C. Massot

Disease expression in women with hereditary angioedema

OBJECTIVE Fluctuations in sex hormones can trigger angioedema attacks in women with hereditary angioedema. Combined oral contraceptive therapies, as well as pregnancy, can induce severe attacks. The course of angioedema may be very variable in different women. STUDY DESIGN Within the PREHAEAT project launched by the European Union, data on 150 postpubertal women with hereditary angioedema were collected in 8 countries, using a patient-based questionnaire. RESULTS Puberty worsened the disease for 62%. Combined oral contraceptives worsened the disease for 79%, whereas progestogen-only pills improved it for 64%. During pregnancies, 38% of women had more attacks, but 30% had fewer attacks. Vaginal delivery was usually uncomplicated. Attacks occurred within 48 hours in only 6% of cases. Those more severely affected during menses had more symptoms during pregnancies, suggesting a hormone-sensitive phenotype for some patients. CONCLUSION The course of angioedema in women with C1 inhibitor deficiency is affected by physiologic hormonal changes; consequently, physicians should take these into account when advising on management.

BRADYKININ RECEPTOR 2 ANTAGONIST (ICATIBANT) FOR HEREDITARY ANGIOEDEMA TYPE III ATTACKS

In 2000, a new type of hereditary angioedema (HAE) without C1 esterase inhibitor (C1-INH) deficiency, HAE type III, was reported.1,2 It occurred especially in women, and the diagnosis was based on recurrent attacks of subcutaneous or submucosal edema, no chronic relapsing urticaria, familial history, and normal C1INH protein and activity levels. Recent findings3 suggest that bradykinin may play a role in the pathogenesis of angioedema. The morbidity and mortality of HAE are related to abdominal attacks and laryngeal edema. Symptoms seem to be induced or worsened by estrogen.4 In these patients, C1-INH function is normal, and a missense gain-of-function mutation in the F12 gene can be found.5 Treatments for HAE type III are not established, but tranexamic acid seems to be effective for prophylaxis of symptoms. Until recently, the main shortterm treatment for severe HAE attacks was C1-INH concentrate.4 A new therapeutic agent, icatibant, a bradykinin B2 receptor antagonist, is effective for the treatment of HAE with C1-INH deficiency. The efficacy and safety of icatibant in patients with HAE (type I or II) presenting with moderate to severe cutaneous or abdominal attacks were tested in 2 double-blind, randomized, multicenter, phase 3 trials, FAST (For Angioedema Subcutaneous Treatment) 1 and 2.6 We report treatment outcomes in 3 women who fulfilled the diagnosis criteria of HAE type III (Table 1). Patients presented with recurrent severe abdominal attacks, edema of the face, and a family history of angioedema. The C1-INH function was moderately low when the patients took an estrogen-containing contraceptive pill or during pregnancy but was normal after it was discontinued or after delivery. We previously described these data in another patient with HAE type III.7 Levels of C1-INH protein and C4 were normal. All 3 patients had no mutation in the SERPING1 gene. Patient 1 had an identified mutation in the F12 gene. Patient 1 received 1 subcutaneous injection of icatibant, 30 mg, for a severe abdominal attack. Symptom improvement began 30 minutes later, with complete resolution of symptoms by 1 hour after icatibant administration. Patient 2 presented with an unusual severe abdominal attack combined with facial edema. An increase in her dose of tranexamic acid did not improve symptoms. She received an injection of icatibant. Symptoms were relieved within 2 hours. Patient 3 was treated for a severe abdominal attack. After the first injection of icatibant, relief of symptoms occurred within 30 minutes. Symptom recurrence after 6 hours necessitated a second injection of icatibant, which resulted in rapid alleviation of symptoms. For all the patients, icatibant administration was followed by a transient local erythematic reaction at the site of injection. No other adverse reactions to icatibant were noted in the 3 patients. We therefore conclude that icatibant is a safe and effective symptomatic treatment for severe attacks in patients with HAE type III.

