scholarly journals OP0162 ABATACEPT TREATMENT FOR PATIENTS WITH EARLY ACTIVE PRIMARY SJÖGREN’S SYNDROME: OPEN-LABEL EXTENSION PHASE OF A RANDOMIZED CONTROLLED PHASE III TRIAL

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 102.2-102
Author(s):  
S. Arends ◽  
J. F. Van Nimwegen ◽  
E. Mossel ◽  
G. S. Van Zuiden ◽  
K. Delli ◽  
...  
Keyword(s):  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Phase Iii ◽  
List Type ◽  
Research Support ◽  
Open Label ◽  
Open Label Extension ◽  
Sjögren‘S Syndrome

Background:Abatacept (CTLA-4-Ig) targets the CD80/CD86:CD28 co-stimulatory pathway required for full T-cell activation and T-cell dependent activation of B-cells. The Abatacept Sjögren Active Patients phase III (ASAPIII) trial is a mono-center, investigator-initiated, placebo controlled study with an open-label extension phase (NCT02067910), which assessed the efficacy and safety of weekly subcutaneous abatacept (125mg) in patients with early active primary Sjögren’s syndrome (pSS). Previous analyses of the double blind phase showed no significant effect of abatacept treatment compared to placebo on the primary endpoint, difference in EULAR Sjögren’s syndrome disease activity index (ESSDAI) at week 24.1Objectives:To evaluate the efficacy and safety of extended (48 weeks) open label abatacept treatment in pSS patients.Methods:Included patients had biopsy-proven pSS, fulfilled the AECG and ACR-EULAR criteria, had disease duration ≤7 years (median 2 years), ESSDAI ≥5, and 89% were anti–SSA positive. All 40 patients who received abatacept (ABA) in week 0-24 were subsequently treated with abatacept from week 24-48. Of the 40 patients who received placebo (PLB) in week 0-24, 2 were lost to follow up, and 38 were treated with abatacept from week 24-48. Systemic disease activity (ESSDAI), patient reported symptoms (ESSPRI), serological outcomes (RF and IgG), ocular staining score (OSS) and unstimulated whole salivary flow (UWS) were assessed. We evaluated whether outcomes improved within treatment groups, from week 0 to subsequent visits and from week 24 to subsequent visits:1.Within ABA→ABA treated patients:a. Week 0-48 to assess overall efficacy.b. Week 24-48 to assess additional efficacy of long term treatment.2.Within PLB→ABA treated patients:a. Week 0-24 to assess whether a placebo effect occurred.b. Week 24-48 to assess short-term efficacy of open label ABA.GEE modeling was used to test significance of changes over time. Missing data were not imputed.Results:ESSDAI and ESSPRI were improved within ABA/ABA patients between week 0-48 with additional efficacy after week 24, and within PLB/ABA patients after switching to ABA. Significant decreases in ESSDAI and ESSPRI were also seen within PLB treated patients between week 0-24 (Figure 1). IgG and RF were improved within ABA/ABA patients between week 0-48 with additional efficacy after week 24, and within PLB/ABA patients after switching to ABA. OSS was improved within ABA/ABA treated patients between week 0-48. UWS only showed significant improvement in week 36 within ABA/ABA treated patients. No changes in IgG, RF, OSS or UWS were seen within PLB treated patients. No deaths occurred. One serious adverse event possibly related to intervention occurred during ABA treatment.Conclusion:ESSDAI and ESSPRI improved significantly during 48-week treatment with abatacept. Placebo treated patients also showed significant improvement in both indices and further improvement occurred after switching to abatacept. Biological activity was decreased by abatacept treatment. 48-week abatacept treatment improved OSS, and might improve UWS. Abatacept was well tolerated by pSS patients.References:[1]van Nimwegen et al. Lancet Rheumatol.Published online 31-01-2020Acknowledgments:This study was funded by Bristol-Myers Squibb. We thank all patients for participation in the ASAP-III trial.Disclosure of Interests:Suzanne Arends Grant/research support from: Grant/research support from Pfizer, Jolien F. van Nimwegen Consultant of: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, Esther Mossel: None declared, Greetje S. van Zuiden Speakers bureau: Roche, Konstantina Delli: None declared, Alja J. Stel: None declared, Bert van der Vegt Consultant of: Advisory board member for Philips and Visiopharm., Erlin A. Haacke: None declared, Lisette Olie: None declared, Leoni Los: None declared, Gwenny M. Verstappen: None declared, Sarah A. Pringle: None declared, Fred K.L. Spijkervet: None declared, Frans G.M. Kroese Grant/research support from: Unrestricted grant from Bristol-Myers Squibb, Consultant of: Consultant for Bristol-Myers Squibb, Speakers bureau: Speaker for Bristol-Myers Squibb, Roche and Janssen-Cilag, Arjan Vissink: None declared, Hendrika Bootsma Grant/research support from: Unrestricted grants from Bristol-Myers Squibb and Roche, Consultant of: Consultant for Bristol-Myers Squibb, Roche, Novartis, Medimmune, Union Chimique Belge, Speakers bureau: Speaker for Bristol-Myers Squibb and Novartis.

