Iguratimod in treatment of primary Sjögren’s syndrome concomitant with autoimmune hemolytic anemia:A case report

BACKGROUND Primary Sjögren's syndrome(pSS)concomitant with autoimmune hemolytic anemia(AIHA)but without eye and mouth dryness is exceedingly rare.Iguratimod(IGU)has been widely used in the treatment of pSS.However,there are few reports about the application of IGU in pSS concomitant with AIHA.CASE SUMMARY Here,we present the case of a patient with pSS concomitant with AIHA but without eye and mouth dryness.The patient was initially diagnosed with hyperplastic anemia and AIHA while pSS was missed,and was finally diagnosed with pSS concomitant with AIHA.The patient was treated with IGU along with prednisone and hydroxychloroquine,and her hemoglobin,reticulocytes and IgG returned to normal levels.CONCLUSION IGU was effective for and well tolerated by our patient with pSS concomitant with AIHA,and may be a promising therapy for the treatment of this disease.

AA Amyloidosis Secondary to Primary Sjögren Syndrome: Can It Be Developed without Chronic Inflammation?

Background: The association of primary Sjögren syndrome (PSS) and AA amyloidosis is a rare occurrence. Objective: To describe the phenotype of patients with this association through our two cases and a literature review. Materials and methods: A report of two cases of AA amyloidosis complicating primary Sjögren syndrome with a literature review. Results: Eight patients of Primary Sjögren’s Syndrome complicated by AA amyloidosis were studies. Six cases were reported in the literature by consulting several databases. 50% of patients had a positive immunological assessment, three cases with kidney damage, and three cases lung damage. Conclusion: The immunological activity in the Primary Sjogren’s Syndrome requires the search not only a lymphoma but also AA amyloidosis apart from any clinical or biological chronic inflammation.

Role of ranulas in early diagnosis of Sjögren’s syndrome: A case report

BACKGROUND Although the presentations of Sjögren’s syndrome(SS)are variable,ranging from mild dryness to wider systemic involvement,ranulas as early clinical signs were scarcely reported.Here,we present an adult patient with SS,who developed a unilateral simple ranula and was diagnosed primary SS 3 years later.We also provide a review of cases of SS and ranulas from 1980 to 2020.CASE SUMMARY A 22-year-old girl was found to have a left painless floor-of-mouth lesion 3 years ago,without obvious trauma or inducement.The diagnosis of a unilateral(left)simple ranula was made,and the ranula was surgically treated.Within 3 years after the ranula surgery,she developed acute lymphadenectasis in unilateral parotid twice without inducement,and ultrasonic examination revealed diffuse lesions in bilateral parotids and submandibular glands,which strongly suggested SS.Serologic tests and the unstimulated whole saliva flow rate confirmed the SS diagnosis.CONCLUSION Our study underlines that ranulas are early clinical signs of SS.As early diagnosis and early intervention of SS are important to obtain better outcomes,our findings underline the need for histopathological test after sublingual adenectomy and imaging detection of exocrine glands for the patients with ranulas.

Peripheral Neuropathies Revealing Gougerot-Sjögren’s Syndrome: Description of 3 Cases

