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- Which Antipsoriatic Drug Has the Fastest Onset of Action?-Systematic Review on the Rapidity of the Onset of Action. [JOURNAL ARTICLE]
- J Invest Dermatol 2013 Feb 20.
The time necessary for a treatment to become effective is crucial for patients and physicians but has been largely neglected in the reporting and comparison of clinical trials in dermatology. The aim of this systematic review is to determine the time until the onset of action (TOA) of systemic agents approved for moderate-to-severe psoriasis. Primary outcome is the TOA defined as the weighted mean time until 25% of the patients achieved a psoriasis area and severity index (PASI) 75 response. Among the biologics, infliximab has the shortest TOA (3.5 weeks), followed by ustekinumab (high dose 4.6/low dose 5.1 weeks/not weight adapted), adalimumab (4.6 weeks), etanercept (high dose 6.6/low dose 9.5 weeks), and alefacept (high dose 15.4 weeks/low dose: no data). Among the conventional treatments, good data are available for cyclosporine A (CsA; TOA: 6.0 weeks) and limited data are found for methotrexate (MTX; TOA: high dose 3.2/low dose 9.9 weeks). No data are available for fumaric acid esters and retinoids. This systematic review provides clinically relevant information on the onset of action of antipsoriatic agents, although the data currently available allow only a limited assessment. Psoriasis trials should consider including TOA as an additional outcome measure.Journal of Investigative Dermatology advance online publication, 9 May 2013; doi:10.1038/jid.2013.78.
- Progressive multifocal leukoencephalopathy and reversible progressive leukoencephalopathy syndrome in dermatologic therapy. [Journal Article]
- J Drugs Dermatol 2013 Feb; 12(2):e20-4.
Progressive multifocal leukoencephalopathy (PML) is a frequently fatal demyelinating disease of the brain caused by activation of the John Cunningham virus. It typically occurs in immunocompromised patients, including transplant recipients on immunosuppressant medications, patients receiving chemotherapy for hematologic malignancies, and patients with human immunodeficiency virus. Unfortunately, there is no effective treatment for PML. By contrast, reversible progressive leukoencephalopathy syndrome (RPLS) is a generally treatable disorder that is diagnosed based on clinical symptoms (eg, altered mental status, visual abnormalities, headache, and seizures) and neuroradiographic changes (eg, cerebral edema). It is classically associated with malignant hypertension and immunosuppressive medications. Symptoms usually resolve over time, or with treatment of the underlying cause. Amid the relatively recent withdrawal of efalizumab from the US market because of its association with PML, and the added warning found on ustekinumab describing RPLS as a possible adverse effect, there has been an increasing level of concern in dermatology that biologics and other systemic medications used in the treatment of psoriasis may be related to an increased risk of specific leukoencephalopathies. In this review, we evaluate the association of prebiologics (eg, cyclosporine, methotrexate, acitretin) and biologics (eg, adalimumab, alefacept, efalizumab, etanercept, infliximab, rituximab, and ustekinumab) with the potential risk of developing PML and RPLS.
- Failure of alefacept in the treatment of vitiligo. [Journal Article]
- J Drugs Dermatol 2013 Feb; 12(2):159-61.
Vitiligo is a common acquired pigmentary disorder with a profound psychosocial impact. The exact pathogenesis of vitiligo is not fully understood; however, vitiligo appears to be an autoimmune disease involving T-cell-mediated melanocyte destruction. Recently, complete clearance of coexisting vitiligo without recurrence over 2 years was reported in 2 psoriasis patients treated with alefacept.To evaluate the safety and efficacy of alefacept in the treatment of vitiligo.After providing informed written consent, 4 adult patients with widespread vitiligo (covering a body surface area ≥5%) were treated with weekly intramuscular injections of 15 mg alefacept for 12 weeks. All patients were monitored clinically, by laboratory investigation, and by digital image analysis. All patients were followed up with for 24 weeks.All patients tolerated alefacept well, without any adverse events. None of the patients showed any repigmentation. However, 1 patient developed new depigmented patches during treatment with alefacept.A pilot study with a small number of patients.Alefacept as a monotherapy for vitiligo treatment did not result in any patient improvement, and further evaluation in larger studies may be required.
- Belatacept and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Am J Transplant 2013 Feb; 13(2):320-8.
