Evaluation of Methotrexate in the Management of Sweet Syndrome

Sweet syndrome is a rare cutaneous condition that is associated with infections, hematologic dyscrasias, medication exposures, pregnancy, and autoimmune diseases. ¹ Although systemic corticosteroids (SCSs) are typically effective, they are associated with potent side effects and may not be warranted for mild cases. ¹ Alternative options include dapsone, colchicine, and potassium iodide; however, non-steroidal treatment of Sweet syndrome lacks extensive study. ² Methotrexate (MTX) can be helpful in managing inflammatory conditions associated with Sweet syndrome, and in our experience, MTX is usually favored by oncologists for patients with histories of cancer. Evidence to support MTX for Sweet syndrome is limited to a case report. ³ We assess MTX in 13 Sweet syndrome patients.

Upon Institutional Review Board approval, a retrospective chart review of patients from Wake Forest Baptist Health who received MTX for Sweet syndrome between 2013 and 2020 was performed. Diagnoses were established based on clinicopathologic correlation using diagnostic criteria that include abrupt onset of lesions with biopsies demonstrating dense neutrophilic infiltrates. Patients without follow-up were excluded. Outcomes were classified as: complete clearance (absence of lesions, asymptomatic), partial response (symptomatic relief with fewer lesions, less erythema), no response.

Our patients were primarily White (85%) females (77%) with mean age 56 ± 10 years (Supplemental Table 1). They presented with several associated conditions (most commonly inflammatory bowel disease [3/13, 23%]), temporally related medication exposures (non-steroidal anti-inflammatory drugs [3/13, 23%], adalimumab [2/13, 15%], clindamycin [1/13, 8%], gabapentin [1/13, 8%]), preceding respiratory tract infections (6/13, 46%), and malignancies (chronic lymphocytic leukemia (1/13, 8%) [treated with fludarabine, cyclophosphamide, rituximab], primary myelofibrosis (1/13, 8%) [treated with ruxolitinib]). ¹ Most patients (62%) presented with fevers (>100.4 degrees Fahrenheit). Disease existed a median 2 months before MTX commencement (median weekly dose 12.5 mg, median duration 6 months). SCSs were unfavorable in patients with hypertension (46%), hypercholesterolemia (38%), diabetes (23%), osteoporosis (15%).

Ten (77%) patients improved and eight (62%) completely cleared with MTX. Initial responses (median 1.5 months) occurred slightly slower than both SCSs (0.25, 0.5 months) and dapsone for Sweet syndrome (1 month). ^4,5 While eight patients initiated MTX with concomitant prednisone, all MTX responders tapered off prednisone within a median 1.5 months, and most responders either continued to improve (4 subsequently completely cleared) or maintained their responses (2) after tapering. Three responders flared (2 during MTX therapy [simultaneously with Crohn’s flares], one 14 months after MTX cessation). Responders were evaluated for flares over a median follow-up period (time from initial response to last follow-up evaluation) of 20.2 months (range 4.1 – 65 months).

Non-responders (3) trialed MTX for shorter durations than responders (median 1 vs 7.5 months) due to treatment-limiting side effects (2 pancytopenia, 1 gastrointestinal upset). One non-responder had chronic lymphocytic leukemia; malignancy-induced cases tend to be recalcitrant and may not resolve even with therapies targeted at the underlying disorder. ²

This study is limited by sample size and the overlapping use of corticosteroids in some patients. The characteristic relapsing-remitting course of Sweet syndrome can furthermore make outcomes difficult to interpret. However, it appears MTX may be an effective alternative to corticosteroids in many patients.