Allergo-immunologie. 1. Nouveautés dans le traitement des crises aiguës d'angioedème héréditaire [Allergy-immunology. New therapies for acute attacks in hereditary angioedema].

Hereditary angioedema is a disease which develops as a result of a deficiency or dysfonction of C1-inhibitor, a key regulator of the complement, coagulation and contact cascades, resulting among others in excessive release of bradykinin. This disease mortality rate is high in absence of immediate and effective treatment, in particular in presence of acute attacks of the upper respiratory tract (laryngeal edema). Until now only administration of a purified C1-inhibitor extract was effective against these symptoms. This paper aims to synthesise essentials knowledge concerning news drugs, in particular icatibant, a selective bradykinin B2- receptor antagonist whose use should be widened to the treatment of angioedema with ACE-inhibitors intolerance.

Effects of intracutaneous injections of sterile water in patients with acute low back pain: a randomized, controlled, clinical trial

Intracutaneous sterile water injection (ISWI) is used for relief of low back pain during labor, acute attacks of urolithiasis, chronic neck and shoulder pain following whiplash injuries, and chronic myofascial pain syndrome. We conducted a randomized, double-blinded, placebo-controlled trial to evaluate the effect of ISWI for relief of acute low back pain (aLBP). A total of 68 patients (41 females and 27 males) between 18 and 55 years old experiencing aLBP with moderate to severe pain (scores ≥5 on an 11-point visual analogue scale [VAS]) were recruited and randomly assigned to receive either ISWIs (n=34) or intracutaneous isotonic saline injections (placebo treatment; n=34). The primary outcome was improvement in pain intensity using the VAS at 10, 45, and 90 min and 1 day after treatment. The secondary outcome was functional improvement, which was assessed using the Patient-Specific Functional Scale (PSFS) 1 day after treatment. The mean VAS score was significantly lower in the ISWI group than in the control group at 10, 45, and 90 min, and 1 day after injection (P<0.05, t-test). The mean increment in PSFS score of the ISWI group was 2.9±2.2 1 day after treatment, while that in the control group was 0.9±2.2. Our study showed that ISWI was effective for relieving pain and improving function in aLBP patients at short-term follow-up. ISWI might be an alternative treatment for aLBP patients, especially in areas where medications are not available, as well as in specific patients (e.g., those who are pregnant or have asthma), who are unable to receive medications or other forms of analgesia because of side effects.

A single nucleotide deletion at the C1 inhibitor gene as the cause of hereditary angioedema: insights from a Brazilian family

Background: Hereditary angioedema is an autosomal dominant disease characterized by episodes of subcutaneous and submucosal edema. It is caused by deficiency of the C1 inhibitor protein, leading to elevated levels of bradykinin. More than 200 mutations in C1 inhibitor gene have been reported. The aim of this study was to analyze clinical features of a large family with an index case of hereditary angioedema and to determine the disease-causing mutation in this family. Methods: Family pedigree was constructed with 275 individuals distributed in five generations. One hundred and sixty-five subjects were interviewed and investigated for mutation at the C1 inhibitor gene. Subjects reporting a history of recurrent episodes of angioedema and/or abdominal pain attacks underwent evaluation for hereditary angioedema. Results: We have identified a novel mutation at the C1 inhibitor gene, c.351delC, which is a single-nucleotide deletion of a cytosine on exon 3, resulting in frameshift with premature stop codon. Sequencing analysis of the hypothetical truncated C1 inhibitor protein allowed us to conclude that, if transcription occurs, this protein has no biological activity. Twenty-eight members of the family fulfilled diagnostic criteria for hereditary angioedema and all of them presented the c.351delC mutation. Variation in clinical presentation and severity of disease was observed among these patients. One hundred and thirty-seven subjects without hereditary angioedema did not have the c.351delC mutation. Conclusion: The present study provides definitive evidence to link a novel genetic mutation to the development of hereditary angioedema in patients from a Brazilian family.