scholarly journals Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial

2020 ◽  
pp. annrheumdis-2020-218599
Author(s):  
Alan N Baer ◽  
Jacques-Eric Gottenberg ◽  
E William St Clair ◽  
Takayuki Sumida ◽  
Tsutomu Takeuchi ◽  
...  
Keyword(s):  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Controlled Trial ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Patient Reported ◽  
Sjögren‘S Syndrome

ObjectivesTo evaluate efficacy and safety of abatacept in adults with active primary Sjögren’s syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial.MethodsEligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren’s Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored.ResultsOf 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI −3.2 abatacept vs −3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified.ConclusionsAbatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.

scholarly journals THU0220 AUTOPHAGY IN SJOGREN’S SYNDROME SALIVARY GLAND EPITHELIAL CELLS (SGECS) IS ASSOCIATED WITH THE SEVERITY OF INFLAMMATION AND EPITHELIAL CELLS ACTIVATION.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 336.2-337
Author(s):  
S. Colafrancesco ◽  
C. Barbati ◽  
V. Iannizzotto ◽  
L. Mastromanno ◽  
S. Nayar ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Epithelial Cells ◽  
Adhesion Molecules ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Research Support ◽  
Salivary Gland Epithelial Cells ◽  
Sjögren‘S Syndrome

