UPSTAND: Characterizing Nociceptive Pain and Disease Burden in AxSpA

A paradigm shift is underway in axial spondyloarthritis (axSpA): as targeted therapies have become increasingly effective at controlling inflammation, it has become clear that a substantial portion of residual symptom burden in these patients is driven not by inflammation, but by non-nociceptive pain — pain that anti-inflammatory drugs are not designed to address.

A post hoc analysis of the UPSTAND observational study, presented at the European Alliance of Associations for Rheumatology (EULAR), held June 3-6 in London, United Kingdom, examined the impact of upadacitinib on this dimension of pain and found that treatment was associated with reductions in both nociplastic and neuropathic pain, while also demonstrating that patients with persistent non-nociceptive pain at week 12 fared substantially worse across multiple symptom domains.¹

Denis Poddubnyy, MD, PhD, MSc (Epi), Professor of Medicine in the Division of Rheumatology at the University of Toronto and Senior Scientist at the Schroeder Arthritis Institute, University Health Network, Toronto, Canada, presented the data and sat down with RheumatologyLive during the meeting to further discuss the importance of looking at non-nociceptive pain.

UPSTAND (NCT04846244) was a 12-month, multicountry, noninterventional observational study evaluating the effectiveness of upadacitinib on pain in adults with axSpA. This post hoc analysis used interim data after all patients completed at least week 12. Patients were stratified by severity of neuropathic pain using the painDETECT questionnaire (<13, 13–18, and >18) and by severity of nociplastic pain using the widespread pain index (WPI: <4, 4–6, and >6). Nociplastic pain fulfilling fibromyalgia (FM) criteria per Wolfe et al. 2016 was assessed using WPI and symptom severity score (SSS) combined; patients with a clinical diagnosis of FM were excluded from UPSTAND at enrollment.¹

Upadacitinib treatment was associated with a progressive shift toward less severe pain categories in both neuropathic and nociplastic pain domains from baseline through weeks 12 and 24. The proportion of patients meeting FM criteria also decreased over time.¹

Non-nociceptive pain at week 12 was associated with worse outcomes across multiple domains. Patients with greater nociplastic or neuropathic pain burden were less likely to achieve ASDAS low disease activity (<2.1), BASDAI <4, Pittsburgh Sleep Quality Index score <5, and Hospital Anxiety and Depression Scale score ≤7 at week 12. Those with higher non-nociceptive pain burden also demonstrated smaller improvements in total back pain, nocturnal back pain, fatigue (BASDAI question 1), and BASFI from baseline to week 12.¹

"We realized that… patient symptoms — residual symptoms, pain outside of what we can control with anti-inflammatory drugs — may not be related to inflammation at all," Poddubnyy said. "…Nociplastic pain may be responsible for most of the symptom burden in cases where we control inflammation well in axial spondyloarthritis, and this is true across all painful inflammatory conditions we deal with."

Poddubnyy noted that approximately 50% of patients with axSpA achieve ASAS40 across clinical trials — a ceiling that was previously interpreted as a sign of insufficient inflammatory control, but is now better understood to reflect the contribution of non-nociceptive pain. He distinguished nociceptive pain (driven by inflammation or structural damage) from neuropathic pain (caused by peripheral nerve damage) and nociplastic pain (perceived pain without nociceptor activation or nerve damage), noting that fibromyalgia represents the most recognized clinical expression of nociplasticity.

Poddubnyy’s disclosures include AbbVie, Canon, Eli Lilly, Greywolf Therapeutics, Janssen, Medscape, Merck, Moonlake, Novartis, Peervoice, Pfizer, and UCB.

References

1. Poddubnyy D, Navarro-Compán V, Basu N, et al. Impact of treatment with upadacitinib on non-nociceptive pain and its relevance for the presence of residual symptoms in axial spondyloarthritis: results from a multicountry observational study [abstract POS0239]. Ann Rheum Dis. 2026;85(suppl 1). doi:10.1136/annrheumdis-2026-eular.B.1009

2. van der Heijde D, et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis. Lancet. 2019;394:2108–2117.