Safety profile of camrelizumab: An analysis based on literature and database review

Yi Huang; Wei Li

doi:10.1371/journal.pone.0354252

. 2026 Jul 23;21(7):e0354252. doi: 10.1371/journal.pone.0354252

Safety profile of camrelizumab: An analysis based on literature and database review

Yi Huang ^1,^*, Wei Li ¹

Editor: Mohammed Misbah Ul Haq²

PMCID: PMC13395421 PMID: 42490631

Abstract

Objective

Real-world studies on the safety of camrelizumab are scarce. This study aimed to investigate the adverse drug reactions (ADRs) associated with camrelizumab and evaluate their clinical characteristics and management.

Methods

We retrieved data on ADRs related to the PD-1 inhibitor camrelizumab from the World Health Organization (WHO) adverse event reporting system database (VigiAccess) for the period from June,2019 to July 2025. Additionally, we conducted a retrospective analysis of case reports and case series on camrelizumab-related ADRs published from 2019 to 2025.

Results

601 ADR reports were included in the VigiAccess database. Asian patients accounted for 99% (597/601), and the majority were male (69%). The most common classification of systemic organs (SOC) is hematological disorders (21.8%), skin reactions (14.3%), and systemic symptoms (8.8%). The main adverse reactions were: Hematological system: bone marrow suppression (10.3%), thrombocytopenia (5.1%); Skin: rash (5.7%), pruritus (4.3%), reactive capillary hyperplasia (RCCEP); systemic: fever (2.6%), chest pain (2.1%); serious events: myocarditis (1.2%), toxic epidermal necrolysis (TEN). Literature analysis included 80 patients (from China), with a median age of 60 years (range 20–84), and 72.5% were male. The main indications are non-small cell lung cancer (20%), nasopharyngeal carcinoma (20%) and hepatocellular carcinoma (11.3%). The median occurrence time of adverse reactions was 8 weeks (ranging from 10 minutes to 88 weeks). Typical ADRs include: cutaneous toxicity (45 cases, 56.3%); RCCEP (32 cases), Stevens-Johnson (SJS)/TEN (5 cases); hematological toxicity (38 cases, 47.5%): bone marrow suppression (22 cases), thrombocytopenia (16 cases); cardiotoxicity (13 cases, 16.25%), mainly myocarditis; Others: immune hepatitis (6 cases), thyroid dysfunction (5 cases).

Conclusion

The ADRs of camrelizumab are primarily hematologic and skin toxicities, with a need to be vigilant for late-onset serious events (e.g., myocarditis, TEN). Early identification and corticosteroid intervention are key management strategies.

1 Introduction

The primary treatment modalities for malignant tumors encompass surgical resection, radiotherapy, and pharmacological interventions. Pharmacotherapy includes conventional chemotherapeutics and novel antitumor agents. Among these, immune checkpoint inhibitors (ICIs), particularly those targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway, represent a groundbreaking advancement in tumor immunotherapy with promising therapeutic prospects. By restoring anti-tumor immunity, ICIs have demonstrated significant clinical benefits and improved overall survival (OS) in patients with various malignancies.[1]

As PD-1/PD-L1 inhibitors gain widespread clinical adoption, reports of associated adverse drug reactions (ADRs) have increased substantially. Unlike cytotoxic chemotherapy, ICI-induced ADRs predominantly manifest as immune-related adverse events (irAEs), affecting diverse organ systems including the skin, gastrointestinal tract, and endocrine glands.[2] Some systematic reviews on ICIs as a class have summarized general irAE profiles, real-world evidence focusing on the safety of individual PD-1 inhibitors, especially those with unique ADR spectra, remains limited.

Camrelizumab, a humanized anti-PD-1 monoclonal antibody, has been approved for treating multiple malignancies such as classical Hodgkin’s lymphoma, hepatocellular carcinoma, non-squamous non-small cell lung cancer, esophageal squamous cell carcinoma, and nasopharyngeal carcinoma. Beyond common irAEs (e.g., hematological and skin toxicities), camrelizumab is distinguished by a unique adverse reaction profile, notably the frequent occurrence of reactive cutaneous capillary endothelial proliferation (RCCEP), a distinctive cutaneous manifestation rarely reported with other PD-1 inhibitors. Additionally, delayed severe events such as myocarditis (reported incidence ~1.2%) and toxic epidermal necrolysis (TEN) warrant heightened clinical vigilance.[3]These idiosyncratic risks underscore the need for a dedicated safety assessment of camrelizumab, which remains underexplored compared to broader ICI reviews.

Against this backdrop, this study addresses a critical gap in current literature. While existing systematic reviews aggregate data across ICIs as a class, our work provides the first comprehensive, dual-perspective analysis of camrelizumab-specific ADRs by integrating two complementary approaches: (1) a global pharmacovigilance analysis using the WHO VigiAccess database to capture large-scale real-world ADR signals that reflect post-marketing surveillance patterns; (2) a systematic evaluation of published case reports/case series to detail clinical manifestations, temporal patterns, and management strategies. This dual-source design is deliberately chosen because VigiAccess provides quantitative signal detection across large populations but lacks clinical granularity, while case reports offer rich clinical phenotyping but are subject to publication bias. By synthesizing these complementary data streams, we achieve a more complete safety profile than either source alone. Notably, camrelizumab’s unique association with reactive cutaneous capillary endothelial proliferation (RCCEP),rarely reported with other PD-1 inhibitors,underscores the necessity of drug-specific analyses beyond generic ICI reviews. Ultimately, our findings aim to optimize clinical decision-making for camrelizumab and contribute nuanced insights into the safety of PD-1 inhibitors with distinct ADR profiles.

2 Methods

This study was designed as a retrospective pharmacovigilance analysis. Data on ADRs related to camrelizumab were retrieved from the publicly available VigiAccess database of the WHO for the period from June, 2019 to July, 2025. The retrieved data were analyzed to assess the safety profile of camrelizumab. Adverse events (AEs) was systematically classified according to Systemic Organ Classification (SOC), Preferred Terms (PT), and the Medical Dictionary of Regulatory Activities (MedDRA). Download and run MedDRA Desktop Browsers available on MedDRA Web site (https://www.Meddra.org/), import PT and the system will automatically output the SOC mapping table. The demographic data extracted encompasses patient characteristics such as gender and age, reporting schedules, geographical distribution, and the specific organ systems affected by adverse events.This study does not require ethical approval because it used the WHO-VigiAccess database, which is a free open access database.

2.1 Descriptive study

2.1.1 Search strategy.

A comprehensive search was conducted in multiple electronic databases, including PubMed and Web of Science, for publications related to camrelizumab from 2019–2025, with the language restricted to English. The search strategy employed was as follows: (((Camrelizumab) OR (SHR-1210))AND (Drug Related Side Effects OR Adverse Reactions)). The inclusion criteria for the articles were: case reports and case series on ADRs induced by camrelizumab, full-text articles in English. The exclusion criteria were: review articles, mechanistic studies, studies with only abstracts available, animal experiments, and duplicate cases.

2.1.2 Explicit quality assessment tool.

The quality of the included case reports was assessed using the standardized CARE (Case report) guidelines checklist for case reports, which includes 13 core items covering title, keywords, abstract, introduction, patient information, clinical findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, patient perspective, and informed consent. Only case reports meeting at least 10 of 13 CARE criteria were included in the final analysis.

