AS patients are on average 8 years delayed in diagnosis?

*For medical professionals to read and reference, together with experts in rheumatology and immunology, to explore the progress of AS diagnosis and treatment
.

On January 22-23, 2022, under the guidance of the Rheumatology and Immunology Branch of the Chinese Medical Association and sponsored by the medical community media, "Riding the Wind and Waves-2021 Annual Inventory of Rheumatology" was successfully held online
.

In this issue, Professor Zhang Liyun of Shanxi Bethune Hospital shared the progress of diagnosis and treatment of ankylosing spondylitis (AS)
.

Prof.
Liyun Zhang shared the issues and progress of the diagnosis and assessment of AS/axSpA, the multi-system involvement of AS/axSpA, and the treatment progress of AS/axSpA
.

The clinical diagnosis of AS/axSpA faces challenges, and new assessment methods bring opportunities▶ Challenge: Delayed diagnosis and overdiagnosis of AS/axSpA At present, the clinical diagnosis of AS/axSpA is often delayed
.

Some studies have found that the average delayed diagnosis time of axSpA is 7.
4±8.
4 years, and the delayed diagnosis is related to the diagnosis of advanced age, female, and rheumatology immunologist (see Figure 1) [1]
.

Another study showed that the average delay in diagnosis of axSpA was 5.
7 years, and the delayed diagnosis was associated with women, human leukocyte antigen B27 (HLA-B27) negativity, and psoriasis (see Figure 2) [2]
.

Figure 1: The relationship between the delayed diagnosis time of axSpA and age, gender, and whether it was diagnosed by a rheumatologist and immunologist Figure 2: The delayed diagnosis time of axSpA, and its relationship with gender, HLA-B27, and psoriasis, radiologist alignment The sensitivity of axial joint imaging findings is very important for the diagnosis of AS/axSpA
.

However, most radiologists are not familiar with the definition of axSpA MRI positive.
Only 75% of radiologists know the term axSpA, and only 31 radiologists know the definitions of sacroiliac joint MRI positive and spine MRI positive, respectively.
% and 25% [3], which is also one of the factors that cause the delayed diagnosis of AS/axSpA
.

Some scholars have summarized the possible reasons for the delayed diagnosis of AS/axSpA at the 2020 American College of Rheumatology (ACR) annual meeting, and believe that they are mainly divided into the following four points: Patients do not know that spondyloarthritis (SpA) may be the cause of chronic back pain ; Non-rheumatology immunologists have unclear understanding of the characteristics of SpA; patients suspected of AS/axSpA are referred to non-rheumatology immunologists for treatment; rheumatology and imaging departments have not optimized cooperation [4]
.

 In addition to delayed diagnosis, clinical overdiagnosis of AS/axSpA exists
.

Physicians often confuse the concepts of AS and axSpA with radiologically negative axial spondyloarthritis (nr-axSpA), so there are still clinical misdiagnosis and missed diagnosis [5]
.

 At the same time, there is a false positive in the diagnosis of axSpA by MRI.
For example, 20%-30% of normal people may have bone marrow edema, up to 40% of athletes can observe bone marrow edema, and up to 60% of postpartum women can be observed in subchondral parts.
Bone marrow edema [6-9]
.

Both of these conditions contribute to the overdiagnosis of AS/axSpA to some extent
.

 Prof.
Liyun Zhang analyzed: "At present, the diagnosis of AS/axSpA still faces challenges such as delayed diagnosis and overdiagnosis, and is affected by many factors
.

We look forward to better diagnostic criteria and classification criteria to help early identification, correct diagnosis, and precision of AS/axSpA.
Classification
.

”▶ Opportunity: AS/axSpA assessment methods emerge in an endless stream, so how to diagnose AS/axSpA more correctly? First of all, we must distinguish the concept and development process of AS, axSpA and nr-axSpA
.

“axSpA is divided into AS and nr-axSpA, nr-axSpA It refers to axSpA in which sacroiliitis changes (such as bone marrow edema) are not found on X-ray examination, but sacroiliitis changes (such as bone marrow edema) are found on MRI examination
.

nr-axSpA may be the early stage of AS, and some nr-axSpA may progress to AS[5,10-11]
.

"Professor Zhang Liyun said
.

