Ileocecal appendix involvement in fabry disease mimicking an acute abdomen

Anderson-Fabry disease (AFD) is a rare, X-linked, lysosomal storage disorder due to a deficiency of alphagalactosidase A. The direct consequence is a lipid storage with the accumulation of glycosphingolipids throughout the body. The clinical picture is highly variable and depends on cellular storage deposition ranging from neurological, cutaneous and renal symptoms to cardiac and gastrointestinal ones. We are reporting about the case of a young female carrier of alpha-galactosidase A (agalA) gene mutation who was treated at our out-clinic practice for minimal neurological involvement (achroparaestesia). She was subsequently admitted in order to undergo appendectomy because of an acute severe abdominal pain. The histological examination of her appendix revealed only a deposition of globotriaosylceramide (Gb3) without any sign of acute inflammation. This case confirms the extreme clinical variability of Fabry disease and how the gastrointestinal involvement diagnosis can be misse

Cephotaxime-associated allergic interstitial nephritis and MPO-ANCA positive vasculitis.

We report a case of reversible acute renal failure after cephotaxime treatment in a patient affected by non-Hodgkin lymphoma. Renal biopsy showed necrotizing vasculitis associated with eosinophil-rich interstitial inflammatory infiltrates and patchy infiltrates of CD20+ lymphoid cells. High serum p-ANCA titers were also detected. Drug withdrawal was closely related with recovery of renal function and disappearance of ANCA. Acute renal failure therefore represented a consequence of ANCA-mediated renal vasculitis and acute interstitial nephritis related to cephotaxime treatment

Updated Evaluation of Agalsidase Alfa Enzyme Replacement Therapy for Patients with Fabry Disease: Insights from Real-World Data

Sandro Feriozzi,1 Cristina Chimenti,2 Ricardo Claudio Reisin3 1Department of Nephrology and Dialysis Unit, Belcolle Hospital Viterbo, Italy; 2Department of Clinical Sciences, Internal Medicine, Anesthesiology and Cardiovascular Sciences, La Sapienza University, Rome, Italy; 3Department of Neurology, Hospital Británico, Buenos Aires, ArgentinaCorrespondence: Sandro Feriozzi, Nephrology and Dialysis Unit, Belcolle Hospital, Strada Sammartinese snc, Viterbo, 01100, Italy, Tel +39/0761338602, Fax +39/076133600, Email [email protected]: The clinical use of agalsidase alfa as enzyme replacement therapy (ERT) for Fabry disease (FD) has spread since 2001, and a large body of evidence of its effectiveness has been collected. This review presents the clinical and laboratory results achieved with agalsidase alfa, which has been published in the literature. Agalsidase alfa infusion slows down or stops the progression of renal damage, expressed by reduction or stabilization of the annual decline of the glomerular filtration rate; yearly decrease of glomerular filtration rate (slope) sometimes is reduced until its stabilization. ERT prevents or reduces the occurrence of hypertrophic cardiomyopathy or slows the increase over time if it is already present. Moreover, regarding neurological manifestations, ERT improves neuropathic pain and quality of life, and recent data indicated that it may also prevent the burden of cerebrovascular disease. In addition to ERT’s clinical benefits, crucial topics like the most appropriate time to start therapy and the role of anti-drug antibodies (ADA) are analyzed. Treatment with agalsidase alfa in patients with FD substantially improves their outcomes and enhances their quality of life in patients with FD.Keywords: Fabry disease, agalsidase alfa, enzyme replacement therapy, clinical outcome in Fabry treated patient

Prompt Agalsidase Alfa Therapy Initiation is Associated with Improved Renal and Cardiovascular Outcomes in a Fabry Outcome Survey Analysis

BACKGROUND: The timing of enzyme replacement therapy initiation in patients with Fabry disease is hypothesized to be critical. In this study, we used Fabry Outcome Survey data to assess the impact of prompt versus delayed initiation of treatment with agalsidase alfa on cardiovascular and renal events in patients with Fabry disease. METHODS: Available genetic data at baseline were used to define patients with mutations associated with classical versus late-onset Fabry disease. Time to cardiovascular or renal events, from treatment initiation until 120 months, was compared for patients in prompt versus delayed groups. “Prompt” was defined as treatment initiation < 24 months from symptom onset (analysis A) or diagnosis (analysis B), and “delayed” was defined as ≥ 24 months from symptom onset (analysis A) or diagnosis (analysis B). Kaplan–Meier curves and Log rank tests compared event-free probabilities and time to first event. Multivariate Cox regression estimated hazard ratios (HRs). RESULTS: Analysis by time from symptom onset included 1374 patients (172 prompt, 1202 delayed). In a multivariate Cox regression analysis, prompt versus delayed treatment initiation significantly reduced the probability of cardiovascular (HR=0.62; P< 0.001) and renal (HR=0.57; P=0.001) events. History of cardiovascular or renal events was associated with increased risk of respective events. Analysis by time from diagnosis included 2051 patients (1006 prompt, 1045 delayed). In a multivariate Cox regression analysis, prompt treatment initiation significantly reduced the probability of cardiovascular events (HR=0.83; P=0.003) after adjusting for history of cardiovascular events, sex, and age at treatment initiation. Univariate analysis showed that the probability of renal events was significantly lower in the prompt group (P=0.018); this finding was attenuated in the multivariate Cox regression analysis. CONCLUSIONS: This analysis suggests that prompt treatment initiation with agalsidase alfa provided better renal and cardiovascular outcomes than delayed treatment in patients with Fabry disease

