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ABSTRACT: Germline mutations in the SLC29A3 gene result in a range of recessive, clinically related syndromes: H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome, Faisalabad histiocytosis, and sinus histiocytosis with massive lymphadenopathy. The main symptoms of these diseases are hyperpigmentation with hypertrichosis, sensorineural deafness, diabetes, short stature, uveitis, and Rosai-Dorfman like histiocytosis. Here, we report the case of an 11-month-old boy with early-onset, recurrent episodes of unprovoked fever lasting 7 to 10 days and associated with pericardial effusion, abdominal pain, diarrhea, and inflammation. Physical examination revealed hyperpigmentation with hypertrichosis, dysmorphic features, and spleen and liver enlargement. Failure to thrive, sensorineural deafness, retarded psychomotor development, and a Rosai-Dorfman like cheek lesion developed subsequently. The febrile episodes did not respond to tumor necrosis factor α antagonists and interleukin-1. Sequencing of the SLC29A3 gene revealed a homozygous missense mutation c.1088G>A (p.Arg363Gln). These observations suggest that a newly identified mutation in the SLC29A3 gene may be associated with an autoinflammatory disorder. Genetic defects in SLC29A3 should be considered in patients with autoinflammatory manifestations, recurrent febrile attacks, and 1 or more of the symptoms found in the broad spectrum of SLC29A3-related disorders (especially hyperpigmentation with hypertrichosis).
PEDIATRICS 03/2013; · 4.47 Impact Factor
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Marie-Olivia Chandesris,
Isabelle Melki,
Angels Natividad,
Anne Puel,
Claire Fieschi,
Ling Yun,
Caroline Thumerelle,
Eric Oksenhendler,
David Boutboul,
Caroline Thomas, [......],
Monique Forveille,
Marie-Alexandra Alyanakian,
Anne Durandy,
Christine Bodemer,
Felipe Suarez,
Olivier Hermine,
Olivier Lortholary,
Jean-Laurent Casanova,
Alain Fischer,
Capucine Picard
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ABSTRACT: Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.
Medicine 06/2012; 91(4):e1-19. · 4.35 Impact Factor
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ABSTRACT: 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.
Rheumatology (Oxford, England) 06/2012; 51(10):1855-9. · 4.24 Impact Factor
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Bertrand Isidor,
Sylvaine Poignant,
Georges Picherot,
André Mégabarné,
Pierre Quartier, Brigitte Bader-Meunier,
Cédric Le Caignec,
Martine Le Merrer,
Geneviève Baujat,
Valérie Cormier-Daire,
Albert David
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ABSTRACT: Juvenile idiopathic arthritis is an inflammatory disease with various onset-forms which can sometimes be difficult to distinguish from genetic inflammatory/rheumatoid-like osteoarthropathies. In this report, we describe two boys with severe chronic arthralgia, stiffness and swelling of joints, motor weakness and joints contractures evolving despite immunosuppressive treatments and for whom all biological and molecular exams failed to identify a prompt diagnosis. Some findings also overlap with pseudorheumatoid dysplasia but WISP3 gene molecular analysis failed to identify any mutation for both patients. Therefore, we propose that these boys show a clinical entity distinct from the actually known genetic inflammatory/rheumatoid-like osteoarthropathies.
