In the age of AS biologics, how can we get rid of tuberculosis?

*Only for medical professionals to read for reference to prevent tuberculosis, the choice of biological agents is very particular about ankylosing spondylitis (AS) is an autoimmune disease, and immune system disorders are the main mechanism of its pathogenesis.

The emergence of biological agents has led AS treatment into the era of biological agents, bringing innovation and upgrading of treatment options.

 At the same time, the safety of biological agents is also widely controversial, especially the increased risk of tuberculosis (TB) infection.

Although the history of human struggle against TB has been tens of thousands of years, until today, we still have not been able to completely control it.

What the hell does this happen? In the age of AS biologics, how should we deal with the potential risk of TB infection? In this issue, we invite Professor Zhang Xiao from Guangdong Provincial People's Hospital to comment and share relevant experiences for us.

 1 Biological agents are the "double-edged sword" in the treatment of AS? Because most of the patients have pale faces, TB was once vividly called the "white plague": it is not only highly infectious and can invade various organs throughout the body, it is also good at long-term incubation and has strong resistance to extreme environments.

TB is caused by Mycobacterium tuberculosis (Mtb).

In most cases, the bacterium always invades the human lungs, which can easily cause tuberculosis.

However, not every infected person will develop the disease.
Only about 5%-10% of infected people will develop active TB.
Most of the remaining infected people can use the human immune response to isolate Mtb from granuloma (a type of immune cell aggregation).
It can effectively control its further growth and become a latent tuberculosis infection (LTBI).

The LTBI population is a huge potential "patient pool".
When their immune function is impaired, Mtb may be reactivated and replicated to develop into active TB.

Therefore, the occurrence of TB is closely related to the immune status of the body [1-3].

Figure 1: The course of the disease after human infection with Mtb [3] The biological agents for the treatment of AS are mainly cytokine targeted agents, including tumor necrosis factor-α (TNF-α) inhibitors and interleukin-17A (IL-17A) inhibition Agent.

These cytokines may play an important role in the body's immune defense against Mtb, and inhibiting it can increase the risk of TB infection.

Relevant literature has pointed out that the use of biological agents, especially those that block innate immunity and adaptive immune-related factors, will increase the risk of opportunistic infections in patients [4].

Therefore, biological agents are a "double-edged sword" in the treatment of AS, which not only bring significant curative effects, but also have certain safety risks.

2TNF-α inhibitor, a helper to help the "true murderer" escape? TNF-α is an important pro-inflammatory factor and immunoregulatory factor, which plays a key role in the body's immune mechanism against Mtb.

It can not only activate macrophages and improve their phagocytic ability of Mtb; it can also cooperate with interferon-γ (IFN-γ) to promote the formation and maturation of phagolysosomes, stimulate the production of reactive nitrogen mediators, control and kill Mtb: The apoptosis of macrophages that phagocytize Mtb is another important way for the host to clear Mtb.
TNF-α participates in the apoptosis process induced by Mtb infection and can promote the apoptosis of phagocytes.

In addition, TNF-α also contributes to the formation and maintenance of peripheral granulomas after Mtb infection, and can block its dissemination [5-9].

Therefore, in theory, anti-TNF-α therapy may lead to reactivation of latent Mtb in the body and increase the risk of TB.

Figure 2: The role of TNF-α in anti-Mtb infection.
A large number of studies have shown that the application of TNF-α inhibitor treatment increases the risk of TB in patients [10], for example: During the period from 1998 to 2002, the US Food and Drug Administration Data from the Adverse Event Reporting System of the Agency (FDA) showed that the incidence of TB in patients treated with TNF-α inhibitors such as infliximab and etanercept (54 cases per 100,000 patients and 28 cases per 100,000 patients, respectively) ) Is significantly higher than the incidence of TB in the overall population (5.
8 cases per 100,000 patients) [11]; a prospective study in France found that the use of TNF-α inhibitors such as infliximab, adalimumab and etanercept The ratios of standardized TB incidence of general treatment patients to the general population were 18.
6 (95% CI, 13.
4-25.
8), 29.
3 (95% CI, 20.
3-42.
4), and 1.
8 (95% CI, 0.
7-4.
3) (Table 1 ) [12].