2.1.3 Explanation for geographic focus.

Camrelizumab is primarily approved and marketed in China, which consequently results in a predominance of clinical experience and case publications originating from this country. As of 2025, China accounts for >90% of global camrelizumab prescriptions. Therefore, focusing on these cases provides the most relevant and concentrated real-world data currently available for this drug, though we acknowledge this limits generalizability to other populations.

2.1.4 PRISMA flow diagram reference.

The inclusion process for case and case series studies is shown in Fig 1, which details the identification, screening, eligibility assessment, and inclusion phases.

2.2 Clinical data extraction

A structured data extraction form was designed to collect clinical information from the identified articles, including patient demographics (gender, age, primary disease, history of drug use or combination therapy), clinical manifestations, other autoimmune-related ADRs, treatments, and outcomes. The extracted data were summarized and analyzed to provide a comprehensive overview of the ADRs associated with camrelizumab.

2.3 Statistical analysis

The extracted data were analyzed using Sigmastat 4.0. Categorical data were presented as counts and percentages, while continuous data were expressed as medians with ranges (minimum and maximum values).

3 Results

3.1 Data limitations statement

It is important to note that the WHO VigiAccess database provides de-identified individual case safety reports without denominator data (total exposed population) or comparison drug data. Consequently, disproportionality analyses such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), or Information Component (IC) could not be performed. The frequencies reported here represent crude counts and proportions among reported cases, not true incidence rates or statistical signals of disproportionate reporting. All associations should be interpreted as descriptive patterns requiring further validation through controlled studies.

3.2 Adverse drug reactions of camrelizumab in WHO-VigiAccess

As of July, 2025, the WHO-VigiAccess database recorded a total of 601 ADR reports associated with camrelizumab. The demographic and clinical characteristics of these reports are summarized in Table 1.

Table 1. Characteristics of ADR reports of Camrelizumab.

Characteristics	Number of cases(N)	Caseproportion,%
Sex
female	185	30.78
male	414	68.89
unknow	2	0.33
Age(years)
12-17	1	0.17
18-44	42	6.99
45-64	315	52.41
65-74	188	31.28
≥65	47	7.82
unknow	8	1.33
Year of reports
2024	3	0.50
2023	490	81.53
2022	107	17.80
2021	1	0.17
Area of reports
Americas	3	0.50
Asia	597	99.33
Oceania	1	0.17

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Among the 601 ADR reports, 99% (597/601) of the patients were from Asia, and 69% were male. Table 2 shows the five most common adverse reactions of camrelizumab as follows: myelosuppression 105 cases (10.28%), white blood cell count decreased 72 cases (7.05%), rash 58 cases (5.68%). There were 52 cases (5.09%) of thrombocytopenia and 46 cases (4.51%) of neutrophil count decreased.

Table 2. Top 30 ADRs of Camrelizumab in the WHO-VigiAccess database.

PTs	Number of cases(N)	proportion,%
Myelosuppression	105	10.28
White blood cell count decreased	72	7.05
Rash	58	5.68
Thrombocytopenia	52	5.09
Neutrophil count decreased	46	4.51
Pruritus	44	4.31
Pyrexia	27	2.64
Hepatic function abnormal	26	2.55
Chest pain	21	2.06
Dyspnoea	19	1.86
Pneumonia	17	1.67
Nausea	16	1.57
Vomiting	15	1.47
Asthenia	14	1.37
Liver injury	14	1.37
Diarrhoea	13	1.27
Haemangioma	13	1.27
Interstitial lung disease	13	1.27
Myocarditis	12	1.18
Hemoglobin decreased	11	1.08
Anaemia	10	0.98
Hyperhidrosis	10	0.98
Chills	9	0.88
Transaminases increased	9	0.88
Telangiectasia	9	0.88
Hypothyroidism	8	0.78
Pancytopenia	7	0.69
Hyperpyrexia	7	0.69
Anaphylactoid reaction	7	0.69
Cough	7	0.69

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The most common system organ classes (SOCs) were hematologic disorders (n = 184, 30.62%), skin reactions (n = 121, 20.13%), and general disorders (n = 74, 12.31%). The comprehensive details regarding the SOC are presented in Table 3.

Table 3. Distribution of AE signals in each SOC.

SOC	Number of cases (N)	proportion,%
Blood and lymphatic system disorders	184	21.78
Cardiac disorders	31	3.67
Congenital, familial and genetic disorders	1	0.12
Endocrine disorders	18	2.13
Eye disorders	6	0.71
Gastrointestinal disorders	55	6.51
General disorders and administration site conditions	74	8.76
Hepatobiliary disorders	50	5.92
Immune system disorders	13	1.54
Infections and infestations	23	2.72
Injury, poisoning and procedural complications	5	0.59
Investigations	123	14.56
Metabolism and nutrition disorders	18	2.13
Musculoskeletal and connective tissue disorders	12	1.42
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	14	1.66
Nervous system disorders	19	2.25
Psychiatric disorders	5	0.59
Renal and urinary disorders	9	1.07
Reproductive system and breast disorders	1	0.12
Respiratory, thoracic and mediastinal disorders	47	5.56
Skin and subcutaneous tissue disorders	121	14.32
Surgical and medical procedures	1	0.12
Vascular disorders	15	1.78

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3.3 Descriptive analysis

A total of 67 studies, including 80 case reports, were identified from the literature search. The clinical characteristics of these cases are summarized in Table 4. Among the 80 cases, 58 were male (72.5%) and 22 were female (27.5%), with a median age of 60 years (range 20–84 years). All cases were from China, as the drug is primarily marketed in this country. The most common indications for camrelizumab treatment were non-small cell lung cancer (NSCLC, 16 cases, 20%), nasopharyngeal carcinoma (NPC, 16 cases, 20%), and hepatocellular carcinoma (HCC, 9 cases, 11.25%). The median time to ADR onset was 8 weeks (range 10 minutes–88 weeks), with 16% of the ADRs occurring within 24 hours of the first dose. A total of 68 patients were receiving concomitant medications.

Table 4. Basic characteristics of the 80 patients included.

