Efficacy Of Topical Calcineurin Inhibitors Research Articles

Clinical observations of complex therapy of atopic dermatitis of moderate severity

Atopic dermatitis (AD) is more common in children, but can also occur in adults. Doctors of different specialties, including pediatricians, dermatologists, allergists-immunologists, gastroenterologists and infectious disease specialists deal with this problem. Despite the efforts of pediatricians, the problem of AD remains pressing. The progressive growth of this disease among children and increased persistence in adulthood make it important to study the mechanisms of AD not only for dermatology, but also for the health care system as a whole. The presence of pruritus is an obligatory manifestation of AD, which entails an inevitable decrease in the quality of life of patients. Thus, there are prerequisites for the emergence of new concepts of pathogenesis and the search for the most effective therapeutic methods of treatment. Currently, AD is considered as an interaction of endogenous (impaired immune response, insufficient function of the epidermal barrier) and exogenous factors (exposure to allergens, chemical or physical irritants, microorganisms). The work presents clinical cases of topical calcineurin inhibitor use in the treatment of moderate-to-severe AD. We presented patients with complaints of rashes accompanied by intense itching, on the skin of the extensor surfaces of the limbs, on the skin of the face and torso. Application of topical cal-cineurin inhibitor resulted in reduction of severity of subjective and objective symptoms of various forms of atd. The efficacy of topical calcineurin inhibitors in the treatment of atd with a pronounced anti-inflammatory and antipruritic effect was confirmed. Long-term staggered scheme of their use is the most pathogenetically justified and safe method of treatment of moderate forms of AD.

Treatment of pediatric periorificial dermatitis with topical calcineurin inhibitor and topical/oral metronidazole.

Pediatric periorificial dermatitis is a papulopustular eruption found around the facial orifices in children. Although the treatment of the disease has been largely anecdotal and experience-based, studies have shown that topical calcineurin inhibitors, as well as other topical and oral antibiotics, such as metronidazole, can be effective treatment options. However, most of the studies with a sizable number of patients have been based on the Caucasian population. Herein, we evaluated the clinical efficacy of topical calcineurin inhibitors and topical/oral metronidazole in 24 Korean patients with pediatric periorificial dermatitis. The majority of the patients showed a complete response to treatment.

PDG6 A SYSTEMATIC LITERATURE REVIEW AND NETWORK META-ANALYSIS (NMA) OF CRISABOROLE 2% OINTMENT FOR THE TREATMENT OF MILD-TO-MODERATE ATOPIC DERMATITIS (AD)

To evaluate the comparative efficacy of crisaborole 2% versus other topical pharmacologic therapies among children (≥ 2 years) and adults with mild-to-moderate AD. MEDLINE, Embase, Cochrane, and the Database of Abstracts of Reviews of Effects were searched from inception to 03/04/2019, for randomized clinical trials reporting the efficacy of topical calcineurin inhibitors, topical corticosteroids, or crisaborole. The outcome of interest was treatment success: achieving an Investigator's Static Global Assessment (ISGA) score of 0-1 (clear or almost clear AD) at 28-43 days, with 28-29 day data used preferentially. A Bayesian model adjusting for baseline risk (variation in vehicle response rates) was used; in addition, the model included class effects (tacrolimus and pimecrolimus in one class; crisaborole in its own class). A complementary log-log model accounted for differential follow-up times. 9 RCTs were included in the NMA. The population included both pediatric and adult patients. Patients on crisaborole 2%, tacrolimus 0.03% and 0.1% were significantly more likely to achieve treatment success at 28-43 days versus vehicle with the largest point estimate observed for the crisaborole 2% comparison (hazard ratio [HR]: 2.07 [95% CrI: 1.76; 2.36]). Patients on crisaborole 2% were more likely to achieve treatment success versus pimecrolimus 1% [HR: 1.62 [95% CrI: 1.04; 2.48]. While the point estimates favored crisaborole 2%, there were no significant differences between crisaborole 2%, tacrolimus 0.03% and 0.1% with respect to treatment success at 28-43 days. The baseline risk model found that the relationship between vehicle rate and relative treatment effect versus vehicle was highly significant (slope = -0.89 [95% CrI: -1.26; -0.47]), making results versus vehicle highly sensitive to vehicle rate chosen (not observed versus other active treatments). Crisaborole 2% was superior to vehicle and pimecrolimus 1%, and comparable to tacrolimus 0.03% and 0.1% in achieving treatment success at 28-43 days.