Introduction: Sjögren’s syndrome is an autoimmune epithelitis with various extraglandular signs, among which are neurological, with a variable frequency according to studies. We report three cases of peripheral neuropathy revealing Gougerot-Sjögren’s syndrome, collected in the Neurology Department of the Fann University Hospital in Dakar (Senegal). Observations: The first patient, aged 48 years, presented with a length-dependent sensitivomotor polyneuropathy associated with retrobulbar optic neuritis, with dry eyes and dry mouth noticed by the patient for several years. The second patient, aged 28 years, was admitted to the hospital with chronic generalized paresthesia in the context of xerostomia and xerophthalmia. The results of the clinical examination and the electroeneuromyogram were in favour of pure sensory neuronopathy. The third patient was 32 years old female, with a history of thyroidectomy and acute inflammatory demyelinating polyneuropathy (AIDP), who was seen for acute ascending flaccid tetraplegia with facial diplegia, preceded by diffuse paresthesia. The diagnosis of recurrence of acute demyelinating polyradiculonueropathy was retained in view of the rapidly increasing character of the deficit, the hyperproteinorachy at the lumbar puncture, and the signs of demyelination at the ENMG. The diagnosis of Gougerot-Sjögren’s syndrome in our three patients was established on the basis of the 2016 ACR/EULAR criteria. Indeed, the anti-SSA antibodies (Ro) were positive in our 3 patients with a biopsy of the salivary glands which showed stage 3 in the first patient and stage 4 in the two others. Corticosteroid therapy and immunosuppressive treatment resulted in a favourable clinical evolution on the neurological and general levels. Conclusion: Gougerot-Sjögren’s syndrome is an autoimmune exocrinopathy that may present with peripheral neuropathy, which may precede the diagnosis of Sjögren’s syndrome, be concomitant or occur during the course of the disease.

Sjögren’s Syndrome Revealed by Obstructive Renal Failure: A Case Report and Review of the Literature

Introduction: Primary Sjögren’s syndrome (SS) is the most common connective tissue disease after rheumatoid arthritis and affects mostly women between 30 and 40 years of age with an estimated prevalence between 0.1% and 0.6%. This observation illustrates an incidental finding of a case of SS in a young female patient in a context of obstructive renal failure (ARF) due to uterine fibroids. Observation: This was a 31-year-old woman hospitalized for anuric AKI (Acute Kidney Injury) with a creatinine level of 1247 μmol/l. Her history included sickle cell disease A/C and an unoperated uterine fibroid diagnosed 3 years ago. Approximately 2 months before her admission, her symptomatology was made of dizziness, physical asthenia, vomiting, poly-arthralgia, morning rash, pollakiuria and oral dryness. Abdominal examination showed a painless transverse mass in the pelvis. Biological examination showed a CRP (C-reactive protein) level of 488 mg/l. The cytobacteriological examination of the urine was normal and the proteinuria was 1.35 g/24 hours. The CT scan showed kidneys measuring 110 mm on the right and 113 mm on the left associated with bilateral pyelo-caliceal dilatation on a large polymyomatous uterus of interstitial and submucosal type. Immunologically, the anti-nuclear factor, the rheumatoid factor and the anti-SSA antibodies were positive. The resumption of the interrogation within the framework of the research of the subjective dry syndrome to find a notion of intermittent xerophthalmia 4 months ago. The Schirmer test was positive in the left eye. The initial management consisted of a polymyomectomy after 3 sessions of hemodialysis. Background treatment combining prednisone 5 mg/day and methotrexate 20 mg/week was started in parallel with the use of artificial tears. The evolution after twelve (12) months of treatment was favorable with a complete disappearance of the signs dry syndrome and full recovery of renal function. Conclusion: SS can have an insidious evolution and remain stable for many years, hence its fortuitous discovery in this case of obstructive ARF on uterine fibroid. In this context we insist on the interest of the immunological assessment in a patient in period of genital activity with a significant proteinuria and non-specific extrarenal signs.

Role of JAK-STAT signaling pathway in pathogenesis and treatment of primary Sjögren’s syndrome

Primary Sjögren’s syndrome(pSS)is a systemic autoimmune disease with high prevalence and possible poor prognosis.Though the pathogenesis of pSS has not been fully elucidated,B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients.It has long been identified that Janus kinases-signal transducer and activator of transcription(JAK-STAT)signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus.Recently,increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells.Signal transducer and activator of transcription 1(STAT1),STAT3,and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development,respectively or synergically.These results reveal the potential application of Janus kinase inhibitors for treatment of pSS,which may fundamentally improve the quality of life and prognosis of patients with pSS.

