Host ABC transporter proteins may influence the efficacy of ivermectin and possibly have broader implications for the development of resistance in parasitic nematodes.

ABC transporter proteins function to extrude compounds from the cell. These proteins present an obstacle for treatment and for overcoming drug resistance as they are expressed by both host and parasite, and function similarly. The contribution of host ABC proteins to drug efficacy was examined using ivermectin and a Brugia malayi model system. Parallel in vitro and in vivo experiments were conducted using equal concentrations of ivermectin. The motilities and fecundity of B. malayi exposed to ivermectin in vitro were significantly lower than those treated in vivo. The higher motilities were correlated with low concentrations of ivermectin in worms extracted from treated hosts. The expression of ABC proteins was significantly higher in worms treated in vitro compared to those treated in vivo as well as in gerbils treated with ivermectin than in non-treated controls. The results suggest that host ABC transporters may influence the efficacy of ivermectin.

Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

OBJECTIVES: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. METHODS: A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. RESULTS: The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). CONCLUSIONS: HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.

ABC transporters influence sensitivity of Brugia malayi to moxidectin and have potential roles in drug resistance.

Some ABC transporters play a significant role in human health and illness because they confer multidrug resistance (MDR) through their overexpression. Compounds that inhibit the drug efflux mechanism can improve efficacy or reverse resistance. Of the eight described ABC transporter subfamilies, those proteins conferring MDR in humans are in subfamilies A, B, C, and G. In nematodes, transporters in subfamilies B and C are suggested to confer resistance to ivermectin. The Brugia malayi ABC transporter superfamily was examined to assess their potential to influence sensitivity to moxidectin. There was an increase in expression of ABC transporters in subfamilies A, B, C, and G following treatment. Co-administration of moxidectin with inhibitors of ABC transporter function did not enhance sensitivity to moxidectin in males; however, sensitivity was significantly enhanced in females and microfilariae. The work suggests that ABC transporters influence sensitivity to moxidectin and have a potential role in drug resistance.

Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis.

BACKGROUND: Psoriasis affects patients both physically and psychologically. OBJECTIVES: To investigate the effect of comorbidities on health-related quality of life (HRQoL) and to determine whether infliximab improved HRQoL in the presence of these conditions. METHODS: In this multicentre, double-blind study, 835 patients with moderate-to-severe plaque psoriasis were randomized to receive infliximab 3 or 5 mg kg(-1) or placebo at weeks 0, 2 and 6. Infliximab-treated patients were re-randomized at week 14 to receive the same treatment every 8 weeks or as needed through week 46; placebo patients crossed over to infliximab 5 mg kg(-1) at week 16. Disease severity (Psoriasis Area and Severity Index, PASI) and HRQoL (Dermatology Life Quality Index, DLQI; 36-item Short-Form Health Survey, SF-36) were measured at various time points. The effect of patient comorbidities on baseline HRQoL was assessed using multiple regression models. The impact of key comorbidities on infliximab treatment effect was also assessed. RESULTS: Disease severity (PASI), depression and psoriatic arthritis (PsA) were predictors of poor baseline HRQoL. At week 10, infliximab 3 and 5 mg kg(-1) significantly improved physical and mental health dimensions of the SF-36 and the DLQI (all P < 0.001). Consistent improvement in HRQoL with infliximab treatment was observed regardless of baseline patient characteristics or comorbidities. Through week 50, HRQoL and PASI scores were most improved with infliximab 5 mg kg(-1) administered every 8 weeks. CONCLUSIONS: Disease severity, depression and PsA were significant predictors of poor HRQoL. Infliximab significantly improved HRQoL, regardless of these characteristics.

Delayed antibiotics for respiratory infections.

