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ID PMID Title PublicationDate abstract
33493343 A novel loss-of-function mutation in LACC1 underlies hereditary juvenile arthritis with ex 2021 Oct 2 OBJECTIVE: To investigate phenotypic and molecular characteristics of a consanguineous family with autosomal-recessive, polyarticular, juvenile isiopathic arthriris (JIA) with extra-articular manifestations, including renal amyloidosis and Crohn's disease, associated with a novel homozygous truncating variant in LACC1. METHODS: Whole exome sequencing (WES) or targeted Sanger verification were performed in 15 participants. LACC1 expression and cytokine array were analysed in patient-derived and CRISPR/Cas9-generated LACC1-knockout macrophages (MÏ•). RESULTS: A homozygous truncating variant (p.Glu348Ter) in LACC1 was identified in three affected and one asymptomatic family member, and predicted harmful by causing premature stop of the LACC1 protein sequences, and by absence from ethnically-matched controls and public variation databases. Expression studies in patient-derived macrophages (MÏ•) showed no endogenous p.Glu348Ter-LACC1 RNA transcription or protein expression, compatible with nonsense-mediated mRNA decay. WES analysis in the asymptomatic homozygous subject for p. Glu348Ter-LACC1 detected an exclusive heterozygous variant (p.Arg928Gln) in complement component C5. Further complement activity analysis suggested a protective role for the p.Arg928Gln-C5 variant as a phenotypic modifier of LACC1-associated disease. Finally, cytokine profile analysis indicated increased levels of pro-inflammatory cytokines in LACC1-disrupted as compared with wild-type MÏ•. CONCLUSIONS: Our findings reinforce the role of LACC1 disruption in autosomal-recessive JIA, extend the clinical spectrum and intra-familial heterogeneity of the disease-associated phenotype, indicate a modulatory effect of complement factor C5 on phenotypic severity, and suggest an inhibitory role for wild-type LACC1 on pro-inflammatory pathways.
34733920 LncRNA THRIL is involved in the proliferation, migration, and invasion of rheumatoid fibro 2021 Sep BACKGROUND: Fibroblast-like synoviocytes (FLSs), which can migrate and directly invade the cartilage and the bone, are crucial players in joint damage in rheumatoid arthritis (RA). Nevertheless, the detailed mechanisms underlying the aberrant activation of RA FLSs remain unclear. Several studies have attempted to explore the relationship between long non-coding RNAs (lncRNAs) and RA pathology; however, the role of lncRNAs in RA is unknown. The present study aimed to determine the functions of tumor necrosis factor-α and heterogeneous nuclear ribonucleoprotein L-related immunoregulatory lincRNA (THRIL) in RA FLSs migration and invasion. METHODS: Small interfering RNA targeting THRIL or lentivirus overexpressing THRIL was used to knockdown or overexpress THRIL. Quantitative reverse transcription polymerase chain reaction (PCR) was employed for the detection of RNA expression. The proliferation rate of RA FLSs was measured using a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. Migration and invasion were detected using a transwell chamber. Downstream targets were identified using a human cell cycle real-time PCR array and a human cell motility real-time PCR array. RESULTS: A significant decrease in THRIL expression was found in RA FLSs compared with cells from healthy control (HC)patients. THRIL is mainly localized in the nucleus. Knockdown of THRIL increased the proliferation, migration, and invasion of RA FLSs. In contrast, THRIL overexpression had the opposite effect. THRIL knockdown increased interleukin-1β (IL-1β)-triggered expression of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13. THRIL overexpression led to a significant decrease in MMP-13 expression in response to stimulation with IL-1β. Furthermore, we observed that the expression levels of cyclin-dependent kinase 1 (CDK1) and G2 and S phase-expressed-1 (GTSE1), both of which are associated with cellular mobility and proliferation, were downregulated with THRIL overexpression. CONCLUSIONS: Reduced expression of lncRNA THRIL represses the proliferation, migration, and invasion of RA FLSs, suggesting that lncRNA THRIL might be a potential target for RA therapy.
