Adverse effects of biologics: a network meta‐analysis and Cochrane overview

Jasvinder A Singh; George A Wells; Robin Christensen; Elizabeth Tanjong Ghogomu; Lara J Maxwell; John K MacDonald; Graziella Filippini; Nicole Skoetz; Damian K Francis; Luciane C Lopes; Gordon H Guyatt; Jochen Schmitt; Loredana La Mantia; Tobias Weberschock; Juliana F Roos; Hendrik Siebert; Sarah Hershan; Chris Cameron; Michael PT Lunn; Peter Tugwell; Rachelle Buchbinder

doi:10.1002/14651858.CD008794.pub2

Table 1. Details on doses used for the dose‐adjusted analysis

	Approved dose and range	Dose used for adjustment
Etanercept	25 mg SQ twice a week	50 mg qweek
Infliximab	3‐5 mg/kg Q8 weeks; may increase to 10 mg/kg	3 mg/kg q8weeks
Adalimumab	40 mg SQ Q2 weeks	40 mg q2weeks
Golimumab	50 mg SQ Q4 weeks	50 mg q4weeks
Certolizumab pegol	400 mg SQ initially, then 200‐mg Qother week or 400 mg monthly	400 mg monthly
Anakinra	100 mg SQ Qday	100 mg qday
Rituximab	500 or 1000 mg ‐2 infusions, 2 weeks apart	500‐1000 mg 2wks apart
Abatacept	500, 750 or 1000 mg Q4 weeks	500‐1000 mg Q4weeks
Tocilizumab	4 mg/kg IV Q4 weeks; may increase to 8mg/kg Q8 weeks	4 mg/kg q4weeks

Table 1. Details on doses used for the dose‐adjusted analysis

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Table 2. Summary of characteristics of included studies

Characteristic	Randomized‐controlled trials, N=160	Open‐label extension studies, N=46
Type of intervention
abatacept	7	2
adalimumab	22	10
anakinra	5	2
certolizumab pegol	6	1
etanercept	39	10
golimumab	8	1
infliximab	40***	18
rituximab	29	1
tocilizumab	5	1
Type of condition
rheumatoid arthritis	62	18
cancer	25	0
psoriasis	14	8
IBD	12	1
ankylosing spondylitis	10	10
psoriatic arthritis	7	7
Crohn's disease	6	0
ulcerative colitis	6	0
other*	18	2
Trial duration, months mean(SD; median)	9.8 (11.5; 6.0)	20.7 (17.9; 13.5)
Trial duration, short < 6 months , N studies	98	9
Trial duration: intermediate (6< mo. ≤12), N studies	27	12
Trial duration: long >12 months , N studies	35	25
Age, years mean(SD; median)	49.9 (8.2; 51)	79.9 (24.2; 87.0)
% Female mean(SD; median)	58.9 (20.4; 61)	57.3 (24.5; 61.7)
% Caucasian mean(SD; median)	85.4(17; 89.7)	79.9 (24.2; 87.0)
IBD = inflammatory bowel disease; SD = standard deviation; other conditions for RCT include: heart failure, multiple sclerosis, COPD, alcoholic hepatitis, diabetes, lupus, active spondylarthropathy, osteoarthritis, asthma, cardiac or renal transplantation, Sjogren's syndrome, polymyalgia rheumatica, autoimmune inner ear disease, giant cell arteritis, pulmonary sarcoidosis, Hepatitis C, cancer anorexia/weight loss syndrome, Wegener's granulomatosis; other conditions for OLE = sarcoidosis, axial spondylarthritis; ** one study (Schiff 2008) had two treatment arms (abatacept and infliximab)

Table 2. Summary of characteristics of included studies

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Table 3. Summary of findings table 1

Biologics for any condition except HIV/AIDS: standard drug dose* and control event rate
Outcome	Comparison intervention	Illustrative comparative risks	Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	NNTH (95% CI)
	Assumed risk with comparator	Corresponding risk with intervention (95% CI)
	Control	Biologics**
Serious adverse events	118 per 1000	127 per 1000 (115 to 142)	OR 1.09 (0.97 to 1.24)	21,152 (76 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Total adverse events	724 per 1000	770 per 1000 (741 to 797)	OR 1.28 (1.09 to 1.50)	14,959 (48 studies)	⊕⊕⊕⊕ high	22 (14 to 60)
Withdrawals due to adverse events	98 per 1000	137 per 1000 (115 to 168)	OR 1.47 (1.20 to 1.86)	22,636 (83 studies)	⊕⊕⊕⊝ moderate¹	26 (15 to 58)
Serious infections	26 per 1000	35 per 1000 (27 to 46)	OR 1.37 (1.04 to 1.82)	21,853 (70 studies)	⊕⊕⊕⊝ moderate¹	108 (50 to 989)
Tuberculosis reactivation	4 per 10,000	20 per 10,000	OR 4.68 (1.18 to 18.60)	30,671 (71 studies)	⊕⊕⊝⊝ low⁴	681 (143 to 14706)
Lymphoma	9 per 10000	1 per 1000	OR 0.53 (0.17 to 1.66)	21,260 (52 studies)	⊕⊕⊝⊝ low⁴	Not statistically significant
Congestive heart failure	8 per 1000	6 per 1000 (1 to 21)	OR 0.69 (0.18 to 2.69)	8847 (24 studies)	⊕⊕⊝⊝ low⁴	Not statistically significant
* = standard drug dose was used for serious adverse events, total adverse events, withdrawals due to adverse events and serious infectiosn only. All doses were combined for tuberculosis reactivation, lymphoma and congestive heart failure because of very limited data. ** = all nine biologics as a group 95% CI = 95% confidence interval or 95% credible interval; NNTH = Number needed to treat for harm; OR = odds ratio Control event rates based on the number of events in the included studies. ¹ The 95% credible interval around the pooled effect includes both no effect and appreciable benefit or harm. ² Out of 19 studies, two studies (Buske 2009; Eve 2009) had inadequate allocation concealment; four studies (Eve 2009; Forstpointner 2004; Hainsworth 2005; Herold 2007) reported no blinding of personnel, participants and outcome assessors; two studies (Buske 2009; Salles 2007) reported no blinding of personnel and participants only. ³ Out of 15 studies, two (Buske 2009; Hiddemann 2005) had inadequate allocation concealment; four studies (Coiffier 1998; Forspointner 2004; Hainsworth 2005; Hiddemann 2005) reported no blinding of personnel, participants and outcome assessors; two studies (Forstpointner 2002; Salles 2007) reported no blinding of personel and participants only. ⁴ Very few events.

