-
Expert Opinion on Emerging Drugs Dec 2023Sjögren's Disease, SjD, is a systemic autoimmune disorder characterized by reduced function of the salivary and lacrimal glands. Patients suffer from dryness, fatigue,... (Review)
Review
INTRODUCTION
Sjögren's Disease, SjD, is a systemic autoimmune disorder characterized by reduced function of the salivary and lacrimal glands. Patients suffer from dryness, fatigue, and pain and may present with or without extra-glandular organ involvement. Symptoms limit SjD patients' quality of life and are the most difficult to improve with therapy. SjD patients are heterogeneous and clustering them into biologically similar subgroups might improve the efficacy of therapies. The need for therapies that address both the symptoms and extra glandular organ involvement of SjD presents an unmet opportunity that has recently attracted a growing interest in the pharmaceutical industry.
AREAS COVERED
The goal of this report is to review recent phase II/III studies in SjD. To accomplish our goal, we performed a literature search for phase II/III studies and abstracts recently presented at conferences.
EXPERT OPINION
This review allows updates the reader on the multitude of recent phase II/III clinical trials. We speculate on how subtypes of SjD will drive future therapeutic targeting and inform pathogenesis.
Topics: Humans; Quality of Life; Sjogren's Syndrome; Severity of Illness Index
PubMed: 37127914
DOI: 10.1080/14728214.2023.2209720 -
Frontiers in Immunology 2023Primary Sjogren's syndrome (pSS) is a prototypical systemic autoimmune disease characterised by lymphocyte infiltration and immune-complex deposition in multiple organs....
BACKGROUND
Primary Sjogren's syndrome (pSS) is a prototypical systemic autoimmune disease characterised by lymphocyte infiltration and immune-complex deposition in multiple organs. The specific distribution of immune cell populations and their relationship with mitochondria remain unknown.
METHODS
Histological analysis was performed to assess the specific distribution of innate and adaptive immune cell populations in labial salivary gland (LSG) samples from 30 patients with pSS and 13 patients with non-pSS. The ultrastructural morphometric features of mitochondria within immune cells were observed under the transmission electron microscope (TEM). RNA sequencing was performed on LSG samples from 40 patients with pSS and 7 non-pSS patients. The Single-sample Gene Set Enrichment Analysis (ssGSEA), ESTIMATE, and CIBERSORT algorithms and Pearson correlation coefficients were used to examine the relationship between mitochondria-related genes and immune infiltration. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify the mitochondria-specific genes and the related pathways based on the immune cell types.
RESULTS
HE staining revealed a massive infiltration of plasma cells with abundant immunoglobulin protein distributed around phenotypically normal-appearing acinar and ductal tissues of patients with pSS. Immunohistochemical analyses revealed that innate immune cells (macrophages, eosinophils and NK cells) were distributed throughout the glandular tissue. Dominant adaptive immune cell infiltration composed of B cells, CD4T cells and CD8 T cells or ectopic lymphoid follicle-like structures were observed in the LSGs of patients with pSS. TEM validated the swelling of mitochondria with disorganised cristae in some lymphocytes that had invaded the glandular tissue. Subsequently, bioinformatic analysis revealed that innate and adaptive immune cells were associated with different mitochondrial metabolism pathways. Mitochondrial electron transport and respiratory chain complexes in the glandular microenvironment were positively correlated with innate immune cells, whereas amino acid and nucleic acid metabolism were negatively correlated with adaptive immune cells. In addition, mitochondrial biogenesis and mitochondrial apoptosis in the glandular microenvironment were closely associated with adaptive immune cells.
CONCLUSION
Innate and adaptive immune cells have distinct distribution profiles in the salivary gland tissues of patients with pSS and are associated with different mitochondrial metabolic pathways, which may contribute to disease progression.
Topics: Humans; Salivary Glands; Sjogren's Syndrome; CD8-Positive T-Lymphocytes; Mitochondria; Metabolome
PubMed: 37497211
DOI: 10.3389/fimmu.2023.1156774 -
Annals of the Rheumatic Diseases Feb 2024To evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren's syndrome (SjS) in a phase 2 randomised, double-blind trial... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial.
