Detection of antinuclear antibodies: recommendations from EFLM, EASI and ICAP.

OBJECTIVES: Antinuclear antibodies (ANA) are important for the diagnosis of various autoimmune diseases. ANA are usually detected by indirect immunofluorescence assay (IFA) using HEp-2 cells (HEp-2 IFA). There are many variables influencing HEp-2 IFA results, such as subjective visual reading, serum screening dilution, substrate manufacturing, microscope components and conjugate. Newer developments on ANA testing that offer novel features adopted by some clinical laboratories include automated computer-assisted diagnosis (CAD) systems and solid phase assays (SPA). METHODS: A group of experts reviewed current literature and established recommendations on methodological aspects of ANA testing. This process was supported by a two round Delphi exercise. International expert groups that participated in this initiative included (i) the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group "Autoimmunity Testing"; (ii) the European Autoimmune Standardization Initiative (EASI); and (iii) the International Consensus on ANA Patterns (ICAP). RESULTS: In total, 35 recommendations/statements related to (i) ANA testing and reporting by HEp-2 IFA; (ii) HEp-2 IFA methodological aspects including substrate/conjugate selection and the application of CAD systems; (iii) quality assurance; (iv) HEp-2 IFA validation/verification approaches and (v) SPA were formulated. Globally, 95% of all submitted scores in the final Delphi round were above 6 (moderately agree, agree or strongly agree) and 85% above 7 (agree and strongly agree), indicating strong international support for the proposed recommendations. CONCLUSIONS: These recommendations are an important step to achieve high quality ANA testing.

Associations between pre- and postnatal antibiotic exposures and early allergic outcomes: A population-based birth cohort study.

BACKGROUND: Early life antibiotic treatment is one likely exposure influencing allergy risk. The objective was to investigate associations between pre- and postnatal antibiotic exposures and the development of allergic manifestations until age 18 months. METHODS: We included 1387 mother-child dyads from the prospective, population-based NorthPop birth cohort study. Data on antibiotic exposures in pregnancy and childhood were collected by web-based questionnaires. Until the child turned 18 months old, parents (n = 1219) reported symptoms of wheeze, eczema, and physician-diagnosed asthma; parents (n = 1025) reported physician-diagnosed food allergy. At age 18 months, serum immunoglobulin E levels to inhalant (Phadiatop) and food (Food mix fx5) allergens were determined. Associations were estimated using bivariable and multivariable logistic regressions. RESULTS: Prenatal antibiotic exposure was positively associated with food sensitization in the crude (OR 1.82, 95% CI 1.01-3.26) but not in the adjusted analyses (aOR 1.58, 0.82-3.05). A borderline significant association was found between prenatal exposure and wheeze (aOR 1.56, 0.95-2.57). Postnatal antibiotics were positively associated with wheeze (aOR 2.14, 1.47-3.11), asthma (aOR 2.35, 1.32-4.19), and eczema (aOR 1.49, 1.07-2.06). Postnatal antibiotics were negatively associated with food sensitization (aOR 0.46, 95% CI 0.25-0.83) but not with food allergy nor sensitization to inhalants. CONCLUSION: Pre- and postnatal antibiotic exposure demonstrated positive associations with allergic manifestations and the former also with food sensitization. In contrast, there was a negative association between postnatal antibiotics and food sensitization. Food sensitization is often transient but may precede respiratory allergies. Future studies should investigate the relationship between antibiotic exposure and food sensitization later in childhood.

Repository of intra- and inter-run variations of quantitative autoantibody assays: a European multicenter study.

OBJECTIVES: No reference data are available on repositories to measure precision of autoantibody assays. The scope of this study was to document inter- and intra-run variations of quantitative autoantibody assays based on a real-world large international data set. METHODS: Members of the European Autoimmunity Standardisation Initiative (EASI) group collected the data of intra- and inter-run variability obtained with assays quantifying 15 different autoantibodies in voluntary participating laboratories from their country. We analyzed the impact on the assay performances of the type of immunoassay, the number of measurements used to calculate the coefficient of variation (CVs), the nature and the autoantibody level of the internal quality control (IQC). RESULTS: Data were obtained from 64 laboratories from 15 European countries between February and October 2021. We analyzed 686 and 1,331 values of intra- and inter-run CVs, respectively. Both CVs were significantly dependent on: the method of immunoassay, the level of IQC with higher imprecision observed when the antibody levels were lower than 2-fold the threshold for positivity, and the nature of the IQC with commercial IQCs having lower CVs than patients-derived IQCs. Our analyses also show that the type of autoantibody has low impact on the assay' performances and that 15 measurements are sufficient to establish reliable intra- and inter-run variations. CONCLUSIONS: This study provides for the first time an international repository yielding values of intra- and inter-run variation for quantitative autoantibody assays. These data could be useful for ISO 15189 accreditation requirements and will allow clinical diagnostic laboratories to assure quality of patient results.

How children and adolescents with juvenile idiopathic arthritis participate in their healthcare: health professionals' views.

BACKGROUND: The study explores how healthcare professionals view participation of children and adolescents with juvenile idiopathic arthritis, in healthcare encounters. METHODS: This qualitative study includes focus groups of HCPs from different professions. The interviews were analysed with qualitative content analysis. RESULTS: The theme "Creating an enabling arena" illuminates how HCPs face possibilities and challenges when enabling children to communicate and participate in clinical encounters. HCPs, parents, and the healthcare system need to adjust to the child. The sub-theme "Bringing different perspectives" describes how children and their parents cooperate and complement each other during healthcare encounters. The sub-theme "Building a safe and comfortable setting" includes how HCPs address the child's self-identified needs and make the child feel comfortable during encounters. The sub-theme "Facilitating methods in a limiting organisation" includes how HCPs' working methods and organization may help or hinder child participation during encounters. CONCLUSIONS: HCPs encourage children and adolescents to make their views known during healthcare encounters by creating an enabling arena. Collaboration and building good relationships between the child, the parents and the HCPs, before and during the healthcare encounters, can help the child express their wishes and experiences. Clinical examinations and use of technology, such as photos, films and web-bases questionnaires can be a good start for a better child communication in healthcare encounters.IMPLICATIONS FOR REHABILITATIONHealthcare professionals in JIA teams experience that they can facilitate communication and participation with children and adolescents in healthcare encounters.When healthcare professionals enable both children, adolescents and their parents to bring their perspectives, these views complement one another and enrich information during healthcare encounters.Children and adolescents are more empowered to participate, when healthcare professionals create a good relationship with the child and their parents, and strengthen the child's knowledge, confidence and autonomy.

How children with juvenile idiopathic arthritis view participation and communication in healthcare encounters: a qualitative study.

BACKGROUND: Children report that they do not participate in their healthcare as much as they want, despite having the lawful right to form their own views and the right to express those views freely in all matters affecting them. Children and parents appeared to be more satisfied when healthcare professionals (HCP) use a participatory style in healthcare encounters. AIM: To explore how children, adolescents and young adults with Juvenile Idiopathic Arthritis (JIA) and parents of children with JIA view their participation and communication in healthcare encounters with healthcare professionals. METHODS: Using a qualitative study design, participatory workshops were held separately for children and young adults with JIA and parents of children with JIA. The workshop data were analysed with Graneheim and Lundman's Qualitative Content Analysis resulting in one main theme and two subthemes. RESULTS: The theme "Feeling alienated or familiar with healthcare encounters" illuminates how children felt alienated at healthcare encounters if they found the encounters emotionally distressing. Children could withhold information regarding their health and function from both HCPs and their family and friends. The subtheme "Distancing oneself from healthcare" describe why children felt reluctant to engage in the healthcare encounters and experienced difficulty expressing how they really felt. The subtheme "Being a normal event in life" describe how children felt more comfortable over time engaging with HCPs when they knew what would happen, and felt that HCPs gave them the necessary support they needed to participate. CONCLUSIONS: Children's participation in healthcare encounters varied depending if children felt alienated or familiar to the healthcare situations. Children distance themselves and are reluctant to engage in healthcare encounters if they find them emotionally distressing and feel disregarded. Over time, children can become more familiar and at ease with healthcare situations when they feel safe and experience personal and positive encounters. When the children are prepared for the encounter, provided with the space and support they want and receive tailored help they are more enabled to participate.

Facilitating Care of Children with Juvenile Idiopathic Arthritis, Orofacial Pain, and Dysfunction: An Interview Study of Specialized Health Professionals.

AIMS: (1) To deepen knowledge on how specialized health care professionals (HCPs) reflect on encounters with children diagnosed with juvenile idiopathic arthritis (JIA) and (2) to outline a theory for orofacial care. METHODS: Grounded theory was used to discover the psychosocial processes involved in communication between HCPs, children, and parents, and this information was used to develop a theory about these processes. Using classic grounded theory, a total of 20 interviews with HCPs were analyzed. RESULTS: One main concern, "secure health and biopsychosocial development," permeated all care. A core category was identified as "create a responsive interaction with the child and family." The data that supported this core category helped to explain how the HCP responded to a patient to promote orofacial health. Based on the dentist's responses to the child, eight subcategories were identified: (1) secure confidential relationships; (2) convey disease-specific knowledge; (3) communicate healthy findings and form mutual insights at examination; (4) encourage health-promoting behaviors; (5) ensure follow-up; (6) share perspectives; (7) guide parenting; and (8) improve knowledge and networks. CONCLUSION: How the dentist shall best understand the needs of a child diagnosed with JIA requires further evaluation. To promote oral health, the child must feel safe, confirmed, and supported with knowledge. Also, further studies are needed on the dentist's collaboration with the pediatrician and the physiotherapist for contributing to overall health.

Anti-neutrophil cytoplasmic antibodies predate symptom onset of ANCA-associated vasculitis. A case-control study.

OBJECTIVES: Anti-neutrophil cytoplasmic autoantibodies [ANCA) are important for diagnosis of ANCA-associated vasculitides (AAV). The timing of antibody development is not well established. To investigate the development of proteinase 3 (PR3)- and myeloperoxidase (MPO)-ANCA, blood samples collected before onset of symptoms of AAV were analysed. METHODS: To identify AAV patients with blood samples predating symptoms, the National Patient Register and Cause of Death register were scrutinized for ICD codes for AAV and linked to the registers of five biobanks. Diagnoses of AAV and time point for symptom onset were confirmed by reviewing 504 case-record. Eighty-five AAV cases (34 males, 51 females) with samples >1 month < 10 years from AAV symptom onset and two controls matched for sex, age, and sampling time for each case were included. Samples were screened using ELISAs for ANCA and further analysed for PR3-or MPO- specificities. RESULTS: In ANCA-screen 35.7% of the pre-symptomatic cases and 3.5% of controls tested positive (p < 0.01). 26.2% of the cases were PR3-ANCA+ and 10.7% MPO-ANCA+. Median (Q1-Q3) predating time for PR3-ANCA+ was 2.7 (0.3-7.7) years and MPO-ANCA+ 2.0 (0.9-3.5) years. PR3-ANCA was demonstrated in samples up to nine years before symptom onset. At symptom onset predating PR3-ANCA+ cases were younger than PR3-ANCA- (P < 0.01), and MPO-ANCA+ were older than MPO-ANCA- (p < 0.05). Predating MPO-ANCA+ cases vs. MPO-ANCA- and vs. PR3-ANCA+ cases had more often at symptoms onset manifestations from lungs, kidneys or peripheral nervous system (p < 0.01 and p < 0.05, respectively). CONCLUSION: The PR3-and MPO-ANCAs are present years before AAV symptom onset and represent distinct diseases.

Current laboratory and clinical practices in reporting and interpreting anti-nuclear antibody indirect immunofluorescence (ANA IIF) patterns: results of an international survey.

BACKGROUND: The International Consensus on Antinuclear Antibody (ANA) Patterns (ICAP) has recently proposed nomenclature in order to harmonize ANA indirect immunofluorescence (IIF) pattern reporting. ICAP distinguishes competent-level from expert-level patterns. A survey was organized to evaluate reporting, familiarity, and considered clinical value of ANA IIF patterns. METHODS: Two surveys were distributed by European Autoimmunity Standardization Initiative (EASI) working groups, the International Consensus on ANA Patterns (ICAP) and UK NEQAS to laboratory professionals and clinicians. RESULTS: 438 laboratory professionals and 248 clinicians from 67 countries responded. Except for dense fine speckled (DFS), the nuclear competent patterns were reported by > 85% of the laboratories. Except for rods and rings, the cytoplasmic competent patterns were reported by > 72% of laboratories. Cytoplasmic IIF staining was considered ANA positive by 55% of clinicians and 62% of laboratory professionals, with geographical and expertise-related differences. Quantification of fluorescence intensity was considered clinically relevant for nuclear patterns, but less so for cytoplasmic and mitotic patterns. Combining IIF with specific extractable nuclear antigens (ENA)/dsDNA antibody testing was considered most informative. Of the nuclear competent patterns, the centromere and homogeneous pattern obtained the highest scores for clinical relevance and the DFS pattern the lowest. Of the cytoplasmic patterns, the reticular/mitochondria-like pattern obtained the highest scores for clinical relevance and the polar/Golgi-like and rods and rings patterns the lowest. CONCLUSION: This survey confirms that the major nuclear and cytoplasmic ANA IIF patterns are considered clinically important. There is no unanimity on classifying DFS, rods and rings and polar/Golgi-like as a competent pattern and on reporting cytoplasmic patterns as ANA IIF positive.

Quality and best practice in medical laboratories: specific requests for autoimmunity testing.

Special conditions associated with laboratory autoimmune testing are not well compatible with recent developments in regulatory frameworks such as EN/ISO 15189 accreditation or in vitro diagnostic medical device regulation (IVD-R). In addition, international recommendations, guidelines and disease criteria are poorly defined with respect to requirements on autoantibody testing. Laboratory specialists from Austria, Belgium, Croatia, Estonia, Finland, France, Germany, Greece, Hungary, Italy, Norway, Poland, Portugal, South Africa, Spain, Sweden, Switzerland, and The Netherlands collected information, reported national experience, and identified quality issues in relation to autoantibody testing that require consensus on interpretation of the regulatory frameworks and guidelines. This process has been organized by the European Autoimmunity Standardisation Initiative (EASI). By identifying the critical items and looking for a consensus, our objective was to define a framework for, in particular, EN/ISO accreditation purposes. Here, we present a review of current publications and guidelines in this field to unify national guidelines and deliver in this way a European handout on quality control and accreditation for laboratories involved in autoantibody testing. We focus on quality items that can be checked during accreditation visits. Despite various local varieties, we encountered an overwhelming dedication to quality assurance in all contributing countries.

Correction to: Health-related quality of life in girls and boys with juvenile idiopathic arthritis: self- and parental reports in a cross-sectional study.

Following publication of the original article [1], the authors reported an error in the data of their article: one girl was by mistake scored as a boy. The authors have made new analyses of the corrected data. The corrected data and the new analyses are listed in this Correction.

Survivin improves the early recognition of rheumatoid arthritis among patients with arthralgia: A population-based study within two university cities of Sweden.

OBJECTIVES: The aim of this study was to validate the use of survivin for preclinical recognition of rheumatoid arthritis (RA) among patients with unexplained arthralgia. METHODS: Serum levels of survivin and the arthritis-specific autoantibodies RF and ACPA were measured in total of 5046 patients with musculoskeletal complains during 12 consecutive months in Gothenburg and in Umeå. Among them, 303 arthralgia patients were identified and prospectively followed. RESULTS: After 48 months, 12.2% of the arthralgia patients developed RA. Most of RA cases had high serum survivin, which increased the relative risk for RA (RR = 5.90, p = 3 × 10-7). Combination of survivin with autoantibodies was present in only 4.6% of the arthralgia patients and increased further the risk of RA and shortened time to RA development. Presence of any single autoantibody in the survivin-negative patients was associated with a minor risk for RA and had RA-free survival similar to the reference group. CONCLUSION: This study shows that measurement of survivin in serum improves estimation of RA risk and prospectively predicts RA development in patients with arthralgia. Survivin may indicate a phase preceding autoantibody production.

Health-related quality of life among Swedish children with Juvenile Idiopathic Arthritis: parent-child discrepancies, gender differences and comparison with a European cohort.

BACKGROUND: This study investigates gender differences in self-reports and between parent and child reports in Health-related Quality of Life (HRQOL), measured with disease-specific and generic instruments for chronic disease. Comparison of HRQOL results in this Juvenile Idiopathic Arthritis (JIA) sample to a European cohort of children with JIA and one of children with other health conditions are also made. METHODS: Fifty-three children with juvenile idiopathic arthritis (JIA), aged 8-18 years, and their parents completed the condition-specific DISABKIDS for JIA, and the DISABKIDS generic instrument for chronic conditions (DCGM-37) in a cross-sectional study. European reference data were used for comparison of child and parental reports. RESULTS: Child self-reports in DCGM-37 and DISABKIDS for JIA showed no gender differences. Parental and child reports of the child's HRQOL differed only in DCGM-37; this was among girls who scored their independence (p = 0.03), physical limitation (p = 0.01), social exclusion (p = 0.03), emotions (p <0.01), and general transformed score (p <0.01) higher than did their parents. Our sample of children with JIA reported more physical limitation compared to samples of European children with JIA (p = 0.01), European children with chronic conditions (p < 0.01), and their parents (p = 0.01 and p < 0.01). The Swedish children reported more problem with understanding compared to the European JIA sample (p = 0.03). Swedish parents perceived their children's independence significantly lower than did the European parents of JIA children (p < 0.01), as well as European parents of children with chronic conditions (p = 0.03). The Swedish parents also perceived their children to have significantly lower social inclusion (p < 0.05) and general transformed score (p = 0.04), in comparison to European parents of children with chronic conditions. CONCLUSIONS: Parent-child differences in assessment of quality of life depend on the HRQOL instrument used, especially among girls. In comparison to European cohorts, our sample of children with JIA experienced more physical limitations and less understanding.

From ANA-screening to antigen-specificity: an EASI-survey on the daily practice in European countries.

OBJECTIVES: One of the main goals of the European Autoimmunity Standardisation Initiative (EASI) is the harmonisation of test-algorithms for autoantibodies related to systemic autoimmune rheumatic diseases (SARD). METHODS: A questionnaire was used to gather information on methodology, interpretation, and the algorithm for detection of anti-nuclear antibodies (ANA) in relation to their antigen-specificity. The questionnaire was sent to 1200 laboratories in 12 European countries. RESULTS: The response rate was 47.2%. The results reveal not only apparent differences between countries, but also within countries. CONCLUSIONS: Awareness of these differences may as such already stimulate harmonisation, but the observed differences may also direct recommendations that may further contribute to achieving the EASI goal of harmonisation of autoimmune diagnostics for SARD.

S-calprotectin (S100A8/S100A9): a potential marker of inflammation in patients with psoriatic arthritis.

OBJECTIVE: To analyse levels of S100A8/S100A9 (calprotectin) and selected cytokines, in blood, in patients with psoriatic arthritis (PsA). METHODS: Sixty-five patients with PsA were examined for clinical manifestations and laboratory measurements of S-calprotectin, ESR, hs-CRP, and selected cytokines. Thirty-two patients had mono-/oligoarthritis and 33 had polyarthritis. S-calprotectin, hs-CRP, and cytokines were measured using ELISA, immunoturbidimetry, and multiplex technology (Bio-Plex). Patients with PsA were compared with 31 healthy controls. RESULTS: S-calprotectin and hs-CRP levels were significantly higher in patients with PsA compared with controls (P<0.001 and P<0.001, resp.). Patients suffering a polyarthritic disease pattern presented with significantly higher levels of S-calprotectin compared with controls and patients with mono-/oligoarthritis (P<0.001 and P=0.017, resp.). The levels of S-calprotectin correlated with hs-CRP (P<0.001; rs=0.441), swollen joint count (P=0.002, rs=0.397), and CXCL10 (P=0.046, rs=0.678) but not with any of the other cytokines evaluated. In multiple logistic regression analysis, S-calprotectin was the only variable significantly associated with psoriatic arthritis (P=0.002, OR=1.006, 95% CI=1.002-1.010). CONCLUSION: S-calprotectin and hs-CRP levels were significantly higher in patients with PsA. A polyarthritic disease pattern showed higher levels of S-calprotectin than mono-/oligoarthritis. S-calprotectin is considered a potential marker of disease activity in patients with PsA.

International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies.

Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1-13), anti-double stranded DNA antibodies (14-18), specific antibodies (19-23) and validation of methods (24-25) were created. Significant differences between experts were observed regarding recommendations 24-25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.

Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations.

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case-control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

Health-related quality of life in girls and boys with juvenile idiopathic arthritis: self- and parental reports in a cross-sectional study.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) affects children and adolescents with both short-term and long-term disability. These children also report lower health-related quality of life (HRQOL) compared to their healthy peers. However, there seems to be some discrepancies between self- and parent-reports, and gender differences need to be further studied. This study aims to describe HRQOL in girls and boys with JIA, and to explore gender differences in self-reports compared to parent-reports of HRQOL in children with JIA. METHODS: Fifty-three children and adolescents with JIA (70% girls and 30% boys) with a median age of 14 years (8-18 years), and their parents, participated in this cross-sectional study in Sweden. Data was systematically collected prior to ordinary visits at a Pediatric outpatient clinic, during a period of 16 months (2009-2010). Disability was assessed with the Childhood Health Assessment Questionnaire (CHAQ), and disease activity by physicians' assessments and Erythrocyte Sedimentation Rate (ESR). The Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) was used to assess self- and parent-reports of HRQOL in the child. RESULTS: In this sample of children with generally low disease activity and mild to moderate disability, more than half of the children experienced suboptimal HRQOL, equally in girls and boys. Significant differences between self- and parent-reports of child HRQOL were most evident among girls, with lower parent-reports regarding the girl's physical- and psychosocial health as well as in the total HRQOL score. Except for the social functioning subscale, where parents' reports were higher compared to their sons, there were no significant differences between boys- and parent-reports. CONCLUSIONS: More than half of the girls and boys experienced suboptimal HRQOL in this sample, with no gender differences. However, there were differences between self- and parent-reports of child HRQOL, with most significant differences found among the girls. Thus, differences between self- and parent-reports of child HRQOL must be taken into account in clinical settings, especially among girls with JIA.

Autoantibodies predate the onset of systemic lupus erythematosus in northern Sweden.

INTRODUCTION: Autoantibodies have a central role in systemic lupus erythematosus (SLE). The presence of autoantibodies preceding disease onset by years has been reported both in patients with SLE and in those with rheumatoid arthritis, suggesting a gradual development of these diseases. Therefore, we sought to identify autoantibodies in a northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms. METHODS: The register of patients fulfilling the American College of Rheumatology criteria for SLE and with a given date of the onset of symptoms was coanalysed with the register of the Medical Biobank, Umeå, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4) was performed with 152 age- and sex-matched controls identified from within the Medical Biobank register (Umeå, Sweden). Antibodies against anti-Sjögren's syndrome antigen A (Ro/SSA; 52 and 60 kDa), anti-Sjögren's syndrome antigen B, anti-Smith antibody, ribonucleoprotein, scleroderma, anti-histidyl-tRNA synthetase antibody, double-stranded DNA (dsDNA), centromere protein B and histones were analysed using the AtheNA Multi-Lyte ANA II Plus Test System on a Bio-Plex Array Reader (Luminex200). Antinuclear antibodies test II (ANA II) results were analysed using indirect immunofluorescence on human epidermal 2 cells at a sample dilution of 1:100. RESULTS: Autoantibodies against nuclear antigens were detected a mean (±SD) of 5.6 ± 4.7 years before the onset of symptoms and 8.7 ± 5.6 years before diagnosis in 63% of the individuals who subsequently developed SLE. The sensitivity (45.7%) was highest for ANA II, with a specificity of 95%, followed by anti-dsDNA and anti-Ro/SSA antibodies, both with sensitivities of 20.0% at specificities of 98.7% and 97.4%, respectively. The odds ratios (ORs) for predicting disease were 18.13 for anti-dsDNA (95% confidence interval (95% CI), 3.58 to 91.84) and 11.5 (95% CI, 4.54 to 28.87) for ANA. Anti-Ro/SSA antibodies appeared first at a mean of 6.6 ± 2.5 years prior to symptom onset. The mean number of autoantibodies in prediseased individuals was 1.4, and after disease onset it was 3.1 (P < 0.0005). The time predating disease was shorter and the number of autoantibodies was greater in those individuals with serositis as a presenting symptom in comparison to those with arthritis and skin manifestations as the presenting symptoms. CONCLUSIONS: Autoantibodies against nuclear antigens were detected in individuals who developed SLE several years before the onset of symptoms and diagnosis. The most sensitive autoantibodies were ANA, Ro/SSA and dsDNA, with the highest predictive OR being for anti-dsDNA antibodies. The first autoantibodies detected were anti-Ro/SSA.

A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease in which the type I interferon pathway has a crucial role. We have previously shown that three genes in this pathway, IRF5, TYK2 and STAT4, are strongly associated with risk for SLE. Here, we investigated 78 genes involved in the type I interferon pathway to identify additional SLE susceptibility loci. First, we genotyped 896 single-nucleotide polymorphisms in these 78 genes and 14 other candidate genes in 482 Swedish SLE patients and 536 controls. Genes with P<0.01 in the initial screen were then followed up in 344 additional Swedish patients and 1299 controls. SNPs in the IKBKE, TANK, STAT1, IL8 and TRAF6 genes gave nominal signals of association with SLE in this extended Swedish cohort. To replicate these findings we extracted data from a genomewide association study on SLE performed in a US cohort. Combined analysis of the Swedish and US data, comprising a total of 2136 cases and 9694 controls, implicates IKBKE and IL8 as SLE susceptibility loci (P(meta)=0.00010 and P(meta)=0.00040, respectively). STAT1 was also associated with SLE in this cohort (P(meta)=3.3 × 10⁻5), but this association signal appears to be dependent of that previously reported for the neighbouring STAT4 gene. Our study suggests additional genes from the type I interferon system in SLE, and highlights genes in this pathway for further functional analysis.