Clinical outcomes for 2788 patients with transthyretin amyloidosis: Tafamidis meglumine early access program in France.

BACKGROUND: Early access experience in France with tafamidis meglumine, a selective transthyretin stabilizer for transthyretin-related amyloidosis cardiomyopathy (ATTR-CM), following transthyretin-related amyloidosis (ATTR) polyneuropathy approval and positive ATTR-ACT study results. AIM: To describe the characteristics and clinical outcomes for patients in the French ATTR-CM tafamidis meglumine early access programme (28 Nov 2018 to 01 Jun 2021). METHODS: Patients with confirmed ATTR-CM received tafamidis meglumine 20mg/day or 80mg/day. Demographic and clinical data were collected prospectively until patients discontinued treatment or died, or the programme ended. RESULTS: Overall, 222 physicians from 126 centres enrolled 2788 patients. The median age was 82years, 81.6% were male and New York Heart Association severity was class I for 12.8%, class II for 60.1% and class III for 27.0%. Overall, 1943 (74.6%) had genetic testing, and the results were available at tafamidis start for 1208 (62.2%) patients: 995 (82.4%) had wild-type ATTR and 213 (17.6%) had hereditary ATTR. Most patients started treatment≤12months after diagnosis (88.3%): 2268 (81.3%) at 20mg/day, with 401 (17.7%) increasing to 80mg/day. Median follow-up duration was 11.8months. New York Heart Association class improved or remained stable for 1299 (77.6%), whereas 376 (22.4%) worsened between inclusion and last follow-up. Among patients initiated at 80mg, 297 (81.1%) improved or remained stable and 69 (18.9%) worsened. New York Heart Association class progression did not vary with age. The 18-month survival rates were 89.8% (95% confidence interval: 87.0-92.0) among patients aged<80years, and 86.5% (95% confidence interval: 83.9-88.7) among those aged≥80years. CONCLUSIONS: Early tafamidis meglumine access was given to 2788 patients with ATTR-CM. New York Heart Association class progression and survival were consistent with previously published data.

Incidence and survival of transthyretin amyloid cardiomyopathy from a French nationwide study of in- and out-patient databases.

BACKGROUND: Precise data about ATTR-CM incidence rates at national level are scarce. Consequently, this study aimed to estimate the annual incidence and survival of transthyretin amyloid cardiomyopathy (ATTR-CM) in France between 2011 and 2019 using real world data. We used the French nationwide exhaustive data (SNDS database) gathering in- and out-patient claims. As there is no specific ICD-10 marker code for ATTR-CM, diagnosis required both amyloidosis (identified by E85. ICD-10 code or a tafamidis meglumine delivery) and a cardiovascular condition (identified by ICD-10 or medical procedure codes related to either heart failure, arrhythmias, conduction disorders or cardiomyopathies), not necessarily reported at the same visit. Patients with probable AL-form of amyloidosis or probable AA-form of amyloidosis were excluded. RESULTS: Between 2011 and 2019, 8,950 patients with incident ATTR-CM were identified. Incidence rates increased from 0.6 / 100,000 person-years in 2011 to 3.6 / 100,000 person-years in 2019 (p < 0.001), reaching 2377 new cases in 2019. Sex ratios (M/F) increased from 1.52 in 2011 to 2.23 in 2019. In 2019, median age at diagnosis was 84.0 years (85.5 for women and 83.5 for men). Median survival after diagnosis was 41.9 months (95% CI [39.6, 44.1]). CONCLUSIONS: This is the first estimate of nationwide ATTR-CM incidence in France using comprehensive real-world databases. We observed an increased incidence over the study period, consistent with an improvement in ATTR-CM diagnosis in recent years.

Choice of Systemic Drugs for the Management of Moderate-to-severe Psoriasis: A Cross-country Comparison Based on National Health Insurance Data.

