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

Schneeweiß, Sebastian; Doherty, Mike; Zhu, Shao; Funch, Donnie; Schlienger, Raymond G.; Fernández-Vidaurre, Carlos; Seeger, John D.

doi:10.1159/000209289

Cited by 68 publications

(86 citation statements)

References 26 publications

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“…10 However, many large-scale analyses have indicated that topical tacrolimus does not increase the risk of malignant lymphoma. [11][12][13][14][15] In addition, topical tacrolimus was effective for the treatment of cutaneous T-cell lymphoma in one case 16 and in the treatment of cutaneous lesions of angioimmunoblastic T-cell lymphoma in another case. 17 These cases are of great interest in terms of the relationship between tacrolimus and lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus-Negative, CD5-Positive Diffuse Large B-Cell Lymphoma Developing after Treatment with Oral Tacrolimus for Mixed Connective Tissue Disease : A Case Report and Review of the Literature

Sekiguchi

Shimada

Imai

et al. 2012

J Clin Exp Hematopathol

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A 69-year-old woman, who had been diagnosed as having Sjögren's syndrome at 37 years old and mixed connective tissue disease at 42 years old, was under treatment with oral prednisolone. In 2009, she was diagnosed as having active systemic lupus erythematosus, and started on treatment with tacrolimus at 3 mg/day. In 2010, para-aortic lymphadenopathy and superficial multiple lymphadenopathy were detected. Tacrolimus was discontinued. Axillary lymph node biopsy revealed Epstein-Barr (EB) virus-negative CD5-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified into clinical stage IIIA and as being at high risk according to the international prognostic index. After the discontinuation of tacrolimus, the lymph nodes reduced temporarily in size. In January 2011, the lymphadenopathy increased again, and the patient received a total of 8 courses of therapy with rituximab, pirarubicin, vincristine, cyclophosphamide and prednisolone, followed by intrathecal injection to prevent central nervous system infiltration, which was followed by complete remission. In February 2012, fluorodeoxyglucose positron emission tomography showed relapse in multiple lymph nodes and central nervous system infiltration. The patient was considered to have iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the WHO, and this is the first reported case of CD5-positive DLBCL and central nervous system infiltration following administration of the drug. The patient was considered to have a poor prognosis as EB virus was negative, discontinuation of tacrolimus was ineffective and there was evidence of central nervous system infiltration. 〔J Clin Exp Hematopathol 52(3) : 211-218, 2012〕

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Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus-Negative, CD5-Positive Diffuse Large B-Cell Lymphoma Developing after Treatment with Oral Tacrolimus for Mixed Connective Tissue Disease : A Case Report and Review of the Literature

Sekiguchi

Shimada

Imai

et al. 2012

J Clin Exp Hematopathol

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“…The risk of TCL associated with use of pimecrolimus cream was insignificantly increased (RR 2.32, 95% CI, 0.89 -6.07) (23,43). A cohort study by Schneeweiss et al reported no significant association between lymphoma and both TCIs (tacrolimus; RR 1.36, 95% CI, 0.47 -3.98, pimecrolimus: RR 1.63, 95% CI, 0.75 -3.54) (24). In case control studies, the risk for developing lymphoma was even more insignificant (21,22).…”

Section: Resultsmentioning

confidence: 99%

“…Many opinion leaders and medical associations, including the American academy of allergy, asthma and immunology (AAAAI), American college of allergy, asthma and immunology (ACAAI), American academy of dermatology, canadian dermatology association (CDA), and Canadian society of allergy and clinical immunology (CSACI) released position statements, expressing disagreement about box warning, promoting the safety of the TCIs and demanding reconsideration of the alert (15)(16)(17)(18). In September 2010, the FDA released a comprehensive review of TCI safety summarizing data from six studies including more than 6 million patients (19)(20)(21)(22)(23)(24)(25)(26). Later on, in May, 2011 according to a total of 72 cases of malignancy that had been reported in children treated with TCI, the FDA issued an addendum (27,28).…”

Section: The Us Fda "Black Box" Warning For Tcis and Fda Comprehensivmentioning

confidence: 99%

“…Legendre et al (2015) performed a meta-analysis of 4 cohort studies and 18 case-control studies, and found a modest increase in risk of lymphoma in patients with AD compared with the general population (43). The increased risk was statistically significant in the meta-analysis of the cohort studies (RR 1.43, 95% CI, 1.12 -1.81) (24,(44)(45)(46). In the meta-analysis of the case-control studies the increased risk for lymphomas was insignificant (OR 1.18, 95% CI 0.94 -1.47) (43).…”