33991197 Clonal expansion of large granular lymphocytes in patients with spondyloarthritis and psor 2021 Nov To determine the prevalence of clonal T-large granular lymphocyte (T-LGL) cells in patients with spondyloarthritis (SpA) and psoriatic arthritis (PsA) and to define possible risk factors for this condition. We present a cross-sectional analysis with retrospective and prospective aspects. 115 SpA patients, 48 PsA patients and 51 controls were recruited between December 28, 2017 and January 23, 2019. Flow cytometry (FACS) was performed to screen for aberrant T-LGL cells. Molecular analysis was then employed to confirm the diagnosis in patients with suggestive FACS findings. Patients with clonal T-LGL populations were followed prospectively by FACS analysis. Electronic patient files were retrospectively analyzed to determine risk factors. Median age was 49 years for SpA, 55.5 years for PsA, and 54 years for controls. Median disease duration of SpA and PsA was 15 years and 11 years, respectively. 79.8% of patients had received biologics at some point, 75.5% had ever received tumor necrosis factor (TNF) inhibitors. 59.5% were treated with TNF inhibitors at the time of study inclusion. We identified clonal T-LGL expansions in 13 individuals equaling a prevalence of 6% (13/214). T-LGL patients were taking TNF inhibitors more frequently at the time of study inclusion (p = 0.022) and were more likely to have ever been treated with TNF inhibition (p = 0.046). Clonal T-LGL expansions can be detected in patients with SpA, PsA and also in healthy controls. Confirming earlier results, exposure to TNFα-blocking agents appears to increase the risk of developing clonal expansions of T-LGL cells.
34276376 The Effect of Chinese Medicine Compound in the Treatment of Rheumatoid Arthritis on the Le 2021 Objectives: To evaluate the current evidence whether Chinese medicine compound (CMC) can reduce the serum levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP). Methods: We comprehensively searched PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure (CNKI), the Database for Chinese Technical Periodicals (VIP), and Wanfang data. We then performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) assessing the CMC therapy methods. This study is registered with PROSPERO, number CRD42020216284. Results: In total, 65 studies were eligible for inclusion, including 6099 patients. The result of the meta-analysis showed that compared with common Western medicine therapy, CMC monotherapy or combined with Western medicine was able to reduce serum RF (SMD= -0.85, 95%CI -1.04 to -0.67) and anti-CCP (SMD= -0.56, 95%CI -0.79 to -0.32) levels to some extent. In the efficacy meta-analysis, a greater number of CMC-treated patients achieved the efficacy criteria after a period of treatment, where the relative risk (RR) was 1.20 [1.08, 1.33] for achieving ACR20, 1.57 [1.38, 1.78] for ACR50, and 2.21 [1.72, 2.84] for ACR70. At the same time, there was a statistically significant difference in the effective rate of the patient's TCM symptoms (RR = 1.22, 95%CI 1.19-1.26). Conclusions: Through this meta-analysis and systematic review, we found that CMC for the treatment of RA is effective in reducing RF and anti-CCP levels and might have better clinical efficacy than Western medicine monotherapy. Some active components are responsible for this efficacy and worth further exploring.
34326752 Secondary Normal-Pressure Hydrocephalus in Rheumatoid Meningitis. 2021 May Normal-pressure hydrocephalus (NPH) is a common cause of gait apraxia, cognitive impairment, and urinary incontinence in the elderly. It is usually a primary idiopathic disorder but can be secondary. We present a case of secondary NPH due to biopsy-confirmed rheumatoid meningitis initially refractory to intravenous (IV) immunotherapy. Our patient reported an excellent response right after shunting. Her gait remains normal one and a half years later. We searched PubMed for similar cases of rheumatoid meningitis with gait abnormality for additional clinicopathologic discussion. The patient's movement disorder initially improved with steroid taper. However, she developed progressive symptoms, later on, refractory to IV solumedrol and rituximab. She underwent ventriculoperitoneal shunting (VPS) and reported an outstanding outcome. This is the first reported biopsy-confirmed case of rheumatoid meningitis causing NPH to undergo shunting for immediate improvement. Previous cases of rheumatoid meningitis-associated Parkinsonism have improved with steroid induction. Although our patient's rheumatoid arthritis is now controlled, her case illustrates that NPH in autoinflammatory conditions may not recover with immune suppression alone. VPS is an option for a faster response in secondary NPH due to rheumatoid meningitis or other inflammatory disorders with progressive symptoms despite standard induction therapy.
