B-CELL SUBSETS DIFFERENCES IN INFLAMMATORY RHEUMATIC DISEASES

1. B-CELL SUBSETS DIFFERENCES IN INFLAMMATORY RHEUMATIC DISEASES João Lagoas Gomes, Dario Ligeiro, Alice Lima, Alexandre Sepriano, Cristiana Teixeira, Carina Lopes, Tiago Costa, Sofia Ramiro, Margarida Mateus, Maria Manuela Costa, Jaime C. Branco, Fernando Pimentel-Santos

2. B-cell subsets in inflammatory rheumatic diseases • Background • Objectives • Material and Methods • Results • Conclusions • Future Perspectives

3. B-cell subsets in inflammatory rheumatic diseases • Background Spondyloarthritis(SpA), Rheumatoid arthritis (RA), Systemic Lupus erithematosus (SLE) are the most common and serious inflammatory arthritis. • Risk • Joint destruction • Functional impairment •  morbidity • Early retirement • QoL •  mortality SpA RA SLE

4. B-cell subsets in inflammatory rheumatic diseases • Background Window of Opportunity • A period, early in the course of the disease when: • the disease process can be altered or maybe even reversed • a complete return to normality – REMISSION- is possible • sustainability 12 weeks

5. B-cell subsets in inflammatory rheumatic diseases • Background Early Diagnosis T2T Better Outcomes Effective Therapies • A period early in the course of the disease when: • the disease process can be altered or maybe even reversed • a complete return to normality – REMISSION • sustainability Remission

6. B-cell subsets in inflammatory rheumatic diseases • Background

7. B-cell subsets in inflammatory rheumatic diseases • Background • RelevanceofBiomarkers for: • EarlyDiagnosis • Prognosis • Therapyselection • New TherapeuticTargets

8. B-cell subsets in inflammatory rheumatic diseases • Background • B cellsinSpA • No auto-antibodies; • Not relevant for physiopathology; • Immune regulatory genes suggesting B-cell dysfunction1; • Clinical trials have shown some efficacy of B-cell depletion in ankylosing spondylitis2.  

9. B-cell subsets in inflammatory rheumatic diseases • Objectives • To assess and compare the subsets of peripheral B-cell compartment in AS with HC, RA and SLE. SpA RA LES HC

10. B-cell subsets in inflammatory rheumatic diseases • Material andMethods Inclusion Criteria • Definitive Diagnosis of SpA, RA and SLE according to respective classification criteria; • Pts, 18 < Age (years) <65; • Capacity for given an informed consent.

11. B-cell subsets in inflammatory rheumatic diseases • Material andMethods Exclusion Criteria • History of any concomitant inflammatory rheumatic disease • Any active or recurrent viral infection that, based on the Investigator's clinical assessment, makes the subject an unsuitable candidate for the study; • Infection(s) requiring treatment with parenteral anti-infectives within 30 days, or oral anti-infectives within 14 days prior the study inclusion; • History of any malignancy; • Receipt of any live vaccine within 4 weeks prior to the study inclusion; • Female who is pregnant or breastfeeding; • Prior exposure to any bDMARD(s)

12. B-cell subsets in inflammatory rheumatic diseases • Material andMethods • Sociodemographic and clinical variables • Peripheral Blood samples: • Inflammatory markers (ESR and CRP); • Immunoglobulin serum levels; • Flow cytometry: B-cell immature transitional stages and mature subsets.

13. B-cell subsets in inflammatory rheumatic diseases • Material and Methods • CD20+CD5+ compartement: • CD27-IgD+ - immature transitional cells • CD24+++CD38+++ - T1 • CD24++CD38++ - T2 • CD24lowCD38+ - T3/pré-naive • CD27+IgD+ – B1a like cells? • CD20+CD5- compartement (mature): • CD27-IgD+ - naive • CD27+IgD+ - non-switched memory (+ MZ like) • CD27+IgD- - memory switched • CD27-IgD- - double negative

14. B-cell subsets in inflammatory rheumatic diseases • Results • 60 pts : 12 HC • SpA (n=22) • RA (n=20) • SLE (n=18) • Low levels of inflammation (ESR, CRP)

15. B-cell subsets in inflammatory rheumatic diseases • Results

16. B-cell subsets in inflammatory rheumatic diseases • Results • Immunoglobulins • Normal range • No differences between groups.

17. B-cell subsets in inflammatory rheumatic diseases • Results • The immature transitional compartment: • SpApts, N range • Not in the RA and SLE groups.

18. B-cell subsets in inflammatory rheumatic diseases • Results • Mature naïve cells, in: • AS, normal range • RA and SLE, decreased

19. B-cell subsets in inflammatory rheumatic diseases • Conclusions • Severe dysfunction in the homeostasis of the B-cell compartment in RA and in particular SLE pts (immature and mature B-cell compartments); • SpApts are not affected.

20. B-cell subsets in inflammatory rheumatic diseases • Future Perspectives • Evaluation of immunoglobin heavy chain (IGH) diversity repertoire by spectratyping • Functional studies appear to be necessary in order to identify differences in key mechanisms of B cell development and differentiation that may play a role in the aetiology and progression of IRD • Pathophysiological mechanisms involving B-cells clearly differentiate AS from RA and SLE.

21. B-cell subsets in inflammatory rheumatic diseases

22. B-cell subsets in inflammatory rheumatic diseases • Aknowledgments • CHLO, Hospital de Egas Moniz • Jaime C. Branco • AlexandreSepriano • Carina Lopes • Fernando Pimentel-Santos • JoãoLagoas Gomes • Maria Manuela Costa • Margarida Mateus • Tiago Costa Rheumatic Disease, Myo and Pain Lab, CEDOC • Jaime C. Branco • Alexandre Sepriano • Carina Lopes • Fernando Pimentel-Santos • João Lagoas Gomes • Tiago Costa Instituto Português do Sangue e Transplantação • Dário Ligeiro • Alice Lima • Cristiana Teixeira • Leiden University Medical Center, Netherlands • AlexandreSepriano • Sofia Ramiro