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Spondyloarthritis
Original research
Early axial spondyloarthritis according to the ASAS consensus definition: characterisation of patients and effectiveness of a first TNF inhibitor in a large observational registry
  1. Adrian Ciurea1,
  2. Andrea Götschi2,
  3. René Bräm3,
  4. Kristina Bürki1,
  5. Pascale Exer4,
  6. Michael Andor5,
  7. Michael J Nissen6,
  8. Burkhard Möller7,
  9. Thomas Hügle8,
  10. Andrea Rubbert-Roth9,
  11. Diego Kyburz10,
  12. Oliver Distler1,
  13. Almut Scherer2 and
  14. Raphael Micheroli1
  1. 1Department of Rheumatology, Zurich University Hospital, University of Zurich, Zurich, Switzerland
  2. 2Swiss Clinical Quality Management Foundation, Zurich, Switzerland
  3. 3Swiss Ankylosing Spondylitis Association, Zurich, Switzerland
  4. 4Gemeinschaftspraxis Rheuma-Basel, Basel, Switzerland
  5. 5Rheumatologie im Zürcher Oberland, Uster, Switzerland
  6. 6Department of Rheumatology, Geneva University Hospital, Geneva, Switzerland
  7. 7Department of Rheumatology and Immunology, Inselspital, Bern, Switzerland
  8. 8Department of Rheumatology, University of Lausanne, Lausanne, Switzerland
  9. 9Department of Rheumatology, Cantonal Hospital St Gallen, St Gallen, Switzerland
  10. 10Department of Rheumatology, University Hospital Basel, Basel, Switzerland
  1. Correspondence to Prof Adrian Ciurea; adrian.ciurea{at}usz.ch

Abstract

Objective To characterise the population fulfilling the Assessment of SpondyloArthritis international Society (ASAS) consensus definition of early axial spondyloarthritis (axSpA) and to determine the effectiveness of a first tumour necrosis factor inhibitor (TNFi) in early versus established axSpA in a large observational registry.

Methods A total of 3064 patients with axSpA in the Swiss Clinical Quality Management registry with data on duration of axial symptoms were included (≤2 years=early axSpA, N=658; >2 years=established axSpA, N=2406). Drug retention was analysed in patients starting a first TNFi in early axSpA (N=250) versus established axSpA (N=874) with multiple-adjusted Cox proportional hazards models. Adjusted logistic regression analyses were used to determine the achievement of the ASAS criteria for 40% improvement (ASAS40) at 1 year.

Results Sex distribution, disease activity, impairments of function and health-related quality of life were comparable between patients with early and established axSpA. Patients with established disease were older, had more prevalent axial radiographical damage and had a higher impairment of mobility. A comparable TNFi retention was found in early versus established disease after adjustment for age, sex, human leucocyte antigen-B27 status, education, body mass index, smoking, elevated C reactive protein and sacroiliac inflammation on MRI (HR 1.05, 95% CI 0.78 to 1.42). The adjusted ASAS40 response was similar in the two groups (OR 1.09, 95% CI 0.67 to 1.78). Results were confirmed in the population fulfilling the ASAS classification criteria.

Conclusion Considering the recent ASAS definition of early axSpA, TNFi effectiveness seems comparable in early versus established disease.

  • Epidemiology
  • Spondylitis, Ankylosing
  • Tumor Necrosis Factor Inhibitors

Data availability statement

Data may be obtained from a third party and are not publicly available. Restrictions apply to the availability of data. The data are owned by a third party, the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) Foundation. Data may be obtained after approval and permission from the license holder (SCQM). Contact information for data requests: scqm@hin.ch.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2023-003455

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • The Assessment in SpondyloArthritis international Society (ASAS) has recently developed a consensus definition for early axSpA, with up to 2 years of axial symptom duration as a mainstay for use in research settings.

    • In previous analyses, different definitions of early axial spondyloarthritis (axSpA) were used, and earlier treatment was not associated with a better response to biological disease-modifying antirheumatic drugs.

    WHAT THIS STUDY ADDS

    • This investigation in a large real-life cohort characterises the population with axSpA fulfilling the ASAS definition of early axSpA.

    • Initiating a first tumour necrosis factor inhibitor during the early disease phase, as newly defined by the ASAS, seems not to lead to better drug retention or better response rates compared with a later start of treatment.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • If the results can be replicated in other cohorts, analyses using shorter cut-offs of axial symptom duration are warranted.

