Why does imaging progress in patients with rigidity?

*Only for medical professionals to read for reference.
Bone remodeling imbalance is an important pathological process in the occurrence and development of AS.

Ankylosing spondylitis (AS) is a common inflammatory autoimmune disease characterized by pathological new bone formation.

In the course of disease progression, the patient’s imaging changes can gradually develop from the initial inflammatory manifestations such as sacroiliac arthritis, spondylitis, intervertebral discitis, etc.
to irreversible structural damage such as vertebral bone and intervertebral space destruction, squatting of the vertebral body, and ligaments Hyperplasia, ligament ossification, spinal stiffness, deformity, etc.

As a result, his mobility is limited, and his quality of life is severely affected.

 Studying the progression of AS imaging and its characteristics, and exploring its pathological bone remodeling mechanism is of great significance to the early diagnosis and treatment of the disease.

In this issue, we will focus on this topic for discussion, and invite Professor Xu Hanshi from the First Affiliated Hospital of Sun Yat-sen University to comment and share.

 What are the characteristics of the imaging changes in 1AS? Although square vertebrae and bamboo vertebrae are characteristic imaging manifestations of AS, not all patients will go through this stage.

AS is a chronic progressive disease.
In each course, patients will show different imaging changes.

Research data shows that less than half of patients will achieve complete spinal fusion during a long course of disease [1].

In the imaging progress of AS, the sacroiliac joint is generally the first part to be affected.
The vast majority of early AS patients present bilateral symmetrical sacroiliitis, causing pain and stiffness in the lower back and buttocks.

Early inflammatory changes such as bone marrow edema can be observed by magnetic resonance imaging (MRI) [2].

As the disease progresses, the patient's articular surface erosion and destruction gradually increase, and the scope gradually expands, ascending to the lumbar, thoracic and cervical spine, which can be manifested as fat deposition, fat infiltration, osteoporosis, and bone loss.

At the same time, pathological new bone formation will cause ligament hyperplasia and ligament ossification.
The formation of new osteophytes will link adjacent vertebral bodies to form a bone bridge, leading to spinal fusion, and the patient will have square vertebrae and "bamboo vertebrae".
And other irreversible structural damage, leading to the decline of its mobility [1-3].

In addition to the imaging progress of the axial spine joints, many patients with AS also have imaging changes in the surrounding joints.
These peripheral joint diseases have been shown to have a significant impact on the prognosis.

The hip joint is the most commonly involved peripheral joint.
It is mostly unilateral in the early stage, and then may develop bilaterally symmetrical.

Foreign reports indicate that the proportion of hip joint involvement in AS patients is close to 40%, while the proportion of AS patients in China may be even higher [4].

Moreover, studies have shown that hip joint involvement is related to more severe axial involvement, and is a high-risk factor for patients with spinal slubular degeneration [1, 5].

Therefore, patients with hip joint involvement need to receive more active clinical treatment (including drug therapy and joint replacement surgery) [6].

Figure 1: AS imaging features (source: those cells in the process of 2AS bone remodeling AS imaging progress and abnormal adjustment of bone remodeling Closely related.

In the normal body, the dynamic coupling balance between bone resorption and bone formation helps maintain bone tissue metabolism and achieve a stable bone remodeling process to maintain the integrity of its own structure.

But under pathological conditions, this balance will be broken [7-8].

From the cellular level, many types of cells participate in the regulation of bone remodeling.

Among them, osteoblasts and osteoclasts are the two key cell types.
Osteoblasts are distributed in clusters along the surface of bone.
They are mainly differentiated from mesenchymal stem cells (MSC) and are responsible for the synthesis, secretion and mineralization of bone matrix.
In the bone tissue, they play the function of new bone formation; and osteoclasts usually contact the surface of calcified bone and are located in the bone cavity.
They are mainly derived from the monocytes of the hematopoietic system and are responsible for bone decomposition and absorption [9]. The mutual adjustment between the two is the basis for achieving a balance between bone formation and bone resorption.
If one party supplies too much or too little, it will cause an imbalance of bone remodeling, resulting in a decrease or increase in bone mass.

