TABLE 2.
Studies on steroid-refractory hepatitis (primary outcome: usage of second-line immunosuppressants)
| Study | Total no. ICI hepatitis | No. received steroids | Steroid dose, duration | Side effects of steroid | Peak ALT levels, IU/L | Unit |
|---|---|---|---|---|---|---|
| Romanski et al10 | 265 | 31 | Cumulative dose of prednisolone (mg) grade 2: 737.5 (375–6000) grade 3: 2325 (575–5987.5) grade 4: 4975 (1867.5–6000) |
Median (range) | ||
| Miller et al11 | 100 | 67 | grade 3: 44 (25–71) days grade 4: 90 (43–121) d |
Anti–CTLA–4: 670 (310–2,574), anti–PD-1/PD-L1 482 (297–2946), combination 414 (300–2991) | Median (IQR) | |
| Smith et al12 | 32 | 31 | Induction: mean 69 (23) (mg) prednisone—equivalent/d (adjusted for weight, mean dose of 0.86 mg/kg 0.21 mg/kg) | Mean (SD) | ||
| Yamamoto et al13 | 21 | 13 | CS 1 mg/kg (5), 0.7 mg/kg (2), 0.5 mg/kg (2), pulse (5) 10 mg (1) | |||
| Owen et al15 | 12 | 10 | 1.8 (1.0–11.4) mo | Median (range) | ||
| Li et al16 | 87 | 87 | Initial mPSL ≥1.5 mg/kg maximum CS dose 2.0 (2.0–2.0) i.v. steroids 80 (92.0%) 60 (40–85) d until achieving a prednisone dose ≤10 mg |
Infection 16 (18.4%), GI bleed 2 (2.3%), hyperglycemia requiring Tx 20 (23.3%), peak glucose 195 (154–286) | 391 (248–606) | Median (IQR) |
| Li et al16 | 128 | 128 | Initial mPSL <1.5 mg/kg maximum steroid dose 1.0 (1.0–1.3) i.v. steroids 42 (32.8%) 44 (32–70) d until achieving a prednisone dose ≤10 mg |
infection 9 (7.0%), GI bleed 3 (2.3%), hyperglycemia requiring Tx 10 (7.8%), peak glucose 166 (137–205) | 314 (234–468) | Median (IQR) |
| Cunningham et al17 | 17 | 15 | DXA 4 mg (1), steroid 1.5 mg/kg i.v. (1), PDN 1 mg/kg (7), PDN taper (2), CS 2 mg/kg i.v. (3) NA |
217 (145–324) | Mean (95% CI) | |
| Sanz-Segura et al18 | 4 | 2 | Oral CS 1 mg/kg/d | |||
| Huffman et al20 | 17 | 16 | Prednisone (14), dexamethasone (2), high-dose methylprednisolone (3) 42 (7–78) d |
261 (IQR: 110–615) | Median (range) Median (IQR) |
|
| Cheung et al21 | 21 | 18 | Dexamethasone (1), prednisolone (11), methylprednisolone (7) | 610 (183–1088.5) | Median (IQR) | |
| Shimomura et al22 | 34 | 7 | High-dose (≥0.5 mg/kg of prednisolone) (6), low-dose (<0.5 mg/kg of prednisolone) (1) | |||
| Swanson et al23 | 2 | 1 | 6 wk | |||
| de la Bruyère et al24 | 12 | 7 | CS 1 mg/kg (3), ≥2 mg/kg (4) 42 (30–44) d |
Median (IQR) | ||
| Swanson et al25 | 6 | 3 | CS 1 mg/kg (5), 0.7 mg/kg (2), 0.5 mg/kg (2), pulse (5) 10 mg (1) 28–77 d |
415 [30–946] | Median (range) | |
| Fan et al27 | 21 | 17 | Prednisone >1 mg/kg/d: 9 58 (14–111) d |
Hyperglycemia (14, 82%), leukocytosis (7, 41%), infection (3, 18%), AMS, melena, venous thromboembolism | Median (IQR) | |