    Introduction

    The concept of a ‘window of opportunity’ is well accepted for rheumatoid arthritis (RA).1 It summarises the findings that treatment with disease-modifying antirheumatic drugs (DMARDs) has an increased potential of preventing functional impairment and radiographical damage in RA if it is initiated within 1–2 years after diagnosis.2 Whether a similar concept holds true for axial spondyloarthritis (axSpA) remains open,3 as early treatment with biological (b)DMARDs was not consistently associated with better outcomes.4 Whether the failure to demonstrate a better response to bDMARDs in early treatment in axSpA might be due to the large heterogeneity of the definition of early disease used in the respective analyses remains unclear. Early axSpA was identified in a recent review of the literature by short symptom duration or short disease duration, with cut-offs ranging from 5 to 10 years, or based on the absence of radiographical sacroiliitis.5 The Assessment in SpondyloArthritis international Society (ASAS) has, therefore, recognised the need for a standardised definition of ‘early axSpA’ and has recently published a consensus definition for research purposes: ‘early axSpA’ is defined as duration of ≤2 years of axial symptoms in patients already diagnosed as having axSpA, irrespective of the presence of radiographical axial damage.6 The definition is complemented by a statement that axial symptoms should include spinal/buttock pain or morning stiffness and that their presence should be considered by a rheumatologist as related to axSpA.6 The proposed consensus definition of early axSpA and its cut-off of 2 years are recognised as ambitious,6 as the diagnostic delay in axSpA in clinical practice is still very long.7 Moreover, there is currently no scientific evidence to support either the chosen cut-off or the start of axial symptoms as mainstays of the definition.6 Therefore, we aimed at characterising the population fulfilling the new definition of early axSpA in a large cohort with available information on the start of first symptoms and also on the start of axial symptoms, as registered by the treating rheumatologist, to better evaluate the feasibility of its use for current research. In a second step, we used the new definition to analyse the effectiveness of treatment with a first tumour necrosis factor inhibitor (TNFi) in early axSpA compared with established axSpA.

    Methods

    Characterisation of patients with early axSpA at inclusion in the Swiss Clinical Quality Management axSpA cohort

    We took advantage of a large ongoing cohort of patients diagnosed with axSpA and recruited between 1 January 2004 and 1 June 2023 in the Swiss Clinical Quality Management (SCQM) registry.8 The treating rheumatologists in private practices, non-academic hospitals and academic institutions9 enter the date of first symptoms and are then asked to enter the presence of back pain of ≥3 months’ duration (yes or no) after interpretation of the patient’s history in the online database. If the answer is yes, the rheumatologist is prompted to specify several items on a list to establish the presence of an inflammatory back pain (IBP) character according to the criteria of ASAS,10 followed by the starting date of axial symptoms.

    In comparison with the ASAS definition of early axSpA, which stipulates that axial symptoms should include spinal/buttock pain or morning stiffness, patients with complete absence of axial pain and only presenting with morning stiffness were not included here. Moreover, only patients with ≥3 months of axial symptom duration are considered, which is not an absolute requirement of the ASAS definition of early axSpA. For both reasons, we might have slightly underestimated the actual proportion of early axSpA in SCQM.

    Rheumatologists enter data on peripheral and axial manifestations, with information stratified by clinical, radiographical and magnetic resonance-tomographical assessments, only if the respective manifestation is present. The number of imaging procedures performed that yielded negative results and the number of procedures with unknown findings are therefore not known.

    Clinical assessments are performed according to the recommendations of ASAS.11 Data on bDMARDs and conventional synthetic DMARDs are entered by the rheumatologist with start and end dates. Data on the use of non-steroidal antirheumatic drugs (NSAIDs) are available as yes or no at the visit level. Laboratory examinations include C reactive protein (CRP) levels and human leucocyte antigen-B27 (HLA-B27) status.

    Patients diagnosed as having axSpA were included in the early axSpA characterisation part of the study if information on the starting time point of axSpA-related back pain of at least 3 months’ duration was registered in SCQM by the treating rheumatologist. Patients fulfilling the 2009 ASAS classification criteria for axSpA12 were included in sensitivity analyses. As 1 January and 1 June were indicated as starting dates of axial symptoms in a higher number of instances than expected, it was considered a proxy for not exactly knowing the date within the respective year. We interval-censored all affected dates by assuming the onset date to fall into the reported onset year, and patients were only included if a differentiation between early and non-early axSpA was still possible (2.7% of patients excluded). In instances not affecting differentiation between early and non-early disease, inexact back pain onset dates (knowledge of month and year or only year of start) were mid-imputed. With regard to patient characteristics, missing variables were replaced by values from the closest visit within a range of 150 days before and 100 days after the considered time point (90 days before and 10 days after for disease activity variables). HLA-B27 status and data on family history were mapped from any other visit.

    Effectiveness of TNFi treatment in early versus established axSpA

    The effectiveness of TNFi treatment was assessed in patients starting a first TNFi after inclusion in SCQM. Drug retention was considered the primary outcome, and we estimated the time individual patients with axSpA maintained their first TNFi treatment when started in early versus established axSpA. Observations were censored at the last visit recorded in SCQM, the last change in medication dosage registered or the patient’s last confirmation of TNFi use via the web-based mySCQM application,13 whatever occurred last. Treatment response, defined as either the proportion of patients achieving the ASAS criteria for 40% improvement (ASAS40) or reaching a 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50), was assessed in exploratory analyses in patients with available disease activity measurement at 1 year (±6 months). Patients who had discontinued their first TNFi in the meantime were considered non-responders (response/tolerance analysis).14

    Statistical analyses

    Baseline characteristics between patients with early versus established axSpA were compared using the Kruskal-Wallis rank-sum test for continuous variables and the Χ2 test for categorical variables. Tests were two sided, with a significance level set at 0.05. Log-rank tests are provided to compare the crude time to treatment discontinuation in early versus established axSpA. The following variables were introduced in multiple-adjusted Cox proportional hazards models to estimate differences in drug retention between early and established disease: age (continuous), sex (female vs male), HLA-B27 status (negative vs positive) and education (vocational and academic vs compulsory, respectively). These variables were considered confounders of our analysis as they may affect not only the outcome but also the exposure (the fact that a patient might be diagnosed earlier and TNFi initiated within 2 years following the start of axial symptoms). The number of missing values per covariate was N=63 for HLA-B27 and N=140 for education. Baseline characteristics are also shown for the population without missing covariates. Ankylosing Spondylitis Disease Activity Score (ASDAS) was added to the main model in a sensitivity analysis. In a further analysis, we added body mass index (BMI), current smoking status, the presence of elevated CRP and the presence of inflammatory MRI changes to the main model. We also checked for the presence of an interaction term between sex and early versus established disease. Event dates were interval-censored to account for the uncertainty of incomplete medication stop dates.

