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BackgroundDuring pregnancy, maternal circulating antibodies cross the placenta. Offspring exposed in utero to tumour necrosis factor inhibitors (TNFi) may experience immunosuppression and subsequent infections in their first year of life due to TNFi entering the fetal bloodstream. TNFi subtypes have differential trans-placental passage capabilities. Most (i.e. adalimumab, infliximab, golimumab) are monoclonal antibodies, with adalimumab and infliximab having the highest transfer, reaching higher fetal than maternal levels. Certolizumab (a pegylated Fab fragment) and etanercept (a fusion protein) display the lowest passage. Thus, depending on the TNFi subtype, the risk of immunosuppression may differ, and some offspring may be exposed to supra-therapeutic doses of TNFi. Therefore, the risk of serious infections in offspring by TNFi subtype needs to be clarified.ObjectivesWe evaluated the risk of serious infections leading to hospitalization in offspring born to mothers with chronic inflammatory diseases who used TNFi during pregnancy depending on whether they had low or high placental transfer.MethodsIn this population cohort study, we identified offspring born in 2011-2019 to women with a prior diagnosis of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, and/or inflammatory bowel diseases in the IBM MarketScan commercial database using commercial claims only. Women were included if they had been continuously enrolled within MarketScan with medical and pharmacy coverage for ≥12 months prior to delivery and had a child linked to them. TNFi exposure was defined as ≥1 filled prescription and/or infusion procedure code during pregnancy. Exposure was further categorized into high (i.e. infliximab, adalimumab, golimumab) and low (i.e. certolizumab, etanercept) placental transfer ability. Serious infections were ascertained based on ≥1 hospitalization with infection as the primary diagnosis in the offspring’s first year of life. We performed multivariable time-to-event analysis using a Cox proportional hazards model, adjusting for maternal age at delivery, chronic inflammatory disease diagnosis, maternal co-morbidities (pre-gestational diabetes, asthma), pregnancy complications (gestational diabetes, preterm birth), and other drug use (corticosteroids and non-biologic DMARDs).ResultsWe identified 26,088 offspring, among whom 2,902 (11.1%) were exposed to TNFi during pregnancy. The majority of offspring (1,506; 51.9%) were born to mothers with inflammatory bowel diseases. Out of the 2,902 offspring with TNFi exposure, 797 (27.5%) and 2,105 (72.5%) were low and high placental transfer drugs, respectively. The frequency of serious infections was 1.3% and 1.8% in those offspring exposed to TNFi with low and high placental transfer, respectively. The incidence rate (IR) of serious infections in offspring exposed to TNFi with high vs. low placental transfer was, respectively, 2.27 (95% confidence interval, CI 1.61, 3.12) cases per 100 person-years at risk vs. IR 1.59 cases per 100 person-years at risk (95% CI 0.76, 2.92). In multivariable analyses, the adjusted hazard ratio for serious infections with the use of TNFi with high versus low placental transfer was 1.20 (95% CI 0.54, 2.64).ConclusionAlthough children exposed to high transfer TNFi may have a higher risk of serious infection, we saw no clear excess risk of serious infections in children exposed in utero to TNFi with high versus low placental transfer due to the wide confidence interval.ReferencesNoneDisclosure of InterestsNone declared

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7–8.8%), while only 1.1% (95% CI: 0.6–1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-β2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0–2.8%) and was associated with musculoskeletal activity and anti-β2 glycoprotein 1 autoantibodies. However, ‘monospecific’ anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

Objective There is a decreased breast cancer risk in systemic lupus erythematosus (SLE) versus the general population. We assessed a large sample of SLE patients, evaluating demographic and clinical characteristics and breast cancer risk. Methods We performed case-cohort analyses within a multi-center international SLE sample. We calculated the breast cancer hazard ratio (HR) in female SLE patients, relative to demographics, reproductive history, family history of breast cancer, and time-dependent measures of anti-dsDNA positivity, cumulative disease activity, and drugs, adjusted for SLE duration. Results There were 86 SLE breast cancers and 4498 female SLE cancer-free controls. Patients were followed on average for 7.6 years. Versus controls, SLE breast cancer cases tended to be white and older. Breast cancer cases were similar to controls regarding anti-dsDNA positivity, disease activity, and most drug exposures over time. In univariate and multivariate models, the principal factor associated with breast cancers was older age at cohort entry. Conclusions There was little evidence that breast cancer risk in this SLE sample was strongly driven by any of the clinical factors that we studied. Further search for factors that determine the lower risk of breast cancer in SLE may be warranted.

