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. 2026 Mar 13;13(3):611–628. doi: 10.1007/s40744-026-00834-5

Impact of Upadacitinib on Reducing Pain in Patients Across the Axial Spondyloarthritis Spectrum: A Post Hoc Analysis of the Phase 2/3 SELECT-AXIS Studies

Xenofon Baraliakos 1,7,✉, Louis Bessette 2, Kurt de Vlam 3, Peter C Taylor 4, Ana Biljan 5, Jamie Urbanik 5, Tianming Gao 5, Victoria S Jasion 5, Koji Kato 5, Ralph Lippe 5, Marina Magrey 6
PMCID: PMC13198570  PMID: 41824252

Abstract

Introduction

This post hoc analysis evaluates the efficacy of upadacitinib (UPA), a Janus kinase inhibitor, across multiple pain endpoints in patients with axial spondyloarthritis (axSpA) through 104 weeks from the phase 2/3 SELECT-AXIS studies.

Methods

Adult patients with radiographic axSpA (r-axSpA; historically ankylosing spondylitis; two studies) who were naïve or had an inadequate response (IR) to biologic disease-modifying antirheumatic drugs (bDMARDs), or with non-radiographic axSpA (nr-axSpA; one study), were randomized to UPA 15 mg (UPA15) once daily or placebo (PBO). Patients treated with PBO were switched to UPA15 at week 14 in the r-axSpA studies and week 52 in the nr-axSpA study. Pain outcomes were assessed through week 104 and analyzed using nonresponder imputation or mixed-model repeated measures and as observed data. Safety data were not evaluated in this analysis but have been published previously.

Results

Across axSpA, higher proportions of patients achieved ≥ 30%/50%/70% reduction from baseline in the patient’s global assessment of pain with UPA15 versus PBO as early as week 1; reductions in pain were generally maintained through week 104 in the continuous UPA15 groups. Patients who switched from PBO to UPA15 showed generally similar responses to the continuous UPA15 groups through week 104. Additional pain endpoints, including minimal clinically important difference and total back pain, showed similar results. Numerically higher proportions of patients who reported early pain improvement (≥ 30% at week 2 or ≥ 50% at week 14) following UPA15 treatment achieved stringent disease control targets, including Assessment of SpondyloArthritis international Society (ASAS) partial remission, Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity, or ASDAS inactive disease at week 104 versus patients who did not report early pain improvement.

Conclusions

These results from the SELECT-AXIS studies support the clinical benefit of UPA15 for reducing pain in patients with axSpA through 104 weeks (2 years).

Trial Registration, ClinicalTrials.gov identifier

NCT03178487 and NCT04169373.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40744-026-00834-5.

Keywords: Ankylosing spondylitis (AS), Assessment of SpondyloArthritis international Society (ASAS), Ankylosing Spondylitis Disease Activity Score (ASDAS), Janus kinase (JAK) inhibitor, Minimal clinically important difference (MCID), Non-radiographic axial spondyloarthritis (nr-axSpA), Pain, Radiographic axial spondyloarthritis (r-axSpA), SELECT-AXIS, Upadacitinib

Plain Language Summary

This analysis looked at how well upadacitinib, a Janus kinase inhibitor, worked to reduce pain in people with a condition called axial spondyloarthritis (axSpA). AxSpA is a type of arthritis that mainly affects the spine and can cause severe pain and stiffness. This analysis included adults with either radiographic axSpA (r-axSpA, previously called ankylosing spondylitis) or non-radiographic axSpA (nr-axSpA) from three studies. People in the studies may or may not have used specific arthritis medicines before. People in the studies were randomly given either upadacitinib (15 mg once daily) or a placebo (a pill with no medicine). At week 14 or 52 of the studies, people treated with a placebo switched to upadacitinib. The researchers wanted to know how much pain improved over 2 years (104 weeks) using several different measures. They found that more people taking upadacitinib than placebo felt at least 30%, 50%, or 70% improvement in their pain compared to the start of the study, and this occurred as early as the first week of treatment. The people who switched from placebo to upadacitinib showed similar pain relief as those who took upadacitinib the entire time. Other measures of more specific types of pain, like total back pain, showed similar results. Also, people who experienced early pain relief were more likely to reach strict disease control goals, such as low disease activity, after 2 years. In summary, this analysis shows that upadacitinib helped reduce pain for people with axSpA for up to 2 years.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40744-026-00834-5.

Key Summary Points

Why carry out this study?
Pain is the most bothersome and debilitating symptom of axial spondyloarthritis (axSpA); effective pain management remains an unmet need for patients with axSpA.
The objectives of this post hoc analysis were to evaluate the efficacy of upadacitinib, a Janus kinase (JAK) inhibitor, across multiple pain endpoints through 2 years in patients with radiographic axSpA (r-axSpA) or non-radiographic axSpA (nr-axSpA), and to explore the association between early pain improvement and long-term stringent disease control targets, from the phase 2/3 SELECT-AXIS studies.
What was learned from the study?
Patients with r-axSpA or nr-axSpA treated with upadacitinib 15 mg showed greater improvements across several pain endpoints versus placebo.
Patients who switched from placebo to upadacitinib 15 mg showed similar reductions in pain as patients treated with upadacitinib continuously, which were maintained through 2 years.
Early pain improvement was associated with achievement of long-term stringent disease control targets, including Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity, in patients with axSpA.
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Introduction

Patients living with axial spondyloarthritis (axSpA), either radiographic axSpA (r-axSpA, historically referred to as ankylosing spondylitis [AS]) [2] or non-radiographic axSpA (nr-axSpA) can experience debilitating pain and stiffness, which can negatively impact their quality of life and work productivity [3–6]. Although pain may be secondary to inflammation, other non-inflammatory factors, such as chronic structural damage or peripheral and central sensitization of pain receptors, may also play a role [7–9]. The primary treatment goals for patients with axSpA are to control symptoms and inflammation, prevent structural damage, and normalize function and social participation by achieving low disease activity (LDA) or remission [10, 11]. Pain can play a key role in achieving these treatment goals. The management of pain remains an unmet need for patients with axSpA, which often requires therapeutic intervention beyond the use of non-steroidal anti-inflammatory drugs (NSAIDs) [12–14].