    The significance of the unadjusted differences in BASDAI50 and ASAS40 responses was assessed using the Fisher’s exact test. Logistic regression analysis was used to estimate an adjusted ratio for ASAS40 and BASDAI50, with adjustments for age, sex, HLA-B27, and education in the main model and additional adjustments for BMI, current smoking status, the presence of elevated CRP, and the presence of inflammatory MRI changes in a sensitivity analysis. All drug retention and treatment response analyses were performed in all patients diagnosed with axSpA and in the population fulfilling the ASAS axSpA classification criteria.

    R statistical software was used for the statistical analyses. Artificial intelligence was only used to check the English grammar in the manuscript (QuillBot).

    Results

    Characterisation of early axSpA at inclusion in SCQM

    Patient disposition in the SCQM axSpA cohort is displayed in figure 1. Out of 3604 patients diagnosed with axSpA by their treating rheumatologist and having information on the start of axial symptoms, 658 patients had axial symptom duration ≤2 years and were classified as having early axSpA6 at the time point of inclusion in SCQM (21.5%). In the population fulfilling the ASAS classification criteria,12 the proportion of patients with early axSpA was 20.3% (N=447 for early disease and N=1753 for established disease). The percentage of early axSpA inclusions per year was constant at around 20%, irrespective of the number of patients fulfilling the ASAS classification criteria included per year since the initiation of the registry (figure 2). The median (IQR) duration since the start of axial symptoms was 0.8 (0.5–1.2) years in early axSpA and 10.1 (5.4–19.0) years in established axSpA (p<0.001; table 1). The median duration since the start of axial symptoms was comparable in the subgroup fulfilling the ASAS classification criteria (table 1). Time from onset of back pain to inclusion is shown for individual patients fulfilling the ASAS classification criteria in figure 3, stratified by early versus established disease. When the start of first symptoms rather than axial symptoms was considered, the median (IQR) symptom duration was only slightly longer: 1.3 (0.8–2.0) years in early axSpA and 10.5 (5.6–19.3) years in established axSpA (p<0.001). While axial symptoms corresponded to the first symptoms in the majority of patients with early axSpA, the time from the first symptom to axial symptoms varied in the remaining population, as shown for individual patients in the online supplemental figure 1. In the population fulfilling the ASAS classification criteria, the disease started with non-axial symptoms in a total of 170 patients with early axSpA (38.0%) and 209 patients with established axSpA (11.9%). The exact nature of these non-axial symptoms is not recorded in SCQM to allow a more detailed analysis.

    Figure 1
    Figure 1

    Patient disposition at inclusion in the SCQM cohort (A) and at start of a first TNF inhibitor (TNFi) (B). ASAS, Assessment of SpondyloArthritis international Society; axSpA, axial spondyloarthritis; SCQM, Swiss Clinical Quality Management; TNF, tumour necrosis factor.

    Figure 2
    Figure 2

    Number of patients with axSpA with early disease fulfilling the ASAS classification criteria included every year in SCQM (A). Proportion of patients with early axSpA for each inclusion year (B). ASAS, Assessment of SpondyloArthritis international Society; axSpA, axial spondyloarthritis; SCQM, Swiss Clinical Quality Management.

    View this table:
    Table 1

    Characteristics of patients with axSpA with early disease and established disease at inclusion in SCQM in the population fulfilling the ASAS axSpA classification criteria, as well as in all patients diagnosed as having axSpA

    Figure 3
    Figure 3

    Years from start of axSpA-related axial symptoms to inclusion in SCQM shown for individual patients with axSpA fulfilling the ASAS classification criteria. (A) Early axSpA (≤2 years by definition); (B) established axSpA (>2 years by definition). Time point of inclusion in SCQM=0. ASAS, Assessment in SpondyloArthritis international Society; axSpA, axial spondyloarthritis; SCQM, Swiss Clinical Quality Management.

    Further, demographic, clinical and imaging characteristics of patients with axSpA with early disease are compared with those of established disease at inclusion for all patients with axSpA and those fulfilling the ASAS classification criteria in table 1. No significant differences could be observed with regard to sex, family history of axSpA or educational level. A trend for a lower proportion of patients being HLA-B27 positive was found in early axSpA, not reaching statistical significance. A lower proportion of patients with early axSpA compared with patients with established axSpA was recruited in academic hospitals, corresponding to the referral bias observed in tertiary institutions. Around 50% of patients with early and established axSpA were included in private rheumatology practices. Peripheral arthritis and uveitis were more often recorded in established disease, while enthesitis, psoriasis and inflammatory bowel disease were comparably distributed between the groups. Regarding axial disease, the majority of patients presented with IBP, although their proportion was higher in established disease (80.6% vs 70.0% in early disease, p<0.001). Inflammatory sacroiliac MRI involvement was more often reported in early disease, while axial radiographical involvement was more frequently registered in established disease. Rheumatologists indicated the presence of sacroiliac radiographical involvement in around 20% of patients with early disease. Mirroring higher radiographical involvement in later disease, spinal mobility as assessed by the Bath Ankylosing Spondylitis Mobility Index (BASMI) was lower in early versus established axSpA. In contrast, disease activity (BASDAI, ASDAS), as well as impairments in function and in health-related quality of life, were comparable in early versus established axSpA (table 1). Ninety per cent of patients with early axSpA were treated with NSAIDs at inclusion, while 25% of patients were already on TNFi treatment. The proportion of patients with established axSpA on current TNFi use was 36%. Only a few patients were on interleukin-17 inhibitors at inclusion in SCQM.

