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Sweet syndrome (acute febrile neutrophilic dermatosis): Management and prognosis

Sweet syndrome (acute febrile neutrophilic dermatosis): Management and prognosis
Literature review current through: Jan 2024.
This topic last updated: Aug 15, 2022.

INTRODUCTION — Sweet syndrome (acute febrile neutrophilic dermatosis) is a neutrophilic dermatosis characterized by the abrupt appearance of edematous and erythematous papules, plaques, or nodules on the skin. Fever, leukocytosis, and internal organ involvement can also occur. Sweet syndrome has been associated with infection, malignancy, pregnancy, and drug exposure. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

Systemic glucocorticoid therapy is a first-line treatment for Sweet syndrome, and usually results in dramatic clinical improvement. Colchicine, dapsone, and potassium iodide are additional effective therapies.

The management and prognosis of Sweet syndrome will be discussed here. Information on the clinical features and diagnosis of Sweet syndrome and an overview of other neutrophilic dermatoses are available separately. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis" and "Neutrophilic dermatoses".)

APPROACH TO TREATMENT — Although a wide variety of therapeutic interventions have been utilized for Sweet syndrome, there is a paucity of high-quality data on the treatment options. Support for the use of therapies for Sweet syndrome is primarily based on case series and individual reports of clinical experience. Systemic therapies, particularly systemic glucocorticoids, are the mainstays of treatment [1-3].

Although spontaneous resolution after weeks to months occurs in an unknown proportion of patients with classical Sweet syndrome, the prominent symptoms and the unpredictable disease course lead us to initiate treatment in most patients. In addition, although our experience indicates that drug-induced Sweet syndrome can improve within several weeks after withdrawal of an offending medication, we have found pharmacologic therapy useful for accelerating clinical improvement in these patients [4].

While malignancy-associated Sweet syndrome has resolved following treatment of an underlying cancer [5], the frequency with which this occurs is unknown. Thus, we typically proceed with the treatment of Sweet syndrome in patients with malignancy-associated disease.

Sweet syndrome can be managed on an outpatient basis. However, because the signs and symptoms of Sweet syndrome can closely resemble serious infection, patients are often hospitalized for evaluation prior to diagnosis. Outpatient management is appropriate once the diagnosis of Sweet syndrome has been made, provided internal organ involvement that requires inpatient management is not present. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on 'Extracutaneous disease'.)

FIRST-LINE THERAPIES — Corticosteroid therapy is considered first-line treatment for Sweet syndrome on the basis of clinical experience that indicates a consistent and rapid response of Sweet syndrome to this intervention. Most patients require systemic therapy to achieve disease control. However, patients who present with a few, localized skin lesions (eg, less than 5 percent body surface area) and without systemic symptoms may respond well to local corticosteroid therapy.

Local therapy may also be used as an adjunct to systemic glucocorticoids or other systemic agents in patients with widespread cutaneous lesions. This is often done in an attempt to reduce dependence on systemic drugs and accelerate lesion healing. The efficacy of such combination therapy has not been formally studied. Our experience suggests that combination therapy is useful.

Systemic glucocorticoids — The rapid and dramatic response of Sweet syndrome to systemic glucocorticoids documented in multiple case reports and case series supports their status as the treatment of choice for Sweet syndrome [2,4,6-9]. The high likelihood of treatment success is reflected in the inclusion of the response to systemic glucocorticoids in the diagnostic criteria (table 1) (see "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic criteria'). Systemic glucocorticoids are effective for both the cutaneous and extracutaneous manifestations of Sweet syndrome.

In adults, we typically begin treatment with oral prednisone at a dose of 0.5 to 1 mg/kg per day. Symptoms often begin to improve within 48 hours and skin lesions usually resolve within one to two weeks [4,7]. Once disease control is attained, we attempt to taper and discontinue prednisone over the course of four to six weeks [4].

In some patients, disease recurs when the dose of prednisone is reduced, thereby inhibiting the tapering and cessation of therapy. Prednisone at the lowest effective dose (often around 10 mg per day; typical range 5 to 20 mg per day) may be continued for an additional two to three months in these patients. Treatment with an alternative systemic first-line agent can also be initiated as a glucocorticoid-sparing agent. (See 'Alternative first-line therapies' below.)

Systemic glucocorticoid therapy, though usually highly effective, is associated with a risk for multiple adverse effects. The risks of systemic glucocorticoid therapy are discussed in greater detail separately. In patients who receive long-term systemic glucocorticoids, measures to protect against osteoporosis are indicated. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Topical and intralesional corticosteroids — Case reports and retrospective studies support the efficacy of local therapy alone in some patients with limited disease [4,6,10]. High potency topical corticosteroids (eg, clobetasol 0.05% ointment) and intralesional corticosteroid injections are utilized (table 2) [6,10]. The comparative efficacy of topical and intralesional administration has not been evaluated. In our experience, intralesional therapy has been useful for thick plaques on the trunk or extremity that do not completely respond to topical therapy.

Topical corticosteroids are usually applied twice daily to the affected area for two to three weeks. The use of occlusion may accelerate the response to therapy.

