Biomarkers in Primary Sjögren's Syndrome

Lymphoma, Non-Hodgkin Clinical Trial

— pSS  

Official title:

Gene Expression of Interferon (INF) and B Lymphocyte Biomarkers as Markers of Systemic Affectation and Lymphoproliferative Disease in Primary Sjögren's Syndrome

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03765593
• Other study ID #: 3398
• Status: Not yet recruiting
• Start date: March 2019
• Est. completion date: March 2021

Study information

• Verified date: December 2018
• Source: National Council of Scientific and Technical Research, Argentina
• Contact: Maria Soledad Retamozo, MD, PhD
• Phone: 005493516981622
• Email: soleretamozo[@]hotmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The clinical spectrum of primary Sjogren Syndrome (pSS)ranges from sicca syndrome to systemic involvement (extraglandular manifestations), including a large number of manifestations that may be the form of presentation or appear after the disease is diagnosed, and that clearly mark the prognosis of the disease.

Gene expression levels of Interferon (INF) and B Lymphocyte Biomarkers as Markers of Systemic Affectation and Lymphoproliferative Disease in, together with clinical and laboratory parameters, will provide significant information about the risk of developing hematological neoplasms in patients with pSS at different stages of the disease, and lead to better management of the disease treatment and therapeutic behaviors.

Using the proposed technique allows us to study the gene expression at the mRNA level of each biomarker, which allows us to anticipate the irreversible changes that take place due to the progress of the pathology in progress, since the molecular changes precede the histological changes and in the pathological diagnosis.

Description:

This project, address the value of these proposed biomarkers in pSS with regard to disease activity and risk stratification of pSS subsets. The investigator's group aim to determine if the proposed biomarkers and their gene expression in saliva, peripheral blood and minor salivary gland samples in patients with pSS are increased to know the degree of their usefulness in daily clinical practice, to indicate which patients have a highest risk of developing a hematological malignancy and to know if these biomarkers are useful to recognize patients who have greater activity of the disease to be able to use it in the follow-up of the disease and as a future responder of the new biological therapies against B cells, INF and monocytes.

Gene expression is a highly regulated mechanism that controls the function and adaptability of all living cells. The field of gene expression analysis has undergone important advances in biomedical research. Today, quantification techniques of mRNA expression have led to improvements in the identification of the gene and the sub-classification of the disease, for example, the expression of specific genes (mRNA) can be quantified by reverse transcription and PCR in quantitative real time. This is the most sensitive technique available to detect and quantify mRNA, where extremely small sample sizes can be used in mRNA quantification. Molecular changes precede histological changes and clinicians in the diagnosis of a pathology. For this reason, studying gene expression at the mRNA level allows us to anticipate irreversible changes that take place due to the progress of the pathology in progress.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: March 2021
• Est. primary completion date: March 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients: cross sectionally patients will be included for clinical suspicion of primary SS or with the diagnosis already established in Rheumatology unit.

The following inclusion criteria will be applied to the study:

• Age > 18 years

• Informed consent of the patient.

Exclusion Criteria:

• Impossibility of obtaining consent (cognitive impairment, other causes).

• Associated systemic autoimmune or rheumatological diseases.

• Chronic viral infections (HCV, HBV, HIV).

Related Conditions & MeSH terms

• Lymphoma, Non-Hodgkin
• Primary Sjögren Syndrome
• Sjogren's Syndrome
• Syndrome

Intervention

Procedure:
• Biopsy Salivary Gland
A minor salivary gland biopsy will be performed at lower lip, with the minimally invasive technique that is carried out in Rheumatology Unit as a routine procedure for the diagnosis of pSS, from there it will be taken between 2-3 glands for the study. RNAlater®(Ambion, Inc., Texas, United States of America) will be stored in solution for the stabilization and preservation of RNA at -80ºC.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
National Council of Scientific and Technical Research, Argentina

References & Publications (22)

Barone F, Bombardieri M, Manzo A, Blades MC, Morgan PR, Challacombe SJ, Valesini G, Pitzalis C. Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren's syndrome. Arthritis Rheum. 2005 Jun;52(6) — View Citation

Brito-Zerón P, Retamozo S, Gheitasi H, Ramos-Casals M. Erratum to: Treating the Underlying Pathophysiology of Primary Sjögren Syndrome: Recent Advances and Future Prospects. Drugs. 2016 Dec;76(18):1799. — View Citation

Brkic Z, Maria NI, van Helden-Meeuwsen CG, van de Merwe JP, van Daele PL, Dalm VA, Wildenberg ME, Beumer W, Drexhage HA, Versnel MA. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren's syndrome and association with disea — View Citation

Daridon C, Devauchelle V, Hutin P, Le Berre R, Martins-Carvalho C, Bendaoud B, Dueymes M, Saraux A, Youinou P, Pers JO. Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary Sjögren's syndrome. Arthritis Rh — View Citation

Hjelmervik TO, Petersen K, Jonassen I, Jonsson R, Bolstad AI. Gene expression profiling of minor salivary glands clearly distinguishes primary Sjögren's syndrome patients from healthy control subjects. Arthritis Rheum. 2005 May;52(5):1534-44. — View Citation

