Publications by authors named "Ulrich Meinzer"

31 Publications

Acute monoarthritis in young children: comparing the characteristics of patients with juvenile idiopathic arthritis versus septic and undifferentiated arthritis.

Sci Rep 2021 Feb 9;11(1):3422. Epub 2021 Feb 9.

Department of General Pediatrics, Pediatric Internal Medicine, Rheumatology and Infectious Diseases, National Reference Centre for Rare Pediatric Inflammatory Rheumatisms and Systemic Autoimmune Diseases RAISE, Robert Debré University Hospital, Assistance Publique-Hôpitaux de Paris, 75019, Paris, France.

Acute arthritis is a common cause of consultation in pediatric emergency wards. Arthritis can be caused by juvenile idiopathic arthritis (JIA), septic (SA) or remain undetermined (UA). In young children, SA is mainly caused by Kingella kingae (KK), a hard to grow bacteria leading generally to a mild clinical and biological form of SA. An early accurate diagnosis between KK-SA and early-onset JIA is essential to provide appropriate treatment and follow-up. The aim of this work was to compare clinical and biological characteristics, length of hospital stays, duration of intravenous (IV) antibiotics exposure and use of invasive surgical management of patients under 6 years of age hospitalized for acute monoarthritis with a final diagnosis of JIA, SA or UA. We retrospectively analyzed data from < 6-year-old children, hospitalized at a French tertiary center for acute mono-arthritis, who underwent a joint aspiration. Non-parametric tests were performed to compare children with JIA, SA or UA. Bonferroni correction for multiple comparisons was applied with threshold for significance at 0.025. Among the 196 included patients, 110 (56.1%) had SA, 20 (10.2%) had JIA and 66 (33.7%) had UA. Patients with JIA were older when compared to SA (2.7 years [1.8-3.6] versus 1.4 [1.1-2.1], p < 0.001). Presence of fever was not different between JIA and SA or UA. White blood cells in serum were lower in JIA (11.2 × 10/L [10-13.6]) when compared to SA (13.2 × 10/L [11-16.6]), p = 0.01. In synovial fluid leucocytes were higher in SA 105.5 × 10 cells/mm [46-211] compared to JIA and UA (42 × 10 cells/mm [6.4-59.2] and 7.29 × 10 cells/mm [2.1-72] respectively), p < 0.001. Intravenous antibiotics were administered to 95% of children with JIA, 100% of patients with SA, and 95.4% of UA. Arthrotomy-lavage was performed in 66.7% of patients with JIA, 79.6% of patients with SA, and 71.1% of patients with UA. In children less than 6 years of age with acute mono-arthritis, the clinical and biological parameters currently used do not reliably differentiate between JIA, AS and UA. JIA subgroups that present a diagnostic problem at the onset of monoarthritis before the age of 6 years, are oligoarticular JIA and systemic JIA with hip arthritis. The development of new biomarkers will be required to distinguish JIA and AS caused by Kingella kingae in these patients.
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http://dx.doi.org/10.1038/s41598-021-82553-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873238PMC
February 2021

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

JAMA 2021 Mar;325(9):855-864

Assistance Publique-Hôpitaux de Paris, Paediatric Emergency Department, Necker-Enfants Malades University Hospital, Université de Paris, Paris, France.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown.

Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C.

Design, Setting, And Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021.

Exposures: IVIG and methylprednisolone vs IVIG alone.

Main Outcomes And Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1.

Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]).

Conclusions And Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.
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http://dx.doi.org/10.1001/jama.2021.0694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851757PMC
March 2021

Response to 'Correspondence on 'Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID19): a multicentre cohort'' by Mastrolia .

Ann Rheum Dis 2020 Oct 6. Epub 2020 Oct 6.

General Pediatrics, Infectious Disease and Internal Medicine Department, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Hôpital Robert Debre, AP-HP, Paris, 75019, France

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http://dx.doi.org/10.1136/annrheumdis-2020-218814DOI Listing
October 2020

Crohn's disease: is the cold chain hypothesis still hot?

J Crohns Colitis 2020 Sep 19. Epub 2020 Sep 19.

Centre de recherche sur l'inflammation, UMR1149 INSERM et Université de Paris, France.

Crohn's disease (CD) is an inflammatory bowel disease of unknown etiology. During the last decades, significant technological advances led to development of -omic datasets allowing a detailed description of the disease. Unfortunately, these have not, to date, resolved the question of the etiology of CD. Thus, it may be necessary to (re)consider hypothesis-driven approaches to resolve the etiology of CD. According to the cold chain hypothesis, the development of industrial and domestic refrigeration has led to frequent exposure of human populations to bacteria capable of growing in the cold. These bacteria, at low levels of exposure, particularly those of the genus Yersinia, are believed to be capable of inducing exacerbated inflammation of the intestine in genetically predisposed subjects. We discuss the consistency of this working hypothesis in light of recent data from epidemiological, clinical, pathological, microbiological and molecular studies.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa192DOI Listing
September 2020

Response to: 'Exaggerated neutrophil extracellular trap formation in Kawasaki disease: a key phenomenon behind the outbreak in western countries?' by Yamashita .

Ann Rheum Dis 2020 Aug 21. Epub 2020 Aug 21.