SHED-derived exosomes ameliorate hyposalivation caused by Sjögren’s syndrome via Akt/GSK-3b/Slug-mediated ZO-1 expression

Background:Sjögren’s syndrome(SS)is an autoimmune disorder characterized by sicca syndrome and/or systemic manifestations.The treatment is still challenging.This study aimed to explore the therapeutic role and mechanism of exosomes obtained from the supernatant of stem cells derived from human exfoliated deciduous teeth(SHED-exos)in sialadenitis caused by SS.Methods:SHED-exos were administered to the submandibular glands(SMGs)of 14-week-old non-obese diabetic(NOD)mice,an animal model of the clinical phase of SS,by local injection or intraductal infusion.The saliva flow rate was measured after pilocarpine intraperitoneal injection in 21-week-old NOD mice.Protein expression was examined by western blot analysis.Exosomal microRNA(miRNAs)were identified by microarray analysis.Paracellular permeability was evaluated by transepithelial electrical resistance measurement.Results:SHED-exos were injected into the SMG of NOD mice and increased saliva secretion.The injected SHED-exos were taken up by glandular epithelial cells,and further increased paracellular permeability mediated by zonula occluden-1(ZO-1).A total of 180 exosomal miRNAs were identified from SHED-exos,and Kyoto Encyclopedia of Genes and Genomes analysis suggested that the phosphatidylinositol 3 kinase(PI3K)/protein kinase B(Akt)pathway might play an important role.SHED-exos treatment down-regulated phospho-Akt(p-Akt)/Akt,phospho-glycogen synthase kinase 3b(p-GSK-3b)/GSK-3b,and Slug expressions and up-regulated ZO-1 expression in SMGs and SMG-C6 cells.Both the increased ZO-1 expression and paracellular permeability induced by SHED-exos were abolished by insulin-like growth factor 1,a PI3K agonist.Slug bound to the ZO-1 promoter and suppressed its expression.For safer and more effective clinical application,SHED-exos were intraductally infused into the SMGs of NOD mice,and saliva secretion was increased and accompanied by decreased levels of p-Akt/Akt,p-GSK-3b/GSK-3b,and Slug and increased ZO-1 expression.Conclusion:Local application of SHED-exos in SMGs can ameliorate Sjögren syndrome-induced hyposalivation by increasing the paracellular permeability of glandular epithelial cells through Akt/GSK-3b/Slug pathway-mediated ZO-1 expression.

IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjögren’s syndrome

Increased numbers of T follicular helper(Tfh)cells have been implicated in the development of autoimmune diseases including primary Sjögren’s syndrome(pSS),but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear.Here,we first found negative correlations between IL-10^(+)regulatory B(Breg)cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjögren’s syndrome(ESS).Moreover,we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice.In culture,IL-10 suppressed human and murine Tfh cell differentiation by promoting STAT5 phosphorylation.By using an adoptive transfer approach and two-photon live imaging,we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2−/−mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2−/−mice transferred with wild-type B cells.In ESS mice,CD19^(+)CD1d^(hi)CD5^(+)Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation.Consistently,CD19^(+)CD24^(+)CD38^(hi) Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion.Furthermore,the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice.Together,these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development.

Traditional Chinese medicine compound ShengJinRunZaoYangXue granules for treatment of primary Sjogren＇s syndrome： a randomized, double-blind, placebo-controlled clinical trial

