Comparative Efficacy of Biologic Disease-Modifying Anti-Rheumatic Drugs for Non-Radiographic Axial Spondyloarthritis: A Systematic Literature Review and Bucher Indirect Comparisons

Systematic Literature ReviewSLR Search Results

The SLR searches yielded 2063 unique publications, of which 118 (reporting on ten unique trials) met the inclusion criteria for the qualitative synthesis. Three trials were not eligible for quantitative synthesis: (1) Haibel 2008 had a non-comparable nr-axSpA population with moderate-to-severe nr-axSpA [33]; (2) ABILITY-3 only enrolled patients who achieved sustained remission during the initial non-randomized phase [34]; (3) PREVAS, whose results were published in abstract form only at the time the systematic review was conducted, examined very early treatment in patients with suspected nr-axSpA [35]. This left a total of seven trials which met the inclusion criteria for the Bucher ITCs. The flow of included studies in the SLR and quantitative synthesis is summarized in Fig. 1.

Fig. 1figure 1

PRISMA study attrition diagram for systematic literature review. AS ankylosing spondylitis, axSpA axial spondyloarthritis, CENTRAL Cochrane Central Register of Controlled Trials, DMARD disease-modifying anti-rheumatic drug, ITC indirect treatment comparison, NSAID non-steroidal anti-inflammatory drug, PD pharmacodynamics, PK pharmacokinetics, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RCT randomized controlled trial, SLR systematic literature review

Study and Patient Characteristics

A summary of the study and patient characteristics of the included trials is presented in Table 2. All seven trials were double-blind, PBO-controlled, and multicenter [12,13,14,15,16, 36, 37]. Randomized phases of the studies ranged between 12 and 52 weeks. Sample sizes in the different treatment arms ranged between 40 and 186 patients. Although the trials had generally homogenous populations, with all seven using the ASAS classification criteria for axSpA [38], EMBARK [12] and GO-AHEAD [13] limited enrollment to patients with earlier disease/symptom duration than the other studies included in the ITC (mean time since symptom onset of 2.5– ≤ 5 years [12, 13]) and GO-AHEAD limited enrollment to patients with earlier disease/symptom duration than the other studies included in the ITC (time since symptom onset of 2.5– ≤ 5 years [12, 13] compared to 7.80–11.30 years [16, 36]). Four trials included only patients who were naïve to TNFis [12,13,14, 16], whereas C-axSpAnd, RAPID-axSpA [11, 21], and PREVENT [15, 36, 37] included some patients who were previously exposed to TNFis (5.70%, 14–20%, and 9.70%, respectively). The subgroups of patients who were TNF-naïve were used for the ITC when available. Sex distribution was comparable across studies (males: 43–64% [12, 14]), and mean age across the trials ranged from 30–41 years [13, 16]. Sex distribution was comparable across studies (males: 43–64% [12, 14]), and mean age across the trials ranged from 30–41 years [13, 16].

Table 2 Study characteristics of RCTs

All trials had a comparable proportion of patients with elevated CRP levels. However, the threshold for the ULN was not consistent across studies (> 5 mg/l, > 15 mg/l, or > 1 × ULN, or > 9 or 9.99 mg/l), as different studies used different central laboratories. In addition, EMBARK and PREVENT used high-sensitivity (hs) CRP levels, for which low values cannot be compared to CRP levels directly.

The mean baseline CRP levels of nr-axSpA patients across the trials reporting this data were as follows:

ABILITY-1: 6.80–7.20 mg/l

COAST-X: 12.10–12.30 mg/l

GO-AHEAD: 13–15 mg/l

C-axSpAnd: 16.10–17.90 mg/l

RAPID-axSpA (AS001): 13.40–19.30 mg/l

Note: The RAPID-axSpA trial evaluated both AS and nr-axSpA patients; only nr-axSpA patients from this trial are included for the purpose of this manuscript.

Risk-of-Bias Assessment

Overall, evaluated trials had a low risk of bias, though the risk was unclear in some instances, particularly for randomization methods and blinding of study outcome assessments (Supplementary Material; Table S2). While all evaluated trials were randomized, the specific methodology and type of randomization (e.g., simple, block, stratified) were often unclear. Studies were also evaluated for other sources of bias not covered in the predefined domains; all trials were designated as low risk for additional biases, except EMBARK, which inconsistently defined its primary outcome (ASAS20 or ASAS40) across sources [12, 39, 40].

