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ID PMID Title PublicationDate abstract
34626797 Administration of an adeno-associated viral vector expressing interferon-β in patients wi 2022 Jan OBJECTIVE: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA. METHODS: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 10(12)-1.2 × 10(13) genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-β immune responses were evaluated. A data review committee provided safety recommendations. RESULTS: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-β, nor IFN-β antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose. CONCLUSION: Single IA doses of 0.6 × 10(12) or 1.2 × 10(12) ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. TRIAL REGISTRATION: NCT02727764.
34322686 Sleep Disturbances are a Significant Predictor of Chikungunya Arthritis Flare Severity. 2021 OBJECTIVE: The primary objective of this research was to explore the link between sleep and flare pain associated with chikungunya virus (CHIKV) infection. The secondary objective was to investigate if cytokines and T regulatory (Treg) cells have an influence on this relationship. METHODS: A cross-sectional study was performed using data collected in Barranquilla, Colombia, which enrolled patients with and without chronic arthritis with a history of chikungunya infection. Flare severity was measured by a version of the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) flare questionnaire adapted for CHIKV arthritis, including metrics for pain, difficulty with physical activity, fatigue, stiffness and difficulty maintaining social activities due to arthritis that contribute to flare severity. In addition, four sleep disturbance items, five inflammatory cytokine levels, four anti-inflammatory cytokine levels, and six Treg levels were measured. Then, multivariable linear regression models were used to test the direct and indirect effects of flare-pain on sleep disturbance, and to determine whether this relationship was mediated by cytokines or Tregs. Finally, the SAS CALIS procedure was used to test path models showing possible causal effects with mediators and confounds. RESULTS: The analysis showed that sleep disturbance is positively correlated with CHIKV arthritis flare pain, and that it is a significant predictor of flare severity after adjusting for demographic variables, cytokine, and T cell levels. Further, neither T cells nor cytokines mediate the pain/sleep relationship in CHIKV arthritis. CONCLUSION: There is a strong association between sleep disturbance and arthritis flare pain and severity; however, this relationship is not mediated by cytokines or T cells. Since this study is unable to determine causation, further research is needed to determine the mechanism underlying the relationship between sleep disturbances and CHIKV arthritis flares.
34977434 Instructive cartilage regeneration modalities with advanced therapeutic implantations unde 2022 May The development of interdisciplinary biomedical engineering brings significant breakthroughs to the field of cartilage regeneration. However, cartilage defects are considerably more complicated in clinical conditions, especially when injuries occur at specific sites (e.g., osteochondral tissue, growth plate, and weight-bearing area) or under inflammatory microenvironments (e.g., osteoarthritis and rheumatoid arthritis). Therapeutic implantations, including advanced scaffolds, developed growth factors, and various cells alone or in combination currently used to treat cartilage lesions, address cartilage regeneration under abnormal conditions. This review summarizes the strategies for cartilage regeneration at particular sites and pathological microenvironment regulation and discusses the challenges and opportunities for clinical transformation.
34874825 Herpes zoster and Janus kinase inhibition in rheumatology and gastroenterology patients: m 2021 Dec 7 Patients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis (UC), have an increased risk of herpes zoster (HZ) infection, compared with the general population. This risk is further increased by the use of immunomodulatory therapies, with a higher incidence of HZ reported in patients receiving Janus kinase (JAK) inhibitors, compared with those receiving other immunomodulatory or biological therapies. Tofacitinib is an oral JAK inhibitor for the treatment of RA, PsA and UC. In this narrative review, we discuss the effects of tofacitinib and other JAK inhibitors on HZ risk in patients with RA, PsA and UC, and strategies for risk management. We also discuss current UK guidelines for HZ vaccination in healthy individuals and patients with chronic inflammatory diseases, consider selected international guidelines, and review current HZ vaccination strategies.