BACKGROUND: Modest benefits of antibiotics for acute upper respiratory tract infections have to be weighed against common adverse reactions, cost and antibacterial resistance. There has been interest in ways to reduce antibiotic prescribing. One strategy is to provide the prescription, but advise delay of more than 48 hours before use, in the hope symptoms resolve first. Advocates suggest this will preserve patient satisfaction. This review asks what effect delayed antibiotics have on clinical outcomes of respiratory infections, antibiotic use and patient satisfaction. OBJECTIVES: To evaluate the prescribing strategy of delayed antibiotics for acute respiratory tract infections compared to immediate or no antibiotics for clinical outcomes, antibiotic use and patient satisfaction. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2006); MEDLINE (January 1966 to January Week 2, 2007), EMBASE (1990 to Week 2, 2007) and Current Contents - ISI Web of Knowledge (1998 to January 2007). SELECTION CRITERIA: Randomised controlled trials (RCTs) involving patients of all ages defined as having an acute respiratory infection were included in which delayed antibiotics were compared to antibiotics used immediately or no antibiotics. Outcomes measured included clinical outcomes, antibiotic use and patient satisfaction. DATA COLLECTION AND ANALYSIS: Data were collected and analysed by three review authors. MAIN RESULTS: Nine trials were eligible on the basis of design and relevant outcomes. For most clinical outcomes there was no difference between delayed, immediate and no antibiotics. Antibiotics prescribed immediately were more effective than delayed for fever, pain and malaise in some studies of patients with acute otitis media and sore throat but for other studies there was no difference. There was no difference for the common cold and bronchitis. Delaying antibiotic prescriptions reduced antibiotic use, and in three studies, reduced patient satisfaction compared to immediate antibiotics. In the other two studies comparing delayed and immediate antibiotics measuring satisfaction, there was no difference. Two studies also included a 'no antibiotics' arm for bronchitis and sore throat: there was no difference in symptom resolution nor patient satisfaction from antibiotic delay. In one study, but not the other, antibiotic use was significantly decreased with no, rather than delayed, antibiotics. AUTHORS' CONCLUSIONS: For most clinical outcomes there is no difference between the strategies. Immediate antibiotics was the strategy most likely to provide the best clinical outcomes in patients with sore throat and otitis media. Delaying or avoiding antibiotics, rather than providing them immediately, reduces antibiotic use for acute respiratory infections. Delay also reduced patient satisfaction in three trials, compared to immediate antibiotics with no difference in two other trials. Delaying antibiotics seems to have little advantage over avoiding them altogether where it is safe to do so.

Interventions for the interruption or reduction of the spread of respiratory viruses.

BACKGROUND: Viral epidemics or pandemics such as of influenza or severe acute respiratory syndrome (SARS) pose a significant threat. Antiviral drugs and vaccination may not be adequate to prevent catastrophe in such an event. OBJECTIVES: To systematically review the evidence of effectiveness of interventions to interrupt or reduce the spread of respiratory viruses (excluding vaccines and antiviral drugs, which have been previously reviewed). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4); MEDLINE (1966 to November 2006); OLDMEDLINE (1950 to 1965); EMBASE (1990 to November 2006); and CINAHL (1982 to November 2006). SELECTION CRITERIA: We scanned 2300 titles, excluded 2162 and retrieved the full papers of 138 trials, including 49 papers of 51 studies. The quality of three randomised controlled trials (RCTs) was poor; as were most cluster RCTs. The observational studies were of mixed quality. We were only able to meta-analyse case-control data. We searched for any interventions to prevent viral transmission of respiratory viruses (isolation, quarantine, social distancing, barriers, personal protection and hygiene). Study design included RCTs, cohort studies, case-control studies, cross-over studies, before-after, and time series studies. DATA COLLECTION AND ANALYSIS: We scanned the titles, abstracts and full text articles using a standardised form to assess eligibility. RCTs were assessed according to randomisation method, allocation generation, concealment, blinding, and follow up. Non-RCTs were assessed for the presence of potential confounders and classified as low, medium, and high risk of bias. MAIN RESULTS: The highest quality cluster RCTs suggest respiratory virus spread can be prevented by hygienic measures around younger children. Additional benefit from reduced transmission from children to other household members is broadly supported in results of other study designs, where the potential for confounding is greater. The six case-control studies suggested that implementing barriers to transmission, isolation, and hygienic measures are effective at containing respiratory virus epidemics. We found limited evidence that the more uncomfortable and expensive N95 masks were superior to simple surgical masks. The incremental effect of adding virucidals or antiseptics to normal handwashing to decrease respiratory disease remains uncertain. The lack of proper evaluation of global measures such as screening at entry ports and social distancing prevent firm conclusions about these measures. AUTHORS' CONCLUSIONS: Many simple and probably low-cost interventions would be useful for reducing the transmission of epidemic respiratory viruses. Routine long-term implementation of some of the measures assessed might be difficult without the threat of a looming epidemic.

Topical analgesia for acute otitis media.

