January 21, 2022

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Biological and clinical research progress of autoimmune diseases

Biological and clinical research progress of autoimmune diseases

Biological and clinical research progress of autoimmune diseases.  This article will share some information about Biological and clinical research on autoimmune diseases.


Psoriasis

Chronic plaque psoriasis (psoriasis vulgaris) is the most common form of psoriasis, common in erythema plaques anywhere on the body. Symptoms include itching, bleeding, and pain; in addition, the disease can also affect appearance and cause psychological stress.

Skin lesions are characterized by incomplete keratinization and thickening of the acanthocyte layer of keratinocytes (psoriatic hyperplasia), polymorphonuclear leukocytes and lymphocytes infiltrate the dermis (CD8+) and epidermis (CD4+).

Psoriatic arthritis (PsA) and Crohn’s disease (CD) often coexist in patients with psoriasis, and the most widely used tool for measuring disease activity is the Psoriasis Area and Severity Index (PASI) , It combines the assessment of severity and affected area into a score from 0 (no disease) to 72 (maximum).

The pathophysiology of psoriasis is very complex and depends to some extent on the genetic genes of the host. There is a strong link between streptococcal infection and psoriasis. HLA-C:06 is a well-characterized genetic risk factor. It may lead to autoreactive CD8+ T cells because it tends to be associated with epidermal keratin. Streptococcal protein fragments with extensive sequence homology. Other gene loci, including components of IL-23 and NF-κB signaling systems, account for about 28% of genetic factors.

The clinical efficacy of a variety of T cell targeted therapies supports the pathogenic effects of T cells, namely abatacept, alefacept and efalizumab. In addition, the FDA approved TNF-α inhibitors for the treatment of psoriasis. The discovery of Th17 cells and the subsequent discovery that IL-17-producing CD4+, CD8+, ILC and γδ T cells are prominent in psoriasis skin lesions. Recently, people have focused their research on the IL-23/17 axis.

In two key clinical trials using anti-IL-12/23 drugs, the PASI75 score of ustekinumab after 12 weeks of treatment accounted for 66.4–75.7%. A direct comparison through a head-to-head test showed that ustekinumab was superior to the TNF antagonist etanercept (56.8% reached PASI 75). Similarly, the efficacy and superiority of briakinumab are also superior to etanercept. Although children with genetic defects in the IL-12 pathway experience mycobacterial infection, in a comprehensive analysis of 5884 patients treated with ustekinumab, no major infections were observed. Because briakinumab has withdrawn from clinical studies, little is known about its safety. In addition, blocking IL-23 with risankizumab, guselkumab, and tildrakizumab also has clinical benefits and advantages in the inhibition of TNF in patients with psoriasis.

The main effector cytokines downstream of IL-23 include IL-17, IL-22 and GM-CSF. Serum IL-17 and IL-22 levels in patients with psoriasis are elevated, and etanercept treatment can reduce these two cytokines. However, only IL-17 levels are associated with PASI scores. Namilumab is a GM-CSF antibody and has no clinical effect on psoriasis. Two IL-17A selective antibodies, secukinumab and ixekizumab, have similar efficacy to anti-IL-23 monoclonal antibodies and are superior to ustekinumab and etanercept. Brodalumab and bimekizumab target IL-17RA and IL-17A/F, respectively, which also proved their clinical efficacy. Recent head-to-head studies of guselkumab and secukinumab indicate that IL-17 inhibition may not be as effective as IL-23 blockade. To date, IL-17 blockers have shown good safety in psoriasis, although a small increase in the frequency of Candida infections (1.7–4.0%) has been observed.

Biological and clinical research progress of autoimmune diseases


Inflammatory bowel disease

Crohn’s disease and ulcerative colitis (UC) are the two main forms of IBD. This disease is caused by the dysregulation of the inflammatory response of genetically susceptible hosts to intestinal microbes. The mucosal barrier function, autophagy pathway and Th17 biological function of these hosts are impaired. The two diseases differ in anatomical location, histology, risk factors and comorbidities. So far, effective therapies approved by the FDA include TNF-α antagonists, vedolizumab and natalizumab, and JAK inhibitor tofacitinib, which have been approved for UC.

