Calcineurin Inhibitors in the Treatment of Adult Autoimmune Hepatitis: A Systematic Review

Abstract

Background and Aims

A considerable number of autoimmune hepatitis (AIH) patients completely or partially fail on first-line treatment. Several studies on the use of calcineurin inhibitors (CNIs) in the treatment of AIH have been published without focusing on indication. The aim was to assess the efficacy of CNIs in the treatment of adult AIH patients, specifically focusing on indication: first-line intolerant and with first-line insufficient response (failure to achieve or maintain remission), and with second versus third-line treatment.

Methods

A literature search included studies on the use of CNIs in adult AIH. Patients with past or present use of CNIs from the Dutch AIH group cohort were added. The primary endpoint was biochemical remission while using CNIs. Secondary endpoints were biochemical response, treatment failure, and adverse effects.

Results

Twenty studies from the literature and nine Dutch patients were included describing the use of cyclosporine in 59 and tacrolimus in 219 adult AIH patients. The CNI remission rate was 53% in patients with insufficient response to first-line treatment and 67% in patients intolerant to first-line treatment. CNIs were used as second-line treatment in 73% with a remission rate of 52% and as third-line treatment in 22% with a remission rate of 26%. Cyclosporine was discontinued in 13% and tacrolimus in 11% of patients because of adverse events.

Conclusions

CNIs as rescue treatment in adult AIH patients are reasonably effective and safe both with insufficient response or intolerance to previous treatment. Prospective studies are needed.

Graphical abstract

Introduction

Autoimmune hepatitis (AIH) is characterized by hypergammaglobulinemia, autoantibodies and interface hepatitis.1,2 Current first-line treatment consists of prednisolone (PRED) and azathioprine (AZA) leading to remission with acceptable side effects in most patients. However, a considerable number of all patients fail first-line treatment because of intolerable side effects or insufficient response (failure to achieve or maintain remission).3 In noncirrhotic patients with intolerable side effects of PRED, budesonide is an excellent option.3,4 For patients with intolerable AZA side effects 6-mercaptopurine (6-MP), 6-thioguanine (6-TG) or mycophenolate mofetil (MMF) are alternatives.3,5–7 Patients with hepatotoxicity from AZA because of a skewed metabolism can be treated by adding allopurinol or switching to 6-TG.7,8 There are a number of alternative therapies,9 but many, like methotrexate, infliximab, rituximab, sirolimus, and everolimus, have been used as salvage treatments only in small case series.10–14

There is much more experience with the use of the calcineurin inhibitors (CNIs) cyclosporine (CYC) and tacrolimus (TAC) in AIH. In a real-world analysis, the reported use of MMF was most frequent, followed by CNIs.9 Calcineurin inhibitors act through suppression of activated T cells via inhibition of the intracytoplasmic enzyme calcineurin, blocking nuclear transcription of proinflammatory cytokines such as interleukin-2.15 Several systematic reviews were published focusing on the efficacy and safety of second and third-line immunosuppressive therapy for AIH in adults, including CNIs. However, interpretation of data was hampered by heterogeneity of outcome measures and dosing and the reason for conversion to a CNI differed.16–21 The aim of this systematic review, which includes novel results of the Dutch national case series, was to assess the efficacy of CNIs in the treatment of adult AIH patients. We distinguished those with intolerance for first-line treatment, those with insufficient response to first-line treatment, and patients with CNIs as second-line versus third-line treatment.

Methods

Literature search

A literature search of Medline, Embase, Web of Science, and the Cochrane database for relevant studies was performed using combinations of the terms “autoimmune hepatitis,” “chronic active hepatitis,” “calcineurin inhibitor,” “cyclosporin,” “ciclosporine,” “Neoral,” “tacrolimus.” “Prograf,” and “Advagraf.” The exact search strategy is shown in Supplementary File 1). The last search was performed in October 2021. Meeting abstracts were excluded. Reference lists of relevant studies were screened for appropriate articles.

Article selection

Studies written in English, Dutch, German, or French describing the use of a CNI in the treatment of AIH patients 18 years of age or older and with sufficient data on treatment with CNIs were included. Treatment-naïve patients and patients with primary biliary cholangitis (PBC)22 or primary sclerosing cholangitis (PSC)23 variant syndromes before starting a CNI were excluded.