General Paediatrics, Department of Infectious Disease and Internal Medicine, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Robert Debré University Hospital, AP-HP, Paris, France

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http://dx.doi.org/10.1136/annrheumdis-2020-218644DOI Listing
August 2020

Phase II Open Label Study of Anakinra in Intravenous Immunoglobulin-Resistant Kawasaki Disease.

Arthritis Rheumatol 2021 Jan 17;73(1):151-161. Epub 2020 Nov 17.

AP-HP, University of Paris Saclay, Bicêtre Hospital, Paris, France.

Objective: Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)- and steroid-resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin-1 in patients with IVIG-resistant KD.

Methods: Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient's body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C-reactive protein (CRP) levels.

Results: Seventy-five percent of patients in the intention-to-treat group and 87.5% in the per-protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1-99.8%) of physician evaluations and on 100% (95% CI 73.5-100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7-81.3%]) and 6 of 12 patients (50% [95% CI 21.1-78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred.

Conclusion: Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG-refractory KD.
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http://dx.doi.org/10.1002/art.41481DOI Listing
January 2021

Response to: 'Correspondence on 'Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort' by Pouletty by Pino .

Ann Rheum Dis 2020 Aug 5. Epub 2020 Aug 5.

General Paediatrics, Department of Infectious Disease and Internal Medicine, Robert Debré University Hospital, AP-HP, Paris, France, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France

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http://dx.doi.org/10.1136/annrheumdis-2020-218614DOI Listing
August 2020

Child-Adult Transition in Sarcoidosis: A Series of 52 Patients.

J Clin Med 2020 Jul 3;9(7). Epub 2020 Jul 3.

AP-HP Pediatric Pulmonology Department and Reference Center for Rare Lung Diseases (RespiRare), Armand Trousseau Hospital, 75012 Paris, France.

(1) Background: Pediatric sarcoidosis is a rare and mostly severe disease. Very few pediatric series with a prolonged follow-up are reported. We aimed to evaluate the evolution of pediatric sarcoidosis in adulthood. (2) Material and methods: Patients over 18-years-old with a pediatric-onset sarcoidosis (≤15-year-old) who completed at least a three-year follow-up in French expert centers were included. Clinical information at presentation and outcome in adulthood were studied. (3) Results: A total of 52 patients were included (34 prospectively in childhood and 18 retrospectively in adulthood), with a mean age of 12 (±2.7) at diagnosis. The median duration time of follow-up was 11.5 years (range 3-44.5). Relapses mostly occurred during treatment decrease (84.5%), others within the three years after treatment interruption (9.1%), and rarely when the disease was stable for more than three years (6.4%). Sarcoidosis was severe in 11 (21.2%) in adulthood. Patients received a high corticosteroid cumulative dose (median 17,900 mg) for a median duration of five years (range 0-32), resulting in mostly mild (18; 35.3%) and rarely severe (2; 3.8%) adverse events. (4) Conclusions: Pediatric-onset sarcoidosis needed a long-term treatment in almost half of the patients. Around one fifth of pediatric-onset sarcoidosis patients had severe sarcoidosis consequences in adulthood.
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http://dx.doi.org/10.3390/jcm9072097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408766PMC
July 2020

Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of the French COVID-19 epidemic: a time-series analysis.

Lancet Child Adolesc Health 2020 09 2;4(9):662-668. Epub 2020 Jul 2.

Department of General Paediatrics, Paediatric Internal Medicine, Rheumatology and Infectious Diseases, National Referee Centre for Rheumatic, Autoimmune and Systemic Diseases in Children, Robert Debré University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Université de Paris, UFR de Médecine Paris Nord, Paris, France; Center for Research on Inflammation, INSERM, UMR1149, Paris, France; Biology and Genetics of Bacterial Cell Wall Unit, Pasteur Institute, Paris, France. Electronic address:

Background: Kawasaki disease is an acute febrile systemic childhood vasculitis, which is suspected to be triggered by respiratory viral infections. We aimed to examine whether the ongoing COVID-19 epidemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with an increase in the incidence of Kawasaki disease.

Methods: We did a quasi-experimental interrupted time series analysis over the past 15 years in a tertiary paediatric centre in the Paris region, a French epicentre of the COVID-19 outbreak. The main outcome was the number of Kawasaki disease cases over time, estimated by quasi-Poisson regression. In the same centre, we recorded the number of hospital admissions from the emergency department (2005-2020) and the results of nasopharyngeal multiplex PCR to identify respiratory pathogens (2017-2020). These data were compared with daily hospital admissions due to confirmed COVID-19 in the same region, recorded by Public Health France.

Findings: Between Dec 1, 2005, and May 20, 2020, we included 230 patients with Kawasaki disease. The median number of Kawasaki disease hospitalisations estimated by the quasi-Poisson model was 1·2 per month (IQR 1·1-1·3). In April, 2020, we identified a rapid increase of Kawasaki disease that was related to SARS-CoV-2 (six cases per month; 497% increase [95% CI 72-1082]; p=0·0011), starting 2 weeks after the peak of the COVID-19 epidemic. SARS-CoV-2 was the only virus circulating intensely during this period, and was found in eight (80%) of ten patients with Kawasaki disease since April 15 (SARS-CoV-2-positive PCR or serology). A second peak of hospital admissions due to Kawasaki disease was observed in December, 2009 (six cases per month; 365% increase ([31-719]; p=0.0053), concomitant with the influenza A H1N1 pandemic.

