Search

Double-positive vasculitis with anti-polynuclear cytoplasm (ANCA) and anti-glomerular basement membrane (GBM) antibodies is a rare entity of systemic vasculitis defined by the presence of ANCA and anti-GBM antibodies. The gradual accumulation of clinical and therapeutic data shows the usefulness of identifying and differentiating this entity from the two vasculitis respectively associated with the isolated presence of each of these two antibodies. Indeed, the double-positive ANCA and anti-GBM vasculitis appears to associate the characteristics of the demography and the extra-renal and pulmonary involvement of the ANCA-associated vasculitis on the one hand, and of the histological type and severe renal prognosis of the anti-MBG vasculitis on the other hand, with the renal involvement which is the only involvement consistently observed in double-positive vasculitis. The aim of this focus is to describe the epidemiological, clinico-biological, histological and prognostic characteristics of this entity, in light of recent literature and ongoing therapeutic changes in the two eponymous vasculitis.

Introduction Une patiente de 62 ans lombalgique chronique multioperee, a presente en 2017 lors d’une chirurgie rachidienne un choc a 60/40 mmHg et une erythrodermie 5 min apres l’administration de cefazoline, atracurium, dexamethasone, ketamine, xylocaine, sufentanyl, propofol. L’evolution a ete favorable sous adrenaline. La tryptasemie etait en faveur d’une reaction d’hypersensibilite immediate (HI). Du ketoprofene a ete administre 1H apres, sans reaction. En 2018, la prise de ketoprofene, esomeprazole, thiocolchicoside a entraine 1 h plus tard : erythrodermie, prurit, chaleur du visage, dysphonie, asthenie traites par prednisolone et dexchlorpheniramine, sans dosage des mediateurs sanguins de degranulation. En 2019, pour ses lombalgies, la patiente a recu a son domicile du ketoprofene IM et est decedee d’un choc anaphylactique. Methodes Realisation de tests cutanes (TC) a 2 mois de la deuxieme reaction pour toutes les molecules recues en 2017 et 2018 et IDR de controle de la cefazoline fait juste avant le test de reintroduction en 2019. Resultats Les premiers TC etant negatifs (ketoprofene douteux a une concentration irritante), une carte d’allergique provisoire contre indiquant toutes les molecules recues et les AINS a ete remise en attendant la suite des explorations. L’IDR de controle de la cefazoline s’etant positivee, les autres β-lactamines ont ete testees, revelant une reactivite croisee a la penicilline G et a l’amoxicilline. Parmi les dosages des IgE, anti-latex, ammoniums IV, penicilline G, V, amoxicilline, ceftriaxone et cefuroxime, seules les IgE anti-penicilline V etaient positives (1,6 kUA/L ; seuil Discussion Contrairement aux allergies alimentaires ou respiratoires, les allergies medicamenteuses sont rarement multiples. L’HI aux AINS est rare et les TC difficiles a interpreter en raison de possibles reactions irritatives. Nous rapportons le cas d’une patiente ayant fait un choc peroperatoire a la cefazoline qui a possiblement masque une allergie vraie au ketoprofene, dont la re-administration lui a ete fatale. Conclusion Ce cas souligne l’importance de l’education du patient, et pose le probleme du partage de l’information des medicaments contre-indiques entre professionnels de sante.

Introduction Les hypersensibilites (HS) aux proteines de liquide amniotique bovin (LAB) sont des affections professionnelles peu frequentes. Les tests cutanes (TC) aux liquides biologiques d’origine animale ne sont pas toujours contributifs ni possibles. De plus, la physiopathologie et les allergenes en cause ont ete peu etudies. Nous presentons 3 cas de patients atopiques, ayant presente des reactions apres des velages. Methodes Nous avons realise des TC (prick-to prick, patch et open test), dosages d’IgE specifiques (ImmunoCap® Phadia) et tests d’activation des basophiles (TAB) (Buhlmann) en reponse a divers allergenes de mammiferes ( Tableau 1 ). Un test de proliferation lymphocytaire (TPL) en presence de LAB ou serum de veau fœtal (SVF) a aussi ete realise (positif si index de stimulation patient/temoin > 3). Resultats Les TAB et TPL ont permis de confirmer l’HS au LAB et d’objectiver les mecanismes impliques avec une reponse mixte IgE mediee et cellulaire retardee a ses proteines. Conclusion Les tests cellulaires peuvent completer utilement les TC non disponibles ou ininterpretables. Ils peuvent aussi objectiver une sensibilisation au LAB, prealable a la declaration d’allergie professionnelle. Une etude chez des veterinaires va debuter pour estimer la prevalence de ces allergies et etudier les allergenes et allergies croisees.