Ustekinumab is approved by the FDA for the treatment of CD and UC. The efficacy of IL-23 targeting drugs brazikumab and risankizumab has also been reported in phase 2 clinical trials. Although IL-12/23 and IL-17-targeted mAbs show consistent efficacy in psoriasis, they have different performance in CD. Neither secukinumab nor brodalumab provide benefits in CD. Brodalumab even caused CD worsening, secukinumab also showed a similar trend, although this study did not find a statistically significant worsening. The lack of efficacy or deterioration of CD may be due to the steady-state role of IL-17 in maintaining tight junctions of the intestinal epithelium. Although IL-17 targeted therapy does not cause IBD in patients with psoriasis or spondyloarthropathy, a small number of new cases of IBD have been observed in multiple non-IBD trials using different IL-17 blockers.


Multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease caused by the infiltration of immune cells through the damaged blood-brain barrier, which promotes central nervous system inflammation, gliosis, axon demyelination and oligodendrocytes Lost. Approximately 85% of patients have relapsing multiple sclerosis (RMS), which loses physical and cognitive functions over time. The remaining 15% of patients suffer from primary progressive multiple sclerosis (PPMS), and neurological function continues to deteriorate. The clinical symptoms are determined by the anatomical location of the inflammation and neurodegeneration process. Inflammatory diseases include adaptive and innate immune cells, including microglia residing in the central nervous system.

The importance of immunity in MS is supported by the strong genetic association between the HLA-DRB1 locus and other immune-related gene loci (such as IL-2 and CD25). The treatment of RMS mainly focuses on immunomodulation. Consistent with genetic studies on MHC class II molecules and disease risk, T cell targeted therapy has shown clinical benefits. Similarly, the benefits of ocrelizumab may be due to the contribution of B cells as APCs, providing costimulatory signals and secreting pro-inflammatory cytokines. All immunomodulatory therapies tested to date have failed to provide clinical benefit for PPMS, with the exception of ocrelizumab. The neurodegenerative score in PPMS seems to be more dominant than the immune component, because patients receiving ocrelizumab have reduced disability but still have a significant deterioration. Future drug discovery focused on neuron regeneration, remyelination, and enhancement of regulatory immune cells may bring additional clinical benefits.

The other two points of view come from the success and failure of different immunomodulatory therapies.

1.  Inconsistency between IL-12/23 and IL-17 targeted therapies.

Although IL-23 is necessary for the development of Th17 cells, the efficacy of anti-IL-12/23 and anti-IL-17a treatments is not consistent. In the phase 2 trial of RMS, secukinumab reduced the number of gadolinium (Gd) enhanced MRI brain damage. In contrast, ustekinumab did not improve Gd-enhancing lesions. Preclinical studies using experimental autoimmune encephalitis (EAE) as a model of MS have shown that IL-23 is important for the occurrence of the disease, but once activated, IL-23 is unnecessary for the effect of EAE in the disease stage.

2.  B cell regulation.

Although anti-CD20 monoclonal antibody treatment is effective for RMS, atacicept (TACI-Fc) blocking BAFF and APRIL treatment increases the clinical recurrence rate. The harmful effects observed by atacicept may be due to the role of BAFF/APRIL in maintaining immunosuppression in IL-10 producing B cells.


Type 2 immune disease

Type 2 immunity has evolved to remove parasites outside the host cell and is regulated by Th2 cell-based cytokines (IL-4, IL-5, IL-9, and IL-13). Studies in the past ten years have shown that type 2 cytokines, especially IL-5 and IL-13, are also composed of group 2 ILC (ILC2s), mast cells, basophils, eosinophils, and CD8+ T cells. And natural killer T cells. These cytokines promote eosinophil differentiation and survival (IL-5); eosinophil tissue homing (IL-13); B cell type conversion to IgE production (IL-4 and IL-13); goblet cells Differentiation and mucus production (IL-13); smooth muscle proliferation and contraction (IL-13); mast cell differentiation, activation (IL-9) and degranulation (cross-linking FcεRI through IgE antigen complex).

