Topical Steroid Withdrawal (Red Skin Syndrome)

Etiology

The etiology of topical corticosteroid withdrawal remains inadequately defined, but the condition typically manifests following the application of medium-to-high-potency fluorinated topical corticosteroids belonging to class I, II, and III for more than 12 weeks. The withdrawal less frequently occurs with short-term use of topical corticosteroids or those classified as low-potency topical corticosteroids.[4] As a type of drug addiction emerging from the inappropriate, excessive use of topical corticosteroids, the reaction occurs when the topical drug is used without supervision for an extended time, without a prescription, or when applied for unrecognized indications (eg, acne vulgaris). For example, use in high potency in age groups (like children and older adults) or on unsuitable body areas like the face and scrotum is not indicated.[5] Continual topical corticosteroid use creates withdrawal or rebound symptoms when the drug is discontinued, leading the patient back to using topical corticosteroids and making discontinuing the medication difficult.[6]

Epidemiology

Topical corticosteroid withdrawal is seen more commonly in women than men and in patients older than 18.[7] Most cases involve patients using topical corticosteroids without supervision for atopic dermatitis, contact dermatitis, or dermatophytosis. The recent surge in incidence is attributed to the escalating use of topical corticosteroids on the skin. Additionally, unsupervised usage of topical corticosteroids for skin conditions, which deviates from established guidelines regarding the quantity, frequency, and duration of topical corticosteroid usage, and unscrupulous products containing corticosteroids are important causes.

Moreover, several topical corticosteroids are readily available over the counter in many parts of the world, incentivizing their use without professional observation and monitoring.[8] Patients may use them based on recommendations from friends, neighbors, and relatives, often without consulting medical professionals.[9] Additionally, a considerable portion of the population may use steroids for skin lightening. For instance, the modified Kligman formula includes mometasone, which patients may not be aware of.[10]

Pathophysiology

The pathogenesis of topical corticosteroid withdrawal involves multiple factors, including the vasoconstrictive effects of topical corticosteroids and potential barrier dysfunction, particularly in patients with atopic dermatitis. Proposed hypotheses encompass tachyphylaxis, dysregulation of glucocorticoid receptor function, and rebound vasodilation, culminating in initiating a cytokine cascade. These clinical features are frequently associated with the withdrawal of corticosteroids.[11][12] The prolonged use of systemic steroids is known to suppress the production of cortisol from the adrenal glands. Since skin also produces cortisol, the extended application of topical corticosteroids, especially in patients with barrier dysfunction, suppresses cortisol production in the skin, leading to impaired immunity and inflammatory response.[13]

One hypothesis suggests topical corticosteroids may reduce nitric oxide production, diminishing vasodilation. Consequently, upon discontinuing topical corticosteroids, the levels of nitrous oxide may rise, resulting in rebound vasodilation and erythema. This phenomenon may partially account for the characteristic bright red, confluent erythema associated with topical corticosteroid withdrawal, colloquially referred to as red skin syndrome. Furthermore, patients with atopic dermatitis might exhibit elevated baseline serum nitrous oxide levels, offering a speculative explanation for the occurrence of topical corticosteroid withdrawal in this patient population.[10]

Another plausible mechanism for topical corticosteroid withdrawal in patients with atopic dermatitis relates to barrier dysfunction. Patients with atopic dermatitis inherently have compromised skin barriers, a condition that can be exacerbated by topical corticosteroid usage and subsequent withdrawal. Notably, mouse studies have indicated that topical corticosteroid cessation leads to increased transepidermal water loss and the upregulation of inflammatory cytokines. Given the preexisting skin barrier dysfunction in patients with atopic dermatitis, the induction of a cytokine cascade may occur when discontinuing topical corticosteroids, which contributes to the development of topical corticosteroid withdrawal.[14]

Histopathology

Histological examination lacks diagnostic value for topical corticosteroid withdrawal due to the nonspecific features. In the erythematoedematous variant of topical corticosteroid withdrawal, the most frequent histopathological characteristics observed included epidermal atrophy, spongiosis, hypogranulosis, a plethora of enlarged blood vessels within the dermal layer, scant perivascular cellular accumulation, prominently enlarged sebaceous structures encircled by inflammatory cells, and collagen deterioration. In a report of 41 patients with topical corticosteroid withdrawal, 36 cases demonstrated histopathological signs indicative of persistent eczema compounded by steroid-induced rosacea-like alterations, while 5 cases exhibited solely chronic eczematous traits.[15] In contrast, the papulopustular subtype is characterized by histological features akin to rosacea, including infiltrates around hair follicles or of a granulomatous nature comprising neutrophils and lymphocytes, expanded blood vessels in the dermal region, and a breakdown of collagen fibers.[16][17]

