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*It is only for medical professionals to read for reference.
How far is rheumatoid arthritis from being cured? This review will give you a lot of inspiration! Cure is the ideal goal for the treatment of all diseases.
However, even in the 21st century, curing rheumatoid arthritis (RA) is still almost impossible to achieve, and it is not easy to achieve "relief".
Recently, a review published in Nature reviews Rheumatology explored the obstacles to achieving a cure for RA.
01 Is it cured if there is no symptom? The treatment of acute diseases is usually aimed at curing.
By definition, in degenerative or inflammatory chronic diseases, cure is rare, and remission is usually a more realistic treatment goal.
Although molecular medicine has made considerable progress, it is generally believed that a cure for this type of disease is still far away.
There is a big difference between cure and remission (Table 1).
Although both mean the disappearance of symptoms, there is still an active underlying disease process in remission, but it does not exist in cure.
Compared with cure, remission usually requires continued treatment, regular follow-up, and risk of recurrence, especially if treatment is interrupted or stopped.
The absence of symptoms cannot be used to distinguish relief from cure.
Table 1 The difference between cure and remission Remission has only been used as a recommended treatment goal in the past 20 years.
The pathogenesis and exact etiology of RA and other rheumatic immune diseases have not been clarified; if the underlying mechanism of RA is not understood, it cannot be cured as a whole.
In clinical practice, rheumatic immunologists usually define RA relief as no joint tenderness or swelling, with special emphasis on no joint swelling.
Composite indicators such as 28 joint disease activity scores (DAS-28, remission is defined as score <2.
6), simplified disease activity index (SDAI, remission is defined as score <3.
3), and clinical disease activity index (CDAI, remission is defined as score <2.
8) ), and the remission criteria of the American College of Rheumatology/European Alliance Against Rheumatism (ACR/EULAR) are widely used.
These indicators are basically the same, and all require no tenderness and swelling of the joints.
Therefore, the relief of RA is achieved on the basis of adequate control of synovitis.
If the cytokine is used to block the treatment correctly, 50% of RA patients can achieve remission.
Although reaching remission is undoubtedly an important milestone in the treatment of RA, it is not the same as a cure, because the remission period usually depends on the continued use of anti-RA therapy.
Relief often means effectively suppressing inflammation, rather than truly eradicating the disease.
After stopping treatment, the recurrence rate of RA is about 40% to 80%, indicating that the underlying pathophysiological process remains active.
Sustained drug-free remission (>12 months) is closer to "cure" RA, but in most early RA patients, sustained drug-free remission is quite rare, accounting for about 9% to 15% of all patients.
02To cure RA, these three problems must be solved.
If you want to cure RA, you first need to control its underlying pathophysiological driving factors.
At present, it is believed that there are three main factors that will affect the transition of RA from remission to cure: adaptive immune related driving factors, intrinsic synovial tissue related driving factors and remote driving factors.
1 The activation of the adaptive immune system may help to achieve the cure of RA.
Clinical observations have shown that extensive autoimmunity not only promotes the onset of RA, but also reduces the possibility of continued drug-free remission.
This indicates that the potential adaptive immune system dysfunction that promotes autoimmunity may be a driving factor of RA, and the failure to restore immune tolerance may hinder the realization of cure.
Therefore, activation of the adaptive immune system may help to achieve a cure for RA.
The most obvious mechanism by which the adaptive immune system affects treatment is the regulation of antigen exposure: for example, modified proteins expressed on the surface of the lung and gingival mucosa will increase due to smoking and other environmental or microbial stimuli.
Quitting smoking can reduce the risk of RA and improve the patient's response to treatment.
Therefore, smoking cessation is a feasible way to make RA remission closer to cure.
It is worth noting that in a post-mortem analysis of a clinical trial of abatacept for treatment of early RA patients, a small number of participants were negative for autoantibodies after treatment with abatacept.
The intervention of abatacept in patients with early RA can induce continuous drug-free remission in some patients, indicating that early intervention of RA adaptive immune response may be a strategy to achieve a cure.
