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Abstract Background East and South East Asian subjects as well as Amerindians and Hispanic subjects are predominantly affected by Vogt-Koyanagi-Harada disease. In Europe, only few studies have described the clinical features and treatment of this disease, especially in France. Methods This retrospective case series was based on data collected from patients with a VKH disease diagnosed from January 2000 to March 2017, provided by three French Tertiary Centers. Results Forty-one patients (16 men and 25 women) were diagnosed: average age at diagnosis was 38.7 years. Patients were mainly from Maghreb (58%), but ethnic origins were multiple. Pleiocytosis was observed in 19 cases (63%) and 17 out of 41 patients showed audio vestibular signs (41%), and 11 showed skin signs (27%). Thirty-four were treated with corticosteroids (83%), 11 with an immunosuppressant treatment (27%) and 5 with biological therapy drugs (13%). Relapse was observed in 41% patients, even though final average visual acuity had improved. We did not find any significant clinical difference in the population from Maghreb compared to other populations, but for age and sex trends, since there was a majority of younger women. Conclusion We report here the second largest French cohort reported to date to our knowledge. The multiethnicity in our study suggests that VKH disease should be evoked whatever patients’ ethnicity.

Staphylococcus aureus induces severe infective endocarditis (IE) where embolic complications are a major cause of death. Risk factors for embolism have been reported such as a younger age or larger IE vegetations, while methicillin resistance conferred by the mecA gene appeared as a protective factor. It is unclear, however, whether embolism is influenced by other S. aureus characteristics such as clonal complex (CC) or virulence pattern. We examined clinical and microbiological predictors of embolism in a prospective multicentric cohort of 98 French patients with monomicrobial S. aureus IE. The genomic contents of causative isolates were characterized using DNA array. To preserve statistical power, genotypic predictors were restricted to CC, secreted virulence factors and virulence regulators. Multivariate regularized logistic regression identified three independent predictors of embolism. Patients at higher risk were younger than the cohort median age of 62.5 y (adjusted odds ratio [OR] 0.14; 95% confidence interval [CI] 0.05–0.36). S. aureus characteristics predicting embolism were a CC30 genetic background (adjusted OR 9.734; 95% CI 1.53–192.8) and the absence of pIB485-like plasmid-borne enterotoxin-encoding genes sed, sej, and ser (sedjr; adjusted OR 0.07; 95% CI 0.004–0.457). CC30 S. aureus has been repeatedly reported to exhibit enhanced fitness in bloodstream infections, which might impact its ability to cause embolism. sedjr-encoded enterotoxins, whose superantigenic activity is unlikely to protect against embolism, possibly acted as a proxy to others genes of the pIB485-like plasmid found in genetically unrelated isolates from mostly embolism-free patients. mecA did not independently predict embolism but was strongly associated with sedjr. This mecA-sedjr association might have driven previous reports of a negative association of mecA and embolism. Collectively, our results suggest that the influence of S. aureus genotypic features on the risk of embolism may be stronger than previously suspected and independent of clinical risk factors.

