Mucocutaneous adverse events to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Since the approval of ipilimumab in 2011, a total of nine ICIs have gained indications for various solid and hematologic malignancies. The expanding use of ICIs in oncology underscores the need for diagnosis and treatment expertise in immune related adverse events (irAE). Cutaneous toxicities are the earliest and most common irAE in this class of therapy. In addition to the more frequent reactions including vitiligo, lichenoid dermatitis, psoriasiform dermatitis, other less common skin toxicities including bullous dermatoses, neutrophilic dermatoses, and autoimmune dermato-rheumatologic diseases have been reported. Even though less than 3% of cutaneous irAEs (irCAEs) are classified as grade 3 or higher events, irCAEs can greatly impact quality of life. Appropriate management of irCAEs is critical to avoid unwarranted interruptions or discontinuation of lifesaving immunotherapy.

Antibodies to the PD-1/PD-L1 or CTLA-4 axis lift the constitutional inhibitory immune response. This enhances anti-tumor lymphocyte activity, but also contributes to immune related adverse events (irAEs) in over a third of patients (4). While any organ system is susceptible, cutaneous irAEs (irCAEs) are among the first and most frequent to develop, affecting 30%-60% of patients (5)(6)(7)(8). Appropriate diagnosis and management of irCAEs is associated with reduced use of immunosuppressive agents and continuation of lifesaving immunotherapy (8). As the approved clinical use of ICIs broadens, recognition and appropriate management of dermatological toxicities becomes increasingly important. In this article we provide an updated review of the clinical spectrum and management of irCAEs. characteristics such as cytokine profiles and human leukocyte antigens may also predict irCAEs (7).
CTLA-4, which is expressed on activated T-cells, inhibits T-cell activation when bound to co-stimulatory molecule CD28 (1, 7). CTLA-4 inhibitors, ipilimumab and tremelimumab interfere with this inhibitory signal and allow for unopposed T-lymphocyte activation.
While enhancing anti-tumor activity, the pharmacological blockade of CTLA-4 and PD-1/PD-L1 promotes autoimmunity via activation of tissue-resident immune cells (5,13). IrAEs can also arise from crossreactivity between tumor cells and self-antigens on normal tissue (5,13). There is evidence to suggest that photodamaged skin is more susceptible to irCAEs (5,14). Ultraviolet-induced cellular injury and subsequent release of self-antigens creates a pro-inflammatory milieu where autoreactive T-cells are already primed before ICI exposure (5,13). Though further studies are needed, oral nicotinamide may help delay the onset of irCAEs (14).

Cutaneous adverse events
The most common irCAEs include pruritus, vitiligo, morbilliform drug, eczematous, lichenoid, and psoriasiform eruptions. Most irCAEs are mild and can be managed without discontinuation of immunotherapy (7,15). Table 2 includes a summary of management of mucocutaneous adverse events in the setting of ICIs. Grade 1-2 eruptions can typically be managed with topical steroids, bland emollients, and oral antihistamines, whereas high-grade eruptions require more specific management based on the rash type (13, 16).

Eczematous reactions
Eczematous dermatitis affects up to 20% of patients on PD-1/ PD-L1 inhibitors and up to 68% of patients on anti-CTLA-4 agents (8). It has an early onset within 6 weeks of therapy (8). Clinical findings include ill-defined coalescing erythematous patches and papules with secondary skin changes and flexural predominance (5). Main histopathological features include epidermal spongiosis and minimal lymphocyte exocytosis with perivascular, lymphocytic infiltrate with eosinophils (7,8).
For recalcitrant grade 3 rash, advanced therapy with dupilumab or omalizumab can be pursued (8).