Current management of moderate-to-severe psoriasis may be heterogeneous between European countries, probably due to differences in the organization of care. The aim of this study was to compare the utilization of systemic treatments for psoriasis between 2 coun-tries. All adults with psoriasis who were registered in the French (SNDS) and the Dutch (VEKTIS) national health insurance databases between 2012 and 2016 were eligible for inclusion. In France, 105,035 (15%) of 684,156 patients and, in the Netherlands, 37,405 (28.6%) of 130,822 patients received at least a systemic agent. In France, the proportion of patients treated with systemic agents was constant, while the type of drugs dispensed shifted from non-biological to biological agents. In the Netherlands, the first systemic treatment was methotrexate and, in France, acitretin. In France, the choice of the first biologic was much more variable than it was in the Netherlands, where a large proportion of patients were dispensed ustekinumab. This study highlights discrepancies between France and the Netherlands concerning the choice of first non-biologic agent and first biologic agent for patients with psoriasis. These discrepancies may be due to differences in the healthcare systems between the 2 countries.

Seasonal influenza vaccine and Guillain-Barré syndrome: A self-controlled case series study.

OBJECTIVE: To evaluate the risk of Guillain-Barré syndrome (GBS) following seasonal influenza vaccination based on French nationwide data. METHODS: All cases of GBS occurring in metropolitan France between September 1 and March 31 from 2010 to 2014 were identified from the French national health data system. Data were analyzed according to the self-controlled case series method. The risk period started 1 day after the patient received vaccine (D1) until 42 days after vaccination (D42). The incidence of GBS during this risk period was compared to that of the control period (D43-March 31). The incidence rate ratio (IRR) was estimated after adjusting for seasonality and presence or not of acute infections. RESULTS: Between September and March, of the 2010/2011 to 2013/2014 influenza vaccination seasons, 3,523 cases of GBS occurred in metropolitan France and were included in the study. Among them, 15% (527 patients) had received influenza vaccination. A total of 140 patients developed GBS during the 42 days following influenza vaccination. The crude risk of developing GBS was not significantly increased during the 42 days following influenza vaccination (IRR, 1.02; 95% confidence interval [CI], 0.83-1.25; p = 0.85). This result remained nonsignificant after adjustment for calendar months and the incidence of acute gastrointestinal and respiratory tract infections (IRR, 1.10; 95% CI, 0.89-1.37; p = 0.38). In contrast, the risk of GBS was fourfold higher after acute respiratory tract infection (IRR, 3.89; 95% CI, 3.52-4.30; p < 0.0001) or gastrointestinal infection (IRR, 3.64; 95% CI, 3.01-4.40; p < 0.0001). CONCLUSIONS: No association between seasonal influenza vaccination and GBS was shown during the 42 days following vaccination.

Burden of fractures in France: incidence and severity by age, gender, and site in 2016.

PURPOSE: Fractures are common events, but the exact incidence and severity of fractures have not been clearly determined for most anatomical sites. We estimated the incidence and severity of fractures in France regardless of the anatomical site. METHODS: Observational cross-sectional study in France in 2016 based on the national health data system. All incident fractures in patients 20 years and older were included. We determined the anatomical fracture site (12 sites) and the severity using a 4-point scale (outpatient care, hospitalization, surgery, and in-hospital death). RESULTS: We identified 562,094 incident fractures, predominantly occurring in women (319,858: 56.9%); with a mean age of 63.6 years, and an exponential increase after the age of 70 years. Distal upper limb (172,591: 30.7%), distal lower limb (84,602: 15.1%), and femoral neck (78,766: 14.0%) accounted for more than one-half of all fractures. Sex and age of onset distributions varied widely according to fracture sites, with earlier onset for distal lower limb fractures (mean age: 54.2 years) and distal upper limb fractures (mean age: 55.2 years) with a men predominance for skull fractures. Only 105,165 (18.7%) fractures were treated on an outpatient basis; 11,913 (2.1%) in-hospital deaths occurred in patients with a mean age of 79.5 years. High mortality was observed for skull (12.9%), rib (4.9%), and femoral fractures (femoral neck 4.3% and proximal lower limb 4.2%). CONCLUSION: We estimated the incidence of fractures in France by sex and anatomical site. We also showed that fractures remain common and serious life events, especially in older people.

The effectiveness and safety of infliximab compared with biosimilar CT-P13, in 3112 patients with ulcerative colitis.

