Background
Patients with axial spondyloarthritis (axSpA) include those with radiographic axSpA (also termed
ankylosing spondylitis [AS]), which requires radiographic evidence of sacroiliitis according to the modified New York criteria [
1], and those with nonradiographic axial spondyloarthritis (nr-axSpA) [
2], who have similar signs and symptoms but without such radiographic changes. Magnetic resonance imaging (MRI) is increasingly used as an imaging tool in patients with axSpA [
3,
4] for diagnosis, classification, and monitoring of disease activity [
5‐
7]. Thus, there is a need to better understand the relationship between inflammation assessed by MRI and disease activity assessed clinically, as well as their impact on long-term physical function in patients with axSpA.
Therapeutic targets are emerging for axSpA. Clinical remission or inactive disease has been recommended as a major treatment target in the most recent updates of the Assessment of SpondyloArthritis international Society (ASAS)/European League Against Rheumatism management recommendations for axSpA and treat-to-target recommendations for spondyloarthritis [
8,
9]. Once this goal is achieved, clinical remission should ideally be maintained over time. Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS ID) is the preferred definition of clinical remission [
9]; however, more data on the long-term impact of remission status on physical function and quality of life are needed [
8].
Treatment options for axSpA include nonsteroidal anti-inflammatory drugs (NSAIDs) and biologic disease-modifying antirheumatic drugs that target tumor necrosis factor (TNF)-α (i.e., anti-TNF agents) [
10] or interleukin (IL)-17 (i.e., anti-IL-17) [
11,
12]. Only anti-TNFs have proven efficacy in patients with nr-axSpA to date [
8]. Adalimumab was effective for the treatment of patients with nr-axSpA in the ABILITY-1 trial [
13]. Greater improvements in disease activity, physical function, and health-related quality of life, as well as reduction of sacroiliac joint (SIJ) and spine inflammation, based on MRI findings were demonstrated after 12 weeks of adalimumab therapy compared with placebo. Positive week 12 results were further supported by sustained clinical response and remission data through year 2 of the study [
14].
This paper reports the final efficacy and safety data from the open-label extension (OLE) of the ABILITY-1 study in patients with nr-axSpA who received adalimumab for up to 3 years. Specifically, we evaluated the relationship between clinical and MRI remission, as well as the impact of sustained clinical remission on long-term physical function.
Discussion
The results of the long-term extension of the ABILITY-1 study demonstrated sustained clinical and functional improvements through 3 years of adalimumab therapy in patients with nr-axSpA. Furthermore, there was a sustained reduction in MRI axial inflammation, which was significantly greater in the SIJ of patients who achieved clinical remission than in those not in remission. Sustained clinical remission was associated with attainment of normal physical function.
In contrast to AS, there is still limited understanding of the disease course and appropriate long-term management of patients with nr-axSpA. The present work adds to the body of evidence that clinical and MRI improvements can be maintained with long-term anti-TNF therapy in patients with nr-axSpA classified by ASAS criteria [
22,
23]. Further, it provides important insights into the relationship between clinical and MRI remission in nr-axSpA, as well as the significance of sustained clinical remission for achieving normal physical function.
We evaluated the efficacy outcomes separately in the total efficacy population (n = 185) and subpopulation of patients with objective signs of inflammation at baseline (MRI/CRP-positive subpopulation; n = 142) for whom anti-TNF therapy, including adalimumab, is currently approved. No major differences were observed in the results, with the MRI/CRP-positive subpopulation representing 77% of the total efficacy population. For completeness, we also provided information for the MRI- and CRP-negative subpopulation.
Throughout the OLE, approximately two-thirds (as observed) or nearly half (NRI) of the patients in the MRI/CRP-positive subpopulation achieved ASAS40 response. Almost half (observed) or around one-third (NRI) of patients were in clinical remission measured as either ASAS PR or ASDAS ID at the end of the study. Furthermore, sustained clinical remission, defined as achieving ASDAS ID at all available visits, was seen in nearly one-fourth of patients through each of year 2 and year 3, with 18% of patients in sustained ASDAS ID throughout both years 2 and 3.
Although the clinical improvements observed in the small MRI- and CRP-negative subpopulation (n = 42) were generally smaller than in the MRI/CRP-positive subpopulation, it appears that some patients without objective evidence of inflammation at baseline responded to adalimumab treatment and maintained clinical improvements through 3 years. However, interpretation should be done with caution because of the small number of patients in this group.
