Clinical Gastroenterology and Hepatology 2018;-:-–-

1 59
2 60
3 61
4 62
5 Increased Mortality Among Patients With vs Without 63
6 64
7 Cirrhosis and Autoimmune Hepatitis 65
8 66
Q7 Floris F. van den Brand,* Koen S. van der Veen,* Ynto S. de Boer,* Nicole M. van Gerven,*
9 67
10 Birgit I. Lissenberg-Witte,‡ Ulrich Beuers,§ Karel J. van Erpecum,k Henk R. van Buuren,¶ 68
11 Jannie W. den Ouden,# Johannus T. Brouwer,** Jan M. Vrolijk,‡‡ Robert C. Verdonk,§§ 69
12 Bart van Hoek,kk Ger H. Koek,¶¶ Joost P. H. Drenth,## Marleen M. J. Guichelaar,*** 70
13 71
Chris J. J. Mulder,* Elisabeth Bloemena,‡‡‡ Carin M. J. van Nieuwkerk,* and Gerd Bouma,* on
14 72
15
behalf of the Dutch Autoimmune Hepatitis Study Group 73
16 74
*Amsterdam Gastroenterology and Metabolism, Department of Gastroenterology and Hepatology, Amsterdam UMC,
17 75
Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; ‡Department of Epidemiology and Biostatistics, Amsterdam UMC,
18 Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; §Department of Gastroenterology and Hepatology, Amsterdam 76
19 UMC, University of Amsterdam, Amsterdam, the Netherlands; kDepartment of Gastroenterology and Hepatology, University 77
20 Medical Center, Utrecht, the Netherlands; ¶Department of Gastroenterology and Hepatology, Erasmus University Medical 78
21 Center, Rotterdam, the Netherlands; #Department of Gastroenterology and Hepatology, Haga Hospital, The Hague, the 79
Netherlands; **Department of Gastroenterology and Hepatology, Reinier de Graaf Groep, Delft, the Netherlands; ‡‡Department
22 80
of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands; §§Department of Gastroenterology and
23 Hepatology, Sint Antonius Hospital, Nieuwegein, the Netherlands; kkDepartment of Gastroenterology and Hepatology, Leiden 81
24 University Medical Center, Leiden, the Netherlands; ¶¶Department of Internal Medicine, division of Gastroenterology and 82
25 Hepatology, Maastricht University Medical Center, Maastricht, the Netherlands; ##Department of Gastroenterology and 83
26 Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands; ***Department of Gastroenterology and 84
Hepatology, Medisch Spectrum Twente, Enschede, the Netherlands; and ‡‡‡Department of Pathology, Amsterdam UMC,
27 85
Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
28 86
29 87
BACKGROUND & AIMS: There have been few reproducible studies of mortality in patients with autoimmune hepatitis
30 (AIH) and its variants. We calculated mortality in a large national cohort of patients with AIH, 88
31 with vs without cirrhosis, in the Netherlands. 89
32 90
33 METHODS: We collected data from 449 patients with established AIH (77% female), from 6 academic and 91
34 10 non-academic hospitals in the Netherlands. We identified 29 patients with AIH and primary 92
35 biliary cholangitis and 35 patients with AIH and primary sclerosing cholangitis (AIH-PSC). 93
36 Mortality and liver transplantation data were assessed from August 1, 2006 through July 31, 94
37 2016. Standardized mortality ratios (SMR) were calculated using age-, sex-, and calendar year- 95
38 matched mortality for the general Dutch population. 96
39 97
40 RESULTS: During the 10-year follow-up period, 60 patients (13%) died (mean age, 71 years; range, 98
41 33–94 years). Twenty-six causes of death were liver related (43%), whereas the others 99
42 could not be attributed to liver disease. Patients with AIH and cirrhosis had significantly 100
higher mortality than the general population (SMR, 1.9; 95% CI, 1.2–3.4), whereas patients
43 101
without cirrhosis did not (SMR, 1.2; 95% CI, 0.8–1.8). Patients with AIH-PSC had the
44 102
largest increase in mortality, compared to the general population (SMR, 4.7; 95% CI, 1.5–
45 14.6), of all groups analyzed. Mortality in patients with AIH and primary biliary cholangitis 103
46 was not greater than the general population. Four or more relapses per decade or not 104
47 achieving remission was associated with an increase in liver-related death or liver trans- 105
48 plantation. Nine patients underwent liver transplantation; 2 died from non-liver related 106
49 causes. Four of 9 patients on the waitlist for transplantation died before receiving a 107
50 donated liver. 108
51 109
52 110
53 111
54 112
55 Abbreviations used in this paper: AIH, autoimmune hepatitis; AIH-PBC, 113
56 autoimmune hepatitis with concurrent primary biliary cholangitis; AIH- 114
PSC, autoimmune hepatitis with concurrent primary sclerosing chol- © 2018 by the AGA Institute
57 angitis; ALT, alanine aminotransferase; IAIHG, International Autoimmune 1542-3565/$36.00 115
58 Hepatitis Group; SMR, standardized mortality ratio. https://doi.org/10.1016/j.cgh.2018.09.046 116

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 2 van den Brand et al Clinical Gastroenterology and Hepatology Vol. -, No. -