Upadacitinib, an oral, selective, and reversible Janus kinase (JAK) inhibitor, has been engineered to have greater inhibitory potency for JAK1 versus JAK2, JAK3, and tyrosine kinase 2 (TYK2) [15, 16]. Pro-inflammatory cytokines involved in axSpA pathogenesis interact directly and indirectly with the JAK/signal transducer and activator of transcription (STAT) signaling pathway, which in turn has been shown to play a key role in the regulation of nociception and perhaps nociplastic pain as well [17]. Upadacitinib has demonstrated efficacy in the phase 2/3 SELECT-AXIS 1 study in patients with active r-axSpA who were naïve to biologic disease-modifying antirheumatic drugs (bDMARDs), as well as in the phase 3 SELECT-AXIS 2 study in patients with active r-axSpA who had an inadequate response or intolerance to bDMARDs (bDMARD-IR) or in patients with active nr-axSpA [18–20]. In addition to improvements in efficacy outcomes with upadacitinib treatment, reductions in pain endpoints up to 64 weeks in patients with bDMARD-naïve r-axSpA from the SELECT-AXIS 1 study have been reported [21]. The objectives of this post hoc analysis were to (1) evaluate the efficacy of upadacitinib across multiple pain endpoints through 104 weeks (2 years) in patients with bDMARD-naïve or bDMARD-IR r-axSpA and in patients with nr-axSpA (including both bDMARD-naïve and bDMARD-IR), and to (2) explore the association between early pain improvement and long-term stringent disease control targets in these patients, from the phase 2/3 SELECT-AXIS studies. The safety of upadacitinib for the treatment of r-axSpA and nr-axSpA has been published previously in the SELECT-AXIS primary publications [18–20], as well as subsequent long-term integrated safety analyses [22–26], and is therefore not further presented here.

Methods

Patients and Trial Design

SELECT-AXIS 1

The methods, including full inclusion and exclusion criteria, and primary results of the SELECT-AXIS 1 study (NCT03178487) have been published previously [19]. In brief, SELECT-AXIS 1 was an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2/3 study. Eligible patients were ≥ 18 years of age and met the modified New York criteria for AS based on central reading of radiographs of the sacroiliac joints. In addition, patients were required to have active disease at baseline, defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 and a patient’s assessment of back pain score ≥ 4 (both using a 0–10 numeric rating scale [NRS]), and had an IR to ≥ 2 NSAIDs or intolerance/contraindication for NSAIDs. bDMARD-naïve patients with active r-axSpA were randomized 1:1 to receive oral upadacitinib 15 mg once daily (QD) or placebo for 14 weeks, followed by a 90-week open-label extension (OLE) period (104 weeks total) during which all patients were treated with upadacitinib 15 mg QD.

SELECT-AXIS 2

The methods, including full inclusion and exclusion criteria, and primary results of the two SELECT-AXIS 2 studies (NCT04169373) have been published previously [18, 20]. SELECT-AXIS 2 was conducted using a master protocol that included two standalone studies with randomization, data collection, analysis, and reporting conducted independently. Both SELECT-AXIS 2 studies were international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trials.

In brief, the SELECT-AXIS 2 r-axSpA study [18] included eligible patients ≥ 18 years of age who met the modified New York criteria for AS based on central reading of sacroiliac joint radiographs. Patients were required to have active disease at screening and baseline visits defined by a BASDAI score ≥ 4 and a patient’s assessment of back pain score ≥ 4 (0–10 NRS for both). In addition, patients had an IR to ≥ 2 NSAIDs or intolerance/contraindication for NSAIDs and were bDMARD-IR (tumor necrosis factor [TNF] inhibitor or interleukin [IL]-17 inhibitor), including patients who discontinued biologics due to lack of efficacy or intolerance. bDMARD-IR patients with active r-axSpA were randomized 1:1 to receive oral upadacitinib 15 mg QD or placebo for 14 weeks, followed by a 90-week OLE period (104 weeks total) during which all patients received upadacitinib 15 mg QD.

The SELECT-AXIS 2 nr-axSpA study [20] included eligible patients ≥ 18 years of age with a clinical diagnosis of nr-axSpA who fulfilled the 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria [27]. Patients who met the modified New York criteria for AS were excluded from the study. Patients were required to have active disease at screening and baseline visits defined by a BASDAI score ≥ 4 and patient’s assessment of back pain score ≥ 4 (0–10 NRS for both). Patients were required to have at least one objective sign of active inflammation at screening based on magnetic resonance imaging (MRI) of the sacroiliac joints, high-sensitivity C-reactive protein (hsCRP) greater than the upper limit of normal (ULN; 2.87 mg/l), or both. In addition, enrolled patients had to have an IR to ≥ 2 NSAIDs or intolerance/contraindication for NSAIDs. At least 20%, but no more than 35%, of patients were permitted to have previous treatment with 1 bDMARD (either TNF or IL-17 inhibitor) and discontinued due to lack of efficacy or intolerance. Patients with active nr-axSpA with or without an IR to bDMARDs were randomized 1:1 to receive oral upadacitinib 15 mg QD or placebo for 52 weeks, followed by a 52-week OLE period (104 weeks total) during which all patients received upadacitinib 15 mg QD.