| Kitagataya et al28 | 17 | 4 | PSL 2 mg/kg/d (2), 1 mg/kg/d (1), 1000 mg (1) | 185.5 (61–2488) | Median (range) | |
| Zheng et al29 | 4 | 3 | mPSL 2 mg/kg, i.v. 3 d |
|||
| Daniello et al30 | 33 | 27 | Initial dose: 87 (92), average dose: 47 (37) 33 (27) d |
Mean (SD) | ||
| Cheng et al31 | 3 | 3 | mPSL 1 g | 372, 1211, 896 | ||
| De Martine et al33 | 16 | 10 | Corticosteroid 0.2 mg/kg/d (2), 0.5 mg/kg/d (2), 1 mg/kg/d (5), 2.5 mg/kg/d (1) | 460 (266–3137) | Median (range) | |
| Imoto et al35 | 56 | 4 | mPSL 1000 mg/d (1), PSL 0.6 mg/kg/d (2), PSL 1 mg/kg/d (2) | 58 (47–129) | Median (range) | |
| Zen et al36 | 10 | 10 | PSL (50 mg/d) (3), PSL (40 mg/d) (3), predonisone (80 mg/d) (1), steroid mini pulse (mPSL, 500 mg/d, 3 d), followed by PSL (50 mg/d) (1), mPSL (1), PSL (1) | 226 (93–504) | Median (IQR) | |
| Riveiro-Barciela et al37 | 28 | 28 | Initial dose 60 (52–70) mg/d 2.3 (1.3–3.1) mo |
Infection (2) | 351 (208–910) | Median (IQR) |
| Gauci et al38 | 21 | 13 | 1 [IQR: 1; 1] (0.3; 2) mg/kg/d 1.8 [IQR: 1.7; 3.5] (1.2–12.6) mo |
663 [IQR: 422; 1380] (173–3537) | Median [IQR] (range) | |
| Patrinely, Jr. et al39 | 164 | 150 | PDN or mPSL (147), DXA (1), hydrocortisone (2)| Initially required low-dose steroids (<50 mg daily or <1 mg/kg) (20), required high-dose steroids (129) |
Adrenal insuff (2), infection (7), GI (3), hyperglycemia/diabetes (22), insomnia (7), mood changes (7), muscle weakness/myalgias (3), osteoporosis (2), weight gain (3), others (6) | ||
| Rini et al40 | 125 | 68 | High-dose (≥ 40 mg/d of prednisone or equivalent) (61), low-dose (7) | |||
| Lin et al41 | 51 | 8 | Prednisone 0.5–2 mg/kg 3–6 wk |
|||
| Personeni et al42 | 9 | 3 | Prednisone 1–2 mg/kg | Grade 3-4: 88 (13 –147) grade 1-2: 37 (11–146) |
Median (range) | |
| Purde et al43 | 11 | 6 | 80 (13–145) days | NA | Median (IQR) | |
| Riveiro-Barciela et al45 | 23 | 19 | Prednisone (12), methylprednisone (7) recurrence (n = 8) 63 (25) non-recurrence (n = 15) 66 (18) median (range) 8 wk (0.5–51 wk) |
280 (188–438) | Median (IQR) mean (SD) |
|
| Alomari et al46 | 23 | 20 | >4 wk (18) < 4 wk (2) | |||
| Miah et al47 | 64 | 46 | PDN (23), DXA (6), mPSL (4) median 45 d (range: 21–120 d) |
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| Matsukane et al49 | 65 | 29 | Low-dose (< 0.5 mg/kg PSL) (n = 93), moderate to high dose (0.5–2.0 mg/kg PSL) (n = 36), i.v. mPSL pulse therapy (500–1000 mg, 3 d) (n = 41) |
Abbreviations: CS, corticosteroid; DXA, dexamethasone; mPSL, methylprednisolone; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PDN, prednisone; PSL, prednisolone.