History and Physical

The most common symptoms of topical corticosteroid withdrawal are:

• Painful skin
• Burning
• Erythema
• Desquamation, exfoliation, or the detachment of skin layers (often manifesting as flaking, shedding, or peeling, with widespread skin involvement)
• Edema
• Paresthesia
• Atrophic changes such as skin thinning and wrinkling
• Exudative, purulent papules
• Steroid-induced dermatitis
• Papules and nodules
• Pain
• Sleep disturbances
• Alopecia
• Tremors or shivering
• Overwhelming fatigue
• Mood alterations, including depression

Erythema and skin pain or burning are the 2 most consistent clinical features of topical corticosteroid withdrawal in all patients. Erythema may manifest within days to weeks after discontinuing topical corticosteroids, commonly originating from the initial eczematous site but spreading to regions not previously affected by eczema. The burning sensation and heightened pain sensitivity indicate potential neurogenic inflammation with notable similarities to erythromelalgia.[14]

Typically 2 main variants of topical corticosteroid withdrawal, including the erythematoedematous and papulopustular subtypes. The erythematoedematous subtype is frequently observed among patients with chronic atopic dermatitis and is marked by burning, redness, swelling, and scaling sensations.[18] Meanwhile, the papulopustular subtype is often seen following steroid use for cosmetic reasons or pigmentation alterations, exhibiting papules, pustules, and redness. Unlike the erythematoedematous subtype, this variant typically lacks burning, stinging, or notable swelling.[17]

Other features or signs may be observed, including:

• Red face syndrome presents as an outbreak, clinically similar to steroid-induced rosacea or iatrosacea. This condition is marked by uniform inflammatory papules and pustules in the centrofacial and periorificial (perioral and periocular) regions. The face appears fiery red, scaly, and covered with papules. Without treatment, the syndrome can lead to irreversible skin thinning and telangiectasia.
• Red sleeve sign is a rebound rash on the upper or lower extremities, stopping sharply at the border where the limb's back and front (or plantar) sides meet. The skin on palms and soles usually remains unaffected except in the most severe cases of topical corticosteroid withdrawal.
• Headlight sign refers to a clear nose and skin around the mouth amidst a red facial complexion. The redness typically halts midway through the cheek, leaving normal skin from this point to the ears.
• Elephant wrinkles are characterized by thickened skin and less elastic skin, seen on the front of the knees and outer sides of the elbows. The resolution of this condition may take several months.[19][20][21]

Other features include skin sensitivity, desquamation, exfoliation, flaking, shedding, peeling, and erythoderma. Steroid dermatitis, alopecia, purulent skin infections, and flare-ups of preexisting dermatoses like dermatophytosis, eczema or psoriasis, alopecia or excessive hair growth, and skin atrophy. Swelling around the eyelids or ankles may be seen. In more pigmented skin, alterations might involve darker or grey tones rather than the typical redness. The clinical features also tend to extend beyond the skin and lead to systemic symptoms like tremors, shivering, lymphadenopathy, overwhelming fatigue, sleep disturbances, mood alterations, and depression.[22]

Evaluation

The diagnostic criteria for topical corticosteroid withdrawal is unclear, but recent literature has identified some key features, including:

• History of prolonged and frequent use of topical steroids on the initial eruption area or face and genitalia
• History of atopy, particularly atopic dermatitis
• Previous use of oral prednisone for skin symptoms
• The rapid development of skin burning or itchiness with widespread redness (erythema) days to weeks after stopping topical steroids, along with oozing, crusting, and exfoliation

One of the primary challenges involves distinguishing between the skin reaction resulting from discontinuing topical corticosteroids and a deterioration in the underlying skin condition for which the steroids were prescribed. Patch testing is beneficial in ruling out contact dermatitis caused by topical corticosteroids, cream components, or other topically applied agents (eg, emollients). However, this could be challenging if insufficient areas of normal skin are available for testing.[12][23][24]

Treatment / Management

Topical corticosteroid withdrawal poses a challenge in clinical management due to the absence of definitive treatment protocols. Therapeutic interventions are varied and demonstrate limited evidence in reducing the duration of the withdrawal symptoms. General therapeutic approaches include the application of emollients and moisturizers coupled with adjunct modalities such as cold compresses, ice, and gabapentin to alleviate burning pain. Antihistamines and doxepin are utilized to address pruritus, while simple analgesics may mitigate the burning pain. Psychological support plays a crucial role in managing the psychosocial impact of topical corticosteroid withdrawal.