Figure 2: Bone remodeling process (source: and rheumatoid arthritis (RA) The bone homeostasis disorder driven by osteoclasts is different.
In AS, pathological new bone formation and bone loss often occur concurrently.
Systemic bone loss is accompanied by local excessive ossification (Figure 3) [10- 11]: On the one hand, in the early stages of the disease process, the increase in the number of osteoclasts and the decrease in the number of osteoblasts lead to excessive loss of trabecular bone and osteopenia in the center of the vertebral body.
Increased risk of spinal deformity.

For example, the results of different cohort studies show that the probability of osteoporosis in AS patients is 19%-62%, while the probability of vertebral fractures is 9%-42% [12]; on the other hand, at the local level, For example, at the attachment point or near the bone erosion site, MSC proliferates and osteoblasts differentiate, leading to the formation of osteophytes, the disappearance of joint spaces, and the destruction of bone rigidity and functional structure.

This is the main pathological feature that distinguishes AS from RA.

Figure 3: The course of AS includes systemic bone loss and local new bone formation [10] 3 Various cytokines regulate AS bone remodeling.
In the process of bone remodeling, the function of various types of cells is subject to a series of complexities.
The regulation of signal molecules, such as the activation of related transcription factors, growth factors and cytokines, and the interaction of various matrix proteins.

Studying the regulatory effects of cytokines on the bone remodeling process of AS is essential for our understanding of its pathogenesis.
They link immune regulation and bone metabolism.
Understanding this connection will help us to deepen and better treat disease.
Targeted exploration.

Many cytokines are important regulators of the functions of osteoclasts, osteoblasts and MSCs.

For example, interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α) can synergistically act on the formation of osteoclasts and promote their functions.
By activating nuclear factor κB (NF-κB), induce And enhance the expression of nuclear factor kappa B receptor activator ligand (RANKL) to promote the survival and migration of osteoclasts, and inhibit the activity of osteoblasts [13]; IL-17 can promote the formation of osteoclasts and increase bone resorption, It can also induce MSC to differentiate into osteoblasts and increase the activity of osteoblasts [14]; on the contrary, Th2 cytokines such as IL-4, IL-13 and IL-10 and interferon (IFN) can inhibit osteoclasts.
Formation and activation [13].

 Table 1: The effects of various cytokines on osteoclasts/osteoblasts and their possible mechanisms of action [13] RANK: nuclear factor kappa B receptor activator; M-CSF: macrophage colony stimulating factor; GM-CSF: Granulocyte-macrophage colony stimulating factor; MCP-1: monocyte chemoattractant protein 1 Although many cytokines have a regulatory effect on bone cells, there are cytokines that play a key role in the pathological mechanisms of different diseases.
The difference.

For example, in the serum and sacroiliac joints of AS patients, although the expression levels of TNF-α and IL-6 were significantly increased, blocking IL-6 receptor signal transduction failed to show clinical efficacy in AS treatment.
It shows that IL-6 is not a key cytokine in the pathogenesis of AS; although TNF-α inhibitors can effectively improve the patient's disease symptoms, physical function and quality of life, it is not clear whether it has a delaying effect on the structural damage in the course of the disease.
Conclusive.

In recent years, it has been found that IL-17 and IL-23 are expressed at a high level in the serum of AS patients.
The treatment program targeting IL-17 can not only significantly alleviate the symptoms and signs of the disease, but also effectively inhibit the progress of imaging [15].

This suggests that IL-17 may be a key cytokine in the process of AS bone remodeling.

4 Summary: AS is a disease with relatively obvious imaging abnormalities in the process of progression.
Skeletal lesions gradually move up from the sacroiliac joint to the spine, which can lead to calcification of the perispine ligaments and result in bone rigidity and high disability rate. In this process of change, the abnormal regulation of bone metabolism and the imbalance of bone remodeling play a key role.
Different types of cells and cytokines are involved.
Studying their mechanism of action will help us explore effective treatment options for diseases.