In addition, the ASAS working group proposed new MRI diagnostic criteria for axSpA, which are divided into MRI positive criteria for axSpA active lesions and MRI positive criteria for axSpA structural damage.
The MRI positive criteria
for
axSpA active lesions are: Bone marrow edema in ≥3 consecutive MRI levels at the location, or ≥4 sacroiliac joint quadrants at any location
.

MRI positive criteria for axSpA structural damage: ≥2 consecutive levels or ≥3 sacroiliac joints Bone erosion in quadrants; fatty lesions in ≥3 consecutive slices or ≥5 sacroiliac joint quadrants; deep fatty lesions ≥1 cm deep in ≥2 sacroiliac joint quadrants.
12-13 Disease assessment
in
AS/axSpA On the other hand, ACR also reported a more simplified evaluation index - Simplified AS Disease Activity Score (Simplified ASDAS, SASDAS), and a more novel evaluation device - Epionics SPINE (ES) device
.

At the same time, the evaluation methods of axSpA are also increasingly diversified and intelligent APP has become a common way of self-assessment of axSpA patients
.

ASDAS is an important indicator for assessing axSpA disease activity, but its calculation requires a scientific calculator or electronic application, which is relatively complicated
.

While SASDAS is a simplified version of ASDAS, which is easier to calculate and execute in clinical practice
.

The EMBARK study showed that the evaluation effect of SASSDAS and ASDAS indicators reached moderate-high consistency (see Figure 3) [14]
.

Figure 3: Comparison of SASDAS and ASDAS index assessment effects ES is a novel device that uses electronic sensors to measure spinal range of motion, including range of motion in rotation, extension, lateral flexion, flexion, and speed of motion
.

ES has high specificity and sensitivity in assessing spinal mobility in axSpA patients (see Figure 4), and is an objective and effective method for evaluating spinal mobility in axSpA patients [15]
.

Figure 4: Specificity and sensitivity of ES in assessing spinal mobility in axSpA patients In addition, more and more axSpA patients are using manual app for self-assessment
.

The survey found that up to 89.
9% of patients use digital health APPs in daily life, and 60% of patients recorded and reported the BathAS Disease Activity Index (BASDAI) and Bath AS Functional Index (BASFI), suggesting that it is feasible for patients to use APP self-assessment of [16]
.

The clinical manifestations of AS/axSpA are diverse, and the quality of life of patients is greatly reduced.
AS/axSpA not only involves the axial and peripheral joints, but also can be accompanied by extra-articular manifestations, and even a variety of diseases
.

AS/axSpA with multisystem involvement will seriously affect the quality of life of patients
.

The extra-articular manifestations of axSpA include psoriasis, inflammatory bowel disease, and uveitis [10]
.

Among them, the prevalence rates of uveitis, psoriasis, and inflammatory bowel disease were 22%, 4%, and 5%, respectively, and the prevalence increased with the prolonged course of axSpA (see Figure 5) [17]
.

In addition, 27% and 16% of SpA patients were positive for calprotectin and high levels of calprotectin, respectively.
Such patients may experience ileal morphology loss, villous atrophy, ileal inflammation, ileal erosion and other intestinal lesions, which may lead to abdominal pain.
, abdominal distension, diarrhea, etc.
[18]
.

"Clinically, we should be highly vigilant of AS/axSpA with extra-articular manifestations as the first symptom
.

" Professor Zhang Liyun emphasized
.

Figure 5: Changes in the prevalence of extra-articular manifestations of axSpA with the course of the disease In addition to extra-articular manifestations, AS patients can also have multiple diseases such as tumors, interstitial lung disease, and aortic regurgitation
.

The results of a retrospective observational study showed that AS not only increased the risk of head and neck squamous cell carcinoma, but also increased the risk of melanoma, squamous cell carcinoma, and basal cell carcinoma of the three skin cancers [19]
.

In addition, axSpA can cause fatigue, catastrophic mood, sleep disturbances, affect work efficiency, and "significantly reduce" quality of life
.

According to reports, the incidence of fatigue assessed by BASDAI-F scale and SF-36VT scale in axSpA patients was 55.
3% and 31.
1%, respectively (see Figure 6) [20]
.

As many as 45.
5% of axSpA patients are high-risk patients with catastrophic mood[21], while 39% of axSpA patients have sleep disorders[22], and the proportion of patients who face difficulty in finding a job due to axSpA is as high as 95.
5%.
Up to 54.
3% of patients reported that their work efficiency was affected by the disease [23]
.

