JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment

Patterns and determinants of stress among consultant physicians working in Saudi Arabia

Fahad D Alosaimi,1 Hossam S Alawad,2 Ayedh K Alamri,2 Abdullah I Saeed,2 Khalid A Aljuaydi,2 Alwaleed S Alotaibi,2 Khalid M Alotaibi,2 Eiad A Alfaris3 1Department of Psychiatry, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia; 2Department of Psychiatry, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia; 3King Saud University Chair for the Development of Medical Education, Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia Background: Physicians experience several work-related stressors that have been mounting up in recent decades. This study aimed to examine perceived stress and its risk factors and consequences among consultant physicians in Saudi Arabia. Methods: A cross-sectional study was conducted from November 2014 to March 2015 among physicians who were assigned rank of consultant. The stress level was assessed using perceived stress scale (PSS).Results: A total of 582 consultants participated. The average age was 46.9&plusmn;7.9 years, 71% were males, 56% were Saudi, 15% were smokers, and 68% slept &le;6 hours per night. The median PSS score was 17 (interquartile range of 14&ndash;21), which represented 44% of maximum possible PSS score. The upper tertile of PSS score (represents a high stress level) was significantly associated with being younger, female, and Saudi. The majority (85%) considered job environment to be stressful and ~50% attributed that to a high workload and a noncooperative administration. In the year preceding this study, half of consultants frequently contemplated or even worked toward changing their medical institutes or even moving to work outside Saudi Arabia because of perception of a stressful working environment. Over the previous year, encountering life stressors, considering job environment as stressful and experiencing passive suicidal ideation, were significantly associated with higher levels of stress. In multivariate analysis, the following factors were independently associated with stress: female gender (odds ratio [OR]=2.41, 95% CI 1.58&ndash;3.70) and perceived stressful working environment (OR=3.66, 95% CI 1.87&ndash;7.17).Conclusion: Consultant physicians in Saudi Arabia experience moderate to high levels of perceived stress that are relatively comparable to physicians worldwide. A significant association was found between stress levels and both female gender and perception of a stressful working environment. Further studies are required to assess physician-based interventions and organization-directed approaches to management of stress among physicians. Keywords: stress, Saudi Arabia, consultants, patterns, risk factor

Phenotypic and Functional Characterization of Mesenchymal Stem/Multipotent Stromal Cells from Decidua Basalis of Human Term Placenta

Mesenchymal stem cell (MSC) therapies for the treatment of diseases associated with inflammation and oxidative stress employ primarily bone marrow MSCs (BMMSCs) and other MSC types such as MSC from the chorionic villi of human term placentae (pMSCs). These MSCs are not derived from microenvironments associated with inflammation and oxidative stress, unlike MSCs from the decidua basalis of the human term placenta (DBMSCs). DBMSCs were isolated and then extensively characterized. Differentiation of DBMSCs into three mesenchymal lineages (adipocytes, osteocytes, and chondrocytes) was performed. Real-time polymerase chain reaction (PCR) and flow cytometry techniques were also used to characterize the gene and protein expression profiles of DBMSCs, respectively. In addition, sandwich enzyme-linked immunosorbent assay (ELISA) was performed to detect proteins secreted by DBMSCs. Finally, the migration and proliferation abilities of DBMSCs were also determined. DBMSCs were positive for MSC markers and HLA-ABC. DBMSCs were negative for hematopoietic and endothelial markers, costimulatory molecules, and HLA-DR. Functionally, DBMSCs differentiated into three mesenchymal lineages, proliferated, and migrated in response to a number of stimuli. Most importantly, these cells express and secrete a distinct combination of cytokines, growth factors, and immune molecules that reflect their unique microenvironment. Therefore, DBMSCs could be attractive, alternative candidates for MSC-based therapies that treat diseases associated with inflammation and oxidative stress