Objectives. To compare costs and quality of life (QoL) between SLE patients with and without renal damage.Methods. Seven hundred and fifteen patients were surveyed semi-annually over 4 yrs on health care use and productivity loss and annually on QoL. Cumulative direct and indirect costs (2006 Canadian dollars) and QoL (average annual change in SF-36) were compared between patients with and without renal damage [Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC/ACR DI)] using simultaneous regressions.Results. At study conclusion, for patients with the renal subscale of the SLICC/ACR DI = 0 (n = 634), 1 (n = 54), 2 (n = 15) and 3 (n = 12), mean 4-yr cumulative direct costs per patient (95% CI) were $20 337 ($18 815, $21 858), $27 869 ($19 230, $36 509), $51 191 ($23 463, $78 919) and $99 544 ($57 102, $141 987), respectively. In a regression where the renal subscale of the SLICC/ACR DI was a single indicator variable, on average (95% CI), each unit increase in renal damage was associated with a 24% (15%, 33%) increase in direct costs. In a regression where each level in the renal subscale was an indicator variable, patients with end-stage renal disease incurred 103% (65%, 141%) higher direct costs than those without renal damage. Cumulative indirect costs and annual change in the SF-36 summary scores did not differ between patients.Conclusions. SLE patients with renal damage incurred higher direct costs, but did not experience a poorer QoL. QoL may be more influenced by concurrent renal activity than accumulated renal damage, which can occur at any time and patients may gradually habituate to their compromised health state.

Objective. There is increasing evidence in support of an association between systemic lupus erythematosus (SLE) and malignancy, but in earlier studies the association could not be quantified precisely. The present study was undertaken to ascertain the incidence of cancer in SLE patients, compared with that in the general population. Methods. We assembled a multisite (23 centers) international cohort of patients diagnosed as having SLE. Patients at each center were linked to regional tumor registries to determine cancer occurrence. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. Cancers expected were determined by multiplying person-years in the cohort by the geographically matched age, sex, and calendar year-specific cancer rates, and summing over all person-years. Results. The 9,547 patients from 23 centers were observed for a total of 76,948 patient-years, with an average followup of 8 years. Within the observation interval, 431 cancers occurred. The data confirmed an increased risk of cancer among patients with SLE. For all cancers combined, the SIR estimate was 1.15 (95% confidence interval [95% CI] 1.05-1.27), for all hematologic malignancies, it was 2.75 (95% CI 2.13-3.49), and for non-Hodgkin's lymphoma, it was 3.64 (95% CI 2.63-4.93). The data also suggested an increased risk of lung cancer (SIR 1.37; 95% CI 1.05-1.76), and hepatobiliary cancer (SIR 2.60; 95% CI 1.25, 4.78). Conclusion. These results support the notion of an association between SLE and cancer and more precisely define the risk of non-Hodgkin's lymphoma in SLE. It is not yet known whether this association is mediated by genetic factors or exogenous exposures.

Objective. We have shown that SLE patients in Canada and the UK incurred 20% and 13% lower health costs than those in the US, respectively, but did not experience worse outcomes as expressed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. We now compare change in quality of life in these patients. Patients and methods. Seven hundred and fifteen SLE patients (Canada 231, US 269, UK 215) completed the SF-36 annually over four years. The annual change in the SF-36 Physical and Mental Component Summary (PCS and MCS) scores over the course of the study were summarized by estimating a linear trend for each individual patient using hierarchical modelling. Cross-country comparison of the slopes in the PCS and MCS scores was then performed using simultaneous regressions. Results. The estimated mean annual changes (95% credible interval [CrI]) in the PCS scores in Canada, the US, and the UK were 0.18 (� 0.07, 0.43), � 0.05 (� 0.27, 0.17), and 0.03 (� 0.20, 0.27), respectively; the mean annual changes in the MCS scores were 0.15 (� 0.04, 0.34), 0.23 (0.09, 0.37), and 0.08 (� 0.10, 0.27), respectively. Regression results showed that the mean annual changes in PCS and MCS scores did not substantially differ across countries. Conclusion. Quality of life remained stable across countries. Despite Canadian and British patients incurring lower health costs, on average, patients experienced similar changes in physical and mental well-being.

Objective. To examine mortality rates in the largest systemic lupus erythematosus (SLE) cohort ever assembled. Methods. Our sample was a multisite international SLE cohort (23 centers, 9,547 patients). Deaths were ascertained by vital statistics registry linkage. Standardized mortality ratio (SMR; ratio of deaths observed to deaths expected) estimates were calculated for-all deaths and by cause. The effects of sex, age, SLE duration, race, and calendar-year periods were determined. Results. The overall SMR was 2.4 (95% confidence interval 2.3-2.5). Particularly high mortality was seen for circulatory disease, infections, renal disease, non-Hodgkin's lymphoma, and lung cancer. The highest SMR estimates were seen in patient groups characterized by female sex, younger age, SLE duration < 1 year, or black/African American race. There was a dramatic decrease in total SMR estimates across calendar-year periods, which was demonstrable for specific causes including death due to infections and death due to renal disorders. However, the SMR due to circulatory diseases tended to increase slightly from the 1970s to the year 2001. Conclusion. Our data from a very large multicenter international cohort emphasize what has been demonstrated previously in smaller samples. These results highlight the increased mortality rate in SLE patients compared with the general population, and they suggest particular risk associated with female sex, younger age, shorter SLE duration, and black/African American race. The risk for certain types of deaths, primarily related to lupus activity (such as renal disease), has decreased over time, while the risk for deaths due to circulatory disease does not appear to have diminished. (Less)

