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ObjectiveTo develop Canadian recommendations for the screening, monitoring, and treatment of uveitis associated with juvenile idiopathic arthritis (JIA).MethodsRecommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-ADOLOPMENT approach. A working group of 14 pediatric rheumatologists, 6 ophthalmologists, 2 methodologists, and 3 caregiver/patient representatives reviewed recent American College of Rheumatology (ACR)/Arthritis Foundation (AF) recommendations and worked in pairs to develop evidence-to-decision (EtD) tables. A survey to assess agreement and recommendations requiring group discussion was completed. EtD tables were presented, discussed, and voted upon at a virtual meeting, to produce the final recommendations. A health equity framework was applied to all aspects of the adolopment process including the EtD tables, survey responses, and virtual meeting discussion.ResultsThe survey identified that 7 of the 19 recommendations required rigorous discussion. Seventy-five percent of working group members attended the virtual meeting to discuss controversial topics as they pertained to the Canadian environment, including timing to first eye exam, frequency of screening, escalation criteria for systemic and biologic therapy, and the role of nonbiologic therapies. Equity issues related to access to care and advanced therapeutics across Canadian provinces and territories were highlighted. Following the virtual meeting, 5 recommendations were adapted, 2 recommendations were removed, and 1 was developed de novo.ConclusionRecommendations for JIA-associated uveitis were adapted to the Canadian context by a working group of pediatric rheumatologists, ophthalmologists with expertise in the management of uveitis, and parent/patient input, taking into consideration cost, equity, and access.

Background: Research objectives should be focused toward advancing knowledge that has meaningful impact on health. However, research agendas are mostly driven by the health care community, with limited input from patients. Aims: In this study, prioirities of uncertainties for the management of fibromyalgia (FM) that could propel future research were identified by a defined process using the James Lind Alliance Priority Setting Partnership (JLA-PSP) methodology. Methods: As a first step, a survey was distributed across Canada that engaged patients, caregivers, and health care professionals to provide narrative input to eight open-ended questions regarding FM care. Responses were thematically condensed and synthesized into an initial list of 43 uncertainties used to guide a comprehensive literature search. Questions already effectively addressed in the literature were excluded, leaving 25 uncertainties that were ranked during a one-day consensus workshop. Results: Three broad themes emerged: the value of personalized targeted treatment and subgrouping of patients; the efficacy of various self-management strategies and educational initiatives; and identification of the ideal health care setting to provide FM care. Opioids and cannabinoids were the only specific pharmacologic interventions ranked as needing further research. Conclusions: The prioritized questions highlight the importance of recognizing the heterogeneity of FM symptoms, the need for a personalized treatment approach, and a better understanding of the value of self-management strategies. This is the first study that uses an established and transparent methodology to engage all FM stakeholders to help inform researchers and funding bodies of clinically relevant research priorities.

ObjectiveTo test the association of early disease severity with grade 12 standards test performance in individuals with childhood-onset chronic rheumatic diseases (ChildCRDs), including juvenile arthritis and systemic autoimmune rheumatic diseases.MethodsWe used linked provincial administrative data to identify patients with ChildCRDs born between 1979 and 1998 in Manitoba, Canada. Primary outcomes were Language and Arts Achievement Index (LAI) scores and Math Achievement Index (MAI) scores from grade 12 standards test results as well as enrollment data. The secondary outcome was enrollment in grade 12 by 17 years of age. Latent class trajectory analysis identified disease severity groups using physician visits following diagnosis. Multivariable linear regression tested the association of disease severity groups with LAI and MAI scores, and logistic regression tested the association of disease severity with age-appropriate enrollment, after adjusting for sociodemographic factors and psychiatric morbidities.ResultsThe study cohort included 541 patients, 70.1% of whom were female. A 3-class trajectory model provided the best fit; it classified 9.7% of patients as having severe disease, 54.5% as having moderate disease, and 35.8% as having mild disease. After covariate adjustment, severe disease was associated with poorer LAI and MAI scores but not with age-appropriate enrollment.ConclusionAmong patients with ChildCRDs, those with severe disease performed more poorly on grade 12 standards tests, independent of sociodemographic and psychiatric risk factors. Clinicians should work with educators and policy makers to advocate for supports to improve educational outcomes of patients with ChildCRDs.

ObjectiveThe aims of this study were (1) to compare grade 12 standardized test results of patients diagnosed with childhood-onset chronic rheumatic diseases (ChildCRD) and unaffected peers; and (2) to identify factors associated with test results of patients with ChildCRD and unaffected peers.MethodsThis was a population-based retrospective cohort study. All patients with ChildCRD (juvenile arthritis and systemic autoimmune rheumatic diseases) from the only pediatric rheumatology center in Manitoba for birth cohorts January 1979 to December 1998 were linked to the provincial administrative databases containing records of healthcare use and education outcomes. Patients were matched by age, sex, and postal codes to their peers who did not have ChildCRD. The primary outcomes were the grade 12 Language Arts Achievement Index (LAI) and the Math Achievement Index (MAI) scores. ChildCRD, sociodemographic, and mental health factors were tested for their associations with LAI and MAI scores using multivariable linear regression.ResultsFive hundred and forty-one patients with ChildCRD were matched to 2713 unaffected peers. Patients with ChildCRD had lower LAI and MAI scores compared to their peers. More patients with ChildCRD failed or did not take the language arts (51% vs 41%, P < 0.001) and math (61% vs 55%, P = 0.02) tests. On multivariable analysis, ChildCRD, lower socioeconomic status, younger maternal age at first childbirth, family income assistance, involvement with child welfare services, and mental health morbidities (between ChildCRD diagnosis and standardized testing), were associated with worse LAI and MAI results.ConclusionThis population-based study showed that patients with ChildCRD performed less well than their peers on grade 12 standardized testing, independent of sociodemographic and mental health comorbidities.

To describe the frequency and severity of parent-reported medication side effects (SEs) in children with juvenile idiopathic arthritis (JIA) relative to physician-reported actionable adverse events (AEs), and to assess their impact on health-related quality of life (HRQoL).Newly diagnosed JIA patients recruited between 2017 and 2019 to the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry were included. Parents reported presence and severity (0 = no problem, 10 = very severe) of medication SEs at every clinic visit. Physicians were asked to report any actionable AE. HRQoL was assessed using the Quality of My Life (QoML) questionnaire (0 = the worst, 10 = the best) and parent's global assessment (0 = very well, 10 = very poor). Analyses included proportion of visits with SEs or actionable AEs, cumulative incidence by Kaplan-Meier methods, and HRQoL impact measured with longitudinal mixed-effects models.SEs were reported at 371 of 884 (42%) visits (95% confidence interval [95% CI] 39, 45%) in 249 patients, with a median of 2 SEs per visit (interquartile range [IQR] 1-3), and median severity of 3 (IQR 1.5-5). Most SEs were gastrointestinal (32.5% of visits) or behavioral/psychiatric (22.4%). SE frequency was lowest with nonsteroidal antiinflammatory drugs alone (34.7%) and highest with prednisone and methotrexate combinations (66%). SE cumulative incidence was 67% (95% CI 59, 75) within 1 year of diagnosis, and 36% (95% CI 28, 44) for actionable AEs. Parent global and QoML scores were worse with SEs present; the impact persisted after adjusting for pain and number of active joints.Parents report that two-thirds of children with JIA experience SEs impacting their HRQoL within 1 year of diagnosis. SE mitigation strategies are needed in managing JIA.

