Arterial involvement in Fabry disease: state of the art and future diagnostic purposes.

Anderson-Fabry disease (FD) is a rare genetic, progressive, and multi-systemic condition, with X-linked inheritance. This is caused by pathogenic variants in the GLA gene, coding for the lysosomal enzyme called alpha-galactosidase A (aGLA), responsible for the cleavage of globotriaosylceramide (Gb3). The reduced or absent activity of aGLA causes the intracellular accumulation of Gb3, particularly in smooth and endothelial muscle cells, which causes cellular dysfunction. The main organs involved are the central nervous system, heart, and kidneys. However, being a ubiquitous enzyme, FD disease must be considered a systemic disease involving the peripheral nervous system, ocular and audio-vestibular systems. Also, the vascular district is damaged but the pathophysiology of vasculopathy in FD is not yet entirely understood. In literature, many vascular diagnostic tests were used to evaluate this specific involvement in FD, i.e., carotid intima media thickness (cIMT), arterial stiffness (AS), flow-mediated dilation (FMD) and atherosclerotic plaques; evaluation of vascular calcifications in FD patients is not presently available. In this review, we examined the current available literature on vascular aspects in FD. Moreover, we presented our global vascular evaluation, based on Radio Frequency Duplex Ultrasound (RF-DU), plaques, and vascular calcifications, to apply to FD patients.

Therapeutic management of idiopathic recurrent serositis: a retrospective study.

OBJECTIVE: Idiopathic recurrent serositis (IRS) is the most frequent serositis encountered in real-life medical sceneries, and its management represents a therapeutic challenge. There are few epidemiologic data related to IRS, though most studies have focused on recurrent pericarditis, revealing that 70% of all forms of pericarditis are idiopathic and caused by innate immunity abnormalities. The aim of this study was to evaluate outcome and recurrence rates of patients with IRS, assessing management modalities used in our Periodic Fever Centre of the Gemelli Hospital, Rome, Italy, in comparison with previous treatments in other centres. PATIENTS AND METHODS: Retrospectively, we analyzed the medical charts of 57 unselected patients with history of IRS managed during the period 1998-2017. RESULTS: A strong heterogeneity emerged by evaluating treatments of this cohort. In particular, in our Centre there was a larger use of combined therapies: 14 patients out of 27 (52%) were treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine, compared to only 2 patients (7.4%) previously treated with combined treatments. We used corticosteroid monotherapy only in 1 case, against 7 from other centres. The mean duration of NSAID treatment in other hospitals was 43.8 days (SD ±27.40) and 191.25 days (SD ±42.23) in our Centre; the mean duration of corticosteroid treatment in other hospitals was 101.5 days (SD ±56.40) and 180.7 days (SD ±84.87) in our Centre. Colchicine was administered in other hospitals for the same duration of NSAIDs, and corticosteroids with an average duration of 111 days (SD ±30); conversely, we administered colchicine for an average duration of 250.12 days (SD ±80.7). Relapses of IRS were reported in 1/3 of cases who had discontinued therapies. CONCLUSIONS: The overall duration of treatments to manage IRS has a weight in terms of patients' outcome. A reduced duration of therapy with corticosteroids and a longer duration of therapy with NSAIDs determine a longer disease-free interval. A significant discriminating effect in terms of risk of IRS recurrence relies in an earlier combination therapy with colchicine independently from the start with either NSAIDs or corticosteroids. Finally, the evaluation of genes causing autoinflammatory diseases has not revealed any pathogenetic variants in a subcohort of 20/57 patients with IRS.

Long-term treatment with anakinra and canakinumab resolves patellar subchondral erosion in neonatal-onset multisystem inflammatory disease.

Not available.