Across the SELECT-AXIS 1 and SELECT-AXIS 2 trials, all patients provided written informed consent, and studies were conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, applicable regulations and guidelines governing clinical study conduct, and the Declaration of Helsinki 1964 and its later amendments. As per Good Clinical Practice (GCP), the trial protocols were approved by an independent ethics committee (IEC)/institutional review board (IRB) at each site.

Outcomes

Pain-related endpoints up to 64 weeks from the SELECT-AXIS 1 bDMARD-naïve r-axSpA study have been published previously [21]. This post hoc analysis focuses on expanding reported pain data for the bDMARD-naïve r-axSpA patient population up to 104 weeks (2 years), as well as pain data from the SELECT-AXIS 2 bDMARD-IR r-axSpA and nr-axSpA studies up to 104 weeks.

Pain outcomes were evaluated as early as week 2 in the bDMARD-naïve r-axSpA study and as early as week 1 in the bDMARD-IR r-axSpA and nr-axSpA studies. Pain endpoints included mean change from baseline in the patient’s global assessment of pain (based on “How much pain have you had because of your condition during the last week?”) on a 0–10 NRS [28, 29], where 0 represents no pain and 10 represents severe pain, as well as the proportion of patients with pain scores ≤ 1 or ≤ 2 (NRS). In addition, the proportion of patients achieving ≥ 30%, ≥ 50%, and ≥ 70% reduction from baseline or a minimal clinically important difference (MCID; defined as ≥ 1-point reduction or ≥ 15% reduction from baseline) in the patient’s global assessment of pain (0–10 NRS) was assessed [28]. The proportion of patients achieving ≥ 30%, ≥ 50%, and ≥ 70% reduction from baseline in the patient’s assessment of total back pain (0–10 NRS), as well as MCID in total back pain, was also assessed.

Associations between early pain improvement (≥ 30% improvement in pain at week 2 or ≥ 50% improvement in pain at week 14) and achievement of long-term stringent disease control targets were assessed across the SELECT-AXIS studies. In this analysis, the percent of patients who achieved Assessment of SpondyloArthritis international Society partial remission (ASAS PR; defined as a value ≤ 2 units on a 0 to 10 scale in all ASAS domains [function, morning stiffness, patient’s global assessment of disease activity, and pain]), Axial Spondyloarthritis Disease Activity Score LDA (ASDAS LDA; defined as a score < 2.1), ASDAS inactive disease (ASDAS ID; defined as a score < 1.3), or MCID in the Bath Ankylosing Spondylitis Functional Index (MCID BASFI, defined as a ≥ 0.6-point decrease from baseline) were assessed at week 104 stratified by percent pain improvement status.

Statistical Analysis

For analyses of the patient’s global assessment of pain, as well as total back pain, nonresponder imputation (NRI) (for the bDMARD-naïve r-axSpA study) or nonresponder imputation incorporating multiple imputation (NRI-MI) to handle missing data due to COVID-19 (for the bDMARD-IR r-axSpA and nr-axSpA studies) was used for binary endpoints and mixed-effect model repeated measures (MMRM) was used for continuous endpoints. For the NRI analysis of binary endpoints, the Cochran–Mantel–Haenszel (CMH) test adjusting for screening hsCRP status as a stratification factor was used; NRI was used for handling of missing data. For the NRI-MI analysis of binary endpoints, the treatment difference, associated confidence interval, and P value to test for differences between treatments were constructed based on the MI inference, which included demographic variables and baseline disease characteristics, as well as longitudinal responses observed at any other visits. Risk difference and standard error were estimated using the CMH test, with screening hsCRP status as a stratification factor for the bDMARD-IR r-axSpA study, and MRI and screening hsCRP status as stratification factors for the nr-axSpA study, within each imputed ‘complete’ dataset. Rubin's rule was used to combine the results from 30 imputed ‘complete’ datasets to obtain the aggregated treatment difference, associated confidence interval, and P value. For analysis of continuous endpoints for all studies, the MMRM models included treatment, visit, and treatment-by-visit interaction as fixed factors and the baseline value as a covariate. The stratification factors of each study were also included in the model. For both binary and continuous endpoints, statistical comparisons between placebo and upadacitinib 15 mg were only performed for data during the placebo-controlled period (i.e., up to week 14 in the r-axSpA studies and up to week 52 in the nr-axSpA study). All P values are nominal and were not multiplicity-controlled. The patient’s global assessment of pain and total back pain data were also assessed using as-observed (AO) analysis and are presented in the supplementary materials.

For descriptive analysis of the proportion of patients with a pain score ≤ 1 or ≤ 2 (NRS), both NRI and AO analysis were performed. Descriptive analysis of the achievement of long-term stringent disease control targets in patients with early pain improvement was analyzed using both NRI and AO. NRI analyses are presented in the main text; AO data are presented in the supplementary materials.

Results

In the bDMARD-naïve r-axSpA study (SELECT-AXIS 1), 93 patients were treated with upadacitinib 15 mg QD and 94 patients were treated with placebo. In the bDMARD-IR r-axSpA study (SELECT-AXIS 2), 211 patients were treated with upadacitinib 15 mg QD and 209 patients were treated with placebo. In the nr-axSpA study (SELECT-AXIS 2, including both bDMARD-naïve and bDMARD-IR patients), 156 patients were treated with upadacitinib 15 mg QD and 157 patients were treated with placebo. Patients with r-axSpA were predominantly male (~ 70%), while patients with nr-axSpA were predominantly female (~ 60%) (Table 1). Baseline pain and disease characteristics were generally similar between treatment groups and across studies, with evidence of a high burden of disease. The patient’s global assessment of pain scores ranged from 6.8 to 7.5 (0–10 NRS), total back pain scores from 6.7 to 7.5 (0–10 NRS), mean BASDAI from 6.3 to 6.9, and mean ASDAS (CRP) from 3.5 to 3.9 at baseline.

