Are You Confident of the Diagnosis?
Wells syndrome was first described by George Wells in 1971 as a “recurrent granulomatous dermatitis with eosinophilia”; it is also known as eosinophilic cellulitis.
Characteristic findings on physical examination
The diagnosis of Wells syndrome is based on clinical presentation and histology. Clinically, Wells Syndrome usually presents on the extremities as burning or itching skin that develops into edematous plaques (Figure 1). These plaques are cool to the touch, differentiating them from lesions of cellulitis and urticaria. Individual lesions of Wells syndrome tend to resolve without scarring in 4 to 6 weeks; however, the disease course is characterized by recurrent episodes, over months to years.
Although Wells syndrome typically lacks systemic involvement, some patients can experience malaise and fever. Several clinical variants of Wells syndrome have been described: plaque-type; annular granuloma-like; urticaria-like; papulovesicular; bullous; papulonodular; and fixed drug eruption-like. The most common clinical presentation in children is plaque-type while the most common presentation in adults is annular granuloma-like.
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Figure 1.
Multiple red erythematous papules coalescing into a plaque
Expected results of diagnostic studies
Peripheral blood eosinophilia is seen in 50% of cases of Wells syndrome. Eosinophil cation protein (ECP) and IL-5 are also elevated in peripheral blood and levels may correlate with disease severity, although ECP and IL-5 are not routinely measured. Since Wells Syndrome has been associated with myeloproliferative diseases, atopy, infections, immunizations, arthropod assault and drugs, it is important to rule out any underlying association at the outset; several laboratory studies should be checked including a complete metabolic panel, complete blood count, erythrocyte sedimentation rate, serum protein electrophoresis/urine protein electrophoresis, a urinalysis and a chest x-ray.
A skin biopsy is often helpful and necessary to make and confirm the diagnosis of Wells syndrome. Histologically, Wells syndrome is characterized by a diffuse deep dermal eosinophilic infiltrate and flame figures, which are nonnecrobiotic collagen fibers coated with eosinophil major basic protein (Figure 2). Papillary edema may be present and can result in subepidermal bullae formation. Epidermal spongiosis and intraepidermal vesiculation may occur.
Figure 2.
Diffuse deep dermal eosinophilic infiltrate with periodic flame figures
Vasculitis is not present and direct immunofluorescence (DIF) is usually negative. Flame figures are not specific for Wells syndrome, and can be seen in other eosinophil-rich disorders, such as bullous pemphigoid, herpes gestationis, tinea pedis, eczema, insect bite reactions, pseudolymphoma, and persistent prurigo of unknown cause; however, the clinical presentation and DIF help to exclude these disorders.
No imaging studies are indicated.
Diagnosis confirmation
The differential diagnosis of Wells syndrome is broad and includes the following: cellulitis; erysipelas; parasitic disorders; insect bites; Lyme disease; chronic urticaria; drug eruptions; granuloma annulare; and allergic contact dermatitis. Many patients with Wells syndrome are erroneously treated for cellulitis before the correct diagnosis is made; however, lesions of Wells syndrome are cool to the touch, thus differentiating it from cellulitis.
Who is at Risk for Developing this Disease?
Wells syndrome is a rare cutaneous disorder that has no gender, age, or race predilection.
What is the Cause of the Disease?
Etiology
The etiology of Wells syndrome is unknown. However, it is thought to be a localized hypersensitivity reaction to a variety of conditions, such as myeloproliferative diseases, atopy, infections, immunizations, arthropod assault and drugs.
Pathophysiology
The pathophysiology of Wells syndrome remains unclear. It has been postulated that there may be an error in the eosinophil homing mechanism. Other authors postulate the expression of the alpha chain of the IL-2 receptor on eosinophils may play a role in eosinophil degranulation and the extent of tissue damage.
Systemic Implications and Complications
Although Wells syndrome typically lacks systemic involvement, some patients can experience malaise and fever. Again, it is imperative to rule out underlying hematologic malignancy and infection in these patients.
Treatment Options
There are many therapeutic options for treating Wells syndrome, as listed in the Table I, ranging from potent topical steroids to cyclosporine.
Table I.
| Medical Treatment | Physical Modalities |
|---|---|
| Topical | UVB (ultraviolet B) |
| Potent corticosteroids | PUVA (psoralen plus UVA) |
| Systemic | |
| Glucocorticoids | |
| Antihistamines | |
| Minocycline | |
| Griseofulvin | |
| Dapsone | |
| Cyclosporine | |
| Interferon-alpha |
Optimal Therapeutic Approach for this Disease
The choice of treatment is dependent on the extent of disease. Combinations of the above therapeutic options are often employed as responses to treatment are often incomplete. To reiterate, it is important to search for conditions associated with Wells syndrome, such as myeloproliferative diseases, atopy, infections, immunizations, arthropod assault and drugs, and treat accordingly. Since this syndrome can have a protracted course, one must balance control of disease activity with the long-term risks and side effects of different treatment modalities.