    Drug retention analyses

    The selection of patients for the retention analyses of a first TNFi is depicted in figure 1B. A total of 1124 patients with axSpA started their first TNFi after inclusion in SCQM and had available data on the start of axial symptoms (250 patients with axial symptom duration ≤2 years at TNFi start (early axSpA; 22%) and 874 patients with longer back pain duration at treatment start (established axSpA)). The baseline characteristics of these patients are shown in table 2. The differences between the two groups were comparable with those at inclusion in SCQM. As expected, patients initiating TNFi treatment had, in comparison with the population at inclusion, higher disease activity levels and a more severe impairment of function and quality of life. Median TNFi retention was slightly shorter in early axSpA (2.0 years; 95% CI 1.4 to 2.8) compared with established axSpA (2.3 years; 95% CI 2.1 to 2.8, log-rank test p=0.04). The reasons for discontinuation included adverse events (15.1%), insufficient response (40.7%), remission (4.0%) and other reasons (15.5) with no differences found between early and established axSpA (online supplemental table 1). The baseline characteristics of patients starting a first TNFi in early versus later disease were confirmed in the population fulfilling the ASAS classification criteria for axSpA (table 2).

    View this table:
    Table 2

    Characteristics of patients with axSpA with early disease and established disease at start of first TNF inhibitor

    The estimated unadjusted HR to discontinue a first TNFi was slightly higher in early versus later axSpA (1.22, 95% CI 1.03 to 1.44). Baseline characteristics of patients with complete data in the adjusted analyses were comparable to all patients included in the retention analysis (table 3). The difference in retention between early and established disease lost significance in the adjusted model 1 (HR 1.07, 95% CI 0.87 to 1.31, table 4). TNFi retention in the two groups further aligned with each other after additional adjustment for ASDAS or, alternatively, for BMI, current smoking, elevated CRP and inflammatory sacroiliac changes on MRI (adjusted models 2 and 3 in table 4). Female sex and HLA-B27 negativity were associated with a higher risk of TNFi discontinuation in these models, while a higher ASDAS or an elevated CRP was associated with longer drug retention (table 4). We found no interaction between sex and early versus established disease (online supplemental table 2), indicating that the differences in TNFi retention between women and men were comparable in early and later axSpA.

    View this table:
    Table 3

    Characteristics of patients with axSpA with early disease and established disease at start of first TNF inhibitor in the main adjusted retention analysis (model 1; patients without missing covariate data)

    View this table:
    Table 4

    Multiple adjusted Cox proportional hazards model for analysis of drug discontinuation of a first TNF inhibitor in early versus established axSpA

    Treatment response analyses

    Response rates at 1 year of treatment with a first TNFi were available in 577 patients for ASAS40 and 570 patients for BASDAI50. We found numerically slightly lower response rates in early versus established disease in unadjusted analyses: 34.4% vs 36.1% for ASAS40 (OR 0.93, 95% CI 0.61 to 1.40) and 32.5% vs 35.4% for BASDAI50 (OR 0.88, 95% CI 0.58 to 1.34). Statistical models adjusted for potential confounders and additional explanatory variables are presented in table 5. No significant differences could be detected between patients with early and established disease for ASAS40 and BASDAI50 responses in these analyses. Male sex, HLA-B27 positivity, higher education and elevated CRP were consistently associated with significantly better response rates in these models (table 5). There was only a trend for inflammatory sacroiliac changes being associated with a better BASDAI50 response, which did not reach statistical significance and was not found for the ASAS40 response.

    View this table:
    Table 5

    Multiple-adjusted response rate analyses at 1 year of treatment with a first TNFi for different outcomes in early versus established axSpA

    The results found in the whole population diagnosed with axSpA were confirmed in patients fulfilling the ASAS classification criteria (table 5). A higher BMI was associated with a significantly reduced treatment response according to BASDAI50 and ASAS40 criteria in this population.

    Discussion

    This first analysis of patients with early axSpA according to the ASAS definition6 in a large observational cohort revealed several important aspects. First, up to 20% of patients recruited over the past two decades had axial symptom duration of ≤2 years and fulfilled the new definition for early axSpA. Second, patients with early axSpA were very comparable with patients with longer axial symptom duration regarding important disease characteristics, with the exception of factors affected by time (such as age, radiographical damage and impairment of spinal mobility). Finally, the effectiveness of TNFi, assessed through the evaluation of their retention as well as ASAS40 and BASDAI50 response rates, was comparable in early and established axSpA.

