Continuing Education Activity

Wells syndrome is characterized by sudden onset of large, inflamed, edematous patches that are often covered with vesicles or bullae; typically, the eruption is preceded by sensations of itching or burning. The lesions may or may not be associated with a low fever, and lesions are preferentially located on the trunk and the extremities. In the days following the initial eruption, the lesions evolve, demonstrating an extension of the patches, which take an annular configuration, with the center healing while the border becomes purple. Inflammatory signs regress within about 10 days while the plaques become indurated and patients typically recover completely and skin appears normal within 4 to 6 weeks. Recurrence is the rule, with variable locations, and the period between recurrences varies from months to several years; however, the prognosis remains good with long-term recovery. This activity reviews the evaluation of Wells syndrome and addresses the role of the interprofessional team in managing this condition.

Objectives:

• Explain the pathophysiology of Wells syndrome.
• Describe the presentation of Wells syndrome.
• Summarize the treatment of Wells syndrome.
• Articulate the role of an interprofessional team in evaluating and improving care for patients with Wells syndrome.

Introduction

Described in 1971, Wells syndrome is a rare dermatosis of unknown etiology. It is characterized by a benign but recurrent evolution. Wells syndrome is mainly observed in adults but can occur at any age.[1][2][3] Family cases have been described, but in most cases, this cutaneous disorder is sporadic.

Etiology

The pathogenesis of Wells syndrome is unknown. It may be explained as an inappropriate eosinophilic reaction to a wide variety of stimuli due to an abnormal function of eosinophil regulatory systems. Many triggering factors have been proposed: insect bites, drugs, allergic contact dermatitis, an underlying myeloproliferative disorder, and infections (e.g., dermatophytes, viruses, Toxocara canis).

Epidemiology

Wells syndrome is a rare dermatosis with fewer than 200 cases published in the literature. It is mainly observed in adults but also in children.[1][3]

Pathophysiology

The pathogenesis of Wells syndrome is obscure. Many triggering factors have been reported including insect bites, viral infections (parvovirus B19, herpes simplex virus, varicella-zoster virus, mumps virus), parasitic infections[4] (Ascaris, Toxocara canis, Giardia), bacterial or fungal infections, drugs (antibiotics, non-steroidal anti-inflammatory drugs, thiazide diuretics, anti-TNF, biomedicines) and vaccines. Association of Wells syndrome with other diseases has also been described such as hematologic malignancies (chronic myeloid leukemia,[5] chronic lymphocytic leukemia, polycythemia vera, non-Hodgkin lymphoma), malignant tumors, ulcerative colitis,[6] eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome),[7] hypereosinophilic syndrome[8]). Wells syndrome may be prior, revealing, or concomitant to these diseases. The fortuitous nature of some of these situations cannot be ruled out, but one must remain vigilant in case of prolonged evolution beyond 6 months, persistent eosinophilia, and/or systemic manifestations associated with Wells syndrome.[9]

The most interesting associations from a pathogenic point of view are certainly those belonging to the spectrum of eosinophilic diseases,[10] such as Shulman syndrome, Churg-Strauss syndrome, and hypereosinophilic syndrome. Wells syndrome could be the first clinical manifestation of these diseases.[7][8][11]

The physiopathogenic links between the triggering factors and the associations mentioned above are not clearly established. Inappropriate activation of a Th2-like T lymphocyte clone, synthesizing IL-5, and other eosinophil-stimulating cytokines in response to various, often unidentified, antigenic stimuli is the commonly accepted assumption.

Histopathology

The histological images vary according to the progressive stage of the lesions. Initially, significant edema and a dermal infiltrate of eosinophils are seen. Some of the eosinophils are degranulated. The sub-acute stage is characterized by images called “flame-figures,” located in the mid to deep dermis. The flame-figures are composed of a central part consisting of collagen fibers and eosinophilic granules, surrounded by a histiocytic and eosinophilic infiltrate.[12] Subsequently, eosinophils tend to disappear and are replaced by phagocytic granulomas, consisting of histiocytes and sometimes giant cells, around the flame figures. The absence of vasculitis is an important negative sign.

The flame-figures are not specific to Wells syndrome and can be observed in many other skin conditions in which degranulation of eosinophils occurs including prurigo, eczema, arthropod bite, scabies, bullous pemphigoid, pemphigus vegetans, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

The study in electron microscopy shows many eosinophils in degranulation, expressing signs of membrane cytolysis. Intact or fragmented free granules are seen in the dermis around the collagen fibers, thus forming the flame figures.[13]

The diversity of clinical aspects of Wells syndrome is probably explained by the level of eosinophilic infiltrate, which may be dermic (superficial or deep), hypodermic thus giving an image of eosinophilic panniculitis,[14] or even subcutaneous.[15]

History and Physical

Wells described the first patient in 1971 as “recurrent granulomatous dermatitis with eosinophilia.” He later renamed the disease “eosinophilic cellulitis.”[1] In 1979, Spiegel and Winkelmann proposed the eponym "Wells syndrome."

