Abstract
Objectives
In this post-hoc analysis of ESTHER trial, we aimed to investigate the longitudinal relationship between inflammation on MRI and the achievement of inactive disease/low disease activity in patients with axial spondyloarthritis (axSpA) treated with long-term tumor necrosis factor (TNF) inhibitor etanercept.
Methods
Of the 76 patients with active axSpA in the ESTHER trial, we included all patients treated with etanercept for at least 6 months for main analysis. All clinical and MRI data from 4.5 years of follow-up were used in the analysis. MRIs of the spine and sacroiliac (SI) joints were performed at baseline, week 24, week 48 and yearly thereafter and were evaluated for active inflammatory lesions according to the Berlin MRI score.
Results
Longitudinal analysis showed that higher SI joint osteitis score was associated with higher Axial Spondyloarthritis Disease Activity Score (ASDAS) at the same time point (β=0.08, 95% CI (0.05; 0.11)) and at the next time point 6 months later (β=0.05, 95% CI (0.02; 0.07)). Furthermore, resolution of osteitis in the SI joint (Berlin MRI osteitis score of ≤1) was associated with lower ASDAS at the next time point (β=−0.26, 95% CI (−0.42; −0.09)), higher odds of achieving ASDAS low disease activity (OR=5.61, 95% CI (1.06; 29.67)) and inactive disease status (OR=2.23, 95% CI (1.01; 4.94)) at the next time point.
Conclusions
The presence of inflammation on SI joints-MRI is associated with higher disease activity in axSpA. Resolution of inflammation on MRI is associated with better clinical outcomes in the long-term follow-up. Thus, achieving complete resolution of inflammation is favourable for meeting the treatment goals in axSpA.
Trial registration number
Keywords: Magnetic Resonance Imaging, Axial Spondyloarthritis, Etanercept, Tumor Necrosis Factor Inhibitors, Spondylitis Ankylosing
WHAT IS ALREADY KNOWN ON THIS TOPIC
It remains unclear whether the presence of inflammation on MRI is associated with higher disease activity in axial spondyloarthritis (axSpA).
Treatment with biological disease-modifying anti-rheumatic drugs reduces MRI-detected inflammation.
MRI findings correlate better with objective inflammatory markers like C reactive protein than with patient-reported outcomes. However, their role in ongoing treatment monitoring is still unclear.
WHAT THIS STUDY ADDS
This study demonstrates that resolving MRI-detected inflammation with etanercept treatment significantly improves long-term clinical outcomes in patients with axSpA.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
While recognising the importance of MRI, it should enhance rather than replace clinical evaluation. MRI complements clinical judgement and supports a tailored treatment strategy by integrating both imaging and clinical information.
Our findings highlight the need for complete control of clinical disease activity for optimal axSpA treatment outcomes, especially in areas with limited access to MRI.
Our study emphasises that a clinical approach should prevail in monitoring treatment in patients with axSpA.
Introduction
The concept of spondyloarthritis (SpA) has historically been centred around ankylosing spondylitis (AS).1 This approach has relied strongly on imaging techniques for diagnosis and classification. This focus on imaging, particularly radiography, was underscored by the 1984 modified New York criteria, which made the radiological evidence of sacroiliitis as a requirement for AS classification.2 With advances in technology, MRI has greatly improved our understanding of axial spondyloarthritis (axSpA). MRI’s ability to detect inflammation in the sacroiliac (SI) joints before it becomes evident in radiographs has allowed for earlier diagnosis and better patient care.3 This led to its inclusion in the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axSpA,4 which now includes an imaging arm that accepts either radiographic sacroiliitis or evidence of active sacroiliitis on MRI.