Background Traditional Chinese medical treatment of primary Sj（o）gren＇s syndrome has advantages over Western medicine in terms of fewer side effects and improved patient conditions.This study was a multicenter,randomized,doubleblind,placebo-controlled clinical trial of the efficacy and safety of ShengJinRunZaoYangXue granules for the treatment of primary Sj（o）gren＇s syndrome,including the symptoms of dry mouth and dry eye.Methods We undertook a 6-week,double-blind,randomized trial involving 240 patients with primary Sj（o）gren＇s syndrome at five centers in East China.A computer-generated randomization schedule assigned patients at a 2∶1 ratio to receive either ShengJinRunZaoYangXue granules or placebo once daily.Patients and investigators were blinded to treatment allocation.The primary endpoints were the salivary flow rate,Schirmer test results,and sugar test results.Intention-to-treat and per-protocol analyses were performed.Results All 240 patients were randomly allocated to either the treatment group （n=160,ShengJinRunZaoYangXue granules） or placebo group （n=80） and were included in the intention-to-treat analysis.After program violation and loss to follow-up,a total of 199 patients were included in the per-protocol analysis.At six week,intention-to-treat and per-protocol analyses of the left-eye Schirmer I test results showed an improved difference of 1.36 mm/5 min （95% CI：0.03 to 2.69 mm/5 min） and 1.35 mm/5 min （95% CI：0.04 to 2.73 mm/5 min）,respectively,and those of the right-eye Schirmer I test results showed an improved difference of 1.12 mm/5 min （95% CI：0.02 to 2.22 mm/5 min） and 1.12 mm/5 min （95% CI：-0.02 to 2.27 mm/5 min）,respectively.There was no significant difference between the two groups before treatment.After treatment,the between-group and within-group before-and-after paired comparison results were statistically significant （P 〈0.05）.Intention-to-treat and per-protocol analyses showed an improved salivary flow rate by 0.04 ml/15 min （95% CI：-0.49 to 0.58 ml/15 min） and 0.04 ml/15 min （95% CI：-0.52 to 0.60 ml/15 min）,respectively,but the differences were not significant.Intention-to-treat and per-protocol analyses showed that the sugar test results were improved by 1.77 minutes （95% CI：0.11 to 3.44 minutes） and 1.84 minutes （95% CI：0.12 to 3.55 minutes）,respectively,but the differences were not significant.For the secondary endpoint,intention-to-treat and per-protocol analyses showed significant improvement in the integrated evaluation of treated patients with dry eye and dry mouth after six weeks of treatment.The incidence of adverse events was 15.6% in the treatment group and 10.0% in the placebo group.Most （94%） adverse events were mild to moderate in the two groups,and only two cases of serious adverse events occurred in the treatment group; both were caused by autoimmune liver disease.Conclusions Six-week treatment with ShengJinRunZaoYangXue granules for primary Sj（o）gren＇s syndrome in this large-scale study improved the symptoms of dry mouth,dry eyes,and low tear flow rate with minimal adverse events.

Primary thymic mucosa-associated lymphoid tissue lymphoma with multiple thin walled lung cysts: case report and literature review

Mucosa-associated lymphoid tissue （MALT） lymphoma of the thymus is rare. We reported a case of a 37-year-old Chinese female with Sjtgren＇s syndrome and hyperglobulinemia. She suffered from chronic cough for 3 weeks. Chest computed tomography （CT） demonstrated a multiloculated cystic mass in mediastinum prevascular space and multiple lung cysts. Laboratory exam of autoimmune markers showed positive of antinuclear antibody （ANA）, Sjtgren＇s syndrome A （SSA）, Sjtgren＇s syndrome B （SSB）, and rheumatoid factors （RF）. Thymectomy with lymph node dissection was performed. The pathology report revealed thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Under immunohistochemical stains, CD20 and Bcl-2 were positive. No evidence of recurrence of disease was found.

