Clinical and experimental rheumatology最新文献

Objectives: N-acetylcysteine (NAC) is used in Sjögren's disease (SjD) based on limited evidence. The aim of this study was to assess the efficacy of NAC for relieving dryness symptoms in SjD.

Methods: In this placebo-controlled double-blind trial, 60 adult SjD females (with low disease activity) were randomised to receive NAC (1,200 mg/day orally) or placebo. At baseline (D0), 30 days (D30) and 90 days (D90), all participants underwent the following evaluations: EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Ocular Surface Disease Index (OSDI), Xerostomia Inventory (XI), Leicester Cough Questionnaire (LCQ), unstimulated/stimulated salivary flow, Schirmer's test, and plasma levels of thiobarbituric acid reactive substances (TBARS), glutathione and NAC.

Results: At inclusion, both groups were balanced for age, ethnicity, disease duration, ESSPRI, OSDI, XI, Schirmer's test, salivary flow, ESSDAI and topical/systemic treatments (p>0.05). No significant differences were observed between NAC and placebo groups on D30 and D90 regarding ESSPRI, XI, OSDI, LCQ, Schirmer's test, stimulated salivary flow, ESSDAI and topical/systemic treatments (p>0.05). Unstimulated salivary flow was significantly higher in the placebo group on D90 (p=0.018). NAC blood concentrations were significantly higher in the NAC group on D30 (p=0.018) and D90 (p<0.001), however, no differences were found in TBARS and glutathione. Further analysis showed decrease≥1 in ESSPRI in the NAC compared with placebo group on D30 (p=0.045), a result not found on D90 (p=0.696).

Conclusions: NAC is recommended as a rescue therapy for SjD. However, our well-designed study provides novel evidence demonstrating its inefficacy for improving dryness symptoms or reducing oxidative stress.

Clinicaltrials: gov-NCT04793646.

Objectives: To assess if isolated mouth or eye dryness constitutes distinct clinical phenotypes in Sjögren's disease (SjD).

Methods: We analysed 1765 patients meeting the 2016 ACR-EULAR SjD criteria, followed up at four centres in Greece and Italy (Universities of Pisa, Italy, and Athens, Harokopion, and Ioannina, Greece). Patients with isolated mouth or eye dryness were identified and matched 1:2 with those experiencing both symptoms, according to age at SjD diagnosis, gender, and disease duration. We defined two study groups: a) patients with ocular dryness only, and b) patients with oral dryness only, based on the AECG validated questionnaires for dryness. We compared glandular and extra-glandular manifestations, serology, and histologic features between each study and their matched controls.

Results: Seventy-two patients with isolated ocular dryness and 74 with isolated oral dryness were compared with 144 and 148 matched controls, respectively. Both groups had a median disease duration of 3 years. Patients with isolated eye dryness had lower frequency of salivary gland enlargement (35.4% vs. 28.7%, p=0.05) and lymphoma (0% vs. 11.3%, p=0.001). Conversely, those with isolated oral dryness had lower rates of arthralgias (39.1% vs. 65.5%, p=0.0003) and arthritis (8.6% vs. 20.3%, p=0.05). Isolated oral dryness was associated with older age at SjD diagnosis (median 53.5 vs. 46, p=0.005) and a higher likelihood of lymphoma (9.4% vs. 0%, p=0.01) compared to isolated ocular dryness.

Conclusions: Isolated ocular or oral dryness occurs in 8% of the general SjD population. Patients with isolated dry eyes have a lower prevalence of lymphoma compared to those with isolated dry mouth.

Objectives: Patients with chronic, incurable conditions rely on their providers to help relieve their symptoms. Dissatisfaction with their care can erode the doctor-patient relationship and reduce the effectiveness of treatment. We investigated the relationships between satisfaction and symptoms, the doctor-patient relationship, and health-related factors in patients with Sjögren's disease (SjD) in Japan.

Methods: Using a questionnaire survey, we evaluated via multinomial logistic regression associations between satisfaction [satisfied, neither (neither satisfied nor dissatisfied), dissatisfied] and symptoms, prescribed medications, anxiety, distress, expectations from treatments, and doctor-patient relationships.

Results: Of 259 patients, 101 (39%) were satisfied, 111 (42.9%) were neither, and 47 (18.2%) were dissatisfied. Patients who were neither or dissatisfied with their current treatment wanted their systemic pain to disappear (adjusted relative risk ratio [aRRR] 3.38, 95% CI 1.66-6.91; aRRR 3.04, 95% CI 1.30-7.15, respectively). Patients who used artificial saliva only were significantly more dissatisfied (aRRR 3.52, 95% CI 1.03-2.04). Both the neither and dissatisfied patients dissatisfied with their doctor's limited understanding of SiD (aRRR 12.69, 95% CI 4.21-38.24; aRRR 32.76, 95% CI 10.09-106.34, respectively) and with the limited opportunities to ask their doctor about their disease (aRRR 0.19, 95% CI 0.06-0.59; aRRR 0.08, 95% CI 0.02-0.24, respectively).

