Eligible studies
We identified 751 citations after search in the 3 databases plus one more after search in the congress abstract databases (Fig. 1). After reading titles and abstracts, we excluded 713 abstracts, mainly because of duplicates or off topic studies. After the complete reading, we excluded 6 articles: 4 because AU were not described during the controlled period, 2 for an unrepresentative population. Finally, we included 33 RCTs (Figs. 1 and 2), allowing 35 comparisons, comprising 4544 patients with axSpA treated with a biologic treatment and 2497 treated with placebo.
Study characteristics
The Additional File 1 provides detailed characteristics of the 33 RCTs included in the analyses. A comparison of a biologic treatment versus placebo was performed in 32 placebo-controlled RCTs (including one RCT comparing 2 biologic treatments, i.e. IXE and ADA, versus placebo), and in a head-to-head RCT comparing IFX versus ETN. Anti-TNF mAb were assessed in 17 RCTs(21–37) (ADA: 4; CTZ: 2; GOL: 4; IFX: 7), ETN was assessed in 10 RCTs(36, 38–46) and anti-IL17A were assessed in 8 RCTs(37, 47–53) (SCZ: 5; IXE: 3). The mean duration of the controlled period was 22.7 weeks ± 18.5 (SD), median: 16 weeks (range: 6-104 weeks).
According to the Cochrane RiOB 2.0 tool, 16 RCTs had a low risk of bias, 17 RCTs presented some concerns and none had a high risk of bias (Additional File 2).
Characteristics of the patients with axSpA
The main characteristics of the intention-to-treat (ITT) population are summarized in Table 1. Because our objective was to collect the AU flares, we included in the analysis the safety populations. A total of 7041 patients were included in the analysis, of whom 2497 received a placebo, 2101 were treated with an anti-TNF mAb, 699 with ETN, and 1744 with an anti-IL17A, with a follow-up of 3264 patients-years. The total cumulative exposure under active treatment was 2265 patients-years.
Table 1
Baseline characteristics of patients with axSpA (ITT population)
| Anti-TNF mAb | Associated placebo population | ETN | Associated placebo population | Anti-IL17A | Associated placebo population | Total placebo population |
N | 2040 | 1289 | 754 | 485 | 1744 | 877 | 2567 |
Gender male (%) | 71.2 | 68.4 | 72.9 | 73.2 | 63.3 | 63.3 | 67.1 |
Mean age | 36.9 | 37.2 | 39.8 | 39.1 | 41.8 | 42.4 | 38.8 |
HLA B27 positive (%) | 74.4* | 83.5* | 76.3** | 77.9* | 76.0* | 75.2* | 79.5* |
Mean duration symptoms (years) | 9.3* | 10.2* | 9.7 | 9.5 | 9.9 | 10.2 | 9.8* |
AU history (%) | 38.6** | 21.5** | 16.0* | 18.2* | 14.9** | 15.4** | 18.7** |
IBD history (%) | 4.7** | 4.6** | 2.4** | 3.7** | 2.1** | 2.1** | 3.4** |
Mean BASDAI | 6.5* | 6.6* | 6.1* | 6.0* | 6.9 | 6.9 | 6.6* |
Concomitant csDMARDs (%) | 35.8* | 39.1* | 33.3* | 27.8* | 32.2 | 33.6 | 35.2* |
Concomitant NSAIDs (%) | 85.1* | 84.2* | 85.2** | 88.4** | 84.4** | 86.8** | 85.2** |
Concomitant steroids (%) | 10.00** | 9.0** | 12.0** | 13.0** | 10.4* | 12.0* | 10.9** |
axSpA: axial spondyloarthritis; ITT: intention-to-treat; HLA: Human Leucocyte Antigen; AU : Anterior Uveitis; IBD : Inflammatory Bowel Disease; BASDAI : Bath Ankylosing Spondylitis Disease Activity Index; csDMARDs : conventional synthetic Disease Modifying Anti Rheumatic Drug; NSAIDs : Non-Steroidal Anti Inflammatory Drugs |
* <25% lacking data |
** >25% lacking data |
The different treatment groups were similar in terms of gender, age, duration of symptoms, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at baseline, concomitant csDMARD, non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids intake. AU and inflammatory bowel disease (IBD) history were less frequent in the ETN and anti-IL17A groups than in the anti-TNF mAb.
Annual incidence of UA
A total of 69 AU flares (de novo or relapses) was reported during the controlled periods: 31 among placebo-treated patients, 10 among anti-TNF mAb-treated patients (CTZ: 6, IFX: 3 and GOL: 1), 5 among ETN-treated patients and 23 among anti-IL17A-treated patients (SCK: 14 and IXE: 9) (Table 2). Crude annual incidence of AU was 1.06%, 2.14%, 2.11% and 3.10%, in the anti-TNF mAb, ETN, anti-IL17A and placebo groups, respectively.