OBJECTIVES
To evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren's syndrome (SjS) in a phase 2 randomised, double-blind trial (NCT04035668; LOUiSSE (LOU064 in Sjögren's Syndrome) study).
METHODS
Eligible patients fulfilling 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for SjS, positive for anti-Ro/Sjögren's syndrome-related antigen A antibodies, with moderate-to-severe disease activity (EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (based on weighted score) ≥ 5, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥ 5) received remibrutinib (100 mg) either one or two times a day, or placebo for the 24-week study treatment period. The primary endpoint was change from baseline in ESSDAI at week 24. Key secondary endpoints included change from baseline in ESSDAI over time, change from baseline in ESSPRI over time and safety of remibrutinib in SjS. Key exploratory endpoints included changes to the salivary flow rate, soluble biomarkers, blood transcriptomic and serum proteomic profiles.
RESULTS
Remibrutinib significantly improved ESSDAI score in patients with SjS over 24 weeks compared with placebo (ΔESSDAI -2.86, p=0.003). No treatment effect was observed in ESSPRI score (ΔESSPRI 0.17, p=0.663). There was a trend towards improvement of unstimulated salivary flow with remibrutinib compared with placebo over 24 weeks. Remibrutinib had a favourable safety profile in patients with SjS over 24 weeks. Remibrutinib induced significant changes in gene expression in blood, and serum protein abundance compared with placebo.
CONCLUSIONS
These data show preliminary efficacy and favourable safety of remibrutinib in a phase 2 trial for SjS.
Topics: Humans; Sjogren's Syndrome; Proteomics; Antibodies; Severity of Illness Index; Pyrimidines
PubMed: 37932009
DOI: 10.1136/ard-2023-224691 -
Clinical and Experimental Rheumatology Dec 2023The link between immune cell function and cell metabolic reprogramming is currently known under the term "immunometabolism". Similarly to the Warburg's effect described... (Review)
Review
The link between immune cell function and cell metabolic reprogramming is currently known under the term "immunometabolism". Similarly to the Warburg's effect described in cancer cells, in activated immune cells an up-regulation of specific metabolic pathways has been described and seems to be pathogenic in different inflammatory conditions.Sjӧgren's syndrome (SS) is a systemic autoimmune disease that affects the exocrine glands and is characterised by a progressive loss of secretory function. Despite the increasing amount of evidence on the ability of metabolism in regulating cell behaviour in inflammatory or tumoral conditions, the field of metabolism in SS is still for the most part unexplored.The aim of this review is to summarise currently available studies evaluating cell metabolism in SS with a particular focus on the possible pathogenic role of metabolic changes in immune and non-immune cells in this condition.
Topics: Humans; Sjogren's Syndrome
PubMed: 38149514
DOI: 10.55563/clinexprheumatol/hhbqej -
La Revue de Medecine Interne Aug 2023Sjögren's disease (SD), also known as Sjögren's syndrome (SS) or Gougerot-Sjögren's syndrome in France, is a rare systemic autoimmune disease in its primary form and... (Review)
Review
Sjögren's disease (SD), also known as Sjögren's syndrome (SS) or Gougerot-Sjögren's syndrome in France, is a rare systemic autoimmune disease in its primary form and is characterised by tropism for the exocrine glandular epithelia, particularly the salivary and lacrimal glands. The lymphocytic infiltration of these epithelia will clinically translate into a dry syndrome which, associated with fatigue and pain, constitutes the symptom triad of the disease. In about one third of patients, SD is associated with systemic complications that can affect the joints, skin, lungs, kidneys, central or peripheral nervous system, and lymphoid organs with an increased risk of B-cell lymphoma. SD affects women more frequently than men (9/1). The peak frequency is around the age of 50. However, the disease can occur at any age, with paediatric forms occurring even though they remain rare. SD can occur alone or in association with other systemic autoimmune diseases. In its isolated or primary form, the prevalence of SD is estimated to be between 1 per 1000 and 1 per 10,000 inhabitants. The most recent classification criteria were developed in 2016 by EULAR and ACR. The course and prognosis of the disease are highly variable and depend on the presence of systemic involvement and the severity of the dryness of the eyes and mouth. The current approach is therefore to identify at an early stage those patients most at risk of systemic complications or lymphoma, who require close follow-up. On the other hand, regular monitoring of the ophthalmological damage and of the dental status should be ensured to reduce the consequences.