33475433 Antibody-based delivery of interleukin-9 to neovascular structures: Therapeutic evaluation 2021 Apr Interleukin-9 is a cytokine with multiple functions, including the ability to activate group 2 innate lymphoid cells, which has been postulated to be therapeutically active in mouse models of arthritis. Similarly, interleukin-9 has been suggested to play an important role in tumor immunity. Here, we describe the cloning, expression, and characterization of three fusion proteins based on murine interleukin-9 and the F8 antibody, specific to the alternatively spliced EDA domain of fibronectin. EDA is strongly expressed in cancer and in various arthritic conditions, while being undetectable in the majority of healthy organs. Interleukin-9-based fusion proteins with an irrelevant antibody specific to hen egg lysozyme served as negative control in our study. The fusion proteins were characterized by quantitative biodistribution analysis in tumor-bearing mice using radioiodinated protein preparations. The highest tumor uptake and best tumor:organ ratios were observed for a format, in which the interleukin-9 moiety was flanked by two units of the F8 antibody in single-chain Fv format. Biological activity of interleukin-9 was retained when the payload was fused to antibodies. However, the targeted delivery of interleukin-9 to the disease site resulted in a modest anti-tumor activity in three different murine models of cancer (K1735M2, CT26, and F9), while no therapeutic benefit was observed in a collagen induced model of arthritis. Collectively, these results confirm the possibility to deliver interleukin-9 to the site of disease but cast doubts about the alleged therapeutic activity of this cytokine in cancer and arthritis, which has been postulated in previous publications.
34120218 Pulmonary nodular lymphoid hyperplasia and Sjögren's syndrome: a case report and literatu 2021 Nov Pulmonary nodular lymphoid hyperplasia, also known as pseudolymphoma, is an uncommon reactive lymphoproliferative disorder of unknown etiology that can be found in Sjögren's syndrome patients. Here, we present a case of a previously healthy woman in which the incidental finding of a lung mass compatible with nodular lymphoid hyperplasia led to the subsequent diagnosis of Sjögren's syndrome. We also performed a literature review for the association between both entities and described the main clinical aspects of the reported cases. Although its rarity, we consider that pulmonary nodular lymphoid hyperplasia should be considered in the differential diagnosis of lung nodules or masses among Sjögren's syndrome patients.
33316834 A Presentation of Pediatric Sjögren's Syndrome with Abducens Nerve Palsy. 2021 Oct Sjögren's syndrome is a systemic autoimmune disease that classically presents with xerophthalmia and xerostomia. However, neurological manifestations occur in 10 to 60% of patients with Sjögren's syndrome and can often precede classic sicca symptoms in Sjögren's syndrome in some cases up to several years. Rarely, cranial neuropathy can be the initial presentation. Here, we present the first case of a 15-year-old girl with left abducens palsy in the setting of a new diagnosis of Sjögren's syndrome. Comprehensive evaluation revealed elevated Sjögren's syndrome-related antigen A-60 antibody. Cerebrospinal fluid analysis was unremarkable. Radiological studies demonstrated evidence of chronic parotitis. Acute treatment included high-dose methylprednisolone and rituximab, and symptoms resolved by follow-up at 2 weeks. The most common neurological disorder of Sjögren's syndrome is pure sensory neuropathy. In pediatric Sjögren's syndrome, neurological complications are rare but include aseptic meningoencephalitis, acute disseminated encephalomyelitis, transverse myelitis, optic neuritis, and cranial neuropathies. In the circumstance of a cranial neuropathy, the trigeminal nerve is most commonly involved but oculomotor nerves can occasionally be affected. Abducens palsies have been described in four patients with Sjögren's syndrome, typically women and all middle aged or older, with our patient being the first pediatric case. Thus, it is important to consider screening for Sjögren's syndrome in the evaluation of pediatric patients with new onset of isolated cranial neuropathy even in the absence of classic sicca symptoms.