117 CONCLUSION: In an analysis of data from a large national cohort of patients with AIH, we found increased 175
118 mortality of patients with cirrhosis, but not of patients without cirrhosis, compared to the 176
119 general Dutch population. Survival was significantly reduced in patients with AIH and features 177
120 of concurrent PSC. 178
121 179
122 Keywords: Long Term; Outcome; Autoimmune Liver Disease; Relapse; Remission. 180
123 181
124 182
125 183
126 utoimmune hepatitis (AIH) is a chronic immune- post-treatment IAIHG score of 12, confirming the 184
127 A mediated inflammatory condition. Therapy is
aimed to prevent disease progression to fibrosis,
diagnosis of AIH. 185
128 Biochemical relapse was defined as an alanine 186
129 cirrhosis, and eventually liver failure and death. Since aminotransferase (ALT) >3 times upper limit of normal 187
130 the introduction of corticosteroid drugs and steroid or an increase of the immunoglobulin G level to >20g/L.1 188
131 sparing thiopurine agents, prognosis has improved Loss of complete biochemical remission was defined as 189
132 dramatically.1,2 While some studies report that patients an increase in ALT above the upper limit of normal on 2 190
133 with AIH have a good prognosis and normal survival,3–5 occasions with a time interval of at least 4 weeks.11 The 191
134 others contradict these findings.6,7 AIH may coexist with time to initial remission was defined as the time between 192
135 primary biliary cholangitis (AIH-PBC) or primary scle- diagnosis and biochemical remission. Variant syndrome 193
136 rosing cholangitis (AIH-PSC) and recent data suggest AIH-PSC was defined as AIH with concurrent PSC based 194
137 that particularly these patients have an impaired on characteristic liver histology and cholangiographic 195
138 outcome.8 findings (magnetic resonance cholangiopancreatography 196
139 We previously assessed the incidence and prevalence and/or endoscopic retrograde cholangiopancreatog- 197
140 of AIH in The Netherlands and generated a database of raphy). The variant with concurrent PBC was defined as 198
141 patients derived from general and tertiary referral hos- AIH with an antimitochondrial antibody titer of >1:80 in 199
142 pitals.9 This cohort has been closely followed. Here, we combination with compatible histology.9 200
143 assessed the mortality and causes of death during 10 Treatment details of immunosuppressive therapy 201
144 years in a clinical cohort of patients with established were assessed from the date of diagnosis to the end of 202
145 with vs without cirrhosis and compared this with the follow-up. The cumulative years of medication were 203
146 general Dutch population. registered as the average dose in milligrams per day over 204
147 1-year intervals. 205
148 206
149 Materials and Methods 207
Mortality and Liver Transplantation
150 208
151 Patient Population 209
Mortality and liver transplantation were assessed
152 210
during 10 years from August 1, 2006, until July 31, 2016
153 Patients with a probable or definite diagnosis of AIH 211
(end of study). Information on mortality and causes of
154 according to the revised original score of the Interna- 212
death were retrieved from medical records and/or by
155 tional Autoimmune Hepatitis Group (IAIHG)10 were 213
contacting the attending physicians or general practi-
156 identified by searching the database of the Dutch Auto- 214
tioners. Liver transplantations were assessed by cross-
157 immune Hepatitis Study Group. The study protocol was 215
checking our cohort with data from the 3 liver trans-
158 approved by the institutional review boards of all 6 ac- 216
plantation centers in the Netherlands. Follow-up ended
159 ademic and 10 general hospitals in the Netherlands that 217
at the date of death or liver transplantation, or at the end
160 participated. 218
of the study. The cumulative person-years at risk was
161 Patients who were alive at the start of the observation 219
4214 years, with a mean of 9.4 years/patient.
162 period (August 1, 2006), did not have a history of liver 220
163 transplantation, and had follow-up data available in the 221
164 medical records were eligible for inclusion. In total, 506 Prognostic Factors 222
165 records were reviewed and 449 patients were included. 223
166 Fifty-seven were excluded for the following reasons: 13 Baseline and follow-up data regarding the age at the 224
167 patients were not alive at start of follow-up; 7 patients start of follow-up, cirrhosis, time to initial remission, 225
168 had undergone liver transplantation before August 1, amount of relapses and loss of remission, immunoglob- 226
169 2006; and 37 patients did not have follow-up data. In ulin G and ALT at diagnosis, variant syndromes, and 227
170 411 (92%) patients in the study-cohort a liver biopsy medication regimes were compared between patients 228
171 was performed, in 38 patients liver biopsy report was who survived and patients with a liver event (liver- 229
172 not performed or the report could not be retrieved. related death or transplantation) in a descriptive 230
173 The diagnosis of AIH was confirmed in all patients manner. Cirrhosis was defined by the pathologist based 231
174 using the revised IAIHG score. All patients had a revised, on liver histology. 232

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 - 2018 Mortality in Autoimmune Hepatitis Patients 3