In addition, removing B cells can not only inhibit RA, but also prevent the formation of autoantibodies and delay the occurrence of diseases.
The strategy of inhibiting B cell activation may become an effective means of RA treatment in the future.
2 Synovial tissue causes immune cells in RA patients to enter the joints? Although autoimmunity is an important factor in determining whether RA can be cured, it may not work alone.
The changes in synovial tissue may precede the entry of immune cells into the joints, and may even be the cause of the entry of immune cells into the joints in RA patients.
Therefore, the synovial tissue factor has also become a potential driving factor of RA.
Macrophages can cause changes in the barrier function of the synovial membrane.
In recent years, there have been major discoveries about the molecular structure, regulation and pro-inflammatory function of synovium.
We now know that the surface of the synovium is covered with a layer of macrophages, which provide a physical barrier (and immune infiltration barrier) between the synovium and the joint space to ensure cell-free synovial fluid.
The occurrence of RA needs to destroy this barrier, and the continuous leakage of the barrier greatly promotes the recurrence of chronic arthritis.
The most important thing is the changes in fibroblast-like synovial cells (FLSs) during the course of RA.
Research data shows that FLSs can act as a driving factor for RA and hinder the realization of cure.
Studies have shown that FLSs undergo time-dependent epigenetic changes during the course of RA.
Drugs that regulate methylation and acetylase are being developed for cancer treatment.
If it is proven in RA that these synovial tissue changes can be safely reversed, it may make RA one step closer to cure.
3 "Remote" factors Other factors besides joints may also cause RA treatment failure.
For example, smoking is a non-joint-related factor that prevents the cure of RA.
The microbial composition of the gastrointestinal tract in patients with early RA has also changed, and this change may even occur in the preclinical stage of the disease.
The metabolites of these microbiota can control the permeability of the gastrointestinal tract and the migration of immune cells from the intestine to the joints.
Therefore, intestinal leakage may be a further driving factor for the influx of immune cells into the joints and promote disease recurrence.
Changes in the central nervous system may also affect the treatment of RA.
Some patients with RA have an allergic reaction to pain during the course of the disease, which may involve changes in the central nervous system.
Psychosocial stress is also a known cause of RA, but the relationship between stress and RA is unclear.
03 Multiple approaches to treat RA Targeting the above-mentioned risk factors of RA, some corresponding treatment strategies can be derived.
In the early stages of RA, it may be easiest to control immune disorders.
Similarly, for type 1 diabetes, the application of anti-CD3 antibodies and other therapies in the pre-diabetes stage can delay the disease for at least a few years, and may even play a preventive effect.
There have been similar early intercept studies for Abatacept.
The restoration of the intra-articular barrier may also be crucial to prevent the recurrence of RA.
Studies have found that in patients with RA in remission, if the proportion of macrophages in the joints expressing markers of endometrial macrophages is lower, the risk of disease outbreaks increases.
Macrophage-mediated recovery of joint barrier function may require a complete joint anatomy, which indicates that early treatment has an important role.
Solving remote factors does not seem so difficult, which may become an important part of RA management.
For example, a diet rich in dietary fiber can change the composition of the gut microbiota, increase the production of immunomodulatory short-chain fatty acids, reduce gastrointestinal permeability, and may alleviate the symptoms of RA.
Although remission is an important treatment goal, its disadvantage is that it is likely to require life-long treatment.
Adequate treatment of early RA, or even for individuals at risk of developing RA, may be the easiest way to achieve cure.
04 Conclusion RA treatment should be based on rapid control of symptoms and signs.
Only by actively using anti-inflammatory therapy for patients with diagnosed RA, it is unlikely to be cured.
Moving from remission to cure will be the next great challenge for RA treatment.
Different from inflammatory factors, treatment measures for the deep driving factors of RA are likely to become the core means to achieve cure.
Eliminating the disease rather than suppressing symptoms may become the main goal of RA treatment in the future.
Reference: [1]Schett, G.
et al.
Why remission is not enough: underlying disease mechanisms in RA that prevent cure.
Nature reviews | Rheumatology.
doi:10.