BACKGROUND: Acute otitis media (AOM) is a spontaneously remitting disease for which pain is the most distressing symptom. Antibiotics are now known to have less benefit than previously assumed. OBJECTIVES: To assess the effectiveness of topical analgesia for AOM. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to May Week 3 2006), EMBASE (1990 to December 2005) and LILACS (1982 to September 2005) without language restriction, and the reference lists of articles. We also contacted manufacturers and authors. SELECTION CRITERIA: Double-blind randomised or quasi-randomised controlled trials comparing an otic preparation with an analgesic effect (excluding antibiotics) versus placebo or an otic preparation with an analgesic effect (excluding antibiotics) versus any other otic preparation with an analgesic effect, in adults or children presenting at primary care settings with AOM without perforation. DATA COLLECTION AND ANALYSIS: Potential studies were screened independently and trial quality was assessed by three authors, and differences were resolved by discussion. Data was then independently extracted from the trials selected by two authors. We contacted the authors of three trials to acquire additional information not available in published articles. MAIN RESULTS: Our searches yielded 356 records; four trials met our criteria. One trial with 54 participants compared treatment with anaesthetic ear drops versus an olive oil placebo immediately at diagnosis. All patients were also given paracetamol. There was a statistically significant pain reduction of 25% in those receiving anaesthetic drops 30 minutes after instillation. Three trials (with one common co-author) compared anaesthetic ear drops with naturopathic herbal ear drops in 274 patients. One of these trials also used antibiotics in both groups. There were statistically significant differences at instillation of drops, or 15 or 30 minutes after the instillation (or both) on one to three days after diagnosis, always favouring the naturopathic group in each trial. AUTHORS' CONCLUSIONS: The evidence from these four randomised controlled trials, only one of which addresses the most relevant question of primary effectiveness, is insufficient to know whether ear drops are effective or not.

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats.

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar-Unilever rats.

Delayed antibiotics for symptoms and complications of respiratory infections.

BACKGROUND: The use of antibiotics for upper respiratory tract infections is controversial. Any benefits have to be weighed against common adverse reactions (including rash, abdominal pain, diarrhoea and vomiting), cost and antibacterial resistance. There has been interest in ways to reduce antibiotic prescribing for acute respiratory infections. One is delaying the use of prescribed antibiotics by more than 48 hours for acute upper respiratory tract infections. Such methods have been shown to reduce prescribing. This review asks what effect this practice has on the clinical course of the illness. OBJECTIVES: To evaluate the clinical effect of delayed antibiotic use in acute upper respiratory tract infections compared to immediate use of antibiotics SEARCH STRATEGY: The following electronic databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2004) which includes the Acute Respiratory Infection Groups' specialised register; MEDLINE (January 1966 to January Week 1 2004), EMBASE (1990 to September 2003) and Current Contents (1998 to 2003). The search was carried out by an expert librarian. Abstracts of identified articles were used to determine which studies were trials. SELECTION CRITERIA: Randomised controlled trials involving patients of all ages defined as having acute otitis media, acute pharyngitis, sore throat, common cold, a viral upper respiratory tract infection, acute sinusitis, and acute bronchitis were included in which delayed antibiotics are compared to antibiotics used immediately. Delayed antibiotic use was defined as the use of or advice to use antibiotics more than 48 hours after the initial consultation. 'Immediate antibiotic use' was defined as the immediate use of oral antibiotics given at the initial consultation. Clinical outcomes measured included: the presence or absence of fever, cough, pain, duration and severity of illness, complications of the disease, adverse effects from the antibiotics. Trial quality was assessed independently by two reviewers who were blinded to the author, journal and results of each study. DATA COLLECTION AND ANALYSIS: Data was collected by two reviewers who were blinded to the author and journal. Data were analysed and reported using RevMan. MAIN RESULTS: Seven trials were eligible on the basis of design and all reported patient-centred outcomes. Methodological quality of included trials was generally high. There was no difference between immediate and delayed antibiotic groups for symptoms on day one and day seven. For most symptom measures there was no significant difference between the immediate and delayed antibiotic groups. Missing data and marked heterogeneity between study outcomes prevented pooling of results as a meta-analysis. Three studies out of six reporting fever, all involving patients with sore throat, indicated that there was more fever in the delayed antibiotic group. The remaining three studies showed no difference. There was no significant symptom difference for patients with cough or the common cold between the two intervention groups. Pain and malaise severity scores at day three significantly favoured the immediate antibiotic group in children with acute otitis media (Little 2001). In this study by Little 2001 of children with otitis media proxies for other malaise related outcomes were reported, including 'last day of crying' which favoured the immediate antibiotic group by approximately 16 hours (0.69 days; 95% CI 0.31 to 1.07). In the same study, just over half a spoon of paracetamol a day less was used in the immediate antibiotic group (0.59; 95% CI 0.25 to 0.93). There was no significant difference between the intervention groups for the adverse outcome of rash. Two studies reported the outcome of vomiting which was reduced in the immediate antibiotic group in children with suspected streptococcal pharyngitis in El-Daher 1991 but there was no difference in children with sore throat in Little 1997. Diarrhoea was reported by three studies of which two showed no difference Little 1997; Arroll 2002a while Little 2001 reported less diarrhoea in the delayed antibiotic group in children with otitis media. REVIEWERS' CONCLUSIONS: When considering treatment options for upper respiratory tract infections, the option of delayed antibiotics has been used in an attempt to reduce the use of antibiotic prescriptions. This review shows that for all symptom scores the evidence varies between trials. Most symptom outcomes show no difference between immediate and delayed antibiotic groups. Three of the six studies, all involving patients with sore throat, indicated that patients in the delayed antibiotic group had significantly more fever that their counterparts in the immediate antibiotic group. The other three showed no difference for the outcome of fever. There is evidence indicating that for children with otitis media, pain and malaise scores are worse in the delayed antibiotic group compared to the immediate antibiotic group. This price must be weighed up against the benefits of reduced antibiotic prescribing. Future randomised controlled trials of delaying antibiotics as an intervention should fully report symptoms as well as changes of prescription rates.