Asthma

Asthma is a common respiratory disease characterized by reversibility, episodic airway obstruction and hyperresponsiveness. Symptoms include wheezing, coughing, waking up at night, and decreased exercise capacity. In some patients with asthma, an acute attack characterized by worsening symptoms and a sharp decline in lung function may occur. Asthma usually occurs in childhood, especially in children with atopic diseases who experienced lower respiratory tract viral infections two years ago. However, it may also develop later in life, often without evidence of allergic inflammation. Incentives include indoor and outdoor air allergens, pollutants such as cigarette smoke, ozone, and sources of infection such as viruses, bacteria, and fungi.

In most patients, short-acting or long-acting beta adrenergic agonists (SABA or LABA) are used to relieve symptoms of wheezing and airway obstruction, and inhaled corticosteroids (ICS) and/or oral leukotriene receptor antagonists are used as Appropriate lactic acid anti-inflammatory strategies to prevent the exacerbation of symptoms can adequately control asthma. Although up to 10% of patients receive high-dose LABA/ICS treatment, their asthma is poorly controlled, frequent systemic corticosteroids are required, the symptoms are heavy, and the condition frequently deteriorates. This subgroup of severe asthma patients represents a large number of unmet medical needs and has become the focus of new biological therapies for inflammatory mediators.

IgE targeted therapy

Omalizumab binds to the Fc region of serum IgE and reduces free circulating IgE by 95%. Since IgE occupying FcεRI on basophils and mast cells is necessary to maintain their plasma membrane expression, after omalizumab treatment, the surface FcεRI expression is reduced by ~90%. In a bronchial allergen challenge study in subjects with mild allergic asthma, omalizumab reduced early and late allergen reactions.

In key clinical trials, patients treated with omalizumab had significantly less asthma exacerbations than patients treated with placebo, but omalizumab treatment did not prevent all asthma exacerbations. Among children with asthma, omalizumab was the most effective in preventing seasonal acute attacks, with the largest reductions observed in spring and autumn compared with placebo. Patients with elevated levels of type 2 biomarkers (including blood eosinophils, FeNO, or serum periostin) have the most benefit in alleviating the condition. In addition, omalizumab also provides modest benefits in other outcome indicators including lung function and symptoms.

When B cells express transmembrane IgE before they differentiate into IgE-secreting plasma cells, quilizumab, an aglycosylated antibody against a unique epitope of transmembrane IgE (enhancing FcγR-mediated depletion) is tested to determine whether it can Depletion of IgE-converted B cell precursors can eliminate this antibody allergic B cell. In bronchial allergen provocation studies, quilizumab treatment attenuated early and late allergen responses and the induction of newly synthesized allergen-specific IgE, but in large studies in patients with moderate to severe asthma, quilizumab treatment did not prevent the disease deterioration. In this study, quilizumab only reduced serum IgE levels by about 25% in 9 months, indicating that the half-life of IgE-producing plasma cells was significantly longer, probably on a time scale of several years.

IL-5 targeted therapy

Three monoclonal antibody therapies against IL-5 have been approved for the treatment of asthma: mepolizumab and reslizumab inhibit the binding of IL-5 to its receptor, while benralizumab, an aglycosylated antibody against IL-5Rα, is additionally consumed IL-5Rα expressing cells, including eosinophils and basophils.

Studies using mepolizumab in patients with severe asthma with a history of airway, blood, and sputum eosinophilia and frequent exacerbations have shown that IL-5 inhibition can lead to a significant decrease in circulating eosinophils, exacerbation of asthma, and oral steroids. However, there was only a slight improvement in lung function and chronic symptom burden. In addition, anti-IL-5 treatment has little effect on circulating IgE levels or FeNO, and reslizumab and benralizumab studies subsequently demonstrated similar results. These studies reveal the central role of IL-5 in driving eosinophilic inflammation, and further reveal the role of eosinophilic airway inflammation in causing some (but not all) asthma exacerbations in patients with type 2 high asthma .

