Mass cytometry reveals atypical immune profile notably impaired maturation of memory CD4 T with Gb3-related CD27 expression in CD4 T cells in Fabry disease.

Fabry disease (FD) is an X-linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti-drug antibodies (ADA). Leucocytes from 41 male patients and 20 controls were analyzed with mass cytometry using both unsupervised and supervised algorithms. FD patients had an increased expression of CD27 and CD28 in memory CD45- and CD45 + CCR7-CD4 T cells (respectively p < 0.014 and p < 0.02). Percentage of CD45RA-CCR7-CD27 + CD28+ cells in CD4 T cells was correlated with plasma lysoGb3 (r = 0.60; p = 0.0036) and phenotype (p < 0.003). The correlation between Gb3 and CD27 in CD4 T cells almost reached significance (r = 0.33; p = 0.058). There was no immune profile associated with the presence of ADA. Treatment with agalsidase beta was associated with an increased proportion of Natural Killer cells. These findings provide valuable insights for understanding FD, linking Gb3 accumulation to inflammation, and proposing new prognostic biomarkers.

History of pre-eclampsia does not appear to be a risk factor for vascular phenotype in women with systemic sclerosis.

BACKGROUND: Vascular phenotype is associated with a poor prognosis in systemic sclerosis (SSc). The identification of its risk factors could facilitate its early detection. OBJECTIVES: To explore risk factors for a vascular phenotype of SSc, among them a history of pre-eclampsia. METHODS: This observational multicentre case-control study enrolled adult women fulfilling European Alliance of Associations for Rheumatology 2013 diagnosis criteria for SSc and having a pregnancy history≥6 months before SSc diagnosis in 14 French hospital-based recruiting centres from July 2020 to July 2022. Cases had specific vascular complications of SSc defined as history of digital ischaemic ulcers, pulmonary arterial hypertension, specific cardiac involvement or renal crisis. Women with SSc were included during their annual follow-up visit and filled in a self-administered questionnaire about pregnancy. A case report form was completed by their physician, reporting data on medical history, physical examination, clinical investigations and current medication. The main outcome was the presence/absence of a personal history of pre-eclampsia before SSc diagnosis, according to the validated pre-eclampsia questionnaire. RESULTS: 378 women were included: 129 cases with a vascular phenotype and 249 matched controls. A history of pre-eclampsia was reported in 5 (3.9%) cases and 12 (4.8%) controls and was not associated with a vascular phenotype (OR=0.96, 95% CI 0.28 to 3.34, p=0.9). Besides, Rodnan skin score and disease duration≥5 years were risk factors for vascular phenotype. CONCLUSIONS: In women with SSc and a pregnancy history≥6 months before SSc, a history of pre-eclampsia is not associated with a vascular phenotype.

Anal Monkeypox Disease: Description of 65 Cases.