Table 3. Summary of findings table 1

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Table 4. Summary of findings table 2

Biologics for any condition except HIV/AIDS: standard drug dose* and control event rate
Intervention	Comparison intervention	Illustrative comparative risks		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	NNTH (95% CI)
		Assumed risk with comparator	Corresponding risk with intervention (95% CI)
		Control	Biologic
Serious adverse events
Abatacept	control	118 per 1000	116 per 1000 ( 76 to 144)	OR 0.89 (0.61 to 1.26)	2052 (5 studies)	⊕⊕⊕⊕ high	Not statistically significant
Adalimumab	control	118 per 1000	114 per 1000 ( 90 to 145)	OR 0.96 (0.74 to 1.27)	4662 (15 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Anakinra	control	118 per 1000	122 per 1000 (82 to 180)	OR 1.04 (0.67 to 1.64)	1900 (3 studies)	⊕⊕⊕⊕ high	Not statistically significant
Certolizumab pegol	control	118 per 1000	174 per 1000 (124 to 237)	OR 1.57 (1.06 to 2.32)	2421 (6 studies)	⊕⊕⊕⊝ moderate¹	18 (9 to 162)
Etanercept	control	118 per 1000	142 per 1000 (111 to 184)	OR 1.24 (0.93 to 1.69)	3931 (21 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Golimumab	control	118 per 1000	123 per 1000 (82 to 184)	OR 1.05 (0.67 to 1.69)	1564 (8 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Infliximab	control	118 per 1000	133 per 1000 (102 to 174)	OR 1.15 (0.85 to 1.57)	3403 (14 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Rituximab	control	118 per 1000	186 per 1000 (85 to 375)	OR 1.71 (0.69 to 4.49)	377 (2 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Tocilizumab	control	118 per 1000	93 per 1000 (52 to 163)	OR 0.77 (0.41 to 1.45)	842 (3 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
All nine biologics	control	118 per 1000	127 per 1000 (115 to 142)	OR 1.09 (0.97 to 1.24)	21,152 (76 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Total adverse events
Abatacept	control	724 per 1000	766 per 1000 (654 to 849)	OR 1.25 (0.72 to 2.15)	1818 (4 studies)	⊕⊕⊕⊕ high	Not statistically significant
Adalimumab	control	724 per 1000	730 per 1000 (637 to 802)	OR 1.03 (0.67 to 1.54)	3266 (10 studies)	⊕⊕⊕⊕ high	Not statistically significant
Anakinra	control	724 per 1000	791 per 1000 (677 to 876)	OR 1.44 (0.80 to 2.68)	2033 (4 studies)	⊕⊕⊕⊕ high	Not statistically significant
Certolizumab pegol	control	724 per 1000	754 per 1000 (651 to 837)	OR 1.17 (0.71 to 1.95)	1829 (5 studies)	⊕⊕⊕⊕ high	Not statistically significant
Etanercept	control	724 per 1000	784 per 1000 (677 to 866)	OR 1.38 (0.80 to 2.46)	1600 (7 studies)	⊕⊕⊕⊕ high	Not statistically significant
Golimumab	control	724 per 1000	765 per 1000 (672 to 839)	OR 1.24 (0.78 to 1.98)	1187 (6 studies)	⊕⊕⊕⊕ high	Not statistically significant
Infliximab	control	724 per 1000	803 per 1000 (726 to 860)	OR 1.55 (1.01 to 2.35)	2330 (9 studies)	⊕⊕⊕⊕ high	13 (8 to 505)
Rituximab	control	724 per 1000	802 per 1000 (562 to 924)	OR 1.54 (0.49 to 4.63)	377 (2 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Tocilizumab	control	724 per 1000	775 per 1000 (599 to 888)	OR 1.31 (0.57 to 3.01)	519 (2 studies)	⊕⊕⊕⊕ high	Not statistically significant
All nine biologics	control	724 per 1000	770 per 1000 (741 to 797)	OR 1.28 (1.09 to 1.50)	14,959 (48 studies)	⊕⊕⊕⊕ high	22 (14 to 60)
Withdrawals due to adverse events
Abatacept	control	98 per 1000	113 per 1000 (59 to 208)	OR 1.17 (0.58 to 2.41)	2054 (5 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Adalimumab	control	98 per 1000	128 per 1000 (81 to 194)	OR 1.35 (0.82 to 2.22)	5268 (18 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Anakinra	control	98 per 1000	150 per 1000 (69 to 301)	OR 1.63 (0.68 to 3.96)	1963 (3 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Certolizumab pegol	control	98 per 1000	125 per 1000 (70 to 226)	OR 1.32 (0.69 to 2.69)	2421 (6 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Etanercept	control	98 per 1000	124 per 1000 (82 to 191)	OR 1.30 (0.82 to 2.17)	5189 (25 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Golimumab	control	98 per 1000	127 per 1000 (64 to 241)	OR 1.34 (0.63 to 2.92)	1549 (7 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Infliximab	control	98 per 1000	203 per 1000 (132 to 310)	OR 2.34 (1.40 to 4.14)	2973 (15 studies)	⊕⊕⊕⊝ moderate¹	10 (5 to 30)