ID	Primary disease	Combination Therapy*	Time to ADR Onset	Reference
1	Non-small cell lung cancer	Yes	3 weeks	[4]
2	Nasopharyngeal carcinoma	Yes	15 minutes after the start of the fifth infusion	[5]
3	Esophageal squamous cell carcinoma	Yes	15 days after 4th cycle	[6]
4	Stage IV left lung adenocarcinoma	Yes	8 days	[7]
5	Acral malignant melanoma	Yes	6 months	[8]
6	Nasopharyngeal squamous cell carcinoma	Yes	18 days after 3rd cycle	[9]
7	Esophageal squamous carcinoma	Yes	1 day after 1st cycle	[9]
8	Cervical esophageal/hypopharyngeal squamous carcinoma	Yes	12 days after 3rd cycle	[9]
9	Non-small cell lung cancer	Yes	1 month	[10]
10	Hepatocellular carcinoma	Yes	3 months	[11]
11	Recurrent nasopharyngeal carcinoma	Yes	4.5 months	[12]
12	Esophageal squamous cell carcinoma	Yes	Immediately	[13]
13	Squamous cell carcinoma of the floor of the mouth	Yes	30 minutes after the 8th camrelizumab infusion	[14]
14	Urethral meatus squamous cell carcinoma	Yes	25 weeks	[15]
15	Lung adenocarcinoma	Yes	5 cycles	[16]
16	Lung adenocarcinoma	Yes	12 cycles	[16]
17	Lung adenocarcinoma	Yes	6 cycles	[16]
18	Gastric adenocarcinoma	Yes	12 cycles	[16]
19	Cervical cancer	Yes	4 cycles	[16]
20	Esophageal squamous cell carcinoma	Yes	4 cycles	[16]
21	Gastric adenocarcinoma	Yes	5th cycle	[17]
22	Metastatic tongue squamous cell carcinoma	No	1 week after 2nd cycle	[18]
23	Non-small cell lung cancer	No	10 days after 2nd cycle	[18]
24	Cervical carcinoma	Yes	1 week after 1st cycle	[19]
25	Nasopharyngeal carcinoma	Yes	3 months	[20]
26	Esophageal squamous cell carcinoma	Yes	8 weeks	[21]
27	Esophageal cancer with hepatic metastases	Yes	6 weeks	[22]
28	Metastatic esophageal squamous cell carcinoma	No	1 year	[23]
29	Hepatocellular carcinoma	Yes	18 days	[24]
30	Stage IV non-small cell lung cancer	Yes	2 weeks	[25]
31	Stage IV hypopharynx cancer	Yes	32 weeks	[26]
32	HBV-related hepatocellular carcinoma	Yes	3 weeks	[27]
33	Non-squamous NSCLC	Yes	6 months	[28]
34	Non-squamous NSCLC	Yes	22 months	[28]
35	Advanced NSCLC	Yes	After 2 cycles	[29]
36	Advanced hepatocellular carcinoma	Yes	3rd cycle	[30]
37	Lung cancer	Yes	2nd cycle	[31]
38	Hepatocellular carcinoma	Yes	21 days	[32]
39	Endometrial serous adenocarcinoma	Yes	1 month	[33]
40	Esophageal squamous cell carcinoma	Yes	6 weeks	[34]
41	Small-cell lung cancer	Yes	8 months	[35]
42	Lung adenocarcinoma with brain and bone metastases	Yes	17 days	[36]
43	Hepatocellular carcinoma	Yes	3 cycles	[37]
44	Gastric adenocarcinoma	Yes	1 month	[38]
45	Rectal endocrine tumor	Yes	10 days after two cycles	[39]
46	Oesophageal squamous cancer	Yes	7 doses of camrelizumab	[40]
47	Small cell lung cancer	Yes	10th dose of camrelizumab	[41]
48	Gastric antrum cancer	Yes	10 months	[42]
49	Advanced non-small-cell lung cancer	Yes	11 months	[43]
50	De novo metastatic nasopharyngeal carcinoma	Yes	16 weeks	[44]
51	Non-small-cell lung carcinoma	No	22 weeks	[45]
52	Hepatocellular carcinoma	Yes	20 weeks	[45]
53	Squamous cell carcinoma of upper lobe of left lung with mediastinal lymph node and liver metastases	Yes	4 days after 5th cycle	[46]
54	Poorly differentiated adenocarcinoma of middle-lower esophagus with lymph node metastasis	Yes	10th cycle	[47]
55	Stage IV Lung adenocarcinoma	Yes	3rd Camrelizumab cycle	[48]
56	Stage IV non-small cell lung cancer	Yes	6 weeks	[49]
57	Metastatic thymoma	No	11 days	[50]
58	Gastric cancer	Yes	6 months	[51]
59	Esophageal squamous cell carcinoma with liver metastasis	No	second dose of camrelizumab	[52]
60	Liver cancer with lung metastasis	Yes	second dose of camrelizumab	[53]
61	Advanced non–small-cell lungcancer	No	three months	[54]
62	Advanced gallbladder carcinoma	Yes	3 days	[55]
63	Esophageal squamous cell carcinoma	Yes	3 weeks	[56]
64	Non-small cell lung cancer	No	first injection	[57]
65	Soft tissue sarcoma	Yes	11 days	[58]
66	NSCLC	Yes	20 days	[59]
67	Liver cancer	Yes	1 week	[60]
68	Lung cancer	Yes	3 weeks	[60]
69	Esophageal cancer with lymph node metastasis	Yes	5 weeks	[61]
70	Advanced esophageal squamous cell carcinoma	Yes	12 days after 3rd cycle	[62]
71	Esophageal cancer	Yes	20 days	[63]
72	Stage IIIB NSCLC	Yes	10 weeks	[64]
73	Stage IVA squamous NSCLC	Yes	6 weeks	[64]
74	Gastric adenocarcinoma	Yes	15 weeks	[65]
75	NSCLC	No	112 days	[66]
76	Metastatic gallbladder adenocarcinoma	Yes	41 days	[67]
77	Lung cancer	Yes	6 months	[68]
78	Stage IV lung adenocarcinoma	Yes	6 weeks	[69]
79	Stage IVa Hodgkin’s lymphoma	No	1 month	[70]
80	Stage IV lung adenocarcinoma	No	2 weeks	[70]

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*Combination Therapy: Yes = combination with chemotherapy/targeted therapy; No = camrelizumab monotherapy.

Note: Detailed treatment regimens (drug dosages, cycles, radiation details) are provided in S1 Supplementary.

3.4 Clinical manifestations, laboratory examination, management and treatment outcomes

Table 5 summarizes the clinical manifestations of adverse reactions in 80 patients: skin toxicity (45 cases, 56.3%); RCCEP (32 cases), SJS/TEN (5 cases); Hematological toxicity (38 cases, 47.5%): bone marrow suppression (22 cases), thrombocytopenia (16 cases); Cardiotoxicity (13 cases, 16.25%), mainly myocarditis; Others: Immune hepatitis (6 cases), thyroid dysfunction (5 cases). Table 5 also summarizes the prognosis of patients after taking corresponding treatments for adverse reactions: The discontinuation rate of camrelizumab: 92.5% (74/80); Glucocorticoid utilization rate: 85% (68/80), median starting dose methylprednisolone 1 mg/kg; Immunoglobulin utilization rate: 13.75% (11/80). After corresponding treatment or drug withdrawal, the improvement rate of patients was 45% (44/80). Among the deaths (7 cases, 8.8%), the causes of death included myocarditis (3 cases), liver failure (2 cases), and septic shock (2 cases).

Table 5. Summary of Clinical Manifestations and Prognosis of ADRs in 80 Patients.