Background:Sjögren’s Syndrome (SS) is characterized by chronic inflammation supported by intrinsic activation of salivary gland epithelial cells (SGECs). Eventually, apoptosis of SGECs ensues, which leads to salivary gland dysfunction and exposition of autoantigens. Autophagy is a stress coping mechanisms of cells implicated in both survival and exposition of autoantigens, and is thereby plausibly implicated in the pathogenesis of SS. At present, the exact relationship between apoptosis and autophagy in SS SGECs is unclear, as is the link between these mechanisms and SGECs activation.Objectives:To explore autophagy in SGECs from patients with SS and to evaluate its relationship with apoptosis and SGECs activation.Methods:Consecutive patients with suspected SS referring to our “Sjogren Clinic” were enrolled, and minor salivary gland (MSG) biopsies were collected for: (1) SGECs culture, (2) PCR analysis, (3) IFI analysis. In SGECs cultures, the expression of autophagy (LC3II), apoptosis (annexin V/PI) and adhesion molecules (ICAM) was investigated by flow cytometry (results expressed as mean % ± SD). The expression of the autophagy gene MAP1LC3II was evaluated by PCR (expressed as 2^deltaCT normalized to GADPH) on both MSG sections and MSG acinar and ductal epithelium samples obtained by laser capture microdissection. Tissue expression of LC3II was evaluated by IFI on SS MSG.Results:Primary SGECs cultures were established from 14 MSG obtained for diagnostic purposes (SS n=8, Sicca n=6). These cells exhibited an inverse correlation between apoptosis and autophagy (p=0.007, r=-0.784), with lower levels of apoptosis (19.7±6.5 vs 24.5±8.5, p=ns) and higher levels of autophagy (59.7±13.1 vs 54.19±19.4, p=ns) in SS compared to Sicca. In SS, MAP1LC3 was positively correlated with Focus Score (p=0.021 r=0.478); however, PCR studies did not reveal significant differences in MAP1LC3 expression between SS (n=26) and Sicca (n=15) (0.024±0.010 vs 0.022±0.008, p=ns). Ductal SGECs (n=4) isolated by laser microdissection of MSG revealed a higher expression of MAP1LC3 (0.005±0.0005 vs 0.003±0.0008; p=0.057) compared to normal acinar epithelium (n=5); a major expression of LC3II in ducts was confirmed by IFI (Image).In SS, a higher expression of ICAM compared to sicca was observed (11.1±3.8 vs 6.9±6.9, p=0.006) and autophagy and apoptosis showed a trend of positive and negative correlation with this molecule, respectively (p=0.683 r=0.118 and p=0.106 r=-0.446).Figure.LC3-II staining in SS MSG [LC3-II+ (green) and Hoechst stain (blue); 60x magnification].Conclusion:In SS, autophagy is upregulated in SGECs and inversely correlated with apoptosis, thus supporting a role of this process in cells’ death prevention during inflammatory process. Indeed, the degree of msg inflammation is correlated more with the activation of autophagy than apoptosis. Interesting, in SS, SGECs autophagy is mainly observed at ductal level and is correlated with higher expression of adhesion molecules suggesting a link between this pathway and changes in SGECs immune phenotype.Disclosure of Interests: :Serena Colafrancesco: None declared, cristiana barbati: None declared, Valentina Iannizzotto: None declared, Linda Mastromanno: None declared, Saba Nayar: None declared, Elena Pipi: None declared, angelica gattamelata: None declared, francesco ciccia Grant/research support from: pfizer, novartis, roche, Consultant of: pfizer, novartis, lilly, abbvie, Speakers bureau: pfizer, novartis, lilly, abbvie, cristiano alessandri Grant/research support from: Pfizer, Francesca Barone: None declared, fabrizio conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi, Roberta Priori: None declared

scholarly journals POS0735 ULTRASOUND-GUIDED CORE NEEDLE BIOPSY FOR SALIVARY GLAND ENLARGEMENT IN SJÖGREN’S SYNDROME: PROCEDURE SAFETY AND PATIENT TOLERANCE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 618-619
Author(s):  
A. Zabotti ◽  
I. Giovannini ◽  
S. Z. Callegher ◽  
V. Manfrè ◽  
M. Lorenzon ◽  
...  
Keyword(s):  
Sjögren’S Syndrome ◽  
Core Needle Biopsy ◽  
Needle Biopsy ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Ultrasound Guided ◽  
Research Support ◽  
Core Needle ◽  
Sjögren‘S Syndrome