Diagnosis of Liver Involvement in Primary Sj(o)gren Syndrome

Liver involvement was one of the first extraglandular manifestations to be reported in patients with primary Sj(o)gren syndrome (SS).In the 1990s,a study of liver involvement in patients with primary SS integrated the evaluation of clinical signs of liver disease,liver function and a complete panel of autoantibodies.Recent developments in the field of hepatic and viral diseases have significantly changed the diagnostic approach to liver involvement in SS.The most recent studies have shown that,after eliminating hepatotoxic drugs and fatty liver disease,the two main causes of liver disease in primary SS are chronic viral infections and autoimmune liver diseases.The differential diagnosis of liver disease in primary SS (viral vs autoimmune) is clinically important,since the two processes require different therapeutic approaches and have different prognoses.With respect to viral infections,chronic HCV infection is the main cause of liver involvement in SS patients from the Mediterranean area,while chronic HBV infection may be the main cause of liver involvement in SS patients from Asian countries.After eliminating viral hepatitis,primary biliary cirrhosis (PBC) should be considered the main cause of liver disease in primary SS.PBC-related SS patients may have a broad spectrum of abnormalities of the liver,including having no clinical or analytical data suggestive of liver disease.Autoimmune hepatitis (AIH) is the second most frequently found autoimmune liver disease to be associated with SS (all reported cases are type I),and nearly 10% of these patients have an AIH-PBC overlap.Finally,IgG4-related disease must be investigated in patients with SS presenting with sclerosing cholangitis,especially when autoimmune pancreatitis or retroperitoneal fibrosis are also present.

Concomitant extrahepatic autoimmune diseases do not compromise the long-term outcomes of primary biliary cholangitis

Background:Primary biliary cholangitis(PBC)patients often have concomitant extrahepatic autoimmune(EHA)diseases including Sjögren’s syndrome(SS),systemic sclerosis(SSc),rheumatoid arthritis(RA),and autoimmune thyroid disease.The present study aimed to describe the prevalence of EHA diseases in PBC and explore the impact of EHA diseases on the long-term outcomes of PBC in Chinese patients.Methods:Medical records of PBC patients diagnosed in our institute were retrospectively reviewed.Pa-tients were followed up by a standardized telephone interview.The endpoints were defined as liver-related death and/or liver transplantation.Results:Totally 247 of the 985(25.1%)PBC patients enrolled in the study had at least one concomi-tant EHA disease.Sjögren’s syndrome(n=140,14.2%)was the most frequent one,followed by rheuma-toid arthritis(RA)(n=56,5.7%)and Hashimoto’s thyroiditis(n=45,4.6%).Patients with EHA dis-eases were more common in females(P<0.001)and in those with a family history of autoimmune disease(P=0.017).Overall,no differences were found between PBC patients with and without EHA dis-eases in terms of biochemical response rates to ursodeoxycholic acid,the incidence of hepatic events,or transplant-free survival.RA and EHA≥2 were protective factors for hepatic events in univariate Cox analysis,but the results became insignificant in multivariate analysis.Conclusions:Concomitant EHA diseases were common in PBC patients but did not compromise the long-term outcomes of PBC.