Recent evidence supports an association between systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL).To describe demographic factors, subtypes, and survival of patients with SLE who develop NHL.A multi-site cohort of 9547 subjects with definite SLE was assembled. Subjects at each centre were linked to regional tumour registries to determine cancer cases occurring after SLE diagnosis. For the NHL cases ascertained, descriptive statistics were calculated, and NHL subtype frequency and median survival time of patients determined.42 cases of NHL occurred in the patients with SLE during the 76,948 patient-years of observation. The median age of patients at NHL diagnosis was 57 years. Thirty six (86%) of the 42 patients developing NHL were women, reflecting the female predominance of the cohort. In the patients, aggressive histological subtypes appeared to predominate, with the most commonly identified NHL subtype being diffuse large B cell (11 out of 21 cases for which histological subtype was available). Twenty two of the patients had died a median of 1.2 years after lymphoma diagnosis.These data suggest aggressive disease in patients with SLE who develop NHL. Continuing work should provide further insight into the patterns of presentation, prognosis, and aetiology of NHL in SLE.

Health consumption and health status in SLE in three countries with different health funding structures were compared.Seven hundred and fifteen SLE patients (Canada 231, USA 269, UK 215) were surveyed semi-annually over 4 yr for health resource utilization and health status. Cross-country comparisons of (i) cumulative health expenditure (calculated by applying 2002 Canadian prices to resources in all countries) and (ii) disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SLICC/ACR DI) at study conclusion were performed after adjustment. Missing expenditure and damage data were managed through multiple imputation using best predictive regressions with all available data from all patients as potential covariates.Four hundred and eighty-five patients provided data at study entry and conclusion and at least four resource questionnaires (Canada 162, USA 157, UK 166); 41 died (Canada 13, USA 18, UK 10); 189 withdrew, were lost to follow-up or provided data at entry and conclusion but fewer than four resource questionnaires (Canada 56, USA 94, UK 39). At conclusion, after imputation, in Canada, the USA and the UK respectively, mean cumulative costs per patient over 4 yr [95% confidence interval (CI)] were $15,845 (13,509, 18,182), $20,244 (17,764, 22,724) and $17,647 (15,557, 19,737) and mean changes in SLICC/ACR DI were 0.49 (0.39, 0.60), 0.63 (0.52, 0.74) and 0.48 (0.39, 0.57). After adjustment for baseline differences, on average (95% CI), Canadian and British patients utilized 20% (8%, 32%) and 13% (1%, 24%) less resources than patients in the USA respectively, but experienced similar health outcomes.Despite patients in the USA incurring higher health expenditures, they did not experience superior health outcomes.

Few longitudinal data exist on the relationship between radiographic damage and self-reported functional disability and direct medical costs in rheumatoid arthritis (RA). We assessed these relationships.One hundred thirty patients with RA (at time of the first available radiograph, mean age 56.6 yrs, 16.9% male, mean disease duration 16.8 yrs) were followed for up to 13.4 years. Semiannually, they reported on functional disability (0 = no difficulty, 3 = unable to do), global severity (0 = very well, 100 = very poor), pain (0 = no pain, 3 = severe pain), and health services utilization through completion of the Stanford Health Assessment Questionnaire (HAQ). Concurrent hand radiographs were scored for erosions and joint space narrowing using the Genant method and a single score summing both erosions and joint space narrowing for both hands was calculated (0 = no damage, 200 = maximum damage). The univariate association of functional disability, global severity, pain, or direct medical costs with concurrent radiographic damage was assessed through Spearman correlations and hierarchical regression models. The hierarchical models permit exploitation of the between-patient and within-patient variation present in our longitudinal data.At the time of the first available radiograph, mean (SD) levels of functional disability, global severity, and pain were 1.3 (0.7), 39.4 (21.0), and 1.1 (0.7), respectively. At entry into the study, the average radiograph score was 49.7 and upon leaving the study it was 66.9. Patients were followed an average of 6.7 years, with radiograph scores increasing at an average rate of 2.5 units/yr. The Spearman correlation [95% confidence interval (CI)] between average per-patient radiograph score and average per-patient HAQ disability index, average per-patient global severity, average per-patient pain score, and average per-patient direct medical costs was, respectively, 0.42 (0.26, 0.55), 0.23 (0.06, 0.39), 0.20 (0.03, 0.36), and 0.06 (-0.11, 0.23). The mean slope (95% CI) for disability on radiograph score was 0.0186 (0.0132, 0.0226), for severity on radiographs 0.1889 (0.1295, 0.2498), and for pain on radiographs 0.0057 (0.0027, 0.0084). As an example, over 10 years, a 25 unit (i.e., 50%) increase in radiograph scores would, on average, be associated with a 0.46 unit (i.e., 35%) increase in disability, a 4.72 unit (12%) increase in global severity score, and a 0.14 unit (13%) increase in pain, all expressed on the HAQ scales. There was little association between radiograph score and direct medical costs.A clinically meaningful association exists between radiographic damage and self-reported functional disability, suggesting that interventions that slow radiographic progression may improve the patient's health status. Such a relationship was not observed between radiographic damage and direct medical costs.