Table 1.

Patient baseline demographics and disease characteristics

Parameter bDMARD-naïve r-axSpA bDMARD-IR r-axSpA nr-axSpA
PBO
N = 94		 UPA 15 mg QD
N = 93		 PBO
N = 209		 UPA 15 mg QD
N = 211		 PBO
N = 157		 UPA 15 mg QD
N = 156
Male, n (%) 69 (73.4) 63 (67.7) 158 (75.6) 153 (72.5) 63 (40.1) 67 (42.9)
Age, mean (SD), years 43.7 (12.1) 47.0 (12.8) 42.2 (11.8) 42.6 (12.4) 42.5 (12.4) 41.6 (12.0)
Time from disease diagnosis, mean (SD), years 6.0 (6.8) 7.8 (10.6) 7.5 (7.5) 7.9 (7.5) 4.4 (5.8) 4.5 (5.5)
Concomitant therapy, n (%)
 NSAIDs 81 (86.2) 71 (76.3) 163 (78.0) 163 (77.3) 113 (72.0) 121 (77.6)
 Oral corticosteroids 12 (12.8) 6 (6.5) 18 (8.6) 27 (12.8) 17 (10.8) 18 (11.5)
 csDMARDs 17 (18.1) 13 (14.0) 62 (29.7) 68 (32.2) 50 (31.8) 41 (26.3)
Prior bDMARDs, n (%) – – 208 (99.5) 211 (100.0) 54 (34.4) 49 (31.4)
PGA of pain (0–10 NRS), mean (SD) 6.9 (1.6) 6.8 (1.6) 7.4 (1.3) 7.5 (1.4) 7.4 (1.4) 7.3 (1.5)
Total back pain (0–10 NRS), mean (SD)a 6.7 (1.8) 6.8 (1.8) 7.4 (1.4) 7.5 (1.5) 7.3 (1.4) 7.2 (1.6)
Nocturnal back pain (0–10 NRS), mean (SD) 6.3 (2.0) 6.4 (2.3) 7.2 (1.5) 7.1 (1.8) 7.0 (1.6) 6.7 (1.9)
Morning stiffness (0–10 NRS), mean (SD)b 6.7 (1.9) 6.5 (2.0) 6.8 (1.6) 6.9 (1.8) 6.7 (1.7) 6.6 (1.8)
BASDAI, mean (SD) 6.5 (1.6) 6.3 (1.8) 6.8 (1.3) 6.8 (1.3) 6.9 (1.2) 6.8 (1.3)
Enthesitis (MASES > 0), n (%) 55 (58.5) 54 (58.1) 162 (77.9) 148 (70.1) 125 (79.6) 125 (80.1)
hsCRP, mg/l, mean (SD) 11.7 (11.1) 9.6 (12.6) 14.5 (17.8) 15.8 (17.7) 10.5 (13.5) 13.6 (24.8)
ASDAS (CRP), mean (SD) 3.7 (0.7) 3.5 (0.8) 3.9 (0.8) 3.9 (0.8) 3.7 (0.6) 3.6 (0.7)
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A portion of these data were previously published in [18–21].

ASDAS Ankylosing Spondylitis Disease Activity Score (ASDAS), BASDAI Bath Ankylosing Spondylitis Disease Activity Index, CRP C-reactive protein, cs conventional synthetic, bDMARD biologic disease-modifying antirheumatic drug, hsCRP high-sensitivity C-reactive protein, IR inadequate response, MASES Maastricht Ankylosing Spondylitis Enthesitis Score, nr-axSpA non-radiographic axial spondyloarthritis, NRS numeric rating scale, NSAID nonsteroid anti-inflammatory drug, PBO placebo, PGA patient’s global assessment, QD once daily, r-axSpA radiographic axial spondyloarthritis, UPA upadacitinib

aBack pain was defined on a NRS (0–10) based on the question, “What is the amount of back pain that you experienced at any time during the last week?”

bMorning stiffness was defined as the mean score of questions 5 (severity of morning stiffness) and 6 (duration of morning stiffness) of the BASDAI

Improvement in the Patient’s Global Assessment of Pain

bDMARD-naïve r-axSpA Patient Population

As reported previously [21], mean change from baseline in the patient’s global assessment of pain (NRS) was greater for the bDMARD-naïve r-axSpA population treated with upadacitinib 15 mg versus placebo from week 2 through week 14 for all timepoints assessed (MMRM analysis: all P < 0.001; Fig. 1A). In addition, higher proportions of patients treated with upadacitinib 15 mg achieved ≥ 30%, ≥ 50%, and ≥ 70% reductions in the patient’s global assessment of pain compared with those treated with placebo as early as week 2 through week 14 (NRI analysis: all comparisons, P < 0.001, excluding week 2 for ≥ 70% reduction; Fig. 1B–D). Similarly, a higher proportion of patients treated with upadacitinib 15 mg versus placebo achieved MCID in the patient’s global assessment of pain from weeks 2 to 14 (NRI analysis: all comparisons, P < 0.05; Fig. 1E). The proportion of patients achieving pain scores ≤ 1 (NRS) or ≤ 2 (NRS) were numerically higher for patients treated with upadacitinib 15 mg versus placebo from weeks 2 to 14 (NRI analysis; Supplemental Figure 1A, B).

