The path of changes in the treatment of ankylosing spondylitis: from "symptomatic treatment" to "comprehensive management"

*Only for medical professionals to read for reference.
As the new era of treatment is coming, what are your expectations? Ankylosing spondylitis (AS) is an ancient disease, and the earliest patients with AS can be traced back to the ancient Egyptians.

Although its existence has been around for a long time, people's cognition and treatment of this disease have developed relatively slowly, and it was not until the past two centuries that there was a major breakthrough.

In recent years, benefiting from the continuous development of various technical means, our understanding of AS disease has made a qualitative leap.

The rise and use of biological agents have gradually upgraded the clinical treatment of AS.
From the era of traditional drugs to the era of biological agents, from failure to completely control symptoms to comprehensive disease management, how many clinical treatments have the new era of AS treatment brought to patients? Benefit? Today, we will review the changing path of AS treatment, look forward to its future development, and invite Professor Huang Anbin from Union Hospital of Tongji Medical College of Huazhong University of Science and Technology to share his views with us.

The change in 1AS disease cognition The change in AS treatment begins with the change in people's cognition.

In the 17th century, Bernard Conner’s description of the clinical features of AS gave it an initial clinical record.
However, despite a large number of independent medical record reports for more than a century, people’s exploration of AS was still in a very primitive state.
The clinical description is vague [1].

The classic description of AS appeared in the 19th century.

During this period, important clinical features of AS were further discovered and described in detail, including peripheral joint and hip joint involvement, spinal stiffness and deformation, etc.
, and the relationship between clinical manifestations and anatomical observations was established [1].

In the 20th century, the cognitive development of AS entered into modern theoretical concepts.

The development of imaging methods has played a key role in this.
The application of X-rays has promoted the understanding of the radiology of AS sacroiliac joints.
Features such as sacroiliac arthritis and ligament osteophytes have been described in detail; and the emergence of MRI has made the disease.
Early inflammatory damage has been observed [1].

In the 1960s, as researchers further studied rheumatoid factors, AS gradually separated from rheumatoid arthritis (RA).

The discovery of the genetic material HLA-B27, which is closely related to AS, further clarifies the cognitive concept that AS is a type of disease independent of RA.

In 1963, the American College of Rheumatology (ACR) officially recognized the name of AS, creating a new era of its research and diagnosis and treatment [1-2].

 Figure 1: The evolution of AS disease cognition 2 How to define the 1.
0, 2.
0 and 3.
0 eras of AS treatment? With the development of disease cognition, the diagnosis and classification criteria of AS are constantly changing.
With the emergence of new drugs, it provides a theoretical and practical basis for the change of AS treatment concepts and strategies.

 Figure 2: Changes in diagnostic criteria, therapeutic drugs, and treatment concepts and strategies (NSAIDs: non-steroidal anti-inflammatory drugs; DMARDs: disease-improving anti-rheumatic drugs; FDA: US Food and Drug Administration; EMA: European Medicines Agency.

) 1 Changes in diagnostic criteria From the Roman criteria to the New York criteria and then to the revised New York criteria, the AS diagnostic criteria have been continuously optimized, and the specificity and sensitivity have been improved.

However, the standard is limited to the evaluation of clinical manifestations such as low back pain, stiffness, and radiographic changes in X-ray detection, and cannot cover the earlier stages of AS [3-5].

In 2009, the International Spondyl Arthritis Assessment Task Force (ASAS) further classified spondyloarthritis (SpA) into axial type and peripheral type, and added genetic background HLA-B27 gene and MRI early joint changes.
In order to achieve early diagnosis and treatment of the disease, and improve the long-term prognosis of patients [6].

2 Changes in therapeutic drugs, concepts and strategies For a long time, AS treatment has always been a huge challenge faced by clinicians.

With the continuous enrichment of treatment methods and the updating of treatment concepts and strategies, AS treatment has undergone a transition from the era of traditional drugs to the era of today's biological agents, and has achieved a leap from 1.
0 to 2.
0 and then to 3.
0.

