Skin Side Effects of Immunotherapy – Why Do They Occur and How Are They Managed?

Introduced into oncology practice in 2012 and already contributing to the lives of millions of cancer patients, immune checkpoint inhibitor -class immunotherapies have unquestionably revolutionized the treatment of patients with malignant melanoma, non-small cell lung cancer and other cancers.

However, approximately 40% of cancer patients treated with immunotherapy may experience immune-related dermatological side effects, ranging from mild rashes and hair and nail changes to rare but life-threatening complications such as Stevens-Johnson syndrome.

An expected side effect of immunotherapy is that the overactivated immune system also starts attacking noncancerous cells. This causes side effects, most of which are mild; indeed, the hoped-for anticancer response to immunotherapy comes at the cost of immune-related side effects that can potentially affect any organ system.

The European Academy of Dermatology and Venereology (European Academy of Dermatology and Venereology = EADV)'s "Dermatology for Cancer Patients" recommendations, in the Journal of the European Academy of Dermatology and Venereology, were published.

EADV members developed recommendations based on clinical experience from published data and made specific recommendations for treating dermatological immune-related side effects in patients receiving immunotherapy.

Immune checkpoint inhibitors include the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy, BMS), as well as inhibitors of programmed death protein 1 (PD-1) and its ligand (PD-L1), including nivolumab (Opdivo, BMS) and pembrolizumab (Keytruda, Merck).

Balancing the Expected Treatment Response and Possible Side Effects

Immunotherapies have a wide range of immune-related side effects (see our related article); however, a guide focusing solely on their dermatological side effects will help doctors identify specific conditions that may require referral to a dermatologist.

Findings so far show that dermatological immunotherapy-related side effects are more common with CTLA-4 inhibition than with PD-1/PD-L1 inhibition (that is, more common with Yervoy than with Opdivo and Keytruda).

Side effects relate to where immunotherapy acts. Inhibiting CTLA-4 acts on a central aspect of the immune system, leading to nonspecific side effects that affect the body more broadly; PD-1, by contrast, affects an interaction in the tumor cell's own region and is therefore somewhat more localized/specific.

Itching

Itching caused by immunotherapy can occur without visible skin changes. A recent study of patients experiencing immunotherapy-related side effects reported isolated itching in approximately one-third of patients.

A meta-analysis found an itching frequency of 13.2% in patients treated with nivolumab and 20.2% in those treated with pembrolizumab, but rates of severe (grade 3) itching were only 0.5% and 2.3%. A different study reported an itching frequency of 47% with ipilimumab.

Recommended treatments for itching include:

• For grade 1 reactions, topical moisturizers with or without medium- to high-potency corticosteroids, nonsedating antihistamines and/or GABA agonists such as pregabalin (Lyrica, etc.),
• For grade 2 itching, gabapentin (Neurontin, etc.), and
• For grade 3 itching, suspending immunotherapy until the itching improves.

Maculopapular Rash

Maculopapular or eczema-like rashes may occur in 68% of patients receiving CTLA-4 inhibitors and 20% of those receiving PD1/PD-L1 inhibitors. Rashes generally appear 3 to 6 weeks after treatment begins.

Description of the photographs: a) Grade 2 itching causes excoriations (skin-picking disorder). Grade 1 (a) and grade 3 (b) maculopapular eruption. A maculopapular rash is generally itchy.

The appearance of immunotherapy-specific side effects in patients is nonspecific, consisting of numerous minimally scaly erythematous macules and papules that coalesce into plaques. Lesions are mainly on the trunk and extensor/outer surfaces of the limbs, and the face is generally spared.

Maculopapular rashes are typically accompanied by itching, but rashes without itching can also occur.

• Mild (grade 1) rashes may respond to moisturizers and potent or superpotent topical corticosteroids.
• Patients with grade 2 rash should also receive oral antihistamines.
• Systemic corticosteroids may be considered for patients with grade 3 rash, but only after ruling out other immune-related side effects, such as psoriasis, that may require specific treatment.

Psoriasis-Like Rash

The authors note that the most common form of psoriasis in patients treated with immunotherapy is plaque psoriasis vulgaris, although other clinical variants also occur.

According to the guide:

• Topical agents (corticosteroids and vitamin D analogs) are prescribed for grade 1 and 2 rashes, and
• For patients with grade 3 or persistent lesions, topical agents are prescribed in addition to systemic treatment.
• If skin-directed treatments do not control the symptoms, systemic treatment and narrowband UVB phototherapy “should be considered.”

Evidence for using systemic treatments for immunotherapy-associated psoriasis-like rashes is limited. Acitretin (Psoretin), a retinoid, can be used safely in patients with cancer. Low-dose methotrexate is also safe to use except in patients with nonmelanoma skin cancers. However, cyclosporine should be avoided because of its potential tumor-promoting effects.

The recommendations also cover treatment of lichen planus-like and vitiligo-like rashes, hair and nail changes, autoimmune bullous disorders and oral mucosal immunotherapy-related side effects.

In addition, the recommendations cover:

• Stevens-Johnson syndrome/TEN,
• Acute generalized exanthematous pustulosis (AGEP),
• Drug reaction with eosinophilia and
• Systemic symptoms/drug-induced hypersensitivity (DRESS/DIHS), among other serious, potentially life-threatening side effects.

The corticosteroid dose can be adjusted according to the severity of serious side effects. The benefit of systemic corticosteroids in treating Stevens-Johnson syndrome is controversial, and some doctors prefer cyclosporine. However, in the context of immunotherapy, using corticosteroids when needed is reasonable and should be recommended. Short-term steroids appear effective in treating acute generalized exanthematous pustulosis.