Background:Persistent enlargement of major salivary glands (SGs) is one of the main risk factors for B-cell lymphoma in primary Sjögren’s syndrome (pSS). The Ultrasound-guided Core Needle Biopsy (US-guided CNB) could be a novel technique for the management of SGs enlargement in pSS (1).Objectives:To evaluate the procedure safety and the patient tolerance of US-guided CNB in pSS patients with major SGs enlargement.Methods:Consecutive patients, with either definite or clinically suspected pSS, and with clinical indication for SGs biopsy due to persistent glandular enlargement were screened for US-guided CNB from September 2019 to December 2020. All patients were evaluated clinically between 1 and 2 weeks and 12 weeks following US-guided CNB. All patients were asked to complete a questionnaire to report post-procedural complications (Figure 1, English version) and intra- and post-procedural pain Visual Analogue Scale (VAS). The complications were classified as transient (<12 weeks) or persistent (≥12 weeks).Results:US-guided CNB was performed in 21 glands (12 parotid and 9 submandibular glands) in 20 pSS patients. 16/20 (80%) patients fulfilled the ACR-EULAR classification criteria for pSS (2). The mean age at the time of biopsy was 62.1 (±11.7) years. US-guided CNB was well tolerated, no long-term complications were reported in the follow-up period (mean 9.5 ±5.7 months). Only transient complications were noticed in 11 patients (55%). In particular, two cases of local swelling at the biopsy site lasting no more than 6 days, one case of local bleeding and subsequently hematoma of the submandibular area, one case of transient facial paresis (lasting less than one hour), seven cases of post-procedural mild local pain, that resolved within 10 days without the need of analgesics (Table 1). The procedure was well tolerated, with a very low reported intra-operative pain (mean VAS 1.74 ±2.49) and a mean post-operative pain VAS of 1.39 (±2.33). The biopsy sampling was diagnostic in 19/20 patients (95%).Conclusion:US-guided CNB represents a novel approach for the management of pSS patients with SGs enlargement. This procedure shows a remarkable patient safety and tolerance, allowing an adequate glandular sampling and definite diagnosis in almost all the studied patients.References:[1]Zabotti A, Zandonella Callegher S, Lorenzon M, Pegolo E, Scott CA, Tel A, et al. Ultrasound-guided core needle biopsy compared with open biopsy: a new diagnostic approach to salivary gland enlargement in Sjögren’s syndrome? Rheumatology (Oxford) 2020.[2]Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, Bowman SJ, Mariette X; International Sjögren’s Syndrome Criteria Working Group. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts. Arthritis Rheumatol. 2017 Jan;69(1):35-45. doi: 10.1002/art.39859. Epub 2016 Oct 26. PMID: 27785888; PMCID: PMC5650478.Table 1.Description of complicationsComplications of US-guided CNBPatients presenting complications, n/N (%)11/20 (55%)Description of transient complicationsSwelling at biopsy site, n2Bleeding, n1Hematoma, n1Local Pain, n7Local infection, n0Sialocele or fistula, n0Anaesthesia/paraesthesia, n0Transient facial palsy (< 1 hour), n1No persistent complications reportedAll the above specified complications were transient (< 12 weeks). No persistent complications were reported in the follow up.Figure 1.Post-biopsy complication QuestionnaireDisclosure of Interests:Alen Zabotti Speakers bureau: UCB, Novartis, Janssen, Paid instructor for: Amgen, Consultant of: Janssen, Ivan Giovannini: None declared, Sara Zandonella Callegher: None declared, Valeria Manfrè: None declared, Michele Lorenzon Consultant of: not relevant for this study, Enrico Pegolo: None declared, Cathryn Ann Scott: None declared, Alessandro Tel: None declared, Massimo Robiony Consultant of: not relevant for this study, Grant/research support from: not relevant for this study, Chiara Zuiani Consultant of: not relevant for this study, Grant/research support from: not relevant for this study, Salvatore De Vita Consultant of: GSK, Roche, Grant/research support from: not relevant for this study

scholarly journals OP0095 A DECISION MODEL OF LABIAL GLAND BIOPSY BASED ON B-MODE ULTRASONOGRAPHY WITH SHEAR-WAVE ELASTOGRAPHY IN PATIENTS WITH SUSPECTED SJÖGREN’S SYNDROME

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 62.1-63
Author(s):  
Y. Mo ◽  
S. Hao ◽  
Q. H. LI ◽  
J. J. Liang ◽  
Y. Luo ◽  
...  
Keyword(s):  
Shear Wave ◽  
Sjögren’S Syndrome ◽  
Decision Model ◽  
Sjögren's Syndrome ◽  
Shear Wave Elastography ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
List Type ◽  
Labial Gland ◽  
Sjögren‘S Syndrome