233 Reference Population 291

234 What You Need to Know 292
235 The expected number of deaths in the AIH cohort was 293
Background
236 calculated using age, gender and calendar year specific 294
Autoimmune hepatitis (AIH) is a chronic immune-
237 mortality risks (2006–2016) retrieved from Statistics 295
mediated inflammatory liver disease. There are few
238 Netherlands. For calculation of the expected death, 296
data and contradictory findings on mortality of pa-
239 mortality rates of 1-year age groups in 1-year periods 297
tients with AIH or its variants.
240 (1  1 format) were used, hence, ageing was taken into 298
241 account. Standardized mortality ratios (SMRs), defined as Findings 299
242 the observed deaths / expected deaths, were used to Survival times of patients with AIH do not differ 300
243 compare the AIH cohort to the general Dutch population. significantly from those of the general Dutch popu- 301
244 Liver-related deaths in our cohort were compared simi- lation unless patients also have cirrhosis or primary 302
245 larly with the general population using expected number sclerosing cholangitis. 303
246 of deaths for the International Classification of 304
247 Diseases–Tenth Revision codes K72-K76 and C22. These Implications for patient care 305
248 codes include deaths due to hepatic failure, cirrhosis, Patients with AIH require close monitoring to pre- 306
249 chronic hepatitis, other (inflammatory) liver diseases, vent cirrhosis. Survival times of patients with AIH are 307
250 and malignant neoplasm of liver and intrahepatic bile shortened by the liver disease itself, rather than by 308
251 ducts, and do not include deaths due to alcoholic, drug- systemic effects of AIH or treatment-related serious 309
252 induced, viral, parasitic, and other infectious liver adverse events. 310
253 diseases. 311
254 312
255 the end of follow-up was 7217 years. All patients had a 313
Statistical Analysis revised AIH score of 12 (post-treatment).10 Viral hep-
256 314
257 atitis B and C was excluded in 446, unknown in 1, and 315
Normally distributed variables were described as positive in 2 patients before AIH was diagnosed. Previ-
258 mean  SD, and non-normally distributed variables were 316
259 ously, the prevalence of hepatitis E was tested in a 317
described as median with range or interquartile range if representative group of 136 patients with AIH in our
260 stated. Categorical data was described as number and 318
261 cohort. No cases of acute hepatitis E virus infection were 319
percentage of total. Overall survival curves were ob- identified, whereas 29 patients had been exposed.12 Anti-
262 tained via Kaplan-Meier estimate. For differences in 320
263 nuclear antibodies and anti–smooth muscle antibodies 321
survival between 2 or more groups the log-rank test was were positive in 61% of tested patients (n ¼ 395) and in
264 used. Patients who received a liver transplantation were 322
265 63% (n ¼ 379), respectively. In total, 86% were positive 323
censored for analysis at the date of transplantation. The for anti-nuclear antibodies or anti–smooth muscle anti-
266 composite endpoint of liver-related death and trans- 324
267 bodies, in 37 (8%) patients results were not available. 325
plantation was used to compare disease related events in Anti-liver/kidney microsomal antibody type 1, charac-
268 AIH and its variants using Cox analysis. Ordinal and 326
269 teristic for AIH type 2, was positive in 17 (6%) of 285 327
continuous variables were compared between 2 groups tested patients. In 61 (14%) patients AMA or histology
270 with the Mann Whitney test (non-normal) or 2-sided 328
271 results were not available. Treatment details of the initial 329
samples t test (normal). For bimodal outcome vari- and last year of treatment are shown in Supplementary
272 ables, 2-sided Fisher’s exact was used. In case continuous 330
273 Table 1. 331
variables of 3 groups were compared, analysis of vari-
274 ance (normal distribution) or the Kruskal-Wallis (non- 332
275 Relapse 333
normal) test was used. Post hoc analyses for correction
276 of multiple testing were performed with the Bonferroni 334
277 in case of analysis of variance and Dunn-Bonferroni in
A total of 200 (45%) patients experienced 1 or more 335
278 case of the Kruskal-Wallis test. The significance level (a)
relapses. Of these patients, 25 (13%) were weaned from 336
279 therapy when this first relapse occurred, and 150 (87%) 337
was set at .05. Statistical analysis were performed with
280 IBM SPSS 22.0 (IBM Corp, Armonk, NY). Kaplan-Meier
patients relapsed while on immunosuppressive therapy. 338
281 curves were computed with GraphPad Prism 7.02 339
282 (GraphPad Software, La Jolla, CA). Mortality 340
283 341
284 During the 10-year follow-up, 55 (14%) AIH patients 342
285 Results died at a mean age of 73 (range, 33–94) years, a median 343
286 time of 142 (range, 12–471) months after diagnosis. In 344
287 Diagnostic characteristics and outcome parameters addition, 2 (7%) patients with AIH-PBC died at the 44 345
288 are summarized in Table 1 and included 385 patients and 54 years of age and 3 (9%) AIH-PSC patients died at 346
289 with AIH, 29 with AIH-PBC, and 35 with AIH-PSC. The the 53, 56, and 57 years of age; all more than 10 years 347
290 cumulative number of patient-years from diagnosis to after diagnosis. 348

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349 Table 1. Characteristics at Diagnosis and Outcome Parameters 407

