scholarly journals Cytokines in Sjögren's syndrome: potential therapeutic targets

2010 ◽  
Vol 69 (6) ◽  
pp. 945-948 ◽  
Author(s):  
Nienke Roescher ◽  
Paul P Tak ◽  
Gabor G Illei
Keyword(s):  
Sjögren’S Syndrome ◽  
Inflammatory Cytokines ◽  
Low Dose ◽  
Sjögren's Syndrome ◽  
Biological Effects ◽  
Controlled Trial ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Early Results ◽  
Sjögren‘S Syndrome

The dysregulated cytokine network in Sjögren's Syndrome (SS) is reflected by local and systemic overexpression of pro-inflammatory cytokines and absent or low levels of anti-inflammatory cytokines. To date, the use of cytokine based therapies in SS has been disappointing. Oral administration of low dose interferon (IFN) α showed inconsistent efficacy in various studies and failed to achieve the primary endpoint in a pivotal randomised controlled trial. Similarly, neither of the two tumour necrosis factor (TNF)-α blockers tested (etanercept and infliximab) showed efficacy in placebo controlled trials. Although the rationale for low dose oral IFN treatment has not been firmly established, TNF blockade was based on solid preclinical data. Therefore, the reason for the lack of efficacy is unclear, but recent data suggest that unexpected biological effects of TNF antagonists may have contributed to this. Cytokines, given their central role in the pathogenesis of SS, remain attractive targets for future treatments, despite the disappointing early results. Inflammatory cytokines are obvious candidates, and agents against several of them are available or under development for other autoimmune diseases similar to SS. New candidate cytokines such as IL-17 and IL-12 and/or IL-23 may provide promising targets for SS. Additionally, as an alternative to systemic treatment, which has the risk of potentially severe side effects, the use of local cytokine directed therapy should be explored.

scholarly journals SMADS-Mediate Molecular Mechanisms in Sjögren’s Syndrome

2021 ◽  
Vol 22 (6) ◽  
pp. 3203
Author(s):  
Margherita Sisto ◽  
Domenico Ribatti ◽  
Sabrina Lisi
Keyword(s):  
Sjögren’S Syndrome ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Sjögren's Syndrome ◽  
Biological Effects ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Mesenchymal Transition ◽  
Sjögren‘S Syndrome

There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-β (TGF-β), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease. TGF-β elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of target genes in collaboration with various co-activators and co-repressors. Until now, therapeutic strategy for primary Sjögren’s syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-β/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation. Although EMT seems to cause pSS SG fibrosis, TGF-β family members have ambiguous effects on the function of pSS SGs. Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in pSS that are dictated by orchestrations of SMADs, and describe TGF-β/SMADs value as both disease markers and/or therapeutic target for pSS.

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 Modulation of Conjunctival Goblet Cell Function by Inflammatory Cytokines

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
L. Contreras-Ruiz ◽  
A. Ghosh-Mitra ◽  
M. A. Shatos ◽  
D. A. Dartt ◽  
S. Masli
Keyword(s):  
Sjögren’S Syndrome ◽  
Inflammatory Cytokines ◽  
Goblet Cell ◽  
Ocular Surface ◽  
Cell Function ◽  
Sjögren's Syndrome ◽  
Goblet Cells ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

Ocular surface inflammation associated with Sjögren’s syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren’s syndrome (Thrombospondin-1 deficient mice). We found that apoptosis of goblet cells was primarily induced by TNF-αand IFN-γ. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage.

Can low dose diagnostic dental radiation trigger Sjögren’s syndrome?

2007 ◽  
Vol 69 (5) ◽  
pp. 995-1000 ◽  
Author(s):  
Biji T. Kurien ◽  
Shirley A. Mathews ◽  
R. Hal Scofield
Keyword(s):  
Sjögren’S Syndrome ◽  
Low Dose ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

scholarly journals The Role of Interferons in the Pathogenesis of Sjögren’s Syndrome and Future Therapeutic Perspectives

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 251
Author(s):  
Nicoletta Del Papa ◽  
Antonina Minniti ◽  
Maurizio Lorini ◽  
Vincenzo Carbonelli ◽  
Wanda Maglione ◽  
...  
Keyword(s):  
Sjögren’S Syndrome ◽  
Inflammatory Cytokines ◽  
Sjögren's Syndrome ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Type I ◽  
Type Ii ◽  
Type I Ifn ◽  
Sjögren‘S Syndrome

There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the ‘so-called’ type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS.

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