34586802 Treating Autoimmune Inflammatory Diseases with an siERN1-Nanoprodrug That Mediates Macroph 2021 Oct 26 The clinical application of small interfering RNA (siRNA) drugs provides promising opportunities to develop treatment strategies for autoimmune inflammatory diseases. In this study, siRNAs targeting the endoplasmic reticulum to nucleus signaling 1 (ERN1) gene (siERN1) were screened. Two cationic polymers, polyethylenimine (PEI) and poly(β-amino amine) (PBAA), which can improve the efficiency of the siRNA transfection, were used as siERN1 delivery carriers. They were implemented to construct a nanodrug delivery system with macrophage-targeting ability and dual responsiveness for the treatment of autoimmune inflammatory diseases. In terms of the mechanism, siERN1 can regulate the intracellular calcium ion concentration by interfering with the function of inositol 1,4,5-trisphosphate receptor 1/3 (IP3R1/3) and thus inducing M2 polarization of macrophages. Furthermore, siERN1-nanoprodrug [FA (folic acid)-PEG-R(RKKRRQRRR)-NPs(ss-PBAA-PEI)@siERN1] acts as a conductor of macrophage polarization by controlling the calcium ion concentration and is an inhibitor of MyD88-dependent Toll-like receptor signaling. The results revealed that the FA-PEG-R-NPs@siERN1 has universal biocompatibility, long-term drug release responsiveness, superior targeting properties, and therapeutic effects in mouse collagen-induced arthritis and inflammatory bowel disease models. In conclusion, this study reveals a potential strategy to treat autoimmune inflammatory disorders.
33623411 Securidaca inappendiculata-Derived Xanthones Protected Joints from Degradation in Male Rat 2021 BACKGROUND: The bark of Securidaca inappendiculata Hassk. is traditionally used for treating inflammatory diseases and bone fractures in China. We have previously validated the xanthone-enriched fraction (XRF) of S. inappendiculata with anti-rheumatic potentials, but mechanism underlying the joints protective effects is still largely unknown. MATERIALS AND METHODS: The male rats with collagen-induced arthritis (CIA) were treated with XRF. The therapeutic efficacy of XRF was evaluated by arthritis score changes, morphological observation of paws, histological examinations and serological analyses. Protein expression in tissues and cells was investigated by either immunohistochemical or immunoblotting methods, while levels of mRNA expression were investigated by RT-qPCR. Metabolites in serum were detected by LC-MS approach. The joints homogenates were used for analyzing possible targeted genes by genome microarray analyses. RESULTS: Treatment with XRF and methotrexate (MTX) led to significant decrease in arthritis scores, and alleviated deformation of paws in CIA rats. In addition, XRF and MTX reduced circulating TNF-α, IL-1β and IL-17α in the serum and down-regulated TLR4/NF-κB and JNK pathways in joints of CIA rats. Compared to MTX, XRF-loading microemulsion significantly protected joints, which was accompanied by dramatic decrease in MMP3. Differential genes-based KEGG enrichment and metabolomics analysis suggested that XRF reduced fatty acids biosynthesis by regulating PPAR-γ signaling. S inappendiculata-derived 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN) up-regulated PPAR-γ expression in macrophages, but suppressed it in pre-adipocytes in vitro, which was synchronized with SIRT1 changes. Adiponectin production and SCD-1 expression in pre-adipocytes were also decreased. Aside the direct inhibition on MMP3 expression in synovioblast, the presence of XAN in macrophages-pre-adipocytes co-culture system further reinforced this effect. CONCLUSION: This study revealed the joint protective  advantages of the bioactive fraction from S. inappendiculata in CIA rats over MTX, and demonstrated that S. inappendiculata-derived xanthones suppressed the erosive nature of synovioblast acquired under inflammatory circumstances by regulating PPAR-γ signaling-controlled metabolism-immunity feedback.