Topics: Humans; Female; Child; Sjogren's Syndrome; Eye; Skin; France
PubMed: 37453854
DOI: 10.1016/j.revmed.2023.07.001 -
Joint Bone Spine Mar 2024The improved understanding of the molecular basis of innate immunity have led to the identification of type I interferons (IFNs), particularly IFN-α, as central... (Review)
Review
The improved understanding of the molecular basis of innate immunity have led to the identification of type I interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of several Immune-mediated inflammatory diseases (IMIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis and Sjögren's syndrome. Here, we review the main data regarding the opportunity to target type I IFNs for the treatment of IMIDs. Type I IFNs and their downstream pathways can be targeted pharmacologically in several manners. One approach is to use monoclonal antibodies against IFNs or the IFN-receptors (IFNARs, such as with anifrolumab). The downstream signaling pathways of type I IFNs also contain several targets of interest in IMIDs, such as JAK1 and Tyk2. Of these, anifrolumab is licensed and JAK1/Tyk2 inhibitors are in phase III trials in SLE. Targeting IFN-Is for the treatment of SLE is already a reality and in the near future may prove useful in other IMIDs. IFN assays will find a role in routine clinical practice for the care of IMIDs as further validation work is completed and a greater range of targeted therapies becomes available.
Topics: Humans; Interferon Type I; Interferons; Lupus Erythematosus, Systemic; Sjogren's Syndrome; Immunity, Innate; Immunomodulating Agents
PubMed: 37640261
DOI: 10.1016/j.jbspin.2023.105627 -
Scientific Reports Nov 2023We compared the efficacy and safety of autologous-serum (AS) and platelet-rich plasma (PRP) eye drops for dry eye (DE) treatment in primary Sjögren's syndrome (SS).... (Randomized Controlled Trial)
Randomized Controlled Trial
We compared the efficacy and safety of autologous-serum (AS) and platelet-rich plasma (PRP) eye drops for dry eye (DE) treatment in primary Sjögren's syndrome (SS). This prospective, randomized, double-blinded clinical study included patients diagnosed with primary SS DE. Thirty-eight participants were randomly assigned to the AS or PRP groups. Corneal and conjunctival staining scores, Schirmer I test, tear film break-up time (TBUT), and ocular surface disease index (OSDI) scores were evaluated at 4 and 12 weeks. Conjunctival impression cytology (CIC) metaplasia grade and goblet cell density grade at 12 weeks were compared with those at baseline. Corneal and conjunctival staining scores and TBUT significantly improved at 4 and 12 weeks in both groups (all p < 0.005). No significant difference between the AS and PRP groups was observed at 4 and 12 weeks. The Schirmer I values, OSDI scores, CIC metaplasia grade, and goblet cell density grade did not significantly change at 4 and 12 weeks in either group. Both AS and PRP eye drops are effective for primary SS DE without a significant difference. Considering that the preparation time of PRP is shorter than that of AS, PRP can be a good alternative treatment for primary SS DE.
Topics: Humans; Dry Eye Syndromes; Metaplasia; Ophthalmic Solutions; Platelet-Rich Plasma; Prospective Studies; Sjogren's Syndrome; Tears
PubMed: 37935760
DOI: 10.1038/s41598-023-46671-2 -
Journal of Clinical Rheumatology :... Aug 2023The aim of this study was to study clinical and biological differences between men and women with primary Sjögren syndrome (pSS) in China and perform a literature... (Review)
Review
OBJECTIVES
The aim of this study was to study clinical and biological differences between men and women with primary Sjögren syndrome (pSS) in China and perform a literature review to confirm if the clinical phenotypes are affected by sex in patients with pSS.
METHODS
Data from 961 patients with pSS treated at a tertiary hospital in China between January 2013 and March 2022 were analyzed based on medical records. Clinical characteristics, including disease manifestations and serological parameters of the disease, were compared between men and women with pSS using the Mann-Whitney U test and χ 2 test.
