1.
Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.
Dugast, E, Soulillou, JP, Foucher, Y, Papuchon, E, Guerif, P, Paul, C, Riochet, D, Chesneau, M, Cesbron, A, Renaudin, K, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016;(11):3255-3261
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Abstract
Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.
2.
The effect of tacrolimus compared with betamethasone valerate on the skin barrier in volunteers with quiescent atopic dermatitis.
Danby, SG, Chittock, J, Brown, K, Albenali, LH, Cork, MJ
The British journal of dermatology. 2014;(4):914-21
Abstract
BACKGROUND Atopic dermatitis (AD) is an inflammatory skin disease arising as a result of immune system and skin barrier defects. Topical corticosteroids are safe and effective treatments for AD, when used in short courses. Prolonged use is associated with skin barrier damage. Topical calcineurin inhibitors are alternative immune-modulating treatments for AD purported to have no negative effects on the skin barrier. OBJECTIVES To compare the effects of betamethasone valerate 0·1% cream (BMVc) and tacrolimus 0·1% ointment (TACo) on the skin barrier. METHODS Twenty volunteers with quiescent AD (no active signs for 6 months) participated in a randomized observer-blind study, wherein BMVc was applied to one forearm and TACo to the other, twice daily for 4 weeks. The biophysical/biological properties of the stratum corneum were assessed before and after treatment. Nine volunteers with active disease and 10 with healthy skin were assessed at untreated sites. RESULTS BMVc significantly reduced skin barrier function, integrity and cohesion, and the levels of pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA) towards the subclinical barrier defect observed in patients with AD (nonlesional sites). TACo preserved skin barrier function, integrity, cohesion and PCA and UCA levels, while significantly increasing skin hydration to levels comparable with healthy skin. Both treatments reduced skin surface pH and trypsin-like protease activity, with TACo doing so to a significantly greater degree. CONCLUSION In quiescent AD, 4 weeks of BMVc treatment adversely affected the biophysical properties of the skin and reduced the levels of natural moisturizing factor, whereas TACo improved the condition of the skin barrier.
3.
Revisiting the immunomodulators tacrolimus, methotrexate, and mycophenolate mofetil: their mechanisms of action and role in the treatment of IBD.
van Dieren, JM, Kuipers, EJ, Samsom, JN, Nieuwenhuis, EE, van der Woude, CJ
Inflammatory bowel diseases. 2006;(4):311-27
Abstract
Inflammatory bowel diseases (IBDs) are thought to result from unopposed immune responses to normal gut flora in a genetically susceptible host. A variety of immunomodulating therapies are applied for the treatment of patients with IBDs. The first-line treatment for IBDs consists of 5-aminosalicylate and/or budesonide. However, these first-line therapies are often not suitable for continuous treatment or do not suffice for the treatment of severe IBD. Recently, efforts have been made to generate novel selective drugs that are more effective and have fewer side effects. Despite promising results, most of these novel drugs are still in a developmental stage and unavailable for clinical application. Yet, another class of established immunomodulators exists that is successful in the treatment of inflammatory bowel diseases. While waiting for emerging novel therapies, the use of these more established drugs should be considered. Furthermore, one of the advantages of using established immunomodulators is the well-documented knowledge on the long-term side effects and on the mechanisms of action. In this review, the authors discuss 3 well-known immunomodulators that are being applied with increased frequency for the treatment of IBD: tacrolimus, methotrexate, and mycophenolate mofetil. These agents have been used for many years as treatment modalities for immunosuppression after organ transplantation, for the treatment of cancer, and for immunomodulation in several other immune-mediated diseases. First, this review discusses the potential targets for immunomodulating therapies in IBDs. Second, the immunomodulating mechanisms and effects of the 3 immunomodulators are discussed in relationship to these treatment targets.