Small Intestinal Bacterial Overgrowth Affects the Responsiveness to Colchicine in Familial Mediterranean Fever.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease due to a MEFV gene mutation. Since Helicobacter pylori infection has been described to increase the severity and frequency of FMF attacks, we evaluate if overgrowth of small intestinal bacterial (SIBO), associated with a release of bacterial products, can affect the response to colchicine in FMF patients poorly responsive to colchicine. METHODS: We revised our Periodic Fever Centre database to detect FMF patients who were poorly responsive to colchicine, without a well-defined cause of drug resistance. They were evaluated for SIBO presence, then treated with decontamination therapy. RESULTS: Among 223 FMF patients, 49 subjects show colchicine resistance, and no other known causes of colchicine unresponsiveness has been found in 25 patients. All 25 patients underwent glucose breath test; 20 (80%) of them were positive, thus affected by SIBO. After a successful decontamination treatment, 11 patients (55%) did not show FMF attacks during the following three months (p < 0.01), while 9 of them revealed a significant reduction of the number of attacks compared to three months before (p < 0.01). CONCLUSION: The SIBO eradication improves laboratory and clinical features of FMF patients. Thus, patients with unresponsiveness to colchicine treatment should be investigated for SIBO.

The use of solid-phase fluorescence spectroscopy in the characterisation of organic matter transformations.

Given its high sensitivity and non-destructive nature, fluorescence excitation-emission matrix (EEM) spectroscopy is widely used to differentiate changes and transformations of dissolved or water-extracted organic matter (OM) in natural environments. The same technique applied directly on solid samples (solid-phase fluorescence spectroscopy, SPF-EEM) provides accurate results when used with pharmaceutical products or food samples, but only a few studies have considered natural OM. This study reports on the use of SPF-EEM on solid compost samples and emphasises the way the different maturation phases can be distinguished with fluorophores closely resembling those found in dissolved samples. A very good correlation has been found with data from Rock-Eval pyrolysis, nuclear magnetic resonance ((13)C CPMAS NMR), and humic-fulvic acid ratios determined by conventional NaOH-extraction. SPF-EEM appears as a much simpler method than the conventional ones to detect transformations in natural OM samples with low mineral contents. However, direct application to soil samples requires some additional studies.

Current advances in the understanding and treatment of mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory metabolic disease that is caused by mutations in the MVK gene. Patients with MKD typically have an early onset in infancy. MKD is characterized by recurrent episodes of high fever, abdominal distress, diffuse joint pain, and skin rashes. In a subset of patients, MKD is also associated with elevated serum immunoglobulin D (IgD) levels (hyperimmunoglobulinemia D syndrome, HIDS). The clinical phenotype of MKD varies widely and depends on the severity of the impaired mevalonate kinase activity. Complete impairment results in the severe metabolic disease, mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentation, including HIDS. The precise molecular mechanisms behind the elevated serum IgD levels and inflammation that occurs in MKD remain unknown. Children who exhibit symptoms of MKD should be tested for mutations in the MKD gene. However, the complexity of MKD often results in delays in its definitive diagnosis and the outcome in adult age is not completely known. Therapeutic options for MKD are based on limited data and include non-steroidal anti-inflammatory drugs, corticosteroids, and biological agents that target specific cytokine pathways. In recent years, some studies have reported promising results for new biological drugs; however, these cases have failed to achieve satisfactory remission. Therefore, further studies are needed to understand the pathogenesis of MKD and identify innovative therapeutic tools for its management.

Giant cell arteritis and polymyalgia rheumatica after influenza vaccination: report of 10 cases and review of the literature.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are inflammatory rheumatic diseases common in people over the age of 50 years. Herein, we report 10 cases of previously healthy subjects who developed GCA/PMR within 3 months of influenza vaccination (Inf-V). A Medline search uncovered additional 11 isolated cases of GCA/PMR occurring after Inf-V. We discuss the role of individual susceptibility, the potential function of immune adjuvants as triggers of autoimmunity post-vaccination, and the correlation of our observation with the 'ASIA' syndrome, i.e. autoimmune/inflammatory syndrome induced by adjuvants and including post-vaccination phenomena.

Association between familial mediterranean fever and retroperitoneal fibrosis: retroperitoneal fibrosis regression after colchicine therapy.

Retroperitoneal fibrosis (RPF) is a disease characterized by inflammatory fibrotic processes affecting the retroperitoneal structures. Familial Mediterranean Fever (FMF) is an autosomal recessive disorder, characterized by fever and attacks of sterile serositis. Colchicine is the only suitable drug for prevention of acute episodes. We describe a case of association between RPF and FMF in a 48-year-old male, in whom therapy with colchicine, besides preventing acute episodes, allowed RPF regression. To date the association between FMF and RPF and the use of colchicine therapy alone for RPF has not been described.