Dor abdominal aguda como apresentação de porfirias

As porfirias são um grupo de oito doenças metabólicas raras, em resultado de uma deficiência enzimática em cada uma das oito enzimas envolvidas na biossíntese do grupo heme. São doenças maioritariamente hereditárias, mas podem também ser adquiridas aquando da exposição a certos fatores ambientais e/ou patológicos. Estes fatores externos, denominados de porfirinogénicos também têm um papel preponderante no diagnóstico das porfirias, uma vez que mimetizam os sintomas clínicos de um ataque agudo de porfiria, contribuindo para subestimar esta doença, levando a um atraso no diagnóstico e diminuído o sucesso do prognóstico. Os ataques agudos de porfiria, nomeadamente na porfiria aguda intermitente, porfiria variegata, coproporfiria hereditária, e deficiência da desidratase do ácido delta-aminolevulínico, apesar de serem doenças multissistémicas, têm em comum como apresentação clínica, a dor abdominal aguda. A pesquisa de porfobilinogénio (PBG) na urina, através da realização do teste de Hoesch, é uma forma rápida e fácil de excluir a suspeita clínica de porfiria. Pretendemos com este trabalho, alertar para a necessidade de um diagnóstico laboratorial atempado, que pela sua simplicidade poderá descartar ou confirmar se a dor abdominal aguda, tão frequente nas urgências hospitalares, será ou não uma manifestação clínica de um ataque agudo de porfiria. Este estudo contribuirá não só para aumentar o nosso conhecimento acerca destas doenças, como também permitirá uma melhor compreensão dos mecanismos de patogenicidade das porfirias, o qual ainda permanece pouco conhecido.

Efficacy and Safety of Canakinumab Vs Triamcinolone Acetonide in Patients with Gouty Arthritis Unable to Use Nonsteroidal Anti-Inflammatory Drugs and Colchicine, and On Stable Urate Lowering Therapy (ULT) or Unable to Use ULT

Background/Purpose: The primary treatment goals for gouty arthritis (GA) are rapid relief of pain and inflammation during acute attacks, and long-term hyperuricemia management. A post-hoc analysis of 2 pivotal trials was performed to assess efficacy and safety of canakinumab (CAN), a fully human monoclonal anti-IL-1_ antibody, vs triamcinolone acetonide (TA) in GA patients unable to use NSAIDs and colchicine, and who were on stable urate lowering therapy (ULT) or unable to use ULT. Methods: In these 12-week, randomized, multicenter, double-blind, double-dummy, active-controlled studies (_-RELIEVED and _-RELIEVED II), patients had to have frequent attacks (_3 attacks in previous year) meeting preliminary GA ACR 1977 criteria, and were unresponsive, intolerant, or contraindicated to NSAIDs and/or colchicine, and if on ULT, ULT was stable. Patients were randomized during an acute attack to single dose CAN 150 mg s.c. or TA 40 mg i.m. and were redosed "on demand" for each new attack. Patients completing the core studies were enrolled into blinded 12-week extension studies to further investigate on-demand use of CAN vs TA for new attacks. The subpopulation selected for this post-hoc analysis was (a) unable to use NSAIDs and colchicine due to contraindication, intolerance or lack of efficacy for these drugs, and (b) currently on ULT, or contraindication or previous failure of ULT, as determined by investigators. Subpopulation comprised 101 patients (51 CAN; 50 TA) out of 454 total. Results: Several co-morbidities, including hypertension (56%), obesity (56%), diabetes (18%), and ischemic heart disease (13%) were reported in 90% of this subpopulation. Pain intensity (VAS 100 mm scale) was comparable between CAN and TA treatment groups at baseline (least-square [LS] mean 74.6 and 74.4 mm, respectively). A significantly lower pain score was reported with CAN vs TA at 72 hours post dose (1st co-primary endpoint on baseline flare; LS mean, 23.5 vs 33.6 mm; difference _10.2 mm; 95% CI, _19.9, _0.4; P_0.0208 [1-sided]). CAN significantly reduced risk for their first new attacks by 61% vs TA (HR 0.39; 95% CI, 0.17-0.91, P_0.0151 [1-sided]) for the first 12 weeks (2nd co-primary endpoint), and by 61% vs TA (HR 0.39; 95% CI, 0.19-0.79, P_0.0047 [1-sided]) over 24 weeks. Serum urate levels increased for CAN vs TA with mean change from baseline reaching a maximum of _0.7 _ 2.0 vs _0.1 _ 1.8 mg/dL at 8 weeks, and _0.3 _ 2.0 vs _0.2 _ 1.4 mg/dL at end of study (all had GA attack at baseline). Adverse Events (AEs) were reported in 33 (66%) CAN and 24 (47.1%) TA patients. Infections and infestations were the most common AEs, reported in 10 (20%) and 5 (10%) patients treated with CAN and TA respectively. Incidence of SAEs was comparable between CAN (gastritis, gastroenteritis, chronic renal failure) and TA (aortic valve incompetence, cardiomyopathy, aortic stenosis, diarrohea, nausea, vomiting, bicuspid aortic valve) groups (2 [4.0%] vs 2 [3.9%]). Conclusion: CAN provided superior pain relief and reduced risk of new attack in highly-comorbid GA patients unable to use NSAIDs and colchicine, and who were currently on stable ULT or unable to use ULT. The safety profile in this post-hoc subpopulation was consistent with the overall _-RELIEVED and _-RELIEVED II population.

