Abstract: An undesirable effect (UE) of a cosmetic product is a harmful reaction attributable to its normal or reasonably foreseeable use. However, the knowledge of UEs, at the population level, is limited by the absence of formal and reliable cosmetovigilance systems, which nevertheless are characterized by underreporting. To test the feasibility of the collection of UEs in our territory we have carried out a pilot project aimed to assess either the notification procedures or the validation/evaluation of the collected forms in our territory. As reporting categories, we have chosen dermatologists and community pharmacists who were asked to notify UEs to cosmetics through a reporting form we have set up. During the period July 2006-December 2007, we have registered 76 reporting forms. Dermatologists who have sent 47 reporting forms represented the main reporting category, followed by community pharmacists (15 reports), other health professionals (9 reports) and consumers (5 reports). Several drawbacks, mainly represented by the incompleteness and inaccuracy of the filled in forms, affected the validation process. Thus, on receipt, we could validate only 34 forms and only after a careful check with each single reporter, we could include in the study other 36 forms. The validation of the collected reports has stressed the importance of a well-structured reporting form, an easy access to notification procedures as well as education and training programme. The evaluation of the validated forms has revealed the need of a controlled term vocabulary for the classification of the observed events and diagnosis, especially with regard to cutaneous reactions that represented almost the totality of the reported events (95.7%). Among the events (n=45) reported by dermatologists, 22 were diagnosed as allergic contact dermatitis (ACD) and 18 as irritant contact dermatitis (ICD). Facial care products (19.7%), followed by body care products (16.9%), perfumes (12.7%) and eye care products (11.3%) were the cosmetics mainly suspected to be responsible for the observed events. Correspondingly, face (n=37), including periorbital and perioral area, forehead, ocular mucous membrane and lips, followed by entire body (n=9) were the body sites reported as more involved. In conclusions, our experience allowed us to identify the main pitfalls of the system we have experienced. These are setting/formulation of the reporting form, notification step, description of the event and diagnosis. A careful settlement of these aspects could substantially contribute to the establishment of an efficient reporting system, although the bias due to underreporting is difficult to eliminate.

Abstract: For many years, a regimen of fluorouracil and cisplatin has been the standard of care for the treatment of patients with metastatic gastric cancer. More recently, triplet regimens that incorporate fluorouracil and cisplatin with epirubicin (ECF) or docetaxel are being used in the management of patients with metastatic disease; ECF is also being used as preoperative treatment of resectable disease. Capecitabine, a prodrug of fluorouracil that can be taken orally, has been assessed as an alternative to intravenous fluorouracil and has demonstrated noninferiority to its parent compound. Several trials have demonstrated the safety and efficacy of regimens combining capecitabine with other known active drugs against gastric cancer in doublet and triplet combinations. Oral capecitabine appears to be more convenient to administer than infused fluorouracil because it may obviate the need for central venous access and its associated risk of complications. All of these findings support consideration of capecitabine among the available drug treatment options for patients with metastatic and those with operable gastric cancers.

Abstract: Abstract Objectives. To review the pharmacoeconomic impact of the use of amlodipine in coronary artery disease (CAD) patients. Methods. A review of the available outcome trials evaluating the clinical effectiveness of amlodipine in hypertensive patients or in patients with CAD or diabetic nephropathy was carried out to identify pharmacoeconomic studies that quantified the economic impact of using amlodipine instead of another treatment. Results. A combined analysis of two trials comparing angiotensin receptor blockers (ARBs) with a calcium channel blocker amlodipine suggested that amlodipine provided more protection against stroke and myocardial infarction than ARBs. In addition, in keeping with previous meta-analyses, calcium channel blockade with amlodipine also prevented more stroke than angiotensin-converting enzyme inhibitors and old drug classes. Pharmacoeconomic analysis conducted in the US and Europe demonstrated that the use of amlodipine resulted in fewer hospitalisations and the need for fewer invasive surgical procedures in the short and long term and at a modest incremental cost. The use of amlodipine resulted in improved clinical outcomes as well as slight savings in cost. Conclusions. Amlodipine is not only cost effective, but predicted to be cost saving when compared with usual care, warranting its consideration as an agent of choice in patients with CAD.