American Journal of Medical Genetics Part A 06/2012; 158A(7):1754-8. · 2.39 Impact Factor
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Virginie Gandemer,
Sylvie Chevret,
Arnaud Petit,
Christiane Vermylen,
Thierry Leblanc,
Gerard Michel,
Claudine Schmitt,
Odile Lejars,
Pascale Schneider,
Francois Demeocq, Brigitte Bader-Meunier,
Francoise Bernaudin,
Yves Perel,
Marie-Francoise Auclerc,
Jean-Michel Cayuela,
Guy Leverger,
Andre Baruchel
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ABSTRACT: Purpose. The prognosis of relapses of ETV6/RUNX1-positive acute lymphoblastic leukemia remains to be evaluated, particularly with regards to the frequency of late relapses. We performed a long term follow-up a retrospective study to address the outcome of ETV6/RUNX1-positive leukemia relapses.Design and Method. Among the 713 children tested for ETV6/RUNX1 enrolled into the FRALLE 93 protocol, 43 ETV6/RUNX1-positive patients relapsed (19.4%). Most were initially stratified as low or intermediate risk groups. Median follow-up after relapse was 54.2 months. All but three received a second-line salvage therapy and 16 underwent an allogeneic transplantation.Results. ETV6/RUNX1 greatly impacted on overall survival after relapse (3 year-survival= 64.7 % for positive versus 46.5 % for negative cases) (p= 0.007). The 5-year cumulative incidence of relapse was 19.4% and testes were more frequently involved in ETV6/RUNX1-positive relapses (p=0.04). 81.4 % were late relapses, early combined or isolated extramedullar relapses. The 5-year survival rate of ETV6-RUNX1-positive acute lymphoblastic leukemia relapses reached 80.6% when relapse occurred after 36 months (vs 34.9%). In univariate analysis, female gender was associated with a poor survival, whereas site of relapse, age at diagnosis, leukocytosis and consolidation strategy had no effect. In multivariate analysis, only the duration of first remission remained associated with outcome.Conclusions. We found an excellent outcome for ETV6/RUNX1-positive leukemia relapses occurring over 36 months post-diagnosis. Duration of first complete remission may thus be a guide to define the treatment strategy of ETV6/RUNX1-positive leukemia relapse.
Haematologica 05/2012; · 6.42 Impact Factor
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Carl E I Janssen,
Carlos D Rose,
Gert De Hertogh,
Tammy M Martin, Brigitte Bader Meunier,
Rolando Cimaz,
Miroslav Harjacek,
Pierre Quartier,
Rebecca Ten Cate,
Caroline Thomee,
Valeer J Desmet,
Alain Fischer,
Tania Roskams,
Carine H Wouters
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ABSTRACT: Blau syndrome (BS) and Crohn disease (CD) are both characterized by granulomatous inflammation and related to nucleotide oligomerization domain 2 (NOD2) mutations.
This study aimed to define the morphologic and immunohistochemical characteristics of granulomas in patients with NOD2-related BS and CD.
Granuloma-containing biopsy specimens from 6 patients with BS and 7 pediatric patients with CD carrying NOD2 mutations or single nucleotide polymorphisms were studied for morphology, cellular composition, and cytokine expression by using hematoxylin and eosin staining and immunohistochemistry.
Biopsy specimens from patients with BS typically showed polycyclic granulomas with large lymphocytic coronas, extensive emperipolesis of lymphocytes within multinucleated giant cells (MGCs), MGC death, and fibrinoid necrosis and fibrosis. In contrast, biopsy specimens from patients with CD showed simple granulomas with subtle/absent lymphocytic coronas, sclerosis of the surrounding tissue, and polymorphonuclear cells. Findings found to be similar in all granulomas were as follows: CD68 and HLA-DR expression by epithelioid cells, monocyte-macrophage lineage cells and MGCs, increased lymphocytic HLA-DR expression, increased CD4(+)/CD8(+) T-cell ratio, and CD20(+) B lymphocytes evenly distributed within and around granulomas. In both patient groups prominent IFN-γ expression was found in and around granulomas, and TNF-α and IL-23 receptor expression was moderate. IL-6, IL-17, and TGF-β expression was prominent in granulomas from patients with BS but sporadic in granulomas from patients with CD. IL-10 expression was absent.
Granulomas from patients with BS and granulomas from patients with NOD2-associated CD show distinct morphologic features and cytokine expression patterns, suggesting that the T(H)17 axis might be involved in the pathogenesis of BS, whereas T(H)1 is important in both patients with BS and patients with CD.