RESULTS
This study included 140 (14.6%) men and 821 (85.4%) women with pSS. Women with pSS demonstrated a higher prevalence of dry mouth, dry eyes, arthralgia, and dental caries ( p < 0.05); higher erythrocyte sedimentation rate and immunoglobulin M levels ( p < 0.05); higher prevalence of leukopenia, neutropenia, anemia, low complement 3, and low complement 4 ( p < 0.05); and higher titers of antinuclear antibody, anti-Sjögren syndrome A, anti-Ro52, and rheumatoid factor positivity ( p < 0.05) than men, whereas men with pSS had a higher prevalence of parotid enlargement and interstitial lung disease ( p < 0.05).
CONCLUSIONS
Women with pSS are associated with more dryness, cytopenia, hypocomplementemia, and autoantibody positivity. Although men with pSS probably have lighter sicca symptoms and lower immunoactivity and serologic responses, regular monitoring of interstitial lung disease in men is vital.
Topics: Humans; Male; Female; Sex Characteristics; Dental Caries; Sjogren's Syndrome; Lung Diseases, Interstitial; Medical Records
PubMed: 37068269
DOI: 10.1097/RHU.0000000000001962 -
Journal of Autoimmunity Dec 2023To investigate the compositional and functional characteristics of the gut microbiota in primary Sjögren's syndrome (pSS) and compare them with those in systemic lupus...
OBJECTIVES
To investigate the compositional and functional characteristics of the gut microbiota in primary Sjögren's syndrome (pSS) and compare them with those in systemic lupus erythematosus (SLE).
METHODS
Stool samples from 78 treatment-naïve pSS patients and 78 matched healthy controls were detected by shotgun metagenomic sequencing and compared with those from 49 treatment-naïve SLE patients. The virulence loads and mimotopes of the gut microbiota were also assessed by sequence alignment.
RESULTS
The gut microbiota of treatment-naïve pSS patients had lower richness and evenness and showed a different community distribution than that of healthy controls. The microbial species enriched in the pSS-associated gut microbiota included Lactobacillus salivarius, Bacteroides fragilis, Ruminococcus gnavus, Clostridium bartlettii, Clostridium bolteae, Veillonella parvula, and Streptococcus parasanguinis. Lactobacillus salivarius was the most discriminating species in the pSS patients, especially in those with interstitial lung disease (ILD). Among the differentiating microbial pathways, the superpathway of l-phenylalanine biosynthesis was also further enriched in pSS complicated with ILD. There were more virulence genes carried by the gut microbiota in pSS patients, most of which encoded peritrichous flagella, fimbriae, or curli fimbriae, three types of bacterial surface organelles involved in bacterial colonization and invasion. Five microbial peptides with the potential to mimic pSS-related autoepitopes were also enriched in the pSS gut. SLE and pSS shared significant gut microbial traits, including community distribution, altered microbial taxonomy and pathways, and enriched virulence genes. However, Ruminococcus torques was depleted in pSS patients but enriched in SLE patients compared to healthy controls.
CONCLUSIONS
The gut microbiota in treatment-naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.
Topics: Humans; Gastrointestinal Microbiome; Sjogren's Syndrome; Lupus Erythematosus, Systemic; Metagenome; Lung Diseases, Interstitial
PubMed: 37120327
DOI: 10.1016/j.jaut.2023.103050 -
International Journal of Molecular... May 2024Sjögren's disease (SjD) is a heterogeneous autoimmune disease characterized by severe dryness of mucosal surfaces, particularly the mouth and eyes; fatigue; and chronic... (Review)
Review
Sjögren's disease (SjD) is a heterogeneous autoimmune disease characterized by severe dryness of mucosal surfaces, particularly the mouth and eyes; fatigue; and chronic pain. Chronic inflammation of the salivary and lacrimal glands, auto-antibody formation, and extra-glandular manifestations occur in subsets of patients with SjD. An aberrant expression of long, non-coding RNAs (lncRNAs) has been described in many autoimmune diseases, including SjD. Here, we review the current literature on lncRNAs in SjD and their role in regulating X chromosome inactivation, immune modulatory functions, and their potential as biomarkers.
Topics: Humans; Sjogren's Syndrome; RNA, Long Noncoding; Biomarkers; Animals; X Chromosome Inactivation; Gene Expression Regulation
PubMed: 38791207
DOI: 10.3390/ijms25105162