Abstract
Objective
To determine the cumulative incidence of difficult-to-manage axial spondyloarthritis (D2M-axSpA) and treatment-refractory axSpA (TR-axSpA) in a recent-onset axSpA inception cohort, identify baseline factors and characterise long-term outcomes.
Methods
Patients from the French prospective DESIR (DEvenir des Spondyloarthrites Indifférenciées Récentes) cohort fulfilling the Assessment of Spondyloarthritis International Society (ASAS) 2009 criteria for axSpA and exposed to ≥1 biologic disease-modifying antirheumatic drug (bDMARD) were included. Patients with D2M-axSpA and TR-axSpA were classified according to both the ASAS definition and an extended definition adapted to historical treatment availability (failure of ≥3 b/targeted synthetic DMARDs regardless of mechanism of action). Cox proportional hazards models were used to identify baseline factors associated with D2M-axSpA. Clinical, imaging and socio-economic outcomes were analysed over up to 10 years of follow-up.
Results
Among 177 patients exposed to ≥1 bDMARD, the cumulative incidence of D2M-axSpA was 6.8% (95% CI 2.4 to 11.0) and 14.4% (95% CI 8.3 to 20.2) using the ASAS and extended definitions, respectively, while TR-axSpA remained rare (0.7% and 3.7%, respectively). Female sex and higher baseline disease activity were associated with the development of D2M-axSpA (extended definition). During follow-up, patients with D2M-axSpA according to the extended definition had a higher prevalence of fibromyalgia (60% vs 22.9%), greater healthcare resource utilisation (cumulative number of medical visits 110 vs 60) and opioid use (100% vs 72%).
Conclusion
In this recent-onset axSpA inception cohort with long-term follow-up, D2M-axSpA was rare, rarely associated with true treatment refractoriness or structural progression and was accompanied by a persistent disease burden carrying a substantial socio-economic impact, highlighting the need for a broader, patient-centred approach to its management.
Trial registration number
Keywords: Axial Spondyloarthritis, Incidence, Analgesics
WHAT IS ALREADY KNOWN ON THIS TOPIC.
WHAT THIS STUDY ADDS
This is the first study to report the cumulative incidence, associated factors and long-term outcomes of D2M-axSpA in a recent-onset axSpA prospective inception cohort.
In this setting, D2M-axSpA was predominantly marked by persistent disease burden, including high disease activity, impaired quality of life and high healthcare service utilisation, rather than with structural progression.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The differences in incidence and clinical characteristics support distinguishing difficult-to-manage from treatment-refractory axSpA in both clinical practice and research.
Management of D2M-axSpA should extend beyond repeated treatment escalation and include multidimensional approaches addressing symptoms, function and comorbidities, namely fibromyalgia.
Introduction
Difficult-to-treat (D2T) is a recent concept developed in inflammatory arthritis in the context of patients showing signs of disease activity despite an increase in the number of targeted treatments available in recent years. This concept was first developed in 2022 for rheumatoid arthritis (RA).1 More recently, the term difficult-to-manage (D2M) has been introduced to reflect challenging management of the disease for the patient and/or physician, going beyond purely treatment-refractory (TR) situations. In this sense, the Assessment of Spondyloarthritis International Society (ASAS) has recently developed a consensus-based definition for D2M axial spondyloarthritis (D2M-axSpA).2 This definition is applicable to patients with a definite diagnosis of axSpA made by a rheumatologist, treated according to the ASAS recommendations, and consists of three criteria being fulfilled: (1) failure of at least two biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) with different modes of action (MoA); (2) insufficient control of signs/symptoms of axSpA and (3) the present signs/symptoms being perceived as problematic by the rheumatologist and/or the patient. Furthermore, a specific subset of patients can be identified as ‘TR-axSpA’ in case of a D2M situation and if ≥2 b/tsDMARDs failed, have high or very high disease activity according to Axial Spondyloarthritis Disease Activity Score (ASDAS) (≥2.1) plus objective signs of inflammatory activity (elevated C reactive protein (CRP) or active inflammation on MRI of sacroiliac joints (SIJ) or spine), and if other causes, likely responsible for signs and symptoms (concurrent conditions, non-compliance, etc) are excluded.
These definitions were formulated as the result of a consensus-based exercise, and data on its real-world applicability are still limited. While several cohort studies have reported on the prevalence and factors associated with D2M-axSpA,3 4 they only considered the treatment-switching component. More recently, two studies applied the full ASAS definition, but both were cross-sectional and conducted in established disease.5 6 Data on the cumulative incidence of D2M-axSpA in patients with recent-onset disease, on its baseline-associated factors and on the long-term clinical and socio-economic outcomes of these patients are lacking. Based on these remarks, we decided to conduct this study, aiming to (1) determine the cumulative incidence of D2M and TR-axSpA, (2) study the factors associated at baseline with patients who will develop D2M over time and (3) characterise the outcome of these patients, in a recent-onset axSpA setting.
Methods
Patients
The DESIR cohort is a French prospective, longitudinal, observational study involving 25 rheumatology centres in France (ClinicalTrials.gov NCT01648907). It enrolled 708 consecutive patients aged >18 years and <50 years with recent-onset inflammatory back pain (>3 months but <3 years) and symptoms highly suggestive of SpA according to the rheumatologist’s assessment (score ≥5 on a Numerical Rating Scale of 0–10, where 0=not suggestive and 10=very suggestive of SpA). Patients were included between December 2007 and April 2010, with visits scheduled every 6 months for the first 2 years and yearly thereafter.7 For the present study, only patients fulfilling the ASAS 2009 criteria for axSpA8 and exposed to at least one bDMARD during follow-up were included. Patients never exposed to a bDMARD were excluded to ensure a homogeneous population, so that the subsequent comparisons reflected differences between D2M and non-D2M patients rather than between bDMARD-exposed and bDMARD-naïve patients.
