OBJECTIVES:Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS:The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS:66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS:Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER:NCT02339441.

Study objective: Hereditary angioedema is a rare disease associated with unpredictable, recurrent attacks of potentially life-threatening edema. Management of severe attacks is currently suboptimal because emergency medical teams are often unaware of new specific treatments. The objective of this trial is to test whether a dedicated national telephone care-management strategy would reduce resource use during severe hereditary angioedema attacks. Methods: We conducted a cluster-randomized multicenter prospective trial of patients with a documented diagnosis of hereditary angioedema (type I, II or FXII hereditary angioedema). Participants were enrolled between March 2013 and June 2014 at 8 participating reference centers. The randomized units were the reference centers (clusters). Patients in the intervention arm were given a national free telephone number to call in the event of a severe attack. Emergency physicians in the SOS-hereditary angicedema (SOS-HAE) call center were trained to advise or prescribe specific treatments. The primary outcome was number of admissions for angioedema attacks. Economic evaluation was also performed. Results: We included 100 patients in the SOS-HAE group and 100 in the control group. During the 2 years, there were 2,368 hereditary angioedema attacks among 169 patients (85%). Mean number of hospital admissions per patient in the 2-year period was significantly greater in the usual-practice group (mean 0.16 [range 0 to 2] versus 0.03 [range 0 to 1]); patient risk difference was significant: -0.13 (95% confidence interval -0.22 to -0.04; P=.02). Probabilistic sensitivity graphic analysis indicated a trend toward increased quality-adjusted life-years in the SOS-HAE group. Conclusion: A national dedicated call center for management of severe hereditary angioedema attacks is associated with a decrease in hospital admissions and may be cost-effective if facilities and staff are available to deliver the intervention alongside existing services.

Background The prevalence of gastrointestinal involvement in systemic sclerosis is higher than 75%. The estimated prevalence of fecal incontinence varies from 22% to 77%, but suffers from recruitment bias and patient reluctance. Our goal was to evaluate the prevalence of fecal incontinence in systemic sclerosis, and to identify associated risk factors. Methods Patients were recruited in the referral systemic sclerosis network of the Lyon University Hospitals, using self-administered questionnaires including constipation, fecal incontinence and Bristol Stool scales, quality of life, anxiety and depression. The cohort was compared with the historical ORALIA cohort that established the prevalence of fecal incontinence in the general population of the Rhône-Alpes region (France). Results Seventy-seven patients were included (mean age: 60 years, range: 32–84), and 86% were female. These were compared to 153 ORALIA individuals matched for age and sex. Fecal incontinence was present in 38% of patients and 6% of the general population. A longer duration of systemic sclerosis was the only characteristic associated with fecal incontinence. Abnormal stool consistency was more frequent in patients with fecal incontinence. Conclusion Fecal incontinence and abnormal stool consistency are common in systemic sclerosis and should be systematically addressed.

Objectives. Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods. Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results. The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (rho = 0.34, P < 0.0001 and rho = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (rho = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (rho = 0.40, P < 0.0001), decreasing hand function (rho = 0.57, P < 0.0001) and increasing fatigue (rho = -0.53, P < 0.0001). Conclusion.The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

Objectives The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. Methods This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or ‘no immunosuppressant’. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. Results Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: −4.0 (−5.2 to −2.7) units for methotrexate, −4.1 (−5.3 to −2.9) for MMF, −3.3 (−4.9 to −1.7) for cyclophosphamide and −2.2 (−4.0 to −0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. Conclusions These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. Trial registration number NCT02339441.