As an interesting episode, an early study of the use of mepolizumab in patients with mild allergic asthma failed to prove any effect on early or late allergen reactions, indicating that eosinophils are not an important part of allergen reactions. Therefore, the benefit of anti-IL-5 therapy in reducing the spontaneous deterioration rate in the key outcome trial raises questions about the convertibility of the bronchial allergen challenge study design in a more realistic environment, and suggests that the clinical endpoint must be consistent with the intervention. Match the biology of the targeted disease.

IL-13/IL-4 targeted therapy

Some antibodies against the IL-4/13 pathway, including lebrikizumab, tralokinumab and dupilumab, have passed key clinical trials and made progress. Drugs that target IL-4 alone (pascolizumab, altrakincept) failed to show benefits, indicating that IL-13 is a key effector cytokine of the two drugs in asthma.

In a small bronchial allergen challenge study, Lebrikizumab proved to be beneficial for patients with mild type 2-high asthma, reducing late allergen reactions, but not early allergen reactions. This result suggests that IL-13 is involved in the recruitment of inflammatory cells secondary to mast cell degranulation mediated by the IgE allergen complex. Therefore, anti-IL-13 is different from anti-IL-5. The latter has no effect on bronchial allergen reactions, while anti-IgE can prevent early and late reactions.

Although dupilumab, lebrikizumab, and tralokinumab all showed efficacy in phase 2 trials, dupilumab performed better in a key phase 3 trial. In repeated phase 3 trials, although both lebrikizumab and tralokinumab achieved a moderate reduction in the rate of deterioration, and lebrikizumab significantly improved lung function, neither drug reached its pre-specified primary endpoint of a reduction in the rate of deterioration. In contrast, dupilumab has achieved significant improvements in lung function and reduced deterioration in patients with type 2 high asthma. Consistent with IgE and IL-5 targeted therapy, post-hoc analysis of the lebrikizumab study showed that it can prevent the peak seasonal exacerbation rate in type 2 high-risk patients.

The different clinical results of IL-13 targeted therapy illustrate the difficulty of interpreting the results of clinical trials. There are several possible explanations to explain the inconsistent trial results:

1 Target selection: Dupilumab inhibits IL-4 and IL-13 signaling.

Although selective targeting of IL-4 has no obvious therapeutic benefit, the possibility that IL-4 becomes important after IL-13 is neutralized still exists. The pharmacodynamic biomarker effects of FeNO, IgE and blood eosinophils mainly reflect the biological characteristics of IL-13, so they are consistent between different drugs. There is no assessment or clear evidence for IL-4 selective biomarkers.

2 Molecular characteristics:

Although there may be subtle molecular differences, Dupilumab still occupies the receptor. In contrast, IL-13 targeting antibodies may be more dependent on their affinity and ability to neutralize ligands in all microenvironments and their spatial configuration relative to their receptors.

3 Study patient population:

Because the lebrikizumab trial does not require recent deterioration as the inclusion criteria, the placebo group has a lower rate of deterioration (less than one patient per year). More than 60% of patients in the placebo group did not worsen, which made them lack information on the main outcome measures. In contrast, the Dupilumab study requires a history of deterioration in the previous year, which leads to a higher rate of deterioration in the trial, and thus a larger window to demonstrate a statistically significant reduction.

4 Biomarkers:

The key lebrikizumab study pre-specified the complex of serum periostin and blood eosinophils, classifying 70% of patients as positive for biomarkers; one of the repeated studies met the main outcome measure for this subgroup , Is statistically significant, while the other item does not. The dupilumab study grouped biomarkers as a secondary outcome indicator, and showed that the benefit was mainly in patients with blood eosinophils> 300/mm3 (approximately 45% of patients). Therefore, the use of more stringent type 2 biomarkers can bring better efficacy for inhibitors of type 2 cytokines.