Extracellular proteases play a crucial role in the invasive behavior of normal and transformed leukocytes. Thus far, however, most of the attention has been focused on members of the family of matrix metalloproteinases. In this work, we show that lymphoma cells can express leukocyte elastase (LE) and recruit the enzyme at their surface via ICAM-1. The expression of LE by lymphoma cells was augmented significantly by stimulation with IL-6 and IL-13, both of which also induced the expression of MMP-9. Although LE and IL-13 transcripts were detected in several non-Hodgkin's lymphomas, immunohistochemical analysis of lymphoma tissues also showed that LE was strongly expressed in infiltrating leukocytes. Given the spectrum of key molecules that can be cleaved by LE and that LE and MMP-9 are involved in the invasive behavior of normal or transformed leukocytes, our results raise the hypothesis that LE plays a crucial role in the multistep processes of inflammation and lymphoma metastasis.

Indirect costs result from diminished productivity and are incorporated in cost-benefit analysis to guide health resource allocation. Valuing the productivity impairment of those not involved in labor market activities is controversial but important for diseases affecting predominantly women if allocation decisions are to be economically efficient and equitable. We compared indirect costs incurred by women with systemic lupus erythematosus (SLE), a prototypical women's disease, calculated under varying assumptions for the value of diminished labor market and non-labor market activity.Six hundred forty-eight female patients with SLE reported on employment status and time lost by themselves and their caregivers from labor market and non-labor market activities over a 6 month period.Average annual indirect costs ranged from $1,424 to $22,604 (1997 Canadian dollars) dependent on the value assigned to labor market and non-labor market activity.Indirect cost estimates that fail to consider longterm labor market absenteeism and diminished non-labor market productivity and do not use gender neutral wages to value labor market activity may lead to decisions that jeopardize resources for women's diseases.

As part of an ongoing study of health resource utilization and diminished productivity in patients with systemic lupus erythematosus (SLE), the use of alternative medical therapies was assessed.A cohort of 707 patients with SLE from 3 countries completed questionnaires on demographics, social support, health status (using the Short Form 36 health survey), satisfaction with health care, health resource utilization (conventional resources and alternative therapies), and time losses in labor market and non-labor market activities. Annual direct and indirect costs (1997 Canadian dollars) were calculated and compared for users and nonusers of alternative medical therapies.Among the 707 patients, 352 (49.8%) were found to use alternative therapies and at similar rates across Canada, the United States, and the United Kingdom. Users were younger and better educated than nonusers, exhibited poorer levels of self-rated health status and satisfaction with medical care, and had minimal to no objective evidence of worse disease (according to the revised Systemic Lupus Activity Measure instrument). The mean of log direct medical costs for conventional resources was higher for users of select alternative therapies compared with nonusers. In a logistic regression, neither the number of alternative therapies used nor the individual therapy increased the probability of incurring indirect costs.The use of alternative medical therapies is common in patients with SLE. Users of many alternative medical therapies accrue greater conventional medical costs compared with nonusers. The use of alternative medical therapy may be a marker for care-seeking behavior associated with higher consumption of conventional medical resources in the absence of demonstrable additional morbidity and should be considered in future cost analyses of patients with SLE.

Dysregulation of metalloproteinase production at tumor sites contributes to the modification of local stromal tissue necessary for tumor development. Gelatinase B (matrix metalloproteinase-9, MMP-9) is one of the key enzymes that have been associated with the progression of several tumors. Paradoxically, MMP-9 expression by tumor cells, most notably by lymphoma cells, is concomitant with the expression of its physiological inhibitor, TIMP-1. Not only are both genes often co-expressed in the most aggressive forms of lymphomas but also both are up-regulated upon contact with stromal cells. Since TIMP-1 is known to regulate growth in several cell types and some aggressive lymphoma cells express TIMP-1 constitutively without MMP-9, it is unclear whether the over-expression of MMP-9 is counterbalanced by TIMP-1 and whether TIMP-1 expression alone could favor the development of lymphoma. To gain further insight into the respective roles of MMP-9 and TIMP-1 in lymphoma, we generated lymphoma cell lines expressing constitutively high levels of MMP-9 or TIMP-1 and compared these cells for the ability to form thymic lymphoma in vivo. Moreover, we generated lymphoma cell lines expressing constitutively high levels of both MMP-9 and TIMP-1 to reproduce the net physiological balance resulting from the expression of both genes simultaneously and to determine which gene overrides the other. Our results show that mice injected with lymphoma cells expressing MMP-9 constitutively developed thymic lymphoma more rapidly than those injected with control lymphoma cells. Over-expression of TIMP-1 alone did not significantly influence tumor progression of lymphoma nor did it delay the capacity of MMP-9 to accelerate the development of thymic lymphoma.

