Transaminase Changes in Korean Rheumatoid Arthritis Patients with Chronic Hepatitis C after Biologic Therapy

Hyun Mi Kwon; Kichul Shin; Jin Young Moon; Shin-Seok Lee; Won Tae Chung; Jisoo Lee; Sang-Heon Lee; Seong-Wook Kang; Chang Hee Suh; Seung-Jae Hong; Ran Song; Jung-Yoon Choe; Yeong Wook Song

doi:10.4078/jrd.2018.25.2.108

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Kwon, Shin, Moon, Lee, Chung, Lee, Lee, Kang, Suh, Hong, Song, Choe, and Song: Transaminase Changes in Korean Rheumatoid Arthritis Patients with Chronic Hepatitis C after Biologic Therapy

Original Article

J Rheum Dis 2018;25(2):108-115.

Published online: 30 April 2018

DOI: https://doi.org/10.4078/jrd.2018.25.2.108

Transaminase Changes in Korean Rheumatoid Arthritis Patients with Chronic Hepatitis C after Biologic Therapy

Hyun Mi Kwon¹, Kichul Shin², Jin Young Moon¹, Shin-Seok Lee³, Won Tae Chung⁴, Jisoo Lee⁵, Sang-Heon Lee⁶, Seong-Wook Kang⁷, Chang Hee Suh⁸, Seung-Jae Hong⁹, Ran Song¹⁰, Jung-Yoon Choe¹¹, Yeong Wook Song^1,¹²

¹Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

²SMG-SNU Boramae Medical Center, Seoul, Korea

³Chonnam National University Hospital, Gwangju, Korea

⁴Dong-A University Hospital, Busan, Korea

⁵Ewha Womans University Mokdong Hospital, Seoul, Korea

⁶Konkuk University Medical Center, Seoul, Korea

⁷Chungnam National University Hospital, Daejeon, Korea

⁸Ajou University Hospital, Suwon, Korea

⁹Kyung Hee University Medical Center, Seoul, Korea

¹⁰Kyung Hee University Hospital at Gangdong, Seoul, Korea

¹¹Daegu Catholic University Medical Center, Daegu, Korea

¹²Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Medical Research Center, Seoul National University, Seoul, Korea

Corresponding to: Yeong Wook Song http://orcid.org/0000-0002-5384-3437 Division of Rheumatology, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. E-mail: ysong@snu.ac.kr

Received 11 October 20178 December 2017 Accepted 29 December 2017

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

Coexisting chronic hepatitis C can be problematic when treating rheumatoid arthritis (RA). This study examined the changes in the transaminase and viral load in hepatitis C virus (HCV)-infected RA patients after initiating biologic agents.

Methods

A multicenter retrospective study was conducted at 12 University Hospitals in Korea between November 2014 and November 2015, and 78 RA patients, who met the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for RA and were concomitantly infected with HCV, were identified. The baseline and longitudinal clinical data, changes in liver function, and viral RNA titers were evaluated.

Results

Seventeen (21.8%) patients were treated with biologic agents, including etanercept (n=8), adalimumab (n=8), infliximab (n=2), tocilizumab (n=2), abatacept (n=1), and golimumab (n=1) (median 1.5 patient-years). Four patients experienced marked increases in transaminase during treatment with adalimumab (n=2) and tocilizumab (n=2). Two patients (one using adalimumab, the other using tocilizumab) were treated with anti-viral agents and showed dramatic improvement in both the viral RNA and transaminase. One patient discontinued adalimumab due to the repeated elevated transaminase levels along with a twofold increase in the viral RNA titer, and the transaminase level subsequently normalized. No case of overt viral reactivation was identified.

Conclusion

The data support that changes in transaminase and/or viral load associated with biologic agents in HCV-infected RA patients are possible. Therefore, the liver function and viral RNA titer should be followed regularly during biologic therapy.

Keywords: Hepatitis C, Rheumatoid arthritis, Biological therapy, Antirheumatic agents

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Figure 1.