Clinical and biological distinctions between type I and type II acquired angioedema

granulomatosis and hypercalcaemia following intravesical bacillus CalmetteGuérin immunotherapy. J Intern Med. 2002;251:272–277. 4. Buchs N, Chevrel G, Miossec P. Bacillus Calmette-Guérin induced aseptic arthritis: an experimental model of reactive arthritis. J Rheumatol. 1998;25:1662–1665. 5. Mas AJ, Romera M, Valverde Garcia J. Articular manifestations after the administration of intravesical BCG. Joint Bone Spine. 2002;69:92–98. 6. Shoenfeld Y, Aron-Maor A, Tanai A, Ehrenfeld M. BCG and autoimmunity: another two-edged sword. J Autoimmun. 2001;16:235–240. 7. Smith MD, Chandran G, Parker A, et al. Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacillus Calmette-Guérin therapy. J Rheumatol. 1997;24:752–758. 8. Bartolomé Pacheco MJ, Martinez Taboada VM, Blanco R, Rodriguez Valverde V, Valle JI, López Hoyos M. Reactive arthritis after BCG immunotherapy: T cell analysis in peripheral blood and synovial fluid. Rheumatology. 2002;41:1119 –1125. 9. Baxter AG, Horsfall AC, Healey D, et al. Mycobacteria precipitate an SLE-like syndrome in diabetes-prone NOD mice. Immunology. 1994;83:227–231. 10. Engelman EG, Sonnenfield G, Dauphinee M. Treatment of NZB/NZW f1 hybrid mice with Mycobacterium bovis strain of BCG or type II interferon preparations accelerates autoimmune disease. Arthritis Rheum. 1981;323:1381–1387.

Lupus érythémateux disséminé survenant après 65 ans

Resume Propos. – Le lupus erythemateux dissemine revele chez des sujets âges a ete peu etudie (une serie de 21 patients de plus de 65 ans publiee). La prise en charge de cette maladie est-elle modifiee dans cette population ? Methodes. – Dix-sept cas de lupus ayant debute apres 65 ans et hospitalises entre 1988 et 2000 sont rapportes retrospectivement. Les resultats sont compares a ceux de sujets plus jeunes. Resultats. – Le sex-ratio femme/homme est a 1,83. L’âge moyen lors de la survenue du premier signe est de 71,9 ± 3,5 ans. La duree moyenne de suivi est de 3,5 ± 2,4 ans. Les principaux signes initiaux sont une alteration de l’etat general (41 %), des manifestations articulaires (35 %), cutanees (35 %), thromboemboliques (24 %) et des pleuresies (18 %). Le rash malaire est exceptionnel (12 %). La nephropathie n’est jamais revelatrice et rarement severe au cours de l’evolution. Comme pour les atteintes neurologiques, l’etiologie doit etre discutee en tenant compte des comorbidites. Sur le plan hematologique, la lymphopenie (82 % des patients) a une specificite contestable. Les anticorps antinucleaires sont constants, avec des anti-ADN natifs dans 82 % des cas, des anticorps anti-antigenes nucleaires solubles dans 50 %, un anticoagulant circulant dans 59 %. Le pronostic est difficile a estimer sur une petite serie, mais la probabilite de survie a 5 ans est de 83 %. La corticotherapie a entraine 50 % de complications graves. Conclusions. – Cette etude permet surtout d’insister sur les manifestations revelatrices particulieres du lupus erythemateux dissemine chez le sujet âge (alteration de l’etat general, thromboses, signes cutanes atypiques), ainsi que sur les difficultes specifiques du diagnostic differentiel et du traitement.