Gout: why is this curable disease so seldom cured?

Gout is the most common inflammatory arthritis and one in which pathogenesis and risk factors are best understood. One of the treatment objectives in current guidelines is 'cure'. However, audits show that only a minority of patients with gout receive adequate advice and treatment. Suboptimal care and outcomes reflect inappropriately negative perceptions of the disease, both in patients and providers. Historically, gout has been portrayed as a benign and even comical condition that is self-inflicted through overeating and alcohol excess. Doctors often focus on managing acute attacks rather than viewing gout as a chronic progressive crystal deposition disease. Urate-lowering treatment is underprescribed and often underdosed. Appropriate education of patients and doctors, catalysed by recent introduction of new urate-lowering treatments after many years with no drug development in the field, may help to overcome these barriers and improve management of this easily diagnosed and curable form of potentially severe arthritis.

Neurologie [Neurology].

In 2015, cerebral stimulation becomes increasingly established in the treatment of pharmacoresistant epilepsy. Efficacy of endovascular treatment has been demonstrated for acute ischemic stroke. Deep brain stimulation at low frequency improves dysphagia and freezing of gait in Parkinson patients. Bimagrumab seems to increase muscular volume and force in patients with inclusion body myositis. In cluster-type headache, a transcutaneous vagal nerve stimulator is efficient in stopping acute attacks and also reducing their frequency. Initial steps have been undertaken towards modulating memory by stimulation of the proximal fornix. Teriflunomide is the first oral immunomodulatory drug for which efficacy has been shown in preventing conversion from clinical isolated syndrome to multiple sclerosis.

Aquaporin-4 Antibodies Are Not Related to HTLV-1 Associated Myelopathy

Introduction: The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1) is very high among Brazilians (,1:200). HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the most common neurological complication of HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be confused with lesions seen in aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorders (NMOSD) on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around 30% of cases. Objective: To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection in patients with NMOSD. Patients and Methods: 23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for HTLV-1 by ELISA and Western blotting. Results: 20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two groups. Conclusions: Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence.

Icatibant , the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

INTRODUCTION: HOE-140/ Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency. AREAS COVERED: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin-receptor interactions. EXPERT OPINION: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.

Optic neuritis in pediatric population: A review in current tendencies of diagnosis and management

Optic neuritis is an inflammation of the optic nerve and may be related to different systemic conditions. The clinical presentation of this pathology usually includes sudden loss of visual acuity (VA) which may be unilateral or bilateral, visual field restriction, pain with eye movements, dyschromatopsia, a relative afferent pupillary defect and optic disk swelling. Optic neuritis in children has specific clinical features and a better prognosis than in adulthood. Although usually appears an underlying viral disease, the main concern for practitioners is the relationship of optic neuritis with multiple sclerosis. In addition to the classical techniques as magnetic resonance imaging (MRI), current tendencies of diagnosis for eye practitioners include new imaging devices as optical coherence tomography (OCT), useful to show a thinning of the retinal fibers layer (RFL) after the inflammatory episode. Regarding the management of these patients, short-term intravenous steroid dosages seem to be the best option to treat acute attacks characterized by a very poor bilateral VA.

[Acute asthma attacks in childhood]

The diagnosis of an acute asthmatic attack in a child is made on a clinical basis. The severity of the exacerbation can be assessed by physical examination and measurement of the transcutaneous oxygenation saturation. A blood gas analysis can be helpful in this assessment. A child with a severe asthma exacerbation should be promptly referred to an emergency department of a hospital. Oxygen should be given to keep the oxygen saturation above 92% and short-acting, selective beta-2 agonists should be administered. Beta-2 agonists can be delivered by intermittent nebulization, continuous nebulization or by metered dose inhaler (MDI) with a spacer They can also be given intravenously in patients who are unresponsive to escalating therapy. The early administration of systemic corticosteroids is essential for the management of acute asthma in children. When tolerated, systemic corticoseroids can be given orally but inhaled corticosteroids are not recommended. Oxygen delivery, beta-2 agonists and steroid therapy are the mainstay of emergency treatment. Hypovolemia should be corrected either intravenously or orally. Administration of multiple doses of ipratropium bromide has been shown to decrease the hospitalization rate in children and adolescents with severe asthma. Clinical response to initial treatment is the main criterion for hospital admission. Patients with failure to respond to treatment should be transferred to an intensive care unit. A critical aspect of management of the acute asthma attack in a child is the prevention of similar attacks in the future.