Category	Specific ADRs	Number of Cases (N)	Proportion (%)
Clinical Manifestations
Skin toxicity	Overall skin toxicity	45	56.3
	Reactive cutaneous capillary endothelial proliferation (RCCEP)	32
	Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN)	5
Hematological toxicity	Overall hematological toxicity	38	47.5
	Bone marrow suppression	22
	Thrombocytopenia	16
Cardiotoxicity	Overall cardiotoxicity (mainly myocarditis)	13	16.25
Others	Immune hepatitis	6
	Thyroid dysfunction	5
Prognosis After Treatment
Camrelizumab discontinuation rate		74	92.5
Glucocorticoid utilization rate	median starting dose: methylprednisolone 1 mg/kg	68	85
Immunoglobulin utilization rate		11	13.75
Improvement rate	after treatment/drug withdrawal	44	45
Deaths	Total deaths	7	8.8
	Myocarditis	3
	Liver failure	2
	Septic shock	2

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Note: Detailed laboratory values (specific troponin levels, CBC results, liver function tests), complete imaging findings, and specific drug dosing regimens are provided in S2 Supplementary.

4 Discussion

4.1 Core safety concerns

Skin toxicity in this study, 56.3% of the cases presented with skin ADR, which was higher than that of other ICIs skin immune-related adverse events (25.1%) [71]. The incidence of RCCEP, a camrelizumab specific reaction, was 40% (32/80), possibly due to the reactivation of the immune response caused by camrelizumab. It disrupts the balance between angiogenic growth factors and anti-angiogenic growth factors, causing abnormal proliferation of skin capillary endothelial cells and ultimately leading to the occurrence of RCCEP, which is an immune stress response.[72]

Hematological toxicity: The incidence of bone marrow suppression caused by WHO-VigiAccess accounted for 10.28% of all adverse reactions, ranking first and accounting for 47.5% of the studies included in the literature, while the incidence of thrombocytopenia was 20%. Hematopoietic stem cells are the origin of blood cell production and can differentiate into various types of blood cells. ICI is often used in combination with chemotherapy or targeted therapy, and the overlapping mechanism may directly or indirectly damage hematopoietic stem cells, exacerbating hematological toxicity.[73] Other chemotherapy drugs can independently activate the immune system. When used in combination with ICI, this dual activation may lead to excessive proliferation of immune cells, thereby attacking hematopoietic stem cells, inhibiting bone marrow hematopoiesis, reducing blood cell production, and increasing hematological toxicity. Therefore, when camrelizumab is used in combination with chemotherapy drugs, regular blood routine monitoring is required.

Serious late-onset events: Late-onset serious ADRs, such as myocarditis (median onset time: 9 weeks) and toxic epidermal necrolysis (TEN) (median onset time: 5.5 weeks), pose significant challenges in the management of patients treated with camrelizumab. These ADRs are associated with high mortality rates (8.8%), emphasizing the need for early detection and intervention.

Early identification and glucocorticoid intervention are key management strategies. The treatment of myocarditis requires adequate rest and vitamin supplementation. During the acute stage, more rest is needed. In the later stage, rest for 1–3 months. Physical labor and strenuous exercise should be avoided within one year. Patients need to regularly monitor their myocardial enzyme spectrum and electrocardiogram to be vigilant about arrhythmia. TEN treatment should be discontinued promptly, with skin care and supportive treatment provided to prevent infection.

4.2 Risk factors

Combination therapy: The majority (85%) of the cases in this study involved the use of camrelizumab in combination with chemotherapy or targeted drugs (e.g., apatinib). This combination therapy approach, while potentially enhancing the therapeutic efficacy, also appears to increase the risk of hepatotoxicity and bleeding through synergistic toxicity. [74]The concurrent use of multiple therapeutic agents can lead to complex pharmacodynamic interactions, which may exacerbate the overall toxicity profile. Therefore, careful consideration should be given to the potential risks and benefits when combining camrelizumab with other therapeutic agents. Close monitoring of liver function tests and coagulation parameters is essential in patients receiving combination therapy to detect and manage any signs of hepatotoxicity or bleeding promptly.

Gender and age: The findings of this study suggest that males (72.5%) and elderly patients (≥75 years) are more susceptible to cardiac toxicity associated with camrelizumab. This observation is consistent with the trends observed for other immune checkpoint inhibitors (ICIs).[75]The increased vulnerability of elderly patients may be attributed to age-related physiological changes, such as decreased organ function and altered pharmacokinetics, which can affect the metabolism and clearance of the drug. Additionally, elderly patients often have a higher prevalence of comorbid conditions, which may further complicate their clinical management. Gender differences in the incidence of cardiac toxicity may be related to biological and hormonal factors that influence the immune response and cardiovascular function. These findings highlight the need for tailored management strategies based on patient demographics to optimize the safety and efficacy of camrelizumab therapy.

4.3 Management strategies

Effective management of camrelizumab-associated adverse drug reactions (ADRs) requires a structured, evidence-based approach prioritizing early recognition, severity-stratified intervention, and outcome optimization. Below, we outline key strategies linked to specific ADR types, emphasizing their proven efficacy in mitigating morbidity and mortality.

Graded intervention: A graded approach to managing ADRs is recommended to ensure appropriate and timely intervention based on the severity of the reaction. For grade 1–2 ADRs, local treatment or temporary discontinuation of the drug may be sufficient to allow the symptoms to resolve. However, for grade 3–4 ADRs, more aggressive management is warranted. Permanent discontinuation of camrelizumab and initiation of corticosteroid therapy (e.g., methylprednisolone 1–2 mg/kg) are advised to control the immune-mediated inflammation effectively.[76] The graded intervention strategy aims to balance the need for effective ADR management with the potential benefits of continued therapy in patients with lower-grade reactions.

Special event management: For myocarditis, a life-threatening ADR with reported mortality up to 50% if untreated. Early combination therapy (within 72 hours of diagnosis) with high-dose corticosteroids (methylprednisolone 1–2 mg/kg/day) + intravenous immunoglobulin (IVIG; 2 g/kg divided over 2–5 days) is strongly recommended. Retrospective cohort studies demonstrate this regimen reduces mortality by 30–40% compared to steroids alone, attributed to synergistic suppression of myocardial autoimmunity and stabilization of left ventricular ejection fraction (LVEF). [9]In cases of TEN, a devastating cutaneous ADR with historical mortality of 30–50%. A multidisciplinary team approach (dermatology, ICU, ophthalmology, nutrition support) is indispensable. First-line therapy combines: (1) high-dose corticosteroids (pulse methylprednisolone 10–15 mg/kg/day for 3 days, then taper), (2) IVIG (3–4 mg/kg/day for 3–4 days) to inhibit Fas-FasL-mediated keratinocyte apoptosis, and (3) plasma exchange (for extensive epidermal detachment >30% BSA). Supportive care (wound care, fluid/electrolyte management, sepsis prophylaxis) reduces secondary complications. Case series report a 20–25% improvement in 28-day survival with this protocol compared to historical controls. For RCCEP, unique to camrelizumab, this benign but cosmetically concerning ADR is managed with local therapy (intralesional corticosteroids, laser ablation) and dose modification (temporary hold for grade 3). Severe cases (50% body surface area) may require permanent discontinuation, though most respond to conservative measures without impacting survival.

4.4 Clinical recommendations

Based on our comprehensive analysis of camrelizumab-associated ADRs, we propose the following evidence-based recommendations to optimize clinical management:

4.4.1 Proactive, time-window-guided monitoring.

(1)
Baseline assessment:Cardiac enzymes (troponin, CK-MB), liver function tests, thyroid function, and complete blood count should be obtained before initiation of camrelizumab.
(2)
Intensive monitoring:Heightened vigilance for ADRs is recommended during the first 8 weeks of treatment, when the majority of events occur.
(3)
Long-term surveillance: For patients on extended therapy, periodic monitoring of cardiac and endocrine function is advised given the potential for delayed-onset irAEs.