350 408
AIH AIH-PBC AIH-PSC P Value
351 409
352 Characteristics at diagnosis 410
353 Patients 385 (86) 29 (6) 35 (8) 411
354 Female 300 (78) 27 (93) 21 (60) .006a 412
355 Age, y 46 (2–88) 46 (16–70) 30 (12–54) <.001b 413
MELD score 10 (0–22) 8 (1–22) 7 (2–17) .327
356 IgG, g/L 29  13 24  13 23  9 .110
414
357 ALT, U/L 518 (214–1052) 274 (85–623) 273 (136–701) .007c 415
358 Cirrhosis 52 (18) 4 (14) 1 (3) .133 416
359 ANA and/or SMA positive 325 (91) 19 (70) 29 (94) 417
360 ANA positive 260 (76) 13 (52) 21 (70) 418
SMA positive 216 (66) 13 (54) 19 (63)
361 10-y follow-up
419
362 Time since diagnosis, y 6 (0–34) 5 (0–8) 5 (0–29) 420
363 Cirrhosis development 20 (6) 0 3 (9) 421
364 Liver transplantation 4 (1) 2 (7) 3 (9) 422
365 Deaths 55 (14) 2 (7) 3 (9) 423
Causes of death
366 Hepatobiliary diseases 22 (40.0) 1 (50.0) 3 (100.0)
424
367 Circulatory system diseases 12 (21.8) 1 (50.0) 425
368 Respiratory system diseases 2 (3.6) 426
369 Malignant diseases 12 (21.8) 427
370 Other causes of death 5 (9.1) 428
Unknown 2 (3.6)
371 429
372 430
373 NOTE. Values are n (%), median (interquartile range), or mean  SD. 431
374 AIH, autoimmune hepatitis; AIH-PBC, autoimmune hepatitis with concurrent primary biliary cholangitis; AIH-PSC, autoimmune hepatitis with concurrent primary
Q4 432
sclerosing cholangitis; ALT, alanine aminotransferase; ANA, ; IgG, immunoglobulin G; MELD, Model for End-Stage Liver Disease; SMA, .
375 a
Post hoc analysis showed significant differences between AIH and AIH-PSC (P ¼ .044), AIH-PSC and AIH-PBC (P ¼ .005). 433
376 b
Post hoc analysis showed significant differences between AIH and AIH-PSC (P < .0001) and between AIH-PBC and AIH-PSC (P < .001). 434
c
Post hoc analysis showed a significant (P ¼ .029) difference between AIH and AIH-PBC.
377 435
378 436
379 The overall standardized mortality rate was increased the revised AIH criteria. These analyses were similar to 437
380 in AIH patients with cirrhosis at any time in the disease the overall included population (Supplementary Table 2). 438
381 course and not in AIH patients without cirrhosis Kaplan Meier estimates of patients with AIH are 439
382 (Table 2). To prevent bias due to an overestimation of shown in Figure 1. Comparison with age and gender- 440
383 IAIHG score in the included population, we performed matched population controls shows an increased 441
384 additional stringent analyses after the exclusion of the 61 overall mortality in patients with AIH. Overall survival of 442
385 patients who did not have histology or AMA results, as AIH-PBC patients was similar (P ¼ .71) and survival of 443
386 biliary changes and a positive AMA may deduct points on AIH-PSC patients was decreased compared with the 444
387 general Dutch population (P ¼ .009) (Supplementary 445
388 Table 2. SMR Figure 1). 446
389 447
390 Observed Expected SMR 95% CI 448
391 449
Liver disease–related death 26 0.5 55.2 37.6–81.7
392 Non–liver disease–related 34 40.6 0.8 0.6–1.2 450
393 death 451
394 Overall mortality 452
395 AIH 55 38.8 1.4 1.1–1.8 453
Noncirrhotic 26 21.5 1.2 0.8–1.8
396 454
Cirrhotica 14 7.3 1.9 1.2–3.4
397 Age 50 y b
12 5.6 2.1 1.3–4.0 455
398 Age >50 y b
43 33.2 1.3 0.9–1.8 456
399 AIH-PBC 2 1.6 1.2 0.3–4.9 457
400 AIH-PSC 3 0.6 4.7 1.5–14.6 458
401 459
402 AIH, autoimmune hepatitis; AIH-PBC, autoimmune hepatitis with concurrent 460
403 primary biliary cholangitis; AIH-PSC, autoimmune hepatitis with concurrent 461
404 primary sclerosing cholangitis; CI, confidence interval; SMR, standardized
Figure 1. Overall survival was decreased (P ¼ .022) in pa- 462
mortality ratio.
405 a
Cirrhosis at any time from diagnosis to the end of follow-up. tients with autoimmune hepatitis (AIH) compared with the 463
406 b
Age at the start of the 10-year follow-up. age- and gender-matched Dutch population. 464

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 - 2018 Mortality in Autoimmune Hepatitis Patients 5