抗SSB抗体阳性和阴性的原发性干燥综合征患者临床及免疫学特征的比较

目的:分析抗干燥综合征抗原B(Sj?gren’s syndrome type B,SSB)抗体阳性的原发性干燥综合征(primary Sjogren’s syndrome,pSS)患者与抗SSB抗体阴性的pSS患者之间临床表现及实验室指标的差异。方法:回顾性收集2009—2019年于北京大学第三医院风湿免疫科住院的pSS患者的病历资料,采用t检验、Mann-Whitney秩和检验、卡方检验和Fisher确切概率法对抗SSB抗体阳性和抗SSB抗体阴性的pSS患者组的临床特征及实验室指标进行分析。结果:共纳入pSS患者142例,其中女性137例,男性5例,平均年龄(54.8±13.3)岁,其中抗SSB抗体阳性患者44例(31.0%)。临床特征方面,抗SSB抗体阳性的pSS患者较抗体阴性患者的就诊年龄和起病年龄更小[就诊年龄:(50.9±14.5)岁vs.(56.5±12.4)岁,P<0.05;起病年龄:(42.2±14.8)岁vs.(49.5±15.3)岁,P<0.05],出现皮疹(29.5%vs.14.3%,P<0.05)、腮腺肿大(27.3%vs.8.2%,P<0.05)、肾小管酸中毒(15.9%vs.4.2%,P<0.05)、免疫性血小板减少(9.1%vs.1.0%,P<0.05)的比例更高;两组患者在口干、眼干、雷诺现象(Raynaud phenomenon)等方面差异无统计学意义。实验室指标方面,抗SSB抗体阳性组患者与阴性组患者相比,类风湿因子(rheumatoid factor,RF)阳性率(85.0%vs.49.4%,P<0.05)及滴度(中位数89.8 IU/mL vs.20.5 IU/mL,P<0.05)、抗核抗体(antinuclear antibody,ANA)滴度(中位数320 vs.160,P<0.05)、抗干燥综合征抗原A(Sjogren’s syndrome type A,SSA)抗体阳性率(97.7%vs.64.3%,P<0.05)、IgG水平(中位数21.0 g/L vs.15.6 g/L,P<0.05)、γ球蛋白升高率(71.4%vs.38.5%,P<0.05)、CD3^(-)CD19^(+)细胞比例[(21.0±11.9)%vs.(13.7±9.6)%,P<0.05]均更高,而CD3^(+)细胞比例[(67.2±14.4)%vs.(76.6±13.1)%,P<0.05]和抗线粒体抗体M2亚型阳性率(10.5%vs.35.6%,P<0.05)相对更低,其余无明显差异。治疗方面,与抗SSB抗体阴性组患者相比,抗SSB抗体阳性组患者应用激素(90.9%vs.73.5%,P<0.05)及免疫抑制剂(54.5%vs.36.7%,P<0.05)的比例更高。结论:与抗SSB抗体阴性pSS患者相比,抗SSB抗体阳性患者的起病年龄更小,临床表现更多样,血清其他自身抗体阳性率/水平及B细胞活化程度更高,治疗上需要应用激素及免疫抑制剂的概率更大,整体倾向于表现出更重的临床表型。

原发性干燥综合征合并血细胞减少中医诊治研究进展

原发性干燥综合征(pSS)是一种慢性炎症性自身免疫病,除累及外分泌腺之外,还可累及多器官、系统,其中以血液系统受累最为常见,多表现为一系或多系血细胞减少。目前对于pSS合并血细胞减少缺乏统一公认的治疗方案,西医治疗多以糖皮质激素、免疫抑制剂为主,而中医药治疗本病具有较好疗效。通过总结pSS合并血细胞减少的中医诊治经验,并对相关研究进行综述后发现,现代医家认为pSS核心病机为气阴亏虚,久之则产生热、毒、瘀等多种病理产物,相互影响,导致全身气血津液失常,引起血细胞减少。本病病位多责之于肝、脾、肾,治以滋阴、益气、养血之法,辅以清热解毒、化瘀通络之法,并根据其合并血细胞减少类型的不同以及是否使用糖皮质激素用药各有侧重。中医药治疗本病较西药治疗能够更好地改善血细胞水平且不良事件发生率更低,具有一定优势。

原发性干燥综合征并肝损害13例临床特征及中医证型分析

目的:分析原发性干燥综合征并肝损害临床特征及中医证型状况,为早期改善患者预后提供参考。方法:选择2018年9月至2022年1月广州中医药大学东莞医院风湿科诊治的原发性干燥综合征患者72例作为研究对象,调查、记录患者的电子病历系统,随访患者的预后,重点记录临床特征及中医证型。结果:72例患者中肝损害13例,占比18.1%,女性13例,临床上首发主要症状以口干、眼干为主。肝损害以GGT、ALP升高为主,ALT、AST升高不明显,13例患者均出现抗核抗体(ANA)阳性,中医分型判定为肝郁脾虚型6例、脾肾不足型4例、气阴两虚型2例、阴虚津亏型1例。13例患者经过中西医结合治疗后都顺利出院,2~3周后复查肝功能恢复至正常。结论:临床医师应对原发性干燥综合征肝损害、自身免疫性肝病的异同有充分认识,分析各种实验室检查结果,及早明确诊断、分析中医证型并给予相应治疗方案。

