Introduction
AntiTNF agents have been recognised as triggers of drug-induced autoimmune-like hepatitis (DI‑ALH); however, less than 100 cases have been reported worldwide, and only a minority involve patients with inflammatory bowel disease (IBD). Robust data in this population are therefore lacking.
Aims & Methods
The primary aim is to describe the characteristics of DI‑ALH associated to antiTNF in adult patients with IBD. Secondary aim is to analyse the impact of combination therapy with immunomodulators.
Multicentre, retrospective, observational case‑control study within the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) Young Group. DI-ALH was defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >x3 upper limit of normal (ULN), alkaline phosphatase (AP) >x2 ULN, or total bilirubin >x2 ULN plus any other enzyme alteration; together with evidence of autoimmunity (autoantibody positivity, IgG increase, or compatible histology). A minimum follow‑up of 6 months with biochemical resolution was required. Each case was matched by age, sex, IBD type, antiTNF agent and year of treatment initiation to three antiTNF–exposed IBD controls without DI‑ALH. Statistical analyses included descriptive statistics and logistic regression.
Results
Twenty DI-ALH cases were included (90% female, 75% Crohn’s disease, 25% ulcerative colitis), with a median follow up 557.5 (353.5, 803) days.
DI‑ALH was associated with infliximab (IFX) in 70% and adalimumab (ADA) in 30%, including 3 patients who developed DI‑ALH with ADA after prior IFX exposure without liver injury. Most cases were clinically mild, hospitalisation occurred in 15%, and no acute liver failure, transplantation or deaths were observed. DI-ALH characteristics and management are described in Table 1.
Sixty matched controls were included, with comparable baseline characteristics and IBD features. Concomitant immunomodulator (azathioprine in all patients) use was less frequent among cases (3, 15%) than in controls (21, 35%) and showed a non‑significant trend towards lower odds of DI‑ALH (OR 0.33, 95%CI 0.09–1.25; p=0.10). DI-ALH cases received lower dose of azathioprine (<1.5 mg/kg, p=0.016), showing a non‑significant protective trend in Firth’s penalised logistic regression (OR 0.05, 95% CI 0.002–1.34; p=0.075).
Symptoms, n (%)
- Asthenia
- Abdominal pain
- Vomiting
- Jaundice
- Pruritus
- Ascites
- Encephalopathy
- Rash
- Fever
- DRESS syndrome
|
10 (50.00)
7 (35.00)
3 (15.00)
2 (10.00)
1 (5.00)
0 (0.00)
0 (0.00)
3 (15.00)
1 (5.00)
0 (0.00) |
Alanine aminotransferase (ALT) U/L, median (IQR)
- At DI-ALH diagnosis
- At its peak
Aspartate aminotransferase (AST) U/L, median (IQR)
- At DI-ALH diagnosis
- At its peak
Alkaline phosphatase (AP) U/L, median (IQR)
- At DI-ALH diagnosis
- At its peak
Gamma-glutamyl transferase (GGT) U/L, median (IQR)
- At DI-ALH diagnosis
- At its peak
Total bilirubin, mg/dL, median (IQR)
|
169 (139, 239), max 939
179.5 (148.5, 385.5), max 939
111.5 (94, 150), max 1207
142 (110, 192), max 1207
97 (70, 195), max 291
249.5 (193.5, 376), max 530
62 (32.5, 232.5), max 432
262 (57, 332), max 484
0.59 (0.40465, 0.8), max 8.6 |
R Factor, mean (SD)
- Hepatocellular, n (%)
- Mixed, n (%)
- Cholestatic, n (%)
| 6.57 (3.97)
- 12 (60.00)
- 6 (30.00)
- 2 (10.00) |
Immunoglobulin levels, mg/dL, median (IQR)
- IgG at DI-ALH diagnosis (n = 18)
- IgG at its peak (n = 16)
- IgG4 at DI-ALH diagnosis (n = 4)
- IgM at DI-ALH diagnosis (n = 17)
- IgA at DI-ALH diagnosis (n = 19)
|
1602.5 (1405, 1980), max 2730
1769.4 (1420, 2075), max 2890
24.5 (14, 163.5), max 296
228 (173, 258), max 561
342 (204, 509.5), max 638 |
- Antinuclear antibodies (ANA) positivity
- Before DI-ALH diagnosis, n (%)
- At DI-ALH diagnosis, n (%)
- ANCA (antineutrophil cytoplasmic antibodies), n (%)
- AntiDNA double string, n (%)
- ASMA (anti‑smooth muscle antibodies), n (%)
- AntiActin, n (%)
- AntiLKM1, n (%)
- AntiSLA, n (%)
- AntiLC1, n (%)
- AntiRo52, n (%)
- AntiPML, n (%)
- AMA (antimitochondrial), AMA-M2, n (%)
- Antisp100, n (%)
- Antigp210, n (%)
|
6 (30.00)
17 (85.00)
3 (15.00)
6 (30.00)
3 (15.00)
1 (5.00)
0 (0.00)
1 (5.00)
0 (0.00)
0 (0.00)
0 (0.00)
