Use Of Topical Calcineurin Inhibitors Research Articles

Association Between the Use of Topical Calcineurin Inhibitors and the Risk of Cancer Among Patients with Atopic Dermatitis: A Nationwide, Population-Based, Retrospective Cohort Study.

The cancer risks associated with treatment withtopical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations. This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers. This study was a nationwide, population-based, retrospective cohort study. Taiwan's National Health Insurance Research Database. Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model. Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs). The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database. After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Exceptfor leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia. Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population.

A Comparison of Topical Corticosteroids and Topical Calcineurin Inhibitors for the Treatment of Atopic Dermatitis

Topical corticosteroids (TCS) are a mainstay of treatment for atopic dermatitis (AD). There are shared physician and patient concerns that TCS use can result in skin atrophy and systemic absorption. The clinical use of topical calcineurin inhibitors (TCI) for AD is relatively limited despite evidence that TCI are safe and effective. Understanding the differences in efficacy and adverse effects between TCS and TCI can help shape prescription practices to the benefit of patients. The objective of this review is to characterize the difference in efficacy and adverse effects between TCS and TCI. A review of the literature between 2002 and 2022 was performed using the PubMed, EMBASE, and Cochrane Library databases. Ten studies comparing TCS of varying potencies with TCI approved for AD treatment were included in the review. Outcome measures were qualified using percent reductions on the modified Eczema Area and Severity Index score and decreases in physician's global evaluation of AD severity. Tacrolimus had statistically significant (P < .05) improvement in disease severity compared with TCS in 4 of the 5 studies that compared against weak TCS. The data suggest greater treatment efficacy of tacrolimus over weak TCS, and inferior performance of pimecrolimus (TCI) compared with both tacrolimus and weak TCS. It is difficult to draw conclusions between moderate, potent, and very potent TCS and TCI due to the small number of studies making comparisons. TCI can improve disease severity, especially on thin or intertriginous skin regions most vulnerable to adverse events with TCS treatment, and their use may help overcome adherence issues due to patient bias against TCS.

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.

Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis

Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors. As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc. We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses. Among individuals 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 optimal treatment of patients with atopic dermatitis. American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Wet Your Whistles: Alcohol-Induced Flushing With Use of Topical Calcineurin Inhibitors.

Localized flushing after alcohol ingestion is a reported adverse effect of 2 topical calcineurin inhibitors, tacrolimus and pimecrolimus, which are approved to treat atopic dermatitis and used off label for other dermatologic conditions. We propose techniques for alleviating this phenomenon.

Long-Term Risk of Skin Cancer and Lymphoma in Users of Topical Tacrolimus and Pimecrolimus: Final Results from the Extension of the Cohort Study Protopic Joint European Longitudinal Lymphoma and Skin Cancer Evaluation (JOELLE).

PurposeEvidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately.Patients and MethodsA cohort study in Denmark, Sweden, UK, and the Netherlands was conducted. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for nonmelanoma skin cancer (NMSC), melanoma, cutaneous T-cell lymphoma (CTCL), non-Hodgkin lymphoma (NHL) excluding CTCL, and Hodgkin lymphoma (HL) in new users of TCIs versus users of moderate/high-potency topical corticosteroids.ResultsThe study included 126,908/61,841 adults and 32,605/27,961 children initiating treatment with tacrolimus/pimecrolimus, respectively. Follow-up was ≥10 years for 19% of adults and 32% of children. Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were <1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25–2.58) for cutaneous T-cell lymphoma. For pimecrolimus, IRRs in adults were <1 for non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and Hodgkin’s lymphoma; and 1.21 (1.03–1.41) for melanoma; and 1.28 (1.20–1.35) for nonmelanoma skin cancer. In children, results were inconclusive due to few events. In adults, incidence rate ratios ≥5 years after first topical calcineurin inhibitor exposure were not higher than in overall analyses.ConclusionOverall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results. Even if causal, the public health impact of these excess risks would be low and confined to the first years of exposure.