BACKGROUND: Monkeypox is a zoonosis endemic in Africa caused by 3 orthopoxvirus clades. Knowledge of the disease is limited, but a worldwide outbreak involving a new route of transmission was declared in April 2022. OBJECTIVE: This study aimed to describe anal symptoms and outcomes in patients infected with Monkeypox virus presenting to an emergency proctology unit in Paris. DESIGN: This was an observational study. SETTING: We reported anal symptoms of all consecutive patients with monkeypox anal infection in a single proctology center between June 16, 2022, and July 26, 2022. Association with sexually transmitted infections and outcomes were also recorded. PATIENTS: Sixty-five men with a mean age of 39.6 (19.9-64.6) years with confirmed monkeypox anal infection were included in the study. MAIN OUTCOME MEASURES: Anal symptoms and their severity were clinically assessed. A favorable outcome consisted of a complete resolution of clinical manifestation. RESULTS: Sexual transmission was reported in 51 patients (78.4%), among whom 63 (97%) were men who have sex with men. Twenty-eight (43%) were living with HIV, and 24 (36.9%) were taking tenofovir/emtricitabine for HIV preexposure prophylaxis. Anal symptoms appeared first in 36 patients (55.4%) and skin rash or other general symptoms in 22 patients (33.8%). Incubation time was 6.9 (1-26) days. Symptoms included painful perianal (n = 42 patients; 64.6%), anal (n = 28, 43%), and rectal (n = 25; 38.4%) ulcerations and perianal vesicles (n = 24; 36.9%). Proctitis was observed in 49 patients (75.4%). It was mild in 20 (40.8%) and intense in 29 (59.2%), and severe proctitis mimicking high intersphincteric suppuration was found in 4 (8.2%). Fifteen patients (23.1%) had concurrent sexually transmitted infection and 3 were hospitalized. Complete symptom resolution occurred within 12 days. LIMITATIONS: We performed a single-center study during a short period of time. CONCLUSIONS: Proctological symptoms are frequent in the current outbreak of monkeypox disease, probably linked to the route of transmission. Rectal ulcerations mimicking high intersphincteric suppuration should be recognized to avoid unnecessary surgery. See Video Abstract . ENFERMEDAD ANAL DE LA VIRUELA DEL MONO DESCRIPCIN DE CASOS: ANTECEDENTES:La viruela del simio mono es una zoonosis endémica en África causada por tres clados de orthopoxvirus. El conocimiento de la enfermedad es limitado, pero en abril de 2022 se declaró un brote mundial que implica una nueva vía de transmisión.OBJETIVO:Describir los síntomas anales y los resultados en pacientes que sufren de infección por Monkeypox que asistieron a una unidad de proctología de emergencia en París.DISEÑO:Un estudio observacional.ESCENARIO:Informamos los síntomas anales de todos los pacientes consecutivos con infección anal por viruela del mono en un solo centro de proctología entre el 16/6/2022 y el 26/7/2022. También se registró la asociación con infecciones de transmisión sexual (ITS) y el resultado.PACIENTES:Sesenta y cinco hombres de 39,6 [19,9-64,6] años con infección anal confirmada.PRINCIPALES MEDIDAS DE RESULTADO:Los síntomas anales y su gravedad se evaluaron clínicamente. Un resultado favorable consistió en una resolución completa de la manifestación clínica.RESULTADOS:La transmisión sexual se informó en 51 (78,4%) pacientes, de los cuales 63 (97%) eran hombres que tuvieron sexo con hombres. Veintiocho (43%) vivían con el VIH y 24 (36,9%) tomaban Emtricitabina/Tenofovir para profilaxis previa por exposición al VIH. Los síntomas anales aparecieron primero en 36 (55,4%) pacientes y la erupción cutánea u otros síntomas generales en 22 (33,8%). El tiempo de incubación fue de 6,9 [1-26] días. Los síntomas incluyeron ulceraciones perianales dolorosas (n = 42 pacientes, 64,6%), anales (n = 28, 43%), rectales (n = 25, 38,4%) y vesículas perianales (n = 24, 36,9%). Se observó proctitis en 49 (75,4%) pacientes. Fue leve en 20 (40,8%) e intensa en 29 (59,2%) y proctitis severa simulando supuración interesfinteriana alta en 4 (8,2%). Quince (23,1%) pacientes presentaban ITS concurrentes y 3 fueron hospitalizados. La resolución completa de los síntomas ocurrió dentro de los 12 días.LIMITACIONES:Estudio de un solo centro y durante corto período de tiempo.CONCLUSIÓN:Los síntomas proctológicos son frecuentes en el brote actual de la enfermedad de la viruela del mono, probablemente relacionados con la vía de transmisión. Las ulceraciones rectales que simulan una supuración interesfinteriana alta deben reconocerse para evitar una cirugía innecesaria. (Traducción-Dr. Fidel Ruiz Healy ).

Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: open-label extension of the ASCEND trial.

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. RESULTS: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. CONCLUSION: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691.

Heart and systemic sclerosis-findings from a national cohort study.