Atypical sarcoidosis: case reports and review of the literature.

Sarcoidosis is a granulomatous disease of unknown origin, with pulmonary findings in more than 90% of patients. Extrapulmonary involvement is common and all organs can be involved (especially lymph nodes, eyes, joints, central nervous system) but it is rare to find an isolated extrapulmonary disease (less than 10% of patients). Granulomatous inflammation of the spleen and the liver is common in patients with systemic sarcoidosis, while hepatosplenic enlargement is unusual and splenic involvement rare. We report two cases of systemic sarcoidosis, that onset with splenic and hepatosplenic disease, and one case with splenic sarcoidosis without pulmonary involvement. In the first case a 53-year-old woman with mild abdominal pain underwent sonography and CT, which revealed one hypoechoic/hypodense splenic lesion. Laboratory tests were normal. In order to exclude a lymphoma, splenectomy was performed: histology revealed a sarcoid granuloma. After surgery the patient was asymptomatic and now, after two years, disease is silent. The second case is a 66-year-old woman with a recent weight loss (8 kg in two months) and alterated liver function tests (AST 61 U/l, ALT 72 U/l, Alkaline phosphatase 748 U/l, g-GT 381 U/l). Since she had a familiar history of colon cancer, abdominal US scan, abdominal CT scan and MRI were performed and showed inter-aorto-caval lymphadenopathies and discreet multiple bilobar hepatic and splenic substitutive lesions, with no signs of primary tumor. Upper and lower GI endoscopy, full gynecological workup, complete set of tumor markers, bone marrow biopsy were performed. All resulted negative for neoplasia. Small pulmonary infiltrations were observed on chest-CT scan but cytology on BAL was normal. Infections were also excluded. An exploratory laparotomy showed whitish peritoneal, hepatic and splenic nodules. The histological exam revealed chronic granulomatous lesions typical for sarcoidosis. During a two-year follow-up after the splenectomy the patient feels well without any treatment. The third patient is a 32-year-old woman with mild epigastric pain after meals. Neck-thoracic CT, bone scintigraphy and upper GI endoscopy were negative. Abdominal US and MR showed splenomegaly with multiple splenic lesions. Splenectomy was performed and histological exam showed chronic granulomatous lesions typical for sarcoidosis. Further laboratory tests were normal, except for ACE (66 UI/l). After the surgery ACE became normal and now, three years later, the patient is still asymptomatic. We conclude that hepatosplenic involvement is less rare than it is thought. It is often oligosymptomatic or accompanied with unspecific manifestations and laboratory abnormalities. The diagnosis could be difficult; in fact typical laboratory findings of sarcoidosis such as ACE, lysozyme, calcium, were not diagnostic. Ultrasonography and CT were important but the diagnosis was established only with the histological examination of suspected lesions. This latter required to differentiate liver and/or spleen sarcoidosis from tuberculosis and other infections, primary biliary cirrhosis, metastasis or malignant lymphoma.

Gastrointestinal amyloidosis: a case of chronic diarrhoea.

Amyloidosis is a rare disease caused by extracellular deposits of insoluble fibrillar proteins in various organs and tissues. There are different forms of amyloidosis distinguished by the type of protein fibrils, by the sites of deposition and by associated conditions. Gastrointestinal involvement is common both in primary and secondary amyloidosis, while isolated gastrointestinal amyloidosis is rare. We describe a case of AL amyloidosis with a gastrointestinal involvement and restrictive cardiomiopathy. A 64 year old woman came to our attention with a history of chronic diarrhoea and weight loss, associated with dysphagia, dry mouth, xerophtalmia, chronic gastritis and depression. Clinical diagnosis has been difficult because of aspecificity of symptoms that mimed other more common diseases, like gastro-paresis, epigastric discomfort, gastric or duodenal ulcers, perforation, malabsorption, intestinal pseudo-obstruction. There is an important risk of misunderstanding and diagnostic delay. Indeed in this patient a diagnosis of irritable colon syndrome was erroneously established two years before admission in our hospital. Therefore gastrointestinal amyloidosis should be considered among differential diagnoses of chronic diarrhoea and weight loss when other more common diseases have been excluded.

Clinical features of familial Mediterranean fever: an Italian overview.