Abstract: OBJECTIVE: In patients with rheumatoid arthritis (RA), long-term therapy with anti-tumor necrosis factor (TNF) antibodies sensitizes the pituitary gland and improves adrenal androgen secretion in prednisolone-naïve patients. However, whether this is similar in psoriatic arthritis (PsA) is not known. The aim of this study was to assess the effect of 12 weeks of etanercept treatment upon the function of the HPA axis in patients with PsA. METHODS:Eleven prednisolone-naïve patients (mean age 47.3+/-8.9 years) with PsA were included. We measured serum levels of adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17OHP), cortisol, and androstenedione (ASD), at baseline and at 4 and 12 weeks after initiation of anti-TNF therapy (etanercept, 50 mg every week as a single dose by sc. injection). Clinical improvement was assessed using the Disease Activity Score-28 (DAS-28). RESULTS: Mean levels of serum ACTH, serum cortisol, serum 17OHP and serum ASD did not markedly change during 12 weeks of etanercept treatment. Similarly, the ratio of serum cortisol divided by serum ACTH did not change during 12 weeks of anti-TNF treatment. However, an increase of serum cortisol relative to serum 17OHP or ASD was related to clinical improvement. This indicates that improvement was linked to higher serum cortisol levels relative to others adrenal hormones. CONCLUSION: This is the first study to demonstrate baseline serum levels and the course of HPA axis-related hormones in patients with PsA. An increase of serum cortisol relative to others adrenocortical hormones (i.e., androstenedione and ACTH) was accompanied by clinical improvement.

Abstract: OBJECTIVE: To evaluate costs, benefits and cost-effectiveness of anti-TNF agents in PsA patients with inadequate response to conventional treatment. METHODS: A total of 107 patients, from nine Italian rheumatology centres, with different forms of PsA were given anti-TNF treatment, mainly etanercept (87%). Information on resource use, health-related quality of life, disease activity, function and laboratory values were collected at baseline and through out the 12 months of therapy. Cost (expressed in euro 2007) and utility (measured by EuroQol) before and after anti-TNF therapy initiation were compared in order to estimate the incremental cost per quality-adjusted life year (QALY) gained, and cost-effectiveness acceptability curve was calculated. RESULTS: At the end of 12 months, there was a significant increase in direct cost due to an increase of drug cost caused by TNF inhibitors that was only partially offset by the decrease in indirect cost. In the last 6 months of therapy, the direct cost increased by euro5052, the cost for the National Health System (NHS) by euro5044 and the social cost by euro4638. However, a gain of 0.12 QALY resulted in a cost per QALY gained of euro40 876 for the NHS and of euro37 591 for the society. The acceptability curve showed that there would be a 97% likelihood that anti-TNF therapy would be considered cost-effective at willingness-to-pay threshold of euro60 000 per QALY gained. CONCLUSION: Cost-effectiveness ratios are within the commonly accepted willingness-to-pay threshold. These results need to be confirmed in larger samples of patients.

Abstract: OBJECTIVE: To investigate the prevalence of antipolymer antibody (APA) in patients with fibromyalgia (FM) and to examine its association with FM severity symptoms. METHODS: The study population consisted of 79 FM patients and 75 controls: 32 with psoriatic arthritis and 43 with rheumatoid arthritis APA levels were indirectly assayed using a commercial ELISA kit from Corgenix (Westmister, Colorado, USA). Optical density (OD) values were recorded on duplicates of each of the reference and patient samples. Among clinical variables we investigated pain, measured according to visual analog scales (VAS: 0-100), fatigue, stiffness, anxiety, depression, all measured by VAS (0-100), and health status measured by Fibromyalgia Impact Questionnaire (FIQ). RESULTS: Sixteen of the 79 FM patients (20.3%) and 12/78 controls (15.4%) were positive for APAs (P = 0.536). Following ROC analysis, area under curve (AUC) was 0.49 (95% CI: 0.40, 0.58). Focusing on FM patients, we observed a correlation between APA titre and pain (tau: - 0.221; P = 0.020) and fatigue (tau: - 0.205; P = 0.032) at univariate analysis. Binomial regression analysis, controlling for clinical and demographic variables, showed that pain (PPR: 0.923; P = 0.007) and fatigue (PPR: 0.948; P = 0.024) were significantly associated with APA test sensitivity. CONCLUSIONS: APA test exhibited a low sensitivity in FM patients and it did not distinguish this group of patients from the controls enrolled in this study. Interestingly, positive APA test prevalence increased with less severe pain or fatigue.