Efficacy of the Topical Calcineurin Inhibitors Tacrolimus and Pimecrolimus in the Treatment of Vitiligo in Infants Under 2Years of Age: A Randomized, Open-Label Pilot Study.

The efficacy of topical calcineurin inhibitors (TCIs) for the treatment of infants with vitiligo aged less than 2years remains to be fully determined. This aim of this pilot study was to assess the efficacy and tolerability of the TCIs tacrolimus and pimecrolimus in infants with vitiligo aged under 2years. Infants with vitiligo aged < 2years were randomly assigned to receive either tacrolimus ointment 0.03% or pimecrolimus cream 1% for a period of 6months. During this period, topical treatment was applied twice daily. The proportion of body surface area of the treated lesions, locations, and possible adverse effects were recorded. In addition, the overall satisfaction scores of the patients' parents was evaluated by virtue of the visual analog scale (VAS). Forty-six infants with vitiligo were enrolled in this study. The overall response rate (> 0% repigmentation) was 100%, while the effectiverate (> 50% repigmentation) of the tacrolimus and pimecrolimus groups was 69.6% and 65.2%, respectively. Meanwhile, the effective rates for vitiligo located on the head and neck, trunk, and extremities were 70%, 64.3% and 50%, respectively, while the response rates for non-segmental and segmental vitiligo were 74.4% and 28.6%, respectively. Only a low incidence of local adverse reactions (including mild redness and skin picking) was reported during the treatment process. Topical tacrolimus ointment 0.03% or pimecrolimus cream 1% have efficacy for vitiligo in infants, which serves to achieve an appropriate level of safety and tolerability during the 6-month period of applications. Thus, TCIs proved to be a therapeutic option for vitiligo in infants under 2years of age.

Update of calcineurin inhibitors to treat inverse psoriasis: A systematic review.

Inverse psoriasis commonly involves skin fold areas including the axillae, perianal skin, intergluteal cleft, inframammary, genital/inguinal, abdominal, and retroauricular folds. Topical calcineurin inhibitors are indicated for the treatment of atopic dermatitis but have also been studied in the treatment of psoriasis. The object of the present study is to define the efficacy of topical calcineurin inhibitors in the treatment of psoriasis. We checked for English-vernacular articles conveyed since 1990 in PubMed, Ovid/Cochrane, and Embase using "tacrolimus," "pimecrolimus," or "topical calcineurin inhibitors," and "psoriasis" as keywords. Eight double-blind studies and seven open studies displayed the ampleness of topical tacrolimus in psoriasis. Included studies demonstrated a considerable efficacy of topical administration of tacrolimus and pimecrolimus in the treatment of psoriasis, especially for facial, genital, and intertriginous areas. The role of topical tacrolimus and pimecrolimus in the treatment of psoriasis seems to be promising as shown by the results of double-blind and open studies. Because these agents do not cause cutaneous atrophy, they have a special role in facial, genital, and intertriginous psoriatic lesions. Both agents await additional investigation to determine their roles.

Atopic dermatitis: a review of topical nonsteroid therapy.

BackgroundAtopic dermatitis is a chronic inflammatory skin condition that affects up to 20% of children and 3% of adults globally. Although topical corticosteroids are considered to be the first-line agents, they can be associated with cutaneous and systemic adverse effects. Since the early 2000s, two new classes of nonsteroid topical therapies, topical calcineurin inhibitors and phosphodiesterase 4 (PDE4) inhibitors, have been introduced and provide a safe treatment alternative.MethodWe performed a search and review of clinical trials that examined the safety and efficacy of topical calcineurin inhibitors and PDE4 inhibitors. The search was conducted using the PubMed database as well as preselected keywords and filters. This review focuses on the safety and efficacy of each therapy.ResultsSixty-nine clinical trials identified in this study have demonstrated the efficacy and safety of topical calcineurin and a single novel PDE4 inhibitor in the treatment of atopic dermatitis. Topical calcineurin inhibitors have been shown to be effective in both achieving lesion clearance as well as reducing relapse when used long-term and proactively. Similarly, in clinical trials the PDE4 inhibitor showed success in lesion clearance and symptom management. All three therapies (pimecrolimus, tacrolimus, crisaborole) are associated with low systemic absorption. No clinical trials to date have shown an increased risk of systemic adverse events or malignancy such as lymphoma. The most commonly reported treatment-related adverse event across all three therapies was application-site discomfort, pain or pruritus. It is important to note that long-term studies are not yet available for the novel PDE4 inhibitor.DiscussionTopical calcineurin inhibitors provide a safe and effective alternative to topical corticosteroid use in the treatment of atopic dermatitis. Although the US Food and Drug Administration (FDA) black box warning for topical calcineurin inhibitors remains, studies have not shown an increased risk of malignancy. These warnings have caused a decline in use in favor of topical steroids. A novel PDE4 inhibitor has shown efficacy and safety in studies up to one year. Further long-term safety data is needed.