In the next issue, we will focus on the "new flow" IL-17A in the cytokine network, and discuss in detail its important role in AS bone metabolism and bone remodeling, so stay tuned! In the early stage of AS, Professor Xu Hanshi's disease symptoms mainly manifested as lumbosacral pain, heel pain, and morning stiffness.

As the disease progresses, this painful symptom intensifies and spreads, gradually affecting the lumbar spine, cervical spine, and the entire spine.

From the imaging point of view, AS patients suffer from abnormal bone metabolism and imbalance in bone remodeling during the course of the disease, leading to systemic bone loss, local excessive ossification, and osteophyte formation.

Therefore, patients have a higher probability of osteoporosis and vertebral fractures, and pathological new bone formation can promote ossified bone bridges in the spine, causing structural and functional damage and even deformities.

Osteoblasts and osteoclasts are the two main cell types in the process of bone remodeling.
They are tightly regulated by different signaling molecules and maintain the balance of bone resorption and bone formation in the normal body.

However, in the pathological process of AS, the expression level of some signal molecules is abnormally increased or decreased.
They act on different bone cells and have different effects on the overall balance process of bone remodeling.

Cytokines are important signal molecules in the body's immune regulation process, and they also play an important role in the bone metabolism process.
They link bone metabolism with immune regulation.

Studies have found that many cytokines play a role in the process of bone remodeling imbalance.

In the abnormal bone metabolism of AS, the expression level of IL-17 is significantly increased, and its targeted therapy has a significant effect in AS, which can inhibit joint bone erosion and reduce local new bone formation, thereby effectively delaying the progress of imaging.

Expert profile Professor Xu Hanshi, deputy director, chief physician, professor, and doctoral supervisor of the Department of Rheumatology and Immunology of the First Affiliated Hospital of Sun Yat-sen University, is mainly engaged in the research on the pathogenesis of rheumatoid arthritis.
So far, he has presided over 8 projects funded by the National Natural Science Foundation of China.
The corresponding author has published more than 20 SCI papers in mainstream international journals such as J Clin Invest, Arthritis Rheum, J Immunol, "Chinese Journal of Clinical Immunity and Allergy", "Chinese Journal of Clinical Immunity and Rheumatology" Editorial Board, "Chinese Journal of Rheumatology" 》Correspondence Editor; Journal of Translational Autoimmunity; Nature Review Rheumatology, Rheumatology, Cell Signal and other international journal reviewers National Natural Science Foundation, Royal Dutch Rheumatism Foundation, Austrian Science Foundation, British Arthritis Research Fund The peer-reviewed experts of the association are the second and third vice chairman of the Rheumatology Branch of the Guangdong Medical Association, the standing committee member of the Rheumatology Branch of the Guangdong Medical Association, the vice chairman of the Rheumatology Branch of the Guangdong Association of Integrative Chinese and Western Medicine, and the Guangzhou Medical Association Rheumatology The vice chairman of the academic branch, the member of the Rheumatology Branch of the China Association for the Promotion of International Medical and Health Care, etc.
References: [1] Jang JH, et al.
Radiology.
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[2] Sun Xuexue, Continuing Medical Education.
2018, 32(4): 135-138.
[3] Ma Xinfa, et al.
Chinese Journal of General Practitioners.
2014, 13(4): 262-264.
[4] Hu Zhengyuan, et al.
Chinese Internal Medicine Journal.
2019, 58(3):167-169.
[5] Atagündüz P, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
Abstract #1882.
[6] Braun J, et al.
Ann Rheum Dis.
2002, 61 Suppl 3(Suppl 3): iii9-23.
[7] Goldring SR.
Curr Rheumatol Rep.
2013, 15(7):342.
[8] Baum R, et al.
Clin Rev Allergy Immunol.
2016, 51(1):1-15.
[9] Hadjidakis DJ, et al.
Ann NY Acad Sci.
2006, 1092:385-96.
[10] Gravallese, EMet al.
Nat Rev Rheumatol.
2018(14):631-640.
[11] Hu Jintao, et al.
Chinese Journal of Osteoporosis.
2019, 25(6): 875-879.
[12] Klingberg E, et al.
J Rheumatol.
2014, 41(7 ):1349-56.
[13] Datta HK, et al.
J Clin Pathol.
2008, 61(5):577-87.
[14] T.
Russell, et al.
Ann Rheum Dis, volume 79, supplement 1, year 2020, page 1117[15] Amarasekara DS, et al.
J Immunol Res.
2015; 2015: 832127.
Brief prescribing information Note: Before prescribing, you should refer to the full prescribing information.
supplement 1, year 2020, page 1117[15] Amarasekara DS, et al.
J Immunol Res.
2015; 2015: 832127.
Brief prescribing information Note: Before prescribing, refer to the full prescribing information.
supplement 1, year 2020, page 1117[15] Amarasekara DS, et al.
J Immunol Res.
2015; 2015: 832127.
Brief prescribing information Note: Before prescribing, refer to the full prescribing information. Drug name: Skuchiyuumab injection Drug specifications: 1ml; 150mg packaging: pre-filled syringe: 1 per box; 2 per box Pre-installed automatic injection pen: 1 per box (pre-installed automatic Injection pens); 2 per box (pre-installed automatic injection pens) Indications: Psoriasis is used to treat adult patients with moderate to severe plaque psoriasis that meet the indications of system therapy or phototherapy.