The 10th C1-inhibitor deficiency workshop will be held between 18 and 21 May 2017 in Budapest (2017.haenetworkshop.hu),among the picturesque surroundings of Margaret Island.As indicated by the name of this event, most of the interest focused on angioedema due to C1-inhibitor deficiency in 1999, when it was first organized.The name is unchanged, but the range of angioedemas has expanded since to include all known varieties of hereditary and acquired angioedemas with a bradykinin-mediated pathomechanism.Looking back to the agenda of this biennial conference, many questions remained unanswered and new issues have arisen despite the enormous scientific progress made.On this occasion, 318 participants have registered from 42 countriesthis is the greatest attendance in the history of the Workshop since the start of the series.Eighty-six presentations have been submitted for this 4-day long scientific forum.The scientific program sounds interesting-it comprises novel achievements by leading scientific teams in basic research into bradykinin-mediated angioedema, the new findings of diagnostics and genetics, promising therapeutic solutions awaiting introduction, and the experience accumulated with the latest therapeutic procedures.Several presentations discuss the efforts related to improving the patients' quality of life.This time, we have invited five prominent experts-namely, Alvin Schmaier (Cleveland, OH, USA), Marco Cicardi (Milan, Italy), Avner Reshef (Tel-Hashomer, Israel), Dumitru Moldovan (Tirgu-Mures, Romania) and Attila Mócsai (Budapest, Hungary).Alvin Schmaier will show us that our knowledge about the underlying mechanisms of bradykinin-mediated angioedemas is still limited-this may be remedied by extending our interest to other forms of angioedema with different pathophysiological backgrounds.Marco Cicardi will expose the similarities and the differences between bradykinin-mediated edema formation, and the idiopathic systemic capillary leak syndrome.Avner Reshef will explore a similar issue in his presentation titled 'Angioedema-Histamine or Bradykinin?' .The lecture on neutrophil granulocytes by Attila Mócsai will take us closer to understanding the pathomechanism of angioedema.The agenda also contains the traditional roundtable session, an opportunity to develop consensus and international guidelines-this year, genetics will be in the limelight.In this session, the keynote lectures will be read by Margarita-Lopez Trascasa (Madrid, Spain) on the extended diagnostic approach integrating serological and genetic methodology; by Anastasios Germenis (Larissa, Greece) on the latest techniques for studying the SERPING1 gene; and by Nancy Brown (Nashville, TN, USA) on the pharmacogenetics of angiotensin-converting enzyme inhibitor-associated angioedema.Notwithstanding the remarkable progress made in South-America and in the former Soviet-bloc countries of Europe, state-of-the-art diagnostic and therapeutic modalities are still not available in many regions of the World.Dumitru Moldovan will review the stages along the way to making these accessible, and the experience accumulated in the effort to achieve high levels of patient care.The conference will be attended both by researchers and by clinicians-medical professionals and nurses, by the representatives of patient organizations, and by pharmaceutical industry experts involved in drug development, in order to assist the efforts of each other through joint thinking.Within the framework of this fruitful cooperation, the pharmaceutical companies also lent financial support to the conference-in addition to their scientific contribution.The travel grants, make it possible for an increasing number of professionals involved in the research or the management of patients with angioedema to attend the Workshop.The generous support by our Sponsors enabled us again to present the "For HAE Patients" award, as well as the "Grant for Young Investigators".The major donors to this event are CSL Behring and Shire.Pharming Group NV, Swedish Orphan Biovitrum, BioCryst Phamaceuticals, KininX SAS also contributed the sponsorship of the Workshop.On occasion of this tenth, jubilee event, the "For HAE Patients" award goes to Bruce Zuraw (San Diego, USA), who will present his lecture 'Let the Treatment Fit the Disease' on the festive session of the scientific section on Day 1.His achievements in bettering the management of patients will be recalled by Antony Castaldo, the chair of the International Patient Organization for C1 Inhibitor Deficiencies.The concluding event of the conference will be the awarding of the 'Grant for Young Investigators' to the top four young presenters.The support referred to above made it possible to publish the submitted abstracts of the Workshop in the journal Allergy, Asthma, and Clinical Immunology, in order to make them available to an even broader range of professionals interested in this subject.

L'hématopoïèse extra-médullaire est une affection rare correspondant au développement ectopique de tissu hématopoïétique en dehors de la moelle osseuse en réponse à une hyperstimulation médullaire. Il s'agit d'un mécanisme compensateur lié à la production insuffisante de cellules sanguines par la moelle osseuse, ou à la destruction de celles-ci en cas d'hémolyse chronique dans un contexte de thalassémie ou de sphérocytose héréditaire, rarement de drépanocytose. Ce phénomène survient principalement dans des sites d'hématopoïèse embryonnaires (rate, foie, ganglions lymphatiques), parfois dans d'autres organes comme les reins, les poumons et le tube digestif. La localisation surrénalienne est inhabituelle. Un volumineuse masse surrénalienne droite avec insuffisance surrénalienne périphérique a été découverte chez une femme de 28 ans suivie pour une drépanocytose homozygote SS. Le bilan radiologique (scanner et scintigraphie aux colloïdes marqués) était en faveur d'un foyer d'hématopoïèse extra-médullaire. Devant l'augmentation progressive et symptomatique de la taille de la lésion, une surrénalectomie a été réalisée avec un examen histologique qui confirmait ce diagnostic. Notre observation décrit un cas exceptionnel d'hématopoïèse extra-médullaire surrénalienne chez une patiente drépanocytaire. Le diagnostic doit être évoqué devant une masse surrénalienne sur un terrain d'hémoglobinopathie.

