Disease-specific ADRs of TNF-α inhibitors as reported by patients with inflammatory rheumatic diseases: a registry-based prospective multicenter cohort study

Figures & data

Figure 1. Flowchart of the study design. Inclusion criteria were (1) one immune-mediated inflammatory disease (IMID), i.e. rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis/axial spondyloarthritis (AS/axSpA) and (2) the use of adalimumab (ADA) and/or etanercept (ETN) for their IMID. ^aThe combined number of patients from both groups (n = 734) exceeds the total number of included patients (n = 729) as 5 patients that had switched in bDMARD treatment reported an ADR with one, but not with the other bDMARD. Dutch Biologic Monitor (DBM); adverse drug reaction (ADR); System Organ Class (SOC); Inflammatory rheumatic diseases (IRDs).

Figure 2. The frequency (%) of patient-reported ADRs per IRD, attributed to the use of anti-TNF drugs. ADRs were grouped under MedDRA® system organ class (SOC). SOCs contributing for less than 1.5% to the total number of SOCs were grouped under ‘other.’ p-Values indicate the difference in frequencies of the ADRs between the different IRDs. Inflammatory rheumatic disease (IRD); rheumatoid arthritis (RA); psoriatic arthritis (PsA); ankylosing spondylitis (AS) including axial spondyloarthritis (axSpA).

Table 1. Characteristics of patients registered in the DBM that use anti-TNF drugs for their IRD.

Patient characteristics	RA (n = 442)	PsA (n = 172)	AS/axSpA (n = 115)	Total (n = 729)
Gender (female), n (%)	310 (70.1)	83 (48.3)	42 (36.5)	435 (59.7)
Age (years) (mean ±SD)	59.7 (12.8)	56.0 (10.5)	50.9 (13.4)	57.4 (12.8)
Smoking, n (%)	60 (13.6)	21 (12.2)	18 (15.7)	99 (13.6)
BMI (kg/m^2) (mean ±SD)	25.9 (5.2)	27.2 (4.9)	26.0 (4.1)	26.2 (5.0)
bDMARD^a, n (%)
Adalimumab	191 (43.2)	93 (52.8)	64 (55.7)	348 (46.6)
Etanercept	262 (59.3)	83 (47.2)	53 (46.1)	398 (53.4)
Adverse drug reactions (ADR) ^b, n (%)
≥1 ADR	221 (49.6)	76 (44.2)	57 (49.1)	354 (48.2)
No ADR	225 (50.4)	96 (55.8)	59 (50.9)	380 (51.8)
Patients with reported combination therapy any time during participation^c, n (%)
Methotrexate	233 (52.7)	59 (34.3)	7 (6.1)	299 (41.0)
Corticosteroids	59 (13.3)	10 (5.8)	4 (3.5)	73 (10.0)
Leflunomide	23 (5.2)	18 (10.5)	0 (0.0)	41 (5.6)
Hydroxychloroquine	48 (10.9)	1 (0.6)	0 (0.0)	49 (6.7)
Aminosalicylates	34 (7.7)	7 (4.1)	5 (4.4)	46 (6.3)
Other combination therapy	12 (2.7)	0 (0.0)	1 (0.9)	13 (1.8)
Patients with reported comorbidities^d, n (%)
Cardiovascular disorder	128 (29.0)	46 (26.7)	30 (26.1)	204 (28.0)
Hypercholesterolemia	92 (20.8)	32 (18.6)	15 (13.0)	139 (19.1)
Respiratory disorder	62 (14.0)	22 (12.8)	10 (10.4)	96 (13.2)
Psychiatric disorder	25 (5.7)	14 (8.1)	4 (3.5)	43 (5.9)
Nervous system disorder	13 (2.9)	3 (1.7)	4 (3.5)	20 (2.7)
Cancer	9 (2.0)	3 (1.7)	4 (3.5)	16 (2.2)
Other comorbidity	86 (19.5)	31 (18.0)	23 (20.0)	140 (19.2)
No comorbidity	142 (32.1)	47 (27.3)	45 (39.1)	234 (32.1)
Unknown	36 (8.1)	25 (14.5)	12 (10.4)	73 (10.0)

The overall percentage may exceed 100% as patients

^aMay have used both ADA and ETN (N = 17);

^bMay have experienced and ADR with one bDMARD but not with the other (N = 5);

^cCan have a combination therapy consisting of more than one drug (N = 83); and/or

^dMay suffer from more than one comorbidity (N = 204). DBM, Dutch Biologic Monitor; IRD, inflammatory rheumatic disease; RA, rheumatoid arthritis; PsA, psoriatic arthritis; AS/axSpA, ankylosing spondylitis/axial spondyloarthritis; SD, standard deviation; BMI, body mass index; ADR, adverse drug reaction.

