Topical calcineurin inhibitors

Topical calcineurin inhibitors (TCIs) are non-steroidal creams / ointments used to treat eczema and a number of other skin conditions. The three TCIs are pimecolimus cream (Elidel ®) and tacrolimus (Protopic ®) 0.03% ointment and 0.1% ointment. It is the opinion of the PCDS, and other leading dermatological organisations, that TCIs can be safely initiated by any health professional experienced in treating eczema - including General Practitioners. This is based on a multitude of literature, expert opinion and clinical practice worldwide.

The three topical calcineurin inhibitor formulations are:

• Elidel ® cream (pimecrolimus); licensed for children 3 months of age and older, adolescents and adults
• Protopic ® (tacrolimus) 0.03% ointment is licensed for ages 2 years and above
• Protopic ®(tacrolimus) 0.1% ointment is licensed for ages 16 years and above

Topical Calcineurin inhibitors (TCIs) have been in widespread use for over 20 years. Calcineurin inhibitors (TCIs) block the release of calcineurin in the skin, preventing the release of cytokines; they have immune-modulating and anti-inflammatory properties. Their topical use is recommended as a second line option in the treatment of atopic eczema (Nice GL 2004/ TA 82 2015). As they do not cause skin atrophy, nor glaucoma they are considered safer than the long-term use of topical steroids, especially on thin skin such as the eyelids (4).

A wide body of dermatological opinion also supports use of TCIs as steroid sparing agents for a range of inflammatory conditions particularly at sites susceptible to adverse effects from the long term use of topical corticosteroids (TCS) such as the face and flexures - refer to the BAD Guidelines for lichen planus, vitiligo (6,7. Gawkrodger 2008; de Menezes, 2016) and the BAD TCI patient information leaflet (1) describing use in seborrheic dermatitis, discoid lupus and other facial conditions.

TCIs are considered second line agents in the management of atopic eczema in part as the skin responds more slowly to TCIs than to TCS, but also because of initial concern (extrapolated from the use of oral Tacrolimus) of a theoretical increased risk of lymphoma with prolonged systemic use. Extensive post marketing surveillance studies over the ensuing 20 has not shown a causal increased risk of cancer, nor skin cancer specifically, in patients using TCIs (2,5,6). The SPCs for Elidel and Protopic (0.1% and 0.03%) have been amended and do not now cite cancer as a potential adverse effect of use.

Why do some ICBs still limit initiation of TCIs to secondary care dermatologists, and why things need to change?

• The primary reason is that relevant healthcare professionals within ICBs are not familar with the evidence and changes to the SmPC in 2022

• NICE (CG57 Atopic eczema in U12) 2004/ 2015 advised that “Topical calcineurin inhibitors (tacrolimus and pimecrolimus) are a second-line option [in the treatment of eczema]. ‘It is recommended that treatment with tacrolimus or pimecrolimus be initiated only by physicians (including general practitioners) with a special interest and experience in dermatology, and only after careful discussion with the patient about the potential risks and benefits of all appropriate second-line treatment options’

• Caution about topical TCIs (and specialist-only prescribing) related to a ‘black box’ warning on the original drug data sheet from the US Federal Drug Administration (FDA) describing a theoretical risk of lymphoma extrapolated from the oral use of tacrolimus

• Topical TCIs have been in widespread use for over 20 years. Extensive post-marketing surveillance has been very reassuring and has not shown a causal increased cancer risk, including skin cancer. Of note is that several of these reviews have been published since the last (2015) NICE review:

• A long-term safety study over 10 years using tacrolimus ointment 0.03% or 0.1% in children did not show an increased risk of cancer or lymphoma (9, see also 3,4,10,11). The application of TCI is not associated with an increased risk of non-melanoma skin cancer, other malignancies or photo-carcinogenicity (13). A (2020) paediatric prospective observational cohort study (APPLES, n = 7954) (14) found no significant association between regular tacrolimus use and lymphoma risk over a 10-year follow-up period. The Joelle study (5) did find an association of TCI use with lymphoma but considered disease severity to be relevant and the likelihood of an impact in practice to be very low. Subsequent evidence pointing to an association between eczema of increasing severity and lymphoma suggests that the inflammatory process may be implicated, not TCIs (15)

