Innovative Use of Topical Calcineurin Inhibitors

doi:10.1016/j.det.2010.03.008

Dermatologic Clinics

Volume 28, Issue 3, July 2010, Pages 535-545

https://doi.org/10.1016/j.det.2010.03.008 Get rights and content

Section snippets

Oral lichen planus

Oral lichen planus is 1 of the best studied off-label uses for topical calcineurin inhibitors. Investigators have shown that tacrolimus and pimecrolimus are effective in double-blind studies.

Vitiligo

Double-blind studies have shown that tacrolimus and pimecrolimus are effective in vitiligo.

Tacrolimus

One double-blind study of 167 patients showed that tacrolimus 0.1% ointment, when applied twice a day to facial or intertriginous psoriasis, was superior to placebo (P = .004), with improvement as early as day 8.⁴⁴ Two other double-blind studies also showed tacrolimus is superior to vehicle,45, 46 and 1 other double-blind study of facial/genital-femoral psoriasis showed tacrolimus 0.03% ointment was superior to calcitriol,⁴⁷ which is a natural, bioactive 1,25-dihydroxyvitamin D₃, available as

Contact dermatitis

For nickel-induced allergic contact dermatitis, double-blind studies showed that tacrolimus is superior to placebo59, 60, 61; pimecrolimus 0.6% cream has been shown to be effective in 1 open study.⁶² In 1 double-blind study of contact dermatitis, there was no difference among tacrolimus 0.1% cream, pimecrolimus 1% cream, clobetasol propionate 0.05% ointment, triamcinolone acetonide 0.1% ointment, and placebo, but there was a clear trend in favor of active drug treatment.⁶³

Additional studies and

Seborrheic dermatitis

Two open studies showed favorable results with tacrolimus 0.1%.70, 71 In 1 double-blind study, pimecrolimus 1% cream was superior to vehicle⁷²; in another study, it was equal to 1% hydrocortisone acetate cream.⁷³ In 1 open study, it was equal to ketoconazole 2% cream⁷⁴; another open study showed that pimecrolimus was more effective than topical metronidazole and topical methylprednisolone.⁷⁵ Thus, multiple approaches to seborrhea exist, including the use of TCI and antifungal agents instead of

Rosacea

Two open studies showed that tacrolimus 0.1% ointment can be effective for rosacea.76, 77 One double-blind and 1 open study showed that pimecrolimus 1% cream is not more effective than vehicle.78, 79 One open study showed that pimecrolimus is not more efficacious than metronidazole cream.⁸⁰ Two open studies showed that pimecrolimus 1% cream can be effective in steroid-induced rosacea.81, 82 Because there is a paucity of evidence in this regard, TCI should be reserved for otherwise recalcitrant

Cutaneous lupus erythematosus

In 1 double-blind study, tacrolimus 0.1% ointment was equal to clobetasol propionate 0.05% ointment in facial lupus erythematosus (LE), especially malar rash, and lesions of discoid LE and subacute cutaneous LE.⁸³ In open studies and case reports, treatment with tacrolimus also led to favorable results.84, 85, 86, 87, 88, 89, 90, 91 A double-blind study showed that pimecrolimus 1% cream was comparable with betamethasone valerate 0.1% cream in discoid lupus.⁹² Pimecrolimus 1% cream was effective

Perioral dermatitis

Two double-blind studies96, 97 showed pimecrolimus 1% cream was superior to vehicle. Additional work is needed in this area.