Table 1 The relative risk of tuberculosis under the treatment of different TNF-α inhibitors [10] JIA: juvenile idiopathic arthritis; RA: rheumatoid arthritis; Ps: plaque psoriasis; PsA: psoriatic arthritis ; Crohn's: Crohn's disease; UC: ulcerative colitis 3IL-17A inhibitor or a more safe choice.
In addition to TNF-α inhibitors, biological agents that can be used for AS treatment include interleukin-17A (IL -17A) Inhibitors.

How does the use of this type of biologics affect the risk of TB occurrence or reactivation in patients? First, let's take a look at the possible role of IL-17 in Mtb infection.

Compared with upstream targets, IL-17 located downstream has a dual role in Mtb infection: in the early stage of immunity, IL-17 induces the production of a series of chemokines, which mediate the recruitment of immune cells at the site of inflammation, and in granulomas.
It plays an important role in the formation and initiates early immune protection [13]; after repeated stimulation of Mtb antigen, over-expression of IL-17 will cause the release of a large number of inflammatory cytokines and excessive recruitment of neutrophils, thereby triggering excessive Immune defense, the immune protection of IL-17 is then transformed into immune damage, leading to tissue damage and necrosis in granulomas, and pathological reactions in the lungs [13-15]. Figure 3: IL-17 and Th17 cells play a role in the process of Mtb infection [14] A.
Early stage of infection; B.
Recruitment of protective cells to form mononuclear granulomas; C.
When IL-23 and IL-6 are highly expressed A large number of IL-17-producing cells accumulate, resulting in immunopathological consequences.
Some researchers have used Mtb to infect peripheral blood mononuclear cells (PBMCs) to form a human granuloma model, and more directly studied TNF-α inhibitors in vitro.
(Adalimumab) and IL-17A inhibitor (Scukuzumab) on Mtb during resting period.

The results of the study showed that a large number of Mtb in the TNF-α inhibitor group turned from the dormant phase to the active phase, while the Mtb in the IL-17A inhibitor group was still in the dormant phase (Figure 4), and its use would not activate the dormant Mtb[16] .

Figure 4: In vitro studies have shown that the use of IL-17A inhibitor skukuzumab will not activate Mtb during resting period.
In addition, animal studies have also shown that IL-17A inhibitors and TNF-α inhibitors have different immune effects on Mtb.
.

Using a mouse model, the researchers proved that the IL-17 pathway is not the core pathway for the host to control the infection of the Mtb H37Rv strain.

Compared with TNF-α inhibitors, the use of IL-17A inhibitors neither impairs the host’s early immune protection, nor does it significantly change the expression of immune regulatory genes related to the host’s defense of pathogens, which can cause Mtb infection or reactivation The risk is low [17].

Clinical studies and real-world data show that IL-17A inhibitors are well tolerated, and the application of scocyumab does not increase the risk of patients with active TB and LTBI reactivation: a pooled analysis of 5 scocyumab treatments A 1-year phase III clinical study of patients with severe psoriasis (PsO) (a total of 2044 cases were included, of which 132 were patients with a previous history of LTBI or TB/LTBI).

Studies have shown that during the one-year period of Skucilumab treatment, all patients with a previous history of LTBI or TB/LTBI did not experience recurrence of TB infection.

In addition, the combination of anti-TB drugs and Skuchiyudan did not increase serious liver adverse events and was well tolerated by patients [16]; Figure 5: Safety data collected from 5 phase III studies Figure 6: Skuchiyudan During the anti-treatment period, patients with a previous history of TB did not have TB infection events.
In the classic series of studies (MEASURE1-4) of the application of Tecchiumab to AS treatment, a total of 1136 patients were included, and no TB infection occurred during the treatment period.
Sensitivity increase report [18-19]; A report in the 2020 American Academy of Dermatology (AAD) Annual Meeting (AAD) analyzed the clinical safety data of 28 studies using cucciyuumab in PsO, PsA, and AS The effect of scochiumab on the reactivation of TB [20].