The Journal of allergy and clinical immunology 04/2012; 129(4):1076-84. · 9.17 Impact Factor
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Marite Rygg,
Angela Pistorio,
Angelo Ravelli,
Mohamad Maghnie,
Natascia Di Iorgi, Brigitte Bader-Meunier,
Carlos Da Silva,
Rosa Roldan-Molina,
Judith Barash,
Cristina Dracou,
Sylvie Gandon Laloum,
Katerina Jarosova,
Chantal Job Deslandre,
Isabelle Koné-Paut,
Franco Garofalo,
Joseph Press,
Claudia Sengler,
Tsivia Tauber,
Alberto Martini,
Nicolino Ruperto
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ABSTRACT: To obtain longitudinal data on growth/puberty in a large-scale, multi-national prospective cohort of juvenile systemic lupus erythematosus (SLE).
Data from 331/557 (59.4%) patients ≤18 years old with juvenile SLE in active phase, with anthropometric data available at four follow-up visits, were studied.
There was a significant reduction in parent-adjusted height z score with time in females and males (p<0.0001), with a significant gender difference (p<0.0001) and with male height being most affected. Median body mass index z score peaked at 6 months and was still significantly above baseline after 26 months (p<0.01), with no gender difference. Standardised height reduction was inversely related to age at onset. Females with onset age <12 years had a median parent-adjusted height z score of -0.87 with no catch-up growth. At the end of the study, growth failure was seen in 14.7% of the females and 24.5% of the males. Height deflection (less than -0.25/year) was found in 20.7% of the females and 45.5% of the males. Delayed pubertal onset was seen in 15.3% and 24% of the females and males, respectively, and delayed/absent menarche was seen in 21.9%, while 36.1% of the females and 44% of the males had some degree of delayed pubertal development. Growth failure baseline determinants were previous growth failure (OR: 56.6), age at first visit ≤13.4 years (OR: 4.2) and cumulative steroid dose >426 mg/kg (OR: 3.6).
The children at risk of having a negative effect on height and pubertal development are prepubertal and peripubertal children treated with >400 mg/kg cumulative dose of corticosteroids.
Annals of the rheumatic diseases 04/2012; 71(4):511-7. · 8.11 Impact Factor
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ABSTRACT: To investigate the functional status of difficult-to-treat JIA patients, including patients receiving biotherapies, and to correlate functional status to disease activity.
All JIA patients consecutively evaluated in a paediatric rheumatology referral centre (November 2008 to March 2009) were enrolled in an observational cross-sectional study. The Childhood HAQ (CHAQ), physician's assessment of overall disease activity, parent's assessment of well-being and pain, and active and limited joint numbers were measured.
We enrolled 95 patients [27% systemic, 29% polyarticular, 22% enthesitis-related arthritis (ERA) and 23% oligoarticular JIA]. Median disease duration was 3.5 years. Treatment included NSAIDs (56%), MTX (23%), CSs (21%) and biologics (45%). Of all patients, 31 and 56%, respectively, had inactive and minimally active disease. The median CHAQ score was 0.375 (range 0-3). Most patients had no or mild functional disability (61%), impaired well-being (63%) or pain (55%); 10% reported severely impaired function and well-being, 19% severe pain. ERA patients reported worse well-being and pain. CHAQ scores correlated with disease activity. Long-lasting disease and biologic treatment were associated with better well-being and pain scores.
Despite the high proportion of severe JIA patients in this cohort, CHAQ values are within the lower range of recent reports, probably related to new therapeutic approaches. Impaired function and well-being remain a challenge for at least 10% of the patients. Impaired well-being and pain in ERA patients require further study. The strong correlation between functional status and well-being underlines the importance of improving function to optimize quality of life.
Rheumatology (Oxford, England) 03/2012; 51(7):1285-92. · 4.24 Impact Factor
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ABSTRACT: Juvenile dermatomyositis is a rare systemic vasculopathy that may sometimes present with acute complications. We report here the case of a 7-year-old boy with severe dermatomyositis associated with thrombocytopenia and blurry vision. The presence of schistocytosis and the secondary occurrence of hemolytic anemia were consistent with a diagnosis of thrombotic thrombocytopenic purpura (TTP). Further investigations demonstrated the association of TTP with muscular microangiopathy and Purtscher-like retinopathy. Retinal and hematologic involvements dramatically improved after the initiation of plasma exchange in emergency. This report emphasizes that early recognition of TTP and prompt plasmapheresis are important in a child with severe juvenile dermatomyositis associated with thrombocytopenia.
