Im-Sook Song; Hyun Soon Sohn; Hyunah Kim; Eunjeong Lim; Mihwa Kwon; Ji-Hye Ha; Jin-Won Kwon

doi:10.12793/tcp.2014.22.2.92

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Song, Sohn, Kim, Lim, Kwon, Ha, and Kwon: Impact of smoking on the effectiveness of TNF-α inhibitors in patients with rheumatoid arthritis or Crohn's disease

Original Article

Translational and Clinical Pharmacology 2014;22(2):92-101.

Published online: 30 December 2014

DOI: https://doi.org/10.12793/tcp.2014.22.2.92

Impact of smoking on the effectiveness of TNF-α inhibitors in patients with rheumatoid arthritis or Crohn's disease

Im-Sook Song^1,^#, Hyun Soon Sohn^2,^#, Hyunah Kim³, Eunjeong Lim¹, Mihwa Kwon¹, Ji-Hye Ha⁴, Jin-Won Kwon^1,^∗

¹College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 700–721, South Korea

²Graduate School of Clinical Pharmacy, CHA University, Gyeonggi-do 463–836, South Korea

³College of Pharmacy, Sookmyung University, Seoul 140–742, South Korea

⁴Clinical Research Division, National Institute of Food and Drug Safety Evaluation (NIFDS) Chungcheongbuk-do 363–700, South Korea

^∗Correspondence: J. W. Kwon; Tel: +82-53-950-8557, Fax: +82-53-950-8580, E-mail: jwkwon@knu.ac.kr

^# These authors contributed equally as co-first authors

Received 16 September 201413 December 2014 Accepted 15 December 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Cigarette smoking may be associated with the augmentation of pro-inflammatory cytokines including Tumor Necrosis Factor-alpha (TNF-α), which may affect the outcomes of pharmacological agents such as TNF-α inhibitors. The purpose of this study was to investigate the impact of smoking on the effectiveness of TNF-α inhibitors in patients with rheumatoid arthritis (RA) or Crohn's disease (CD). We used systematic literature review methods. A total of 1,147 articles were selected after exclusion of duplicates through a database search. Among them, 28 articles were finally selected through a review of titles and abstracts and a subsequent review of full articles. The effectiveness of TNF-α inhibitors in patients with RA or CD among the selected articles was summarized by their smoking status. Meta-analysis was performed with random effect model. When current smokers were compared with non-smokers for response after adjustments through meta-analysis among patients with RA, current smokers had 59% less response than non-smokers with statistical significance (Pooled adjusted OR=0.41, 95% CI=0.17–0.95). In patients with CD, current smokers tended to have lower clinical response than non-smokers, but statistical significance was not shown. In subgroup analyses for luminar CD or fistulizing CD, current smokers tended to have a lower response in luminar CD (Pooled OR=0.62, 95% CI=0.34–1.14), but smoking status was not associated with drug response in fistulizing CD. This study raises awareness of the adverse effects of smoking in terms of clinical response in patients treated with TNF-α inhibitors.

Keywords: TNF-α inhibitors, smoking, rheumatoid arthritis, Crohn's disease

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Figure 1.

Flow chart of article selection

Figure 2.

Meta-analysis of clinical response to TNF-α inhibitors in patients with rheumatoid arthritis. A. current smokers vs. non-smokers, B. current smokers vs. non-smokers after adjustment, C. ever-smokers vs. never-smokers

Figure 3.

Meta-analysis of clinical response to TNF-α inhibitors between current smokers and non-smokers in patients with Crohn's disease

Figure 4.

Meta-analysis of clinical response to TNF-α inhibitors in patients with luminar or fistulizing Crohn's disease. A. current smokers vs. non-smokers in patients with luminar Crohn's disease, B. current smokers vs. nonsmokers in patients with fistulizing Crohn's disease

Table 1.

Summary of clinical response to TNF-alpha inhibitors in patients with rheumatoid arthritis

