Safety Of Topical Calcineurin Inhibitors Research Articles

Unboxing the black box on topical calcineurin inhibitors and cancer risk

The topical calcineurin inhibitors, tacrolimus and pimecrolimus, are effective immunomodulators used in the management of moderate-to-severe atopic dermatitis. Topical tacrolimus ointment (0·03% and 0·1%) was approved by the US Food and Drug Administration (FDA) in 2000, and pimecrolimus cream (1%) in 2001, as second-line agents in children aged 2 years or older. However, in 2006, the FDA announced a black-box warning stating that the long-term safety of topical calcineurin inhibitors had not been established,1 citing post-marketing reports of increased risks of lymphoma and skin cancers in mainly isolated case reports, organ transplant recipients, and animal studies.

Revisiting the safety of topical calcineurin inhibitors in patients with atopic dermatitis

Topical calcineurin inhibitors (TCI) have emerged from the shadow of topical corticosteroids as another first-line remedies for treating acute flares of atopic dermatitis (AD). The effectiveness of TCI in maintenance therapy is also undeniable. The wider use of TCI increases the relevance of the issue of their safety. The adherence of physicians and their patients to the treatment with TCI is constrained by a controversial FDA black box warning against these drugs based on the theoretical risk of skin tumors, especially lymphoma. This warning, formulated in 2005, has been repeatedly refuted. However, there have been studies that at least partially supported cautious use of TCI. In recent years, the results of large cohort prospective studies clarifying the issue of oncological safety of TCI have been published. The review highlights the results of various studies with optimistic, pessimistic and balanced conclusions regarding the safety of TCI, primarily their effect on tumorigenesis, in order to better inform physicians about the benefit/risk balance when using these drugs in AD patients. The data presented in this review indicate that there is no increased risk of melanoma and other forms of skin cancer in TCI users, but these data do not completely rule out the risk of skin lymphoma. However, the very low level of potential risk to an individual patient gives physicians the right to neglect this risk when choosing TCI as a treatment option for AD.

No evidence of increased cancer incidence in children using topical tacrolimus for atopic dermatitis

Long-term safety of topical calcineurin inhibitors is not well understood. APPLES (AProspective Pediatric Longitudinal Evaluation to Assess the Long-Term Safety of Tacrolimus Ointment for the Treatment of Atopic Dermatitis; NCT00475605) examined incidence of lymphoma and other cancers in a pediatric population with atopic dermatitis. To quantify incident malignancies during 10years in children with atopic dermatitis who used topical tacrolimus for ≥6weeks. Standardized incidence ratios for cancer events were analyzed relative to sex-, age-, and race-matched control data from national cancer registries. There were 7954 eligible patients enrolled at 314 sites in 9 countries. During 44,629 person-years, 6 confirmed incident cancers occurred (standardized incidence ratio, 1.01; 95% confidence interval, 0.37-2.20). No lymphomas occurred. Observational prospective cohort study. The cancer incidence was as expected, given matched background data. This finding provides no support for the hypothesis that topical tacrolimus increases long-term cancer risk in children with atopic dermatitis.

Modern approaches to external therapy of sensitive skin area in atopic dermatitis in children: focus on topical calcineurin inhibitors

Due to high prevalence in the pediatric population, chronic recurrent course and difficulties in choosing the local therapy, atopic dermatitis is an urgent problem for pediatricians, dermatologists and allergists. The review presents data on the prevalence and features of the clinical manifestations of atopic dermatitis in various age periods. The authors consider structural, functional and immunological features of the skin barrier are considered in detail under normal and under pathological conditions. They emphasize the problems of quality of life, compliance and steroidophobia of patients with atopic dermatitis. Particular attention is paid to the concept of sensitive skin, the definition of this concept and the localization of sensitive skin area on the surface of the body. The article describes approaches to the method of choosing external therapy according to the European guidelines for the treatment of atopic dermatitis in 2018. It presents a modern practical algorithm for prescribing local anti-inflammatory drugs (topical glucocorticosteroids, topical calcineurin inhibitors) taking into account the severity of the clinical manifestations of the disease and the areas of application (sensitive skin areas/other parts of the body). The authors provide evidence of the efficacy and safety of topical calcineurin inhibitors, in particular pimecrolimus, in the treatment of patients with mild to moderate severity of atopic dermatitis, especially in sensitive skin areas.

Topical calcineurin inhibitors in the treatment of oral lichen planus: a systematic review and meta-analysis.

