What's the latest update on the ongoing clinical trials related to Axial Spondyloarthritis?

Axial spondyloarthritis (axSpA) is a chronic inflammatory disorder that predominantly affects the axial skeleton—the spine and sacroiliac joints—and can lead to substantial pain, functional impairment, and decreased quality of life. Over the past several decades, significant strides have been made in understanding the pathophysiology, clinical manifestations, and optimal management strategies to alleviate its burden. With an evolving therapeutic landscape that now embraces biologics and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), ongoing clinical trials play a pivotal role in optimizing treatment paradigms for axSpA.

Axial spondyloarthritis is an umbrella term that encompasses both radiographic axSpA (historically known as ankylosing spondylitis or AS) and non-radiographic axSpA (nr-axSpA). The disease is characterized by chronic inflammation at the entheses (sites where tendons and ligaments attach to bones) which eventually leads to structural damage, new bone formation, and, in advanced cases, spinal ankylosis. Recent advances in immunopathogenesis have highlighted important contributors such as tumor necrosis factor (TNF) and interleukin-17 (IL-17) in driving inflammation, as well as the emerging role of Janus kinase (JAK) pathways that mediate cytokine signaling in this process. The dynamic interplay between immune-mediated inflammation and aberrant repair mechanisms explains how early intervention might not only reduce symptoms but also prevent irreversible structural changes over time.

Axial spondyloarthritis typically manifests in young adulthood, with symptom onset frequently occurring before the age of 45. The epidemiological studies indicate that the global prevalence of AS ranges between 0.5 to 1%, while nr-axSpA may be even more common when early, pre-radiographic cases are considered. Despite a significant genetic predisposition (notably a strong association with HLA-B27), axSpA remains challenging to diagnose due to the nonspecific nature of early symptoms such as inflammatory back pain, morning stiffness, and fatigue. The disease carries an enormous impact on an individual’s physical function, work productivity, and overall quality of life, underscoring the need for improved diagnosis, treatment algorithms, and ultimately, a reduction in long-term healthcare burden.

Clinical trials in axSpA serve as a critical bridge between our scientific understanding of disease mechanisms and the translation of these insights into effective therapies. In recent years, the landscape of clinical research in axSpA has expanded considerably with the advent of novel therapeutic targets.

Clinical trials in axSpA are conducted in several phases to systematically evaluate safety, efficacy, optimal dosing, and long-term outcomes. Early phase trials (Phase I and II) focus on safety and preliminary effectiveness, often using surrogate endpoints such as improvements in biomarkers (e.g., C-reactive protein levels) and imaging inflammation on MRI. Phase III trials, such as the SELECT-AXIS 2 study, are larger, randomized, placebo-controlled studies that confirm efficacy while further monitoring for adverse events and establishing a favorable risk–benefit profile in more diverse patient populations. Additionally, extension studies and real-world observational cohorts are increasingly performed to provide long-term data on drug retention rates, radiographic progression, and quality-of-life improvements.

Given the complexity of axSpA—including differences between nr-axSpA and AS—clinical trials are also utilizing refinements in inclusion criteria, such as MRI and CRP-elevated patients, in order to improve the homogeneity of study populations and the sensitivity to detect treatment effects. Adaptive and stratified trial designs are now incorporated to better mirror the heterogeneous nature of the disease and to facilitate personalized treatment strategies.

The insights derived from these clinical trials are essential not only for obtaining regulatory approval but also for guiding clinical decision-making. Successful phase III trials have led to the approval of TNF inhibitors, IL-17 inhibitors, and recently, JAK inhibitors for axSpA. For instance, the tofacitinib and upadacitinib trials have provided strong evidence supporting the efficacy of JAK inhibitors, which are particularly attractive because of their oral administration route and potential cost advantages. Moreover, clinical trials help resolve uncertainties created by heterogeneous patient responses—by utilizing treat-to-target strategies and incorporating robust patient-reported outcomes—and have begun to redefine standard care in axSpA. As such, these trials directly inform both clinical guidelines and future research agendas by identifying markers of treatment response and potential areas for further therapeutic innovation.

The current portfolio of clinical trials in axSpA reflects an era of expanding treatment options and a growing emphasis on early, targeted intervention. Several trials are actively exploring novel mechanisms of action and optimizing treatment strategies through personalized approaches.

One of the hallmark ongoing studies is the SELECT-AXIS 2 trial evaluating upadacitinib, a selective JAK1 inhibitor. Presented by AbbVie in a recent update, this Phase III trial enrolled patients with both non-radiographic axSpA and treatment-refractory ankylosing spondylitis who had an inadequate response to biologic DMARDs. Participants in this trial are being assessed for improvements in standard efficacy endpoints such as the Assessment of SpondyloArthritis International Society 40% (ASAS40) response criterion, reductions in pain, improved physical function and quality of life, and decreases in MRI-detected inflammation at key anatomical sites including the sacroiliac joints and spine.