Collected data
For this study, data from all time points of the first 10 years of follow-up of the DESIR study visits were included:
Demographic and clinical variables: age, sex, body mass index (BMI), presence of human leucocyte antigen-B27, personal and family history, symptom duration, diagnostic delay and existence of a triggering factor before the symptoms were collected at baseline (ie, inclusion in the DESIR cohort). Clinical examination, including presence of arthritis, dactylitis, enthesitis, extra-musculoskeletal manifestations (EMMs) and Physician Global Assessment (PhGA) were collected at each visit.
Patient-reported outcomes were collected at each visit: ASDAS, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Quality of Life (ASQoL) and Patient Global Assessment (PtGA).
Comorbidities: presence of obesity, smoking, hypertension, dyslipidaemia, diabetes and major adverse cardiovascular events (defined as a composite outcome of myocardial infarction, stroke and heart failure) and fibromyalgia were collected at each visit. It should be noted that fibromyalgia was defined as a Fibromyalgia Rapid Screening Tool score ≥5/6.9 These data were available from the 7-year visit onwards. For previous visits, including at inclusion, fibromyalgia was defined by a score ≥8 on three out of the first five BASDAI scores as this definition previously showed high specificity for fibromyalgia recognition in patients with axSpA.10
Biological and imaging data: CRP was collected at each visit. Radiographs of the spine and MRI of the spine and SIJ were performed at baseline, 2, 5 and 10 years of follow-up with collection of the number of syndesmophytes, modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) for radiographs and spine and SIJ Spondyloarthritis Research Consortium of Canada (SPARCC) inflammatory score and number of SIJ fatty lesions for MRI with central reading to limit measurement bias.
Treatment: at each visit, the following information was available: treatment with bDMARDs; use of non-steroidal anti-inflammatory drugs (NSAIDs) over the past 6 months, as assessed by the ASAS NSAID score and use of mild or strong opioids, including the dates of use.
Medico-economic and healthcare resource utilisation data: for each annual visit, the following data covering the previous 12 months were collected: work absenteeism (number of sick leave days attributed to spondyloarthritis), long-term sick leave and disability status, number of visits to the general practitioner, the rheumatologist and the physical therapist, the number of blood tests, the number of visits to the emergency department and the number and duration of hospital stays.
Definitions of D2M and TR-axSpA
The ASAS definition was adapted to the data available in DESIR. This resulted in the combination of three criteria: (1) failure of ≥2 bDMARDs with ≥2 different MoAs; (2) at least one sign of active or progressive disease, defined by: (a) persistent disease activity, defined by ASDAS ≥2.1; (b) active disease, defined by the presence of a clinical synovitis, enthesitis or dactylitis, or by CRP ≥5 mg/L, a SPARCC inflammatory score >0 or a sacroiliac SPARCC inflammatory score >0; (c) progressive disease, defined by the formation of >2 new syndesmophytes between 0 and 2 years of follow-up or >3 new syndesmophytes between 2 and 5 years of follow-up or >5 new syndesmophytes between 5 and 10 years of follow-up; (d) reduction in quality of life, defined by an ASQoL score ≥811 (the ASAS-Health Index was not used as it was not available at the start of the DESIR cohort); (3) as the ‘problematic’ nature of symptom management was not recorded in the DESIR cohort, the PtGA ≥5/10 scores were used as a surrogate in a similar manner to other studies. TR was defined if D2M criteria were met, an ASDAS ≥2.1 and the presence of a CRP ≥5 mg/L and or a spine or sacroiliac SPARCC inflammatory score >0.
In the DESIR cohort, inclusions were made in the second half of the 2000s, at a time when tumour necrosis factor inhibitors (TNFi) were the only bDMARDs available. The first IL-17 inhibitor (IL-17i) was approved for prescription in France in November 2015. The expected number of patients exposed to at least two different MoAs was low. Applying the requirement of different MoAs retrospectively would therefore have classified patients according to the calendar period in which their treatment was escalated, rather than purely according to their disease behaviour, introducing a period-related and availability-related bias. Therefore, as a prespecified sensitivity analysis, an ‘extended’ definition of D2M and TR was also used in order to capture the same underlying construct while remaining applicable across the entire follow-up, replacing the first criterion with failure of three or more bDMARDs regardless of MoA, instead of two or more with different MoAs.12
Statistical analysis
Baseline characteristics of the cohort at inclusion (M0) were described using descriptive statistics. Continuous variables were expressed as means and SD, and categorical variables as counts and percentages. The times to fulfil the D2M definitions were expressed as medians and IQRs.
The proportion of patients fulfilling the D2M-axSpA and TR-axSpA definitions at 10 years were calculated. Then, the cumulative incidence of D2M-axSpA and TR-axSpA over follow-up was estimated using the Kaplan-Meier method, with censoring at the last available follow-up date. Time origin was the inclusion in the DESIR cohort (baseline visit).