The long-term risk of lymphoma and skin cancer did not increase after topical calcineurin inhibitor use and phototherapy in a cohort of 25,694 patients with vitiligo

Topical calcineurin inhibitors have been used to treat vitiligo, either alone or in combination with phototherapy; however, the long-term safety of these agents remains controversial. To investigate the risk of lymphoma and skin cancer in vitiligo patients who received topical calcineurin inhibitors or phototherapy. A multicenter retrospective cohort study of 25,694 vitiligo patients who received topical calcineurin inhibitors or phototherapy for 6weeks or more between 2001 and 2019 was performed. Cumulative doses of topical calcineurin inhibitors and total phototherapy sessions were determined. Outcomes were the development of lymphoma or skin cancer after enrollment, confirmed through chart review and pathology reports. During 95,203 person-years, 13 cases of lymphoma, 22 of actinic keratosis, 15 of nonmelanoma skin cancer, and 5 of melanoma were observed. The risk of lymphoma and skin cancer was not significantly increased by topical calcineurin inhibitor dose or phototherapy sessions. The interaction between the topical calcineurin inhibitors and phototherapy was not associated with an increased risk of skin cancer. Retrospective study, individual follow-up duration less than 4years, and no adjustment for comorbidities and medication history. Not generalizable to other races. The long-term risk of skin cancer or lymphoma was not associated with the use of topical calcineurin inhibitors, phototherapy, and both treatments in combination in patients with vitiligo.

Eritema Periocular Induzido pelo Álcool: Efeito Adverso Raro de Tacrolimus

A crescente incidência da alopecia fibrosante frontal tornou frequente o uso tópico dos inibidores da calcineurina na região frontal para controlo da atividade da doença. Relatamos um raro efeito adverso induzido por tacrolimus e concomitante ingestão de álcool.&#x0D; &#x0D;

The use of topical calcineurin inhibitors for pyoderma gangrenosum in inflammatory bowel disease: A case series

The use of topical calcineurin inhibitors for pyoderma gangrenosum in inflammatory bowel disease: A case series

Inflammatory Bowel Disease Clinical

Inflammatory Bowel Disease Clinical

Combination of non-ablative fractional photothermolysis and 0.1% tacrolimus ointment is efficacious for treating idiopathic guttate hypomelanosis

Background: The efficacy of fractional photothermolysis and topical use of calcineurin inhibitors as treatments of idiopathic guttate hypomelanosis (IGH) have been reported. Data on combination treatments are lacking. Objectives: To evaluate the efficacy and safety of 1550-nm ytterbium/erbium fiber laser combined with 0.1% tacrolimus ointment as a treatment of IGH.Methods: In each patient with IGH, two lesions were assigned as a treatment group, whilst two lesions on another side were chosen as control. Four treatments by fractional 1550-nm ytterbium/erbium fiber laser were delivered every four weeks combined with a twice daily topical application of 0.1% tacrolimus ointment. Lesional skin color was measured by colorimeter. Digital and dermoscopic digital photographs were taken and evaluated by three dermatologists. Results: A total of 120 lesions were treated. Combination treatment normalized the relative lightness index of IGH which reached statistical significant compared with the control at week 12, after three sessions of laser treatment (p = 0.026). Physicians’ assessment score revealed that 91.67% of the lesions on treatment side showed an improvement. Swelling and redness were the most common side effects which spontaneously resolved. Conclusion: Fractional 1550-nm ytterbium/erbium fiber laser combined with topical 0.1% tacrolimus ointment was effective for IGH.

Current Views on the Pathogenesis and Principles of External Treatment of Atopic Dermatitis in Children

The article analyzes the current data on the pathogenesis of atopic dermatitis. It discusses the role of the damaged dermal barrier structure in the development of food allergies and presents the results confirming the theory of transdermal sensibilisation to allergens in addition to hereditary and exogenous factors. Current local treatment of atopic dermatitis using topical glucocorticosteroids (tGCs) aimed at reducing the severity of symptoms is often associated with the risk of complications. The data on the effective use of topical calcineurin inhibitors (TCI) to eliminate the side effects of tGCs are presented. The results of the possible use of pimecrolimus in the form of 1% cream for gradual withdrawal of tGCs in the long-term use are shown. The data of reviews and meta-analyses for the last decade are given showing that there is no evidence that the use of TIC is associated with an increased risk of lymphoma. The authors conclude that pimecrolimus in the form of 1% cream is the best medication for topical therapy in children with mild and moderate form of the disease. It is also considered the best preparation for the proactive treatment of atopic dermatitis in the long period of time in order to prevent recurrences.