Advanced systemic mastocytosis (AdvSM) encompasses heterogeneous mastocytosis subtypes and is associated with poor outcomes. Although midostaurin was the first tyrosine kinase inhibitor to be approved for AdvSM patients, long-lasting responses are limited. The mutation-Adjusted Risk Score (MARS), the International Prognostic Scoring System for mastocytosis (IPSM) and the Global Prognostic Score for Systemic Mastocytosis (GPSM) have been established to characterize the outcomes of patients with overall AdvSM. However, given the outcome's dependency on the AdvSM subtype, prognostic characterization within each subtype is critical. We aimed to study the predictive ability using Harrell's concordance index of prognostic scores according to the AdvSM subtype. We conducted a nationwide retrospective study using the French mastocytosis reference center's registry and included all midostaurin-treated patients with C finding. Overall, 170 patients were identified: 46 aggressive SM (ASM), 11 mast cell leukemia (MCL), and 113 SM with associated hematological neoplasm (SM-AHN). All risk scores improved their discriminative value for overall survival (OS) when combined with the AdvSM subtype. The best predictive value was for adjusted MARS (C-index = 0.689), followed by GPSM (C-index = 0.677) and IPSM (C-index = 0.618). In a multivariable analysis, MARS stratification and the AdvSM subtype were both prognostic for OS. Accordingly, five subgroups of patients with AdvSM and a different median OS were identified: 9.9 months for MCL, 24 months for intermediate/high-risk SM-AHN, 33 months for intermediate/high-risk ASM, 58 months for low-risk SM-AHN and was not reached for low-risk ASM (p < 0.001). The AdvSM subtype and the MARS are the most predictive of OS and should prompt specific management., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Objective: Data on the long-term outcome of patients with childhood-onset Systemic Lupus Erythematosus (cSLE) are scarce. Aims of this study were to describe the long-term outcomes of cSLE and to identify factors associated with the development of damage and persistent disease activity., Methods: We conducted a retrospective multicentre study using data from the PEDIALUP registry of the Juvenile Inflammatory Rheumatism (JIR) cohort database. Demographic characteristics, clinical manifestations, laboratory, radiological, histological and treatment data were collected from medical records during follow-up., Results: A total of 138 patients with cSLE, diagnosed between 1971 and 2015, were included. With a median follow-up of 15.4 [9.6-22.4] years, 51% of patients had a SLICC-Damage Index score ≥ 1 at last follow-up with the musculoskeletal, cutaneous, renal, neurological, and cardiovascular damage being the most common manifestations. The proportion of patients with a SLICC-DI score ≥ 1 increased significantly with the duration of the follow-up (p< 0.001). On multivariate analysis, duration of follow-up was associated with increased risk of cumulative damage (OR 1.08, 95% CI 1.01, 1.15, p= 0.035). At the last visit, 34% of patients still had active disease with a SLEDAI score of ≥ 6. On multivariate analysis, Sub-Saharan African ethnicity was associated with 7-fold increased odds of having active disease at the last visit compared with Caucasians (OR 7.44, 95% CI 2.24, 24.74, p= 0.0002)., Conclusion: The prevalence of damage remains high in patients with cSLE even when the diagnosis of c-SLE has been made in the recent decades., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools., Methods: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist., Results: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002)., Conclusions: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Asthmatic patients with antibody deficiencies (AD) have more severe disease and higher risk of exacerbations. No data exist about the efficacy of biologics in severe asthma (SA) patients with AD., Objective: To evaluate the efficacy of biologics in SA patients with and without AD., Methods: A case-control real-life study was conducted including 68 patients divided into 2 groups: group 1 with SA-AD and group 2 with SA., Results: Treatment with biologics for 6 months was effective for decreasing the number of exacerbations, hospitalizations, and emergency department (ED) visits and improving the Asthma Control Questionnaire (ACQ) score; biologics also proved a systemic corticosteroid-sparing effect. Despite benefits, the number of exacerbations, hospitalizations, and ED visits, the mean ACQ score, and the cumulative dose of systemic corticosteroids remain higher in group 1 than in group 2, with lower lung function parameters. The rates of responses in group 1 were inferior to those in group 2, with a decrease by ≥50% of exacerbation rate in 76% versus 97% of patients (P = .006), no hospitalization in 44% versus 91% of patients (P < .001), no ED visit in 56% versus 82% of patients (P = .018), a significant improvement of the ACQ score by ≥0.5 in 68% versus 100% of patients (P < .001), and an increase of forced expiratory volume in the first second by >10% in 32% versus 65% of patients (P = .007)., Conclusions: Despite evident benefits, SA patients with AD have suboptimal responses to biologics compared with those immunocompetent. A multidisciplinary approach is necessary to optimize the management of these patients in practice., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal., Objective: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT., Methods: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases., Results: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT + patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT - patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01)., Conclusion: Here we confirm the increase incidence of anaphylaxis in HαT + mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by defective enzyme activity involved in the catalysis of glycosaminoglycans. Published data on adult patients with MPS remains scarce. Therefore, the present qualitative survey study was aimed at understanding knowledge of the disease, unmet needs, expectations, care, and overall medical management of adult/adolescent patients with MPS I, II and VI and their caregivers in France., Results: A total of 25 patients (MPS I, n p  = 11; MPS II, n p  = 9; MPS VI, n p  = 5) were included and about 36 in-depth interviews (caregivers alone, n c  = 8; patients-caregiver pair, n c+p  = 22; patients alone, n p  = 6) were conducted. Except one (aged 17 years), all patients were adults (median age: 29 years [17-50]) and diagnosed at median age of 4 years [0.4-30], with mainly mothers as caregivers (n c  = 16/19). Patients were classified into three groups: Group A, Patients not able to answer the survey question because of a severe cognitive impairment (n p  = 8); Group B, Patients able to answer the survey question with low or no cognitive impairment and high motor disability (n p  = 10); and Group C, Patients able to answer the survey question with low or no cognitive impairment and low motor disability (n p  = 7). All groups were assessed for impact of disease on their daily lives based on a scale of 0-10. Caregivers in Group A were found to be most negatively affected by the disease, except for professional activity, which was most significantly impacted in Group B (4.7 vs. 5.4). The use of orthopaedic/medical equipments, was more prevalent in Groups A and B, versus Group C. Pain management was one of the global unmet need expressed by all groups. Group A caregivers expected better support from childcare facilities, disability clinics, and smooth transition from paediatric care to adult medicine. Similarly, Group B caregivers expected better specialised schools, whereas Group C caregivers expected better psychological support and greater flexibility in weekly infusion schedules for their patients., Conclusions: The survey concluded that more attention must be paid to the psychosocial status of patients and caregivers. The preference for reference centre for follow-up and treatment, hospitalizations and surgeries were evident. The most significant needs expressed by the patients and caregivers include better understanding of the disease, pain management, monitoring of complications, flexibility in enzyme replacement therapy, home infusions especially for attenuated patients, and improved transitional support from paediatric to adult medicine., (© 2022. The Author(s).)