33278589 High prevalence of salivary gland ultrasound abnormalities in systemic sclerosis. 2021 Mar OBJECTIVE: To evaluate salivary gland (SG) involvement in patients with systemic sclerosis (SSc) using SG ultrasound (SGUS). METHODS: Patients with SSc (n=62), primary Sjögren's syndrome (pSS) (n=59), and idiopathic Sicca syndrome (n=43) were evaluated using the outcome measures in rheumatology clinical trial (OMERACT) definitions of the SGUS scoring system. The hyperechogenic bands using the 0-3 scoring system, intraglandular power Doppler signal (PDS), and SG volumes were also assessed. RESULTS: The proportion of patients with OMERACT grades (≥2) among the four SGs was significantly higher in SSc (51.6%) and pSS (62.7%) groups than those in the idiopathic Sicca syndrome group (4.7%). Patients with SSc and pSS had significantly higher total fibrosis grades than controls. No difference in fibrosis grades was observed between SSc and pSS groups. The PDS scores of SGs were higher in the SSc group than in the idiopathic Sicca syndrome group. SG volumes did not differ between the groups. SSc patients with SGUS grades ≥2 had more anti-centromere antibodies (ACA) (65.6% vs. 30.0%) than individuals with grades 0-1. SSc patients with fibrosis grades ≥2 reported more Sicca symptoms than those with grades 0-1. Inhomogeneity and hyperechogenic bands within the SGs were not associated with organ involvement in SSc. CONCLUSIONS: More than half of patients with SSc, specifically with ACA, showed SG involvement. SG fibrosis was more prominent in SSc than in idiopathic Sicca syndrome and was associated with subjective Sicca symptoms. However, hyperechoic bands within the SGs are not features that can differentiate between SSc and pSS.
33989125 Clinical manifestations in anti-Ro52/SS-A antibody-seropositive patients with Sjögren's s 2021 Dec Background: The relationship between anti-Ro52/SS-A antibody (anti-Ro52) and the clinical manifestations of Sjögren's syndrome (SS) has not been fully clarified. We determined the clinical factors relevant to SS patients with anti-Ro52.Methods: We conducted a retrospective study of 149 subjects suspicious for SS and 50 healthy control subjects. We analyzed items of the American-European Consensus Group (AECG) criteria and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI).Results: SS was documented in 115 subjects. Anti-Ro52 was observed in 70 SS patients. Anti-Ro52 positivity showed a significantly higher association with anti-Ro60 positivity than with anti-centromere antibody (ACA) positivity (p < 0.05). Regarding the difference in the anti-Ro52 concentration, we observed six significantly relevant components: two AECG components and four non-AECG components. The anti-Ro52 concentration well-discriminated three clinical factors (ROC AUC >0.75), i.e., ACA seropositivity, ESSDAI score ≥1, and RF, and it moderately discriminated high serum IgG, focus score ≥1, and anti-La/SS-B antibody seropositivity (ROC AUC >0.7). A linear relationship between the ESSDAI score and the anti-Ro52 concentration was observed.Conclusion: A significant association between clinical factors (including the ESSDAI) and the anti-Ro52 concentration were revealed. Anti-Ro52 was more highly associated with anti-Ro60 positivity than with ACA positivity.
34393170 Sjögren's Syndrome with Pleural Effusion: Difficult to Distinguish from Tuberculous Pleur 2022 Feb 15 An 84-year-old woman visited our hospital for dyspnea due to right pleural effusion, with lymphocytic dominance and a high adenosine deaminase (ADA) level, that had been noted 1 month earlier. She was suspected of having tuberculosis pleurisy; however, anti-tuberculosis treatment yielded no improvements. She was diagnosed with pleural effusion due to primary Sjögren's syndrome (SjS) based on her dry eyes and mouth, positivity for anti-Sjögren's-syndrome-related antigen A/B, and histopathologic findings of a lip biopsy and thoracoscopic pleural biopsy. Her symptoms improved after starting steroid therapy. Cases of pleural effusion due to SjS with a high ADA level may be misdiagnosed as tuberculosis pleurisy.
33830848 Ocular Pathophysiology of Sjögren's Syndrome. 2021 May 19 The purpose of this review is to delve into the clinical and research understanding of the pathophysiology and presentation of Sjögren's-related keratoconjunctivitis sicca in order address the diagnostic and management challenge that it represents, as well as to provide a basis for appreciating the pharmacotherapies designed to treat the ophthalmic symptoms of Sjögren's disease.