Introduction La vascularite dite double-positive ANCA et anticorps anti-membrane basale glomerulaire (MBG) est une entite rare de vascularite systemique cumulant la presence d’ANCA et d’anticorps anti-MBG. Les caracteristiques epidemiologiques, clinico-biologiques et therapeutiques de cette entite restent mal connues. Materiels et methodes Nous avons realise une revue systematique de la litterature (de 1989 -date du premier cas rapporte- a janvier 2019) anglophone et francophone pour les vascularites double-positives a partir de la base de donnee PubMed via les mots-cles suivants : (« Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis » [MeSH] OR « Antibodies, Antineutrophil Cytoplasmic » [MeSH]) AND (« Anti-Glomerular Basement Membrane Disease » [MeSH] OR « anti-MBG » [All Fields]). Resultats Au total, 449 cas de vascularites double-positives ont ete identifies. Le sex-ratio des patients etait legerement en faveur des hommes (55,1 %) avec un âge moyen au diagnostic de 60,7 ans. Cette entite representait 34,4 % des vascularites a anti-MBG et 6,84 % des vascularites a ANCA. Les ANCA etaient de facon predominante diriges contre la myeloperoxydase (71,3 %), tandis que de rares cas de triple positivite (3,81 %) etaient rapportes. La duree moyenne d’evolution des symptomes chez ces patients etait de 12,7 semaines. L’atteinte renale etait constante et le plus souvent severe, caracterisee par une hematurie et une proteinurie. La creatininemie moyenne au diagnostic etait de 544 μmol/L (76,7 % des patients presentaient une creatininemie > 500 μmol/L au diagnostic) et une majorite de patients (72,1 %) presentait une glomerulonephrite avec proliferation extra-capillaire a l’histologie. L’immunofluorescence montrait des depots lineaires d’IgG et de C3 dans la majorite des cas (71,9 %) et parfois des depots granuleux d’IgG et de C3 (14 %). L’atteinte respiratoire (59 %) etait dominee par les hemorragies intra-alveolaires (53,1 %). Concernant les autres manifestations, les patients double-positifs presentaient une alteration de l’etat general avec une asthenie (42,9 %), une perte de poids (42,9 %), une hyperthermie (42,9 %) et d’autres manifestations systemiques plus rares incluant une eruption cutanee (18,4 %), des arthralgies (15,4 %), des myalgies (12,2 %), des atteintes neurologiques peripheriques (9 %), des atteintes ORL (27,7 %) ou ophtalmologiques (9 %). Le pronostic a 1 an de ces patients etait sombre avec seulement 42,7 % de patients sevres de la dialyse, un taux de mortalite et un taux de rechute respectivement de 41,1 % (parmi 95 patients) et 9,7 % (parmi 93 patients). Ces patients ont recu un traitement immunosuppresseur dans 88 % des cas et/ou des echanges plasmatiques dans 55,6 % des cas. Conclusion La vascularite dite double-positive associe les caracteristiques des deux vascularites eponymes, partageant avec la vascularite a ANCA un plus vaste spectre clinique ainsi qu’un taux de rechute extra-renal plus eleve, et avec celle a anti-MBG la quasi-constance de l’atteinte renale qui est de plus forte severite et de moins bon pronostic. Son individualisation au sein des vascularites primitives est donc licite et justifie la mise en place d’etudes cliniques therapeutiques a part entiere.