To compare health care expenditure and health status for patients with systemic lupus erythematosus (SLE) between nations with distinct mechanisms for funding and delivering health care services.Seven hundred eight patients with SLE from 2 centers in each of 3 countries (Canada 229, United States 268, United Kingdom 211) underwent physician assessment of disease activity and damage and reported on physical and psychosocial well being, satisfaction, social support, and health resource utilization. To compare overall utilization, constant prices (1997 Canadian dollars) were applied across countries for each service, enabling diverse resources to be collapsed into a single expression.After adjusting for important patient covariates, Canadian, compared to American and British patients, reported significantly superior health status in 3 of 8 Medical Outcome Survey Short Form-36 (SF-36) subscales, the SF-36 physical component summary score, and the visual analog scale of general health status. There was no consistent trend in patient satisfaction. Overall annual resource utilization did not vary significantly, with mean annual per patient expenditures (adjusted for demographics, disease duration, activity, damage, social support, health status, patient satisfaction, and age and sex adjusted country-specific SF-36 general population norms) totalling $4853, $5285, and $4760 for Canada, US, and the UK, respectively. However, within each resource category, differences were observed. Canadians saw more specialists than the British, the British more generalists. Canadians and Americans were more frequent users of the emergency room; Americans of laboratory/imaging procedures. Canadians had higher hospital costs than Americans.After adjustment, Canadian patients reported better well being than their counterparts. Despite considerable differences in the mechanisms of health care funding and service mixture, overall resource utilization did not vary significantly between the countries, although there was a trend towards more intense use of inpatient services in Canada and outpatient services in the United States.

It has been hypothesized that the intercellular adhesion receptors used by normal cells could also be operative in the spreading of circulating malignant cells to target organs. In the present work, we show that genetic ablation of the ICAM-1 gene confers resistance to T cell lymphoma metastasis. Following i.v. inoculation of LFA-1-expressing malignant T lymphoma cells, we found that ICAM-1-deficient mice were almost completely resistant to the development of lymphoid malignancy compared with wild-type control mice that developed lymphoid tumors in the kidneys, spleen, and liver. Histologic examinations confirmed that ICAM-1-deficient mice, in contrast to wild-type mice, had no evidence of lymphoid infiltration in these organs. The effect of ICAM-1 on T cell lymphoma metastasis was observed in two distinct strains of ICAM-1-deficient animals. Nonetheless, lymphoma cells migrated with the same efficiency to target organs in both normal and ICAM-1-deficient mice, indicating not only that ICAM-1 expression by the host is essential in lymphoma metastasis, but also that this is so at stages subsequent to homing and extravasation into target organs. These results point to posthoming events as a focus of future investigation on the control of metastasis mediated by ICAM-1.

To assess the effect of the tobacco tax cuts made in 1994 on the smoking habits of Canadians.Population-based retrospective cohort study.Data from the Survey on Smoking in Canada conducted by Statistics Canada on 11,119 respondents 15 years of age and older, who were interviewed about their smoking habits on 4 occasions, approximately every 3 months from January 1994 to February 1995.Changes in smoking prevalence, incidence, quit rates and mean number of cigarettes smoked per day in the provinces where tobacco taxes were cut and in those where taxes were not cut.During the survey, smoking prevalence decreased in all provinces, whether or not cigarette taxes had been cut. However, the prevalence of smoking was greater in the provinces where tobacco taxes had been cut than in those where they had not, and this difference increased from 2.0% at the beginning of the survey to 3.4% by the end (p0.001). In addition, rates of starting cigarette smoking were higher and smoking quit rates were lower in the provinces where taxes had been cut than in those where taxes had not been cut.Although smoking rates are declining in Canada, tobacco tax cuts appear to have slowed the rate of decline by inducing more nonsmokers to take up smoking and leading fewer smokers to quit.

Background Data suggest that Aboriginal people may experience lower rates of food allergy compared with the general population. However, there have not been any population-based studies to estimate the prevalence of food allergy among Aboriginal People in Canada. Given this gap in the literature, the goal of this study is to estimate the prevalence of food allergy among Canadian Aboriginal people (First Nations, Metis or Inuit), and to compare these estimates with the general population. Methods We performed a nationwide, cross-sectional telephone survey of all Canadian provinces and territories. Census Canada 2006 data were used to identify postal codes containing a high proportion of Aboriginal people and telephone numbers were randomly selected. The household respondent was queried on whether any household member had a food allergy. Prevalence estimates and 95% Confidence Intervals (CI) were calculated for the nine most common food allergens (peanut, tree nut, fish, shellfish, sesame, milk, egg, wheat, and soy) and for all foods, among individuals reporting Aboriginal status and for the general population. Results Out of 12,747 households contacted, 6,403 responded (50.2% response rate, representing 15,043 individuals), of which 2,264 reported Aboriginal status (15.1% of individuals). All allergies except peanut and fish are more common among the general population than Aboriginal people, although the difference is only significant for tree nut [1.22% (95% CI, 1.00%, 1.44%) vs. 0.57% (95% CI, 0.31%, 0.98%)], shellfish [1.60% (95% CI, 1.35%, 1.86%) vs. 0.93% (95% CI, 0.58%, 1.41%)], milk [1.97% (95% CI, 1.64%, 2.29%) vs. 0.49% (95% CI, 0.24%, 0.87%)], wheat [0.77% (95% CI, 0.57%, 0.96%) vs. 0.13% (95% CI, 0.03%, 0.39%)] and all foods [8.07% (95% CI, 7.47%, 8.67%) vs. 4.90% (95% CI, 4.05%, 5.87%)]. Conclusion Our study suggests that the self-reported prevalence of several food allergies is lower in the Aboriginal population as compared with a representative sample of the general Canadian population. The lower prevalence of self-reported food allergy in the Aboriginal population may be attributable to several factors: genetics, differences in dietary habits and the environment, and inequities in access to health care, education and information about food allergy. These findings support a need for better education and access to health care services for Aboriginal communities, and future studies to explore the role of genetics, diet and environment in the development of food allergy.