34951923 New developments in Sjogren's syndrome. 2021 Dec 24 SS is a chronic, autoimmune condition characterized by lymphocytic infiltration of the exocrine glands and B-cell dysfunction. Current treatment strategies are largely empirical and offer only symptomatic relief for patients. There are no proven treatments that alter disease progression or treat the systemic manifestations of disease. B-cell depletion is used in patients with systemic disease but its overall clinical efficacy has not been demonstrated in two large randomized controlled trials. Studies are now focussing on alternative strategies to target B-cells, including co-stimulation targets, with promising data. It is increasingly clear that clinical trials in SS will require patient stratification and relevant and sensitive outcome measures to identify successful treatment modalities.
33406284 Palisaded neutrophilic granulomatous dermatitis, interstitial granulomatous dermatitis and 2021 Apr Palisaded neutrophilic granulomatous dermatitis (PNGD) and interstitial granulomatous dermatitis (IGD) are rare granulomatous disorders. Differential diagnosis of PNGD and IGD is often difficult, but both conditions occasionally exist together. We report here the first potential overlapping case of PNGD, IGD, and Immunoglobulin A (IgA) vasculitis associated with incomplete Sjögren's syndrome. An 81-year-old woman who had been followed up for interstitial pneumonia and incomplete Sjögren's syndrome was referred to our clinic. She had multiple erythematous plaques and nodules on her entire body and purpura on her legs. Biopsied specimens showed granuloma formation with neutrophilic infiltration and degenerated collagen fibers in the center. In addition, interstitial granuloma and so-called "floating sign" in the periphery and leukocytoclastic vasculitis were noted. Elastica-van Gieson staining revealed phagocytosis of elastic fibers by multinucleated giant cells around the granulomas. Direct immunofluorescence showed IgM, IgA, and C3 deposition in vascular walls. We made a diagnosis of an overlap syndrome of PNGD, IGD, and IgA vasculitis in a background of incomplete Sjögren's syndrome. No such case has been previously reported. The pathogenesis of the present case may be associated with Sjögren's syndrome.
33145631 Sjögren syndrome associated with protein-losing enteropathy: case-based review. 2021 Jun The association between Sjögren's syndrome (SS) and protein-losing enteropathy (PLE) was scarcly reported. To analyze the clinical, therapeutic, and outcome characteristics of patients with SS and PLE and also to delineate the potential mechanisms and pathways connecting the gut to SS targeted organ's pathology. Systematic screening was conducted using PubMed/MEDLINE, LILACS, SciELO, Web of Science, and Cochrane, dating 1980 to 2020. SS and PLE were the key words. Eighteen patients with SS and PLE were summarized. The patient's ages ranged between 20 and 88 years, and only 4 were males. Primary SS was observed in most cases. Anti-Ro was detected in 100% of the cases while anti-La was reported in 64% of them. The clinical manifestations were protein loss, edema of the lower limbs, pleural effusion, ascites, facial edema, anasarca, diarrhea, and weight loss. Among these clinical manifestations, edema of the lower limbs was the most severe. Albumin concentration was 0.9-3.4 g/dL which increased to 2.8-4.3 g/dL after treatment. Small bowel biopsy was performed in all of the cases. Concerning the therapy, all the patients received systemic glucocorticoids. All of them improved. The period of onset of improvement ranged from 3 weeks to 36 months (an average of 3 months). The early diagnosis and appropriate therapy of PLE in patients with anti-Ro positive SS and who present edema, anasarca, or hypoalbuminemia is vital for a beneficial outcome. An excellent clinical improvement in all the cases was observed when treated early enough by cortico-therapy, thus preventing patient's deterioration, complications, and reducing morbidity and potential mortality.
32934134 Salivary Gland Focus Score Is Associated With Myocardial Fibrosis in Primary Sjögren Synd 2021 Jun OBJECTIVE: The risk of clinically manifested major cardiovascular (CV) events in primary Sjögren syndrome (pSS) remains unclear. This study aimed to assess myocardial fibrosis in pSS and investigate the associated disease characteristics by cardiac magnetic resonance imaging (cMRI). METHODS: We performed a cross-sectional study of patients with pSS without cardiac symptoms. Labial gland biopsy was documented in 44 patients (85%). Patients without CV risk factors underwent contrast-enhanced cMRI. Late gadolinium enhancement (LGE) was used to assess myocardial fibrosis. Myocardial edema was assessed using T2-weighted imaging (T2WI). We compared the left ventricular (LV) geometry and function between the groups with and without LGE. Further, we explored the associations of cMRI abnormalities with pSS characteristics. RESULTS: Fifty-two women with pSS (median age 55, IQR 47.0-65.7 yrs) were enrolled in the study. LGE was observed in 10 patients (19%), two of whom showed high intensity on T2WI. High intensity on T2WI was observed in 3 patients (5.8%). LV mass index and LV mass/end-diastolic volume tended to be higher in the LGE-positive group than in the LGE-negative group (P = 0.078 and 0.093, respectively). Salivary gland focus score (FS) ≥ 3 was independently associated with LGE-positive in the multivariable analysis (OR 11.21, 95% CI 1.18-106.80). CONCLUSION: Subclinical myocardial fibrosis, as detected by cMRI, was frequent in patients with pSS without cardiac symptoms. Abnormal cMRI findings were associated with salivary gland FS ≥ 3.