Data extraction

The data extracted from the studies included the type of CNI, sample size, sex, age, disease duration before CNI, treatment duration before CNI, medications before CNI, reason for starting CNI (e.g. intolerance or insufficient response), line of treatment (i.e. second or third), dosage of CNI, dosing based on trough levels (i.e. yes or no, lower and upper limit), duration of CNI treatment, co-medication with CNI, adverse effects and result of CNI treatment (definitions see below), reasons for stopping CNI treatment and duration of follow-up after starting CNI. Authors were not contacted for missing data. Quality of the studies was assessed using the GRADE approach.24

Case series

From the larger Dutch AIH group cohort, all patients with probable and definite AIH according to the international criteria, ≥18 years of age, and with past or present use of CNIs before April 2018 were included in the analysis.2 The larger Dutch AIH group cohort in April 2018 consisted of over 1,300 patients with AIH and AIH variant (overlap) syndromes of all academic and large nonacademic centers in the Netherlands. Informed consent was obtained from each patient included in the study, and the study protocol conformed to the ethical guidelines of latest revision of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee.

Definitions

Treatment failure, response, and remission were defined according to the 2019 AASLD guidelines.25 As IgG and/or gamma globulin changes in articles were seldom reported after diagnosis and during treatment, they were not included in the definitions. Intolerance was stopping because of related side effects. Insufficient response was failure to achieve or maintain remission as determined by the treating physician or as stated in the articles. Treatment failure was a rise in, or stable aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or intolerance. Biochemical response was a drop in AST and ALT below twice the upper limit of the reference or at least a 50% reduction in AST and ALT, without remission. Biochemical remission was normalization of AST and ALT. Efficacy of CNI treatment in the studies was reassessed according to the definitions as far as possible, which could lead to a discrepancy between the original study and results reported in this systematic review. Response to CNIs in the Dutch case series was determined by chart review. Follow-up was defined as time from starting CNI treatment until the last visit. Second-line treatment was defined as starting CNI treatment after treatment with corticosteroids with or without a thiopurine. Third-line treatment was defined as starting CNI after treatment with a second thiopurine, MMF or other immunosuppressants.

Endpoints

The primary endpoint was biochemical remission while using CNI. The secondary endpoints were biochemical response or treatment failure while using CNI.

Statistical analysis

Fisher’s exact test, chi-square test for trend and the Mann-Whitney U test were used with p <0.05 as the level of statistical significance. SPSS v.21 was used for the statistical analysis.

Results

A total of 20 studies were identified and included in this systematic review. Eleven studies reported the use of CYC in 58 patients, and 11 report the use of TAC in 211 patients (Fig. 1).15,26–44 Details of the GRADE scoring across the studies per outcome are summarized in Supplementary Table 1. The quality of the evidence was rated very low for all outcomes. From the Dutch AIH group cohort, nine patients with past or present use of CNI were identified. Eight were treated with TAC and one with CYC and are included in Table 1.

Fig. 1. Flow chart of the literature search for the publications included in the systematic review.

Table 1. Baseline characteristics, pretreatment and treatment details, and treatment outcomes of the Dutch case series.

	Cyclosporine (n=1)	Tacrolimus (n=8)
	First-line treatment intolerance (n=1)	First-line treatment intolerance (n=3)	First-line treatment insufficient response (n=5)
Baseline characteristics
Sex (male/female)	0/1	0/3	3/2
Age at diagnosis (years)	20	56 (36–65)	28 (26–63)
Disease duration (years)	8	7 (2–12)	8 (2–16)
IgG/gamma globulin elevated at diagnosis	1	2/2 (100%)	3/4 (75%)
ANA	1	2/3 (67%)	3/5 (60%)
ASMA	1	3/3 (100%)	4/5 (80%)
SLA	0	1/1 (100%)	0/2 (0%)
LKM	0	0/2 (0%)	0/3 (0%)
AMA	0	0/3 (0%)	0/4 (0%)
Liver biopsy at diagnosis	1	3/3 (100%)	5/5 (100%)
Interface hepatitis	1	2/3 (67%)	5/5 (100%)
Plasma cell infiltrate	1	2/3 (67%)	5/5 (100%)
Biliary changes	1	1/3 (33%)	3/4 (75%)
Cirrhosis at diagnosis	0	0/3 (0%)	1/5 (20%)
Pretreatment details
Max AZA dosage (mg/day)	50	100 (75–100)	100 (50–200)
PRED/Budesonide (N)†	1/0	2/2	5/4
Pretreatment duration (months)	1	2 (1–5)	18 (4–184)
Second-line treatment before CNI, reason for start CNI	No	1 MMF, insufficient response; 1 MMF, intolerance	No
CNI treatment details
Treatment duration (months)	94	8 (1–34)	27 (14–60)
Maximum dose	4.5 (mg/kg/day)	4 (1–5) (mg/day)	4.5 (3–8) (mg/day)
Through level (ng/mL)	100–400	4–15	4–15
Co-medication†	PRED, BUD	2 PRED; 1 PRED, BUD	3 PRED; 2 PRED, BUD
Stopped	0	2	2
Result of CNI treatment
Remission	0	0	1 (20%)
Response	0	0	4 (80%)
Treatment failure	1	3 (100%)	0
Long-term outcome of CNI treatment
Remission/response CNI	0	0	5 (100%)
Stable disease‡	1	2	0
Progression, decompensated cirrhosis	0	1	0
Follow-up (months)	98	26 (8–34)	27 (14–60)

