate MADCAM-1 expression in inflammatory

synovitis
5
. Salmi et al previously reported on adhesion molecules on HEVs in inflamed
synovium identifying that intercellular adhesion molecule-1 (ICAM-1/CD54) and vascular
adhesion protein-1 (VAP-1) were prominently expressed in synovial HEVs, and all other
adhesion molecules were present at much lower levels with complete absence of mucosal
addressin (MADCAM-1)
5
. Studies have suggested 41 on lymphocytes binds VCAM-1
preferentially at the 4 subunit and is linked to chronic established synovitis whereas ICAM-
1, overexpressed in tissue from early synovitis, is pivotal in activation and cell binding into
inflamed synovial tissue
6,7
. Reports of adherence of immunoblasts (activated lymphocytes)
to high endothelial venules (HEVs) in rheumatoid arthritis (RA) synovium showed only
partial inhibition by monoclonal antibody (mAb) to 41 (25%) and very little inhibition
(5%) by mAb to 47 suggesting no functional significance of 4in RA synovitis
8
. The
rate of lymphocyte migration into synovium was found to be determined by expression of
ICAM-1 on HEVs in RA
9
. In contrast to the specificity of MADCAM-1, selectively present
in gut mucosal lymphoid organ HEVs, the role of ICAM-1 and VAP-1 in synovial HEVs are
more likely to contribute to the influx of circulating immune cells during 47 blockade
2
.
However, possible differences in adhesion molecule pathways between RA and SpA
synovitis may exist
10
. We wonder if the authors plan to stain for these relevant adhesion
molecules and ligands in their samples?
Definitive data on the presence of adhesion molecules at spinal and peripheral joint
entheses is lacking, but increased47 expressing type 3 innate lymphoid cells (ILC3s) were
reported in a small study in the gut and non-entheseal iliac crest bone marrow of patients with
ankylosing spondylitis (AS)
11
. The same study reported MADCAM-1 in iliac crest bone
marrow aspirates from a small number of cases where, in our opinion, the
immunohistochemistry staining showed non-specific or stromal staining in addition to
marrow venule staining
11
.

Interestingly, just as no reports of arthritis occurred in clinical trials for VDZ in IBD,
neither have there been any reports of arthritis with natalizumab, a humanised mAb that binds
41 and 47 integrin, which was trialled successfully in Crohn’s disease (CD) and
multiple sclerosis (MS), but increased reports of progressive multifocal leukoencephalopathy,
have been a limitation
12
. The synovial blockade of the lymphocyte 41-synovial VCAM-1
interaction might be expected to lessen this paradoxical arthritis development, since unlike
MADCAM-1, VCAM-1 synovial expression has been shown. We wonder if Alivernini et al
have any cohort data on natalizumab to address this topic since 41 and its receptor may be
expressed in the synovium. Treatment with natalizumab in one patient with both AS and
multiple sclerosis was reported suggesting 41 and 47 inhibition may be effective for co-
treatment of both diseases
13
. Nevertheless, the evidence for synovitis supports an underlying
MADCAM-1 independent process for lymphocyte infiltration into the synovium via other
mechanisms including an inflammatory effect from adjacent entheses. We feel that the
underlying complex pathogenetic link between IBD and SpA in the context of VDZ
associated SpA is not yet fully understood and further research would be required to confirm
such mechanisms.
Disclosure statement
The authors HM-O and DM have received grants, honoraria or speaker fees from Abbvie,
Celgene, Janssen, Pfizer, UCB, Lilly and Novartis. SD has declared no conflicts of interest.

References
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Journal ArticleDOI
TL;DR: Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalIZumab as induction therapy in patients with elevated C-reactive protein and active Crohn's disease.
Abstract: Background & Aims: A randomized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn’s disease. Methods: Patients (N 509) with moderately to severely active Crohn’s disease and active inflammation characterized by elevated C-reactive protein concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at Weeks 0, 4, and 8. The primary end point was induction of response (>70-point decrease from baseline in the Crohn’s Disease Activity Index score at Week 8 sustained through Week 12). Additional efficacy end points included the proportion of patients with sustained remission (Crohn’s Disease Activity Index score <150 points) and response or remission over time. Results: Response at Week 8 sustained through Week 12 occurred in 48% of natalizumab-treated patients and 32% of patients receiving placebo (P < .001). Sustained remission occurred in 26% of natalizumab-treated patients and 16% of patients receiving placebo (P .002). Week 4 response rates were 51% for natalizumab and 37% for placebo (P .001). Responses remained significantly higher at subsequent assessments (P < .001) in natalizumab-treated patients. Natalizumab-treated patients also had significantly higher remission rates at Weeks 4, 8, and 12 (P < .009). The frequency and types of adverse events were similar between treatment groups. Conclusions: Natalizumab induced response and remission at Week 8 that was sustained through Week 12. Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn’s disease. Natalizumab was well tolerated in this study.