Cutaneous Crohn disease

One double-blind study showed that tacrolimus 0.1% ointment is superior to placebo in perianal or anal ulcerative Crohn disease, but is unlikely to be effective if there are fistulae.⁹⁸ In 1 open study, tacrolimus 0.5% ointment was effective in oral and perineal Crohn disease.⁹⁹ In 1 patient treated with tacrolimus 0.05% in Orabase for orofacial Crohn disease, systemic absorption with a blood level of 9 μg/mL was documented.¹⁰⁰

Tacrolimus

In 1 open study of 84 patients (49 women, 32 men, 3 girls) with lichen sclerosus (79 with anogenital lichen sclerosus, 5 with extragenital lichen sclerosus) treated with tacrolimus 0.1% twice a day for 16 weeks, clearance of active lichen sclerosus was reached in 43% of patients at 24 weeks.¹⁰¹ Favorable results were also seen in smaller open studies in patients with vulvar lichen sclerosus102, 103 and lichen sclerosus of the penis.¹⁰⁴ Several case reports have also shown favorable results in

Morphea/scleroderma

A double-blind study showed that tacrolimus 0.1% ointment was more effective than petrolatum in morphea.¹¹⁷ An open study showed favorable results in localized scleroderma.¹¹⁸ Additional research is necessary.

Netherton syndrome

In 1 study, 3 patients with Netherton syndrome treated with 0.1% tacrolimus had very high blood tacrolimus levels, up to 37.2 μg/L, but none showed signs or symptoms of toxic effects of tacrolimus.¹¹⁹ Tacrolimus should be used with extreme caution, if at all, in patients with Netherton syndrome.

Tacrolimus: lack of efficacy

One open study¹²⁰ and 3 case reports121, 122, 123 showed that tacrolimus 0.1% ointment is not effective in alopecia areata. One double-blind study of 22 patients with hemodialysis-related pruritus showed that tacrolimus was not more effective than vehicle.¹²⁴ Additional studies and case reports showed that tacrolimus was not effective in frontal fibrosing alopecia,¹²⁵ factitial panniculitis,¹²⁶ and UV-induced erythema.¹²⁷

Pimecrolimus: lack of efficacy

Studies have shown lack of efficacy of pimecrolimus in alopecia areata¹²⁸ and acne vulgaris.¹²⁹ One prospective study of cetuximab-induced papulopustular eruption¹³⁰ showed pimecrolimus did not result in clinically meaningful benefit, but 1 case report¹³¹ did show efficacy.

Other disorders

Investigators have shown that tacrolimus and pimecrolimus can be effective in many other disorders, sometimes as adjunctive therapy.

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Cited by (37)