Thymic lymphomas develop in C57BL/Ka mice within 36 weeks after split-dose X-irradiation. Lymphoma development can be abrogated in such mice by the injection of syngeneic bone marrow from healthy donors. The abrogation mechanism is unknown, but since bone marrow supplies the thymus with precursors of thymocytes and of dendritic cells, we tested the ability of early thymocytes and of immortalized thymic dendritic cells to abrogate lymphomagenesis. Fifteen weeks after irradiation, mice which had received bone marrow or dendritic cells had an equally low incidence of lymphoma, whereas mice which had received thymocytes or which had been only irradiated developed equally high levels of lymphomas, indicating that thymic dendritic cells played a key role in the prevention of lymphoma development. When thymuses from 15-week survivors were tested for pre-lymphoma cells, those from dendritic cell-treated mice proved to be endowed with a level of lymphomagenic potential intermediate between that from bone marrow-treated mice (nonlymphomagenic) and that from untreated or thymocyte-treated mice (highly lymphomagenic). These data indicate that lymphoma abrogation by bone marrow cells involves the participation of marrow-derived thymic dendritic cells.

T U E S D A Y 911 Role Of Disulfide Bridges In The Proteolytic Susceptibility And Allergenicity Of Ara H 6, A Major Allergen From Peanut B. Guillon, S. Hazebrouck, K. Adel-Patient, E. Paty, P. Scheinmann, J. M. Wal, H. Bernard; INRA, Gif sur Yvette, FRANCE, Hopital Necker Enfants Malades, Paris, FRANCE. RATIONALE: Five disulfide (S-S) bridges stabilize the structure of Ara h 6. We investigated the impact of each S-S bridge on Ara h 6 susceptibility to pepsin and trypsin digestion and on its immunoreactivity. METHODS: Progressive deletion of the S-S bridges by substituting alanine for cysteine was performed on a recombinant Ara h 6. Proteolysis by pepsin and trypsin were followed using SDS-PAGE and the peptides produced during digestion were identified by mass spectrometry. Immunoreactivity of the recombinant proteins and their proteolytic fragments was assessed by IgE binding studies using sera from 5 peanut-allergic patients sensitized to Ara h 6. The capacity to induce the degranulation of humanized ratmast cells passively sensitized with human specific IgE was also evaluated. RESULTS: The recombinant Ara h 6 and the mutant lacking the C-terminal (C84-C124) S-S bridge exhibited identical structure to and the same immunoreactivity as the natural counterpart. The loss of an additional S-S bridge slightly decreased the protein immunoreactivity. However, the susceptibility to proteolysis was highly dependant on the S-S bridge deleted. Complete degradation of Ara h 6 by pepsin and trypsin occurred when the central S-S bridges (C26-C58 or C59-C107) were mutated, thus leading to a total loss of allergenicity after digestion. Immunoreactivity of Ara h 6 was conserved only when a heterodimeric structure, characteristic of the 2S albumin, was preserved after digestion. CONCLUSIONS: The central S-S bridges stabilize the protease-resistant coreofArah 6 andhave amajor role on its structure andbiological properties. 912 The Use of Epinephrine for the Treatment of Initial Allergic Reactions to Peanut M. Ben-Shoshan, L. Soller, R. Alizadehfar, J. Fragapane, L. Joseph, Y. St. Pierre, L. Harada, M. Allen, A. Clarke; McGill University Montreal Children Hospital, Montreal, QC, CANADA, Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Center, Montreal, Quebec, Canada, Montreal, QC, CANADA, Division of Clinical Epidemiology, Department of Medicine, McGill University Health Center, Montreal, QC, CANADA, Departments of Epidemiology and Biostatistics, McGill University, Montreal, QC, CANADA, Anaphylaxis Canada, Toronto, ON, CANADA, Allergy/Asthma Information Association, Toronto, ON, CANADA, Division of Allergy and Clinical Immunology, Department of Medicine, McGill University Health Center, Montreal, QC, CANADA. RATIONALE: To assess the use of epinephrine to treat initial allergic reactions to peanut in health care facilities (HCF). METHODS: Parents of children with an allergist-confirmed peanut allergy recruited from the Montreal Children’s Hospital and from PanCanadian food allergy advocacy associations were queried on the management of the initial allergic reactions. RESULTS: Six hundred twenty-nine individuals reported an initial allergic reaction to peanut. Median age of initial reaction was 1.6 years (IQR, 1.1, 2.6) and 46.1% (95% CI, 42.2, 50.1) were brought to HCFs. Epinephrine was administered to 23.1% (95% CI, 18.4, 28.4) of those brought to HCFs. Among those with moderate/severe reactions, 55.2% (95% CI, 50.5, 59.7) were brought to HCFs, and 24.9% (95% CI, 19.7, 30.7) of these received