Objectives: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases., Methods: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019., Results: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10). Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years). Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued., Conclusion: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs., Competing Interests: Competing interests: XM received consulting fees from BMS, Novartis, Sanofi, Pfizer, UCB, Janssen, GSK, Galapagos and BMS and is RMD Open associate editor. JE-G received grants from BMS, Lilly, Pfizer (payments made to University of Strasbourg Foundation; no access to TATA data) and consulting fees from BMS, Galapagos, Abbvie, Janssen, Novartis, Pfizer, Sanofi, Gilead, Roche, Chugai and Lilly., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Systemic sclerosis (SSc) is a systemic autoimmune disease with heterogeneous clinical presentation and prognosis. JAK inhibitors reduced cutaneous and pulmonary fibrosis in mice models of SSc. Clinical data regarding the efficacy and safety of JAK inhibitors in SSc patients are scarce., Methods: We performed a systematic literature review of patients with SSc defined by the 2013 ACR/EULAR criteria and treated with JAK inhibitors, searching in Medline, Cochrane library and Embase databases., Results: Fifty-nine patients (mean age 47 ± 15 years) were included. Median treatment duration was 12 [6-12] months. JAK inhibitors (tofacitinib in 47 patients and baricitinib in 12 patients) were prescribed as first line therapy in 35 patients (59%). A significant cutaneous response (decrease in the mRSS - modified Rodnan skin score - of >5 points and ≥ 25% from baseline) was reported in 52 patients (88%). Among patients with interstitial lung disease (ILD) (n = 31), 28/29 patients had no ILD progression during follow-up time (missing data in 2 patients). Only 2 patients had a disease progression during treatment (including one patient with progressive skin fibrosis). Cutaneous response was more frequently observed in treatment naïve SSc patients. Decrease of the mRSS after treatment initiation was more significant in treatment naïve SSc patients. Eighteen non-serious side-effects were noted in 12 patients (20%), without treatment interruption: 6 infections, 6 gastrointestinal disorders, 4 hepatitis and 3 dyslipidemias., Conclusion: JAK inhibitors could represent a safe and effective treatment option for skin fibrosis and ILD in systemic sclerosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Fabry disease (FD) is a rare inherited lysosomal storage disorder caused by the deficiency of the enzyme alpha-galactosidase A. This deficiency leads to an accumulation of glycosphingolipids leading to progressive and multisystemic disease, including renal, cardiac, and neurological damages. FD may also have neuro-otological and visual impairments, which can generate postural control alterations, inner ear, and vision being involved in this function. This study aimed to evaluate the impact of FD on postural control., Methods: In total, fourteen adult patients (8 men/6 women, mean age = 37.6 ± 11.4 years) and two children (mean age = 11 years) with FD and 19 healthy adults (12 men/7 women, mean age = 36.5 ± 16.9 years) and two healthy children (mean age = 10.5 years) took part in this study. Postural control was evaluated by a sensory organization test combining three visual situations (eyes open, eyes closed, and sway referenced visual surround motion) with two platform situations (stable platform and sway referenced platform motion), aiming to calculate a composite equilibrium score (CES), a high score being representative of good postural control. Somatosensory (R SOM ), visual (R VIS ), and vestibular (R VEST ) contributions to postural control were calculated, a low score reflecting a poor use of the indicated sensory input., Results: The CES was lower in adult patients with FD compared with the healthy subjects ( p < 0.001). R VIS ( p = 0.001) and R VEST ( p = 0.003) were lower in patients with FD compared with the control group, whereas no difference in R SOM was observed., Conclusion: Inner ear and visual pathologies associated with the central nervous system impairments are factors of postural control impairments. Physical activities, which can also be rehabilitative, by maintaining or increasing the weight of proprioception, may help diminish dependency on altered sensorial inputs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Peultier-Celli, Jaussaud, Kaminsky, Deibener-Kaminsky, Feillet and Perrin.)

Background: Hereditary angioedema (HAE) is characterized by unpredictable and potentially life-threatening attacks of cutaneous and submucosal swelling. Over the past decade, new agents, based on a better understanding of the underlying biologic mechanisms of HAE, have changed the face of long-term prophylaxis (LTP). Objective: The objective was to describe current practices and unmet needs with regard to LTP for HAE in expert centers in France. Methods: The study was conducted in France in 2020. Based on their experience with patients with HAE who had visited their center at least once in the past 3 years, physicians from 25 centers who are expert in the management of HAE were requested to fill in a questionnaire that encapsulated their active patient list, criteria for prescribing LTP, and medications used. They were asked about potential unmet needs with currently available therapies. They were asked to express their expectations with regard to the future of HAE management. Results: Analysis was restricted to 20 centers that had an active patient file and agreed to participate. There were 714 patients with C1 inhibitor (C1-INH) deficiency, of whom 423 (59.2%) were treated with LTP. Altered quality of life triggered the decision to start LTP, as did the frequency and severity of attacks. Ongoing LTP included androgens (28.4%), progestins (25.8%), lanadelumab (25.3%), tranexamic acid (14.2%), intravenous C1-INHs (5.6%), and recombinant C1-INH (0.7%). Twenty-nine percent of the patents with LTP were considered to still have unmet needs. Physicians' concerns varied among therapies: poor tolerability for androgens and progestins, a lack of efficacy for tranexamic acid and progestins, dosage form, and high costs for C1-INHs and lanadelumab. Physicians' expectations encompassed more-efficacious and better-tolerated medications, easier treatment administration for the sake of improved quality of life of patients, and less-expensive therapies. Conclusion: Despite the recent enrichment of the therapeutic armamentarium for LTP, physicians still expressed unmet needs with currently available therapies.

Background: Amoxicillin crystalluria (AC), potentially responsible for acute kidney injury (AKI), is reported more and more frequently in patients treated with high doses of intravenous amoxicillin (HDIVA). The main objective of this study was to evaluate AC incidence in these patients. The secondary objectives were to identify factors associated with AC and to evaluate its impact on the risk of AKI., Methods: This multicentre, observational, cohort study was conducted between Mar 18, 2014 and Aug 16, 2019 in Dijon, Nancy, and Reims University Hospitals as well as Châlon-sur-Saône, Charleville-Mézières, and Troyes general hospitals in France. Adult patients (≥18 years) treated with HDIVA and having been tested for AC at least once during treatment were included. Clinical, biological, and therapeutic characteristics of the patients were collected. A univariable mixed logistic regression model assessed the factors associated with AC. A multivariable Cox model with AC as a time-dependent variable assessed the prognostic factors for AKI. ClinicalTrials.gov number: NCT02853292., Findings: Of the 112 included patients, 27 (24.1%, 95% CI [16.2-32.0]) developed at least one episode of AC within a mean of 5.1 days. The factors associated with its occurrence were the concomitant use of angiotensin converting enzyme (ACE) inhibitors (OR=4.6, 95% CI [2.2-9.3], p<0.0001) and the decrease of urinary pH (OR=2.1 for one pH point decrease, 95% CI [1.2-3.7], p=0.009). 20 patients (17.9%) presented with AKI, within a mean time of 10.9 days. The main factor associated with the occurrence of AKI was the occurrence of AC (aHR=7.4, 95% CI [2.5-22.2], p=0.0003)., Interpretation: AC occurred in a quarter of patients treated with HDIVA and was highly prognostic of AKI., Funding: None., Competing Interests: We declare no competing interests., (© 2022 The Author(s).)

