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
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Reply: Comment on “Emergence 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 4in 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.