Table 3.
Domains of significant risk factors of cutaneous immune-related adverse events.
| Areas | Domains | Subdomains | Risk factors | CirAEs subtypes |
|---|---|---|---|---|
| Demographic factors | ||||
| Basic information | Age | ≥ 65 | Maculopapular (29) | |
| - (50) | ||||
| ≥ 70 | BP (15) | |||
| - (22, 47) | ||||
| > 75 | - (41) | |||
| Higher age | - (40) | |||
| Gender | Female (post-menopausal)(age ≥52) | - (26) | ||
| Female | - (26) | |||
| Maculopapular (51) | ||||
| Male | - (30, 31) | |||
| Race | White | - (53) | ||
| Asian ancestry | - (44) | |||
| Body status | ECOG PS | 0-1 | - (40, 43, 63) | |
| BMI | >25 | - (23) | ||
| 25 < BMI ≤ 29.9 (Overweight) | - (28) | |||
| > 30 (Obese) | - (28) | |||
| High BMI | - (44) | |||
| Smoking status | Smoking history | Maculopapular (59) | ||
| - (27, 42) | ||||
| Smoking index > 400 | Maculopapular (59) | |||
| Clinical features | Previous treatment history | Skin disease history | Atopic dermatitis | - (55) |
| Cutaneous inflammatory skin diseases | - (24) | |||
| Morphea | - (55) | |||
| Psoriasis | - (55) | |||
| Pemphigus | - (55) | |||
| Other chronic disease history | Inflammatory/auto-immune disease | - (12) | ||
| Atopy | - (12) | |||
| Chronic kidney disease stage 3-4 | - (41) | |||
| Drug allergy history | Drug allergy ≥ 1 | Maculopapular (51) | ||
| Pruritus (37) | ||||
| Nonspecific rash (37) | ||||
| Drug allergies ≥ 3 | - (37) | |||
| Penicillin allergy | - (37) | |||
| History of treatment | Chemotherapy history | Maculopapular (51) | ||
| Treatment regimens | Therapy options | Camrelizumab | RCCEP (64) | |
| Anti-PD-1 | - (56) | |||
| Anti-CTLA-4 therapy | Maculopapular (34) | |||
| Pruritus (34) | ||||
| Anti-PD-(L)1 + anti-CTLA-4 | Maculopapular (34) | |||
| Pruritus (34) | ||||
| - (56) | ||||
| ICIs + TVEC therapy | - (39) | |||
| ICIs + chemotherapy | Pruritus (46) | |||
| ICIs + targeted therapy | - (27) | |||
| Treatment cycles or dose | ≥2 cycles | - (27) | ||
| Longer cycles | - (12) | |||
| High dose of ipilimumab (10mg/kg>3mg/kg) |
- (25) | |||
| Combination drug therapy | No corticosteroid used | - (58) | ||
| Not combined with antiangiogenic drugs | - (61) | |||
| Not use aspirin | Maculopapular (60) | |||
| SJS (60) | ||||
| Vitiligo (60) | ||||
| Cancer types | Nonskin cancer | Renal cell carcinoma | - (56) | |
| Skin cancer | Melanoma | BP (15) | ||
| Maculopapular (46) | ||||
| Vitiligo (46) | ||||
| Multiple toxicities (46) | ||||
| - (56) | ||||
| Non-acral cutaneous melanoma | - (45) | |||
| Nonmelanoma skin cancer | BP (15) | |||
| TNM stage | ≥ 2 | Maculopapular (51) | ||
| Biomarkers | Blood cell counts and ratios | Higher eosinophil count (> 0.5 g/L) | - (12) | |
| AEC > 0.205 × 10^9/L | - (21) | |||
| Eosinophil (EOS%) >1.75% | - (36) | |||
| Higher ALC | - (57) | |||
| Lower NLR | - (40, 43, 63) | |||
| NLR <2.86 | - (32) | |||
| PLR < 156 | - (38) | |||
| Lower LDH | - (40) | |||
| CD4+/CD8+ ratio < 1.10 at baseline | - (58) | |||
| CD4 + PLT + high percentage of circulating leukocyte-PLT complexes | - (62) | |||
| Cytokines | Higher BTLA | Maculopapular (16) | ||
| Higher GM-CSF | Maculopapular (16) | |||
| Higher IL-4 | Maculopapular (16) | |||
| CCL19 increased from baseline to day 42 (threshold of 132–9 pg/mL) | Vitiligo (33) | |||
| High Ang-1 | - (54) | |||
| High CD40L | - (54) | |||
| Immunomodulatory molecules | Higher TIM-3 | Maculopapular (58) | ||
| Higher PD-(L)1 expression | Maculopapular (58) | |||
| PD-L1 expression ≥ 1% | - (16) | |||
| Autoantibodies | Higher anti-BP 180 IgG | BP (35) | ||
| Genetic markers | HLADRB1*11:01 | Pruritus (13) | ||
CirAEs, cutaneous immune-related adverse events. BP, bullous pemphigoid. ECOG PS, Eastern Cooperative Oncology Group performance status. BMI, body mass index. RCCEP, reactive cutaneous capillary endothelial proliferation. PD-(L)-1, programmed cell death (ligand)-1. CTLA-4, cytotoxic T lymphocyte antigen-4. TVEC, talimogene laherparepvec. SJS, Stevens-Johnson syndrome. TNM, tumor node metastasis. AEC, absolute eosinophil count. ALC, absolute lymphocyte count. NLR, neutrophil to lymphocyte ratio. PLR, platelet-to-lymphocyte ratio. LDH, lactate dehydrogenase. PLT, platelet. BTLA, B- and T-lymphocyte attenuator. GM-CSF, granulocyte-macrophage colony stimulating factor. IL-4, interleukin-4. Ang-1, angiopoietins-1. TIM-3, T cell immunoglobulin and mucin domain 3. -, unspecified cirAEs subtypes, overall cirAEs.