Figure 6: Fatigue in patients with axSpA AS/axSpA has entered the era of biological therapy, and further research is needed for precise treatment.
In recent years, biological agents have been widely used in the field of rheumatism
.

As AS treatment gradually entered the era of biologics, AS patients' BASDAI, erythrocyte sedimentation rate (ESR), depression, and pain were improved [24]
.

It is worth mentioning that tumor necrosis factor-α (TNF-α) inhibitors can not only improve the axial inflammation, but also improve the structural damage of the spine and sacroiliac joints [25]
.

Both the 2016 ASAS/EULAR guidelines and the 2019 ACR/SAA/SPARTAN guidelines recommend that patients with AS who maintain high disease activity after treatment with non-steroidal anti-inflammatory drugs (NSAIDs) can use TNF-α inhibitors [26-27]
.

Therefore, precision therapy is the future development direction of AS.
At present, there have been some preliminary explorations in this area, and some progress has been made in predicting the treatment response of AS patients to biologics and the risk of recurrence after discontinuation of biologics
.

Regarding how to judge the response of AS patients to biologics before medication, the results of the study show that the higher the baseline body mass index (BMI), fat body mass index (FMI), and fat-free body mass index (FFMI) of AS patients, the worse the response to biologics [28]
.

There are even studies that have established a predictive model that can effectively predict the treatment response of AS patients to TNF-α inhibitors (see Figure 7), and also have high C-reactive protein (CRP), severe nocturnal pain, low BMI, younger age, and patients.
A higher overall score indicates a better response to TNF-α inhibitor therapy in AS patients [29]
.

Figure 7: Predictive power of predictive models for response to TNF-α inhibitor therapy There are also studies on how to determine the risk of relapse in nr-axSpA patients after discontinuation of biologics
.

High-sensitivity C-reactive protein (hs-CRP) ≤ 3 mg/L and negative MRI and ≤ 3 mg/L can be used as predictors for the maintenance of remission in nr-axSpA patients receiving TNF-α inhibitor therapy
.

nr-axSpA patients experienced relapse after TNF-α inhibitor withdrawal, and the predictors of remission after retreatment were: male, age <40 years, and no enthesitis [30]
.

Finally, Professor Zhang Liyun pointed out: "At present, there are many studies on the therapeutic targets of AS/axSpA, including TNF-α, interleukin (IL)-17, JAK kinase, IL-23, IL12/IL-23, phospho-diphosphate Esterase 4 (PDE-4), etc.

Among them, TNF-α inhibitors and IL-17 inhibitors have been approved for marketing in China, and JAK inhibitors have been approved for marketing in the
US Food and Drug Administration (FDA)
.

Therefore, the precise treatment of AS/axSpA needs further research
.

