What is the relationship between IL-17A and the pain of ankylosing spondylitis?

*It is only for medical professionals to read and refer to the pain of AS patients, not to be underestimated.

Pain is the main symptom of patients with ankylosing spondylitis (AS), involving a wide range of parts, including sacroiliac joints, hip joints and joints such as knees, ankles, feet, wrists, and shoulders, which can cause morning stiffness, fatigue, sleep disorders and other symptoms occur.

The persistence of pain has caused a great disease burden on patients, and seriously affected their health-related quality of life.

During the treatment of AS, pain relief is the most urgent need of patients with AS, and it is also one of the key goals for symptom control.

Interleukin-17A (IL-17A) is a key target for the treatment of AS.

Studies have found that it is closely related to the occurrence of pain.
Targeting IL-17A can help regulate pain responses at multiple levels and angles.
What is going on? Today, let’s talk about the relationship between IL-17A and AS pain, and invite Professor Jiang Ping from the Affiliated Hospital of Shandong University of Traditional Chinese Medicine to comment and share on this topic.

1 Neural-immune interactions, which jointly mediate the occurrence of disease pain The chronic pain caused by the AS disease process is jointly intervened by the nervous system and the immune system, and patients often have neuropathic pain and inflammatory pain.

As we all know, pain signals can be transmitted by the nervous system, and how does the immune system participate in the occurrence of pain? In fact, the regulation of immune pathways mediated by immune cells, pro-inflammatory cytokines and chemokines can participate in signal transduction between neurons, causing changes in the structure and function of the nervous system, thereby mediating the regulation of pain response[ 1-2].

Among them, cytokines, as signal-transmitting molecules of interaction between cells, play an important role in the occurrence and maintenance of inflammatory diseases.

They have a considerable effect on sensory neurons and can directly act on pain receptors to cause depolarization or play an indirect role to stimulate the release of neurotransmitters/neuropeptides.

In the acute phase of inflammation, cytokines induce pain sensitization through the phosphorylation of receptor-related kinases and ion channels; while in chronic inflammation, they may affect the increase of receptor transcription and secondary signal transduction.
And play a role [3-5].

2 What role does IL-17A play in the occurrence of pain? IL-17A can be seen in multiple pathological processes during the occurrence and development of AS.

It not only drives chronic inflammation and regulates the pathological process of enthesitis, but also participates in the whole process of AS bone metabolism.

So, does IL-17A also have a place in the mechanism of pain response? As a pro-inflammatory cytokine, IL-17A plays a key role in a variety of neurological diseases, such as multiple sclerosis, epilepsy syndrome, and ischemic brain injury.

IL-17A and its receptors are expressed in many nerve tissues.
They can not only regulate the activation of neurons and the growth of neurites, but also affect the proliferation of neurons, glial cells and other supporting cells.
Send out signals, affect nerve function and signal conduction.

In addition, it also mediates the interaction of neuroimmunity and participates in the generation of pain disorders [2].

Specifically, IL-17A can participate in the occurrence of pain in the following ways[2,7-8]: In terms of immune activation, IL-17A can mediate inflammation by infiltrating local inflammatory cells and releasing inflammatory factors.
Sexual pain.

For example, after directly injecting IL-17A into the joint cavity of arthritic mice, IL-17A can enhance the perception of pain by activating immune cells and promoting the release of inflammatory mediators (such as TNF-α, IL-1β, and prostaglandins) [6].

In terms of the nervous system, IL-17A is synthesized and released in the central nervous system and peripheral nervous system, and acts on both.

In the central nervous system, IL-17A further promotes the migration of lymphocytes by activating blood-brain barrier endothelial cells, and has direct or indirect effects on a variety of nerve cells, such as activating microglia and astrocytes to promote The release of inflammatory factors and pain mediators [such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF)] is increased and participates in the regulation of pain signals; in the peripheral nervous system, IL-17A can increase peripheral nociceptors Sensitivity, which activates the signal pathway of neurons in the dorsal root of the spinal cord, contributes to the enhancement of pain during neuropathic pain and inflammatory pain (Figure 1).

Figure 1: IL-17A plays a role in neuro-immune interactions and participates in pain control.
Based on this, we speculate that IL-17A also plays an important role in the occurrence of pain in AS patients.

Targeting IL-17A may regulate pain response from multiple levels.

3IL-17A inhibitors have a positive effect on pain relief in AS patients! In the field of AS treatment, currently the most widely used biologics are tumor necrosis factor (TNF-α) inhibitors.

