Immune-related adverse events

Immunotherapy has opened up new horizons for cancer treatment (Topalian SL et al. 2012). In particular, immune checkpoint inhibitors (ICIs) for the CTLA-4 and PD-1/PD-L1 pathways have been used to treat various solid tumors. ICIs currently approved by the Food and Drug Administration (FDA) include anti-CTLA-4(ipilimumab), PD-1 inhibitors(pembrolizumab and nivolumab) and the PD-L1 inhibitors (atezolizumab, tislelizumab, durvalumab and avelumab). The superiority of the effect of these drugs compared to conventional cytotoxic chemotherapy is undisputed, despite numerous side effects. For some time now, combination therapies of various immune checkpoint inhibitors (ICIs) with cytotoxic chemotherapeutic agents have been initiated, whereby increased side effects are to be expected (Choi J et al. 2020; Tang J et al. 2018).

Common immune-related adverse events (irAEs) include gastrointestinal, endocrine and dermatologic ADRs (Choi J et al. 2020; Chen W et al. 2024). Fatal irAEs include neurotoxicity, cardiotoxicity and pulmonary toxicity. The incidence of irAEs is higher with ICI combination therapies than with ICI monotherapies (Wolchok JD et al. 2017). Therefore, a close monitoring system is required for early detection.

IRAEs are assessed and treated according to the Common Terminology Criteria for Adverse Events, the guidelines of the European Society for Medical Oncology and the guidelines of the American Society of Clinical Oncology (Choi J et al. 2020).

• Toxicity grade 1: Exanthema of the skin
• Toxicity Grade 2: Target lesions cover <10% of the body surface and are not associated with genuine skin manifestations.
• Toxicity Grade 3: Target lesions cover 10-30% of the body surface and are not associated with genuine skin manifestations
• Toxicity grade 4: Target lesions cover >30% of the body surface, severe life-threatening symptoms, generalized exfoliative/ulcerative/bullous exanthema

Joints: Clinical symptoms include joint swelling, warmth, redness or recent joint pain. Erosive joint damage or changes can progress rapidly. Assessment of joint erosion by sonography or magnetic resonance imaging may be helpful in diagnosis. If the diagnosis is delayed and joint deformities occur, permanent restriction of movement or chronic symptoms may result. If a suspicious symptom occurs, it is important to diagnose the disease early and treat it in consultation with a rheumatologist. Compared to other irAEs, the side effect is chronic and persistent and often requires long-term treatment.

Incidence: Typical irAEs associated with the joints include arthralgia, inflammatory arthritis and tenosynovitis (Jagpal A et al. 2019). In clinical studies, arthralgia is reported in 3-7% and inflammatory arthritis in 1% of cases. Risk factors include combination therapy with ICI, long-term use of ICI and previous occurrence of other irAEs. The occurrence of inflammatory arthritis is rare and occurs later than other irAEs. Occasionally, inflammatory arthritis occurs more than one year after discontinuation of ICI treatment (Cappelli LC et al. 2017). In addition, the diagnosis of inflammatory arthritis is often delayed compared to other symptoms when patients are specifically asked about joint pain.

Treatment strategies: As with other irAEs, systemic steroids are used for treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular steroid injections may be helpful in supportive treatment (Naidoo J et al. 2017). For side effects above grade 3, immunomodulatory therapy approaches, such as disease-modifying antirheumatic drugs, are indicated.

Skin: The skin is most commonly affected by increased autoimmunity; therefore dermatologic toxicity is the most common irAEs (Jaber SH et al. 2016). Common symptoms include psorasiform and lichenoid exanthema, bullous pemphigoid, vitiligo, alpecia areata, cutaneous lupus erythematosus in light-stressed skin areas (described with tislelizumab, an IgG4 antibody with high PD-1 affinity and low FcgammaRI affinity - Chen W et al. 2024).

The frequently pruritic exanthema occurs mainly on the trunk and extremities (Belum VR et al. 2016). The head, palms of the hands and soles of the feet are often affected later. Biopsies of the lesions show different patterns to match the clinical morphology. In severe cases, toxic epidermal necrolysis, Stevens-Johnson syndrome, vasculitis and drug reactions with eosinophilia and systemic symptoms may occur (Lacouture ME et al. 2014; Voskens CJ et al. 2013). Sweet syndrome, cutaneous sarcoidosis and bullous skin diseases have been reported very rarely (Lacouture ME et al. 2014).

Incidence: Dermatologic ADRs occur more rapidly than ADRs in other organs. They are observed approximately one month after the start of treatment with anti-CTLA-4 up to 34 weeks after the start of treatment with PD-1/PD-L1 inhibitors (Tarhini A 2013). Dermatologic toxicities generally occur in 25% of cases (Minkis K et al. 2013). They are more frequent and more severe with anti-CTLA-4 than with PD-1/PD-L1 inhibitors. With anti-CTLA-4 therapy, dermatologic toxicity can be dose-dependent. It occurs more frequently with ICI combination therapies. Among the various symptoms of dermatologic toxicity, itchy exanthema and vitiligo are considered the preferred markers of response to ICI treatment (Minkis K et al. 2013).

In most cases, dermatologic toxicity is mild and can be treated with topical corticosteroids or antihistamines. Gabapentin, a neurokinin-1 receptor antagonist, and doxepin can be used for severe itching. For side effects > grade 2, oral prednisone (1 mg/kg/day) is recommended. If the patient's condition continues to deteriorate while taking systemic steroids, additional immunomodulatory therapy should be considered, e.g. with infliximab, cyclophosphamide and mycophenolate mofetil (Choi J et al. 2020).

Treatment of grade 1 toxicities is conservative and maintenance ICI therapy is considered based on symptoms and affected organs.

For grade 2 toxicity, "interruption of immunotherapy" and oral prednisone treatment should be considered.

For grade 3 or 4 toxicity, ICIs should be discontinued and higher doses of systemic steroids should be considered. If patients do not respond to steroids, immunomodulatory therapy should be initiated. If systemic steroids and immunomodulatory therapies fail to relieve symptoms, intravenous immunoglobulin or plasmapheresis treatment should be considered for potentially life-threatening irAEs. Re-treatment with ICIs is only recommended once the irAE has reduced to grade 1 or the symptoms have disappeared.

For potentially life-threatening irAEs or grade 4 irAEs, re-treatment with ICIs is not recommended (Choi J et al. 2020).

Some irAEs have been associated with a favorable clinical-oncological outcome, but this is still controversial (Teulings HE et al. 2015).

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