Background:Focal lymphocytic sialadenitis defined as focus score (FS) ≥1 on labial gland (LG) biopsy plays an integral role in various classification criteria of Sjögren’s syndrome (SS). However, suspected patients often hesitate to receive a biopsy; and rheumatologists hope a decision for biopsy based on a high predicted incidence of FS≥1, or against biopsy based on an absolutely low predicted incidence.Objectives:To build a decision model of LG biopsy based on B-mode ultrasonography (US) with shear-wave elastography (SWE) in patients with suspected SS.Methods:Patients who had at least one symptom of oral dryness (based on AECG questions) or had anti-SSA positive were recruited and signed a written informed consent. Bilateral parotid (PG) and submandibular glands (SMG) were examined with B-mode US which graded the echostructure of each gland on a scoring system scaled 0 to 4 (US score), and SWE which described the elasticity of glands. Then LG biopsy was performed.Results:(1)Ninety-one patients whose mean age was 43±15 years were enrolled and 93% of them were female. Anti-SSA was detected in 77 patients (85%) and 28 patients (31%) showed unstimulated whole saliva flow rate (USFR)≤0.1mL/mim. There were 57 patients (63%) showing FS≥1 on LG biopsy. Sixty-three patients (69%) were classified as primary SS, 10 patients (10%) were secondary SS, 18 patients (20%) were uCTD and one patient was RA without SS.(2)US scores were equal between PG and SMG in 59 patients (65%), while the rest patients showed different US scores between two glands: 7 patients (8%) showed higher US scores in PG and 25 patients (27%) showed higher scores in SMG. In each pair of glands US scores were equal. SWE values in PG or SMG of US score 1, 2 or 3 were significantly higher than those of US score 0, while SWE values in glands of US score 4 became declined and showed no significant difference from those with US score 0 (Figure 1A).(3)Heatmap showed US scores in either major salivary gland of patients with FS≥1 on LG biopsy were significantly higher than those with FS<1 (all p<0.001, Figure 1B). ROC curve showed a total US score (including bilateral PG and SMG) ≥9 and a total SWE value (including bilateral PG and SMG)≥30 could significantly recognize patients with FS≥1, respectively with specificity of 100% and 93% (Figure 1C). In this cohort, among 51 patients with a total US score ≥9 and/or a total SWE value≥30, 49 patients (96%) showed FS≥1 on LG biopsy; while two outliers showed total US scores were both 8 although combined SWE values≥30. Other 29 patients showed total US scores≤6 with total SWE values <30 and only one patient (3%) showed FS≥1 on LG biopsy. The remaining 11 patients showed total US scores were 8 with total SWE values <30 and 64% of them (n=7) showed FS≥1.Conclusion:A preliminary decision model of LG biopsy based on B-mode US with SWE in patients with suspected SS were built in Table 1. For example, rheumatologists should reassess the need for biopsy if the incidence of FS≥1 would be <5%. Another cohort of patients with suspected SS is needed for further validation.Table 1.A preliminary decision model of LG biopsy based on B-mode US with SWE in patients with suspected SSAlgorithm*Comments on the decision of LG biopsyA total US score≥9 and/or a total SWE≥30The specificity of FS≥1 on biopsy is >93%. Biopsy is recommended. In some special cases (e.g. contraindicated to biopsy), this item is a potential alternative to LG biopsy.A total US score 7~8 with a total SWE <30It is hard to predict the result of FS, so biopsy is strongly recommended.A total US score≤6 with a total SWE <30The incidence of FS≥1 would be <5%. Rheumatologists should reassess the need for biopsy.References:NoneDisclosure of Interests:None declared

scholarly journals OP0306 CD11C-SPECIFIC ABLATION OF SHP1 INDUCES AUTOIMMUNE SIALADENITIS SIMILAR TO SJÖGREN’S SYNDROME

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 189.1-190
Author(s):  
M. Kinoshita ◽  
Y. Kaneko ◽  
M. Watanabe ◽  
Y. Imai ◽  
S. Shrestha ◽  
...  
Keyword(s):  
Salivary Glands ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Conditional Knockout ◽  
Negative Regulator ◽  
Research Support ◽  
Chugai Pharmaceutical ◽  
Sjögren‘S Syndrome

