Baseline demographics and clinical data.
Eighty-one consecutive patients with axSpA starting Ifx therapy were included. All patients had predominant axial involvement and 64 (79%) also presented some peripheral (enthesitis, arthritis, dactylitis) or extra-musculoskeletal involvement (uveitis, psoriasis, inflammatory bowel disease). Baseline demographic and clinical characteristics are shown in Table 1. Median (RIQ) age was 45 (37.5–53) years, 55% were men, and 22% currently smokers.
Table 1
Baseline characteristics of patients with axial spondyloarthritis (axSpA) (total population, non-responders and responders)
Characteristics | Total population (n = 81) | ΔASDAS < 1.1 (n = 45) | ΔASDAS ≥ 1.1 (n = 36) | p value |
Age, years* | 45 (37.5–53) | 43(37–53) | 46.5 (38–54) | 0.5 |
Body mass index* | 26.6 (24.4–29.7) | 27.8 (24.5–29.5) | 25.6 (23.1–30.5) | 0.5 |
Male, n (%) | 48 (55%) | 21 (47%) | 24 (67%) | 0.2 |
Disease duration, years* | 8.3 (4-17.1) | 7.3 (3.3–12.5) | 8.4 (5.5–19.8) | 0.07 |
HLA-B27 positive, n (%) | 43/70 (61%) | 19/36 (53%) | 24/34(71%) | 0.1 |
Smoking status, n (%) | | | | 0.2 |
- Currently smoker | 18 (22%) | 12 (28%) | 6 (50%) | |
- Non-smoker | 47 (58%) | 24 (56%) | 23 (61%) | |
- Ex-smoker | 14 (17%) | 5 (12%) | 9 (24%) | |
Subtype of SpA, n (%) | | | | 0.3 |
- Ankylosing Spondylitis | 42 (52%) | 18 (42%) | 24 (63%) | |
- Undifferentiated SpA | 30 (37%) | 20 (47%) | 10 (26%) | |
- Psoriatic SpA | 3 (4%) | 2 (5%) | 1 (3%) | |
- Spondyloarthropathy with inflammatory bowel disease | 6 (7%) | 3 (7%) | 3 (8%) | |
ASDAS ** | 3.5 (1) | 3.1(0.9) | 3.8 (1) | < 0.001 |
BASDAI ** | 6 (2) | 5.7 (2) | 6.2 (2) | 0.27 |
CRP levels * | 7.6 (3-25.7) | 4.2 (2.1–10.3) | 16.3(5.5–31.5) | 0.001 |
Monotherapy, n (%) | 35 (43%) | 20 (44%) | 15 (42%) | 0.17 |
Concomitant treatment: | | |
Methotrexate, n (%) | 27 (33%) | 12 (27%) | 15 (47%) | 0.01 |
Others csDMARDs, n (%) | 32 (39%) | 17 (38%) | 15 (42%) | 0.3 |
Prednisone, n (%) | 15 (19%) | 7 (16%) | 8 (22%) | 0.08 |
*Median (interquartile range); ** mean (SD)ASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index ; CRP, C-reactive protein (mg/L); csDMARD, conventional disease-modifying anti-rheumatic drug. |
At W52, 45 (56%) patients were classified in the group of non-R and 36 (44%) were classified as R. Globally, 41 (51%) patients dropped-out the Ifx therapy during follow-up (Median, IQR: 3, 1.3–5.9 years).
Baseline ASDAS were significantly lower in patients who did not achieve clinically important improvement [(mean ± SD) [3.9(1) in the R-group vs 3.1(0.9) in the non-R-group, p < 0.001], as well as CRP levels (median and IQR) [16.3 (5.5–31.5) in the R-group vs 4.2 (2.2–10.3) in the non-R-group, p = 0.001]]. Twenty-seven (33%) patients received concomitant MTX because of extra-axial manifestations, 18 (47%) in the R group and 9 (21%) in the non-R group; p = 0.01. None of the other baseline variables was significantly associated with clinical improvement (Table 1).
Association between early serum ITL and baseline variables with non-clinical improvement at week 52.
Figure 1 shows serum ITL values at W2, 6 and 12 in non-R and R groups. At all studied-time points values in the non R-group were lower compared to the R group: at W2 [37.6 (22-50.8) µg/ml vs 38.9 (27–52) µg/ml; p = 0.7] and W6 [18.7 (12.6–26.6) µg/ml vs 24.2 (13.6–34.6) µg/ml; p = 0.2], although only at W12 did they were statistically different [4.1 (0.9–8.3) µg/ml vs 7.1 (4.3–11.3) µg/ml; p = 0.007].
An ROC curve for not achieving clinically important improvement at W52, as defined by ΔASDAS < 1.1, was calculated in relation to the serum ITL at W12 (Fig. 2). The area under the curve (AUC) was 0.678 (95% confidence interval (CI): 0.558–0.797), p = 0.007). The cut-off value chosen to discriminate between non-R and R (with a sensitivity of 55%, specificity of 70%, PPV of 63% and NPV of 64%) was at Ifx serum trough concentrations of 6.7 µg/mL. Out of the 77 patients with available serum samples at W12, 45 (58%) had serum ITL below the threshold and 32 (42%) above it. Most patients in the non-R group had serum ITL < 6.7 µg/ml (29/41 (71%) below vs 12/41 (29%) above; p = 0.02) (Fig. 3).
In the univariable analysis, two variables were significantly associated with not achieving clinically important improvement at W52: serum ITL below 6.7 µg/ml at W12 (OR: 3.0; 95% CI: 1.2–7.7) and lower baseline ASDAS (OR: 2.4; 95%CI: 1.4-4.0). In the multivariable analysis, both variables, serum Ifx levels < 6.7 µg/mL at W12 (OR: 3.8; 95%CI: 1.3–11.2) and lower baseline ASDAS (OR: 2.3; 95%CI: 1.3–3.9) remained significantly associated with the non-clinically important improvement at W52.
Predictive value of early serum ITL (W12) to predict drug survival and secondary inefficacy over long-term follow up.
Mean survival time on the treatment was significantly shorter in patients with ITL < 6.7 µg/mL at W12, compared to those with levels above this cut-off: 5.0 years (95% CI: 3.8–6.2) vs 7.6 years (95% CI: 4.8–6.9); p = 0.04 (Fig. 4).
To evaluate the association between ITL at W12 and the predictive accuracy of secondary inefficacy, we performed an analysis in which those patients who dropped-out (n = 6) before 52 weeks of treatment were excluded. There were no differences between this cohort (n = 75) and the original cohort with 81 patients in terms of both clinical and demographic baseline characteristics (data not shown). Out of 75 axSpA patients, 28 (37%) developed secondary inefficacy and 7 (17%) dropped-out due to other reasons (adverse effects, loss of follow-up etc). The median (IQR) time under Ifx therapy of 28 patients with secondary inefficacy was 2.1(1.4–4.8) years and the median for patients who dropped-out for other reasons (n = 8) was 2.4 (0.7-4). The logistic regression analysis showed that Ifx concentrations below the cut-off at W12 (OR: 3.5; 95%CI: 1.2–10.2), but lacking baseline ASDAS (OR: 0.9; 95%CI: 0.5–1.5), were statistically associated with dropping out of treatment due to secondary inefficacy.
In addition, most of the patients who dropped-out due to secondary inefficacy had Ifx concentrations < 6.7 µg/mL at W12: 19/26(73%) with ITL, while only 7/26(27%) had at an ITL above the cut off at W12; p = 0.01 (Fig. 5).