epinephrine. Epinephrine auto-injector (EAI) was prescribed in 58.0% (95% CI, 51.5, 64.3) of cases brought to HCF. Factors associated with epinephrine treatment in a HCF were the presence of a severe reaction [OR 3.26 (95% CI, 1.72, 6.15)] and a family history of atopy [OR 2.25 (95% CI, 1.20, 4.20)]. Factors associated with EAI prescription were use of epinephrine for the initial reaction: [OR 5.23 (95% CI, 2.39, 11.45)]; living in Quebec: [OR 2.55 (95%CI, 1.43, 4.56)] and calendar year of initial reaction [OR 1.09 95% CI 1.02, 1.16)]. CONCLUSIONS: Our results reveal underuse of epinephrine and low rates of EAI prescriptions in HCFs. Guidelines prompting epinephrine use and prescription to all individuals presenting with a likely allergic reaction to peanut are required. 913 Food Avoidance Following Physician Diagnosis Of Food Allergy: Results From A Canadian Study L. Soller, J. Fragapane, M. Ben-Shoshan, D. Harrington, R. Alizadehfar, L. Joseph, Y. St-Pierre, S. Godefroy, S. J. Elliott, A. E. Clarke; McGill University, Montreal, QC, CANADA, McMaster University, Hamilton, ON, CANADA, Health Canada, Ottawa, ON, CANADA, Waterloo University, Waterloo, ON, CANADA. RATIONALE: To identify predictors associated with avoidance of known allergens. METHODS: Individuals reporting physician-diagnosed allergy to peanut, tree-nut, fish, shellfish and/or sesame in a nationwide telephone survey conducted in 2008/9 were asked about avoidance of the food since diagnosis. Multivariate logistic regression performed to identify predictors (education, allergen, characteristics of most severe reaction) associated with avoidance. RESULTS:Of 10,596 households surveyed, 3666 responded, representing 9667 individuals, (35%) of which 208 (2.15% [95% CI, 1.86, 2.44]) reported at least one physician-diagnosed allergy to the above-mentioned foods. 202 of 208 (97%) provided sufficient information to be included in the analysis. Of these, individuals with an allergy to peanut/tree-nut/sesame were less likely to avoid compared to those with fish/shellfish (Odds Ratio (OR) 0.062 [95% CI, 0.025, 0.15]). Individuals who received epinephrine during their most severe reaction were more likely to avoid than those who did not (OR 4.51 [95% CI, 1.70, 12.0]). CONCLUSIONS: We hypothesize that those with fish/shellfish allergy are more able to avoid their known allergen as it is easily identifiable whereas many foods are labeled as containing trace amounts of peanut/ tree-nut/sesame and hence are more difficult to avoid. Those who received epinephrine presumably are better able to appreciate the potential severity of a subsequent reaction and hence were more diligent about avoidance. Given the unpredictability of allergic reactions to peanut/tree-nut/sesame, all allergic individuals, even thosewith a previousmild reaction, should receive education regarding importance of food avoidance. Additionally, food labels should be clearer so that allergic individuals can easily avoid foods containing peanut/tree-nut/sesame.

In addition to their role as peptide binding proteins, MHC class II proteins can also function as signal transducing molecules. Recent work using B cells expressing genetically engineered truncated MHC class II molecules has suggested that signaling through the cytoplasmic domains of these proteins plays an important role in the generation of signals required for the activation of some T cell hybrids. Treatment of truncated Ia-expressing B cells with cAMP-elevating agents corrects the deficiency in Ag presentation by these cells. We report that the MHC class II-mediated signal appears to act by a mechanism that increases the efficiency of Ag presentation by B cells thereby lowering the amount of specific Ag required for T cell activation. We further show that the induction of the cAMP-induced signal in B cells is inhibited by cycloheximide and cytochalasin A, implicating protein synthesis as well as cytoskeletal rearrangements in Ag presentation to accessory signal- dependent hybrids. In contrast, these agents do not block Ag presentation to a T cell hybrid previously shown not to require the cAMP-induced signal for activation. The signal-dependent T hybrid is additionally dependent on LFA-1-ICAM-1 interaction for activation, whereas the signal-independent hybrid is not. These observations suggest the existence of two types of T cell hybrid with respect to their requirements for activation: those that require only the recognition of MHC class II-peptide complexes without accessory signals, as shown by their ability to respond to purified Ia on planar membranes, and those that, in addition to recognition of MHC II/Ag, require LFA-1-ICAM-1 interaction and the delivery of additional signal(s) induced in the B cell via signal transduction through MHC class II molecules.