PEDIATRICS 03/2012; 129(3):e821-4. · 4.47 Impact Factor
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ABSTRACT: Systemic-onset juvenile idiopathic arthritis is an inflammatory disease of unknown cause and is not commonly associated with kidney involvement. We describe 3 patients with systemic-onset juvenile idiopathic arthritis with high disease activity who developed antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis 1-6 years after the onset of systemic-onset juvenile idiopathic arthritis. Renal and systemic-onset juvenile idiopathic arthritis remission occurred in one patient under anti-interleukin 1 (anti-IL-1) treatment associated with immunosuppressive drugs. The other 2 patients developed end-stage renal disease, and one of those patients died. This report suggests that the diagnosis of ANCA-associated glomerulonephritis must be considered in patients with systemic-onset juvenile idiopathic arthritis with persistently active systemic disease who present with proteinuria. Furthermore, use of an anti-IL-1 agent might be an effective therapeutic option.
American Journal of Kidney Diseases 12/2011; 59(3):439-43. · 5.43 Impact Factor
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Nicolino Ruperto,
Pierre Quartier,
Nico Wulffraat,
Patricia Woo,
Angelo Ravelli,
Richard Mouy, Brigitte Bader-Meunier,
Sebastiaan J Vastert,
Emanuele Noseda,
Daniele D'Ambrosio,
Jean Lecot,
Abhijit Chakraborty,
Alberto Martini,
Andrea Chioato
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ABSTRACT: To assess dosing, preliminary safety, and efficacy of canakinumab, a fully human anti-interleukin-1β (anti-IL-1β) antibody, in children with systemic juvenile idiopathic arthritis (JIA) and active systemic features.
In this phase II, multicenter, open-label, dosage-escalation study, children with systemic JIA who were ≥4 years of age, had fever, and were receiving ≤0.4 mg/kg/day of corticosteroids were administered a single subcutaneous dose of canakinumab, 0.5-9 mg/kg of body weight, and were redosed upon relapse. Response to treatment was assessed according to an adaptation of the American College of Rheumatology (ACR) pediatric criteria for improvement.
A total of 23 children ages 4-19 years with active disease were enrolled. Of these, 1 patient was excluded from analysis, and 3 of the reenrolled patients were included twice in the efficacy analysis. By day 15 of the first treatment cycle, 15 of 25 patients (60%) had achieved an adapted ACR Pediatric 50 response, with 4 of them achieving inactive disease status. Response was sustained over time, with 11 of 13 patients able to maintain their response throughout the study. In 8 of the 11 responders who had been receiving steroids at baseline, the steroid dosage was decreased from a mean of 0.38 mg/kg/day to 0.13 mg/kg/day over the first 5 months, and 4 of them were able to discontinue steroids. At a dose of 4 mg/kg of canakinumab given subcutaneously every 4 weeks, the median percentage of patients predicted to relapse within 4 weeks was estimated to be 6% (95% confidence interval 1-21). Therapy was generally well tolerated and few patients experienced injection-site reactions.
Canakinumab has a promising preliminary safety and efficacy profile in this limited cohort. Based on the findings of this trial, further studies in a larger population of children with systemic JIA are warranted.
