Budget impact analysis of anakinra in the treatment of familial Mediterranean fever in Italy.

INTRODUCTION: Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease that significantly reduces occupational productivity and quality-of-life in affected patients. Italy has an estimated FMF prevalence of 1 in 60,000 people. While colchicine is the primary treatment for FMF, biologics are administered to intolerant and non-responder patients. Anakinra and canakinumab are the only biologics approved and reimbursed for FMF in Italy. Both medicines have demonstrated efficacy in FMF patients yet differ in treatment costs. This study aimed to perform a budget impact analysis (BIA) following anakinra's reimbursement for FMF treatment, considering pharmaceutical costs from the Italian National Healthcare Service (NHS) perspective. METHODS: A 'Reference scenario' (all patients treated with canakinumab) was compared to an 'Alternative scenario', with increased anakinra market shares. The target population was estimated based on the Italian population, epidemiological and market research data. Drugs costs were estimated based on Summary of Product Characteristics and net ex-factory prices. Sensitivity analyses were implemented to test results' robustness. RESULTS: The base case analysis showed an overall cumulative expenditure of €30,586,628 for 'Reference scenario' and € 16,465,548 for 'Alternative scenario'. A cumulative savings of €14,121,080 (46.2%) was calculated over 3 years as a result of the reimbursement and increasing uptake of anakinra. The sensitivity analyses, even considering a discount of 50% for canakinumab, confirmed the base case results. CONCLUSIONS: Anakinra's introduction, in FMF treatment, provides a financially sustainable option for Italian patients, with savings increasing according to greater use of anakinra.

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.

Neutron diffraction evidence for local spin canting, weak Jahn-Teller distortion, and magnetic compensation in Ti1-x Mn x Co2O4 spinel.

A systematic study using neutron diffraction and magnetic susceptibility is reported on Mn substituted ferrimagnetic inverse spinel Ti1-x Mn x Co2O4 in the temperature interval 1.6 K [Formula: see text] T [Formula: see text] 300 K. Our neutron diffraction study reveals cooperative distortions of the TO6 octahedra in the Ti1-x Mn x Co2O4 system for all the Jahn-Teller active ions T = Mn3+ , Ti3+ and Co3+ , having the electronic configurations 3d 1, 3d 4 and 3d 6, respectively which are confirmed by the x-ray photoelectron spectroscopy. Two specific compositions (x = 0.2 and 0.4) have been chosen in this study because these two systems show unique features such as; (i) noncollinear Yafet-Kittel type magnetic ordering, and (ii) weak tetragonal distortion with c/a < 1, in which the apical bond length d c (T B -O) is longer than the equatorial bond length d ab (T B -O) due to the splitting of the e g level of Mn3+ ions into [Formula: see text] and [Formula: see text]. For the composition x = 0.4, the distortion in the T B O6 octahedra is stronger as compared to x = 0.2 because of the higher content of trivalent Mn. Ferrimagnetic ordering in Ti0.6Mn0.4Co2O4 and Ti0.8Mn0.2Co2O4 sets in at 110.3 and 78.2 K, respectively due to the presence of unequal magnetic moments of cations, where Ti3+ , Mn3+ , and Co3+ occupy the octahedral, whereas, Co2+ sits in the tetrahedral site. For both compounds an additional weak antiferromagnetic component could be observed lying perpendicular to the ferrimagnetic component. The analysis of static and dynamic magnetic susceptibilities combined with the heat-capacity data reveals a magnetic compensation phenomenon (MCP) at T COMP = 25.4 K in Ti0.8Mn0.2Co2O4 and a reentrant spin-glass behaviour in Ti0.6Mn0.4Co2O4 with a freezing temperature of ∼110.1 K. The MCP in this compound is characterized by sign reversal of magnetization and bipolar exchange bias effect below T COMP with its magnitude depending on the direction of external magnetic field and the cooling protocol.

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

Not available.

Breakdown of Magnetic Order in the Pressurized Kitaev Iridate ß-Li_{2}IrO_{3}.

Temperature-pressure phase diagram of the Kitaev hyperhoneycomb iridate ß-Li_{2}IrO_{3} is explored using magnetization, thermal expansion, magnetostriction, and muon spin rotation measurements, as well as single-crystal x-ray diffraction under pressure and ab initio calculations. The Néel temperature of ß-Li_{2}IrO_{3} increases with the slope of 0.9 K/GPa upon initial compression, but the reduction in the polarization field H_{c} reflects a growing instability of the incommensurate order. At 1.4 GPa, the ordered state breaks down upon a first-order transition, giving way to a new ground state marked by the coexistence of dynamically correlated and frozen spins. This partial freezing in the absence of any conspicuous structural defects may indicate the classical nature of the resulting pressure-induced spin liquid, an observation paralleled to the increase in the nearest-neighbor off-diagonal exchange Γ under pressure.

Home infusion program with enzyme replacement therapy for Fabry disease: The experience of a large Italian collaborative group.

Fabry disease (FD) [OMIM 301500] is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive multisystem accumulation of globotriaosylceramide (Gb3). Although the introduction of Enzyme Replacement Therapy (ERT) resulted in a variety of clinical benefits, life-long intravenous (IV) treatment with ERT with an every other week schedule, may interfere with daily life activities and impact on QoL. We report here a multicentric, observational, longitudinal data analysis on a large cohort of 85 Italian FD patients (45 males, 40 females) from 11 out of 20 Italian regions, who received a cumulative number of 4269 home infusions of agalsidase alfa. For the whole cohort, the average duration of home therapy was 1 year and 11 months (range 3 months-4 years and 6 months), and during this period, compliance to treatment (number of infusions performed vs scheduled) reached 100%. The EQ-5 VAS scale was administered to patients to evaluate the self-reported QoL, 58% of patients showing an increase of EQ-5 VAS score at follow up compared to baseline (home treatment start) or remaining stable. A mild increase of average disease severity, measured through Mainz Severity Score Index (MSSI), was found during hospital treatment (p < 0,007), while it remained stable between the first home therapy infusion and last follow up. Interestingly, 4 out of 7 (57%) patients, showing an improvement in FD-related clinical status after starting home therapy, had previously a sub-optimal compliance to treatment during the period of hospital treatment management. Only 4 adverse non serious reactions (0,093%) were reported totally in 2 patients during home treatment. We conclude that home infusions in eligible patients with FD are safe, contribute to improve treatment compliance and therapeutic clinical outcomes, and may have a positive impact on self-perceived QoL.

Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation.

Essentials Corn Trypsin Inhibitor (CTI) is a selective inhibitor of coagulation Factor XII (FXII). Molecular modelling of the CTI-FXIIa complex suggested a canonical inhibitor binding mode. Mutagenesis revealed the CTI inhibitory loop and helices α1 and α2 mediate the interaction. This confirms that CTI inhibits FXII in canonical fashion and validates the molecular model. SUMMARY: Background Corn trypsin inhibitor (CTI) has selectivity for the serine proteases coagulation factor XII and trypsin. CTI is in widespread use as a reagent that specifically inhibits the intrinsic pathway of blood coagulation but not the extrinsic pathway. Objectives To investigate the molecular basis of FXII inhibition by CTI. Methods We performed molecular docking of CTI, using its known crystal structure, with a model of the activated FXII (FXIIa) protease domain. The interaction model was verified by use of a panel of recombinant CTI variants tested for their ability to inhibit FXIIa enzymatic activity in a substrate cleavage assay. Results The docking predicted that: (i) the CTI central inhibitory loop P1 Arg34 side chain forms a salt bridge with the FXIIa S1 pocket Asp189 side chain; (ii) Trp22 from CTI helix α1 interacts with the FXIIa S3 pocket; and (iii) Arg43 from CTI helix α2 forms a salt bridge with FXIIa H1 pocket Asp60A. CTI amino acid substitution R34A negated all inhibitory activity, whereas the G32W, L35A, W22A and R42A/R43A substitutions reduced activity by large degrees of 108-fold, 41-fold, 158-fold, and 100-fold, respectively; the R27A, W37A, W39A and R42A substitutions had no effect. Synthetic peptides spanning CTI residues 20-44 had inhibitory activity that was three-fold to 4000-fold less than that of full-length CTI. Conclusions The data confirm the validity of a canonical model of the FXIIa-CTI interaction, with helix α1 (Trp22), central inhibitory loop (Arg34) and helix α2 (Arg43) of CTI being required for effective binding by contacting the S1, S3 and H1 pockets of FXIIa, respectively.

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.

Systemic complications of esophageal lichen planus.

Lichen planus is an uncommon inflammatory mucocutaneous disorder affecting the skin and its appendages, as well as oral and genital mucosa. Involvement of the esophageal mucosa is rare and causes significant morbidity, with dysphagia and risk of long-term complications, such as esophageal strictures and stenosis. Esophageal lichen planus is an underreported condition in the spectrum of lichenoid tissue reactions, presenting the risk of systemic manifestations. We describe a patient with severe, long-standing esophageal lichen planus, which had led to marked weight-loss, malnutrition syndrome and chronic respiratory distress due to recurrent aspiration pneumonia. Diagnosis was confirmed by the presence of concomitant muco-cutaneous lesions and characteristic endoscopic and histological findings. Systemic therapy with cyclosporine A and micronutrient supplementation led to rapid clinical improvement. Early diagnosis of esophageal lichen planus as well as effective systemic immunosuppressive treatment is crucial in order to prevent short- and long-term complications.

Haemophagocytic syndrome associated with mucormycosis infection.

Several clinical forms of mucormycosis are recognized. The tendency of mucoraceous zygomycetes to invade the blood vessels often produces a disseminated infection. A case of disseminate mucormycosis complicated by a haemophagocytic syndrome (HS) in a 32-year-old Caucasian male is reported in this article. Few cases of infection-associated HS (IAHS), involving infections caused by fungi, have been reported. In all the recorded cases, the fungal infection coexists with malignant lymphoma, immunodeficiency and a long-term steroid therapy for renal transplant or Crohn's disease. This is the second described case of the HS due to mucormycosis.

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.

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene.

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.

Lattice effects and entropy release at the low-temperature phase transition in the spin-liquid candidate kappa-(BEDT-TTF)2Cu2(CN)3.

The spin-liquid candidate kappa-(BEDT-TTF)2Cu2(CN)3 has been studied by measuring the uniaxial expansion coefficients alpha(i), the specific heat, and magnetic susceptibility. Special emphasis was placed on the mysterious anomaly around 6 K--a potential spin-liquid instability. Distinct and strongly anisotropic lattice effects have been observed at 6 K, clearly identifying this feature as a second-order phase transition. Owing to the large anomalies in alpha(i), the application of Grüneisen scaling has enabled us to determine the corresponding specific heat contribution and the entropy release. Comparison of the latter with available spin models suggests that spin degrees of freedom alone cannot account for the phase transition. Scenarios involving charge degrees of freedom are discussed.

Severe giant cell arteritis associated with essential thrombocythaemia.

Giant-cell arteritis (GCA) is a chronic vasculitis of the elderly usually involving the ophthalmic arteries, which can result in visual loss. High platelet counts may have some pathogenic significance in the obstruction of the ophthalmic circulation and a few cases of associated essential thrombocythaemia and GCA have been described. Here we report a case of severe temporal arteritis associated with essential thrombocythaemia.

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