Conventional disease-modifying antirheumatic drug (DMARD) use in rheumatoid arthritis patients with chronic hepatitis C. HCQ: hydroxychloroquine, MTX: methotrexate, SSLZ: sulfasalazine, LEF: leflunomide, TAC: tacrolimus, CsA: cyclosporine A.

Table 1.

Characteristics of patients with chronic hepatitis C at the time of rheumatoid arthritis diagnosis

Variable	Biologic DMARD ever-users (n=17)	Conventional DMARD only-users (n=61)	Total patients (n=78)
Age (yr)	52.8±13.1	57.1±10.6	56.2±11.2
Female gender	14 (82.4)	46 (75.4)	60 (76.9)
Disease duration of RA (yr)	10.0±6.1	7.1±4.6	7.8±5.0
BMI (n=69)	20.2±6.6	23.7±0.5	23.1±3.3
Alcohol consumer (n=69)	1 (5.9)	7 (11.5)	8 (11.6)
Smoker (n=71)	0	10 (16.4)	10 (14.1)
Previous	0	7 (11.5)	7 (9.0)
Current	0	3 (4.9)	3 (3.8)
RF positive (n=78)	15 (88.2)	46 (75.4)	61 (78.2)
Titer (IU/mL) (n=69)*	246.7±278.5	108.6±170.3	140.7±206.8
Anti-CCP positive (n=55)	9 (81.8)	32 (72.7)	41 (74.5)
Titer (IU/mL) (n=38)^†	112.3±131.7	46.2±36.7	103.6±125.1
ESR (mm/h) (n=76)^‡	50.2±21.6	39.4±25.0	41.8±24.5
CRP (mg/dL) (n=71)^§	2.1±2.2	1.9±3.4	2.0±3.2
Comorbidities (n=77)
Fatty liver	2 (11.8)	6 (9.8)	8 (10.4)
Diabetes mellitus	2 (11.8)	11 (18.0)	13 (16.9)
Hypertension	3 (17.6)	25 (41.0)	28 (36.4)
Duration of HCV infection, years HCV genotype (n=24)	7.6±1.9	6.6±3.3	8.0±5.9
Genotype 1a	0	0	0
Genotype 1b	1 (5.9)	6 (9.8)	7 (9.0)
Genotype 2a	2 (11.8)	14 (23.0)	16 (20.5)
Genotype 2b	0	1 (1.6)	1 (1.3)
Anti-viral treatment	1 (5.9)	14 (23.0)	15 (19.2)
Peg-interferon	0	4 (6.6)	4 (5.2)
Ribavirin	0	1 (1.6)	1 (1.3)
Peg-interferon+ribavirin	2 (11.8)	8 (13.1)	10 (12.8)
Sofosbuvir+ribavirin	0	0	0
HBV co-infection	1 (5.9)	2 (3.3)	3 (3.9)

Values are presented as mean±standard deviation or number (%). DMARD: disease-modifying antirheumatic drug, RA: rheumatoid arthritis, BMI: body mass index, RF: rheumatoid factor, Anti-CCP: anticyclic citrullinated protein antibody, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, HCV: hepatitis C virus, HBV: hepatitis B virus. p-values were generated by using Mann-Whitney U test;

^* p=0.024

^† p=0.300

^‡ p=0.080

^§ p=0.402.

Table 2.

Biologic agents used in 17 rheumatoid arthritis patients with chronic hepatitis C

Agents	Mean treatment duration (months)	Duration of exposure (patientㆍ years)
Etanercept (n=8)	35.6 (4.1∼87.4)	23.7
Adalimumab (n=8)	31.2 (8.6∼73.3)	20.8
Infliximab (n=2)	10.4 (6.3∼14.4)	1.7
Tocilizumab (n=2)	22.9 (18.1∼27.8)	3.8
Abatacept (n=1)	14.1	1.2
Golimumab (n=1)	1.9	0.2

Values are presented as mean (minimum to maximum) or mean only.

Table 3.