Fig. 1.

Fig. 1

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Improvement in the patient’s global assessment of pain following UPA 15 mg treatment in patients with bDMARD-Naïve r-axSpA through 104 weeks (MMRM or NRI). MCID is defined as ≥ 1-point reduction or ≥ 15% reduction from baseline on a 0–10 NRS. The dotted line indicates the end of the double-blind, placebo-controlled period at 14 weeks and the start of the open-label extension period, where all patients were treated with UPA 15 mg regardless of initial treatment at randomization. aSample sizes varied per week for the MMRM analysis: continuous UPA 15 mg, n = 67–89; PBO to UPA 15 mg, n = 69–92. Nominal *P ≤ .05; ***P ≤ .001. bDMARD biologic disease-modifying antirheumatic drug, MCID minimal clinically important difference, MMRM mixed-effect model repeated measures, NRI nonresponder imputation, NRS numeric rating scale, PBO placebo, QD once daily, r-axSpA radiographic axial spondyloarthritis, UPA upadacitinib

In patients treated continuously with upadacitinib 15 mg, reductions in pain were generally maintained or further improved through week 104 (Fig. 1A–E and Supplemental Figure 1A, B). Among patients who switched from placebo to upadacitinib 15 mg at week 14, similar reductions in pain to those in the continuous upadacitinib 15 mg group were observed across the various pain endpoints through week 104 (Fig. 1A–E and Supplemental Figure 1A, B).

bDMARD-IR r-axSpA Patient Population

Mean change from baseline in the patient’s global assessment of pain was greater for the bDMARD-IR r-axSpA population treated with upadacitinib 15 mg versus placebo from week 1 (MMRM analysis: P = 0.0003) through week 14 (MMRM analysis: P < 0.0001; Fig. 2A). Higher proportions of patients treated with upadacitinib 15 mg versus placebo achieved ≥ 30% (NRI-MI analysis: P = 0.0047; Fig. 2B) or ≥ 50% (NRI-MI analysis: P = 0.0007; Fig. 2C) reductions in the patient’s global assessment of pain as early as week 2. Reductions in pain following upadacitinib 15 mg treatment versus placebo were observed through week 14, with higher proportions of patients achieving ≥ 30% reduction and ≥ 50% reduction at week 14 (NRI-MI analysis: both comparisons, P < 0.0001). Achievement of ≥ 70% reduction in the patient’s global assessment of pain was higher with upadacitinib 15 mg versus placebo at week 4 (NRI-MI analysis: P = 0.0192) and was maintained or further improved through week 14 (NRI-MI analysis: P < 0.0001; Fig. 2D). Similarly, the proportion of patients achieving MCID for the patient’s global assessment of pain was higher with upadacitinib 15 mg versus placebo as early as week 1 (NRI-MI analysis: P = 0.0003; Fig. 2E), with continued achievement of MCID through week 14. The proportion of patients achieving pain scores (NRS) ≤ 1 or ≤ 2 were numerically higher from weeks 2 to 14 for patients treated with upadacitinib 15 mg versus placebo (NRI-MI analysis; Supplemental Figure 1C, D).

Fig. 2.

Fig. 2

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Improvement in the patient’s global assessment of pain following UPA 15 mg treatment in patients with bDMARD-IR r-axSpA through 104 weeks (MMRM or NRI-MI). MCID is defined as ≥ 1-point reduction or ≥ 15% reduction from baseline on a 0–10 NRS. The dotted line indicates the end of the double-blind, placebo-controlled period at 14 weeks and the start of the open-label extension period, where all patients were treated with UPA 15 mg regardless of initial treatment at randomization. aSample sizes varied per week for the MMRM analysis: continuous UPA 15 mg, n = 168–208; PBO to UPA 15 mg, n = 176–208. Nominal *P ≤ .05; **P ≤ .01; ***P ≤ .001. bDMARD-IR, biologic disease-modifying antirheumatic drug—inadequate response, MCID minimal clinically important difference, MMRM mixed-effect model repeated measures, NRI-MI nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, NRS numeric rating scale, PBO placebo, QD once daily, r-axSpA radiographic axial spondyloarthritis, UPA upadacitinib

Reductions in pain were generally maintained or further improved through week 104 across the various pain endpoints in patients treated with upadacitinib 15 mg continuously, as well as in patients who switched from placebo to upadacitinib 15 mg at week 14 (Fig. 2A–E and Supplemental Figure 1C, D).

nr-axSpA Patient Population

Mean change from baseline in the patient’s global assessment of pain was also greater for patients with nr-axSpA treated with upadacitinib 15 mg versus placebo from week 1 through week 52 (MMRM analysis; Fig. 3A). A higher proportion of patients treated with upadacitinib 15 mg versus placebo achieved ≥ 30% reduction in the patient’s global assessment of pain as early as week 1 (NRI-MI analysis: P = 0.0304; Fig. 3B) and ≥ 50% reduction as early as week 2 (NRI-MI analysis: P = 0.0001; Fig. 3C). Reductions in the patient’s global assessment of pain were maintained or further improved over time, with higher proportions of patients treated with upadacitinib 15 mg versus placebo achieving ≥ 30% reduction and ≥ 50% reduction in pain at week 52 (NRI-MI analysis: both comparisons, P < 0.001). Achievement of ≥ 70% reduction in the patient’s global assessment of pain was higher with upadacitinib 15 mg versus placebo at week 2 (NRI-MI analysis: P = 0.0071) and week 8 (NRI-MI analysis: P = 0.0012), with these differences maintained or further improved thereafter through week 52 (NRI-MI analysis; Fig. 3D). The proportion of patients achieving MCID was greater for upadacitinib 15 mg versus placebo at weeks 12, 18, 24, and 52 (NRI-MI analysis; Fig. 3E). The proportions of patients achieving pain scores (NRS) ≤ 1 or ≤ 2 were numerically higher for patients treated with upadacitinib 15 mg versus placebo through week 52 (NRI-MI analysis; Supplemental Figure 1E, F).

