Tacrolimus In Atopic Dermatitis Research Articles

321 Cancer risk with topical pimecrolimus and tacrolimus for atopic dermatitis: systematic review and Bayesian meta-analysis

Abstract Atopic dermatitis affects millions worldwide and is effectively managed by topical treatments, including topical calcineurin inhibitors, pimecrolimus and tacrolimus. In 2005 and 2011, the FDA released reviews associating topical calcineurin inhibitors with a theoretical cancer risk, albeit an uncertain association. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors. We systematically identified randomized controlled trials, comparative, and non-comparative non-randomized studies from database inception to 6 June 2022, from MEDLINE, EMBASE, GREAT, LILACS, ICTRP, FDA, EMA, company registers and relevant citations. We included studies in any language addressing the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors for greater than 3 weeks. We excluded split-body studies. We conducted a Bayesian meta-analysis and used the GRADE approach to determine the certainty of the evidence. A multidisciplinary panel including patients, advocacy groups and care providers, set an a priori threshold of 1 in 1000 risk difference as a clinically important effect. We analysed 121 studies (52 randomized controlled trials and 69 non-randomized studies) including 3.4 million patents followed for a mean of 11 months (range: 0.7–120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was neither different from controls (absolute risk 4.70 per 1000 with topical calcineurin inhibitor exposure vs. 4.56 per 1000 without; odds ratio 1.03 [95% credible interval 0.94–1.11], moderate-certainty evidence) nor the general US population (4.6 per 1000). Findings were similar in infants, children, and adults, and were robust to trial sequential, subgroup and sensitivity analyses. Among infants, children and adults with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the management of patients with atopic dermatitis. Our findings provide actional information to inform updated clinical practice guidelines, product labels and continuing education for care providers, to clarify the safe usage of topical calcineurin inhibitors.

EFFECT OF TOPICAL FLAVONOID FRACTION FROM ARTEMISIA ANNUA IN COMPARISON WITH TACROLIMUS ON INDUCED ATOPIC DERMATITIS IN MICE

Background:Atopic dermatitis is a chronic inflammation of skin disease that is characterized by recurrent acute pruritus and dry skin. Mostly, atopic dermatitis is predominant in young children. The problems of increasing prevalence and high impact of disease on quality of patients and family's life, necessities identifying many atopic dermatitis prevention planes. Objective:To determine the effect of Artemisia annua flavonoids fraction in comparison with tacrolimus in atopic dermatitis like mice model. Methods:This study is a prospective, randomized, placebo and controlled animal designed. Thirty-two male Albino mice that six weeks age included in this study. The mice were randomly divided into four groups. Group I without treatment (Healthy). Group II only inducer, phthalic anhydride used. Groups II, III, and IV subjected to phthalic anhydride solution, which was applied on the dorsum of the back skin at 9 A.M. three times a week for four weeks. After three hours of phthalic anhydride application, treatment is used for group III (Tacrolimus 0.03% ointment), and group IV (flavonoids fraction 1.2 mg /kg ointment) topically once daily at 12 P.M. for three times a week for four weeks). Serum IgE and immunohistochemistry of skin tissue IL-4 score, and IL-13 score were measured. Results:High significant decrease in immunohistochemistry of skin tissue IL-4, and IL-13 in flavonoid fraction group were found. Conclusion:The flavonoid fraction has an effect on the skin immunohistochemistry parameters and probably on atopic dermatitis like mice model. Keywords:Atopic dermatitis, Artemisia annua, flavonoids Citation:Hameed MF, Abu-Raghif AR, Kadhim EJ. Effect of topical flavonoid fraction from Artemisia annua in comparison with tacrolimus on induced atopic dermatitis in mice. Iraqi JMS. 2019; 17(3&4): 231-237. doi: 10.22578/IJMS.17.3&4.10

Topical tacrolimus in adult atopic dermatitis: a consensus based on a 15-year experience.

