C-reactive protein as an early marker of immune-related adverse events
Immune checkpoint inhibitors (ICIs) are effective against a wide variety of cancers. However, they also induce a plethora of unique immune-related adverse events (irAEs). Since for many organ systems symptoms can be unspecific, differential diagnosis with progression of disease or infection may be difficult. C-reactive protein (CRP) has been suggested as a marker for infection. The purpose of this study was to evaluate the diagnostic value of CRP in differentiating infectious causes from autoimmune side effects induced by ICIs.
In order to investigate the role of CRP in irAEs, we screened our patient data base. Only events with full infectious workup were included. In total 88 events of irAEs in 37 melanoma patients were analyzed. CRP levels before and during irAEs were evaluated. Statistical analyses were conducted using the Chi-square test for categorical variables.
At the onset of irAE, CRP rose in 93% of cases to a mean of 52.7 mg/L (CI 35.1–70.3) from 8.4 mg/L at baseline (normal < 5 mg/L) (P < 0.0001). Other causes of CRP elevation including infectious diseases were excluded, and procalcitonin (PCT) levels were normal in 92% of events. Importantly, in 42% of cases CRP elevations preceded clinical symptoms.
CRP elevation can predict the onset of irAEs in patients treated with ICIs in the absence of infectious disease.
KeywordsAdverse events C-reactive protein Immune checkpoint inhibitors Melanoma
The present work was performed in the fulfillment of the requirements for obtaining the degree “Dr. med.”. We thank Sabine Schüpferling (Department of Dermatology) for laboratory assistance.
Compliance with ethical standards
Study participants gave written consent for anonymous analyzation of data. This study was approved by the institutional review board of the medical faculty of the University Erlangen and all procedures performed in studies were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declarations.
Conflict of interest
The authors declare that they have no conflict of interest.
- Atallah-Yunes SA, Kadado AJ, Kaufman GP, Hernandez-Montfort J (2019) Immune checkpoint inhibitor therapy and myocarditis: a systematic review of reported cases. J Cancer Res Clin, OncolGoogle Scholar
- Balar AV, Castellano D, O’Donnell PH et al (2017) First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. https://doi.org/10.1016/s1470-2045(17)30616-2 Google Scholar
- Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline. J Clin Oncol 36:1714–1768. https://doi.org/10.1200/jco.2017.77.6385 CrossRefGoogle Scholar
- Haas M, Heinemann V, Kullmann F et al (2013) Prognostic value of CA 19-9, CEA, CRP, LDH and bilirubin levels in locally advanced and metastatic pancreatic cancer: results from a multicenter, pooled analysis of patients receiving palliative chemotherapy. J Cancer Res Clin Oncol 139:681–689. https://doi.org/10.1007/s00432-012-1371-3 CrossRefGoogle Scholar
- Ricciuti B, Genova C, De Giglio A et al (2018) Impact of immune-related adverse events on survival in patients with advanced non-small cell lung cancer treated with nivolumab: long-term outcomes from a multi-institutional analysis. J Cancer Res Clin Oncol 145:479–485. https://doi.org/10.1007/s00432-018-2805-3 CrossRefGoogle Scholar
- Schadendorf D, Wolchok JD, Stephen Hodi F et al (2017) Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: A pooled analysis of randomized phase II and III trials. J Clin Oncol. 35:3807–3814. https://doi.org/10.1200/JCO.2017.73.2289 CrossRefGoogle Scholar
- Schindler K, Harmankaya K, Kuk D, Mangana J, Michielin O, Hoeller C, Dummer R et al (2014) Correlation of absolute and relative eosinophil counts with immune-related adverse events in melanoma patients treated with ipilimumab. ASCO Annual meeting, abstracts, meeting library. In: J Clin Oncol 325Google Scholar
- Simeone E, Gentilcore G, Giannarelli D et al (2014) Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 63:675–683. https://doi.org/10.1007/s00262-014-1545-8 CrossRefGoogle Scholar
- Stucci S, Palmirotta R, Passarelli A et al (2017) Immune-related adverse events during anticancer immunotherapy: Pathogenesis and management. Oncol, LettGoogle Scholar