Rituximab	control	98 per 1000	229 per 1000 (45 to 756)	OR 2.74 (0.43 to 28.48)	377 (2 studies)	⊕⊕⊝⊝ low^1,3	Not statistically significant
Tocilizumab	control	98 per 1000	166 per 1000 (65 to 371)	OR 1.83 (0.64 to 5.42)	842 (3 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
All nine biologics	control	98 per 1000	137 per 1000 (115 to 168)	OR 1.47 (1.20 to 1.86)	22,636 (83 studies)	⊕⊕⊕⊝ moderate¹	26 (15 to 58)
Serious infection
Abatacept	control	26 per 1000	25 per 1000 (11 to 58)	OR 0.97 (0.40 to 2.31)	2052 (5 studies)	⊕⊕⊕⊕ high	Not statistically significant
Adalimumab	control	26 per 1000	32 per 1000 (17 to 60)	OR 1.23 (0.65 to 2.40)	4847 (15 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Anakinra	control	26 per 1000	98 per 1000 (32 to 310)	OR 4.05 (1.22 to 16.84)	3436 (4 studies)	⊕⊕⊕⊝ moderate¹	14 (4 to 181)
Certolizumab pegol	control	26 per 1000	113 per 1000 (39 to 330)	OR 4.75 (1.52 to 18.45)	1683 (4 studies)	⊕⊕⊕⊕ high	12 (4 to 79)
Etanercept	control	26 per 1000	33 per 1000 (19 to 61)	OR 1.29 (0.72 to 2.45)	4630 (19 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Golimumab	control	26 per 1000	29 per 1000 (12 to 65)	OR 1.11 (0.45 to 2.59)	1334 (6 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Infliximab	control	26 per 1000	36 per 1000 (20 to 65)	OR 1.41 (0.75 to 2.62)	2652 (13 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
Rituximab	control	26 per 1000	7 per 1000 (1 to 55)	OR 0.26 (0.03 to 2.16)	377 (2 studies)	⊕⊕⊝⊝ low^1,2	Not statistically significant
Tocilizumab	control	26 per 1000	22 per 1000 (5 to 87)	OR 0.84 (0.20 to 3.56)	842 (3 studies)	⊕⊕⊕⊝ moderate¹	Not statistically significant
All nine biologics	control	26 per 1000	35 per 1000 (27 to 46)	OR 1.37 (1.04 to 1.82)	21,853 (70 studies)	⊕⊕⊕⊝ moderate¹	108 (50 to 989)
Tuberculosis reactivation
All nine biologics	control	4 per 10,000	20 per 10,000	OR 4.68 (1.18 to 18.60)	30,671 (71 studies)	⊕⊕⊝⊝ low⁴	681 (143 to 14706)
Lymphoma
All nine biologics	control	9 per 10000	1 per 1000	OR 0.53 (0.17 to 1.66)	21,260 (52 studies)	⊕⊕⊝⊝ low⁴	Not statistically significant
Congestive heart failure
All nine biologics	control	8 per 1000	6 per 1000 (1 to 21)	OR 0.69 (0.18 to 2.69)	8847 (24 studies)	⊕⊕⊝⊝ low⁴	Not statistically significant
* = standard drug dose was used for serious adverse events, total adverse events, withdrawals due to adverse events and serious infectiosn only. All doses were combined for tuberculosis reactivation, lymphoma and congestive heart failure because of very limited data. 95% CI = 95% confidence interval or 95% credible interval; NNTH = Number needed to treat for harm; OR = odds ratio Control event rates based on the number of events in the included studies. ¹ The 95% credible interval around the pooled effect includes both no effect and appreciable benefit or harm. ² Out of 19 studies, two studies (Buske 2009; Eve 2009) had inadequate allocation concealment; four studies (Eve 2009; Forstpointner 2004; Hainsworth 2005; Herold 2007) reported no blinding of personnel, participants and outcome assessors; two studies (Buske 2009; Salles 2007) reported no blinding of personnel and participants only. ³ Out of 15 studies, two (Buske 2009; Hiddemann 2005) had inadequate allocation concealment; four studies (Coiffier 1998; Forspointner 2004; Hainsworth 2005; Hiddemann 2005) reported no blinding of personnel, participants and outcome assessors; two studies (Forstpointner 2002; Salles 2007) reported no blinding of personnel and participants only. ⁴ Very few events.