Efficacy of Topical Calcineurin Inhibitors in Oral Lichen Planus.

Oral lichen planus (OLP) is associated with severe pain and significant impairment for patients. To evaluate the safety and efficacy of topical calcineurin inhibitors (TCI) in the treatment of OLP. Medline and the Cochrane Database were searched using the keywords "calcineurin inhibitor OR tacrolimus OR pimecrolimus" AND "oral lichen planus." Four retrospective studies that looked at the effects of tacrolimus on OLP; 4 randomized, double-blind clinical trials (RDBCT) comparing tacrolimus with topical corticosteroids; and 5 RDBCT comparing pimecrolimus with placebo or triamcinolone were noted. Six open prospective and multiple case reports assessing the efficacy of calcineurin inhibitor for treatment of diverse types of OLP were found. There is strong evidence to suggest that the use of tacrolimus 0.1% ointment and pimecrolimus 1% cream is superior or equally efficacious as traditional therapies for OLP. Topical calcineurin inhibitors are well tolerated, with no significant systemic adverse effects.

Efficacy of Topical Calcineurin Inhibitors in Psoriasis

Topical calcineurin inhibitors (tacrolimus and pimecrolimus) are indicated for the treatment of atopic dermatitis but have also been studied in the treatment of psoriasis. To define the efficacy of topical calcineurin inhibitors in the treatment of psoriasis. We searched for English-language articles published since 1990 in PubMed, Ovid/Cochrane, and Embase using "tacrolimus," "pimecrolimus," or "topical calcineurin inhibitors" and "psoriasis." Nine double-blind and 13 open studies demonstrated the efficacy of topical tacrolimus in psoriasis, especially for facial, genital, and intertrigious psoriasis, and four double-blind and one open study demonstrated the efficacy of topical pimecrolimus. The evidence (double-blind and open studies) is strong that topical tacrolimus and, to a lesser extent, pimecrolimus have efficacy in the treatment of psoriasis. Since these agents do not cause cutaneous atrophy, they likely have a special role in facial, genital, and intertriginous psoriasis. Further studies would help define their roles in psoriasis.

Efficacy of topical calcineurin inhibitors in vitiligo

Topical tacrolimus and pimecrolimus are indicated for the treatment of atopic dermatitis, but they have been studied in many off-label uses. We reviewed the English language literature to define their roles in treatment of vitiligo. Double-blind studies show that tacrolimus 0.1% ointment combined with excimer laser is superior to placebo, especially for UV resistant areas, such as bony prominences of the extremities. When used alone, tacrolimus 0.1% ointment is almost as effective as clobetasol propionate 0.05% ointment. Other studies suggest it can also be effective for facial lesions. Double blind studies show that pimecrolimus 1% cream combined with narrow band UVB is superior to placebo, especially for facial lesions. Additional studies would further clarify the role of topical calcineurin inhibitors in vitiligo.