Background Treatments for juvenile idiopathic arthritis (JIA) are changing rapidly. Healthcare providers and families require up-to-date knowledge of current treatment practices and expected outcomes to inform their decisions. Objectives To assess changes in treatment practices and outcomes for children in a new Canadian inception cohort diagnosed with JIA in 2017-2018, compared to children in the Research in Arthritis in Canadian Children emphasizing Outcomes cohort (ReACCh-Out) diagnosed in 2005-2010 1. Methods A new investigator-driven Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) JIA Registry was started in February 2017 to prospectively collect information on children enrolled within 3 months of JIA diagnosis. Information about disease activity, treatments, outcomes and adverse events is collected at all clinic visits. Registry data were extracted in October 2018 and clinical characteristics at presentation, use of anti-rheumatic medications, attainment of inactive disease, cJADAS10 scores and adverse events were described. Selected findings were compared to those observed in the ReACCh-Out cohort. The proportion of patients (cumulative incidence) receiving various treatments and their outcomes were estimated with Kaplan Meier survival methods. Results A total of 166 patients enrolled a median of 6 weeks after diagnosis at 10 centres were included. Median age at diagnosis was 9 years (IQR 3, 13), 61% were female and 51% had oligoarthritis. At enrolment, subjects had a median of 2 active joints (IQR 1, 3), a Physician Global Assessment of 3 (1.5, 4) and a Parent Global Assessment of 1 (0, 3). The median cJADAS10 score was 6.5 (4, 10). Table 1 compares baseline characteristics and the cumulative incidence of medication use and inactive disease at one year after diagnosis with those observed in the ReACCh-Out cohort, diagnosed on average 10 years earlier. Figure 1 shows the Kaplan Meier curves for attainment of inactive disease. Conclusion In Canada, treatments for newly diagnosed patients with JIA have intensified in the last 10 years, and 35% will now start their first biologic within 1 year of diagnosis. Short-term outcomes have improved, 81% of current patients now attaining inactive disease within one year of diagnosis. Funding: The Arthritis Society, Canada. References [1] Guzman J, Oen K, Tucker LB, et al. The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort. Ann Rheum Dis.2015;74:1854-60 Acknowledgement Funding: The Arthritis Society, Canada. Disclosure of Interests Jaime Guzman: None declared, Michelle Batthish Speakers bureau: Novartis, Abbvie, Roberta Berard: None declared, Roxana Bolaria: None declared, David Cabral: None declared, Gaelle Chedeville: None declared, Ciaran Duffy: None declared, Kerstin Gerhold: None declared, Tommy Gerschman: None declared, Adam Huber: None declared, Jean-Philippe Proulx-Gauthier: None declared, Alan Rosenberg: None declared, Dax Rumsey: None declared, Heinrike Schmeling Grant/research support from: F. Hoffmann-La Roche Ltd, Natalie Shiff: None declared, Gordon Soon: None declared, Lori Tucker: None declared

Background Accessible markers to predict the development of atopic diseases are highly desirable but yet matter of debate. Objective We investigated the role of blood eosinophils at 4 weeks and 7 months of life and their association with developing atopic dermatitis (AD) in a birth cohort of children with atopic heredity. Methods Infant blood samples for eosinophil counts were taken from 559 infants at 4 weeks and from 467 infants at 7 month of life with at least one atopic parent. Elevation of blood eosinophils was defined as ≥ 5% of total leukocytes and the asscociation for the occurrence of AD was assessed by entering 2 × 2 tables and the odds ratios were estimated followed by hypothesis testing against the alternate working hypothesis: odds ratio 1. Survival analysis was carried out estimating the Kaplan-Meier product limit estimator from the life-time table of AD score and time to AD manifestation stratified by the eosinophil binary score. Results Elevated blood eosinophils observed at 4 weeks were significantly associated with the occurrence of AD in the whole cohort at the age of 7 months (p = 0.007), 1 year (p = 0.004), 2 years (p = 0.007) and 3 years (p = 0.006) of life. AD occurred app. 12 weeks earlier in infants with elevated blood eosinophils at 4 weeks of life. Blood eosinophil counts ≥5% at 7 months of life failed to show significance for AD; for eosinophils at 4.5% a significant association at 7 months (p = 0.005), and 1 year of life (p = 0.039), 2 years (p = 0.033) and 3 years (p = 0.034) was observed. Conclusion Elevated blood eosinophils at age 4 weeks have a predictive value for the onset of atopic dermatitis in infancy and early childhood in children with high risk for atopy. Early eosinophil counts may therefore be helpful for counseling parents to provide infant skincare but furthermore identify individuals for interventional trials aiming at allergy prevention.

Objective. To compare the 24-month course of health-related quality of life (HRQoL) in patients with long-standing RA treated with a conventional synthetic (cs) or a first, second or third biologic (b) DMARD in daily rheumatological care. Methods. Patients enrolled in the German biologics register RABBIT who were observed over at least 12 months were stratified according to the nth bDMARD started at enrolment. HRQoL was captured by the SF36 health survey. Within strata of sequential bDMARD therapy, we examined patients’ HRQoL at baseline and at follow-ups in comparison with the general population, the 24-month course of HRQoL of different bDMARDs and the proportion of patients exceeding the minimal detectable improvement of physical and mental health sum scores. Results. All patients reported remarkably lower scores of physical and mental health than the general population at baseline and month 12. In each stratum of sequential bDMARD therapy, patients improved significantly by month 12 and remained stable until month 24. The improvement of HRQoL was not attributable to a particular bDMARD. The following proportions of patients exceeded the minimal detectable improvement of at least 17.85 Physical Component Scale scores or 22.18 Mental Component Scale score points: csDMARD (n = 1113) 31.1%/22.3%, first bDMARD (n = 1352) 39.9%/29.7%, second bDMARD (n = 730) 37.3%/26.2% and third bDMARD (n = 680) 34.2%/30.9%. Conclusion. Lasting improvement of both physical and mental health is achievable even for severely affected RA patients with a history of more than one bDMARD failure. Nevertheless, impairment of HRQoL in RA patients is enormous compared with the general population.

There is convincing evidence from both human and animal studies suggesting that the infant intestinal microbiota plays an important role in regulating immune responses associated with the development of allergic diseases. To date there are, however, still no definite bacterial taxa or particular subsets of the microbiota that have been consistently associated with allergic diseases, which is mainly attributable to the methodological dissimilarities between studies. As such there is a need to apply different methodological concepts to enhance a deeper and more refined understanding of the relationship between the gut microbiota and allergies. Within our recent studies we reported that colonization by clostridia in early infancy increased the risk of atopic dermatitis. Using subsequent mediation analysis, we demonstrated that birth mode and having older siblings strongly impacted the infant microbiota which in turn affected the risk of atopic dermatitis. The results of these mediation analyses contributed stronger evidence for a causal link of birth mode and birth order on allergy risk through modulation of the microbiota composition.