Although TNF-α is considered to play an important role in the formation and maintenance of neuropathic pain, the relevant mechanism is still unclear.

Studies have shown that even after long-term TNF-α inhibitor treatment, up to 40% of AS patients have a pain score> 4 (total score range 0-10 points), that is, persistent pain is reported [9].

IL-17A inhibitors are innovative drugs in the field of AS treatment, and their mechanism of action is different from previous biological agents, bringing us many surprises and expectations.

Skukuzumab is the first and only IL-17A inhibitor approved for AS indications in China.
Although it has been on the market in China for a short time, it has accumulated rich clinical research abroad.
And real-world application data.

Facts have proved that targeting IL-17A can effectively regulate the pain response in the pathological process of AS, and Skucilumab has a significant pain relief effect on patients with AS, and helps to improve the pain caused by many symptoms and manifestations.

The MEASURE series of studies is a classic study exploring the efficacy of Scucciyuumab in the treatment of AS.

In the MEASURE study, Skucilumab treatment of AS patients can quickly and lastingly relieve their low back pain, heel pain, and pain-related clinical manifestations such as morning stiffness and fatigue (Figure 2) [10-12].

Figure 2: Skucilumab treatment can quickly relieve symptoms such as pain, morning stiffness, fatigue, heel pain and other symptoms.
In addition, at the annual meeting of the American College of Rheumatology (ACR) last year, the researchers announced the 24-week results of the SKIPPAIN study [13].

This study evaluated the effect of Skuchiyuumab on the relief of spinal pain in patients with axial spondyloarthritis (axSpA).

The results showed that at the 8th week of treatment, the proportion of patients with a pain numerical score scale (NRS) of <4 in the skucilizumab group was significantly higher than that in the placebo group; and at 24 weeks, the patients in each group had more spinal pain.
Relief, especially in the dose-increasing group and the patients who switched from placebo to the treatment group of skucilizumab (Figure 3), shows that skucilizumab has a rapid and long-lasting effect on the relief of patients' spinal pain.

Figure 3: The results of the SKIPPAIN study show that Skuqiyuumab can quickly and significantly improve spinal pain in patients with axSpA.
In addition to the pain of the axial joint, Skuqiyuumab also has a significant effect on the relief of peripheral joint pain.

The analysis of the pooled study of MEASURE 1-4 showed that after 16 weeks of treatment with Skucilumab, about 1/3 of patients' peripheral joint tenderness achieved 100% improvement [14] (Figure 4).

Figure 4: Skuchyumumab has a significant improvement effect on peripheral joint tenderness.
4 Summary Low back pain, heel pain.
.
.
Pain is the main clinical manifestation of AS, and it is also a symptom that patients desperately want to relieve.

Pain in AS is the result of a complex interaction between immune, peripheral nervous system, and central nervous system activities.

IL-17A regulates pain at the same time from multiple levels.
Multiple studies have shown that the IL-17A inhibitor scocilizumab can significantly alleviate the axial and peripheral joint pain in patients with AS.
Not only that, but the symptoms related to pain are like morning stiffness.
Fatigue, fatigue, etc.
have also been significantly alleviated, and physical function has been improved as a result, and patients can obtain good curative effects. Professor Jiang Ping AS is an immune-mediated chronic inflammatory joint disease that mainly involves the axial bone, peripheral bone and soft tissues.
Its pathological feature is that the inflammation at the attachment points and joints leads to pathological new bone formation and progressive sacral The iliac joint is rigid.

The main clinical symptoms are pain, morning stiffness, fatigue, ligament osteophytes, bone fusion, bone rigidity and even disability, which seriously affect the patient's physical function and quality of life.

Based on this, the International Spondyl Arthritis Assessment Organization (ASAS) proposed the treatment goals of AS: control the symptoms and inflammation of the disease, maintain the patient's function and social participation, prevent the progression of structural damage, and improve the health-related quality of life.

Since AS was named in 1904, its diagnosis and treatment have undergone many changes, and the progress of immunology has promoted the continuous innovation of treatment programs.

With the gradual in-depth research on the pathogenesis of AS, there are more and more explorations of AS therapeutic targets, such as targeting IL-1, IL-6, IL-12/IL-23, etc.
, but most of them have suffered a lot.
Sha, regretfully exited.

Current research recognizes that IL-17A is a key target for the treatment of AS.

