1. Introduction
Vedolizumab (VDZ) is a humanized IgG1 monoclonal antibody selectively
targeting the integrin α4β7 and blocking its interaction with MAdCAM-1,
a ligand of lymphocytic homing receptors, impeding the trafficking of
lymphocytes to the gut mucosa [1]. Its use for the treatment of
Crohn’s disease (CD) and ulcerative colitis (UC) has continued to grow
since approval by the United States Food and Drug Administration and the
European Union in 2014 [2]. Large trials have illustrated its
efficacy in both inducing and maintaining clinical responsiveness in
patients with moderate to severe CD and UC [3,4].
As a result of the increasing utilization of VDZ, researchers have
attempted to evaluate whether its mechanism of action results in an
improvement or clinical worsening of extraintestinal manifestations
(EIM). On the one hand, active EIMs are thought to correspond with
mucosal inflammation of the gut, in part as a result of a shared epitope
among different organ systems [5]. Therefore, VDZ should offer a
therapeutic benefit for those features outside of the gastrointestinal
tract (GIT). At the same time, the EIMs may actually stem from systemic
inflammation and not from the GIT, and accordingly, may not respond to
VDZ. In fact, many have theorized that trafficking of leukocytes away
from the gut has resulted in their increased circulation and homing to
other extraintestinal sites such as the joints [6].
Many retrospective observational studies have found that patients with
inflammatory bowel disease (IBD) develop new-onset or worsening of
arthralgias when treated with VDZ, often listed as one of the most
common adverse events (AE) [7-12]. Similarly, multiple prospective
observational studies have reported on the development of joint pains
associated with VDZ treatment, even in patients who achieve clinical
remission within the gut [13-16]. There have also been numerous open
label trials describing both the worsening of and the development of new
arthralgias [17-19]. In addition, a number of case series have
depicted a total of 20 patients with joint complaints associated with
VDZ use, most commonly triggered during the first four months of
treatment, generally with axial involvement, only one fifth of whom had
a background history of musculoskeletal complaints, and which developed
despite effective control of gut inflammation in 80% of cases
[20-22].
On the other hand, multiple papers have found that the development of
arthralgias is rare in IBD patients treated with VDZ [23,24]. Some
have even shown an improvement or altogether resolution of joint pains
in conjunction with VDZ treatment and control of gut inflammation
[25-27]. Still, others have shown that both may occur- resolution of
baseline arthritis/arthralgias and incident new cases of arthropathy-
when patients treated show clinical response to VDZ along the GIT
[28].
While the correlation between VDZ and arthropathies have been previously
explored, studies may have been confounded by several factors: the
inherent association between IBD and spondyloarthropathy, the possible
tapering of other immunosuppressive medications prior to VDZ initiation,
and the often poor reporting of musculoskeletal complaints among
non-rheumatologic clinicians. Accordingly, no clear conclusions have
been drawn about the nature of this relationship. We sought to perform a
systematic review to evaluate the randomized controlled trials (RCT)
assessing VDZ for the treatment of IBD in which arthralgias emerged.