    The fact that 20% of patients recruited to SCQM fulfilled the definition of early axSpA is, on the one hand, reassuring. Although the median diagnostic delay in axSpA is still long,7 a relevant proportion of patients in real-life clinical practice are diagnosed in this early disease stage, guaranteeing the feasibility of future studies using this definition, preconditioned that our results are confirmed in other healthcare systems. On the other hand, we could not identify a trend for earlier recognition of axSpA over the years, at least with regard to the proportion of patients identified within 2 years after the onset of axial symptoms. This highlights the need to intensify the already considerable international and national efforts to improve disease recognition.15 The fact that the first symptoms were not axial symptoms in a significant number of patients fulfilling the ASAS consensus definition of ‘early axSpA’ indicates that the presence of peripheral or extramusculoskeletal manifestations might lead to an earlier recognition of axial disease. Indeed, a recent study found a high prevalence of both overall and previously undiagnosed SpA in patients with acute anterior uveitis.16

    Important disease characteristics were comparable between the early and later stages of the disease: sex distribution, proportions of HLA-B27 positivity and of a positive family history of axSpA, markers of disease activity, function and health-related quality of life. Radiographical axial involvement and impairment of spinal mobility as assessed by the BASMI were, as expected, more prominent in established axSpA. Only a few earlier cohorts provide some comparison for the characteristics of our 658 patients with early axSpA at inclusion in SCQM. Inclusion criteria for a small cohort (N=68) from the Netherlands (ESpAC) comprised the presence of IBP of ≤2 years’ duration with onset of back pain before the age of 40 years and persistence for at least 3 months.17 18 Importantly, diagnosis of axSpA before inclusion was not strictly required, and the presence of additional spondyloarthritis features was preferred but not mandatory. Presumably as a consequence of these specific inclusion criteria, only 38% of patients were of male sex, only 46% were HLA-B27 positive and only 35% had inflammatory sacroiliac MRI changes. These features stand in some contrast with our findings, showing a well-balanced sex distribution and considerably higher proportions of patients with HLA-B27 positivity and MRI sacroiliac inflammation (60% and 58%, respectively). Our patients’ characteristics at inclusion in SCQM are more in line with findings from the French DESIR cohort,19 which included patients with IBP of ≤3 years’ duration in the context of overall symptoms suggestive of spondyloarthritis: male sex 46%, HLA-B27 positivity 57%. The proportion of patients with radiographical axSpA found in our patients with early axSpA (20%) was comparable with findings in cohorts of short IBP duration (20% in ESpAC and 26% in DESIR).17 19 Inflammatory axial MRI changes were more prevalent in patients with early axSpA from the SCQM registry (58% for the sacroiliac joints and 31% for the spine) than in patients with IBP of short duration from the DESIR cohort (32% and 20%, respectively).19 The higher inflammation load in patients in the SCQM registry might be explained by the fact that patients considered for bDMARD treatment are preferably recruited. The reason for this observation is the circumstance that, according to regulatory authorities, rheumatologists can deduct the costs of bDMARDs from their global treatment expenditures if the patients are followed in the clinical quality management programme that is at the core of SCQM.20

    While the number of research questions to be evaluated in an early axSpA disease stage is substantial, the issue of a potential ‘window of opportunity’ for early treatment to allow for better outcomes remains at the forefront.3 21

    Our multiple-adjusted retention and response analyses did not demonstrate better TNFi effectiveness in early versus established axSpA. The ASAS40 response rate found here in early axSpA (34%) is lower than in two prospective trials of infliximab in patients with symptom duration ≤3 years (60% and 75%, respectively).22 23 These studies used, however, additional criteria to select their patients. The presence of inflammatory sacroiliac MRI changes was an absolute requirement for both studies, and all patients were additionally HLA-B27 positive in the first study,22 while all patients were cotreated with an NSAID in the second study.23 As both studies did not compare the treatment response in early versus established disease, the issue of additional criteria for adequate patient selection in early disease to be able to provide evidence for a window of opportunity in axSpA is still open. Comparison with these studies is further hampered by the observational nature of our analysis, which constrained us to measure the outcome at a rather late time point (1 year) and to consider patients who had discontinued the TNFi in the meantime as non-responders, regardless of the reason for discontinuation (response/tolerance analysis). Interestingly, our adjusted analyses did not identify the presence of sacroiliac joint inflammation as a predictor of better drug retention or treatment response. In contrast, HLA-B27 positivity was associated with treatment effectiveness here and is known to be an independent predictor of sacroiliac inflammation on MRI.18 We have previously demonstrated that CRP and male sex seem to better describe the variability of treatment responses than HLA-B27 in individual patients.24 An elevated CRP or a higher ASDAS was consistently associated with significantly better TNFi effectiveness in the analyses presented here. Indeed, CRP was shown to be the best predictor of good response in numerous prospective trials in both radiographical and non-radiographical disease and seems better than sacroiliac inflammation detected by MRI, as demonstrated in subgroup analyses.25–29 Moreover, the amount and intensity of MRI inflammation might better predict response than the mere presence of sacroiliac bone marrow oedema.30 Extensive sacroiliac bone marrow oedema is also a strong predictor of the development of structural lesions, in contrast to limited or intermediate inflammatory lesions.31 Male sex was shown to be a predictor of future sacroiliac inflammation detected by MRI in patients with IBP of short duration.18 It is also known to be a predictor of treatment response in both radiographical32 and non-radiographical33 axSpA and to be associated with accelerated radiographical progression at the levels of the sacroiliac joints34 and the spine.35 The impact of sex on treatment response seemed not to be different in early versus established axSpA, as demonstrated by the interaction analyses shown here.

    Future analyses of treatment response and radiographical progression in early versus established disease are therefore warranted. Whether additional requirements on the amount of axial or systemic inflammation might help solve the conundrum of a window of opportunity in axSpA will potentially have to be investigated. As spinal radiographical progression is only minimal in the non-radiographical disease state,36 an adequate length of the investigations might be crucial.

    The prospective study design in one of the largest national axSpA cohorts treated under real-life conditions using validated assessments and the systematic collection of the start of axial symptoms in addition to the start of first symptoms represent its major strengths. The main analyses were performed on the whole population diagnosed as having axSpA. However, as the definition of early axSpA is intended to be used for research purposes only, we have presented data for the subgroup fulfilling the ASAS classification criteria12 in parallel to further enhance the homogeneity of the study population.

    As a major limitation of our analyses, MRIs were not collected systematically in SCQM to allow for the validation of the sacroiliac and spinal involvement indicated by the rheumatologist.37 38 Additional limitations are related to the observational nature of our investigation and the fact that we might not have been able to adjust for unknown remaining confounders. Recall bias with regard to the start of symptoms is a limitation inherent to the consensually chosen definition of early axSpA.6 It is supposed to be more limited within a range of 2 years than with longer symptom duration.

    In conclusion, 20% of patients with axSpA in this contemporary real-life axSpA cohort were included in an early disease stage according to the new consensus definition of early axSpA. While important patient characteristics are comparable in early and established axSpA, our results do not suggest better TNFi retention and better response rates in early axSpA in the context of a cut-off of 2 years of axial symptom duration as defined by ASAS. Comparable analyses in patients with shorter symptom duration might represent a next step for future analyses of early axSpA in suitable observational cohorts.

    Data availability statement

    Data may be obtained from a third party and are not publicly available. Restrictions apply to the availability of data. The data are owned by a third party, the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) Foundation. Data may be obtained after approval and permission from the license holder (SCQM). Contact information for data requests: scqm@hin.ch.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study was approved by the Ethics Committee of the Canton of Zurich (BASEC 2022-0272) and written informed consent was obtained from all patients.

    Acknowledgments

    We thank all rheumatologists and their patients for participation in SCQM. The entire SCQM staff were instrumental for data management and support. A list of rheumatology practices and hospitals that are contributing to the SCQM registries can be found on: http://www.scqm.ch/institutions.

    References

    1. ↵
      1. van Nies JA,
      2. Krabben A,
      3. Schoones A, et al
      . What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis 2014;73:861–70. doi:10.1136/annrheumdis-2012-203130
      OpenUrlAbstract/FREE Full Text
    2. ↵
      1. Burgers LE,
      2. Raza K,
      3. van der Helm-van Mil AH
      . Window of opportunity in rheumatoid arthritis - definitions and supporting evidence: from old to new perspectives. RMD Open 2019;5. doi:10.1136/rmdopen-2018-000870
    3. ↵
      1. Benavent D,
      2. Capelusnik D,
      3. Ramiro S, et al
      . Looking through the window of opportunity in axial spondyloarthritis? Joint Bone Spine 2023;90:105603. doi:10.1016/j.jbspin.2023.105603
      OpenUrl
    4. ↵
      1. Capelusnik D,
      2. Benavent D,
      3. van der Heijde D, et al
      . Treating spondyloarthritis early: does it matter? Results from a systematic literature review. Rheumatology (Oxford) 2023;62:1398–409. doi:10.1093/rheumatology/keac532
      OpenUrl
    5. ↵
      1. Benavent D,
      2. Capelusnik D,
      3. van der Heijde D, et al
      . How is early spondyloarthritis defined in the literature? Rsults from a systematic review. Semin Arthritis Rheum 2022;55:152032. doi:10.1016/j.semarthrit.2022.152032
      OpenUrl
    6. ↵
      1. Navarro-Compán V,
      2. Benavent D,
      3. Capelusnik D, et al
      . ASAS consensus definition of early axial spondyloarthritis. Ann Rheum Dis 2023. doi:10.1136/ard-2023-224232
    7. ↵
      1. Hay CA,
      2. Packham J,
      3. Ryan S, et al
      . Diagnostic delay in axial spondyloarthritis: a systematic review. Clin Rheumatol 2022;41:1939–50. doi:10.1007/s10067-022-06100-7
      OpenUrl
    8. ↵
      1. Ciurea A,
      2. Kissling S,
      3. Bürki K, et al
      . Current differentiation between radiographic and non-radiographic axial spondyloarthritis is of limited benefit for prediction of important clinical outcomes: data from a large, prospective, observational cohort. RMD Open 2022;8:e002067. doi:10.1136/rmdopen-2021-002067
    9. ↵
      1. Ciurea A,
      2. Weber U,
      3. Stekhoven D, et al
      . Treatment with tumor necrosis factor inhibitors in axial spondyloarthritis: comparison between private rheumatology practices and academic centers in a large observational cohort. J Rheumatol 2015;42:101–5. doi:10.3899/jrheum.140229
      OpenUrlAbstract/FREE Full Text
    10. ↵
      1. Sieper J,
      2. van der Heijde D,
      3. Landewé R, et al
      . New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the assessment of spondyloarthritis international society (ASAS). Ann Rheum Dis 2009;68:784–8. doi:10.1136/ard.2008.101501
      OpenUrlAbstract/FREE Full Text
    11. ↵
      1. Sieper J,
      2. Rudwaleit M,
      3. Baraliakos X, et al
      . The assessment of spondyloarthritis international society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009;68 Suppl 2:ii1–44. doi:10.1136/ard.2008.104018
      OpenUrlPubMed
    12. ↵
      1. Rudwaleit M,
      2. van der Heijde D,
      3. Landewé R, et al
      . The development of assessment of spondyloarthritis international society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009;68:777–83. doi:10.1136/ard.2009.108233
      OpenUrlAbstract/FREE Full Text
    13. ↵
      1. Shaw Y,
      2. Courvoisier D,
      3. Scherer A, et al
      . Do mobile apps improve shared decision making and disease management in the rheumatic diseases? An evaluation of apps in a swiss rheumatology registry. Ann Rheum Dis 2019:125–6. doi:10.1136/annrheumdis-2019-eular.382
    14. ↵
      1. Ciurea A,
      2. Exer P,
      3. Weber U, et al
      . Does the reason for discontinuation of a first TNF inhibitor influence the effectiveness of a second TNF inhibitor in axial spondyloarthritis. Arthritis Res Ther 2016;18:71. doi:10.1186/s13075-016-0969-2
    15. ↵
      1. Navarro-Compán V,
      2. Ermann J,
      3. Poddubnyy D
      . A glance into the future of diagnosis and treatment of spondyloarthritis. Ther Adv Musculoskelet Dis 2022;14:1759720X221111611. doi:10.1177/1759720X221111611
    16. ↵
      1. Rademacher J,
      2. Müllner H,
      3. Diekhoff T, et al
      . Keep an eye on the back: spondyloarthritis in patients with acute anterior uveitis. Arthritis Rheumatol 2023;75:210–9. doi:10.1002/art.42315
      OpenUrl
    17. ↵
      1. Heuft-Dorenbosch L,
      2. Landewé R,
      3. Weijers R, et al
      . Performance of various criteria SETS in patients with inflammatory back pain of short duration; the maastricht early spondyloarthritis clinic. Ann Rheum Dis 2007;66:92–8. doi:10.1136/ard.2006.053918
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. van Onna M,
      2. Jurik AG,
      3. van der Heijde D, et al
      . HLA-B27 and gender independently determine the likelihood of a positive MRI of the sacroiliac joints in patients with early inflammatory back pain: a 2-year MRI follow-up study. Ann Rheum Dis 2011;70:1981–5. doi:10.1136/annrheumdis-2011-200025
      OpenUrlAbstract/FREE Full Text
    19. ↵
      1. Dougados M,
      2. d’Agostino M-A,
      3. Benessiano J, et al
      . The DESIR cohort: a 10-year follow-up of early inflammatory back pain in France: study design and baseline characteristics of the 708 recruited patients. Joint Bone Spine 2011;78:598–603. doi:10.1016/j.jbspin.2011.01.013
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Ciurea A,
      2. Scherer A,
      3. Exer P, et al
      . Tumor necrosis factor α inhibition in radiographic and nonradiographic axial spondyloarthritis: results from a large observational cohort. Arthritis Rheum 2013;65:3096–106. doi:10.1002/art.38140
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Robinson PC,
      2. Brown MA
      . The window of opportunity: a relevant concept for axial spondyloarthritis. Arthritis Res Ther 2014;16:109. doi:10.1186/ar4561
      OpenUrlCrossRefPubMed
    22. ↵
      1. Barkham N,
      2. Keen HI,
      3. Coates LC, et al
      . Clinical and imaging efficacy of Infliximab in HLA-B27-positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum 2009;60:946–54. doi:10.1002/art.24408
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Sieper J,
      2. Lenaerts J,
      3. Wollenhaupt J, et al
      . Efficacy and safety of Infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, part 1. Ann Rheum Dis 2014;73:101–7. doi:10.1136/annrheumdis-2012-203201
      OpenUrlAbstract/FREE Full Text
    24. ↵
      1. Fröhlich F,
      2. Micheroli R,
      3. Hebeisen M, et al
      . HLA-B27 as a predictor of effectiveness of treatment with TNF inhibitors in axial spondyloarthritis: data from the swiss clinical quality management registry. Clin Rheumatol 2023;42:1267–74. doi:10.1007/s10067-022-06490-8
      OpenUrl
    25. ↵
      1. Glintborg B,
      2. Ostergaard M,
      3. Krogh NS, et al
      . Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years' surveillance in the danish nationwide danbio registry. Ann Rheum Dis 2010;69:2002–8. doi:10.1136/ard.2009.124446
      OpenUrlAbstract/FREE Full Text
    26. ↵
      1. Arends S,
      2. Brouwer E,
      3. van der Veer E, et al
      . Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther 2011;13:R94. doi:10.1186/ar3369
    27. ↵
      1. Sieper J,
      2. Heijde D, et al
      . Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis. Ann Rheum Dis 2013;72:815–22. doi:10.1136/annrheumdis-2012-201766
      OpenUrlAbstract/FREE Full Text
    28. ↵
      1. Dougados M,
      2. van der Heijde D,
      3. Sieper J, et al
      . Symptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 2014;66:2091–102. doi:10.1002/art.38721
      OpenUrl
    29. ↵
      1. Sieper J,
      2. van der Heijde D,
      3. Dougados M, et al
      . A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous Golimumab in patients with active Nonradiographic axial Spondyloarthritis. Arthritis Rheumatol 2015;67:2702–12. doi:10.1002/art.39257
      OpenUrl
    30. ↵
      1. Braun J,
      2. Blanco R,
      3. Marzo-Ortega H, et al
      . Secukinumab in non-radiographic axial Spondyloarthritis: subgroup analysis based on key baseline characteristics from a randomized phase III study, PREVENT. Arthritis Res Ther 2021;23:231. doi:10.1186/s13075-021-02613-9
      OpenUrlPubMed
    31. ↵
      1. Arnbak B,
      2. Jensen TS,
      3. Schiøttz-Christensen B, et al
      . What level of inflammation leads to structural damage in the sacroiliac joints? A four-year magnetic resonance imaging follow-up study of low back pain patients. Arthritis Rheumatol 2019;71:2027–33. doi:10.1002/art.41040
      OpenUrl
    32. ↵
      1. Hebeisen M,
      2. Neuenschwander R,
      3. Scherer A, et al
      . Response to tumor necrosis factor inhibition in male and female patients with ankylosing spondylitis: data from a swiss cohort. J Rheumatol 2018;45:506–12. doi:10.3899/jrheum.170166
      OpenUrlAbstract/FREE Full Text
    33. ↵
      1. Neuenschwander R,
      2. Hebeisen M,
      3. Micheroli R, et al
      . Differences between men and women with nonradiographic axial spondyloarthritis: clinical characteristics and treatment effectiveness in a real-life prospective cohort. Arthritis Res Ther 2020;22:233. doi:10.1186/s13075-020-02337-2
      OpenUrlPubMed
    34. ↵
      1. Micheroli R,
      2. Kissling S,
      3. Bürki K, et al
      . Sacroiliac joint radiographic progression in axial spondyloarthritis is retarded by the therapeutic use of TNF inhibitors: 12-year data from the SCQM registry. RMD Open 2022;8:e002551. doi:10.1136/rmdopen-2022-002551
    35. ↵
      1. Ensslin C,
      2. Micheroli R,
      3. Kissling S, et al
      . Impact of sex on spinal radiographic progression in axial spondyloarthritis: a longitudinal swiss cohort analysis over a period of 10 years. RMD Open 2023;9:e003340. doi:10.1136/rmdopen-2023-003340
    36. ↵
      1. Hebeisen M,
      2. Micheroli R,
      3. Scherer A, et al
      . Spinal radiographic progression in axial spondyloarthritis and the impact of classification as nonradiographic versus radiographic disease: data from the swiss clinical quality management cohort. PLoS One 2020;15:e0230268. doi:10.1371/journal.pone.0230268
    37. ↵
      1. van den Berg R,
      2. Lenczner G,
      3. Thévenin F, et al
      . Classification of axial SpA based on positive imaging (radiographs and/or MRI of the sacroiliac joints) by local rheumatologists or radiologists versus central trained readers in the DESIR cohort. Ann Rheum Dis 2015;74:2016–21. doi:10.1136/annrheumdis-2014-205432
      OpenUrlAbstract/FREE Full Text
    38. ↵
      1. Jacquemin C,
      2. Rubio Vargas R,
      3. van den Berg R, et al
      . What is the reliability of non-trained investigators in recognising structural MRI lesions of sacroiliac joints in patients with recent inflammatory back pain? Results of the DESIR cohort. RMD Open 2016;2:e000303. doi:10.1136/rmdopen-2016-000303