The presentation of protein Ag with MHC class II proteins involves the uptake of the protein Ag by endocytosis followed by processing, probably proteolysis, in an intracellular acidic compartment. However, there remains considerable controversy as to the precise route taken by the antigen and the MHC class II protein during this process. The unusual stability of Ag-MHC class II protein complexes has led to speculation that antigen can only associate with newly synthesized MHC class II molecules. An alternate possibility is that the MHC class II binding site can be regenerated within the cell during internalization and recycling of MHC class II proteins. To address these possibilities, three different murine B lymphoma lines were tested for their ability to process and present native protein Ag in the presence of the protein synthesis inhibitor cycloheximide or the protein synthesis inhibitor cycloheximide or the protein export inhibitor, Brefeldin A. Both agents blocked the presentation of native OVA or native hen egg lysozyme to Ag-specific T cell hybridomas. No effect was seen on peptide presentation or on presentation to allo- or autoreactive T cells. Inasmuch as Brefeldin A has been previously shown to block protein export without affecting protein internalization or protein degradation in the endocytic pathway, the simplest interpretation of these data is that antigenic fragments generated in the APC after uptake by the endocytic pathway, preferentially associate with newly synthesized rather than mature MHC class II proteins.

B cell transfectants expressing MHC class II (Ia) molecules with truncated cytoplasmic domains are defective in both antigen presentation and in anti-Ia induced intracellular signaling. In this report we show that the Ag presentation defect in a truncated-Ia expressing transfectant can be overcome by providing the second messenger for the Ia-mediated signaling event. Preincubation with dibutyryl-cAMP restored the ability of the truncated Ia expressing-transfectant to stimulate IL-2 release by otherwise nonresponsive T hybrids. This provides direct functional evidence that signaling via the cytoplasmic domains of MHC class II proteins leads to the generation of accessory signals in the B cell that are important in T cell activation. The dibutyryl-cAMP induced signal must be on the same cell as the restricting element, does not bypass the requirement for occupancy of the T cell receptor with its normal ligand, and is lost upon fixation of the cells. Thus T cell-B cell interaction involves a two way communication in which both cells sense and respond to the formation of the antigen/MHC/TCR complex.

The phenotypic expression of genetically determined resistance to radiation leukemia virus (RadLV)-induced leukemia in mice has been shown to reside in the bone marrow. Because the bone marrow contains precursors of natural killer (NK) cells, known to play a role in retrovirally induced infections, and because these cells have been suggested as participating in resistance to radiation-induced leukemia, it was pertinent to establish whether their levels differed in strains of mice susceptible and resistant to leukemia. We therefore tested splenic NK cell levels in C57BL/Ka (susceptible) and B10.A(5R) (resistant) mice before viral inoculation, immediately after viral inoculation, and throughout the preleukemic period and showed that they were not different. This indicates that splenic NK cell levels have no bearing on the resistance to RadLV-induced leukemia and that other immune or non-immune mechanisms must be sought.

T-cell differentiation is known to be mediated by lympho-stromal interactions. However, the precise role of cellular complexes formed during this process is far from clear. We have previously established a thymic medullary epithelial cell-line, E-5, and have shown the adherence of thymocytes by a receptor-mediated-mechanism. We report here that the thymocytes able of complex-formation with E-5 cells appear at day 16 of gestation. Moreover, while the proportion of such thymocytes is constant throughout post-natal life, their absolute number decreases with thymic involution. We have also investigated the influence of the genetic background of thymocytes on adherence and found that polymorphic regions of H-2 genes were not involved in contact recognition. Therefore, this type of lympho-stromal interactions is unlikely to participate in the education to self MHC-restriction. However, thymocytes from B6/lpr mice, which spontaneously develop systemic lupus erythematosus (SLE) and have impaired T-cell differentiation, were shown incapable of adhering to E-5 cells. These results are interpreted as showing that interaction between thymocytes and medullary epithelial cells reflect a discrete stage of T-cell differentiation.

Methods Individuals with an allergist-confirmed peanut allergy were recruited from the Montreal’s Children Hospital and Canadian food allergy advocacy organizations. Data were collected on initial allergic reactions to peanut and treatment inside and outside HCFs. Results Of 751 individuals who had an allergic reaction to peanut, 613 responded (81.6%). Initial reactions were mild in 28.4% (95% CI, 25.0-32.1%), moderate in 50.6% (46.654.6%), and severe in 20.9% (17.8-24.3%). Average age of initial reaction was 2.1 years (2.0-2.3). Among participants, 11.6% (9.1-14.7%) were diagnosed with peanut allergy (based on skin and IgE testing) prior to the initial reaction. Of the 613 participants, 32.1% (28.5-36.0%) were treated in HCFs only, 51.7% (47.7-55.7) outside HCFs only, and 16.2% (13.4-19.3%) in both. 21.3% (17.026.3%) of all reactions treated in HCFs received epinephrine (table) versus only 3% (1.8-5.1%) treated outside. Of those with moderate or severe initial reactions, 58.2% (53.5-62.8%) were treated in HCFs, and 23.9% (19.1-29.6%) of these received epinephrine. See table 1.