Aim: We investigated the longitudinal development of several antibiotic resistance genes (ARGs) of the infant gut resistome during the first months after birth. Materials & methods: Fecal samples from 120 infants collected at the ages of 5, 13 and 31 weeks were analyzed and subjected to qPCR for the detection of several ARGs. Results: The prevalence of ARGs significantly increased for ermB, tetM and tetQ, while it decreased for aac(6′)-aph(2′). Birth mode and breastfeeding significantly affected tetQ prevalence. Correlations to bacterial taxa suggest that fluctuations in some ARGs are (partly) attributed to shifts in bacteroides colonization rates. Conclusion: Acquisition of ARGs in the gut microbiota occurs shortly after birth and resistome composition fluctuates over the course of several months, reflecting changes in microbial community structure.

Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype.

Background The aim was to estimate the impact of individual risk factors and treatment with various disease-modifying antirheumatic drugs (DMARDs) on the incidence of myocardial infarction (MI) in patients with rheumatoid arthritis (RA). Methods We analysed data from 11,285 patients with RA, enrolled in the prospective cohort study RABBIT, at the start of biologic (b) or conventional synthetic (cs) DMARDs. A nested case–control study was conducted, defining patients with MI during follow-up as cases. Cases were matched 1:1 to control patients based on age, sex, year of enrolment and five cardiovascular (CV) comorbidities. Generalized linear models were applied (Poisson regression with a random component, conditional logistic regression). Results In total, 112 patients developed an MI during follow-up. At baseline, during the first 6 months of follow-up and prior to the MI, inflammation markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) but not 28-joint-count disease activity score (DAS28) were significantly higher in MI cases compared to matched controls and the remaining cohort. Baseline treatment with DMARDs was similar across all groups. During follow-up bDMARD treatment was significantly more often discontinued or switched in MI cases. CV comorbidities were significantly less often treated in MI cases vs. matched controls (36 % vs. 17 %, p

Hintergrund Die planmasige Aktualisierung der S3-Leitlinie zum Fibromyalgiesyndrom (FMS; AWMF-Registernummer 041/004) wurde ab Marz 2011 vorgenommen.

BACKGROUND The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. MATERIALS AND METHODS The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinaren Vereinigung fur Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. RESULTS AND CONCLUSION The diagnosis FMS in children and adolescents is not established. In so-called juvenile FMS (JFMS) multidimensional diagnostics with validated measures should be performed. Multimodal therapy is warranted. In the case of severe pain-related disability, therapy should be primarily performed on an inpatient basis. The English full-text version of this article is available at SpringerLink (under "Supplemental").

Atopic diseases, the new “epidemic of the 21st century” and a central health problem of industrial nations, call for development of innovative primary prevention concepts. The idea of the new concept is to promote naturally protective factors such as dietary factors, microbial components or allergens themselves to modulate the immune-system to inhibit predominance of Th2 immune responses, to keep the immunological balance and therefore to prevent development of atopic sensitization as first step in the “atopic march”. The present review gives an overview of current experimental and immunomodulatory procedures and their underlying mechanisms during pregnancy and lactation as especially sensitive periods for primary prevention by environmental factors.

Erstellung einer interdisziplinaren Leitlinie auf S3-Niveau zur Diagnostik und Therapie des juvenilen Fibromyalgiesyndroms (JFMS) in Kooperation von 10 medizinischen bzw. psychologischen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen. Eine Literatursuche nach allen kontrollierten Studien zur Therapie des FMS wurde unter Benutzung der Cochrane Collaboration Reviews (1993–12/2006), Medline (1980-12/2006), PsychInfo (1966–12/2006) und Scopus (1980–12/2006) durchgefuhrt. Die Vergabe von Evidenzklassen erfolgte mittels des Systems des Oxford Centre for Evidence-Based Medicine. Empfehlungsgrade wurden nach der Empfehlungsgraduierung der nationalen Versorgungsleitlinien vergeben und in einem mehrstufigen nominalen Gruppenprozess erstellt. Schmerzen bei Kindern/Jugendlichen in mehreren Korperregionen mit einer Dauer >3 Monaten ohne erkennbare somatische Ursache werden als juveniles FMS (JFMS) oder als „Schmerzverstarkungssyndrom“ (SVS) bezeichnet. Ein multimodales Konzept mit psycho- und physiotherapeutischen Verfahren, Entspannungstherapien und Schulungsprogrammen wird empfohlen (Empfehlungsgrad offen). Diese Leitlinien werden zu einer besseren Erkennung und standardisierten Versorgung von JFMS-Patienten beitragen und die Durchfuhrung klinischer Studien erleichtern.

Atopic diseases, the new "epidemic of the twenty-first century" and a central health problem of industrial nations, call for the development of innovative primary prevention strategies. The present review provides an overview of current experimental and immunomodulatory procedures and their underlying mechanisms.

Background New preventive strategies against the development of allergic diseases focus on potentially immunomodulatory components, such as bacterial LPSs. Optimal time frames for initiating immunomodulation to receive a sufficient effect against allergen sensitization are still unclear. Objective Using a mouse model, we investigated the influence of prenatal LPS exposure on later allergen-mediated sensitization and airway inflammation in the offspring. Methods Pregnant BALB/c mice were repeatedly exposed to aerosolized LPS (LPS Escherichia coli ; 3× per week, day 7 of gestation time up to delivery). Some of the offspring were further exposed to aerosolized LPS before allergen sensitization with ovalbumin (OVA; administered intraperitoneally day 28 up to day 42) and OVA airway challenges (days 56-58). Positive control animals were placebo exposed to PBS instead of LPS, and negative control animals were first placebo exposed and later placebo sensitized with PBS instead of OVA. Results Compared with positive control animals, prenatal LPS exposure suppressed (1) allergen-specific sensitization (IgE production), (2) eosinophilic airway inflammation (reduced numbers of eosinophils in bronchoalveolar lavage fluids), and (3) in vivo airway reactivity in response to methacholine. These effects occurred only when prenatal was combined with further postnatal LPS exposure. Suppression of allergen-mediated inflammatory responses was associated with increased Toll-like receptor and T-bet expression by lung tissues and a shift toward predominantly T H 1 immune responses in spleen cells cultured with OVA in vitro . Conclusion Prenatal initiated and postnatal sustained LPS exposure increased endotoxin susceptibility and prevented later allergen sensitization in offspring through inhibition of T H 2 immune responses. Clinical implications Immunomodulation with bacterial compounds during gestation time might be an effective mode for first-step primary prevention against allergic diseases.

Background: Interleukin-18 (IL-18) plays an important role in the regulation of TH1 as well as TH2 immunologic responses and thus in the development of chronic inflammatory diseases. Positive association studies of polymorphisms in IL-18 with different diseases have underlined the involvement of IL-18 in the pathogenetics processes. Our interest was to test polymorphisms of IL-18 for association with a typical TH1-mediated disease – juvenile idiopathic arthritis – and the TH2-mediated disease bronchial asthma in Caucasian children. Methods: We genotyped five polymorphisms that were in association with chronic inflammatory diseases (−607C, −137C, 113G, 127T, and −133G). This was performed by restriction fragment length polymorphism in populations of asthmatic children, control individuals, and children with antinuclear antibodies (ANA)-positive juvenile idiopathic arthritis. Statistical analysis was performed by the Armitage trend test; haplotypes were calculated by the Arlequine program. Results: No significant association was found between any single nucleotide polymorphism or any haplotype and bronchial asthma or ANA-positive juvenile idiopathic arthritis. Conclusion: We conclude that the effect of IL-18 in the immunologic context of diseases like bronchial asthma or juvenile arthritis might be too complex to be reflected in a simple one-way association study. Furthermore, the polymorphisms under investigation might be nonfunctional.