Anti-Ro52 (or anti-TRIM21) antibodies are part of the family of anti-Ro/SSA antibodies, historically markers of Sjögren syndrome and systemic lupus erythematosus. Anti-Ro52 antibodies represent one the most frequently encountered autoantibodies in patients with connective tissue disease (primary Sjögren syndrome, systemic lupus erythematosus, systemic sclerosis and idiopathic inflammatory myopathies). Because of their lack of specificity and detection in patients with non-autoimmune disorders, the usefulness of anti-Ro52 testing in connective tissue diseases is still matter of debate among clinicians and immunologists. Autoantibodies are mainly diagnostic markers for autoimmune diseases but some of them can also be directly involved in the generation of tissue damage. Over the past decade several authors reported associations of anti-Ro52 antibodies with some clinical features - especially interstitial lung disease - and survival in patients with connective tissue diseases. There is also a growing evidence of the role of anti-Ro52 antibodies in the pathogenesis of connective tissue diseases. In this review, we comprehensively discuss the clinical associations of anti-Ro52 antibodies in the different connective tissue diseases and the recent advances on their potential role in the inflammatory response., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Among interstitial pneumonia with autoimmune features (IPAF) patients, identifying those at risk to develop a connective tissue disease (CTD) during the disease course is a key issue. The aim of this study was to evaluate the incidence of definite CTD diagnosis in IPAF patients during follow-up., Methods: We performed a multicentric cohort study of interstitial lung disease (ILD) from 2010 to 2017 in pneumology and immunology departments of tertiary care centers. Patients with a known cause of ILD (including established CTD) at diagnosis were excluded. Among patients with idiopathic ILD and at least three years of follow-up, two groups (IPAF and non-IPAF) were retrospectively analyzed at time of diagnosis., Results: A total of 249 patients with ILD were enrolled, including 70 IPAF and 179 non-IPAF patients. After a mean follow-up time of 77 ± 44 months, 18/70 IPAF patients (26%) had a CTD diagnosis - 9 antisynthetase syndrome, 8 systemic sclerosis and 1 overlap myositis - compared with 4/179 non-IPAF patients (2%). IPAF patients were at higher risk of CTD occurrence at 3 years of follow-up compared to non-IPAF patients (HR 10.1, 95% CI 3.1-33.1, p < 0. 01). IPAF patients progressing to CTD tended to be younger, more often female and have more frequently puffy fingers, capillaroscopy abnormalities and antisynthetase antibodies at diagnosis., Conclusions: We found that a significant proportion of IPAF patients had associated CTD diagnosis during follow-up. Prospective studies are needed to confirm baseline predictive factors of CTD occurrence in IPAF patients., (Copyright © 2021 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Post-acute consequences of COVID-19, also termed long COVID, include signs and symptoms persisting for more than 12 weeks with prolonged multisystem involvement; most often, however, malnutrition is ignored., Method: The objective was to analyze persistent symptoms, nutritional status, the evolution of muscle strength and performance status (PS) at 6 months post-discharge in a cohort of COVID-19 survivors., Results: Of 549 consecutive patients hospitalized for COVID-19 between 1 March and 29 April 2020, 23.7% died and 288 patients were at home at D30 post-discharge. At this date, 136 of them (47.2%) presented persistent malnutrition, a significant decrease in muscle strength or a PS ≥ 2. These patients received dietary counseling, nutritional supplementation, adapted physical activity guidance or physiotherapy assistance, or were admitted to post-care facilities. At 6 months post-discharge, 91.0% of the 136 patients (n = 119) were evaluated and 36.0% had persistent malnutrition, 14.3% complained of a significant decrease in muscle strength and 14.9% had a performance status > 2. Obesity was more frequent in patients with impairment than in those without (52.8% vs. 31.0%; p = 0.0071), with these patients being admitted more frequently to ICUs (50.9% vs. 31.3%; p = 0.010). Among those with persistent symptoms, 10% had psychiatric co-morbidities (mood disorders, anxiety, or post-traumatic stress syndrome), 7.6% had prolonged pneumological symptoms and 4.2% had neurological symptoms., Conclusions: Obese subjects as well as patients who have stayed in intensive care have a higher risk of functional loss or undernutrition 6 months after a severe COVID infection. Malnutrition and loss of muscle strength should be considered in the clinical assessment of these patients.

Objectives: Clinical significance of anti-Ro52 antibodies in connective tissue diseases (CTD) is controversial. Anti-Ro52 antibodies might be associated with a more severe CTD phenotype, especially interstitial lung disease (ILD). The aims of this study were to evaluate ILD prevalence and severity, the prevalence of micro- or macroangiopathy and CTD-associated cancers in CTD with anti-Ro52 antibodies., Methods: CTD patients with anti-Ro52 antibody screening by immunoblot at diagnosis were enrolled. Two groups were retrospectively formed according to the presence of anti-Ro52 antibodies with an unbiased 1:1 matching on CTD types. Unsupervised multiple correspondence analysis and hierarchical clustering analysis were used to aggregate anti-Ro52 positive patients in subgroups., Results: 408 CTD patients were included. Anti-Ro52 antibodies were detected in 33 % of CTD patients. Anti-Ro52 antibodies were associated with ILD at CTD diagnosis (47.8% vs. 23.0%, OR 3.3 95% IC 1.4 to 8.0, p = 0.008), even after adjusting for the presence of anti-Ro60 antibodies, especially in patients with antisynthetase syndrome, primary Sjögren syndrome and systemic sclerosis. Micro- or macroangiopathy was more frequent in anti-Ro52 positive CTD patients (18.6% vs. 9.7%, p = 0.02) and CTD patients with anti-Ro52 antibodies experienced more frequent relapses and required more immunosuppressive drugs. Clusters 4 and 5 identified anti-Ro52 positive CTD patients with severe ILD and with clinical features of systemic sclerosis or antisynthetase syndrome respectively., Conclusions: We found that anti-Ro52 antibodies were independently associated with ILD in CTD patients irrespective of CTD type. Anti-Ro52 antibodies could be associated with severity and a more relapsing disease course in CTD patients., (Copyright © 2021. Published by Elsevier B.V.)

Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications., (© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

The nutritional sequelae of COVID-19 have not been explored in a large cohort study., Objectives: To identify factors associated with the change in nutritional status between discharge and 30 days post-discharge (D30). Secondary objectives were to determine the prevalence of subjective functional loss and severe disability at D30 and their associated factors., Methods: Collected data included symptoms, nutritional status, self-evaluation of food intake, Performance Status (PS) Scale, Asthenia Scale, self-evaluation of strength (SES) for arms and legs at discharge and at D30. An SES <7 was used to determine subjective functional loss. A composite criteria for severe disability was elaborated combining malnutrition, subjective functional loss and PS >2. Patients were classified into three groups according to change in nutritional status between discharge and D30 (persistent malnutrition, correction of malnutrition and the absence of malnutrition)., Results: Of 549 consecutive patients hospitalised for COVID-19 between 1 March and 29 April 2020, 130 died including 17 after discharge (23.7%). At D30, 312 patients were at home, 288 (92.3%) of whom were interviewed. Of the latter, 33.3% were malnourished at discharge and still malnourished at D30, while 23.2% were malnourished at discharge but no longer malnourished at D30. The highest predictive factors of persistent malnutrition were intensive care unit (ICU) stay (OR=3.42, 95% CI: 2.04 to 5.75), subjective functional loss at discharge (OR=3.26, 95% CI: 1.75 to 6.08) and male sex (OR=2.39, 95% CI: 1.44 to 3.97). Subjective functional loss at discharge (76.8%) was the main predictive factor of subjective functional loss at D30 (26.3%) (OR=32.6, 95% CI: 4.36 to 244.0). Lastly, 8.3% had a severe disability, with a higher risk in patients requiring an ICU stay (OR=3.39, 95% CI: 1.43 to 8.06)., Conclusion: Patients who survived a severe form of COVID-19 had a high risk of persistent malnutrition, functional loss and severe disability at D30. We believe that nutritional support and rehabilitation should be strengthened, particularly for male patients who were admitted in ICU and had subjective functional loss at discharge., Trial Registration Number: NCT04451694., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypomagnesemia and hypermagnesemia could have serious implications and possibly lead to progress from a mild form to a severe outcome of Covid-19. Susceptibility of subjects with low magnesium status to develop and enhance this infection is possible. There is little data on the magnesium status of patients with Covid-19 with different degrees of severity. This study was conducted to evaluate prevalence of dysmagnesemia in a prospective Covid-19 cohort study according to the severity of the clinical manifestations and to identify factors associated. Serum magnesium was measured in 300 of 549 patients admitted to the hospital due to severe Covid-19. According to the WHO guidelines, patients were classified as moderate, severe, or critical. 48% patients had a magnesemia below 0.75 mmol/L (defined as magnesium deficiency) including 13% with a marked hypomagnesemia (<0.65 mmol/L). 9.6% had values equal to or higher than 0.95 mmol/L. Serum magnesium concentrations were significantly lower in female than in male (0.73 ± 0.12 vs 0.80 ± 0.13 mmol/L), whereas the sex ratio M/F was higher in severe and critical form (p<0.001). In a bivariate analysis, the risk of magnesium deficiency was significantly and negatively associated with infection severity (p<0.001), sex ratio (M/F, p<0.001), oxygenotherapy (p<0.001), stay in critical care unit (p=0.028), and positively with nephropathy (p=0.026). Logistic regression analysis revealed that the strongest predictors of magnesium deficiency were female sex (OR=2.67, p<0.001) and nephropathy (OR=2.12, p=0.032) and after exclusion of sex ratio, the severity of infection (OR=0.46, p=0.04 and OR=0.39 p=0.01), for critical and moderate forms, respectively. This transversal study reveals a high prevalence of hypomagnesemia in hospitalized patients for Covid-19, while high-level serum magnesium concentration was more prevalent in critical form.

Background: East and South East Asian subjects as well as Amerindians and Hispanic subjects are predominantly affected by Vogt-Koyanagi-Harada disease. In Europe, only few studies have described the clinical features and treatment of this disease, especially in France., Methods: This retrospective case series was based on data collected from patients with a VKH disease diagnosed from January 2000 to March 2017, provided by three French Tertiary Centers., Results: Forty-one patients (16 men and 25 women) were diagnosed: average age at diagnosis was 38.7 years. Patients were mainly from Maghreb (58%), but ethnic origins were multiple. Pleiocytosis was observed in 19 cases (63%) and 17 out of 41 patients showed audio vestibular signs (41%), and 11 showed skin signs (27%). Thirty-four were treated with corticosteroids (83%), 11 with an immunosuppressant treatment (27%) and 5 with biological therapy drugs (13%). Relapse was observed in 41% patients, even though final average visual acuity had improved. We did not find any significant clinical difference in the population from Maghreb compared to other populations, but for age and sex trends, since there was a majority of younger women., Conclusion: We report here the second largest French cohort reported to date to our knowledge. The multiethnicity in our study suggests that VKH disease should be evoked whatever patients' ethnicity.

Background: Although antibody deficiency (AD) is a well-known cause of recurrent respiratory infections, there are few data on its impact in adults with asthma. The objective of the present study was to assess outcomes in adults with severe asthma and AD after treatment with either azithromycin or subcutaneous immunoglobulins (SCIg)., Methods: We performed a 5-year, prospective, observational, two-centre study of adults with severe asthma and AD in France. Bronchiectasis was ruled out by high-resolution computed tomography. Patients were treated for one year with either azithromycin (250 mg every other day) or SCIg (0.4-0.6 g/kg/months, weekly). All patients were evaluated for exacerbations, asthma control and lung function at baseline and then one year after treatment initiation., Results: Thirty-nine patients with severe asthma were included in the study: 14 had been treated with azithromycin and 25 had been treated with SCIg. Before the initiation of treatment for AD, all patients had an Asthma Control Questionnaire (ACQ-7) score > 1.5 (mean ± SD: 2.71 ± 0.53) despite treatment at GINA step 4 or 5, and had a high exacerbation rate requiring oral corticosteroids and/or rescue antibiotics (∼7.2 ± 2.1/patient/year). One year after treatment initiation, we observed a significantly higher FEV1 (mean: 0.18 ± 0.22 L) and ACQ-7 score (1.26 ± 0.68), and a significantly lower exacerbation rate (1.63 ± 1.24/patient/year)., Conclusions: Treatment of AD dramatically improved asthma outcomes - suggesting that adults with severe asthma and recurrent respiratory infections should be screened and (if appropriate) treated for AD., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles., Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included., Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04)., Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.