Table 4. Summary of findings table 2

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Table 5. Incidence of safety outcomes from RCTs

Outcome	Total # studies with data	# Events*: biologic group	# People: biologic group	Incidence in biologic group	# Events*: control group	# people: control group	Incidence in control group	Total # events	Total # people studied	Total duration of studies (mths (yrs))
SAE	125	2926	26032	11.24%	1747	13,614	12.83%	4673	39,646	2613 (217.8)
S Infections	117	731	25,486	2.87%	325	13,741	2.37%	1056	39,227	2923 (243.6)
Total AE	115	20,686	24,208	85.45%	11,115	13,241	83.94%	31,801	37,449	2462 (205.2)
With d/t AE	128	1577	26,553	5.94%	683	14,172	4.82%	2260	40,725	2909.2 (242.4)
TB	71	32	20,765	0.154%	3	9915	0.030%	35	30,671	646.1 (53.8)
Lymphoma	52	14	14,254	0.098%	6	7006	0.086%	20	21,260	518.3 (43.2)
CHF	24	27	5768	0.468%	17	3079	0.552%	44	8847	255.6 (21.3)
All drug doses included # Events* = number of events or people with events

Table 5. Incidence of safety outcomes from RCTs

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Table 6. Standard meta‐analyses results

	Serious adverse events	Total adverse events	Withdrawals due to adverse events	Serious Infection	TB reactivation	Lymphoma	Congestive heart failure
Abatacept	0.90 (0.64 to 1.28)	1.24 (0.97 to 1.60)	0.97 (0.57 to 1.63)	1.06 (0.52 to 2.16)	0.50 (0.03 to 8.11)	1.52 (0.06 to 37.53)	1.56 (0.06 to 38.44)
Adalimumab	0.95 (0.74 to 1.22)	0.99 (0.63 to 1.56)	1.21 (0.84 to 1.75)	1.03 (0.53 to 2.01)	2.14 (0.33 to 13.78)	0.95 (0.10 to 9.19)	Not estimable
Anakinra	1.04 (0.68 to 1.61)	1.69 (0.84 to 3.42)	0.65 (0.09 to 4.50)	3.24 (0.97 to 10.82)	Not estimable	0.08 (0.00 to 2.08)	Not estimable
Certolizumab	1.24 (0.85 to 1.80)	1.16 (0.86 to 1.56)	1.17 (0.69 to 1.97)	3.15 (1.24 to 7.98)	4.43 (0.50 to 39.09)	0.33 (0.01 to 8.09)	Not estimable
Etanercept	1.12 (0.87 to 1.44)	1.14 (0.88 to 1.48)	0.98 (0.73 to 1.32)	1.12 (0.73 to 1.70)	1.48 (0.06 to 36.93)	2.40 (0.38 to 15.31)	0.84 (0.05 to 14.26)
Golimumab	1.04 (0.64 to 1.68)	1.30 (0.85 to 1.99)	1.26 (0.57 to 2.79)	1.24 (0.61 to 2.53)	3.04 (0.12 to 75.13)	Not estimable	2.84 (0.11 to 71.99)
Infliximab	1.06 (0.82 to 1.37)	1.51 (0.92 to 2.47)	1.99 (1.04 to 3.80)	1.34 (0.85 to 2.12)	2.82 (0.65 to 12.18)	3.00 (0.12 to 74.79)	Not estimable
Rituximab	1.59 (0.51 to 4.89)	1.69 (0.97 to 2.96)	1.93 (0.18 to 21.22)	0.39 (0.07 to 2.11)	‐‐‐	‐‐‐	‐‐‐
Tocilizumab	0.90 (0.51 to 1.61)	1.36 (0.95 to 1.96)	1.49 (0.74 to 3.01)	1.28 (0.34 to 4.82)	Not estimable	‐‐‐	Not estimable
	1.04 (0.94 to 1.16)	1.28 (1.11 to 1.48)	1.22 (1.02 to 1.47)	1.23 (0.99 to 1.52)	2.30 (0.95 to 5.55)	1.05 (0.36 to 3.06)	1.46 (0.25 to 8.63)

Table 6. Standard meta‐analyses results

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Table 7. Treatment comparison to control: serious adverse events ‐ network meta‐analysis MTC

OR RE Model	Standard Dose Model Median (95% CI)
Abatacept	0.89 (0.61 to 1.26)
Adalimumab	0.96 (0.74 to 1.27)
Anakinra	1.04 (0.67 to 1.64)
Certolizumab	1.57 (1.06 to 2.32)*
Etanercept	1.24 (0.93 to 1.69)
Golimumab	1.05 (0.67 to 1.69)
Infliximab	1.15 (0.85 to 1.57)
Rituximab	1.71 (0.69 to 4.49)
Tocilizumab	0.77 (0.41 to 1.45)
Overall	1.09 (0.97, 1.24)
Data points Residual deviance DIC	(133) 153.8 758.95
* = statistically significant; OR = odds ratio; RE model = random‐effects model; 95% CI = 95% credible interval; DIC = Deviance information criteria

Table 7. Treatment comparison to control: serious adverse events ‐ network meta‐analysis MTC

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Table 8. Treatment comparison to control: total adverse events ‐ network meta‐analysis MTC

OR RE Model	Standard Dose Model Median (95% CI)
Abatacept	1.25 (0.72 to 2.15)
Adalimumab	1.03 (0.67 to 1.54)
Anakinra	1.44 (0.80 to 2.68)
Certolizumab	1.17 (0.71 to 1.95)
Etanercept	1.38 (0.80 to 2.46)
Golimumab	1.24 (0.78 to 1.98)
Infliximab	1.55 (1.01 to 2.35)*
Rituximab	1.54 (0.49 to 4.63)
Tocilizumab	1.31 (0.57 to 3.01)
Overall	1.28 (1.09, 1.50)*
Data points Residual deviance DIC	(101) 113 642.73
* = statistically significant; OR = odds ratio; RE model = random‐effects model; 95% CI = 95% credible interval; DIC = Deviance information criteria

Table 8. Treatment comparison to control: total adverse events ‐ network meta‐analysis MTC

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Table 9. Treatment comparison to control: withdrawals due to adverse events ‐ network meta‐analysis MTC

OR RE Model	Standard Dose Model Median (95% CI)
Abatacept	1.17 (0.58 to 2.41)
Adalimumab	1.35 (0.82 to 2.22)
Anakinra	1.63 (0.68 to 3.96)
Certolizumab	1.32 (0.69 to 2.69)
Etanercept	1.30 (0.82 to 2.17)
Golimumab	1.34 (0.63 to 2.92)
Infliximab	2.34 (1.40 to 4.14)*
Rituximab	2.74 (0.43 to 28.48)
Tocilizumab	1.83 (0.64 to 5.42)
Overall	1.47 (1.20, 1.86)*
Data points Residual deviance DIC	(165) 161.1 764.72
* = statistically significant; OR = odds ratio; RE model = random‐effects model; 95% CI = 95% credible interval; DIC = Deviance information criteria

Table 9. Treatment comparison to control: withdrawals due to adverse events ‐ network meta‐analysis MTC

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Table 10. Treatment comparison to control: serious infections ‐ network meta‐analysis MTC