Interpretation: Our study further suggests that viral respiratory infections, including SAR-CoV-2, could be triggers for Kawasaki disease and indicates the potential timing of an increase in incidence of the disease in COVID-19 epidemics. Health-care providers should be prepared to manage an influx of patients with severe Kawasaki disease, particularly in countries where the peak of COVID-19 has recently been reached.

Funding: French National Research Agency.
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http://dx.doi.org/10.1016/S2352-4642(20)30175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332278PMC
September 2020

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort.

Ann Rheum Dis 2020 08 11;79(8):999-1006. Epub 2020 Jun 11.

General Paediatrics, Department of Infectious Disease and Internal Medicine, Reference centre for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Paris, France, Robert Debré University Hospital, AP-HP, Paris, France

Background: Current data suggest that COVID-19 is less frequent in children, with a milder course. However, over the past weeks, an increase in the number of children presenting to hospitals in the greater Paris region with a phenotype resembling Kawasaki disease (KD) has led to an alert by the French national health authorities.

Methods: Multicentre compilation of patients with KD in Paris region since April 2020, associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ('Kawa-COVID-19'). A historical cohort of 'classical' KD served as a comparator.

Results: Sixteen patients were included (sex ratio=1, median age 10 years IQR (4·7 to 12.5)). SARS-CoV-2 was detected in 12 cases (69%), while a further three cases had documented recent contact with a quantitative PCR-positive individual (19%). Cardiac involvement included myocarditis in 44% (n=7). Factors prognostic for the development of severe disease (ie, requiring intensive care, n=7) were age over 5 years and ferritinaemia >1400 µg/L. Only five patients (31%) were successfully treated with a single intravenous immunoglobulin (IVIg) infusion, while 10 patients (62%) required a second line of treatment. The Kawa-COVID-19 cohort differed from a comparator group of 'classical' KD by older age at onset 10 vs 2 years (p<0.0001), lower platelet count (188 vs 383 G/L (p<0.0001)), a higher rate of myocarditis 7/16 vs 3/220 (p=0.0001) and resistance to first IVIg treatment 10/16 vs 45/220 (p=0.004).

Conclusion: Kawa-COVID-19 likely represents a new systemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children. Further prospective international studies are necessary to confirm these findings and better understand the pathophysiology of Kawa-COVID-19. NCT02377245.
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http://dx.doi.org/10.1136/annrheumdis-2020-217960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299653PMC
August 2020

Clinical Characteristics of Acne Fulminans Associated With Chronic Nonbacterial Osteomyelitis in Pediatric Patients.

J Rheumatol 2020 12 1;47(12):1793-1799. Epub 2020 Apr 1.

A. Faye, MD, PhD, Department of General Pediatrics, Pediatric Infectious Diseases and Pediatric Rheumatology, Hôpital Robert Debré, AP-HP, National Reference Centre for Rare Pediatric Inflammatory Rheumatisms and Systemic Auto-immune diseases (RAISE), and Biology and Genetics of Bacterial Cell Wall Unit, Institut Pasteur, Paris.

Objective: Acne fulminans (AF) is a rare, explosive systemic form of acne. Chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is a primarily pediatric autoinflammatory disorder characterized by sterile osteolytic bone lesions. Concomitant occurrence of CNO/CRMO and AF is very rare, and little is known about the epidemiological and clinical particularities of this association. The aim of this retrospective observational study was to describe the characteristics of pediatric patients with CNO/CRMO associated to AF.

Methods: Electronic mailing lists of French medical societies were used to call for patients with CNO/CRMO and AF. A search for published patients with CNO/CRMO and AF was performed by screening PubMed.

Results: We identified 5 original patients and 10 patients from the literature. All patients were adolescent boys. Mean age at disease onset was 14.8 years. Nine of 15 patients had received isotretinoin before the sudden onset of AF. Osteoarticular symptoms appeared within < 1-3 months after the onset of AF. The mean numbers of clinical and radiological bone lesions were 3.6 and 5.6, respectively. The percentages of patients with involvement of vertebrae, pelvis, chest, and cranial were 40%, 40%, 33.3%, and 6.6%, respectively. Arthritis was observed in 69.2% of patients and sacroiliac arthritis in 46.2%.

Conclusion: CNO/CRMO associated to AF occurs predominantly in male adolescents and is characterized by frequent involvement of the axial skeleton and arthritis. Epidemiological and clinical features of these patients differ from general CNO/CRMO cohorts. Clinical management requires careful handling of isotretinoin doses.
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http://dx.doi.org/10.3899/jrheum.191232DOI Listing
December 2020

Camptodactlyly in Pediatric Practice: Blau Syndrome.

J Pediatr 2020 06 26;221:257-259. Epub 2020 Feb 26.

Department of General Pediatrics, Paediatric Internal Medicine, Rheumatology and Infectious Diseases, National Reference Centre for Rare Paediatric Inflammatory Rheumatisms and Systemic Auto-immune diseases RAISE, Robert Debré University Hospital, Assistance Publique-Hôpitaux de Paris; Université Paris Diderot-Sorbonne Paris-Cité, INSERM, UMR1149; Biology and Genetics of Bacterial Cell Wall Unit, Pasteur Institute, Paris, France.