4.4.2 Patient education and reporting.

Patients should be educated on common ADRs and instructed to report any new or worsening symptoms promptly.Healthcare providers should maintain high index of suspicion for irAEs, particularly in patients with pre-existing autoimmune conditions.

4.5 Limitations and generalizability considerations

A notable limitation of this study lies in the geographical concentration of adverse drug reaction (ADR) reports within the WHO VigiAccess database. As identified, approximately 99% of camrelizumab-related reports in VigiAccess originated from Asian countries, with a predominant contribution from China, where camrelizumab was first approved and has been widely adopted in clinical practice since 2019. This regional skew raises concerns regarding the global generalizability of our pharmacovigilance findings. The observed ADR profile may therefore primarily reflect the safety experience of Asian patient populations, particularly those in East Asia, and may not fully represent the safety profile in other ethnic groups or healthcare contexts.

Several factors likely contribute to this geographical concentration: (1) camrelizumab received its first regulatory approval in China in May 2019 and was primarily marketed in Asia during the study period; (2) reporting practices and pharmacovigilance infrastructure vary significantly across regions, potentially leading to under-reporting from non-Asian countries; (3) genetic polymorphisms in drug metabolism and immune response genes may influence ADR susceptibility, though our data cannot directly test this hypothesis.

Furthermore, the VigiAccess database lacks denominator data (total number of patients exposed to camrelizumab), precluding calculation of true incidence rates and limiting our analysis to descriptive frequencies. As a passive reporting system, VigiAccess is also subject to inherent limitations including reporting bias, incomplete data fields, and inability to establish causal relationships between camrelizumab and reported events. The observed associations should be interpreted as pharmacovigilance signals requiring further validation rather than confirmed adverse reactions.

While this limitation tempers broad extrapolation, it is important to contextualize the findings within Asia’s role as a key region for camrelizumab use. The data still provide valuable insights into the safety profile of the drug in its most extensively studied population. However, future research should prioritize multi-center, cross-ethnic studies integrating additional global databases (e.g., FAERS, EudraVigilance) and prospective observational cohorts to validate these observations and clarify potential racial/ethnic variations in camrelizumab-associated ADRs. Such efforts will be critical to refining risk stratification and personalized safety monitoring strategies worldwide.

5 Conclusion

This study provides a comprehensive analysis of camrelizumab-related adverse events using both VigiAccess data and a case-based literature review. The dual-source approach enhances our understanding of the drug’s safety profile. Key safety concerns include hematological disorders, skin reactions, and serious events such as myocarditis and toxic epidermal necrolysis. Monitoring priorities should focus on the first 8 weeks of treatment, when most ADRs occur. Future research should address the limitations of the current study, including geographical reporting bias and the need for disproportionality analyses. Additionally, further investigation into the management of camrelizumab-related ADRs and their long-term outcomes is warranted.

Supporting information

S1 Supplementary. Detailed treatment plan and the time of the first adverse reaction occurrence.

(DOC)

pone.0354252.s001.doc^{(647KB, doc)}

S2 Supplementary. Detailed laboratory values,complete imaging findings, and specific drug dosing regimens.

(DOC)

pone.0354252.s002.doc^{(230KB, doc)}

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was supported by the Health Research Project of the Hunan Provincial Health Commission (Grant Number: D202313018845). Therefore, please help add the following information to the Financial Disclosure statement:“Funder: Hunan Provincial Health Commission, Award Number: D202313018845”.

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Dear authors.,

The manuscript entitled ‘Safety Profile of Camrelizumab: An Analysis Based on Literature and Database Review’ presents valuable work. However, to enhance readability, clinical relevance, and overall impact for the readers, the following comments should be addressed.

1. The novelty should be highlighted more clearly in the Introduction part, what does this add beyond existing systematic reviews of immune checkpoint inhibitors?

2. 99% of Vigi Access reports are from Asia, the results may not be generalizable globally. The manuscript should acknowledge under reporting bias in other regions and discuss how this might influence the safety profile.

3. The descriptive analysis of 80 case reports is rich, but the methodology for inclusion/exclusion lacks detail (e.g., was quality of reports assessed?). A PRISMA-style flow diagram is provided, but clearer justification for focusing on Chinese cases is needed.

4. The results rely mainly on descriptive percentages. Consider additional signal detection methods (e.g., disproportionality analysis: ROR, PRR) to strengthen conclusions about specific ADRs.

5. Present study lack of clinical relavence While the manuscript lists ADR frequencies, it does not sufficiently emphasize management strategies and their outcomes (e.g., how effective were steroids or immunoglobulin in preventing mortality?). A more explicit clinical recommendations section would add value

6. Some terms appear inconsistent (e.g., “yyocarditis” instead of “myocarditis,” “carrelizumab” instead of “camrelizumab” in search strategy). Proofreading is needed for typographical and grammatical errors.

7. The conclusion currently repeats results. It should be sharpened to emphasize key practice implications. e.g., the importance of monitoring hematologic and cardiac toxicities at specific time windows (early vs. late onset).

8. At the outset, the manuscript is categorized as a Research Article, but the title and study design clearly indicate it is a Review. It would be more appropriate to revise the article type to Review for consistency with the content.

**********

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Reviewer #1: Yes: Ranakishor Pelluri Ph.D

Department of Pharmacy Practice

KL College of Pharmacy

Koneru Lakshmaiah Education Foundation

(Deemed to be University)

Vaddeswaram, Guntur-522302, India.

**********

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PLoS One. 2026 Jul 23;21(7):e0354252. doi: 10.1371/journal.pone.0354252.r002

Author response to Decision Letter 1

25 Dec 2025

Manuscript Number: PONE-D-25-43837

Paper Title: Safety Profile of Camrelizumab: An Analysis Based on Literature and Database Review

We sincerely thank you for taking the time and effort to review our manuscript and for providing highly constructive and valuable suggestions. These opinions are crucial for enhancing the quality and rigor of our thesis. We have comprehensively revised the manuscript based on the suggestions of all the reviewers.We submitted 3 files, including a clean version, a version of the manuscript with key changes, and this file. In the following, we respond to each of your concerns and recommendations.

Referee 1/problem 1:1. The novelty should be highlighted more clearly in the Introduction part, what does this add beyond existing systematic reviews of immune checkpoint inhibitors?

Reply 1:We thank the reviewer for this important suggestion. We have revised the Introduction to more explicitly state the novelty and gap our study aims to fill. Specifically, we highlight that while systematic reviews on immune checkpoint inhibitors (ICIs) as a class exist, real-world evidence focused specifically on the safety profile of camrelizumab,is a PD-1 inhibitor with a unique adverse reaction like reactive cutaneous capillary endothelial proliferation (RCCEP)—remains scarce. Our study adds value by combining a global pharmacovigilance database analysis (WHO-VigiAccess) with a detailed systematic review of published case reports to provide a comprehensive, dual-perspective analysis of camrelizumab's ADRs.

Change in manuscript:The final paragraph of the Introduction has been strengthened to clearly articulate this novelty (Page 2).