465 Survival of the composite endpoint of liver-related Table 3. Patient Characteristics Stratified by Survival of 523
466 mortality or liver transplantation was impaired in AIH Liver-Related Event 524
467 patients with cirrhosis compared patients without 525
Liver-Related
468 cirrhosis (Figure 2). Patients who reached this composite Death or Liver P 526
469 endpoint had significantly more cirrhosis, higher inter- Survival Transplantation Value 527
470 national normalized ratio and lower platelet and albumin 528
471 levels compared with patients who survived (Table 3). Patients 414 (92) 35 (8) 529
472 In uni- and multivariate Cox analysis age, cirrhosis, Female, % 78 71 .399 530
Cirrhosis anytime 68 (16) 11 (31) .013
473 AIH-PSC, 4 or more relapses per decade, or not achieving Relapse þ LOR 2 (0–4) 2 (0–4) .876
531
474 remission were predictors for the composite liver- Remission achieved 375 (91) 29 (83) .126 532
475 related endpoint, whereas AIH-PBC, a pediatric disease Time to remission, mo 4 (0–167) 3 (1–35) .825 533
476 onset, gender, or <4 relapses per decade were not Second- or third-line 42 (10) 13 (37) <.001 534
477 (Table 4). Additional analysis of liver-related deaths in therapy 535
First-line treatment 387 (95) 34 (97) .643
478 AIH patients without censoring liver transplantations Prednisone and 292 (72) 26 (77) -
536
479 shows that patients who died of liver-related events had azathioprine 537
480 histological proven cirrhosis more often compared Prednisone monotherapy 62 (15) 6 (18) - 538
481 with patients who survived (41% vs 19%; P ¼ .01). In Azathioprine monotherapy 33 (8) 1 (3) - 539
482 this Cox regression analysis, histological proven cirrhosis At the time of diagnosis 540
Age, y 43 (2–88) 47 (10–81) .183
483 (P < .001), corrected for age at baseline, was a predicting MELD score 10 (0–32) 11 (5–22) .199
541
484 factor (P ¼ .001) for liver-related death. Creatinine, mmol/L 73 (40–158) 66 (47–98) .195 542
485 Supplementary Figure 2 shows survival of the com- Bilirubin, mmol/L 38 (4–719) 48 (9–353) .368 543
486 posite liver-related endpoint for patients with AIH, AIH- INR 1.1 (0.8–4.7) 1.3 (1.0–4.1) .006 544
487 PBC, and AIH-PSC. Albumin, g/L 38 (17–54) 35 (26–44) .013 545
Platelets ( 109/L) 210 (61–634) 142 (63–232) <.001
488 Twenty-three patients developed cirrhosis during ALT, U/L 484 (13–4693) 228 (36–3080) .259
546
489 therapy, of whom 15 had fibrosis (stage 1–3) at diag- IgG, g/L 26 (7–91) 23 (9–51) .860 547
490 nosis. In all cases, cirrhosis was histologically confirmed 548
491 before August 1, 2006. Both patients who had cirrhosis 549
NOTE: Values are n (%) or median (range), unless otherwise indicated.
492 at diagnosis (hazard ratio, 2.5; 95% confidence interval, ALT, alanine aminotransferase; IgG, immunoglobulin G; INR, international
550
493 1.0–6.2; P ¼ .05) and patients who developed cirrhosis normalized ratio; LOR, loss of remission; MELD, Model for End-Stage Liver 551
494 after diagnosis (hazard ratio, 4.6; 95% confidence in- Disease. 552
495 terval, 1.5–14.0; P < .01) had an increased risk of liver- 553
496 related death or liver transplantation, when compared AIH-PBC (SMR, 48.3; 95% confidence interval, 554
497 with patients without cirrhosis. 6.8–343.2), and AIH-PSC (SMR, 278.3; 95% confidence 555
498 The cause of death was established in 58 patients interval, 89.8–863.0) compared with the general Dutch 556
499 (Table 1). Hepatobiliary disease accounted for 26 deaths, 557
500 resulting in a marked increase of liver-related mortality Table 4. Survival of Liver-Related Death and Liver 558
501 in AIH (SMR, 50.0; 95% confidence interval, 33.0–76.0), Transplantation 559
502 560
Univariate Multivariate
503 561
504 HR (95% CI) P Value HR (95% CI) P Value 562
505 563
506 Age 1.0 (1.0–1.0)a .02a 1.1 (1.0–1.1)a <.01a 564
Gender 0.7 (0.3–1.5) .4
507 Cirrhosis 2.1 (1.0–4.3)a .05a 2.2 (1.1–4.6)a .04a
565
508 AIH-PBC 1.5 (0.5–5.0) .5 566
509 AIH-PSC 2.5 (1.0–6.1) .04a 4.8 (1.7–13.7)a <.01a 567
510 Pediatric onset 0.4 (0.1–1.4) .4 568
511 Relapses per 569
decade
512 0b - - - -
570
513 0.1–1.99 1.2 (0.5–2.9) .7 571
514 2.0–3.99 2.2 (0.8–6.3) .2 572
515 4.0 5.4 (1.4–20.2)a .01a 5.7 (1.4–23.6)a .02a 573
516 Remission not 2.9 (1.0–8.2)a .05a 3.9 (1.2–12.7)a .02a 574
achieved
517 575
518 576
519 Figure 2. Survival of the composite endpoint of liver-related AIH, autoimmune hepatitis; AIH-PBC, autoimmune hepatitis with concurrent 577
death or liver transplantation was significantly decreased in
520 patients with autoimmune hepatitis and cirrhosis compared
primary biliary cholangitis; AIH-PSC, autoimmune hepatitis with concurrent 578
primary sclerosing cholangitis; CI, confidence interval; HR, hazard ratio.
521 with autoimmune hepatitis patients without cirrhosis (P ¼ a
. Q5 579
522 .030). b
Reference category. 580

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 6 van den Brand et al Clinical Gastroenterology and Hepatology Vol. -, No. -

