Comparative effects of biological therapies on the severity of skin symptoms and health-related quality of life in patients with plaque-type psoriasis: a meta-analysis
ABSTRACT The comparative effects of biological response modifiers (BRMs) on the severity of psoriasis and its effects on health-related quality of life (HRQoL) have not been evaluated.
To conduct a meta-analysis to assess the effects of available biological agents on the severity of psoriasis, as well as to provide data on the effects of these agents on HRQoL.
Medline and other databases were searched for randomized controlled trials (>or= 10 weeks' duration in adults) comparing biological therapies for moderate-to-severe psoriasis with placebo. A Mantel-Haenszel fixed-effects model was employed to estimate the pooled relative risks (RR) of patients achieving >or= 75% reduction of baseline Psoriasis Area and Severity Index (PASI 75) after >or= 10 weeks of treatment. Similar analyses were also conducted on PASI 50 and PASI 90. Using a random-effects model, we estimated the likelihood of achieving PASI 50, PASI 75, and PASI 90 at 10-12 weeks and 24 weeks. Data on the effects of different BRMs (vs. placebo) on HRQoL were also presented. Numbers (%) of patients discontinuing treatment were presented as a general index of drug tolerability.
Patients receiving infliximab 5 mg/kg intravenously at weeks 0, 2, and 6, then every 8 weeks, had the highest RR of achieving PASI 75, with a pooled RR value of 25.48 (95% confidence interval [CI], 14.04-46.23); followed by etanercept 50 mg administered subcutaneously (SC) twice weekly with RR = 11.92 (95% CI, 8.17-17.39); etanercept 25 mg SC twice weekly with RR = 10.68 (95% CI, 6.15-18.57); efalizumab 1-2 mg/kg SC per week with RR = 7.47 (95% CI, 5.20-10.73); and alefacept administered weekly (various doses) with RR = 3.37 (95% CI, 2.18-5.23). (All RR values were estimated vs. placebo.) Similar findings were observed with regard to proportions of patients achieving PASI 50 and PASI 90. The random-effects analysis suggested that infliximab significantly increased the likelihood of achieving PASI 50, PASI 75, and PASI 90 compared with placebo at 10-12 weeks; however, there were no significant differences between biological treatments at 24 weeks. Each BRM improved HRQoL compared with placebo according to findings from the Dermatology Life Quality Index. Proportions of patients discontinuing treatment were similar in active-treatment and placebo groups.
Infliximab significantly reduced disease severity by both fixed- and random-effects models. All biological therapies improved HRQoL compared with placebo, and proportions of patients discontinuing treatment were similar in active-treatment and placebo groups. The analysis is potentially limited by statistical factors and did not systematically account for different toxicity profiles, but the findings establish a foundation for head-to-head comparative trials.
Article: Efalizumab[Show abstract] [Hide abstract]
ABSTRACT: Pharmacologic Properties Efalizumab inhibits the interaction of LFA-1 with its ligand, intercellular adhesion molecule-1, thereby interfering with at least three important events in the T-cell-mediated immunopathology of psoriasis (i.e. initial activation, trafficking, and reactivation of T cells). Therapeutic Efficacy The efficacy of efalizumab as monotherapy has been evaluated in adults with chronic moderate-to-severe plaque psoriasis (e.g. baseline psoriasis area severity index [PASI] score ≥12). A 12-week course of subcutaneous efalizumab 1 mg/kg/week (including an initial conditioning dose of 0.7 mg/kg/week) was superior to placebo in reducing physician-assessed disease severity in five randomized, double-blind, multicenter studies. The proportion of patients who achieved a ≥75% improvement in PASI from baseline (PASI 75) at week 12 (primary endpoint in four studies) ranged from 22% to 38.9% with efalizumab versus 2.4–5% with placebo (p < 0.001). Treatment with efalizumab was also more effective than placebo in improving patient-reported outcomes; these included health-related quality of life (HR-QOL), as assessed using dermatologic-specific and generic instruments, and psoriasis-related cutaneous symptoms. Significant improvements in physician- and patient-assessed endpoints were seen after 2–4 weeks’ therapy. In one large study (n = 793), the efficacy of efalizumab in the majority subgroup of 526 subjectively defined ‘high-need’ patients (i.e. those for whom at least two currently available systemic therapies were unsuitable due to lack of efficacy, intolerance, or contraindication) was similar to that in the total study population. Extending the duration of treatment with efalizumab 