Referee 1/problem 2: 99% of Vigi Access reports are from Asia, the results may not be generalizable globally. The manuscript should acknowledge under reporting bias in other regions and discuss how this might influence the safety profile.

Reply 2: We agree with the reviewer that the geographical concentration of reports is a significant limitation affecting the generalizability of the VigiAccess results. As requested, we have now explicitly acknowledged this as a "Limitation" in the Discussion section. We discuss the potential for under-reporting in non-Asian populations and how this might lead to an incomplete understanding of the ADR profile in different ethnicities. We suggest that the observed profile may be particularly reflective of Asian patients and that future studies in more diverse populations are needed.

Change in manuscript:A new paragraph titled "Limitations" has been added to the Discussion section (Page 46).

Referee 1/problem 3: The descriptive analysis of 80 case reports is rich, but the methodology for inclusion/exclusion lacks detail (e.g., was quality of reports assessed?). A PRISMA-style flow diagram is provided, but clearer justification for focusing on Chinese cases is needed.

Reply 3:We appreciate this suggestion to enhance methodological rigor.

Quality Assessment:We have added a sentence to the Methods section stating that the quality of the included case reports was assessed using the standardized CARE guidelines checklist for case reports. This ensures that the included studies reported essential clinical information adequately.

Justification for Chinese Cases:We have provided a clearer justification in the Methods section ("Descriptive Study" subsection). We explain that camrelizumab is primarily approved and marketed in China, which naturally leads to a predominance of clinical experience and case publications from this country. Therefore, focusing on these cases provides the most relevant and concentrated real-world data currently available for this drug.

Change in manuscript:The Methods section now includes details on quality assessment and a better justification for the geographic focus (Page 4).

Referee 1/problem 4: The results rely mainly on descriptive percentages. Consider additional signal detection methods (e.g., disproportionality analysis: ROR, PRR) to strengthen conclusions about specific ADRs.

Reply 4:This is an excellent suggestion for deepening the pharmacovigilance analysis. However, due to the limitations in obtaining original data on adverse drug reactions from the WHO, we were unable to strengthen the signal of a potential causal relationship through disproportionality analysis using the ROR,PRR.

Referee 1/problem 5: Present study lack of clinical relavence While the manuscript lists ADR frequencies, it does not sufficiently emphasize management strategies and their outcomes (e.g., how effective were steroids or immunoglobulin in preventing mortality?). A more explicit clinical recommendations section would add value.

Reply 5:We thank the reviewer for highlighting this crucial aspect. To significantly enhance the clinical relevance, we have restructured the "Management Strategies" subsection in the Discussion. It now more explicitly links specific ADRs to their management outcomes based on our literature review. For example, we elaborate on the effectiveness of corticosteroids and IVIG in improving outcomes for myocarditis, and the multidisciplinary approach for TEN. Furthermore, we have created a new standalone section in the Conclusion titled "Clinical Recommendations," which provides concise, actionable guidance for clinicians on monitoring, patient education, and intervention timing (e.g., specific time windows for monitoring hematologic and cardiac parameters).

Change in manuscript:The "Management Strategies" part of the Discussion has been expanded. A new "Clinical Recommendations" section has been added to the Conclusion (Page 44-45).

Referee 1/problem 6: Some terms appear inconsistent (e.g., “yyocarditis” instead of “myocarditis,” “carrelizumab” instead of “camrelizumab” in search strategy). Proofreading is needed for typographical and grammatical errors.

Reply 6:We sincerely apologize for these typographical errors. We have conducted a thorough proofreading of the entire manuscript.

"yyocarditis" has been corrected to "myocarditis".

"carrelizumab" in the search strategy has been corrected to "camrelizumab".

All similar inconsistencies and grammatical errors have been carefully identified and corrected.

Change in manuscript: The entire manuscript has been proofread and corrected.

Referee 1/problem 7: The conclusion currently repeats results. It should be sharpened to emphasize key practice implications. e.g., the importance of monitoring hematologic and cardiac toxicities at specific time windows (early vs. late onset).

Reply 7:We agree completely. The Conclusion has been entirely rewritten to avoid mere repetition of results. It now succinctly summarizes the key findings and immediately pivots to the key clinical practice implications, as suggested by the reviewer. We explicitly emphasize the need for:

Vigilant monitoring for early-onset hematological toxicities and late-onset serious events like myocarditis and TEN.

Proactive management strategies, including the critical time windows for specific interventions.

Change in manuscript:The Conclusion section has been significantly revised and sharpened (Page 46).

Referee 1/problem 8: At the outset, the manuscript is categorized as a Research Article, but the title and study design clearly indicate it is a Review. It would be more appropriate to revise the article type to Review for consistency with the content.

Reply 8:Thank you for this correct observation. We agree that the study design, which combines a systematic literature review with a database analysis, is best classified as a Review. We have changed the manuscript category to "Review" as recommended.

Once again, we are deeply grateful for your thorough and constructive comments, which have significantly strengthened our manuscript. We hope that our revisions and responses are now satisfactory and that the manuscript is acceptable for publication.

Sincerely,

Yi Huang

Attachment

Submitted filename: Response to Reviewers.doc

pone.0354252.s004.doc^{(38.5KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0354252.r003

Decision Letter 1

Mohammed Misbah Ul Haq

15 Feb 2026

-->PONE-D-25-43837R1-->-->Safety Profile of Camrelizumab: An Analysis Based on Literature and Database Review-->-->PLOS One

Dear Dr. Huang,

Please submit your revised manuscript by Apr 01 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Mohammed Misbah Ul Haq, Pharm-D

Academic Editor

PLOS One

Journal Requirements:

Additional Editor Comments :

Reviewer Comments

General Assessment

This manuscript presents a combined analysis of real-world pharmacovigilance data from the WHO-VigiAccess database and a descriptive review of published case reports on camrelizumab-associated adverse drug reactions (ADRs). The topic is clinically relevant, particularly given the increasing use of camrelizumab and its distinct toxicity profile (e.g., RCCEP). However, several methodological, interpretative, and presentation issues must be addressed before the manuscript can be considered for publication. Substantial revisions are required to improve scientific rigor, transparency, and clinical relevance.

Major Comments

1. Novelty and Positioning of the Study

While the manuscript addresses camrelizumab-related adverse events, the novel contribution beyond existing reviews of immune checkpoint inhibitors (ICIs) is not sufficiently articulated.

• The Introduction should clearly state what new knowledge this study provides compared with prior ICI safety reviews and post-marketing surveillance analyses.

• The rationale for combining VigiAccess data with a case-based literature review should be explicitly justified.

Recommendation: Strengthen the final paragraph of the Introduction to clearly define the knowledge gap and the specific added value of this dual-source approach.

2. Limitations of VigiAccess Data and Reporting Bias

Approximately 99% of ADR reports originate from Asia, which raises concerns about geographical reporting bias and limited global generalizability.

• Under-reporting in non-Asian regions should be explicitly acknowledged.

• The implications of ethnicity, regional prescribing patterns, and regulatory approval status on the observed safety profile should be discussed.

Recommendation: Add a dedicated Limitations subsection in the Discussion addressing reporting bias, lack of denominator data, and inability to infer causality.

