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    Home > Active Ingredient News > Immunology News > Current progress in the treatment of primary Sjogren's syndrome

    Current progress in the treatment of primary Sjogren's syndrome

    • Last Update: 2021-12-06
    • Source: Internet
    • Author: User
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    ← Swipe left and right to view, click [Read the original text] to learn more → Sjögren's syndrome (SjS) is a common rheumatism characterized by autoimmune exocrine diseases
    .

    SjS that occurs alone is called primary Sjögren's syndrome (pSS), and secondary to another rheumatism is defined as secondary SjS
    .

    pSS mainly occurs in women, and its estimated prevalence in the general population is about 10/10000
    .

    The pathological hallmark of pSS is the presence of infiltrating lymphocytes in salivary glands and lacrimal gland tissues
    .

    Glandular dysfunction caused by autoimmune damage can cause dry eyes and mouth, which is the main clinical feature of pSS
    .

    pSS can also involve multiple organ systems and cause extraglandular manifestations, leading to different clinical manifestations
    .

    Moreover, patients with pSS have a higher risk of developing lymphoma than healthy controls
    .

    The treatment plan of pSS mainly includes local medication and systemic treatment
    .

    However, for systemic drugs including conventional disease-relieving anti-rheumatic drugs (DMARDs), most placebo-controlled trials have found no difference in disease activity and fatigue scores from baseline compared with placebo
    .

    There is an urgent need to develop effective pSS systemic treatments
    .

    Targeted therapies including biological DMARD and targeted synthetic DMARD have achieved great success in other rheumatic diseases such as rheumatoid arthritis (RA)
    .

    In the past two decades, more and more clinical trials have evaluated targeted therapies related to pSS
    .

    The pathogenesis of pSS, diagnosis and treatment of pSS are complex and involve many factors, including genetic factors, internal defects in the glands, environmental inducements and other factors
    .

    Both innate immunity and acquired immunity play a key role in the pathogenesis of pSS
    .

    The interaction between general genetic predispositions, environmental triggers, and internal defects in the glands can lead to the activation of autoreactive immune cells and autoimmune attacks on the exocrine gland epithelium (Figure 1)
    .

    Those damaged glandular epithelial cells produce chemokines and pro-inflammatory cytokines, which can amplify autoimmune responses by increasing immune infiltration into glandular tissues
    .

    These pathological processes can cause progressive damage to the exocrine glands, and dryness symptoms can occur in patients with impaired exocrine gland function
    .

    Figure 1.
    Overview of the pathological process involved in the occurrence of pSS B cell excessive activation is a pathogenic sign of pSS, which promotes the production of a large number of autoantibodies
    .

    Some autoantibodies can bind to autoantigens to generate immune complexes, which can be deposited in multiple organ systems and cause damage to corresponding tissues
    .

    B cells can secrete pro-inflammatory cytokines during the occurrence of pSS and present antigens to T cells
    .

    In some cases of pSS, the gland tissue has tertiary lymphoid structure (TLS) or ectopic germinal center (GC)-like structure, which can promote autoimmunity and destroy gland tissue
    .

    Some patients with pSS may develop lymphoma after polyclonal activation of autoimmune B cells
    .

    Therefore, B cells are the key immune cells involved in the pathogenesis of pSS, and have long been regarded as the key target of intervention
    .

    In addition to B cells, T cells such as helper T cells 17 (TH17), follicular T helper cells (TFH) and cytotoxic T lymphocytes (CTL) are also important participants in pSS
    .

    Those T cells can promote the activation of B cells and directly cause damage to the exocrine glands
    .

    Moreover, abnormalities of innate immunity are also involved in the pathogenesis of pSS
    .

    Finally, the inherent defects of the glandular epithelium can also promote the occurrence of pSS through a variety of mechanisms, including providing chronic activation signals
    .

    Intrinsic defects in these glands have been regarded as potential therapeutic targets for pSS
    .

    Nevertheless, the pathogenesis of pSS has not yet been fully clarified, and more research is needed to reveal suitable therapeutic targets
    .

    Current progress of pSS targeted therapy The current partial targeted therapy has become a potential therapeutic drug for pSS, including B cell depleting agents, B cell activation inhibitors, and drugs targeting co-signaling molecules or pro-inflammatory cytokines (Figure 1)
    .

    However, there is still very little evidence for pSS targeted therapy.
    The US Food and Drug Administration (FDA) or European Medicines Agency (EMA) has not approved any biologics to treat pSS
    .

    Figure 2.
    Potential biologics for pSS treatment.
    B cell targeted therapy.
    Excessive activation of pSSB cells is a pathogenic sign of pSS pathogenesis and has long been regarded as a therapeutic target of pSS
    .

    B cell targeted therapy pSS mainly includes B cell depleting agents (targeting B cell specific surface antigens) and B cell activation inhibitors
    .

    Inhibiting B cell activation by targeting B cell activation ligands or their receptors is a relatively mature strategy for the treatment of systemic lupus erythematosus (SLE)
    .

    B cell activation ligands such as B cell activation factor (BAFF, also known as TNFSF13B or BLyS) and proliferation inducing ligand (APRIL, also known as TNFSF13) are key therapeutic targets
    .

    Receptors such as BAFF receptor (BAFF-R, also known as BR3 or TNFRSF13C), transmembrane activator and CAML interacting factor (TACI, also known as TNFRSF13B), B cell maturation antigen (BCMA), etc.
    are also important targets for intervention
    .