Indirect Treatment ComparisonStatistical Heterogeneity

Opportunities to investigate statistical heterogeneity in the results were minimal, as the only comparison in the ITCs with more than one trial was CZP vs. PBO, which included the C-axSpAnd and RAPID-axSpA trials in some analyses. No notable or statistically significant heterogeneity was found in most cases (I2 = 0; tau = 0) or only minimal heterogeneity (I2 < 25%) was identified for most of the included outcomes. Nevertheless, modestly elevated heterogeneity was identified in ASDAS-MI among the bDMARD-naïve subgroup at 12 weeks (I2 of 32.20%).

Results for the Main Analyses

The key results from the ITCs of CZP vs. the different comparators are presented in Table 3, Fig. 2a and Supplementary Figs. 1–8. Statistically significant advantages for CZP were seen against each comparator treatment for at least one outcome; when differences were not statistically significant, a numerical advantage was seen for CZP compared to all other interventions across all endpoints.

Table 3 Summary of base-case ITC results (CZP vs. comparator bDMARDs at 12–16 weeks)Fig. 2figure 2

ASAS40 ITC results. *CZP Pooled (CZP 200 Q2W + CZP Q4W) is analyzed instead of CZP 200 mg. **Random-effect model (analyses are otherwise fixed-effect models). ADA adalimumab, ASAS Assessment in Ankylosing Spondylitis, CI confidence interval, CRP C-reactive protein, CZP certolizumab pegol, ETN etanercept, GOL golimumab, IXE ixekizumab, LD loading dose, MRI magnetic resonance imaging, NL non-loading dose, OR odds ratio, Q2W every other week, Q4W every 4 weeks, SEC secukinumab

CZP vs. ADA (number of studies included in the ITC, n = 3): At 12 weeks, statistically significant odds favoring CZP pooled over ADA 40 mg were estimated for BASDAI (with differences of mean change from baseline (95% CI) of − 0.94 [− 1.53, − 0.34]), BASFI (− 1.27 [− 1.99, − 0.55]) and total spinal pain (− 0.98 [− 1.66, − 0.29]) among patients who were naïve to prior bDMARD therapy. However, no significant differences were found between the two treatments for ASAS20/40 and ASDAS-ID/MI responses.

CZP vs. ETN (n = 2): At 12 weeks, CZP 200 mg showed statistically significantly higher odds of achieving ASAS20, ASAS40, and ASDAS-ID response compared with ETN 50 mg with ORs (95% CIs) of 4.78 (1.89, 12.09), 4.90 (1.65, 14.56), and 10.60 (1.65, 68.26), respectively, among patients who were naïve to prior bDMARD therapy with symptom duration between 3 months and 5 years. CZP 200 mg also demonstrated statistically significant improvement in BASDAI and BASFI scores in this population compared to ETN, with differences of mean change from baseline and corresponding 95% CIs of − 1.59 (− 2.63, − 0.55) and − 1.67 (− 2.53, − 0.81), respectively.

CZP vs. GOL (n = 2): At 16 weeks, CZP 200 mg had statistically significantly higher odds of achieving ASDAS-ID response than GOL (OR: 4.19; 95% CI: 1.09, 16.14) among patients who were naïve to prior bDMARD therapy with disease duration no more than 5 years. Results for ASAS20, ASAS40, BASDAI, BASFI, and total spine pain were not statistically significant.

CZP vs. IXE (n = 3): At 16 weeks, bDMARD-naïve patients who received CZP 200 mg were statistically significantly more likely than those receiving IXE Q2W and IXE Q4W to achieve response on the binary outcomes of ASAS20 (vs. Q2W: OR [95%CI] of 2.82 [1.39, 5.74], vs. Q4W: 3.15 [1.54, 6.43]), ASAS40 (vs. Q2W: 2.69 [1.09, 6.61], vs. Q4W: 3.30 [1.33, 8.18]), and ASDAS-ID (vs. Q2W: 3.96 [1.04, 14.91], vs. Q4W: 5.10 [1.34, 19.42]). CZP 200 mg also yielded statistically significant improvements in scores on the continuous outcomes of BASDAI (vs. Q2W: MD [95%CI] of − 1.09 [− 1.85, − 0.34], vs. Q4W: − 1.43 [− 2.19, − 0.68]), BASFI (vs. Q2W: − 1.02 [− 1.86, − 0.19], vs. Q4W: − 1.29 [− 2.13, − 0.46]), and total spinal pain (vs. Q2W: − 1.28 [− 2.10, − 0.46], vs. Q4W: − 1.52 [− 2.35, − 0.69]). At 52 weeks, CZP 200 mg maintained a statistically significant advantage in ASAS40 over IXE Q4W (OR: 2.50; 95% CI: 1.02, 6.13); however, this was not maintained vs. IXE Q2W. Results were also not significantly in favor of CZP 200 mg for improvements in BASDAI at 52 weeks.