The use of adjunctive hyperbaric oxygen in treatment of orthopedic infections and problem wounds: an overview and case reports.

We summarize indications, contraindications, and therapeutic guidelines for the use of adjunctive hyperbaric oxygen therapy (HBO) in problem wounds and selected orthopaedic infections. Three typical cases that all were successfully treated with HBO are presented: a chronic osteomyelitis which was a sequela to an open tibia fracture, a second- and third-degree burn injury of the entire lower extremity, and a case of chronic osteomyelitis in an insulin-dependent diabetic.

Tracking of non-rigid articulatory organs in X-ray image sequences.

This article presents a system for the automated tracking of non-rigid anatomic structures in two-dimensional image sequences, which was primarily applied to X-ray image sequences of the vocal tract. In this particular application articulatory organs have to be measured to investigate the complex dynamic characteristics of human speech production. Of particular interest is a robust boundary detection of non-rigid organs such as lips and tongue. To solve this ill-posed detection problem under the presence of transparently superimposing structures, varying textural appearances of organs and noise, a two-level system is proposed. At the lower level, several edge-, region-, and motion-based image operators are combined to exploit their respective benefits and concomitantly compensate for their deficiencies. For the sake of precision, the result of these operators are not represented as larger tokens, such as line segments, but remain pixel-related cues or image evidences. At the higher level, an active contour-based component allows for the introduction of a priori knowledge about the object to be detected.

Stumbling toward equity: the role of government in kidney transplantation.

In Mortal Peril, Professor Epstein is critical of the current, regulated system for organ donation and suggests that a market for organ tissue would better meet the needs of patients. In this response to Professor Epstein, Professor Laura Dooley and Dr. Robert Gaston pair their skills to attack Professor Epstein's analysis. As they have done on several other occasions, Professors Dooley and Gaston argue that the kidney donation and transplantation arena is fraught with racial inequity, and that Professor Epstein's proposal for a market in kidneys will exacerbate this inequity. The authors maintain that to prevent the poor from being excluded from transplants, the government plays a critical (if imperfect) role in the allocation of these scarce resources. Furthermore, government intervention is acceptable to correct past discrimination because there is scientific evidence that the disproportionate incidence of kidney failure in African Americans is related to the evolutionary pressures of slave trading and slavery. Professors Dooley and Gaston also defend their previous efforts to change the government system of allocation and characterize the government's willingness to adopt their recommendations as an appropriate response to scientific research rather than a governmental susceptibility to lobbying from special interest groups. Finally, the authors criticize Professor Epstein's argument that dialysis is a viable alternative to transplantation because there are significant differences in "quality of life, morbidity and survival." Professors Dooley and Gaston conclude that government intervention is necessary for maintaining the equity in kidney transplantation that a market system would not.

Clinical and histopathological characterization of a large animal (ovine) model of collagen-induced arthritis.