Description of the baseline characteristics associated with subsequent D2M-axSpA definition fulfilment: baseline characteristics measured at inclusion were compared descriptively between patients who subsequently developed D2M-axSpA during follow-up and those who did not, in order to characterise baseline differences between these groups. These comparisons were performed using the extended definition of D2M-axSpA, which was used as the primary definition for analytical purposes, as the small number of D2M-axSpA cases according to the ASAS definition precluded meaningful baseline comparisons. For the same reason, no baseline comparisons were performed between patients with TR-axSpA and patients without TR-axSpA. To identify baseline factors associated with the risk of developing D2M-axSpA over time and to account for differences in follow-up duration and censoring, time-to-event analyses were performed using Cox proportional hazards models. A separate model was built for each baseline factor of interest, selected on the basis of the preceding descriptive comparisons, clinical relevance and previously reported associations in the literature. Each model was adjusted only for the confounders relevant to that specific exposure-outcome association, identified a priori from clinical and causal reasoning and excluded variables acting as potential mediators. The proportional hazards assumption was assessed for each model using Schoenfeld residuals.
Description of the outcomes of patients with D2M-axSpA: comparisons were unadjusted bivariate analyses and are reported as descriptive group differences. The following variables were compared between D2M and non-D2M patients (using the extended definition for the same reasons as above) over the 10-year follow-up period: structural progression using the difference in mSASSS, imaging scores (SPARCC spine and SIJ inflammatory scores at 10 years), prevalence of patients with ≥3 fatty lesions at any point during follow-up, prevalence of any peripheral involvement (synovitis, enthesitis, dactylitis), comorbidities and major adverse cardiovascular event, mean and highest consumption of NSAIDs, use of any opioids or strong opioids during follow-up as well as prolonged use of opioids, defined as a continuous prescription ≥6 months. Medico-economic healthcare resource utilisation outcomes were also assessed using mean values per year, prevalence at any time and cumulative values over the 10 year follow-up, as well as prevalences of long-term sick leave and disability pension.
Between-group comparisons used the Mann-Whitney U test for continuous variables and the χ2 test for categorical variables (Fisher’s exact test when any expected cell count was <5). Because the analysis of the long-term outcome was descriptive rather than inferential, these comparisons are reported without p values. All statistical tests were two-sided, and a p value <0.05 was considered statistically significant. No imputation was performed for missing data; all analyses were performed on available cases. Analyses were performed using R V.4.3.1 (R Foundation for Statistical Computing, Vienna, Austria) and RStudio V.2025.05.1.
Results
Of the 708 patients included in the DESIR cohort, 420 patients met the ASAS 2009 classification criteria, including 177 patients exposed to bDMARDs, who were therefore included in this study (figure 1). Overall, 123 patients (69.5%) completed all scheduled follow-up visits. The baseline characteristics are presented in table 1. According to the ASAS definition, nine and one patients met the definitions of D2M and TR-axSpA, respectively, representing cumulative proportions of 5.1% and 0.6%. According to the extended definition, 20 and five patients met the definitions of D2M and TR-axSpA, respectively, representing cumulative proportions of 11.3% and 2.8%. Using survival analysis, the risk (cumulative incidence) of becoming D2M and TR was 6.8% (95% CI 2.4% to 11.0%) and 0.7% (95% CI 0.0% to 2.1%), respectively, using the ASAS definition, and 14.4% (95% CI 8.3% to 20.2%) and 3.7% (95% CI 0.4% to 6.9%), respectively, using the extended definition (figure 2).
Figure 1. Flow chart of the included patients with number and proportion of patients with difficult-to-manage (D2M) and treatment-refractory (TR) axial spondyloarthritis (axSpA). ASAS, Assessment of Spondyloarthritis International Society; bDMARD, biologic disease-modifying antirheumatic drug.
Table 1. Baseline characteristics of all patients, according to D2M-axSpA status based on the ASAS definition and the extended definition.
| Characteristic* | Missing values | All patients N=177 |
D2M (ASAS) patients N=9 |
Non-D2M (ASAS) patients N=168 |
D2M (extended) patients N=20 |