CZP vs. SEC (n = 2): In comparison to both SEC non-loading dose (NL) and SEC loading dose (LD) at 16 weeks in patients with nr-axSpA regardless of prior treatment, there were statistically significant results favoring CZP pooled for ASAS20 (NL: OR [95%CI] of 3.37 [1.88, 6.01], LD: 3.56 [2.00, 6.36]), ASAS40 (NL: 3.76 [1.98, 7.12], LD: 3.88 [2.05, 7.35]), and BASFI (NL: − 1.53 [− 2.46, − 0.60], LD: − 1.38 [− 2.31, − 0.45]). Trends for ASAS40 were also similar for the bDMARD-naïve nr-axSpA population (NL: 4.35 [1.98, 9.56], LD: 4.48 [2.04, 9.85]) and the statistical significance was maintained through 52 weeks in both populations. The comparison for ASDAS-ID estimated statistically significant results favoring CZP over SEC LD at 16 weeks (2.62 [0.86, 8.01]) and not 52 weeks. No statistically significant results in favor of CZP were found for ASDAS-MI and BASDAI, and no statistically significant differences for ASDAS-ID were seen between CZP and SEC NL at 12 and 52 weeks, or for SEC LD at 52 weeks.

MRI/CRP Subgroup Results

All trials included in the SLR reported subgroup ASAS40 data by baseline MRI or CRP status except for RAPID-axSpA; however, the trials varied in terms of whether subgroup data were provided for MRI-positive or -negative and/or CRP-positive and -negative groups. A summary of the ASAS40 findings by baseline MRI/CRP status is presented in Table 4.

Table 4 Base case and subgroup ASAS 40 response

The baseline rate of elevated CRP in the CZP arm of C-axSpAnd trial was 52.60%. Across the comparator trials included in the subgroup ITC analyses, the baseline rates of elevated CRP ranged from 32% (ABILITY-1) to 58% (PREVENT). The baseline percentage of patients with sacroiliitis on MRI in the CZP and PBO arms of C-axSpAnd were 74.70 and 74.80%, respectively. In the comparator trials, the baseline levels of sacroiliitis on MRI ranged from 46% (ABILITY-1) to 82% (EMBARK).

The ITC results in these subgroups demonstrated that CZP was superior to SEC among patients who were MRI + /CRP- or MRI−/CRP + and ETN among patients who were MRI + /CRP− at improving ASAS40. CZP was comparable to GOL and IXE in improving ASAS40 across the different subgroups. The results for these analyses were nearly identical regardless of the cut-off used to define normal CRP levels (i.e., 5 mg/l or 10 mg/l).

MRI-/CRP + subgroup: Among the subgroup of patients who were MRI−/CRP + , CZP 200 mg was associated with statistically significantly higher odds of achieving ASAS40 compared with SEC 150 mg LD and NL at week 16, with ORs (95% CIs) of 4.56 (1.03, 20.21) and 5.29 (1.18, 23.60), respectively (Fig. 2c). In this subgroup, we did not find statistically significant differences between CZP treatment and other bDMARDs (ETN, GOL, and IXE) in achieving ASAS40.

MRI + /CRP- subgroup: Among the subgroup of patients who were MRI + /CRP−, CZP 200 mg was associated with statistically significantly higher odds of achieving ASAS40 compared with ETN 50 mg, SEC 150 mg LD or NL at week 16, with ORs (95% CIs) of 11.11 (1.92, 64.3), 4.96 (1.77, 13.88) and 3.95 (1.41, 11.03), respectively (Fig. 2d). Similar to the MRI−/CRP + subgroup, CZP treatment in patients with MRI + /CRP− was associated with comparable odds of achieving ASAS40 relative to GOL and IXE.

MRI + /CRP + subgroup: Among the subgroup of patients who were MRI + /CRP + , there were no statistically significant results favoring CZP 200 mg over any of the comparators at week 16 (Fig. 2b). Across the trials in this analysis, the proportion of bDMARD-treated patients with ASAS40 response was higher in the MRI + /CRP + subgroups compared with the ITT populations (Table 4).

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