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The world's first enthesitis guidelines released! Find out the "invisible killer" behind the SpA

 Last Update: 2022-11-01
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The screening and evaluation of enthesitis in patients with SpA is of great significance
to improve the prognosis of patients with SpA.

The attachment point is the part of the tendon, ligaments, joint capsule, fascia that connects to the bone, and enthesitis is inflammation
in these areas.
Enthesitis is a hallmark feature of spondyloarthritis (SpA) and its core pathophysiology
.
But it has long been neglected
.
Studies have shown that the average clinical delay between the onset of enthesitis symptoms and the diagnosis is as long as eight years ^[1].

Long-term persistent enthesitis can cause tendon injury, bone erosion and other local structural damage, and through body repair, eventually lead to the formation of attachment osteophytes and related anatomical structure functional damage, seriously affecting the quality of life ^{of patients [1].}
Therefore, it is of great clinical significance
to pay attention to enthesitis, and early screening and evaluation.

Fig.
1 Enthesitis is the core pathophysiological mechanism of SpA^[1]. However, at present, China still lacks authoritative guidelines to provide guidance
for this purpose.
In order to fill this gap, Professor Gu Jieruo of the Department of Rheumatology and Immunology of the Third Affiliated Hospital of Sun Yat-sen University took the lead in compiling the Clinical Practice Guidelines for the Screening and Evaluation of Enthesitis in Patients with Spondyloarthritis ^[1], which was recently published in the journal Frontiers in Immunology
.

Read the seventeen recommendations carefully to fully grasp the screening and evaluation

of enthesitis This guideline is intended to guide rheumatologists in screening and diagnosing enthesitis in specific populations of SpA patients and to improve rheumatologists' understanding and awareness
of enthesitis testing.
It covers the significance of enthesitis screening/evaluation, enthesitis assessment tools, ultrasonography for enthesitis, and MRI for enthesitis ^[1].

1

Pay attention to enthesitis and make good use of assessment tools

The guidelines begin with three "highly recommended" recommendations that emphasize the importance of
screening patients for enthesitis for SpA.
Guidelines state that given that (1) evidence of enthesitis can facilitate early diagnosis of SpA; (2) Enthesitis may aggravate the disease burden of SpA patients; (3) Enthesitis is closely related to the severity of the disease of SpA, regardless of whether SpA patients have clinical symptoms of enthesitis, it is strongly recommended to screen for enthesitis
.

Pain at the site of attachment is a common manifestation of enthesitis, and in clinical practice, asking whether a patient with SpA has pain at the site is the first step in
identifying enthesitis.
Clinical examination is the most commonly used method to evaluate enthesitis in patients with SpA, with the advantage of simple operation and no examination equipment, but its sensitivity is low, only about 20%, and it is often confused with pain in other joint structures, so clinical examination is only recommended as a preliminary means
to identify enthesitis.

Common enthesitis assessment tools include the Mudor Enthesitis Index (MEI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), Leeds Enthesitis Index (LEI), etc.
, which can help clinicians quantify disease severity and provide reference information
for treatment decisions and treatment response.
Among them, MASES is easy to use, so it has been widely used
in clinical practice and clinical trials.

Table 1 Guide recommendations 1-5
2

Ultrasonography is the first-line method of evaluating enthesitis

Because ultrasonography is inexpensive and radiation-free, it has become a first-line test or evaluation for
enthesitis.
Compared with physical examination and x-rays, ultrasound detection of enthesitis is more sensitive and can detect both inflammatory and structural lesions
.
Therefore, guidelines strongly recommend the use of ultrasound to assess patients for enthesitis, especially grayscale ultrasound (GSUS) and energy Doppler ultrasound (PDUS).

According to the OMERACT definition, disease lesions of enthesitis on ultrasonography include hypoechoia, increased attachment thickness, erosion, calcification/attachment osteophytes, and Doppler signaling
at attachment points.

Many different scoring or grading systems have been developed for the evaluation of enthesitis, including the Ultrasound Enthesitis Index (SEI), MASEI, and D'Agostino scoring systems
.
MASEI comprehensively evaluates enthesitis of the proximal plantar fascia, distal Achilles tendon, distal and proximal patellar ligaments, distal quadriceps, and triceps tendons, is rapid, simple, and widely used, and includes energy Doppler signaling and upper extremity enthesitis, and is therefore conditionally recommended
by the guidelines.

Table 2 Guide recommendations 6-10
3

MRI for enthesitis is promising

MRI is a reliable tool for evaluating enthesitis, providing high-resolution evidence
of tissue abnormalities at the site of attachment.
Many studies have shown that MRI is as sensitive as ultrasound for enthesitis, and that the two tests are more consistent
.
However, guidelines give conditional recommendations
for MRI due to the availability and cost of the device.
With the further development of MRI imaging technology, magnetic resonance ultrashort echo time series (UTE) also shows great promise
in the examination of enthesitis.

