Reiterative infusions of MSCs improve pediatric osteogenesis imperfecta eliciting a pro-osteogenic paracrine response: TERCELOI clinical trial.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility, with a wide range in the severity of clinical manifestations. The majority of cases are due to mutations in the COL1A1 or COL1A2 genes, which encode type I collagen. Mesenchymal stem cells (MSCs), as the progenitors of the osteoblasts, the main type I collagen secreting cell type in the bone, have been proposed and tested as an innovative therapy for OI with promising but transient outcomes. METHODS: To overcome the short-term effect of MSCs therapy, we performed a phase I clinical trial based on reiterative infusions of histocompatible MSCs, administered in a 2.5-year period, in two pediatric patients affected by severe and moderate OI. The aim of this study was to assess the safety and effectiveness of this cell therapy in nonimmunosuppressed OI patients. The host response to MSCs was studied by analyzing the sera from OI patients, collected before, during, and after the cell therapy. RESULTS: We first demonstrated that the sequential administration of MSCs was safe and improved the bone parameters and quality of life of OI patients along the cell treatment plus 2-year follow-up period. Moreover, the study of the mechanism of action indicated that MSCs therapy elicited a pro-osteogenic paracrine response in patients, especially noticeable in the patient affected by severe OI. CONCLUSIONS: Our results demonstrate the feasibility and potential of reiterative MSCs infusion for two pediatric OI and highlight the paracrine response shown by patients as a consequence of MSCs treatment.

Changes in vitamin D levels in patients with systemic lupus erythematosus: Effects on fatigue, disease activity, and damage.

OBJECTIVE: To analyze whether changes in serum 25-hydroxyvitamin D (25[OH]D) levels affect activity, irreversible organ damage, and fatigue in systemic lupus erythematosus (SLE). METHODS: We performed an observational study of 80 patients with SLE included in a previous cross-sectional study of 25(OH)D, reassessed 2 years later. Oral vitamin D(3) was recommended in those with low baseline 25(OH)D levels. The relationship between changes in 25(OH)D levels from baseline and changes in fatigue (measured by a 0-10 visual analog scale [VAS]), SLE activity (measured by the Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), and irreversible organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) were analyzed. RESULTS: Sixty patients took vitamin D(3). Mean 25(OH)D levels increased among all treated patients (P = 0.044), in those with baseline vitamin D levels <30 ng/ml (P < 0.001), and in those with baseline vitamin D levels <10 ng/ml (P = 0.005). Fifty-seven patients (71%) still had 25(OH)D levels <30 ng/ml and 5 (6%) had 25(OH)D levels <10 ng/ml. Inverse significant correlations between 25(OH)D levels and the VAS (P = 0.001) and between changes in 25(OH)D levels and changes in the VAS in patients with baseline 25(OH)D levels <30 ng/ml (P = 0.017) were found. No significant correlations were seen between the variation of the SLEDAI or SDI values and the variation in 25(OH)D levels (P = 0.87 and P = 0.63, respectively). CONCLUSION: Increasing 25(OH)D levels may have a beneficial effect on fatigue. Our results do not support any effects of increasing 25(OH)D levels on SLE severity, although they are limited by the insufficient 25(OH)D response to the recommended regimen of oral vitamin D(3) replacement.

Predictors of major infections in systemic lupus erythematosus.

INTRODUCTION: Infections commonly complicate the course of systemic lupus erythematosus (SLE). Our aim is to investigate the clinical predictors of major infections in patients with SLE. METHODS: A nested case-control study design was used within the prospective Lupus-Cruces cohort. The endpoints of the study were major infections. Cases were defined as patients with a major infection. Two controls (SLE patients without major infections), matched for time of follow-up until the event and age at diagnosis, were selected for each case. Univariate analysis and logistic regression models were used for the analysis of data. RESULTS: Two hundred and forty-nine patients (83 cases, 166 controls) were selected. Eighty-three episodes of major infections were analyzed; E. coli, S. aureus, M. tuberculosis and S. pneumoniae being the most frequent isolates. Univariate analysis identified several variables related with infection: lung and renal involvement, at or previous to the study point; leukopenia at the study point; antiphospholipid antibody-positivity and treatment with prednisone within 3 months previous to the study point, and the dose of prednisone received. Treatment with antimalarials, on the other hand, showed a strong inverse association with major infections. Logistic regression models identified treatment with antimalarials (odds ratio (OR) = 0.06, 95% confidence interval (CI) = 0.02 to 0.18), prednisone dose (OR = 1.12, 95% CI = 1.04 to 1.19) and lung involvement (OR = 4.41, 95% CI = 1.06 to 18.36) as significant and independent predictors of major infections. No significant interactions among these three variables were found. Further adjustment for potential confounders related with antimalarial treatment did not change the results. CONCLUSIONS: The risk of major infections in patients with SLE is mostly influenced by treatment. Prednisone treatment, even at moderate doses, increases the risk, whilst antimalarials have a protective effect.