MRI scans taken at 1 and 2 years showed a significant and sustained suppression of inflammation in both the SIJ and spine. An interesting observation was an apparent better responsiveness of the MRI inflammation in the SIJ than in the spine to adalimumab treatment. The reductions in the mean SPARCC MRI scores were relatively larger, and a higher proportion of patients achieved MRI remission (SPARCC MRI score < 2) in the SIJ than in the spine among patients with positive MRI at baseline; SIJ vs spine MRI remission rates were 65% vs 48% and 71% vs 52% at years 1 and 2, respectively. There also seemed to be a better numerical agreement between clinical and MRI remission in the SIJ than in the spine. Among patients with positive baseline MRI, a larger proportion of patients in clinical remission (ASDAS ID) reached MRI remission in the SIJ than in the spine at year 1 (73% vs 53%). Furthermore, significantly greater mean improvements from baseline were observed at years 1 and 2 for the SIJ SPARCC MRI scores in patients achieving ASDAS ID than in those not in ASDAS ID. The differences between patients in ASDAS ID vs those not in ASDAS ID were not significant for the spine SPARCC MRI scores.
Of note, the baseline MRI scores were numerically greater in the SIJ than in the spine, especially in the MRI/CRP-positive subpopulation, in spite of the mean symptom duration of around 10 years in this nr-axSpA population. It is generally believed that axial inflammation starts in the SIJ and then involves the spine in axSpA [
24], but there was still considerable inflammation in the SIJ in this nr-axSpA study population. Another possible explanation for the somewhat lower effect on the spine MRI scores is that not all the lesions detected in the spine were specific for axSpA [
25] or were responsive to anti-TNF treatment. It is also interesting that in the EMBARK study with etanercept in nr-axSpA, more patients achieved MRI remission in the spine than in SIJ after 2 years in a cohort with much shorter symptom duration (mean 2.4 years) [
23]. However, the differences between the proportions of patients achieving either remission in the SIJ or spine were not significant between those with or without sustained ASDAS ID or low disease activity in that study. The definitions of MRI remission were less stringent, especially for the spine, in the EMBARK study than in the ABILITY-1 study [
23].
A discordance between clinical and MRI disease activity in axSpA has been noted before [
26‐
28]. In our study, only 40% and 44% of patients with positive baseline MRI who achieved ASDAS ID also attained overall MRI remission (both in SIJ and spine) at years 1 and 2, respectively. Numerically more patients achieving overall MRI remission among those with positive baseline MRI also met ASDAS ID criteria at years 1 and 2 (67% and 62%, respectively). Currently, clinical and not MRI remission is suggested as a treatment target [
8,
9] because the impact of persistent MRI inflammation in the SIJ or spine on long-term physical function or structural progression in patients with axSpA who are in clinical remission is unknown. Further studies are needed in this area.
Evidence that has accumulated over the past few years in AS suggests a direct relationship of clinical disease activity with physical function and syndesmophyte formation [
29‐
31]. The long-term impact of achieving and maintaining clinical remission in nr-axSpA has not previously been evaluated. Our results demonstrate the importance of sustained clinical remission (defined as ASDAS ID) for achieving normal physical function over time. All patients in sustained clinical remission achieved normal physical function at years 2 and 3, as compared with only 44–49% of patients not in sustained clinical remission. All patients with normal physical function at baseline maintained it until the end of the OLE with adalimumab, regardless of achieving sustained clinical remission or not. The total number of patients with normal physical function at baseline was small, however, and no definite conclusions can be drawn on the importance of sustained clinical remission for the maintenance of normal physical function. It also needs to be noted that our definition of sustained clinical remission was very strict, requiring ASDAS ID at all study visits. Our findings lend further support to ASDAS ID as a clinically meaningful definition of clinical remission [
32]. They also substantiate the treat-to-target recommendation that once the target of clinical remission is achieved, remission should ideally be maintained throughout the patient’s disease course [
9].
It is known that the extent of structural damage along with the degree of inflammation measured by disease activity determine physical function in AS [
28,
29]. Limitations of our analyses include the lack of assessment of structural damage, which made it impossible to correlate sustained clinical remission or MRI remission with structural progression. MRI was also not performed at year 3, limiting the analyses of MRI findings to the years 1 and 2 time points. Safety data collected over 3 years did not reveal new safety concerns in nr-axSpA compared with the known safety profile of adalimumab in other immune-mediated inflammatory diseases, particularly in AS [
33].
Competing interests
DvdH has received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB and is director of Imaging Rheumatology B.V. JS has received research grants, consulting fees, and speaker’s fees from AbbVie, Merck, Pfizer, and UCB. WPM has received research grants and consulting fees from AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis, Pfizer, SYNARC, and UCB and is chief medical officer of CaRE Arthritis. RGL has received consulting or advisory board fees from AbbVie, BioClinica, Janssen, Parexel, and UCB. SC, MH, JKA, and ALP are full-time employees of AbbVie and may hold stock and/or options.