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ABSTRACT: 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.
Seminars in arthritis and rheumatism 04/2012; · 4.72 Impact Factor
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Thao Pham,
Hervé Bachelez,
Jean-Marie Berthelot,
Jacques Blacher,
Yoram Bouhnik,
Pascal Claudepierre,
Arnaud Constantin,
Bruno Fautrel,
Philippe Gaudin,
Vincent Goëb, [......],
Alain Saraux,
Thierry Schaeverbeke,
Martin Soubrier,
Anne Sudre, Tu-Anh Tran,
Manuelle Viguier,
Olivier Vittecoq,
Daniel Wendling,
Xavier Mariette,
Jean Sibilia
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ABSTRACT: To develop and/or update fact sheets about TNFα antagonists treatments, in order to assist physicians in the management of patients with inflammatory joint disease.
1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Société Francaise de Rhumatologie. Each fact sheet was revised by several experts and the overall process was coordinated by three experts.
Several topics of major interest were selected: contraindications of TNFα antagonists treatments, the management of adverse effects and concomitant diseases that may develop during these therapies, and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA and SpA, initiation and monitoring of TNFα antagonists treatments, management of patients with specific past histories, and specific clinical situations such as pregnancy; 2. diseases other than RA, such as juvenile idiopathic arthritis; 3. models of letters for informing the rheumatologist and general practitioner; 4. and patient information.
These TNFα antagonists treatments fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on these therapies. They will be available continuously at www.cri-net.com and updated at appropriate intervals.
Joint, bone, spine: revue du rhumatisme 05/2011; 78 Suppl 1:15-185. · 2.25 Impact Factor
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ABSTRACT: B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-γ play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-α triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-γ gene imprinting factors. IFN-α primed naive B-cells for IFN-γ production and increased IFN-γ gene responsiveness to IL-12. IFN-γ continues this polarization by re-inducing T-bet and up-regulating IL-12Rβ2 expression. IFN-α and IFN-γ therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-α, IFN-γ and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity.
PLoS ONE 01/2011; 6(4):e19366. · 4.09 Impact Factor
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Isabelle Koné-Paut,
Martha Darce-Bello,
Farahd Shahram,
Marco Gattorno,
Rolando Cimaz,
Seza Ozen,
Luca Cantarini,
Ilknur Tugal-Tutktun,
Samir Assaad-Khalil,
Michael Hofer,
Jasmin Kuemmerle-Deschner,
Saida Benamour,
Souleymane Al Mayouf,
Christine Pajot,
Jordi Anton,
Albert Faye,
Wafa Bono,
Susan Nielsen,
Alexia Letierce, Tu-Anh Tran
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ABSTRACT: To set-up an international cohort of patients suspected with Behçet's disease (BD). The cohort is aimed at defining an algorithm for definition of the disease in children.
International experts have defined the inclusion criteria as follows: recurrent oral aphthosis (ROA) plus one of following-genital ulceration, erythema nodosum, folliculitis, pustulous/acneiform lesions, positive pathergy test, uveitis, venous/arterial thrombosis and family history of BD. Onset of disease is <16 years, disease duration is ≤3 years, future follow-up duration is ≥4 years and informed consent is obtained. The expert committee has classified the included patients into: definite paediatric BD (PED-BD), probable PED-BD and no PED-BD. Statistical analysis is performed to compare the three groups of patients. Centres document their patients into a single database.
At January 2010, 110 patients (56 males/54 females) have been included. Mean age at first symptom: 8.1 years (median 8.2 years). At inclusion, 38% had only one symptom associated with ROA, 31% had two and 31% had three or more symptoms. A total of 106 first evaluations have been done. Seventeen patients underwent the first-year evaluation, and 36 had no new symptoms, 12 had one and 9 had two. Experts have examined 48 files and classified 30 as definite and 18 as probable. Twenty-six patients classified as definite fulfilled the International Study Group criteria. Seventeen patients classified as probable did not meet the international criteria.
The expert committee has classified the majority of patients in the BD group although they presented with few symptoms independently of BD classification criteria.
Rheumatology (Oxford, England) 10/2010; 50(1):184-8. · 4.24 Impact Factor
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Rheumatology (Oxford, England) 10/2009; 48(12):1618-9. · 4.24 Impact Factor
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ABSTRACT: To compare the clinical and laboratory features and the rate of echocardiographic coronary artery abnormalities in patients with complete and incomplete forms of Kawasaki disease (KD) and to determine which additional clinical criteria might support a suspicion of KD.
We retrospectively reviewed the medical records of patients with KD who were admitted to the general pediatrics department of the Kremlin Bicêtre Teaching Hospital, France, between January 1995 and May 2006. We compared patients with a fever and four or five of the principal criteria (complete KD) to the other patients (incomplete KD). Clinical and laboratory features were abstracted from the records.
We identified 63 patients with a mean age of 33 months (+/-31). The male-to-female ratio was 2.47. Four patients were excluded. Of the remaining 59 patients, 39 had complete KD and 20 incomplete KD. The group with complete KD had significantly higher rates of changes in the extremities, conjunctival injection, exanthem, and enanthem; and a significantly lower rate of coronary artery dilation (48.7% vs. 90% in the incomplete KD group, P=0.002). Serum levels of alanine aminotransferase and gamma glutamyl transferase were significantly higher in the complete KD group. No significant differences were found between the two groups regarding age, sex, blood cell counts, or laboratory markers for inflammation. Pyuria was found in 45.4% of patients with complete KD and in 30.8% of those with incomplete KD (P=0.17). Of 14 patients who underwent ophthalmological evaluation, two had uveitis; both of them had complete KD.