So, how to define and divide the 1.
0, 2.
0 and 3.
0 eras of AS treatment? 1.
0 era (the era of traditional therapeutic drugs): When the clinical characteristics of AS are not yet clear, the treatment of AS is mainly based on symptom control.

Traditional therapeutic drugs include non-steroidal anti-inflammatory drugs (NSAIDs), hormones, and traditional synthetic disease-improving anti-rheumatic drugs (csDMARDs).
Among them, NSAIDs are the main means to control symptoms [7-8].

However, many research evidences and clinical experience show that traditional treatment drugs cannot completely control the symptoms of AS, improve the condition, and cannot meet clinical needs [8-9].

 Figure 3: Traditional treatments cannot completely control the symptoms of AS.
With the deepening of basic disease research and the advancement of drug research and development methods, biological agents have gradually entered people's field of vision.
They have strong targeting and can accurately block important links in the pathogenesis.
, Bringing huge changes to the treatment and management of AS.

At present, tumor necrosis factor inhibitors (TNFi) and interleukin-17 (IL-17) inhibitors are the main biological agents for the treatment of AS.

2.
0 era (TNFi era): TNFi is the earliest biological agent used for AS treatment.
Its target TNF-α plays an important role in AS and is the core cytokine that mediates the inflammation process of AS [10-13].

The application of TNFi in the treatment of AS has accumulated a large amount of evidence-based medical evidence.
Compared with the era of traditional drug treatment, TNFi can quickly and effectively alleviate the symptoms of AS and reduce disease activity in patients, and the treatment level has achieved a leapfrog development [14-15].

In 2010, ASAS and the European Alliance for Anti-Rheumatism (EULAR) updated the AS treatment opinions, and proposed four main goals, namely, control symptoms and inflammation, prevent progressive structural damage, maintain/normalize function and social participation, and maximize Improve the patient’s health-related quality of life [16].

This puts forward higher standards of recommendations and requirements for the treatment of AS.
However, studies have found that TNFi has a limited inhibitory effect on the progression of AS imaging and structural destruction [17].

3.
0 Era (Interleukin Era): In 2015, the IL-17A inhibitor Recchiumab was approved by the European Medicines Agency (EMA) for the treatment of AS, which further pushed the treatment of AS into the IL era.

IL-17A plays an important role in many links in the occurrence and development of AS.
It participates in the development of enthesitis and the process of pathological new bone formation, which can lead to irreversible structural damage [18-21].

After IL-17A inhibitors specifically block this target, they can regulate the pathological process of the disease at multiple levels and achieve better therapeutic effects.

3 What kind of new treatment era does the treatment plan targeting IL-17A paint? What kind of new treatment prospects does the 3.
0 era of AS treatment, the IL era, bring us? As mentioned above, the treatment goals of AS are gradually being improved with the renewal of diagnosis and treatment concepts and methods, and on this basis, the concept of standard treatment is formed.

AS standard treatment emphasizes not only symptomatic treatment, but also the overall management of the disease, and ultimately achieves the optimization of patients' health-related quality of life and social participation (Figure 4) [22].

Compared with conventional treatment, standard treatment is more helpful to control disease activity, improve patient health, and has certain economic benefits, saving more costs in long-term treatment [23].

Figure 4: An international working group composed of rheumatologists and dermatologists such as Professor Smolen proposed in 2017 "Achieve standard treatment of axial and peripheral SpA (especially psoriatic arthritis)" expert recommendation.
However, AS meets the standard There are still many uncertainties in the realization of treatment.

What is "standard"? How to achieve standard treatment? How many benefits are there for the treatment of standards? How to maximize its benefits.
.
.
These problems lie on the road to AS standard treatment and need further research to confirm.

The emergence of targeted IL-17A treatment options has taken us one step further on the road to achieving standard treatment.

Why inhibiting IL-17A can pave the way for the realization of standard treatment? 1 High-quality symptoms control Many symptoms of AS, such as low back pain, morning stiffness, etc.
, are all related to inflammation.