Median (range), number positive/number measured or known (%). ^†Multiple patients were treated with PRED and consecutively with BUD; ^‡No disease progression compared with baseline situation, and without remission or response. AZA, azathioprine; BUD, budesonide; CNI calcineurin inhibitor; MMF, mycophenolate mofetil.

Cyclosporine

Eleven studies described the use of CYC in 58 patients. Five were case reports26–28,30,37 and six were case series.15,29,31,32,43,44 In three case series, the patients treated with CYC were a portion of the entire case series. Data in these studies was variably reported for the entire case series, only the patients treated with CYC or only the pretreated patients.15,32,44 In the Dutch cohort one patient using CYC was identified (Table 1). Taken together a total of 59 patients on CYC were described, 39 women (66%), 20 men (34%). Table 2 describes data on the initial treatment before starting CYC, and Table 3 describes data while on CYC treatment. In seven studies and the Dutch cohort, CYC dosage was adjusted based on through levels.15,27–30,32,43 Overall 59% of the patients reached remission, 22% had a response without remission, 12% had treatment failure on CYC, and 7% of CYC treatment responses could not be determined from the provided data. All 21 patients with known time to remission reached remission within 6 months after initiation of CYC. Treatment with CYC was discontinued in 32 patients (54%). Reasons for discontinuing were intolerable side effects in nine patients (15%), persistent remission in seven (12%), insufficient response in five (8%), and on the patient’s own initiative in one (2%). In 10 patients, the reason for discontinuation could not be determined.

Table 2. Systematic review of cyclosporine in adult AIH patients: data on treatment before starting cyclosporine.

Study		N	Age min-max (year)	Pretreatment	Treatment duration before start CNI min-max (months)	Reason for starting CNI
Mistilis	1985	1	51	PRED/AZA	59	Intolerance
Person	1993	1	31	PRED/AZA	15	Insufficient response
Sherman	1994	4	27–52	4 PRED/AZA	6–36	4 Insufficient responses
Lawrence	1994	1	39	PRED/AZA	25	Insufficient response
Senturk	1995	1	33	PRED/AZA	8	Insufficient response
Fernandes	1999	5	19–62	2 PRED; 3 PRED/AZA	3–12	5 Insufficient responses
Malekzadeh†	2001	10	16–44	7 PRED; 3 PRED/AZA	?	5 Insufficient responses; 5 Intolerance
Wah-Kheong	2012	1	50	PRED/AZA	23	Intolerance
Pape†‡	2019	9	19–66	3 PRED/AZA; 5 PRED/AZA, MMF; 1 PRED/AZA, 6-MP	?	5 Insufficient responses; 4 Intolerance
Noguchi	2020	8	30–55	2 PRED; 6 mPRED	1–3	8 Insufficient responses
Roberts†	2020	17	35 (median)	15 PRED/AZA; 1 PRED/6-MP; 1 PRED; 3 MMF	?	12 Insufficient responses; 5 Intolerance
Dutch cohort		1	20	1 PRED/AZA	1	1 Intolerance
Summary		59	16–66	50 CYC as second-line treatment; 9 CYC as third-line treatment		42 Insufficient responses; 17 Intolerance

^†Portion of the entire case series. ^‡Treatment duration not reported for cyclosporine patients only. 6-MP, 6-mercaptopurine; AZA, azathioprine; CYC, cyclosporine; MMF, mycophenolate mofetil; mPRED, methylprednisolone; PRED, prednisolone.