Beyond its diagnostic role, MRI has been explored for its potential in therapeutic management.5,7 This potential could be particularly relevant when assessing the efficacy of biological therapies, as the presence or resolution of inflammation on MRI could become a key point for the need of therapy adjustment. However, several challenges remain that complicate this use in clinical practice. First, the relationship between MRI findings and achieving clinical remission remains unclear. Studies have shown that while MRI can effectively visualise inflammation, it does not consistently correlate with clinical symptoms and patient outcomes.5 8 9 Second, differentiating between inflammation-related and mechanically induced bone marrow oedema may be challenging for the use of MRI as a treatment target. Finally, the limited feasibility of repeated MRI examinations due to availability and costs represents a challenge for daily clinical practice.
Therefore, the clinical approach remains central to the daily management of patients with SpA, and neither clinical remission nor treat-to-target recommendations specifically incorporate imaging outcomes in the assessment of disease activity.10 11 The ASAS-EULAR recommendations for the management of axSpA emphasise clinical remission or achievement of low disease activity as the primary targets for SpA, endorsing the Axial Spondyloarthritis Disease Activity Score (ASDAS)1 as the preferred tool for this assessment.10 12
To date, there is no clear evidence whether the presence of inflammation on MRI in patients treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs or tsDMARDs) could be a decisive tool for management in axSpA. In this study, we aimed to explore how the presence of inflammation in the SI joints and spine longitudinally relates to disease activity and the achievement of low disease activity/inactive disease state in patients with axSpA treated with the TNF inhibitor etanercept.
Methods
Study design
The design, inclusion criteria and detailed data on clinical, radiographic and MRI outcomes of the ESTHER trial are reported in detail elsewhere.13,15 Briefly, the study included a total of 76 patients with axSpA with a disease duration of ≤5 years and active inflammation in the SI joints and/or spine on baseline MRI. Retrospectively, these patients all met the ASAS classification criteria for axSpA.
The study consisted of three phases (figure 1).
Figure 1. Flow chart of the study design of the ESTHER study until week 240. ASAS, Assessment of SpondyloArthritis International Society; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index.
Phase 1 (week 0 to week 48): at baseline, patients were randomised to receive either etanercept (n=40) or sulfasalazine (n=36) for 1 year. Visits took place at baseline and every 2 weeks until week 24, then every 12 weeks for the remaining first year.
Phase 2 (week 48 to week 108): patients who achieved study remission, defined as ASAS partial remission plus absence of inflammation on MRI, discontinued treatment and were closely monitored without active treatment every 6 weeks until the end of the second year. Patients who did not achieve remission16 continued on etanercept (or switched to etanercept if previously on sulfasalazine) until the end of the study. Flares in patients without active treatment, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) increase of at least two points from the year 1 visit, were (re-) treated with etanercept. Patients without flares stopped the study at week 108. Visits occurred at weeks 50, 54, 60 and every 12 weeks thereafter.17
Phase 3 (week 108 to week 540): all patients who continued the study received etanercept until the end of the study, with visits every 12 weeks.
Demographics, medical history and human leukocyte antigen (HLA)-B27 status were collected at baseline. Disease-relevant data (ASDAS (C reactive protein (CRP)-based version),18 BASDAI, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index), laboratory parameters, including CRP, and any non-steroidal anti-inflammatory drug (NSAID) intake were assessed at each visit. Whole-body MRI was performed at baseline, week 24, week 48 and every year thereafter until year 4.
For the present analyses, we used all clinical (demographic, disease activity and laboratory) and MRI data collected over 4.5 years from baseline (figure 1). This includes 4 years of clinical and MRI follow-up, with an additional 6 months of clinical follow-up. Although clinical data were collected more frequently, we used data from baseline and from every 6 months for this analysis. We used imaging data from MRIs performed at baseline, 6 months, 1 year and yearly through year 4.
MRI assessment
MRIs of the spine and SI joints, as part of the whole-body MRIs, were performed at baseline, week 24 and yearly thereafter. Two trained and calibrated radiologists, blind to treatment allocation and time points, scored the spinal and SI joint MRIs independently, and the mean score of both readers was calculated as the final score for osteitis according to the Berlin MRI scoring system. The scoring for osteitis in the SI joints was performed per quadrant of the SI joint, with a score ranging from 0 (no lesion) to 3 (≥66% of the quadrant involved) in a total of 8 quadrants per patient with a total range from 0 to 24, as previously described.13 15 In parallel, osteitis evaluation in the spine was carried out for each vertebral unit, with a score range similar to the SI joint range: from 0 (no lesion) to 3 (≥66% of the vertebral unit involved) in a total of 23 units per patient with a total range from 0 to 69.13 15
Statistical analysis
We used descriptive statistics to summarise the baseline characteristics of the study population. We presented continuous variables as mean±SD, and categorical variables as frequencies and percentages.