Ankylosing spondylitis is used for adult patients with ankylosing spondylitis with poor conventional treatment.

Usage and dosage: This product must be used under the guidance and supervision of a doctor with experience in treatment.

Dosage The recommended dose for psoriasis is 300 mg each time, and the initial subcutaneous injection is performed at 0, 1, 2, 3, and 4 weeks, and then the dose is maintained every 4 weeks.

The 300 mg dose is administered in 2 injections, 150 mg per injection.

At the same time, for patients weighing less than 60kg, the dose can be considered 150mg.

The recommended dose of this product for ankylosing spondylitis is 150 mg each time, initially subcutaneously injected at 0, 1, 2, 3, and 4 weeks, and then administered once every 4 weeks to maintain this dose.

Usage This product should be administered by subcutaneous injection.

If possible, injections at the site of psoriasis lesions should be avoided.

Before injection, take this product out of the refrigerator, and use it after the temperature rises to room temperature (15-30 minutes) without removing the needle cap.

This product must be used within 1 hour after being taken out of the refrigerator.

Before administration, check the product visually for particulate matter and discoloration.

If there are visible particles in the liquid, or the liquid is turbid or discolored, it must not be used.

Contraindications: Patients with severe hypersensitivity reactions to the active ingredients of this product or any of the excipients are contraindicated.

Clinically important active infections (for example: active tuberculosis, see [Precautions]).

Note: Infection: This product may increase the risk of infection.

In clinical studies, infections were observed in patients treated with this product (see [Adverse Reactions]), most of which were mild or moderate.

Patients with a history of chronic infection or recurrent infection should use this product with caution.

Patients should be instructed to consult a doctor when signs or symptoms suggest infection.

If the patient develops a serious infection, the patient should be closely monitored and the product should be stopped until the infection subsides.

No increase in susceptibility to tuberculosis has been reported in clinical studies, but patients with active tuberculosis should not be treated with this product.

Patients with latent tuberculosis should consider anti-tuberculosis treatment before receiving treatment with this product.

Inflammatory bowel disease: Patients with active inflammatory bowel disease (such as Crohn's disease, ulcerative colitis) should use this product with caution.

In clinical studies, cases of exacerbation of inflammatory bowel disease were observed in both the Skuchiyuumab group and the placebo group, and some cases were more severe.

