Urticarial dermatitis

INTRODUCTION — The term "urticarial dermatitis" describes an intensely pruritic, recalcitrant skin eruption characterized by erythematous papules and plaques that resemble urticaria but last longer than 24 hours and are sometimes accompanied by eczematous lesions [1]. Histologically, urticarial dermatitis is described by most pathologists as a "dermal hypersensitivity reaction," a nonspecific reaction pattern that is seen in a broad range of skin conditions, including drug reactions, scabies, and the prodromal phase of bullous pemphigoid [2]. However, in a substantial subgroup of patients, no underlying cause can be determined, and the diagnosis of "urticarial dermatitis" is appropriate.

EPIDEMIOLOGY — The incidence and prevalence of urticarial dermatitis are unknown. It occurs most frequently in individuals older than 50 years, with a slight female predominance [3,4].

PATHOGENESIS — The etiology and pathogenesis of urticarial dermatitis are incompletely understood.

●One hypothesis is that urticarial dermatitis is a lymphocyte-mediated (type IV) hypersensitivity reaction. Clinical and histologic similarities have been noted between urticarial dermatitis and eruptions that occur in patients treated with anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies to break self-tolerance during immunotherapy for cancer [5]. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors", section on 'Pathogenesis'.)

●It has been suggested that urticarial dermatitis may represent a waning of the regulatory function of the immune system, which allows a reaction to develop against a self-antigen.

●Urticarial dermatitis may rarely be the presentation of occult malignancy [2-4,6,7].

There have been a number of reports of cutaneous eruptions following coronavirus disease 2019 (COVID-19) infection or vaccination that showed typical histopathologic features of a dermal hypersensitivity reaction [8-11]. While these reactions are histologically similar to urticarial dermatitis, they tend to be relatively short lived and are not a contraindication to future COVID-19 vaccination.

PATHOLOGY — The pathologic features of urticarial dermatitis are nonspecific and include a normal stratum corneum, mild epidermal edema with minimal spongiosis, and a superficial to mid-dermal perivascular infiltrate of lymphocytes and eosinophils with occasional neutrophils (picture 1) [2,12]. A few basal apoptotic keratinocytes are sometimes present. Similar features may be seen in a variety of skin conditions, including drug reactions, arthropod assault, viral infections, and prodromal stage of bullous pemphigoid.

CLINICAL MANIFESTATIONS — Patients with urticarial dermatitis typically present with an extremely pruritic, persistent eruption of dull red papules coalescing into plaques, associated with areas of urticated erythema, sometimes accompanied by eczematous lesions (picture 2C). In contrast with urticaria, lesions last for more than 24 hours and often for many days or weeks [1].

The eruption usually involves the trunk and extremities (picture 2A-B). The palms, soles, and face are typically spared. Lichenification and excoriation from rubbing and scratching is commonly seen in affected areas. In particular, the author has seen the trunk and proximal extremities as the most consistently involved areas. In typical cases, 5 to 10 percent of the body surface area is involved, with up to 50 percent involved in the most severe cases.

The eruption follows a chronic, relapsing course. Spontaneous regression is unusual.

DIAGNOSIS — Because the clinical and histologic features of urticarial dermatitis are nonspecific, the diagnosis is one of exclusion.

●Approach – A detailed history, including medication history, a complete physical examination, a skin biopsy, and additional testing (eg, complete blood cell count, direct immunofluorescence, skin scraping, patch testing), should be considered in the attempt to identify possible triggers and exclude other skin diseases that may present with similar clinical and pathologic features. Age-appropriate malignancy screening may be appropriate to rule out an underlying malignancy (table 1).

●Skin biopsy – In a patient with clinical findings consistent with urticarial dermatitis, the first step is a skin biopsy to confirm that neither significant spongiosis nor interface changes are prominent. At the initial visit, it is reasonable to consider performing a second biopsy for direct immunofluorescence to rule out prodromal bullous pemphigoid, as well as a scraping or polymerase chain reaction (PCR) test to rule out scabies.