1038/s41584-020-00543-5.
How far is rheumatoid arthritis from being cured? This review will give you a lot of inspiration! Cure is the ideal goal for the treatment of all diseases.
However, even in the 21st century, curing rheumatoid arthritis (RA) is still almost impossible to achieve, and it is not easy to achieve "relief".
Recently, a review published in Nature reviews Rheumatology explored the obstacles to achieving a cure for RA.
01 Is it cured if there is no symptom? The treatment of acute diseases is usually aimed at curing.
By definition, in degenerative or inflammatory chronic diseases, cure is rare, and remission is usually a more realistic treatment goal.
Although molecular medicine has made considerable progress, it is generally believed that a cure for this type of disease is still far away.
There is a big difference between cure and remission (Table 1).
Although both mean the disappearance of symptoms, there is still an active underlying disease process in remission, but it does not exist in cure.
Compared with cure, remission usually requires continued treatment, regular follow-up, and risk of recurrence, especially if treatment is interrupted or stopped.
The absence of symptoms cannot be used to distinguish relief from cure.
Table 1 The difference between cure and remission Remission has only been used as a recommended treatment goal in the past 20 years.
The pathogenesis and exact etiology of RA and other rheumatic immune diseases have not been clarified; if the underlying mechanism of RA is not understood, it cannot be cured as a whole.
In clinical practice, rheumatic immunologists usually define RA relief as no joint tenderness or swelling, with special emphasis on no joint swelling.
Composite indicators such as 28 joint disease activity scores (DAS-28, remission is defined as score <2.
6), simplified disease activity index (SDAI, remission is defined as score <3.
3), and clinical disease activity index (CDAI, remission is defined as score <2.
8) ), and the remission criteria of the American College of Rheumatology/European Alliance Against Rheumatism (ACR/EULAR) are widely used.
These indicators are basically the same, and all require no tenderness and swelling of the joints.
Therefore, the relief of RA is achieved on the basis of adequate control of synovitis.
If the cytokine is used to block the treatment correctly, 50% of RA patients can achieve remission.
Although reaching remission is undoubtedly an important milestone in the treatment of RA, it is not the same as a cure, because the remission period usually depends on the continued use of anti-RA therapy.
Relief often means effectively suppressing inflammation, rather than truly eradicating the disease.
After stopping treatment, the recurrence rate of RA is about 40% to 80%, indicating that the underlying pathophysiological process remains active.
Sustained drug-free remission (>12 months) is closer to "cure" RA, but in most early RA patients, sustained drug-free remission is quite rare, accounting for about 9% to 15% of all patients.
02To cure RA, these three problems must be solved.
If you want to cure RA, you first need to control its underlying pathophysiological driving factors.
At present, it is believed that there are three main factors that will affect the transition of RA from remission to cure: adaptive immune related driving factors, intrinsic synovial tissue related driving factors and remote driving factors.
1 The activation of the adaptive immune system may help to achieve the cure of RA.
Clinical observations have shown that extensive autoimmunity not only promotes the onset of RA, but also reduces the possibility of continued drug-free remission.
This indicates that the potential adaptive immune system dysfunction that promotes autoimmunity may be a driving factor of RA, and the failure to restore immune tolerance may hinder the realization of cure.
Therefore, activation of the adaptive immune system may help to achieve a cure for RA.
The most obvious mechanism by which the adaptive immune system affects treatment is the regulation of antigen exposure: for example, modified proteins expressed on the surface of the lung and gingival mucosa will increase due to smoking and other environmental or microbial stimuli.
Quitting smoking can reduce the risk of RA and improve the patient's response to treatment.
Therefore, smoking cessation is a feasible way to make RA remission closer to cure.
It is worth noting that in a post-mortem analysis of a clinical trial of abatacept for treatment of early RA patients, a small number of participants were negative for autoantibodies after treatment with abatacept.
The intervention of abatacept in patients with early RA can induce continuous drug-free remission in some patients, indicating that early intervention of RA adaptive immune response may be a strategy to achieve a cure.