The main focus of our analysis was the longitudinal evaluation of patients who were under continuous etanercept therapy for at least 6 months. To explore the association between osteitis on MRI in the SI joints and spine (exposure variables) and disease activity measured by the ASDAS (the outcome variable), we applied Generalised Estimating Equations (GEE) with an autoregressive correlation structure to capture the longitudinal relationship by accounting for within-participant effects, ensuring that the outcome at each time point is predicted by its value at the previous time point. We evaluated model robustness and selected the correlation structure using the Quasi likelihood under the Independence model Criterion. We also assessed two categorical variables as secondary outcomes: (1) ASDAS Inactive Disease (ASDAS-ID) defined as ASDAS <1.3 and (2) ASDAS Low Disease Activity (ASDAS-LDA) defined as ASDAS <2.1. We used ASDAS ≥2.1 to define active disease status, which includes both high and very high disease activity categories.
We used the MRI osteitis scores in the SI joints and spine both as continuous and as categorical variables based on a cut-off of ≤1 (both for the SI joints and spine), which we considered clinically relevant and reflected the complete resolution of inflammation. This approach allowed us to identify both linear and non-linear relationships between MRI osteitis and ASDAS.
We conducted two sets of longitudinal analyses with an autoregressive correlation structure:
Outcome 1—ASDAS at the current time point (cross-sectional association): The first set of GEE models evaluated the association between MRI-detected osteitis and ASDAS at the current time point longitudinally. We performed this analysis in the entire study population (all patients treated with etanercept and sulfasalazine at baseline) and only in patients who received continuous etanercept for at least 6 months. These models were adjusted for sex, age, HLA-B27 positivity, symptom duration and any NSAID intake. These variables were selected based on their associations according to expert knowledge and published literature.
Outcome 2—ASDAS at the next time point (temporal association (after 6 months of MRI)): The second set of GEE models focused on the association between MRI-detected osteitis and ASDAS 6 months after the MRI performance. We performed this analysis only in patients receiving continuous etanercept for at least 6 months. In addition to adjusting for the same covariates as in the first set, we also included the current ASDAS as a covariate in this model due to its confounding role between exposure and outcome.
For continuous outcomes, we presented the results as beta coefficients (β) with 95% CIs. For binary outcomes, such as achieving ASDAS-ID and ASDAS-LDA at the next time point, we presented these results as ORs with their corresponding 95% CIs.
Results
Patient characteristics
We included data from the 76 patients in the original study in the present analyses for cross-sectional associations, and from 69 patients who received at least 6 months of etanercept treatment to assess the longitudinal associations. The baseline characteristics of all patients and subgroup of patients were similar and presented in table 1. The mean age was 32.7±8.5 years, and more than half of the participants were men, representing 57.9% of the study population. HLA-B27 positivity was observed in 62 (81.6%) of the patients. The mean symptom duration at baseline was 2.8±1.7 years. Clinically, patients showed high disease activity at baseline, as evidenced by mean CRP, BASDAI and ASDAS levels of 10.9±14.2 mg/L, 5.7±1.3 points and 3.4±0.8 points, respectively. A substantial majority, 69 (90.8%) patients, were on NSAIDs at the time of study inclusion. 39 (51.3%) patients were classified as having radiographic axSpA at baseline, based on pelvic radiographs. Baseline MRI osteitis scores of SI joints and spine MRI were 6.7±5.8 and 1.9±3.3, respectively, indicating varying degrees of inflammation in both the SI joints and spine.
