Type I High-IFN Gene Signature in Associated with Higher Essdai at Enrollmment and Follow-up in the Prospective Multicenter Assess Cohort of 395 Patients

Jacques-Eric Gottenberg¹, Pierre-Etienne BOST², Benno Schwikowski², Raphaele Seror³, Valérie Devauchelle-Pensec⁴, Philippe Dieudé⁵, Jean-Jacques Dubost⁶, Anne Laure Fauchais⁷, Vincent Goeb⁸, Eric Hachulla⁹, Pierre Yves Hatron¹⁰, Claire Larroche¹¹, Véronique Le-Guern¹², Jacques Morel¹³, Aleth Perdriger¹⁴, Emmanuelle Dernis¹⁵, Stephanie Rist Bouillon¹⁶, Alain Saraux¹⁷, Damien Sène¹⁸, Jean Sibilia¹⁹, Olivier Vittecoq²⁰, Gaetane Nocturne²¹, Sarah TUBIANA²², Philippe Ravaud²³ and Xavier Mariette²⁴, ¹Department of Rheumatology, Strasbourg University Hospital, Strasbourg, France, ²Pasteur Institute, System biologique, PARIS, France, ³Department of Rheumatology, Assistance Publique–Hopitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France, ⁴Department of Rheumatology, Brest University Hospital, Brest, France, ⁵Rheumatology, Hôpital Bichat, Paris, France, ⁶Rheumatology department CHU Clermont-Ferrand, Clermont-Ferrand, France, ⁷Rheumatology, Limoges, France, ⁸Rheumatologie, Rheumatology Department CHU Teaching Hospital Amiens, Amiens, France, ⁹CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France, Lille, France, ¹⁰Internal Medicine, Lille, France, ¹¹Internal Medicine, Paris, France, ¹²service de médecine interne, Department of Internal Medicine, Referral Center for Rare Autoimmune and Systemic Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, France, ¹³Rheumatology, CHU Lapeyronie and Montpellier University, Montpellier, France, ¹⁴Service de Rhumatologie, CHRU de Rennes, Rennes, France, ¹⁵Service de Rhumatologie, CH du Mans, Le Mans, France, ¹⁶Rhumatologie, Hopital La Source, La Source, France, ¹⁷Rheumatology, Brest University Hospital, Brest, France, ¹⁸Department of Internal Medicine, Pitié-Salpêtrière Hospital, Paris, France, ¹⁹Department of Rheumatology, Strasbourg University Hospital, Strasbourg, France, ²⁰INSERM U905 & Normandy University, Institute for Research and Innovation in Biomedicine, Rouen, France, ²¹INSERM U1184, IMVA, Paris Sud University,LabEx LERMIT, Le Kremlin Bicêtre, France, ²²CRB Bichat, PARIS, France, ²³Hôpital Hôtel Dieu, Paris, France, ²⁴Université Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, Paris, France

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: biomarkers and interferons, Sjogren's syndrome

Session Information

Date: Sunday, November 5, 2017

Title: Sjögren's Syndrome I: Clinical Assessment and Trial Outcomes

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose:

The type I interferon (IFN) signature is a hallmark of the pathogenesis of primary Sjögren’s syndrome (pSS). However, little is known regarding the clinical utility of assessing this signature in a large cohort of patients prospectively followed up.

Methods:

395 patients with pSS were enrolled in the « ASSessment and Evolution of Systemic complications in primary Sjögren’s syndrome ». Patients have been followed up every year ever since and completed their 5-year follow-up. At baseline, along evaluation of clinical disease activity using international scores, ESSDAI and ESSPRI, serum B-cell activation biomarkers, and whole blood RNA were collected in all enrolled patients. The type I IFN signature was evaluated using the gene expression of IFI27, IFI44 et OAS3 (ref1).