Familial Mediterranean Fever (FMF) is the most frequent periodic febrile syndrome among the autoinflammatory syndromes (AS), nowadays considered as innate immunity disorders, characterized by absence of autoantibodies and autoreactive T lymphocytes. FMF is a hereditary autosomal recessive disorder, characterized by recurrent, self-limiting episodes of short duration (mean 24e72 h) of fever and serositis. In FMF, periodic attacks show inter- and intra-individual variability in terms of frequency and severity. Usually, they are triggered by apparently innocuous stimuli and may be preceded by a prodromal period. The Mediterranean FeVer gene (MEFV) responsible gene maps on chromosome 16 (16p13) encoding the Pyrine/Marenostrin protein. The precise pathologic mechanism is still to be definitively elucidated; however a new macromolecular complex, called inflammasome, seems to play a major role in the control of inflammation and it might be involved in the pathogenesis of FMF. The most severe long-term complication is type AA amyloidosis, causing chronic renal failure. Two types of risk factors, genetic and non-genetic, have been identified for this complication. Currently, the only effective treatment of FMF is the colchicine. New drugs in a few colchicine resistant patients are under evaluation

Cyclosporine A: good response for patients affected by autoimmune disorders and HCV infection?

INTRODUCTION: In autoimmune disorders (ADs), if Hepatitis C Virus (HCV) is present, immunosuppressive treatment could increase virus replication. Cyclosporine A (CsA), in standard therapeutic doses, has been proven able to inhibit HCV cyclophilin in vitro. Therefore CsA could improve the therapy of HCV patients with ADs. AIM: In these patients, we started an open pilot study to evaluate the safety of 3 mg/kg CsA and the ability to reduce steroid therapy. PATIENTS AND METHODS: Five females and 1 male were recruited; mean age 66 +/- 8 years, mean disease duration 13 +/- 5 years. Three patients are affected by Psoriasic Arthritis, 1 by Rheumatoid Arthritis, 1 by Sjogren Syndrome, and 1 by Myasthenia Gravis. None of them had chronic active hepatitis. HCV genotypes were type 2 (in 3 cases) and type 1 (in 3 cases). Patients were treated with 3 mg/kg of CsA for a period of time ranging from 6 to 12 months. The starting mean dose of prednisone was 12.5 mg/day. Liver function tests were checked monthly and serum HCV-RNA load was checked by RT-PCR before and 2 months into the therapy. RESULTS: The prednisone dose was reduced from 12.5 mg/day to 7.5 mg/day. The aminotransferases levels were unchanged after 6 months. In patients with low HCV-RNA levels before treatment, no modifications of viral load were observed, whereas patients with increased levels at onset showed mild reduction 2 months into the treatment. CONCLUSIONS: Immunosuppressive treatment of ADs patients with HCV infection can be safely provided with the integration of CsA.

Wegener's granulomatosis: an update on diagnosis and therapy.

Wegener's granulomatosis (WG) is a unique clinicopathological disease characterized by necrotizing granulomatous vasculitis of the respiratory tract, pauci-immune necrotizing glomerulonephritis and small-vessel vasculitis. Owing to its wide range of clinical manifestations, WG has a broad spectrum of severity that includes the potential for alveolar hemorrhage or rapidly progressive glomerulonephritis, which are immediately life threatening. WG is associated with the presence of circulating antineutrophil cytoplasm antibodies (c-ANCAs). The most widely accepted pathogenetic model suggests that c-ANCA-activated cytokine-primed neutrophils induce microvascular damage and a rapid escalation of inflammation with recruitment of mononuclear cells. The diagnosis of WG is made on the basis of typical clinical and radiologic findings, by biopsy of involved organ, the presence of c-ANCA and exclusion of all other small-vessel vasculitis. Currently, a regimen consisting of daily cyclophosphamide and corticosteroids is considered standard therapy. A number of trials have evaluated the efficacy of less-toxic immunosuppressants and antibacterials for treating patients with WG, resulting in the identification of effective alternative regimens to induce or maintain remission in certain subpopulations of patients. Recent investigation has focused on other immunomodulatory agents (e.g., TNF-alpha inhibitors and anti-CD20 antibodies), intravenous immunoglobulins and antithymocyte globulins for treating patients with resistant WG.