Table 1. Baseline characteristics of study population.
| Variable | All patients (n=76) | Patients with at least 6 months on etanercept (n=69) |
| Age, years, mean±SD | 32.7±8.5 | 33.2±8.4 |
| Sex, male, n (%) | 44.0 (57.9) | 39 (56.5) |
| HLA-B27, n (%) | 62.0 (81.6) | 58 (84.1) |
| Symptom duration, years, mean±SD | 2.8±1.7 | 2.9±1.7 |
| Positive family history for SpA, n (%) | 24.0 (31.6) | 22 (31.9) |
| Psoriasis ever, n (%) | 10.0 (13.3) | 10 (14.7) |
| Uveitis ever, n (%) | 12.0 (15.8) | 12 (17.4) |
| Inflammatory bowel disease ever, n (%) | 3.0 (3.9) | 3 (4.3) |
| SJC, mean±SD | 1.9±4.4 | 2.0±4.5 |
| Current peripheral arthritis, n (%) | 33.0 (43.4) | 31 (44.9) |
| Enthesitis count, mean±SD | 3.4±4.1 | 3.4±4.0 |
| Current enthesitis, n (%) | 49.0 (64.5) | 45 (65.2) |
| CRP, mean±SD | 10.9±14.2 | 10.1±13.0 |
| BASDAI, mean±SD | 5.7±1.3 | 5.7±1.3 |
| ASDAS, mean±SD | 3.4±0.8 | 3.3±0.8 |
| Current intake of NSAID, n (%) | 69.0 (90.8) | 62 (89.9) |
| Patients with r-axSpA, n (%) | 39.0 (51.3) | 35 (50.7) |
| SI joint osteitis score, mean±SD | 6.7±5.8 | 6.9±5.9 |
| Spine osteitis score, mean±SD | 1.9±3.3 | 1.7±3.0 |
ASDAS, Axial Spondyloarthritis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CRP, C reactive protein; NSAID, non-steroidal anti-inflammatory drug; r-axSpA, radiographic axial spondyloarthritis; SI, sacroiliac; SJC, swollen joint count
Longitudinal analyses of the association between MRI and disease activity at the current time point
Table 2 shows the results of adjusted multivariable GEE analyses, which provide cross-sectional associations between osteitis on SI joints and spine MRI and disease activity as measured by ASDAS. In the entire population (regardless of treatment), a higher SI joint osteitis score was associated with higher ASDAS (β=0.08, 95% CI (0.05; 0.11)). Similarly, we observed the same trend when using an inflammation score cut-off of 1 for negative versus positive MRI for SI joints: patients with negative MRI (osteitis score ≤1) had lower ASDAS levels (β=−0.37, 95% CI (−0.60; −0.15)) as compared with those with residual inflammation on MRI (osteitis score >1). In patients who were continuously treated with etanercept for at least 6 months during the follow-up, the association between SI joint osteitis score and ASDAS remained, though it was less pronounced. However, the spine osteitis score did not demonstrate a clear association with ASDAS compared with SI joint osteitis, both in the overall population and the etanercept-treated subgroup.
Table 2. Associations between osteitis on MRI (in the SI joints and spine) and disease activity at the current time point in patients with axSpA, as determined using multivariable longitudinal generalised estimating equations.
| Models | Outcome | |
| ASDAS current time point,* β (95% CI) | ASDAS current time point,† β (95% CI) | |
| SI joint osteitis score (per one point increase) | 0.08 (0.05; 0.11) | 0.04 (0.01; 0.08) |
| SI joint osteitis score (≤1 vs >1) | −0.37 (−0.60; −0.15) | −0.17 (−0.33; −0.01) |
| Spine osteitis score (per one point increase) | 0.06 (0.02; 0.10) | 0.01 (−0.04; 0.07) |
| Spine osteitis score (≤1 vs >1) | −0.19 (−0.44; 0.06) | −0.01 (−0.20; 0.18) |
Each model in the multivariable regression analysis was adjusted for sex, age, HLA-B27 positivity, symptom duration, and NSAID intake.
