Sjögren's syndrome

Disease ID:1136
Name:Sjögren's syndrome
Associated with:2 targets
1 immuno-relevant target
6 immuno-relevant ligands
Synonyms
Sicca syndrome | Sjögren-Gougerot syndrome
Description
Sjögren's syndrome is a chronic autoimmune disorder characterized by the triad of dry eyes (keratoconjunctiva sicca), sensation of oral dryness (xerostomia) and/or swelling of the salivary glands secondary to lymphocytic infiltration and destruction of the exocrine glands.
Database Links
Orphanet: ORPHA378

Targets

CXCR5
References:  4
Ligand interactions: 
Ligand Comments
CXCL13
Serum CXCL13 is elevated in patients with SS, compared to healthy controls. Expression of CXCL13 in ectopic lymphoid-like follicles in salivary glands ...
BAFF receptor
Comments:  Molecular target for SS- see NCT02962895 which is designed to evaluate clinical efficacy of anti-BAFF-R mAb VAY736 in SS patients.

Ligands

Key to terms and symbols Click ligand name to view ligand summary Click column headers to sort
Ligand References Clinical and Disease comments
leniolisib
Immuno Disease Comments: Completed Phase 2 clinical trial NCT02775916 as monotherapy for primary SS.
Clinical Use: Being evaluated in clinical trial in patients with genetically activated PI3Kδ (i.e. patients with APDS/PASLI; see Phase 2/3 trial NCT02435173). Positive results from NCT02435173 are reported by Rao et al. (2017) [8], showing that leniolisib was well tolerated and improved laboratory and clinical parameters in APDS patients. | View clinical data
Bioactivity Comments: Data are presented for Example 67 in patent WO2012004299 [2]. | View biological activity
seletalisib
Immuno Disease Comments: Phase 2 clinical candidate for primary SS, but trial NCT02610543 was terminated as they struggled to recruit patients.
Clinical Use: First-in-human results were reported by Helmer et al. (2017) [5]. This article reports data from clinical trials NCT02303509 (safety and tolerability in healthy and psoriatic subjects) and NCT02207595 (safety and tolerability in healthy subjects only). A proof of concept Phase 2 trial in patients with primary Sjögren's syndrome has been terminated due to difficulty in enrolling suitable patient numbers (NCT02610543). | View clinical data
CFZ533
Immuno Disease Comments: Phase 2 clinical candidate for primary Sjögren's syndrome- see NCT02291029
Clinical Use: CFZ533 is being evaluated in clinical trials as a therapy for some autoimmune conditions and for preventing/reducing solid organ transplant rejection. Click here to link to ClinicalTrials.gov's full list of CFZ533 trials. | View clinical data
Bioactivity Comments: CFZ533 (mAb1) shows no agonist activity in an in vitro assay using isolated human PBMCs, blocks -mediated PBMC proliferation (IC50 58 ng/ml), inhibits CD40L-mediated TNF-α release from human monocyte derived dendritic cells (IC50 40 ng/ml), and has ADCC activity of < 1% (measuring specific lysis) [6]. | View biological activity
belimumab
Immuno Disease Comments: In clinical trial for this indication- see NCT02631538, in combination with rituximab.
Clinical Use: Approved as an adjunctive treatment for systematic lupus erythematosus (SLE) [7]. The original formulation of belimumab was administered intravenously. In July 2017, a new self-injectable subcutaneous formulation of belimumab for the treatment of adult patients with active, autoantibody‑positive SLE was FDA approved, which allows patients to self-administer their medicine at home rather than going to medical facilities to receive their i.v. infusions.
Additional indications being evaluated with belimumab include vasculitis (Phase 3), and myaesthenia gravis and transplant rejection (both Phase 2). | View clinical data
petesicatib
Immuno Disease Comments: Completed Phase 2 evaluation in SS- see NCT02701985.
Clinical Use: (RO5459072 or RG7625) has completed Phase 2 clinical evaluation in Sjögren's syndrome (NCT02701985) and Phase 1 in celiac disease (NCT02679014), but there are no active clinical trials registered with ClinicalTrials.gov. | View clinical data
Bioactivity Comments: Petesicatib (RO5459072) is selective for cathepsin S compared to other cathepsin isozymes examined [10]. | View biological activity
CXCL13 1,3,9
Immuno Disease Comments: Serum CXCL13 is elevated in patients with SS, compared to healthy controls. Expression of CXCL13 in ectopic lymphoid-like follicles in salivary glands of SS patients has been suggested as a potential disease marker. CXCL13 levels are reduced by blockade of lymphotoxinβ receptor in the NOD mouse model of SS.

References

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1. Barone F, Bombardieri M, Manzo A, Blades MC, Morgan PR, Challacombe SJ, Valesini G, Pitzalis C. (2005) Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren's syndrome. Arthritis Rheum., 52 (6): 1773-84. [PMID:15934082]

2. Cooke NG, Fernandes GDSP, Graveleau N, Hebach C, Hogenauer K, Hollingworth G, Smith AB, Soldermann N, Stowasser F, Strang R et al.. (2012) Tetrahydro-pyrido-pyrimidine derivatives. Patent number: WO2012004299. Assignee: Novartis Ag. Priority date: 06/07/2010. Publication date: 12/01/2012.

3. Fava RA, Kennedy SM, Wood SG, Bolstad AI, Bienkowska J, Papandile A, Kelly JA, Mavragani CP, Gatumu M, Skarstein K et al.. (2011) Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome. Arthritis Res. Ther., 13 (6): R182. [PMID:22044682]

4. Hansen A, Lipsky PE, Dörner T. (2007) B cells in Sjögren's syndrome: indications for disturbed selection and differentiation in ectopic lymphoid tissue. Arthritis Res. Ther., 9 (4): 218. [PMID:17697366]

5. Helmer E, Watling M, Jones E, Tytgat D, Jones M, Allen R, Payne A, Koch A, Healy E. (2017) First-in-human studies of seletalisib, an orally bioavailable small-molecule PI3Kδ inhibitor for the treatment of immune and inflammatory diseases. Eur. J. Clin. Pharmacol., 73 (5): 581-591. [PMID:28160012]

6. Heusser C, Rush J, Vincent K. (2012) Silent fc variants of anti-cd40 antibodies. Patent number: WO2012065950. Assignee: Novartis Ag. Priority date: 15/11/2010. Publication date: 24/05/2012.

7. Lutalo PM, D'Cruz DP. (2014) Update on belimumab for the management of systemic lupus erythematosus. Expert Opin Biol Ther, 14 (11): 1701-8. [PMID:25303323]

8. Rao VK, Webster S, Dalm VASH, Šedivá A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M et al.. (2017) Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood, 130 (21): 2307-2316. [PMID:28972011]

9. Salomonsson S, Jonsson MV, Skarstein K, Brokstad KA, Hjelmström P, Wahren-Herlenius M, Jonsson R. (2003) Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome. Arthritis Rheum., 48 (11): 3187-201. [PMID:14613282]

10. Tato M, Kumar SV, Liu Y, Mulay SR, Moll S, Popper B, Eberhard JN, Thomasova D, Rufer AC, Gruner S et al.. (2017) Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury. Sci Rep, 7 (1): 2775. [PMID:28584258]