Low urinary 6-sulphatoxymelatonin concentrations in acute migraine

Substantial evidence points to melatonin as playing a role in the regulation of circadian rhythms, sleep, and headache disorders. The objective of the study was to assess 6-sulphatoxymelatonin (aMT6s) levels in a large consecutive series of patients with migraine, comparing with controls. A total of 220 subjects were evaluated-146 had migraine and 74 were control subjects. Urinary samples were collected into the same plastic container since 8:00 p.m. to 8:00 a.m. of the next day (12-h period) and aMT6s was measured with quantitative ELISA technique. Among patients with migraine, 53% presented pain on the day of the urine samples collection. Their urinary aMT6s concentration was significantly lower than in the urine of patients without pain [14.0 +/- 7.3 vs. 49.4 +/- 19.0; t(143) = -15.1; 95% CI = -40.0 to -30.8; P<0.001]. There was no significant difference in the aMT6s concentration of patients with migraine without pain on the day of their urine samples collection and controls [49.4 +/- 19.0 vs. 42.5 +/- 27.9; t(140) = 1.7; 95% CI = -1.2 to 14.8; P = 0.094]. To our knowledge, this is the first study to demonstrate reduction in melatonin levels during attacks in episodic and chronic migraine.

Influence of environmental temperature and humidity on the acute ventilatory response to exercise in asthmatic adolescents

Asthma is a chronic inflammatory disorder of the respiratory airways affecting people of all ages, and constitutes a serious public health problem worldwide (6). Such a chronic inflammation is invariably associated with injury and repair of the bronchial epithelium known as remodelling (11). Inflammation, remodelling, and altered neural control of the airways are responsible for both recurrent exacerbations of asthma and increasingly permanent airflow obstruction (11, 29, 34). Excessive airway narrowing is caused by altered smooth muscle behaviour, in close interaction with swelling of the airway walls, parenchyma retractile forces, and enhanced intraluminal secretions (29, 38). All these functional and structural changes are associated with the characteristic symptoms of asthma – cough, chest tightness, and wheezing –and have a significant impact on patients’ daily lives, on their families and also on society (1, 24, 29). Recent epidemiological studies show an increase in the prevalence of asthma, mainly in industrial countries (12, 25, 37). The reasons for this increase may depend on host factors (e.g., genetic disposition) or on environmental factors like air pollution or contact with allergens (6, 22, 29). Physical exercise is probably the most common trigger for brief episodes of symptoms, and is assumed to induce airflow limitations in most asthmatic children and young adults (16, 24, 29, 33). Exercise-induced asthma (EIA) is defined as an intermittent narrowing of the airways, generally associated with respiratory symptoms (chest tightness, cough, wheezing and dyspnoea), occurring after 3 to 10 minutes of vigorous exercise with a maximal severity during 5 to 15 minutes after the end of the exercise (9, 14, 16, 24, 33). The definitive diagnosis of EIA is confirmed by the measurement of pre- and post-exercise expiratory flows documenting either a 15% fall in the forced expiratory volume in 1 second (FEV1), or a ≥15 to 20% fall in peak expiratory flow (PEF) (9, 24, 29). Some types of physical exercise have been associated with the occurrence of bronchial symptoms and asthma (5, 15, 17). For instance, demanding activities such as basketball or soccer could cause more severe attacks than less vigorous ones such as baseball or jogging (33). The mechanisms of exercise-induced airflow limitations seem to be related to changes in the respiratory mucosa induced by hyperventilation (9, 29). The heat loss from the airways during exercise, and possibly its post-exercise rewarming may contribute to the exercise-induced bronchoconstriction (EIB) (27). Additionally, the concomitant dehydration from the respiratory mucosa during exercise leads to an increased interstitial osmolarity, which may also contribute to bronchoconstriction (4, 36). So, the risk of EIB in asthmatically predisposed subjects seems to be higher with greater ventilation rates and the cooler and drier the inspired air is (23). The incidence of EIA in physically demanding coldweather sports like competitive figure skating and ice hockey has been found to occur in up to 30 to 35% of the participants (32). In contrast, swimming is often recommended to asthmatic individuals, because it improves the functionality of respiratory muscles and, moreover, it seems to have a concomitant beneficial effect on the prevalence of asthma exacerbations (14, 26), supporting the idea that the risk of EIB would be smaller in warm and humid environments. This topic, however, remains controversial since the chlorified water of swimming pools has been suspected as a potential trigger factor for some asthmatic patients (7, 8, 20, 21). In fact, the higher asthma incidence observed in industrialised countries has recently been linked to the exposition to chloride (7, 8, 30). Although clinical and epidemiological data suggest an influence of humidity and temperature of the inspired air on the bronchial response of asthmatic subjects during exercise, some of those studies did not accurately control the intensity of the exercise (2, 13), raising speculation of whether the experienced exercise overload was comparable for all subjects. Additionally, most of the studies did not include a control group (2, 10, 19, 39), which may lead to doubts about whether asthma per se has conditioned the observed results. Moreover, since the main targeted age group of these studies has been adults (10, 19, 39), any extrapolation to childhood/adolescence might be questionable regarding the different lung maturation. Considering the higher incidence of asthma in youngsters (30) and the fact that only the works of Amirav and coworkers (2, 3) have focused on this age group, a scarcity of scientific data can be identified. Additionally, since the main environmental trigger factors, i.e., temperature and humidity, were tested separately (10, 28, 39) it would be useful to analyse these two variables simultaneously because of their synergic effect on water and heat loss by the airways (31, 33). It also appears important to estimate the airway responsiveness to exercise within moderate environmental ranges of temperature and humidity, trying to avoid extreme temperatures and humidity conditions used by others (2, 3). So, the aim of this study was to analyse the influence of moderate changes in air temperature and humidity simultaneously on the acute ventilatory response to exercise in asthmatic children. To overcome the above referred to methodological limitations, we used a 15 minute progressive exercise trial on a cycle ergometer at 3 different workload intensities, and we collected data related to heart rate, respiratory quotient, minute ventilation and oxygen uptake in order to ensure that physiological exercise repercussions were the same in both environments. The tests were done in a “normal” climatic environment (in a gymnasium) and in a hot and humid environment (swimming pool); for the latter, direct chloride exposition was avoided.