Table 2
AU Flares reported in the included RCTs
| | | Treatment | Placebo |
First Author | Treatment | Study duration (weeks) | Patients (n) | Uveitis (n) | Patients (n) | Uveitis (n) |
Van der Heijde D.26 | ADA | 24 | 208 | 0 | 107 | 0 |
Sieper J.27 | ADA | 12 | 95 | 0 | 97 | 0 |
Huang F.25 | ADA | 12 | 229 | 0 | 115 | 0 |
Landewé R.31 | CTZ | 24 | 218 | 2 | 107 | 3 |
Deodhar A.22 | CTZ | 52 | 159 | 4 | 158 | 8 |
Inman R.28 | GOL | 24 | 278 | 0 | 77 | 0 |
Deodhar A.33 | GOL | 16 | 105 | 0 | 103 | 2 |
Sieper J.23 | GOL | 16 | 97 | 0 | 100 | 0 |
Bao C.34 | GOL | 24 | 169 | 1 | 44 | 0 |
Van der Heijde D.29 | IFX | 18 | 202 | 0 | 75 | 0 |
Barkham N.24 | IFX | 16 | 20 | 0 | 20 | 0 |
Inman R.21 | IFX | 12 | 39 | 0 | 37 | 0 |
Marzo-Ortega H.32 | IFX | 30 | 28 | 1 | 14 | 0 |
Sieper J.30 | IFX | 28 | 105 | 0 | 52 | 0 |
Braun J.35 | IFX | 12 | 34 | 1 | 35 | 3 |
Jennifer D.46 | ETN | 16 | 20 | 0 | 20 | 0 |
Davis J.C.43 | ETN | 24 | 138 | 3 | 139 | 8 |
Brandt J.44 | ETN | 6 | 14 | 0 | 16 | 0 |
Calin A.42 | ETN | 12 | 45 | 0 | 39 | 0 |
Van der Heijde D.40 | ETN | 12 | 305 | 0 | 51 | 1 |
Barkham N.38 | ETN | 12 | 15 | 0 | 17 | 0 |
Dougados M.39 | ETN | 12 | 39 | 0 | 43 | 0 |
Dougados M.41 | ETN | 8 | 42 | 0 | 48 | 0 |
Dougados M.45 | ETN | 12 | 106 | 0 | 109 | 0 |
Deodhar A.47 | IXE | 16 | 212 | 5 | 104 | 0 |
Van der Heijde D.37 | IXE | 16 | 164 | 1 | 86 | 0 |
Deodhar A.53 | IXE | 52 | 198 | 3 | 104 | 2 |
Baeten D.51 | SEC | 28 | 24 | 0 | 6 | 0 |
Baeten D.50 | SEC | 16 | 394 | 7 | 196 | 2 |
Pavelka K.49 | SEC | 16 | 150 | 0 | 75 | 0 |
Kivitz A.48 | SEC | 16 | 233 | 0 | 117 | 0 |
Deodhar A.52 | SEC | 52 | 369 | 7 | 186 | 2 |
Giardina A.36 | IFX | 104 | 25 | 1 | x | x |
ETN | 25 | 2 | x | x |
Pairwise meta-analysis
The AU incidence reported in patients with axSpA treated with anti-TNF mAb was significantly lower than with placebo (OR = 0.499, CI95% [0.256–0.973] p = 0.041). There was no significant difference in AU incidence between ETN (OR = 0.499, CI95% [0.198–1,259] p = 0.141) or anti-IL17A (OR = 1,345, CI95% [0.465–3,886] p = 0.585) and placebo (Fig. 3a, 3b and 3c). No publication bias is suggested according to the Egger’s regression test (p = 0.308) for each category of biologic treatment.
Subgroup analyses following pre-specified criteria to compare the incidence of uveitis in each subgroup for each biologic versus placebo showed no significant differences according to axSpA phenotype, disease duration, risk of bias or focus on AU history.
Network meta-analysis
Incidence of AU flares was lower with anti-TNF mAb compared to placebo (OR = 0.46; IC95% [0.24–0.90]) (Fig. 4). There was also a significant difference for a decreased incidence of AU with anti-TNF mAb compared to anti-IL17A (OR = 0.34; CI95% [0.12–0.92]) (Table 3). The other comparisons between biologics, or between biologics and placebo were not significant (Table 3). The Cochran’s Q test was 0.57 (p = 0.903) ascertaining the absence of heterogeneity/inconsistency between RCTs included.
Table 3
Comparison for the preventive effect on AU flares (OR and 95% CI)
Anti-TNF mAb | | | |
0.8406 [0.2953; 2.3927] | Etanercept | | |
0.3369 [0.1240; 0.9157]* | 0.4008 [0.1246; 1.2892] | Anti-IL17A | |
0.4647 [0.2406; 0.8975]* | 0.5528 [0.2299; 1.3288] | 1.3792 [0.6357; 2.9921] | Placebo |
*p < 0.05 |
OR: Odd-Ratio; CI: Confidence Interval; AU: Anterior Uveitis; TNF: Tumor Necrosis Factor; mAb: monoclonal antibody; IL17A: interleukin-17A |
P-scores that measure the mean extent of certainty that a treatment is better than the competing treatments were 0.86, 0.728, 0.274 and 0.137 in the anti-TNF mAb, ETN, placebo, and anti-IL17A groups, respectively. Ranking treatments by using P-scores suggested that incidence of AU was the lowest with anti-TNF mAb and the highest with anti-IL17A.
The examination of the funnel plot does not provide suspicion of an asymmetrical distribution of the points representing the studies.