A Study on the Immunoregulatory Role of the PD1 Pathway in Juvenile Idiopathic Arthritis.

Objectives: To investigate the immunoregulatory role of the Programmed-cell-Death-protein-1 (PD1) pathway, an inhibitory immune checkpoint, in Juvenile Idiopathic Arthritis (JIA). Methods: The PD1 expression on CD4+ and CD8+ T-cells was determined by flow cytometry and the PD1 soluble form (sPD1) levels by ELISA, in peripheral blood (PB)/serum and synovial fluid (SF) samples of JIA patients and healthy controls (HCs). We searched for any association in-between the biomarkers and with JIA activity. Results: 101 Caucasian patients (69 female), aged 12 (8-15) years, and 20 HCs participated in this study. The PB PD1 expression on T-cells was higher in: a. JIA patients vs HCs (CD4: 1.24% vs 0.32%, p=0.007, CD8: 1.6% vs 0.4%, p=0.002). b. active vs inactive JIA (CD4: 1.44% vs 0.87%, p=0.072, CD8: 2.1% vs 0.93%, p=0.005). The SF PD1 expression on T-cells correlated strongly and positively with the disease activity (CD4: ρ=0.55, p=0.022, CD8: ρ=0.555, p=0.026). The SF PD1 expression on CD8 T-cells was higher in patients on-treatment vs those off-treatment (21.3% vs 5.83% p=0.004). The sPD1 levels were higher in the SF vs the serum (801pg/ml vs 367.2, p=0.013), without an association with disease activity. Conclusion: These results indicate an up-regulation of the PD1-pathway in JIA, at least quantitatively, especially in active disease. sPD1 is compartmentally produced at the inflamed joints. Further investigation in a larger sample of JIA patients may verify these observations and contribute to unravelling the precise role of the PD1 pathway in the pathogenesis and persistence of the joint inflammation.

The Impact of a Physiotherapy Tele-Rehabilitation Program on the Quality of Care for Children with Juvenile Idiopathic Arthritis.

Objectives: To investigate the applicability and impact of a physiotherapy tele-rehabilitation program (TRP) on children with Juvenile Idiopathic Arthritis (JIA) and their families. Methods: Thirty JIA patients, applying an individualized home-exercise program (HEP), were randomly divided in the tele-rehabilitation (TRG, n=15) and control group (CG, n=15). Each TRG patient participated in a 30-minute tele-session, under a paediatric physiotherapist's supervision, twice a week, for 12 weeks. Before and after the TRP (T1 and T2, respectively), all participants and a parent/guardian completed the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) questionnaire and a questionnaire regarding the HEP implementation and compliance. Residual disease was estimated at T1 and T2. At T2, TRG patients/parents completed a questionnaire evaluating the TRP. One month after T2, a reassessment of compliance with the HEP was performed. Results: The patients' median age was 12.8 (8-16) years. At T2, the TRG patients performed the HEP significantly more frequently (p=0.023), for a longer time (p=0.034) and with less urging (p=0.004), compared to T1. Moreover, they exhibited significantly increased compliance with HEP (p=0.001), better functionality (p=0.008), better quality of life (p=0.007) and less pain (p=0.017). The CG patients showed no significant changes. Residual disease improved in both groups (TRG:p=0.002, CG:p=0.018), but more in the TRG (p=0.045). TRP's applicability and total benefit were rated as excellent by patients/parents. Finally, one month after T2, compliance with the HEP was still greater than at T1(p=0.001). Conclusion: An interactive physiotherapy TRP can be implemented effectively for JIA patients, providing an additional tool for their rehabilitation.

Novel biomarkers for early targeted and individualized treatment in Juvenile Idiopathic Arthritis.