●Interpretation of pathology findings

•Nonspecific findings, including mild epidermal edema with minimal spongiosis and a mild, superficial to mid-dermal, perivascular, inflammatory infiltrate (picture 1), often reported as "dermal hypersensitivity reaction," support the diagnosis of urticarial dermatitis. (See 'Pathology' above.)

•The presence of prominent spongiosis on histopathologic examination effectively rules out urticarial dermatitis and places the skin eruption in the category of eczematous dermatoses.

•The finding of significant interface change makes it more likely that a drug reaction is the trigger, while the absence of interface change makes it highly unlikely that changing the patient's medications will be helpful.

•When the biopsy result is consistent with "dermal hypersensitivity reaction," no further evaluation (beyond review of systems and confirming that age-appropriate malignancy screening is up to date) is necessary, and treatment for urticarial dermatitis is commenced.

DIFFERENTIAL DIAGNOSIS — Conditions that may present as urticarial dermatitis include:

●Prodromal bullous pemphigoid – In bullous pemphigoid, the development of bullae may be preceded by a prodromal phase characterized by intense pruritus and eczematous, papular, or urticaria-like skin lesions (picture 3) that may persist for weeks to months or, infrequently, may remain as the only manifestation of the disease. The presence of any vesicles or blisters and the histologic finding of eosinophilic spongiosis and a mid- to deep-dermal infiltrate of lymphocytes and eosinophils suggest the diagnosis of bullous pemphigoid. The diagnosis can be confirmed by a skin biopsy for direct immunofluorescence and serologic test for antibodies against the basement membrane antigens BP180 and BP230. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

●Scabies – Scabies can mimic urticarial dermatitis clinically and histologically. Clinical findings that favor scabies include an ill-defined eruption, more significant scaling, involvement of the hands and/or feet, involvement of the male genitalia, and a history of nocturnal pruritus. On histology, scabies lesions show more spongiosis and a dense inflammatory infiltrate of lymphoid cells and histiocytes, with an admixture of eosinophils and plasma cells. However, in cases in which the two entities cannot be confidently differentiated, a positive response to empiric therapy for scabies has diagnostic value. (See "Scabies: Epidemiology, clinical features, and diagnosis".)

●Drug hypersensitivity reaction – On histologic examination, the finding of significant interface dermatitis with the presence of individual necrotic keratinocytes suggests a drug reaction. A history of exposure to a high-risk medication in the previous weeks further supports the diagnosis [13]. (See "Exanthematous (maculopapular) drug eruption" and "Lichenoid drug eruption (drug-induced lichen planus)".)

●Allergic contact dermatitis – Patch testing may be helpful to confirm or exclude allergic contact dermatitis, although the histology of the two entities is typically quite distinct, with allergic contact dermatitis showing a typical spongiotic dermatitis without significant mid-dermal or deep dermal involvement. (See "Clinical features and diagnosis of allergic contact dermatitis" and "Patch testing".)

●Atopic dermatitis – On histopathology, the finding of an intact basement membrane zone may distinguish urticarial dermatitis from late-onset eczematous dermatosis [14]. However, additional studies are needed to better clarify the differences between these two entities.

MANAGEMENT

General principles — The initial challenge in the management of patients with urticarial dermatitis is in deciding when to stop looking for an underlying cause, especially reactions to medications, and initiate treatment. It is the author's experience that in most cases with typical clinical lesions and pathologic findings consistent with the diagnosis of urticarial dermatitis, it is quite uncommon to find an underlying cause, and treatment should not be withheld while ruling out other diagnoses.

In our experience, common medications that are not directly impacting immunologic activity (eg, antihypertensives, proton pump inhibitors, antidiabetic medications) are very rare as causes of urticarial dermatitis, and we only recommend trial discontinuations of medications when significant interface change (suggestive of drug reaction) is noted on the biopsy. When pursuing this approach, we focus on medications that were initiated within the 12 months prior to onset of symptoms, and we recommend a three-month discontinuation of each agent. As noted previously, medications that act directly on the immune system, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors or rituximab, are more likely culprits [15]. (See 'Pathogenesis' above.)

