Søren Thue Lillevang

A population-based study of neuromyelitis optica in Caucasians

Background: Epidemiologic studies have suggested different prevalence of neuromyelitis optica (NMO) in different ethnic groups. However, data on the incidence and prevalence of NMO in Caucasians are scarce. Objective: To estimate the incidence and prevalence of NMO in a predominantly Caucasian population based on the Wingerchuk 2006 criteria. Methods: The study was a population-based retrospective case series with longitudinal follow-up. Patients with multiple sclerosis (MS), optic neuritis (ON), acute transverse myelitis (TM), and NMO from the 4 neurology and 3 ophthalmology departments in the Region of Southern Denmark having been diagnosed between 1998 and 2008 were investigated. Patients were included based on 1) episodes of ON or TM and 2) an initial brain MRI not diagnostic for MS. An immunofluorescence assay was used to determine aquaporin-4 (AQP-4) antibodies. Results: A total of 477 patients with MS, TM, or ON were evaluated: 163 fulfilled the inclusion criteria, 42 (26%) qualified for the diagnosis of NMO, 26 (62.0%) of these were AQP4 antibody positive. All except one were Caucasian, the female:male ratio was 2.8:1, and mean age at onset was 35.6 years (range 15–64 years). The clinical presentation was heterogeneous including TM, longitudinally extensive TM, ON, and brainstem syndromes. The yearly incidence rate of NMO in the population was estimated to be 0.4 per 105 person-years (95% confidence interval [CI] 0.30–0.54) and the prevalence was 4.4 per 105 (95% CI 3.1–5.7). Conclusions: Despite being a rare disease, NMO is more common in a Caucasian population than earlier believed.

Clinical Benefit of a Gluten-Free Diet in Type 1 Diabetic Children With Screening-Detected Celiac Disease: A population-based screening study with 2 years’ follow-up

OBJECTIVE—This study was performed to 1) determine the prevalence of celiac disease in Danish children with type 1 diabetes and 2) estimate the clinical effects of a gluten-free diet (GFD) in patients with diabetes and celiac disease. RESEARCH DESIGN AND METHODS—In a region comprising 24% of the Danish population, all patients <16 years old with type 1 diabetes were identified and 269 (89%) were included in the study. The diagnosis of celiac disease was suspected in patients with endomysium and tissue transglutaminase antibodies in serum and confirmed by intestinal biopsy. Patients with celiac disease were followed for 2 years while consuming a GFD. RESULTS—In 28 of 33 patients with celiac antibodies, an intestinal biopsy showed villous atrophy. In 5 patients, celiac disease had been diagnosed previously, giving an overall prevalence of 12.3% (95% CI 8.6–16.9). Patients with celiac disease had a lower SD score (SDS) for height (P < 0.001) and weight (P = 0.002) than patients without celiac disease and were significantly younger at diabetes onset (P = 0.041). A GFD was obtained in 31 of 33 patients. After 2 years of follow-up, there was an increase in weight SDS (P = 0.006) and in children <14 years old an increase in height SDS (P = 0.036). An increase in hemoglobin (P = 0.002) and serum ferritin (P = 0.020) was found, whereas HbA1c remained unchanged (P = 0.311) during follow-up. CONCLUSIONS—This population-based study showed the highest reported prevalence of celiac disease in type 1 diabetes in Europe. Patients with celiac disease showed clinical improvements with a GFD. We recommend screening for celiac disease in all children with type 1 diabetes.

Detection of bacterial contamination of platelet components: six years’ experience with the BacT/ALERT system

BACKGROUND:  Hemovigilance has shown that bacteria cause more fatalities than other infections together. Surveillance for detection of bacteria in platelets (PLTs) was initiated. Concomitantly, the storage period for PLTs was extended from 5 to 7 days to reduce cost.

Leukocyte-depletion of blood components does not significantly reduce the risk of infectious complications : Results of a double-blinded, randomized study

Abstract. Allogeneic blood transfusions are claimed to be an independent risk factor for postoperative infections in open colorectal surgery due to immunomodulation. Leukocyte-depletion of erythrocyte suspensions has been shown in some open randomized studies to reduce the rate of postoperative infection to levels observed in nontransfused patients. Using a double-blinded, randomized design, we studied the postoperative infection rate in patients undergoing open colorectal surgery transfused with either leukocyte-depleted erythrocyte suspensions (LD-SAGM) or non-leukocyte-depleted erythrocyte suspensions (SAGM). Unselected patients (n 279) were allocated to receive LD-SAGM (n 139) or SAGM (n 140) if transfusion was indicated. Forty-five percent were transfused, yielding 48 patients in the LD-SAGM group and 64 in the SAGM group. Thirteen patients were excluded because they received one type of transfusion in spite of randomization to the other type. No significant differences in the rates of postoperative infections (P=0.5250) or postoperative complications (P=0.1779) were seen between the two transfused groups. Infection rates were 45% and 38% in the transfused groups and 21% and 23% in the nontransfused groups. No significant difference between the transfused groups was seen on any single infectious event, mortality rate, or duration of hospitalization. Leukocyte-depletion of erythrocyte suspensions transfused to patients undergoing open colorectal surgery does not reduce postoperative infection rates.