IL-17A plays an important role in chronic inflammation and pain response.
Inhibition of IL-17A can achieve high-quality symptom control combining "fast, deep and wide", that is, rapid onset, long-lasting relief and wide range of action (medium Axis, peripheral joints, enthesitis, etc.
), suitable for different patient populations and to meet different clinical needs [24-27].

2Bone protection IL-17A not only causes inflammation, but also changes bone metabolism, and participates in the immune regulation process of systemic bone loss and local new bone formation.

Inhibition of IL-17A can effectively delay the progression of AS imaging, prevent structural damage, and protect the patient's structural function.
This is a goal that has not been achieved by previous treatment programs and is a huge advantage of IL-17A inhibitors in the treatment of AS [21, 28-31].

3 Good safety IL-17A is at the end of the cytokine network, and inhibiting IL-17A has little effect on the normal immune response [32].

IL-17A inhibitors did not increase the common risk of infection during the use of other biological agents, such as increased susceptibility to tuberculosis or reactivation of hepatitis B.

In the long-term application process, the risk of major adverse events is similar to the overall AS population [33].

Therefore, based on the 2.
0 era, the treatment plan targeting IL-17A further realizes the upgrade of treatment, provides more comprehensive disease treatment and management for AS patients, and helps achieve standard treatment.

This is a beautiful blueprint drawn for us in the AS Therapy 3.
0 era.

4 Summary People have gone through a long process of evolution in the development of cognition and treatment of AS disease.

From the era of traditional medicine treatment to the era of biological preparations, AS treatment has made milestone progress and innovations, and entering the IL era is a breakthrough in the comprehensive upgrade of AS treatment, which has brought impact to AS treatment concepts and treatment methods.
The changes will help realize the overall management of the disease. Regarding the research on the mechanism of IL-17A in the multiple pathological processes of AS, we will elaborate in the follow-up series of articles, so stay tuned~ Professor Huang Anbin AS is an ancient disease.
With the continuous improvement of research and understanding, The nature and treatment of AS have also made continuous progress.

AS occurs mostly in young people, especially men, so it has a great impact on labor loss, physical pain and patients’ lives.
People have always been looking for better ways to solve patients’ pain and improve labor productivity.
This is a health problem.
It is also a social issue.

In the past 20 years, through the joint efforts of scientists and rheumatic immunology experts, a series of progress has been made in finding the cause, pathogenesis and treatment methods.
From the New York diagnostic standard in 1984 to the current ASAS standard, The diagnosis has also carried out a specific and standardized expert consensus.

The treatment has also undergone several eras of changes, from traditional anti-inflammatory drug treatment, to TNFi inhibitory treatment, and then to the current treatment of IL-related factor inhibitors, each treatment plan has brought a revolutionary change.

Traditional NSAIDs are only effective for some people in treatment, and can only improve symptoms, and it is difficult to delay the progress of imaging.
After continuous hard research, in the era of TNFi, patients' symptoms can be partially resolved, so that patients can get clinical symptom relief, and even partially Delaying the progress of imaging can both relieve the patient’s pain and restore part of the patient’s functions.
After the advent of IL-17 inhibitors, it has taken another milestone in achieving standard treatment, while controlling inflammation and relieving clinical symptoms.
, It can also delay the progress of imaging, and can improve the situation of most patients with limited activities.
The patient's experience is not only less pain, but also functional activities are also improved, which improves the self-care ability and work ability of life.

Of course, there are still many contradictory issues that need to be further studied.
For example, what about the side effects of drugs? There are also restrictions on treatment of different groups of people.
For example, patients with hepatitis B, tuberculosis, and tumors may benefit from limited benefits due to the side effects of traditional TNFi and traditional drug treatments.
In particular, the therapeutic effect of TNFi can reach anti-inflammatory standards, but Can induce infection, so its benefits are limited. The introduction of IL-17A inhibitors is superior to TNFi in terms of mechanism, and its side effects are relatively much lower than TNFi.
It is very promising in the next clinical treatment, and it can be said to be very promising.
A treatment method, of course, drug research requires a lot of manpower, material resources and financial resources.
The advent of a new drug requires time and clinical observation to complete it.
Even after it is marketed, it also needs to continue clinical experiment observation to complete it.

