Immune-mediated treatment of inflammatory diseases: past, present and future

"It is the best age, the worst age, the age of wisdom.
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It is the incredible age, the season of light, the season of darkness, the spring of hope.
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------- ("The Story of Two Cities", Charles Dickens, 1859) Immune-mediated inflammatory disease (IMID) is a group of common and clinically diverse diseases, and there is no cure
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They have common potential pathogenesis characteristics, but there are also specific pathways that can define the characteristics of clinical phenotype, age and gender distribution, tissue location, and treatment response
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IMID includes rheumatoid arthritis (RA), spondyloarthritis (SpA), connective tissue diseases, skin inflammatory diseases (including psoriasis and atopic dermatitis), inflammatory bowel disease (IBD), asthma and autoimmunity Sexual neurological diseases such as multiple sclerosis
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Therefore, they constitute a major systemic medical challenge
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In addition, these diseases are usually accompanied by various comorbidities, including cardiovascular diseases, metabolic and skeletal diseases, and cognitive deficits, which further affect the quality of life and increase mortality
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In the past two decades, IMID's therapeutic drugs have undergone major changes, from broad-spectrum immunomodulators to specific preparations to the use of targeted drugs, which have also had a significant impact on the subsequent course of treatment
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Lessons from previous treatments Since the 1940s, glucocorticoids have been the main treatment drugs for various IMIDs
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Although glucocorticoids have multiple uses and good efficacy, studies have shown that treatment benefits decrease over time and have significant toxicity in bone, cardiovascular system, and metabolic functions
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Other major therapeutic drugs include methotrexate, azathioprine, sodium gold thiomalate (gold salt), sulfasalazine, hydroxychloroquine, D-penicillamine and mycophenolate Adverse events, the sequential use or combined use of these drugs must be very cautious
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Two important developments herald a major change in the disease landscape.
The first is the breakthrough application of cytokine blockade and anti-tumor necrosis factor (TNF) in the treatment of RA
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These applications have brought rapid progress in immuno-targeted therapeutic drugs, including biologics and small molecule therapeutic drugs, targeting a wide range of cytokines and their receptors, inflammatory cell trafficking and cell regulatory ligand receptors, and cell depletion strategies
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With the above changes, the second major advancement is the realization that strict control of inflammation is essential to the outcome of treatment
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Therefore, substantial strategic changes have taken place in the clinical methods of IMID management, with more emphasis on early diagnosis and intervention to achieve the goal of remission or low disease activity, while preventing target organ damage, which has a positive impact on the quality of life and longevity
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The importance of pathogenic mechanisms In the early stages of the development of IMIDs biopharmaceuticals, many lessons are worth learning
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Cell depletion methods, such as the use of monoclonal antibodies targeting T cells (CD3, CD4, or CDw52 specific [alenduzumab]), have shown promise in open-label studies, but in the design of controlled trials, they are compatible with transplantation and cancer.
Compared with field experience, these methods always fail
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This may be partly due to the non-exhaustion of related T cells in the inflammatory site (such as synovial tissue), the emergence of a dominant clonotype, as shown in the trial of alemtuzumab in the treatment of RA, or a subpopulation of protective regulatory T cells Exhausted
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These results prompted a re-evaluation of pathogenesis models, especially the advantages of adaptive immune mechanisms and discrete T cell subsets in the established stages of driving IMID
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At the same time, rethinking the trial design and paying attention to the development of new composite outcome indicators requires a fine evaluation of the clinical efficacy of IMID
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Since then, the view from early sepsis studies that the functional redundancy of cytokine biology will rule out the success of targeted immune interventions for specific cytokines has been completely refuted clinically
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The application of TNF and IL-1 inhibitors in RA and shortly thereafter in IBD can best prove this
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In the 1990s, TNF and IL-1 pathways had similar characteristics of perceived immune function (both cytokines are present in disease tissues, and it seems feasible to be targets in in vivo disease models), TNF inhibitors (instead of IL-1 inhibitor) has achieved important success in the clinical application of RA
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These results prove that although IL-1 is a functionally important cytokine in RA animal models, in human RA, its role in sustained inflammation is not as critical as TNF.
Targeting TNF alone is a highly effective Method
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When IL-1 inhibitors were successfully developed to treat single-gene autoinflammatory diseases such as Muckle–Wells syndrome and later inflammasome-driven diseases such as gout, the view that IL-1 was a disadvantaged therapeutic target lacking hierarchical advantages was later adopted.
