Evaluation of Cyclosporine for the Treatment of DRESS Syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening hypersensitivity reaction characterized by skin eruption, fever, hematologic abnormalities, and multiorgan involvement. If unrecognized, this condition may be fatal, with a mortality rate of up to 10%.¹ Treatment involves discontinuation of treatment with the culprit drug, supportive care, and in severe eruptions with end-organ dysfunction, systemic immunosuppression with glucocorticoids. However, patients with contraindications to glucocorticoids may benefit from treatment with cyclosporine, a calcineurin inhibitor with anti-apoptotic effects on cytotoxic T cells. Cyclosporine also inhibits production of interleukin-5, which generates eosinophilia and drug-specific T cells that mediate DRESS.² While cyclosporine represents an alternative treatment for DRESS, little is known about its utility.^3,4

This was a retrospective case-control study of adult patients admitted to Massachusetts General Hospital or Brigham and Women’s Hospital from January 1, 2008, to May 1, 2019, with DRESS diagnosed by dermatology consultation. Patients with a European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) score greater than 5 were included (scores of 0-2, no case of DRESS, scores 2-3, possible case of DRESS, scores 4-5, probable case of DRESS, and scores greater than 5, definite case of DRESS). Dermatology consultation and progress notes were reviewed by one of us (E.D.N.) to identify cases treated with intravenous or oral cyclosporine (3-5 mg/kg divided twice daily for 7 days, tapered to 1.5-2.5 mg/kg divided twice daily for 7 days) and 4 age- and sex-matched controls treated with intravenous methylprednisolone, 1 to 2 mg/kg daily, with variable prednisone taper dose. Primary outcomes assessed include time to halted progression of eruption (defined by cessation of eruption worsening) and improvement and resolution of erythema and laboratory abnormalities. Secondary outcomes include hospitalization duration. The study was approved by the Partners Healthcare institutional review board with a waiver of informed patient consent owing to the use of deidentified data from the electronic medical records database. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for case-control studies.

The data from 5 patients treated with cyclosporine and 21 patients who received systemic glucocorticoids were analyzed (female, 69.2% [n = 18]; mean [SD] age, 43 [13.1] in the cyclosporine group and 44.5 [16.6] in the corticosteroid group) (Table 1). The use of systemic steroids in 3 patients was contraindicated; 2 patients had a history of steroid-induced psychosis, and 1 patient had diabetes. One patient began treatment with cyclosporine because of development of mucosal lesions. Mean (SD) treatment duration with cyclosporine was 12.5 days (4.0), whereas patients received treatment with systemic steroids for a mean (SD) of 48.5 days (53.0).

Cyclosporine treatment was associated with cessation of the eruption within 2 days (Table 2). Time from treatment initiation to cessation of progression was shorter in the cyclosporine group compared with the corticosteroid group (mean [SD] 2.0 [1.2] days vs 2.76 [2.34] days, respectively). Time from treatment initiation to resolution of erythema was shorter in the cyclosporine group compared with the corticosteroid group (mean [SD] 3.5 [2.4] days vs 5.5 [3.7] days, respectively). Cyclosporine treatment resulted in shorter duration of hospitalization compared with systemic corticosteroid treatment (mean [SD] 8.1 [5.0] days vs 16.2 [9.7] days, respectively). Normalization of fevers occurred more rapidly in patients treated with cyclosporine than patients treated with corticosteroids (mean [SD] 3.0 [1.6] days vs 4.1 [1.9] days), as did normalization of leukocytosis (mean [SD] 8.2 [3.8] days vs 13.2 [7.9] days), eosinophilia (mean [SD] 6.0 [2.1] days vs 7.3 [5.9] days), and hepatocellular markers (mean [SD] 11.7 [3.2] days vs 13.4 [11.0] days). Most patients tolerated the systemic medications well; 8 (38.1%) patients in the control group experienced eruption recrudescence on prednisone taper, requiring dosage escalation.

This study provides additional evidence that cyclosporine may be an effective treatment for DRESS. Cyclosporine was associated with reduced disease progression and improved findings in clinical and laboratory markers compared with steroids and with a shorter length of hospital stay. Notably, culprit drugs (ACE-inhibitors, calcium-channel blockers) in patients treated with cyclosporine are uncommonly reported to be associated with severe DRESS. Longer exposure to systemic corticosteroids may be associated with adverse effects. Furthermore, immunosuppression from steroids may be associated with viral reactivation and with a steroid-dependent variant of DRESS.⁵ In contrast, cyclosporine treatment of a cohort of patients with psoriatic arthritis with viral seropositivity was not associated with reactivation.⁶ In this cohort, cyclosporine was used for a shorter window and was not associated with relapse. Despite initial improvement in all cyclosporine patients, 2 patients discontinued therapy from adverse effects, which were reversible on discontinuation. These findings suggest cyclosporine performs no worse than systemic steroids and may indicate a role for cyclosporine as monotherapy in DRESS.

Limitations of this study include small sample size and data stemming from 2 academic institutions. Other limitations include variable dose of corticosteroids and the retrospective nature of the study.

Systemic agents should be selected with consideration of the disease severity and patient comorbidities. These findings require further assessment by a randomized clinical trial.

Accepted for Publication: January 2, 2020.

Corresponding Author: Daniela Kroshinsky, MD, MPH, Department of Dermatology, Massachusetts General Hospital, 50 Staniford St, 2nd Floor, Boston, MA 02114 (dkroshinsky@mgh.harvard.edu).

Published Online: March 11, 2020. doi:10.1001/jamadermatol.2020.0048

Author Contributions: Ms Nguyen and Dr Kroshinsky had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Nguyen, Yanes, Kroshinsky.

Drafting of the manuscript: Nguyen.

Critical revision of the manuscript for important intellectual content: Yanes, Imadojemu, Kroshinsky.

Statistical analysis: Nguyen, Imadojemu.

Administrative, technical, or material support: Yanes, Kroshinsky.

Supervision: Imadojemu, Kroshinsky.

Conflict of Interest Disclosures: None reported.

Meeting Presentation: This paper was presented at the 77th annual meeting of the Society of Investigative Dermatology; May 9, 2019; Chicago, Illinois.