TCS (topical corticosteroids) are the first-line drug in the treatment of oral lichen planus (OLP). However, the value of topical calcineurin inhibitors (TCI) including tacrolimus, pimecrolimus and ciclosporin for OLP is still controversial. To compare the efficacy and safety of TCI vs. TCS for OLP. The authors searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science and four Chinese databases from 1950 to May 2018. The randomized controlled trials comparing TCI and TCS for OLP reported at least one of the following outcomes: improvement of clinical signs and/or symptoms, relapse, blood levels of TCI and adverse events. Twenty-one trials involving 965 patients were included in the analysis. For the treatment of OLP (3-8 weeks), TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy. Tacrolimus-TCS resulted in similar outcomes, with relapse at 3 weeks to 6 months. Blood levels of TCI were usually undetectable. In addition, tacrolimus showed a statistically higher incidence of local adverse events than TCS for short-term treatment. A few systemic adverse events occurred in the tacrolimus and ciclosporin groups, but they were not serious. The evidence for tacrolimus (n = 12), pimecrolimus (n = 3) and ciclosporin (n = 6) demonstrated that treatment with TCI may be an alternative approach when OLP does not respond to the standard protocols. Tacrolimus 0·1% should be the first drug of choice when selecting TCI for short-term treatment in recalcitrant OLP. Further well-designed trials are warranted to evaluate the long-term efficacy and safety of TCI. What's already known about this topic? The main topical drug for oral lichen planus (OLP) is topical corticosteroids (TCS). Patients with OLP who are not responsive to TCS or are at risk of adverse events from TCS need other alternative drugs. Topical calcineurin inhibitors (TCI), including tacrolimus, pimecrolimus and ciclosporin, have become a hot topic in a variety of mucocutaneous immune-mediated diseases. What does this study add? TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy for the short-term treatment of OLP. The local adverse events of tacrolimus were higher than with TCS. A few systemic adverse events were reported with TCI, but they were all tolerable and not serious. The limited evidence for pimecrolimus (three trials) and ciclosporin (six trials) requires further studies to evaluate the short-term and long-term efficacy and safety of TCI compared with TCS.

Efficacy and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis: meta-analysis of randomized clinical trials.

IntroductionCalcineurin inhibitors, novel topical immunomodulators, may constitute a superior alternative for glucocorticosteroids in atopic dermatitis (AD) topical treatment.AimDetermination of efficacy and safety of each topical calcineurin inhibitor (TCI) formulation, 0.3% or 0.1% tacrolimus and 1% pimecrolimus, for the treatment of moderate to severe AD in comparison with glucocorticosteroids.Material and methodsCochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, GREAT database, trials registers and reference lists were searched up to February 2018. Randomised controlled trials of TCI, compared to corticosteroids (TCS), reporting efficacy or safety outcomes were selected. Quality of trials and evidence of each outcome were evaluated according to Cochrane Collaboration recommendations and tools. The primary outcomes were physician’s global assessment of improvement and occurrence of adverse events (AEs).ResultsFourteen trials involving 7376 children and adults with AD were included. Calcineurin inhibitors were significantly more effective than various potency TCS, neither least potent to lower mid-strength nor mid-strength to potent TCS (RR = 1.24, 95% CI: 1.06–1.44). The major AEs were skin burning and pruritus, their incidence was higher in TCI treatment (RR = 3.32, 95% CI: 2.90–3.80; RR = 1.59, 95% CI: 1.34–1.80).ConclusionsCalcineurin inhibitors seem to be more effective and contrarily they elicit more AEs than TCS.

PERSISTENT SUBCLINICAL INFLAMMATION IN THE SKIN AS A RISK FACTOR FOR RELAPSE IN ATOPIC DERMATITIS: FROM PATHOPHYSIOLOGY TO TREATMENT

Lowgrade cutaneous inflammation, which persists after induction of remission of atopic dermatitis (AD), determines the risk of repeated relapses and progression of the disease. It has been well established that subclinical inflammation in the skin of atopic patients may be inhibited by topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI), and proactive courses of these drugs prolong remission of the disease. In terms of prolonged application, TCI have some advantages over TCS in the context of safety. However, the routine use of TCI in AD is constrained by many practitioners who do not accept the concept of subclinical chronic inflammation and the strategy of maintenance antiinflammatory therapy on areas prone to repeated relapses, as well as obsolete myths about the association of TCI application with increased risk of cutaneous lymphoma. The review presents modem data on the pathophysiology of AD with a focus on subclinical skin inflammation, which persists after regression of acute manifestations of the disease, and the possibilities of suppressing this inflammation with TCI. Data on the safety of TCI for longterm use and the absence of prooncogenic potential are given. In addition, the relevance and expediency of pimecrolimus use in children under 2 years of age are emphasized.