BACKGROUND: CT-P13, a biosimilar of the reference product infliximab, has been approved for the treatment of ulcerative colitis on the basis of the results of trials conducted in patients with spondyloarthritis and rheumatoid arthritis. AIM: To compare the effectiveness and safety of CT-P13 and the reference product in infliximab-naive patients with ulcerative colitis METHODS: A comparative real-life equivalence cohort study was conducted using the French nationwide health administrative database. Infliximab-naive patients with ulcerative colitis over 15 years of age who started infliximab with no other indications for infliximab were included. The primary outcome was a composite endpoint (death, ulcerative colitis-related surgery, all-cause hospitalisation and reimbursement for other biologics). Equivalence was defined as a 95% CI of the hazard ratio (HR) of CT-P13 vs the reference product, in a multivariable marginal Cox model situated within prespecified margins of (0.80-1.25). RESULTS: A total of 3112 patients were included between 1 January 2015 and 30 June 2017: 1434 received the reference product, 1678 received CT-P13. Overall, 710 patients in the reference product group and 743 patients in the CT-P13 group met the composite endpoint. In multivariable analysis of the primary outcome, CT-P13 was equivalent to the reference product (HR 1.04; 95% CI: 0.94-1.15). The number of serious infections was lower in the CT-P13 group (HR 0.65; 95% CI: 0.48-0.88). There was no difference in the incidence of solid or haematologic malignancy (HR 0.81; 95% CI: 0.41-1.60). CONCLUSIONS: The effectiveness of CT-P13 is equivalent and the risk of serious infections could be lower than that of the reference product for infliximab-naive patients with ulcerative colitis.

Association of Age With Short-term and Long-term Mortality Among Patients Discharged From Intensive Care Units in France.

Importance: An aging population is increasing the need for intensive care unit (ICU) beds. The benefit of ICU admission for elderly patients remains a subject of debate; however, long-term outcomes across all adult age strata are unknown. Objective: To describe short-term and long-term mortality (up to 3 years after discharge) across age strata in adult patients admitted to French ICUs. Design, Setting, and Participants: Using data extracted from the French national health system database, this cohort study determined in-hospital mortality and mortality at 3 months and 3 years after discharge of adult patients (older than 18 years) admitted to French ICUs from January 1 to December 31, 2013, focusing on age strata. The dates of analysis were November 2017 to December 2018. Exposure: Intensive care unit admission. Main Outcomes and Measures: In-hospital mortality and mortality at 3 months and 3 years after hospital discharge. Results: The study included 133 966 patients (median age, 65 years [interquartile range, 53-76 years); 59.9% male). Total in-hospital mortality was 19.0%, and 3-year mortality was 39.7%. For the 108 539 patients discharged alive from the hospital, 6.8% died by 3 months, and 25.8% died by 3 years after hospital discharge. After adjustment for sex, comorbidities, reason for hospitalization, and organ support (invasive ventilation, noninvasive ventilation, vasopressors, inotropes, fluid resuscitation, blood products administration, cardiopulmonary resuscitation, renal replacement therapy, and mechanical circulatory support), risk of mortality increased progressively across all age strata but with a sharp increase in those 80 years and older. In-hospital and 3-year postdischarge mortality rates, respectively, were 30.5% and 44.9% in patients 80 years and older compared with 16.5% and 22.5% in those younger than 80 years. Total 3-year mortality was 61.4% among patients 80 years and older vs 35.1% in those younger than 80. After age and sex standardization, excess mortality was highest among young patients during their first year after hospital discharge and persisted into the second and third years. In contrast, the mortality risk was close to the general population risk among elderly patients (≥80 years). Age and reason for hospitalization were strongly associated with long-term mortality (9-, 13-, and 20-fold increase in the risk of death 3 years after ICU discharge in patients aged 80-84, 85-89, and ≥90 years, respectively, compared with patients aged <35 years), while organ support use during ICU showed a weaker association (all organ support had 1.3-fold or lower increase in the risk of death). Conclusions and Relevance: Results of this study suggest that aging was associated with an increased risk of mortality in the 3 years after hospital discharge that included an ICU admission, with a sharp increase in those 80 years and older. However, compared with the general population matched by age and sex, excess long-term mortality was high in young surviving patients but not in elderly patients.

