Treatment Outcomes of Immune-Related Cutaneous Adverse Events

Abstract

Purpose: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics.

Methods: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed.

Results: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype (P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043).

Conclusion: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.

FIG 1.

Clinical manifestation of immune-related cutaneous adverse events before (left) and after (right) treatment. (A) Patient with melanoma receiving ipilimumab plus nivolumab with grade 3 maculopapular rash managed with oral prednisone. (B) Patient with lymphoma receiving chemotherapy plus atezolizumab with grade 2 psoriasiform rash treated with ustekinumab. (C) Patient with melanoma receiving nivolumab with grade 3 bullous pemphigoid-like eruption treated with rituximab. (D) Patient with renal-cell carcinoma on nivolumab with grade 3 eczematous rash and pruritus managed with dupilumab.

FIG 2.

Immune checkpoint inhibitor (ICI) type and associated immune-related cutaneous adverse event (ircAE) phenotypes. Bar height represents the proportion of ircAEs of specified phenotype attributable to either anti–cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with or without anti–programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) or anti–PD-1/PD-L1 monotherapy. Values within columns reflect the absolute frequency of ircAE attributable to ICI therapy. MPR, maculopapular rash.

FIG 3.

Time to presentation to dermatology and resolution of immune-related cutaneous adverse events (ircAEs). Boxes represent interquartile range (IQR; Q1, Q3), central vertical line indicates median, outer vertical lines indicate range or Q3 + (1.5 × IQR) for subsets with outliers, and text indicates range inclusive of outliers (minimum to maximum [min-max]). (A) For time to presentation, number indicates ircAE frequency. (B) For time to resolution, number indicates ircAEs that resolved. IM, systemic immunomodulator; min-max, minimum-maximum; MPR, maculopapular rash.

FIG 4.

Immune-related cutaneous adverse event (ircAE) management and outcomes. Bars depict the frequency of ircAEs managed within a particular treatment category, and bar color corresponds to outcome category (no improvement, moderate improvement, significant improvement). Percentages after bars reflect ircAE response rate to therapy—rate of moderate or significant improvement—within the particular treatment category. Significant improvement = improvement by 2 Common Terminology Criteria for Adverse Events grades or resolution of ircAE; moderate improvement = improvement by 1 grade; no improvement = no change or increase in grade. Other ircAE phenotypes include eczematous rash, acneiform rash, urticarial rash, vitiligo, alopecia, xerosis, erythema multiforme, Stevens-Johnson syndrome, folliculitis, Grover disease, granulomatous dermatitis, dyshidrotic eczema, lichen sclerosis, mucositis, and panniculitis. Topicals refers to topical corticosteroid use alone. Oral antipruritics include antihistamines, pregabalin, gabapentin, and aprepitant with and without the use of topical corticosteroids. Systemic immunomodulators (IMs) include oral corticosteroids, methotrexate, cyclosporine, mycophenolate mofetil, apremilast, and biologic agents (eg, rituximab) with and without the use of topical corticosteroids or oral antipruritics. (*) Outcome distribution significantly associated with ircAE treatment category (Pearson χ², overall, P < .001; pruritus, P = .03; lichenoid, P = .02). MPR, maculopapular rash.

FIG 5.

Proposed algorithm for the management of immune-related cutaneous adverse events. ICI, immune checkpoint inhibitor; IgE, immunoglobulin E; IL-6, interleukin-6; MPR, maculopapular rash; NB-UVB, narrowband UV B; OTC, over the counter.