For more severe symptoms, gabapentin, phototherapy, or immunosuppressants might be recommended. Limited use of sleeping aids and anxiolytics is appropriate in certain situations.[17] Specific strategies involve the cessation of topical corticosteroids as the primary intervention, necessitating vigilant monitoring for potential rebound reactions. The method of discontinuation, abrupt cessation versus tapering, remains a matter of debate. Some advocate for a tapering dose of oral corticosteroids, while others may consider a low-potency topical corticosteroid with minimal allergenic potential. For patients with the papulopustular type of topical corticosteroid withdrawal, tetracycline antibiotics and calcineurin inhibitors have reportedly been effective. In cases of atopic dermatitis, dupilumab may be considered.[10][22][25](A1)

Differential Diagnosis

Identifying topical corticosteroid withdrawal requires a meticulous approach to differential diagnosis within dermatological conditions. Considerations involve various skin disorders presenting with similar manifestations, notably including:

• Contact dermatitis
• Atopic dermatitis
• Rosacea
• Cutaneous T-cell lymphoma
• Psoriasis
• Red scrotum syndrome

Contact dermatitis mimics topical corticosteroid withdrawal symptoms, featuring erythema, edema, and vesicles. Atopic dermatitis flares might exhibit similar signs of eczematous dermatitis, while rosacea could manifest with flushing and papulopustular lesions resembling steroid withdrawal symptoms. Cutaneous T-cell lymphoma typically presents as persistent or progressive patches, plaques, or nodules. Psoriasis may show red, scaly plaques, occasionally mistaken for symptoms akin to topical corticosteroid withdrawal.[17] Another clinical condition routinely confused with topical corticosteroid withdrawal is red scrotum syndrome. The syndrome is marked by a persistent reddening of the front part of the scrotum, which can also affect the base of the penis. The disease is characterized by symptoms such as itching, burning, and discomfort. However, the etiology might not always be steroid-induced, with most cases being idiopathic or neurological.[26] A thorough evaluation should be performed to rule out these alternate diagnoses.

Prognosis

No definitive treatments exist to distinctly shorten the resolution period for topical corticosteroid withdrawal. However, complete recovery may take anywhere between 6 to 18 months. In a minority of cases, topical corticosteroid withdrawal may present a prolonged course extending up to 5 years following cessation.[27][28][29]

Complications

Many complications may occur if topical corticosteroid withdrawal is not appropriately addressed. These include:

• Severe pruritus and sleep disturbances: Patients withdrawing from topical corticosteroids often have intense itching (pruritus), which can severely disrupt sleep.
• Tachyphylaxis: This refers to the diminished response to topical steroids over time, often seen in conditions like psoriasis and atopic dermatitis. 
• Exacerbation of original skin conditions or rebound phenomenon: Abrupt discontinuation of topical corticosteroid therapy can worsen initial skin disorders like atopic dermatitis, resulting in increased flare-ups.
• Secondary cutaneous infections: Withdrawal from these medications can compromise the skin barrier, making patients more susceptible to secondary skin infections.
• Skin atrophy: This is the most frequently occurring issue. Topical steroids cause thinning in the epidermis and dermis, leading to skin that appears lax, wrinkled, and transparent. Over time, the atrophy can result in reduced cellular layers in the skin, hypopigmentation, and visible veins.
• Striae: Striae distinct from those caused by weight gain or pregnancy can develop.
• Contact allergy: Steroid withdrawal can lead to contact hypersensitivity, which may worsen or prolong existing skin conditions.
• Rosacea: Older women may experience topical steroid-induced rosacea, marked by papules and pustules, which can worsen with withdrawal.
• Pigmentary changes: Both hyperpigmentation and hypopigmentation can occur, with the latter more noticeable in patients with Fitzpatrick skin types IV, V, or VI.[30][31][32][33][34][35]