Fig. 3.

Fig. 3

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Improvement in the patient’s global assessment of pain following UPA 15 mg treatment in patients with nr-axSpA through 104 weeks (MMRM or NRI-MI). MCID is defined as ≥ 1-point reduction or ≥ 15% reduction from baseline on a 0–10 NRS. The dotted line indicates the end of the double-blind, placebo-controlled period at 52 weeks and the start of the open-label extension period, where all patients were treated with UPA 15 mg regardless of initial treatment at randomization. aSample sizes varied per week for the MMRM analysis: continuous UPA 15 mg, n = 124–150; PBO, n = 114–153. Nominal *P ≤ .05; **P ≤ .01; ***P ≤ .001. MCID minimal clinically important difference, MMRM mixed-effect model repeated measures, nr-axSpA non-radiographic axial spondyloarthritis, NRI-MI nonresponder imputation incorporating multiple imputation to handle missing data due to COVID-19, NRS numeric rating scale, PBO placebo, QD once daily, UPA upadacitinib

Similar to the trends observed in the r-axSpA patient populations, reductions in pain were generally maintained or further improved through week 104 in patients with nr-axSpA treated continuously with upadacitinib 15 mg. For patients with nr-axSpA who were initially randomized to placebo and switched to upadacitinib 15 mg at week 52, responses were similar but slightly lower (Fig. 3A–E and Supplemental Figure 1E, F).

Improvement in the Patient’s Assessment of Total Back Pain

bDMARD-naïve r-axSpA Patient Population

The proportion of bDMARD-naïve patients with r-axSpA who achieved ≥ 30%, ≥ 50%, or ≥ 70% reductions, as well as those achieving MCID, in total back pain was higher with upadacitinib 15 mg versus placebo at week 14 (NRI analysis: all comparisons, P < 0.01; Supplemental Figure 2A–D). Results were either further improved or maintained at weeks 52 and 104 and were generally similar among patients treated with upadacitinib 15 mg continuously and those who switched from placebo to upadacitinib 15 mg at week 14 (Supplemental Figure 2A–D).

bDMARD-IR r-axSpA Patient Population

Higher proportions of patients with bDMARD-IR r-axSpA who received upadacitinib 15 mg versus placebo achieved ≥ 30%, ≥ 50%, and ≥ 70% reductions, as well as MCID, in total back pain at week 14 (NRI-MI analysis: all comparisons, P ≤ 0.001; Supplemental Figure 2E–H). Results were largely maintained through week 104, with a similar magnitude of response achieved among patients who switched from placebo to upadacitinib 15 mg at week 14 (Supplemental Figure 2E–H).

nr-axSpA Patient Population

In agreement with results from patients with r-axSpA, higher proportions of patients with nr-axSpA who received upadacitinib 15 mg versus placebo achieved ≥ 30%, ≥ 50%, and ≥ 70% reductions in total back pain at week 14 (NRI-MI analysis: all comparisons, P ≤ 0.01; Supplemental Figure 2I–K). The proportion of patients that achieved MCID in total back pain was similar between upadacitinib 15 mg versus placebo at week 14 (NRI-MI analysis: P = 0.1822) but higher in patients receiving upadacitinib 15 mg versus placebo at week 52 (NRI-MI analysis: P = 0.0449; Supplemental Figure 2L). Improvements in total back pain with continuous upadacitinib 15 mg treatment were generally maintained at week 104, with slightly lower values observed in patients who switched from placebo to upadacitinib 15 mg at week 52 (Supplemental Figure 2I–L).

Association Between Early Pain Improvement and Long-Term Stringent Disease Control Targets

bDMARD-naïve r-axSpA Patient Population

Numerically higher proportions of bDMARD-naïve patients with r-axSpA treated with upadacitinib 15 mg who reported early pain improvement (≥ 30% pain improvement at week 2 or ≥ 50% pain improvement at week 14) achieved ASDAS LDA at week 104 versus patients who did not report early pain improvements (NRI analysis; Fig. 4B). Similar results were observed for ASAS PR (NRI analysis; Fig. 4A), ASDAS ID (NRI analysis; Fig. 4C), and MCID in BASFI (NRI analysis; Fig. 4D), with numerically higher proportions of patients who reported early pain improvements at week 2 or week 14 achieving stringent disease control targets at week 104.

Fig. 4.