Because drug research invests a lot of research funds, a bottleneck was encountered when the drug came out, that is, the drug was more expensive, and the patient's accessibility was also limited to a certain extent, and as the benefit of the drug became greater and greater There may be more and more users, and the corresponding treatment costs will gradually decrease.
What is particularly gratifying is that the national level also recognizes the problem of patient accessibility, so the gradual price reduction of drugs is also included in the scope of medical insurance.
Benefits are more, and its accessibility is also improved.

As the benefits of this new method and new method are getting bigger and bigger, and the price is getting lower and lower, the health status of the entire AS group will gradually improve, and clinicians will become more and more confident.

[27] Mease PJ, et al.
Ann Rheum Dis, volume 79, supplement 1, year 2020, page 430.
[28] Ebihara S, et al.
Autoimmunity.
2015, 48: 259-266.
[29] Ellen M Gravallese , et al.
Nat Rev Rheumatol.
2018 Nov;14(11): 631-640.
[30] Braun J, et al.
Ann Rheum Dis.
2017 Jun;76(6):1070-1077.
[31] Braun J , et al.
Rheumatology (Oxford).
2019;58(5):859-868.
[32] Patel DD, et al.
Ann Rheum Dis.
2013;72 (Suppl 2), ii116-23.
[33] Blair HA , et al.
Drugs, 2016, 76(10):1023-1030.
Looking back on the journey of "treasure" discovery: IL-17A's quest for the secrets of the "three-headed and six-armed" IL-17A, how to use its diverse biology Features? Explore the key role of IL-17A in ankylosing spondylitis.
Why can it be a key target for treatment? Looking back at the story of monoclonal antibodies, and seeing how to continue to write the legend, how to know horsepower, and to explore the truth about the secondary failure of biological preparations, do biological preparations need to use loading doses? The clinical evidence has the final say! Taking the "unusual" road, IL-17A inhibitors have overcome obstacles and pursue excellence all the way! [30] Braun J, et al.
Ann Rheum Dis.
2017 Jun;76(6):1070-1077.
[31] Braun J, et al.
Rheumatology (Oxford).
2019;58(5):859-868.
[32] Patel DD, et al.
Ann Rheum Dis.
2013;72 (Suppl 2), ii116-23.
[33] Blair HA, et al.
Drugs, 2016, 76(10):1023-1030.
Previous review Embark on a journey of "treasure" discovery: IL-17A Quest, how does IL-17A, "three-headed and six-armed", exert its diverse biological functions? Explore the key role of IL-17A in ankylosing spondylitis.
Why can it be a key target for treatment? Looking back at the story of monoclonal antibodies, and seeing how to continue to write the legend, how to know horsepower, and to explore the truth about the secondary failure of biological preparations, do biological preparations need to use loading doses? The clinical evidence has the final say! Taking the "unusual" road, IL-17A inhibitors have overcome obstacles and pursue excellence all the way! [30] Braun J, et al.
Ann Rheum Dis.
2017 Jun;76(6):1070-1077.
[31] Braun J, et al.
Rheumatology (Oxford).
2019;58(5):859-868.
[32] Patel DD, et al.
Ann Rheum Dis.
2013;72 (Suppl 2), ii116-23.
[33] Blair HA, et al.
Drugs, 2016, 76(10):1023-1030.
Previous review Embark on a journey of "treasure" discovery: IL-17A Quest, how does IL-17A, "three-headed and six-armed", exert its diverse biological functions? Explore the key role of IL-17A in ankylosing spondylitis.
Why can it be a key target for treatment? Looking back at the story of monoclonal antibodies, and seeing how to continue to write the legend, how to know horsepower, and to explore the truth about the secondary failure of biological preparations, do biological preparations need to use loading doses? The clinical evidence has the final say! Taking the "unusual" road, IL-17A inhibitors have overcome obstacles and pursue excellence all the way!