Clinical Trial Details
— Status: Active, not recruiting
Administrative data
NCT number |
NCT04887597 |
Other study ID # |
EBIO |
Secondary ID |
|
Status |
Active, not recruiting |
Phase |
Phase 4
|
First received |
|
Last updated |
|
Start date |
March 18, 2019 |
Est. completion date |
September 2022 |
Study information
Verified date |
May 2021 |
Source |
University of Erlangen-Nürnberg Medical School |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
The purpose of this Phase IV study is to determine the effect of secukinumab on total immune
cell numbers obtaines by entheseal biopsy in the inflamed human entheses in patients with
Psoriatic Arthritis. This is a single arm, single centre, prospective, open label study with
secukinumab.
Description:
Psoriatic arthritis (PsA) is a heterogeneous inflammatory rheumatologic disorder
characterized by inflammatory arthritis, enthesitis, dactylitis and spondylitis, affecting 6%
to 39% of the patients suffering from psoriasis. The exact prevalence of PsA is unknown.
Estimates of incidence vary from 0.3% to 1% of the population. Disease onset typically occurs
between the ages of 30 and 55 years, and affects both genders equally. PsA is classified as a
seronegative spondyloarthropathy (SpA) because it shares certain features with other
conditions included in that group. Indeed, spinal involvement has been reported in
approximately 50% of patients with PsA. In addition, PsA is associated with enthesitis and
dactylitis, which are extra-articular features common to SpA. Finally, the majority of
patients with PsA are negative for the rheumatoid factor. Recent studies have challenged the
assertion that PsA is a more benign disease than rheumatoid arthritis. There is an increasing
body of evidence that suggests that PsA patients experience progressive joint destruction
over a relatively short period of time. The results from these studies indicate that PsA is
erosive and deforming in nearly half of the patients, with joint damage appearing in the
first years of disease onset. Other investigators later confirmed that 41% of the patients
developed erosive disease within 2 years of onset of symptoms.
Diagnosis and treatment as early as possible has become the standard of care in rheumatoid
arthritis in order to prevent disease progression, irreversible functional impairment and
premature death. Since the 1970s, it has also been recognized that each inflammatory lesion
(joint synovitis, tenosynovitis, dactylitis, enthesitis, sacroiliitis, and spondylitis) can
develop without symptoms or signs that are recognizable by the patient and the physician.
Such patients can be considered to have subclinical or "occult" PsA. Support for this notion
comes from imaging studies providing evidence for the existence of subclinical inflammatory
changes in patients with psoriatic skin disease using MRI or high-resolution ultrasound
scans.
The investigators focused on the concept of "pre-clinical" changes in their own observational
study. Patients suffering from psoriasis with no present or past signs of joint
manifestations to stringently rule out clinical joint involvement, have been investigated.
The investigators recently described that patients with psoriasis, but without PsA, exhibit
entheseophytes as the result of pathological bone formation in the joints as a pathological
hallmark of PsA. Recent work has identified enthesial pathology as a specific part of the PsA
disease process. Entheses may represent the primary site of musculoskeletal changes in
psoriasis patients developing PsA. In particular, the understanding of enthesial structures
as an organ with a high degree of structural and functional organisation and the coining of
the term 'synovio-entheseal complex' have extended the view on PsA. These concepts are of
potential importance in searching for the discrete changes of the joints in patients with
psoriatic skin disease. This finding reinforces the pathophysiological role of the entheses
in patients with psoriatic disease. Apparently, enthesial changes can occur in the sole
presence of skin disease and do not require the clinical arthritis corroborating the concept
of an intrinsic clinical connection between the skin and the entheses, which has been
previously suggested by molecular studies referring to the role of interleukin-23 as a linker
between skin and enthesial pathology.
In the peripheral joints, entheses can be found at the attachment of the collateral ligaments
and the circumferential insertion of the capsule itself, which are also known as
'synovio-entheseal complexes' and are highly prone to structural bone changes. Furthermore,
functional entheses exist at the dorsal and palmar sites of the MCHs serving as pulleys for
the extensor and flexor tendons, respectively. Importantly, these mechanically exposed
locations were identical with the sites of new bone formation, suggesting a tight connection
between mechanical factors and the bone response observed in psoriasis patients.
Findings provide new evidence for the existence of a Deep Koebner Phenomenon at the enthesial
sites in psoriasis patients. In its original description, this phenomenon corresponds to the
trigger of inflammation and acro-osteolysis by a discrete traumatic injury. New findings
extend the concept of the Deep Koebner Phenomenon suggesting a pathological tissue response
to mechanical stress in psoriasis patients. This response affects the mechanically exposed
sites of the body, which are the skin and the entheses. The specific importance of
entheseophyte formation in psoriasis patients is also supported by the observation that the
burden of bone erosions was not significantly enhanced in psoriasis patients compared with
healthy controls.
Moreover enthesitis is a frequent manifestation in PsA and SpA. Dependent on studies between
23% and 70% of patients with PsA/SpA show enthesitis. Enthesitis is characterized by
inflammation at specific anatomical sites, where ligaments, tendons and joint capsules attach
to bone. The main clinical manifestations of enthesitis is pain while swelling is infrequent.
Pain can be severe, persistent and resistent to treatment.
Up-to-date no synovial or enthesial tissue biomarkers are available to stratify treatment
strategies in regard to an anti-inflammatory response to bDMARD therapies in active psoriatic
arthritis with enthesitis. Looking at other medical disciplines such as the oncology field,
where detailed histological, immunohistochemical and even genetic analysis of tumor tissue
for a personalized diagnostic, therapeutic and prognostic decision are performed, in
rheumatology (inflammatory discipline) we are still far from a personalized diagnostic,
therapeutic and prognostic approach based on tissue biomarker to better help and advice
patients. Fortunately, a growing variety of medications such as bDMARDs are available,
however investigators are still in a "try and error" situation.
Obtaining and analyzing enthesial tissue biopsies prior and after treatment with an anti-IL17
monoclonal antibody (secukinumab) might allow the investigators to identify biomarkers for
treatment responses, using histological, immunohistochemical, molecular and flow cytometry
techniques to further add information to the understanding of inflammation and entheses
repair processes.
Virtually all information on enthesitis to date is based on either preclinical models or the
clinical assessment of tender points in humans creating a huge unmet need for a better
understanding of human enthesitis. To date only one single biopsy study of enthesitis has
been carried out, which assessed acute enthesiopathy in peripheral SpA patients. In light of
the availability of drugs with high clinical efficacy on enthesitis, such as IL-17 blockers,
and the preclinical evidence for a role of the IL-23/IL-17 pathway in enthesitis, human
studies are needed to assess how and to what extent IL-17 inhibition ameliorates enthesitis.
Serum studies can hardly replace biopsy studies in this respect, since many of the processes
in enthesitis are local.
Based on this situation the investigators propose a combined biopsy-imaging study in patients
with PsA with active clinical enthesitis of the lateral epicondyle of the humerus or achilles
tendon. Patients will receive a 6-month treatment with secukinumab and the effect on
enthesial inflammation will be assessed by histology and mRNA assessment as well as combined
imaging.