Wells syndrome has a sudden onset. In the classic form, symptomatology is marked by large well limited inflammatory erythematous and edematous patches that are often covered with vesicles or bullae. The lesions are located preferentially on the trunk and the extremities. The eruption is preceded by sensations of itching or burning. General signs are rare. A low fever can be associated with cutaneous symptoms. The evolution in the following days is marked by an extension of the patches, which take an annular configuration, with the center healing while the border becomes purple. Inflammatory signs regress within approximately 10 days while the plaques become indurated. Restitutio ad integrum usually occurs in 4 to 6 weeks. Recurrence is the rule, with variable locations. The period between recurrences varies from a few months to several years; however, the prognosis remains good with long-term recovery.

Evaluation

Biologically, the main element is peripheral blood eosinophilia which is found in about 50% of cases during the acute phase.

Treatment / Management

The treatment of Wells syndrome is not codified. Apart from the etiological treatment of a triggering or associated disease, corticosteroids and dapsone are the two main treatments for Wells syndrome.

Therapeutic Agents

• Corticosteroids: It is the reference treatment for all reactional dermatoses whether neutrophilic or eosinophilic. General corticotherapy reduces the duration and importance of relapses in 10% of cases.[2] Initial doses range from 0.5 to 1 mg/kg/day, with rapid tapering. During the decrease of the treatment, it is not uncommon to observe a relapse of the lesions, which can lead, in certain cases, to a real corticosteroid dependence. Local corticosteroids represent an interesting alternative to general corticosteroids, especially in superficial forms, with inconsistent results of the order of 50%.[2] However, it should not be used in deep hypodermic or extended forms.
• Dapsone: Dapsone is an interesting therapeutic alternative to corticosteroids, with doses ranging from 50 to 200 mg daily. It would reduce the duration of relapses. The optimal duration of treatment is not clearly defined but can be several months in the absence of adverse effects requiring discontinuation of treatment. It can be used alone or in combination with other treatments, including corticosteroids. It can also serve as a relay for general corticosteroids, especially in cases of corticosteroid dependence.
• Antihistamines: Antihistamines, especially hydroxyzine if pruritus, is important and maybe tried as a first intention, because of their excellent tolerance even if their effectiveness does not seem to exceed 25% of the cases.[2] They sometimes allow the practitioner to avoid the use of general steroid treatment. The dosage varies from 50 to 100 mg/day. Hydroxyzine can be combined with other antihistamines.
• Other treatments: These are all anecdotal, with their interest being reported in only a few clinical cases.[16] Colchicine, PUVA (psoralen and ultraviolet A) therapy, interferon-alpha, cyclins [17], synthetic antimalarials, ciclosporin, and anti-TNF agents can be mentioned.[18]

Therapeutic Strategy

In most cases, general corticosteroids (10 to 80 mg daily) allow rapid healing. Tapering the dose over one month is generally well tolerated. Continued low-dose therapy with corticosteroids allows preventing recurrences. Dapsone may be prescribed as first-line treatment in low inflammatory forms. It also seems to give good results in case of corticosteroids resistance [13]. IFN-alpha and IFN-beta could represent interesting alternatives.[19][20] For mild cases, topical corticosteroids may be sufficient. Finally, the treatment of an associated disease, when it is found, is essential. It must be prescribed as a first-line treatment and can cure Wells syndrome.[21]

Differential Diagnosis

Acute bacterial cellulitis is eliminated in front of the absence of infectious context (fever, leukocytosis) and recurrent evolution. The histopathologic findings of bacteria cellulitis can also include significant edema, but neutrophils are the predominant inflammatory cell in these infections. In rare cases, clinical and histological similarities have been described with chronic erythema migratory. Eosinophilic annular erythema is also a differential diagnosis, but this entity is considered by many to be a subset of Wells syndrome.

Enhancing Healthcare Team Outcomes

Wells syndrome can be easily mistaken for acute bacterial cellulitis; therefore, first-line practitioners should be well aware of this dermatosis.

Moreover, Wells syndrome can be associated with other diseases such as hematologic malignancies (chronic myeloid leukemia,[5] chronic lymphocytic leukemia, polycythemia vera, non-Hodgkin lymphoma), malignant tumors, ulcerative colitis,[6] eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome),[7] hypereosinophilic syndrome,[8] which implies cooperation with dermatologists, hematologists, oncologists, and internists to improve patient-centered care.

Furthermore, the diagnosis of Wells syndrome is mainly based on the histological study and the identification of flame-figures, but these findings are not specific to Wells syndrome and can be observed in many other skin conditions such as prurigo, eczema, arthropod bite, scabies, bullous pemphigoid, pemphigus vegetans, and eosinophilic granulomatosis with polyangiitis. Therefore, clinicopathologic conferences are highly recommended to establish the correct diagnosis.