五运六气与干燥综合征发病特点及中医证候的相关性研究

目的:探讨原发性干燥综合征(pSS)患者出生时的五运六气等相关信息与pSS发病所累及的系统损害及中医证候的相关性。方法:采用回顾性研究方法,从门诊及住院部收集2020年1月—2021年12月就诊的pSS患者,收集其出生时的运气学相关信息资料,统计运、气因素出现的频次,分析其与pSS发病所累及的系统损害及中医证候相关的运气因素,并运用中医理论进行分析、总结、探讨。结果:岁运因素中“土不及”是pSS患者的易患禀赋因素;岁运因素中“土不及”、六气因素中的“太阴司天、太阳在泉”及“厥阴司天、少阳在泉”是pSS气阴两虚证的易患禀赋因素;岁运因素中“土不及”“木太过”“金太过”“水太过”“水不及”,六气因素中“少阴司天、阳明在泉”及“少阳司天、厥阴在泉”为阴虚津亏证pSS的易患禀赋因素;岁运因素中“火太过”,六气因素中“太阴司天、太阳在泉”“少阴司天、阳明在泉”是阴虚热毒证pSS的易患禀赋因素;岁运因素中“木太过”“金不及”“木不及”,六气因素中“厥阴司天、少阳在泉”为阴虚血瘀证pSS的易患禀赋因素;岁运因素中“土不及”“金不及”,六气因素中“太阴司天、太阳在泉”为pSS患者关节受累的易患禀赋因素;岁运因素中“土不及”“金不及”为pSS患者肺受累的易患禀赋因素;岁运因素中“火太过”“土太过”“土不及”,六气因素中“厥阴司天、少阳在泉”为pSS患者血液系统受累的易患禀赋因素。结论:原发性干燥综合征的发病特点及其中医证候与五运六气具有一定的相关性。

Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sjögren’s syndrome by modulating the function of myeloid-derived suppressor cells

Sjögren’s syndrome(SS)is a systemic autoimmune disease characterized by progressive inflammation and tissue damage in salivary glands and lacrimal glands.Our previous studies showed that myeloid-derived suppressor cells(MDSCs)exhibited impaired immunosuppressive function during disease progression in patients with SS and mice with experimental Sjögren’s syndrome(ESS),but it remains unclear whether restoring the function of MDSCs can effectively ameliorate the development of ESS.In this study,we found that murine olfactory ecto-mesenchymal stem cell-derived exosomes(OE-MSC-Exos)significantly enhanced the suppressive function of MDSCs by upregulating arginase expression and increasing ROS and NO levels.Moreover,treatment with OE-MSC-Exos via intravenous injection markedly attenuated disease progression and restored MDSC function in ESS mice.Mechanistically,OE-MSC-Exo-secreted IL-6 activated the Jak2/Stat3 pathway in MDSCs.In addition,the abundant S100A4 in OE-MSC-Exos acted as a key factor in mediating the endogenous production of IL-6 by MDSCs via TLR4 signaling,indicating an autocrine pathway of MDSC functional modulation by IL-6.Taken together,our results demonstrated that OE-MSC-Exos possess therapeutic potential to attenuate ESS progression by enhancing the immunosuppressive function of MDSCs,possibly constituting a new strategy for the treatment of Sjögren’s syndrome and other autoimmune diseases.

Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sjögren’s syndrome

Immunoproteasome activation in immune cells is involved in the modulation of immune responses.Increasing evidence indicates that proteasome inhibitors show beneficial effects in treating autoimmune diseases,but it remains unclear whether proteasome inhibition is an effective approach for suppressing autoimmune development in Sjo?gren’s syndrome(SS).Our previous work has demonstrated a critical role for Th17 cells in the development of experimental SS(ESS)in mice.In this study,we detected high levels of low-molecular-weight protein 7(LMP7),a key subunit of the immunoproteasome,in Th17 cells from ESS mice.Moreover,treatment with bortezomib(BTZ),a proteasome inhibitor,markedly suppressed Th17 differentiation in both murine and human naive T cells in culture.Furthermore,ESS mice treated with BTZ displayed significantly higher saliva flow rates and a reduction in tissue destruction in the salivary glands compared with vehicle-treated ESS mice.Notably,BTZ-treated ESS mice showed markedly decreased Th17 cells,germinal center B cells and plasma cells in the peripheral lymphoid organs.In addition,adoptively transferred wild type naive CD4+T cells rapidly differentiated into Th17 cells and induced salivary dysfunction in IL-17-deficient mice immunized for ESS induction.However,BTZ treatment profoundly suppressed the donor T-cell-derived Th17 response and ameliorated the reduction in salivary secretion in IL-17-deficient recipient mice.Taken together,our findings demonstrate that proteasome inhibition can effectively ameliorate ESS by suppressing the Th17 response,which may contribute to the development of a novel therapeutic strategy for the treatment of SS.

Application of immunosuppressant facilitates the therapy of optic neuritis combined with Sj（o）gren＇s syndrome

Background Optic neuritis （ON） is often the first symptom of multiple sclerosis （MS） and neuromyelitis optica （NMO） while there has been very little research reported on ON combined with Sj（o）gren＇s syndrome （SS）.The aim of this study is to provide different treatments and services for and NMO patients combined with SS.Methods Twenty-seven patients with ON combined SS were divided into two groups：corticosteroid group （C group,methylprednisolone sodium succinate,14 patients） and corticosteroid＋ immunosuppressant group （C＋I group,leflunomide,13 patients）.ON relapse times in 1 year after treatment,number of patients who relapsed to NMO/MS in 1 years,visual acuity and retina nerve fiber layer （RNFL） thickness were measured.Mann Whitney-Wilcoxon test was used to compare continuous variables and Chi-square test or Fisher＇s exact test was to compare proportions.Results ON combined with SS patients had higher incidence rates in middle-aged women who have binocular damage and heavier visual function damage or when there is an easy relapse,and the patients are often hormone dependent.The patients are more likely anti-aquaporin-4 IgG seropositive （70.4％）.They are liable to form a centrocecal scotoma and tubular vision.The times of relapse decreased in patients who used immunosuppressant,and a significant difference was found between immunosuppressant and non-immunosuppressant groups in visual acuity recovery during 6-month followup period （P ＜0.05）; however,the RNFL thickness at the four quadrants was not significantly different.Conclusions The effect of immunosuppressant plus corticosteroid on the early onset of ON combined with SS was to provide ON remedy and to prevent recurrence in clinics.This study provides a significant reference for the prevention and treatment of ON on the basis of immunosuppressant and corticosteroid.

IgG4相关性疾病和原发性干燥综合征相关细胞因子谱的对比

目的:从分子水平探讨IgG4相关性疾病(IgG4-RD)和原发性干燥综合征(pSS)的相关细胞因子特征。方法:获得了17个小唾液腺(9个来自pSS患者,8个来自非pSS患者作为对照)、7个颌下腺(4个来自IgG4-RD患者,3个来自切除的颌下腺肿瘤周围的肉眼正常组织作为对照)的样本RNA-Seq数据,分析IgG4-RD和pSS来源样品中的差异表达基因和富集途径,以揭示这两种疾病的免疫炎症特征。结果:尽管三级淋巴结构(TLS)相关细胞因子(例如CXCL13、CCL19等)的表达显著增加,但对于受累组织的先天免疫反应特征,在IgG4-RD中观察到更显著成纤维细胞相关细胞因子及其受体的表达,巨噬细胞和中性粒细胞相关的细胞因子及其受体在pSS中有更为显著的表达。此外,IgG4-RD受累唾液腺中经典信号通路的富集模式也与pSS不同:在IgG4-RD中,JAK-STAT信号通路、NF-κB信号通路显著富集,而在pSS中,与细胞趋化性相关通路显著富集。结论:在IgG4-RD和pSS之间的转录水平上,相关细胞因子间有不同的分子和生物过程模式,这可能指导其后续的机制研究和药物靶点选择。