"Reference: [1] Garrido-Cumbrera M, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10) .
[ACR 2020 abstract 1865].
[2] Redeker I, et al.
Rheumatology (Oxford).
2019; 58( 9): 1634-1638.
[3] Bennett AN, et al.
J Rheumatol.
2017; 44(6): 780-785.
[4] Prof.
Karl Gaffney, presented in 2020 ACR.
[5] ACR study grouppresented in 2020 ACR.
[6] Weber U, et al.
Arthritis Rheumatol.
2018; 70(5): 736-745.
[7] de Winter J, et al.
Arthritis Rheumatol.
2018; 70(7): 1042-1048.
[8] Hoballah A, et al.
Ann Rheum Dis.
2020; 79(8): 1063-1069.
[9] Renson T, et al.
Ann Rheum Dis.
2020; 79(7): 929-934.
[10] Lianne Gensler presented in 2020 ACR.
[11] Baraliakos X, et al.
Clin Rheumatol.
2014; 33(10): 1359-65.
[12] Maksymowych W, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ ACR 2020 abstract 2019].
[13] Maksymowych W, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 2020].
[14] Schneeberger E, et al.
Arthritis Rheumatol.
2020; 72(suppl 10).
[abstract 1885].
[15] Kleter D, et al.
Arthritis Rheumatol.
2020; 72(suppl 10).
[abstract 1888].
[16] Kiltz U, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1890].
[17] Fitzgerald G, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1312].
[18] Romero-Sanchez C, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1855].
[19] Merjanah S, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1326].
[20] Lim W, et al.
Arthritis Rheumatol.
2020: 72 (suppl 10).
[21] Coste B, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1318].
[22] Garrido-Cumbrera M, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1322].
[23] Garrido-Cumbrera M, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1866].
[24] Ridley L, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1873].
[25] ACR 2020 Abstract2022.
[26] van der Heijde D, etal .
Ann Rheum Dis.
2017; 76(6): 978-991.
[27] Ward MM, et al.
Arthritis Care Res (Hoboken).
2019; 71: 1285-1299.
[28] Rios Rodriguez V, et al.
Arthritis Rheumatol.
2020; 12 (suppl 10).
[abstract 1376].
[29] Wang R, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1346].
[30] Van den Bosch F, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR2020 abstract 2028].
Expert ProfileProfessor Zhang LiyunChief Physician, Doctor of Medicine, Doctoral/Postdoctoral Supervisor Special allowance from the State Council Director of the Rheumatology and Immunology Department of Shanxi Bethune Hospital Founder and first director of the Department of Rheumatology and Immunology of Shanxi Bethune Hospital Director of the Laboratory of Human Cell Tissue Organ Regenerative Medicine Transformation Center of Shanxi Bethune Hospital Director of the Office of the Drug Clinical Trial Institute of Shanxi Bethune Hospital Visiting Scholar of the University of Pennsylvania School of Medicine National Natural Science Foundation of China Vice-chairman of the Rheumatology and Immunity Special Committee of the Chinese Society of Biomedical Engineering Chairman of the Committee Vice President of Rheumatology Branch of Shanxi Medical AssociationArthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1873].
[25] ACR 2020 Abstract2022.
[26] van der Heijde D, etal.
Ann Rheum Dis.
2017; 76(6): 978-991.
[27] Ward MM, et al.
Arthritis Care Res (Hoboken).
2019; 71: 1285-1299.
[28] Rios Rodriguez V, et al.
Arthritis Rheumatol.
2020; 12 (suppl 10).
[abstract 1376].
[ 29] Wang R, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1346].
[30] Van den Bosch F, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR2020 abstract 2028].
Expert Profile Professor Zhang Liyun Chief Physician, Doctor of Medicine, Doctoral Student/Postdoctoral Supervisor Director of the Laboratory of Human Cell Tissue Organ Regenerative Medicine Translation Center of Bethune Hospital, Director of the Office of Drug Clinical Trials, Shanxi Bethune Hospital, Visiting Scholar, National Natural Science Foundation of Pennsylvania, University of Pennsylvania School of Medicine Member of the Standing Committee of the Rheumatology Branch Member of the Rheumatology and Immunology Branch of the Chinese Medical Doctor Association Member of the Standing Committee of the Rheumatology and Immunology Professional Committee of the Cross-Strait Medical and Health Exchange Association Chairman of the Rheumatology Professional Committee of the Shanxi Medical Association Vice President of the Rheumatology Branch of the Shanxi Medical AssociationArthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1873].
[25] ACR 2020 Abstract2022.
[26] van der Heijde D, etal.
Ann Rheum Dis.
2017; 76(6): 978-991.
[27] Ward MM, et al.
Arthritis Care Res (Hoboken).
2019; 71: 1285-1299.
[28] Rios Rodriguez V, et al.
Arthritis Rheumatol.
2020; 12 (suppl 10).
[abstract 1376].
[ 29] Wang R, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR 2020 abstract 1346].
[30] Van den Bosch F, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR2020 abstract 2028].
