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.

Coagulation activation in extracorporeal hemodialysis.

The authors evaluated the behavior of protein C activity, factor X and factor VII coagulant activity and serum lipoprotein(a) before and after dialytic treatment in patients on maintenance hemodialysis. They observed depressed protein C activity that significantly (p < 0.005) increased and became normal immediately after hemodialysis while factor X and factor VII increased (p < 0.01; p < 0.05) despite heparinization together with amount of serum lipoprotein(a). In vitro incubation (30' at 37 degrees C) of uremic and healthy blood showed a decrease in serum lipoprotein(a) concentration. After heparin addition (final concentration 0.5 U/ml) lipoprotein(a) increased in the uremic blood only. The clinical and physiopathological implications of these results are discussed.

[Coagulation in hemodialysis]. / Coagulazione in emodialisi.

The authors have evaluated the behaviour of protein C activity, factor X and factor VII coagulant activity, and serum lipoprotein(a) before and after haemodialytic treatment in the plasma of patients on maintenance haemodialysis. The plasma level of protein C activity, depressed before haemodialysis, significantly increased during the course of haemodialysis; factor X and factor VII increased as well despite heparinization; serum lipoprotein(a) was abnormally elevated before haemodialysis and did not change after haemodialysis. In vitro incubation (30' at 37 degrees C) of uremic and healthy blood samples resulted in a decrease of serum lipoprotein(a) concentration. After heparin addition (final concentration 0.5 U/ml) lipoprotein(a) became higher in uremic blood only.

Recombinant human erythropoietin and high flux haemodiafiltration.

Since 1982, 32 uraemic patients were treated in our institution by high flux haemodiafiltration (H-HDF) in order to shorten significantly the dialytic treatment session. H-HDF used a high surface area filter (1.4-1.9 m2) with high hydraulic permeability (polyacrylonitrile and polysulfone), at high blood flow (450 ml/min) and high rates of reinfusion of substitution fluid (22 l/session). In this way the dialytic session was shortened to 140 +/- 19 min, maintaining a good cardiovascular stability and high dialytic efficiency (Kt/V > 1.1). Human recombinant erythropoietin rHuEpo introduced in the therapy of this group in 1987 has resulted in an improvement of renal anaemia, but also a prolongation of the time of dialytic treatment due to a decrease in the efficiency of filters. During the period of the study, the treatment time increased from 140 +/- 19 min to 168 +/- 25 min with a concomitant increase of haematocrit and haemoglobin (from 24% to 36% and from 7.9 to 10.5 g/dl, respectively). H-HDF maintains a noticeable increase in dialytic efficacy with good cardiovascular stability, but the goal of a significant reduction in the time of treatment can no longer be obtained.

Automatic continuous venovenous hemodiafiltration in cardiosurgical patients.

Intermittent substitutive treatments in severely ill patients with acute renal failure are difficult or not suitable because of technical problems and/or hemodynamic instability. Continuous venovenous hemodiafiltration allows an adequate, slow removal of fluid, electrolytes, and waste products by combining diffusive and convective solute transport. Eight patients with acute renal failure, after cardiovascular surgery and cardiogenic shock, were treated by continuous venovenous hemodiafiltration. An automatic system (Equaline System, Amicon Division, USA) was employed. Venous accesses (femoral or subclavian) were used with double lumen catheters. A polysulfone filter (0.4 m2) was used in the study. Blood flow was 30 ml/min and dialysate flow rate 16.6 ml/min. Sterile pyrogen-free hemofiltration substitution fluid was used as dialysate. Mean duration of treatment was 10.3 +/- 3.2 days. After 72 hours blood urea nitrogen levels dropped from 136 +/- 46.13 to 53.5 +/- 12.3 mg/dl and creatinine levels dropped from 6.9 +/- 1.7 to 2.6 +/- 0.9 mg/dl. A controlled steady-state was then maintained. Mean urea clearance was 21 +/- 5.3 ml/min; mean ultrafiltration rate was 20.3 +/- 4.1 L/day. Continuous venovenous hemodiafiltration, with the Equaline System, is effective for the clearance of waste products and is able to maintain perfect fluid balance in catabolic patients with acute renal failure and multiple organ failure.

Low-antigen-content diet in the treatment of patients with IgA nephropathy.

Since dietary macromolecular antigens can be involved in the pathogenesis of IgA nephropathy (IgAN), the effect of a low-antigen-content diet was evaluated in 21 patients (10 women, 11 men, mean age 27.7 +/- 10 years) with immunohistochemical findings of active IgAN. The diet was followed for a 14-24-week period (mean 18.8 +/- 6); in all cases the effects of the treatment were evaluated by clinical and serological parameters, and in 11 patients also by repeat renal biopsy. After dietetic therapy a significant reduction of urinary proteins was recorded (P < 0.001); in particular, heavy proteinuria (> 1 g/day), present in 12 cases during the 6 months preceding the treatment, was markedly reduced or disappeared in 11. At post-treatment control biopsy mesangial and parietal deposits of immunoglobulins, complement C5 fraction and fibrinogen were significantly reduced. The improvement of the objective parameters such as heavy proteinuria, a strong predictor of a poor prognosis, and of immunohistochemical alterations indicate that a low-antigen diet can positively affect patients with IgAN. These results could be ascribed to a reduction of nephritogenic food antigen input and to a putative functional restoration of the mononuclear phagocytic system.

High-flux hemodiafiltration: 5 years experience.