581 population. Patients who died due to hepatobiliary dis- mortality in AIH patients SMR.3–6,13–18 As far as we 639
582 ease encountered multiple (n ¼ 47) complications know the current study comprises the largest cohort of 640
583 contributing to death (Supplementary Table 3). The 3 patients with established AIH and a follow-up of >10 641
584 patients who died due to hepatocellular carcinoma had years. Patients were recruited from general hospitals, 642
585 cirrhosis. The estimated incidence of mortality due to tertiary referral centers, and transplantation hospitals 643
586 HCC in patients with cirrhosis at diagnosis in our study and thus reflects a realistic representation of “real 644
587 was 3.6 per 1000 patient-years at risk. In 2 patients, the world” AIH. The findings of our study are reassuring. 645
588 cause of death could not be unraveled. Survival of pa- Patients without cirrhosis have a normal life expectancy. 646
589 tients who deceased due to non–liver-related causes was Only patients with cirrhosis and particularly AIH-PSC 647
590 not different from the general population, indicating that patients have an impaired survival, which can be 648
591 excess mortality is driven by the underlying liver disease entirely attributed to liver-related complications. No 649
592 (Table 2). excess mortality was seen in deaths unrelated to the 650
593 Death likely related to immunosuppressive therapy underlying liver disease which is in line with findings of 651
594 occurred in one 44-year-old patient who died due to a Hoeroldt et al,6 suggesting that the liver disease and no 652
595 pulmonary aspergillus infection while being treated with other factors, including therapy, are responsible for the 653
596 budesonide, ciclosporin, and mycophenolate mofetil. excess mortality. 654
597 Mortality due to extrahepatic malignancies included We found that liver disease was responsible for 655
598 melanoma (n ¼ 1), lung cancer (n ¼ 2), prostate cancer approximately one third of the deaths in AIH patients, 656
599 (n ¼ 1), colorectal cancer (n ¼ 3), vulvar cancer (n ¼ 1), consistent with 39%–55% of deaths accounted to liver 657
600 urothelial cancer (n ¼ 1), ovarian cancer (n ¼ 1), and 2 disease in other studies.7,15 These studies did not report 658
601 metastatic malignancies with unknown primary tumors. the number of patients with variant syndromes, which 659
602 Patients who died due to hepatobiliary causes generally constitutes a proportion of 10%–15% of AIH 660
603 deceased at a significantly younger age than did those patients.19 In this study, we addressed differences in 661
604 who died of other causes (median age 68 vs 80 years, outcomes among AIH, AIH-PBC, and AIH-PSC. We found 662
605 P ¼ .013). Subgroup analysis for age at start of follow-up that increased overall mortality rate was most profound 663
606 revealed that patients 50 years of age or younger had a in the relatively young group of AIH-PSC patients, which 664
607 higher SMR than patients older than 50 years of age, was entirely attributable to the underlying liver disease. 665
608 compared with the all-cause mortality of the general No excess mortality was seen for AIH-PBC patients. 666
609 population (Table 2). This could be explained by the low Although the latter finding may be explained by the small 667
610 number of deaths in the general population 50 years of number of patients in this group, it is consistent with 668
611 age or younger. other reports in the literature.20 AIH-PBC was defined as 669
612 Survival rates of patients who were managed in aca- AIH with features of PBC and compatible histology, 670
613 demic hospitals and nonacademic hospitals were com- which is less stringent than the Paris criteria; however, 671
614 parable (87% vs 84%; P ¼ .27). we were not able to perform a centralized review of bi- 672
615 opsies. The incidence of mortality due to HCC in patients 673
616 Liver Transplantation with cirrhosis at diagnosis was markedly lower in our 674
617 study than the incidence of HCC in found by Tansel 675
618 During the 10-year follow-up, 9 (2%) patients were et al.21 This may in part be explained by the difference in 676
619 transplanted at a median age of 48 (range, 27–67) years, study design. Furthermore, we cannot exclude that the 677
620 of whom 4 were AIH patients (1%), 2 were AIH-PBC HCC incidence is underestimated because of missing 678
621 patients (7%) and 3 were AIH-PSC patients (9%). cases, as cross-referencing with the Dutch cancer registry 679
622 Seven transplanted patients were alive at the end of was not possible. 680
623 follow-up, 2 died of extrahepatic malignancies (lung In our cohort of relatively young patients, 8% of the 681
624 cancer and melanoma) and were censored for mortality patients reached the composite liver disease endpoint of 682
625 analysis at the date of transplantation. In addition, 4 AIH, liver-related death or liver transplantation over a 10- 683
626 2 AIH-PBC, and 3 AIH-PSC patients were positively year period. Cirrhosis, age, AIH-PSC, more than 4 re- 684
627 screened for, but did not receive, a liver transplantation. lapses per decade, and not achieving remission were 685
628 Two AIH, 1 AIH-PBC, and 1 AIH-PSC patient died of liver- prognostic for this composite liver-related outcome in 686
629 related disease while waiting for a donor liver. uni- and multivariate Cox analysis, which is in line with 687
630 other studies.6,22 Prior studies have shown that pediatric 688
631 onset patients have a more aggressive disease course, yet 689
632 Discussion we did not observe a correlation between a pediatric 690
633 onset and liver-related endpoints, which is likely due to 691
634 Published data on mortality rates in AIH patients and the relatively low number of pediatric onset patients in 692
635 its variants are scarce and contradictory. In some small our cohort.23,24 693
636 and mostly single center studies the observed mortality Patients who reached the composite liver-related 694
637 rates of AIH patients was comparable to the general outcome had lower platelet counts, lower albumin Q3 695
638 population.3–5 Other larger studies showed an increased levels, an increased international normalized ratio, and 696

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 - 2018 Mortality in Autoimmune Hepatitis Patients 7