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http://dx.doi.org/10.1016/j.jpeds.2020.01.057DOI Listing
June 2020

Defining the risk of first intravenous immunoglobulin unresponsiveness in non-Asian patients with Kawasaki disease.

Sci Rep 2020 02 20;10(1):3125. Epub 2020 Feb 20.

Université Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, Inserm, 1018, Le Kremlin Bicêtre, France.

About 10-20% of patients with Kawasaki disease (KD) are unresponsive to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations. We investigated the accuracy of 3 Japanese scoring systems and studied factors associated with IVIg unresponsiveness in a large multiethnic French population of children with KD to build a new scoring system. Children admitted for KD between 2011-2014 in 65 centers were enrolled. Factors associated with second line-treatment; i.e. unresponsiveness to initial IVIg treatment, were analyzed by multivariate regression analysis. The performance of our score and the Kobayashi, Egami and Sano scores were compared in our population and in ethnic subgroups. Overall, 465 children were reported by 84 physicians; 425 were classified with KD (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 14-61%). On multivariate regression analysis, predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count <2400/mm and time to treatment <5 days. The best sensitivity (77%) and specificity (60%) of this model was with 1 point per variable and cut-off ≥2 points. The sensitivity remained good in our 3 main ethnic subgroups (74-88%). We identified predictors of IVIg resistance and built a new score with good sensitivity and acceptable specificity in a non-Asian population.
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http://dx.doi.org/10.1038/s41598-020-59972-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033244PMC
February 2020

Persistent osteoarticular pain in children: early clinical and laboratory findings suggestive of acute lymphoblastic leukemia (a multicenter case-control study of 147 patients).

Pediatr Rheumatol Online J 2020 Jan 2;18(1). Epub 2020 Jan 2.

Unité d'Onco-Hémato-Immunologie pédiatrique, CHU Angers, 4 rue Larrey, 49933, Angers, France.

Background: The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with persistent bone or joint pain for at least 1 month.

Methods: We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups.

Results: Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 [95%CI: 30-793] (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 [95%CI: 11.4-236]), neutrophils < 2 × 10/L (regression coefficient: 3.9, OR 50 [95%CI: 4.3-58]), and platelets < 300 × 10/L (regression coefficient: 2.6, OR 14 [95%CI: 2.3-83.9]) were associated with the presence of ALL (area under the ROC curve: 0.96 [95%CI: 0.93-0.99]).

Conclusions: Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils < 2 × 10/L or platelets < 300 × 10/L.
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http://dx.doi.org/10.1186/s12969-019-0376-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941319PMC
January 2020

Predictors of Intravenous Immunoglobulin Nonresponse and Racial Disparities in Kawasaki Disease.

Pediatr Infect Dis J 2018 11;37(11):e279-e280

Service de pédiatrie générale, maladies infectieuses et médicine interne, Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l'enfant (RAISE), Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, Paris, France, Université Paris Diderot-Sorbonne Paris-Cité, Centre de recherche sur l'inflammation, Institut National de la Santé et de la Recherche Médicale, Paris, France Service de pédiatrie générale, maladies infectieuses et médicine interne, Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l'enfant (RAISE), Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, Paris, France, Université Paris Diderot-Sorbonne Paris-Cité, Centre de recherche sur l'inflammation, Institut National de la Santé et de la Recherche Médicale, Paris, France, Institut Pasteur, Unité biologie et génétique de la paroi bactérienne, Paris, France.

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http://dx.doi.org/10.1097/INF.0000000000002083DOI Listing
November 2018

Kawasaki disease: abnormal initial echocardiogram is associated with resistance to IV Ig and development of coronary artery lesions.

Pediatr Rheumatol Online J 2018 Jul 18;16(1):48. Epub 2018 Jul 18.

Service de pédiatrie générale, maladies infectieuses et médecine interne, Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l'enfant (RAISE), Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, 75019, Paris, France.

Background: Kawasaki disease (KD) is an acute febrile systemic vasculitis that affects small and medium blood vessels. Intensified treatments for the most severely affected patients have been proposed recently, and the early identification of KD patients at high risk for coronary artery aneurysms (CAA) is crucial. However, the risk scoring systems developed in Japan have not been validated in European populations, and little data is available concerning the link between initial echocardiogram findings other than high z-scores and cardiac prognosis.

Methods: In order to investigate whether the presence of any abnormalities, other than high z-scores in first echocardiogram, are associated with resistance to IV immunoglobulins and/or subsequent development of CAA, we retrospectively analyzed data from children diagnosed with KD between 2006 and 2016 at a tertiary Hospital in Paris, France.

Results: A total of 157 children were included. The initial echocardiogram was performed after a median of 7 days of fever and was abnormal in 48 cases (31%). The initial presence of any echocardiographic abnormality (coronary artery dilatation, CAA, pericardial effusion, perivascular brightness of the coronary arteries, left-ventricular dysfunction and mitral insufficiency) was strongly associated with resistance to intravenous immunoglobulin (p = 0.005) and development of coronary artery lesions within the first 6 weeks of disease (p = 0.01). All patients (n = 7) with persistent coronary abnormalities at 1 year already had an abnormal initial echocardiogram. Severity scoring systems from Japan had low sensitivity (0-33%) and low specificity (71-82%) for predicting immunoglobulin resistance or cardiac involvement.

