C-reactive protein as a biomarker for immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors in the adjuvant setting

Abstract

The objective of this study was to evaluate the utility of serum C-reactive protein (CRP) as biomarker for the early diagnosis of immune-related adverse events (irAEs) in melanoma patients treated with immune checkpoint inhibitors (ICIs) in the adjuvant setting, and its potential correlation with relapse-free survival (RFS). Prospectively collected data from 72 melanoma patients treated with adjuvant ICIs were pooled. CRP values at diagnosis of 10 irAEs were descriptively analysed. Correlations between RFS and the occurrence of irAEs, the grade of the irAE, the extent of CRP-elevation and the use of corticosteroids for irAE treatment were investigated. A total of 191 irAEs (grade 1/2, n = 182; grade 3/4, n = 9) occurred in 64 patients [skin toxicity (n = 70), fatigue (n = 50), thyroiditis (n = 12), musculoskeletal toxicity (n = 11), sicca syndrome (n = 10), other (n = 23), pneumonitis (n = 6), colitis (n = 4), hepatitis (n = 3) and hypophysitis (n = 2)]. In pneumonitis and hypophysitis, the median CRP levels at diagnosis exceeded the upper limit of normal (ULN, 5 mg/L). After a median follow-up of 26.5 months, 28 patients (39%) had been diagnosed with a melanoma relapse. Patients who experienced no irAE were at the highest risk for relapse (P = 0.008). A trend was observed for patients diagnosed with an irAE that was associated with an elevated CRP (>2xULN) to be at higher risk for relapse as compared to those diagnosed with an irAE and CRP <ULN (P = 0.054). CRP has potential as biomarker for the early detection of selected irAEs. Dynamic evaluation can guide irAE diagnosis, regression or relapse. The observed correlation between irAEs associated with an elevated CRP and risk for recurrence deserves further investigation. Melanoma

Increased Circulating Levels of CRP and IL-6 and Decreased Frequencies of T and B Lymphocyte Subsets Are Associated With Immune-Related Adverse Events During Combination Therapy With PD-1 Inhibitors for Liver Cancer

“…CRP and IL-6 levels are also associated with the occurrence of irAEs. Patients with melanoma displayed elevated CRP levels when irAEs occurred, and with a CRP level more than twice the ULN were more likely to have irAEs than those with a CRP level less than the ULN (35,36). In a case report, the baseline CRP level increased from 14.2 to 138.9 mg/L when pneumonitis occurred (37).…”

“…In fact, many of these cytokines have been implicated in the inflammation underlying autoimmune diseases (21,(31)(32)(33)(34). C-reactive protein (CRP) and IL-6, which are commonly used clinical indicators of inflammation and autoimmune diseases, have been proven to be associated with the occurrence of irAEs in melanoma and non-small cell lung cancer patients; however, the changes in the levels of these factors in liver cancer patients who experienced irAEs are unclear (35)(36)(37)(38)(39). Furthermore, whether an adverse event is an irAE must be determined.…”

Immune Checkpoint Inhibitor-Associated Colitis: From Mechanism to Management

“…Several serum markers like CRP, LDH, and fecal calcitonin and their association with CIC prognosis have been investigated. Justine et al revealed that patients with elevated CRP level had a higher risk of irAE recurrence (223). LDH ≥618 IU/L was related to a poor prognosis in CIC patients (60).…”

Hypothyroidism-induced kidney dysfunction: an under-recognized phenomenon in patients on immune checkpoint inhibitors

“…As thyroid irAEs are more common and generally occur earlier than renal irAEs, this phenomenon should be considered and prompt the concurrent evaluation of thyroid status when AKI occurs during ICI therapy. CRP has shown promise as a non-invasive biomarker for the early detection of selected irAEs [ 5 , 6 ] and to discriminate between ICI related AKI from other causes [ 7 ]. Interestingly, the median CRP level was not elevated in ICI-thyroiditis in one series [ 5 ].…”

“…CRP has shown promise as a non-invasive biomarker for the early detection of selected irAEs [ 5 , 6 ] and to discriminate between ICI related AKI from other causes [ 7 ]. Interestingly, the median CRP level was not elevated in ICI-thyroiditis in one series [ 5 ]. While elevated CRP by itself is not diagnostic of irAE due to its poor specificity, we propose that a non-elevated CRP may be used to discriminate between the different AKI etiologies in the right context, provided that the patient is not on corticosteroids exceeding physiological doses [ 7 ].…”