• The stated cancer risk remains in the precautions section of the drug data sheet, despite recent evidence, but the cancer risk has been removed from the sections on adverse effects for both Protopic and Elidel in the SPC and PIL. The European guidelines advise that ‘Clinicians should be aware of the black-boxed warning on the use of TCI inhibitors and may discuss this with patients to improve adherence, even if observational studies have not found a convincing association between long-term TCI use and cancer development' 

• EU clinical guidelines (which support the use of TCIs in all age group including in pregnancy), the British Association of Dermatologists (BAD) and The American Academy of Dermatologists do not limit the initiation of TCIs to specialists only. The PCDS agrees that topical calcineurin inhibitors can be safely initiated by physicians experienced in treating eczema (as per SPCs). In the interest of promoting easier access to safe and effective treatments for their patients, the PCDS encourages updating of local ICB/ICS prescribing formularies to reflect the changes to the Summary of product Characteristics' of Protopic and Elidel and national guidelines about use of TCIs in other conditions where their steroid sparing effects are desirable. Recognising the expertise held by a breadth of clinicians in the primary care team the PCDS considers it likely that other HCP may also acquire appropriate experience to initiate TCIs safely

Useful references include:

1. Topical calcineurin inhibitors - BAD Patient Hub (skinhealthinfo.org.uk). Topical calcineurin inhibitors factsheet (November 2023).docx (eczema.org)
2. Lam M, Zhu JW, Tadrous M, Drucker AM. Association Between Topical Calcineurin Inhibitor Use and Risk of Cancer, Including Lymphoma, Keratinocyte Carcinoma, and Melanoma: A Systematic Review and Meta-analysis. JAMA Dermatol. 2021 May 1;157(5):549-558. doi: 10.1001/jamadermatol.2021.0345. PMID: 33787818; PMCID: PMC8014232.
3. Siegfried EC, Jaworski JC, Kaiser JD, Hebert AA. Systematic review of published trials: long-term safety of topical corticosteroids and topical calcineurin inhibitors in pediatric patients with atopic dermatitis. BMC Pediatr. 2016;16:75
4. Cochrane review based on 5885 participants in 20 RCTs (Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM. Topical tacrolimus for atopic dermatitis. Cochrane Database Syst Rev. 2015 Jul 1;2015(7):CD009864. doi: 10.1002/14651858.CD009864..)
5. 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). Clin Epidemiol. 2021;13:1141-1153
6. Taieb, 2013 Guideline for the diagnosis and management of vitiligo
7. Bergqvist, 2020 Vitiligo: A Review
8. A. Wollenberg et al European guideline (EuroGuiDerm) on atopic eczema – part II: non‐systemic treatments and treatment recommendations for special AE patient populations - Wollenberg - 2022 - Journal of the European Academy of Dermatology and Venereology - Wiley Online Library
9. Paller AS, Fölster-Holst R, Chen SC et al. No evidence of increased cancer incidence in children using topical tacrolimus for atopic dermatitis. J Am Acad Dermatol 2020; 83: 375–381
10. Niveditha Devasenapathy Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus for atopic dermatitis: a systematic review and meta-analysis The lancet, Child and adolescent Health January 2023 Volume 7, issue 1, p13-25 https://doi.org/10.1016/S2352-...(22)00283-8
11. Taieb, 2013 Pimecrolimus in atopic dermatitis: consensus on safety and the need to allow use in infants Pediatr Allergy Immunol 2015 Jun;26(4):306-15 Epub 2015 Apr 13.
12. Ohtsuki M, Morimoto H, Nakagawa H. Tacrolimus ointment for the treatment of adult and pediatric atopic dermatitis: review on safety and benefits. J Dermatol 2018; 45: 936–942
13. Ring J, Barker J, Behrendt H et al. Review of the potential photo-carcinogenicity of topical calcineurin inhibitors: position statement of the European dermatology forum. J Eur Acad Dermatol Venereol 2005; 19: 663–671
14. Amy S. Paller, MD et al No evidence of increased cancer incidence in children using topical steroids for atopic dermatitis APPLES study
15. Kathryn Mansfield et al et al Association Between Atopic Eczema and Cancer in England and Denmark JAMA Dermatol. 2020 Oct 1;156(10):1086-1097. 2 large population-based studies performed in different settings do not support associations between atopic eczema and most cancers. However, an association was observed between atopic eczema and lymphoma, particularly NHL, that increased with eczema severity. This finding warrants further study as new immunomodulatory systemic therapeutics are brought to market that may alter cancer risk