Conclusions: In European populations with mixed ethnic backgrounds, the presence of any abnormalities at the initial echocardiogram may contribute to early identification of patients with severe disease.
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http://dx.doi.org/10.1186/s12969-018-0264-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052519PMC
July 2018

Early Arthritis Is Associated With Failure of Immunosuppressive Drugs and Severe Pediatric Crohn's Disease Evolution.

Inflamm Bowel Dis 2018 10;24(11):2423-2430

Université Paris Diderot, INSERM UMR1149, Paris, France.

Background: Crohn's disease (CD) is a chronic relapsing inflammatory disease. To optimize therapeutic decision making, it is essential to identify parameters that allow early prediction of a severe disease course. The aim of this study was to assess the link between arthritis and medium-term therapeutic failure in pediatric CD.

Methods: We conducted a population-based cohort study with prospectively collected electronic data. To be included, patients must be younger than 17 years and have a confirmed CD diagnosed between 2005 and 2014. The primary outcome was the percentage of patients with at least 1 therapeutic failure of immunosuppressive drugs during the 2 years after the CD diagnosis, with a propensity score analysis.

Results: We included 272 patients with CD. The median age was 12.1 years (interquartile [10.1-14.2]). Sixty-five patients (23.9%) developed arthritis, which predominantly occurred during the first year after CD diagnosis. We found a highly significant association between arthritis and therapeutic failure of immunosuppressive drugs after 2 years (OR = 6.9; 95% confidence interval [CI], 2.7-18.0; P < 0.0001; propensity score matching analysis). Arthritis was also significantly associated with introduction of biotherapy due to luminal disease 2 years after diagnosis (OR = 3.2, 95% CI, 1.8-6.0; P = 0.0001). Similar results were obtained after 4 years, and arthritis was significantly associated with a higher number of hospitalizations for luminal flare-up or complications after 4 years (OR = 2.2; 95% CI, 1.2-3.9; P = 0.007).

Conclusions: Arthritis was strongly associated with medium-term therapeutic failure of pediatric CD. Occurrence of arthritis early in the disease may justify closer follow-up visits or specific therapeutic management.
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http://dx.doi.org/10.1093/ibd/izy137DOI Listing
October 2018

Familial and syndromic lupus share the same phenotype as other early-onset forms of lupus.

Joint Bone Spine 2017 Oct 28;84(5):589-593. Epub 2016 Dec 28.

Immunologie et rhumatologie pédiatrique, Hôpital Necker, APHP, 75015 Paris, France. Electronic address:

Objective: Studies of early-onset systemic lupus erythematosus (SLE) have identified monogenic forms of the disease. The primary objective of this study was to compare the clinical and laboratory features of the first patients included in the GENIAL/LUMUGENE cohort to those reported in previous publications. The secondary objective was to determine whether subgroups with a distinctive pattern of clinical and biological features are seen in predominantly genetic forms of SLE.

Methods: GENIAL/LUMUGENE is a French nationwide study of the clinical, immunological, and genetic features of juvenile-onset SLE (clinicaltrials.gov #NCT01992666). Clinical and laboratory data from the first 64 patients younger than 18 years who were included in the first part of the study were collected retrospectively. Predefined criteria were used to divide the patients into three subgroups: syndromic SLE (n=10) and familial SLE (n=12) - both presumed to have a strong genetic component - and other forms of early-onset SLE (n=42).

Results: The predefined criteria for identifying subgroups based on knowledge of the clinical and epidemiological features of monogenic SLE showed a significantly younger age at onset in syndromic SLE (P<0.05) and a lower frequency of joint manifestations in familial SLE.

Conclusions: In this study, clinical and epidemiological data alone failed to identify a specific patient subgroup characterized by the same disease presentation or progression. This result may be related to the small sample size or indicate marked heterogeneity of juvenile-onset SLE. Genetic studies using new sequencing techniques in these patients might identify genetic factors responsible for marked phenotypic variability.
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http://dx.doi.org/10.1016/j.jbspin.2016.12.008DOI Listing
October 2017

Treatment of Erdheim-Chester disease with canakinumab.

Rheumatology (Oxford) 2014 Dec 17;53(12):2312-4. Epub 2014 Sep 17.

Department of Pediatrics, Nîmes University Hospital, Nîmes, INSERM U 844, University of Montpelier 1, Montpellier, Department of Pediatric Radiology, Department of Pediatrics, Assistance Publique Hôpitaux de Paris, Bicêtre University Hospital, Le Kremlin Bicêtre, University of Poitiers, Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC) Poitiers, Laboratory of Genetics, Rare and Autoinflammatory Diseases, Department of Genetics, LBM - Montpellier University Hospital, INSERM U844, Montpellier and Department of General Pediatrics and Internal Medicine, Assistance Publique Hôpitaux de Paris, Robert Debré University Hospital, University of Paris, Paris, France.

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http://dx.doi.org/10.1093/rheumatology/keu344DOI Listing
December 2014

Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection.