OR RE Model	Standard Dose Model Median (95% CI)
Abatacept	0.97 (0.40 to 2.31)
Adalimumab	1.23 (0.65 to 2.40)
Anakinra	4.05 (1.22 to 16.84)*
Certolizumab	4.75 (1.52 to 18.45)*
Etanercept	1.29 (0.72 to 2.45)
Golimumab	1.11 (0.45 to 2.59)
Infliximab	1.41 (0.75 to 2.62)
Rituximab	0.26 (0.03 to 2.16)
Tocilizumab	0.84 (0.20 to 3.56)
Overall	1.37 (1.04, 1.82)*
Data points Residual deviance DIC	(115) 123.2 494.12
* = statistically significant; OR = odds ratio; RE model = random‐effects model; 95% CI = 95% credible interval; DIC = Deviance information criteria

Table 10. Treatment comparison to control: serious infections ‐ network meta‐analysis MTC

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Table 11. Pairwise treatment comparison: serious adverse events ‐ network meta‐analysis MTC

Comparison	Standard Dose Model OR (95% CI)
Adalimumab vs Etanercept	0.78 (0.52 to 1.16)
Certolizumab vs Etanercept	1.27 (0.77 to 2.06)
Golimumab vs Etanercept	0.85 (0.49 to 1.44)
Abatacept vs Etanercept	0.71 (0.44 to 1.12)
Infliximab vs Etanercept	0.93 (0.60 to 1.42)
Rituximab vs Etanercept	1.38 (0.53 to 3.84)
Anakinra vs Etanercept	0.84 (0.49 to 1.43)
Tocilizumab vs Etanercept	0.62 (0.30 to 1.24)

Certolizumab vs Adalimumab	1.63 (1.01 to 2.62)*
Golimumab vs Adalimumab	1.09 (0.64 to 1.88)
Abatacept vs Adalimumab	0.92 (0.58 to 1.42)
Infliximab vs Adalimumab	1.19 (0.79 to 1.79)
Rituximab vs Adalimumab	1.77 (0.68 to 4.82)
Anakinra vs Adalimumab	1.08 (0.64 to 1.82)
Tocilizumab vs Adalimumab	0.79 (0.40 to 1.59)

Golimumab vs Certolizumab	0.67 (0.37 to 1.23)
Abatacept vs Certolizumab	0.56 (0.33 to 0.94)
Infliximab vs Certolizumab	0.73 (0.45 to 1.21)
Rituximab vs Certolizumab	1.09 (0.41 to 3.07)
Anakinra vs Certolizumab	0.66 (0.37 to 1.21)
Tocilizumab vs Certolizumab	0.49 (0.23 to 1.03)

Abatacept vs Golimumab	0.84 (0.47 to 1.48)
Infliximab vs Golimumab	1.09 (0.62 to 1.90)
Rituximab vs Golimumab	1.63 (0.59 to 4.75)
Anakinra vs Golimumab	0.99 (0.52 to 1.90)
Tocilizumab vs Golimumab	0.73 (0.34 to 1.59)

Infliximab vs Abatacept	1.30 (0.84 to 2.08)
Rituximab vs Abatacept	1.94 (0.73 to 5.43)
Anakinra vs Abatacept	1.17 (0.67 to 2.14)
Tocilizumab vs Abatacept	0.86 (0.42 to 1.81)

Rituximab vs Infliximab	1.49 (0.57 to 4.13)
Anakinra vs Infliximab	0.91 (0.53 to 1.57)
Tocilizumab vs Infliximab	0.67 (0.33 to 1.34)

Anakinra vs Rituximab	0.60 (0.21 to 1.68)
Tocilizumab vs Rituximab	0.44 (0.14 to 1.37)

Tocilizumab vs Anakinra	0.74 (0.34 to 1.60)
*=statistically significant; OR = odds ratio; 95% CI = 95% credible interval

Table 11. Pairwise treatment comparison: serious adverse events ‐ network meta‐analysis MTC

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Table 12. Pairwise treatment comparison: total adverse events ‐ network meta‐analysis MTC

Comparison	Standard Dose Model OR (95% CI)
Adalimumab vs Etanercept	0.74 (0.36to 1.45)
Certolizumab vs Etanercept	0.85 (0.39to 1.77)
Golimumab vs Etanercept	0.90 (0.43 to 1.83)
Abatacept vs Etanercept	0.90 (0.40 to 1.94)
Infliximab vs Etanercept	1.12 (0.54 to 2.22)
Rituximab vs Etanercept	1.11 (0.31 to 3.80)
Anakinra vs Etanercept	1.04 (0.45 to 2.36)
Tocilizumab vs Etanercept	0.95 (0.34 to 2.54)

Certolizumab vs Adalimumab	1.14 (0.60 to 2.24)
Golimumab vs Adalimumab	1.20 (0.65 to 2.30)
Abatacept vs Adalimumab	1.22 (0.61 to 2.45)
Infliximab vs Adalimumab	1.51 (0.84 to 2.76)
Rituximab vs Adalimumab	1.50 (0.45 to 4.93)
Anakinra vs Adalimumab	1.40 (0.69 to 3.00)
Tocilizumab vs Adalimumab	1.27 (0.51 to 3.29)

Golimumab vs Certolizumab	1.06 (0.53 to 2.10)
Abatacept vs Certolizumab	1.07 (0.50 to 2.22)
Infliximab vs Certolizumab	1.32 (0.68 to 2.53)
Rituximab vs Certolizumab	1.31 (0.38 to 4.40)
Anakinra vs Certolizumab	1.22 (0.57 to 2.73)
Tocilizumab vs Certolizumab	1.11 (0.42 to 2.94)