Belatacept is an inhibitor of CD28/B7 costimulation that is clinically indicated as a calcineurin inhibitor (CNI) alternative in combination with mycophenolate mofetil and steroids after renal transplantation. We sought to develop a clinically translatable, nonlymphocyte depleting, belatacept-based regimen that could obviate the need for both CNIs and steroids. Thus, based on murine data showing synergy between costimulation blockade and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched renal allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on costimulation blockade-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Belatacept and sirolimus therapy successfully prevented rejection in all animals. Tolerance was not induced, as animals rejected after withdrawal of therapy. The regimen did not deplete T cells. Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen, despite causing an intended depletion of memory T cells, and caused a marked reduction in regulatory T cells. Furthermore, alefacept-treated animals had a significantly increased incidence of CMV reactivation, suggesting that this combination overly compromised protective immunity. These data support belatacept and sirolimus as a clinically translatable, nondepleting, CNI-free, steroid-sparing immunomodulatory regimen that promotes sustained rejection-free allograft survival after renal transplantation.
- Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy. [Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.]
- Am J Transplant 2013 Feb; 13(2):312-9.
Calcineurin inhibitors (CNI) and steroids are known to promote insulin resistance, and their avoidance after islet transplantation is preferred from a metabolic standpoint. Belatacept, a B7-specific mediator of costimulation blockade (CoB), is clinically indicated as a CNI alternative in renal transplantation, and we have endeavored to develop a clinically translatable, belatacept-based regimen that could obviate the need for both CNIs and steroids. Based on the known synergy between CoB and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched islet allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on CoB-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation. All received belatacept and sirolimus; six also received alefacept. Belatacept and sirolimus significantly prolonged rejection-free graft survival (median 225 days compared to 8 days in controls receiving basiliximab and sirolimus; p = 0.022). The addition of alefacept provided no additional survival benefit, but was associated with Cytomegalovirus reactivation in four of six animals. No recipients produced donor-specific alloantibodies. The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys, but induction with alefacept provides no survival benefit and increases the risk of viral reactivation.
- Therapeutics: Silencing psoriasis. [Journal Article]
- Nature 2012 Dec 20; 492(7429):S58-9.
- Expression of IL-20 in synovium and lesional skin of patients with psoriatic arthritis: differential response to alefacept treatment. [JOURNAL ARTICLE]
- Arthritis Res Ther 2012 Sep 24; 14(5):R200.
INTRODUCTION:Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T-cell activation) has been shown to result in improvement in psoriasis but has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key proinflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown.
METHODS:Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open-label study. Skin biopsies were taken before and after 1 and 6 weeks, whereas synovial biopsies were obtained before and 4 and 12 weeks after treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n = 10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated with digital image analysis. Double staining was performed with IL-20 and CD68 (macrophages), and conversely with CD55 (fibroblast-like synoviocytes, FLSs) to determine the phenotype of IL-20-positive cells in PsA synovium. IL-20 expression in skin sections (n = 6) was analyzed semiquantitatively.
RESULTS:IL-20 was abundantly expressed in both PsA and RA synovial tissues. In inflamed PsA synovium, CD68+ macrophages and CD55+ FLSs coexpressed IL-20, and its expression correlated with the numbers of FLSs. IL-20 expression in lesional skin of PsA patients decreased significantly (P = 0.04) 6 weeks after treatment and correlated positively with the Psoriasis Area and Severity Index (PASI). IL-20 expression in PsA synovium was not affected by alefacept.
CONCLUSIONS:Conceivably, the relatively limited effectiveness of alefacept in PsA patients (compared with anti-tumor necrosis factor (TNF) therapy) might be explained in part by persistent FLS-derived IL-20 expression.
- Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data. [Journal Article, Review]
- Br J Dermatol 2012 Nov.:3-11.
Conventional non-biologic systemic agents are regarded as second-line therapy for the treatment of moderate-to-severe plaque psoriasis after topical treatments. However, long-term data have highlighted a number of safety concerns associated with their prolonged use. Biologic agents targeting specific immune mediators have emerged as an alternative treatment option for patients with moderate-to-severe plaque psoriasis who are unresponsive to, or intolerant of, non-biologic systemic agents. Although several biologics have demonstrated good efficacy and tolerability in short-term trials, treatment guidelines recommend them as third-line therapies due to a relative lack of long-term safety data. Here, we have reviewed the long-term (≥ 1 year) safety data from randomized controlled trials, open-label extension studies and meta-analyses of etanercept, infliximab, efalizumab, adalimumab, alefacept and ustekinumab in the treatment of adults with moderate-to-severe plaque psoriasis. With the exception of efalizumab, which has been withdrawn from both the European and U.S. markets due to long-term safety concerns, these biologics are generally well tolerated in long-term studies, and offer a viable alternative to conventional non-biologic agents in patients with moderate-to-severe plaque psoriasis.
- Comparison of Ustekinumab With Other Biological Agents for the Treatment of Moderate to Severe Plaque Psoriasis: A Bayesian Network Meta-analysis. [Journal Article]
- Arch Dermatol 2012 Dec 1; 148(12):1403-10.