J Infect Dis 2015 Apr 23;211(8):1241-50. Epub 2014 Jul 23.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163 Paris Descartes University-Sorbonne Paris Cité, Imagine Institute.

Background: Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa.

Methods: We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy.

Results: We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele.

Conclusions: These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.
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http://dx.doi.org/10.1093/infdis/jiu412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447834PMC
April 2015

Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency.

Rheumatology (Oxford) 2012 Oct 26;51(10):1855-9. Epub 2012 Jun 26.

Department of Pediatrics and Pediatric Rheumatology, National Referral Centre of Auto-inflammatory Diseases, CEREMAI, CHU Bicêtre, Assistance Publique Hôpitaux de Paris, University of Paris Sud, Le Kremlin Bicêtre, , France.

Objective: To describe the efficacy and safety of IL-1-targeting drugs, anakinra and canakinumab, in patients with mevalonate kinase deficiency (MKD).

Methods: A questionnaire was sent to French paediatric and adult rheumatologists to retrospectively collect information on disease activity before and after treatment with IL-1 antagonists from genetically confirmed MKD patients. We assessed the frequency of crises and their intensity using a 12-item clinical score built for the purpose of the study.

Results: Eleven patients were included. Anti-IL-1-targeting drugs were used continuously in all but one patient who received anakinra on demand. Daily anakinra (nine patients) or canakinumab injections every 4-8 weeks (six patients, in four cases following anakinra treatment) were associated with complete remission in four cases and partial remission in seven. The median score during MKD attacks decreased from 7/12 before treatment to 3/12 after anakinra and 1/12 after canakinumab. The number of days with fever during attacks decreased from 5 before treatment to 3 after anakinra and 2 after canakinumab. Marked decrease of C-reactive protein and serum amyloid A protein were recorded. Side effects were mild or moderate; they consisted of local pain and inflammation at injection site, infections and hepatic cytolysis.

Conclusion: Continuous IL-1 blockade brings substantial benefit to MKD patients. Controlled trials are necessary to further assess the clinical benefit and treatment modalities in these patients.
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http://dx.doi.org/10.1093/rheumatology/kes097DOI Listing
October 2012

Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling.

J Clin Invest 2012 Jun 8;122(6):2239-51. Epub 2012 May 8.

Université Paris-Diderot, UMR843, Paris, France.

Intestinal barrier function requires intricate cooperation between intestinal epithelial cells and immune cells. Enteropathogens are able to invade the intestinal lymphoid tissue known as Peyer's patches (PPs) and disrupt the integrity of the intestinal barrier. However, the underlying molecular mechanisms of this process are poorly understood. In mice infected with Yersinia pseudotuberculosis, we found that PP barrier dysfunction is dependent on the Yersinia virulence plasmid and the expression of TLR-2 by hematopoietic cells, but not by intestinal epithelial cells. Upon TLR-2 stimulation, Y. pseudotuberculosis-infected monocytes activated caspase-1 and produced IL-1β. In turn, IL-1β increased NF-κB and myosin light chain kinase activation in intestinal epithelial cells, thus disrupting the intestinal barrier by opening the tight junctions. Therefore, Y. pseudotuberculosis subverts intestinal barrier function by altering the interplay between immune and epithelial cells during infection.
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http://dx.doi.org/10.1172/JCI58147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366397PMC
June 2012

Yersinia pseudotuberculosis effector YopJ subverts the Nod2/RICK/TAK1 pathway and activates caspase-1 to induce intestinal barrier dysfunction.

Cell Host Microbe 2012 Apr;11(4):337-51

Université Paris-Diderot, Paris, France.

Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJ(C172A), acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1β. Finally, IL-1β within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response.
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http://dx.doi.org/10.1016/j.chom.2012.02.009DOI Listing
April 2012

Muckle-Wells syndrome and male hypofertility: a case series.

Semin Arthritis Rheum 2012 Dec 17;42(3):327-31. Epub 2012 Apr 17.

Department of Pediatrics, Pediatric Rheumatology, Reference Center for AutoInflammatory Diseases CEREMAI, Bicêtre Hospital, Assistance Publique des Hôpitaux de Paris, Université Paris Sud, Le Kremlin-Bicêtre, France.

Objectives: Muckle-Wells syndrome (MWS) is a rare autoinflammatory disorder associated with NLRP3 gene mutations, which cause excessive caspase-1 activation and processing of interleukin (IL)-1β and IL-18. Here we investigated whether MWS disease may be associated with impaired fertility in male patients.

Methods: Medical records of all male MWS patients with NLRP3 mutations followed in our tertiary center for inherited autoinflammatory diseases were reviewed retrospectively for data indicating fertility problems.

Results: Six of 9 patients were unable to have children despite regular sexual activity during at least 2 years; 3 succeeded in having children through in vitro fertilization. Infertility was the main reason for divorce in 1 patient. Spermiogram analyses were available in 8 of the 9 patients. Oligozoospermia was observed in 5 patients and azoospermia in 3 patients. In 2 patients, treatment with IL-1-targeting drugs for 6 and 12 months, respectively, had a moderate or no effect on spermatozoa counts. In 2 patients testosterone levels were low and testosterone treatment significantly increased spermatozoa counts in 1 of them.