In general, inhibitors of IgE, IL-5 and IL-4/13 have a significant effect on asthma patients, and about half of severe asthma exacerbations can be prevented. However, there is no effective type 2 cytokine targeted therapy that can completely prevent asthma from exacerbating or eliminate daily symptoms, especially in patients with type 2 low asthma.

Other ways of not relying on type 2 immunity in asthma

Although the biological treatment for type 2 asthma patients has achieved great success, no treatment for the subgroup of type 2 low asthma patients has been approved, and people are gradually focusing on other pathways that do not rely on type 2 cytokines.

Monoclonal antibodies targeting TSLP are currently being studied in phase 3 trials. In a phase 2b study, it reduced the exacerbation rate of patients with type 2-low asthma and type 2 high asthma, and its lung function advantage was mainly in patients with type 2 high asthma. In addition, clinical trials of inhibitors targeting TNF-α and IL-17 have failed to produce positive results in asthma patients, although these studies did not use biomarkers to select patients based on evidence of the activity of these pathways, so it may be missed A small number of possible benefits.

Type 2 immune diseases other than asthma

The disease mechanisms that exist in asthma also play an active role in other indications. Therefore, these biological treatments provide new insights and treatment options for other indications:

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by epithelial barrier dysfunction, eczema, and high levels of IL-13, IgE, and eosinophil infiltration. The itching scratch cycle will exacerbate the itching of the skin, during this cycle bacterial skin flora is introduced into the dermis, thereby promoting further inflammation. Dupilumab is the first biological therapy approved to effectively treat AD, and Lebrikizumab and tralokinumab also show activity in the treatment of AD.

Chronic spontaneous urticaria (CSU) is a skin disease that produces autoantibodies against FcεRIα and IgE, and frequent degranulation of mast cells causes measles. Omalizumab is the first treatment to use antihistamines in CSU to show significant benefits beyond symptoms, indicating the important role of IgE-FcεRI interaction in the pathogenesis of CSU.

Rare eosinophilias include eosinophilia syndrome (HES), a systemic disease characterized by infiltration of circulating eosinophils and tissues, including the skin, gastrointestinal tract, and lungs, with Activated eosinophils; eosinophilic granuloma with multiple inflammation (EGPA, also known as Churg-Strauss syndrome), an autoimmune disease with eosinophil-mediated vasculitis. Mepolizumab and other IL-5 inhibitors have proven effective in HES, and most patients reduce eosinophil infiltration and symptoms by more than half; Mepolizumab has been approved for the treatment of EGPA patients.

Some patients with chronic obstructive pulmonary disease (COPD) have type 2 features and elevated levels of eosinophils, which is a common airway disease in smokers. However, IL-5 and IL-13 targeted therapies have not proven to have significant efficacy in COPD, even in the subpopulations with elevated eosinophils. These negative results probably reflect the relatively insufficient contribution of type 2 cytokines to the pathogenesis of COPD.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that mainly affects the joints, but it may also have systemic extra-articular manifestations. The clinical diagnostic criteria include the number of affected joints, the duration of symptoms, the presence of rheumatoid factor (RF) or anti-citrullinated peptide antibodies, and evidence of acute phase reactants, CRP, or abnormal erythrocyte sedimentation rate. Standard methods for measuring the effectiveness of therapeutic drugs in clinical trials are the use of American College of Rheumatology (ACR) standards, comprehensive assessment of physiological conditions, measurement of acute phase reactants, and patient and physician evaluations. ACR20, 50, and 70 represent 20%, 50%, and 70% improvement, respectively.

At present, treatments targeting 5 biological targets have been approved by the FDA for the treatment of different subgroups of RA patients. However, no type of treatment can increase the placebo-corrected ACR50 score by more than 33%. This supports that RA represents a heterogeneous clinical syndrome with multiple immune mechanisms, and different immune mechanisms lead to a common Clinical manifestations.