Background: Gaucher disease is a rare inborn error of lysosomal metabolism, characterized by lysosomal storage of the β-glucosylceramide. Bleedings observed in type-1 Gaucher disease (GD1) are commonly attributed to a low platelet count, but they can also occur when the platelet count is normal or slightly low. Abnormal platelet function has been described and deficiencies in coagulation factors too, such as factors II, V, VII, VIII, IX, X, XI, XII, and von Willebrand factor. However, studies are few in number, involving few patients and having varying conclusions. The aim of this study was to analyze clotting factor deficiencies in a larger cohort of French patients with GD1., Methods: This is an observational national study. The coagulation parameters were collected during routine GD1 monitoring and described retrospectively., Results: We highlighted low levels of various coagulation factors in 46% of the patients with GD1. The most frequent coagulation abnormalities encountered were factor V, X, XI, and XII deficiencies. Deficits were usually mild and coagulation abnormalities tended to be more frequent in non-splenectomized patients., Conclusions: In conclusion, frequent and varied coagulation abnormalities were found in a high proportion of GD1 patients., Competing Interests: We confirm that all authors have no conflict of interest to disclose either related to product or companies named in the article or to competing products or companies., (Copyright 2019, Serratrice et al.)

Background: Ehlers-Danlos syndrome (EDS) hypermobility-type is the most common hereditary disorder of the connective tissue. The tissue fragility characteristic of this condition leads to multi-systemic symptoms in which pain, often severe, chronic, and disabling, is the most experienced. Clinical observations suggest that the complex patient with EDS hypermobility-type is refractory toward several biomedical and physical approaches. In this context and in accordance with the contemporary conceptualization of pain (biopsychosocial perspective), the identification of psychological aspects involved in the pain experience can be useful to improve interventions for this under-recognized pathology., Purpose: Review of the literature on joint hypermobility and EDS hypermobility-type concerning psychological factors linked to pain chronicity and disability., Methods: A comprehensive search was performed using scientific online databases and references lists, encompassing publications reporting quantitative and qualitative research as well as unpublished literature., Results: Despite scarce research, psychological factors associated with EDS hypermobility-type that potentially affect pain chronicity and disability were identified. These are cognitive problems and attention to body sensations, negative emotions, and unhealthy patterns of activity (hypo/hyperactivity)., Conclusions: As in other chronic pain conditions, these aspects should be more explored in EDS hypermobility-type, and integrated into chronic pain prevention and management programs. Implications for Rehabilitation Clinicians should be aware that joint hypermobility may be associated with other health problems, and in its presence suspect a heritable disorder of connective tissue such as the Ehlers-Danlos syndrome (EDS) hypermobility-type, in which chronic pain is one of the most frequent and invalidating symptoms. It is necessary to explore the psychosocial functioning of patients as part of the overall chronic pain management in the EDS hypermobility-type, especially when they do not respond to biomedical approaches as psychological factors may be operating against rehabilitation. Further research on the psychological factors linked to pain chronicity and disability in the EDS hypermobility-type is needed.

Background: Although anaphylaxis has been considered a priority public health issue in the world allergy community, epidemiological data on morbidity and mortality remain suboptimal. We performed the first multicenter epidemiological study in French emergency departments (EDs). The study covered 7 EDs over a period of 1 year. The objectives were to identify areas that are amenable to change and to support ongoing national and international efforts for better diagnosis, management, and prevention of anaphylaxis., Methods: Ours was a descriptive study based on data routinely reported to French institutional administrative databases from 7 French public health institutions in the Lorraine region between January and December 2015. Data were collected based on the anaphylaxisrelated codes of the International Classification of Diseases (ICD)-10, and cases were clinically validated as anaphylaxis., Results: Of the 202 079 admissions to the EDs, 4817 had anaphylaxis-related codes; of these, 323 were clinically validated as anaphylaxis. Although 45.8% were severe, adrenaline was prescribed in only 32.4% of cases. Of the 323 cases, 57.9% were subsequently referred for an allergy work-up or evaluation (after or during hospitalization), and 17.3% were prescribed autoinjectable epinephrine., Conclusion: Our results highlight an urgent need for improved public health initiatives with respect to recognition and treatment of anaphylaxis. We flag key problems that should be managed in the coming years through implementation of national and international actions.