The study found that among the 12,319 patients who received scocilizumab treatment, there were no reports of active TB adverse events during the treatment period, indicating that scocilizumab did not increase the risk of active TB, nor did it increase the risk of LTBI reactivation.

Therefore, the combination of in vitro studies, animal models and clinical data proves that compared with TNF-α inhibitors, the IL-17A inhibitor Recchiyuumab has a lower risk of TB infection events, and is the safety of AS biologics.
Higher treatment options.

Summary: Biological treatment may lead to the occurrence of TB infection events, and the effects of different cytokines on Mtb are different.

Compared with TNF-α, targeting IL-17 may have a relatively small impact on the risk of TB.

When AS patients (especially LTBI patients) are considering the use of biological treatments, in order to minimize the risk of TB, TB screening should be carried out before treatment (LTBI and active TB patients should complete the corresponding anti-TB treatment), and also during treatment Priority should be given to biologics with lower risks, such as the IL-17A inhibitor Skucilumab.

Note: Recucci Yumab ​​is not suitable for patients with active TB.
Professor Zhang Xiao’s emergence of biological agents has brought innovation and upgrades in treatment options.
At the same time, the safety of biological agents is also widely controversial, especially TNF- The problem of the risk of tuberculosis (TB) infection caused by alpha inhibitors. As we all know, TNF-α is an important pro-inflammatory factor and immunomodulatory factor, which plays a key role in the body's immune mechanism against Mtb.
On the other hand, TNF-α contributes to the formation and maintenance of peripheral granulomas after Mtb infection.
Blocking its dissemination; it can be seen that TNF-a inhibitors are a "double-edged sword" in the treatment of AS, which not only bring significant effects, but also have certain safety risks.

IL-17A inhibitors and TNF-α inhibitors have significant differences in the immune effects of Mtb.
Animal and clinical studies have proved that the IL-17 pathway is not the core pathway for the host to control the infection of the Mtb H37Rv strain; compared with TNF-α inhibitors, The use of IL-17A inhibitors neither impairs the host's early immune protection, nor does it significantly change the expression of immunoregulatory genes related to the host's defense of pathogens, and its risk of causing Mtb infection or reactivation is relatively low.

   Therefore, when considering the use of biologics for the treatment of AS, especially for LTBI and patients with high risk of TB, the lower-risk biologics (IL-17A inhibitor scocilizumab) should be preferred.

Expert profile Professor Zhang Xiao, administrative director of the Department of Rheumatology, Guangdong Provincial People's Hospital, subject leader, visiting professor and part-time doctoral tutor of Macau University of Science and Technology, professor and postgraduate tutor of Southern Medical University/South China University of Technology, chairman of the Rheumatology Branch of Guangdong Medical Association, Chinese Physician Association Vice President of the Rheumatology Professional Committee, Vice President of the China Rheumatology Medical Association, Director of the Guangdong-Hong Kong-Macao Greater Bay Area Rheumatology Specialist Association Director of the Eighth Standing Committee of the Chinese Medical Association Rheumatology Association, Deputy Director of the Rheumatology Professional Committee of the Guangdong Medical Association Member of the editorial board of "Chinese Journal of Rheumatology", "Chinese Journal of Clinical Immunity and Allergy" and "Journal of Evidence-Based Medicine", "Chinese Journal of Internal Medicine" and "Chinese Journal of Medicine" Correspondence Editor, Deputy Editor-in-Chief of the Chinese Edition of ARD Journal Guangdong Provincial Natural Science Foundation review experts participated in the completion and ongoing of more than 10 national, provincial and ministerial scientific research projects, presided over 2 national natural projects, obtained 3 provincial and municipal scientific research results, published nearly 100 papers, and included more than 10 SCI Reference: [1]O'Garra A, et al.
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This article does not represent the position of this platformDrugs.
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2019, 21:111.
[20]Boni E.
Elewski, et al.
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#15261.
This article does not represent the position of this platform