Elevation of FK506 production by regulatory pathway engineering and medium optimization in Streptomyces tsukubaensis
2021, Process Biochemistry
Citation Excerpt :
FK506 (tacrolimus) was first isolated from the fermentation broth of Streptomyces tsukubaensis by Fujisawa Pharmaceutical Company in 1984 [1–6] and was used as one of the best immunosuppressants for the prevention of transplant rejection by inhibiting the signal transduction required for T cell activation and growth [1,2,6].
FK506 (tacrolimus) is a 23-membered macrolide antibiotic with immunosuppressive activity, which is now widely used clinically in bone marrow, liver, and kidney transplantation. However, large-scale industrial use of FK506 is limited due to its low yield. In this study, we employed a series of strategies to enhance FK506 production. First, a strong promoter gapdhp was identified in S. tsukubaensis L19 through the XylE reporter system. Then two cluster-situated regulators (CSRs), FkbN and Tcs7, were co-overexpressed under the control of gapdhp to generate strain L24, which showed significant improvement in FK506 titer from 171 mg/L to 434 mg/L. Supplementing the growth medium with alanine and isoleucine further improved production to 493 mg/L and 542 mg/L, respectively. Next, the significant components of the medium were determined by Plackett-Burman (PB) design, with optimum values of yeast extract, cottonseed meal and KH₂PO₄ found to be 15.9 g/L, 17.2 g/L, and 5.0 g/L, respectively. Using Box-Behnken (BB) design based on response surface methodology (RSM), a model was developed to predict the maximum titer with 747 mg/L. With the optimized medium, scale-up production of FK506 by strain L24 in a 5 L fermenter reached a maximum titer of 756 mg/L after 192 h fermentation.
Optimization of media and culture conditions for the production of tacrolimus by Streptomyces tsukubaensis in shake flask and fermenter level
2020, Biocatalysis and Agricultural Biotechnology
Citation Excerpt :
Owing to its high potency (around 100 time more potent than cyclosporine), tacrolimus is one of the most widely used medicines for the treatment of graft rejection (Motamedi and Shafiee, 1998). It has been used after the transplantation of allogenic kidney, heart and liver as an immunosuppressant, and also for treatment of inflammatory skin diseases, Apart from this, FK506 has been reported to show neuroprotective and neuroregenerative activities (Lin, 2010; Rath, 2013; Sierra-Paredes and Sierra-Marcuño, 2008). Food and Drug Administration (FDA), in 1994 first time approved FK506 for the treatment of liver transplanted patient (Goto et al., 1991, 1987; Kino et al., 1987; Kino and Goto, 1993; Meier-Kriesche et al., 2006).
Goal of present research based on optimization of tacrolimus production by One-factor-at-a-time method and response surface methodology (RSM) using Streptomyces tsukubaensis NBRC 108819. Plackett–Burman Design was adopted for the selection of main nutrients inducing the production of tacrolimus. Out of 19 factors studied by Plackett–Burman Design, three variables (ammonium sulphate, yeast extract and 1, 2 propylene glycol) influenced the tacrolimus production most significantly. Thus in Central Composite Design the optimum concentrations of ammonium sulphate, yeast extract and 1, 2 propylene glycol were optimized for the maximum production of tacrolimus. The optimum medium composition for tacrolimus production was glucose (4 g/L), yeast extract (14.32 g/L), 1, 2 propylene glycol (1.49%), glycine (0.2 g/L) and ammonium sulphate (30 g/L). Optimized medium by statistical approach demonstrated the significant effect on tacrolimus production and increased it production from 205 ± 22.0 mg/L to 604 ± 54.6 mg/L in comparison to basal media. In addition optimized conditions were also used at bioreactor level to scale up the fermentation process in which tacrolimus production was attained 616 ± 52.2 mg/L after 168 h fermentation.
Topical Calcineurin Inhibitors
2020, Comprehensive Dermatologic Drug Therapy, Fourth Edition
With the ever-evolving landscape of pharmacotherapy and the greater understanding of various dermatological conditions, topical inhibitors play a vital role as treatment alternatives and treatment approaches of different conditions patients may experience. These nonsteroidal anti-inflammatory agents are a commonly used class for the treatment of atopic dermatitis. Unlike topical corticosteroids, these immunomodulating agents work to reduce inflammation through targeting cytokine production without affecting the collagen production of the skin and therefore avoiding atrophy of the skin. This overall benefit may serve as a valuable alternative for the treatment of inflammatory conditions in the pediatric population, in whom topical corticosteroids are not an option because of their clinical circumstances or lack of favor by caregivers. There are two types of topical calcineurin inhibitors—tacrolimus ointment (Protopic 0.03% and 0.1%) and cream (Elidel 1%), the lipophilic nature of which allows for their use as topical agents. The evidence concerning their safety is still questioned amongst health and safety regulatory boards throughout the world, with some showing concern regarding their use and others not. However, we can be confident about their efficacy and that they offer a reasonable and efficacious approach after assessing an individual's needs.
Beyond the Booth: Excimer Laser for Cutaneous Conditions
2020, Dermatologic Clinics
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Combination therapy has significantly higher rates of repigmentation in comparison to excimer laser monotherapy. Topical calcineurin inhibitors, such as tacrolimus60–63 and pimecrolimus,64 khellin 4% ointment,65 hydrocortisone 17-butyrate cream,66 and tetrahydrocurcuminoid cream,67 have demonstrated improved efficacy when used in combination with excimer laser therapy. A study combining NBUVB with excimer laser reported an increase in treatment response in patients who were previously resistant to conventional NBUVB monotherapy.68
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Periorbital erythema following alcohol ingestion during treatment with topical tacrolimus
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View all citing articles on Scopus

: Dr Lin has been a paid speaker for Astellas Pharma Canada, Inc.