Ioannidis JP, Vassiliou VA, Moutsopoulos HM. Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren's syndrome. Arthritis Rheum. 2002 Mar;46(3):741-7. — View Citation

Jonsson R, Gordon TP, Konttinen YT. Recent advances in understanding molecular mechanisms in the pathogenesis and antibody profile of Sjögren's syndrome. Curr Rheumatol Rep. 2003 Aug;5(4):311-6. Review. — View Citation

Kassan SS, Thomas TL, Moutsopoulos HM, Hoover R, Kimberly RP, Budman DR, Costa J, Decker JL, Chused TM. Increased risk of lymphoma in sicca syndrome. Ann Intern Med. 1978 Dec;89(6):888-92. — View Citation

Lavie F, Miceli-Richard C, Quillard J, Roux S, Leclerc P, Mariette X. Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjögren's syndrome. J Pathol. 2004 Apr;202(4):496-502. — View Citation

Mariette X, Roux S, Zhang J, Bengoufa D, Lavie F, Zhou T, Kimberly R. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren's syndrome. Ann Rheum Dis. 2003 Feb;62(2):168-71. — View Citation

Martin T, Weber JC, Levallois H, Labouret N, Soley A, Koenig S, Korganow AS, Pasquali JL. Salivary gland lymphomas in patients with Sjögren's syndrome may frequently develop from rheumatoid factor B cells. Arthritis Rheum. 2000 Apr;43(4):908-16. — View Citation

Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM. BLyS: member of the tu — View Citation

Nezos A, Gravani F, Tassidou A, Kapsogeorgou EK, Voulgarelis M, Koutsilieris M, Crow MK, Mavragani CP. Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagene — View Citation

Quartuccio L, Baldini C, Bartoloni E, Priori R, Carubbi F, Corazza L, Alunno A, Colafrancesco S, Luciano N, Giacomelli R, Gerli R, Valesini G, Bombardieri S, De Vita S. Anti-SSA/SSB-negative Sjögren's syndrome shows a lower prevalence of lymphoproliferati — View Citation

Quartuccio L, Salvin S, Fabris M, Maset M, Pontarini E, Isola M, De Vita S. BLyS upregulation in Sjogren's syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology (Oxford — View Citation

Retamozo S, Flores-Chavez A, Consuegra-Fernández M, Lozano F, Ramos-Casals M, Brito-Zerón P. Cytokines as therapeutic targets in primary Sjögren syndrome. Pharmacol Ther. 2018 Apr;184:81-97. doi: 10.1016/j.pharmthera.2017.10.019. Epub 2017 Oct 29. Review. — View Citation

Rose T, Grützkau A, Hirseland H, Huscher D, Dähnrich C, Dzionek A, Ozimkowski T, Schlumberger W, Enghard P, Radbruch A, Riemekasten G, Burmester GR, Hiepe F, Biesen R. IFNa and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus. Ann Rheum Dis. 2013 Oct;72(10):1639-45. doi: 10.1136/annrheumdis-2012-201586. Epub 2012 Oct 31. — View Citation

Rose T, Szelinski F, Lisney A, Reiter K, Fleischer SJ, Burmester GR, Radbruch A, Hiepe F, Grützkau A, Biesen R, Dörner T. SIGLEC1 is a biomarker of disease activity and indicates extraglandular manifestation in primary Sjögren's syndrome. RMD Open. 2016 D — View Citation

Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B c — View Citation

Szodoray P, Alex P, Jonsson MV, Knowlton N, Dozmorov I, Nakken B, Delaleu N, Jonsson R, Centola M. Distinct profiles of Sjögren's syndrome patients with ectopic salivary gland germinal centers revealed by serum cytokines and BAFF. Clin Immunol. 2005 Nov;1 — View Citation

Theander E, Vasaitis L, Baecklund E, Nordmark G, Warfvinge G, Liedholm R, Brokstad K, Jonsson R, Jonsson MV. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjögren's syn — View Citation

Wildenberg ME, van Helden-Meeuwsen CG, van de Merwe JP, Drexhage HA, Versnel MA. Systemic increase in type I interferon activity in Sjögren's syndrome: a putative role for plasmacytoid dendritic cells. Eur J Immunol. 2008 Jul;38(7):2024-33. doi: 10.1002/e — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Gene expression levels in immune cells in salivary gland biopsy samples from participants with and without pSS	To identify a biomarker of disease activity, measured by the real-time PCR reactions (qRT-PCR).	Up to 24 months
Primary	Gene expression levels in immune cells in blood samples from participants with and without pSS	To identify a biomarker of disease activity, measured by the real-time PCR reactions (qRT-PCR).	Up to 24 months
Primary	Gene expression levels in immune cells in saliva samples from participants with and without pSS	To identify a biomarker of disease activity, measured by the real-time PCR reactions (qRT-PCR).	Up to 24 months
Secondary	Immunoglobulins	The change from baseline in IgG, IgM and IgA levels at 24 months.	Up to 24 months
Secondary	Complement levels C3 and C4	The change from baseline in complement levels at 24 months.	Up to 24 months
Secondary	Rheumatoid Factor	The change from baseline in titer of rheumatoid factors at 24 months.	Up to 24 months
Secondary	Cryoglobulins	The change from baseline in titer of cryoglobulins at 24 months.	Up to 24 months