697 cirrhosis more frequently, compared with patients who rate can entirely be attributed to liver-related 755
698 survived. The differences in laboratory values are likely a complications. 756
699 result of cirrhosis; however, this could not be confirmed 757
700 in our study in an independent multivariate analysis, 758
Supplementary Material
701 because of incomplete data capture on the laboratory 759
702 parameters. In support of this figure, cirrhosis was 760
703 identified using albumin, international normalized ratio, Note: To access the supplementary material accom- 761
704 and the platelet count in a meta-analysis of patients with panying this article, visit the online version of Clinical 762
705 liver disease.25 Gastroenterology and Hepatology at www.cghjournal.org, 763
706 Survival of patients with cirrhosis in our cohort was, and at https://doi.org/10.1016/j.cgh.2018.09.046. 764
707 again, reduced when liver-related deaths without liver References 765
708 transplantations were analyzed, furthermore confirming 1. Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and man- 766
709 the prognostic value of cirrhosis. Hence, even when agement of autoimmune hepatitis. Hepatology 2010; 767
710 transplantation is successful, cirrhosis is still prognostic 51:2193–2213. 768
711 for liver-related death. Both patients with cirrhosis at 2. Lamers MM, van Oijen MG, Pronk M, et al. Treatment options for 769
712 diagnosis and patients who developed cirrhosis during autoimmune hepatitis: a systematic review of randomized 770
controlled trials. J Hepatol 2010;53:191–108.
713 the disease course had an impaired survival of the 771
3. Yoshizawa K, Matsumoto A, Ichijo T, et al. Long-term outcome
714 composite liver-related endpoint, compared with pa- 772
of Japanese patients with type 1 autoimmune hepatitis. Hep-
715 tients without cirrhosis. Not surprisingly, second- or 773
atology 2012;56:668–676.
716 third-line therapy were more frequently required during 774
4. Kanzler S, Lohr H, Gerken G, et al. Long-term management and
717 the disease course of patients who eventually reached prognosis of autoimmune hepatitis (AIH): a single center expe-
775
718 the composite liver-related endpoint. Malignancies have rience. Z Gastroenterol 2001;39:339–341, 344–348. 776
719 been reported in relation to long-term immunosuppres- 5. Malekzadeh Z, Haghazali S, Sepanlou SG, et al. Clinical features 777
720 sive therapy.26 In our cohort no excess of non–liver- and long term outcome of 102 treated autoimmune hepatitis 778
721 related mortality including mortality due to malignancies patients. Hepat Mon 2012;12:92–99. 779
722 was noticed, although 1 patient died of causes related to 6. Hoeroldt B, McFarlane E, Dube A, et al. Long-term outcomes of 780
723 immunosuppressive therapy. The decreased survival was patients with autoimmune hepatitis managed at a nontransplant 781
724 driven by the underlying liver disease and not by sys- center. Gastroenterology 2011;140:1980–1989. 782
725 temic effects of AIH or treatment related serious adverse 7. Gronbaek L, Vilstrup H, Jepsen P. Autoimmune hepatitis in 783
726 events. The number of patients subjected to liver trans- Denmark: incidence, prevalence, prognosis, and causes of 784
727 plantation was low (2%) in our cohort compared with death. A nationwide registry-based cohort study. J Hepatol 785
728 reported numbers of 10%27 and 5%15 reported in 2006 2014;60:612–617. 786
729 and 2010, respectively. In our cohort another 9 (2%) 8. Yang F, Wang Q, Wang Z, et al. The natural history and prog- 787
nosis of primary biliary cirrhosis with clinical features of auto-
730 patients were listed for liver transplantation, of whom 4 788
immune hepatitis. Clin Rev Allergy Immunol 2016;50:114–123.
731 died without being transplanted. Patients with variant 789
9. van Gerven NM, Verwer BJ, Witte BI, et al. Epidemiology and
732 syndromes were more likely to be placed on the trans- 790
clinical characteristics of autoimmune hepatitis in the
733 plantation list than AIH patients. Netherlands. Scand J Gastroenterol 2014;49:1245–1254.
791
734 The strengths of this study are defined by the largest 10. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune
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735 number of included patients with established AIH in both Hepatitis Group Report: review of criteria for diagnosis of 793
736 transplant, nontransplant and general referral hospitals, autoimmune hepatitis. J Hepatol 1999;31:929–938. 794
737 and the certainty that no patients who reached an 11. van Gerven NM, Verwer BJ, Witte BI, et al. Relapse is almost 795
738 endpoint were missed. In addition, the design of this universal after withdrawal of immunosuppressive medication in 796
739 cohort study, following onward those AIH patients who patients with autoimmune hepatitis in remission. J Hepatol 797
740 were alive in 2006, allowed for a SMR assessment 2013;58:141–147. 798
741 compared with the general Dutch population. However, 12. van Gerven NM, van der Eijk AA, Pas SD, et al. Seroprevalence 799
742 those patients who had reached an endpoint before of hepatitis E virus in autoimmune hepatitis patients in the 800
743 baseline were excluded due to this study design. This fact Netherlands. J Gastrointestin Liver Dis 2016;25:9–13. 801
744 and the expected boundaries of a retrospective study, 13. Dhaliwal HK, Hoeroldt BS, Dube AK, et al. Long-term prognostic 802
745 such as missing data, precluding large scale multivariate significance of persisting histological activity despite biochem- 803
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746 regression analysis, are limitations that should be noted. 804
2015;110:993–999.
747 We aimed to address these issues by performing a 805
14. Ngu JH, Gearry RB, Frampton CM, et al. Mortality and the risk of
748 stringent analysis approach in those patients with 806
malignancy in autoimmune liver diseases: a population-based
749 missing data in histology and AMA status. study in Canterbury, New Zealand. Hepatology 2012;
807
750 In conclusion, patients with AIH without cirrhosis 55:522–529. 808
751 have a similar survival rate as the general population. 15. Werner M, Wallerstedt S, Lindgren S, et al. Characteristics and 809
752 Patients with AIH and cirrhosis and patients with an AIH- long-term outcome of patients with autoimmune hepatitis 810
753 PSC variant syndrome have a significant increased risk of related to the initial treatment response. Scand J Gastroenterol 811
754 death and liver transplantation. This impaired survival 2010;45:457–467. 812