Atopic dermatitis (AD) is one of the most common cutaneous inflammatory diseases both in adults and in children. It is a chronic, remitting-relapsing dermatitis, primarily managed by dermatologists, but also by allergists and primary care physicians. Due to coexistence of comorbidities, often a multidisciplinary team is required. Topical calcineurin inhibitors (TCIs - i.e. tacrolimus and pimecrolimus) are a class of steroid-sparing, anti-inflammatory agents that have been shown to be efficacious for the treatment of AD acute flares and in maintenance therapy. In particular, the application of tacrolimus ointment twice daily reduces AD severity and pruritus. Moreover, maintenance therapy with an intermittent application of tacrolimus to recurrent skin sites (proactive therapy) decreases frequency and severity of relapses. Many studies have also assessed the efficacy of TCIs in disorders other than AD. Although US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) issued a "black box warning" regarding the possible cancerogenic activity of these drugs, there is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. A panel of dermatologists have thoroughly discussed the use of tacrolimus in AD after 15-year experience. The experts focused on AD flare treatment, maintenance therapy and management of side effects. Consensus was reached on some areas of interest, namely the stages of AD in which tacrolimus is recommended, the amount of drug to be applied, how to manage side effects, and how to improve patient's compliance. Moreover, the panel of experts recommended to perform randomized clinical trials to confirm the efficacy of tacrolimus off-label use, which led to successful outcomes in other skin diseases.

The Use of Topical Calcineurin Inhibitors in Atopic Dermatitis

In recent years, two topical calcineurin inhibitors have emerged as effective alternatives to corticosteroids for the treatment of atopic dermatitis. Decisions regarding first line therapy between pimecrolimus and tacrolimus are often based on anecdotal evidence. Herein, we review the current evidence supporting the use of pimecrolimus and tacrolimus in atopic dermatitis as well as key differences in safety, tolerability, and cost between the drugs.

The Role of Immune Response to Staphylococcus aureus Superantigens and Disease Severity in Relation to the Sensitivity to Tacrolimus in Atopic Dermatitis

Fukushima H, Hirano T, Shibayama N, et al. Int Arch Allergy Immunol. 2006;141:281–289 PURPOSE OF THE STUDY. To examine the prevalence and role of Staphylococcus aureus superantigens on the pathophysiology and immunosuppressive drug sensitivity in patients with atopic dermatitis (AD). STUDY POPULATION. Twenty-nine patients with AD and 13 healthy control patients were included in the study. METHODS. Twenty-nine patients with AD were classified into 2 groups on the basis of their clinical AD scores: a low-score group (n = 14), corresponding to patients with mild-to-moderate AD, and a high-score group (n = 15), corresponding to patients with severe AD. Plasma antistaphylococcal enterotoxin B or toxic-shock syndrome toxin-1 (TSST-1) immunoglobulin E (IgE) levels were measured for the patients and healthy subjects by enzyme-linked immunosorbent assay. Also, individual drug sensitivity was estimated by determining the drug concentrations that would provide 50% inhibition (IC50) of peripheral blood mononuclear cell (PBMC) proliferation in vitro. RESULTS. The levels of plasma anti-staphylococcal enterotoxin B or TSST-1 IgE in the patients with severe AD were significantly higher than those in the patients with mild-to-moderate AD (P < .05 and P < .01, respectively). When stimulated with concanavalin A in vitro, PBMCs in the patients with severe AD exhibited low sensitivity to the suppressive efficacy of tacrolimus (FK506) as compared with the patients with mild-to-moderate AD (P < .01). Furthermore, there was a significant correlation between the IC50 values of FK506 and plasma anti–TSST-1 IgE levels (P < .01). CONCLUSIONS. PBMCs in patients with severe AD exhibited lower sensitivity to FK506 and had higher plasma levels of anti–TSST-1 IgE as compared with the patients with mild AD. S aureus superantigens seem to be one of the causes of decreased PBMC sensitivity to FK506; therefore, an alternative treatment would be useful on the basis of individual drug-sensitivity data and anti–TSST-1 IgE levels. REVIEWER COMMENTS. Patients with AD commonly develop superinfections that require antimicrobial treatment. This study suggests that untreated superinfection may contribute to the ineffectiveness of topical medications that are commonly used as routine skin care for patients with AD. Attentiveness to the presence of concomitant skin infection is necessary for comprehensive skin care for patients with AD.