Table 3. Systematic review of cyclosporine in adult AIH patients: data on cyclosporine treatment.

Study		n	Age min-max (year)	Start dosage min-max (mg/kg/day)	Through level min-max (ng/mL)	Co-medication	Treatment duration min-max (months)	Adverse effects	Result of treatment	Follow-up min-max (months)
Mistilis	1985	1	51	3	No	PRED	24	Rise in Creatinine	Response	24
Person	1993	1	31	?	80–130	PRED/AZA	21	No	Remission	39
Sherman	1994	4	27–52	3	180–220	1 No; 3 PRED/AZA	4–26	4 Gingival hyperplasia; 1 Paresthesia; 1 Rise in creatinine	2 Remission; 1 Response; 1 Treatment failure	4–26
Lawrence	1994	1	39	2.5	200	No	9	No	Response	9
Senturk	1995	1	33	3	100–300	No	15	1 Rise in creatinine	Remission	15
Fernandes	1999	5	19–62	2–5	No	2 No; 3 PRED	12–63	2 Hypertrichosis; 2 Gingival hyperplasia; 1 Varicella zoster	4 Remission; 1 Response	12–63
Malekzadeh†	2001	10	16–44	2–5	100–300	?	?–6	Yes‡	4 Remission; 5 Response; 1 Treatment failure	Unknown
Wah-Kheong	2012	1	50	?	No	PRED	9	No	Remission	9
Pape†§	2019	9	19–66	1.2–3.8	?	3 No; 4 PRED; 1 AZA; 1 BUD	?	Headache; Flu-like symptoms; Gingival hyperplasia	4 Remission; 1 Treatment failure; 4?	?
Noguchi	2020	8	30–55	2–5	150–200	2 PRED; 6 mPRED	1–17	3 Tremor; 1 Rise in creatinine; 1 Thrombo-cytopenia; 1 CMV reactivation	8 Remission	7–118
Roberts†	2020	17	35 (median)	120 (median, mg/day)	No	?	240 (median)	4 Rise in creatinine; 4 Gingival hyperplasia; 3 Skin disorders; 3 Infection; 2 Hypertension; 1 Neurological¶	10 Remission; 4 Response; 3 Treatment failure	308 (median)
Dutch cohort		1	20	4.5	100–400	PRED	94	No	1 Treatment failure	98
Summary		59	16–66			8 No; 12 PRED; 6 mPRED; 4 PRED/AZA; 1 AZA; 1 BUD; 27?			35 Remission; 13 Response; 7 Treatment failure; 4?

^†Portion of the entire case series; ^‡Frequencies of side effects only reported for the entire case series; ^§Treatment duration and follow-up not reported for cyclosporine patients only; ^¶Included tremor, paresthesia, headache, migraine, anxiety. AZA, azathioprine, BUD, budesonide; CYC, cyclosporine; mPRED, methylprednisolone; PRED, prednisolone.

Cyclosporine: adverse effects

In most studies, adverse effects were reported collectively, not per patient, and multiple adverse effects could occur in one patient. Supplementary Figure 1 shows the minimal number of patients per side effect reported. Eleven of the 87 patients (13%) discontinued CYC because of intolerable adverse effects, one with uncontrollable hypertension, one with paresthesia, one with bloody diarrhea, one with flu-like symptoms, one with kidney failure, one with thrombocytopenia. The reason was not reported in five patients.

Tacrolimus

Eleven studies described the use of TAC in a total of 211 patients. One was a case report39 and 10 were case series.15,33–36,38,40–42,44 In five case series, the patients treated with TAC were a part of the entire case series. Data in these studies was variably reported for the entire case series or only for patients treated with TAC.15,34,39,40,44 In the Dutch cohort, eight patients with past or present use of TAC were identified and are included in Table 1. Taken together a total of 219 AIH patients on TAC were described, including 151 women (69%) and 56 men (26%) The sex of 12 patients could not be determined.