Regarding this hypothesis, three types of synovial pathology were first described in 1984: (a) a large number of lymphatic invasion and germinal centers (GCs), (b) a large number of lymphatic invasion without GCs, and (c) fibroblasts/ Synovial hyperplasia, with fewer lymphoid cells. Recently, with the help of molecular technology and immunohistochemistry, three types of synovial pathology have been defined according to histological and genetic characteristics: lymphoid myeloid, diffuse myeloid and pauci immunity. The three types of synovial pathology are seen in the early stage (average duration of less than 6 months) and late stage (average duration of more than 3 years). The histological definition of lymphoid myeloid lesions is the presence of T cells, B cells, plasma cells and myeloid cells, accompanied by high lymphatic gene expression. Among the types of lymphoid myeloid lesions, GC-like structures are the most common. These patients respond more significantly to tocilizumab or B cell depletion. The type of diffuse myeloid lesions is mainly myeloid in histological and molecular characteristics. These patients have a preferential response to TNF-α targeted drugs. The immunopathological type of pauci is characterized by fibroblasts and rare immune cells. This type of pathology is characterized by lower acute phase reactants and serological characteristics, and tends to invade larger joints (such as the knee), but there is still evidence of obvious disease activity. These pathological types emphasize the heterogeneity of RA patients, and the best treatment methods for various synovial pathological types need to be further determined to improve the patient’s response.

Opportunities and Challenges

In the past thirty years, advances in biological therapy have brought tremendous benefits to patients, and have gained an important understanding of basic immunology and disease pathogenesis. These clinical trials also revealed major challenges in the development of new therapies, partly due to disease heterogeneity and clinical research design, including patient selection, endpoint selection, and biomarker discovery and research. There are still a large number of unmet clinical needs in the research and development of new drugs, and tools and methods for discovering new targets and new biomarkers continue to emerge. Some of the exciting developments include:

1. Target discovery based on human genetics:

The reduction in the cost of DNA sequencing has enabled new applications of human genetics in target discovery. Modified screening of genetic factors that change the severity of disease may provide clues to therapeutic targets. For example, IL-6R has been identified as a candidate regulator of the age of onset of Alzheimer’s disease.

2. New drug platform:

Although most biological therapies to date have focused on neutralizing a single target, advances in biological therapies now allow multiple different antigens or pathways to be targeted within a single molecule. With the advent of gene editing technology, it has become possible to design functions into human cells. In cancer, CAR-T cells have shown good application prospects, and in autoimmunity, CAR-Treg cells are being used as a means to induce antigen-specific tolerance to self-antigens. With the rapid development of CRISPR technology, cells can be designed to perform multiple functions, and the complexity of this work has almost no theoretical limit. Therefore, engineered cell therapy has great prospects.

3. Microbiota:

In the past decade, it has become increasingly apparent that the microbes living in our bodies play a vital role in homeostasis and disease. The patient’s microbiome can be used as an important prognostic or predictive disease biomarker. At present, a variety of efforts aimed at the microbiome are underway to pursue therapeutic effects. These technologies have special prospects in the field of mucosal diseases.

4. Understand the biological response after intervention:

With the improvement of the sensitivity of new technologies and technology platforms, we use DNA, epigenetics, single-cell transcriptomics, metabolomics, proteomics, exosomes and imaging The ability to study human biology will provide more insights into human biology and the response to therapeutic interventions. Analysis of the differences between responders and non-responders may reveal more targeted pathways.

5. Application of big data:

With the accumulation and proper annotation of clinical, biomarker and response data, the application of machine learning to these data sets may provide new treatment avenues.

Many of the challenges of understanding the biology of human diseases and developing new therapies are balanced by these emerging new technologies and insights. Their application will undoubtedly enhance our understanding of human diseases and enhance our ability to provide clinical benefits for unmet medical needs.

(source:internet, reference only)


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