Frequency, mutual exclusivity and clinical associations of myositis autoantibodies in a combined European cohort of idiopathic inflammatory myopathy patients.

OBJECTIVES: To determine prevalence and co-existence of myositis specific autoantibodies (MSAs) and myositis associated autoantibodies (MAAs) and associated clinical characteristics in a large cohort of idiopathic inflammatory myopathy (IIM) patients. METHODS: Adult patients with confirmed IIM recruited to the EuroMyositis registry (n = 1637) from four centres were investigated for the presence of MSAs/MAAs by radiolabelled-immunoprecipitation, with confirmation of anti-MDA5 and anti-NXP2 by ELISA. Clinical associations for each autoantibody were calculated for 1483 patients with a single or no known autoantibody by global linear regression modelling. RESULTS: MSAs/MAAs were found in 61.5% of patients, with 84.7% of autoantibody positive patients having a sole specificity, and only three cases (0.2%) having more than one MSA. The most frequently detected autoantibody was anti-Jo-1 (18.7%), with a further 21 specificities each found in 0.2-7.9% of patients. Autoantibodies to Mi-2, SAE, TIF1, NXP2, MDA5, PMScl and the non-Jo-1 tRNA-synthetases were strongly associated (p < 0.001) with cutaneous involvement. Anti-TIF1 and anti-Mi-2 positive patients had an increased risk of malignancy (OR 4.67 and 2.50 respectively), and anti-SRP patients had a greater likelihood of cardiac involvement (OR 4.15). Interstitial lung disease was strongly associated with the anti-tRNA synthetases, anti-MDA5, and anti-U1RNP/Sm. Overlap disease was strongly associated with anti-PMScl, anti-Ku, anti-U1RNP/Sm and anti-Ro60. Absence of MSA/MAA was negatively associated with extra-muscular manifestations. CONCLUSIONS: Myositis autoantibodies are present in the majority of patients with IIM and identify distinct clinical subsets. Furthermore, MSAs are nearly always mutually exclusive endorsing their credentials as valuable disease biomarkers.

Autoantibody Specificities and Type I Interferon Pathway Activation in Idiopathic Inflammatory Myopathies.

Myositis is a heterogeneous group of autoimmune diseases, with different pathogenic mechanisms contributing to the different subsets of disease. The aim of this study was to test whether the autoantibody profile in patients with myositis is associated with a type I interferon (IFN) signature, as in patients with systemic lupus erythematous (SLE). Patients with myositis were prospectively enrolled in the study and compared to healthy controls and to patients with SLE. Autoantibody status was analysed using an immunoassay system and immunoprecipitation. Type I IFN activity in whole blood was determined using direct gene expression analysis. Serum IFN-inducing activity was tested using peripheral blood cells from healthy donors. Blocking experiments were performed by neutralizing anti-IFNAR or anti-IFN-α antibodies. Patients were categorized into IFN high and IFN low based on an IFN score. Patients with autoantibodies against RNA-binding proteins had a higher IFN score compared to patients without these antibodies, and the IFN score was related to autoantibody multispecificity. Patients with dermatomyositis (DM) and inclusion body myositis (IBM) had a higher IFN score compared to the other subgroups. Serum type I IFN bioactivity was blocked by neutralizing anti-IFNAR or anti-IFN-α antibodies. To conclude, a high IFN score was not only associated with DM, as previously reported, and IBM, but also with autoantibody monospecificity against several RNA-binding proteins and with autoantibody multispecificity. These studies identify IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood and support IFN-α as a possible target for therapy in these patients.

Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies: a European-wide case study.