Conclusions: MWS may be associated with subfertility and infertility in male patients. Consequently, sexual health and fertility should be assessed systematically in adolescent and adult male patients. Additional studies are required to establish the frequency of subfertility in male MWS patients, to understand when subfertility occurs in the disease natural history, and, finally, to investigate whether early management with IL-1-targeting drugs, or testosterone treatment or early sperm cryo-conservation may help to allow procreation.
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http://dx.doi.org/10.1016/j.semarthrit.2012.03.005DOI Listing
December 2012

Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature.

Semin Arthritis Rheum 2011 Oct 1;41(2):265-71. Epub 2011 Feb 1.

Division of Paediatric Rheumatology, CEREMAI, Hôpital de Bicêtre, University of Paris Sud, Le Kremlin Bicêtre Cedex, France.

Objectives: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disorder common in Mediterranean populations. FMF is associated with mutations of the MEFV gene, which encodes pyrin. Functional studies suggest that pyrin is implicated in the maturation and secretion of IL-1. The IL-1 receptor antagonist or anti-IL1 monoclonal antibody may therefore represent a new approach to treat FMF. The aim of this report was to evaluate and discuss treatment of FMF with interleukin-1 targeting drugs.

Methods: Electronic mailing lists of French pediatric and adult rheumatologist associations were used to call for FMF patients treated with interleukin-1 antagonists. A search for published FMF patients treated with interleukin-1 targeting drugs was performed by screening PubMed.

Results: Here, we report 7 cases of FMF patients treated with anakinra and/or canakinumab and discuss the clinical situations that may indicate the use of IL-1 blocking agents in FMF. The use of interleukin-1 targeting drugs was beneficial to all patients. The reasons for using interleukin-1 targeting drugs in FMF patients were as follows: (1) incomplete control of disease activity despite colchicine treatment; (2) high serum amyloid A levels despite colchicine treatment; (3) impossibility to use colchicine treatment because of severe side effects; (4) FMF in association with vasculitis.

Conclusions: Interleukin-1 targeting drugs may be good candidates when looking for an alternative or supplementary treatment to colchicine. These observations highlight the need for controlled trials to further evaluate the safety and efficacy of interleukin-1 antagonists in FMF patients.
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http://dx.doi.org/10.1016/j.semarthrit.2010.11.003DOI Listing
October 2011

Nod2 regulates the host response towards microflora by modulating T cell function and epithelial permeability in mouse Peyer's patches.

Gut 2010 Feb 15;59(2):207-17. Epub 2009 Oct 15.

INSERM, U843, Paris, France.

Nucleotide oligomerisation domain 2 (NOD2) mutations are associated with susceptibility to Crohn's disease and graft-versus-host disease, two human disorders related with dysfunctions of Peyer's patches (PPs). In Nod2(-/-) mice transcellular permeability and bacterial translocation are increased in PPs. In this study, we show that both anti-CD4(+) and anti-interferon gamma (anti-IFNgamma) monoclonal antibodies abrogate this phenotype and reduce the expression of tumour necrosis factor (TNF) receptor 2 and the long isoform of myosin light chain kinase, thus demonstrating that immune T cells influence the epithelial functions. In turn, intraperitoneal injection of ML-7 (a myosin light chain kinase inhibitor) normalises the values of CD4(+) T cells, IFNgamma and TNFalpha. This reciprocal cross-talk is under the control of the gut microflora as shown by the normalisation of all parameters after antibiotic treatment. Toll-like receptor 2 (TLR2) and TLR4 expression were increased in Nod2(-/-) mice under basal conditions and TLR2 and TLR4 agonists induced an increased transcellular permeability in Nod2(+/+) mice. Muramyldipeptide (a Nod2 agonist) or ML-7 was able to reverse this phenomenon. It thus appears that Nod2 modulates the cross-talk between CD4(+) T cells and the epithelium recovering PP and that it downregulates the pro-inflammatory effect driven by the ileal microflora, likely by inhibiting the TLR pathways.
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http://dx.doi.org/10.1136/gut.2008.171546DOI Listing
February 2010

Crohn's disease and early exposure to domestic refrigeration.

PLoS One 2009 29;4(1):e4288. Epub 2009 Jan 29.

Digestive Disease Research Center, Medical Sciences, University of Tehran, Tehran, Iran.

Background: Environmental risk factors playing a causative role in Crohn's Disease (CD) remain largely unknown. Recently, it has been suggested that refrigerated food could be involved in disease development. We thus conducted a pilot case control study to explore the association of CD with the exposure to domestic refrigeration in childhood.

Methodology/principal Findings: Using a standard questionnaire we interviewed 199 CD cases and 207 age-matched patients with irritable bowel syndrome (IBS) as controls. Cases and controls were followed by the same gastroenterologists of tertiary referral clinics in Tehran, Iran. The questionnaire focused on the date of the first acquisition of home refrigerator and freezer. Data were analysed by a multivariate logistic model. The current age was in average 34 years in CD cases and the percentage of females in the case and control groups were respectively 48.3% and 63.7%. Patients were exposed earlier than controls to the refrigerator (X2 = 9.9, df = 3, P = 0.04) and refrigerator exposure at birth was found to be a risk factor for CD (OR = 2.08 (95% CI: 1.01-4.29), P = 0.05). Comparable results were obtained looking for the exposure to freezer at home. Finally, among the other recorded items reflecting the hygiene and comfort at home, we also found personal television, car and washing machine associated with CD.

