Erythrokeratodermas

Management Strategy

Erythrokeratodermas (EK) are heritable, chronic disorders that often require lifelong treatment. Management depends on the location, severity, and extent of hyperkeratosis, which may vary over time and from patient to patient. The spectrum may range from fixed hyperkeratotic plaques over the knees and elbows to generalized hyperkeratosis with accentuated skin markings and peeling, or thickened plates with a spiny, hystrix-like appearance. Palmoplantar keratoderma (PPK) is a common feature and often debilitating due to pain from fissures, deep cracks, or digital ischemia when circular constriction bands form, and can limit ambulation and working with the hands.

The topical management of EK remains a therapeutic cornerstone, although it can be disappointing in some cases. Topical treatment of mild, localized hyperkeratosis is symptomatic and focuses on hydration , lubrication, and keratolysis. Whereas, in some patients, emollients such as petrolatum twice daily may suffice, most patients require topical treatment with keratolytic agents . Lactic acid (6%–12%) and urea applied once or twice daily in combination with emollients are effective, although their use may be limited, especially in children, because of irritation. Other α-hydroxy acids, salicylic acid (2%–6%), propylene glycol, glycolic acid, vitamin D analogs (calcipotriol), or combinations of these are alternative treatment options. Topical treatment with retinoids and derivatives has been successful in some patients (especially with EKVP) but ineffective in others. Regimens with synthetic retinoids, such as short-contact topical tazarotene therapy combined with moisturizers, seem promising in EKVP. PPK may also benefit from soaking, mechanical removal, or surgical parings of excessive hyperkeratosis. In addition, avoidance of trauma to the skin, such as sudden temperature changes, friction, and mechanical irritation, may be beneficial.

Systemic retinoids are the treatment of choice in EK with extensive or generalized skin involvement. Although highly effective in EKVP, the therapeutic response in other EKs is less satisfactory and consistent, especially in Olmsted syndrome. The effects of acitretin or etretinate are superior to those of systemic isotretinoin. It seems advantageous to start at low doses of acitretin for 3–6 weeks and then to gradually increase the dose until the desired therapeutic effect is achieved. The minimal effective maintenance dose for EKVP is usually lower than for patients with other forms of EK or ichthyosis. Both morphologic components respond well to retinoid treatment, resulting in rapid, dramatic improvement or clearing of hyperkeratosis and significant moderation or resolution of erythema. Nevertheless, using retinoids should always be considered carefully, as chronic therapy is required for continuing results, and long-term side effects, especially in children, may ensue. Intermittent cycles of systemic retinoid treatment may be considered to balance between beneficial therapeutic and adverse effects.

In contrast to EKVP, topical and systemic treatment of Olmsted syndrome is challenging. Oral retinoids (acitretin, etretinate), corticosteroids, methotrexate, or surgical parings achieve only poor-to-moderate relief. Anecdotal s ystemic rapamycin (sirolimus), an mTOR pathway inhibitor, was effective in a few patients, reducing erythema, periorificial hyperkeratotic plaques, and pain, while PPK showed modest or no improvements. Pain medications (opioids, topical lidocaine, cold applications) were temporarily effective in managing chronic pain. One adult and two case series totaling seven children with Olmsted syndrome due to TRPV3 mutations demonstrated rapid response and sustained improvement of debilitating PPK, flexural contractions, pruritus, pain, and other associated symptoms with oral EGFR tyrosine kinase inhibitor erlotinib hydrochloride . This treatment approach is based on a gain-of-function effect of pathogenic TRPV3 variants, which in vitro and in transgenic mice leads to augmented activation of transient receptor potential cation channels in keratinocytes and may induce transactivation of EGFR with activation of the downstream mTOR pathway. No significant adverse effects have been reported; moderate hair loss and other minor side effects were tolerable or manageable with dose adjustments. Nevertheless, long-term treatment with EGFR inhibitors might be necessary in these patients, and requires careful monitoring and dose adjustments based on tolerability and side effects.

Anecdotally, PUVA therapy alone or combined with acitretin (Re-PUVA) has been beneficial in the treatment of PSEK, while narrowband UVB (NB-UVB) therapy has been effective for a patient with EKVP. Few patients have been reported with clearing of skin lesions under oral treatment with low-dose vitamin A or a polyaromatic retinoid (arotinoid ethylester).

The variable erythema in EKVP or residual periorificial lesions in Olmsted syndrome and KSDR -related PSEK often result in cosmetic concerns, which can be limited by masking uncovered skin with makeup and camouflage. Serious discomfort due to burning and pruritus at erythematous lesions can be therapeutically challenging. If systemic aromatic retinoid therapy alone fails to reduce or suppress erythema and the associated burning and itching sensations, symptomatic relief has been achieved in anecdotal cases with systemic therapy using sedating H ₁ -antihistamines.