Abatacept vs Golimumab	1.01 (0.49 to 2.07)
Infliximab vs Golimumab	1.26 (0.66 to 2.33)
Rituximab vs Golimumab	1.25 (0.36 to 4.07)
Anakinra vs Golimumab	1.16 (0.55 to 2.52)
Tocilizumab vs Golimumab	1.06 (0.41 to 2.74)

Infliximab vs Abatacept	1.24 (0.65 to 2.39)
Rituximab vs Abatacept	1.23 (0.35 to 4.23)
Anakinra vs Abatacept	1.15 (0.52 to 2.66)
Tocilizumab vs Abatacept	1.05 (0.39 to 2.8)

Rituximab vs Infliximab	0.99 (0.30 to 3.24)
Anakinra vs Infliximab	0.93 (0.45 to 1.98)
Tocilizumab vs Infliximab	0.84 (0.33 to 2.16)

Anakinra vs Rituximab	0.93 (0.27 to 3.44)
Tocilizumab vs Rituximab	0.85 (0.21 to 3.50)

Tocilizumab vs Anakinra	0.91 (0.32 to 2.52)
* = statistically significant; OR = odds ratio; 95% CI = 95% credible interval

Table 12. Pairwise treatment comparison: total adverse events ‐ network meta‐analysis MTC

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Table 13. Pairwise treatment comparison: withdrawals due to adverse events ‐ network meta‐analysis MTC

Comparison	Standard Dose Model OR (95% CI)
Adalimumab vs Etanercept	1.04 (0.51 to 2.02)
Certolizumab vs Etanercept	1.02 (0.44 to 2.32)
Golimumab vs Etanercept	1.03 (0.41 to 2.514)
Abatacept vs Etanercept	0.90 (0.38 to 2.10)
Infliximab vs Etanercept	1.81 (0.89 to 3.68)
Rituximab vs Etanercept	2.11 (0.30 to 22.43)
Anakinra vs Etanercept	1.26 (0.45 to 3.34)
Tocilizumab vs Etanercept	1.41 (0.43 to 4.53)

Certolizumab vs Adalimumab	0.98 (0.43 to 2.33)
Golimumab vs Adalimumab	1.00 (0.40 to 2.49)
Abatacept vs Adalimumab	0.87 (0.37 to 2.09)
Infliximab vs Adalimumab	1.74 (0.86 to 3.70)
Rituximab vs Adalimumab	2.04 (0.30 to 22.18)
Anakinra vs Adalimumab	1.21 (0.44 to 3.32)
Tocilizumab vs Adalimumab	1.36 (0.42 to 4.43)

Golimumab vs Certolizumab	1.01 (0.35 to 2.78)
Abatacept vs Certolizumab	0.88 (0.33 to 2.31)
Infliximab vs Certolizumab	1.77 (0.75 to 4.22)
Rituximab vs Certolizumab	2.07 (0.28 to 23.37)
Anakinra vs Certolizumab	1.23 (0.40 to 3.65)
Tocilizumab vs Certolizumab	1.39 (0.39 to 4.85)

Abatacept vs Golimumab	0.87 (0.31 to 2.48)
Infliximab vs Golimumab	1.75 (0.70 to 4.53)
Rituximab vs Golimumab	2.05 (0.27 to 24.09)
Anakinra vs Golimumab	1.22 (0.38 to 3.90)
Tocilizumab vs Golimumab	1.36 (0.37 to 5.12)

Infliximab vs Abatacept	2.01 (0.87 to 4.77)
Rituximab vs Abatacept	2.35 (0.32 to 26.5)
Anakinra vs Abatacept	1.40 (0.45 to 4.32)
Tocilizumab vs Abatacept	1.57 (0.44 to 5.65)

Rituximab vs Infliximab	1.16 (0.17 to 12.87)
Anakinra vs Infliximab	0.70 (0.24 to 1.91)
Tocilizumab vs Infliximab	0.78 (0.24 to 2.54)

Anakinra vs Rituximab	0.59 (0.05 to 4.61)
Tocilizumab vs Rituximab	0.67 (0.05 to 5.67)

Tocilizumab vs Anakinra	1.12 (0.29 to 4.49)
* = statistically significant; OR = odds ratio; 95% CI = 95% credible interval

Table 13. Pairwise treatment comparison: withdrawals due to adverse events ‐ network meta‐analysis MTC

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Table 14. Pairwise treatment comparison: serious infections ‐ network meta‐analysis MTC

Comparison	Standard Dose Model OR (95% CI)
Adalimumab vs Etanercept	0.95 (0.38 to 2.29)
Certolizumab vs Etanercept	3.68 (1.01 to 16.3)*
Golimumab vs Etanercept	0.86 (0.28 to 2.39)
Abatacept vs Etanercept	0.76 (0.25 to 2.12)
Infliximab vs Etanercept	1.09 (0.45 to 2.56)
Rituximab vs Etanercept	0.20 (0.02 to 1.74)
Anakinra vs Etanercept	3.15 (0.80 to 14.5)
Tocilizumab vs Etanercept	0.65 (0.13 to 3.07)

Certolizumab vs Adalimumab	3.90 (1.03 to 17.17)*
Golimumab vs Adalimumab	0.90 (0.29 to 2.63)
Abatacept vs Adalimumab	0.80 (0.26 to 2.33)
Infliximab vs Adalimumab	1.15 (0.46 to 2.81)
Rituximab vs Adalimumab	0.21 (0.02 to 1.89)
Anakinra vs Adalimumab	3.33 (0.83 to 15.4)
Tocilizumab vs Adalimumab	0.69 (0.14 to 3.32)

Golimumab vs Certolizumab	0.23 (0.04 to 0.97)*
Abatacept vs Certolizumab	0.20 (0.04 to 0.86)*
Infliximab vs Certolizumab	0.29 (0.07 to 1.08)
Rituximab vs Certolizumab	0.05 (0.004 to 0.59)*
Anakinra vs Certolizumab	0.86 (0.14 to 5.18)
Tocilizumab vs Certolizumab	0.17 (0.02 to 1.08)