Reference	Design	Age Mean (SD)	Drug	Treatment period	Smoking Status	Outcome (EULAR criteria)	Results		Included studies in Meta-Analysis
Canhao et al., 2012	PCS	52.6	ADA, ETA, INF	≥1Y	Ever-S (n=132), Never-S (n=485)	GR	Ever-S vs. Never-S	AOR=0.98 (0.97–0.99)	X
Saevarsdottir et al., 2011	PCS	53	ADA, ETA, INF	3,6M	C-S (n=98), Ex-S (n=90), Non-S (n=113)	GR	C-S vs. Ex-S vs. Non-S (3M)	28% (28/98) vs. 39% (35/90) vs. 43% (49/113)	X
							C-S vs. Non-S (6M)	AOR=0.52 (0.29–0.96)
							C-S vs. Ex-S vs. Non-S (3M)	AOR=0.55 (0.31–0.96)
Abhishek et al., 2010	RCS	–	ADA, ETA, INF	3M	C-S (n=71), Ex-S (n=173), Non-S (n=133)	GR+R	C-S vs. Ex-S vs. Non-S (3M)	81.6% (58/71) vs. 90.8% (157/173) vs. 92.5% (123/133)	O
							Ever-S vs Never-S (3M)	88.1% (215/244) vs. 92.5% (123/133)
							C-S vs. Non-S (3M)	AOR=0.20 (0.05–0.83)
							C-S vs. (Ex-S+Non-S) (3M)	AOR=0.30 (0.11–0.81)
Hyrich et al., 2006	PCS	55 (12)	INF, ETA	6M	C-S (n=601), Non-S (n=1,535)	GR+R	C-S vs. Non-S (6M)	74.5% (448/601) vs. 76.2% (1738/2278)	^O
								INF: AOR=0.77 (0.60–0.99)
								ETA: AOR=1.06 (0.80–1.41)
Mattey et al., 2009	PCS	56.3	ADA, ETA, INF	3,12M	Ever-S (n=103), Never-S (n=51)	GR+R	Ever-S vs. Never-S (3M)	79.6% (82/103) vs. 94.1% (48/51)	O
							Ever-S vs. Never-S (3M)	AOR=1.98 (1.34–3.13)
							Ever-S vs. Never-S (12M)	46.6% (48/103) vs. 64.7% (33/51)
							Ever-S vs. Never-S (12M)	AOR=1.65 (1.18–2.30)
Soderlin et al., 2012	PCS	55.5	ADA, ETA, INF	3,6,12M	C-S (n=216), Ex-S (n=345), Non-S (n=373)	GR+R	C-S vs. Non-S (3M)	AOR=0.53 (0.32–0.87)	O
							C-S vs. Non-S (6M)	OR=0.92 (0.55–1.54)
							C-S vs. Non-S (12M)	OR=1.12 (0.60–2.12)

PCS=Prospective Cohort Study; RCS=Retrospective Cohort Study; ETA=Etanercept; INF=Infliximab; ADA=Adalimumab; OR=Odds Ratio; AOR=Adjusted Odds Ratio; GR=Good Response; R=Response; Current-Smoker=C-S; Ex-Smoker=Ex-S; Non-Smoker=Non-S.

Table 2.

Summary of clinical response to TNF-alpha inhibitors in patients with Crohn's disease

