The establishment of precision medicine is considered particularly important in heterogeneous autoimmune diseases (e.g., psoriatic arthritis, systemic lupus erythematosus), which reveal clinical and molecular heterogeneity. The selection of optimal treatment strategies for individual patients may be more important and complex in autoimmune diseases than in other diseases. Two factors are important in precision medicine: patient stratification and use of targeted. When both factors work, patients are likely to have good outcomes. However, research into precision medicine and its practice in systemic autoimmune diseases is lacking. In contrast, the usefulness of peripheral immune cell phenotyping in the evaluation of immunological characteristics and stratification into subgroups of individual patients with systemic autoimmune diseases such as immunoglobulin 4-related disease, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis was reported. Furthermore, the potential of precision medicine using biological disease-modifying antirheumatic drugs based on peripheral immune cell phenotyping was recently demonstrated for psoriatic arthritis in the clinical setting. Precision medicine has not yet been sufficiently investigated in real world clinical settings. However, a dawn of precision medicine has emerged. We should shed further light on precision medicine in PsA and other autoimmune diseases. Here, we first review the usefulness of peripheral immune cell phenotyping in systemic autoimmune diseases and the potential of precision medicine in PsA based on this method.
In cancer care, genomic research has garnered attention since around 1990. Ever since the Precision Medicine Initiative for cancer care was proposed in the State of the Union address delivered by then-US President Obama in January 2015, attention has been drawn to precision medicine, wherein patients with cancer are classified based on oncogenic driver mutations, and the molecular-targeted drug that best matches each mutation is used for treatment (1).
The establishment of precision medicine is considered particularly important in heterogeneous autoimmune diseases such as psoriatic arthritis (PsA), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These diseases show clinical and molecular heterogeneity. In these diseases, various symptoms require simultaneous improvement; however, the number of available treatment options is limited. With the elucidation of pathological conditions of these autoimmune diseases, molecules involved in the pathological processes have been clarified. It has become clearer which molecules should now be targeted for treatment. Advances in monoclonal antibody technology, and the emergence of Janus kinase inhibitors (JAK-i) have made molecular-targeted therapy possible. However, in many autoimmune diseases, due to the heterogeneity of the disease, centrally involved molecules differ depending on individual patient. Differences in patient's molecular profiles can render molecular-targeted therapy inefficient. Therefore, patient stratification according to differences in the patient's molecular profile would allow for more efficient treatment outcomes by precision medicine as opposed to one-size-fits-all approach (2). However, although precision medicine is being developed for cancer and rare diseases, research on its development and use in systemic autoimmune and rheumatic diseases is lacking.
Pdf) Precision Medicine Of Autoimmune Diseases
PsA is a rheumatic disease with high clinical heterogeneity; it is sometimes accompanied by nail psoriasis, spine, entheses, and eyes (iritis). In the pathogenesis of PsA, various cytokines such as interferon gamma, interleukin (IL)-12, IL-23, IL-17, IL-6, and tumor necrosis factor alpha (TNF-α) play important roles. Recently, biological disease-modifying antirheumatic drugs (bDMARDs) targeting TNF-α, IL-17A, IL-17A/F, IL-17 receptor, IL-12/23 (p40), and IL-23 (p19) and targeted synthetic DMARDs (tsDMARDs) targeting Janus kinase have demonstrated efficacy and are widely used in routine clinical practice (3–22). Abatacept, a selective T-cell co-stimulation modulator, has been also approved by US Food and Drug Administration (23). EULAR recommends using targeted therapies, such as TNF-inhibitors (TNF-i), IL-17-inhibitors (IL-17-i), IL-12/23-inhibitors (IL-12/23-i), JAK-i, and phosphodiesterase 4 inhibitors (PDE4-i), especially in patients with PsA who fail to adequately respond to synthetic DMARDs (24). Therefore, first of all, it is important to consider whether a patient needs to use biologics or not. Despite the availability of b/tsDMARDs, some patients are resistant to treatment. While these drugs target different molecules, clinical trials directly comparing TNF-i and IL-17-i have shown at least a comparable efficacy on musculoskeletal manifestations (25, 26). This suggests that individual patients diagnosed with PsA may possess different therapeutic targets to attain an optimal response. The diversity of pathologies in patients with such heterogeneous diseases may result in treatment resistance if key aspects or molecules of a disease in that individual are not properly targeted. However, no optimal drug selection method has been established, and some patients are resistant to these drugs and require treatment changes.
To date, precision medicine has not been achieved for any autoimmune disease. In contrast, we recently demonstrated the usefulness of peripheral immune cell phenotyping in the evaluation of immunological characteristics (phenotypic differences) and stratification of patients into subgroups in individual patients with IgG4-related disease (IgG4-RD), SLE, RA, and anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis (27–30). Moreover, we reported the potential of precision medicine based on this method in the real clinical setting of PsA (31). Here, we first review the usefulness of peripheral immune cell phenotyping in some systemic autoimmune diseases and the potential of precision medicine in PsA based on this method.
The strategy of precision medicine involves patient stratification to improve diagnosis and treatment outcomes. In brief, the therapeutic target is narrowed by stratifying patients within a single disease. These two factors are important for achieving precision medicine: patient stratification and the use of targeted therapies (2). When both factors work, patients are likely to have good outcomes.
