Childhood generalized pustular psoriasis: longtime remission with combined infliximab and methotrexate treatment.

An 8-year old boy with generalized pustular psoriasis unresponsive to several topical and systemic treatments responded dramatically with long-lasting remission to infliximab in combination with methotrexate. Combined therapy might offer a new therapeutic strategy yielding long-term remission.

Mass Spectrometry-Based Lipidomics of Brown Adipose Tissue and Plasma of New-Born Lambs Subjected to Short-Term Cold Exposure.

During cold exposure, brown adipose tissue (BAT) holds the key mechanism in the generation of heat, thus inducing thermogenic adaptation in response to cooler environmental changes. This process can lead to a major lipidome remodelling in BAT, where the increase in abundance of many lipid classes plays a significant role in the thermogenic mechanisms for heat production. This study aimed to identify different types of lipids, through liquid chromatography-mass spectrometry (LC-MS), in BAT and plasma during a short-term cold challenge (2-days), or not, in new-born lambs. Fifteen new-born Romney lambs were selected randomly and divided into three groups: Group 1 (n = 3) with BAT and plasma obtained within 24 h after birth, as a control; Group 2 (n = 6) kept indoors for two days at an ambient temperature (20-22 °C) and Group 3 (n = 6) kept indoors for two days at a cold temperature (4 °C). Significant differences in lipid composition of many lipid categories (such as glycerolipids, glycerophospholipids, sphingolipids and sterol lipids) were observed in BAT and plasma under cold conditions, compared with ambient conditions. Data obtained from the present study suggest that short-term cold exposure induces profound changes in BAT and plasma lipidome composition of new-born lambs, which may enhance lipid metabolism via BAT thermogenic activation and adipocyte survival during cold adaptation. Further analysis on the roles of these lipid changes, validation of potential biomarkers for BAT activity, such as LPC 18:1 and PC 35:6, should contribute to the improvement of new-born lamb survival. Collectively, these observations help broaden the knowledge on the variations of lipid composition during cold exposure.

RNAseq Analysis of Brown Adipose Tissue and Thyroid of Newborn Lambs Subjected to Short-Term Cold Exposure Reveals Signs of Early Whitening of Adipose Tissue.

During the early postnatal period, lambs have the ability to thermoregulate body temperature via non-shivering thermogenesis through brown adipose tissue (BAT), which soon after birth begins to transform into white adipose tissue. An RNA seq approach was used to characterize the transcriptome of BAT and thyroid tissue in newborn lambs exposed to cold conditions. Fifteen newborn Romney lambs were selected and divided into three groups: group 1 (n = 3) was a control, and groups 2 and 3 (n = 6 each) were kept indoors for two days at an ambient temperature (20-22 °C) or at a cold temperature (4 °C), respectively. Sequencing was performed using a paired-end strategy through the BGISEQ-500 platform, followed by the identification of differentially expressed genes using DESeq2 and an enrichment analysis by g:Profiler. This study provides an in-depth expression network of the main characters involved in the thermogenesis and fat-whitening mechanisms that take place in the newborn lamb. Data revealed no significant differential expression of key thermogenic factors such as uncoupling protein 1, suggesting that the heat production peak under cold exposure might occur so rapidly and in such an immediate way that it may seem undetectable in BAT by day three of life. Moreover, these changes in expression might indicate the start of the whitening process of the adipose tissue, concluding the non-shivering thermogenesis period.

Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction.

Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

Golimumab in juvenile idiopathic arthritis-associated uveitis unresponsive to Adalimumab.

OBJECTIVE: To assess the efficacy of golimumab (GLM) as a treatment option for juvenile idiopathic arthritis (JIA)-associated uveitis refractory to adalimumab (ADA). METHODS: Retrospective single-centre study including patients with JIA receiving GLM for active uveitis after failing ADA. JIA- and uveitis-related data, including intraocular inflammation, best-corrected visual acuity, corticosteroid-sparing potential, and ocular complications were evaluated at start of GLM treatment, at 1 month and 3 months, and every 3 months thereafter during GLM administration. We further investigated the association of response to GLM with primary and secondary failure of ADA treatment. RESULTS: Ten patients were studied, all female (17 affected eyes, mean age 14.3 + 6.7 yrs., mean follow-up 25.2 + 21.7 mos). Two patients were switched to GLM because of primary non-response to ADA. Eight were switched because of loss of response (LOR). In 5 of the latter LOR was associated with neutralizing anti-ADA-antibodies. Response to GLM was observed in all 8 patients with LOR, while the 2 patients with primary non-response to ADA also did not respond to GLM. Three of the 8 responders experienced LOR. At the end of follow-up 4 of the 5 remaining responders had achieved complete response. One had achieved partial response. CONCLUSION: GLM is an efficacious therapeutic option in patients who experience LOR to ADA. Our data indicate that patients without primary response to ADA should be rather switched to a biologic agent with a different mode of action instead of further blocking the TNF-alpha pathway.