Urticarial dermatitis is typically refractory to treatment with topical corticosteroids, oral antihistamines, and UVB phototherapy [3,4]. Systemic corticosteroids, either oral or parenteral, are rapidly effective in reducing pruritus and skin inflammation, although recurrence is common as the dose is tapered. Other systemic immunosuppressive agents, such as mycophenolate mofetil, methotrexate, cyclosporine, and azathioprine, have been reported as effective [4,16-18].

Evidence to guide therapy is extremely limited, with one report of two patients responding to mycophenolate mofetil [17] and a larger case series of 50 patients showing that cyclosporine improved all assessed parameters (itch intensity, erythema, interference with activities of daily living, and sleep) by approximately 50 percent over a six-week period [18].

Treatment of underlying conditions — In patients in whom the etiology of urticarial dermatitis has been determined, appropriate treatment of the underlying condition should be instituted in conjunction with the symptomatic treatment discussed below. (See "Management and prognosis of bullous pemphigoid" and "Scabies: Management".)

If a drug hypersensitivity reaction is suspected (primarily based on histology showing more interface reaction than is typical for urticarial dermatitis), all medications that are not essential should be withdrawn for at least three months. (See "Exanthematous (maculopapular) drug eruption" and "Lichenoid drug eruption (drug-induced lichen planus)".)

First-line therapy — Urticarial dermatitis is typically refractory to treatment with topical corticosteroids. Systemic corticosteroids are the first-line therapy to achieve rapid relief from the unremitting pruritus.

●Prednisone is initiated at 40 mg per day. This dose is maintained for up to one week and then tapered down to 10 mg every other day or to the lowest dose that maintains symptomatic relief. Our most common regimen is 40 mg for two days, 20 mg for two days, 10 mg for two days, and then 10 mg every other day for four to eight weeks.

●Intramuscular triamcinolone acetonide given as single 40 mg intramuscular injection at intervals of 6 to 12 weeks may be an alternative to oral corticosteroids. In patients with body weight over 100 kg, 80 mg may be given. This treatment can be repeated up to three to four times.

Most patients experience a prompt recurrence of symptoms when corticosteroids are discontinued or tapered. To avoid a prolonged therapy with systemic corticosteroids, other systemic immunosuppressive agents (eg, methotrexate, mycophenolate mofetil) can be initiated prior to discontinuing corticosteroids. The author prefers low-dose methotrexate over azathioprine and mycophenolate because of its favorable side effect profile and evidence showing that it increases the activity of regulatory T cells [19,20].

After determining the lowest corticosteroid dose necessary to control symptoms, methotrexate can be initiated at a weekly dose of 10 to 15 mg in conjunction with the lowest dose of corticosteroids that controls symptoms. Corticosteroids are discontinued after four to eight weeks. If there is no relapse in the following two months, the weaning of methotrexate is initiated, with a dose reduction of 2.5 mg per week every two to three months. In case of relapse, the last effective dose is resumed.

Data on the efficacy of systemic corticosteroids and immunosuppressive agents for the treatment of urticarial dermatitis are scant. Their use is based upon limited evidence from small, observational studies and clinical experience [3,4,16,17].

Second-line therapies — For patients whose disease does not respond to methotrexate, a second-line, steroid-sparing agent (eg, mycophenolate, cyclosporine, or dupilumab) may be used.

●Mycophenolate mofetil – The author initiates mycophenolate mofetil at 30 to 40 mg/kg per day in two divided doses. Treatment is continued at the same dose for at least two months and then corticosteroids are discontinued. If symptoms do not recur in the two months following corticosteroid discontinuation, mycophenolate mofetil is tapered off. The dose can be reduced by 500 mg per day every two to three months. If there is a relapse, the last effective dose is resumed.