Effects of Baseline Left Ventricular Hypertrophy and Decreased Renal Function on Cardiovascular and Renal Outcomes in Patients with Fabry Disease Treated with Agalsidase Alfa: A Fabry Outcome Survey Study

PURPOSE: The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment. METHODS: Eligible patients were males and females aged ≥18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan-Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; ≤50 g/m2.7 in males and ≤48 g/m2.7 in females) at treatment initiation (baseline), and in patients with a low estimated glomerular filtration rate (eGFR; <90 mL/min/1.73 m2) versus normal eGFR at baseline. Multivariate Cox regression analysis was used for examining the association between key study variables and the risks for cardiovascular and renal events. FINDINGS: Among the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio [HR] = 1.57; 95% CI, 1.21-2.05; P < 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94-3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04-1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73-12.68; P < 0.001) compared with patients with a normal eGFR at baseline. IMPLICATIONS: In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065

La nefropatia in corso di malattia di Anderson-Fabry: nuove raccomandazioni sulla diagnosi, il follow up e la terapia

La malattia di Anderson-Fabry \ue8 una malattia ereditaria legata al cromosoma X che causa il deficit totale o parziale dell\u2019enzima alfa galattosidasi A con conseguente accumulo di glicosfingolipidi in vati tessuti ed organi. Ci\uf2 determina una malattia multi sistemica con prevalente interessamento renale, cardiaco e del sistema nervoso centrale e periferico. I numerosi studi eseguiti su tale malattia negli ultimi anni hanno consentito un notevole miglioramento delle conoscenze sui principali aspetti della malattia come la diagnosi, la gestione del paziente e la terapia. Allo stato attuale infatti la terapia enzimatica sostitutiva ha dimostrato di essere in grado di modificare il decorso naturale della malattia, in particolar modo tanto pi\uf9 la diagnosi \ue8 tempestiva e la terapia \ue8 impostata precocemente. Pur tuttavia, la malattia di Fabry rimane una malattia di difficile diagnosi, e in cui alcuni aspetti come la gestione del paziente affetto, della femmina eterozigote o l\u2019inizio della terapia enzimatica sono ancora controversi. Al fine quindi di aggiornare precedenti raccomandazioni nazionali si \ue8 costituito un gruppo di lavoro (Anderson-Fabry DiseaseItalian Board) con lo scopo di raggiungere un consensus multidisciplinare, coinvolgendo nefrologi, cardiologi, genetisti, pediatri e neurologi, sul tema del management clinico-terapeutico della malattia. Il gruppo di lavoro nefrologico in particolare, ha portato alla definizione di una serie di raccomandazioni che rappresentano l\u2019oggetto di tale pubblicazione e che possono rappresentare un valido strumento nelle mani sia di clinici esperti della malattia ma anche di medici con limitata esperienza per la definizione diagnostica, la gestione clinica e la terapia della malattia di Anderson-Fabry

The GALA project. practical recommendations for the use of migalastat in clinical practice on the basis of a structured survey among Italian experts

Background: Oral migalastat has recently been approved for the treatment of Anderson-Fabry disease (FD) in patients aged ≥16 years with amenable mutations on the basis of two phase III trials, FACETS and ATTRACT. However, with the introduction of migalastat into clinical practice, it is important to correctly identify the patients who may gain the most benefits from this therapy. Due to the relatively recent availability of migalastat, its role in clinical practice still has to be included in guidelines or recommendations. On these bases, a multidisciplinary group of Italian Experts in the treatment of FD has run the GALA project, with the aim to collect the opinions of expert physicians and to propose some starting points for an experience-based use of migalastat. Results: Overall, although studies and data from longer-term follow-up with migalastat are still emerging, available evidence is consistent in showing that this molecule does represent a suitable therapy for the treatment of FD, in patients aged ≥16 years and with amenable mutations. The use of migalastat as an oral option appears to be overall safe, and experience thus far indicates potential for improving quality of life, controlling GI symptoms, stabilizing renal function and reducing cardiac hypertrophy. Conclusion: Migalastat can be considered either as a first-line therapy - given its efficacy, extensive tissue penetration, convenient oral regimen, and the current limited therapeutic options available - or in patients on enzyme-replacement therapy (ERT) who experience side effects, with poor compliance to chronic i.v. therapy, or with clinical evidence of progression of the disease