34806155 Fine Comparison of the Efficacy and Safety Between GB242 and Infliximab in Patients with R 2022 Feb INTRODUCTION: This phase III trial (NCT04178850) evaluated the efficacy, safety, and immunogenicity of GB242, an infliximab biosimilar, vs. infliximab (Remicade(®)) reference product in patients with moderate-to-severe active rheumatoid arthritis (RA) combination with methotrexate (MTX) therapy. METHODS: Patients were randomized in a 1:1 ratio to receive either GB242 or INF (3 mg/kg). Therapeutic equivalence of clinical response according to the American College of Rheumatology 20% (ACR20) response rate at week 30 was declared if the two-sided 95% CI for the treatment difference was within ± 14%. The comparison of GB242 with INF also included the proportion of patients achieving a week 30 ACR 50 response, ACR70 response, change in Disease Activity Score 28 (DAS28), as well as safety and immunogenicity. RESULTS: A total of 570 subjects were randomized into GB242 (N = 285) or INF (N = 285) and 283 subjects in each group were analyzed. At week 30, the ACR20 was 62.54% for the GB242 group (95% CI 56.62-68.20%) and 56.89% for the INF group (95% CI 50.90-62.74%). The difference between the two groups was 5.65% with a 95% CI of - 2.48 to 13.74. ACR50 response was 37.12% for GB242 and 32.86% for INF at week 30. ACR70 response was 19.79% for GB242 and 16.96% for INF at week 30, respectively. The incidence of treatment-emergent adverse events was comparable (77.4% in GB242 vs. 80.2% in INF) and detection of antidrug antibodies (ADA) to infliximab up to week 30 (60.8% in GB242 vs. 59.4% in INF) was comparable. CONCLUSIONS: GB242 demonstrated equivalent efficacy to INF at week 30. Moreover, GB242 was well tolerated, with a similar immunogenicity and safety profile comparable to INF.
34113254 Traditional Chinese Medicine Qingre Huoxue Treatment vs. the Combination of Methotrexate a 2021 Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). Qingre Huoxue treatment (Qingre Huoxue decoction (QRHXD)/Qingre Huoxue external preparation (QRHXEP)) is a therapeutic scheme of TCM for RA. To date, there have been few studies comparing the efficacy and safety of QRHXD and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for the treatment of active RA. This was investigated in a multicenter, double-blind, randomized controlled trial involving 468 Chinese patients with active RA [disease activity score (DAS)-28 > 3.2] treated with QRHXD/QRHXEP (TCM group), methotrexate plus hydroxychloroquine [Western medicine (WM) group], or both [integrative medicine (IM) group]. Patients were followed up for 24 weeks. The primary outcome measure was the change in DAS-28 from baseline to 24 weeks. The secondary outcome measures were treatment response rate according to American College of Rheumatology 20, 50, and 70% improvement criteria (ACR-20/50/70) and the rate of treatment-related adverse events (TRAEs). The trial was registered at ClinicalTrials.gov (NCT02551575). DAS-28 decreased in all three groups after treatment (p < 0.0001); the score was lowest in the TCM group (p < 0.05), while no difference was observed between the WM and IM groups (p > 0.05). At week 24, ACR-20 response was 73.04% with TCM, 80.17% with WM, and 73.95% with IM (based on the full analysis set [FAS], p > 0.05); ACR-50 responses were 40.87, 47.93, and 51.26%, respectively, (FAS, p > 0.05); and ACR-70 responses were 20.87, 22.31, and 25.21%, respectively, (FAS, p > 0.05). Thus, treatment efficacy was similar across groups based on ACR criteria. On the other hand, the rate of TRAEs was significantly lower in the TCM group compared to the other groups (p < 0.05). Thus, QRHXD/QRHXEP was effective in alleviating the symptoms of active RA-albeit to a lesser degree than csDMARDs-with fewer side effects. Importantly, combination with QRHXD enhanced the efficacy of csDMARDs. These results provide evidence that QRHXD can be used as an adjunct to csDMARDs for the management of RA, especially in patients who experience TRAEs with standard drugs. Clinical Trial Registration: ClinicalTrials.gov, identifier NCTNCT025515.