Non-D2M (extended) patients N=157 |
P value† |
|---|---|---|---|---|---|---|---|
| Age (years) | 0 | 31.2 (7.8) | 31.7 (10.1) | 31.2 (7.7) | 32.3 (8.3) | 31.1 (7.7) | 0.48 |
| Female sex | 0 | 87 (49.2%) | 7 | 80 (47.6%) | 16 (80.0%) | 71 (45.2%) | 0.003 |
| Follow-up duration (years) | 0 | 8.9 (2.4) | 10.0 (0.3) | 8.9 (2.5) | 9.5 (1.8) | 8.8 (1.0) | 0.53 |
| HLA-B27 | 0 | 152 (85.9%) | 7 | 145 (86.3%) | 16 (80.0%) | 136 (86.6%) | 0.42 |
| BMI (kg/m2) | 1 (0.6%) | 24.0 (3.8) | 22.1 (4.1) | 24.1 (3.8) | 24.1 (4.8) | 23.9 (3.7) | 0.79 |
| Family history of spondyloarthritis | 9 (5.1%) | 84 (50.0%) | 3 | 81 (50.9%) | 5 (27.8%) | 79 (52.7%) | 0.047 |
| Smoking | 0 | 79 (44.6%) | 4 | 75 (44.6%) | 10 (50.0%) | 69 (43.9%) | 0.61 |
| Hypertension | 0 | 4 (2.5%) | 0 (0%) | 4 (2.3%) | 0 (0%) | 4 (2.3%) | 1 |
| Fibromyalgia | 0 | 29 (16.4%) | 1 | 28 (16.7%) | 4 (20%) | 25 (15.9%) | 0.75 |
| Symptom duration (years) | 0 | 1.6 (0.8) | 2.0 (1.0) | 1.6 (0.8) | 1.7 (1.0) | 1.6 (0.8) | 0.53 |
| Symptom duration before first DMARD (years) | 0 | 1.6 (0.9) | 2.1 (1.0) | 1.6 (0.9) | 1.7 (1.0) | 1.6 (0.9) | 0.41 |
| Diagnostic delay | 0 | 1.2 (1.0) | 1.0 (1.0) | 1.2 (1.0) | 1.0 (0.8) | 1.2 (1.0) | 0.33 |
| Triggering factor (all) | 0 | 49 (27.7%) | 6 | 43 (25.6%) | 10 (50.0%) | 39 (24.8%) | 0.02 |
| Peripheral involvement | 0 | 103 (58.2%) | 3 | 71 (42.3%) | 7 (35.0%) | 67 (42.7%) | 0.51 |
| Uveitis | 124 (70.1%) | 14 (26.4%) | 0 (0%) | 14 (26.9%) | 1 (25.0%) | 13 (26.5%) | 0.95 |
| Psoriasis | 0 | 32 (18.1%) | 1 | 31 (18.5%) | 3 (15%) | 29 (18.5%) | 0.70 |
| Inflammatory bowel disease | 0 | 10 (5.6%) | 0 | 10 (6.0%) | 0 (0%) | 10 (6.4%) | 0.61 |
| Patient Global Assessment | 1 (0.6%) | 5.8 (2.5) | 6.1 (2.1) | 5.8 (2.6) | 6.8 (2.0) | 5.6 (2.6) | 0.047 |
| Physician Global Assessment | 0 | 5.2 (2.2) | 5.6 (1.7) | 5.2 (2.2) | 6.3 (1.5) | 5.0 (2.3) | 0.02 |
| ASDAS | 8 (4.5%) | 3.1 (0.9) | 3.4 (0.9) | 3.1 (0.9) | 3.6 (0.9) | 3.0 (0.9) | 0.004 |
| BASDAI | 0 | 5.0 (1.9) | 5.9 (2.4) | 4.9 (1.9) | 6.2 (1.4) | 4.8 (1.9) | <0.001 |
| BASFI | 0 | 37.5 (22.2) | 52.1 (28.7) | 36.7 (21.7) | 53.8 (22.8) | 35.4 (21.4) | <0.001 |
| ASQoL | 4 (2.3% | 10.9 (4.5) | 13.7 (2.7) | 10.8 (4.5) | 14.3 (2.4) | 10.5 (4.5) | <0.001 |
| CRP (mg/L) | 6 (3.4%) | 13.4 (18.4) | 13.2 (17.2) | 13.4 (18.5) | 17.0 (20.6) | 12.8 (18.1) | 0.57 |
| Radiographic sacroiliitis | 3 (1.7%) | 44 (25.3%) | 2 | 42 (25.5%) | 6 (30.0%) | 38 (24.7%) | 0.61 |
| mSASSS | 12 (6.8%) | 0.51 (1.85) | 0.04 (0.11) | 0.54 (1.90) | 0.51 (1.6) | 0.51 (1.9) | 0.63 |
| Number of syndesmophytes | 77 (43.5%) | 0.2 (0.7) | 0 (0) | 0.2 (0.8) | 0.39 (1.1) | 0.20 (0.7) | 0.67 |
| SPARCC MRI SIJ score | 75 (42.4%) | 5.5 (8.6) | 5.0 (10.1) | 5.5 (8.6) | 4.7 (9.1) | 5.6 (8.6) | 0.12 |
| SPARCC MRI spine score | 75 (42.4%) | 5.4 (13.7) | 1.8 (4.1) | 5.6 (14.2) | 2.0 (4.2) | 5.8 (14.4) | 0.22 |
Values are expressed as mean (SD) for quantitative variables and numbers (percentages) for qualitative variables. Percentages are not reported for subgroups with fewer than 10 patients.
P values correspond to comparisons between patients with D2M-axSpA and non-D2M-axSpA according to the extended definition.
ASAS, Assessment of Spondyloarthritis International Society; ASDAS, Axial Spondyloarthritis Disease Activity Score; ASQoL, Ankylosing Spondylitis Quality of Life score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Disease Functional Index; BMI, body mass index; CRP, C reactive protein; DMARD, disease-modifying antirheumatic drug; D2M-axSpA, difficult-to-manage axial spondyloarthritis; HLA-B27, human leucocyte antigen-B27; mSASSS, modified Stoke Ankylosing Spondylitis Spinal Score; SIJ, sacroiliac joint; SPARCC, Spondyloarthritis Research Consortium of Canada.
Figure 2. Cumulative incidence of difficult-to-manage (D2M) axial spondyloarthritis (axSpA) over time using the Assessment of Spondyloarthritis International Society (ASAS) (left) and extended definitions (right). bDMARD, biologic disease-modifying antirheumatic drug.
The occurrence of D2M-axSpA was rare during the first years following initiation of the first bDMARD and began to increase mainly after approximately 6 years of follow-up. The median time to the fulfilment of the D2M definitions was 7.6 (IQR 6.8–7.7) years for the ASAS definition and 7.6 (IQR 6.4–8.4) years for the extended definition. Whether using the ASAS or extended definition, the majority of patients with D2M-axSpA (89% and 85%, respectively) met the persistent disease activity criterion (2a, ASDAS ≥2.1) together with the impaired quality of life criterion (2d). Radiographic progression (2c) was not met by any patient under the ASAS definition and by only two patients under the extended definition.