Expert Profile Professor Zhang Liyun Chief Physician, Doctor of Medicine, Doctoral Student/Postdoctoral Supervisor Director of the Laboratory of Human Cell Tissue Organ Regenerative Medicine Translation Center of Bethune Hospital, Director of the Office of Drug Clinical Trials, Shanxi Bethune Hospital, Visiting Scholar, National Natural Science Foundation of Pennsylvania, University of Pennsylvania School of Medicine Member of the Standing Committee of the Rheumatology Branch Member of the Rheumatology and Immunology Branch of the Chinese Medical Doctor Association Member of the Standing Committee of the Rheumatology and Immunology Professional Committee of the Cross-Strait Medical and Health Exchange Association Chairman of the Rheumatology Professional Committee of the Shanxi Medical Association Vice President of the Rheumatology Branch of the Shanxi Medical Associationet al.
Ann Rheum Dis.
2017; 76(6): 978-991.
[27] Ward MM, et al.
Arthritis Care Res (Hoboken).
2019; 71: 1285-1299.
[28] Rios Rodriguez V, et al.
Arthritis Rheumatol.
2020; 12 (suppl 10).
[abstract 1376].
[29] Wang R, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR2020 abstract 2028].
Expert Profile Professor Zhang Liyun Chief Physician, MD, Doctoral Student/Postdoctoral Supervisor Vice-President of Shanxi Bethune Hospital Rheumatology and Immunology Department Founder and first department director Expert, Vice Chairman of Rheumatology and Immunology Committee of Chinese Society of Biomedical Engineering, Standing Committee Member of Rheumatology Branch of Chinese Medical Association, Member of Rheumatology and Immunology Branch of Chinese Medical Doctor Association Chairman of the Professional Committee Vice President of the Rheumatology Branch of Shanxi Medical Associationet al.
Ann Rheum Dis.
2017; 76(6): 978-991.
[27] Ward MM, et al.
Arthritis Care Res (Hoboken).
2019; 71: 1285-1299.
[28] Rios Rodriguez V, et al.
Arthritis Rheumatol.
2020; 12 (suppl 10).
[abstract 1376].
[29] Wang R, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR2020 abstract 2028].
Expert Profile Professor Zhang Liyun Chief Physician, MD, Doctoral Student/Postdoctoral Supervisor Vice-President of Shanxi Bethune Hospital Rheumatology and Immunology Department Founder and first department director Expert, Vice Chairman of Rheumatology and Immunology Committee of Chinese Society of Biomedical Engineering, Standing Committee Member of Rheumatology Branch of Chinese Medical Association, Member of Rheumatology and Immunology Branch of Chinese Medical Doctor Association Chairman of the Professional Committee Vice President of the Rheumatology Branch of Shanxi Medical Association2020; 72 (suppl 10).
[ACR 2020 abstract 1346].
[30] Van den Bosch F, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR2020 abstract 2028].
Introduction Professor Zhang Liyun Chief Physician, Doctor of Medicine, Doctoral Student/Postdoctoral Supervisor Special Allowance Expert of the State Council Director of the Laboratory of Organ Regenerative Medicine Translation Center Director of the Office of Drug Clinical Trials, Shanxi Bethune Hospital Visiting Scholar, University of Pennsylvania School of Medicine, National Natural Science Foundation of China Review Expert Member of the Rheumatology Branch of the Chinese Medical Doctor Association2020; 72 (suppl 10).
[ACR 2020 abstract 1346].
[30] Van den Bosch F, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
[ACR2020 abstract 2028].
Introduction Professor Zhang Liyun Chief Physician, Doctor of Medicine, Doctoral Student/Postdoctoral Supervisor Special Allowance Expert of the State Council Director of the Laboratory of Organ Regenerative Medicine Translation Center Director of the Office of Drug Clinical Trials, Shanxi Bethune Hospital Visiting Scholar, University of Pennsylvania School of Medicine, National Natural Science Foundation of China Review Expert Member of the Rheumatology Branch of the Chinese Medical Doctor AssociationExpert Profile Professor Zhang Liyun Chief Physician, Doctor of Medicine, Doctoral Student/Postdoctoral Supervisor Special Allowance Expert of the State Council Director of the Laboratory of Tissue Organ Regenerative Medicine Translation Center Director of the Office of Drug Clinical Trials, Shanxi Bethune Hospital Visiting Scholar, University of Pennsylvania School of Medicine Member of the Standing Committee of the Rheumatology and Immunology Branch of the Chinese Medical Doctor Association Member of the Standing Committee of the Rheumatology and Immunology Professional Committee of the Cross-Strait Medical and Health Exchange Association Chairman of the Rheumatology Professional Committee of the Shanxi Medical AssociationExpert Profile Professor Zhang Liyun Chief Physician, Doctor of Medicine, Doctoral Student/Postdoctoral Supervisor Special Allowance Expert of the State Council Director of the Laboratory of Tissue Organ Regenerative Medicine Translation Center Director of the Office of Drug Clinical Trials, Shanxi Bethune Hospital Visiting Scholar, University of Pennsylvania School of Medicine Member of the Standing Committee of the Rheumatology and Immunology Branch of the Chinese Medical Doctor Association Member of the Standing Committee of the Rheumatology and Immunology Professional Committee of the Cross-Strait Medical and Health Exchange Association Chairman of the Rheumatology Professional Committee of the Shanxi Medical Association
.

Main research directions: basic and clinical research of rheumatic immune diseases, basic and clinical translational research of cell and immunotherapy for rheumatic diseases
.