Tacrolimus and mycophenolate mofetil as second-line treatment in autoimmune hepatitis: Is the evidence of sufficient quality to develop recommendations?

Table 1 Baseline characteristics and summary of findings of the 21 studies included in our meta-analysis of second-line treatments for autoimmune hepatitis refractory patients

Ref.	Year	Country	Patients (n)	Female	Mean age	Design	Biochemical remission (%)	Follow-up	Mean dose2
Tacrolimus
Zolfino et al[29]	2002	United Kingdom	5	3/5	28.4 ± 12.26	Retrospective	2/5 (40)	NR	2-4
Aqel et al[30]	2004	United States	11	10/11	63	Retrospective	10/11 (91)	161	3.0
Chatur et al[31]	2005	Canada	3	NR	NR	Retrospective	0/3 (0)	26.5 (10–54)	2-4
Larsen et al[32]	2007	Denmark	9	8/9	36 ± 16.06	Retrospective	9/9 (100)	21.25 ± 8.37	2 (2-4)
Yeoman et al[33]	2011	United Kingdom	9	5/9	39.5 ± 18.07	Retrospective	7/9 (77.8)	NR	NR
Tannous et al[34]	2011	United States	13	10/13	40.6 ± 12.5	Retrospective	12/13 (92.3)	1-65	2-6
Than et al[35]	2016	German, United Kingdom	17	11/17	34.5 ± 15.03	Retrospective	9/17 (53)	84 ± 53.45	2 (0.5-5)1
Efe et al[36]	2017	Europe, United States, Canada, and China	80	60/80	34.7 ± 11.78	Retrospective	58/80 (72.5)	85.75 ± 37.83	3 (0-6)1
Pape et al[17]	2020	Belgium, Netherlands	10	8/10	38 ± 13.67	Retrospective	5/10 (50)	14.5 ± 6.47	3.5 ± 1.72
MMF
Richardson et al[37]	2000	United Kingdom	7	6/7	27.28 ± 10.45	Retrospective	5/7 (71.4)	43 ± 13.92	2
Zolfino et al[29]	2002	United Kingdom	2	1/2	17.5 ± 2.12	Retrospective	0/2 (0)	NR	2
Devlin et al[38]	2004	Canada	5	4/5	54 ± 2.10.83	Retrospective	5/5 (100)	NR	1-2
Chatur et al[31]	2005	Canada	11	NR	NR	Retrospective	7/11 (63.6)	26.5 (10–54)	0.5-2
Czaja et al[39]	2005	United States	7	NR	NR	Retrospective	0/7 (0)	19 ± 7	0.5-3
Inductivo-Yu et al[40]	2007	United States	15	11/15	60 ± 15	Retrospective	11/15 (73.3)	41	2
Hlivko et al[41]	2008	United States	12	NR	NR	Retrospective	8/12 (66.7)	NR	0.5-2
Hennes et al[42]	2008	Germany	36	28/36	41.5 ± 13.24	Retrospective	14/36 (39)	35.38 ± 21.4	1.75 (0.5-3)1
Wolf et al[43]	2009	United States	16	NR	NR	Retrospective	12/16 (75)	NR	1-2
Sharzehi et al[44]	2010	United States	17	13/17	50	Retrospective	8/17 (48)	12	0.5-2
Yeoman et al[33]	2011	United Kingdom	2	1/2	31.5 ± 19.51	Retrospective	1/2 (50)	NR	NR
Baven-Pronk et al[45]	2011	The Netherlands	30	24/30	NR	Retrospective	14/30 (46.7)	39.5 ± 22.51	0.5-3
Jothimani et al[46]	2014	India, United Kingdom	19	16/19	52.25 ± 16.52	Retrospective	14 /19 (73.6)	45.4 ± 21.13	1-2
Roberts et al[47]	2018	Australia	105	92/105	52.5 ± 3.65	Retrospective	63/105 (60)	38.75 ± 10.14	2.0 (1.0-2.0)1
Efe et al[36]	2017	Europe, United States, Canada, and China	121	96/121	41.25 ± 13.45	Retrospective	84/121 (69.4)	66.25 ± 31.77	1 (0-2)1
Giannakopoulos et al[18]	2019	Sweden	22	12/22	50 ± 12.57	Retrospective	10/22 (45.5)	71 (10-54)1	2.0 (1.0–2.5)1

¹Median.

²Mean dose in tacrolimus studies is defined as mg/d and in mycophenolate mofetil studies is defined as g/d. NR: Not reported; MMF: Mycophenolate mofetil.

Table 2 Summary of findings and quality assessment of evidence per our outcomes of interest using the Grading of Recommendations Assessment, Development and Evaluation approach

Outcomes	Certainty assessment							Patient (n)	Certainty	Importance
	Studies (n)	Study design	Risk of bias	Inconsis-tency	Indirect-ness	Imprecision	Other considerations	Per event/in total (%)
Tacrolimus
Biochemical remission	9	Observational	Serious1	Serious2	Not serious	Not serious	None	112/157 (71.3)	+OOO Very low	Critical
Adverse events	7	Observational	Serious1	Serious2	Not serious	Not serious	None	28/143 (19.6)	+OOO Very low	Important
Mortality	9	Observational	Serious1	Not serious	Not serious	Not serious	None	14/157 (8.9)	+OOO Very low	Critical
MMF
Biochemical remission	16	Observational	Serious1	Serious2	Not serious	Not serious	Dose response gradient	256/427 (59.9)	+OOO Very low	Critical
Adverse events	13	Observational	Serious1	Serious2	Not serious	Not serious	None	97/416 (23.3)	+OOO Very low	Important
Mortality	16	Observational	Serious1	Not serious	Not serious	Not serious	Publication bias strongly suspected	22/427 (5.2)	+OOO Very low	Critical

¹Failure to develop and apply appropriate eligibility criteria.

²Statistically significant heterogeneity. MMF: Mycophenolate mofetil.