Introduction L’histamine et la tryptase beta sont les mediateurs mastocytaires utilisables pour confirmer la nature anaphylactique d’un choc. Le dosage de la tryptase n’est pas specifique de l’isoforme beta et implique de comparer la valeur mesuree au pic a la valeur a l’etat basal. Une augmentation de la tryptase n’est pas toujours detectable dans les reactions de grade 1. Le dosage de l’histamine de demi-vie courte necessite un prelevement precoce (idealement er signes). La mise a jour de la nomenclature des actes de biologie medicale considere cet acte comme obsolete. Nous avons voulu evaluer la pertinence du dosage de l’histamine dans l’exploration d’un choc en complement de la tryptase. Methodes Une etude retrospective menee par 7 laboratoires francais entre 2011 et 2015 a permis l’analyse de 273 reactions (dont 38 provenaient de l’etude francilienne NASA). Pour 269, l’agent responsable etait un medicament. Les reactions ont ete classees en grade 1 (15 %), 2 (25 %), 3 (27 %), 4 (5 %) ou indetermine (28 %). Seuls les patients avec tests cutanes positifs (162, 60 %) ont ete classes allergiques. Resultats Les courbes ROC calculees avec les valeurs au pic pour la tryptase (ThermoFisher) et pour l’histamine (Beckman Coulter RIA/ELISA) donnent des AUC a 0,88 et 0,86 respectivement. L’index de Youden permet de calculer un seuil optimal de positivite de 8 μg/L pour la tryptase et de 18 nmol/L pour l’histamine. L’analyse de la cinetique (pic > taux basal × 1,2 +2 μg/L), y compris quand le pic de tryptase est Conclusion L’analyse des variations de cinetique de la tryptase et l’optimisation du seuil de positivite a 8 μg/L permettent d’obtenir une bonne sensibilite pour ce seul mediateur. Mais, en absence d’augmentation par rapport au taux basal, le dosage de l’histamine peut etre informatif pour l’allergologue.

T lymphocyte expansion is triggered through interaction of interleukin 2 (IL-2) with its high-affinity receptor (IL-2R). This molecule is a heterodimer comprising an antigen-inducible component, the Tac chain (P55). Activation of T lymphocytes also generates a soluble form of this P55 called S-IL-2R. S-IL-2R is elevated in many T-cell-related pathologies (leukemia, autoimmunity, etc.). In graft recipients, rejection is a result of T-cell activation by graft antigens and therefore might induce a release of S-IL-2R in the circulation; this parameter is now said to be a good indicator of rejection. We have performed a study in renal graft recipients in order to assess the usefulness of circulating S-IL-2R particularly to discriminate the origin of renal failure in cases of rejection or of cyclosporin-A (CsA)-induced nephrotoxicity. We demonstrated that there are no differences between isolated values in the clinical groups at the time of diagnosis. Variations in S-IL-2R are increased compared to steady-state periods during rejection and cytomegalovirus infections, although not in CsA toxicity episodes. However, at the individual level there are too many false-positive and false-negative results, making this parameter no more meaningful than serum creatinine levels alone or even in association (as tested in logistic discriminant analysis). In addition, it seems that the variations in S-IL-2R are partly related to renal function itself, as suggested by the correlation between S-IL-2R levels and serum creatinine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Introduction Le neuro-lupus (NL) peut se manifester par des symptomes psychiatriques isoles tels que des hallucinations, une humeur depressive ou une anxiete. Ainsi, une presentation psychiatrique du lupus pourrait potentiellement conduire a tort, a une hospitalisation en milieu psychiatrique. La prise en charge du NL est une urgence, son traitement repose sur l’association d’une corticotherapie et d’un immunosuppresseur. Aucune etude ne s’est, jusqu’ici, interessee au depistage de NL dans un service de psychiatrie. Patientes et methodes Nous avons realise, entre 2012 et 2014, une etude monocentrique, prospective, au sein de 3 services de psychiatrie du CHU de Caen, dans le but de depister d’eventuels NL. Un depistage par le dosage des anticorps antinucleaires (AAN), des anticorps anti-ADN et des anti-antigenes nucleaires solubles, etait propose de maniere systematique a toute patiente, âgee de 18 a 50 ans, hospitalisee en psychiatrie. Resultats Cent patientes d’âge moyen 33,1 ± 8,44 ans [18–50] ont ete inclues dans l’etude. Une patiente a ete exclue car elle presentait un antecedent de lupus. Les pathologies psychiatriques etaient reparties comme suit : depression (46 %), schizophrenie (13 %), trouble de la personnalite (10 %), et trouble anxieux (2 %). Un quart des patientes n’avaient pas de pathologie psychiatrique averee. Le nombre moyen d’annees depuis le diagnostic de la pathologie psychiatrique etait de 9,89 ± 22,08 [0–23,6]. Soixante-dix pour cent des patientes etaient hospitalisees dans une unite de long sejour et 30 % l’etaient dans une unite de court sejour. Trente-deux pour cent avaient des AAN positifs (≥ 1/160) dont deux patientes avaient un titre au 1/1280. Aucune patiente ne presentait d’anticorps anti-ADN et une patiente avait des anti-SSA positif. Trois patientes ont ete vues en consultation de medecine interne, du fait d’anomalie biologique (anti-SSA positif ou AAN positifs a taux eleve), aucun NL n’a ete diagnostique. Conclusion Cette etude n’a pas permis de depister de NL dans une population de femmes jeunes hospitalisees en psychiatrie. Ainsi le dosage systematique des AAN, lors d’hospitalisation en psychiatrie ne parait pas probant.