Conclusions: Pain and the use of artificial saliva alone markedly affected medical satisfaction and we expected the future advance in these two areas, pain and dryness, will improve satisfaction. It is most important for doctors to better understand SjD.

Objectives: The Janus kinases-signal transducer and activator of transcription (JAK-STAT) signalling pathway plays a crucial role in autoimmunity and the signalling pathways of many cytokines in Sjögren's disease (SjD). Therefore, the aim of this study was to investigate both the therapeutic and immunomodulatory effects of the oral JAK3/JAK2/JAK1 inhibitor tofacitinib in a murine model of SjD.

Methods: Tofacitinib or vehicle was administered orally to the mice with SjD for 6 weeks. Salivary flow rate was measured every three weeks. Pathological changes of salivary gland were detected by haematoxylin-eosin staining, and the percentages of subsets of CD4+ T cells and B cells in the cervical lymph nodes (cLNs) and spleen was determined by flow cytometry.

Results: Tofacitinib significantly ameliorated submandibular gland inflammation compared to the control group, as evidenced by reduced lymphocytic infiltration. Salivary flow rates improved significantly in tofacitinib treated mice compared to controls, indicating restored salivary gland function. The treatment also led to a substantial decrease in follicular helper T (Tfh) cells and the Tfh/Treg ratio in both the spleen and cLNs. Additionally, the frequencies of T helper 1 (Th1) and T helper 17 (Th17) cells were reduced in the spleen and cLNs.

Conclusions: Our data indicated that tofacitinib reduced percentages of effector T cells in an animal model of SjD. In addition, tofacitinib alleviated salivary gland inflammation and hypofunction, offering new insights into the clinical management of SjD.

Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterised by immune-driven damage to the exocrine glands, leading to diminished salivary and tear production. While the pathogenesis of pSS remains incompletely understood, its clinical presentations vary widely, and no specific treatments are currently available. Toll-like receptor 7 (TLR7) belongs to the Toll-like receptor family and is crucial for the innate immune response, notably in recognising pathogenic patterns. TLR7 is predominantly found in the endoplasmic reticulum (ER) and endosomes, where it identifies single-stranded RNA (ssRNA). Upon ligand binding, TLR7 activates the Myd88-dependent signalling cascade, eliciting an immune response.Dysregulation and variations in TLR7 expression are implicated in several autoimmune disorders. In genetically predisposed individuals, factors such as infections, endocrinological abnormality and metabolic abnormalities can cause TLR7 dysregulation, aggravating pSS symptoms and progression. While studies on TLR7 in pSS are limited, they offer insights into the disease's pathophysiological processes, vital for the treatment and prognosis. This article explores the mechanisms of TLR7 dysregulation, its involvement in pSS pathogenesis, and prospective therapeutic significance.

Objectives: Primary Sjögren's syndrome is a chronic autoimmune disease with an inflammation of exocrine glands. It can be difficult to diagnose due to frequently unspecific symptoms, such as fatigue and myalgia. The aim of this study was to investigate the journey of patients prior to the diagnosis of primary Sjögren's syndrome and how this affects the patient-reported outcomes.

Methods: The study included 170 patients from the outpatient clinic with an age of at least 18 years that were diagnosed with primary Sjögren's syndrome (ICD-10 M35.0) and fulfilled ACR/EULAR 2016 criteria at least 12 months before. Socio-demographic details, patient-reported outcomes and the history of diagnosis were obtained via a structured questionnaire.

Results: The average diagnostic latency for this group of patients with Sjögren's syndrome is 5.98 years, with a median of 2 years. The cohort was divided into two groups based on the median of two years: one with a longer and the other with a shorter diagnostic delay. The group with a longer diagnostic delay was in a significantly poorer general health condition and was significantly more likely to report a negative impact on the general performance. Patients with longer diagnostic delay reported significantly more physician visits and suffered significantly more frequently from vaginal dryness, gastrointestinal symptoms and breathlessness as initial symptoms.

Conclusions: Our findings underline the importance of awareness of Sjögren's syndrome and interdisciplinary training of physicians to improve the patient related outcomes due to a reduced diagnostic latency.

Objectives: Recent research has increasingly focused on improving symptoms in patients with Sjögren's syndrome (SS). This study aims to evaluate the efficacy of oral pilocarpine in treating SS, synthesising the latest scientific evidence from randomised controlled trials (RCTs).