Incomplete KD shares with complete KD a risk of coronary artery disease. The diagnosis of incomplete KD is challenging but can be supported by the presence of features other than the principal criteria, such as acute anterior uveitis or unexplained pyuria.
Joint, bone, spine: revue du rhumatisme 10/2009; 76(5):481-5. · 2.25 Impact Factor
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ABSTRACT: Erdheim-Chester disease is a rare, non-Langerhans systemic histiocytosis characterized by bilateral sclerosis of the metaphyseal regions of the long bones and infiltration in other organs. The histopathologic hallmark is defined by a mononuclear infiltrate of foamy histiocytes and rare pathognomonic Touton giant cells with extensive fibrosis. This condition is exceptional in children. We report here a case of Erdheim-Chester disease in a 10-year-old girl with retroperitoneal infiltration and bone involvement, for whom the diagnosis was only established after a 3-year course with multiple biopsies. It is also the first pediatric case successfully treated with interferon-alpha suggesting that interferon-alpha can be a safe and efficient first-line therapy for this disease in children.
Journal of Pediatric Hematology/Oncology 09/2009; 31(10):782-6. · 1.16 Impact Factor
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ABSTRACT: To assess the clinical characteristics of patients living in France and carrying a single MEFV mutation.
A retrospective chart review of patients referred to us for recurrent fevers. Genetic testing: systematic screening of exons 2 and 10 was performed in the MEFV gene. A subset of patients was also investigated for other auto-inflammatory genes.
We analysed 94 patients (sex ratio:1). Forty-two percent of them were Jews and 17% were Arabs. The median age of onset was 2 years (3 months-47 years). Fever was >39 degrees C in 80% of them, while the duration and frequency of an attack varied (<24 h: 8%; 1-3 days: 56%; >3 days: 36%; >2 months: 15%; 1-2 months: 48%; and <1 month: 37%, respectively). Peritonitis occurred in 97%, pleuritis in 25%, arthralgia in 53%; skin rashes in 20%, aphthosis in 18% and lymphadenopathy in 9%. MEFV mutations were M694V (60%) and M694I (7%). The R92Q TRAPS mutation was retrieved in 3/21 patients tested and the V377I MKD mutation in 1/6. Associated diseases in these patients were periodic fever, aphthosis pharyngitis and adenitis syndrome (4), AS (5), Crohn's disease (2) and Castleman's disease (1).
The clinical picture of French heterozygote patients with recurrent fevers resembles that of homozygote patients. Most of them required colchicine treatment.
Rheumatology (Oxford, England) 07/2009; 48(7):840-2. · 4.24 Impact Factor
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ABSTRACT: Multicentric Castleman disease (MCD), or multicentric angiofollicular lymph node hyperplasia, is an idiopathic lymphoproliferative disorder that is only seldom reported in children. The clinical and laboratory findings that characterize this peculiar disorder are thought to result from increased interleukin (IL)-6 production. We report herein the case of a 13-year-old boy with a long history of hectic fevers and abdominal pain, accompanied by stunted growth and elevated biologic markers of inflammation. Surgical biopsies of a pancreatico-splenic mass and of mesenteric lymph nodes revealed mixed-type MCD, which was diagnosed 6 years after the first clinical symptoms appeared. He received combination chemotherapy (cyclophosphamide, vinblastine) associated with a monoclonal B-cell antibody (Rituximab). This treatment was well tolerated but ineffective. Given the reported success of IL-1 blocking agents for treating Still disease, another IL-6 linked disorder, we attempted to treat him with anakinra, an IL-1RA agonist. His overall state normalized and both his clinical and biologic signs dramatically improved. This is the first report of anakinra treatment for MCD. We conclude that anti-IL-1 blocking agents could be an interesting treatment alternative for MCD, a chronic debilitating disease, which still carries a poor prognosis.
Journal of Pediatric Hematology/Oncology 01/2009; 30(12):920-4. · 1.16 Impact Factor
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Tu-Anh Tran,
Marie-Ghislaine de Goër de Herve,
Houria Hendel-Chavez,
Bamory Dembele,
Emilie Le Névot,
Karim Abbed,
Coralie Pallier,
Cécile Goujard,
Jacques Gasnault,
Jean-François Delfraissy,
Anne-Marie Balazuc,
Yassine Taoufik
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ABSTRACT: In HIV-infected patients on long-term HAART, virus persistence in resting long-lived CD4 T cells is a major barrier to curing the infection. Cell quiescence, by favouring HIV latency, reduces the risk of recognition and cell destruction by cytotoxic lymphocytes. Several cell-activation-based approaches have been proposed to disrupt cell quiescence and then virus latency, but these approaches have not eradicated the virus. CD4+CD25+ regulatory T cells (Tregs) are a CD4+ T-cell subset with particular activation properties. We investigated the role of these cells in virus persistence in patients on long-term HAART.
We found evidence of infection of resting Tregs (HLADR(-)CD69(-)CD25(hi)FoxP3+CD4+ T cells) purified from patients on prolonged HAART. HIV DNA harbouring cells appear more abundant in the Treg subset than in non-Tregs. The half-life of the Treg reservoir was estimated at 20 months. Since Tregs from patients on prolonged HAART showed hyporesponsiveness to cell activation and inhibition of HIV-specific cytotoxic T lymphocyte-related functions upon activation, therapeutics targeting cell quiescence to induce virus expression may not be appropriate for purging the Treg reservoir.
Our results identify Tregs as a particular compartment within the latent reservoir that may require a specific approach for its purging.
PLoS ONE 02/2008; 3(10):e3305. · 4.09 Impact Factor
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JAIDS Journal of Acquired Immune Deficiency Syndromes 07/2007; 45(2):247-9. · 4.43 Impact Factor