The aim of this study was to analyze humoral xenoreactivity of various Old World primate species sera against pig islets and the effects of these sera on pig islet viability and function after culture.Freshly isolated or cultured adult pig islets were analyzed by immunohistology or by cytofluorimetry for Old World primate xenoreactive natural antibody (XNA) binding and complement deposition. Complement-mediated cytotoxicity was evaluated by 51Cr release assays. After 4 days of culture in 50% sera from Old World primates, the morphology and in vitro metabolic function of pig islets were also analyzed.Chimpanzee, Macaca mulatta (rhesus), or baboon XNA binding was detectable only on intra-islet endothelial cells (ECs). Incubation of pig islets with sera from all Old World primate species tested showed C3 and C4 deposition on ECs and on some surrounding endocrine cells. However, membrane attack complex (MAC) showed a pattern of positivity similar to XNA binding, i.e., restricted to ECs only. No deposition of factor B was detected. Although complement cascade was activated, no cytotoxicity was observed after incubation of islets with chimpanzee serum, whereas between 10% and 35% 51Cr specific release was obtained with rhesus, baboon, or Macaca fascicularis sera. Despite this cytotoxic effect, purified pig islets showed a normal morphology and a well-preserved insulin release in response to an acute glucose stimulus, after prolonged culture with 50% serum obtained from all primate species considered.Despite the fact that pig beta-cell function was not affected by the serum of any of the primate species tested, some of them yielded significant lysis of islet cells, presumably as a result of a cytotoxic effect on intra-islet ECs. These data show that Old World primate sera from different species do not have equivalent effect on pig islets; these differences should be taken into account in preclinical trials of pig islet xenotransplantation.

The expression of xenogeneic epitopes and the activation of human complement by adult pig islets after prolonged culture have hitherto not been described.Freshly isolated and cultured islets were analyzed by fluorescence-activated cell sorter analysis, fluorescence microscopy, and immunohistology for expression of Gal(alpha1,3)Gal epitopes, binding of human xenoreactive natural antibodies (XNA), and complement deposition.Freshly isolated and cultured islets showed detectable Gal(alpha1,3)Gal expression and human XNA binding limited to intraislet capillary endothelial cells. No significant modification in Gal(alpha1,3)Gal expression and human XNA binding levels was detected in adult pig islets cultured for up to 4 days compared with freshly isolated islets. Incubation of pig islets with human serum demonstrated the deposition of C3, C4, and membrane attack complex, but not factor B with a similar pattern to XNA. However C3 and C4 showed a more widespread deposition. Despite complement activation, no cytotoxic effect on islets was detected after 4 hr of incubation with human serum capable of killing porcine endothelial cells. Even after 4 days of culture in 50% intact human serum, pig islets retained both their normal morphology and a normal insulin response to glucose stimulation.Neither islet cell lysis nor, more importantly, any alteration in beta cell function occurred, which suggests that adult pig islets may not be directly damaged by serum after xenotransplantation in humans. Nevertheless, complement activation in vivo could trigger rapid cellular rejection mechanisms through islet cell opsonization and release of bioactive fragments.