Detection of Antiendothelial Cell Antibodies by an Enzyme-Linked Immunosorbent Assay Using Antigens from Cell Lysate: Minimal Interference with Antinuclear Antibodies and Rheumatoid Factors

ABSTRACT The objective of the present work was to set up a routine test adapted to screening for antiendothelial cell antibodies (AECAs) in serum samples with minimal interference from antinuclear antibodies (ANAs) or rheumatoid factors (RFs). We compared the titers of AECAs titrated following two enzyme-linked immunosorbent assays (ELISAs): (i) an ELISA with ethanol-fixed EA.hy926 monolayers as the antigenic substrate and (ii) an ELISA with nucleus-depleted lysates prepared from EA.hy926 cells and normalized for protein (1.0 to 1.7 mg/ml) and DNA (≤0.1 μg/ml) contents as a surrogate substrate (postnuclear supernatant ELISA [PNS-ELISA]). The AECA titers in 51 serum samples, including 28 samples containing ANAs, were compared. A significantly positive correlation (r = 0.77; P < 0.001) between the two series was shown only for the ANA-negative serum samples. Conversely, ANAs or RFs in samples were shown not to interfere in tests for AECAs by the PNS-ELISA. AECAs recognize their antigenic targets in postnuclear supernatants, which is representative of the endothelial antigenic content, with improvement of the reliability of the assay, a prerequisite to application of the assay for their evaluation in clinical practice.

Méningites chroniques : étiologies, diagnostic et thérapeutique

Purpose. – Chronic meningitis are very uncommon and account for less than 10% of all meningitis cases. Their symptoms are uncunth and there outcome is insidious. Therefore, they remain often unknown. There are only a few published reports on this disease, so diagnosis and therapeutic approachs are difficult. Current knowledge and key points. – Positive chronic meningitis diagnosis is easy. However, determining the cause of chronic meningitis remains dilemma, as many infectious and noninfectious processes (including inflammatory, neoplastic or autoimmune aetiologies or as a result of a chemical exposure) can result in the chronic meningitis syndrome. In order to institute a pertinent treatment, sometimes urgently needed, diagnostic approach must be extremely rigourous and accutely orientated. Nevertheless, although extensive investigations, 30% of the aetiologies remain undetermined. Only two choices are left for the medical physician: an aggressive attitude based on complementary investigations or a contemplated therapy with a close clinical and biological control. On the other hand, when the patients condition is quickly deterioring without a clear and proved aetiology, it is sometimes necessary to institute an empirical treatment, not always properly determined and sometimes contreversial. Besides, few reports on prognosis and outcome od idiopathic chronic meningitis have been published. Future prospects and projects. – After a review of aetiologies and diagnostic investigations chronic meningitis, we propose a practical experience attitude about management and treatment of chronic meningitis. Thus, large-scale studies about the follow up chronic meningitis in long term, in particular those without aetiology, treated or no, should improve the outcome of this chonic syndrom.

Contribution of anti-Hsp70.1 IgG Antibody Levels to the Diagnostic Certainty of Clinically Suspected Ocular Toxoplasmosis

PURPOSE Laboratory diagnosis of ocular toxoplasmosis, the major cause of posterior uveitis worldwide, can be improved. Heat shock protein (Hsp) 70 is involved in cellular infection by Toxoplasma gondii but also in the immune response to this parasite. The authors postulate that infected patients may exhibit serum IgG anti-Hsp70.1 antibodies and that determining the presence of these antibodies could improve the diagnosis of suspected ocular toxoplasmosis. METHODS This retrospective case-control study included 26 laboratory-confirmed cases of ocular toxoplasmosis (group A), 41 clinically suspected cases (group B), and 67 currently healthy blood donors who were chronically infected with T. gondii (group C). Laboratory and clinical data were analyzed according to the ocular presentation and Goldmann-Witmers coefficient. Serum and aqueous humor were sampled at the time of uveitis. Serum anti-Hsp70.1 antibody levels were obtained by ELISA. The probability of ocular toxoplasmosis was estimated by a logistic regression analysis that combined data from serum IgG anti-Hsp70.1 and aqueous-humor IgG anti-T. gondii antibody levels. RESULTS Serum IgG anti-Hsp70.1 antibody levels were significantly increased in groups A and B when compared to the levels in control group C (P ≤ 0.0034). These levels correlated with the retinal lesion size (r = 0.301; P < 0.0349). Logistic probability and anti-Hsp70.1 antibodies in sera confirmed that 10 of 23 cases in group B were true ocular toxoplasmosis. CONCLUSIONS Anti-Hsp70 may play a role in the immunopathogenesis of ocular Toxoplasma infection. This study showed that the anti-Hsp70.1 antibody and the logistic probability test can confirm clinically suspected ocular toxoplasmosis.