Abatacept vs Golimumab	0.88 (0.26 to 3.07)
Infliximab vs Golimumab	1.27 (0.45 to 3.81)
Rituximab vs Golimumab	0.24 (0.02 to 2.26)
Anakinra vs Golimumab	3.68 (0.84 to 19.96)
Tocilizumab vs Golimumab	0.75 (0.15 to 4.32)

Infliximab vs Abatacept	1.44 (0.53 to 4.07)
Rituximab vs Abatacept	0.27 (0.02 to 2.68)
Anakinra vs Abatacept	4.20 (0.96 to 22.06)
Tocilizumab vs Abatacept	0.86 (0.16 to 4.76)

Rituximab vs Infliximab	0.19 (0.02 to 1.65)
Anakinra vs Infliximab	2.90 (0.75 to 13.41)
Tocilizumab vs Infliximab	0.60 (0.12 to 2.88)

Anakinra vs Rituximab	15.73 (1.42 to 238.30)*
Tocilizumab vs Rituximab	3.20 (0.25 to 49.00)

Tocilizumab vs Anakinra	0.20 (0.03 to 1.35)
* = statistically significant; OR = odds ratio; 95% CI = 95% credible interval

Table 14. Pairwise treatment comparison: serious infections ‐ network meta‐analysis MTC

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Table 15. Stratified meta‐analysis findings (unadjusted for dose)

Factor	Total adverse events		Serious adverse effects		Serious infections		Withdrawals due to adverse effects
Factor	OR (95% CI)	Tau squared	OR (95% CI)	Tau squared	OR (95% CI)	Tau squared	OR (95% CI)	Tau squared
Overall biologics (vs control)	1.06 (1.03 to 1.10) P = 0.0006	1.064	1.17 (0.90 to 1.53) P = 0.2448	0.846	1.39 (1.18 to 1.64) P = 0.0003	1.187	1.43 (1.23 to 1.66) P < 0.0001	1.126
By drug (vs Control)	P = 0.0216	1.064	P = 0.3126	0.897	P = 0.0043	1.144	P = 0.0006	1.075
Abatacept	1.05 (0.93 to 1.17)		1.01 (0.77 to 1.31)		1.11 (0.66 to 1.87)		1.14 (0.71 to 1.84)
Adalimumab	1.00 (0.93 to 1.08)		0.92 (0.74 to 1.15)		1.24(0.81 to 1.88)		1.21 (0.86 to 1.71)
Anakinra	1.01 (0.88 to 1.16)		1.00 (0.67 to 1.49)		1.83(0.85 to 3.95)		1.61 (0.86 to 3.01)
Certolizumab pegol	1.05 (0.91 to 1.21)		1.49 (1.06 to 2.02)		2.82 (1.27 to 6.29)		1.39 (0.85 to 2.29)
Etanercept	1.10 (1.01 to 1.20)		1.13 (0.90 to 1.41)		1.10 (0.74 to 1.65)		1.25 (0.90 to 1.72)
Golimumab	1.06 (0.93 to 1.20)		1.00 (0.71 to 1.41)		1.37 (0.77 to 2.44)		1.35 (0.79 to 2.30)
Infliximab	1.16 (1.07 to 1.27)		1.19 (0.99 to 1.43)		1.97 (1.41 to 2.75)		2.15 (1.60 to 2.89)
Rituximab	1.04 (0.96 to 1.13)		1.02 (0.84 to 1.23)		1.12 (0.81 to 1.54)		1.21 (0.77 to 1.89)
Tocilizumab	1.10 (0.97 to 1.26)		1.14 (0.79 to 1.63)		1.67 (0.92 to 3.06)		1.54 (0.88 to 2.67)

TNF‐alpha inhibitor:	P = 0.0021	1.031	P = 0.4927	0.858	P = 0.0002	1.121	P < 0.0001	1.061
Yes	1.07 (1.03 to 1.12)		1.25 (0.92 to 1.71)		1.41 (1.13 to 1.75)		1.41 (1.18 to 1.68)
No	1.06 (1.00 to 1.12)		0.99 (0.62 to 1.59)		1.37 (1.05 to 1.78)		1.50 (1.13 to 1.99)

Type of Biologic:	P = 0.0097	1.033	P = 0.7289	0.868	P = 0.0004	1.097	P < 0.0001	1.042
TNF‐alpha antibody	1.06 (1.01 to 1.12)		1.30 (0.91 to 1.87)		1.48 (1.15 to 1.90)		1.63 (1.09 to 2.43)
TNF‐alpha receptor	1.09 (1.00 to 1.19)		1.11 (0.59 to 2.09)		1.17 (0.74 to 1.83)		1.79 (0.95 to 3.38)
Others	1.06 (1.00 to 1.12)		1.00 (0.62 to 1.60)		1.37 (1.05 to 1.78)		1.72 (0.96 to 3.08)

Trial duration:	P < 0.0001	0.634	P < 0.0001	N.E.	P < 0.0001	1.031	P < 0.0001	0.809
Short (<6 mo)	1.08 (1.03 to 1.13)		1.03 (0.93 to 1.15)		1.60 (1.23 to 2.08)		1.76 (1.22 to 2.52)
Intermediate (6‐12 mo)	1.04 (0.97 to 1.12)		1.10 (0.96 to 1.27)		1.38 (0.96 to 1.99)		1.29 (0.69 to 2.40)
Long (>12mo)	1.04 (0.97 to 1.12)		0.83 (0.76 to 0.90)		1.19 (0.93 to 1.54)		1.56 (0.88 to 2.78)