Results:

IFN-high signature is associated with an earlier onset of the disease and a higher systemic disease activity at enrollment

The type I interferon signature was assessed in 366 patients at enrollment. 187 patients (51.1%) had a high IFN signature and 179 had a low IFN signature (49.9%). Patients with a high IFN signature had a significantly earlier onset of symptoms (median age at first symptoms: 44 [34 ;54] years versus 50 [42 ;58] years in patients with low IFN signature, p< 0.0001). ESSDAI was significantly higher in high-IFN patients (4 [2 ;8] versus 2 [1 ;7] in low-IFN patients, p=0.01). ESSPRI tended to be lower in high IFN patients (5.3 [3.3 ; 6.7] vs 5.7 [4.2 ;7.3], p= 0.07. IFN-high patients had significantly more frequently active hematological and biological domains of ESSDAI (71.9% and 72.1%, respectively) than IFN-low patients (47.6 and 34.5%, respectively, p<0.0001 for both comparisons) and tended to have more frequently active lymphadenopathy (80 vs 52.8%, p= 0.1), glandular (66.7 vs 50%, p= 0.2) and muscle (80 vs 53%, p= 0.37) domains of ESSDAI.

IFN high signature is associated with a higher systemic disease activity during the prospective follow-up

Median ESSDAI during the 5-year follow-up was significantly higher in IFN-high than IFN-low patients (3.6 [2 ;7.33] vs 2.8[1 ;6], p=0.003).

Among the 5 patients who developed a lymphoma during the prospective follow-up , 4 out of 5 (80%) were IFN-high at enrollment (versus 50.6% in patients without lymphoma and 43.8% in patients with a history of lymphoma).

Immunological correlates

High IFN signature was highly associated with anti-SSA and anti-SSB antibodies (9.4% in anti-SSA/SSB negative patients, 66.7% in anti-SSA-positive only patients and 87.5% in anti-SSA and anti-SSB-positive patients, p< 0.0001).

IFN score was inversely correlated with components of the hematological domain and C3, C4 and was significantly correlated with IgG (r= 0.53, p< 0.0001), kappa and lambda free light chains of Ig (r=0.46 and 0.48, p< 0.0001 for both), RF (r= 0.45,p< 0.0001), beta-2 microglobulin (r= 0.61, p<0.0001), and BAFF(r=0.36, p< 0.0001).

Conclusion:

IFN gene signature is associated with a more active and systemic disease in a 5-year multicenter prospective cohort and with increased serum markers of B-cell activation. This reinforces the rationale to target type I IFN in pSS-related systemic complications.

Ref 1 Petri M, Behrens T et al Lupus 2009

Disclosure: J. E. Gottenberg, BMS, Gilead, Medimune,Pfzer SanofiAventis, Ucb, 2; P. E. BOST, None; B. Schwikowski, None; R. Seror, None; V. Devauchelle-Pensec, Roche-Chugai provided me tocilizumab for the SEMAPHORER study, 2; P. Dieudé, None; J. J. Dubost, None; A. L. Fauchais, None; V. Goeb, Roche SAS, 5,Chugai Pharma France, 5; E. Hachulla, None; P. Y. Hatron, None; C. Larroche, None; V. Le-Guern, None; J. Morel, None; A. Perdriger, None; E. Dernis, None; S. Rist Bouillon, None; A. Saraux, None; D. Sène, None; J. Sibilia, None; O. Vittecoq, None; G. Nocturne, None; S. TUBIANA, None; P. Ravaud, None; X. Mariette, None.

To cite this abstract in AMA style:

Gottenberg JE, BOST PE, Schwikowski B, Seror R, Devauchelle-Pensec V, Dieudé P, Dubost JJ, Fauchais AL, Goeb V, Hachulla E, Hatron PY, Larroche C, Le-Guern V, Morel J, Perdriger A, Dernis E, Rist Bouillon S, Saraux A, Sène D, Sibilia J, Vittecoq O, Nocturne G, TUBIANA S, Ravaud P, Mariette X. Type I High-IFN Gene Signature in Associated with Higher Essdai at Enrollmment and Follow-up in the Prospective Multicenter Assess Cohort of 395 Patients [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/type-i-high-ifn-gene-signature-in-associated-with-higher-essdai-at-enrollmment-and-follow-up-in-the-prospective-multicenter-assess-cohort-of-395-patients/. Accessed .

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