Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin.

Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.

Management of severe atopic dermatitis in children.

Severe childhood atopic dermatitis refers to the presence of recurrent, widespread, eczematous dermatitis that significantly interferes with the daily activities and/or the quality of life of the affected child and family. The vast majority of children with severe, long-standing atopic dermatitis can be managed with the appropriate use of topical treatments, including long-term maintenance therapy and adjunctive treatments. In the recalcitrant patient, second line therapies such as narrowband ultraviolet light therapy and systemic immunosuppressants such as cyclosporine, azathioprine, mycophenolate moefetil, and methotrexate have been shown to be safe and effective in children with severe atopic dermatitis and can lead to sustained clinical improvement. To date, biologic therapy has not been uniformly effective in childhood atopic dermatitis. Management of severe childhood atopic dermatitis, including topical and adjunctive treatments and second-line therapies including systemic immunosuppressants will be reviewed here.

Lessons of leprosy: the emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity.

BACKGROUND: Leprosy was the first disease classified according to the thymus derived T-cell in the 1960s and the first disease classified by the cytokine profile as intact interferon-γ (IFN-γ) and interleukin-2 (IL2) or TH1 (tuberculoid) and deficient IFN-γ and IL2 or TH2 (lepromatous), in the 1980s. OBJECTIVE: In the present study, we set out to explore the T helper 17 (TH17) lymphocyte subset, the hallmark of T-cell plasticity, in skin biopsies from patients with erythema nodosum leprosum (ENL) who were treated with thalidomide. METHOD: RNA was extracted from paraffin embedded tissue before and after thalidomide treatment of ENL and RT-PCR was performed. RESULTS: IL17A, the hallmark of TH17, was consistently seen before and after thalidomide treatment, confirming the TH17 subset to be involved in ENL and potentially up-regulated by thalidomide. CONCLUSION: A reduction in CD70, GARP, IDO, IL17B (IL-20), and IL17E (IL-25), coupled with increases in RORγT, ARNT, FoxP3, and IL17C (IL-21) following thalidomide treatment, opens the door to understanding the complexity of the immunomodulatory drug thalidomide, which can operate as an anti-inflammatory while simultaneously stimulating cell-mediated immunity (CMI). We conclude that TH17 is involved in the immunopathogenesis of ENL and that thalidomide suppresses inflammatory components of TH17, while enhancing other components of TH17 that are potentially involved in CMI.

Patient perception of risk factors associated with chronic kidney disease morbidity and mortality.

BACKGROUND: Educational interventions aimed at empowering patients are successful in chronic disease management. The purpose of this study was to assess patient knowledge of risk factors and complications associated with chronic kidney disease (CKD). METHODS: We determined the perception of risk factors for CKD and its complications in 229 participants with a diagnosis of CKD stage 3 and 4 who completed an anonymous questionnaire. We evaluated predictors of better knowledge as measured by total correct responses using linear regression. RESULTS: The majority (89.1%) but not all of participants were aware of their diagnosis of CKD. Almost a third (31.5%) of patients that were aware of a diagnosis of CKD did not know their serum creatinine level compared to only 15.4% of participants with diabetes who did not know their last serum glucose level. Most participants identified hypertension (92.1%) and diabetes (86%) as risk factors for CKD, but male sex (59%) and African American race (71.6%) were selected less frequently. While glucose, proteinuria and blood pressure control were commonly associated by participants as known methods to slow progression of CKD, smoking control (79.5%) and use of renin-angiotensin system inhibitors (63.8%) were less known. After adjustment for sociodemographic factors, younger age and presence of a college degree were the only independent predictors of knowledge of CKD risk factors. CONCLUSIONS: Access to CKD education needs to be tailored to the health literacy status of each patient. Educational interventional research studies are needed in early-stage CKD to determine impact on clinical outcomes.

Electron-beam computerized tomography correlates with coronary angiogram in chronic kidney disease patients.

BACKGROUND/AIM: Electron-beam computerized tomography (EBCT) is able to noninvasively quantify coronary artery calcification (CAC). Chronic kidney disease (CKD) patients frequently have CAC, and clinicians are puzzled regarding the clinical significance of this finding and the diagnostic accuracy of coronary EBCT in CKD. The aim of this study was to determine the correlation in CKD patients between CAC measured by EBCT and 50% stenosis determined by coronary angiography (CA), the gold standard to identify atherosclerotic lesions. METHOD: We recruited 37 patients with CKD from a single institution and compared their coronary EBCT and CA results using standard statistical analysis. RESULTS: Patients with at least one vessel with > or = 50% stenosis by CA had higher mean CAC scores [2,407.9 +/- (SD) 3,165.3 vs. 227 +/- 443.4; p < 0.001] and higher median CAC scores (1,052 vs. 25.8; p < 0.001) as compared with those having no stenosis > or = 50%. The sensitivity was 85.7%, and the specificity 82.6% using 50% stenosis as the definition for coronary artery disease and using a CAC score of 400 as a cutoff value for the EBCT results. The area under the receiver operating characteristic curve was 0.84. The diagnostic accuracy (proportion of correct results) was 83.8%. The negative predictive value was 90.5%. The receiver operating characteristic curve suggests that the optimal cutoff value for CAC scores in our cohort is 315.9, increasing the area under the receiver operating characteristic curve to 0.91. The total coronary artery stenosis was significantly associated with the CAC score (p = 0.01). CONCLUSIONS: EBCT has a very good predictive value for obstructive coronary artery disease. EBCT could be used as a screening tool in CKD patients with a low-to-intermediate risk for coronary artery disease.