Summary Background Histamine-1-receptor (H1R)-antagonists were shown to influence various immunological functions on different cell types and may thus be employed for immune-modulating strategies for the prevention of primary immune responses. Objective The aim of this study was to investigate the effects of an H1R-antagonist on allergen-induced sensitization, airway inflammation (AI) and airway hyper-reactivity (AHR) in a murine model. Methods BALB/c mice were systemically sensitized with ovalbumin (OVA) (six times, days 1–14) and challenged with aerosolized allergen (days 28–30). One day prior to the first and 2 h prior to every following sensitization, mice received either 1 or 0.01 μg of desloratadine (DL) or placebo per os. Results Sensitization with OVA significantly increased specific and total IgE and IgG1 serum levels, as well as in vitro IL-5 and IL-4 production by spleen and peribronchial lymph node (PBLN) cells. Sensitized and challenged mice showed a marked eosinophilic infiltration in broncho-alveolar lavage fluids and lung tissues, and developed in vivo AHR to inhaled methacholine. Oral treatment with DL prior to OVA sensitization significantly decreased production of OVA-specific IgG1, as well as in vitro Th2-cytokine production by spleen and PBLN cells, compared with OVA-sensitized mice. Moreover, eosinophilic inflammation and development of in vivo AHR were significantly reduced in DL-treated mice, compared with sensitized controls. Conclusion Treatment with H1R-anatagonist prior to and during sensitization suppressed allergen-induced Th2 responses, as well as development of eosinophilic AI and AHR. This underscores an important immune modulating function of histamine, and implies a potential role of H1R-anatagonists in preventive strategies against allergic diseases.

Background: Exposure to endotoxins, allergens, or both in early life might regulate the development of tolerance to allergens later in life. Objective: We investigated whether continuous exposure of infant mice to aerosolized endotoxin, allergen, or both inhibits subsequent allergen-induced immune and inflammatory responses. Methods: Infant BALB/c mice were pre-exposed to aerosolized endotoxin, ovalbumin (OVA), or both (3 times a week for the first 4 weeks of life) before systemic sensitization (days 1-14) and repeated airway challenge (days 28-30) with OVA. Results: Compared with that seen in negative control animals, systemic sensitization and airway allergen challenges induced high serum levels of allergen-specific IgE (0.7 ± 0.09 vs 0.02 ± 0.01 OD units), predominant T H 2-type cytokine production (IL-5 by splenic mononuclear cells in vitro, 1.2 ± 0.2 vs 0.04 ± 0.06 ng/mL), airway inflammation (bronchoalveolar lavage fluid leukocytes, 125 ± 15 vs 64 ± 7/μL; eosinophils, 28 ± 5 vs 1 ± 0/μL) and development of in vivo airway hyperreactivity (maximal enhanced pause, 11 ± 1.9 vs 4 ± 0.2). Pre-exposure with LPS before sensitization increased production of specific IgG2a (67 ± 10 vs 32 ± 5 U/mL) but failed to prevent T H 2-mediated immune responses. Pre-exposure with OVA or with OVA plus LPS completely suppressed allergen sensitization, airway inflammation, and development of in vivo airway hyperreactivity; values were similar to those of negative control animals. Inhibition was due to allergen-specific T-cell anergy indicated by omitted allergen-specific T H 2 and T H 1 immune responses. In addition, combined exposure to endotoxin and allergen induced a general shift toward an unspecific T H 1 immune response. Conclusion: Exposure with endotoxins before allergen sensitization is not able to induce unresponsiveness but might decrease the susceptibility for sensitization to a variety of common allergens. (J Allergy Clin Immunol 2003;112:389-96.)

Background: Binding of allergens with IgE to the IgE receptors on mast cells and basophils results in the release of inflammatory mediators as sulfidoleukotrienes (SLTs), triggering allergic cascades that result in allergic symptoms, such as asthma and rhinitis. Objective: We sought to investigate whether anti-IgE (Oma-lizumab), a humanized monoclonal anti-IgE antibody, in addition to specific immunotherapy (SIT) affects the leukotriene pathway. Methods: Ninety-two children (age range, 6-17 years) with sensitization to birch and grass pollens and with seasonal allergic rhinitis were included in a phase III, placebo- controlled, multicenter clinical study. All subjects were randomized to one of 4 treatment groups. Two groups subcutaneously received birch SIT and 2 groups received grass SIT for at least 14 weeks before the start of the birch pollen season. After 12 weeks of SIT titration, placebo or anti-IgE was added for 24 weeks. The primary clinical efficacy variable was symptom load (ie, the sum of daily symptom severity score and rescue medication score during pollen season). Blood samples taken at baseline and at the end of study treatment after the grass pollen season were used for separation of leukocytes in this substudy. After in vitro stimulation of the blood cells with grass and birch pollen allergens, SLT release (LTC4, LTD4, and LTE4) was quantified by using the ELISA technique. Results: Before the study treatment, SLT release to birch and grass pollen exposure did not differ significantly among the 4 groups. Under treatment with anti-IgE + SIT-grass (n = 23), a lower symptom load occurred during the pollen season compared to placebo + SIT-grass (n = 24, P = .012). The same applied to both groups receiving birch SIT (n = 23 and n=22, respectively; P = .03). At the end of treatment, the combination of anti-IgE plus grass SIT, as well as anti-IgE plus birch SIT, resulted in significantly lower SLT release after stimulation with the corresponding allergen (416 ng/L [5th-95th percentile, 1-1168] and 207 ng/L [1-860 ng/L], respectively) compared with placebo plus SIT (2490 ng/L [384-6587 ng/L], P = .001; 2489 ng/L [1-5670 ng/L], P = .001). In addition, treatment with anti-IgE was also followed by significantly lower SLT releases to the allergens unrelated to SIT (grass SIT: 300 ng/L [1-2432 ng/L] in response to birch allergen; birch SIT: 1478 ng/L [1-4593 ng/L] in response to grass pollen) in comparison with placebo (grass SIT: 1850 ng/L [1-5499 ng/L], P = .001; birch SIT: 2792 ng/L [154-5839 ng/L], P = .04]. Conclusion: Anti-IgE therapy reduces leukotriene release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy independent of the type of SIT allergen used. (J Allergy Clin Immunol 2002;110:728-35.)

Exposure early in life to organic dusts containing immunomodulatory components such as endotoxins and immunizing components such as aeroallergens may greatly influence whether subsequent encounters with allergens lead rather to sensitization or unresponsiveness. We investigated the effects of endotoxin in the context of allergen-mediated immune responses in a murine model of allergen sensitization. Systemic sensitization with ovalbumin induced high serum levels of allergen-specific IgE, predominant Th2-type cytokine production, eosinophilic airway inflammation and in vivo airway hyperreactivity. Endotoxins were either applied systemically prior to sensitization, or via the airways prior to airway challenges, or by repeated inhalation during the first weeks of life prior to subsequent sensitization. Different effects of endotoxins on allergen-induced immune responses may be attributed to differences in dosing, route of application, time relationship with allergen sensitization and the concurrent exposure to endotoxin and allergen. The results of these studies may help to define the effects of endotoxin on allergen-mediated immune reactions and to further delineate the important interrelationships between environment and disease development. Finally, this may lead to new strategies in the prevention and treatment of allergic diseases.

