Cutaneous adverse events in multiple sclerosis patients treated with daclizumab

Abstract

Objective: To analyze the spectrum and mechanisms of cutaneous adverse events (AEs) in patients with multiple sclerosis treated with daclizumab high-yield process (DAC-HYP).

Methods: A total of 31 participants in an institutional review board-approved open-label phase I study of DAC-HYP (NCT01143441) were prospectively evaluated over 42 months for development of cutaneous AEs. Participants provided written informed consent. Fifteen participants were naive to anti-CD25 therapy (cohort B), while 16 had received daclizumab (Zenapax; Hoffmann-La Roche) IV for 4-9 years (mean 5.8 years) prior to enrollment (cohort A). Immunohistochemistry was performed on pretreatment and posttreatment skin biopsies of normal-appearing skin (cohort B only) and on lesional biopsies in participants presenting with rash (both cohorts).

Results: Cutaneous AEs occurred in 77% of patients, the majority presenting with patches of eczema requiring no treatment. Moderate to severe rash developed in 6 participants (19%) and required discontinuation of DAC-HYP in 4 (13%). More severe rashes presented psoriasiform phenotype, but lesional biopsies lacked features of either psoriasis or drug hypersensitivity eruptions. Instead, irrespective of clinical severity, lesional biopsies showed nonspecific features of eczematous dermatitis, but with prominent CD56+ lymphocytic infiltrates. Pretreatment and posttreatment biopsies of normal-appearing skin demonstrated no histopathologic changes.

Conclusions: Observed cutaneous AEs are likely related to the immunomodulatory effects DAC-HYP exerts on innate lymphoid cells, including natural killer cells. Vigilance and timely management of skin reactions may prevent treatment discontinuation in participants with severe rash.

Figure 1. Summary of mucocutaneous events

Figure 2. Spectrum and timing of cutaneous manifestations during daclizumab high-yield process therapy

Typical eczematous patches with well-circumscribed areas of erythema with overlying scale developed at month 9 (A), month 6 (B and C), and month 10 (D). Widespread eczematous patches developed at treatment months 12 (E), 9 (F), and 33 (G), in the latter patient becoming confluent 1 month later (H). Psoriasiform nail changes developed at month 12 (I), evolving to destruction and loss of the nail plate by month 14 (J, K), followed by regrowth 6 months later (L). Facial rash with erythema and swelling of the eyelids (M, N; months 0.5 and 5, respectively) and diffuse facial erythema developed at month 30 (O). (P) Gingivitis at treatment month 10. (Q–S) Palmar erythema and desquamation at treatment month 33, month 12, and month 30, respectively.

Figure 3. Histology of skin eruptions during daclizumab high-yield process therapy

Hematoxylin & eosin sections of affected skin show inflammatory dermatitis, characterized by focal spongiosis with lymphocytic exocytosis (red arrows) and mounds of hyperparakeratosis (black arrows). (Original magnifications: A, C, D, F: ×400; B, E: ×200.)

Figure 4. Immunohistochemistry of daclizumab high-yield process skin eruptions

Biopsy from a patient with severe rash. Immunohistochemical staining of lymphocytic infiltrate reveals superficial perivascular inflammation with exocytosis (Original magnification: ×400.)

Figure 5. Biopsies from patients with rash

(A) Severe, (B, C) moderate, and (D) mild rash. Immunohistochemical staining of biopsies reveals lymphocytic superficial perivascular inflammation with exocytosis. (Original magnifications: ×200.)