Systemic ciclosporin and tacrolimus in dermatology

Ciclosporin and tacrolimus are calcineurin inhibiting immunosuppressant agents useful in the treatment of immune-mediated inflammatory dermatoses. Available data and clinical experience demonstrate ciclosporin's efficacy in treating psoriasis, atopic dermatitis, pyoderma gangrenosum, lichen planus, autoimmune bullous disease (in combination with corticosteroids), recalcitrant chronic idiopathic urticaria, and chronic dermatitis of the hands and feet. Although the role of topical tacrolimus in atopic dermatitis is well established, such experience with the oral formulation of tacrolimus has been limited. However, there are several case studies and anecdotal reports of the successful use of oral tacrolimus in various dermatoses. In this article we discuss the utility of systemic ciclosporin and tacrolimus in dermatology.

The Role of Immune Response to Staphylococcus aureus Superantigens and Disease Severity in Relation to the Sensitivity to Tacrolimus in Atopic Dermatitis

Background:Staphylococcus aureus-producing superantigens (SAgs), such as staphylococcal enterotoxin B (SEB) or toxic shock syndrome toxin-1 (TSST-1), are frequently observed in atopic dermatitis (AD). However, little has been done to establish the association of immune responses to SAgs and the therapeutic response to immunosuppressive drugs in AD. Therefore, we investigated the prevalence and role of SAgs in the pathophysiology and immunosuppressive drug sensitivity in AD patients. Methods: We classified 29 patients into two groups on the basis of their clinical AD scores: a low-score group (n = 14) corresponding to mild to moderate patients and a high-score group (n = 15) corresponding to severe patients. We estimated the plasma anti-SEB or TSST-1 IgE of these patients and healthy subjects by ELISA. We also estimated individual drug sensitivity by determining drug concentrations that would give 50% inhibition (IC₅₀) of peripheral-blood mononuclear cell (PBMC) proliferation in vitro. Results: The levels of plasma anti-SEB or TSST-1 IgE in the severe patients were significantly higher than those in the mild to moderate patients (p < 0.05 and p < 0.01, respectively). When stimulated with concanavalin A in vitro, PBMCs in the severe patients exhibited low sensitivity to the suppressive efficacy of tacrolimus (FK506) as compared to the mild to moderate patients (p < 0.01). Furthermore, there was a significant correlation between the IC₅₀s of FK506 and plasma anti-TSST-1 IgE levels (p < 0.01). Conclusions: We showed that PBMCs in severe AD patients exhibited lower sensitivity to FK506, and had higher plasma levels of anti-TSST-1 IgE as compared to the mild AD patients. SAgs appear to be one of the causes of decreased PBMC sensitivity to FK506, and therefore an alternative treatment would be useful based on the individual drug sensitivity data and anti-TSST-1 IgE levels.

Expression of adhesion molecules in atopic dermatitis is reduced by tacrolimus, but not by hydrocortisone butyrate: a randomized immunohistochemical study

Topical tacrolimus represents an effective and well-tolerated treatment for atopic dermatitis (AD). Its known effects include reduced production of proinflammatory cytokines and reduced chemokine gradient. We performed lesional skin biopsies on adult patients affected by moderate-to-severe AD. Then, patients were randomized to receive local treatment with tacrolimus ointment 0.1% and hydrocortisone butyrate ointment 1%. On the 21st day of treatment, another skin specimen was taken. Nine patients treated with tacrolimus and seven treated with hydrocortisone successfully concluded the trial. By immunohistochemistry (alkaline phosphatase/antialkaline phosphatase method), we demonstrated that endothelial leucocyte adhesion molecule (ELAM)-1, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 showed different intensities and patterns of expression in untreated AD lesions. Tacrolimus-treated specimens featured a significant reduction of the expression of ELAM-1, VCAM-1 and ICAM-1, while hydrocortisone-treated lesions did not. Inhibition of adhesion molecule expression may represent another selective mechanism of action of topical tacrolimus in AD.

