Long-Term Retention Rate of Golimumab in Patients With Rheumatoid Arthritis, Psoriatic Arthritis, and Spondyloarthritis in a Real-Life Setting.

METHODS: We conducted a single-center, medical records review study of all patients with RA, PsA, and SpA on GLM treatment attending a large rheumatology department from 2010 to 2017. Times from start to end of GLM treatment were collected, as well as sociodemographic, clinical, and safety variables. Golimumab retention rate was estimated by the Kaplan-Meier method, and comparison across diseases was analyzed with the Mantel-Haenszel statistic (log-rank test). Cox proportional hazards regression models were used to identify factors associated with GLM discontinuation. RESULTS: In the study period, a total of 212 patients (61 RA, 48 PsA, 103 SpA) were prescribed GLM. Retention rates were 72% in the first year, 61% in the second, 56% in the third, and 38% at 5 years. Differences were statistically significant across diseases (median times to GLM discontinuation were 50.2, 46.0, and 38.7 months for RA, SpA, and PsA, respectively) and according to the number of previous biologic therapies (55.2 months in biologic-naive patients vs 14.0 months in patients with ≥2 previous biologics; p < 0.001). The use of concomitant conventional synthetic disease-modifying antirheumatic drugs was associated with a lower probability of discontinuation (hazards ratio [HR], 0.57; 95% confidence interval [CI], 0.33-0.97). Female sex (HR, 1.84; 95% CI, 1.07-3.17) and having used 2 biologics before GLM (HR, 2.99; 95% CI, 1.76-5.06) were associated with increased discontinuation rates. Twenty-three patients (10.9%) had at least 1 serious adverse event. CONCLUSIONS: In a real-life setting, GLM shows appropriate long-term safety-effectiveness ratio.

Platelet and immune characteristics of immune thrombocytopaenia patients non-responsive to therapy reveal severe immune dysregulation.

Multifactorial mechanisms leading to diminished platelet counts in immune thrombocytopaenia (ITP) might condition the ability of patients with ITP to respond to treatments. Examining their platelet and immune features, we aimed to detect singular characteristics of patients with ITP who do not respond to any treatment. We studied patients with chronic primary ITP who had been without treatment, or untreated (UT-ITP), for at least six months; included were responders to agonists of thrombopoietin receptors (TPO-RA), patients who showed no response to first- and second-line treatments (NR-ITP), and healthy controls. Platelets from NR-ITP patients exposed a reduced amount of sialic acid residues. Increased loss of platelet surface sialic acid residues was associated with increased platelet apoptosis. NR-ITP patients had an increased fraction of naive lymphocyte (L) B cells and a reduced LTreg (Lymphocyte T-regulator) subset. They also presented an anomalous monocyte and NK (Natural Killer) cells distribution. TPO-RA-treated patients seemed to recover an immune homeostasis similar to healthy controls. In conclusion, our results indicate a severe deregulation of the immune system of NR-ITP. The inverse correlation between loss of sialic acid and LTreg count suggests a potential relationship between glycan composition on the platelet surface and immune response, positing terminal sugar moieties of the glycan chains as aetiopathogenic agents in ITP.

Relation of Doppler ultrasound synovitis versus clinical synovitis with changes in native complement component levels in rheumatoid arthritis patients treated with biologic disease-modifying anti-rheumatic drugs.

OBJECTIVES: The complement system plays a fundamental role in mediating the activity of rheumatoid arthritis (RA). Biologic therapy can reduce native complement component levels and its activation. We aimed to study the relation of Doppler ultrasound (US) synovitis versus clinical synovitis with changes in native complement component levels in RA patients on biologic therapy. METHODS: This was a cross-sectional study. Ninety-seven consecutive patients with RA on biologic therapy for at least 3 months were recruited. Clinical, laboratory and Doppler US assessments were performed. The Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI) and a 12-joint US assessment were carried out. Synovitis was semiquantitatively scored in B-mode and power Doppler (PD) mode. RESULTS: A significant decrease in native complement (i.e. C3 and C4) and C-reactive protein (CRP) levels was observed. This was highly significant for C3 decrease (p<0.0005), and C4 decrease (p<0.0005). Synovitis detected by PD US showed significant negative association with C3 change (p<0.008), where patients with higher C3 change were more likely to have PD US inactive status on assessment. CONCLUSIONS: Our results suggested that disease inactive status determined by PD US but not by clinical assessment can be related with decrease in complement in RA patients treated with biologic therapy.

Perforin expression by CD4+ regulatory T cells increases at multiple sclerosis relapse: sex differences.

Multiple sclerosis (MS) represents the leading cause of neurological deficit among young adults, affecting women more frequently than men. In MS, the extent of central nervous system lesions is determined by the net balance between self-reactive and regulatory T-cells at any given time, among other factors, as well as by the effect of inflammatory response. Here, we studied both CD4+ and CD8+ T(Reg) in parallel in blood and CSF during MS relapse. A recruitment of both regulatory CD4+ and CD8+ T cells (T(Reg)) within the cerebrospinal fluid (CSF) takes place during MS relapse. Not previously described, the presence of CD4+ T(Reg) in CSF was higher in women than in men, which could account for the sexual dimorphism in the incidence of MS. A direct correlation between plasma oestradiol (E2) and IL-2 levels was observed, in line with a putative circuit of E2 and perforin expression by CD4+ T(Reg) playing a role in MS. Also, serum IFN-alpha was higher in females, with direct correlation with serum E2 levels. This is the first study to analyze perforin expression by CD4+ T(Reg) in MS, which was greatly enhanced in CSF, what points out a relevant role of this molecule in the suppressive effects of the CD4+ T(Reg) in MS, and contributes to the understanding of MS pathophysiology.

Estradiol-dependent perforin expression by human regulatory T-cells.

BACKGROUND: CD4+CD25+FoxP3+ regulatory T-cells (nT(Reg)) have been shown to suppress immune responses to autoantigens and to other diverse antigens, this suppression is mainly mediated by a cell contact-dependent mechanism not yet fully defined. It has been reported that both human natural and induced T(Reg) exert cytotoxic activity against autologous target cells, which suggests that the perforin/granzyme pathway may be a relevant candidate mechanism for the suppressive function of T(Reg). Previous reports have shown that oestradiol (E2) modulates T(Reg) percentages and function. METHODS: We have evaluated in pregnant and non-pregnant subjects perforin intracellular expression in CD4+CD25+FoxP3+ regulatory T-cells by flow cytometry in whole blood, ex-vivo purified nT(Reg) and ex-vivo purified nT(Reg) after TCR and E2 stimulation. The expression of cellular degranulation markers was also phenotypically determined. RESULTS: We show that E2 expands T(Reg), enhances in vitro T(Reg) function and induces a T(Reg) phenotype in activated responder (CD4+CD25) T-cells, further increasing the expression of perforin on T(Reg) than in vitro T-cell receptor activation alone. We found surface lysosomal-associated membrane glycoproteins (LAMP)-1 and LAMP-2 expression by T(Reg), which is a sign of cell degranulation and therefore of cytotoxicity exerted by these cells. CONCLUSION: Our data demonstrates the presence of functional T(Reg) cytotoxic properties in biological systems and support the concept that E2 enhances the number and function of T(Reg) suggesting the potential interaction between E2 and immunoregulatory mechanisms.