The Achilles tendon and plantar fascia are among
the most common sites of enthesitis in patients with SpA.
The OMERACT Arthritis Working Group developed and validated the MRI scoring system for heel enthesitis (HEMRIS) based on MRI imaging in 2019, which has been proven to be reliable
in clinical research and practice.

Table 3 Guidelines recommend 11-17

for the treatment of enthesitis, directly targeting the key target IL-17A

Basic research shows that enthesitis is mainly caused by innate immune response, and γδ T cells, which play an important role in both innate and adaptive immunity, play a key role
in the occurrence and development of enthesitis.
γδ T cells are also a major source of
interleukin-17 (IL-17) and tumor necrosis factor (TNF).
The production of IL-17 is a key step in enhancing the inflammatory response, which can induce resident mesenchymal cells to produce a variety of cytokines and inflammatory mediators (including granulocyte-macrophage colony-stimulating factor, IL-6, IL-8, etc.
), and promote the migration and activation of neutrophils
.
Neutrophils, on the other hand, are important effector cells for attachment site inflammation, which further enhance the inflammatory response by releasing proteases and reactive oxygen species and aggravate the painful symptoms
of enthesitis.
Therefore, IL-17 is an "amplifier" of enthesitis ^[2].

Fig.
2 IL-17 is an amplifier for enthesitis ^[2]

that targets IL-17, can it effectively treat enthesitis in patients with SpA? Multiple clinical studies have given a positive answer ^[3-6].

One analysis included MEASURE 1-4 studies of MASES >0 for 52 weeks in AS patients treated with couchimumab
.
In an analysis of 969 patients, patients in the skuchilumab group had significantly better improvement in MASES score than placebo in both total MASS score and axial enthesitis at 16 weeks, with efficacy lasting up to 52 weeks, and more than one-third of patients achieved complete resolution of enthesitis at 16 weeks ^[3].

Fig.
3 MASES scores decreased between axial enthesitis and peripheral enthesitis in the group treated with skuchiumab

Among patients with PsA, the FUTURE 5 study showed that the proportion of patients with PsA who treated cocuminumab with enthesitis resolved significantly higher than that in the placebo group at 16 weeks ^[4].
At two-year follow-up, more than eighty percent of patients achieve resolution of enthesitis ^[5].
The ACHILLES study is a large double-blind, randomized controlled, parallel, phase 3b clinical trial of 204 patients with PsA/axSpA with Achilles tendon attachment enthesitis, randomized to either couchimumab or placebo for 24 weeks, and then switched to couchimumab
.
The results showed that the remission rate of Achilles tendon enthesitis was higher in the skuchiumab group at week 24, and the remission rate of Achilles tendon enthesitis at 24 weeks in the subgroup with a BMI of <30 kg/^m2 was 49.
2%, which was significantly better than that in the placebo group
.
The improvement in pain scores relative to baseline in the couchimumab group was also significantly better than that in the placebo group (p=0.
027) [6].

summary

Enthesitis is an important feature of SpA, and long-term persistent enthesitis may lead to damage to bone and joint function and seriously affect normal life
.
Therefore, clinical attention should be paid to the diagnosis and treatment
of enthesitis in patients with SpA.
The release of the new version of the guidelines can further promote people's attention to enthesitis, and also provide scientific, reasonable and relevant guidance suggestions
for the screening and evaluation of enthesitis.
The advent of biologics provides a new means for the treatment of enthesitis, which can accurately target key cytokines and effectively improve clinical symptoms
.
Clinical studies have shown that skuchilumab can effectively promote the resolution of enthesitis and improve the symptoms
of Achilles tendon enthesitis in the treatment of AS and PsA.

Expert profile
Professor Gu Jieruo

Leader of the Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-sen University
Director of Guangdong Clinical Research Center for Immunological Diseases
Expert of special contribution allowance of the State Council
Recipient of the National Natural Science Foundation of China Outstanding Youth Fund

References: [1]Wu X,et al.
Front.
Immunol.
13:978504.
[2]Schett G,et al.
Nat Rev Rheumatol.
2017 Nov 21; 13(12):731-741.
[3]Schett G,et al.
J Rheumatol.
2021 Aug; 48(8):1251-1258.
[4]Mease P,et al.
Ann Rheum Dis.
2018 Jun; 77(6):890-897.
[5]Mease PJ,et al.
RMD Open.
2021 Jul; 7(2):e001600.
[6]Behrens F,et al.
Rheumatology(Oxford).
2022 Jul 6; 61(7):2856-2866.
This article is intended solely to provide scientific information to healthcare professionals and does not represent the position of
the Platform.

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