Table 4 describes data on the initial treatment before starting TAC, and Table 5 describes data while on TAC treatment. In seven studies and the current Dutch case series, the TAC dosage was adjusted based on through levels.15,33,35,36,38,41,42 Overall, 59% of the patients reached remission, 15% had a response without remission, and 14% had treatment failure on TAC. Twelve percent of TAC treatment responses could not be determined from the provided data. All 24 patients with a known time to remission reached remission within 12 months after initiation of TAC. Treatment with TAC was discontinued in 39 patients (18%). The reasons for discontinuing TAC were intolerable adverse effects in 24 patients (11%), an insufficient response to TAC treatment in nine (4%), persistent remission in two (1%), because of an adjustment of the diagnosis (from AIH to AIH-PSC variant syndrome) in two (1%), and TAC was stopped on the patient’s own initiative in two (1%).

Table 4. Systematic review of tacrolimus in adult AIH patients: data on treatment before starting tacrolimus.

Study		n	Age min-max (year)	Pretreatment	Treatment duration before start CNI min-max (months)	Reason for starting CNI
Aqel	2004	11	44–84	10 PRED/AZA, 1 PRED	6–14	11 Insufficient responses
Chatur†	2005	5	Adult	5 PRED? AZA	?	Not specified
Larsen	2007	9	16–64	6 PRED/AZA, 3 PRED/MMF	3	9 Insufficient responses
Tannous	2011	13	40.6 (mean)	?	?	Not specified
Than	2016	17	16–70	5 PRED/AZA, 3 PRED/AZA, CYC, 3 PRED/AZA, MMF, 1 PRED, 1 BUD, 1 AZA, 1 PRED/AZA, 6-MP, CYC, 1 PRED/AZA, 6-MP, MMF, CYC, 1 PRED/AZA, 6-MP, MMF	?	16 Insufficient responses; 1 Intolerance
Rubin†	2016	1	61	1 PRED/AZA, MMF	42	1 Insufficient response
Al Taii	2017	23	15–49	23 PRED, 19 AZA, 10 MMF, 9 BUD	?	23 Insufficient responses
Efe†	2017	87	10–67	80 AZA, PRED, or BUD; 7 AZA, PRED or BUD, MMF	3–182	53 Insufficient responses; 34 Intolerance
Pape†§	2019	6	21–57	2 PRED/AZA, 2 PRED/AZA, MMF, 1 PRED/6-TG, MMF; 1 PRED/AZA, 6-TG	?	5 Insufficient responses; 1 Intolerance
Ferre-Aracil	2020	23	48‡	20 PRED, 3 BUD, 22 Thiopurine, 5 MMF, 1 CYC	Median 24, IQR 84	20 Insufficient responses; 3 Intolerance
Roberts†	2020	16	17 (median)	15 AZA, PRED, or BUD; 1 6-MP, PRED or BUD; 11 MMF	?	15 Insufficient responses; 1 Intolerance
Dutch cohort		8	26–65	1 BUD/AZA, MMF, 1 PRED/AZA, MMF, 1 PRED/AZA, 5 PRED/AZA, BUD	1–184	5 Insufficient responses; 3 Intolerance
Summary		219	10–84	153 TAC as second-line treatment; 53 TAC as third-line treatment; 13?	1–184	158 Insufficient responses; 43 Intolerance; 18 Not specified

^†Portion of the entire case series; ^§Treatment duration not reported for tacrolimus patients only. 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; AZA, azathioprine; BUD, budesonide; CYC, cyclosporine; MMF, mycophenolate mofetil; PRED, prednisolone; UDCA, ursodeoxycholic acid.

Table 5. Systematic review of tacrolimus in adult AIH patients: data on tacrolimus treatment.