Sclérose tubéreuse de Bourneville sans altération intellectuelle, diagnostiquée à l'âge adulte

INTRODUCTION Tuberous sclerosis complex (TSC) is an autosomal dominant inherited phakomatosis, usually diagnosed in childhood and characterized by cutaneous and neurological tumors, the latter often leading to epilepsy and mental retardation. EXEGESIS We report a case of TSC diagnosed in a 33-year-old man, without any known family history of phakomatosis, presenting with facial angiofibromas, hypomelanotic macules, a giant-cell astrocytoma and retinal phakomas without any mental impairment or epilepsy. CONCLUSION TSC may occur in patients who do not have any family history of phakomatosis because de novo mutations are frequent. TSC may be diagnosed in adulthood since a high phenotypic variability is observed. Facial angiofibromas are highly suggestive of tuberous sclerosis complex. They should lead to brain imaging in search for astrocytoma, subependymal nodules and cortical tubers which number is directly correlated with the risk of seizures and the degree of mental impairment.

Unusual Evolution in Wegener's Granulomatosis: Recovery of Pulmonary Involvement While Renal Disease Progressed to End-Stage

A 54-year-old male patient was admitted for acute respiratory distress with fever. He was suffering from chronic sinusitis/rhinitis and had persistent otitis for the past 2 months before admission despite several antibiotics courses. He developed a complex pulmonary involvement (embolism and diffuse alveolar hemorrhage) with acute glomerular disease (proteinuria and hematuria but initially no renal failure). Clinical suspicion of Wegener’s granulomatosis was confirmed by the positive high titer of antineutrophil cytoplasmic antibodies (c-ANCA with antiproteinase 3 specificity) and despite a negative nasal biopsy. Treatment including cyclophosphamide and methylprednisolone intravenous pulses permitted pulmonary recovery over 4 weeks contrasting with the development of rapidly progressive glomerulonephritis and polyneuropathy of lower limbs. Renal biopsy showed pauci-immune crescentic and necrotizing glomerulonephritis. However, despite additional plasma exchanges, acute kidney injury worsened and the patient ended up in dialysis. Such a dissociated evolution was unexpected in this case since pulmonary and renal involvements reflected the same pathological process (small vessels vasculitis/capillaritis) and the same pathogenic mechanism (antiproteinase 3 autoantibodies).

Organising pneumonia and mesenteric plasmocytoma: a fortuitous association?

Pathophysiologically [1] organising pneumonia (OP) involves filling of the lumen of the distal air spaces by tissue containing inflammatory cells, fibroblasts and myofibroblasts in a relatively non-dense extracellular matrix. Its particular feature is its low content of type I collagen, probably explaining why the intra-alveolar structures are reversible. It has three clinical forms, the most classical of which involves multiple alveolar opacifications mimicking infectious pneumonia and often migratory (formerly known as bronchiolitis obliterans organizing pneumonia [BOOP]): the two other, rarer forms, are the pseudoneoplastic nodular forms (with single or multiple nodules) and the infiltrating form. The standard treatment is corticosteroid therapy to which they are generally sensitive. The occasional relapses can be treated with immunosuppressants including cyclophosphamide and azathioprine. The diagnosis requires a lung biopsy. OP can be cryptogenic (with no identified cause) or may occur in defined situations: medicinal products, infections and connective tissue diseases. Haematological diseases can occasionally be associated with OP. We describe the case of a 66-year-old female patient who presented with concomitant nodular OP and mesenteric plasmocytoma.