Baseline characteristics measured at inclusion were compared descriptively between patients who subsequently developed D2M-axSpA and those who did not, using the extended definition (table 1). Patients who developed D2M-axSpA were more frequently female (80.0% vs 45.2%), less frequently reported a family history of spondyloarthritis (27.8% vs 52.7%) but more often reported triggering factors (infection, physical or psychological trauma) (50.0% vs 24.8%) preceding disease onset. They also had higher baseline PhGA (6.3 vs 5.0), PtGA (6.8 vs 5.6, p=0.047), ASDAS (3.6 vs 3.0), BASDAI (6.2 vs 4.8, p<0.001), BASFI (53.8 vs 35.4) and ASQoL scores (14.3 vs 10.5). In contrast, no major differences were observed for BMI, smoking status, EMMs or baseline imaging scores.
To identify baseline factors associated with the risk of developing D2M-axSpA over time, time-to-event analyses were performed using Cox proportional hazards models (table 2). Sex, being a constitutional variable without antecedent confounders, was modelled without adjustment; all other exposures were adjusted for sex, identified a priori as the dominant common cause of the exposure and the outcome. In exposure-specific Cox models, female sex (HR 5.14, 95% CI 1.72 to 15.40), higher baseline ASDAS (HR 1.97 per unit, 95% CI 1.13 to 3.42) and the presence of a triggering factor before disease onset (HR 2.82, 95% CI 1.17 to 6.84) were associated with the subsequent development of D2M-axSpA (extended definition). Baseline fibromyalgia and family history of SpA were not significantly associated. The proportional-hazards assumption, assessed using Schoenfeld residuals, was met for all models.
Table 2. Adjusted Cox proportional hazards models of baseline factors associated with time to classification as D2M-axSpA according to the extended definition.
| Variable | HR (95% CI) | P value |
|---|---|---|
| Female sex (vs male) | 5.14 (1.72 to 15.40) | 0.003 |
| ASDAS (per unit), adjusted for sex | 1.97 (1.13 to 3.42) | 0.017 |
| Triggering factor before onset, adjusted for sex | 2.82 (1.17 to 6.84) | 0.021 |
| Fibromyalgia at baseline, adjusted for sex | 0.85 (0.28 to 2.56) | 0.78 |
| Family history of SpA, adjusted for sex | 0.37 (0.13 to 1.05) | 0.061 |
ASDAS, Axial Spondyloarthritis Disease Activity Score; D2M-axSpA, difficult-to-manage axial spondyloarthritis.
The data on the outcomes are presented in table 3. These comparisons are descriptive and were not adjusted for potential confounders. Over the 10-year follow-up, patients who developed D2M-axSpA according to the extended definition were more frequently diagnosed with fibromyalgia compared with non-D2M patients (60% vs 22.9%). In contrast, the prevalence of EMMs, peripheral involvement, imaging outcomes or metabolic comorbidities appeared similar. The small number of patients with diabetes (n=3) and major adverse cardiovascular events (n=4) did not allow for any comparisons to be made. Patients with D2M-axSpA (using the extended definition) were all exposed to opioids, had more long-term exposure to all opioids (70% vs 42%) and more frequent exposure to strong opioids (35% vs 11%). They also showed a markedly higher burden across all medico-economic outcomes compared with non-D2M patients, including greater cumulative sick leave (168.9 (149.5) vs 62.9 (120.4) days), higher rates of disability pension (45% vs 11%), more medical visits (109.6 (73.8) vs 59.3 (40.1) cumulative visits), more emergency department visits (2.2 (1.7) vs 1.3 (1.5)) and more hospitalisation days (11.8 (23.4) vs 5.5 (11.1)) (figure 3).
Table 3. Long-term clinical, imaging and socio-economic outcomes over 10 years of follow-up for all patients according to D2M-axSpA status under the ASAS and extended definitions.