Vitiligo
Vitiligo is mostly reported in patients with metastatic melanoma (1,5,7,8). In skin of color patients, it can have a significant psychosocial impact, particularly in cosmetically sensitive areas. In contrast to intrinsic vitiligo, it affects sun exposed surfaces more commonly and is less likely to koebnerize (1,5). Poliosis can be seen at the same time (8). Onset is delayed, usually months after ICI initiation (8). Strict photoprotection is recommended. Though treatment is not required, topical steroids, topical janus kinase inhibitors, and nbUVB can be considered (31) Vitiligo usually persists after ICI discontinuation (1,8).
As in classic BP, histopathology demonstrates subepidermal clefting with eosinophils. DIF shows linear deposits of IgG and C3 at the epidermal site or roof of the split (7,8,18). Antibodies against BP180 and less frequently BP230 are often elevated (8,18). BP may lead to ICI discontinuation in up to 70% of patients and can often be more resistant to treatment (30). As even small body surface area (BSA) involvement can be significant, high potency topical steroids are often used in conjunction with systemic therapies. First line systemic agents include oral steroids and doxycycline with or without niacinamide. An SSA should be started at presentation for grade 2 or higher eruptions to avoid ICI interruption and reliance on systemic steroids (20). Omalizumab, dupilumab, rituximab, intravenous immunoglobulin (IVIG), methotrexate can be used for grade 2-3 disease (5, 10, 15, 18-20). Importantly, BP can persist after discontinuation of ICIs emphasizing the need for selecting SSAs (1,8).
LPP has overlapping features of BP and lichen planus. It has been reported mainly in the setting of nivolumab and pembrolizumab (32)(33)(34). Clinical features are heterogeneous with papules, plaques, erosions, and bullae on trunk and extremities. Oral involvement is common with one case series showing 50% (33). Histopathologic features include subepidermal blister with lichenoid or vaculoar interface dermatitis. DIF demonstrates linear IgG and C3 along the basement membrane zone. Serologies are positive for BP180 antibodies, while antibodies to BP230 have not been reported thus far (33)(34)(35)(36)(37).
PD-1/PD-L1 inhibitors can be associated with SJS/TEN-like eruptions, which unlike true SJS/TEN, evolve over weeks from milder morbilliform rashes (10, 18,19). Thus it is crucial for patients with morbilliform eruptions to be monitored for red-flag symptoms, such as targetoid lesions or bullae that could indicate progression to a SCAR. SJS/TEN-like eruptions can also occur de novo weeks to months after ICI initiation (18). These reactions are milder than true SJS/TEN with less eye involvement and less denuded skin. Careful ICI rechallenge can be considered for SJS/TEN-like eruptions, if patients lack an alternative anti-cancer therapy (18). For true SJS/ TEN, however, rechallenge is contraindicated (13, 18).
Drug reaction with eosinophilia and systemic symptoms (DRESS) to ICIs is rare and it presents with fever, generalized morbilliform eruption, and concurrent systemic irAEs such as hepatitis, colitis, azotemia (18). Management includes discontinuation of ICIs and high dose steroids tapered slowly over 6-8 weeks. SSAs such as TNF-inhibitors, tocilizumab, or dupilumab may be considered (18).
Granulomatous reactions, including sarcoidosis or sarcoid-like reactions have been associated with anti-CTLA-4 and anti-PD-1/ PD-L1 therapy with onset anywhere from two weeks to two years (6,8,9). Cutaneous sarcoidosis is seen more frequently in melanoma patients on ipilimumab (9). Other organs including the eyes, lymph nodes, and lungs can be affected (9,17,19,40). ICI-induced sarcoid appears to have a mild course and in many cases discontinuation of ICIs may not be indicated (47).

Hair and nail toxicities
Alopecia areata or universalis, poliosis, changes in hair texture, and less commonly hair repigmentation have been reported, though hair toxicities to ICIs are less frequent than with conventional chemotherapy (8-10, 19, 48-50). Eosinophilic folliculitis after nivolumab leading to scarring alopecia was described in one report (51). Though ICI-induced alopecia is rare (1% for PD-1/PD-L1 inhibitors and 5% for CTLA-4 inhibitors), it can greatly impact quality of life (8,49,50,52). Severe disease may warrant systemic immunomodulators such as JAK inhibitors, though a risk-benefit analysis must be performed to avoid interference with immunotherapy. Some cases may spontaneously resolve (49).
Lichen planus and psoriasis of the nail can present with or without cutaneous disease (16,25). Non-specific nail toxicities include plate thinning, onycholysis, onychorrhexis, and splitting (8,16). Diffuse onychodystrophy and paronychia were reported with nivolumab (53). Two cases of clinical onycholysis presenting histologically with lichenoid changes were described, also in the setting of nivolumab (54).
One case of immune-mediated glossitis was described in association with pembrolizumab, subsequently improving on oral prednisone (58).

Grading criteria
Grading follows the CTCAE, which focuses on BSA involvement (59). The severity of irCAEs should not be merely based on BSA but rather on symptoms and specific dermatosis. For instance, a morbilliform eruption with >30% BSA can be managed conservatively without ICI discontinuation in contrast to SJS with <5% BSA (10). A modified grading criteria produced by the American Society of Clinical Oncology focuses on symptoms and quality of life and appears more applicable to irCAEs (60) (Supplementary Tables S1, 9 S2).

Summary
In general, irCAEs indicate a positive anti-tumor response (11,12,61). This has been well documented with vitiligo, which is predictive of response, progression-free survival, and overall survival in patients with metastatic melanoma (1,7,9,12,13). Progression free survival was seen to be higher in patients who experienced flares of psoriasis (18). Though the data is limited, alopecia was also found to have a positive tumor response (49).
Most irCAEs can be managed without discontinuation of ICIs. For high-grade eruptions that necessitate high doses of systemic steroids or other immunosuppressant, choice of therapy must be carefully evaluated to avoid dampening anti-tumor response (13, 18). There is increasing support for prioritizing targeted, nonsteroidal immunomodulators with less T-cell impact (13, 18). However, there is lack of data on the effect of SSA, such as biologics, on immunotherapy underscoring the need for further studies in this area of oncodermatology.

Author contributions
Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: FM, ABP, PVK, AB, WM. Drafting the work or revising it critically for important intellectual content: FM, ABP. Provide approval for publication of the content: FM, ABP. Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: ABP. All authors contributed to the article and approved the submitted version. their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.