Carnitine palmitoyltransferase type 2 (CPT2) deficiency, a mitochondrial fatty acid oxidation disorder (MFAOD), is a cause of myopathy in its late clinical presentation. As for other MFAODs, its diagnosis may be evocated when blood acylcarnitine profile is abnormal. However, a lack of abnormalities or specificity in this profile is not exclusive of CPT2 deficiency. Our retrospective study reports clinical and biological data in a cohort of 11 patients with circulating acylcarnitine profile unconclusive enough for a specific diagnosis orientation. In these patients, CPT2 gene studies was prompted by prior fluxomic explorations of mitochondrial β-oxidation on intact whole blood cells incubated with pentadeuterated ([16- 2 H 3 , 15- 2 H 2 ])-palmitate. Clinical indication for fluxomic explorations was at least one acute rhabdomyolysis episode complicated, in 5 of 11 patients, by acute renal failure. Major trigger of rhabdomyolysis was febrile infection. In all patients, fluxomic data indicated deficient CPT2 function showing normal deuterated palmitoylcarnitine (C16-Cn) formation rates associated with increased ratios between generated C16-Cn and downstream deuterated metabolites (Σ deuterated C2-Cn to C14-Cn). Subsequent gene studies showed in all patients pathogenic gene variants in either homozygous or compound heterozygous forms. Consistent with literature data, allelic frequency of the c.338C > T[p.Ser113Leu] mutation amounted to 68.2% in our cohort. Other missense mutations included c.149C > A[p.Pro50His] (9%), c.200C > G[p.Ala200Gly] (4.5%) and previously unreported c.1171A > G[p.ser391Gly] (4.5%) and c.1420G > C[p.Ala474Pro] (4.5%) mutations. Frameshift c.1666-1667delTT[p.Leu556val*16] mutation (9%) was observed in two patients unknown to be related., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To assess quality of life and satisfaction regarding immunoglobulin-replacement therapy (IgRT) treatment according to the route (intravenous Ig [IVIg] or subcutaneous Ig [SCIg]) and place of administration (home-based IgRT or hospital-based IgRT)., Subjects and Methods: Children 5-15 years old treated for primary immunodeficiency disease (PIDD) with IgRT for ≥3 months were included in a prospective, noninterventional cohort study and followed over 12 months. Quality of life was assessed with the Child Health Questionnaire - parent form (CHQ-PF)-50 questionnaire. Satisfaction with IgRT was measured with a three-dimensional scale (Life Quality Index [LQI] with three components: factor I [F I ], treatment interference; F II , therapy-related problems; F III , therapy settings)., Results: A total of 44 children (9.7±3.2 years old) receiving IgRT for a mean of 5.6±4.5 years (median 4.1 years) entered the study: 18 (40.9%) were receiving hospital-based IVIg, two (4.6%) were receiving home-based IVIg, and 24 (54.6%) were treated by home-based SCIg. LQI F III was higher for home-based SCIg than for hospital-based IVIg ( P =0.0003), but there was no difference for LQI F I or LQI F II . LQI F III significantly improved in five patients who switched from IVIg to SCIg during the follow-up when compared to patients who pursued the same regimen (either IVIg or SCIg). No difference was found on CHQ-PF50 subscales, LQI F I , or LQI F II ., Conclusion: Home-based SCIg gave higher satisfaction regarding therapy settings than hospital-based IVIg. No difference was found on other subscales of the LQI or CHQ-PF50 between hospital-based IVIG and home-based SCIG., Competing Interests: Disclosure The study was sponsored by Octapharma France. The sponsor validated the study design, participated in the interpretation of data, had no role in the writing of the study report, and supported the decision to submit the manuscript for publication. BB, GJC, CH, PC, and RJ are part of the scientific committee for the VISAGES study and earned fees from Octapharma. IP, NA, AA, PC, GJC, RJ, BB, and CH were investigators for the VISAGES study. BB, PC, GJC, CH, and RJ take part in several scientific boards and also in several studies led by Octapharma. PC works as an independent statistician and earned fees from Octapharma to conduct the statistical analysis and draft the manuscript. The authors report no other conflicts of interest in this work.

Background: IgG replacement therapy (IgRT) in primary immunodeficiencies (PID) is a lifelong treatment which may be administered intravenously (IVIg) or subcutaneously (SCIg), at hospital or at home. The objective of the VISAGE study was to investigate if route and/or place for IgRT impact patients' satisfaction regarding IgRT and quality of life (QoL) in real-life conditions., Methods: The study enrolled PID patients at least 15 years old receiving IgRT for at least 3 months. Satisfaction and QoL were evaluated at enrollment and over a 12-month follow-up period by Life Quality Index (LQI) which measures 3 dimensions of satisfaction: treatment interference, therapy related problems and therapy settings (factors I, II and III) and SF-36 v2 questionnaire., Results: The study included 116 PID patients (mean age 42 ± 18 years, 44 % males, 58 % with scholar or professional occupation) receiving IgRT for a mean of 8.5 ± 8.4 years. At enrollment they were receiving either home-based SCIg (51 %), hospital-based IVIg (40 %) or home-based IVIg (9 %). Patients exhibited a high degree of satisfaction regarding IgRT whatever the route and place for administration. LQI factor I was higher for home-based SCIg (86 ± 2) than for hospital-based IVIg (81 ± 3) and home-based IVIg (73 ± 5; p = 0.02 versus home-based SCIg); no difference was found for LQI factor II; LQI factor III was higher for home-based SCIg (92 ± 2) than for hospital-based IVIg (87 ± 5) and hospital-based IVIg (82 ± 3; p = 0.005 versus home-based SCIg). By contrast, every dimension of QoL was impaired. Over the follow-up period, 10 patients switched from hospital-based IVIg to home-based SCIg and improved LQI factor I (p = 0.004) and factor III (p = 0.02), while no change was noticed in LQI factors II and QoL. Meanwhile, no change in satisfaction or QoL was found in patients with stable route of IgRT. When asked on their preferred place of treatment all but one patient with home-based treatment would choose to be treated at home and 29 % of patients treated at hospital would prefer home-based IgRT., Conclusion: PID patients expressed a high degree of satisfaction regarding IgRT, contrasting with impaired QoL. In real-life conditions awareness of patient's expectations regarding the route or place of IgRT may be associated with further improvement of satisfaction.

Objective: To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc)., Methods: Randomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05)., Results: Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12)., Conclusions: The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit., Trial Registration Number: NCT01295736., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular dysplasia characterized by mucocutaneous telangiectasia and visceral arteriovenous malformations. Hepatic involvement with vascular malformations may lead to portal hypertension, biliary ischemia, and high-output cardiac failure. There is no curative treatment for the disease. Liver transplantation is indicated for life-threatening complications, but it carries significant risk due to surgery and immunosuppressive treatment. Some case reports or small open studies suggest that bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, should be efficient in limiting bleeding and in reducing liver disease in HHT.We report a case of a 63-year-old woman with HHT presenting with ischemic cholangiopathy. Liver transplant was indicated, but given a previous encouraging report showing a regression of biliary disease with bevacizumab in 3 patients with HHT this drug was proposed. No significant efficacy but a severe adverse effect was observed after 3 months: bilateral pulmonary embolisms, thrombosis in the right atrial cavity, and thrombosis of the right hepatic vein were evidenced. Bevacizumab was stopped; anticoagulant started. Four months later, the patient received a transplanted liver. She feels well 1 year later.This case report intends to provide the information for clinicians to consider the use of bevacizumab in HHT. Whereas several uncontrolled series and case reports have suggested the efficacy of this drug in reducing bleeding and liver disease, no severe side effects were mentioned to date. For the first time in HHT we report a life-threatening side effect of this drug and no efficacy. Moreover, systemic thrombosis, the observed complication, may preclude transplantation. To date, caution seems still indispensable when considering the use of bevacizumab in HHT.