Study		n	Age min-max (year)	Start dosage min-max (mg/day)	Through level min-max (ng/mL)	Co-medication	Treatment duration min-max (months)	Adverse effects	Result of treatment	Follow-up min-max (months)
Aqel	2004	11	44–84	1	<6	9 PRED/AZA; 1 PRED; 1 PRED/Sirolimus	1–36	4 Headache; 1 Hypertension; 1 Tremor; 1 Generalized edema; 1 Vivid dreams	9 Remission; 2 Treatment failure	?–36
Chatur†	2005	5	Adult	1–4	No	3 PRED; 2 PRED/MMF	6–?	1 Abdominal pain; 1 Tremor	1 Remission; 3 Response; 1 Treatment failure	10–54
Larsen	2007	9	16–64	2–4	<6	6 PRED/AZA; 3 PRED/MMF	12–37	1 Tremor	3 Remission; 6 Response	12–37
Tannous	2011	13	40.6‡	2–6	?	?	1–65	1 Nausea and vomiting; 1 Hair loss; 1 HUS; 1 SSC	11 Remission; 2 Treatment failure	1–65
Than	2015	17	16–70	0.5–5	<6	6 PRED; 5 PRED/AZA; 2 AZA; 2 BUD/MMF; 1 BUD/AZA; 1 PRED/MMF	12–136	2 Headache; 1 Tremor; 1 Psychosis; 1 Abdominal pain; 1 Nausea and vomiting	5 Remission; 3 Treatment failure; 9?	12–204
Rubin†	2016	1	61	5	No	1 PRED/MMF	12	1 Renal failure	1 Treatment failure	39–147
Al Taii	2017	23	15–49	5 (mean)	?	?	35 (median)	2 Gastrointestinal hemorrhage*	6 Remission; 10 Response; 7 Treatment failure	?
Efe†	2017	87	10–67	1–8	No	20 No; 8 MMF; 59?	?	4 Neurologic; 2 Hypertension and generalized edema; 2 Gastrointestinal; 1 Hair loss; 1 Renal failure	65 Remission; 10 Treatment failure; 12?	7–190
Pape†¶	2019	6	21–57	1–5	?	1 No; 5 PRED	?	3 Tremor; 2 Nausea; 1 Diarrhea; 1 Vertigo	5 Remission; 1?	?
Ferre-Aracil	2020	23	48‡	?	?	2 No; 16 Steroids; 6 MMF; 6 Thiopurine	16 (median, IQR 20)	3 Tremor; 2 Headache; 1 Diabetes; 1 Hypertension; 1 Diarrhea; 1 Neuropathy and ototoxicity	18 Remission; 1 Treatment failure; 4?	3–242
Roberts	2020	16	17 (median)	2.0 (median)	No	?	102 (median)	9 Neurological#; 3 Fatigue; 2 Infection; 2 Rise in creatinine; 2 Skin disorders; 1 Hyperkalemia	6 Remission; 10 Response	102 (median)
Dutch cohort		8	26–65	1–8	4–15	5 PRED; 3 PRED → BUD	1–60	3 Tremor; 3 Headache; 1 Abdominal pain; 1 Nausea; 1 Diarrhea; 1 Insomnia	1 Remission; 4 Response; 3 Treatment failure	8–60
Summary		219	10–84	1–8	4–15	23 No; 20 PRED/AZA; 20 PRED; 8 MMF; 7 PRED/MMF; 3 PRED → BUD; 2 AZA; 2 MMF/BUD; 1 AZA/BUD; 1 PRED /Sirolimus; 95?	1–136		130 Remission; 33 Response; 30 Treatment failure; 26?	1–204

^†Portion of the entire case series; ^‡Mean; ^§Frequencies of side effects only reported for the entire case series; ^¶Treatment duration and follow-up not reported for tacrolimus patients only; ^#Included tremor, paresthesia, headache, migraine, anxiety; *Gastrointestinal hemorrhage most likely was a complication of cirrhosis and not related to the drug. AZA, azathioprine; BUD, budesonide; HUS, hemolytic uremic syndrome; MMF, mycophenolate mofetil; PRED, prednisolone; SCC, squamous cell carcinoma; TAC, tacrolimus.

Tacrolimus: adverse effects

In most studies, adverse effects were reported collectively, not per patient, and multiple adverse effects could occur in one patient. Some studies only reported major events or reasons for stopping TAC treatment. Supplementary Figure 2 shows the minimal number of patients per side effect reported. Twenty four of the 219 patients (11%) stopped using TAC because of intolerable adverse effects, five patients with gastrointestinal adverse effects (diarrhea,/abdominal pain or unspecified), five with neurological adverse effects (unspecified), three with hypertension and/or tremor and/or edema, two with renal failure, two with gastrointestinal hemorrhage, one with headache and vomiting, one with headache and tremor, one with hair loss, one with hemolytic uremic syndrome, one with a squamous cell carcinoma. The reason was not specified in two patients.