Section: Atopic Dermatitis Per Se and Increased Risk For Lymphomamentioning

confidence: 99%

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Topical Calcineurin Inhibitors and Malignancy Risk

et al. 2017

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Context: The approval of topical calcineurin inhibitors (TCIs) has been a significant breakthrough for the treatment of atopic dermatitis due to much lower systemic absorption and not causing skin atrophy even after long-term use that have made them become popular replacements for topical corticosteroids being almost equally effective. In January 2006, the US food and drug administration (FDA), followed later also by the European medicine agency (EMEA), issued the "black box" warning causing controversy regarding a potential increased risk of lymphoma in patients with atopic dermatitis and treated with TCIs. Evidence Acquisition: PubMed and MEDLINE ® databases were systematically searched utilizing a variety of terms relating to the subject matter. Articles written only in English over the past 15 years were analyzed and selected for review. Results: So far, no scientific evidence of the association has been found between use of TCIs, and increased incidence of skin cancers and lymphomas in patients with AD. The systematic review and meta-analysis by Legendre et al. found the role of TCIs unlikely to be a significant risk factor of lymphoma in those patients. Conclusions:Despite an extensive body of evidence regarding the TCIs safety, the box warning still remains leaving the physicians and patients unduly uncertain and confused about the safety of TCI use.

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“…3,4) In contrast, other studies revealed no significant differences between TL use and non-use with regard to an increased risk of lymphoma. 5,6) Due to short durations and potential study biases in these reports, results have been controversial. Thus, the FDA has advised that monitoring for occurrence of TL-related cancer be continued.…”

mentioning

confidence: 99%

Effect of Physiological Changes in the Skin on Systemic Absorption of Tacrolimus Following Topical Application in Rats

Hazama

Maekawa

Miki

et al. 2016

Biological & Pharmaceutical Bulletin

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Tacrolimus (TL) ointment is a topical treatment for atopic dermatitis, a disease that exhibits various skin conditions. The effect of skin pathologies on the systemic absorption of TL and related side effects remains unknown. This study aimed to investigate factors affecting the cutaneous absorption of TL. We prepared various skin models in hairless rats by tape stripping, injection of prophlogistic material solution (PMS), and continuous subcutaneous adrenaline (Adr) infusion. In vivo absorption studies were conducted, with measurements of transepidermal water loss (TEWL) and skin blood flow as physiological parameters. Very little TL absorption was observed through intact skin. Greater TL absorption was noted in skins with high TEWL values and fully stripped skin with PMS injections. In contrast, Adr infusion, which reduced skin blood flow, resulted in decreased TL absorption through fully stripped skin. Combined use of TL and Adr on skin with PMS injections resulted in suppression of TL absorption. Our results revealed that TL absorption following topical application is affected by alterations in the skin barrier, blood flow, and vascular permeability. We propose an administration plan for TL in a flowchart as a means of preventing systemic side effects.Key words tacrolimus; cutaneous absorption; atopic dermatitis; inflamed skin; transepidermal water loss; skin blood flow Tacrolimus (TL, FK506, molecular weight of 803.5) is a 23-membered macrolide lactone isolated from the bacterium Streptomyces tsukubaensis. For over two decades, TL has been widely used as a calcineurin inhibitor immunosuppressant for organ transplantation, given intravenously and orally. A topical formulation of TL (Protopic ® ointment, available in two TL ointment concentrations: 0.1% for adults and 0.03% for children) has also shown potent immunosuppressive activity and has been used as second line treatment for atopic dermatitis (AD) that cannot be controlled by topical corticosteroids.1,2) In 2006, the U.S. Food and Drug Administration (FDA) issued a black-box warning regarding a potential carcinogenic risk associated with TL ointment. Since then, some cohort studies and case-control studies have been conducted in order to reveal the association between topical use of TL and an increased risk of malignancy. Hui et al. and Arana et al. identified an increased risk of T-cell lymphoma with TL use.3,4) In contrast, other studies revealed no significant differences between TL use and non-use with regard to an increased risk of lymphoma.5,6) Due to short durations and potential study biases in these reports, results have been controversial. Thus, the FDA has advised that monitoring for occurrence of TL-related cancer be continued.AD is a chronically relapsing inflammatory skin disease with severe pruritus and eczema. The skin barrier function in AD patients is disrupted and exhibits an increase in transepidermal water loss (TEWL). [7][8][9] This skin disruption allows TL to permeate the skin despite a large molecular weight. 10,11) TL exerts ...

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

Cited by 68 publications

References 26 publications

Epstein-Barr Virus-Negative, CD5-Positive Diffuse Large B-Cell Lymphoma Developing after Treatment with Oral Tacrolimus for Mixed Connective Tissue Disease : A Case Report and Review of the Literature

Epstein-Barr Virus-Negative, CD5-Positive Diffuse Large B-Cell Lymphoma Developing after Treatment with Oral Tacrolimus for Mixed Connective Tissue Disease : A Case Report and Review of the Literature

Topical Calcineurin Inhibitors and Malignancy Risk

Effect of Physiological Changes in the Skin on Systemic Absorption of Tacrolimus Following Topical Application in Rats

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