Refute
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The core pathogenic role of IL-1 in the latter case is now fully understood
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Therefore, the highly evolved understanding of the pathogenesis of IMID is essential
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Figure 1.
Timeline of treatment strategies for immune-mediated inflammatory diseases.
TNF inhibitors have clarified the concept of public gene pathways in a series of clinical applications, including axial SpA, IBD, psoriasis and psoriatic arthritis (PsA)
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However, the importance of specific pathways is also recognized again
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For example, although inhibition of IL-6 receptor and IL-6 is successful in RA and vasculitis, this approach fails in psoriasis and axial SpA
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Inhibition of IL-17A is effective for psoriasis, PsA and axial SpA, but not for RA and IBD
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In fact, inhibiting IL-17A may lead to worsening of IBD disease, indicating the important function of IL-17A in the intestinal tract
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The importance of controlling inflammation and immune activation is the same as the experience of specifically targeting immune pathways in IMID.
It is recognized that when inflammation is fully controlled, the disease outcome is best
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Therefore, the field has turned to the early active use of targeted therapy to control inflammation
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This method can prevent irreversible tissue damage, such as RA inflammation and subsequent destruction of articular cartilage and bone
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Therefore, the current state-of-the-art IMID treatment requires a large proportion of patients to obtain high response and relief under acceptable side effects
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It is increasingly recognized that IMID should be defined based on its absolute immunological activity status rather than the level of disease activity relative to the previous point in time
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The final key lesson is the realization that if IMID is actively controlled early and achieve immunological remission, we can stop treatment in the short term
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But in most cases, the disease will recur
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Early use of biological agents is more effective than late-stage disease intervention
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The reason is not clear, but it can reflect a clinical state that is easier to deal with in the early stage of the disease, with less damage to the target organ, thus increasing the body's potential for recovery
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However, this clinical observation may indicate that the immunological pathogenesis of IMID is constantly evolving over time.
Therefore, we should explore similar models in IMID over time and use the resulting targets sequentially.
To treatment
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The current drugs for the treatment of IMID are currently commonly used biological agents to treat a wide range of IMID; the key targeted pathways and diseases are summarized as shown in the figure.
These drug targets include cytokines and their receptors or cell subgroups, with the purpose of changing transport and regulating cells Activation state or cell exhaustion, for example, based on the advantages of T cell subpopulations, type 1, type 2 and type 17 T cell related diseases have been successfully targeted for intervention
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Figure 2.
Key targets for the management of immune-mediated inflammatory diseases.
Another important development is the use of small molecule inhibitors as IMID therapeutics
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However, the human kinome has proven to be particularly attractive for discovering targets for small molecule therapeutic drugs
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A series of highly selective JAK inhibitors, especially JAK1, has attracted much attention due to its oral bioavailability
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However, such drugs require special consideration of cardiovascular system toxicity, host defense, and cancer risk.
Currently, some unexpected adverse events including thrombosis have been reported
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Early studies examined the role of TNF inhibitors in RA, and clarified the role of TNF in endothelial cell activation, leukocyte recruitment to target inflammatory tissue sites, promotion of acute phase response, and promotion of nociception and cognitive dysfunction
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These studies also help to examine the mechanism of action of TNF inhibitors and other drug classes in IBD
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The ineffectiveness of the TNF receptor-IgG1 fusion protein etanercept compared with monoclonal TNF inhibitors was observed in IBD, which may be based on the different effects on the depletion or apoptosis of mucosal lymphocyte subpopulations expressing membrane TNF
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Subsequently, extensive research on the mode of action of biological agents and JAK inhibitors has provided valuable insights into the pathogenesis of different diseases, and a perception hierarchy of immune pathways that drive different tissue damage has emerged
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Imaging, high-sensitivity molecular analysis of peripheral blood cell types, and tissue biopsy methods have clarified the basic biological immune pathways of IMIDs
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Another interesting observation relates to the discreteness and different responses of affected tissues, even in individual patients
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For example, in axial SpA, TNF inhibitors, IL-17A inhibitors, and IL-23 inhibitors can all produce responses in the skin, synovium, and tendon ends
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However, IL-17A and IL-23 inhibitors have a better response effect in the skin, and under normal circumstances, more than 50% of patients can achieve disease clearance
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TNF and IL-23 inhibitors appear to be more effective in managing gastrointestinal inflammation, while IL-17A inhibitors are ineffective
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TNF and IL-17A inhibitors (but not IL-23 inhibitors) can effectively reduce the inflammation of the axial skeleton
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These differences in response may be the result of unique cytokines that persist these different disease states
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However, there is another possibility that the targeted tissue itself is the dominant arbiter of disease pathogenesis.