Another notable ongoing trial is the S-OLARIS trial, which is a Phase II proof-of-concept study investigating the efficacy of sonelokimab, a dual IL-17A/F inhibitor. In this open-label study, approximately 25 patients with active axSpA receive sonelokimab at a dosage of 60 mg subcutaneously. A unique aspect of this trial is the combined use of positron emission tomography (PET) with MRI to evaluate changes in bone uptake of 18F-NaF in the sacroiliac joints and spine as a primary endpoint, thereby marrying innovative imaging modalities with traditional clinical assessments. Although primarily exploratory, the trial holds promise for establishing an imaging biomarker framework to monitor the therapeutic impact on both inflammation and structural changes.

Additional trials continue to investigate the rank efficacy among available agents. For example, comparative studies are underway that test TNF inhibitors such as adalimumab and certolizumab pegol in various subgroups (radiographic versus non-radiographic axSpA) with stratified assessments of radiographic progression and long-term retention rates. These trials not only affirm the clinical efficacy of these biologics but are also designed to capture critical data regarding their ability to halt structural damage over extended periods. Other studies exploring advanced biologics and small molecules continue to push the envelope on potential inflammatory mechanisms underlying axSpA, including targeting the IL-23/IL-17 axis and other intracellular signaling kinases beyond JAK1.

Some trials in early-phase development are also assessing the role of csDMARDs and non-pharmacologic interventions in combination with these novel therapies to evaluate NSAID and DMARD-sparing potential. These trials are particularly significant in resource-constrained settings where cost and accessibility remain important factors, such as in certain regions of India where generic formulations have dramatically reduced treatment expenses. By integrating treatment de-escalation protocols and real-world data, these studies aim to provide robust evidence on how early intervention with targeted therapies could modify the disease course altogether.

Recent interim results from the SELECT-AXIS 2 trial have demonstrated statistically significant improvements in the primary endpoint of ASAS40 response for both non-radiographic and radiographic cohorts at week 14, with rates approximately doubling compared to placebo. In addition, secondary endpoints—such as patient-reported assessments of back pain and functional improvement via the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS)—also showed meaningful improvements. These benefits were accompanied by notable reductions in MRI-detected inflammation, supporting the underlying biological rationale for JAK inhibition in axSpA.

Moreover, the S-OLARIS trial is emerging as a promising driver of future imaging techniques that may be applied in both clinical trials and routine practice. The incorporation of PET/MRI imaging to quantify the change in 18F-NaF uptake has provided investigators with a sensitive tool to monitor changes in bone turnover and inflammation simultaneously. Early trends from this trial indicate a reduction in PET signals correlating with clinical improvement, although full publications of these results are pending.

Other trials have reinforced the long-term benefit of established treatments. For example, four-year imaging outcomes from the RAPID-axSpA study with certolizumab pegol have reported sustained reductions in MRI inflammation and minimal radiographic progression in both AS and nr-axSpA patient groups. These findings lend credibility to the concept that early, effective control of inflammation can alter the trajectory of structural damage if maintained over extended periods. Similarly, observational studies evaluating adalimumab in non-radiographic axSpA have reported high percentages of patients achieving significant reductions in disease activity scores, which in turn were predictive of lower rates of radiographic damage over two years.

Parallel to these larger scale trials, several small-scale and adaptive trials investigating novel therapeutic targets (such as GM-CSF inhibitors and dual IL-17 inhibitors like bimekizumab) have shown promising early-phase results. For instance, preliminary data from Phase II studies of bimekizumab have underscored rapid improvement in clinical symptoms while demonstrating a sound safety profile over 52 weeks, expanding the potential therapeutic armamentarium for axSpA. Collectively, these findings emphasize that the clinical trial landscape in axSpA is robust, diverse, and increasingly oriented toward precision medicine and treat-to-target strategies.

The ongoing clinical trials in axial spondyloarthritis are not only generating compelling evidence regarding the efficacy and safety of emerging treatments but also laying the groundwork for a more personalized approach to disease management in routine clinical practice.

The latest clinical trial updates suggest that targeted therapies—in particular, JAK inhibitors and novel agents like sonelokimab—could substantially modify current treatment guidelines. An increased emphasis on early intervention, real-time imaging assessments, and patient-centered outcome measures are all poised to transform how clinicians approach axSpA management. For instance, with the demonstrated efficacy of upadacitinib in the SELECT-AXIS 2 trial, clinicians now have an effective oral therapeutic option that may be especially appealing for patients who are reluctant to use injectable biologics. This could lead to higher rates of treatment adherence and overall improved long‐term outcomes.