    Table 1.
    B cell targeted therapy treatment pSS targeted costimulatory signal therapy pSS co-signaling molecule plays a key role in regulating autoimmune response and is an important therapeutic target for rheumatic diseases
    .

    Among them, Abatacept is a CTLA-4 Ig fusion protein that can bind to CD80/CD86, inhibit the CD28-CD80/86 costimulatory interaction, and reduce CD28-mediated T cell costimulation
    .

    Preclinical studies have shown that the CD40-CD40L costimulatory pathway is a key factor in pSS, and targeting this pathway can inhibit pSS-related pathophysiology
    .

    Iscalimab (CFZ533) is a blocking but non-exhaustive anti-CD40 monoclonal antibody that can block the CD40-CD40L pathway
    .

    ICOS-ICOSL is a key costimulatory signal pathway involved in T cell activation, and Prezalumab is an anti-ICOSL monoclonal antibody that has potential efficacy in the treatment of SLE
    .

    Table 2.
    Summary of clinical trials targeting the same stimulating factor.
    Pro-inflammatory cytokine antibodies.
    Because pro-inflammatory cytokines such as interleukin-6 (IL-6) play a key role in B cell activation and participate in the pathogenesis of pSS, they target Biological preparations of these cytokines may have potential benefits in the treatment of pSS
    .

    However, none of these biologics targeting pro-inflammatory cytokines can effectively treat pSS
    .

    A placebo-controlled trial conducted in 28 patients with pSS showed that compared with placebo, IL-1 receptor (IL-1R) antagonist anakinra inhibited interleukin-1 (IL-1) The fatigue score has no significant effect on the change from baseline
    .

    A recent placebo-controlled trial (NCT01782235) conducted in 110 pSS patients reported that compared with placebo, tocilizumab blocking interleukin-6 receptor (IL-6R) does not improve the systemic involvement of pSS patients And symptoms
    .

    These results indicate that biologics targeting TNFα, IL-6 or IL-1β have no significant effect on pSS
    .

    Over-activated interferon-α (IFNα) pathway is a key feature of pSS
    .

    FNα can promote the activation of B cells and directly damage the glandular tissues.
    It is a promising therapeutic target for pSS
    .

    Table 3 Summary of clinical trials evaluating small molecule inhibitors of pro-inflammatory cytokine antibodies or key signaling pathways in SjS Has a new role
    .

    The excessive activation of JAK/STAT signal transduction is involved in the pathogenesis of pSS, indicating that JAK is a feasible target for intervention
    .

    Several preclinical studies have shown the potential of JAK inhibitors in the treatment of pSS.
    However, a clinical trial (NCT03100942) failed to prove the efficacy of JAK1 inhibitor filgotinib in the treatment of pSS
    .

    Phosphatidylinositol 3-kinase delta isoform (PI3K delta) is a key regulator of B cell proliferation and activation, and its inhibitors can effectively treat lymphoma
    .

    Excessive activation of PI3Kδ pathway was found in the salivary glands of patients with pSS, leading to the onset of pSS
    .

    Two clinical trials (NCT02610543, NCT02775916) evaluated the efficacy of PI3Kδ inhibitors (including seletalisib and leniolisib) in the treatment of pSS, but no beneficial effects were found
    .

    However, a clinical trial (NCT02610543) showed that in pSS patients treated with seletalisib, ESSDAI and ESSPRI showed a trend of improvement
    .

    SYK is a key signaling molecule that plays a key role in regulating BCR and Fc receptor signaling pathways
    .

    The role of SYK inhibitors in the treatment of rheumatic diseases has attracted more and more attention
    .

    An unpublished placebo-controlled Phase II trial (NCT03100942) evaluated the efficacy of lanrepibe (GS-9876, SYK inhibitor) in pSS, but failed to determine its beneficial effects
    .

    Other biologics for pSS therapy There are several other types of targeted therapies under evaluation for pSS therapy
    .

    RSLV-132 (an RNase Fc fusion protein) nuclease treatment can increase RNA digestion activity and reduce circulating RNA including RNA autoantigens
    .

    A placebo-controlled phase ii trial (NCT03247686) in 28 patients with pSS found that patients treated with RSLV-132 nuclease had clinically significant improvements in ESSPRI scores and fatigue
    .

    The activation of cathepsin S is related to the pathogenesis of pSS
    .

    However, in an unpublished placebo-controlled Phase II trial (NCT02701985) evaluating the efficacy of RO5459072 (petesicatib, cathepsin S inhibitor) on pSS, it was found that the ESSDAI and ESSPRI scores between petesicatib and placebo treatment groups were lower than the baseline There is no significant difference in the changes
    .

    The editor concludes that there is still very little evidence for the efficacy of targeted therapy for pSS, and the FDA or EMA has not approved any biologics to treat pSS
    .

    The efficacy and long-term safety characteristics of these promising biologics in the treatment of pSS need to be confirmed in larger placebo-controlled trials
    .

    In order to reveal more suitable intervention targets, further mechanism studies are needed to reveal the key pathogenic factors in pSS
    .

    Moreover, early diagnosis and gland function-centered outcome indicators may help to improve the current status of pSS system therapy, and more research on these aspects is necessary
    .

    Reference: Wang, B.
    , Chen, S.
    , Li, Y.
    et al.
    Targeted Therapy for Primary Sjögren's Syndrome: Where are We Now?.
    BioDrugs (2021).
    https://doi.
    org/10.
    1007/s40259- 021-00505-7▼Click [Read the original text] to learn more~
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