556 citations



Journal ArticleDOI
TL;DR: Gut-derived IL-17+ and IL-22+ILC3 are expanded in the peripheral blood, SF and inflamed BM of patients with AS, suggesting the presence of an active homing axis between the gut and the inflamed sacroiliac joints.
Abstract: Background The aim of the study was to better characterise the immunological origin and the behaviour of interleukin (IL)-23-responsive innate lymphoid cells (ILCs) in the gut, synovial fluid (SF) and bone marrow (BM) of patients with ankylosing spondylitis (AS). Methods ILC1, ILC2 and ILC3 cells were determined and characterised by confocal microscopy and flow cytometry in ileal and BM biopsies, in peripheral blood (PB) and SF mononuclear cells obtained from patients with AS and controls. Mucosal vascular addressin cell adhesion molecule 1 (MADCAM-1), IL-7, IL-15 and aggregates of lymphoid tissue inducer cells (LTi) were evaluated by immunohistochemistry. The in vitro ability of epithelial cells in driving the differentiation of ILC3 and the effect of tumour necrosis factor inhibitors (TNFi) on the frequency of ILC3 and the expression of MADCAM1 were also assessed. Results ILC3 characterised as Lyn − RORc − Tbet + NKp44 + cells were significantly expanded in the gut, SF and BM of patients with AS compared with controls, produced high levels of IL-17 and IL-22 and expressed α4β7. MADcAM1 was overexpressed in BM and ileal high endothelial venules. IL-7 was significantly increased in AS gut, especially in the context of Paneth cells, and accompanied by the presence of aggregates of c-kit/IL-7R + cells (LTi). In in vitro experiments, epithelial cells from patients with AS actively induced differentiation of ILC3 from LTi. TNFi efficacy was accompanied by a significant decrease in the percentage of intestinal and circulating ILC3 and in the expression of MADCAM1. Conclusions Gut-derived IL-17 + and IL-22 + ILC3 are expanded in the peripheral blood, SF and inflamed BM of patients with AS, suggesting the presence of an active homing axis between the gut and the inflamed sacroiliac joints.

189 citations



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TL;DR: End endothelial P-selectin and VAP-1 mediate binding of mucosal effector cells to synovium in a leukocyte subtype-selective manner and antiadhesive therapy against these inducible molecules should ablate the pathogenetic cascade leading to inappropriate homing of leukocytes to joints in arthritis.
Abstract: Inflammation and infection of the gut can be followed by reactive arthritis at a distant joint. Leukocyte recruitment into synovium is essential for this process, but nothing is known about the endothelial adhesion molecules in synovial membrane which direct the homing of activated, gut-derived leukocytes to joints. Here we analyzed the expression of the known endothelial adhesion molecules in inflamed synovium and their function in binding of mucosal leukocytes. Intercellular adhesion molecule-1 (ICAM-1/CD54) and vascular adhesion protein-1 (VAP-1) were most prominently expressed in synovial vessels. All other adhesion molecules were found at lower levels in inflamed synovia, except mucosal addressin which was absent. Binding of macrophages isolated from lamina propria of the gut to synovial endothelium was almost entirely P-selectin-dependent. In contrast, small intestinal lymphocytes and immunoblasts both relied mainly on VAP-1 in recognition of synovial vessels. Thus, endothelial P-selectin and VAP-1 mediate binding of mucosal effector cells to synovium in a leukocyte subtype-selective manner. Antiadhesive therapy against these inducible molecules should ablate the pathogenetic cascade leading to inappropriate homing of leukocytes to joints in arthritis.

133 citations


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