| Characteristic* | Number of missing values | All patients N=177 |
D2M (ASAS) patients N=9 |
Non-D2M (ASAS) patients N=168 |
D2M (extended) patients N=20 |
Non-D2M (extended) patients N=157 |
|---|---|---|---|---|---|---|
| Obesity | 1 (0.6%) | 50 (28.4%) | 2 | 48 (28.7%) | 7 (35.0%) | 43 (27.6%) |
| Smoking | 0 | 102 (57.6%) | 5 | 97 (57.7%) | 13 (65.0%) | 89 (56.7%) |
| Hypertension | 0 | 15 (8.5%) | 1 | 14 (8.3%) | 2 (10.0%) | 13 (8.3%) |
| Dyslipidaemia | 0 | 32 (18%) | 3 | 29 (17%) | 6 (30%) | 26 (17%) |
| Diabetes | 0 | 3 (2%) | 0 | 3 (2%) | 0 (0%) | 3 (2%) |
| Major adverse cardiovascular events | 0 | 4 (2%) | 0 | 4 (2%) | 0 (0%) | 4 (3%) |
| Fibromyalgia | 0 | 48 (27.1%) | 6 | 42 (25.0%) | 12 (60%) | 36 (22.9%) |
| Peripheral involvement | 0 | 157 (88.7%) | 9 | 148 (88.1%) | 20 (100%) | 137 (87.3%) |
| Uveitis | 105 (59.3%) | 36 (50.0%) | 3 | 33 (48.5%) | 5 (71.4%) | 31 (47.7%) |
| Psoriasis | 0 | 69 (39.0%) | 5 | 64 (38.1%) | 9 (45.0%) | 60 (38.2%) |
| Inflammatory bowel disease | 0 | 24 (13.6%) | 0 | 24 (14.3%) | 2 (10.0%) | 22 (14.0%) |
| mSASSS progression | 87 (49.2%) | 49 (54.4%) | 2 | 47 (56.6%) | 6 (54.5%) | 43 (54.4%) |
| At least three fatty lesions on MRI at any point | 118 (66.7%) | 35 (59.3%) | 2 | 47 (56.6%) | 3 (60%) | 32 (59.3%) |
| SPARCC SIJ inflammatory score at 10 years | 84 (47.5%) | 1.89 (4.95) | 0.27 (0.60) | 1.98 (5.08) | 0.15 (0.44) | 2.08 (5.18) |
| SPARCC spine inflammatory score at 10 years | 91 (51.4%) | 3.75 (6.84) | 0.43 (0.74) | 4.04 (7.06) | 2.67 (5.29) | 3.91 (7.05) |
| Mean ASAS NSAID score over follow-up | 0 | 33.90 (24.91) | 37.23 (24.16) | 33.72 (25.01) | 47.85 (32.71) | 32.12 (23.27) |
| Maximum ASAS NSAID score over follow-up | 0 | 91.08 (41.23) | 108.36 (53.46) | 90.15 (40.47) | 114.94 (55.40) | 88.04 (38.23) |
| Any opioid use | 0 | 133 (75.1%) | 9 | 124 (74%) | 20 (100%) | 113 (72%) |
| Opioid prescription ≥6 months | 0 | 80 (45.1%) | 5 | 75 (45%) | 14 (70%) | 66 (42%) |
| Any strong opioid use | 0 | 25 (14%) | 2 | 23 (14%) | 7 (35%) | 18 (11%) |
| Cumulative number of sick leave days | 0 | 74.97 (128.18) | 99.61 (69.37) | 73.65 (130.58) | 169.80 (149.48) | 62.89 (120.48) |
| Long-term sick leave | 0 | 21 (11.9%) | 3 | 18 (11%) | 4 (20%) | 17 (11%) |
| Disability pension related to SpA | 0 | 27 (15.2%) | 5 | 22 (13%) | 9 (45%) | 18 (11%) |
| Rheumatologist visits/year | 0 | 2.55 (2.09) | 2.96 (2.12) | 2.53 (2.09) | 4.14 (3.46) | 2.35 (1.76) |
| General practitioner visits/year | 0 | 5.64 (5.09) | 8.52 (5.20) | 5.49 (5.05) | 9.07 (8.12) | 5.20 (4.41) |
| Cumulative medical visits | 0 | 64.97 (47.63) | 107.11 (53.13) | 62.71 (46.42) | 109.60 (73.78) | 59.29 (40.11) |
| Physiotherapy visits/year | 0 | 13.74 (20.05) | 24.12 (28.92) | 13.19 (19.43) | 21.01 (25.16) | 12.82 (19.20) |
| Cumulative ED visits | 0 | 1.44 (1.52) | 3.22 (1.30) | 1.34 (1.47) | 2.20 (1.67) | 1.34 (1.47) |
| At least one ED visit | 0 | 116 (65.5%) | 9 | 107 (64%) | 15 (75%) | 101 (64%) |
| Cumulative hospitalisation days | 0 | 6.18 (13.12) | 7.28 (8.42) | 6.12 (13.34) | 11.78 (23.35) | 5.47 (11.10) |
| At least one hospitalisation | 0 | 133 (75.1%) | 8 | 125 (74%) | 19 (95%) | 114 (73%) |
Values are expressed as mean (SD) for quantitative variables and numbers (percentages) for qualitative variables. Percentages are not reported for subgroups with fewer than 10 patients. Unless otherwise specified, categorical variables denote occurrence at any time during follow-up (ever/never) and continuous variables are cumulative over the 10-year follow-up; SPARCC SIJ and spine scores are the values measured at 10 years.
P values correspond to comparisons between patients with D2M-axSpA and non-D2M-axSpA according to the extended definition, with the Mann-Whitney U test for continuous variables and the χ2 test for categorical variables (Fisher’s exact test when any expected cell count was <5).
ASAS, Assessment of Spondyloarthritis International Society; D2M-axSpA, difficult-to-manage axial spondyloarthritis; ED, emergency department; mSASSS, modified Stoke Ankylosing Spondylitis Spinal Score; NSAID, non-steroidal anti-inflammatory drug; SIJ, sacroiliac joint; SPARCC, Spondyloarthritis Research Consortium of Canada.
Figure 3. Cumulative medico-economic outcomes (A) sick leave days, (B) medical visits, (C) emergency department visits, (D) hospitalisation days over 10 years of follow-up in patients with D2M-axSpA (extended definition) (red) and non-D2M-axSpA (blue). Dashed lines represent the 95% CIs. D2M, difficult-to-manage.
Discussion
In this 10-year inception cohort of patients with recent onset axSpA, the cumulative incidence of D2M disease in patients exposed to bDMARDs was very low when applying the ASAS definition but increased when using an extended definition adapted to historical therapeutic availability. In exposure-specific Cox models, female sex, higher baseline disease activity and the presence of a triggering factor before disease onset were associated with the subsequent development of D2M-axSpA. These patients had a higher opioid use and socio-economic burden.
