Cutaneous adverse reactions to calcineurin inhibitors

What are calcineurin inhibitors?

Calcineurin inhibitors are drugs that work by inhibiting the calcium-dependent protein phosphatase calcineurin, an enzyme that results in activation of T lymphocytes through the upregulation of interleukin-2 and related cytokines, and leads to immunosuppression [1].

• The oral calcineurin inhibitors are ciclosporin and tacrolimus.
• Topical calcineurin inhibitors are tacrolimus (available as 0.03% or 0.1% ointment) and pimecrolimus (1% cream) [2,3].

What are topical calcineurin inhibitors used for?

The calcineurin inhibitors tacrolimus and pimecrolimus are indicated for the treatment of atopic dermatitis.

They are commonly used off-label in dermatology for:

• Facial, flexural, and genital psoriasis
• Seborrhoeic dermatitis
• Chronic hand dermatitis
• Contact dermatitis
• Vitiligo
• Morphoea
• Lichen sclerosus
• Cutaneous lupus erythematosus
• Oral and erosive vulval lichen planus [2,4].

Topical calcineurin inhibitors are free of many adverse effects of topical corticosteroids, such as striae, cutaneous atrophy, glaucoma, rebound flares and systemic absorption, or the potential for hypothalamic pituitary–adrenal axis (HPA) suppression.

Atopic dermatitis of the eyelid

Psoriasis of axilla

Vitiligo affecting lips and perioral skin

What are oral calcineurin inhibitors used for?

Oral calcineurin inhibitors are commonly used for immunosuppression after solid organ transplantation. Occasionally, ciclosporin and tacrolimus may also be used to treat immune-mediated diseases including psoriasis and atopic dermatitis; however, their use is mainly restricted to patients who have failed to respond to conventional therapy [3].

What are the cutaneous side effects of topical calcineurin inhibitors?

The most commonly reported side effect of topical calcineurin inhibitors is local skin irritation (burning, pruritus, and erythema) at the application site. However, this is usually transient and decreases over time (usually within one month).

Other adverse effects may include:

• Allergic contact dermatitis
• Folliculitis
• Reactivation of infection (herpes simplex and viral warts)
• Enhancement of facial flushing after alcohol ingestion
• Rosacea-like dermatitis
• Facial acne
• Molluscum contagiosum
• Tinea incognita.

There is no evidence to support the theoretical concern that topical calcineurin inhibitors may increase the risk of malignancy, such as basal cell carcinoma, cutaneous squamous cell carcinoma, melanoma and cutaneous lymphoma. Information reporting this risk is based on data from animal studies, case reports in a small number of patients, and knowledge of how these drugs work [2,4,5].

Atopic dermatitis of the eyelid

Psoriasis of axilla

Vitiligo affecting lips and perioral skin

What are the cutaneous side effects of oral calcineurin inhibitors?

The adverse effects of tacrolimus and ciclosporin are generally similar. These include:

• Gingival hyperplasia
• Hypertrichosis (this is more common with ciclosporin)
• Drug-induced alopecia (higher doses of tacrolimus and ciclosporin are associated with an increased risk of hair loss)
• Drug-induced pruritus
• Drug-induced acne
• Flushing
• Generalised hyperhidrosis
• An increased risk of cutaneous squamous cell carcinoma [1,3].

Gum hypertrophy due to ciclosporin

Hypertrichosis due to ciclosporin

A histologically confirmed, moderately well differentiated squamous cell carcinoma of the dorsal hand

What are the non-cutaneous side effects of calcineurin inhibitors?

Calcineurin inhibitors can cause a number of side effects besides the effect on the skin.

Oral calcineurin inhibitors

Oral calcineurin inhibitors can cause the following side effects:

• Nephrotoxicity (the most common adverse effect)
• Hypertension
• Neurotoxicity (tremors, severe headache, visual abnormalities, seizures, encephalopathy, and coma)
• Metabolic abnormalities (glucose intolerance, hyperlipidaemia, hyperuricaemia, hyperkalaemia, hypomagnesemia, liver dysfunction with jaundice)
• Infections (bacterial, viral, and fungal)
• Increased risk of malignancy (benign and malignant lymphoproliferative disorders)
• Gastrointestinal side effects (nausea, vomiting, diarrhoea, and abdominal discomfort) [1,3].

Topical calcineurin inhibitors

Topically applied calcineurin inhibitors do not cause significant suppression of the immune system, as less than 0.1% of the applied dose is absorbed. Large epidemiological studies have not found topical calcineurin inhibitors to be correlated with an increased risk of lymphoma or other malignancies [6].