OBJECTIVES: Heart involvement is one of the leading causes of death in systemic sclerosis (SSc). The prevalence of SSc-related cardiac involvement is poorly known. Our objective was to investigate the prevalence and prognosis burden of different heart diseases in a nationwide cohort of patients with SSc. METHODS: We used data from a multicentric prospective study using the French SSc national database. Focusing on SSc-related cardiac involvement, we aimed to determine its incidence and risk factors. RESULTS: Over the 3528 patients with SSc 312 (10.9%) had SSc-related cardiac involvement at baseline. They tended to have a diffuse SSc subtype more frequently, more severe clinical features, and presented more cardiovascular risk factors. From the 1646 patients available for follow-up analysis, SSc-related cardiac involvement was associated with an increased risk of death. There was no significant difference in overall survival between SSc-related cardiac involvement, ischaemic heart disease or pulmonary arterial hypertension. Regarding survival analysis, 98 patients developed SSc-related cardiac involvement at five years (5-year event rate: 11.15%). Regarding reduced LVEF < 50% and left ventricular diastolic dysfunction, the 5-year event rate was 2.49% and 5.84% respectively. Pericarditis cumulative incidence at five years was 3%. Diffuse SSc subtype was a risk factor for SSc-related cardiac involvement and pericarditis. Female sex was associated with less left ventricular diastolic dysfunction incidence. CONCLUSIONS: Our results describe the incidence and prognostic burden of SSc-related cardiac involvement at a large scale, with gender and diffuse SSc subtype as risk factors. Further analyses should assess the potential impact of treatment on these various cardiac outcomes.

Takotsubo syndrome occurring in systemic diseases: A French multicenter retrospective case-control study and literature review.

OBJECTIVE: Describe the characteristics of patients presenting with TTS during the course of a broad spectrum of systemic diseases, in comparison to classic TTS. METHODS: French multicenter retrospective case-control study completed by a literature review. RESULTS: 19 new cases were included in the study. The literature review identified 25 previously published cases. Among the 44 patients, 41 were females, with a median age of 67 years. The main underlying systemic diseases were systemic lupus erythematosus for seven, rheumatoid arthritis for six and primary Sjögren's syndrome for five. A TTS trigger was found in 34 cases, including a systemic disease flare-up in 28. The flare-up was treated in 15 cases, mainly with corticosteroids. One patient died during the episode, unrelated to the TTS. With a median follow-up of 24 months, all patients had recovered a normal LVEF, one had presented a recurrence of TTS, and none had died of a cardiac cause. Finally, the 19 new patients were compared with 19 classic TTS. The disease characteristics were extremely similar, with no significant difference in terms of clinical, electrocardiographic, biological and echocardiographic presentation. CONCLUSION: A broad spectrum of systemic diseases may rarely be accompanied by TTS, particularly during disease flare-ups. Although uncommon, TTS should be borne in mind in the presence of any cardiac symptomatology during the course of a systemic disease. Compared with classic TTS, their clinical, biological and echographic presentation is unremarkable. The prognosis for TTS appears to be good, with the consistent recovery of LVEF and no cardiac-related deaths.

Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study.

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment guidelines. These consensus recommendations are intended to provide guidance for the treatment and monitoring of patients with Fabry disease receiving migalastat. Methods: A modified Delphi process was conducted to determine consensus on treatment decisions and monitoring of patients with Fabry disease receiving migalastat. The multidisciplinary panel comprised 14 expert physicians across nine specialties and two patients with Fabry disease. Two rounds of Delphi surveys were completed and recommendations on the use of biomarkers, multidisciplinary monitoring, and treatment decisions were generated based on statements that reached consensus. Results: The expert panel reached consensus agreement on 49 of 54 statements, including 16 that reached consensus in round 1. Statements that reached consensus agreement are summarized in recommendations for migalastat treatment and monitoring, including baseline and follow-up assessments and frequency. All patients with Fabry disease and an amenable mutation may initiate migalastat treatment if they have evidence of Fabry-related symptoms and/or organ involvement. Treatment decisions should include holistic assessment of the patient, considering clinical symptoms and organ involvement as well as patient-reported outcomes and patient preference. The reliability of α-Gal A and globotriaosylsphingosine as pharmacodynamic response biomarkers remains unclear. Conclusion: These recommendations build on previously published guidelines to highlight the importance of holistic, multidisciplinary monitoring for patients with Fabry disease receiving migalastat, in addition to shared decision-making regarding treatments and monitoring throughout the patient journey. GRAPHICAL ABSTRACT.

Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B).

BACKGROUND: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients. METHODS: The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process. RESULTS: The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research. CONCLUSION: These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT).

Pseudomonas aeruginosa prosthetic joint-infection outcomes: Prospective, observational study on 43 patients.