Reference	Design	Age Mean (Y±SD)	Drug	Indication	Outcome measure time	Definition of smoking (unit: cigarette)	Definition of outcome	Outcome Smoker vs. Nonsmoker	Included studies in Meta-Analysis
Chaparro et al., 2011	RCS	39±12	INF	LCD, FCD, Perianal CD	Patients with ≥3 administrations, mean follow-up=41M	≥1/day	LCD: Decrease of ≥3 in HBI FCD: Decrease of ≥50% in the number of draining fistulae	AHR=2.05 (p=0.019)	X
Parsi et al., 2004	RCS	40	INF	FCD	FCD: at 4 wks from 3 administrations (0,2,6 wk)	≥5/day within 6M from drug administration	Partial: Decrease of ≥50% in the number of draining fistulae Complete: closure of fistulae or cessation of fistulae drainage	Relapse from complete responders AOR=1.8 (0.8–4.02)	X
Zorzi et al., 2012	PCS	35,36 (Median)	ADA, INF	CD	54 wks	–	Remission: CDAI<150 with no use of steroid	AOR=0.49 (0.26–0.92)	X
Aguas et al., 2012	PCS	42.3	ADA	Intestinal resection for ileal or ileocolonic CD	Every other wk during 12M after surgery	–	No relapse during 12M after surgery	50% (2/4) vs. 84% (21/25)	O
Arnott et al., 2003	PCS	34	INF	LCD, FCD	LCD: at 4 wks from 1 administration, FCD: at 4 weeks from 3 administrations (0,2,6 wk)	≥5/day within 6M from drug administration	LCD: Decrease of ≥3 in HBI FCD: Decrease of ≥50% in the number of draining fistulae	52.4% (11/21) vs. 84.0% (42/50)	O
Arnott et al., 2003	PCS	34	INF	LCD, FCD		≥5/day within 6M from drug administration		AOR=0.24 (0.06–0.91)	O
Fefferman et al., 2004	PCS	40	INF	LCD, FCD	LCD: at 4wks from 1 administration, FCD: at 4weeks from 3 administrations (0,2,6 wk)	3 ≥7/wk at drug ad-ministra- tion	Symptom improvement	69.6% (32/46) vs. 79.9% (123/154)	O
Hlavaty et al., 2005	PCS	LCD (34.6±12.1) FCD (38.9±14.5)	INF	LCD, FCD	LCD: at 4 weeks from 1 administration, FCD: at 5 weeks from 3 administrations (0,2,6 wk)	–	LCD: Decrease of ≥70 CDAI FCD: Decrease of ≥50% in the number of draining fistulae	60.0% (45/75) vs. 60.6% (83/137)	O
Katz et al., 2012	RCS	25 ±13	INF	CD	Over 1 Y	–	Symptom improvement and continuous treatment	27.3% (9/33) vs. 51.1% (69/135)	O
Kevans et al., 2006	PCS	29	INF	LCD, FCD	LCD: after 1 administration, FCD: after 3 administrations (0,2,6 wk)	Presence of smoking at drug administration	Symptom improvement	73.3% (33/45) vs.70.8% (34/48)	O
Kong et al., 2013	–	34	INF	CD, Ulcerative colitis:	Smoker: 86 wks Non-smoker: 59 wks	–	Complete response: cure of diarrhea and stomach cramp, closure of all fistulae	37.5% (3/8) vs. 59.1% (13/22)	O
Laharie et al.,2005	RCS	35±14	INF	LCD (35±14Y)	8 wk-response	≥5 / Day within 6M from drug administration	Decrease of ≥100 in CDAI	61.9% (13/21) vs. 65.2% (15/23)	O
Lin et al., 2012	RCS	39.9	INF	Lost-responders after INF injection per 8 wks during ≥6 M	Over 3 times per 6 wks	s -	Symptom improvement	66.7% (2/3) vs.81.5% (22/27)	O
Luna-Chadid et al., 2004	PCS	38	INF	FCD	FCD: at 4 weeks from 3 administrations (0,2,6 wk)	≥5 / Day within 6M from drug administration	Decrease of ≥50% in fistulae	85.2% (46/54) vs. 75.9% (41/54)	O
Molnar et al., 2012	RCS	25.9	ADA, INF	Active CD refractory (n= 44), FCD (n=4), LCD (n=13)	1 Y (administration per 4–8 wks)	–	Non-response: Dose increase, Change treatment, Surgery required, Continuous steroid treatment	80% (16/20) vs. 56% (23/41)	O
Nichita et al., 2010	RCS	38±11	ADA	CD	At 4–6 wks after injection (every other wk)	–	Decrease of ≥ 3 in HBI	79.3% (23/29) vs.88.5% (23/26)	O
Orlando et al., 2005	PCS	30.1	INF	LCD, FCD	LCD: at 12 wks after 1^st injection (1–3 injections) FCD: at 12 wks after 1^st injection (0,2,6 wk)	≥7/wk at drug ad-ministra- tion	LCD: Decrease of ≥ 70 in CDAI, FCD: Decrease of ≥50% in the number of draining fistulae	77.2% (187/242) vs. 80.7% (322/399)	O
Papami-chael et al., 2012	PCS	32 (Median)	ADA	FCD (n=10) Penetrating CD (n=5)	24M	–	Endoscopic relapse	50.0% (4/8) vs. 71.4% (5/7)	O
Parsi et al., 2002	RCS	36	INF	LCD, FCD	LCD: at 4 weeks from 1 administration, FCD: at 4 weeks from 3 administrations (0,2,6 wk)	≥5/day within 6M from drug administration	LCD: Decrease of ≥ 3 in HBI FCD: Decrease of ≥ 50% in the number of draining fistulae	48.6% (17/35) vs. 76.9% (50/65)	O
Parsi et al., 2002	RCS	36	INF	LCD, FCD		≥5/day within 6M from drug administration		LCD: AOR=0.09 (0.02–0.38) FCD: AOR=0.42 (0.06–2.82)	O
Rudolph et al., 2008	RCS	37	INF	CD	After 3 administrations (0,2,6 wk)	Smoking within 6M from drug administration	Improvement of initial clinical response	92.1% (35/38) vs. 86.9% (139/160)	O
Rudolph et al., 2008	RCS	37	INF	CD	After 3 administrations (0,2,6 wk)	Smoking within 6M from drug administration	Improvement of initial clinical response	Smokers among initial responders (n=174) had lower response duration (HR=2.63, p=0.005)	O
Sakuraba et al., 2012	PCS	34.1	INF	CD patients who had surgeries of ≥ 2 and no adverse reaction	24M	–	Clinical remission (patients did not show increase of >50 in CDAI)	66.7% (2/3) vs. 57.1% (4/7)	O
Triantafil-lidis et al., 2010	PCS	39±14	ADA	CD	At 4 wks	–	Decrease of >70 in CDAI	100% (11/11) vs. 89.5% (17/19)	O
Vermeire et al., 2002	PCS	–	INF	LCD (n=137) FCD (n=103)	LCD: at 4 weeks from 1 administration, FCD: at 4 weeks from 3 administrations	–	LCD: Decrease of >70 in CDAI FCD: Decrease of ≥50% in the number of draining fistulae	75.5% (80/106) vs. 69.5% (89/128)	O
Vermeire et al., 2002	PCS	–	INF	LCD (n=137) FCD (n=103)		–		AOR=1.38 (0.647–2.8)	O

PCS=Prospective Cohort Study; RCS=Retrospective Cohort Study; Wks=weeks; INF=Infliximab; ADA=Adalimumab; CDAI=Crohn's Disease Activity Index; HBI=Harvey-Bradshaw index; FCD=Fistulizing Crohn's Disease; LCD=Lumina Crohn's Disease; AHR=Adjusted Hazard Ratio; AOR=Adjusted Odds Ratio

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