The introduction of hemodiafiltration in the substitutive treatment of chronic renal failure has arisen from the need to find new techniques that could improve the efficiency of the traditional systems and, therefore, to treat adequately chronic uremia in the shortest possible time. 61 months of experience at our institution have shown that such a goal can be achieved, offering also practical advantages such as a better quality of life for the patients as well as the possibility to treat a greater number of them.

Clinical experience with a new hemodiafiltration (HDF) system.

Purity of reinfusion fluid and dialysate is mandatory in high flux, high efficiency substitutive treatments for chronic uremia, particularly when using bicarbonate concentrates. Bags of sterile and pyrogen free substitution fluid are in part responsible for the high costs of these treatments. In order to overcome these problems, the authors tested a new monitoring system (MPS-10, Gambro) for high efficiency hemodiafiltration (HDF) in which the reinfusion fluid was prepared from bicarbonate dialysate by filtration. During 5 months time, 96 on-line HDF treatments were performed in five chronic uremic patients. We found the infusion fluid and dialysate containing bicarbonate free from bacteria and endotoxins, with a correct weight balance obtained by the monitoring system. The authors believe that MPS-10 is a safe and adequate system for the production of sterile, pyrogen free dialysate and reinfusion fluid for on-line HDF, hemodialysis (HD), and hemofiltration (HF).

Soft and hard hemodiafiltration (HDF).

Soft and Hard Hemodiafiltration (HDF). A 32-month study was made to assess efficiency and clinical tolerance in a comparison between "soft" and "hard" HDF. Soft HDF was performed in 18 patients using a polyacrylonitrile AN 69 S 1.2m2 membrane and hard HDF in 12 patients using a polyacrylonitrile hollow-fibre 1.8m2 membrane. Different technical parameters were used for each of the two methods. Biochemical data registered during a single session showed the efficiency of both kinds of treatment and in this study clinical tolerance and patient well-being were significantly better than with hemodialysis. Hard HDF permits considerable shortening of treatment time.

Hypotensive effect of plasma exchange in immune complex nephritis.

The effect of plasma exchange (PE) on blood pressure (BP) in 20 hypertensive patients (9 with mixed cryoglobulinemia, 7 with systemic lupus erythematosus, and 4 with idiopathic glomerulonephritis) was evaluated retrospectively. In each PE 1.5-2.5 L of plasma was replaced with an equal volume of 4% albumin polysaline solution. The frequency of PE was three times per week for the first 2 weeks and twice per week subsequently. Sixteen patients were on hypotensive treatment at the onset of PE. Their systolic/diastolic BP was 171 +/- 4.7/102 +/- 3.0 mm Hg (mean +/- 1 SEM). After 4 weeks, BP decreased to 141 +/- 2.8/89 +/- 2.3 mm Hg (p less than 0.001), although in 10 patients antihypertensive drug therapy had been reduced or discontinued. The most marked decrease of BP occurred after the first week (152 +/- 5.3/92 +/- 2.9 mm Hg), and this decrement correlated remarkably well with pressure levels before PE despite the great heterogeneity of the individual patients (for diastolic BP, r = 0.87, p less than 0.001; for systolic BP, r = 0.60, p less than 0.01). A mild decrease of serum creatinine was observed during PE, but its time course was different from that of BP, and did not correlate with this parameter.

beta 2-Microglobulin and other low molecular weight proteins in haemodiafiltrates and in haemofiltrates.

Uraemic patients underwent haemodialysis by cuprophan membrane, or haemodiafiltration by polyacrylonitrile membrane, or haemofiltration by acetate cellulose membrane. Plasma samples drawn before and after treatment with the dialyser were gel-filtered on Sephadex G-75. A comparison of the chromatograms showed that the treatment causes a removal of middle molecules, which is more consistent when haemodiafiltration and haemofiltration are used. Protein removal was examined in the fluids from the three dialysers. It was observed that proteins (300 +/- 45 mg and 410 +/- 60 mg respectively) were removed when polyacrylonitrile and acetate cellulose membranes were used, but not in the case of cuprophan membrane. beta 2-Microglobulin was the protein lost in the greatest amount.

Plasma exchange in the treatment of lupus nephritis.

Seven women with severe Systemic Lupus Erythematosus Nephritis were treated with Plasma Exchange, without any additional therapy with cytotoxic agents. All patients had failed to respond to high doses of corticosteroids and, in 3 cases, to 6-methylprednisolone pulses. In 4 patients the indication for plasma exchange treatment was a rapid deterioration of renal function, and in the others a need to better control symptoms without using toxic corticosteroid dosages. The total number of plasma exchange sessions ranged from 14 to 57 depending on the patient. After PE treatment, serum creatinine values significantly decreased in all 4 patients with rapidly developing, nephritis while in the others it remained unchanged. No major side effects were recorded and no relapse of renal disease occurred whenever Plasma Exchange treatment was gradually tapered or discontinued. These data suggest that prolonged Plasma Exchange treatment without the concomitant administration of cytotoxic agents may be effective in the treatment of steroid resistant severe lupus nephritis.

IgA nephropathy (Clinical, pathological and immunological findings).

Seventy-five biopsy samples from patients with chronic renal disorders were examined by the usual techniques of light microscopy and immunofluorescence; in fifteen patients IgA nephropathy was found. These patients were young adults; the onset of the disease was characterized by macrohematuria, and recurrent episodes of hematuria were observed. Histological examination revealed proliferative endothelio-mesangial glomerulonephritis at various stages of development with focal or diffuse patterns; immunofluorescence revealed constant and intense positive reactions for IgA mainly in association with C3. It is assumed that there is a relationship connecting the more advanced histological changes, a more severe clinical course and the presence of IgM deposits.