Abstract: Studies on autoantibody production in patients treated with tumor necrosis factor-alpha (TNF-alpha) inhibitors reported contradictory results. We investigated in a prospective study the efficacy of a treatment with human monoclonal anti-TNF-alpha antibody (adalimumab) in patients with rheumatoid arthritis (RA) and we evaluated the relationship between treatment efficacy and the incidence and titers of disease-associated and non-organ-specific autoantibodies. Fifty-seven patients with RA not responsive to methotrexate and treated with adalimumab were enrolled. Antinuclear, anti-double-stranded(ds)DNA, anti-extractable nuclear antigens, anti-cardiolipin (aCL), anti-beta2 glycoprotein I (anti-beta2GPI) autoantibodies, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibodies were investigated at baseline and after 6 and 12 months of follow-up. Comparable parameters were evaluated in a further 55 patients treated with methotrexate only. Treatment with adalimumab induced a significant decrease in RF and anti-CCP serum levels, and the decrease in antibody titers correlated with the clinical response to the therapy. A significant induction of antinuclear autoantibodies (ANA) and IgG/IgM anti-dsDNA autoantibodies were also found in 28% and 14.6% patients, respectively, whereas aCL and anti-beta2GPI autoantibodies were not detected in significant quantities. No association between ANA, anti-dsDNA, aCL and anti-beta2GPI autoantibodies and clinical manifestations was found. Clinical efficacy of adalimumab is associated with the decrease in RF and anti-CCP serum levels that was detected after 24 weeks and remained stable until the 48th week of treatment. Antinuclear and anti-dsDNA autoantibodies, but not anti-phospholipid autoantibodies, can be induced by adalimumab but to a lower extent than in studies with other anti-TNF blocking agents.

Abstract: The most frequent cause of mortality and morbidity in industrialized countries is coronary artery disease (CAD), which in Europe alone is responsible for around two million deaths per year. In 2001 it accounted for about 260,000 hospital discharges in Italy. The costs of CAD treatment in Italy--which were borne by the Italian state, the third-party payer--amounted to 800 million euros. We propose to assess the pharmacoeconomic implications of using amlodipine besylate treatment in Italy for patients with coronary artery disease. The study is based on a post-hoc cost-effectiveness analysis that compared standard care supplemented by amlodipine besylate with ordinary standard care over a 36-month time horizon. The clinical outcome data were based on the prospective randomized evaluation of vascular effect of norvasc trial (PREVENT). Direct medical costs referred to the purchase costs of amlodipine besylate and the cost of National Health Service (NHS) hospitalization. The costs were discounted back at an annual rate of 5%. Patients administered amlodipine besylate exhibited a significant risk reduction with respect to any major vascular event or procedure when compared to the placebo group. The reduction mainly referred to unstable angina events and revascularization procedures. We estimated that the total cost of adding amlodipine besylate to standard care amounted to 139,050 euros per 1000 patients treated for 36 months. This represents a cost of 1780 euros per patient remaining free of any vascular event. Results were sensitive to both clinical and economic variables. The incremental costs of the alternative therapy ranged from 296 euros to 5066 per patient free of any event in, respectively, the best and worst scenario. Amlodipine besylate therapy can be a cost-effective strategy for CAD treatment in Italy. Our economic evaluation demonstrated, first, that by reducing vascular events and the need for revascularization procedures savings were achieved in hospital expenditure, and, second, that such savings could significantly offset drug costs.