2 (10.00)
0 (0.00)
0 (0.00) |
Liver biopsy, n (%)
- Portal lymphoplasmacytic infiltrate
- Interface hepatitis
- Perivenulitis
- Emperipolesis
- Hepatocellular rosette formation
- Lobular hepatitis
- Panacinar hepatitis
- Pyknotic hepatitis
- Pericentral hepatitis
- Massive necrosis
- Eosinophilic infiltrate
- METAVIR Fibrosis: F0, F1, F2, F3, F4
|
10 (100.00)
5 (50.00)
1 (10.00)
0 (0.00)
0 (0.00)
5 (50.00)
1 (10.00)
1 (10.00)
1 (10.00)
1 (10.00)
6 (60.00)
3 (30.00), 4 (40.00), 2 (20.00), 1 (10.00), 0 (0.00). |
CIOMS/RUCAM, mean (SD)
- 0. Excluded, n (%)
- 1-2. Unlikely, n (%)
- 3-5. Possible, n (%)
- 6-8. Probable, n (%)
- > 8. Very probable or definitive, n (%)
RECAM, mean (SD)
- < -3. Excluded, n (%)
- -3, 3. Possible, n (%)
- 4, 7. Probable, n (%)
- > 7. Very probable, n (%)
| 5.64 (1.92)
- 0 (0.00)
- 1 (5.00)
- 7 (35.00)
- 11 (55.00)
- 1 (5.00)
0.95 (4.35)
- 3 (15.79)
- 9 (47.37)
- 6 (31.58)
- 1 (5.26)
|
DI-ALH management
- AntiTNF withdrawal
- Corticosteroid treatment, n (%)
- Budesonide
- Oral Systemic Corticosteroids
- IV Systemic Corticosteroids followed by Oral Systemic Corticosteroids
- Time under corticosteroid treatment, days, mean (SD)
- Azathioprine treatment for DI-ALH (used during less than 1 year and suspended afterwards), n (%)
|
19 (95.00)
10 (50.00)
- 4 (40.00)
- 4 (40.00)
- 2 (20.00)
115.2 (68.04)
1 (5.00) |
Alternative treatment to antiTNF, n (%)
- Non maintenance treatment
- Causal antiTNF maintained (adalimumab)
- Vedolizumab
- Ustekinumab
- Risankizumab
- Tofacitinib
- Upadacitinib
- Long-term immunomodulator, n (%)
|
6 (30.00)
1 (5.00)
4 (20.00)
5 (25.00)
1 (5.00)
1 (5.00)
2 (10.00)
0 (0.00) |
AntiTNF re-exposure after DI-ALH, n (%)
|
18 (90.00)
1 (5.00) * No DI-ALH occurred.
1 (5.00) |
Conclusion
AntiTNF related DI‑ALH in IBD is usually mild and resolves with drug withdrawal and/or corticosteroid treatment. No protective effect of concomitant immunomodulator (azathioprine) use was demonstrated, although the doses administered in DI‑ALH cases were lower than those used in controls.
References
Hoofnagle JH, Björnsson ES. Drug-Induced Liver Injury - Types and Phenotypes. N Engl J Med. 2019;381(3):264-273. doi:10.1056/NEJMRA1816149
Andrade RJ, Aithal GP, de Boer YS, et al. Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report. J Hepatol. 2023;79(3):853-866. doi:10.1016/J.JHEP.2023.04.033
Björnsson HK, Gudbjornsson B, Björnsson ES. Infliximab-induced liver injury: Clinical phenotypes, autoimmunity and the role of corticosteroid treatment. J Hepatol. 2022;76(1):86-92. doi:10.1016/J.JHEP.2021.08.024
Lohse AW, Chazouillères O, Dalekos G, et al. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015;63(4):971-1004. doi:10.1016/J.JHEP.2015.06.030
Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci. 2011;56(4):958-976. doi:10.1007/S10620-011-1611-4
Van Gerven NMF, Verwer BJ, Witte BI, et al. Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. J Hepatol. 2013;58(1):141-147. doi:10.1016/J.JHEP.2012.09.009
Andrade RJ, Robles-Diaz M, Castiella A. Characterizing Drug-Induced Liver Injury With Autoimmune Features. Clin Gastroenterol Hepatol. 2016;14(12):1844-1845. doi:10.1016/J.CGH.2016.07.022
Disclosure
OML has received educational funding from Takeda, Abbvie, Johnson&Johnson, Kern Pharma, Alfasigma, Pfizer, Lilly, Sandoz, Dr. Falk Pharma, Ferring, and Tillotts, and has also served as a speaker for Takeda, Abbvie, Alfasigma, and Lilly.
CO has served as a speaker or received educational funding from Johnson&Johnson, Lilly, Abbvie, Kern, Takeda, Pfizer, Alfasigma, Tillotts and Fresenius.
APD received financial support for travelling and educational activities from Johnsson and Johnsson, AbbVie, Takeda, Alfasigma, Lilly, Faes Farma and Ferring.
EBM has served as speaker for Janssen, Lilly, Tillotts Pharma, Chiesi, Kern, Takeda, and Alfasigma.
YZ has served as a speaker, or has received research or education funding or advisory fees from: AbbVie, Adacyte Therapeutics, Alfa-Sigma, Amgen, Boehringer Ingelheim, Dr Falk Pharma, FAES Pharma, Fresenius Kabi, Ferring, Galapagos, Janssen-J&J, Kern Pharma, Lilly, MSD, Pfizer, Sanofi, Sandoz, Takeda, Tillots Pharma, PSI.