Background:Dendritic cells (DCs) play important roles in inducing immune response as well as maintaining immune tolerance. Src homology 2 domain-containing protein tyrosine phosphatase-1 (Shp1) is a negative regulator of signaling in hematopoietic cells and is expressed in a variety of immune cells including DCs. Shp1 homozygous mutant mice (motheaten mice) develop multiple immunological abnormalities and they die around four weeks after birth because of severe pneumonitis. Motheaten mice produce large amounts of autoantibodies, and besides, B-1a cells, a distinct B cell subset, which are an important source of autoantibodies increase in these mice. The functional abnormality of DCs in motheaten mice has not been characterized, but DCs and macrophages increase in various organs of motheaten mice.To analyze the function of Shp1 in DCs, we generated Shp1 conditional knockout mice (Shp1 CKO) in whichShp1gene is specifically depleted in CD11c+cells. We found that aged shp1 CKO developed autoimmune glomerulonephritis. We also found that they developed severe tubulointerstitial nephritis (TIN) at the age of 40 weeks, which is characterized by the infiltration of CD11c+and F4/80+cells. CD4+T cells from Shp1 CKO produce much more amount of IFNγ. Collectively, Shp1 in DCs acts as a key regulatory molecule to protect against autoimmunity.Objectives:We analyzed salivary glands of CKO to confirm whether they have autoimmune sialadenitis because TIN is known to be the most common renal manifestations of Sjögren’s syndrome in human.Methods:Shp1 CKO are generated by crossing a mouse line carrying floxedShp1allele to mice expressing Cre recombinase under the control of the CD11c promoter. Sex- and age-matchedPtpn6fl/fllittermates withoutCregene were studied as controls. We analyzed secretory function of the salivary glands in response to pilocarpine stimulation in Shp1 CKO at the age of 40 weeks or older. We then performed histological examination of salivary glands (submandibular glands and sublingual glands) with light-microscopy and immunohistochemical staining. The mononuclear cells prepared from the salivary glands were analyzed by flow cytometry (FCM). We also quantified anti-SSA/Ro60 antibodies and anti-SSB/LA antibodies by ELISA.Results:Shp1 CKO secreted less saliva flow compared to control mice by pilocarpine stimulation. Histological study showed Shp1 CKO exhibited massive infiltration of inflammatory cells in salivary glands associated with periductal foci and periductal fibrosis. Most of infiltrated cells were stained by anti- CD4 or B220 mAbs. FCM revealed that B cells increased in the salivary glands of Shp1 CKO. In addition, B-1a cells also increased in the salivary glands of the mice. The levels of anti-SSA/Ro60 antibodies and anti-SSB/LA antibodies were increased in Shp1 CKO.Conclusion:CD11c-specific ablation of Shp1 induces the ectopic generation of lymphoid structure in salivary glands and impairment of salivary secretion. Autoantibody profile in Shp1 CKO resembled that in human Sjögren’s syndrome. Our findings suggest that aged Shp1 CKO have the potential to become a new mouse model for the analysis of Sjögren’s syndrome.References:[1]Green C. M. et al. J Heredity. 1975; 250-258.[2]Kaneko T. et al. J Immunology. 2012; 5397-540.[3]Watanabe M. et al. Biochem Biophys Rep. in press.Disclosure of Interests:Masato Kinoshita: None declared, Yoriaki Kaneko Grant/research support from: CHUGAI PHARMACEUTICAL CO., LTD.Astellas Pharma Inc.b, Speakers bureau: CHUGAI PHARMACEUTICAL CO., LTD.Astellas Pharma Inc., Mitsuharu Watanabe: None declared, Yoichi Imai: None declared, Shreya Shrestha: None declared, Junya Suwa: None declared, Yuko Ohishi: None declared, Hiroko Hamatani: None declared, Masao Nakasatomi: None declared, Toru Sakairi: None declared, Hidekazu Ikeuchi Speakers bureau: CHUGAI PHARMACEUTICAL CO., LTD.Astellas Pharma Inc., Yoshihisa Nojima: None declared, Keiju Hiromura Grant/research support from: CHUGAI PHARMACEUTICAL CO., LTD.Astellas Pharma Inc., Speakers bureau: CHUGAI PHARMACEUTICAL CO., LTD.Astellas Pharma Inc.