Safety and Efficacy of Tacrolimus Ointment 0.1% (Protopic™) in Atopic Dermatitis: A Canadian Open-Label Multicenter Study

Most previously published trials of topical tacrolimus in atopic dermatitis were of relatively short duration and comprised a limited population with moderate-to-severe disease. The goal of the study was to evaluate the safety and efficacy over a 6-month period of tacrolimus 0.1% ointment in children and adults with a broader severity spectrum of atopic dermatitis. An open-label multicenter trial in patients 2 years and older was used. Primary safety and tolerability assessments included skin infection and application site adverse events. Efficacy parameters were body surface area involvement, pruritus score, and overall response. There were 240 patients recruited at 23 study sites. Significant improvement from baseline was noted for all efficacy endpoints in both pediatric and adult patients. Skin infections occurred in 26% of patients. Burning sensation with product application, reported by 38% of patients, was transient and of mild-to-moderate severity in the majority. Tacrolimus 0.1% ointment was safe, well tolerated, and efficacious in treatment of atopic dermatitis in children and adults over six months.

Safety and Efficacy of Tacrolimus Ointment 0.1% (Protopic™) in Atopic Dermatitis: A Canadian Open-Label Multicenter Study

Background: Most previously published trials of topical tacrolimus in atopic dermatitis were of relatively short duration and comprised a limited population with moderate-to-severe disease. Objective: The goal of the study was to evaluate the safety and efficacy over a 6-month period of tacrolimus 0.1% ointment in children and adults with a broader severity spectrum of atopic dermatitis. Methods: An open-label multicenter trial in patients 2 years and older was used. Primary safety and tolerability assessments included skin infection and application site adverse events. Efficacy parameters were body surface area involvement, pruritus score, and overall reponse. Results: There were 240 patients recruited at 23 study sites. Significant improvement from baseline was noted for all efficacy endpoints in both pediatric and adult patients. Skin infections occurred in 26% of patients. Burning sensation with product application, reported by 38% of patients, was transient and of mild-to-moderate severity in the majority. Conclusion: Tacrolimus 0.1% ointment was safe, well tolerated, and efficacious in treatment of atopic dermatitis in children and adults over six months.

Immunopharmacological effects of topical tacrolimus in atopic dermatitis

Rationale In several clinical studies topical immunomodulators have been shown to be effective in the treatment of atopic dermatitis (AD). As calcineurin inhibitors, they directly act on T cells by inhibiting the transcription of cytokines. We examined the cellular infiltrate of skin lesions of 10 AD patients and characterized the cytokine pattern expressed by the infiltrating cells before and after therapy with topical tacrolimus 1% ointment b.i.d.. Methods Systemic effects were assessed by differential white blood cell counts, immunophenotyping, and functional T cell tests, such as lymphocyte proliferation and cytokine production. Skin biopsies were examined for histological alterations (HE staining), composition of inflammatory infiltrate (immunofluorescence) and cytokine expression (immunofluorescence, ELISA). Results All patients showed a significant clinical improvement of their skin lesions. In the peripheral blood, a decrease of leucocytes, including eosinophils and neutrophils, was noticed. Immunophenotyping suggested no alterations in the distribution of lymphocyte subpopulations. Histological examination revealed a marked regression of spongiosis, acanthosis and density of the inflammatory infiltrate in the dermis. The numbers of T cells and eosinophils as well as their expression of T helper 2 cytokines were reduced after therapy. In contrast, the number of epidermal CD1a positive cells increased as a consequence of topical tacrolimus treatment. Conclusions Our results suggest that topical tacrolimus mediates dramatic anti-inflammatory effects within the skin of AD patients without causing systemic immunosuppression.

Tacrolimus: A new topical immunomodulatory therapy for atopic dermatitis

Tacrolimus: A new topical immunomodulatory therapy for atopic dermatitis

Atopic dermatitis: An update

Atopic dermatitis: An update