Despite the availability of guidelines for the specific treatment of hereditary angioedema (HAE) attacks, HAE morbidity and mortality rates remain substantial. HAE attacks are a major medical issue requiring specific treatment as well as a considerable socio-economic burden. We report a protocol designed to test whether a dedicated call centre is more effective than usual practice in the management of patients experiencing an HAE attack.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyomavirus (JCPyV) in immunocompromised patients, including solid organ transplant recipients. We report 2 cases of PML late after liver transplantation (144 and 204 months) and review the few other published cases. The clinical course of PML is characterized by a rapid progressive neurological decline coinciding with the presence of white matter lesions on magnetic resonance images. No direct antiviral therapy is available against the JCPyV. The prognosis is therefore extremely poor. Restoration of the immune response achieved by tapering or ending the immunosuppressive therapy is the basis of treatment in transplanted patients. One of our patients is alive 3 years after diagnosis after total withdrawal of immunosuppressive therapy. The other presented severe rejection when tapering immunosuppression and died 26 months after diagnosis.

The aim of this study was to describe the clinical and biological features of Mevalonate kinase deficiency (MKD) in patients diagnosed in adulthood. This is a French and Belgian observational retrospective study from 2000 to 2014. To constitute the cohort, we cross-check the genetic and biochemical databases. The clinical, enzymatic, and genetic data were gathered from medical records. Twenty-three patients were analyzed. The mean age at diagnosis was 40 years, with a mean age at onset of symptoms of 3 years. All symptomatic patients had fever. Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). One patient developed recurrent seizures. Three patients experienced renal involvement (13.6%). Two patients had angiomyolipoma (9.1%). All but one tested patients had elevated serum immunoglobulin (Ig) D level. Twenty-one patients had genetic diagnosis; most of them were compound heterozygote (76.2%). p.Val377Ile was the most prevalent mutation. Structural articular damages and systemic AA amyloidosis were the 2 most serious complications. More than 65% of patients displayed decrease in severity and frequency of attacks with increasing age, but only 35% achieved remission. MKD diagnosed in adulthood shared clinical and genetic features with classical pediatric disease. An elevated IgD concentration is a good marker for MKD in adults. Despite a decrease of severity and frequency of attacks with age, only one-third of patients achieved spontaneous remission.

OBJECTIVE:Bradykinin-mediated angioedema is characterized by transient attacks of localized edema of subcutaneous or submucosal tissues and can be life-threatening when involving the upper airways. The aim of this study was to determine the features of acute attacks that might be associated with admission to an ICU.PATIENTS AND METHODS:We carried out a retrospective, multicenter, observational study in consecutive patients attending one of six reference centers in France for acute bradykinin-mediated angioedema attacks. Patients had been hospitalized for an acute episode at least once previously. Acute attacks requiring ICU admission were compared with acute attacks that had not required ICU admission.RESULTS:Overall, 118 acute attacks in 31 patients were analyzed (10 patients with hereditary angioedema, 19 patients with angiotensin-converting enzyme inhibitor-induced angioedema, and two patients with acquired C1-inhibitor deficiency angioedema). In multivariate analysis, upper airway involvement, corticosteroid, and C1-inhibitor concentrate administration were associated with ICU admission. Seven episodes (18%) needed airway protection. The evolution was favorable in 38 of 39 attacks warranting ICU admission: patients were able to get out of the service (mean ICU stay 4±5 days). One death was observed by asphyxiation because of laryngeal swelling.CONCLUSION:Upper airway involvement is an independent risk factor for ICU admission. Corticosteroid use, which is an ineffective treatment, and C1-inhibitor concentrate use are factors for ICU admission. The presence of upper airway involvement should be a warning signal that the attack may be severe.

Sarcoidosis is a systemic granulomatous disorder of unknown aetiology. It may rarely affect the gastrointestinal tract.We reported a 54-year-old woman with a delayed diagnosis of duodenal sarcoidosis. She presented with gastric and right upper abdominal pain associated with vomiting and marked weight loss. Abdominal computed tomographic scan showed non-compressive retroperitoneal lymph nodes and histological examination revealed non-caseating epithelioid granulomas typical of sarcoidosis. Diagnosis of duodenal sarcoidosis was obtained at the third gastroscopy. The patient's condition improved quickly with corticosteroid therapy.Gastrointestinal sarcoidosis should be looked for in patients with digestive symptoms and another sarcoid localisation. Furthermore, it is important to repeat gastroscopy to confirm diagnosis because treatment improved most patients.