scholarly journals The Immune Factors Involved in the Pathogenesis, Diagnosis, and Treatment of Sjogren's Syndrome

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Yi-fan Huang ◽  
Qian Cheng ◽  
Chun-miao Jiang ◽  
Shu An ◽  
Lan Xiao ◽  
...  
Keyword(s):  
Immune System ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Autoimmune Disorder ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Diagnosis And Treatment ◽  
Open Label ◽  
T Lymphocyte Subsets ◽  
Sjögren‘S Syndrome

Sjogren's syndrome (SS) is a systemic, autoimmune disorder characterized by salivary insufficiency and lymphocytic infiltration of the exocrine glands. Even though the mechanism of its pathology and progression has been researched ever since its discovery, the roles of different parts of immune system remain inconclusive. There is no straightforward and simple theory for the pathogenesis and diagnosis of Sjogren’s syndrome because of the multiple kinds and functions of autoantibodies, changing proportion of different T-lymphocyte subsets with the progression of disease, unsuspected abilities of B lymphocytes discovered recently, crosstalk between cytokines connecting the factors mentioned previously, and genetic predisposition that contributes to the initiation of this disease. On the other hand, the number of significant reports and open-label studies of B-cell depletion therapy showing clinical efficacy in sjogren’s syndrome has continued to accumulate, which provides a promising future for the patients. In a word, further elucidation of the role of different components of the immune system will open avenues for better diagnosis and treatment of SS, whose current management is still mainly supportive.

Efficacy and safety of mizoribine for the treatment of Sjögren's syndrome: a multicenter open-label clinical trial

2007 ◽  
Vol 17 (6) ◽  
pp. 464-469 ◽  
Author(s):  
Shingo Nakayamada ◽  
Kazuyoshi Saito ◽  
Hisanori Umehara ◽  
Noriyoshi Ogawa ◽  
Takayuki Sumida ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Sjögren’S Syndrome ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Efficacy And Safety ◽  
Open Label ◽  
Sjögren‘S Syndrome

scholarly journals OP0302 IANALUMAB (VAY736), A DUAL MODE OF ACTION BIOLOGIC COMBINING BAFF RECEPTOR INHIBITION WITH B CELL DEPLETION, REACHES PRIMARY ENDPOINT FOR TREATMENT OF PRIMARY SJOGREN’S SYNDROME

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 187.1-188
Author(s):  
T. Dörner ◽  
S. J. Bowman ◽  
R. Fox ◽  
X. Mariette ◽  
A. Papas ◽  
...  
Keyword(s):  
B Cell ◽  
Sjögren’S Syndrome ◽  
Primary Endpoint ◽  
Dose Response ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Research Support ◽  
Rate Analysis ◽  
Sjögren‘S Syndrome