Experience of using tacrolimus as a part of a complex therapy of atopic dermatitis

This review presents the results of international and Russian clinical studies conducted to assess the efficacy and safety of topical calcineurin inhibitors (TCIs) for the treatment of atopic dermatitis. The main mechanisms of action of TCIs are described. The authors demonstrate the advantages of Tacrolimus belonging to the TCI group. Due to the hydrophilic drug form and pharmacoeconomic index promoting compliance with treatment, it is possible to consider the new drug Tacropic (0.1% and 0.03% Tacrolimus ointments) as the optimum topical drug for the treatment of moderate to severe and severe forms of atopic dermatitis in adults and children.

Pimecrolimus vs. tacrolimus for the topical treatment of unresponsive oral erosive lichen planus: a 8 week randomized double‐blind controlled study

Oral lichen planus (OLP) is a chronic inflammatory disease, affecting nearly 1-2% of the population; Proposed therapies are usually symptomatic and numerous drugs have been used, but recently, it has been published that there is insufficient evidence to support the effectiveness of any specific treatment as being superior. To the best of our knowledge, direct evaluation of the efficacy of topically applied pimecrolimus and tacrolimus in the treatment of atrophic-erosive OLP, refractory to topical steroids, is still lacking. To assess the efficacy and safety of topical calcineurin inhibitors for unresponsive OLP. An 8 week randomized, double-blind controlled trial, followed by a 6 month follow-up period. Patients were treated with either pimecrolimus 1% cream or tacrolimus 0.1% ointment, both mixed with an equivalent amount of 4% hydroxyethyl cellulose gel. The medications were to be applied twice daily for 2 months. Each patient was examined at the beginning of therapy, and then every 2 weeks during the treatment and every 3 months of follow-up. Main outcome measures were: (i) to compare the effectiveness of topically applied pimecrolimus and tacrolimus; (ii) to evaluate which is more cost-effective; (iii) to determine which drug is faster in reducing signs and symptoms and (iv) which gives the longest remission. Thirty patients were involved in the study. Both drugs were effective at inducing clinical improvement, with no statistical difference. Pimecrolimus creams revealed a significantly better stability of the therapeutic effectiveness (P = 0.031). Both medications would currently appear to be a treatment of choice for patients with unresponsive atrophic-erosive OLP. Pimecrolimus seemed to be more effective in providing long-term resolution of signs and symptoms. Future efforts are however needed to obtain more objective evidence of the benefit of these medications in the treatment of immunologically mediated oral mucosal lesion.

Comparative Effectiveness of Topical Calcineurin Inhibitors in Adult Patients with Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by extreme pruritis and lichenified papules and plaques that may begin in or persist into adulthood. Topical corticosteroids are first-line prescription therapy for AD; they are efficacious and have a well established safety profile. The topical calcineurin inhibitors tacrolimus and pimecrolimus were approved by the US FDA in 2000 and 2001, respectively, as second-line topical therapy for AD. This review evaluates the available studies on the comparative effectiveness, safety, cost, and impact on quality of life of topical corticosteroids and topical calcineurin inhibitors for the treatment of adult AD. Tacrolimus was found to be as effective as class III-V topical corticosteroids for AD of the trunk and extremities, and more effective than low-potency class VI or VII corticosteroids for AD of the face or neck. Pimecrolimus was less effective than both tacrolimus and low-potency topical corticosteroids for moderate to severe AD. The short-term safety studies found that, compared with topical corticosteroid-treated adults, patients treated with topical calcineurin inhibitors had an increased frequency of application-site reactions, an equivalent infection risk, and a decreased risk of skin atrophy. The long-term safety of topical calcineurin inhibitors remains under investigation. Currently published studies that evaluated the comparative cost and quality-of-life effects compared tacrolimus with less potent topical corticosteroids despite the availability of equivalent potency corticosteroids. Further cost and quality-of-life studies are needed that compare topical calcineurin inhibitors with stronger classes of topical corticosteroids over longer time periods. The available clinical trials data do not suggest an efficacy advantage for topical calcineurin inhibitors over topical corticosteroids in adults with AD of the trunk and extremities, and there is not yet adequate evidence to support topical calcineurin inhibitors as first-line therapy for adult AD.