3. Methodology of Literature-Based Case Analysis

The descriptive analysis of 80 published cases is detailed, but methodological transparency is insufficient.

• Inclusion and exclusion criteria require clearer justification.

• It is unclear whether the quality of included case reports was formally assessed.

• The rationale for focusing exclusively on Chinese cases, although plausible, needs to be clearly explained in the Methods.

Recommendation:

• Specify whether a standardized tool (e.g., CARE guidelines) was used to assess case report quality.

• Justify the geographic focus based on drug approval status and availability.

• Ensure the PRISMA flow diagram is clearly referenced and explained in the text.

4. Absence of Signal Detection or Comparative Analysis

The pharmacovigilance analysis is limited to descriptive statistics.

• No disproportionality analyses (e.g., ROR, PRR) are presented to support potential safety signals.

• While data access limitations may exist, this should be explicitly stated.

Recommendation:

If disproportionality analysis is not feasible, clearly acknowledge this limitation and avoid language suggesting causal associations.

5. Clinical Relevance and Management Outcomes

Although ADR frequencies are well described, clinical implications are insufficiently emphasized.

• Management strategies (e.g., corticosteroids, IVIG) are mentioned but not systematically linked to outcomes.

• Mortality and recovery data should be interpreted in a more clinically meaningful manner.

Recommendation:

Expand the Discussion to explicitly connect specific ADRs with management approaches and outcomes, and consider adding a short Clinical Recommendations subsection summarizing actionable points for clinicians.

6. Article Type Misclassification

Despite being categorized as a Research Article, the study design primarily reflects a review combined with database analysis.

Recommendation:

Revise the article type to Review (or clarify with the editorial office) to better align with the content and methodology.

Minor Comments

1. Multiple typographical and terminology errors are present (e.g., “yyocarditis” instead of “myocarditis”).

2. Drug names should be used consistently throughout (e.g., camrelizumab vs. alternative spellings).

3. Some tables are overly detailed and may benefit from streamlining or relocation to supplementary material.

4. The Conclusion section currently repeats results rather than emphasizing implications.

Recommendation:

Careful proofreading is required, and the Conclusion should be rewritten to highlight key safety concerns, monitoring priorities, and future research needs.

Overall Recommendation

Major Revision

The manuscript addresses an important clinical topic but requires substantial revision to improve methodological clarity, acknowledge limitations appropriately, strengthen clinical interpretation, and ensure consistency with journal standards.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #2: (No Response)

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: (No Response)

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #2: (No Response)

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: (No Response)

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: (No Response)

**********

-->6. Review Comments to the Author

Reviewer #2: (No Response)

**********

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #2: Yes: Dr. Hammad Baig

**********

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PLoS One. 2026 Jul 23;21(7):e0354252. doi: 10.1371/journal.pone.0354252.r004

Author response to Decision Letter 2

9 Apr 2026

Dear Editor and Reviewers,

Thank you very much for your thorough review and valuable comments on our manuscript. We have carefully revised the manuscript according to all comments. Below is our point-by-point response:

MAJOR COMMENTS

1. Novelty and Positioning of the Study

Comment: The Introduction should clearly state what new knowledge this study provides compared with prior ICI safety reviews. The rationale for combining VigiAccess data with a case-based literature review should be explicitly justified.

Response: We have completely rewritten the final paragraph of the Introduction to explicitly articulate the three innovative aspects of this study:

Specific Revision Location: Final paragraph of Introduction (original "Against this backdrop..." paragraph)

Revised Text:

"Against this backdrop, this study addresses a critical gap in current literature. While existing systematic reviews aggregate data across ICIs as a class, our work provides the first comprehensive, dual-perspective analysis of camrelizumab-specific ADRs by integrating two complementary approaches: (1) a global pharmacovigilance analysis using the WHO VigiAccess database to capture large-scale real-world ADR signals that reflect post-marketing surveillance patterns; (2) a systematic evaluation of published case reports/case series to detail clinical manifestations, temporal patterns, and management strategies. This dual-source design is deliberately chosen because VigiAccess provides quantitative signal detection across large populations but lacks clinical granularity, while case reports offer rich clinical phenotyping but are subject to publication bias. By synthesizing these complementary data streams, we achieve a more complete safety profile than either source alone. Notably, camrelizumab's unique association with reactive cutaneous capillary endothelial proliferation (RCCEP),rarely reported with other PD-1 inhibitors,underscores the necessity of drug-specific analyses beyond generic ICI reviews. Ultimately, our findings aim to optimize clinical decision-making for camrelizumab and contribute nuanced insights into the safety of PD-1 inhibitors with distinct ADR profiles."

2. Limitations of VigiAccess Data and Reporting Bias

Comment: Approximately 99% of ADR reports originate from Asia, raising concerns about geographical reporting bias. Under-reporting in non-Asian regions should be acknowledged. Implications of ethnicity, regional prescribing patterns, and regulatory approval status should be discussed.

Response: We have added a dedicated "Limitations and Generalizability Considerations" subsection in the Discussion:

New Text:

“Limitations and Generalizability Considerations

While this limitation tempers broad extrapolation, it is important to contextualize the findings within Asia's role as a key region for camrelizumab use. The data still provide valuable insights into the safety profile of the drug in its most extensively studied population. However, future research should prioritize multi-center, cross-ethnic studies integrating additional global databases (e.g., FAERS, EudraVigilance) and prospective observational cohorts to validate these observations and clarify potential racial/ethnic variations in camrelizumab-associated ADRs. Such efforts will be critical to refining risk stratification and personalized safety monitoring strategies worldwide."

3. Methodology of Literature-Based Case Analysis

Comment: Methodological transparency is insufficient. Inclusion/exclusion criteria require clearer justification. Whether the quality of included case reports was formally assessed is unclear. The rationale for focusing exclusively on Chinese cases needs clear explanation.

Response: We have supplemented the "Descriptive Study" subsection in the Methods section as follows:

Specific Revisions:

1. Explicit quality assessment tool:

2. Explanation for geographic focus:

3. PRISMA flow diagram reference:

The inclusion process for case and case series studies is shown in Figure 1 (PRISMA flow diagram), which details the identification, screening, eligibility assessment, and inclusion phases.

4. Absence of Signal Detection or Comparative Analysis

Comment: The pharmacovigilance analysis is limited to descriptive statistics. No disproportionality analyses (e.g., ROR, PRR) are presented. This limitation should be explicitly stated.

Response: We have added the following statement at the beginning of the Results section (in addition to the Discussion):

New Text:

“Data Limitations Statement: It is important to note that the WHO VigiAccess database provides de-identified individual case safety reports without denominator data (total exposed population) or comparison drug data. Consequently, disproportionality analyses such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), or Information Component (IC) could not be performed. The frequencies reported here represent crude counts and proportions among reported cases, not true incidence rates or statistical signals of disproportionate reporting. All associations should be interpreted as descriptive patterns requiring further validation through controlled studies."

5. Clinical Relevance and Management Outcomes

Comment: ADR frequencies are well described, but clinical implications are insufficiently emphasized. Management strategies are mentioned but not systematically linked to outcomes. Mortality and recovery data should be interpreted more meaningfully.