Background:Primary Sjogren’s syndrome (pSS) is a multi-organ autoimmune disease mainly affecting excretory glands and characterised by B-cell hyperactivity. No approved systemic treatment is available. Ianalumab (VAY736) is an anti-B-cell activating factor (BAFF) receptor fully human monoclonal antibody, engineered for direct ADCC-mediated B-cell depletion.Objectives:This phase 2b study aimed at establishing a dose-response relationship over a range of VAY736 doses, using change from baseline (BL) in EULAR Sjogren’s Syndrome Disease Activity index (ESSDAI) over 24 Weeks (Wks) as primary endpoint. The study is ongoing with a second blinded treatment period up to Wk52. Here we report efficacy and safety Wk24.Methods:190 patients (pts) were randomised 1:1:1:1 to receive monthly s.c. doses of VAY736 (5, 50, 300mg) or placebo (PBO). Prior to 1st-dose of study treatment, pts received methylprednisolone i.v. 250mg. Eligible pts fulfilled American European Consensus Group (AECG) criteria, were anti-Ro/SSA+, had ESSDAI ≥6 and EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) ≥5. Statistical methods included MCP-Mod to assess dose-response on change of ESSDAI from BL and responder rate analysis to calculate the proportion of pts with ≥3 points improvement on ESSDAI. Secondary endpoints included ESSPRI, Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), Physician’s (PhGA) and Patient’s Global Assessments (PaGA), SF-36, stimulated salivary flow (sSF), Schirmer’s test.Results:Primary endpoint was met with statistically significant dose-response for ESSDAI (Figure). The largest ESSDAI reduction was 1.92 points over PBO for VAY736 300mg at Wk24. Responder rate analysis on ESSDAI revealed for 300mg vs PBO responder rates of 42/47 (89.4%) vs 30/49 (61.2%), a difference of 28.1% (p=0.0019). No differences were seen for 5mg and 50mg vs PBO. PhGA change from BL was significantly different between 300mg and PBO (p=0.022). A numerical trend for sSF improvement for VAY736 300mg compared to PBO was notable at Wk24 (p=0.092). For secondary endpoints ESSPRI and FACIT-F, VAY736 treatment showed no benefits over PBO. PBO responses were generally high. Incidence of treatment emergent AEs was comparable across all studied groups, whereby site injection reactions were most frequent, mostly mild and showed a dose-response.Conclusion:Primary endpoint assessing ESSDAI was met, showing statistically significant dose-response for ianalumab with clinically important improvement for 300mg vs PBO. Preliminary safety profile of ianalumab was good.Figure.ESSDAI Change from Baseline over Time up to Week 24 Reveals a Statistically Significant Dose Response RelationshipDisclosure of Interests:Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen, Simon J. Bowman Consultant of: Astrazeneca, Biogen, BMS, Celgene, Medimmune, MTPharma, Novartis, Ono, UCB, xtlbio, Glapagos, Speakers bureau: Novartis, Robert Fox Consultant of: Novartis, Pfizer and Lilly, Xavier Mariette Consultant of: BMS, Gilead, Medimmune, Novartis, Pfizer, Servier, UCB, Athena Papas Grant/research support from: Novartis, Consultant of: Novartis, Thomas Grader-Beck Grant/research support from: Abbvie, Celgene, Consultant of: Novartis, Lilly, Ben A Fisher Consultant of: Novartis, Roche, BMS and Servier, Filipe Barcelos Consultant of: Pfizer and Lilly, Salvatore De Vita Consultant of: Roche, Human Genome Science, Glaxo Smith Kline and Novartis, Hendrik Schulze-Koops Grant/research support from: Pfizer Inc, Robert J Moots: None declared, Guido Junge Shareholder of: Novartis, Employee of: Novartis, Janice Woznicki Shareholder of: Novartis, Employee of: Novartis, Monika Sopala Shareholder of: Novartis, Employee of: Novartis, Wen-Lin Luo Shareholder of: Novartis, Employee of: Novartis, Wolfgang Hueber Shareholder of: Novartis, Employee of: Novartis

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