Fabry disease (FD) is a lysosomal disorder leading to progressive systemic involvement, including microvascular damage that leads to neurological and cardiovascular disorders. We hypothesize that the latter could be documented at an early stage by performing a microcirculation study with nailfold capillaroscopy and evaluation of Raynaud phenomenon.The objective was to measure the prevalence of Raynaud phenomenon and nailfold capillaroscopic abnormalities in FD.This cross-sectional study included a standardized questionnaire and a nailfold capillaroscopy that assessed previously reported patterns in FD (dystrophic and giant capillaries, avascular fields, irregular architecture, dilatation and density of capillaries, hemorrhage), and was conducted on 32 Fabry patients and 39 controls. Capillaroscopic photographs were reviewed by 2 independent blinded investigators.Twelve Fabry patients (38%) suffered from Raynaud phenomenon, 5 were males (ie, 50% of male Fabry patients), compared with 2 controls (13%) (P < 0.001), of whom none were males (P < 0.001). Raynaud phenomenon was concomitant or before the occurrence of pain in the extremities in 42% of Fabry patients.More ramified capillaries were significantly observed in Fabry patients (12/32, 38%) than in controls (5/39, 13%, P = 0.016).Secondary Raynaud phenomenon should lead to screening for FD, especially in men. By extension, in high-risk populations for FD, the presence of Raynaud phenomenon and ramified capillaries should be assessed.

We investigated measles humoral immunity levels in a cohort of HIV-infected adult patients in France and attempted to identify risk factors for antimeasles antibodies seronegativity. Being born after 1983 [odds ratio (OR) 4.40; 95% confidence interval (95% CI) 1.26-14.09; P = 0.0013] and a nadir CD4⁺ cell count below 100 cells/μl (OR 4.79; 95% CI 1.61-14.82; P = 0.0048) were the two factors independently associated with measles seronegativity. Systematic measles antibody screening should be performed in HIV-infected individuals born in the era of measles vaccination (after 1983 in France).

Objective: To assess whether African ethnicity is independently associated with a poorer CD4 reconstitution with highly active antiretroviral therapy (HAART) compared to Caucasian ethnicity., Methods: We conducted a retrospective epidemiological study among 575 HIV-1-positive patients at our center and defined immunological success as the presence of blood CD4 lymphocyte counts>500 cells/mm3 in more than 50% of the values collected from 6 to 48 months after beginning HAART. Patients displaying an HIV-1 viral load>200 copies/ml or more than one HIV-1 viral load between 20 and 200 copies/ml during follow-up, were excluded. Patients with baseline blood CD4 counts>500 cells/mm3 were also excluded., Results: Two hundred and eighty patients met the inclusion criteria and no exclusion criteria. After 48 months of HAART, blood CD4 lymphocyte counts were lower in Africans than in Caucasians: 449 (65-975) vs. 569 (131-1698) cells/mm3 (p=0.02). Immunological success was present in 142/220 (64.5%) Caucasians vs. 29/60 (48.3%) Africans (p=0.02). African ethnicity was independently associated with the absence of immunological success (odds ratio 2.22, 95% confidence interval 1.097-4.504; p=0.02) despite similar baseline blood CD4 counts (219 vs. 204 cells/mm3, p=0.72)., Conclusion: Our findings suggest that African ethnicity is independently associated with a poorer CD4 reconstitution during HAART than Caucasian ethnicity., (Copyright © 2013. Published by Elsevier Ltd.)

Aim: Fabry's disease is an X-linked inherited lysosomal storage disorder caused by the deficient activity of alpha-galactosidase A. The interrelationships between clinical symptoms in Fabry patients have not yet been fully established. Using cluster and multivariate analysis, the aim of the study was to determine the relationships among clinical symptoms and organ involvement, and predictive clinical symptoms for disease severity., Methods: Clinical data obtained from 108 French Fabry patients were retrospectively collected and analysed using multiple correspondence analysis and hierachical ascendant classification. Multivariate analysis was also performed to determine among clinical symptoms predictors for cardiac disease (HRT), renal involvement (KDN) and brain complication (STR)., Results: The cohort comprised 41 male patients (aged 28.9 ± 11.6 years) and 67 female patients (aged 40.4 ± 15.5 years). Three main clusters of clinical symptoms could be delineated, characterising disease progression: the first cluster grouped digestive disorders (found in 30% of the patients) and exercise intolerance (32%), the second, cluster dyshidrosis (47%), acroparesthesia (67%), angiokeratoma (44%) and cornea verticillata (54%), the third, cluster grouped KDN (30%), HRT (39%) and STR (25%) and hearing loss (44%). In univariate analysis, the patient age predicted HRT and KDN, dyshidrosis predicted HRT and STR, angiokeratoma predicted KDN and cornea verticilla and hearing loss predicted KDN, HRT and STR. In multivariate analysis, hearing loss and age were independent predictors of organ complication., Conclusion: Among the various interrelated clinical symptoms occurring in Fabry disease, patients with dyshidrosis and particularly hearing disorders appear to be at higher risk of organ complications., (© 2013 Blackwell Publishing Ltd.)

Introduction: Prothrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008., Methods: All consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex®) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion., Results: Of 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 ± 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 ± 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 ± 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR., Conclusions: Severe bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes.