Patient characteristics (Table 1)A total of 429 patients were included: 203 received a mAb and 226 ETA (supplementary figure S1). At baseline, extra-articular symptoms, especially inflammatory bowel disease, were less frequent with ETA than mAb treatment. Other baseline characteristics did not differ between the two groups.
Table 1: Baseline characteristics
|
Monoclonal antibodies
|
Soluble receptor (etanercept)
|
Total
|
Number of patients
|
203/429 (47.3)
|
226/429 (52.7)
|
429/429
|
SpA (excluding PsA)
|
146/203(71.9)
|
156/226(69.0)
|
302/429 (70.4)
|
PsA
|
57/203 (28.1)
|
70/226 (31.0)
|
127/429 (29.6)
|
Men
|
128/203 (63.1)
|
133/226 (58.8)
|
261/429 (60.8)
|
Age, years, mean (SD)
|
42.4 (12.3)
|
44.0 (12.9)
|
43.2 (12.4)
|
HLA B27
MD
|
111/175 (63.4)
28/203 (13.8)
|
119/182 (65.3)
44/226 (19.5)
|
230/357 (64.4)
72/429 (16.8)
|
Time between diagnosis and introduction of the first TNF inhibitor, years, mean (SD)
MD
|
6.9 (8.2)
8/203 (3.9)
|
7.6 (8.7)
12/226 (5.3)
|
7.3 (8.5)
20/429 (4.7)
|
History of extra-articular symptoms before treatment
MD
|
137/197 (69.5)*
6/203 (3.0)
|
119/217 (54.8)*
9/226 (4.0)
|
256/414 (61.8)
15/429 (3.5)
|
Uveitis
MD
|
41/188 (21.8)
15/203(7.4)
|
33/214 (15.4)
12/226 (5.3)
|
74/402 (18.4)
27/429 (6.3)
|
Psoriasis
MD
|
72/188 (38.3)
15/203 (7.4)
|
81/210 (38.6)
16/226 (7.1)
|
153/398 (38.4)
31/429 (7.2)
|
IBD
|
19/203 (9.4)*
|
2/226 (0.9)*
|
21/429 (4.9)
|
csDMARD treatment
Patients with sDMARD
Patients without sDMARD
MD
|
54/130 (41.5)
76/130 (58.5)
73/203 (36.0)
|
56/151 (37.1)
95/151 (62.9)
75/226 (33.2)
|
110/281 (39.1)
171/281 (60.9)
148/429 (34.5)
|
Methotrexate
|
44/130 (33.6)
|
44/151 (29.1)
|
88/281 (31.3)
|
Leflunomide
|
2/130 (1.5)
|
2/151 (1.3)
|
4/281 (1.4)
|
Sulfasalazine
|
8/130 (6.2)
|
10/151 (6.6)
|
18/281 (6.4)
|
Data are n (%) unless indicated.
*p<0.05
MD: missing data, SD: standard deviation, IBD: inflammatory bowel disease , PsA: psoriatic arthritis; sDMARD, synthetic disease-modifying anti-rheumatic drug
Uveitis occurrence:
Qualitative description: In total, 73 (6.3%) patients had a history of uveitis, 27 during the year before TNFi start; 19 of 396 (4.4%) patients with available data had at least one uveitis episode during the first year of treatment. With all TNFi lines, 52 (12.9%) patients had at least one uveitis episode (Table 2).
Quantitative description: During the first year of TNFi treatment, 43 uveitis episodes were reported. With all TNFi lines, 170 uveitis episodes were reported; 117 occurred with the first TNFi agent (Table 2).
Table 2: Occurrence of uveitis during the different time intervals of the study
|
Patients with at least one uveitis (qualitative analysis)
|
Total number of uveitis cases (quantitative analysis)
|
|
Between diagnosis and start of the first TNF inhibitor
|
73
|
117
|
|
Last year before TNF inhibitor
|
27
|
28
|
|
First year of TNF inhibitor
|
ETA
|
9
|
ETA
|
15
|
mAb
|
10
|
mAb
|
28
|
Total
|
19
|
Total
|
43
|
First TNF inhibitor
|
ETA
|
23
|
ETA
|
50
|
mAb
|
19
|
mAb
|
67
|
Total
|
42
|
Total
|
117
|
All TNF inhibitor lines
|
ETA
|
48
|
ETA
|
62
|
mAb
|
31
|
mAb
|
108
|
Total
|
52
|
Total
|
170
|
|
|
|
|
|
|
ETA, etanercept; mAb, monoclonal antibodies
Propensity score allocation
The variables selected for the propensity score were: occurrence of at least one uveitis in the whole period preceding the introduction of the first TNFi, age, sex, history of inflammatory bowel disease, delay between the diagnosis date and introduction of the first TNFi, and diagnosis of rheumatism (PsA or SpA) (supplementary table S1). This score balanced the population characteristics and probability of being assigned ETA as the first-line TNFi in both groups of patients (Supplementary figure S2, Supplementary figure S3). Despite imperfect performances, this propensity score mainly affected and balanced the two variables that were the most strongly associated with the type of TNFi prescribed and/or to the occurrence of uveitis during first year of treatment, namely “history of IBD” and “history of uveitis”.