Insufficient response versus intolerance to first-line treatment

A total of 200 patients were treated with a CNI because of an insufficient response to first-line treatment (Tables 2 and 4). Remission was reached in 105 patients (53%), 37 (19%) had a response without remission and 13 (7%) had treatment failure on CNI. In 45 patients (22%), the result of CNI treatment could not be linked to the reason for starting a CNI or could not be determined from the provided data (Fig. 2). A total of 60 patients were treated with a CNI because of intolerance to first-line treatment (Table 2 and Table 4). Remission was reached in 40 patients (67%), one patient (2%) had a response without remission, and 6 (10%) had treatment failure on CNI. In 13 patients (22%) result of CNI treatment could not be linked to the reason for starting a CNI or could not be determined from the provided data (Fig. 2). There were no significant differences in remission rate, response rate, treatment failure (chi-square for trend, p=0.498), treatment duration (median 22.5 vs. 29 months, p=0.934) or follow-up (median 24 vs. 25 months, p=0.726) between patients treated with CNI because of insufficient response to first-line treatment and because of intolerance to first-line treatment (Fig. 2).

Fig. 2. Results of calcineurin inhibitor treatment.

Insufficient response versus intolerance, and second-line versus third-line treatment.

Second versus third-line treatment

A total of 203 patients (73%) received CNIs as second-line treatment (Tables 2 and 4). Remission was reached in 106 patients (52%), 20 (10%) had a response and 20 (10%) had treatment failure. In 57 patients (28%), the result of CNI treatment could not be linked to the line of treatment or could not be determined from the provided data (Fig. 2). A total of 62 patients (22%) received CNIs as third-line treatment (Tables 2 and 4). Remission was reached in 16 patients (26%), 10 (16%) had a response, and four (6%) had treatment failure. In 32 patients (52%) the result of CNI treatment could not be linked to the line of treatment or could not be determined from the provided data (Fig. 2).

There was no significant difference in the numbers of patients receiving CYC as second- (n=50, 85%) or third-line (n=9, 15%) treatment compared with the number of patients receiving TAC as second- (n=153, 74%) or third-line (n=53, 26%) treatment (p=0.116). Patients receiving CNI as second-line treatment had a significantly higher remission rate compared with patients receiving CNI as third-line treatment. In patients receiving CNI as third-line treatment the outcome was significantly more often unknown compared with the outcomes of patients receiving CNI as second-line treatment (chi-square for trend, p<0.001; Fig. 2).

Discussion

This systematic review of the literature, with the addition of a novel Dutch case series, summarizes and evaluates the use of CNIs in the treatment of over 250 difficult-to-treat adult AIH patients over the last decades. Although several systematic reviews were published on CNIs in the treatment of adult AIH, interpretation of the published data is hampered by heterogeneity of the outcome measures.16–21 In this systematic review, we addressed that problem by redefining the treatment outcomes in the articles according to established definitions.16–20 In studies describing the use of MMF in the treatment of AIH, the reason for starting MMF (e.g. intolerance or insufficient response to first-line treatment) appeared to be an important factor.5,45,46 A recently published position statement also emphasized the importance of the reason for changing treatment.47 Importantly, in this current systematic review there was no difference in response to CNI treatment in patients with intolerance to treatment versus patients with insufficient response to first-line treatment.

The efficacy of both CYC and TAC in the treatment of adult AIH patients seems fairly good, with remissions rates of 59% for both CYC and TAC. If reported, most remissions were achieved within the first year of treatment, which is prognostically favorable.25 CNI monotherapy was used in a minority, 14% in CYC patients and 11% on TAC, while most patients were treated in combination with corticosteroids and/or another immunosuppressants (Tables 3 and 5). In patients using CNIs because of insufficient response to first-line treatment, the remission rate was 53% (Fig. 2). Two previously published reviews reported pooled remission rates of 41% and 32% on MMF.21,48 Compared with MMF, CNIs seem more effective in that group, but there is no available head-to-head comparison.

In patients using CNIs for intolerance to first-line treatment remission rate was 67% (Fig. 2), which seems less effective compared to MMF with pooled remission rates in first-line intolerant patients of 74% and 82%.21,48 As the adverse effect profile of MMF is also more favorable than that of TAC,49 it seems rational to use MMF as second-line treatment in patients with intolerance to first-line treatment, although TAC can certainly be considered in such patients. CNIs were predominately used as second-line treatment, which seemed to be more effective than as third-line treatment, but interpretation is hampered by the fact that data on treatment outcome was more often missing in the third-line treatment group.