32780886 Does Nasal Secretion Decrease in Sjögren Syndrome and Does This Affect Nasal Function? 2021 Feb OBJECTIVE: Sjögren syndrome is a systemic inflammatory disease causing gland dysfunction. Few (and contradictory) reports on the mucosal effects of Sjögren syndrome have appeared. Here, we objectively demonstrate nasal dryness in Sjögren syndrome patients and explore the effect of such dryness on olfaction. METHODS: Thirty-four consecutive patients with primary Sjögren syndrome were enrolled in this cross-sectional study. The control group consisted of 21 age- and sex-matched volunteers. Medical histories and nasal findings were recorded. The Connecticut Chemosensory Clinical Research Center test was used to evaluate olfactory function. All subjects underwent mucucociliary clearance analysis (the saccharin test and peak nasal inspiratory flowmetry). The intranasal Schirmer test was used to evaluate the nasal cavity. RESULTS: The nasal Schirmer test scores were 8.4 mm (right) and 8 mm (left) (P = .041, P = .016, respectively, compared to controls). The Chi-squared test revealed significant differences (compared to controls) in nasal dryness (P = .001), postnasal drip (P = .04), and smell (a decrease) (P = .005). Neither olfactory function nor mucociliary clearance differed between the groups. We noted a trend toward a positive correlation between olfactory function and the nasal Schirmer score but statistical significance was not attained. CONCLUSION: The intranasal Schirmer test objectively showed that Sjögren syndrome patients exhibited nasal cavity dryness; this is useful in terms of follow-up. This did not affect olfactory function. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:370-373, 2021.
34962246 Evolution of clinical, histological and serological features in a Primary Sjὄgren´s Syn 2021 Oct OBJECTIVE: The classification and/or diagnosis of Primary Sjögren's Syndrome (PSS) requires a multidimensional approach. Although age and the duration of sicca symptoms can affect the clinical, serological and histological features found at initial evaluation, these are not considered when using classification criteria as a guide for PSS diagnosis. Our study aimed to explore if there is any relationship between the duration of symptoms and clinical, histopathological and serological findings. METHODS: An observational, retrospective study was performed. All the evaluated subjects were part of the "sicca cohort". Patients' clinical, serological and histological characteristics were assessed according to the duration of symptoms. A Receiving Operator Characteristic (ROC) curve was performed to establish the duration of symptoms (months) that predicted a PSS diagnosis. Binary regression models and odds ratios were used to evaluate the association between the duration of symptoms and the clinical, serological, and histopathological profiles. RESULTS: One hundred and sixteen patients were included; 97(83.62%) fulfilled PSS criteria. Of the 116 patients, thirty-six (31.03%) had < 15 months presenting with sicca symptoms when receiving a diagnostic approach. A duration of symptoms >15 months was associated with an altered Schirmer test (OR 2.76; 95% CI 1.15-6.61, P=0.02), low salivary flow rate (OR 3.5; 95% CI 1.34-9.13, P=0.01), ≥1 foci score (OR 1.21; 95% CI 1-1.45, P=0.04), ocular (OR 7.8; 95% CI 1.49-40.81, P=0.02) and severe oral symptoms (OR 2.61; 95% CI 1.16-5.87, P=0.02). CONCLUSION: The time of evolution of symptoms plays a fundamental role in the clinical, histological and serological profiles in PSS.