The presence of an embryo affects day 14 uterine transcriptome depending on the nutritional status in sheep. b. Immune system and uterine remodeling.

Transcriptomics and bioinformatics were used to investigate the potential interactions of undernutrition and the presence of the conceptus at the time of maternal recognition of pregnancy on uterine immune system and remodeling. Adult Rasa Aragonesa ewes were allocated to one of two planes of nutrition for 28 days: maintenance energy intake (control; 5 cyclic, 6 pregnant ewes) providing 7.8 MJ of metabolisable energy and 0.5 maintenance intake (undernourished; 6 cyclic, 7 pregnant ewes) providing 3.9 MJ of metabolisable energy per ewe. Uterine gene expression was measured using Agilent 15 K Sheep Microarray chip on day 14 of estrus or pregnancy. Functional bioinformatics analyses were performed using PANTHER (Protein ANalysis THrough Evolutionary Relationships) Classification System. Pregnancy affected the expression of 18 genes in both control and undernourished ewes, underscoring the relevance for embryo-maternal interactions. Immune system evidenced by classical interferon stimulated genes were activated in control and -in a lesser extent-in undernourished pregnant vs cyclic ewes. Genes involved in uterine remodeling such as protein metabolism were also upregulated with the presence of an embryo in control and undernourished ewes. However, relevant genes for the adaptation of the uterus to the embryo were differentially expressed between pregnant vs cyclic ewes both in control and undernourished groups. Undernutrition alone led to an overall weak activation of immune system pathways both in cyclic and pregnant ewes. Data revealed that cellular and immune adaptations of the uterus to pregnancy are dependent on the nutritional status.

Chronic non-bacterial osteomyelitis: a comparative study between children and adults.

BACKGROUND: To compare clinical presentation, diagnostic and treatment strategies, and outcome between pediatric and adult patients with chronic non-bacterial osteomyelitis (CNO). METHODS: Retrospective single-centre comparative study of pediatric and adult patients diagnosed with chronic recurrent multifocal osteomyelitis (CRMO)/CNO or synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome treated at the Medical University of Graz. RESULTS: 24 pediatric patients diagnosed with CRMO/CNO and 10 adult patients diagnosed with SAPHO syndrome were compared. Median age at diagnosis was 12.3 years (range 7.9-18.9) in the pediatric group and 32.5 years (range 22-56) in the adult group. Median time to diagnosis was shorter in children than in adults (0.3 vs. 1.0 years). Initial clinical presentation, laboratory and histopathological findings were similar in children and adults. Mean numbers of bone lesions were comparable between pediatric and adult patients (3.1 vs. 3.0), as were rates of skin involvement (33% vs. 30%). Sternal involvement was more frequent in adults whereas involvement of clavicle and long bones was more frequent in children (41.7% vs.10, 33% vs. 10%). Computerized tomography (CT) was used more often in adults, whereas whole-body magnetic resonance imaging (MRI) was used only in children. Bisphosphonates were applied more often in children and outcome was better in children than in adults (62.5% vs.30%). CONCLUSION: Results of our study suggest that CNO/CRMO and SAPHO syndrome in children and adults might represent a single clinical syndrome that needs a similar diagnostic and therapeutic approach.

Drug monitoring in long-term treatment with adalimumab for juvenile idiopathic arthritis-associated uveitis.

OBJECTIVES: Assessing influence of anti-adalimumab (ADA) antibodies (AAA) on serum trough ADA levels and uveitis activity in long-term ADA treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. PATIENTS AND INTERVENTIONS: This prospective observational study included 20 patients from a single centre treated with ADA for active uveitis refractory to conventional disease-modifying antirheumatic drugs. AAA, serum ADA trough levels and uveitis activity were evaluated at regular intervals up to 6 years. RESULTS: AAA were detected in nine patients (45%). Permanent AAA in seven were associated with undetectable ADA trough levels and loss of response (LOR). Transient AAA were detected in four with measurable ADA trough levels and response of uveitis to treatment, followed in two by permanent AAA associated with LOR. Use of concomitant immunosuppression was significantly higher in patients without AAA (p<0.05). CONCLUSIONS: AAA-associated LOR frequently occurs in long-term treatment with ADA for JIA-associated uveitis. Concomitant immunosuppressive therapy significantly reduces the risk of LOR due to AAA.