Figure 3 summarizes the options after first-line treatment failure. Despite this, a small number of patients will fail CNI treatment because of intolerance (13 % CYC and 11% TAC) or failure to achieve or maintain remission. If treatment failure occurs when CNIs were used as second-line treatment, MMF is the most logical next option, regardless of the reason (intolerance or insufficient response) for switching to CNIs. MMF is the most investigated alternative. As discussed above, it achieves reasonable remission rates, and it is the most used second-line treatment in a real world analysis.9,21,48 If treatment failure occurs when CNIs are used as third-line treatment, and unless MMF has not already been used, patients depend on salvage therapies like methotrexate, infliximab, rituximab, sirolimus, and everolimus.10–14 It is recommended to send patients to specialized centers for second and third-line or salvage treatment.

Fig. 3. Treatment options after first-line treatment failure.

There is extensive experience and safety data with the use of CNIs in liver and other organ transplantation. Of the CNIs, TAC currently is the drug of choice in almost 90% of liver transplantations because of easier drug monitoring, better long-term graft and patient survival with less rejection compared to CYC, and the availability of a once-daily prolonged-release formula, which has a positive impact on patient adherence.50 Currently, most treating physicians probably prefer TAC over CYC if a CNI is needed in AIH, but there are no published head-to-head comparisons in AIH patients.

Safety

Overall, CNI treatment seems to be well tolerated in adult AIH patients. Thirteen percent stopped using CYC and 11% stopped using TAC because of intolerable adverse effects, including only three patients because of renal problems. Minor adverse effects were more prevalent, but can often be controlled by adjustment of the dosage. One reason why CNIs were so well tolerated may be the relatively low through levels maintained compared with the levels obtained in solid organ, including liver, transplantation. Most studies of the use of TAC mainly aimed for through levels of < 6 ng/mL. In the Dutch cohort, the target through levels were below 6 ng/mL in five of the eight patients. The target levels were higher in three patients, but were still below 15 ng/mL. One of the three patients had dose-related adverse effects that were controlled by lowering the dose. Therefore, initially aiming at a TAC trough level of 3–7 ng/mL seems reasonable, especially if combined with other immunosuppression.

Limitations

Despite the more granular data compared with other reviews on the subject, this systematic review, including a novel Dutch case series, has some limitations. The very low rating of the data per outcome according to the GRADE approach (Supplementary Table 1) introduces a high risk of publication and selection bias. All the selected studies were case reports or case series. There is only one case report with treatment failure as a result of CNI treatment, possibly reflecting underreporting of such cases. Most publications reported the results of retrospective studies, resulting in heterogeneity and missing data. Baseline characteristics and treatment outcome were often reported independently, making it impossible to analyze the influence of patient characteristics, such as cirrhosis or sex, on treatment outcome and follow-up was often short. Despite the limitations, conclusions could be drawn from the combined data that may be important for guiding the choices that need to be made in difficult-to-treat AIH. The data may also be the basis for future prospective studies that are currently being planned.

Conclusions

Despite the limitations mentioned and bearing in mind that the quality of the evidence is low, it can be concluded that:

• CNIs appear effective in patients failing first-line treatment, with remission rates of 59% for CYC and TAC.

• CNIs seem to be more effective than MMF in patients with an insufficient response to first-line treatment, with remission rates of 53%.

• CNIs seem to be less effective than MMF in patients intolerant to first-line treatment, but is has a remission rate of 67%.

• CNIs seemed to be more effective as second-line treatment than as third-line treatment. Interpretation was hampered by missing data and selection bias.

• CNI treatment in adult AIH appeared to be well tolerated.

Abbreviations

6-MP

6-mercaptopurine

6-TG

6-thioguanine

AIH

autoimmune hepatitis

ALT

alanine aminotransferase

AST

aspartate aminotransferase

AZA

azathioprine

CNI

calcineurin inhibitor

CYC

cyclosporine

MMF

mycophenolate mofetil

PBC

primary biliary cholangitis

PRED

prednisolone

PSC

primary sclerosing cholangitis

TAC

tacrolimus

Data sharing statement

The data for this study are available from the corresponding author upon reasonable request.