35382368 Attitudes of patients with spondylarthritis or rheumatoid arthritis regarding biological t 2021 Dec OBJECTIVES: In this study, we aimed to investigate the medical treatment attitudes of patients with spondylarthritis or rheumatoid arthritis (RA) who were using biological drugs during the novel coronavirus-2019 (COVID-19) pandemic. PATIENTS AND METHODS: In this multi-center, cross-sectional study, a total of 277 patients (178 males, 99 females; median age: 45 years; range, 20 to 77 years) who were using biological disease-modifying anti-rheumatic drugs (bDMARDs) for rheumatic diseases and were reached by phone between June 1st, 2020 and June 30th, 2020 were included. Demographic characteristics, working status, type of the rheumatic disease, comorbidities, smoking habits, and type of the bDMARDs were recorded. Disease activity was evaluated using the Visual Analog Scale (VAS). The patients were asked whether they continued the treatment plan, as it was before or changed and, if changed, how they changed the plan and what happened after the change. RESULTS: Of the patients, 229 had spondylarthritis and 48 had RA. A total of 36.1% of the patients were smokers, and the most common comorbidity was hypertension (17.3%). Totally, 5.8% of the patients had a history of contact with a COVID-19 positive person. Only three (1.1%) patients were diagnosed with COVID-19 infection and none of them died. Of the patients, 64.3% continued their treatment, while 35.7% adopted various changes. Most patients made the decision about the treatment plan on their own (n=160, 57.8%), while 38.3% of them consulted their physicians and 13.9% of them consulted any health staff. The only significant parameter for changing the drug course was receiving intravenous bDMARDs (by infusion at hospital) (p=0.001). These patients had also a higher disease activity as measured by VAS, compared to the patients receiving non-infusion therapy (p=0.021). As a result of these changes, severity of the symptoms increased in 91 (32.9%) patients. Disruption of regular biological treatment and prior infusion therapy more likely worsened the complaints (p<0.001 and p=0.024, respectively). CONCLUSION: Intravenous bDMARD therapy seems to be the main factor affecting the continuity of the treatment in the pandemic period. During the pandemic period, alternative treatment options should be considered other than infusion therapy not to interrupt the treatment of these patients.
34783890 Impact of rheumatoid arthritis on sexuality: adaptation and validation of the Qualisex que 2021 Nov 16 Patients with rheumatoid arthritis (RA) have a significantly increased risk of sexual dysfunction. However, it is not properly included in commonly used questionnaires to assess health-related quality of life in RA. Qualisex is a questionnaire developed in France to assess the impact of RA on patients´ sexual function. Our aim was to adapt and validate this questionnaire for use with Spanish RA patients. Two independent translations and a backward translation were obtained. The final version was tested in a pilot study with 10 RA patients to detect any aspects that could hinder interpretation. The validity and reliability of the linguistically validated questionnaire were studied in a multicenter cross-sectional study, with a longitudinal component for reliability estimation. 125 RA patients were included. The response process, discrimination, internal consistency, internal structure, convergent validity (correlation with MGH-SFQ questionnaire, DAS-28, physician global assessment, patient global health assessment, RAID, HAQ, HADS and SF-12(©)) and reliability were analyzed. The inclusion of two extra items was proposed in the pilot study. The validity analysis detected responses for item 10 that were not coherent with responses for the rest of items. The Cronbach alpha coefficient was 0.971. The highest correlation (0.665) was obtained with MGH-SFQ (questionnaire measuring sexual functioning), followed by RAID (0.516). The intra-class correlation was 0.880 (95% CI 0.815; 0.923), higher than 0.85, which indicates excellent reliability. All parameters used to assess this questionnaire show highly acceptable values. Qualisex allows for a global score of RA patients' sexual functioning and can be self-administered.