Efficacy of Topical Calcineurin Inhibitors in Lichen Planus

Topical calcineurin inhibitors have been studied in many skin disorders, including lichen planus. To evaluate published reports of the use of topical calcineurin inhibitors in lichen planus. We searched PubMed, Ovid/Cochrane, and Embase using the keywords "tacrolimus," "pimecrolimus," "topical calcineurin inhibitors," and "lichen planus. " We examined 5 double-blind studies, 1 investigator-blinded study, 10 open prospective studies, 6 retrospective studies, and 28 case reports evaluating tacrolimus or pimecrolimus for oral, vulvovaginal, and cutaneous lichen planus. Strong evidence (double-blind and open studies) supports the use of topical tacrolimus ointment in oral lichen planus, with efficacy at least equal to topical clobetasol propionate 0.05% ointment. Treatment of oral lichen planus with topical tacrolimus ointment can result in demonstrable blood tacrolimus levels, but without clinically significant adverse events. Strong evidence (double-blind and open studies) supports the use of topical pimecrolimus 1% cream in oral lichen planus, with efficacy equal to that of topical triamcinolone acetonide 0.1% paste. For vulvovaginal lichen planus, pimecrolimus was superior to placebo in one double-blind study, and tacrolimus was effective in open studies. Only case reports support the efficacy of topical calcineurin inhibitors in cutaneous lichen planus.

Treatment of cutaneous lupus erythematosus

In patients with cutaneous lupus erythematosus (CLE) and mild skin involvement, local therapy consisting of topically applied pharmacological agents, e.g., topical/intralesional steroids, may be sufficient. Recent reports have also shown efficacy of topical calcineurin inhibitors in patients with CLE, particularly on the face. Special attention receives consistent sun protection through photoresistant clothing and application of light-shielding substances with highly potent chemical or physical UVA- and UVB-protective filters. These substances should be applied in sufficient amount (ca. 2 mg/cm(2)) at least 20-30 minutes before sun exposure in order to avoid induction and exacerbation of cutaneous lesions. The mainstay of treatment for disfiguring and widespread skin manifestations in patients with CLE, irrespective of the subtype of the disease, is antimalarial agents. Our understanding of the use of combinations of antimalarials and proper dosing according to the ideal bodyweight limits problems with toxicity. Further therapies, such as methotrexate, or retinoids, dapsone, mycophenolate mofetil, and thalidomide in selected cases, can be helpful for patients with resistant disease; however, side effects need to be taken into consideration. Recent advances in biotechnology resulted in the development of novel systemic agents, but randomized controlled trials are necessary for the approval of new therapeutic strategies in CLE.

Topical Calcineurin Inhibitors in Pediatric Atopic Dermatitis

Atopic dermatitis (AD) is a common disease in children. Despite good skin care and trigger avoidance, many children with AD require pharmacologic treatment to manage their disease. In recent years, topical calcineurin inhibitors (TCIs) have been used as an alternative to topical corticosteroids to treat some children with AD. However, revisions to the US labeling for TCIs (i.e. a boxed warning and a medication guide) have generated concern among pediatricians regarding TCI safety and raised questions about the appropriate use of TCIs in the pediatric population. Data from several well designed studies support the efficacy of TCIs in the treatment of AD. Safety concerns arise from a small number of reported malignancies, animal toxicology studies, and the potential adverse effects (including immunosuppression and risk of lymphoma) observed in patients who received systemically administered calcineurin inhibitors for suppression of solid-organ transplant rejection. Several factors indicate that these effects do not occur with topical administration: (i) systemic levels following topical administration are at least 10-fold lower than with oral administration; (ii) the small number of lymphomas reported to date in persons exposed to TCI use are not consistent with the types seen in transplant patients or other immunosuppressed patients; and (iii) no adverse effects on the immune system (as assessed by measures including vaccination response and skin delayed-type hypersensitivity reaction) have been observed in clinical trials of TCIs in children with AD. Overall, TCIs have an established safety and efficacy profile as long-term maintenance therapy in children with AD.

Safety and Efficacy of Topical Calcineurin Inhibitors in the Treatment of Childhood Atopic Dermatitis