Objectives: Analysis the outcomes of Pseudomonas aeruginosa prosthetic joint infection (PJI), and of their clinical and microbiological characteristics, surgical strategies and antibiotic treatments. Methods: Monocenter cohort study in a Bone-and-Joint-Infection Referral Center (08/2004 to 10/2018) including all consecutive P. aeruginosa PJIs. Data were extracted from the prospective database, including the following events: relapses, new PJIs, related deaths. Results: Median [IQR]: among the 43 patients included (28 females; 72 [63-80] years old; 27 hip, 15 knee, and 1 shoulder PJIs), 29 (67%) had underlying comorbidities, 12 (28%) had previously been treated for another PJI and 9 (21%) had undergone previous surgeries for their P. aeruginosa PJI. Eleven (26%) PJIs were polymicrobial, 16 (37%) strains were wild type, 8 (19%) ciprofloxacin-resistant. PJIs were classified as late chronic (n = 33), early postoperative (n = 9) or acute hematogenous infection (n = 1). Forty patients underwent surgery: 27 one-stage and 5 two-stage exchanges, 3 debridement and implant retention, and 5 other surgical strategies. Antibiotic treatments were: 29 received 41 [37-43] days of combination therapy (IV anti-pseudomonal ß-lactam and 3-5 days of amikacin, then ß-lactam and oral ciprofloxacin), followed by oral ciprofloxacin for a total of 12 weeks; 10 received only IV antibiotics for 83 [77-86] days, including 37 [32-46] days of combination therapy; 49 days of ceftazidime alone for 1. During follow-up lasting 33 [24-64.5] months, 2 relapses, 3 new PJIs, and 2 related deaths occurred. Thirty-three (82%) patients and 93% of those managed with one-stage exchange experienced no event. Conclusion: Outcomes of our cohort's P. aeruginosa PJIs-predominantly monomicrobial, chronic, ciprofloxacin-susceptible, treated with one-stage exchange and prolonged IV antibiotics-were 82% favorable.

Cutibacterium acnes Prosthetic Joint Infections: Is Rifampicin-Combination Therapy Beneficial?

No consensus has been reached on the optimal antibiotic regimen to treat Cutibacterium acnes PJIs (Ca-PJIs). In vitro studies showed excellent rifampicin efficacy against biofilm-associated C. acnes infections, but clinical studies did not confirm the superiority of rifampicin-combined therapy over monotherapy. This prospective cohort study was undertaken to analyze the outcomes of 70 patients who underwent exchange arthroplasty for chronic monomicrobial Ca-PJI and were treated with rifampicin or without between 2004 and 2019. The 37 patients treated from January 2004 to August 2014 were prescribed rifampicin-combination therapy and the 33 treated from September 2014 to December 2019 received monotherapy without rifampicin. The primary endpoint was the 2-year Kaplan-Meier-estimated reinfection-free probability, including relapses and new-pathogen PJIs. The 2-year reinfection-free rate was high and not different for patients who had received rifampicin or not (89.2% vs. 93.8%, respectively; p = 0.524). None of the patients relapsed and six developed new-pathogen PJIs. Our results do not support a benefit of rifampicin-combination therapy for patients who underwent exchange arthroplasty for chronic Ca-PJIs.

Streptococcal and Staphylococcus aureus prosthetic joint infections: are they really different?

BACKGROUND: Staphylococci and streptococci are the most frequent pathogens isolated from prosthetic joint infections (PJIs). The aim of this study was to analyze the outcome of streptococcal and methicillin-susceptible Staphylococcus aureus (MSSA) PJIs. METHODS: All monomicrobial streptococcal and MSSA PJIs managed in a French Referral Center (2010-2017) were sampled from the prospective PJIs cohort study. The primary outcome of interest was the cumulative reinfection-free survival at a 2-year follow-up. RESULTS: Two hundred and nine patients with 91 streptococcal and 132 staphylococcal infections were analyzed. Patients with streptococcal PJI were older, and infection was more frequently hematogenous. Reinfection-free survival rates at 2-years after all treatment strategies were higher for patients with streptococcal PJI (91% vs 81%; P = .012), but differed according to the strategy. After exchange arthroplasty, no outcome differences were observed (89% vs 93%; P = .878); after debridement, antibiotics and implant retention (DAIR), the reinfection-free survival rate was higher for patients with streptococcal PJI (87% vs 60%; P = .062). For patients managed with prolonged suppressive antibiotic therapy (SAT) alone, those with streptococcal PJIs had a 100% infection-free survival (100% vs 31%; P < .0001). CONCLUSIONS: Reinfection-free survival after DAIR and SAT was better for patients with streptococcal than those with MSSA PJIs. No difference was observed after prosthesis exchange.

