Dermatologic Reactions to Immune Checkpoint Inhibitors

Skin Toxicities and Immunotherapy

Vincent Sibaud

Disclosures

Am J Clin Dermatol. 2018;19(3):345-361. 

In This Article

Skin Rashes

Nonspecific Maculopapular Rash

Incidence. A pruritic maculopapular rash represents the most frequent cutaneous irAE observed with PD-1/PD-L1 and CTLA-4 inhibitors.[3,7,9,10,20,23] Its incidence is slightly higher with anti-CTLA-4 treatment and with the therapeutic combination of anti-PD-1/CTLA-4 (Table 1).[4,13–18] The overall incidence (by meta-analysis) varies between 24.3% [95% confidence interval (CI) 21.4–27.6], 16.7% (95% CI 11.9–23), and 14.3% (95% CI 8.7–22.7) for ipilimumab,[21] pembrolizumab, and nivolumab,[12] respectively. The rate of grade ≥ 3 rash [i.e., affecting more than 30% of the body surface area (BSA)], however, remains below 3% in monotherapy.[13–18]

In comparison, the risk of developing a maculopapular rash with PD-L1 inhibitors appears to be lower. It affects less than 10% of treated patients.[24–28]

Clinical Presentation. The lesions most often start after the first few treatment cycles (sometimes as of the first cycle). Their onset is slightly earlier with ipilimumab or when immune checkpoint inhibitors are prescribed in combination (5 weeks with anti-PD-1 vs 3–4 weeks with anti-CTLA-4 antibodies, and 2 weeks with the combination of ipilimumab and nivolumab, on average).[4–6,10,12,20,29] Delayed eruptions have, however, also been reported.[12,30] The lesions can also worsen after each cycle of treatment.[21]

The clinical presentation is relatively nonspecific, characterized by a morbilliform, maculopapular rash that remains most often of low grade (grades 1 and 2).[12,19,20] It occurs mainly on the trunk and to a lesser degree on the upper limbs and spreads peripherally to the extremities[12,23,29] (Figure 1 and Figure 2). The face is commonly spared.[9,12] The lesions mainly consist of faint erythematous macules associated with flat-topped, minimally scaly papules which can be confluent. Prominent eruptions on photoexposed sites have occasionally been reported (Figure 2).[11,12,19] Lesions are usually itchy,[30] although sometimes the lesions develop in an asymptomatic manner.[29] Though common, such dermatologic adverse events are often self-limited and quite manageable.[12]

Figure 1.

a–c Pruritic maculopapular rash involving the trunk

Figure 2.

a, b Grade 3 maculopapular rash, predominantly on photoexposed areas (photo courtesy of M. Lacouture, MD, Memorial Sloan Kettering Cancer Center, NY, USA)

This nonspecific maculopapular rash can also represent the initial manifestation of a more characteristic skin disorder induced by immune checkpoint inhibitors, including lichenoid reactions, psoriasis (de novo or flare of known psoriasis), Grover's disease, bullous pemphigoid, or much more rarely life-threatening cutaneous drug reactions (see corresponding sections). It is therefore absolutely paramount to perform an exhaustive dermatologic evaluation (including a skin biopsy in particular) for any atypical, severe, persistent, recurrent or poorly tolerated rash.[3,9]

Histopathologic and Biological Findings. Histopathologic studies carried out in this context have remained relatively scarce.[29–33] The most common feature is an eczema-like spongiotic dermatitis with associated superficial perivascular T-lymphocyte infiltrate which can extend to epidermis, patchy necrotic keratinocytes and scattered to florid eosinophils.[3,9,11,29,31,32,34] Histopathologic aspects can be very reminiscent of a dermal hypersensitivity reaction.[11] Immunohistochemical studies individualize a predominantly CD3/CD4-positive,[21,29,33–35] a mixed CD4+/CD8+[30] or a prominent cytotoxic CD8-positive lymphocytic infiltrate[31,34] (Figure 3). Less frequently, a lichenoid reaction can also be encountered[9,23,31–36] (Figure 4), as well as other characteristic histopathologic aspects (e.g., psoriasis, Grover's disease, bullous pemphigoid, and granulomatous sarcoid-like dermatitis) (see corresponding sections).

Figure 3.

a Eczema-like changes combining a superficial perivascular T-cell infiltrate, a marked spongiosis, a patchy exocytosis and eosinophils (hematoxylin–eosin stain, 109 magnification); bd immunostaining reveals a predominantly CD3-positive (b)/CD4-positive (c) lymphocytic infiltrate, with a weak CD8 staining (d) (9 5 magnification)

Figure 4.

a Lichenoid reaction with band-like T-cell infiltrate, vacuolar interface dermatitis with apoptotic keratinocytes, hyperkeratosis, and hypergranulosis (hematoxylin–eosin stain, 109 magnification); bd immunostaining reveals a predominantly CD3-positive (b)/CD4-positive (c) lymphocytic infiltrate, with a weak CD8 staining (d) (59 magnification)

A concomitant increase in the peripheral blood eosinophil count has been reported with ipilimumab-induced skin rash.[29] In our experience, it can be also noted with anti-PD-1 agents.