All time points independent from treatment were included in this analysis (n=313).
Only time points with continuous etanercept (at least 6 months) were included in this analysis (n=186).
ASDAS, Axial Spondyloarthritis Disease Activity Score; axSpA, axial spondyloarthritis; NSAIDnon-steroidal anti-inflammatory drugSI, sacroiliac
Longitudinal analyses of the association between MRI and disease activity at the next time point
Our study showed that the resolution of SI joint inflammation (a cut-off of ≤1 point in inflammation score on MRI) after at least 6 months of continuous etanercept treatment was associated with lower ASDAS levels at the next assessment point. This was particularly evident in patients whose ASDAS scores were between 1.3 and 2.1; in this subgroup, the absence of inflammation on MRI—performed at the same time point as the ASDAS—was associated with lower ASDAS levels at the next time point. However, at time points where ASDAS was below 1.3, MRI findings of inflammation did not significantly impact the ASDAS in the next assessment. In contrast, at time points where ASDAS was greater than 2.1, the presence of inflammation on MRI was associated with higher ASDAS levels at the next assessment (figure 2 and table 3).
Figure 2. Association between ASDAS and MRI assessments across timepoints ‘MRI+’ was defined as osteitis score in SI joint MRI of >1; ‘MRI−’ was defined as osteitis score in SI joint MRI of ≤1. ASDAS, Axial Spondyloarthritis Disease Activity Score.
Table 3. ASDAS levels and categories at next timepoint (after 6 months) based on ASDAS category and presence of inflammation on SI joint-MRI at current timepoint in patients with axSpA on continuous etanercept therapy, as determined using multivariable longitudinal generalised estimating equations.
| ASDAScurrenttime point, Mean±SD | ASDASnexttime point, Mean±SD | ASDAS>2.1nexttime point, n (%) | ASDAS1.3–2.1nexttime point, n (%) | ASDAS<1.3nexttime point, n (%) | |
| ASDAS >2.1 & MRI+ | 2.7±0.4 (n=24) | 2.3±0.6 (n=20) | 11 (55.0) | 8 (40.0) | 1 (5.0) |
| ASDAS >2.1 & MRI− | 2.6±0.5 (n=7) | 1.7±0.8 (n=5) | 1 (20.0) | 3 (60.0) | 1 (20.0) |
| ASDAS 1.3–2.1 & MRI+ | 1.7±0.2 (n=24) | 1.7±0.7 (n=22) | 4 (18.2) | 10 (45.5) | 8 (36.4) |
| ASDAS 1.3–2.1 & MRI− | 1.6±0.2 (n=25) | 1.3±0.5 (n=24) | 1 (4.2) | 9 (37.5) | 14 (58.3) |
| ASDAS <1.3 & MRI+ | 0.8±0.3 (n=51) | 1.0±0.6 (n=45) | 5 (11.1) | 5 (11.1) | 35 (77.8) |
| ASDAS <1.3 & MRI− | 0.7±0.3 (n=55) | 0.9±0.5 (n=51) | 1 (2.0) | 7 (13.7) | 43 (84.3) |
ASDAS, Axial Spondyloarthritis Disease Activity Score; axSpA, axial spondyloarthritis; SI, sacroiliac
Table 4 details the results of longitudinal multivariable GEE analyses that focused on patients who received continuous etanercept treatment for a minimum of 6 months and summarises the association between MRI osteitis and ASDAS at the next time point. The analysis included three outcomes measured 6 months after MRI: ASDAS, ASDAS-LDA and ASDAS-ID. Our data showed that a higher SI joint osteitis score at the current time point was associated with a higher ASDAS score at the next time point (β=0.05, 95% CI (0.02; 0.07)). Moreover, the resolution of osteitis in the SI joint MRI, as indicated by a score of ≤1 compared with >1, was significantly associated with lower ASDAS at the next time point (β=−0.26, 95% CI (−0.42; −0.09)) and increased the odds of achieving LDA and ID status at the next time point (ORs: 5.61, 95% CI (1.06; 29.67) and 2.23, 95% CI (1.01; 4.94), respectively). In contrast, the spinal osteitis score did not demonstrate a clear temporal association with all three outcomes at the next time point. Each model in this analysis was adjusted for multiple predefined covariates, including the ASDAS at the current time point.