Collagen induced arthritis (CIA) is the most studied and used rheumatoid arthritis (RA) model in animals, as it shares many pathological and immunological features of the human disease. The aim of this study was to characterize clinical and immunological aspects of the ovine CIA model, and develop lameness and histopathological scoring systems, in order to validate this model for use in therapeutic trials. Sheep were sensitized to bovine type II collagen (BCII), arthritis was induced by injection of bovine collagen type II into the hock joint and the response was followed for two weeks. Clinical signs of lameness and swelling were evident in all sheep and gross thickening of the synovium surrounding the tibiotarsal joint and erosion on the cartilage surface in the arthritic joints. Leucocyte cell counts were increased in synovial fluid and there was synovial hyperplasia, thickening of the intimal layer, inflammation and marked angiogenesis in the synovial tissue. There was a large influx of monocytes and lymphocytes into the synovial tissue, and increased expression of TNF-α and IL-1ß in arthritic intima, angiogenesis and upregulation of VCAM-1. CIA in sheep appears to be an excellent large animal model of RA and has the potential for testing biological therapeutics for the treatment of rheumatoid arthritis.

Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: Results from the induction and maintenance psoriatic arthritis clinical trial 2.

OBJECTIVE: To evaluate the effect of infliximab on progression of structural damage over 1 year in patients with active psoriatic arthritis (PsA) enrolled in the Induction and Maintenance Psoriatic Arthritis Clinical Trial 2. METHODS: In this double-blind, placebo-controlled study, 200 patients with active PsA were randomly assigned (1:1 ratio) to receive infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, and 6, and every 8 weeks thereafter through week 54. At week 24, patients initially assigned to receive placebo crossed over to receive infliximab (5 mg/kg). Based on predefined criteria, patients randomized to receive placebo could enter early escape by receiving infliximab (5 mg/kg) starting at week 16, and patients randomized to receive infliximab could have the dose increased to 10 mg/kg starting at week 38. Patients were analyzed according to the treatment they were randomized to receive. Radiographs of hands and feet were obtained at baseline and at weeks 24 and 54. Two readers blinded to treatment assignment and radiograph sequence independently evaluated erosions and joint space narrowing using the Sharp/van der Heijde scoring method modified for PsA. RESULTS: At week 24, patients randomized to receive infliximab 5 mg/kg had significantly less radiographic progression compared with patients randomized to receive placebo, with mean +/- SD changes from baseline in the total Sharp/van der Heijde score of -0.70 +/- 2.53 and 0.82 +/- 2.62, respectively (P < 0.001). At week 54, mean +/- SD changes from baseline in the total Sharp/van der Heijde score were -0.94 +/- 3.40 in patients randomized to receive infliximab and 0.53 +/- 2.60 in those receiving placebo/infliximab (P = 0.001). CONCLUSION: Infliximab significantly inhibits radiographic progression in patients with PsA as early as 6 months after starting treatment, and the beneficial effect continues through 1 year of infliximab therapy.

Infliximab maintains a high degree of clinical response in patients with active psoriatic arthritis through 1 year of treatment: results from the IMPACT 2 trial.

OBJECTIVE: To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis (PsA) enrolled in the IMPACT 2 trial. METHODS: In this double blind, placebo controlled, phase III study, 200 patients with active PsA were randomised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, and every 8 weeks thereafter through 1 year. Patients with persistent disease activity could enter early escape at week 16, and all remaining placebo patients crossed over to infliximab at week 24. Patients randomised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38. Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses. Major clinical response (that is, maintenance of ACR 70 response for 24 continuous weeks) was assessed for the first time in PsA. RESULTS: Through 1 year of treatment, 58.9% and 61.4% of patients in the randomised infliximab and placebo/infliximab groups, respectively, achieved ACR 20; corresponding figures for PASI 75 were 50.0% and 60.3%. At week 54, major clinical response was achieved by 12.1% of patients in the infliximab group. The safety profile of infliximab through week 54 was consistent with that seen through week 24. Two malignancies occurred: basal cell skin cancer (placebo) and stage I Hodgkin's lymphoma (infliximab). CONCLUSION: Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment.

Infliximab improves health related quality of life and physical function in patients with psoriatic arthritis.