Conclusion: This study supports the opinion that CD is associated with exposure to domestic refrigeration, among other household factors, during childhood.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004288PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629547PMC
May 2009

Nod2 mediates susceptibility to Yersinia pseudotuberculosis in mice.

PLoS One 2008 Jul 23;3(7):e2769. Epub 2008 Jul 23.

INSERM, U843, Université Paris 7, Hôpital Robert Debré, Paris, France.

Nucleotide oligomerisation domain 2 (NOD2) is a component of the innate immunity known to be involved in the homeostasis of Peyer patches (PPs) in mice. However, little is known about its role during gut infection in vivo. Yersinia pseudotuberculosis is an enteropathogen causing gastroenteritis, adenolymphitis and septicaemia which is able to invade its host through PPs. We investigated the role of Nod2 during Y. pseudotuberculosis infection. Death was delayed in Nod2 deleted and Crohn's disease associated Nod2 mutated mice orogastrically inoculated with Y. pseudotuberculosis. In PPs, the local immune response was characterized by a higher KC level and a more intense infiltration by neutrophils and macrophages. The apoptotic and bacterial cell counts were decreased. Finally, Nod2 deleted mice had a lower systemic bacterial dissemination and less damage of the haematopoeitic organs. This resistance phenotype was lost in case of intraperitoneal infection. We concluded that Nod2 contributes to the susceptibility to Y. pseudotuberculosis in mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002769PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447872PMC
July 2008

CARD15/NOD2 is required for Peyer's patches homeostasis in mice.

PLoS One 2007 Jun 13;2(6):e523. Epub 2007 Jun 13.

U843, INSERM, Paris, France; UMR-S843, Université Paris Diderot, Paris, France.

Background: CARD15/NOD2 mutations are associated with susceptibility to Crohn's Disease (CD) and Graft Versus Host Disease (GVHD). CD and GVHD are suspected to be related with the dysfunction of Peyer's patches (PP) and isolated lymphoid follicles (LFs). Using a new mouse model invalidated for Card15/Nod2 (KO), we thus analysed the impact of the gene in these lymphoid formations together with the development of experimental colitis.

Methodology/principal Findings: At weeks 4, 12 and 52, the numbers of PPs and LFs were higher in KO mice while no difference was observed at birth. At weeks 4 and 12, the size and cellular composition of PPs were analysed by flow cytometry and immunohistochemistry. PPs of KO mice were larger with an increased proportion of M cells and CD4(+) T-cells. KO mice were also characterised by higher concentrations of TNFalpha, IFNgamma, IL12 and IL4 measured by ELISA. In contrast, little differences were found in the PP-free ileum and the spleen of KO mice. By using chamber experiments, we found that this PP phenotype is associated with an increased of both paracellular permeability and yeast/bacterial translocation. Finally, KO mice were more susceptible to the colitis induced by TNBS.

Conclusions: Card15/Nod2 deficiency induces an abnormal development and function of the PPs characterised by an exaggerated immune response and an increased permeability. These observations provide a comprehensive link between the molecular defect and the Human CARD15/NOD2 associated disorders: CD and GVHD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1885825PMC
June 2007

Ileal involvement is age dependent in pediatric Crohn's disease.

Inflamm Bowel Dis 2005 Jul;11(7):639-44

Department of Paediatric Gastroenterology, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, Paris, France.

Background: Lymphoid follicles (LFs) have been suggested to play a role at the early stage of Crohn's disease (CD) lesions. In the small bowel, LFs are grouped, forming Peyer's patches, which develop early in fetal life, grow in size and number until puberty, and undergo involution. In contrast, colonic LFs are isolated and undergo little change during life. As a result, if LFs play a role in the occurrence of CD lesions, the distribution of ileal and colonic lesions is expected to be altered in small children.

Methods: Medical records of 2 independent French (n = 136) and Swedish (n = 55) cohorts of consecutive pediatric CD were reviewed. Disease sites and age of onset were recorded, and the age-dependent probability to develop ileal lesions was computed. The CARD15/NOD2 genotype was also analyzed when available (n = 99).

Results: The curves of disease occurrence were significantly different in case of CD with or without ileal lesions (P < 0.0001). At the age of 8 years, the probability (95% confidence interval) of small bowel involvement was 0.19 (0.07-0.39). It increased until 16 years of age to 0.61 (0.54-0.68). It was slightly higher in patients carrying 1 or more CARD15/NOD2 mutations [0.75 (0.55-0.89)] than in wild-type patients [0.46 (0.34-0.58)]. CARD15 mutations also influenced the age of onset of ileal disease (P < 0.02).

Conclusions: In children, ileal CD lesions are delayed compared with colonic lesions. This observation is in agreement with the previously proposed hypothesis of a pathophysiological role of Peyer's patches in ileal CD. The rarity of small bowel lesions should be a warning to be cautious when classifying chronic colitis in small children.
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http://dx.doi.org/10.1097/01.mib.0000165114.10687.bfDOI Listing
July 2005