Table 4. Associations between osteitis on MRI (in the sacroiliac joints and spine) and disease activity at the next time point (after 6 months) in patients with axSpA on continuous etanercept therapy, as determined using multivariable longitudinal generalised estimating equations.
| Models | Outcome | ||
| ASDAS next time point, β (95% CI) | ASDAS-LDA next time point, OR (95% CI) | ASDAS-ID next time point, OR (95% CI) | |
| SI joint osteitis score (per one point increase) | 0.05 (0.02; 0.07) | 0.71 (0.59; 0.87) | 0.85 (0.70; 1.04) |
| SI joint osteitis score (≤1 vs >1) | −0.26 (-0.42; −0.09) | 5.61 (1.06; 29.67) | 2.23 (1.01; 4.94) |
| Spine osteitis score (per one point increase) | −0.03 (-0.07; 0.02) | 1.31 (0.92; 1.88) | 1.06 (0.78; 1.42) |
| Spine osteitis score (≤1 vs >1) | −0.09 (-0.29; 0.12) | 1.33 (0.24; 7.53) | 2.11 (0.66; 6.74) |
Each model in the multivariable regression analysis was adjusted for sex, age, HLA-B27 positivity, symptom duration, NSAID intake, and ASDAS at the current time point.
ASDAS, Axial Spondyloarthritis Disease Activity Score; ID, inactive disease; LDA, low disease activity; NSAIDnon-steroidal anti-inflammatory drugSI, sacroiliac
Discussion
Our study seeks to clarify the potential role of MRI in the clinical decision-making process for the management of axSpA, particularly after initiating treatment, by exploring the relationship between the persistence of MRI inflammation in the SI joints and spine and disease activity in patients with axSpA receiving treatment with a TNF inhibitor. We found that resolution of inflammation is predictive of lower disease activity or remission over time.
In our study, the absence of inflammation in MRI was associated with lower disease activity (ASDAS-LDA or ASDAS-ID). These findings are consistent with numerous randomised controlled trials and observational studies that have linked MRI-detected inflammation to disease activity and noted its regression with effective bDMARD treatment19,22; however, the role of MRI for ongoing monitoring of treatment response and disease activity remains unclear. To date, research has shown that while MRI findings correlate poorly with patient-reported outcomes in axSpA management, instead they correlate fairly with inflammatory status, when objective markers of inflammation, such as CRP, are considered.8 23 24
Our research not only shows the association between MRI findings and disease activity but also goes one step further by demonstrating the role of MRI in predicting future disease activity state, providing important clinical implications beyond the academic interest. In the present study, we observed that patients with persistent high disease activity, despite treatment, often present ongoing inflammation on MRI and maintain high disease activity at the subsequent time point evaluations. This observation suggests that in the context of high disease activity, MRI may not be necessary to adjust treatment strategies; instead, a direct change in treatment may be appropriate based only on clinical assessments. In contrast, patients in remission tend to remain in remission regardless of MRI findings, suggesting no need for a change in treatment. Similarly, patients with LDA generally maintain their disease activity status or even progress into remission over time, regardless of MRI findings. In this last subgroup, a positive MRI indicating inflammation may suggest that resolution of inflammation could be slower than symptom improvement. On the other hand, an MRI showing no inflammation implies that the presence of symptoms may be due to non-inflammatory factors, such as degenerative joint or disc disease, or non-nociceptive pain. Therefore, the use of MRI in follow-up, particularly in patients treated with TNF inhibitor and presenting with suboptimal symptom control, should aim to find alternative explanations for symptoms besides inflammation.