OBJECTIVES: To evaluate the effect of infliximab on health related quality of life (HRQoL) and physical function in patients with active psoriatic arthritis (PsA) in the IMPACT 2 trial. METHODS: 200 patients with PsA unresponsive to conventional treatment were randomised to intravenous infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22; patients with inadequate response entered early escape at week 16. HRQoL was assessed using the Short Form-36 (SF-36) at weeks 0, 14, and 24. Functional disability was assessed using the Health Assessment Questionnaire (HAQ) at every visit through week 24. Associations between changes in quality of life (SF-36) and articular (American College of Rheumatology (ACR)) and dermatological (Psoriasis Area and Severity Index (PASI)) responses were examined. RESULTS: Mean percentage improvement from baseline in HAQ was 48.6% in the infliximab group compared with worsening of 18.4% in the placebo group at week 14 (p < 0.001). Furthermore, 58.6% and 19.4% of infliximab and placebo treated patients, respectively, achieved a clinically meaningful improvement in HAQ (that is, > or = 0.3 unit decrease) at week 14 (p < 0.001). Increases in physical and mental component summary (PCS and MCS) scores and all eight scales of the SF-36 in the infliximab group were greater than those in the placebo group at week 14 (p < or = 0.001). These benefits were sustained through week 24. Patients achieving ACR20 and PASI75 responses had the greatest improvements in PCS and MCS scores. CONCLUSIONS: In patients with PsA, infliximab 5 mg/kg significantly improved HRQoL and physical function compared with placebo through 24 weeks.

Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial.

BACKGROUND: Psoriasis has a well-documented, markedly negative effect on patient quality of life. OBJECTIVES: To evaluate the impact of long-term infliximab maintenance therapy on health-related quality of life (HRQoL) in patients with psoriasis. METHODS: The Dermatology Life Quality Index (DLQI) and 36-item Short Form Health Survey (SF-36) were administered as part of the pivotal double-blind, placebo-controlled efficacy and safety EXPRESS study of infliximab in chronic plaque psoriasis. In total, 378 patients with moderate-to-severe psoriasis were enrolled at 32 centres in Europe and Canada. Patients were randomized to receive either placebo or infliximab 5 mg kg(-1) induction at weeks 0, 2 and 6 followed by maintenance every 8 weeks; placebo patients crossed over at week 24 to receive the infliximab induction and maintenance regimen. RESULTS: At week 10, infliximab-treated patients had significantly greater improvement in DLQI scores (P < 0.001) and SF-36 physical and mental component summary scores (P < 0.001) than placebo-treated patients. Significant improvement (P < 0.001) was also seen in all eight SF-36 subscales, and was greatest for the "Bodily Pain" and "Social Functioning" scales. Significant improvement in HRQoL persisted with maintenance infliximab treatment at week 24 (P < 0.001), with patients achieving a Psoriasis Area and Severity Index score of 0 reporting the greatest benefit. Treatment-related HRQoL improvement remained substantial at week 50. CONCLUSIONS: Infliximab induction and maintenance regimens resulted in rapid, substantial, sustained and clinically meaningful improvement in both dermatology-specific and general quality of life indices in patients with psoriasis, with total clearance resulting in maximum improvement.

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial.

OBJECTIVES: To evaluate further in a phase III, double blind trial the efficacy of infliximab in patients with active psoriatic arthritis (PsA), as observed in the smaller IMPACT trial. METHODS: 200 patients with active PsA unresponsive to previous treatment were randomised to infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. Patients with inadequate response entered early escape at week 16. The primary measure of clinical response was ACR20. Other measures included Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), and dactylitis and enthesopathy assessments. RESULTS: At week 14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved an ACR20 response and 77% of infliximab patients and 27% of placebo patients achieved PsARC (both p<0.001). Among the 85% of patients with at least 3% body surface area psoriasis involvement at baseline, 53/83 (64%) patients receiving infliximab had at least 75% improvement in PASI compared with 2/87 (2%) patients receiving placebo at week 14 (p<0.001). These therapeutic effects were maintained through the last evaluation (week 24). Fewer infliximab patients than placebo patients had dactylitis at week 14 (18% v 30%; p = 0.025) and week 24 (12% v 34%; p<0.001). Fewer infliximab patients (22%) than placebo patients (34%) had active enthesopathy at week 14 (p = 0.016); corresponding figures at week 24 were 20% and 37% (p = 0.002). Infliximab was generally well tolerated, with a similar incidence of adverse events in each group. CONCLUSIONS: Infliximab 5 mg/kg through 24 weeks significantly improved active PsA, including dactylitis and enthesopathy, and associated psoriasis.