Effectiveness and Safety of Reference Infliximab and Biosimilar in Crohn Disease: A French Equivalence Study.

Background: CT-P13 is a biosimilar of the reference product (RP) infliximab, with demonstrated efficacy and safety for some inflammatory arthritides. It was approved for the treatment of Crohn disease (CD) on that basis, without specific studies examining its effects in CD. Objective: To compare the effectiveness and safety of CT-P13 and RP in infliximab-naive patients with CD. Design: Comparative equivalence cohort study. Setting: Système National des Données de Santé (SNDS), a French nationwide health administrative database (1 March 2015 to 30 June 2017). Patients: 5050 infliximab-naive patients with CD who were older than 15 years, had started treatment with RP (n = 2551) or CT-P13 (n = 2499), and had no other indications for infliximab. Measurements: The primary outcome was a composite end point of death, CD-related surgery, all-cause hospitalization, and reimbursement of another biologic therapy. Equivalence was defined as a 95% CI of the hazard ratio (HR) of CT-P13 versus RP in a multivariable marginal Cox model situated within prespecified margins (0.80 to 1.25). Results: Overall, 1147 patients in the RP group and 952 patients in the CT-P13 group met the composite end point (including 838 and 719 hospitalizations, respectively). In multivariable analysis of the primary outcome, CT-P13 was equivalent to RP (HR, 0.92 [95% CI, 0.85 to 0.99]). No differences in safety outcomes were observed between the 2 groups: serious infections (HR, 0.82 [CI, 0.61 to 1.11]), tuberculosis (HR, 1.10 [CI, 0.36 to 3.34]), and solid or hematologic cancer (HR, 0.66 [CI, 0.33 to 1.32]). Limitation: The SNDS does not contain all relevant clinical data (for example, disease activity). Conclusion: This analysis of real-world data indicates that the effectiveness of CT-P13 is equivalent to that of RP for infliximab-naive patients with CD. No difference was observed for safety outcomes. Primary Funding Source: Caisse Nationale de l'Assurance Maladie.

Surgery and risk of Guillain-Barré syndrome: A French nationwide epidemiologic study.

OBJECTIVE: To assess the association between Guillain-Barré syndrome (GBS) and recent surgery based on French nationwide data. METHODS: Data were extracted from the French health administrative databases (SNIIRAM/PMSI). All patients hospitalized for GBS between 2009 and 2014 were identified by ICD-10 code G61.0 as main diagnosis. Patients previously hospitalized for GBS in 2006, 2007, and 2008 were excluded. Surgical procedures were identified from the hospital database. Hospitalizations for surgery with no infection diagnosis code entered during the hospital stay were also identified. The association between GBS and a recent surgical procedure was estimated using a case-crossover design. Case and referent windows were defined as 1-60 days and 366-425 days before GBS hospitalization, respectively. Analyses were adjusted for previous episodes of gastroenteritis and respiratory tract infection, identified by drug dispensing data. RESULTS: Of the 8,364 GBS cases included, 175 and 257 patients had undergone a surgical procedure in the referent and case windows, respectively (adjusted odds ratio [OR] = 1.53, 95% confidence interval [CI]: 1.25-1.88). A slightly weaker association was observed for surgical procedures with no identified infection during the hospitalization (OR = 1.40, 95% CI: 1.12-1.73). Regarding the type of surgery, only surgical procedures on bones and digestive organs were significantly associated with GBS (OR and 95% CI = 2.78 [1.68-4.60] and 2.36 [1.32-4.21], respectively). CONCLUSION: In this large nationwide epidemiologic study, GBS was moderately associated with any type of recent surgery and was more strongly associated with bone and digestive organ surgery.

Healthcare expenditure of multiple sclerosis patients in 2013: A nationwide study based on French health administrative databases.