Arthritis & Rheumatism 09/2011; 64(2):557-67. · 7.87 Impact Factor
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Bénédicte Neven,
Aude Magerus-Chatinet,
Benoit Florkin,
Delphine Gobert,
Olivier Lambotte,
Lien De Somer,
Nina Lanzarotti,
Marie-Claude Stolzenberg, Brigitte Bader-Meunier,
Nathalie Aladjidi, [......],
Eric Jeziorski,
Guy Leverger,
Gérard Michel,
Felipe Suarez,
Eric Oksenhendler,
Olivier Hermine,
Stéphane Blanche,
Capucine Picard,
Alain Fischer,
Frédéric Rieux-Laucat
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ABSTRACT: Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder characterized by early-onset, chronic, nonmalignant lymphoproliferation, autoimmune manifestations, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline (ALPS-FAS) or somatic mutations (ALPS-sFAS) of the TNFRSF6 gene coding for FAS. Although the clinical features of ALPS have been described previously, long-term follow-up data on morbidity and mortality are scarce. We performed a retrospective analysis of clinical and genetic features of 90 ALPS-FAS and ALPS-sFAS patients monitored over a median period of 20.5 years. Heterozygous germline mutations of TNFRSF6 were identified in 83% of probands. Somatic TNFRSF6 mutations were found in 17% of index cases (all located within the intracellular domain of FAS). Sixty percent of the ALPS-FAS patients with mutations in the extracellular domain had a somatic mutation affecting the second allele of TNFRSF6; age at onset was later in these patients. No other genotype-phenotype correlations could be found. Long-term analysis confirmed a trend toward spontaneous remission of lymphoproliferation in adulthood but mixed outcomes for autoimmune manifestations. We observed significant and potentially life-threatening disease and treatment-related morbidity, including a high risk of sepsis after splenectomy that calls for careful long-term monitoring of ALPS patients. We also noted a significantly greater occurrence of disease-related symptoms in male than in female patients.
Blood 09/2011; 118(18):4798-807. · 9.90 Impact Factor
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Brigitte Bader-Meunier,
Benoit Florkin,
Jean Sibilia,
Cécile Acquaviva,
Eric Hachulla,
Gilles Grateau,
Olivier Richer,
Claire Michèle Farber,
Michel Fischbach,
Véronique Hentgen, [......],
Cécile Laroche,
Bénédicte Neven,
Thierry Lequerré,
Alexis Mathian,
Isabelle Pellier,
Isabelle Touitou,
Daniel Rabier,
Anne-Marie Prieur,
Laurence Cuisset,
Pierre Quartier
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ABSTRACT: The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD).
This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations.
Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients.
MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.
PEDIATRICS 06/2011; 128(1):e152-9. · 4.47 Impact Factor
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Brigitte Bader-Meunier,
Hélène Decaluwe,
Christine Barnerias,
Romain Gherardi,
Pierre Quartier,
Albert Faye,
Vincent Guigonis,
Anne Pagnier,
Karine Brochard,
Jean Sibilia,
Jacques-Eric Gottenberg,
Christine Bodemer
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ABSTRACT: To evaluate the safety and efficacy of rituximab (RTX) in juvenile dermatomyositis (JDM) in off-trial patients.
We conducted a multicenter prospective study of patients with JDM included in the French Autoimmunity and Rituximab (AIR) registry.
Nine patients with severe JDM were studied. The main indication for RTX treatment was severe and/or refractory muscle involvement (7 patients), severe calcinosis (1 patient), or severe chronic abdominal pain associated with abdominal lipomatosis (1 patient). RTX was associated with corticosteroids, immunosuppressive drugs, and plasma exchange therapy in 9/9, 5/9, and 2/9 patients, respectively. Mild infections of the calcinosis sites occurred in 2 patients and an infusion-related event in 1. Complete clinical response was achieved in 3/6 patients treated with RTX for muscle involvement. In these responders steroid therapy was stopped or tapered to < 15% of the baseline dosage, with no relapse, with a followup ranging from 1.3 to 3 years. Calcinosis did not improve in the 6 affected patients.
This small series suggests that rituximab may be effective for treating muscle and skin involvement in a small subset of children with severe JDM, and that its safety profile was satisfactory. Further studies are needed to identify predictive factors of response to RTX in patients with severe JDM.
The Journal of Rheumatology 06/2011; 38(7):1436-40. · 3.69 Impact Factor
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Tracy A Briggs,
Gillian I Rice,
Sarah Daly,
Jill Urquhart,
Hannah Gornall, Brigitte Bader-Meunier,
Kannan Baskar,
Shankar Baskar,
Veronique Baudouin,
Michael W Beresford, [......],
Nigel Smith,
Marcin Szynkiewicz,
Alice Wiedeman,
Carine Wouters,
Leo A H Zeef,
Jean-Laurent Casanova,
Keith B Elkon,
Anthony Janckila,
Pierre Lebon,
Yanick J Crow
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ABSTRACT: We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log(10) odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.