Topical and oral glucocorticoids are usually initiated first, at doses of 10-80mg of prednisone daily. Doses greater than 1mg/kg daily may be needed in severe disease. Topical steroids are usually high potency, such as fluocinonide and clobetasol (Class I and II).
Antihistamines, nonsedating as well as sedating, are also first-line treatment. Antihistamines along with minocycline, at a dose of 100mg twice daily, are often helpful in controlling disease once glucocorticoids are tapered or in patients in whom glucocorticoids are contraindicated.
Dapsone, at a dose of 100 to 200mg per day for 2 weeks or longer, has been shown to be effective in more difficult to control disease, however, this medication can be hard for patients to tolerate due to its side effects of gastrointestinal distress, anemia, leukopenia, hepatitis and cutaneous hypersensitivity.
Cyclosporine, at a dose of 1.25 or 2.5mg/kg daily for 3 to 6 weeks, and Interferon-alpha can be tried if a patient’s disease is not controlled on the previously mentioned medications.
Phototherapy, narrow band ultraviolet (UV) B preferred to broadband UVB, as well as psoralen plus UVA (PUVA), is often used as an adjuvant to the above therapeutic modalities.
Patient Management
Explain the natural history of Wells syndrome to the patient before beginning treatment. This is often a chronic condition; however, it may also spontaneously improve without any treatment in weeks, months or years.
Tell the patient that Wells syndrome is not dangerous in most cases; as such, the risks of any potential systemic treatments must be carefully weighed against potential benefit. Patients should be followed based on their level of disease activity and in accordance with the appropriate monitoring for the drug or modality they are being treated with. An endpoint to treatment is based on what the patient hopes to have accomplished, be it cosmetic and or functional/symptomatic improvement.
Unusual Clinical Scenarios to Consider in Patient Management
Although Wells syndrome is not dangerous in most cases in and of itself, it has been associated with myeloproliferative diseases, such as Hodgkin’s and non-Hodgkin’s lymphoma and rarely solid tumors, such as colon cancer (one case report). Thus, it is important to check a complete metabolic panel, complete blood count and serum protein electrophoresis/urine protein electrophoresis, urinalysis, and a chest X-ray at the time of diagnosis, as well as to make sure patients are up to date on age appropriate cancer screening. It is also important to perform a malignancy workup for any patient with a diagnosis of Wells syndrome that develops B-symptoms such as fevers, night sweats, weight loss, pruritus and decreased appetitie or lethargy, as this may signal an associated lymphoma.
What is the Evidence?
Bolognia, JL, Jorizzo, JL, Rapini, RP. Dermatology. 2008. pp. 406-8. (A review of the history, epidemiology, pathogenesis, clinical presentation, histopathology, differential diagnosis and treatment of Wells syndrome.)
Chung, CL, Cusack, CA. “Wells syndrome: An enigmatic and therapeutically challenging disease”. J Drugs Dermatol. vol. 5. 2006. pp. 908-11. (A case report of Wells syndrome followed by a description of its pathogenesis, clinical and histological presentation, and treatment.)
Caputo, R, Marzano, AV, Vezzoli, P, Lunardon, L. “Wells syndrome in adults and children: A report of 19 cases”. Arch Dermatol. vol. 142. 2006. pp. 1157-61. (A retrospective medical record review of 19 patients with Wells syndrome that addresses the clinical presentation, clinical course, and response to treatment of patients with Wells syndrome. The article describes seven clinical variants of Wells syndrome.)
Moossavi, M, Mehregan, DR. “Wells’ syndrome: A clinical and histopathologic review of seven cases”. Int J Dermatol. vol. 42. 2003. pp. 62-7. (A review of Wells syndrome based on case presentations of seven patients with Wells syndrome.)
James, WD, Berger, TG, Elston, DM. Andrews’ diseases of the skin: Clinical dermatology. 2006. pp. 144(A review of the history, epidemiology, pathogenesis, clinical presentation, histopathology, differential diagnosis, and treatment of Wells syndrome.)
Wolverton, SE. Comprehensive dermatologic drug therapy. 2007. pp. 247(An in-depth reference of medications used in dermatology.)
Marks, R. “Eosinophilic cellulitis – a response to treatment with dapsone: case report”. Aust J Derm. vol. 21. 1980. pp. 10-12. (A case report of a 26-year-old-woman with an 18-month history of Wells syndrome treated successfully with dapsone 200mg per day for 2 weeks. The patient experienced a recurrence after cessation of treatment and was again successfully treated with dapsone, this time at 100mg daily for 2 weeks. The patient’s Wells syndrome did not recur after her second course of dapsone.)
Herr, H, Koh, JK. “Eosinophilic cellulitis (Well’s syndrome) successfully treated with low-dose cyclosporine”. J Korean Med Sci. vol. 16. 2001. pp. 664-8. (Two case reports of eosinophilic cellulitis that responded completely to low-dose cyclosporine.)
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