Based on our experience with patients who, despite prior varicella zoster vaccination, developed herpes zoster while on mycophenolate, the author initiates prophylactic therapy with 1000 mg daily of valacyclovir in all patients on mycophenolate at a daily dose of 1000 mg or greater [21]. However, this approach is controversial. Whether all patients treated with mycophenolate for urticarial dermatitis need antiviral prophylaxis has not been determined.

●Oral cyclosporine – Low-dose oral cyclosporine has been reported as an effective therapeutic option for urticarial dermatitis in a series of 50 patients [18]. Patients were started on an average dose of 3 mg/kg per day for at least two weeks. Cyclosporine was then gradually tapered over the subsequent weeks and then discontinued. No relapses were observed. In the author's experience, cyclosporine given at a dose of 3 mg/kg per day is effective in inducing a rapid improvement of symptoms. However, patients typically need treatment for 6 to 12 months before cyclosporine can be discontinued without a relapse, and the side effect profile of cyclosporine can make it difficult to maintain therapy for this long.

●Dupilumab – Dupilumab was reported as effective in six patients with pruritus and the histologic pattern of a dermal hypersensitivity reaction unresponsive to standard therapies, such as systemic corticosteroids and mycophenolate mofetil [22]. Dupilumab is an appealing treatment option because it is not immunosuppressive, does not require laboratory monitoring, and does not have any reported drug-drug interactions. However, costs may limit its off-label use. The author typically uses it only if other second-line agents are not effective, contraindicated, or led to intolerable adverse effects.

Third-line therapies — Other therapies that are occasionally used in the treatment of patients with urticarial dermatitis include azathioprine, dapsone, and continued low-dose systemic corticosteroids. However, data supporting these treatments are lacking.

Azathioprine is given at a starting dose of 2 to 2.5 mg/kg per day in patients with normal levels of thiopurine methyltransferase. Corticosteroids are discontinued after eight weeks and azathioprine subsequently tapered off with a dose reduction of 50 mg per day every two to three months, with a return to last effective dose in the case of relapse.

It is important to remember that approximately 2 percent of patients who initiate azathioprine will experience a potentially life-threatening hypersensitivity reaction in the first weeks of therapy [23]. Thus, the author only uses this agent in patients in whom urticarial dermatitis failed to respond to mycophenolate, methotrexate, and cyclosporine. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

PROGNOSIS — Data on the long-term outcomes for patients with urticarial dermatitis are lacking. It is the author's experience that most patients can discontinue treatment over a one- to two-year period.

SUMMARY AND RECOMMENDATIONS

●Definition – The term "urticarial dermatitis" describes a recalcitrant pruritic skin eruption characterized clinically by erythematous papules and plaques that resemble urticaria but last for more than 24 hours and are sometimes accompanied by eczematous lesions. Urticarial dermatitis is thought to be a lymphocyte-mediated delayed hypersensitivity reaction. (See 'Introduction' above and 'Pathogenesis' above.)

●Clinical presentation – Patients typically present with an extremely pruritic, persistent eruption of dull red papules coalescing into plaques that most often involves the trunk and proximal extremities (picture 2A, 2C). (See 'Clinical manifestations' above.)

●Diagnosis and differential diagnosis – The diagnosis is based upon clinical and histologic features. Other conditions that mimic urticarial dermatitis must be ruled out, including prodromal bullous pemphigoid, scabies, and drug hypersensitivity reactions. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Management – Urticarial dermatitis is typically refractory to treatment with topical corticosteroids. We suggest systemic corticosteroids rather than topical corticosteroids as the first-line therapy to achieve rapid relief of symptoms (Grade 2C). Treatment can be started with prednisone 40 mg for one week and then tapered down to 10 mg every other day or to the lowest dose that maintains symptom control. Other systemic immunosuppressants (eg, methotrexate, mycophenolate mofetil, cyclosporine) may be used as steroid-sparing agents. (See 'Management' above.)