Concomitant medication:	P = 0.0723	1.066	P = N/A	0.831	P = 0.0176	1.210	P = 0.0004	1.148
MTX +Other DMARD	1.06 (1.01 to 1.12)		1.18 (0.80 to 1.74)		1.26 (0.96 to 1.65)		1.36 (1.08 to 1.71)
MTX	1.04 (0.90 to 1.21)		1.74 (0.63 to 4.84)		1.72 (0.90 to 3.30)		1.33 (0.79 to 2.26)
Other DMARD(s)	1.08 (1.02 to 1.14)		1.05 (0.71 to 1.54)		1.31 (1.00 to 1.72)		1.65 (1.26 to 2.15)
None	1.05 (0.96 to 1.14)		1.33 (0.71 to 2.50)		1.79 (1.14 to 2.80)		1.34 (0.91 to 1.96)

Disease condition:	P = 0.0166	1.087	P < 0.0001	0.679	P < 0.0001	1.013	P < 0.0001	0.982
Ankylosing spondylitis	1.25 (1.08 to 1.44)		1.58 (0.56 to 4.48)		1.45 (0.27 to 7.74)		3.34 (0.78 to 14.24)
Cancer	1.05 (0.96 to 1.15)		1.00 (0.47 to 2.10)		1.15 (0.80 to 1.67)		2.48 (0.84 to 7.32)
IBD	0.98 (0.88 to 1.09)		0.70 (0.31 to 1.60)		1.28 (0.67 to 2.44)		1.01 (0.37 to 2.77)
Psoriasis	1.17 (1.06 to 1.30)		1.25 (0.5 to 3.08)		0.70 (0.28 to 1.77)		1.34 (0.52 to 3.45)
Psoriatic arthritis	1.03 (0.87 to 1.22)		0.59 (0.18 to 2.01)		0.29 (0.07 to 1.25)		1.26 (0.31 to 5.07)
Rheumatoid arthritis	1.05 (1.00 to 1.09)		1.31 (0.92 to 1.88)		1.55 (1.23 to 1.95)		1.44 (0.95 to 2.20)
Other*	1.07 (0.96 to 1.19)		1.37 (0.77 to 2.44)		1.61 (1.09 to 2.36)		3.65 (1.67 to 8.18)
N = number of; OR = odds ratio; CI = confidence interval; P = P value; TNF‐alpha inhibitor = tumor necrosis factor ‐ alpha inhibitor; N/A = not applicable; N.E. = not estimable; MTX = methotrexate; DMARD = disease modifying anti‐rheumatic drug; IBD = inflammatory bowel disease; Other* = other disease conditions ‐ includes: heart failure, multiple sclerosis, COPD, alcoholic hepatitis, diabetes, lupus, active spondylarthropathy, osteoarthritis, asthma, cardiac or renal transplantation, Sjogren's syndrome, polymyalgia rheumatica, autoimmune inner ear disease, giant cell arteritis, pulmonary sarcoidosis, Hepatitis C, cancer anorexia/weight loss syndrome, Wegener's granulomatosis, Crohn's disese and ulcerative colitis. The results in this table are not adjusted for dose. Note: we defined the comparison of TNF antibody versus receptor versus other as follows: TNF antibody (infliximab, golimumab, certolizumab pegol, adalimumab) versus TNF receptor (etanercept) versus other (tocilizumab, rituximab, abatacept). The ‘other’ types of concomitant medication included DMARDs, steroids and/or NSAIDs. Note: we did not have enough data for the models to run on the stratified analysis for congestive heart failure, lymphoma, and TB reactivation outcomes.

Table 15. Stratified meta‐analysis findings (unadjusted for dose)

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Table 16. Estimates of safety outcomes from extension studies

	Abatacept		Adalimumab		Anakinra		Certolizumab pegol		Etanercept		Golimumab		Infliximab		Rituximab		Tocilizumab
Patients	604		2564		427		781		5342		137		917		1039		143
Estimated Patient Months	22926		34526		8113		9372		173016		1644		17855		49872		8580

Outcome measure	Counts	Risk	Counts	Risk	Counts	Risk	Counts	Risk	Counts	Risk	Counts	Risk	Counts	Risk	Counts	Risk	Counts	Risk
Serious AE, events	132	46.0%	227	9.0%	.	.	93	11.9%	355	10.4%	22	16.1%	116	12.9%	316	30.4%	77	53.8%
Serious AE, patients	287	.	2522	.	.	.	781	.	3406	.	137	.	898	.	1039	.	143	.
Serious Infections, events	.	.	62	2.5%	.	.	7	0.9%	178	3.9%	3	2.2%	42	5.1%	84	8.1%	25	17.5%
Serious Infections, patients	.	.	2476	.	.	.	781	.	4577	.	137	.	831	.	1039	.	143	.
TB, events	0	0.0%	2	0.1%	.	.	5	0.6%	1	0.0%	0	0.0%	1	0.1%	0	0.0%	.	.
TB, patients	287	.	2275	.	.	.	781	.	3198	.	137	.	746	.	1039	.	.	.
Lymph cancer, events	0	0.0%	4	0.2%	.	.	1	0.1%	9	0.4%	0	0.0%	1	0.1%	0	0.0%	.	.
Lymph cancer, patients	287	.	2417	.	.	.	781	.	2279	.	137	.	668	.	1039	.	.	.
Cong. Heart Failure, events	.	.	2	0.1%	.	.	.	.	5	0.3%	1	0.7%	0	0.0%	.	.	.	.
Cong. Heart Failure, patients	.	.	2275	.	.	.	.	.	1712	.	137	.	668	.	.	.	.	.
WD d/t AE, events	59	9.8%	143	6.5%	46	10.8%	39	5.0%	240	5.5%	11	8.0%	70	7.8%	38	3.7%	32	22.4%
WD d/t AE, patients	604	.	2214	.	427	.	781	.	4327	.	137	.	898	.	1039	.	143	.

Table 16. Estimates of safety outcomes from extension studies

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