Nature Genetics 02/2011; 43(2):127-31. · 35.53 Impact Factor
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Nathalie Aladjidi,
Guy Leverger,
Thierry Leblanc,
Marie Quitterie Picat,
Gérard Michel,
Yves Bertrand, Brigitte Bader-Meunier,
Alain Robert,
Brigitte Nelken,
Virginie Gandemer,
Hélène Savel,
Jean Louis Stephan,
Fanny Fouyssac,
Julien Jeanpetit,
Caroline Thomas,
Pierre Rohrlich,
André Baruchel,
Alain Fischer,
Geneviève Chêne,
Y Perel
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ABSTRACT: Autoimmune hemolytic anemia is a rare condition in children. Little is known about its initial presentation and the subsequent progression of the disease.
Since 2004, a national observational study has been aiming to thoroughly describe cases and identify prognostic factors. Patients from all French hematologic pediatric units have been included if they had a hemoglobin concentration less than 11 g/dL, a positive direct antiglobulin test and hemolysis. Evans' syndrome was defined by the association of autoimmune hemolytic anemia and immunological thrombocytopenic purpura. Data from patients' medical records were registered from birth to last follow-up. Autoimmune hemolytic anemia was classified as primary or secondary. Remission criteria, qualifying the status of anemia at last follow-up, were used with the aim of identifying a subgroup with a favorable prognosis in continuous complete remission.
The first 265 patients had a median age of 3.8 years at diagnosis. In 74% of cases the direct antiglobulin test was IgG/IgG+C3d. Consanguinity was reported in 8% of cases and first degree familial immunological diseases in 15% of cases. Evans' syndrome was diagnosed in 37% of cases. Autoimmune hemolytic anemia was post-infectious in 10%, immunological in 53% and primary in 37% of cases. After a median follow-up of 3 years, 4% of children had died, 28% were still treatment-dependent and 39% were in continuous complete remission. In multivariate analysis, IgG and IgG+C3d direct antiglobulin tests were associated with a lower rate of survival with continuous complete remission (adjusted hazard ratio, 0.43; 95% confidence interval, 0.21-0.86).
This nationwide French cohort is the largest reported study of childhood autoimmune hemolytic anemia. The rarity of this condition is confirmed. Subgroups with genetic predisposition and underlying immune disorders were identified.
Haematologica 01/2011; 96(5):655-63. · 6.42 Impact Factor
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ABSTRACT: The objective of this study was to report the use of Mycophenolate Mofetil (MMF) in Juvenile Dermatomyositis (JDM). A retrospective chart review of children diagnosed with JDM having received MMF was performed. Response was evaluated 3 months after the onset of MMF by comparing muscle strength and steroid dosage before and after treatment. A good response was defined by global improvement concerning weakness and fatigability as evaluated subjectively by the physician along with a gain of at least 4 points on each of 2 muscle testings (Manual Muscle Testing, MMT and Childhood Myositis Assessment Score, CMAS) and/or a decrease of >15% of the corticosteroid dosage. Eight patients were identified. Except for one, all had received MMF secondary to an initial therapy of conventional immunosuppressants. Six patients showed good response by our predefined criteria. Changes of muscle testing scores ranged between +0 to +21 points (mean = +10.6) for the MMT and between +3 and +11 (mean = +7) for the CMAS. Corticosteroid tapering varied from 0 to 50%, with a mean of 18%. In most cases, follow-up was available for many months (up to 26); overall, we observed only one complication: a transient neutropenia in a patient concurrently receiving another immunosuppressant. This small series is the first published report on the use of MMF in JDM and suggests it is safe. Prospective larger studies are required to further elucidate the use of MMF in JDM.