Beyond drug-specific benefits, the treat-to-target model is becoming increasingly central to clinical trial designs and is expected to drive everyday practice. The concept of regularly monitoring disease activity using validated composite indices—such as the ASDAS—and swiftly modifying treatment regimens if targets are not met has already shown promise in rheumatoid arthritis and is now being adapted for axSpA. This strategy is further supported by trials that demonstrate a correlation between early control of inflammation and reduced radiographic progression, suggesting that timely, effective treatment may not only improve symptoms but also alter the natural history of the disease. As clinical trials continue to capture multi-dimensional data (including imaging, patient-reported outcomes, and biomarkers), the potential for tailoring therapies to individual patient profiles will dramatically increase.

Looking forward, several key areas warrant further exploration. One major research direction is the refinement of diagnostic algorithms by incorporating advanced imaging modalities and novel serum biomarkers. Ongoing trials like the S-OLARIS trial are exploring the integration of PET with MRI to gauge bone metabolism and inflammation in a highly sensitive manner, which may offer earlier and more precise detection of treatment effects. Concurrently, studies focused on identifying reliable, targeted serum biomarkers—such as those emerging from genetic and proteomic research—could enhance early diagnosis, facilitate risk stratification, and predict treatment response.

Another future research trajectory involves direct head-to-head studies comparing established biologics to newer agents such as JAK inhibitors, not only in terms of efficacy but also with respect to safety, cost-effectiveness, and patient preference. Trials that incorporate longer-term endpoints, including the prevention of structural damage and improvement in quality of life, will be essential in validating the long-term benefits of these therapies. In regions where access to treatments is limited by cost, studies assessing generic formulations and their NSAID or DMARD-sparing capabilities will be particularly valuable, as they could inform resource allocation and guideline adaptations in healthcare systems with constrained budgets.

Furthermore, adaptive trial designs that stratify patients based on genetic predisposition, imaging findings, and baseline inflammatory markers are on the horizon. These precision medicine approaches will enable researchers to customize interventions for specific subpopulations within axSpA, thereby improving overall response rates and optimizing safety profiles. In parallel, real-world observational studies and registries will continue to play a vital role in validating and extending the findings from randomized controlled trials. Their insights into long-term drug retention rates, real-world safety, and functional improvements could help bridge the gap between controlled clinical trial environments and everyday clinical practice.

Lastly, interdisciplinary collaboration is becoming increasingly important. Integrating expert input from rheumatologists, radiologists, immunologists, and health economists is critical to fully understand the multifaceted nature of axSpA. The development of international guidelines based on multi-regional and multi-center trial data will further ensure that emerging therapies are appropriately contextualized within diverse healthcare systems and patient populations. The integration of patient-reported outcomes and preferences—as highlighted in conjoint analysis surveys—also underscores the need for shared decision-making tools that bring evidence-based medicine closer to the patient’s day-to-day experience.

In summary, the latest updates on ongoing clinical trials in axial spondyloarthritis are highly promising and reflect an era of innovation and personalized medicine. The current clinical trial portfolio includes landmark studies such as the SELECT-AXIS 2 trial of upadacitinib, which has demonstrated significant improvements in both non-radiographic and radiographic axSpA with an attractive oral formulation and favorable safety profile. Meanwhile, novel imaging-driven studies such as the S-OLARIS trial are exploring dual (PET/MRI) endpoints that will refine how efficacy and structural improvements are measured. Complementary trials assessing long-term outcomes with established treatments like certolizumab pegol and adalimumab are reinforcing the principle that early and sustained control of inflammation can lead to reduced structural damage and improved patient-reported outcomes over extended durations.

From a broader perspective, these studies collectively underscore the importance of integrating advanced imaging techniques, novel biomarkers, and adaptive trial designs into research and clinical practice. They also highlight the potential of a treat-to-target paradigm in influencing treatment strategies—ensuring that patients receive timely and effective interventions tailored to their unique disease profiles. Looking to the future, ongoing research is poised to further optimize therapeutic outcomes by comparing the efficacy of emerging drugs, refining early diagnostic criteria, and embracing precision medicine approaches. Ultimately, the hope is that these comprehensive efforts will not only alleviate symptoms but also modify the disease course, thereby significantly reducing the long-term burden of axSpA on patients and healthcare systems worldwide.

In conclusion, the current clinical trial landscape in axial spondyloarthritis signifies a robust and multifaceted effort to improve patient outcomes through innovative therapies and early intervention. The convergence of improved trial methodologies, advanced imaging, and a more personalized approach to treatment heralds a future in which the management of axSpA is not only more effective but also more aligned with the needs and preferences of individual patients. Continued investment in both large-scale randomized trials and real-world observational studies will be essential to sustain this momentum, ensuring that the rapid pace of innovation translates into tangible benefits in routine clinical practice.