Objectives Deregulated production of IL-17 and IL-21 contributes to the pathogenesis of autoimmune disorders like SLE and RA. Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to suppress production of IL-17 and IL-21 by SLE T cells or human Th17 cells. Methods ROCK activity in PBMCs from 29 SLE patients, 31 RA patients, and 28 healthy controls was determined by ELISA. SLE T cells or in vitro-differentiated Th17 cells were treated with Y27632 (a pan-ROCK inhibitor), KD025 (a selective ROCK2 inhibitor), or simvastatin (which inhibits RhoA, a major ROCK activator). ROCK activity, IL-17, and IL-21 production were assessed. The transcriptional profile altered by ROCK inhibitors was evaluated by NanoString technology. Results ROCK activity levels were significantly higher in SLE and RA patients than healthy controls. Th17 cells exhibited high ROCK activity that was inhibited by Y276327, KD025, or simvastatin; each also decreased IL-17 and IL-21 production by purified SLE T cells or Th17 cells. Immune profiling revealed both overlapping and distinct effects of the different ROCK inhibitors. Conclusions ROCK activity is elevated in PBMCs from SLE and RA patients. Production of IL-17 and IL-21 by SLE T cells or Th17 cells can furthermore be inhibited by targeting the RhoA-ROCK pathway via both non-selective and selective approaches.

A clinically significant aPL profile is associated with an increased risk of organ damage accrual during a 15-year follow-up in SLE patients.

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BackgroundThe effect of antiphospholipid antibodies (aPL) on organ damage in Systemic Lupus Erythematosus (SLE) patients remains unclear as there is a limited number of studies with contrasting conclusions.ObjectivesThe aim of this study was to assess the relative contribution of aPL to organ damage in SLE patients.MethodsSLE patients (based on American College of Rheumatology [ACR] Classification Criteria) with less than 10 years of disease duration at registry entry were identified from the SLE registry of two centers. Clinical information retrieved included: demographics, disease duration, organ damage assessed by the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI), and aPL profile. A “clinically significant” aPL profile was defined as: positive lupus anticoagulant test, anticardiolipin antibody IgG/M >40 GPL or MPL, and/or anti-β2Glycoprotein-I IgG/M > the 99th percentile), on two or more occasions, at least 12 weeks apart, within ±1 year of registry entry. The outcome variables were any increase of SDI at 5, 10 and/or 15 years of follow-up (time 0 was defined as registry entry). For univariate analysis the demographic and clinical characteristics of patients with and without a SDI increase at 5, 10 and 15 years were compared (Chi square or Fisher's exact test for categorical data, Student t test or Mann-Whitney-Wilcoxon for continuous data as appropriate). The Generalized Estimated Equations (GEE) model was used as multivariate analysis to detect significant factors for increased SDI at 5, 10 and/or 15 years.ResultsWe identified 262 patients with less than 10 years of disease duration, at least 5 years of prospective follow-up and a complete aPL profile (76% Caucasian, 8% African-American, 6% Asian, and 86% female). Mean age at diagnosis was 31 years (±12) and mean age at registry entry was 33 years (±12) with a mean disease duration of 1 year (±2). Eighty-eight (33%) patients had a clinically significant aPL profile. Twenty-one percent, 42%, and 57% of patients had new organ damage in 5, 10, and 15 years, respectively (Table I). On the univariate analysis: a) a significant aPL profile (p:0.02) and a older age at diagnosis (p:0.04) were significantly associated to any increase of SDI at 5 years; b) a shorter disease duration was significantly associated to any increase of SDI at 10 years (p:0.003) and 15 years (p:0.008); and c) male gender showed a tendency for any increase of SDI at 15 years without reaching significance (p:0.054). The GEE model showed that patients with a significant aPL profile (p:0.006,Odds Ratio, [OR]:1.9, 95% Confidence Interval,[CI]:1.2-3.1), older age at diagnosis (p:0.007, OR: 1.02, 95%CI 0.006-0.04) or male sex (p:0.017,OR: 1.9,95%CI 1.1-3.3) were more likely to experience an increase of SDI during the follow-up (Table II).ConclusionsOur data demonstrate that: a) one-third of SLE patients have clinically significant aPL profiles; b) 21%, 42% and 57% of SLE patients have new organ damage in 5, 10 and 15 years; c) clinically significant aPL-profiles, older ag...