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    Footnotes

    • Twitter @ramicheroli

    • Authors’ contributions AC, AG and RM conceptualised and designed the study. AC, AR-R, BM, KB, MA, MJN, OD, PE, RB, RM and TH substantially contributed to the acquisition of clinical data. AG and AS processed the data and performed the statistical analyses. All authors contributed to the interpretation of the data. AC wrote the article, and all coauthors critically revised the manuscript for important intellectual content. AC had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors agreed on the final content of the submitted manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests The SCQM Foundation is supported by the Swiss Society of Rheumatology and by AbbVie, AstraZeneca, Eli Lilly, iQone Healthcare, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Samsung Bioepis and Sandoz. AC received honoraria for lectures from AbbVie and Novartis. AR-R received consulting fees from AbbVie, Janssen and Pfizer; honoraria for lectures from AbbVie, Janssen, Novartis and Pfizer; as well as support for attending meetings from Janssen and Pfizer. AS received consulting fees from Pfizer and support for attending meetings from Gilead. BM received speaking fees from AbbVie, Janssen, Novartis and Pfizer, as well as support for attending meetings from Janssen. DK received a research grant from AbbVie, honoraria for presentations from AbbVie and Eli Lilly, support for attending meetings from Janssen and Eli Lilly, as well as payments for participation in advisory boards from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer and Roche. MJN received consulting and/or speaking fees from AbbVie, Eli Lilly, Janssen, Novartis and Pfizer, as well as a research grant from Novartis. OD received consulting fees from AbbVie. PE received financial support from UCB to attend a meeting. RM received honoraria for lectures or presentations from AbbVie, Eli Lilly, Janssen, Gilead and Pfizer. TH received royalties from Curmed, payments for lectures and presentations from Pfizer, Fresenius Kabi, AbbVie, Merck Sharp & Dohme, Galapagos, Eli Lilly and Novartis. He participated in advisory boards for DETECTRA and holds stock or stock options of Atreon SA and Vtuls. AG, KB, MA and RB declare they have no conflicts of interest.

    • Patient and public involvement statement Patients were involved in the reporting and dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.