34051867 Pain and fatigue are predictors of quality of life in primary Sjögren's syndrome. 2021 May 29 BACKGROUND: Few studies have evaluated the relation of quality of life (QoL) with symptoms and disease activity in primary Sjögren's syndrome (pSS). There is also scant information on the predictors of QoL in this population. The aim of this study was to assess QoL in patients with pSS and to investigate their possible predictors. METHODS: In a cross-sectional study, 77 patients with pSS were evaluated using the following questionnaires: Functional Assessment of Chronic Illness Therapy Fatigue Subscale (FACIT-Fatigue), EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Short Form-36 Health Survey (SF-36) and World Health Organization Quality of Life Assessment (WHOQOL-BREF). Seventy-seven healthy controls responded to the SF-36 and WHOQOL-BREF. The Mann-Whitney test, t-test, Pearson and Spearman correlation, and multiple regression analysis were used in the statistical analysis. RESULTS: Patients with pSS and healthy controls were matched by gender and age. The mean scores for the ESSDAI, ESSPRI and FACIT-Fatigue were 3.34 ± 4.61, 6.58 ± 2.29 and 26.17 ± 11.02, respectively. Patients had a lower employment rate (36.4% versus 62.3%, p < 0.01) and higher work disability (10.4% versus 1.3%, p < 0.01). SF-36 and WHOQOL-BREF values were lower in patients with pSS (p < 0.001), except in the WHOQOL-BREF environment domain. Pain (ESSPRI), fatigue (FACIT-Fatigue), antinuclear antibody (ANA), anti-Ro-SSA and economic class (Brazilian Economic Classification Criteria - CCEB) were independent predictors of QoL. CONCLUSIONS: The main predictors of poor QoL in patients with pSS were pain and fatigue, and these symptoms had an impact regardless of disease activity, age, schooling, marital status, work disability and fibromyalgia.
33830371 Ophthalmic manifestations in patients with collagen vascular disorders: a hospital-based r 2021 Aug AIM: To study frequency and characteristics of ocular manifestations in Indian patients with collagen vascular disorders. METHODS: The medical records of 73 patients (Males: Females 16:57) aged between 22 and 78 years (mean ± SD = 43.5 ± 12.9 years) with collagen vascular diseases were analyzed retrospectively for demography, subtypes of collagen vascular disease, and findings of complete ophthalmic examination. RESULTS: Lupus erythematosus (LE) in 39(53.4%, (SLE 18, DLE 21), systemic sclerosis in 27(37%), dermatomyositis in 5(6.8%), and primary Sjögren's syndrome in 2(2.7%) patients, respectively, were observed. Only 35(47.9%) patients had ocular manifestations. In LE keratoconjunctivitis sicca (n = 6), keratitis (n = 5), severe blepharitis (n = 3), retinopathy (n = 2), and optic neuritis in one patient, respectively, were major ocular manifestations. Major abnormalities occurring in systemic sclerosis included restricted eyelid mobility of variable severity (n = 8), eyelid telangiectasia (n = 5), keratoconjunctivitis sicca (n = 6), cataract (n = 5), shallow fornices (n = 4), conjunctival surface disease (n = 4), and uveitis, keratitis, episcleritis in one patient each, respectively. One patient with dermatomyositis had heliotrope rash. Two patients with primary Sjögren's syndrome had keratoconjunctivitis sicca. CONCLUSIONS: The study shows that LE frequently presented with keratoconjunctivitis sicca, retinopathy, and optic neuritis. Systemic sclerosis commonly develops eyelid immobility, blepharitis and telangiectasia, ocular surface disease and keratoconjunctivitis sicca, corneal abnormalities, and uveitis. A comprehensive ocular evaluation is imperative for early detection and management particularly of ocular surface disease, uveitis, and retinopathy to prevent potential sight-threatening complications. Limitations include retrospective study design and small number of patients for stratification.
32803681 Juvenile primary Sjögren's syndrome with ranula: is ranula a clinical sign that leads to 2021 Apr Juvenile primary Sjögren's syndrome (pSS) is rare. Although recurrent parotitis is reported to be the most common symptom of juvenile pSS, the clinical symptoms and features of the syndrome are not well understood and are poorly defined. Here we report a rare case of juvenile pSS in a patient with plunging ranula. The patient had no symptoms other than swelling of the oral floor and had no symptoms of parotitis. Magnetic resonance imaging (MRI) revealed the diagnosis of plunging ranula. In addition, the findings of the bilateral parotid glands on MRI and subsequent ultrasonography (US) strongly suggested SS. On the basis of these imaging findings and laboratory data, a pediatric rheumatologist confirmed the diagnosis of juvenile pSS. The ranula may be one clinical sign of SS. However, this association remains generally unknown. Hypothesizing that SS might cause ranula development, we retrospectively investigated cases of patients with ranula who underwent MRI at our hospital. We found that many of these patients (> 20%) had characteristic findings strongly suggestive of SS. This result suggests that SS-induced changes in the sublingual glands are one cause of ranula formation. We think that ranula is a sign of early-stage SS. Therefore, patients with ranulae, whether adults or children, should undergo careful assessment of not only the sublingual glands but also the parotid and submandibular glands with MRI and/or US to investigate possible SS. This assessment may lead to early detection of SS.