Management. The clinical severity of the eruption needs to be thoroughly measured prior to any therapeutic decision. This is assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE criteria) (version 4.02), taking into account the extent of the lesions (grade 1, < 10% of the BSA; grade 2, 10–30% of the BSA; grade 3, > 30% of the BSA) and above all the negative impact on health-related quality of life, such as limitation of instrumental activities of daily living (e.g., preparing meals, shopping for groceries or clothes, using the telephone, managing money, daily shopping, and preparing meals) or self-care activities of daily living (e.g., bathing, dressing and undressing, feeding self, using the toilet, and taking medications) (Figure 5).

Figure 5.

Proposed management algorithm for maculopapular rashes. ADL activities of daily living, BSA body surface area

In the vast majority of cases, immune checkpoint inhibitors can be maintained,[1,4,12,20] and treatment withholding (either temporarily or permanently) is only rarely needed. Early recognition, diagnosis, intervention and adequate monitoring, however, are required for maintaining dose intensity and mitigating the severity of cutaneous adverse events.[4,29] Moreover, appropriate counseling and management are critical to minimize deterioration in quality of life. It should be also noted that these cutaneous irAEs, which most often can be managed by tailored treatments, are often long lasting, regressing only slowly even when systemic corticosteroids are prescribed.[4]

The management strategy mainly includes prescription of systemic antihistamines, high- to very-high-potency topical steroids (e.g., betamethasone or clobetasol propionate, cream or ointment) and/or topical moisturizers.[4–9,12,20] The use of systemic corticosteroids (0.5–1 mg/kg/day) is, in principle, restricted to the management of persistent and severe reactions (i.e., ≥ grade 3). It is, however, uncommonly required in clinical practice; its introduction should be considered collectively and in a multidisciplinary approach, and only after a thorough dermatologic evaluation including a skin biopsy. In particular, the absence of a more specific skin disorder, which may require specific management (see corresponding sections), needs to be ascertained. The same reasoning should be applied for any atypical or persistent lesions. In this regard, we have recently proposed a modified management algorithm[9] for use by practicing oncologists (Figure 5). According to the product safety information of these products, immunotherapy should theoretically be suspended when systemic corticosteroids are prescribed, and should be resumed when the steroid dose is ≤ 10 mg/day of prednisone equivalent. It has been recently reported, however, that the use of systemic corticosteroids or other immune-modulating drugs in patients treated with anti-PD-1 agents does not seem to interfere with anticancer immune response.[4]

Lichenoid Reactions

A certain number of these maculopapular rashes in fact correspond with lichenoid reactions, with lichenoid interface dermatitis and variable degrees of basal vacuolar changes. This is seen particularly with anti-PD-1/PD-L1 agents.[9,12,23,30–36] The diagnosis is generally made after a histologic analysis, and it is likely that the incidence has remained greatly underestimated. According to some authors,[23,30] it represents the most prevalent identified histologic feature in patients treated with anti-PD-1 therapy. It does not correspond strictly to our own experience, with a higher incidence of eczema-like dermatitis with spongiosis.

Clinical Presentation. The lesions start after several weeks or months of treatment[23,30,34–36] and tend to be delayed in comparison to other forms of maculopapular rash.[34,36] The clinical presentation is variable, and a wide spectrum of lesions can be observed, which can also develop in combination. These lichenoid reactions range from typical lichen planus with flat-topped papules and visible Whickham striae to hypertrophic or papulosquamous lesions. Pruritus can be severe and debilitating.[30] Once again, lesions mainly occur on the trunk and the limbs,[23,34–36] although a spreading of the lesions is possible.[12,19,30] A palmoplantar involvement is not uncommon (Figure 6).[19,30] Distinct inverse distribution has also been described,[37] as well as lichen planus pemphigoides or lichen sclerosus atrophicus.[19,34] Lastly, concomitant genital, oral or ungual involvement is possible and needs to be systematically searched (Figure 6).[19,23,30,36,38]

Figure 6.

Lichenoid reaction involving the skin (a) and oral mucosa (b), with visible reticular striae

Histopathologic findings. Histologically, a superficial band-like lymphohistiocytic infiltrate along the dermal–epidermal junction is seen, with patchy-to-florid vacuolar interface dermatitis and basilar/suprabasilar apoptotic keratinocytes, associated—to varying degrees—with hypergranulosis, acanthosis, spongiosis and eosinophils (Figure 4).[12,23,30,34–36] A marked parakeratosis was identified in this setting.[23,32,38] Ancillary immunostaining individualizes a mixed CD4+/CD8+or a predominantly CD4+ T-cell infiltrate.[21,29,30,34,35] Finally, lichenoid dermatitis can be also associated with spongiotic changes together with an epidermal eosinophil infiltrate, as described by Shi et al..[30]

Management. Treatment is based on topical steroids and, much more rarely, on oral corticosteroids, phototherapy, or acitretin.[19,30,34–36] In most cases, the immune checkpoint blockade therapy can be maintained,[30,31,34,35,37] although the psychosocial impairment can be pronounced. Lesions that last for months after the discontinuation of immunotherapy may also be encountered.