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813 16. Feld JJ, Dinh H, Arenovich T, et al. Autoimmune hepatitis: effect 24. Maggiore G, Bernard O, Hadchouel M, et al. Treatment of 871
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816 17. Al-Chalabi T, Underhill JA, Portmann BC, et al. Impact of gender 25. Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver 874
on the long-term outcome and survival of patients with auto- disease have cirrhosis? JAMA 2012;307:832–842.
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822 dromes: the International Autoimmune Hepatitis Group (IAIHG) 880
823 position statement on a controversial issue. J Hepatol 2011; 881
824 54:374–385. 882
825 20. Al-Chalabi T, Portmann BC, Bernal W, et al. Autoimmune hep- Reprint requests 883
826 atitis overlap syndromes: an evaluation of treatment response, Address requests for reprints to: Gerd Bouma, Amsterdam UMC, Vrije Uni-
versiteit Amsterdam, Department of Gastroenterology and Hepatology,
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827 long-term outcome and survival. Aliment Pharmacol Ther 2008; Amsterdam Gastroenterology and Metabolism, de Boelelaan 1117, Amster- Q8 885
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Acknowledgments
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830 terminants of hepatocellular carcinoma in autoimmune hepatitis: Dutch Autoimmune Hepatitis Study Group collaborators: T.C.M.A. Schreuder Q6 888
831 a systematic review and meta-analysis. Clin Gastroenterol (University Medical Center Groningen), E.J. van der Wouden (Isala Hospital,
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Conflicts of interest
The authors disclose no conflicts.
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929 987
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965 Supplementary Figure 1. Kaplan-Meier estimates of overall survival. (A) Survival of patients with autoimmune hepatitis with
1023
966 primary sclerosing cholangitis (AIH-PSC) was decreased compared with the age- and gender-matched population (P ¼ .009) 1024
967 (B) Cumulative survival of AIH with concurrent primary biliary cholangitis (AIH-PBC) did not differ from the age- and gender- 1025
968 matched population (0.714). 1026
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983 Supplementary Figure 2. Survival functions of patients with 1041
autoimmune hepatitis (AIH), AIH with concurrent primary
984 biliary cholangitis (AIH-PBC) and AIH with primary sclerosing 1042
985 cholangitis (AIH-PSC) for the composite endpoint of liver- 1043
986 related death or liver transplantation (P ¼ .081). 1044

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1045 Supplementary Table 1. Treatment Details of in the First and Last Year of Treatment 1108
1046 1109
1047 Initial Year of Treatment Last Year of Treatment 1110
1048 1111
1049 Patients Dose (mg/d) Patients Dose (mg/d) 1112
1050 Prednisone 304 (86) 10 (1–60) 164 (40) 5 (1–40) 1113
1051 Budesonide 4 (1.1) 8 (3–9) 45 (11) 6 (1–9) 1114
1052 Azathioprine 233 (66) 50 (4–200) 256 (62) 75 (13–200) 1115
1053 Second line 1116
1054 Mycophenolate mofetil 4 (1.1) 1500 (250–2000) 23 (5.5) 1000 (500–2000) 1117
1055 Ciclosporin 1 (0.3) 150 6 (1.4) 125 (50–200) 1118
1056 Tacrolimus — — 5 (1.2) 5 (1–7) 1119
1057 Mercaptopurine — — 7 (1.7) 50 (25–75) 1120
Thioguanine 1 (0.3) 16 3 (0.7) 21 (3–50)
1058 1121
1059 1122
1060 NOTE. Values are n (%) or median (interquartile range). The mean time interval between initial and last year of treatment was 16  7 years. 1123
1061 1124
1062 1125
1063 1126
1064 1127
1065 1128
1066 1129
1067 1130
1068 1131
1069 1132
1070 1133
1071 1134
1072 1135
1073 1136
1074 1137
1075 1138
1076 1139
1077 1140
1078 1141
1079 1142
1080 1143
1081 1144
1082 1145
1083 1146
1084 Supplementary Table 3. Complications Contributing to 1147
1085 Death in Patients Who Died of 1148
1086 Supplementary Table 2. Stringent SMR Analysis Hepatobiliary Diseases 1149
1087 1150
1088 Death AIH AIH-PBC AIH-PSC 1151
1089 n ¼ 22 n¼1 n¼3 1152
1090 Observed Expected SMR 95% CI 1153
Decompensated cirrhosis or liver 17 1 2
1091 1154
Liver disease–related death 23 0.4 56.7 37.7–85.3 insufficiency
1092 1155
Non–liver disease–related 32 36 0.9 0.6–1.3 Gastrointestinal hemorrhage 6 1
1093 death Hepatocellular carcinoma 2 1 1156
1094 Overall mortality Cholangiocarcinoma 1 1157
1095 AIH 50 33.4 1.5 1.1–2.0 Hepatorenal syndrome 4 1 1158
1096 Noncirrhotic 24 20.5 1.2 0.8–1.7 Spontaneous bacterial 3 1159
1097 Cirrhotica 14 7.2 1.9 1.2–3.3 peritonitis 1160
1098 Age 50b 13 5.6 2.3 1.3–4.0 Hepatic encephalopathy 3 1161
1099 Age >50 yb 37 27.8 1.3 1.0–1.8 Respiratory insufficiencya 2 1162
1100 AIH-PBC 2 1.4 1.4 0.4–5.6 Sepsis 1 1163
AIH-PSC 3 0.6 5.0 1.6–15.6 Severe coagulopathy 2
1101 1164
1102 1165
1103 NOTE. AIH, autoimmune hepatitis; AIH-PBC, autoimmune hepatitis with con- NOTE. Some patients encountered more than 1 complication. 1166
1104 current primary biliary cholangitis; AIH-PSC, autoimmune hepatitis with con- AIH, autoimmune hepatitis; AIH-PBC, autoimmune hepatitis with concurrent 1167
1105 current primary sclerosing cholangitis; CI, confidence interval; SMR, primary biliary cholangitis; AIH-PSC, autoimmune hepatitis with concurrent 1168
standardized mortality ratio. primary sclerosing cholangitis.
1106 a a 1169
Cirrhosis at any time from diagnosis to the end of follow-up. One patient died due to Aspergillus pneumoniae and another patient had
1107 b
Age at the start of the 10-year follow-up. severe dyspnea subsequent to liver failure. 1170

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