A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients

The association between polymorphisms in the programmed death (PD-1) gene and susceptibility to systemic lupus erythematosus (SLE) was determined using genomic DNA, isolated from a population-based cohort of 95 SLE patients and 155 healthy controls. Polymorphisms in the complete PD-1 gene except the large intron 1 were detected by sequencing. Furthermore, the patients were stratified according to the presence or absence of lupus nephropathy. The influence of the detected single nuclear polymorphisms (SNPs) on this specific clinical disease parameter was determined. In total, we identified 12 single nucleotide polymorphisms, of which six were novel and eight were considered to be rare (the frequency of the minor allele of these was less than 1% in our study populations). We found a significant association of an intronic 6867C/G SNP in the PD-1 gene with the presence of lupus nephropathy. As the 6867C/G SNP is located in a putative binding site for the transcriptional repressor ZEB, the associated allele of this SNP potentially alters the transcriptional regulation of PD-1. This report, for the first time, indicates that a 6867C/G SNP of the PD-1 gene is associated with lupus nephropathy in Caucasian SLE patients.

Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica

Objective Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Methods Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results Results of tests on 92 controls identified 12assays as highly specific (0–1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5–100%) of all 21 assays. The specificities (85.8–100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. Conclusions The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

Increasing prevalence of coeliac disease in Denmark: a linkage study combining national registries

Aim:  To determine the prevalence and incidence of diagnosed coeliac disease (CD) in Danish children and adolescents and to describe trends over time.

HLA, PTPN22 and PD-1 associations as markers of autoimmunity in neuromyelitis optica.

Background: Neuromyelitis optica (NMO) is a disease with autoimmune characteristics. A genetic autoimmune dependency for NMO has not been clarified in detail. Objective: To investigate immunogenetic aspects of NMO. Methods: Forty-one patients with NMO and 42 patients with multiple sclerosis (MS) were diagnosed in a population-based Caucasian cohort. HLA DQA1, DQB1, and DRB1 alleles were determined. Polymorphisms in programmed death 1 (PD-1) PD-1.3 G/A and protein tyrosine phosphatase non-receptor 22 (PTPN22) 1858 C/T were genotyped. Results: In the NMO group 15% had other autoimmune disorders and 39% had family occurrence of autoimmunity, comparable to MS. A higher frequency of a family history (17%) of NMO and MS was found in the NMO group (p < 0.026). The frequency of HLA-DQB1*0402 allele was increased in NMO (p after Bonferroni correction, cp < 0.035) and the HLA-DRB1*15 and DQB1*06 alleles were increased in MS (cp < 0.0027, cp < 0.01), compared to controls. No associations of the PTPN22 1858 T were detected. The PD-1.3A allele was increased both in NMO (p < 0.0023) and in MS patients (p < 0.028) compared to controls. Conclusion: Patients with NMO had frequent co-existence of autoimmunity and family occurrence of NMO and MS. The PD-1.3A allele was associated with NMO. The data suggest genetic autoimmune dependency of NMO.

Peroxisome Proliferator‐Activated Receptor α, δ, γ1 and γ2 Expressions are Present in Human Monocyte‐Derived Dendritic Cells and Modulate Dendritic Cell Maturation by Addition of Subtype‐Specific Ligands

It has recently been shown by Chang et al. (J Immunol 2000;165:3584–91) that the maturation of dendritic cells (DC) in the presence of long‐chain fatty acids redirects DC into Th0/Th2‐inducing cells suggesting the involvement of a receptor for long‐chain fatty acids like members of the peroxisome proliferator‐activated receptors (PPAR) superfamily. Here, we show that immature and mature monocyte‐derived DC (Mo‐DC) express PPARα, PPARδ, PPARγ1 and PPARγ2 mRNA with the highest level of PPARγ1 mRNA. We were only able to observe the expression of PPARγ1 protein by Western blotting probably because the protein level of the other subtypes is below the detection limit. Synthetic ligands specific for PPARα, PPARδ or PPARγ added at day 0–6 have similar effect on the maturation of Mo‐DC driving the maturation of Mo‐DC with atypical phenotype, reduced expression of IL‐10, IL‐12 p35 and IL‐12 p40 mRNA and with reduced stimulatory effects in mixed leucocyte reaction (MLR). Our data suggest that naturally occurring PPAR ligands like fatty acids and fatty acid derivates have anti‐inflammatory effects by redirecting DC into a less stimulatory mode.

Sex-specific association of the human PTPN22 1858T-allele with type 1 diabetes

Type 1 diabetes (T1D) is a common organ‐specific autoimmune disease of complex aetiology, involving the interaction of a large number of disease‐associated genes. By comparison of a Danish population sample of 253 Caucasian children and adolescents with T1D and a control group consisted of 354 unrelated healthy blood donors, the present study provides evidence of an isolated association of the disease‐associated PTPN22 1858T‐allele with T1D to the female sex. Furthermore, the present data suggest that PTPN22 genotypes affect the age of onset in a sex‐specific manner. The increased frequency of the risk allele and its association with age at onset in female T1D children and adolescents indicates that the genetic contribution to disease pathogenesis is more prominent in females in this population of Danish patients.