Methods: We systematically searched PubMed, Embase, the Cochrane Library, and the Science Citation Index for relevant randomised controlled trials (RCTs) published up to November 2023. Cochrane is used to assess the quality of literature studies and to extract data from included articles. The main results were summarised and analysed by Revman5.4.

Results: The meta-analysis included eight related RCTs involving 383 patients. All included studies were of moderate to high quality using the Cochrane Collaboration's tools for assessing the risk of bias.The results showed no significant improvement in Schirmer's test for the right [(RR 1.25, 95 % CI -0.68 to 3.18, heterogeneity I2=97%),] left eye (RR 5.15, 95%CI-1.73 to 12.02, heterogeneity I2=97%), right breakup time with fluorescein (RR 1.91, 95%CI -0.46 to 4.27, heterogeneity I2=89%) and left breakup time with fluorescein (RR 1.74, 95%CI -0.29 to 3.77, heterogeneity I2=87%) between ss and control groups. However, significant improvements were observed in the whole saliva test [(RR 0.20, 95%CI 0.09 to 0.30, heterogeneity I2=90%)], and Bijsterveld's score for both left (RR -4.18, 95%CI -7.14 to -1.21, I²=90%) and right eyes (RR -4.11, 95%CI -7.37 to -0.85, I²=92%), as well as in fluorescein 1% staining for the left (RR -0.81, 95%CI -1.26 to -0.36, I²=0%) and right eyes (RR -0.74, 95%CI -1.19 to -0.28, I²=0%).

Conclusions: Based on the current evidence, oral pilocarpine does not significantly improve Schirmer's test results or breakup time with fluorescein BUT in patients with SS. However, it does enhance outcomes in the Whole Saliva Test, Bijsterveld's score, and fluorescein 1% staining. These findings support the partial efficacy of pilocarpine in treating SS, with notable improvements in specific diagnostic measures. Further research is needed to fully understand the benefits of pilocarpine.

Objectives: Deltex1 is a transcriptional target of NFAT that promotes T cell anergy. However, whether Deltex1 affects the properties of regulatory T cells (Tregs), which are involved in the pathogenesis of Sjögren's disease (SjD), is unknown.

Methods: T cells were purified from peripheral blood using a negative selection method. Deltex1 mRNA levels were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR). The mean fluorescent intensity (MFI) of Treg-associated molecules and the cytokine positivity of CD4+ FoxP3+ Tregs were analysed using flow cytometry. The European League against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) and Patient- Reported Index (ESSPRI) were used to evaluate systemic disease activity and symptoms in SjD.

Results: Deltex1 expression in T cells was significantly lower in SjD patients than in age- and sex-matched healthy controls (p<0.001). Deltex1 mRNA levels in T cells negatively correlated with visual analog scale scores for fatigue, ESSDAI, and ESSPRI (r=-0.334, p=0.035; r=-0.364, p=0.021; and r=-0.340, p=0.032, respectively). Low Deltex1 levels correlated with some clinical manifestations of SjD, including immune thrombocytopenia, vasculitis, and autoimmune thyroiditis (p=0.014, 0.002, and 0.001, respectively). The MFI of PD-1, CTLA-4, TIM-3, LAG-3 on Tregs and the percentage of interferon-γ+, interleukin (IL)-4+, IL-17A+ Tregs were significantly higher in the low Deltex1 group (Deltex1/GAPDH ≤0.02) than in the high Deltex1 group (Deltex1/GAPDH > 0.02) (p<0.05).

Conclusions: Deltex1 may affect the properties of Tregs; thus, it is a potential biomarker of disease activity in SjD.

Objectives: To explore whether the balance of CD226 and TIGIT is disturbed in CD3+CD56-TCRαβ+CD4-CD8- (DN) T cells and have a better understanding of the potential role of DN T cells in the pathogenesis of primary Sjögren's syndrome (pSS).

Methods: The percentage of DN T cells as well as the expression of CD226 and TIGIT was identified by flowmetry. After in vitro stimulation, we further detected the expression of activation and cytotoxic marker, as well as intracellular cytokines secreted by DN T cells.

Results: DN T cells were found to expand in the peripheral blood of pSS patients (1.77±0.66%) and correlate with IgG (r=0.451, p<0.05), C3 (r=-0.438, p<0.05) and C4 (r=-0.470, p<0.05). Imbalanced CD226/TIGIT was observed on peripheral DN T cells of pSS patients, especially the overexpression of inhibitory immunoreceptor TIGIT. The expression ratio of TIGIT and CD226 on DN T cells was elevated in pSS patients and correlated with ESSDAI scores≥5 (r=0.743, p<0.05). Besides, these DN T cells were found to be activated and show strong cytotoxicity.

Conclusions: The balance between CD226 and TIGIT on DN T cells was disturbed and correlated with the disease activity in pSS patients, which may be implicated in the pathogenesis of pSS.