Due to the interaction of inflammatory cells and tissue-specific matrix components, the target tissue may even define the main immune pathways that drive local diseases.
Fight against the common pre-genome, epigenome, microbiome and microenvironment
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The future prospects of IMID therapy There are still many unmet clinical needs in IMID, and it is currently impossible to restore immune disorders to a normal state
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Although biological agents can help relieve the condition and control inflammation, the pain still persists
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In the current study, some kinases targeting TYK2 and IRAK4 provide hope for future treatments
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Cell therapy drugs have also received extensive attention, such as the use of stem cells, modified regulatory T cells, chimeric antigen receptor T cells, and tolerant dendritic cells
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We recommend the following principles
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Figure 3.
Future methods of immune-mediated inflammatory disease treatment.
New targets.
More and more applications of tissue analysis have revealed the latest targets of IMID, especially psoriasis, atopic dermatitis, IBD and inflammatory slip.
Biopsy samples that are easily available in membrane diseases can not only be used to study the mechanism of action, but also are increasingly used to identify the molecular phenotype of the disease
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Combining with bioinformatics methods can reveal novel molecules or cell subpopulations as targets
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Single-cell RNA sequencing methods also raise the possibility of discovering rare but functionally important cell subgroups
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Single-cell analysis of tissue biopsy samples also allows us to focus on non-immune cells, especially cells in the interstitial tissue
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In recent studies, it has been determined that subpopulations of stromal cells can be separated according to different biomarkers and exhibit different functions in the context of tissue inflammation
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The next stage of the new strategy molecular revolution will be the application of (epi) genome, transcriptomics, proteomics and metabolomics methods
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These methods are being extensively tested for their ability to predict the natural history of disease in IMID patients, the best treatment options, and the characteristics of possible adverse events
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Through blood analysis, progress is being made especially in RA, psoriasis and IBD
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So far, we still lack critical verification of this molecular approach, but we are optimistic about its long-term success
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It will further involve the strategy of inducing remission and then maintaining it, which may come from identifying immune or matrix pathways related to the clinical remission status of IMID
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This method is considered to be the standard treatment in oncology, but it is not very accepted in IMID treatment
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Are we confident in developing immune-targeted drugs that are "effective" only in the context of mitigation/maintenance? A major challenge remains a reliable assessment of the immune status
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With the emergence of more and more electronic health records, the relevant combination of big data and large biological repositories will facilitate comparison in IMID
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For example, the IMID-Bio-UK metaconsortium, which includes data on diseases such as RA, PsA, psoriasis, systemic lupus erythematosus, Sjogren’s syndrome, primary biliary cholangitis, and autoimmune hepatitis, can be used to analyze these elements.
Consortium data query, and then discover or verify the determined path
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Tolerance induction and other new methods The "Holy Grail" in the field of IMID is still the restoration of immune homeostasis
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Many interesting methods are particularly focused on the expansion of regulatory T cell subsets (such as IL-2), the introduction of tolerant dendritic cells, and other methods
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Another emerging approach is to use chimeric antigen receptor T cells against B cells in autoantibody-producing diseases such as systemic lupus erythematosus
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Another opportunity lies in identifying the molecular pathways that support the occurrence of immune-related adverse events after the administration of cancer checkpoint inhibitors
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Finally, with increasing recognition of the upstream pathways driving IMID (for example, the role of the microbiome and smoking in RA pulmonary disease), there will be more opportunities for prevention methods
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The editor concludes that the pattern of IMID therapeutic drugs has changed, from the worst to the best, representing the success of modern molecular medicine applications driven by the increasingly integrated field of experimental medicine
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However, we have not yet reached remission in a sufficient number of IMID patients, and tissue repair remains an important issue
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The quality of life of many patients is still unsatisfactory, especially patients with complex rheumatic diseases and patients with nervous system IMID
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Despite the remarkable progress and many valuable lessons in the past two decades, perhaps we are still in the spring of hope when it comes to finding curative treatments
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References McInnes, IB, Gravallese, EM Immune-mediated inflammatory disease therapeutics: past, present and future.
Nat Rev Immunol 21, 680–686 (2021).
https://doi.
org/10.
1038/s41577-021-00603- 1