A randomized, placebo-controlled clinical trial evaluating olipudase alfa enzyme replacement therapy for chronic acid sphingomyelinase deficiency (ASMD) in adults: One-year results.

PURPOSE: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults. METHODS: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics. RESULTS: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P = .0004), spleen volume (39% decrease vs 0.5% increase, P < .0001), and liver volume (28% vs 1.5% decreases, P < .0001). Splenomegaly-related score decreased in both groups (P = .64). Other clinical outcomes improved in the olipudase alfa group compared with the placebo group. There were no treatment-related serious adverse events or adverse event-related discontinuations. Most adverse events were mild. CONCLUSION: Olipudase alfa was well tolerated and associated with significant and comprehensive improvements in disease pathology and clinically relevant endpoints compared with placebo in adults with ASMD.

Sphingosine-1-Phosphate Levels Are Higher in Male Patients with Non-Classic Fabry Disease.

Fabry disease is an X-linked lysosomal disease in which defects in the alpha-galactosidase A enzyme activity lead to the ubiquitous accumulation of glycosphingolipids. Whereas the classic disease is characterized by neuropathic pain, progressive renal failure, white matter lesions, cerebral stroke, and hypertrophic cardiomyopathy (HCM), the non-classic phenotype, also known as cardiac variant, is almost exclusively characterized by HCM. Circulating sphingosine-1-phosphate (S1P) has controversially been associated with the Fabry cardiomyopathy. We measured serum S1P levels in 41 patients of the FFABRY cohort. S1P levels were higher in patients with a non-classic phenotype compared to those with a classic phenotype (200.3 [189.6−227.9] vs. 169.4 ng/mL [121.1−203.3], p = 0.02). In a multivariate logistic regression model, elevated S1P concentration remained statistically associated with the non-classic phenotype (OR = 1.03; p < 0.02), and elevated lysoGb3 concentration with the classic phenotype (OR = 0.95; p < 0.03). S1P levels were correlated with interventricular septum thickness (r = 0.46; p = 0.02). In a logistic regression model including S1P serum levels, phenotype, and age, age remained the only variable significantly associated with the risk of HCM (OR = 1.25; p = 0.001). S1P alone was not associated with cardiac hypertrophy but with the cardiac variant. The significantly higher S1P levels in patients with the cardiac variant compared to those with classic Fabry suggest the involvement of distinct pathophysiological pathways in the two phenotypes. S1P dosage could allow the personalization of patient management.

Do clinical guidelines facilitate or impede drivers of treatment in Fabry disease?

BACKGROUND: Variable disease progression confounds accurate prognosis in Fabry disease. Evidence supports the long-term benefit of early intervention with disease-specific therapy, but current guidelines recommend treatment initiation based on signs that may present too late to avoid irreversible organ damage. Findings from the 'PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease' (PREDICT-FD) initiative included expert consensus on 27 early indicators of disease progression in Fabry disease and on drivers of and barriers to treatment initiation in Fabry disease. Here, we compared the PREDICT-FD indicators with guidance from the European Fabry Working Group and various national guidelines to identify differences in signs supporting treatment initiation and how guidelines themselves might affect initiation. Finally, anonymized patient histories were reviewed by PREDICT-FD experts to determine whether PREDICT-FD indicators supported earlier treatment than existing guidance. RESULTS: Current guidelines generally aligned with PREDICT-FD on indicators of renal involvement, but most lacked specificity regarding cardiac indicators. The prognostic significance of neurological indicators such as white matter lesions (excluded by PREDICT-FD) was questioned in some guidelines and excluded from most. Some PREDICT-FD patient-reported signs (e.g., febrile crises) did not feature elsewhere. Key drivers of treatment initiation in PREDICT-FD were: (A) male sex, young age, and clinical findings (e.g., severe pain, organ involvement), (B) improving clinical outcomes and preventing disease progression, and (C) a family history of Fabry disease (especially if outcomes were severe). All guidelines aligned with (A) and several advocated therapy for asymptomatic male patients. There was scant evidence of (B) in current guidance: for example, no countries mandated ancillary symptomatic therapy, and no guidance advocated familial screening with (C) when diagnosis was confirmed. Barriers were misdiagnosis and a lack of biomarkers to inform timing of treatment. Review of patient histories generally found equal or greater support for treatment initiation with PREDICT-FD indicators than with other guidelines and revealed that the same case and guideline criteria often yielded different treatment recommendations. CONCLUSIONS: Wider adoption of PREDICT-FD indicators at a national level could promote earlier treatment in Fabry disease. Clearer, more concise guidance is needed to harmonize treatment initiation in Fabry disease internationally.