Rheumatology International 12/2010; 32(3):711-6. · 1.88 Impact Factor
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Aymeric Dallocchio,
Danièle Canioni,
Frank Ruemmele,
Agnès Duquesne,
Jean-Yves Scoazec,
Raymonde Bouvier,
François Paraf,
Jeanne Languepin,
Carine H Wouters,
Marcel Guillot,
Pierre Quartier, Brigitte Bader-Meunier
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ABSTRACT: To identify juvenile idiopathic arthritis (JIA) patients who developed IBD during treatment with anti-TNF-alpha agents and better characterize the IBD clinical and pathological presentation.
A retrospective French multicentre study included patients with a diagnosis of JIA according to the ILAR criteria who developed IBD while under anti-TNF-alpha therapy before 18 years of age. Intestinal biopsies were collected and reviewed by the same pathologist.
Eight patients were included. They had been treated with etanercept from 11 to 78 months before IBD onset. Gastro-intestinal symptoms included abdominal pain (six patients), diarrhoea (four patients), anorexia (four patients), anal abscess (three patients) and oral ulcers (one patient). Five patients presented with Crohn's disease (CD) and three with indeterminate IBD, of whom four had severe pancolitis. Clinical remission of IBD was obtained in all patients after discontinuation of etanercept and initiation of IBD-specific therapy, including infliximab in six patients.
IBD must be suspected in JIA patients treated with etanercept who develop intestinal symptoms, including anal abscess. This series raises the possibility of a relationship between etanercept therapy and the occurrence of IBD in a subset of patients with JIA.
Rheumatology (Oxford, England) 09/2010; 49(9):1694-8. · 4.24 Impact Factor
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Hermann Heimpel,
Andreas Matuschek,
Momin Ahmed, Brigitte Bader-Meunier,
Adriana Colita,
Jean Delaunay,
Loic Garcon,
Florinda Gilsanz,
Jeroen Goede,
Josef Högel, [......],
Rosi Leichtle,
Juan Munoz,
Silverio Perrotta,
Carlo Piscopo,
Raffaele Renella,
Klaus Schwarz,
Gabriela Smolenska-Sym,
Sunitha Wickramasinghe,
Alberto Zanella,
Achille Iolascon
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ABSTRACT: Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders characterized by ineffective erythropoiesis and striking abnormalities of erythroblast morphology. The mutated genes are known for the most frequent types, CDA I and II, but data about their frequency do not exist. The objective of this retrospective study was to estimate the frequency of CDA I and II, based on all cases reported in the last 42 yr in publications and identified registries or surveys. Reports were collected of 124 and 377 confirmed cases of CDA I and CDA II cases, respectively. The cumulated incidence of both types combined varied widely between European regions, with minimal values of 0.08 cases/million in Scandinavia and 2.60 cases/million in Italy. CDA II is more frequent than CDA I, with an overall ratio of approximately 3.2, but the ratio also varied between different regions. The most likely explanations for the differences are both differences in the availability of advanced diagnostic procedures and different levels of the awareness for the diagnosis of the CDAs. The estimations reported here are most probably below the true incidence rates, because of failure to make the correct diagnosis and to underreporting. Limited data do not suggest differing levels of risk in identified ethnic groups.
European Journal Of Haematology 07/2010; 85(1):20-5. · 2.61 Impact Factor
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ABSTRACT: The complement system plays an ambivalent role in systemic lupus erythematosus (SLE) nephritis. On one hand, it appears to mediate tissue damage through activation of the classical pathway by immune complexes, on the other hand complete deficiencies in either C1q, C1r, C2 or C4 have been associated with SLE. Here we report the development of biopsy proven lupus nephritis in a patient with a homozygous nonsense mutation in the C1s, a condition resulting in a complete impairment of the classical pathway but preserving the lectin pathway. Histological examination of the glomeruli disclosed positive C4d immunostaining suggesting that lectin pathway is involved in the lesional process. Rituximab treatment resulted in B cell depletion and renal remission, demonstrating that classical pathway does not play a major role in anti-CD20 antibodies therapeutic effects. This unique observation emphasizes the complex role of complement system in the development of lupus nephritis.
Arthritis care & research. 02/2010; 62(9):1346-50.