Patients with active inflammatory bowel disease treated with this product should be closely monitored.

Hypersensitivity reactions: In clinical studies, rare immediate allergic reactions have been observed in patients treated with this product.

If an immediate allergic reaction or other severe allergic reaction occurs, this product should be stopped immediately and appropriate treatment measures should be taken.

People who are sensitive to latex: The detachable needle cap in the prefilled syringe of this product contains derivatives of natural rubber latex, and no natural rubber latex is detected in the needle cap.

Vaccine: Live vaccine should not be used simultaneously with this product.

Medication for special populations: Medication for children: The safety and effectiveness of this product in patients under 18 years of age have not been determined.

Elderly medication: Elderly patients do not need to adjust the dose.

Medication for pregnant women and lactating women: Pregnant women: There are limited data on the use of this product for pregnant women.

Use this product during pregnancy only when the benefits are clearly greater than the potential risks.

Breastfeeding women: breastfeeding women should use this product with caution.

Adverse reactions: The most frequently reported adverse drug reactions (ADRs) of this product are upper respiratory tract infections (the most common are nasopharyngitis and rhinitis).

Very common (≥1/10): Upper respiratory tract infections are common (≥1/100 to <1/10): oral herpes, diarrhea, runny nose occasionally (≥1/1,000 to <1/100): oral candidiasis , Neutropenia, tinea pedis, conjunctivitis, otitis externa, lower respiratory tract infection, inflammatory bowel disease, urticaria rare (≥1/10,000 to <1/1,000): immediate allergic reaction, exfoliative dermatitis ( There are case reports in patients with psoriasis) The frequency of occurrence is unknown: Mucosal and skin candidiasis (including esophageal candidiasis) Description of selected adverse reactions Infection In the clinical study of this product for the treatment of plaque psoriasis, the treasurer During the control period, 28.
7% and 18.
9% of patients in the Chiyuumab group and placebo group respectively reported infections.
Most of these infections were mild to moderate upper respiratory tract infections, and there was no need to stop this product.
treatment.

Cases of mucosal and cutaneous candidiasis have also increased.
These cases are mild to moderate in severity and do not need to stop treatment.

The infection rate observed in the clinical study of this product for the treatment of ankylosing spondylitis and other indications is similar to the result observed by this product in the study of psoriasis.

Neutropenia In the phase III clinical study of psoriasis, the frequency of neutropenia was observed in the Skuchiyuumab group than in the placebo group, but most cases were mild and transient.
And reversible.

The frequency of neutropenia in patients with indications such as ankylosing spondylitis is similar to that of patients with psoriasis, and rare cases of neutropenia below 0.
5×109/L (CTCAE grade 4) have been reported.
.

Hypersensitivity reactions In clinical studies, rare cases of urticaria and immediate allergic reactions have been observed.

Clinical studies on the immunogenicity of this product in the treatment of psoriasis, ankylosing spondylitis and other indications show that less than 1% of patients develop anti-recozumab antibodies during the 52-week treatment period.

Half of the anti-drug antibodies that appeared during treatment were neutralizing antibodies, but they had nothing to do with drug failure or abnormal PK.

Drug interactions: Live vaccines should not be used simultaneously with this product.

In a study of this product in the treatment of plaque psoriasis, there was no interaction between this product and midazolam (CYP 3A4 substrate).

In the study of this product in the treatment of arthritis (including ankylosing spondylitis, etc.
), when this product was administered with methotrexate (MTX) and/or corticosteroids at the same time, no interaction was observed.

A review of the changes in the treatment of ankylosing spondylitis in the past: from "symptomatic treatment" to "total management", the new medical insurance catalogue is officially implemented.
What changes will it bring to AS diagnosis and treatment? The latest medical insurance drug list is implemented, IL-17A inhibitors will benefit more rigid patients! "Inflammation" must be lost, and anti-inflammatory methods: The relationship between IL-17A and inflammation is explored.
What is the relationship between IL-17A and the pain of ankylosing spondylitis?