Abstract: In Italy, revascularization interventions increased from 44,600 in 1996 to more than 100,000 in 2001. In particular, the occurrence of percutaneous transluminal coronary angioplasty (PTCA) increased from 239 cases per million population in 1994 to about 1300 cases per million population in 2001. This trend has caused a concomitant increase in revascularization costs, which have doubled in few years, rising from Euro 421 millions in 1996 to Euro 850 millions in 2001. In 2001, PTCA amounted to 55% of total cost of revascularizations. The aim of this study was to assess the pharmacoeconomic consequences of amlodipine besylate therapy administered in patients at high risk of restenosis after PTCA. We conducted a cost-effectiveness analysis comparing therapy with amlodipine besylate added to standard care versus standard care alone. Information on clinical outcomes was drawn from the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES). Medical costs were estimated with reference to drug therapy and hospitalizations for coronary events and revascularization procedures. The study was conducted from the perspective of the Italian third party payer (National Health Service). The analysis was applied to a time horizon of 4 months. Amlodipine besylate resulted less expensive and more effective than standard care. It reduced mortality, morbidity for coronary reasons and the need of revascularization procedures. The cost per 1000 patients was estimated at Euro 1,166,000 in the placebo and Euro 950,000 in the amlodipine besylate group, resulting into a cost saving of Euro 216,000, that is 18.5% of total cost of standard care. Results are sensitive to the cost of amlodipine besylate and the cost of hospitalizations, but therapy with amlodipine besylate resulted dominant even in the most unfavorable hypothesis.

Abstract: BACKGROUND: Beta-blockers have provided evidence of improving survival in chronic heart failure patients. Specifically, the Cardiac Insufficiency Bisoprolol Study II has shown a significant reduction in mortality and morbidity among patients with moderate to severe chronic heart failure treated with bisoprolol. Our aim was to investigate the economic consequence of bisoprolol therapy in chronic heart failure patients in Italy. METHODS: Data were derived from the Cardiac Insufficiency Bisoprolol Study II trial. We conducted a cost-effectiveness analysis, comparing standard care with bisoprolol vs standard care with placebo in the perspective of the Italian National Health Service. We identified and quantified medical costs: drug costs according to the Italian National Therapeutic Formulary; specialist visits for initiation and up-titration of bisoprolol therapy and hospitalizations were quantified based on the Italian National Health Service tariffs (2005). Effects were measured in terms of mortality and morbidity reduction (number of deaths, life-years gained and frequency of hospitalizations). We considered an observational period of 1.3 years, i.e. the average follow-up recorded in the trial. Discounting was not performed because of the relatively short follow-up of patients. We conducted one- and multiway sensitivity analyses on unit cost and effectiveness. We also conducted a threshold analysis. RESULTS: The overall cost of care per 1000 patients treated for 1.3 years was estimated in Euro 2,075,548 in the bisoprolol group and in Euro 2,396,265 in the placebo group, resulting in a net saving of Euro 320,718. The number of additional patients alive with bisoprolol was 55 per 1000 patients, the number of lifeyears gained was 36 at 1.3 year. CONCLUSIONS: Bisoprolol therapy is dominant since it is both less costly and more effective than standard care. Results of sensitivity analysis showed that bisoprolol therapy remains dominant even to changes in unit cost of drug and hospitalizations.

Abstract: BACKGROUND: The potential clinical implications of autoimmunity during treatment with infliximab are unclear. AIM: To determine the frequency and correlation of autoantibody formation in patients with Crohn's disease treated with infliximab in a routine clinical setting. METHODS: Sixty-three patients with refractory/inflammatory (31) and/or fistulising Crohn's disease (32), received an infliximab infusion at a dose 5 mg/kg in weeks 0, 2 and 6, and were evaluated for the development of antinuclear, anti-double-stranded DNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB and antihistone antibodies. The correlates with pharmacological treatments, the response to infliximab and adverse events were evaluated. RESULTS: Antinuclear antibodies were found in five of the 63 patients (8%) at baseline and in 26 (42%) after 10 weeks (P < 0.001). Of the 26 antinuclear antibody-positive patients who were further subtyped, nine of 63 (17%) had anti-double-stranded DNA (P = 0.003), and 1.5% were extractable nuclear antigen (ENA) and antihistone-positive. Five patients were initially positive for anticardiolipin antibodies and two more patients became positive during infliximab treatment. New autoantibody formation was more frequent in the patients with inflammatory/refractory disease than in those with fistulising disease (17 vs. 7; P = 0.02). One patient developed drug-induced lupus without major organ damage. CONCLUSIONS: Autoantibody formation occurs in 42% of patients (8% of these patients were positive before infliximab treatment) with Crohn's disease receiving induction treatment with infliximab, but the clinical significance of this remains to be determined.