B-F5, a mouse IgG1 anti-CD4 MoAb, was used in recipients of a first cadaveric kidney allograft. Eighteen patients received 30 mg/day MoAb with a quadruple sequential therapy. All but one kidney were functioning at 6 months, with a mean serum creatinine of 153 micromol/L. However, 50% of the patients had an acute rejection episode within the first three months, and most of the early episodes (i.e.,1 month) occurred in patients with low levels of circulating MoAb. The biological analysis showed a strong depleting effect on the CD4+ cell counts, a saturation by the MoAb of the remaining circulating CD4+ cells, and no detectable immunization against B-F5. Although the biological parameters indicate an action of B-F5 in vivo, the clinical data associated with poor MoAb bioavailability suggest the need for an improved pharmacokinetic behavior of the MoAb to determine its use for prophylaxis of early rejection.

The effect of CsA on antigen-induced IL-2 receptor expression was studied on a human T lymphocyte clone (4AS) obtained from cells infiltrating a rejected human kidney. Stimulation of 4AS clone cells with specific antigen (D.BLCL) was strongly inhibited by CsA (50% inhibition of tritiated thymidine uptake at about 12.5 ng/ml). Addition of recombinant IL-2 only partially restored 4AS growth inhibition, suggesting that another antigen-induced activation signal such as IL-2-receptor expression could be impaired by CsA. Using 125I-labeled human recombinant IL-2 and 125I-labeled 33B3.1 (a MoAb directed against TAC antigen), we found that expression of both high and low affinity sites was decreased when clone cells were stimulated with D.BLCL in the presence of CsA and exogenous IL-2 (about 50% inhibition in the presence of 500 ng/ml of CsA). Northern blot analysis of IL-2-receptor m.RNA (TAC antigen m.RNA) showed that inhibition occurred at least in part at the pretranscriptional level.

Monoclonal antibodies (MoAbs) against human interleukin 2 receptor (IL-2-R) have been shown to prevent early kidney rejection in animals and humans. We report here the effect of an anti-IL-2-R MoAb (33B3.1) inhibiting IL-2 binding high-affinity sites on activated lymphocytes in 10 declared acute rejection episodes of first cadaveric kidney grafts. Six patients were under cyclosporine treatment only at the time of diagnosis of the rejection. All rejection episodes but one were biopsy-proved cellular rejections. Treatment consisted of intravenous infusions of 33B3.1 at 20 mg/day x 2 days, followed by 10 mg/day for 8 additional days. In case of MoAb ineffectiveness at day 5, anti-IL-2-R MoAb was discontinued and a rescue treatment of corticosteroid boluses (CSb) was given. If not, in all cases corticosteroids (CS) were given (1 mg/kg) at the end of MoAb treatment (day 10) and tapered off thereafter. Two rejection episodes immediately responded to 33B3.1 treatment. During 33B3.1 treatment four other patients had only a stabilization of their blood creatinine concentration, which nevertheless returned to prerejection levels after day 10 when anti-IL-2-R was discontinued and CS administered at 1 mg/kg (no rescue treatment). The four remaining patients had an increase of their blood creatinin levels at day 5 despite 33B3.1 treatment, and their renal function only improved with CSb rescue treatment. One of these patients lost the graft despite rescue treatment, as well as a 9-day course of antithymocyte globulin. Trough levels of MoAb reached a plateau as early as day 2 (approximately 6 micrograms/ml). All patients developed antibodies (IgM and IgG) after day 14. In no instance could unresponsiveness be related to low circulating 33B3.1 trough levels or to early host anti-MoAb immune response (IgM or IgG). We conclude that 33B3.1, known to be effective in preventing early rejection, has only inconsistent and/or incomplete effects on the ongoing rejection process. Our data suggest that once IL-2-dependent clones are expanded in the rejected graft, interference with IL-2/IL-2-R signals does not block the effector mechanisms sustaining acute rejection.