Background: The release of cytokines [interleukin-6 (IL-6), IL-8 and tumor necrosis factor-α (TNF-α)] by skin cells is involved in the pathogenesis of atopic dermatitis (AD). Objective: To evaluate the effect of low-dose cyclosporin A (CyA) on clinical symptoms and cytokine secretion in severe pediatric AD. Methods: Ten children with severe AD (SCORAD index >50) were treated for 8 weeks with CyA. The initial dose of 2.5 mg/kg/day was titrated to a maximum of 5 mg/kg/day until a SCORAD reduction of ≧35% was achieved (‘treatment response’). After stopping CyA all patients entered a 4-week follow-up period. Cytokine secretion (IL-6, IL-8 and TNF-α) from patients’ PBMC was assessed by ELISA before and after CyA treatment and was compared with 18 healthy nonatopic controls. Only the data of patients, who responded to CyA and did not experience a relapse during the follow-up period, were evaluated for this paper. Results: Seven patients responded to CyA without relapse during the follow-up period. The median SCORAD index in these patients improved from 71 at baseline to 22 after CyA treatment (p < 0.001). AD patients’ PBMC produced more IL-6, IL-8 and TNF-α than PBMC of controls. Suppression of IL-6 (p < 0.05) and IL-8 (p < 0.05) production was observed after CyA treatment. TNF-α levels were unchanged by CyA in all patients. Conclusions: The reduction in severity of pediatric AD with CyA is associated with decreased production of IL-6 and IL-8, but not TNF-α by PBMC.

Background: Epidemiologic studies suggest an inverse correlation between infections and development of atopy. The purpose of this study was to test the hypothesis whether a preexisting T h 1 -type immune response elicited by BCG immunization could suppress allergic sensitization and airway hyperreactivity in an animal model. Methods: BALB/c mice were immunized with BCG and/or sensitized to ovalbumin. Results: BCG immunization alone resulted in cutaneous type-IV hypersensitivity reactions to tuberculin and granulomatous lesions in the liver. Splenic mononuclear cells (MNCs) produced increased levels of IFN-γ after activation by Concanavalin A (ConA). Ovalbumin sensitization alone resulted in increased production of IL-4 after activation by ConA. Ovalbumin-sensitized animals also demonstrated markedly elevated anti-ovalbumin IgE/IgG1 serum antibody titers and increased airway reactivity after allergen challenges by means of the airways. BCG immunization 14 days before the start of ovalbumin sensitization markedly hindered the development of allergic responses as indicated by (1) increased IFN-γ and normalized IL-4 and IL-10 production by splenic MNCs after activation with ConA, (2) a reduced proliferation rate of splenic MNCs after ovalbumin restimulation, (3) partial prevention of ovalbumin-specific IgE/IgG1 serum antibody titers but elevated (nonallergic) anti-ovalbumin IgG2a serum antibody titers, (4) prevention of airway responsiveness, (5) reduced eosinophilic influx into the airway lumen, and (6) reduced levels of IL-4 and IL-5 in broncho alveolar lavage fluids. Conclusion: In this model BCG immunization established a T h 1 -type immune response that hinders allergic sensitization and the development of increased airway reactivity. (J Allergy Clin Immunol 1998;102:867-74.)

Anti-tumor necrosis factor α (TNFα) medications have revolutionized the care of children and adults with chronic arthritis. They are quick acting, highly effective, and remarkably safe, particularly in children with juvenile idiopathic arthritis (JIA). Anti-TNFα agents come in 2 basic varieties: monoclonal antibodies to TNFα (e.g., infliximab, adalimumab) and a fusion protein containing a TNF receptor (etanercept). Although hypersensitivity reactions are not uncommon with some of the TNFα antibodies (e.g., infliximab), there are only rare reports of anaphylaxis to subcutaneous injections of etanercept in adults with rheumatoid arthritis. Herein, we report 2 cases of anaphylaxis in children with JIA after etanercept injections. Although rare, pediatricians need to be aware of this potentially dangerous occurrence.

RA is known to be associated with an increased risk of serious infection. Even more than 50 years ago, observational studies showed a greater than 2-fold increased risk of serious infection in RA. This was reinforced by various subsequent cohort studies. The elevated susceptibility of patients with RA can be explained by the pathobiology of the disease itself, the impact of chronic comorbid conditions, as well as sequelae of immunosuppressive treatment. It has been suggested that premature ageing of the immune system in RA contributes to weakened protection against infectious organisms. In addition, chronic comorbid conditions such as diabetes or chronic lung or kidney disease, disease-related functional disability, as well as lifestyle factors such as smoking, increase the risk in individual patients. For a long time glucocorticoids (GCs) have been used as potent immunosuppressive drugs in RA. There is evidence that they increase the risk of serious infections up to 4-fold in a dose-dependent manner. TNF-α inhibitors increase the serious infection risk up to 2-fold. They have, however, the potential to outweigh their risk when higher GC doses can be tapered down. If patients need higher dosages of GCs in addition to treatment with biologic agents, their risk of infection is substantial. This combination should be used carefully and, if possible, avoided in patients with additional risk factors such as older age or comorbid conditions.

Background: Immune-modulation such as tolerance induction appears to be an upcoming concept to prevent development of atopic diseases. Pregnancy might present a critical period for preventing allergic sensitization of the progeny. We investigated the effect of maternal allergen exposures during pregnancy on allergen-induced sensitization and airway inflammation in the offspring in a murine model. Methods: BALB/c mice were exposed to aerosolized ovalbumin (OVA) three times per week from day 7 of pregnancy until delivery (day 0). Offspring were systemically sensitized by six intraperitoneal injections with OVA between postnatal days 21 and 35, prior to airway allergen challenges on days 48, 49, and 50. Analyses were performed on day 52. To examine long-lasting effects of maternal OVA exposures some offspring were sensitized between days 115 and 129; analyses took place on day 147. Results: Compared to maternal placebo exposures, maternal OVA exposures suppressed OVA-specific IgE serum levels and inhibited development of allergen-induced airway inflammation in the OVA-sensitized offspring on both days 52 and 147. This protective effect was associated with a shift from a predominant Th2 immune response toward a predominant production of the cytokines IFN-γ and IL-10. Further, maternal OVA exposures were associated with development of CD25+Foxp3+ regulatory T cells (Tregs) in the OVA-sensitized offspring. Depletion of Tregs or neutralization of IL-10 prior to allergen sensitization re-established OVA-induced sensitization and eosinophilic airway inflammation in the OVA-sensitized offspring. Conclusions: In our model, maternal allergen exposures during pregnancy prevented later allergen-mediated sensitization and airway inflammation by allergen-specific tolerance induction in the offspring.