1 mg/kg/week from 12 to 24 weeks was associated with further reductions in disease severity as well as maintained improvements in patient HR-QOL and other selfreported outcomes. Similarly, additional or maintained improvements in physician-assessed outcomes were observed when treatment with efalizumab 1 mg/kg/week was continued beyond 12 weeks in the noncomparative CONTROL I and II studies; the latter was a large trial in 1255 evaluable patients who had failed to respond to, had a contraindication to, or were intolerant of, other systemic therapies. Efalizumab therapy was effective in reducing disease severity in subgroups of patients with difficult-to-treat forms of plaque psoriasis affecting the scalp, hands/feet, or nails who were enrolled in these studies. The long-term efficacy of efalizumab has been demonstrated in clinical studies in which the drug has been administered continuously (mostly at a maintenance dosage of 1 mg/kg/week) for up to 3 years. Efalizumab is a suppressive therapy intended for continuous administration. Among patients who achieved a PASI 75 response, 86% experienced psoriasis relapse (after a median time of 67 days), and 14% experienced psoriasis rebound (after a median time of 36 days), following abrupt discontinuation of efalizumab (pooled data). Retreatment with a 12-week course of efalizumab was effective in reducing disease severity in patients who previously discontinued treatment (the response rate in terms of the proportion of patients who achieved a ≥50% improvement in PASI from baseline, or attained a dynamic physician’s global assessment rating of good, excellent, or cleared, was ≈56%). Tolerability Weekly subcutaneous injections of efalizumab were generally well tolerated. The most common adverse events in patients treated with efalizumab 1 mg/kg/week (includes an initial conditioning dose of 0.7 mg/kg) in 12-week, double-blind, placebo-controlled trials were mild-to-moderate, acute flu-like symptoms (e.g. headache, chills, nausea, myalgia, and fever) that began within 2 days following the first two injections. Most of these events were self-limiting or could be managed with acetaminophen (paracetamol) or NSAIDs.American Journal of Clinical Dermatology 01/2009; 10(1). DOI:10.2165/0128071-200910010-00009 · 2.52 Impact Factor
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ABSTRACT: Cell–matrix and cell–cell interactions are important physiological determinants of cell growth, survival and transformation. Cell adhesion to the extra cellular matrix (ECM) via integrins also crucially influences the organization of the cytoskeleton. It triggers a cascade of intracellular biochemical events, which regulate cell viability and growth. We have studied the relationship between cell attachment to the substratum and cytoskeletal organization and cell survival and transformation. Our results demonstrate that in the absence of attachment to the substratum, adhesion-dependent fibroblasts exhibit rapid loss of viability. However, a small percentage of cells survive even after remaining non-adherent for 16h. The adherent and non-adherent cells differ from one another both morphologically and physiologically. The latter show a loss of α5β1 integrin expression on their surface and bind non-specifically to the substratum and ECM, thereby activating certain pathways more efficiently than adherent cells. We have also shown that non-adherent cells grow faster and have worse cytoskeletal organization after attachment to the substratum, and do not form focal adhesions or actin stress fibres. Hence, our data suggests that rat fibroblasts in prolonged suspension exhibit some properties that are comparable to cells undergoing transformation, by adapting integrin-dependent or independent signalling pathways for their survival.Cell Biology International 12/2002; 26(12):1043-1055. DOI:10.1006/cbir.2002.0964 · 1.64 Impact Factor
Conference Paper: Failure analysis of plastic packaged optocoupler light emitting diodes[Show abstract] [Hide abstract]
ABSTRACT: Failure mechanisms in plastic packaged optocouplers have been investigated. The high failure rate of the optocouplers, specifically the reverse bias leakage current of the light emitting diodes (LEDs), was found to be moisture-related. Using scanning electron microscopy coupled with energy dispersive X-ray microanalysis, a significant concentration of copper was detected on the surface of failed LEDs, possibly migrated from the copper leadframe. By applying infra-red photoemission microscopy it was found that bandgap emission was associated with the reverse leakage path in the area of the pn junction of the LEDs.Electronics Packaging Technology, 2003 5th Conference (EPTC 2003); 01/2004