BACKGROUND: Little is known about expenditure items of multiple sclerosis (MS) patients over recent years in France. OBJECTIVE: To describe healthcare expenditure among MS patients and identify the main expenditure drivers. METHODS: All healthcare expenditure reimbursed by French National Health Insurance to MS patients in 2013 was described on the basis of nationwide health administrative databases (SNIIRAM/PMSI). Expenditure was described globally and according to age and sex. RESULTS: The average expenditure among the 90,288 MS patients included was €11,900 per patient. Pharmacy and hospitalisation accounted for 47% and 23% of healthcare expenditure, respectively (38% and 22% of MS patients were treated with disease-modifying therapies and hospitalised overnight or longer, respectively). Average expenditure did not differ according to age. However, pharmacy expenditure decreased with age (from 71% between the ages of 20 and 29 years to 18% between the ages of 70 and 79 years), whereas hospitalisation expenditure increased with age (from 15% to 35%). Paramedical fees accounted for 2% of expenditure between the ages of 20 and 29 years and 24% between the ages of 70 and 79 years. CONCLUSION: Overall, pharmacy expenditure was the main expenditure item, which decreased with increasing age, while hospitalisation and paramedical expenditure increased with increasing age.

Dental procedures, antibiotic prophylaxis, and endocarditis among people with prosthetic heart valves: nationwide population based cohort and a case crossover study.

Objective To assess the relation between invasive dental procedures and infective endocarditis associated with oral streptococci among people with prosthetic heart valves.Design Nationwide population based cohort and a case crossover study.Setting French national health insurance administrative data linked with the national hospital discharge database.Participants All adults aged more than 18 years, living in France, with medical procedure codes for positioning or replacement of prosthetic heart valves between July 2008 and July 2014.Main outcome measures Oral streptococcal infective endocarditis was identified using primary discharge diagnosis codes. In the cohort study, Poisson regression models were performed to estimate the rate of oral streptococcal infective endocarditis during the three month period after invasive dental procedures compared with non-exposure periods. In the case crossover study, conditional logistic regression models calculated the odds ratio and 95% confidence intervals comparing exposure to invasive dental procedures during the three month period preceding oral streptococcal infective endocarditis (case period) with three earlier control periods.Results The cohort included 138 876 adults with prosthetic heart valves (285 034 person years); 69 303 (49.9%) underwent at least one dental procedure. Among the 396 615 dental procedures performed, 103 463 (26.0%) were invasive and therefore presented an indication for antibiotic prophylaxis, which was performed in 52 280 (50.1%). With a median follow-up of 1.7 years, 267 people developed infective endocarditis associated with oral streptococci (incidence rate 93.7 per 100 000 person years, 95% confidence interval 82.4 to 104.9). Compared with non-exposure periods, no statistically significant increased rate of oral streptococcal infective endocarditis was observed during the three months after an invasive dental procedure (relative rate 1.25, 95% confidence interval 0.82 to 1.82; P=0.26) and after an invasive dental procedure without antibiotic prophylaxis (1.57, 0.90 to 2.53; P=0.08). In the case crossover analysis, exposure to invasive dental procedures was more frequent during case periods than during matched control periods (5.1% v 3.2%; odds ratio 1.66, 95% confidence interval 1.05 to 2.63; P=0.03).Conclusion Invasive dental procedures may contribute to the development of infective endocarditis in adults with prosthetic heart valves.

Guillain-Barré syndrome in France: a nationwide epidemiological analysis based on hospital discharge data (2008-2013).

Guillain-Barré syndrome (GBS) is potentially life threatening and typically occurs after an infection. No detailed information is available concerning the epidemiological characteristics of GBS in France. We estimated age- and sex-specific incidence rates (IRs) based on a French nationwide hospital discharge database. All patients hospitalized for GBS between 2008 and 2013 were identified by International Classification of Diseases-10 code G61.0 as principal diagnosis. Patients previously hospitalized for GBS in 2006 and 2007 were excluded. Sensitivity analyses were performed by considering alternative case definitions, based on more restrictive sets of codes. A total of 9,391 patients were identified, leading to an overall crude IR of 2.42 per 100,000 person-years (world standardized IR = 2.00). IRs increased with age, reaching a peak in the 70-79-year age group. IR was 46% higher in men than in women, and 44% higher in winter than in summer. In children, the highest IR was observed at the age of 2 years. These patterns were not modified by the use of alternative case definitions. This French nationwide study showed similar GBS epidemiological patterns in adults to those reported in other countries. We also report a childhood incidence peak around the age of 2 years, as previously observed in Latin American and Chinese populations.