Acid Sphingomyelinase Deficiency: Sharing Experience of Disease Monitoring and Severity in France.

Acid sphingomyelinase deficiency (ASMD) is a rare inherited lipid storage disorder caused by a deficiency in lysosomal enzyme acid sphingomyelinase which results in the accumulation of sphingomyelin, predominantly within cells of the reticuloendothelial system located in numerous organs, such as the liver, spleen, lungs, and central nervous system. Although all patients with ASMD share the same basic metabolic defect, a wide spectrum of clinical presentations and outcomes are observed, contributing to treatment challenges. While infantile neurovisceral ASMD (also known as Niemann-Pick disease type A) is rapidly progressive and fatal in early childhood, and the more slowly progressive chronic neurovisceral (type A/B) and chronic visceral (type B) forms have varying clinical phenotypes and life expectancy. The prognosis of visceral ASMD is mainly determined by the association of hepatosplenomegaly with secondary thrombocytopenia and lung disease. Early diagnosis and appropriate management are essential to reduce the risk of complications and mortality. The accessibility of the new enzyme replacement therapy olipudase alfa, a recombinant human ASM, has been expedited for clinical use based on positive clinical data in children and adult patients, such as improved respiratory status and reduced spleen volume. The aim of this article is to share the authors experience on monitoring ASMD patients and stratifying the severity of the disease to aid in care decisions.

Diagnostic Value of 18F-FDG PET/CT vs. Chest-Abdomen-Pelvis CT Scan in Management of Patients with Fever of Unknown Origin, Inflammation of Unknown Origin or Episodic Fever of Unknown Origin: A Comparative Multicentre Prospective Study.

Fluorodesoxyglucose Positron Emission Tomography (PET/CT) has never been compared to Chest-Abdomen-Pelvis CT (CAPCT) in patients with a fever of unknown origin (FUO), inflammation of unknown origin (IUO) and episodic fever of unknown origin (EFUO) through a prospective and multicentre study. In this study, we investigated the diagnostic value of PET/CT compared to CAPCT in these patients. The trial was performed between 1 May 2008 through 28 February 2013 with 7 French University Hospital centres. Patients who fulfilled the FUO, IUO or EFUO criteria were included. Diagnostic orientation (DO), diagnostic contribution (DC) and time for diagnosis of both imaging resources were evaluated. One hundred and three patients were included with 35 FUO, 35 IUO and 33 EFUO patients. PET/CT showed both a higher DO (28.2% vs. 7.8%, p < 0.001) and DC (19.4% vs. 5.8%, p < 0.001) than CAPCT and reduced the time for diagnosis in patients (3.8 vs. 17.6 months, p = 0.02). Arthralgia (OR 4.90, p = 0.0012), DO of PET/CT (OR 4.09, p = 0.016), CRP > 30 mg/L (OR 3.70, p = 0.033), and chills (OR 3.06, p = 0.0248) were associated with the achievement of a diagnosis (Se: 89.1%, Sp: 56.8%). PET/CT both orients and contributes to diagnoses at a higher rate than CAPCT, especially in patients with FUO and IUO, and reduces the time for diagnosis.

Cochleovestibular involvement in patients with Fabry disease: data from the multicenter cohort FFABRY.