Undoubtedly, MRI of the sacroiliac joints and spine has made great progress in the early diagnosis of axSpA by visualising both inflammation and structural damage with greater and earlier clarity than traditional radiographs. However, the current debate focuses on the place of MRI in the management of axSpA.25 26 While recognising the importance of MRI, we believe it should serve to enhance, not replace clinical evaluation, understanding that MRI complements clinical judgement and supports a more personalised treatment strategy that integrates both imaging and clinical information. Echoing this, our results underscore the practicality of clinical judgement in axSpA management, which is particularly relevant in regions with limited resources and MRI availability. This position is in line with ASAS-EULAR10 and American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network27 recommendations for the management of axSpA, which does not recommend routine MRI for monitoring due to its uncertain value and high costs. However, these guidelines acknowledge the benefit of MRI in ambiguous cases where it may clarify the cause of symptoms and influence clinical decision-making.
The main limitation of this study is the relatively small sample size, which may impact the extrapolation of results to the broader axSpA patient population, known for its clinical heterogeneity. Another limitation is the missing data with regard to body mass index and smoking that were not included in the adjustment set, but, considering our causal assumptions and the existing literature, we chose to adjust for the minimal set of confounders that directly affect both the outcome and the exposure. In addition, the focus on etanercept as the only therapeutic intervention may not capture the full spectrum of responses to different bDMARDs or tsDMARDs. Although many time points correspond to patients already in remission or low disease activity, which could introduce a bias towards treatment responders, the statistical approach applied to handle repeated measures helped address this limitation. Additionally, despite some MRI Berlin scores being zero or near zero, the study’s longitudinal design and statistical methods provide useful insights into the association between inflammation and disease activity. Another consideration is that patients included in this study had early disease, with this being their first biological treatment. Consequently, the findings may not fully apply to patients with longer disease duration and established structural damage. Finally, the lack of association between spinal osteitis and ASDAS outcomes could be explained by the relatively low levels of spinal inflammation observed in our cohort. In contrast, SI joint osteitis was more prominent, which may have contributed to the stronger association with disease activity. The low prevalence of spinal inflammation likely reduced the ability to observe any relationship between spinal osteitis and ASDAS. Despite its limitations, the study is strengthened by its longitudinal design, which allows for long-term observation of treatment effects, and the use of GEE in the statistical analysis, which increases the robustness of the results by accounting for repeated measures and minimising overfitting through appropriate confounder selection. Moreover, the scoring of MRIs by two independent radiologists across six time points adds an extra layer of reliability and uniqueness to the study.
In summary, our study clearly demonstrates that the resolution of inflammation on MRI as a result of treatment with a TNF inhibitor etanercept is strongly associated with better clinical outcomes on a long run in patients with axSpA.
supplementary material
Acknowledgements
The authors thank the ESTHER investigators R. Alten, M. Bohl-Bühler, G.-R. Burmester, T. Klopsch, A. Krause, F. Mielke, U. Prothmann, S. Zinke, the former study physician I.-H. Song and the statisticians J. Listing and A. Weiß for their valuable contributions to the study. The authors extend their gratitude also to the patients included in the study for their participation, and B. Mandt, B. Buß and P. Tietz for their dedication to study monitoring and coordination over the years.
Footnotes
Funding: This work was supported by an unrestricted grant from Pfizer, who also provided the study medication. The work of J.R. was supported by BIH-Charité Clinical Scientist Program funded by the Charité-Universitätsmedizin Berlin and the Berlin Institute of Health.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: This study involves human participants and was approved. All patients provided their written informed consent in accordance with the ethical principles of the Declaration of Helsinki, and the study was approved by the ethics committee of the federal state of Berlin (Landesamt für Gesundheit und Soziales, Ethikkommission Berlin; ZS EK 14 EA4/100/05). This trial is registered in EudraCT registry under the number 2005-002320-34 and on www.clinicaltrials.gov under the identifier NCT00844142.
Data availability free text: Data are available upon reasonable request. The ethics committee limits the sharing of patient-level data. Summary data may be shared upon reasonable request to the corresponding author.
Data availability statement
Data are available upon reasonable request.
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Data Availability Statement
Data are available upon reasonable request.