BACKGROUND: The programmed cell death protein-1 (PD-1) and its ligands (PD-L 1 and 2) suppress immune responses, thus promoting self-tolerance. Among the immunomodulatory cells, acting through the PD-1 pathway, are the B-regulatory cells (Bregs). The role of the PD-1 pathway in Juvenile Idiopathic Arthritis (JIA) has not been adequately studied. AIMS OF THE STUDY: To investigate the immunophenotypic profile of T- and B-cells and the activity of the PD-1 pathway in JIA patients. More specifically, we will examine the levels of: a) the soluble form of PD-1 (sPD-1), b) Bregs; and the expression levels of: c) PD-1 on CD4+ and CD8+ T-cells, d) PD-L1 on Bregs and CD19+ B-cells, in blood and synovial fluid samples, at various stages of the disease (onset, relapse, remission, on or off treatment). The above biomarkers will be investigated for correlation with JIA activity. METHODS: A case-control study of JIA patients (expected number: 60) and healthy controls (n: 20). Total expected number of samples: 100 of peripheral blood, 120 of serum (solely for soluble markers) and 60 of synovial fluid. The patients' demographic data and treatment will be recorded. JIA will be classified according to the ILAR and the recently proposed PReS/PRINTO criteria. JIA activity will be assessed using the JADAS-10 tool. The biomarkers will be determined using multiparametric-polychromatic flow cytometry (quintuple fluorescence protocol) and immunoenzymatic assay ELISA. ANTICIPATED BENEFITS: Further elucidation of the immunophenotypic expression and variation of the abovementioned molecules and cells during active inflammation and remission in JIA. Thereby, the present study is expected to contribute to: a) the modern research and understanding of the confirmed immune dysfunction at the cellular level, which leads to the development of serious autoimmune diseases in childhood, such as JIA, and b) the search for biomarkers that could be targets of early "intelligent" treatment and thereby could support the implementation of precision-medicine. The early diagnosis and targeted treatment of JIA are crucial for the maintenance of normal physical functioning and the psychosocial balance of the still growing adolescent/child.

Dissecting the damage in Northern Greek patients with childhood-onset systemic lupus erythematosus: a retrospective cohort study.

The improved survival of childhood-onset systemic lupus erythematosus (cSLE) has resulted in longer patients' exposure to disease inflammation, medications and/or comorbid diseases, which can all contribute to the development of organ damage. The aim of this study was to assess the evolution of damage accrual in cSLE patients overtime and investigate for predisposing factors. Disease characteristics and treatment in 47 Northern Greek Caucasian cSLE patients were retrospectively reviewed. The Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI) was used for damage assessment and the European Consensus Lupus Activity Measurement (ECLAM) to monitor cSLE activity. After a median disease duration of 7.4 years, 17/47 patients (36 %) had developed damage (SDI > 0). The most frequent domains damaged were the ocular (41 %), neuropsychiatric (35 %) and peripheral vascular (35 %) one. Peripheral vascular and neuropsychiatric damage was seen more frequently during the first 5 years of the disease. Longer exposure to azathioprine was associated with higher SDI at the end of follow-up (ß = 0.008 for every additional month of use, p = 0.041). The mean annual flare frequency was associated with a shorter time interval until the development of the first damage (hazard's ratio, HR 2.38 for each unit of increase, p = 0.018), while hydroxychloroquine use was associated with longer time interval (HR 0.19, p = 0.007). The lower rates of damage accrual in this study compared to other cohorts might be due to milder disease phenotype in Greek Caucasian cSLE patients, prompt diagnosis and effective disease control. Damage was noticed early in the disease course, and one-third of patients had an SDI > 0 at study completion. Disease flares and a severe disease course leading to prolonged use of immunosuppressives were significant risk factors, while hydroxychloroquine use was protective against cSLE damage accrual.

Safety and efficacy of rituximab in refractory pediatric systemic lupus erythematosus nephritis: a single-center experience of Northern Greece.

Lupus nephritis (LN) is the major determinant of outcome in pediatric systemic lupus erythematosus (pSLE), and its treatment remains a challenge. The aim of this study was to report the experience of our center in treating with rituximab (RTX) SLE patients with severe LN. Four pSLE patients with biopsy-proven LN, who are refractory to conventional immunosuppressive treatment, received four doses of 375-500 mg/m(2) RTX, 2-3 weeks apart. All patients were concurrently receiving corticosteroids (CSs) and mycophenolate mofetil. Patients' clinical and laboratory findings were recorded at RTX initiation, after each infusion and at 3.4 ± 2.1 month intervals thereafter. pSLE activity was assessed using the European Consensus Lupus Activity Measurement (ECLAM), while LN activity using 24-hour urine protein excretion and serum cystatin C. Patients were followed up for 6-21 months (median: 16 months). Full Β-cell depletion was noticed 2-4 weeks after RTX initiation and lasted 4-7 months. All patients achieved complete LN remission 3.5 months (range: 2-4) after RTX initiation, which was retained in 3 patients through the follow-up period. One patient relapsed 15 months after RTX initiation and received one additional RTX dose. ECLAM scores and CSs doses were markedly reduced in all patients, while complement levels were increased. No side effects or infections were observed. In conclusion, RTX is an alternative, safe and efficient treatment for refractory LN.