Psoriasis

The risk of developing psoriasis with anti-PD-1/PD-L1 or anti-CTLA-4 agents is also well-established,[9,39] even though the actual incidence still needs to be determined. Exacerbation or occurrence of psoriatic arthritis and even more skin psoriasis can be observed.[40–43]

Clinical Presentation. In the majority of cases, patients have a personal history of psoriasis. De novo psoriasis is also possible, which may occur later after several months of treatment.[9,19,43–45] Plaque psoriasis is the most frequent presentation, although guttate, pustular or inverse psoriasis and sebopsoriasis have been described.[43] The scalp can also be affected, as can the palmoplantar areas (Figure 7).[46] Psoriatic arthritis can also occur,[41] even in patients with no personal or family history of psoriasis.

Figure 7.

ae Guttate, palmar and plaque psoriasis induced by anti-PD-1/PD-L1 agents; f skin biopsy revealing an intense and confluent epidermal hyperkeratosis, with parakeratosis and acanthosis (hematoxylin–eosin stain, 109 magnification). PD-1 programmed cell death protein 1, PD-L1 programmed death ligand 1

Pathogenesis. The pathogenesis has yet to be defined. However, it has been shown that the PD-1 axis downregulates T-helper cell 1 (Th1)/Th17 signaling pathway.[47] Therefore, PD-1 blockade could promote a secondary overexpression of proinflammatory cytokines mediated by Th17 lymphocytes. In this regard, Tanaka et al. recently found that these patients presented elevated serum levels of interleukin-6.[45]

Histopathologic Findings. The histologic features are strictly similar to those seen in classic psoriasis vulgaris (Figure 7). On the other hand, a lower expression of PD-L1 and PD-1 by the keratinocytes has been reported for the PD-1-induced psoriasis.[44]

Management. Management needs to be carried out using a multidisciplinary approach. In most cases, immunotherapy can be maintained and the patient managed by topical treatments (e.g., vitamin D analogs, topical corticosteroids).[9,43] Acitretin and UVB therapy have also been administered in some cases.[43] There are no data available regarding the efficacy and safety of anti-tumor necrosis factor alpha (anti-TNF-α) in this context. In our experience, however, we have not observed a significant improvement in patients with severe psoriasis. This corroborates the recent data of Tanaka et al., suggesting a mechanism that is not directly dependent on TNF-α in these patients.[45]

Finally, several patients developing psoriatic arthritis with anti-PD-1 therapy have been successfully managed with methotrexate and low doses of corticosteroids, without treatment discontinuation.[48,49]

Life-threatening Cutaneous Drug Reactions

Maculopapular rash can also represent the initial clinical manifestation of a more severe cutaneous drug reaction. Although it has been extremely rarely described with these monoclonal antibodies, several cases of extensive exfoliative dermatitis, Stevens-Johnson syndrome, or toxic epidermal necrolysis have nonetheless been reported.[3,19,29,31,50,51] In this context, Vivar et al. noted a dense CD8-positive T-cell infiltrate within the dermal– epidermal–junction, together with an increase in PD-L1 expression in both lymphocytes and keratinocytes.[50] It should also be emphasized that these severe cutaneous adverse reactions can also be delayed, developing after only several cycles of treatment.[50,51] The occurrence of erythema multiforme, acute generalized exanthematous pustulosis or drug reaction with eosinophilia and systemic symptoms (DRESS) has also been described with anti-CTLA-4 or anti-PD-1 therapies.[23,52–55]

Finally, the incidence of infusion-related reactions appears to be higher with anti-PD-L1 antibodies, especially with avelumab (about 10%, during the first or second administration).[56,57]

Grover's Disease

The occurrence of Grover's disease has occasionally been reported with ipilimumab.[58–60] More recently, we and other authors have also noted Grover's disease with anti-PD-1 therapy.[33] The clinical presentation is polymorphic, presenting as a more or less diffuse pruritic papulokeratotic or vesicular eruption.[58–60] The diagnosis is only confirmed after a skin biopsy, and its incidence is hence probably underestimated. Suprabasal acantholysis is isolated (Darier-like form), and is associated with a predominantly CD4+ T-lymphocyte dermal infiltrate.[59,60] A Th2-mediated immunologic mechanism has been proposed.[60] The lesions appear fairly rapidly after the initiation of the treatment,[58–60] and they can last for several months after the discontinuation of immunotherapy.[59,60]

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