Clinical, Laboratory And Multi Omics Data To Leverage Machine Learning For Personalized Diagnostics
To stratify patients, some methods or strategies (e.g., genomic, proteomics, metabolomics) are considered available similar to cancer care. However, acquiring tissue biopsies from patients with autoimmune diseases is logistically more difficult than acquiring samples from patients with cancer. Peripheral immune cell phenotyping, which clarifies the differentiation stage such as naïve or memory T cells, the differences in lineage or functional differences represented by T helper (Th)1 and Th2 cells or Th17 cells, and the activation status or involvement of cellular signaling molecules in the pathological process, is useful for classifying individual patients based on immunological characteristics and can often reflect the pathological condition of involved organs or tissues themselves (32).
We performed peripheral immune cell phenotyping in 16 patients with IgG4-RD (28). Compared with healthy controls (HCs), IgG4-RD showed comparable proportions of Th1 and Th17 cells but higher proportions of Treg and follicular helper T (Tfh) cells. The proportions of class-switched memory B cells, particularly plasmablasts, were higher in IgG4-RD. A histopathological examination revealed marked Tfh cell infiltration, and the increase in Tfh cells in the peripheral blood reflected their degree of infiltration into the tissue. It indicated that peripheral immune cell phenotyping can reveal the immunological status and reflect the immunological condition of the involved lesion (tissue and organ). The abundance of Tfh cells was reported also in another cohort with 15 IgG4-RD patients (33). In this study, there was a correlation between Tfh2 cells, serum IgG4 levels and IL-4 producing plasmablasts. Various other attempts of immune phenotyping in IgG4-RD patients have been performed. In the study with 67 IgG4-RD patients, the frequency of circulating pan-innate lymphoid cells (ILCs) and ILC1s were lower than in HCs, whereas circulating ILC2s were higher in IgG4-RD. Circulating ILC2s correlated positively with CD19
CTLs in blood and tissues were observed also in another cohort with 101 IgG4-RD patients. After clinical remission by B cell-depletion therapy with rituximab, the resolution of these CD4
Mrff Funding To Advance Precision Medicine For Juvenile Idiopathic Arthritis
CTLs were demonstrated (36). The role of immune cells in pathogenesis of IgG4-RD and treatment impact are becoming clearer by immune phenotyping (37).
We also attempted to stratify 143 patients with SLE by immune phenotyping (27). We showed that patients with SLE can be statistically stratified into three subgroups: patients who did not show characteristic features other than a high proportion of plasmablasts, those with a high percentage of Tfh cells, and those with a high percentage of activated and memory Treg cells and a low percentage of naïve Treg cells. Similar attempt in patients' stratification based on immune phenotyping was performed in 105 IgG4-RD patients. In this study, IgG4-RD patients were divided into 3 subgroups by cluster analysis: subgroup 1 with low memory B cells and normal Breg, subgroup 2 with high memory B cells and low Breg, and subgroup 3 with high plasmablasts and low naive B cells. Subgroups 2 and 3 were more likely to be resistant to treatment (38). Patients with a high percentage of Tfh cells were more resistant to treatment with immunosuppressants, in addition to high-dose of glucocorticoids (39). The proportions of CXCR5
Tfh cells were also reported to be associated with disease activity in SLE (40, 41). Not only peripheral immune phenotyping, mass cytometry is identifying responsible cell subsets and markers characteristic of SLE heterogeneity. Transcriptome analysis is discovering molecular networks responsible for disease activity, disease subtype and future relapse. The elucidation of disease heterogeneity in SLE toward further development of precision medicine is becoming clearer by immune cells phenotyping and recent technological advances in single-cell and omics analysis (42).
Precision Medicine For Autoimmune Diseases: 9780128195222: Medicine & Health Science Books @ Amazon.com
Double-negative B cells, and plasmacytoid dendritic cells (pDCs) were higher in patients with active RA than in HCs (29). Treatment with TNF-is reduced the proportion of pDCs, while tocilizumab reduced the proportion of double-negative B cells but increased proportions of naïve and activated Treg cells.
CTLs were demonstrated (36). The role of immune cells in pathogenesis of IgG4-RD and treatment impact are becoming clearer by immune phenotyping (37).
We also attempted to stratify 143 patients with SLE by immune phenotyping (27). We showed that patients with SLE can be statistically stratified into three subgroups: patients who did not show characteristic features other than a high proportion of plasmablasts, those with a high percentage of Tfh cells, and those with a high percentage of activated and memory Treg cells and a low percentage of naïve Treg cells. Similar attempt in patients' stratification based on immune phenotyping was performed in 105 IgG4-RD patients. In this study, IgG4-RD patients were divided into 3 subgroups by cluster analysis: subgroup 1 with low memory B cells and normal Breg, subgroup 2 with high memory B cells and low Breg, and subgroup 3 with high plasmablasts and low naive B cells. Subgroups 2 and 3 were more likely to be resistant to treatment (38). Patients with a high percentage of Tfh cells were more resistant to treatment with immunosuppressants, in addition to high-dose of glucocorticoids (39). The proportions of CXCR5
Tfh cells were also reported to be associated with disease activity in SLE (40, 41). Not only peripheral immune phenotyping, mass cytometry is identifying responsible cell subsets and markers characteristic of SLE heterogeneity. Transcriptome analysis is discovering molecular networks responsible for disease activity, disease subtype and future relapse. The elucidation of disease heterogeneity in SLE toward further development of precision medicine is becoming clearer by immune cells phenotyping and recent technological advances in single-cell and omics analysis (42).
Precision Medicine For Autoimmune Diseases: 9780128195222: Medicine & Health Science Books @ Amazon.com
Double-negative B cells, and plasmacytoid dendritic cells (pDCs) were higher in patients with active RA than in HCs (29). Treatment with TNF-is reduced the proportion of pDCs, while tocilizumab reduced the proportion of double-negative B cells but increased proportions of naïve and activated Treg cells.
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