For intralesional injection, we utilize triamcinolone acetonide in a concentration between 3 and 10 mg/mL. A dose close to the lower end of this range is preferred for thin plaques or for plaques in sites that are prone to corticosteroid-induced cutaneous atrophy, such as the face. We limit the total injected dose to 20 mg per treatment session. Lesions that respond partially can be retreated after two to four weeks. Patients who fail to respond sufficiently to local therapy are treated with systemic agents.

Potential adverse effects of local corticosteroid therapy include cutaneous atrophy and pigmentary alteration. The adverse effects of topical and intralesional corticosteroids are reviewed in greater detail separately. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects' and "Intralesional corticosteroid injection", section on 'Adverse effects and pitfalls'.)

Alternative first-line therapies — Colchicine, dapsone, and potassium iodide are less frequently utilized for Sweet syndrome than systemic glucocorticoids. These agents are used as first-line therapies when avoidance of systemic glucocorticoid therapy is preferred due to patient comorbidities or other factors. As noted above, they can also be used as glucocorticoid-sparing agents. We typically utilize colchicine or dapsone first due to the availability and generally favorable tolerability of these agents. (See 'Systemic glucocorticoids' above.)

Colchicine — Case reports and retrospective studies support the use of colchicine in Sweet syndrome [11-14]. Similar to systemic glucocorticoids and potassium iodide, the response to treatment is rapid. In a retrospective study of 20 adults with Sweet syndrome who were treated with colchicine (1 to 1.5 mg per day) for a mean of 15 days (range 10 to 21 days), 18 patients responded to colchicine therapy [13]. Fever resolved within 24 to 72 hours, arthralgias disappeared within two to four days, and cutaneous lesions improved within two to five days. None of the 16 responders who were available for follow-up (range 2 to 10 years post-treatment) reported relapses after the discontinuation of therapy. Of note, patients with malignancy-associated Sweet syndrome were not included in this study, and relapses within 10 years after colchicine therapy were reported in another retrospective study [14].

In the United States, colchicine is available in 0.6 mg capsules or tablets. Patients are generally treated with a total of 1.2 to 1.8 mg of colchicine per day, which can be divided into one to three doses. In locations where colchicine is available in 0.5 mg pills, a total dose of 1 or 1.5 mg per day is sufficient. The drug can be discontinued upon achievement of disease control, which typically occurs within one to three weeks.

Gastrointestinal toxicity (nausea, vomiting, diarrhea) are the most frequent complications of colchicine therapy [15]. More severe adverse effects, such as myopathy, neuropathy, and marrow suppression, may occur, especially in the setting of renal insufficiency or hepatic impairment [16]. In addition, colchicine has multiple drug interactions, and concomitant therapies should be reviewed prior to treatment.

Dapsone — Dapsone is utilized in the treatment of multiple skin disorders characterized by neutrophilic infiltrates. Case reports document successful treatment of Sweet syndrome with dapsone [4,17-20]. For adults with Sweet syndrome, dapsone is typically initiated at a low dose (eg, 25 mg per day) and increased as tolerated to reach a total daily dose of 100 to 200 mg per day. Dramatic clinical improvement has been noted within one to three weeks in treated patients [18,20].

Major side effects of dapsone include hemolytic anemia, methemoglobinemia, agranulocytosis, and peripheral neuropathy. Due to the increased risk for significant drug-induced hemolytic anemia in patients with glucose-6-phosphate (G6PD) deficiency, we test for G6PD deficiency prior to the initiation of dapsone therapy. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia'.)

Potassium iodide — Case series support the efficacy of potassium iodide in Sweet syndrome in adults [6,21]. In one series, seven of eight patients treated with 300 mg of potassium iodide three times daily had a dramatic response to treatment [21]. Tenderness, arthralgias, and high fever resolved within 48 hours, and cutaneous lesions resolved within four days. Five patients, all of whom who began potassium iodide early in the course of Sweet syndrome (within four to eight days), had no relapses after completing a two-week course of treatment. Two patients did well during treatment, but relapsed after drug discontinuation. One patient did not respond to therapy.

The mechanism through which potassium iodide leads to improvement in Sweet syndrome and other neutrophilic dermatoses is not well understood. Theories include immune suppression related to potassium-iodide induced release of heparin, inhibition of neutrophil production of oxygen intermediates, or suppression of neutrophil chemotaxis [4].

In adults, potassium iodide may be prescribed as pills (300 mg three times daily) or as a 1000 mg/mL saturated solution (SSKI). The treatment regimen for the solution begins with three drops with a standard medicine dropper (20 drops/mL) three times daily in water or juice to disguise the taste. The dose of potassium iodide is 50 mg per drop, resulting in a total of 450 mg administered per day. The dose is subsequently increased by one drop at each scheduled dosing up to a total of 7 to 10 drops three times daily (1050 to 1500 mg per day) [4].

Potential adverse effects of potassium iodide include gastrointestinal distress, small bowel ulcerations (tablets), hypothyroidism, pulmonary edema, and a serious hypersensitivity reaction [15]. Sipping the medication with a straw may help to avoid drug-related tooth discoloration.