Fig. 4

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Association between early pain improvement (≥ 30% improvement in pain at week 2 or ≥ 50% improvement in pain at week 14) and long-term stringent disease control targets following UPA 15 mg treatment in patients with bDMARD-Naïve r-axSpA, bDMARD-IR r-axSpA, or nr-axSpA at 104 weeks (NRI). ASAS PR was defined as a value ≤ 2 units on a 0–10 scale in all ASAS domains (function, morning stiffness, patient’s global assessment of disease activity, and pain), ASDAS LDA was defined as a score < 2.1, ASDAS ID was defined as a score < 1.3, and MCID in BASFI was defined as a ≥ 0.6-point decrease from baseline. All patients initially randomized to placebo received open-label UPA 15 mg starting at week 14 (bDMARD-naïve and bDMARD-IR r-axSpA) or week 52 (nr-axSpA). ASAS PR Assessment of SpondyloArthritis international Society partial remission, ASDAS Ankylosing Spondylitis Disease Activity Score, BASFI Bath Ankylosing Spondylitis Functional Index, bDMARD biologic disease-modifying antirheumatic drug, ID inactive disease, IR inadequate response, LDA low disease activity, MCID minimal clinically important difference, nr-axSpA non-radiographic axial spondyloarthritis, NRI nonresponder imputation, PBO placebo, QD once daily, r-axSpA radiographic axial spondyloarthritis, UPA upadacitinib

bDMARD-IR r-axSpA Patient Population

Numerically higher proportions of bDMARD-IR patients with r-axSpA treated with upadacitinib 15 mg who reported early pain improvement versus those who did not also achieved ASAS PR, ASDAS LDA, ASDAS ID, and MCID in BASFI at week 104 (NRI analysis; Fig. 4E–H).

nr-axSpA Patient Population

Similar to the results for patients with r-axSpA, numerically higher proportions of patients with nr-axSpA who reported early pain improvement following upadacitinib 15 mg treatment versus those who did not achieved ASAS PR, ASDAS LDA, ASDAS ID, and MCID in BASFI at week 104 (NRI analysis; Fig. 4I–L).

AO Analysis of Pain Endpoints

Across all pain endpoints assessed through week 104, findings from the AO analyses were generally similar to the more conservative MMRM and NRI analyses described above (AO analyses provided in Supplemental Figures 3–8).

Discussion

This post hoc analysis of the phase 2/3 SELECT-AXIS 1 and SELECT-AXIS 2 studies in patients with r-axSpA who were bDMARD-naïve or bDMARD-IR, and in patients with nr-axSpA, demonstrated rapid, clinically meaningful, and sustained benefits of upadacitinib 15 mg treatment across multiple pain outcomes, including the patient’s global assessment of pain and the patient’s global assessment of total back pain. A previous publication assessed the impact of upadacitinib 15 mg on several pain endpoints up to 64 weeks in bDMARD-naïve patients with r-axSpA from SELECT-AXIS 1 [21]. Here, we have expanded upon this prior publication to include the assessment of additional pain endpoints in bDMARD-naïve patients with r-axSpA from SELECT-AXIS 1, as well as the addition of patients with bDMARD-IR r-axSpA and nr-axSpA from SELECT-AXIS 2, to provide a more complete assessment of upadacitinib 15 mg treatment through 104 weeks (2 years) for multiple pain endpoints across the axSpA spectrum.

Across all subtypes of axSpA, greater proportions of patients treated with upadacitinib 15 mg rapidly achieved meaningful improvements in the patient’s global assessment of pain as early as week 1, which were maintained or further improved through the double-blind, placebo-controlled period, as well as long-term through 104 weeks. Similar results were observed for the patient’s global assessment of total back pain. In general, consistent results were observed across the axSpA spectrum, with a similar direction and trend in pain improvement, though for some endpoints, numerically lower pain responses were observed in the nr-axSpA patient population. Patients with r-axSpA who switched from placebo to upadacitinib 15 mg at week 14, or patients with nr-axSpA who switched at week 52, showed generally similar responses across pain endpoints through week 104 as patients treated with upadacitinib continuously.

Across patients with axSpA, numerically higher proportions of patients treated with upadacitinib 15 mg who reported early pain improvement achieved ASAS PR, ASDAS LDA, ASDAS ID, or MCID in BASFI at week 104 compared to patients who did not report early pain improvement. A previous publication found that a higher proportion of patients with PsA who reported early pain improvements following upadacitinib 15 mg treatment achieved long-term stringent disease control targets and quality of life outcomes compared to patients who did not report early pain improvement [30]. Although these data are descriptive, they help to provide additional evidence for the benefit of early pain improvement on long-term stringent disease control in patients with axSpA, which could help clinicians assess the likelihood of treatment success earlier in the disease course. Early reductions in inflammatory activity may correlate with central pain modulation, which could explain sustained control over time. Furthermore, early pain response is especially important given that over 50% of patients with axSpA reported that one of their most frequent fears was suffering pain (55.1%) and one of their most frequent hopes was eliminating pain (54.2%) in the International Map of Axial Spondyloarthritis (IMAS) survey [31].

Improvements in pain endpoints have been shown previously with bDMARD treatment, including TNF inhibitors and IL-17 inhibitors, as well as with JAK inhibitors, in patients with r-axSpA, PsA, or rheumatoid arthritis (RA) [21, 32–35]. Rapid pain relief, even as soon as 24 h after treatment, has been reported in patients with RA or PsA administered JAK inhibitors [36, 37]. Pain has been shown to be associated with fatigue, reduced quality of life, and functional and work impairment [3–6], and thus pain management is an important part of the treatment for patients with axSpA [13, 14]. Additional research is needed to better understand the impact of therapies on various types of pain (i.e., neuropathic, nociplastic, nociceptive). Of note, in the UPSTAND observational study, treatment with upadacitinib in patients with axSpA has been associated with improvements in non-inflammatory pain mechanisms, including nociplastic and neuropathic pain [38, 39].

Safety data were not evaluated in this post hoc analysis, but the safety profile of upadacitinib for the treatment of axSpA has been described previously [18–20, 22–25]. Recent safety assessments, which include long-term extension data from the SELECT-AXIS 1 and SELECT-AXIS 2 studies, have shown generally consistent rates of overall adverse events (AEs) and AEs of special interest as described in previous reports, with no new safety risks identified with long-term upadacitinib treatment in axSpA [25, 26].