33443605 Lymphocyte subpopulations in Sjögren's syndrome are distinct in anti-SSA-positive patient 2021 Jul OBJECTIVES: Sjögren's syndrome (SjS) patients exhibit great phenotypical heterogeneity, reinforced by the positiveness of anti-SSA antibody. We aimed to evaluate lymphocyte subpopulations in SSA-positive (SSA+SjS) and SSA-negative (SSA-SjS) SjS patients, Sicca patients, and healthy controls (HC), and to investigate associations between lymphocyte subpopulations and disease activity in SjS. METHODS: According to the fulfilment of the ACR/EULAR 2016 classification criteria, patients were included as SjS or as Sicca. HC were selected from the Ophthalmology outpatient clinic. Lymphocyte subpopulations were characterized by flow cytometry. Statistical analysis was performed with GraphPad Prism(TM), with statistical significance concluded if p < 0.05. RESULTS: We included 53 SjS patients (38 SSA+ and 15 SSA-), 72 Sicca, and 24 HC. SSA+SjS patients presented increased IL-21(+)CD4(+) and CD8(+) T cells compared to Sicca and HC, whereas compared to SSA-SjS patients, only IL-21(+)CD4(+) T cell percentages were increased and Tfh17 percentages and numbers were decreased. Compared to Sicca and HC, SSA+SjS patients had higher levels of CD24(Hi)CD38(Hi) B cells, naïve B cells, and IgM(-/+)CD38(++) plasmablasts, and lower levels of memory B cells, including CD24(Hi)CD27(+) B cells. SSA+SjS patients with clinically active disease had positive correlations between ESSDAI and IL-21(+)CD4(+) (p = 0.038, r = 0.456) and IL-21(+)CD8(+) T cells (p = 0.046, r = 0.451). CONCLUSIONS: In SjS, a distinct lymphocyte subset distribution profile seems to be associated with positive anti-SSA. Moreover, the association between ESSDAI and IL-21(+)CD4(+) and IL-21(+)CD8(+) (follicular) T cells in SSA+SjS patients suggests the involvement of these cells in disease pathogenesis and activity, and possibly their utility for the prognosis and assessment of response to therapy. Key Points • SSA+SjS patients have a pronounced naïve/memory B cell imbalance. • SSA+SjS patients have more active disease associated with IL-21(+)CD4(+) and IL-21(+)CD8(+) follicular T cell expansion. • IL-21(+)CD4(+) and IL-21(+)CD8(+) T cell quantification may be useful for the prognosis and assessment of response to therapy.
33892792 Application of systems biology-based in silico tools to optimize treatment strategy identi 2021 Apr 23 BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) are manifestations of an autoinflammatory disorder with complex pathophysiology and significant morbidity, together also termed Still's disease. The objective of the current study is to set in silico models based on systems biology and investigate the optimal treat-to-target strategy for Still's disease as a proof-of-concept of the modeling approach. METHODS: Molecular characteristics of Still's disease and data on biological inhibitors of interleukin (IL)-1 (anakinra, canakinumab), IL-6 (tocilizumab, sarilumab), and glucocorticoids as well as conventional disease-modifying anti-rheumatic drugs (DMARDs, methotrexate) were used to construct in silico mechanisms of action (MoA) models by means of Therapeutic Performance Mapping System (TPMS) technology. TPMS combines artificial neuronal networks, sampling-based methods, and artificial intelligence. Model outcomes were validated with published expression data from sJIA patients. RESULTS: Biologicals demonstrated more pathophysiology-directed efficiency than non-biological drugs. IL-1 blockade mainly acts on proteins implicated in the innate immune system, while IL-6 signaling blockade has a weaker effect on innate immunity and rather affects adaptive immune mechanisms. The MoA models showed that in the autoinflammatory/systemic phases of Still's disease, in which the innate immunity plays a pivotal role, the IL-1β-neutralizing antibody canakinumab is more efficient than the IL-6 receptor-inhibiting antibody tocilizumab. MoA models reproduced 67% of the information obtained from expression data. CONCLUSIONS: Systems biology-based modeling supported the preferred use of biologics as an immunomodulatory treatment strategy for Still's disease. Our results reinforce the role for IL-1 blockade on innate immunity regulation, which is critical in systemic autoinflammatory diseases. This further encourages early use on Still's disease IL-1 blockade to prevent the development of disease or drug-related complications. Further analysis at the clinical level will validate the findings and help determining the timeframe of the window of opportunity for canakinumab treatment.