Impact of an education-centered medical home on quality at a student-volunteer free clinic.

BACKGROUND: The continuity provided by longitudinal clerkships has documented benefits to medical student education. Yet, little quantitative data exist on the association between longitudinal clerkships and patient outcomes. OBJECTIVE: This study compares screening metrics of a longitudinal clerkship called the education-centered medical home (ECMH) with the standard clinical model at a student-volunteer free clinic (SVFC). In the ECMH model, the same attending physician staffs one half-day of clinic with same group of students weekly for 4 years. Standard clinical models are staffed with students and physicians who come to the SVFC based on availability. DESIGN: ECMH students aimed to increase human immunodeficiency virus (HIV) screening rates in their patient panel as part of a quality improvement project. Students prepared individualized care plans prior to patient visits that included whether screening had been performed. They were also reminded to confirm completion of testing. Percentages of patients screened for HIV before and after establishment of the ECMH were compared with four standard clinical models. Screening rates for breast, colon, and cervical cancer, as well as hepatitis C, served as secondary endpoints. RESULTS: While screening rates were initially similar between models (43.2% and 34.8% for the ECMH and standard clinical panels, respectively, p = 0.32), HIV screening rates increased from 43.2% to 95.0% in the ECMH compared with a significantly smaller increase from 35.0% to 50.0% in the standard clinical panel (p < 0.0001). Additionally, the ECMH resulted in statistically significantly increased screening rates for cervical cancer (p < 0.001) and hepatitis C (p < 0.0001). CONCLUSIONS: This study demonstrates an association between a longitudinal ECMH clerkship and improved quality metrics at an SVFC. Even measures not targeted for intervention, such as colorectal cancer and hepatitis C, showed significant improvement in screening rates when compared with the standard clinical model.

HLA genotyping as first-line screening tool for coeliac disease in children with juvenile idiopathic arthritis.

OBJECTIVES: Coeliac disease (CD) and juvenile idiopathic arthritis (JIA) often coexist. This association warrants assessment for CD in patients with JIA. We evaluated the clinical relevance and cost-effectiveness of human leucocyte antigen (HLA) genotyping in first-line screening for development of CD in children with JIA. PATIENTS AND INTERVENTIONS: 95 patients with JIA were screened for CD using CD-specific antibodies. In case of positivity, a small intestinal biopsy was performed to confirm diagnosis. In addition, HLA genotyping was performed. 110 age-matched and sex-matched Caucasian children from the same geographical area served as controls. RESULTS: CD was diagnosed in 4 of 95 patients with JIA (4.2%), a rate significantly higher compared with controls (p<0.02) and 14 times higher than in the general population. Twenty-six patients (27.4%) had one of the variants of the risk genotypes. All four patients diagnosed with CD had a HLA-DQ2.5 genotype: one was homozygote, the remainder heterozygote. Twenty-two patients are, judging by their HLA genotypes, at risk of developing CD and require repeated serological screening. None of the 69 patients without HLA-DQ2/DQ8 genotypes had CD-specific antibodies. Screening with HLA genotyping becomes cheaper than screening without after the second determination. CONCLUSIONS: In our cohort of patients with JIA, lack of HLA-DQ2/DQ8 genotypes identified a majority not at risk of CD in whom repeated serological testing is unnecessary. Genotyping is nowadays the most efficient and cost-effective way to screen for CD risk in JIA.

Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation.

BACKGROUND: Loss-of-function CECR1 mutations cause polyarteritis nodosa (PAN) with childhood onset, an autoinflammatory disorder without significant signs of autoimmunity. Herein we describe the unusual presentation of an autoimmune phenotype with constitutive type I interferon activation in siblings with adenosine deaminase 2 (ADA2) deficiency. CASE PRESENTATION: We describe two siblings with early-onset recurrent strokes, arthritis, oral ulcers, discoid rash, peripheral vascular occlusive disease and high antinuclear antibody titers. Assessment of interferon signatures in blood revealed constitutive type I interferon activation. Aicardi-Goutières syndrome (AGS) was suspected, but no mutation in the known AGS genes were detected. Whole exome sequencing identified compound heterozygosity for a known and a novel mutation in the CECR1 gene. Functional consequences of the mutations were demonstrated by marked reduction in ADA2 catalytic activity. CONCLUSIONS: Our findings demonstrate that ADA2 deficiency can cause an unusual autoimmune phenotype extending the phenotypic spectrum of PAN. Constitutive interferon I activation in patient blood suggests a possible role of type I interferon in disease pathogenesis which may have therapeutic implications.