Qualitative analysis comparing uveitis incidence with ETA versus mAbs
The crude incidence of at least one uveitis episode within 1 year after starting the first TNFi was numerically lower for patients with ETA than mAbs but not significantly (OR = 0.81 [0.32, 2.03], p = 0.65) and was still lower on adjustment for the propensity score but not significantly (OR = 0.94 [0.35, 2.54], p = 0.90) (Table 3). During the first-line TNFi treatment (Fig. 1b), the probability of at least one uveitis episode was higher with ETA than mAbs but not significantly (OR = 1.39 [0.71, 2.72], p = 0.3) and was higher on adjustment for the propensity score but still not significantly (OR = 1.89 [0.90, 4.01, p = 0.09) (Table 3).When considering all prescribed therapeutic lines of TNFi agents, the probability of at least one uveitis episode was numerically higher with ETA than mAbs but not significantly (OR = 1.57 [0.71, 3.46], p = 0.27) and was further increased on adjustment for the propensity score but still not significantly (OR = 1.98 [0.90, 4.37 ], p = 0.08) (Table 3).
Quantitative analysis comparing uveitis incidence with ETA versus mAbs
On quantitative analysis, the risk of uveitis within 1 year after starting the first TNFi was lower with ETA than mAbs but not significantly (RR = 0.54 [0.24; 1.24], p = 0.15) and was still lower on adjustment for the propensity score but not significantly (RR = 0.62 [0.26, 1.46]) (p = 0.27) (Table 3). When considering the first-line TNFi treatment, risk of uveitis was reduced with ETA versus mAbs but not significantly (RR = 0.97 [0.66, 1.43], p = 0.89) and was increased on adjustment for the propensity score but not significantly (RR = 1.10 [0.70; 1.72], p = 0.68) (Table 3). When considering total TNFi treatment exposure (all prescribed therapeutic lines), risk of uveitis was higher with ETA than mAbs but not significantly (RR = 1.01 [0.61; 1.69], p = 0.96) and was further increased on adjustment for the propensity score but still not significantly (RR = 1.21 [0.68, 2.16], p = 0.53) (Table 3).
Table 3: Incidence of uveitis with mAb and ETA, without and with adjustment for propensity score (PS)
|
|
ETA versus mAb (reference=mAb)
|
|
Qualitative analysis
|
Quantitative analysis
|
OR [95% CI]
|
p
|
RR [95% CI]
|
p
|
First year of TNF inhibitor treatment
|
Unadjusted for PS
|
0.81 [0.32, 2.03]
|
0.65
|
0.54 [0.24, 1.24]
|
0.15
|
Adjusted for PS
|
0.94 [0.35, 2.54]
|
0.90
|
0.62 [0.26, 1.46]
|
0.27
|
First-line TNF inhibitor
|
Unadjusted for PS*
|
1.39 [0.71, 2.72]
|
0.30
|
0.97 [0.66, 1.43]
|
0.89
|
Adjusted for PS*
|
1.89 [0.90, 4.01]
|
0.09
|
1.10 [0.70, 1.72]
|
0.68
|
All therapeutic lines of TNF inhibitors
|
Unadjusted for PS*
|
1.57 [0.71, 3.46]
|
0.27
|
1.01 [0.61; 1.69]
|
0.96
|
Adjusted for PS*
|
1.98 [0.90, 4.37]
|
0.08
|
1.21 [0.68, 2.16]
|
0.53
|
OR, odds ratio; RR, relative risk; 95% CI, 95% confidence interval
* Adjusted for duration of TNF inhibitor treatment
Uveitis occurrence before and during TNFi treatment
We found no significant decrease in number of participants with at least one uveitis episode when comparing the incidence of uveitis between the year before starting treatment and the first year of the first-line TNFi (p=0.17) (Fig. 1a, Table 4). When comparing the incidence of uveitis over the previous year and after the TNFi start, the main analysis did not find any significant difference between the two groups (0.0066 uveitis/patient-months in the previous year and 0.011 uveitis/patient-months in the first TNFi year, p=0.80; Table 5). As well, the sensitivity analysis (number of uveitis episodes set to 1) did not reveal a significant difference between the two incidences (p=0.69; Table 5).
We compared the incidence of uveitis with first-line TNFi treatment versus the incidence during the time between the diagnosis of SpA and the introduction of the first TNFi (Fig. 1b). The qualitative analysis showed a significant decrease in number of patients with at least one uveitis episode (p=0.0002) (supplementary table S2). The quantitative analysis as well as the sensitivity analysis revealed no significant difference in pre-treatment and treatment incidences (p= 0.19 and p= 0.16, respectively) (Supplementary table S3).
Finally, we compared the incidence of uveitis between the total period under TNF treatment, considering all therapeutic lines, and between the date of diagnosis and introduction of the first TNFi (Fig. 1c). The qualitative analysis revealed a significant decrease in incidence under treatment (p=0.049) (supplementary table S2), whereas the quantitative analysis revealed a significant increase in incidence under treatment (p=0.04 for the main analysis and p=0.03 for the sensitivity analysis; supplementary table S3).
Table 4: Qualitative analysis of the occurrence of at least 1 uveitis before and during the first year of TNF inhibitor treatment in patients with SpA or PsA
|
|
Uveitis ≥1 during the first year of TNF inhibitor
|
Yes
|
No
|
p
|
Uveitis ≥1 in the year before TNF inhibitor
|
Yes
|
10
|
17
|
0.17
|
No
|
9
|
325
|
Table 5: Quantitative analysis of the incidence of uveitis in the last year before and during the first year of TNF inhibitor treatment in patients with SpA or PsA
|
|
Main analysis n=350
|
Sensitivity analysis n=351
|
In the last year before TNF inhibitor
|
Uveitis/patient-months, mean (SD)
|
0.0066 (0.0333)
|
0.0066 (0.0333)
|
Uveitis/100 patient-years
|
7.92
|
7.92
|
In the first year of TNF inhibitor
|
Uveitis/patient-months, mean (SD)
|
0.011 (0.080)
|
0.011 (0.080)
|
Uveitis/100 patient-years
|
13.2
|
13.2
|
p value
|
0.80
|
0.69
|