In addition, removing B cells can not only inhibit RA, but also prevent the formation of autoantibodies and delay the occurrence of diseases.
The strategy of inhibiting B cell activation may become an effective means of RA treatment in the future.
2 Synovial tissue causes immune cells in RA patients to enter the joints? Although autoimmunity is an important factor in determining whether RA can be cured, it may not work alone.
The changes in synovial tissue may precede the entry of immune cells into the joints, and may even be the cause of the entry of immune cells into the joints in RA patients.
Therefore, the synovial tissue factor has also become a potential driving factor of RA.
Macrophages can cause changes in the barrier function of the synovial membrane.
In recent years, there have been major discoveries about the molecular structure, regulation and pro-inflammatory function of synovium.
We now know that the surface of the synovium is covered with a layer of macrophages, which provide a physical barrier (and immune infiltration barrier) between the synovium and the joint space to ensure cell-free synovial fluid.
The occurrence of RA needs to destroy this barrier, and the continuous leakage of the barrier greatly promotes the recurrence of chronic arthritis.
The most important thing is the changes in fibroblast-like synovial cells (FLSs) during the course of RA.
Research data shows that FLSs can act as a driving factor for RA and hinder the realization of cure.
Studies have shown that FLSs undergo time-dependent epigenetic changes during the course of RA.
Drugs that regulate methylation and acetylase are being developed for cancer treatment.
If it is proven in RA that these synovial tissue changes can be safely reversed, it may make RA one step closer to cure.
3 "Remote" factors Other factors besides joints may also cause RA treatment failure.
For example, smoking is a non-joint-related factor that prevents the cure of RA.
The microbial composition of the gastrointestinal tract in patients with early RA has also changed, and this change may even occur in the preclinical stage of the disease.
The metabolites of these microbiota can control the permeability of the gastrointestinal tract and the migration of immune cells from the intestine to the joints.
Therefore, intestinal leakage may be a further driving factor for the influx of immune cells into the joints and promote disease recurrence.
Changes in the central nervous system may also affect the treatment of RA.
Some patients with RA have an allergic reaction to pain during the course of the disease, which may involve changes in the central nervous system.
Psychosocial stress is also a known cause of RA, but the relationship between stress and RA is unclear.
03 Multiple approaches to treat RA Targeting the above-mentioned risk factors of RA, some corresponding treatment strategies can be derived.
In the early stages of RA, it may be easiest to control immune disorders.
Similarly, for type 1 diabetes, the application of anti-CD3 antibodies and other therapies in the pre-diabetes stage can delay the disease for at least a few years, and may even play a preventive effect.
There have been similar early intercept studies for Abatacept.
The restoration of the intra-articular barrier may also be crucial to prevent the recurrence of RA.
Studies have found that in patients with RA in remission, if the proportion of macrophages in the joints expressing markers of endometrial macrophages is lower, the risk of disease outbreaks increases.
Macrophage-mediated recovery of joint barrier function may require a complete joint anatomy, which indicates that early treatment has an important role.
Solving remote factors does not seem so difficult, which may become an important part of RA management.
For example, a diet rich in dietary fiber can change the composition of the gut microbiota, increase the production of immunomodulatory short-chain fatty acids, reduce gastrointestinal permeability, and may alleviate the symptoms of RA.
Although remission is an important treatment goal, its disadvantage is that it is likely to require life-long treatment.
Adequate treatment of early RA, or even for individuals at risk of developing RA, may be the easiest way to achieve cure.
04 Conclusion RA treatment should be based on rapid control of symptoms and signs.
Only by actively using anti-inflammatory therapy for patients with diagnosed RA, it is unlikely to be cured.
Moving from remission to cure will be the next great challenge for RA treatment.
Different from inflammatory factors, treatment measures for the deep driving factors of RA are likely to become the core means to achieve cure.
Eliminating the disease rather than suppressing symptoms may become the main goal of RA treatment in the future.
Reference: [1]Schett, G.
et al.
Why remission is not enough: underlying disease mechanisms in RA that prevent cure.
Nature reviews | Rheumatology.
doi:10.
1038/s41584-020-00543-5.