33879581 Application of the OMERACT Grey-scale Ultrasound Scoring System for salivary glands in a s 2021 Apr AIM: To describe salivary gland involvement in patients suspected of Sjögren's syndrome (SS) using the OMERACT Ultrasound Scoring System for SS. Next, using different ultrasound cut-offs, to assess the performance of the scoring system for diagnosis and fulfilment of 2016 ACR/EULAR SS classification criteria. METHODS: All patients referred to our department with a suspicion of SS in a 12-month period were included. All underwent grey-scale ultrasound of the parotid and submandibular glands prior to clinical examination, Schirmer's test, unstimulated salivary flow, blood samples including autoantibody analysis. Labial biopsy was performed according to clinicians' judgement. Images of the four glands were scored 0-3 according to the scoring system and a consensus score was obtained using a developed ultrasound atlas. RESULTS: Of the 134 patients included in the analysis, 43 were diagnosed with primary SS (pSS) and all fulfilled the 2016 American College of Rheumatology (ACR)/EULAR classification criteria. More patients with pSS compared with non-pSS had score ≥2 in at least one gland (72% vs 13%; p<0.001). In patients with score ≥2 in any gland, significantly more had positive autoantibodies, sialometry, Schirmer's test and positive labial biopsy compared with those with scores ≤1. The best ultrasound cut-off value for diagnosing pSS was ≥1 gland with a score ≥2 (sensitivity=0.72, specificity=0.91). CONCLUSION: The OMERACT Ultrasound Scoring System showed good sensitivity (0.72) and excellent specificity (0.91) for fulfilling 2016 ACR/EULAR criteria using cut-off score >2 in at least one gland. Our data supports the use of ultrasound for diagnosing pSS and supports incorporation of ultrasound in the classification criteria.
33561807 P2Y(2) receptor antagonism resolves sialadenitis and improves salivary flow in a Sjögren' 2021 Apr OBJECTIVE: Sjögren's syndrome (SS) is a chronic autoimmune exocrinopathy characterized by lymphocytic infiltration of the salivary and lacrimal glands and decreased saliva and tear production. Previous studies indicate that the G protein-coupled P2Y(2) nucleotide receptor (P2Y(2)R) is upregulated in numerous models of salivary gland inflammation (i.e., sialadenitis), where it has been implicated as a key mediator of chronic inflammation. Here, we evaluate both systemic and localized P2Y(2)R antagonism as a means to resolve sialadenitis in the NOD.H-2(h4),IFNγ(-/-),CD28(-/-) (NOD.H-2(h4) DKO) mouse model of SS. DESIGN: Female 4.5 month old NOD.H-2(h4) DKO mice received daily intraperitoneal injections for 10 days of the selective P2Y(2)R antagonist, AR-C118925, or vehicle-only control. Single-dose localized intraglandular antagonist delivery into the Wharton's duct was also evaluated. Carbachol-induced saliva was measured and then submandibular glands (SMGs) were isolated and either fixed and paraffin-embedded for H&E staining, homogenized for RNA isolation or dissociated for flow cytometry analysis. RESULTS: Intraperitoneal injection, but not localized intraglandular administration, of AR-C118925 significantly enhanced carbachol-induced salivation and reduced lymphocytic foci and immune cell markers in SMGs of 5 month old NOD.H-2(h4) DKO mice, compared to vehicle-injected control mice. We found that B cells represent the primary immune cell population in inflamed SMGs of NOD.H-2(h4) DKO mice that express elevated levels of P2Y(2)R compared to C57BL/6 control mice. We further demonstrate a role for P2Y(2)Rs in mediating B cell migration and the release of IgM. CONCLUSION: Our findings suggest that the P2Y(2)R represents a novel therapeutic target for the treatment of Sjögren's syndrome.