PURPOSE: Fabry disease (FD) is a lysosomal storage disease responsible for cochleovestibular involvement. Exact prevalence and pathophysiological mechanisms behind ENT affections are still poorly known. Treating FD with enzyme replacement therapy (ERT) does not seem to significantly improve the ENT symptoms, while the impact of migalastat has yet to be determined. METHODS: We carried out a retrospective multi-centre study on 47 patients from the FFABRY cohort who had an ENT consultation in the context of their FD. The information collected were as follows: clinical examination, videonystagmoscopy, pure-tone speech audiometry, videonystagmography or VHIT (Video Head Impulse Test). Severe hearing loss was defined as greater than 70 dB. RESULTS: The median age of our cohort was 52 years with a non-negligible proportion of non-classic variants and female carriers. 72.3% of the patients complained of at least one of the following symptoms: hearing loss, tinnitus or vertigo. Pure-tone audiometry was abnormal in 61.7% of the patients (29/47), while speech audiometry was abnormal for 41.7% of the patients. The age of the patients and hypertrophic cardiomyopathy were significantly associated with the existence of an anomaly in pure-tone audiometry results. Severe hearing loss (> 70 dB) was significantly more common in male patients. DISCUSSION: Hearing loss is particularly frequent in FD and is not limited to classic phenotypes. Close ENT follow-up is essential for Fabry patients to detect those who might benefit from hearing aid. Further studies are needed to define the impact of migalastat on cochleovestibular symptoms.

Prevalence of Cancer in Acid Sphingomyelinase Deficiency.

Acid sphingomyelinase deficiency (ASMD) is an inherited lysosomal disease characterised by a diffuse accumulation of sphingomyelin that cannot be catabolised into ceramide and phosphocholine. We studied the incidence of cancer in ASMD patients. We retrospectively reviewed the medical records of the adult chronic visceral ASMD patients in our cohort. Thirty-one patients (12 females, 19 males) were included with a median age of 48.7 y. (IQ: 30.3-55.1). Five cancers were observed in 1 female (breast cancer) and 4 males (two lung cancers, one thyroid cancer and one bladder cancer), resulting in a prevalence of 16.1%. The existence of cancer was associated with a more severe ASMD characterised by a larger spleen (25 cm (22.5-25) vs. 18 cm (17-20); p = 0.042); lower diffusing capacity of the lung for carbon monoxide (DLCO; 29.5 % (17.8-43.0) vs. 58.5 % (49.8-69.5%); p = 0.01) and tobacco use (100% vs. 45%; p = 0.04). Three patients died, all from cancer (p = 0.002). The prevalence of cancer appeared to be strikingly elevated in our cohort of patients, without any specificity in the type of cancer. Systematic screening for cancer should be performed, and carcinogenic substances such as tobacco should be avoided in patients with ASMD.

Parsing Fabry Disease Metabolic Plasticity Using Metabolomics.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal disease due to a deficiency in the activity of the lysosomal α-galactosidase A (GalA), a key enzyme in the glycosphingolipid degradation pathway. FD is a complex disease with a poor genotype-phenotype correlation. FD could involve kidney, heart or central nervous system impairment that significantly decreases life expectancy. The advent of omics technologies offers the possibility of a global, integrated and systemic approach well-suited for the exploration of this complex disease. MATERIALS AND METHODS: Sixty-six plasmas of FD patients from the French Fabry cohort (FFABRY) and 60 control plasmas were analyzed using liquid chromatography and mass spectrometry-based targeted metabolomics (188 metabolites) along with the determination of LysoGb3 concentration and GalA enzymatic activity. Conventional univariate analyses as well as systems biology and machine learning methods were used. RESULTS: The analysis allowed for the identification of discriminating metabolic profiles that unambiguously separate FD patients from control subjects. The analysis identified 86 metabolites that are differentially expressed, including 62 Glycerophospholipids, 8 Acylcarnitines, 6 Sphingomyelins, 5 Aminoacids and 5 Biogenic Amines. Thirteen consensus metabolites were identified through network-based analysis, including 1 biogenic amine, 2 lysophosphatidylcholines and 10 glycerophospholipids. A predictive model using these metabolites showed an AUC-ROC of 0.992 (CI: 0.965-1.000). CONCLUSION: These results highlight deep metabolic remodeling in FD and confirm the potential of omics-based approaches in lysosomal diseases to reveal clinical and biological associations to generate pathophysiological hypotheses.