Background Lower prevalence of atopy was found in children with continuous exposure to livestock and thus to microbial compounds. In animal models exposure to endotoxin (LPS) decreases allergic sensitization and airway inflammation. Objective We sought to evaluate the effect of orally applied bacterial lysate in infancy on the prevalence of atopic dermatitis (AD) after the treatment phase at 7 months of age. Methods This randomized, placebo-controlled trial included 606 newborns with at least single heredity for atopy. From week 5 until the end of month 7, infants were treated orally with bacterial lysate containing heat-killed gram-negative Escherichia coli Symbio and gram-positive Enterococcus faecalis Symbio or its placebo. Children were followed until 3 years of age. Results There was no difference in the primary outcome between the active and placebo groups in the total study group. AD prevalence was significantly reduced at the end of the intervention phase (31 weeks of age) in the subgroup of infants with single heredity for atopy (relative risk, 0.52; 95% CI, 0.3-0.9). Ten percent (15/154) of infants in the active group had AD compared with 19% (27/145, P = .030) in the placebo group. This was more pronounced in the group of infants with paternal heredity for atopy (11% vs 32%, P = .004; relative risk, 0.34; 95% CI, 0.2-0.7). Conclusion Feeding of bacterial lysate might have prevented the development of AD, especially in children with paternal atopy, possibly indicating a preventive property only in subjects with a limited risk for atopy.

To write a systematic review on the etiology and pathophysiology of the fibromyalgia syndrome (FMS) and of chronic widespread pain (CWP).An interdisciplinary level-3 guideline (i.e. systematic literature search and assessment, logic analysis, formal consensus procedure) for the diagnosis and therapy of FMS was created in cooperation with 10 medical and psychological societies and 2 patient self-help organizations. A literature search was performed covering all available review articles on the etiology and pathophysiology of FMS and CWP using the Cochrane Collaboration Reviews (1993-12/2006), Medline (1980-2006), PsychInfo (1966-12/2006), and Scopus (1980-12/2006). For the assignment of evidence classes the system of the Oxford Centre for Evidence-Based Medicine was applied. Consensus was achieved by a multi-step nominal group procedure.FMS aggregates in families (evidence level 2c). Physical and psychological stress at the workplace are risk factors for the development of CWP and FMS. Affective disorders are risk factors for the development and maintenance of FMS. Operant learning mechanisms and sensitization are risk factors for the chronification of FMS (evidence levels 2b). Several factors are associated with the pathophysiology of FMS, but the causal relationship is unclear. This includes alterations of central pain pathways, hyporeactivity of the hypothalamus-pituitary-adrenal axis, increased systemic pro-inflammatory and reduced anti-inflammatory cytokine profiles and disturbances in the dopaminergic and serotonergic systems.FMS is the common final product of various etiological factors and pathophysiological mechanisms.

Infection with influenza virus has been associated with seemingly opposing effects on the development of asthma. However, there are no data about the effects of mucosal vaccination with inactivated influenza on the inception of allergic asthma. To assess the immunological effects of inhaled inactivated influenza vaccine, using two different types of flu vaccines, on the inception of allergic sensitization and allergen-mediated airway disease in a mouse model. BALB/c mice were intranasally or intratracheally vaccinated with whole or split influenza virus vaccine (days -1 or -1, 27) before systemic sensitization with ovalbumin (OVA) (days 1, 14) and repeated airway allergen challenges (days 28-30). Allergen sensitization (IgE serum levels), airway inflammation (differential cells in bronchoalveolar lavage fluid) and airway hyper-reactivity (AHR) (in vivo lung function) were analysed. The intranasal instillation of whole influenza vaccine before allergen sensitization significantly reduced the serum levels of total and OVA-specific IgE as well as allergen-induced AHR. Prevention was due to an allergen-specific shift from a predominant T helper (Th)2- towards a Th1-immune response. Application of split influenza vaccine did not show the same preventive effect. Intranasal administration of inactivated whole influenza vaccine reduced subsequent allergen sensitization and prevented allergen-induced AHR. Our results show that the composition of the influenza vaccine has a major influence on subsequent development of allergen-induced sensitization and AHR, and suggest that mucosal inactivated whole influenza vaccination may represent a step towards the development of a preventive strategy for atopic asthma.

Background: Farming has been widely reported to be associated with decreased risk of developing atopic disorders, but underlying immunomodulatory mechanisms are still not fully defined. We delineated T-cell functions after induction of mucosal tolerance in the context of intranasally delivered organic dust compounds, lipopolysaccharides (LPS). Methods: BALB/c mice were pretreated intranasally with ovalbumin (OVA) with or without LPS (Escherichia coli) three times (days –21, –14, –7) prior to systemic OVA sensitization (days 1 and 14) and airway allergen challenges (days 28–30). CD4+ spleen T cells from pretreated and sensitized donors were characterized for cytokine function, and transferred into naive recipients prior to subsequent OVA sensitization and challenges. Results: Intranasal OVA pretreatment suppressed Th2-mediated immune and inflammatory responses and enhanced frequency of regulatory T cells in OVA-sensitized and -challenged mice. Addition of LPS to OVA, but not LPS alone, inhibited development of allergen-induced sensitization and eosinophilic airway infiltration, and markedly enhanced allergen-specific IgG1 serum levels and frequencies of IL-10- and IFN-γ-producing CD4+ T cells. Transfer of CD4+ spleen T cells from OVA-pretreated animals protected naive recipients against subsequent allergen sensitization and airway disease, whereas transfer from LPS/OVA-pretreated animals only protected against allergen sensitization. Conclusion: Microbial LPS modulated mucosal tolerance by inducing allergen-specific IgG1 production and distinct effector CD4+ T cells with a mixed regulatory/Th1 phenotype. Organic dust components such as LPS might therefore be important immune modulators in naturally occurring or preventive allergen-specific tolerance induction.

Background: Co-vaccination with cellular pertussis vaccine down-regulates allergic sensitization to diphtheria and tetanus antigens. Using a murine model, we investigated whether vaccination with diphtheria/tetanus toxoids, administered separately or simultaneously with the whole cell vaccine of Bordetella pertussis, inhibits subsequent allergen-induced immune and inflammatory responses. Methods: BALB/c-mice were vaccinated intracutaneously with a combination of diphtheria and tetanus toxoids or a combination of diphtheria and tetanus toxoids with a whole cell vaccine of B. pertussis (three times, days −21 to −7) prior to systemic sensitization (days 1–14) and repeated airway challenges (days 28–30) with ovalbumin. Results: Compared with negative controls, systemic sensitization and airway allergen challenges induced high serum levels of allergen-specific IgE, predominant Th2-type cytokine production, airway inflammation and development of in vivo airway hyperreactivity. Vaccination with diphtheria and tetanus toxoids prior to sensitization suppressed IgE formation and development of eosinophilic airway inflammation. Co-vaccination with a whole cell pertussis vaccine inhibited allergen sensitization, airway inflammation and development of in vivo airway hyperreactivity. Prevention was due to an allergen-specific and general shift from a predominant Th2 towards a predominant Th1 immune response. Conclusion: Vaccination with diphtheria and tetanus toxoids alone or in combination with whole cell pertussis vaccine prior to allergen sensitization prevented allergen-induced Th2 immune responses. Vaccine antigens may down-regulate allergic responses to a range of common allergens.

Background Spreading of sensitization with clinical manifestation of allergy is often observed in atopic individuals. Objective To investigate the effects of an established primary allergen sensitization on immune responses and airway inflammation/reactivity on secondary allergen sensitization and airway challenges in a murine model. Methods Balb/c mice were primarily sensitized intraperitoneally with ovalbumin or PBS, followed by systemic sensitization and airway challenges with latex extract as a secondary, unrelated allergen. Purely sham-sensitized animals were included as controls. In a second set of experiments, the primary and secondary allergens were switched. Results Sensitization with ovalbumin before sensitization with latex resulted in increased production of total and latex-specific (Hev b 3–specific) IgE and IgG 1 , and enhanced secretion of T H 2-cytokines by spleen mononuclear cells cultured with mitogen compared with single latex-sensitized mice. Furthermore, airway challenges of double-sensitized mice (ovalbumin + latex) with latex caused a significant increase in airway reactivity compared with purely latex-sensitized and challenged animals. These effects were dependent on dosing and timing of the primary sensitization in relation to the secondary sensitization and independent of the primary allergen used. Conclusion Primary sensitization boosted systemic T H 2 immune responses and enhanced the development of airway reactivity after sensitization and airway challenges with a secondary, unrelated allergen. This effect of consecutive priming was dependent on the strength of the primary sensitization but independent of the allergen used. The results explain the increased susceptibility toward sensitization spreading in atopic individuals. Clinical implications Because sensitization spreading is facilitated by primary sensitization, early prevention measurements or immunotherapy should be considered at this stage of monosensitization.

The role of CD8(+) T cells in the development of allergic airway disease is controversial. On the one hand, CD8(+) T cells are known to inhibit the development of airway hyperreactivity (AHR) in murine models of asthma. In humans, IL-10-producing CD8(+) T cells were shown to act as regulatory cells, inhibiting both proliferation and cytokine secretion of T cells. On the other hand, CD8(+) T cells can promote IL-5-mediated eosinophilic airway inflammation and the development of AHR in animal models. To examine this, we investigated the role of CD8(+) T cells during the induction of allergen-induced AHR and demonstrated a protective effect of CD8(+) T cells. Depletion of CD8(+) T cells prior to the immunization led to increased Th2 responses and increased allergic airway disease. However, after development of AHR, CD8(+) T cells that infiltrated the lungs secreted high levels of IL-4, IL-5 and IL-10, but little IFN-gamma, whereas CD8(+) T cells in the peribronchial lymph nodes or spleen produced high levels of IFN-gamma, but little or no Th2 cytokines. These data demonstrate protective effects of CD8(+)T cells against the induction of immune responses and show a functional diversity of CD8(+) T cells in different compartments of sensitized mice.

Background It has previously been shown that various inflammatory diseases, such as diabetes mellitus, bronchial asthma, chronic inflammatory bowel diseases, and rheumatoid arthritis, are in some circumstances genetically linked to the same chromosomal regions. Consequently, common genes underlying the pathogenetics of these diseases have been proposed. Chronic inflammatory disorders can be subdivided by their predominant immune response, either T H 1 or T H 2. For example, juvenile idiopathic arthritis (JIA) is a T H 1 disease, and bronchial asthma is a T H 2 disease. Objectives The present study investigated the polymorphism Arg110Gln within the IL13 gene, a strong T H 2 cytokine. We attempted to determine whether it is associated with these 2 diseases and whether this would reflect the T H 1/T H 2 paradigm. Methods Arg110Gln was typed in 4 different populations: asthmatic children, atopic children, children with JIA, and a control population. Statistical analysis was performed by using logistic and linear regression analysis of serum IgE levels and the Armitage trend test. Results The variant Gln110 was shown to be associated with increased total serum IgE levels in our atopic population ( P = .006) and was weakly associated with bronchial asthma ( P = .04). There was no association of the variant with JIA when compared with the control population. However, the variant Gln110 was significantly less frequent in children with JIA compared with its presence in children with bronchial asthma ( P = .007). Conclusion This is the first study to compare the same gene variant in T H 1 and T H 2 chronic inflammatory diseases. The results suggest that the same gene variant might protect from one disease and make an individual susceptible to the other.

Contact with immunomodulatory factors, such as LPS, in early infancy is associated with decreased allergen sensitization.We sought to study the effects of systemic or airway exposure with LPS on the development of allergen sensitization, eosinophilic airway inflammation, and increased in vivo airway reactivity (AR) in a mouse model.BALB/c mice were systemically sensitized with ovalbumin (OVA) plus adjuvant on days 1 and 14 and challenged through the airways with allergen on days 34 to 36. We performed measurement of OVA-specific IgE serum levels, in vitro T(H)2 cytokine production, differential cell counts in bronchoalveolar lavage fluids, and assessment of in vivo AR to inhaled methacholine by means of barometric whole-body plethysmography.Systemic LPS administration before OVA sensitization reduced OVA-specific IgE serum levels (426 +/- 76 vs 880 +/- 104 U/mL, P.01), T(H)2 cytokine production by splenic mononuclear cells (IL-4: 0.08 +/- 0.01 vs 0.17 +/- 0.01 ng/mL; IL-5: 1.98 +/- 0.52 vs 4.11 +/- 0.54 ng/mL; P.01), and extent of airway eosinophilia (total cell counts: 93 vs 376 x 10(3)/mL; eosinophils: 23% vs 51%; P.01) compared with that in OVA-sensitized mice. Local LPS administration to sensitized mice before airway allergen challenges particularly induced IFN-gamma production by peribronchial lymph node cells in vitro (1718 +/- 315 vs 483 +/- 103 ng/mL, P.01) associated with reduced airway eosinophilia compared with that seen in OVA-sensitized mice. Development of increased AR was not affected by systemic or local LPS exposure. Inhibitory effects of LPS on allergen sensitization and eosinophilic airway inflammation were inhibited by administration of anti-IL-12 antibodies before LPS exposure.These data indicate that local and systemic application of LPS modulates systemic and local T(H)1/T(H)2 immune responses in a distinct but similarly IL-12-dependent mode.