The TR phenotype, defined by objective evidence of persistent inflammation, represented only a minority of patients classified as D2M-axSpA. This observation suggests that D2M disease is more often driven by persistent non-inflammatory symptoms, including chronic pain syndromes, which are frequently observed in axSpA.13 Distinguishing between these two phenotypes is therefore essential, as they likely require different management strategies.14 Although fibromyalgia was not associated with the risk of D2M-axSpA at baseline, its higher prevalence at 10-year follow-up among D2M patients supports the hypothesis that chronic pain mechanisms may contribute to this phenotype. In RA, D2T disease has been conceptualised as comprising inflammatory and non-inflammatory refractory states.15 A similar framework may be applicable to axSpA, where persistent symptoms and disease impact can occur in the absence of structural progression or objective inflammatory worsening.16
The results of our study are similar to those reported in the literature. Two French cohort studies, one based on national health insurance data3 and the other on monocentric clinical data,4 reported a higher prevalence of D2M-axSpA, at 19.6% and 28.3%, respectively. However, these studies were based on more recent data, with more possibilities of different bDMARDs, and used definitions based only on treatment rotation, without considering signs of active or progressive disease. In our previous study, female gender, peripheral involvement and psoriasis were associated with D2M. In the study by Philippoteaux et al, female gender was not a factor associated with D2M. However, a higher BASDAI at baseline and fibromyalgia were significantly associated with D2M in multivariate analysis. Several studies have also been conducted using the ASAS definition. In a Dutch cross-sectional study including 236 patients with axSpA exposed to b/tsDMARD, the prevalence of D2M-axSpA was 9.7% and that of TR-axSpA was 1.7%.5 In the RABBIT-SpA (Rheumatoide Arthritis – Beobachtung der Biologika-Therapie - Spondyloarthritiden) registry, the prevalence of D2M-axSpA was 8.5% and that of TR-axSpA was 2.5%.6 Female gender and high baseline disease activity were associated with D2M-axSpA, as was CRP, unlike our study. The proportions found using the extended definition, designed to take into account the limited therapeutic possibilities during cohort follow-up, were therefore similar to those in the literature. However, as only bDMARD-exposed patients were included, the reported cumulative incidence reflects this selected population and should not be interpreted as the incidence in the overall axSpA cohort. In contrast, applying the more recent ASAS definition likely led to an underestimation of these phenotypes. This suggests that the ASAS definition may not be suitable for use with older datasets such as the DESIR cohort.
Interestingly, the vast majority of patients meeting the definition of D2M-axSpA fulfilled the criteria for active or progressive disease based on high ASDAS scores, signs of active disease and impaired quality of life. However, radiographic progression was found in only two patients using the extended definition and in none using the ASAS definition. These findings are consistent with the hypothesis that D2M-axSpA reflects persistent disease activity rather than ongoing structural damage in this recent onset population. However, this low rate should be interpreted in the context of the DESIR cohort as a whole, in which sacroiliac structural progression over 10 years was limited.17 It may therefore reflect the recent-onset nature of the cohort rather than a feature specific to the D2M phenotype.
The factors associated with the D2M-axSpA phenotype are similar to those associated with multiswitching, including female gender and a high PtGA at baseline.18 In addition, the presence of a triggering factor prior to disease onset—such as physical or psychological trauma, pregnancy or infection—was associated with the development of D2M-axSpA. Previous studies have suggested that trauma-related axSpA may be characterised by a higher prevalence of peripheral involvement,19 which has been associated with D2M in some cohorts,6 20 although this was not observed in our study. Psychological trauma has also been shown to transiently increase disease activity in patients with established SpA.21 Similarly, infections preceding disease onset have been associated with more active disease phenotypes compared with SpA without prior infection.22 Taken together, these observations suggest that the higher prevalence of D2M-axSpA in patients with a triggering factor may primarily reflect a higher disease activity burden rather than a distinct pathogenic mechanism.
All D2M patients had received at least one opioid prescription, and 85% met criteria for chronic opioid use, consistent with previously reported data from the DESIR cohort showing that up to 30% of patients with recent-onset axSpA follow a persistent opioid prescription trajectory, associated with higher subjective disease activity scores despite adequate control of objective inflammation.23 This high prevalence of opioid use, despite multiple lines of biologic therapy, consistent with what has been found in other studies on D2M-axSpA,6 24 further supports the hypothesis that non-inflammatory pain mechanisms are central to the D2M phenotype. Regarding NSAIDs, D2M patients showed similar frequency of use but significantly higher peak ASAS NSAID scores, suggesting more intensive use without sustained efficacy. Overall, this pattern of high opioid consumption alongside intensive but insufficient NSAID use highlights the need for a multidisciplinary approach to pain management in D2M-axSpA.
Beyond clinical outcomes, this study provides, for the first time to our knowledge, data on the socio-economic burden of D2M-axSpA. Over 10 years, patients with D2M-axSpA accumulated more sick leave days, had higher rates of disability pension and consulted healthcare professionals more frequently, resulting in almost twice as many cumulative medical visits compared with non-D2M patients. These findings are consistent with data from the literature showing that uncontrolled disease activity is a major driver of work disability and healthcare costs.25 26 Importantly, the magnitude of these differences suggests that D2M-axSpA represents a clinical challenge and a substantial burden for patients, employers and healthcare systems. These data reinforce the need for early identification of at-risk patients and a patient-centred approach that includes social and occupational support in D2M scenarios.