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Innovative Use of Topical Calcineurin Inhibitors

Section snippets

Oral lichen planus

Vitiligo

Tacrolimus

Contact dermatitis

Seborrheic dermatitis

Rosacea

Cutaneous lupus erythematosus

Perioral dermatitis

Cutaneous Crohn disease

Tacrolimus

Morphea/scleroderma

Netherton syndrome

Tacrolimus: lack of efficacy

Pimecrolimus: lack of efficacy

Other disorders

First page preview

Oral Surg Oral Med Oral Pathol Oral Radiol Endod

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Comparative effect of tacrolimus 0.1% ointment and clobetasol 0.05% ointment in patients with oral lichen planus

J Clin Periodontol

Long-term efficacy and safety of topical tacrolimus in the management of ulcerative/erosive oral lichen planus

Eur J Dermatol

Erosive mucosal lichen planus: response to topical treatment with tacrolimus

Br J Dermatol

Treatment of chronic erosive oral lichen planus with low concentrations of topical tacrolimus: an open prospective study

Arch Dermatol

A comparison of treatment of oral lichen planus with topical tacrolimus and triamcinolone acetonide ointment

Acta Derm Venereol

Treatment of erosive oral lichen planus with topical tacrolimus

J Dermatolog Treat

Response of oral lichen planus to topical tacrolimus in 37 patients

Arch Dermatol

Pimecrolimus cream 1% in erosive oral lichen planus–a prospective randomized double-blind vehicle-controlled study

Br J Dermatol

Treatment of oral erosive lichen planus with 1% pimecrolimus cream: a double-blind, randomized, prospective trial with measurement of pimecrolimus levels in the blood

Arch Dermatol

Topical tacrolimus and the 308-nm excimer laser: a synergistic combination for the treatment of vitiligo

Arch Dermatol

Combined excimer laser and topical tacrolimus for the treatment of vitiligo: a pilot study

Dermatol Surg

A randomized, placebo-controlled, double-blind trial comparing narrowband UV-B Plus 0.1% tacrolimus ointment with narrowband UV-B plus placebo in the treatment of generalized vitiligo

Arch Dermatol

A double-blind randomized trial of 0.1% tacrolimus vs 0.05% clobetasol for the treatment of childhood vitiligo

Arch Dermatol

Response of vitiligo to once- vs. twice-daily topical tacrolimus: a controlled prospective, randomized, observer-blinded trial

J Eur Acad Dermatol Venereol

Narrow-band UVB phototherapy combined with tacrolimus ointment in vitiligo: a review of 110 patients

J Eur Acad Dermatol Venereol

Lack of efficacy of tacrolimus in the treatment of vitiligo in the absence of UV-B exposure

Arch Dermatol

Efficacy and safety of tacrolimus cream 0.1% in the treatment of vitiligo

Int J Dermatol

Occlusive treatment enhances efficacy of tacrolimus 0.1% ointment in adult patients with vitiligo: results of a placebo-controlled 12-month prospective study

Acta Derm Venereol

Tacrolimus ointment 0.1% produces repigmentation in patients with vitiligo: results of a prospective patient series

Cutis

Topical tacrolimus for treatment of childhood vitiligo in Asians

Clin Exp Dermatol

Topical immunomodulators are effective for treatment of vitiligo

J Dermatol

The efficacy of pimecrolimus 1% cream plus narrow-band ultraviolet B in the treatment of vitiligo: a double-blind, placebo-controlled clinical trial

J Dermatolog Treat

Efficacy and safety of pimecrolimus (ASM 981) 1% in the treatment of vitiligo