Clinical characteristics of biologic users in rheumatoid arthritis patients with chronic hepatitis C

No	Gender	Age (yr)	Disease duration of RA (yr)	RF titer (IU/mL)	Anti-CCP titer (IU/mL)	Duration of HCV infection (yr)	HCV RNA titer before biologic use (IU/mL)	Prophylactic anti-viral therapy	Biologic agent(s)	Treatment duration (mo)	Concomitant DMARD use	Baseline AST/ALT (U/L)	Follow-up HCV RNA titer (IU/mL) (mo)	Peak AST/ALT (U/L) within the 2nd year (mo)	Subsequent anti-viral therapies
1	F	71	7.1	NC	1.5	16.2	17,600	No	ETX	87.4	None	190/218	NC	105/39 (8)	-
2	F	69	10.5	634	35.5	4.3	2,760,000	Previous (IFN+RBV)	ETX	5.3	MTX	41/28	NC	33/22 (9)	-
3	F	37	15.1	152	＞100	4.8	Negative	No	ETX	67.5	None	21/16	Negative	40/22 (24)	-
4	F	76	18.8	68.1	28.3	4.7	NC	No	ETX	18.5	None	22/9	NC	30/10 (9)	-
5	F	58	8.5	224	NC	0.3	NC	No	ETX → ABT	4.1→3.8	MTX → MTX	15/9	NC	21/18 (15)	-
6	F	73	17.3	175	NC	17.3	Negative	No	ETX → ADA	19.6→19.1	MTX → None	17/12	Negative	23/15 (8)	-
7	F	78	7.8	36	NC	Unknown	3,811,947	No	ETX → GOL → TCZ	9.8→1.9 →27.7	None	68/34	NC	165/140 (21.3) →53/13 (22.6)	-
8	F	59	3.5	218.2	NC	18.5	NC	No	ADA	29.4	MTX, HCQ	85/83	25,590 (3) →52,512 (27)	238/162 (16)	-
9	F	69	21.5	43	69	1.3	NC	No	ADA	40.6	MTX	37/20	2,330,000 (24.7) →17,500 (27.5)	134/75 (24.7) →44/23(27.5)	IFN +RBV
10	F	39	8.8	12.3	NC	8.8	Negative	No	ADA	73.3	MTX	12/8	Negative	24/28 (6)	-
11	M	62	7.8	26.1	96.1	7.6	NC	No	ADA	8.6	MTX	18/25	NC	22/29 (6)	-
12	F	42	3.4	67.5	＞200	3.5	Negative	No	ADA	29.7	MTX	26/13	NC	23/11 (9)	-
13	F	68	1.6	405.9	NC	2.9	NC	No	ADA	11.1	MTX	18/15	＜15 (34.5) →15 (43.1)	20/13 (24)	-
14	F	68	18.1	960.8	＞100	6.8	Negative	No	ADA →ETX	Unknown	Unknown	Unknow n	NC	Unknown	-
15	M	74	7	251	＞600	7	NC	No	IFX	6.3	SSLZ	18/13	NC	19/14 (4)	-
16	F	53	3.9	26.5	＜7	22.3	NC	No	IFX	14.4	None	69/18	205,000 (21.1)	48/26 (9)	-
17	M	73	9.4	647	＞100	25.5	839,227	No	TCZ	18.1	SSLZ	37/30	2,110,902 (4.5)	366/438 (18.1)	Sofosbuvir
													→ 3,958,308 (14.4	)	+RBV

RA: rheumatoid arthritis, RF: rheumatoid factor, Anti-CCP: anticyclic citrullinated protein antibody, HCV: hepatitis C virus, DMARDs: disease-modifying antirheumatic drugs, AST: aspartate aminotransferase, ALT: alanine transaminase, NC: not checked, IFN: interferon, RBV: ribavirin, ETX: etanercept, ABT: abatacept, ADA: adalimumab, GOL: golimumab, TCZ: tocilizumab, MTX: methotrexate, HCQ: hydroxychloroquine, SSLZ: sulfasalazine.

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