Parental Tobacco Smoking and Acute Myeloid Leukemia: The Childhood Leukemia International Consortium.

The association between tobacco smoke and acute myeloid leukemia (AML) is well established in adults but not in children. Individual-level data on parental cigarette smoking were obtained from 12 case-control studies from the Childhood Leukemia International Consortium (CLIC, 1974-2012), including 1,330 AML cases diagnosed at age <15 years and 13,169 controls. We conducted pooled analyses of CLIC studies, as well as meta-analyses of CLIC and non-CLIC studies. Overall, maternal smoking before, during, or after pregnancy was not associated with childhood AML; there was a suggestion, however, that smoking during pregnancy was associated with an increased risk in Hispanics (odds ratio = 2.08, 95% confidence interval (CI): 1.20, 3.61) but not in other ethnic groups. By contrast, the odds ratios for paternal lifetime smoking were 1.34 (95% CI: 1.11, 1.62) and 1.18 (95% CI: 0.92, 1.51) in pooled and meta-analyses, respectively. Overall, increased risks from 1.2- to 1.3-fold were observed for pre- and postnatal smoking (P < 0.05), with higher risks reported for heavy smokers. Associations with paternal smoking varied by histological type. Our analyses suggest an association between paternal smoking and childhood AML. The association with maternal smoking appears limited to Hispanic children, raising questions about ethnic differences in tobacco-related exposures and biological mechanisms, as well as study-specific biases.

Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study.

OBJECTIVE: To assess the risk of pulmonary embolism, ischaemic stroke, and myocardial infarction associated with combined oral contraceptives according to dose of oestrogen (ethinylestradiol) and progestogen. DESIGN: Observational cohort study. SETTING: Data from the French national health insurance database linked with data from the French national hospital discharge database. PARTICIPANTS: 4 945 088 women aged 15-49 years, living in France, with at least one reimbursement for oral contraceptives and no previous hospital admission for cancer, pulmonary embolism, ischaemic stroke, or myocardial infarction, between July 2010 and September 2012. MAIN OUTCOME MEASURES: Relative and absolute risks of first pulmonary embolism, ischaemic stroke, and myocardial infarction. RESULTS: The cohort generated 5 443 916 women years of oral contraceptive use, and 3253 events were observed: 1800 pulmonary embolisms (33 per 100 000 women years), 1046 ischaemic strokes (19 per 100 000 women years), and 407 myocardial infarctions (7 per 100 000 women years). After adjustment for progestogen and risk factors, the relative risks for women using low dose oestrogen (20 µg v 30-40 µg) were 0.75 (95% confidence interval 0.67 to 0.85) for pulmonary embolism, 0.82 (0.70 to 0.96) for ischaemic stroke, and 0.56 (0.39 to 0.79) for myocardial infarction. After adjustment for oestrogen dose and risk factors, desogestrel and gestodene were associated with statistically significantly higher relative risks for pulmonary embolism (2.16, 1.93 to 2.41 and 1.63, 1.34 to 1.97, respectively) compared with levonorgestrel. Levonorgestrel combined with 20 µg oestrogen was associated with a statistically significantly lower risk than levonorgestrel with 30-40 µg oestrogen for each of the three serious adverse events. CONCLUSIONS: For the same dose of oestrogen, desogestrel and gestodene were associated with statistically significantly higher risks of pulmonary embolism but not arterial thromboembolism compared with levonorgestrel. For the same type of progestogen, an oestrogen dose of 20 µg versus 30-40 µg was associated with lower risks of pulmonary embolism, ischaemic stroke, and myocardial infarction.

Conditions of prescription of anti-TNF agents in newly treated patients with inflammatory bowel disease in France (2011-2013).