34610996 ANA-positive primary immune thrombocytopaenia: a different clinical entity with increased 2021 Oct OBJECTIVE: Primary immune thrombocytopaenia (ITP) is highly heterogeneous. ANA-positive primary ITP may resemble the preclinical stage of connective tissue diseases (CTDs), but is still considered primary ITP due to a controversial CTD risk assessment in this group. The objective of this study was to clarify the risk of CTD in ANA-positive patients with primary ITP. METHODS: We performed a retrospective cohort study and a meta-analysis. 586 patients with newly diagnosed primary ITP were followed up and Cox regression analyses were used to analyse the associations of ANA positivity and other immune parameters with CTD development. RESULTS: The mean follow-up time was 37 (19-56) months. ANA was positive in 21.33% (125 of 586) of patients with primary ITP in our retrospective cohort, and the overall rate of ANA positivity in the meta-analysis was 17.06% (369 of 2163). The adjusted HR for CTD in ANA-positive primary ITP was 6.15 (95% CI 2.66 to 14.23, p<0.001). Five patients in the ANA-positive group developed SLE (5 of 125, 4.0%), significantly higher than in the ANA-negative group (0 of 461, 0%). A clinical model combining ANA, anti-Sjogren's syndrome A antibody and C3 was successfully developed to predict the risk of CTD in patients with primary ITP. Increased risk of CTD (risk ratio=12.43, 95% CI 7.91 to 19.55, p<0.00001), especially SLE (risk ratio=30.41, 95% CI 13.23 to 69.86, p<0.00001), among ANA-positive patients with primary ITP was confirmed by a meta-analysis of previous studies and the present study. CONCLUSIONS: The findings suggest that ANA-positive primary ITP is a clinical entity distinct from other primary ITPs and is associated with increased risk of developing CTDs, especially SLE.
34446113 Labial gland-derived mesenchymal stem cells and their exosomes ameliorate murine Sjögren' 2021 Aug 26 BACKGROUND: Sjögren's syndrome (SS) is a chronic, systemic autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The disease severely affects the health and life of patients, and the treatment of SS has always been a clinical challenge and essentially palliative. Mesenchymal stem cells (MSCs) have been reported to exert immunomodulatory effects and as a potential novel therapeutic strategy for SS. Labial gland-derived MSCs (LGMSCs) are a population of resident stem cells in the labial gland, first isolated by our group. Exosomes released by MSCs contain a large variety of bioactive molecules and considered to function as an extension of MSCs. METHODS: LGMSCs were isolated from patients who were needed surgery to remove the lip mucocele and LGMSCs derived exosomes (LGMSC-Exos) were isolated by ultracentrifugation. The non-obese diabetic (NOD) mice were treated with LGMSCs or LGMSC-Exos by tail vein injection. The saliva flow rate of mice was determined and salivary glands were dissected and stained with hematoxylin and eosin. In vitro, peripheral blood mononuclear cells (PBMCs) from SS patients were cocultured with LGMSCs or LGMSC-Exos. Percentage of T helper 17 (Th17) cells and regulatory T (Treg) cells were determined by flow cytometry. The serum levels of cytokines in NOD mice and in the supernatant of the co-culture system by ELISA. RESULTS: Treatment with LGMSCs or LGMSC-Exos reduced inflammatory infiltration in the salivary glands, and restored salivary gland secretory function in NOD mice. Importantly, LGMSCs or LGMSC-Exos were demonstrated to inhibit the differentiation of Th17 cells but promote the induction of Treg cells in NOD mice and PBMCs from SS patients in vitro, accompanied by reduced interleukin 17 (IL-17), interferon gamma, and IL-6 levels and enhanced transforming growth factor beta and IL-10 secretion by T cells. CONCLUSIONS: LGMSCs are potential candidates for MSCs-based therapy and LGMSC-Exos might be utilized for establishing a new cell-free therapy against SS.