Approximately 10-20% of infants in industrialized countries experience atopic dermatitis. In recent decades topical corticosteroids have been the first-choice therapy for treatment of flares. However, this form of therapy may induce skin atrophy, especially after application to facial lesions or with long-term use. Thus, development of new anti-inflammatory topical agents for the treatment of childhood atopic dermatitis was needed. The topical calcineurin inhibitors tacrolimus and pimecrolimus have an effect on various cells of the cutaneous immune system, specifically on T cells, by inhibiting the phosphatase calcineurin and preventing the transcription of proinflammatory cytokines. In several clinical studies of children and adults with atopic dermatitis, topical calcineurin inhibitors were found to be effective both on the face and the trunk and extremities, in both short- and long-term treatment regimens. Tachyphylaxis or rebound were not observed. In most patients an improvement of their eczema occurred during the first week of treatment, as measured by subjective and objective clinical signs of atopic dermatitis. Treatment significantly reduced the incidence of flares and the need for corticosteroids in children and adults. Treatment success, commonly defined as 'excellent improvement' or 'clearing of all lesions', was observed in more than one-third of all children treated with 0.03% or 0.1% tacrolimus or 1% pimecrolimus. Topical application of pimecrolimus and tacrolimus does not lead to significant blood concentrations of these agents in the majority of children with atopic dermatitis, and any increase in blood concentrations decreases after a few days of therapy. No changes in laboratory parameters were observed in short- and long-term studies in patients with atopic dermatitis. The most common adverse effect following the application of topical calcineurin inhibitors is mild to moderate symptoms of irritation such as burning, erythema and pruritus, which occurred in up to 20% of all children treated with tacrolimus and 10% of children treated with pimecrolimus, and usually faded after a few days. In contrast to topical corticosteroids, calcineurin inhibitors do not induce skin atrophy, even after long-term use. Topical calcineurin inhibitors have been proven to be effective and have a good safety profile during short-term and long-term use for up to 1 year with pimecrolimus and up to 4 years with tacrolimus. Given the lack of extensive experience with use of topical calcineurin inhibitors over longer periods, regular use of these agents, particularly in children, should be undertaken only after careful consideration of individual cases. Sun protection should also be advised.

Calcineurin‐Hemmer und Sirolimus: Wirkmechanismen und Anwendung in der Dermatologie

Zusammenfassung: Kontrollierte Studien und klinische Erfahrungen geben Hinweise darauf, dass systemisch angewendetes Ciclosporin A und Tacrolimus wirksame Therapien der Psoriasis sind und dass Ciclosporin A auch zur Besserung bei atopischem Ekzem führt. Eine Reihe weiterer entzündlicher und nichtentzündlicher Hauterkrankungen sprechen vermutlich ebenfalls auf diese Medikamente an. Die weit verbreitete und langfristigere Anwendung von Ciclosporin A und Tacrolimus ist jedoch durch Nebenwirkungen eingeschränkt. Die molekularen Wirkungsmechanismen von Ciclosporin A, Tacrolimus und einem verwandten Medikament, Sirolimus, wurden gut belegt. Sie finden in den T‐Zellen statt und umfassen die Hemmung kritischer signalgebender Bahnen, welche die T‐Zell‐Aktivierung regulieren. Beispielsweise hemmen Ciclosporin und Tacrolimus die Calcineurin‐Phosphatase‐Aktivität und somit die Aktivierung des Transkriptionsfaktors NFAT. Die therapeutische Effektivität von lokal angewendeten Calcineurin‐Inhibitoren bei atopischem Ekzem hat das Interesse am Wirkungsmechanismus dieser Medikamente bei Hauterkrankungen neu entfacht. Kürzlich hat sich gezeigt, dass das Expressionsmuster von Calcineurin und NFAT in nicht zum Immunsystem gehörenden Geweben wie der Haut liegt. Die Relevanz dessen für den Wirkungsmechanismus von systemisch und lokal angewendeten Calcineurin‐Inhibitoren und Sirolimus bei Hauterkrankungen wird diskutiert.

Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology.

Controlled trials and clinical experience indicate that systemic cyclosporin A and tacrolimus are effective treatments for psoriasis, and that cyclosporin A also improves atopic eczema. A variety of other inflammatory and non-inflammatory skin diseases are probably also responsive to these drugs. However, the widespread and longer-term use of cyclosporin A and tacrolimus are limited by side effects. The molecular mechanisms of action of cyclosporin A, tacrolimus and a related drug, sirolimus, have been well defined in T cells and involve inhibition of critical signalling pathways that regulate T cell activation. For example cyclosporin and tacrolimus inhibit calcineurin phosphatase activity and thereby inhibit activation of the transcription factor NFAT. The therapeutic efficacy of topical calcineurin inhibitors in atopic eczema have restimulated interest in the mechanism of action of these drugs in skin disease. Recently the expression pattern of calcineurin and NFAT has been defined in non-immune tissues including the akin. The relevance of this to the mechanism of action of systemic and topical calcineurin inhibitors and sirolimus in skin disorders is discussed.