BACKGROUND: Tumour necrosis factor inhibitors (anti-TNFs) are active but expensive drugs that induce and maintain remission in patients with Crohn's disease (CD) and ulcerative colitis (UC). AIMS: To assess the trends in anti-TNF prescription and the conditions of prescription of these drugs in patients with inflammatory bowel disease (IBD) in France. METHODS: Incidence study of anti-TNF use was performed based on French medico-administrative databases (SNIIRAM/PMSI). IBD patients who initiated adalimumab or infliximab between 2011 and 2013 were selected. RESULTS: The number of new anti-TNF users increased from 4571 to 5875 between 2011 and 2013 (+29%). More specifically, the number of patients not treated with immunosuppressants (IS) during the previous 12 months increased from 2100 to 3007 (+43%), among whom 379 patients in 2011 and 570 patients in 2013 started combination therapy (+50%). These trends were observed for both CD and UC. Patients who were naïve of IS were hospitalised more frequently than those treated with IS prior to anti-TNF therapy. CONCLUSION: This study shows a rapid increase in new prescriptions of anti-TNF for both CD and UC in France between 2011 and 2013. These results suggest a change in medical practices, with anti-TNF agents prescribed more often as first-line maintenance treatment.

A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology.

Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility (Pcombined=3.32 × 10(-15), OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis-eQTL for CDKN2B, with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage (P=0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology.

Home paint exposures and risk of childhood acute lymphoblastic leukemia: findings from the Childhood Leukemia International Consortium.

PURPOSE: It has been suggested that home paint exposure increases the risk of childhood acute lymphoblastic leukemia (ALL). METHODS: We obtained individual level data from eight case-control studies participating in the Childhood Leukemia International Consortium. All studies had home paint exposure data (sometimes including lacquers and varnishes) for the pregnancy period with additional data for the 1-3-month period before conception in five, the year before conception in two, and the period after birth in four studies, respectively. Cytogenetic subtype data were available for some studies. Data were harmonized to a compatible format. Pooled analyses of individual data were undertaken using unconditional logistic regression. RESULTS: Based on 3,002 cases and 3,836 controls, the pooled odds ratio (OR) for home paint exposure in the 1-3 months before conception and risk of ALL was 1.54 [95% confidence interval (CI) 1.28, 1.85], while based on 1,160 cases and 1,641 controls for exposure in the year before conception, it was 1.00 (95% CI 0.86, 1.17). For exposure during pregnancy, using 4,382 cases and 5,747 controls, the pooled OR was 1.14 (95% CI 1.04, 1.25), and for exposure after birth, the OR was 1.22 (95% CI 1.07, 1.39), based on data from 1,962 cases and 2,973 controls. The risk was greater for certain cytogenetic subtypes and if someone other than the parents did the painting. CONCLUSIONS: Home paint exposure shortly before conception, during pregnancy, and/or after birth appeared to increase the risk of childhood ALL. It may be prudent to limit exposure during these periods.

Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium.

Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval [CI]: 1.25, 1.55) (using 2,785 cases and 3,635 controls), 1.43 (95% CI: 1.32, 1.54) (5,055 cases and 7,370 controls) and 1.36 (95% CI: 1.23, 1.51) (4,162 cases and 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49 (95% CI: 1.02, 2.16) (173 cases and 1,789 controls), 1.55 (95% CI: 1.21, 1.99) (344 cases and 4,666 controls) and 1.08 (95% CI: 0.76, 1.53) (198 cases and 2,655 controls), respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate the associations between home pesticide use and childhood leukemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood.

Childhood acute lymphoblastic leukemia and indicators of early immune stimulation: a Childhood Leukemia International Consortium study.

The associations between childhood acute lymphoblastic leukemia (ALL) and several proxies of early stimulation of the immune system, that is, day-care center attendance, birth order, maternally reported common infections in infancy, and breastfeeding, were investigated by using data from 11 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2010). The sample included 7,399 ALL cases and 11,181 controls aged 2-14 years. The data were collected by questionnaires administered to the parents. Pooled odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Day-care center attendance in the first year of life was associated with a reduced risk of ALL (odds ratio = 0.77, 95% confidence interval: 0.71, 0.84), with a marked inverse trend with earlier age at start (P < 0.0001). An inverse association was also observed with breastfeeding duration of 6 months or more (odds ratio = 0.86, 95% confidence interval: 0.79, 0.94). No significant relationship with a history of common infections in infancy was observed even though the odds ratio was less than 1 for more than 3 infections. The findings of this large pooled analysis reinforce the hypothesis that day-care center attendance in infancy and prolonged breastfeeding are associated with a decreased risk of ALL.