RECALCITRANT DISEASE — Clinical experience suggests that pulse glucocorticoid therapy may be effective for severe Sweet syndrome or Sweet syndrome that fails to respond sufficiently to other therapies [22-24]. In adults, intravenous methylprednisolone at doses of up to 500 to 1000 mg per day may be administered for three to five days. Treatment is followed by an oral glucocorticoid taper or another systemic immunosuppressive therapy [23,24].

In addition, oral retinoids (eg, acitretin [25], etretinate [26]), cyclosporine [27,28], methotrexate [29,30], thalidomide [31], and anakinra [32] have been successfully utilized for Sweet syndrome in patients who have failed to respond to standard therapies. Newer case reports have suggested benefit from rituximab, adalimumab, infliximab, tocilizumab, ustekinumab, and the Janus kinase (JAK) inhibitor baricitinib in refractory cases [33-37].

OTHER THERAPIES — A variety of additional treatments have been reported to be effective for Sweet syndrome in small numbers of patients [4]. In an open study in which 18 adults with Sweet syndrome were treated with 150 mg per day of indomethacin for one week followed by 100 mg per day for two weeks if initial signs of improvement were detected, 17 of 18 patients responded well to treatment [38]. Fever and arthralgias improved within two days and disease remissions occurred within two weeks. Relapses were not observed during the follow-up period (12 to 36 months). However, the development of Sweet syndrome during indomethacin treatment has been reported [17].

Other agents that have been associated with clinical improvement in Sweet syndrome in case reports include various nonsteroidal anti-inflammatory drugs, tetracyclines, clofazimine, azathioprine, and other antibiotics [4,7,22,38,39]. High-dose indomethacin appeared beneficial in a small, uncontrolled study.

CHILDREN — The initial approach to the treatment of Sweet syndrome is similar in adults and children. As in adults, Sweet syndrome in children usually responds rapidly to systemic glucocorticoid therapy. We typically begin treatment with prednisone at a dose of 1 mg/kg day in children; other authors have utilized initial doses of 2 mg/kg of prednisone per day [2,40]. Experience with other therapies for Sweet syndrome is limited, and data on the efficacy and optimal dosing of other agents considered useful for Sweet syndrome are lacking in children.

PROGNOSIS — Without treatment, the duration of Sweet syndrome is unpredictable; spontaneous resolution may occur after weeks to months [41]. The proportion of patients who achieve spontaneous resolution is unknown since no placebo controlled randomized trials have been performed in Sweet syndrome, and most patients receive treatment. In one retrospective study of 80 patients from six different dermatology departments in the United Kingdom, spontaneous resolution was documented in 16 patients who did not happen to receive treatment [10]. Another retrospective study of 48 adults with Sweet syndrome documented resolution without therapeutic intervention in three patients [42].

The cutaneous lesions of Sweet syndrome usually heal without scarring [22,41] provided ulceration has not occurred. However, postinflammatory hyperpigmentation that takes months to resolve may occur at the sites of recently healed lesions. While major involvement of internal organs can occur in Sweet syndrome, death from Sweet syndrome is rare.

Relapse may occur after the tapering or discontinuation of systemic glucocorticoids or other therapies and may be more likely to occur in patients with malignancy-associated disease (table 3). Recurrences of Sweet syndrome occur in approximately 30 percent of patients with classical Sweet syndrome [22]. The rate of recurrence may be as high as 69 percent in the setting of underlying hematologic malignancy [43,44].

SUMMARY AND RECOMMENDATIONS

Disease overview – Sweet syndrome (acute febrile neutrophilic dermatosis) is an inflammatory disorder characterized by the presence of inflammatory papules, plaques, or nodules on the skin, systemic symptoms, and neutrophilic infiltration of the skin. Sweet syndrome is often divided into three categories based on etiology: classical Sweet syndrome, malignancy-associated Sweet syndrome, and drug-induced Sweet syndrome (table 3). (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis", section on 'Classification'.)

Initial treatment for adults:

Mild disease without significant systemic symptoms – For adults who present with mild Sweet syndrome (eg, less than 5 percent body surface area involvement and absence of significant systemic symptoms), we suggest the use of high potency topical corticosteroids or intralesional corticosteroid injections as initial treatment due to the relative safety of these interventions (Grade 2C).

Extensive disease and/or systemic symptoms – For adults with more extensive involvement and/or systemic symptoms, we suggest treatment with systemic glucocorticoid therapy (Grade 2C). (See 'First-line therapies' above.)

For adults with Sweet syndrome who cannot be treated with systemic glucocorticoids due to comorbidities or other factors, we suggest treatment with colchicine or dapsone (Grade 2C). Potassium iodide is also effective. (See 'Alternative first-line therapies' above.)

Initial treatment for children – For children with Sweet syndrome, we suggest systemic glucocorticoid therapy (Grade 2C). Data on the use of alternative therapies in children are limited. (See 'Children' above.)

Refractory disease – Pulsed intravenous glucocorticoids and other immunomodulatory therapies may be effective for patients with refractory disease. (See 'Recalcitrant disease' above.)

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