14 Years after Discovery: Clinical Follow-up on 15 Patients with Inducible Co-Stimulator Deficiency.

BACKGROUND: Inducible co-stimulator (ICOS) deficiency was the first monogenic defect reported to cause common variable immunodeficiency (CVID)-like disease in 2003. Since then, 16 patients have been reported worldwide with an increasing range of clinical phenotypes. OBJECTIVE: We sought to compare the clinical and immunological phenotype and provide clinical follow-up and therapeutic approaches for treating ICOS-deficient patients. METHODS: We describe the clinical and laboratory data of 15 patients with available clinical data. Previous publications and clinical assessment were used as data sources. RESULTS: The observed ICOS gene mutations were all deletions leading to undetectable protein expression. The clinical phenotype of ICOS deficiency is much broader than initially anticipated and includes not only CVID-like disease but an increased susceptibility to viral and opportunistic infections, as well as cancer. Impaired B-cell development led to decreased memory B-cells in all patients, and hypogammaglobulinemia in all but one patient. Circulating CXCR5+ CD4+ follicular T-helper-cell numbers were also reduced in all patients. Treatment included immunoglobulin replacement, regular antibiotic prophylaxis, corticosteroids, and steroid-sparing agents. Three patients underwent hematopoietic stem cell transplantation; one of them died due to capillary leak syndrome on day 5 posttransplantation. CONCLUSION: The disease spectrum of ICOS deficiency is expanding from solely B-cell to combined B- and T-cell immunodeficiency, suggesting genetic and environmental modifiers. Genetic diagnosis is the only tool to distinguish ICOS deficiency from other immunological defects. Patients with antibody deficiency, autoimmunity, and combined immunodeficiency should be screened for ICOS mutations.

Anti-thymocyte globulin induces neoangiogenesis and preserves cardiac function after experimental myocardial infarction.

RATIONALE: Acute myocardial infarction (AMI) followed by ventricular remodeling is the major cause of congestive heart failure and death in western world countries. OBJECTIVE: Of relevance are reports showing that infusion of apoptotic leucocytes or anti-lymphocyte serum after AMI reduces myocardial necrosis and preserves cardiac function. In order to corroborate this therapeutic mechanism, the utilization of an immunosuppressive agent with a comparable mechanism, such as anti-thymocyte globulin (ATG) was evaluated in this study. METHODS AND RESULTS: AMI was induced in rats by ligation of the left anterior descending artery. Initially after the onset of ischemia, rabbit ATG (10 mg/rat) was injected intravenously. In vitro and in vivo experiments showed that ATG induced a pronounced release of pro-angiogenic and chemotactic factors. Moreover, paracrine factors released from ATG co-incubated cell cultures conferred a down-regulation of p53 in cardiac myocytes. Rats that were injected with ATG evidenced higher numbers of CD68+ macrophages in the ischemic myocardium. Animals injected with ATG evidenced less myocardial necrosis, showed a significant reduction of infarct dimension and an improvement of post-AMI remodeling after six weeks (infarct dimension 24.9% vs. 11.4%, p<0.01). Moreover, a higher vessel density in the peri-infarct region indicated a better collateralization in rats that were injected with ATG. CONCLUSIONS: These data indicate that ATG, a therapeutic agent successfully applied in clinical transplant immunology, triggered cardioprotective effects after AMI that salvaged ischemic myocardium by down-regulation of p53. This might have raised the resistance against apoptotic cell death during ischemia. The combination of these mechanisms seems to be causative for improved cardiac function and less ventricular remodeling after experimental AMI.

Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency.

The homozygous deletion of the inducible costimulator (ICOS), an activation-induced member of the CD28 family on T cells, causes an antibody deficiency syndrome in affected humans. The identification of a total of 9 ICOS-deficient patients revealed that this monogenic disease comprises the full clinical phenotype described for common variable immunodeficiency (CVID), including recurrent bacterial infections, adult as well as childhood onset, splenomegaly, autoimmune phenomena (autoimmune neutropenia), intestinal lymphoid hyperplasia, and malignancy (carcinoma of the vulva). All patients exhibited a profound hypogammaglobulinemia and a disturbed B-cell homeostasis. The severe reduction of class-switched memory B cells resulted from poor germinal center formation in the absence of ICOS. The additional decrease of naive B cells was associated with a partial inhibition of the early B-cell development at the pre-B-I stage. T-cell homeostasis seemed not to be affected, but low IL-10 production by ICOS-deficient T cells may contribute to the disturbed germinal center reaction. Human ICOS deficiency is indistinguishable from CVID and thus serves as a monogenic model for this complex syndrome.