Characterization and management of exfoliative cheilitis: a single-center experience

Exfoliative cheilitis (EC) is a rare inflammatory condition affecting the vermilion of the lips and characterized by production of a thick keratin scale. Given the limited available data, the approach to optimal management of EC remains unclear. The objective of this retrospective study was to characterize the clinical features, management, and outcomes of a series of patients with EC. Fifteen patients with a median age of 59 years and a female-to-male ratio of 2:1 were diagnosed with EC from 2000 to 2010. Parafunctional lip licking (53%) and a history of psychiatric disorders (40%) were common. Ten patients (66%) returned for follow-up, with an overall response rate (partial or complete) of 80% at a median of 2 months, most frequently associated with the use of topical calcineurin inhibitors or moisturizing agents. Management of EC with topical calcineurin inhibitors and moisturizing agents is associated with clinical improvement, but prospective trials are needed.

Predictors of Basal Cell Carcinoma in High-Risk Patients in the VATTC (VA Topical Tretinoin Chemoprevention) Trial

Basal cell carcinoma (BCC) is the most common cancer in the United States today, and patients who have had one are likely to have multiple carcinomas over time. Predictors of new BCCs on the face and ears among those at very high risk have not been studied in detail. We sought to do so prospectively in the context of a 6-year trial. We found that the number of BCCs in the prior 5 years was the most important predictor. Age, sun sensitivity, occupational sun exposure before the age of 30 years (but not afterward), lower educational level, history of eczema, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and more sunscreen use in the week, but not the 6 months, before enrollment were also independent predictors, but sunburns, baseline sun exposure, and other sun-protective measures, other skin cancers, and actinic keratoses were not. None of the eczema patients had a history of topical calcineurin use. The cumulative risk of BCC was 55% at 5 years. These findings document the key risk factors in this very high-risk population, suggesting that the history of eczema may increase the risk in those at high risk and that early sun exposure is important even in this group, and underscoring the need for chemopreventive strategies.

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.

Induced Lentiginosis With Use of Topical Calcineurin Inhibitors

Induced Lentiginosis With Use of Topical Calcineurin Inhibitors

Evaluation of cancer risk related to atopic dermatitis and use of topical calcineurin inhibitors

Cases of lymphoma or cutaneous cancer have been observed following use of topical calcineurin inhibitors (TCIs), but it is unclear whether TCI use increases cancer risk. We used published literature to assess the extent to which atopic dermatitis (AD) or TCI use is associated with lymphoma, melanoma, basal cell carcinoma and squamous cell carcinoma. We searched the literature and summarized the results of all studies that provided data on the absolute or relative frequency of any malignancy among patients with AD or eczema or among patients using TCIs. The relative risk for all lymphoma in broad populations of AD or eczema ranged from 0·7 to 1·8. Available data on lymphoma following TCI use were inconsistent and insufficient to draw a conclusion about the causal role of TCIs. We found no evidence indicating that melanoma or nonmelanoma skin cancer is associated with TCI use. A bias analysis showed that cutaneous T-cell lymphomas initially misdiagnosed and treated as AD would lead to overestimation of the association between TCI use and lymphoma. However, there are only sparse data on specific malignancies among TCI-treated patients. The short duration of typical TCI exposure hinders conclusions about longer exposure. There is insufficient evidence in the epidemiological literature to infer whether TCIs do or do not cause malignancy.