33645922 Stratification of Patients With Sjögren's Syndrome and Patients With Systemic Lupus Eryth 2021 Sep OBJECTIVE: Similarities in the clinical and laboratory features of primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE) have led to attempts to treat patients with primary SS or SLE with similar biologic therapeutics. However, the results of many clinical trials are disappointing, and no biologic treatments are licensed for use in primary SS, while only a few biologic agents are available to treat SLE patients whose disease has remained refractory to other treatments. With the aim of improving treatment selections, this study was undertaken to identify distinct immunologic signatures in patients with primary SS and patients with SLE, using a stratification approach based on immune cell endotypes. METHODS: Immunophentyping of 29 immune cell subsets was performed using flow cytometry in peripheral blood from patients with primary SS (n = 45), patients with SLE (n = 29), and patients with secondary SS associated with SLE (SLE/SS) (n = 14), all of whom were considered to have low disease activity or be in clinical remission, and sex-matched healthy controls (n = 31). Data were analyzed using supervised machine learning (balanced random forest, sparse partial least squares discriminant analysis), logistic regression, and multiple t-tests. Patients were stratified by K-means clustering and clinical trajectory analysis. RESULTS: Patients with primary SS and patients with SLE had a similar immunologic architecture despite having different clinical presentations and prognoses. Stratification of the combined primary SS, SLE, and SLE/SS patient cohorts by K-means cluster analysis revealed 2 endotypes, characterized by distinct immune cell profiles spanning the diagnoses. A signature of 8 T cell subsets that distinctly differentiated the 2 endotypes with high accuracy (area under the curve 0.9979) was identified in logistic regression and machine learning models. In clinical trajectory analyses, the change in damage scores and disease activity levels from baseline to 5 years differed between the 2 endotypes. CONCLUSION: These findings identify an immune cell toolkit that may be useful for differentiating, with high accuracy, the immunologic profiles of patients with primary SS and patients with SLE as a way to achieve targeted therapeutic approaches.
32920529 Palpebral lobe of the human lacrimal gland: morphometric analysis in normal versus dry eye 2021 Oct AIM: To study the morphological features of the palpebral lobe of the main lacrimal gland in normal and dry eyes. METHODS: This cross-sectional study included 25 healthy subjects and 83 patients with dry eye disease (DED). The aetiological groups of DED were cicatrising conjunctivitis (CC, n=35), evaporative dry eyes (EDE, n=25) and Sjogren's syndrome (SS, n=23). The palpebral lobes in both eyes were evaluated using slit-lamp biomicroscopy and photography for size (exposed area in mm(2)), shape (convex or flat), presence of cicatrisation (scarring and/or symblepharon) and appearance of the overlying conjunctival vessels. RESULTS: The palpebral lobes in the normal and EDE group were similar in terms of size (41.5±15.6 mm(2) vs 39±12.2 mm(2), p=0.203), convex shape (100%) and absence of cicatrisation or vascular engorgement (0%). However, as compared to normal controls, the size of the palpebral lobe was markedly reduced in the SS (27.9±12.3, p<0.0001) and CC (18.1±13.7, p<0.0001) groups. The size of the lobes was asymmetric in the CC group (p<0.0001) and differed significantly from the SS group (p=0.0003). Flat contour (79% vs 50%, p=0.0028), subepithelial scarring with or without symblepharon (52% vs 13%, p<0.0001) and engorged conjunctival vessels (96% vs 63%, p=0.00011) were seen in a significantly higher proportion of lobes in the CC as compared to the SS group. CONCLUSION: The morphological features of the palpebral lobe of the main lacrimal gland are significantly distorted in aqueous deficient dry eyes due to CC and SS; however, the lobes in patients with EDE are similar to normal eyes.
30770922 Genetics and epigenetics in primary Sjögren's syndrome. 2021 May 14 Primary Sjögren's syndrome (pSS) is considered to be a multifactorial disease, where underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to disease development. In the last 5 years, the first genome-wide association studies in pSS have been completed. The strongest signal of association lies within the HLA genes, whereas the non-HLA genes IRF5 and STAT4 show consistent associations in multiple ethnicities but with a smaller effect size. The majority of the genetic risk variants are found at intergenic regions and their functional impact has in most cases not been elucidated. Epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNAs play a role in the pathogenesis of pSS by their modulating effects on gene expression and may constitute a dynamic link between the genome and phenotypic manifestations. This article reviews the hitherto published genetic studies and our current understanding of epigenetic mechanisms in pSS.