Response: We have added a new "Clinical Recommendations" subsection in the Discussion and expanded the Management Strategies section:

New "Clinical Recommendations" Subsection:

Clinical Recommendations

Based on our comprehensive analysis of camrelizumab-associated ADRs, we propose the following evidence-based recommendations to optimize clinical management:

(1) Proactive, time-window-guided monitoring:

Baseline assessment:Cardiac enzymes (troponin, CK-MB), liver function tests, thyroid function, and complete blood count should be obtained before initiation of camrelizumab.

Intensive monitoring: Heightened vigilance for ADRs is recommended during the first 8 weeks of treatment, when the majority of events occur.

Long-term surveillance: For patients on extended therapy, periodic monitoring of cardiac and endocrine function is advised given the potential for delayed-onset irAEs.

(2) Patient education and reporting:

Patients should be educated on common ADRs and instructed to report any new or worsening symptoms promptly.

Healthcare providers should maintain high index of suspicion for irAEs, particularly in patients with pre-existing autoimmune conditions.

6. Article Type Misclassification

Comment: Despite being categorized as a Research Article, the study design primarily reflects a review combined with database analysis.

Response: We have revised the article type to Review to better align with the content and methodology.

MINOR COMMENTS

1. Multiple typographical and terminology errors have been corrected (e.g., "yyocarditis" → "myocarditis").

2. Drug names have been standardized throughout the manuscript.

3. Tables have been streamlined for clarity.

4. The Conclusion section has been rewritten to emphasize implications rather than repeating results.

We believe these revisions have significantly improved the manuscript. We hope the revised version is now suitable for publication. Thank you again for your valuable feedback and guidance.

Sincerely,

Yi Huang

Attachment

Submitted filename: Response to Reviewers.docx

pone.0354252.s005.docx^{(57.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0354252.r005

Decision Letter 2

Mohammed Misbah Ul Haq

7 Jul 2026

Safety Profile of Camrelizumab: An Analysis Based on Literature and Database Review

PONE-D-25-43837R2

Dear Dr. Yi Huang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Dr. Mohammed Misbah Ul Haq, Pharm-D

Academic Editor

PLOS One

Additional Editor Comments:

Both reviewers recommend acceptance and agree that the authors have satisfactorily addressed all substantive concerns raised during previous review rounds. The manuscript is technically sound, clearly presented, and the data support the conclusions. Reviewer 4 suggested a few minor editorial improvements (typographical correction and brief additions to the Discussion regarding comparison with other PD-1 inhibitors and Camrelizumab dosing), which do not affect the scientific validity of the manuscript. I recommend acceptance.

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: Yes

Reviewer #4: Yes

**********

-->6. Review Comments to the Author

Reviewer #3: General Comments:

The authors have done a commendable job in revising the manuscript. The transition from a "Research Article" to a "Review" better reflects the study's nature, which relies on the WHO-VigiAccess database and a systematic literature review. The dual-perspective approach provides a comprehensive overview of the safety profile of Camrelizumab, which is particularly valuable for clinicians managing patients on this specific PD-1 inhibitor.

Specific Strengths:

Technical Soundness: The methodology is now clearly defined and appropriate for a pharmacovigilance study. Combining large-scale database trends with detailed clinical case reports allows for a more nuanced understanding of both common and rare adverse drug reactions (ADRs).

Clinical Utility: The "Time-to-onset" analysis and the subsequent recommendations for intensive monitoring during the first 8 weeks of treatment provide actionable insights for clinical practice.

Data Clarity: The tables have been significantly improved and streamlined, making the distribution of ADRs across different system organ classes (SOC) easy to interpret.

Language and Presentation: The manuscript is now well-written in standard academic English. The authors have successfully addressed previous typographical and terminological errors (e.g., correcting "myocarditis").

Ethics and Integrity:

The study appears to adhere to publication ethics. The use of the VigiAccess public database and published literature does not raise privacy concerns, and the authors have appropriately cited their sources. There are no concerns regarding dual publication.

Conclusion:

In its current form, the manuscript meets the standards of PLOS ONE. It provides a rigorous analysis of real-world safety data for Camrelizumab, filling a gap in the existing literature. I recommend the manuscript for publication.

Reviewer #4: The manuscript entitled, " Safety Profile of Camrelizumab: An Analysis Based on Literature and Database

Review" has been revised thoroughly by the authors incorporating the changes as per the recommendations and comments of the reviewers. Further, supplementary data is also organised as suggested. Overall, the quality of the manuscript has improved. Minor observations include: 1.In the table 1- category under sex and age-to be marked as unknown (in place of unknow). 2. Supporting literature and content regarding safety profiles of other PD-I inhibitors for comparison may be given in the discussion under management strategies. 3. Relevant information on dose of Camrelizumaband its effects is lacking.

In view of this, it is recommended that the manuscript may be considered at editorial level for acceptance after receiving author's response addressing the minor comments mentioned.

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #3: Yes: Yahya Ali Abdulkareem Abodea

Reviewer #4: No

**********

PLoS One. doi: 10.1371/journal.pone.0354252.r006

Acceptance letter

Mohammed Misbah Ul Haq

PONE-D-25-43837R2

PLOS One

Dear Dr. Huang,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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Supplementary Materials

S1 Supplementary. Detailed treatment plan and the time of the first adverse reaction occurrence.

(DOC)

pone.0354252.s001.doc^{(647KB, doc)}

S2 Supplementary. Detailed laboratory values,complete imaging findings, and specific drug dosing regimens.

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pone.0354252.s002.doc^{(230KB, doc)}

Attachment

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Safety profile of camrelizumab: An analysis based on literature and database review

Yi Huang

Wei Li

Roles

Abstract

Objective

Methods

Results

Conclusion

1 Introduction

2 Methods

2.1 Descriptive study

2.1.1 Search strategy.

2.1.2 Explicit quality assessment tool.

2.1.3 Explanation for geographic focus.

2.1.4 PRISMA flow diagram reference.

Fig 1. Article selection methodology.

2.2 Clinical data extraction

2.3 Statistical analysis

3 Results

3.1 Data limitations statement

3.2 Adverse drug reactions of camrelizumab in WHO-VigiAccess

Table 1. Characteristics of ADR reports of Camrelizumab.

Table 2. Top 30 ADRs of Camrelizumab in the WHO-VigiAccess database.

Table 3. Distribution of AE signals in each SOC.

3.3 Descriptive analysis

Table 4. Basic characteristics of the 80 patients included.

3.4 Clinical manifestations, laboratory examination, management and treatment outcomes

Table 5. Summary of Clinical Manifestations and Prognosis of ADRs in 80 Patients.

4 Discussion

4.1 Core safety concerns

4.2 Risk factors

4.3 Management strategies

4.4 Clinical recommendations

4.4.1 Proactive, time-window-guided monitoring.

4.4.2 Patient education and reporting.

4.5 Limitations and generalizability considerations

5 Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Mohammed Misbah Ul Haq

Roles

Author response to Decision Letter 1

Decision Letter 1

Mohammed Misbah Ul Haq

Roles

Author response to Decision Letter 2

Decision Letter 2

Mohammed Misbah Ul Haq

Roles

Acceptance letter

Mohammed Misbah Ul Haq

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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