Three Times Weekly Tacrolimus Ointment Reduces Relapse in Stabilized Atopic Dermatitis: A New Paradigm for Use

Paller AS, Eichenfield LF, Kirsner RS, et al. Pediatrics. 2008;122(6). Available at: www.pediatrics.org/cgi/content/full/122/6/e1210PURPOSE OF THE STUDY. To evaluate the safety and efficacy of intermittent topical tacrolimus as maintenance therapy in patients with moderate-to-severe atopic dermatitis.STUDY POPULATION. Subjects 2 to 15 years of age with moderate-to-severe atopic dermatitis.METHODS. Subjects underwent stabilization with either 0.05% aclometasone ointment or 0.03% tacrolimus in a double-blind fashion for 4 days, followed by twice-daily, open-label, 0.03% tacrolimus treatment for all subjects. Subjects who became “clear” or “almost clear” entered phase II (maintenance phase) and underwent double-blind, random assignment to either 0.03% tacrolimus or vehicle applied once daily, 3 times per week, for up to 40 weeks. Emollients were permitted, but corticosteroid use was prohibited; open-label tacrolimus use was permitted to treat relapses.RESULTS. A total of 206 patients were randomly assigned, and 50 subjects completed the study. There were no significant differences between groups at baseline. Aclometasone-treated patients showed more improvement in the acute phase than did tacrolimus-treated patients, and there were no differences in application-site adverse events between groups. During maintenance, tacrolimus-treated patients had a significantly greater number of disease-free treatment days, compared with vehicle-treated patients (mean: 174 vs 107 days; P = .0008), and a longer time to first relapse (median: 116 vs 31 days; P < .04).CONCLUSIONS. Long-term intermittent application of 0.03% tacrolimus to clinically normal-appearing but previously affected skin was significantly more effective than vehicle at maintaining disease stabilization in patients with moderate-to-severe atopic dermatitis. The safety profile of intermittently applied tacrolimus was similar to that of vehicle.REVIEWERS COMMENTS. Atopic dermatitis is a chronic relapsing disease. Prevention of relapse is aimed at skin hydration and avoidance of triggers. Adverse effects of topical steroids limit their long-term use and, although there are concerns that calcineurin inhibitors may carry an increased risk of malignancy, long-term data on the safety of topical calcineurin inhibitors contradict this notion. This study shows promise that intermittent application of 0.03% tacrolimus offers a novel, steroid-sparing approach to maintaining stabilization of atopic dermatitis that seems both safe and efficacious.

Atopic dermatitis and alternative management strategies

To discuss the significance of studies published over the previous year regarding the pathogenesis and treatment of atopic dermatitis, including prevention, skin care, environmental modifications, nutrition, education, and anti-inflammatory medications. Recent evidence shows that 42.5% of the caregivers of children with atopic dermatitis had used alternative therapies, most commonly due to fears of topical steroid side-effects and dissatisfaction with conventional treatment. Common questions, such as the potential utility of prenatal probiotics for prevention of atopic dermatitis, as well as the interplay of food allergies and eczema will be discussed in detail. New research continues to show the efficacy and safety of topical calcineurin inhibitors and atopiclair. We will review advances in the understanding of the pathogenesis of atopic dermatitis, and the latest research on therapies available to clinicians to aid them in discussions with their patients. Atopic dermatitis impacts negatively the quality of life of both patients and their families. General pediatricians play a pivotal role in the management of this chronic condition. Management should focus on providing sound advice and easing fears regarding topical steroids, as well as pursuing conservative treatments that have the potential to prevent flares.

Safety of Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis

Atopic dermatitis is a chronic, highly pruritic, and frequently recurring inflammatory skin disease that can be burdensome to affected individuals as well as to their family members, the health care system, and society as a whole. Immunomodulatory agents, such as topical corticosteroids and topical calcineurin inhibitors (TCIs), target the underlying immunopathology of atopic dermatitis and are the foundation of pharmacologic treatment for disease exacerbations. Recent recommendations from the United States Food and Drug Administration prompted the addition of a black-box warning and medication guide for tacrolimus ointment and pimecrolimus cream (both TCIs). The recommendations were based on a theoretical risk of malignancy derived from safety profiles, animal data, and reported cases of malignancy from clinical trials and postmarketing safety surveillance of oral calcineurin inhibitors. We know of no data that suggest that TCI use increases the risk of malignancy. Several dermatologic associations have issued statements supporting the safety of TCIs, and independent oncology experts have concluded that reported lymphomas were not related to TCI use. The black-box warning added to the TCI prescribing information also states that no causal link has been established. Effective treatment of atopic dermatitis can help alleviate the burden this disease imposes, and TCIs remain important treatment options.

Safety of topical calcineurin inhibitors in atopic dermatitis: Evaluation of the evidence

Topical calcineurin inhibitors (pimecrolimus, Elidel, East Hanover, NJ; and tacrolimus, Protopic, Tokyo, Japan) have been approved for the use in atopic dermatitis since the year 2000. These compounds represent a relatively safe class of topical anti-inflammatory, nonsteroidal therapy. However, in January of 2006, the US Food and Drug Administration issued a black box warning on these compounds about possible concerns of increased long-term malignancy risk due to systemic immunosuppression. To date, studies from clinical trials, systemic absorption, and post-marketing surveillance show no evidence for this systemic immunosuppression or increased risk for any malignancy.