Acute renal failure after massive honeybee stings

Two clinical cases of patients who survived after numerous attacks of Africanized bees (600 and 1500 bee stings, respectively) are reported. Clinical manifestation was characterized by diffuse and widespread edema, a burning sensation in the skin, headache, weakness, dizziness, generalized paresthesia, somnolence and hypotension. Acute renal failure developed and was attributed to hypotension, intravascular hemolysis, myoglobinuria due to rhabdomyolysis and probably to direct toxic effect of the massive quantity of injected venom. They were treated with antihistaminic, corticosteroids and fluid infusion. One of them had severe acute renal failure and dialysis was required. No clinical complication was observed during hospital stay and complete renal function recovery was observed in both patients. In conclusion, acute renal failure after bee stings is probably due to pigment nephropathy associated with hypovolemia. Early recognition of this syndrome is crucial to the successful management of these patients.

Aseptic meningoencephalitis mimicking transient ischaemic attacks.

PURPOSE: To highlight meningoencephalitis as a transient ischaemic attack (TIA) mimic and suggest clinical clues for differential diagnosis. METHODS: This was an observational study of consecutively admitted patients over a 9.75-year period presenting as TIAs at a stroke unit. RESULTS: A total of 790 patients with TIAs and seven with TIA-like symptoms but a final diagnosis of viral meningoencephalitis were recognised. The most frequent presentations of meningoencephalitis patients were acute sensory hemisyndrome (6) and cognitive deficits (5). Signs of meningeal irritation were minor or absent on presentation. Predominantly lymphocytic pleocytosis, hyperproteinorachia and a normal cerebrospinal fluid (CSF)/serum glucose index (in 5 out of 6 documented patients) were present. Meningeal thickening on a brain magnetic resonance imaging (MRI) scan was the only abnormal imaging finding. Six patients received initial vascular treatment; one thrombolysed. Finally, six patients were treated with antivirals and/or antibiotics. Although neither bacterial nor viral agents were identified on extensive testing, viral meningoencephalitis was the best explanation for all clinical and laboratory findings. CONCLUSIONS: Aseptic meningoencephalitis should be part of the differential diagnosis in patients presenting as TIA. The threshold for a lumbar puncture in such patients should be set individually and take into account the presence of mild meningeal symptoms, age and other risk factors for vascular disease, the results of brain imaging and the basic diagnostic work-up for a stroke source.