OBJECTIVES: HLA-DRB1*03 is strongly associated with anti-Jo-1-positive idiopathic inflammatory myopathies (IIM) and there is now increasing evidence that Jo-1 antigen is preferentially expressed in lung tissue. This study examined whether smoking was associated with the development of anti-Jo-1 antibodies in HLA-DRB1*03-positive IIM. METHODS: IIM cases were selected with concurrent information regarding HLA-DRB1 status, smoking history and anti-Jo-1 antibody status. DNA was genotyped at DRB1 using a commercial sequence-specific oligonucleotide kit. Anti-Jo-1 antibody status was established using a line blot assay or immunoprecipitation. RESULTS: 557 Caucasian IIM patients were recruited from Hungary (181), UK (99), Sweden (94) and Czech Republic (183). Smoking frequency was increased in anti-Jo-1-positive IIM cases, and reached statistical significance in Hungarian IIM (45% Jo-1-positive vs 17% Jo-1-negative, OR 3.94, 95% CI 1.53 to 9.89, p<0.0001). A strong association between HLA-DRB1*03 and anti-Jo-1 status was observed across all four cohorts (DRB1*03 frequency: 74% Jo-1-positive vs 35% Jo-1-negative, OR 5.55, 95% CI 3.42 to 9.14, p<0.0001). The frequency of HLA-DRB1*03 was increased in smokers. The frequency of anti-Jo-1 was increased in DRB1*03-positive smokers vs DRB1*03-negative non-smokers (42% vs 8%, OR 7.75, 95% CI 4.21 to 14.28, p<0.0001) and DRB1*03-positive non-smokers (42% vs 31%, p=0.08). In DRB1*03-negative patients, anti-Jo-1 status between smokers and non-smokers was not significantly different. No significant interaction was noted between smoking and DRB1*03 status using anti-Jo-1 as the outcome measure. CONCLUSION: Smoking appears to be associated with an increased risk of possession of anti-Jo-1 in HLA-DRB1*03-positive IIM cases. The authors hypothesise that an interaction between HLA-DRB1*03 and smoking may prime the development of anti-Jo-1 antibodies.

Breastfeeding enhances the antibody response to Hib and Pneumococcal serotype 6B and 14 after vaccination with conjugate vaccines.

BACKGROUND: This study was performed in order to investigate the relationship between breastfeeding and the antibody response after vaccination with conjugate vaccines against Hib and pneumococcal diseases. METHODS: This was an open non-randomised multi-centre study enrolling 101 healthy Swedish infants. PncCRM was administered concomitantly with DTaP/IPV/Hib at 3, 5, and 12 months at separate site. Duration of breastfeeding was calculated for days of almost exclusive as well as of total (any form of) breastfeeding. RESULTS: At 13 months of age 6 out of 83 children did not reach 0.2mug/ml against serotype 6B, and five of these were breastfed less than 90 days (Fisher's Exact test, P=0.011). Four children did not reach 1mug/ml against Hib and all those were breastfed less than 90 days (Fisher's Exact test, P=0.008). One month after the second dose, at 6 months of age, children breastfed 90 days or more showed significantly higher GMC against serotype 14 (P=0.003). CONCLUSION: This study indicates that children exclusively breastfed 90 days or more might get a better serological protection against Hib, and the pneumococcal serotypes 6B and 14 after vaccination, compared to children less breastfed.

Colour slides or digital photography in diabetes screening--a comparison.

PURPOSE: The aim of this study was to compare digital images with slides in detecting and grading diabetic retinopathy, and to assess the retinopathy screening performed by ophthalmic nurses. METHOD: 283 consecutive patients were examined using digital colour and redfree photography (Topcon Imagenet System 1.53) and 35 mm slides (Topcon TRC-50 VT fundus camera, Kodachrome 64 colour film). The images were graded by the worst eye according to the Wisconsin classification by an ophthalmologist and ophthalmic nurse independently. RESULTS: There was exact agreement between grades obtained from the colour slides and the digital colour images in 82% (weighted kappa 0.88; 95% CI 0.80-0.96), and in 85% when redfree images were used as an adjunct to the digital colour images There was a tendency towards undergrading of the digital colour images and overgrading of the digital redfree images, compared with the colour slides. Inter- and intragrader agreement (weighted kappa) varied between 0.77 and 0.84 for digital photography and between 0.88 and 0.90 for colour slides CONCLUSION: Good to excellent agreement was found between the grading of colour slides and digital colour images, the latter, however, associated with a slightly lower reliability. The adjunct of redfree images seemed to facilitate the detection of retinopathic lesions.

Contribution of interleukin-6 in distinguishing between mild respiratory disease and neonatal sepsis in the newborn infant.

The purpose of this study was to investigate if early samples of interleukin-6 (IL-6) could distinguish early bacterial sepsis from respiratory diseases in the newborn. IL-6 and C-reactive protein (CRP) were measured at onset of symptoms in newborns evaluated for sepsis during the first week of life. Five groups of children were investigated: proven sepsis, clinical sepsis, respiratory distress syndrome (RDS), transient tachypnoea of the newborn (TTN) and controls. IL-6 was also analysed at the time when CRP was at its maximum level. The results showed that initial IL-6 distinguished proven and clinical sepsis from TTN, but not from RDS. Initial CRP was of no value for diagnosis. Our conclusion is that early IL-6 makes it possible to avoid antibiotics in children with TTN and contributes to the diagnosis of sepsis faster than CRP.