Background At least one third of patients with long-standing RA starting treatment with a biologic (b)DMARD will have to change the substance within three years due to inefficacy or adverse events. The question arises, which treatment responses we can expect after one or more failures of biologic therapies and whether there are differences in the effectiveness between individual substances used as second- or third-line bDMARDs. Objectives We aimed to investigate the effectiveness of a first, second or at least third bDMARD therapy in RA patients observed in the German biologics register RABBIT. Methods Patients who started a bDMARD therapy and were enrolled in RABBIT between 2007 and 2012 were eligible for the present analysis. They were stratified in bDMARD treatment states according to the nth bDMARD they started at enrolment (1st bDMARD: n=1,989, 2nd bDMARD: n=1,017, 3rd bDMARD: n=1,113). The 12-month course of disease activity captured by the composite disease activity score in 28 joints (DAS28CrP) was examined by linear mixed effects models. Adjustment was made for the baseline parameters sex, rheumatoid factor, DAS28CrP, the number of prior non-biologic (nb)DMARDs and the number of comorbidities, as well as for the observation time. Results Patients who received a second or at least third bDMARD were more often female and rheumatoid factor positive, had a longer disease duration, more co-morbid conditions, lower functional capacity and more pain. In the stratum of the first bDMARD, 81% of the patients received TNF inhibitors, 8% rituximab and 9% tocilizumab. The most frequent second bDMARD was rituximab (39%), followed by a second TNF inhibitor (34%) and tocilizumab (18%). Abatacept (17%), rituximab (57%) and tocilizumab (17%) were mostly used substances in the 3rd bDMARD treatment status. Patients of all bDMARD treatment states, including patients enrolled with at least a third bDMARD, showed significant improvement of disease activity after 12 months of treatment. After adjustment for baseline differences, patients treated with the first, second, or at least third bDMARD improved considerably from the adjusted mean baseline DAS28CrP of 5.2 to a mean DAS28CrP (95% CI) at month 12 of 3.4 (3.3–3.6), 3.6 (3.5–3.7), and 3.8 (3.6–3.9), respectively. The difference between the 1st and 3rd bDMARD treatment status could mainly be explained by differences in clinical baseline values and treatment history of the patients. Within the first two strata no significant differences in the outcome between the individual bDMARDs were observed. Particularly in the 3rd bDMARD treatment status, we found an advantage for tocilizumab, most likely due to the direct suppression of CrP (and ESR) responses via IL-6 blockade. Conclusions Patients with previous failures of bDMARDs had poorer baseline clinical values and lower responses than those on a first bDMARD. When using real-life data to compare different substances, it has to be taken into account that there are strong preferences which of the substances are used first. Therefore, stratification or adjustment for respective bDMARD treatment states may be appropriate for head-to-head comparisons of bDMARDs in the unselected spectrum of patients with long-standing RA. Disclosure of Interest K. Gerhold Grant/research support: RABBIT is supported by a joint unconditional grant from AbbVie, Bristol-Myers Squibb, MSD Sharp & Dohme, Pfizer, Roche and UCB, A. Richter: None declared, A. Strangfeld: None declared, P. Herzer: None declared, M. Bohl-Buhler: None declared, S. Berger: None declared, J. Listing: None declared, A. Zink: None declared DOI 10.1136/annrheumdis-2014-eular.3586

AA amyloidosis is the most severe complication of hereditary autoinflammatory diseases. In TRAPS it has been reported to occur in approximately 25% of patients in the absence of an effective treatment. However, susceptibility to AA is difficult to predict. Identification of key risk factors affecting the development of AA would improve the clinical management of TRAPS patients, by allowing a more tailored treatment approach.

Background Rheumatoid arthritis is associated with increased cardiovascular morbidity and mortality including acute myocardial infarction (AMI). Chronic systemic inflammation and accelerated atherosclerosis contribute to this risk. In daily practice, RA-patients with higher disease activity are more likely to receive treatment with biologic agents. However, there is insufficient evidence whether and how these drugs influence CV-risk. Objectives We aimed to evaluate the impact of treatment with biologic and non-biologic disease modifying anti-rheumatic drugs (bDMARDs, nbDMARDs) on the risk of AMI. Methods Nested case-control study with patients enrolled in the German biologics register RABBIT between May 2001 and October 2011. Cases were patients who developed an AMI during follow-up. Diagnoses of AMI were re-validated at on-site visits. Medical records as well as hospital reports were analysed. The availability of 9597 control patients without AMI enabled us to apply an comprehensive matching algorithm. In addition to matching for age, sex and year of enrolment, agreement was ensured for the following prevalent co-morbid conditions: heart failure, other coronary heart disease, hypertension, hyperlipoproteinemia and cerebrovascular disease. Regarding the exposure to biologic agents we applied a 3-month risk window (9 months for rituximab). McNemar test and paired t-tests were applied. Results In 68 patients AMI was re-confirmed. We found considerably more controls (N = 46) exposed to any bDMARD than cases (N = 32), although the difference was statistically not significant (p=0.07). The disease activity score (DAS28), use of glucocorticoids or functional capacity were not associated with the risk of AMI. Statistically significant predictors of AMI were elevated erytrocyte sedimentation rate (ESR, p Conclusions Using data from a large observational cohort, we confirmed the importance of chronic inflammation for the risk of AMI. Whereas acute phase reactants were significantly associated, the composite measure DAS28 was not. The biologic link of AMI with measures of systemic inflammation may be closer than with signs and symptoms of joint inflammation (including also pain and patient global assessment). In addition, due to the matching procedure, chronic comorbid conditions were highly prevalent in this sample which may have contributed to the higher DAS28 in the nested case-control study than in the entire cohort. The kind of treatment (biologic or non-biologic DMARDs) did not have an influence on the risk of AMI beyond their influence on controlling inflammation. Disclosure of Interest Y. Meissner Grant/research support from: Supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB., D. Kuhl-Habich Grant/research support from: Supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB., J. Kekow: None Declared, K. Rockwitz: None Declared, A. Liebhaber: None Declared, A. Grasler: None Declared, K. Gerhold Grant/research support from: Supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB., J. Listing Grant/research support from: Supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB., A. Strangfeld Grant/research support from: Supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB., A. Zink Grant/research support from: Supported by a joint, unconditional grant from AbbVie, Bristol-Myers Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB.

Background Health-related quality of life (HRQoL) has been identified as a key indicator of disease burden in chronic diseases such as rheumatoid arthritis (RA). Objectives To measure the effectiveness of biologic (b) versus non-biologic (nb) disease modifying anti-rheumatic drugs (DMARDs) on physical and mental health as two main dimensions of HRQoL in patients with RA. Methods Patients enrolled in the German biologics register RABBIT between 2006 and 2011 with a minimal observation time of 12 months were included. HRQoL was captured by the patient-assessed mental and physical health scales of the SF-36 questionnaire at baseline, and at months 12 and 24 of follow-up. Propensity score matching was used to adjust for baseline differences between the groups. The score is based on the probability of receiving a biologic agent modeled by means of logistic regression. Adjustments were made for sex and the baseline variables disease duration, rheumatoid factor, number of previous DMARDs, disease activity (DAS28), functional ability (FFbH), joint erosions, and co-morbidities. We applied sequential regression modeling for multiple imputation of missing values. To take different observation periods between individuals of the ITT groups into account, the two-year course of HRQoL was predicted by multi-level modeling adjusted for sex and the baseline variables rheumatoid factor, disease duration, joint erosions, DAS28 and FFbH. Results Data of 109 abatacept-treated patients, 1040 patients treated with TNF-α inhibitors, 461 rituximab-treated patients, 268 tocilizumab-treated patients, and of 254 patients treated with nbDMARDs were included in the analysis. At baseline all patients treated with bDMARDs had higher disease activity, and poorer values of all physical and mental health subscales than patients treated with nbDMARDs. Physical and, even more noticeable, mental health improved in all patients independently from therapy, particularly within the first 12 months. This improvement was superior in patients treated with bDMARDs compared to patients treated with nbDMARDs. Patients adhered to the level of improvement between months 12 and 24 (Table 1). Conclusions In all treatment groups, patients’ HRQoL improved beyond control of disease activity and physical function. Since patients maintained the level of improvement between months 12 and 24, the benefit in the two main dimensions of HRQoL, physical and mental health, can be considered as a sustainable effect of treatment. Disclosure of Interest K. Gerhold Grant/research support from: AbbVie, Bristol-Myers-Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB., A. Richter Grant/research support from: AbbVie, Bristol-Myers-Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB., M. Schneider: None Declared, H. J. Bergerhausen: None Declared, W. Demary: None Declared, A. Liebhaber: None Declared, A. Zink Grant/research support from: AbbVie, Bristol-Myers-Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB., A. Strangfeld Grant/research support from: AbbVie, Bristol-Myers-Squibb, MSD SHARP & DOHME, Pfizer, Roche, and UCB.