A limitation of this post hoc analysis is that patients were not randomized to treatments according to their pain level at baseline; however, baseline pain characteristics were generally well-balanced across treatment groups within each study. Second, as is a common limitation when assessing patient-reported outcomes, these analyses were based on subjective patient assessments of pain. Third, this post hoc analysis is primarily a descriptive, hypothesis-generating analysis, particularly for associations between early pain improvement and long-term stringent disease control targets, and therefore, causality could not be investigated. Fourth, as stated in the methods, P values are nominal and were not multiplicity-controlled, which could lead to an increased risk of type I error. Fifth, patients enrolled in clinical trials often differ from those seen in routine clinical practice; therefore, the extrapolation of these findings to the broader patient population should be made with caution. However, upadacitinib has demonstrated improvement in pain, as early as day 1, in a real-world setting in the UPSTAND observational study [38, 39].

Conclusions

Overall, these findings from the phase 2/3 SELECT-AXIS studies support the rapid, clinically meaningful, and sustained benefits of upadacitinib 15 mg treatment on pain in patients with active r-axSpA (bDMARD-naïve or bDMARD-IR) or active nr-axSpA through 104 weeks. Pain management remains an unmet need for patients with axSpA, and these findings may be useful to clinicians when making treatment decisions to support patient care.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 2317 KB) (2.3MB, pdf)

Acknowledgements

AbbVie and the authors thank the patients, study sites, and investigators who participated in these clinical trials.

Medical Writing/Editorial Assistance

Medical writing support was provided by Janet Matsuura, PhD, of ICON (Blue Bell, PA, USA) and was funded by AbbVie, as well as Monica R.P. Elmore, PhD of AbbVie. Editorial support was provided by Catherine Barone, PhD of AbbVie. During the preparation of this manuscript, the authors and/or medical writer used Generative Artificial Intelligence to create the first draft of the Plain Language Summary (PLS). After using Generative Artificial Intelligence, the authors and/or medical writer reviewed and edited the PLS, as needed, and take full responsibility for the content of the publication.

Author Contribution

Xenofon Baraliakos and Ana Biljan participated in the design of the study. Louis Bessette and Kurt de Vlam participated in the acquisition of data. Tianming Tao, Ana Biljan, and Jamie Urbanik participated in the analysis of data. All authors (Xenofon Baraliakos, Louis Bessette, Kurt de Vlam, Peter C. Taylor, Ana Biljan, Jamie Urbanik, Tianming Gao, Victoria S. Jasion, Koji Kato, Ralph Lippe, and Marina Magrey) participated in the interpretation of data and contributed to the drafting and critical revision of the manuscript for important intellectual content. All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. No honoraria or payments were made for authorship.

Funding

AbbVie funded these trials (NCT03178487 and NCT04169373) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. AbbVie funded the journal’s Rapid Service Fee.

Data Availability

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, synopses, or statistical analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Use Agreement (DUA). Data requests can be submitted at any time after approval in the US and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ then select “Home”.

Declarations

Conflict of Interest

Financial arrangements of the authors with companies whose products may be related to the present manuscript are listed, as declared by the authors. Xenofon Baraliakos has received research grants and consultancy fees from Novartis, Pfizer, AbbVie, Eli Lilly, UCB Pharma, Galapagos, Janssen, Celgene, and Amgen. Louis Bessette has received grant/research support from Amgen, BMS, Janssen, UCB, AbbVie, Pfizer, Merck, Celgene, Lilly, Novartis, Sanofi, and Gilead; received speaker fees from Amgen, BMS, Janssen, UCB, AbbVie, Pfizer, Merck, Celgene, Lilly, Novartis, Organon, and Sanofi; and served as an officer or board member for Amgen, BMS, Janssen, UCB, AbbVie, Pfizer, Merck, Celgene, Lilly, Novartis, Sanofi, Organon, and Gilead. Kurt de Vlam has received grant/research support from Amgen, UCB, and MSD; consultancy fees from Amgen, AbbVie, Celgene, Eli Lilly, Galapagos, Novartis, Allegro, and UCB; and speaker fees from Amgen, Celgene, Eli Lilly, Galapagos, Novartis, and UCB. Peter C. Taylor has received grant/research support from Alfasigma; speaker fees from AbbVie; and consulting fees from Lilly, AbbVie, Alfasigma, Gilead, Janssen, Sanofi, Nordic Pharma, UCB, Immunovant, and MoonLake. Ana Biljan, Jamie Urbanik, Tianming Gao, Victoria S. Jasion, Koji Kato, and Ralph Lippe are full-time, salaried employees of AbbVie Inc. and may own AbbVie stock or stock options. Marina Magrey has received research grants from Amgen, AbbVie, BMS, and UCB Pharma and has received consulting fees from UCB, Novartis, Eli Lilly, Pfizer, and Janssen.

Ethical Approval

Across the SELECT-AXIS 1 and SELECT-AXIS 2 trials, all patients provided written informed consent, and studies were conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, applicable regulations governing clinical trial conduct, and the Declaration of Helsinki 1964 and its later amendments. As per Good Clinical Practice (GCP), the trial protocols were approved by an independent ethics committee (IEC)/institutional review board (IRB) at each site.

Footnotes

Prior Publication: A portion of these data were originally presented at the European Congress of Rheumatology (EULAR) 2023 Annual Congress (Milan, Italy; May 31–June 3, 2023) [1].

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (PDF 2317 KB) (2.3MB, pdf)

Data Availability Statement

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, synopses, or statistical analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Use Agreement (DUA). Data requests can be submitted at any time after approval in the US and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ then select “Home”.

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