Update on the use of topical calcineurin inhibitors in cutaneous lupus erythematosus

Cutaneous manifestations of lupus erythematosus (CLE) are manifold, presenting with unspecific skin manifestations or well-defined clinical dermatological entities. Their relation to each other as well as to systemic lupus erythematosus is variable, yet diagnostically and therapeutically challenging. Therapeutic decisions have to be based on the activity and distribution as well as the type of skin lesions and the extent of systemic disease. Limited skin manifestations may be amply tackled by topical therapy, so far, mainly relying on corticosteroids. In many cases, however, internal treatment has to be combined by using antimalarials, in addition to strict UV-protection. The advent of topical calcineurin inhibitors has contributed substantially to the armamentarium of external treatment options. By specifically interfering with intracytoplasmic signal transduction to activate the nuclear factor of activated T-cells (NF-AT), they are able to modulate various inflammatory mechanisms. The two available compounds, pimecrolimus and tacrolimus, do not induce the skin atrophy characteristic of corticosteroids. They have been studied in a number of case reports, but only in a few randomized, comparative studies. Both are well-tolerated, but differentially effective in the various subsets of CLE. Further studies are needed to directly compare the two compounds to each other, as well as to topical corticosteroids, before final recommendations can be made.

Topical Treatments with Pimecrolimus, Tacrolimus and Medium- to High-Potency Corticosteroids, and Risk of Lymphoma

Background/Aims: A potential risk of lymphoma associated with the use of topical calcineurin inhibitors is debated. We assessed the risk of lymphoma among patients treated with topical pimecrolimus, tacrolimus or corticosteroids. Methods: We conducted a cohort study using health insurance claims data. Cohorts of initiators of topical pimecrolimus, tacrolimus and corticosteroids, along with cohorts of persons with untreated dermatitis and randomly sampled enrollees were identified from January 2002 to June 2006. Lymphomas were identified using insurance claims and adjudicated by medical records review. We adjusted for confounders by propensity score matching. Results: Among 92,585 pimecrolimus initiators contributing 121,289 person-years of follow-up, we identified 26 lymphomas yielding an incidence of 21/100,000 person-years. This incidence of lymphoma was similar to that among tacrolimus users (rate ratio, RR = 1.16; 95% confidence interval, CI = 0.74–1.82) as well as corticosteroid users (RR = 1.15; 95% CI = 0.49–2.72). All three topical treatments were associated with an increased risk of lymphoma compared with the general population (RR_Pim = 2.89; RR_Tac = 2.82; RR_Cort = 2.10) suggesting increased detection of preexisting lymphomas. Conclusion: This study did not find an increased risk of lymphoma among initiators of topical pimecrolimus relative to other topical agents during an average follow-up of 1.3 years. Longer-term studies may be needed.

Topical pimecrolimus and tacrolimus do not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation

Pimecrolimus and tacrolimus are topical calcineurin inhibitors developed specifically for the treatment of atopic eczema. Experience with long-term use of topical calcineurin inhibitors is limited and the risk of rare but serious adverse events remains a concern. We have previously demonstrated the absence of carcinogenic effect of tacrolimus alone and in combination with simulated solar radiation (SSR) on hairless mice. The aim of this study is to determine whether pimecrolimus accelerates photocarcinogenesis in combination with SSR or pimecrolimus and tacrolimus accelerate photocarcinogenesis in combination with UVA. We used 11 groups of 25 hairless female C3.Cg/TifBomTac immunocompetent mice (n = 275). Pimecrolimus cream or tacrolimus ointment was applied on their dorsal skin three times weekly followed by SSR (2, 4, or 6 standard erythema doses, SED) or UVA (25 J/cm(2)) 3-4 h later. This was done up to 365 days in the SSR-treated groups and up to 500 days in the UVA-treated groups. Pimecrolimus did not accelerate the time for development of the first, second or third tumor in any of the groups. Median time to the first tumor was 240 days for the control-2SED group compared with pimecrolimus-2SED group (233 days), control-4SED group (156 days) compared with pimecrolimus-4SED group (163 days) and control-6SED group (162 days) compared with pimecrolimus-6SED group (170 days). Only one mouse in each of the three UVA groups developed a tumor. We conclude that pimecrolimus in combination with SSR and both pimecrolimus and tacrolimus in combination with UVA do not accelerate photocarcinogenesis in hairless mice.