Introduction. - Sarcoidosis is a systemic granulomatous disorder of unknown aetiology. It may rarely affect the gastrointestinal tract.Case report. - We reported a 54-year-old woman with a delayed diagnosis of duodenal sarcoidosis. She presented with gastric and right upper abdominal pain associated with vomiting and marked weight loss. Abdominal computed tomographic scan showed non-compressive retroperitoneal lymph nodes and histological examination revealed non-caseating epithelioid granulomas typical of sarcoidosis. Diagnosis of duodenal sarcoidosis was obtained at the third gastroscopy. The patient's condition improved quickly with corticosteroid therapy.Conclusion. - Gastrointestinal sarcoidosis should be looked for in patients with digestive symptoms and another sarcoid localisation. Furthermore, it is important to repeat gastroscopy to confirm diagnosis because treatment improved most patients. (C) 2015 Published by Elsevier Masson SAS on behalf of the Societe nationale francaise de medecine interne (SNFMI).

Les angiœdèmes acquis par déficit en C1 inhibiteur sont rares et les séries rapportées dans la littérature ne dépassent pas une vingtaine de cas. Leur symptomatologie et le risque de survenue de formes graves semblent identiques à ceux des formes héréditaires. L'épidémiologie des angiœdèmes acquis en France est inconnue, la fréquence des maladies associées n'est pas déterminée et la prise en charge tant de la pathologie sous-jacente (immunosuppresseurs, rituximab) que des crises aiguës avec notamment l'utilisation des thérapeutiques spécifiques (inactivant et concentrés de C1 inhibiteur) semble très disparate. L'objectif de ce travail était de rapporter les résultats d'un observatoire national des angiœdèmes acquis en précisant les caractéristiques cliniques et biologiques, les pathologies associées et l'évolution sous traitement. Les critères d'inclusion étaient une diminution du C1 inhibiteur antigène et fonctionnel avec ou sans anticorps anti-C1 inhibiteur. Les critères d'exclusion étaient les angiœdèmes héréditaires et médicamenteux. Sur les 64 cas rapportés, 59 % étaient des femmes. Les premiers symptômes apparaissaient à 64 ans en moyenne, et le diagnostic était porté après un délai moyen de 59 mois. L'œdème de la face et les douleurs abdominales étaient les manifestations principales (71 et 66 % des patients). Seize pour cent des patients étaient hospitalisés en réanimation, et l'un d'eux est décédé des suites d'un arrêt cardiaque asphyxique. Un anticorps anti-C1 inhibiteur était présent dans 59 % des cas. La pathologie associée était un lymphome de bas grade chez 24 patients, dont 16 lymphomes de la zone marginale), une gammapathie monoclonale de signification indéterminée chez 20 patients, un myélome dans un cas, et restait indéterminée dans 24 % des cas. Le rituximab permettait de diminuer la fréquence des crises chez 77 % des cas traités (n = 27), la chimiothérapie était efficace dans 75 % des cas d'hémopathie maligne (n = 9), alors que la réponse aux corticoïdes était médiocre : 38 % chez les 13 patients traités. L'acide tranexamique était efficace en traitement de fond chez 77 % des 35 patients traités, rarement compliqué de thromboses veineuses (n = 3), et, utilisé lors des crises à plus fortes doses il permettait de réduire la durée des crises dans 67 % des cas. Le méthotrexate a permis de diminuer la fréquence des crises chez 3 des 4 patients traités. L'inactivant prescrit chez 36 % % des patients était constamment efficace. Les concentrés de C1 inhibiteurs étaient surtout utilisés en prévention d'un geste invasif, et efficaces dans 80 % des cas. Après un suivi moyen de 4,9 ans, un décès a été observé, attribuable à une crise laryngée. Cette série confirme la prévalence des lymphomes de bas grade, et particulièrement les lymphomes de la zone marginale, associés aux angiœdèmes acquis. Les crises abdominales sont un mode de révélation fréquent, conduisant à un retard diagnostique. Les formes graves, et potentiellement létales, ne sont pas rares alors que le recours aux concentrés de C1 inhibiteur et à l'icatibant, pourtant constamment efficace, est limité. L'acide tranexamique est un traitement prophylactique utile. Le rituximab est à proposer en cas d'hémopathie de bas grade ou de gammapathie monoclonale de signification indéterminée. Ces résultats sont, à notre connaissance, la plus large série d'angiœdèmes acquis non médicamenteux. Un protocole thérapeutique prospectif est envisagé.