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- Predictors of outcome and immunological markers in patients with Systemic lupus erythematosusPublication . Inês, Luís Pedro Bolotinha de Sousa; Fonseca, Fernando Pereira; Silva, José António Pereira daBackground Systemic lupus erythematosus (SLE) is the prototypic multisystem autoimmune disease, with a broad spectrum of clinical presentations encompassing almost all organs and a chronic course, which can vary from mild to life-threatening. There is a major unmet need for outcome prediction enabling tailoring management and therapeutic interventions for SLE patients. Objectives To improve outcome prediction in SLE, the specific aims of this thesis were: (1) to evaluate the performance of the ACR and the SLICC classification criteria sets for SLE; (2) to evaluate the effect of the classification criteria fulfilled at time of SLE diagnosis and other predictors on long-term outcomes of damage and mortality; (3) to identify clinical predictors for SLE flares of disease activity; (4) to increase knowledge about the relationships between immunological markers and SLE disease activity. Methods We conducted a cross-sectional observational study of 2055 patients with a clinical diagnosis of SLE followed at 17 centers and registered in the Portuguese and Spanish national registries; the sensitivity of the ACR and SLICC classification criteria was compared using the McNemar’s test; the sensitivity of the two classification sets was further examined in five subgroups defined according to disease duration. We conducted a prospective inception cohort study of 192 SLE patients from time of diagnosis and followed up to 10 years at the CHUC Lupus Clinic; we assessed with multivariate Cox models the 10-year outcomes of damage and mortality, according to SLE classification status (fulfilling the ACR or only the SLICC criteria) at inception, and adjusting for potential baseline confounders. We conducted a prospective cohort study of 202 SLE patients followed up to 24 months at the CHUC Lupus Clinic over 1083 visits; we evaluated potential clinical predictors for disease activity flares with multivariate Cox regression models adjusting for potential confounders factors and estimating hazard ratios. We conducted cross-sectional studies of two groups of SLE patients, one with clinically active and another with inactive disease recruited at the CHUC Lupus Clinic and a group of healthy subjects enrolled at the same site; one peripheral blood sample was collected from each participant and analyzed with flow cytometry multiparametric immunophenotyping protocols to define relationships between immunological markers in B cells, Th17 cells and NK cells and SLE classification and disease activity status. Results The cross-sectional study on performance of classification criteria showed that the sensitivity for SLE clinical diagnosis was higher with the SLICC than with the ACR classification criteria (93.2% versus 85.6%, p<0.0001). From patients not fulfilling the ACR criteria, 62.8% could be classified with the SLICC. Patients within 5 years since disease onset presented the largest difference in sensitivity between the SLICC and the ACR criteria (respectively 89.3% and 76.0%, p<0.0001). In the 10-year prospective inception cohort study, patients meeting the ACR criteria compared to those with only the SLICC criteria at inception presented during follow-up with more cases of lupus nephritis (35.1% versus 13.8%, p<0.01), but less thrombotic antiphospholipid syndrome (4.5% versus 17.2%, p<0.01). The Cox models showed no significant differences in risk for damage or death between groups. In the 24-month prospective cohort study, the multivariate Cox models demonstrated that the risk of flare was more than two-fold, four-fold and three-fold higher for patients with SLE diagnosis up to 25 years, previous lupus nephritis or baseline immunosuppressant treatment, respectively. In the cross-sectional immunophenotyping studies, analysis of B cell subsets showed that differential expression of BAFFR, CD81 and CD38 in the transitional B cells allowed identifying two major clusters: the cluster 1 integrated all healthy subjects and 79% of SLE patients with clinically inactive disease, while in the cluster 2 there was only patients with SLE and 82% of those with clinically active disease. The analysis of Th17 cells showed no significant differences in the frequency of Th17 among healthy subjects and SLE patients, as well as among patients with clinically inactive and active disease. The analysis of NK cells showed a lower number and frequency of NK cells in SLE patients as compared to healthy subjects, regardless of disease activity status, and a lower frequency of CD56dim NK cells expressing CXCR3 was a marker of clinically active SLE (12.5% versus 24.1% in the active and inactive SLE group, respectively, p<0.01). Conclusions The SLICC classification criteria are more sensitive and may allow a SLE classification earlier in the disease course than the previous ACR criteria. Patients fulfilling at inception either of the classification criteria present no differences in the major long-term outcomes of organ damage and mortality. Patients with a SLE diagnosis before age 25, lupus nephritis or immunosuppressant treatment/severe SLE present higher risk for flares of disease activity; patients fulfilling at inception only the SLICC classification criteria may present higher risk of thrombotic antiphospholipid syndrome: these clinical predictors thus provide a basis for tailoring management strategies of SLE patients. Immunophenotyping studies suggested that SLE patients present: an upregulation of B cells, with subset clusters able to differentiate SLE patients from healthy subjects and clinically active from inactive SLE; a downregulation of NK cells, and less clear changes of Th17 cells. We provide proof-of-concept that a panel of immunological markers may provide a basis for biologic validation of clinical definitions for SLE disease activity states.