Table 2. Logistic regression estimates of patient characteristics associated with the reporting of ADRs categorized by SOC.

		Univariate analysis		Multivariate analysis
SOC	Variable	Crude OR (95%-CI)	p	Adjusted OR (95%-CI)	p
Gastrointestinal disorders
	Indication (AS/axSpA)	0.28 (0.06 – 0.93)	0.057	0.23 (0.03 – 0.91)	0.065
	Indication (RA)	0.76 (0.38 – 1.58)	0.439	0.61 (0.28 – 1.34)	0.203
	Age			1.02 (0.99 – 1.05)	0.267
	bDMARD (ETN)			1.11 (0.58 – 2.16)	0.754
	Combination therapy
	Corticosteroid use			0.50 (0.14 – 1.36)	0.221
	MTX use			1.24 (0.63 – 2.42)	0.536
	Gender (Female)			1.46 (0.69 – 3.26)	0.337
	Observations	360		342
Musculoskeletal and connective tissue disorders
	Indication (AS/axSpA)	0.47 (0.12 – 1.45)	0.213	0.46 (0.10 – 1.61)	0.257
	Indication (RA)	1.14 (0.57 – 2.48)	0.717	1.10 (0.51 – 2.51)	0.812
	Age			1.04 (1.01 – 1.08)	0.005*
	bDMARD (ETN)			0.68 (0.36 – 1.26)	0.221
	Combination therapy
	Corticosteroid use			1.15 (0.48 – 2.51)	0.743
	MTX use			0.88 (0.45 – 1.68)	0.696
	Gender (Female)			1.02 (0.51 – 2.11)	0.960
	Observations	360		342
Respiratory, thoracic and mediastinal disorders
	Indication (AS/axSpA)	4.75 (1.34 – 22.21)	0.024*	5.17 (1.28 – 26.31)	0.028*
	Indication (RA)	4.69 (1.63 – 19.87)	0.012*	6.24 (2.01 – 27.71)	0.005*
	Age			1.04 (1.01 – 1.08)	0.008*
	bDMARD (ETN)			0.37 (0.18 – 0.73)	0.005*
	Combination therapy
	Corticosteroid use			2.49 (1.11 – 5.42)	0.023*
	MTX use			0.34 (0.15 – 0.74)	0.008*
	Gender (Female)			1.36 (0.62 – 3.16)	0.450
	Observations	360		342
Other SOC
	Indication (AS/axSpA)	3.59 (1.32 – 10.87)	0.016*	4.33 (1.48 – 13.89)	0.009*
	Indication (RA)	1.26 (0.052 – 3.54)	0.634	1.09 (0.42 – 3.17)	0.867
	Age			1.01 (0.98 – 1.04)	0.523
	bDMARD (ETN)			0.68 (0.33 – 1.36)	0.274
	Combination therapy
	Corticosteroid use			1.47 (0.55 – 3.52)	0.415
	MTX use			1.00 (0.45 – 2.19)	0.999
	Gender (Female)			1.74 (0.78 – 4.21)	0.194
	Observations	360		342

ADRs were grouped under SOC and results are shown in odds ratios (OR) with 95% confidence intervals (CI) and p-values. The categorical variable ‘indication’ consisted of 3 categories of which RA and AS/axSpA were analyzed with reference to PsA. The variables bDMARD (ETN) and gender (female) were assessed with reference to bDMARD (ADA) and gender (Male), respectively. All variables were registered at time of enrollment. 95% CI, 95% confidence interval; ADA, adalimumab; AS/axSpA, ankylosing spondylitis/axial spondyloarthritis; ETN, etanercept; MTX, methotrexate; OR, odds ratio; p, p-value; RA, rheumatoid arthritis; SOC, system organ class.

*Indicates a p-value below 0.05.

Table

ADA	Adalimumab
ADRs	Adverse drug reactions
AEs	Adverse events
(A)OR	(Adjusted) odds ratio
AS/axSpA	Ankylosing spondylitis/axial spondyloarthritis
bDMARD	Biologic disease-modifying anti-rheumatic drug
BH	Benjamini–Hochberg
CI	Confidence interval
DBM	Dutch biologic monitor
ETN	Etanercept
FFH	Fischer–Freeman–Halton exact test
HCP	Health-care professionals
IMID	Immune-mediated inflammatory disease
IRD	Inflammatory rheumatic disease
MedDRA®	Medical Dictionary for Regulatory Activities
MTX	Methotrexate
PsA	Psoriatic arthritis
PT	Preferred term
RA	Rheumatoid arthritis
SD	Standard deviation
SOC	System organ class
TNF-α	Tumor necrosis factor-α

Data availability statement

The data are not publicly available due to legal restrictions related to data privacy protection. However, the data are available from the corresponding author upon reasonable request after authorization from the DBM board.