It is closely related to the occurrence of pain.
Targeting IL-17A helps to regulate pain response in multiple levels and from multiple angles.

The results of the MEASURE series of studies show that IL-17A inhibitors can quickly and lastingly relieve low back pain, heel pain, and pain-related clinical manifestations such as morning stiffness and fatigue.

Especially exciting is that it can delay the progress of imaging, improve the condition of most patients with restricted activities, so that patients can quickly relieve pain, improve functional activities, and improve self-care ability and work ability.

For patients whose non-steroidal anti-inflammatory drugs (NSAIDs) are not well controlled and TNF inhibitors are contraindicated or are still active after TNF inhibitor treatment, ACR combined with the American Spondylitis Association (SAA) guidelines recommend the use of IL-17A inhibitors Get treatment.

I believe that with the development of medicine, there will be continuous progress in the etiology, pathogenesis and treatment of AS, as soon as possible to safely reach the standard as soon as possible, to meet the treatment needs of patients, to benefit more patients, and to start a happy and healthy life.

Expert profileProfessor Jiang Ping Doctor of Medicine, Professor, Chief Physician, Doctoral Supervisor, National Excellent Clinical Talents of Traditional Chinese Medicine, Member of the Rheumatism Professional Committee of the Chinese Society of Chinese Medicine, Member of the Diagnostics Professional Committee of the Chinese Society of Chinese Medicine, Executive Director of the World Federation of Chinese Medicine Professional Committee of Internal Economics Shandong Traditional Chinese Medicine Vice-chairman of the Rheumatology Professional Committee of the Society, Vice-chairman of the Rheumatism Professional Committee of the Shandong Association of Integrated Traditional Chinese and Western Medicine, Vice-chairman of the Rheumatology Professional Committee of the Chinese Medicine Physician Branch of the Shandong Medical Doctor Association Member of the Osteoporosis and Bone Mineral Diseases Branch of the Shandong Medical Association Published 5 SCI papers on scientific fund projects and Shandong Science and Technology Development Plan and other provincial and ministerial projects.
More than 40 academic papers in core journals won 1 second prize of Science and Technology Progress Award of the International Contribution Award of Traditional Chinese Medicine and Shandong Science and Technology Progress Award.
1 second prize and 1 third prize each, 1 second prize of Shandong Provincial Teaching Achievement Award, etc.
References: [1] Vanderwall AG, et al.
Front Immunol.
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[2] Moynes DM , et al.
Brain Behav Immun.
2014, 41:1-9.
[3] BL Kidd, et al.
British Journal of Anaesthesia.
2001, 87(1): 3-11.
[4] Wang Kaiqiang, et al.
Foreign Medicine , 2001, 22(5): 313-315.
[5] Zhou Lijun, et al.
Chinese Journal of Pain Medicine, 2013, 19(11): 679-684.
[6] Pinto LG, et al.
Pain.
2010, 148: 247-256.
[7] Bidad K, et al.
Nat Rev Rheumatol.
2017, 13(7):410-420.
[8] Sun C, et al.
Mol Med Rep.
2017, 15(1):89- 96.
[9] Kieskamp S, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
Abstract #1321.
[10] Marzo-Ortega et al.
2019 ACR Annual Meeting.
Poster 1504.
[11] Deodhar A, et al.
Clin Exp Rheumatol.
2019 Mar-Apr;37(2):260-269.
[12] Magrey M, et al.
Drugs Real World Outcomes.
2019 Jun;6(2):83 -91.
[13] Poddubnyy D, et al.
Arthritis Rheumatol.
2020; 72 (suppl 10).
Abstract #0899.
[14] PJ Mease, et al.
Annual European Congress of Rheumatology (EULAR) E-CONGRESS, June 3 -6, 2020, #THU0397.
Short prescribing information Note: Before prescribing, you should 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.
The initial subcutaneous injection is performed at 0, 1, 2, 3, and 4 weeks, and 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 the age of 18 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.

Do you need to use a loading dose for biologics in the past review? The clinical evidence has the final say! Taking the "unusual" road, IL-17A inhibitors have overcome obstacles and pursue excellence all the way! The path of change in the treatment of ankylosing spondylitis: from "symptomatic treatment" to "full management", the new medical insurance catalogue is officially implemented.
What changes will it bring to the diagnosis and treatment of AS? The latest medical insurance drug list is implemented, IL-17A inhibitors will benefit more rigid patients! "Inflammation" must be lost, anti-inflammation knows how: IL-17A and inflammation