This study has several strengths. It is based on a prospective, multicentre cohort, with an average follow-up of >9 years. It includes a wide range of data and is based on central reading of imaging examinations. In addition, the use of an inception cohort makes it possible to characterise the factors associated with D2M at a (very) early stage of the disease.
This study has some limitations: as inclusions were made in the late 2000s, few patients could have been exposed to a class of bDMARDs other than TNFi, which limited the use of the ASAS definition, requiring two different MoAs. Nevertheless, the use of a similar definition (failure of ≥3 b/tsDMARDs regardless of MoA), which should be regarded as a pragmatic adaptation to the historical therapeutic context of the DESIR cohort, led to results similar to what has already been observed in the literature. However, this definition is not equivalent to the ASAS definition: because it does not require treatment failure across different MoAs, patients identified as D2M-axSpA in this study may not be directly comparable to those defined by the ASAS criteria. In addition, criterion 3 (disease perceived as difficult to manage by the patient and/or doctor) was not specifically collected in the DESIR database. The method used to assess this criterion has not yet been standardised, particularly for cohorts built before the various definitions were published. However, this criterion was nevertheless taken into account in this study through the PtGA, as has been done in other studies. Moreover, DESIR includes patients with a short disease duration and consequently shorter cumulative exposure to successive treatment lines; such patients are inherently less likely to have met the D2M definition than those with longer-standing disease, which may also contribute to the lower frequency of D2M-axSpA in this study. Finally, the small number of D2M and TR patients may have led to a lack of power for certain analyses, particularly with regard to EMMs and multivariable analyses, which may explain the differences compared with other data in the literature.
To summarise, in this recent-onset axSpA inception cohort with long-term follow-up, D2M-axSpA affected a small proportion of patients and was rarely associated with treatment refractoriness or structural progression. Female sex, high disease activity at disease onset and the presence of a triggering factor before disease onset were the main baseline factors associated with subsequent D2M-axSpA development. Beyond disease activity, D2M-axSpA carried a substantial socio-economic burden, with markedly increased work absenteeism, disability pension rates, opioid use and healthcare resource utilisation over 10 years, illustrating that the impact of this phenotype extends well beyond the clinical setting. Finally, the requirement for exposure to multiple biologic MoAs may limit the applicability of the ASAS definition in older axSpA cohorts, and an adapted definition should be considered in this context. Future studies should clarify the respective roles of symptoms, inflammation and structural damage in defining this phenotype.
Acknowledgements
The DESIR cohort is conducted with Assistance Publique—Hôpitaux de Paris (AP-HP), Paris, France, as the sponsor and under the umbrella of the French Society of Rheumatology. The authors would like to thank the Clinical Research Unit Paris Centre (AP-HP), Paris, France, and the Institut national de la santé et de la recherche médicale (Inserm) for their support. The authors would also like to thank the investigators: Professor Maxime Dougados, Professor André Kahan, Dr Julien Wipff, Dr Anna Molto (Paris-Cochin), Professor Olivier Meyer, Professor Philippe Dieudé (Paris-Bichat), Professor Pierre Bourgeois, Professor Laure Gossec (Paris-La Pitié-Salpêtrière), Professor Francis Berenbaum (Paris-Saint-Antoine), Professor Pascal Claudepierre (Créteil), Professor Maxime Breban, Professor Maria-Antonietta D’Agostino, Professor Félicie Costantino (Boulogne-Billancourt), Professor Michel De Bandt, Dr Bernadette Saint-Marcoux (Aulnay-sous-Bois), Professor Philippe Goupille (Tours), Professor Jean-François Maillefert (Dijon), Professor Xavier Puechal, Dr Emmanuelle Dernis (Le Mans), Professor Daniel Wendling, Professor Clément Prati (Besançon), Professor Bernard Combe, Professor Cédric Lukas (Montpellier), Professor Liana Euller-Ziegler, Professor Véronique Breuil (Nice), Professor Pascal Richette (Paris Lariboisière), Professor Pierre Lafforgue, Professor Thao Pham (Marseille), Professor Patrice Fardellone, Dr Patrick Boumier, Dr Pauline Lasselin (Amiens), Professor Jean-Michel Ristori, Professor Martin Soubrier, Professor Anne Tournadre (Clermont-Ferrand), Dr Nadia Mehsen (Bordeaux), Professor Damien Loeuille (Nancy), Professor René-Marc Flipo (Lille), Professor Alain Saraux (Brest), Professor Corinne Miceli, Dr Stephan Pavy (Le Kremlin-Bicêtre), Professor Alain Cantagrel, Professor Adeline Ruyssen Witrand (Toulouse), Professor Olivier Vittecoq and Professor Thierry Lequerre (Rouen).
Footnotes
Funding: The DESIR cohort is supported by unrestricted grants from, in decreasing order of financial support, Pfizer France, Biogen, AbbVie, UCB, Lilly, Galapagos, Novartis, MSD, Fresenius and Celltrion Healthcare.
Data availability free text: Data are available on request, and after validation by the DESIR scientific committee.
Patient consent for publication: Not applicable.
Ethics approval: This study was approved by the local ethics committee (EudraCT no. 2007-A00608-45; ethics committee file no. 2457; dated 17 September 2007). The study was conducted according to the Good Clinical Practice guidelines. All participants provided informed consent to participate in the study before taking part.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement
Data are available on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available on reasonable request.