Described in 1976 and individualized in 1979, 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. Family cases have been described, but in most cases, this cutaneous disorder is sporadic.
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).
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 (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, chronic lymphocytic leukemia, polycythemia vera, non-Hodgkin lymphoma), malignant tumors, ulcerative colitis, eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome), hypereosinophilic syndrome). 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.
The most interesting associations from a pathogenic point of view are certainly those belonging to the spectrum of eosinophilic diseases, such as Shulman syndrome, Churg-Strauss syndrome, and hypereosinophilic syndrome. Wells syndrome could be the first clinical manifestation of these diseases.
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.
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. 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.
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, or even subcutaneous.
Wells described the first patient in 1971 as “recurrent granulomatous dermatitis with eosinophilia.” He later renamed the disease “eosinophilic cellulitis.” 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 the 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.
Biologically, the main element is peripheral blood eosinophilia which is found in about 50% of cases during the acute phase.
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.
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 . IFN-alpha and IFN-beta could represent interesting alternatives. 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.
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.
Wells syndrome can be easily mistaken for an 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, chronic lymphocytic leukemia, polycythemia vera, non-Hodgkin lymphoma), malignant tumors, ulcerative colitis, eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome), hypereosinophilic syndrome, 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.