Recent Pharmacological Advancement in The Management of Ankylosing Spondylitis

 

Dr.Vivek Kumar Tiwari, Dr. Shameem Ahmad Khan*, Dr.Anuj Rastogi, Dr Sabeel Ahamd

 

Junior Resident, Department of Orthopaedic, Integral Institute of Medical Sciences and Research, Integral University, Lucknow, Uttar Pradesh, India

Professor and Head, Department of Orthopaedic, Integral Institute of Medical Sciences and Research, Integral University, Lucknow, Uttar Pradesh, India

Professor, Department of Orthopaedic, Department of Orthopaedic, Integral Institute of Medical Sciences and Research, Integral University, Lucknow, Uttar Pradesh, India

Assistant professor , Department of Orthopaedics, Integral Institute of Medical Sciences And Research, Integral University, Lucknow, Uttar Pradesh, India.

 

Corresponding Author: Dr Shameem Ahmad Khan*

Email ID:  shameem@iul.ac.in

 

ABSTRACT

Background: Over the last decade the therapeutic landscape for ankylosingspondylitis (AS; radiographic axial spondyloarthritis) has expanded beyond NSAIDs and tumour-necrosis factor inhibitors (TNFi) to include IL-17 inhibitors, dual IL-17A/F blockade, and Janus kinase (JAK) inhibitors. This review synthesizes randomized trials, long-term extension data, guideline updates, and comparative effectiveness analyses published in the last ~10 years to summarize efficacy, safety, and practical treatment sequencing for AS.

Methods: We performed a structured literature search of PubMed/NCBI (2015–2025), clinicaltrials.gov and major rheumatology conference proceedings for RCTs, meta-analyses, and guideline documents addressing pharmacologic treatments for AS. Data were extracted for trial design, population, efficacy outcomes (ASAS20/40, BASDAI change, ASDAS, MRI inflammation), radiographic progression, and safety events.

Results: NSAIDs remain first-line for symptomatic control; however, substantial proportions of patients require escalation. TNFi agents have robust RCT and long-term data demonstrating symptom control, improved function, and MRI improvement. IL-17A inhibitors (secukinumab, ixekizumab) demonstrated substantial ASAS responses in phase-3 trials and are guideline-endorsed alternatives. Dual IL-17A/F blockade with bimekizumab produced strong phase-3 responses in BE-MOBILE1/2 and 52-week analyses, expanding options. JAK inhibitors (upadacitinib, tofacitinib) produce clinically meaningful improvements and provide an oral targeted option; long-term safety monitoring focuses on infection and thromboembolic risks. Comparative network meta-analyses suggest TNF monoclonal antibodies and IL-17A/F agents among the most efficacious, with nuanced differences by extra-articular disease (IBD/uveitis) and adverse-event profiles. Evidence on structural (radiographic) modification is emerging; some data suggest reduced radiographic progression with early and sustained control but definitive disease-modifying claims remain cautious.

Conclusions: The last decade brought multiple high-quality RCTs and approvals, enlarging the personalized treatment armamentarium for AS. Choice of agent should consider axial efficacy, extra-articular disease, safety profile, patient preference, and cost/access. Future priorities include head-to-head comparative trials, biomarkers for precision selection, longer radiographic outcome trials, and optimal sequencing/de-escalation strategies

KEYWORDS: AnkylosingSpondylitis,  TNF Inhibitors,  IL-17A Inhibitors,  JAK Inhibitors, Disease Modification.

How to Cite: Dr.Vivek Kumar Tiwari, Dr. Shameem Ahmad Khan, Dr.Anuj Rastogi, Dr Sabeel Ahamd, (2026) Recent Pharmacological Advancement In The Management Of Ankylosing Spondylitis, European Journal of Clinical Pharmacy, Vol.8, No.1, pp. 2368-2374

INTRODUCTION

Ankylosingspondylitis (AS) is the archetypal radiographic axial spondyloarthritis (axSpA) characterized by chronic inflammatory back pain, sacroiliitis, and progressive spinal structural change that can lead to ankylosis and functional impairment. Management goals are to control pain and inflammation, preserve physical function and quality of life, prevent or limit structural progression where possible, and treat extra-articular manifestations such as uveitis, inflammatory bowel disease (IBD), and psoriasis [1–3]. Over the past decade, the pharmacologic landscape for AS evolved rapidly: while non-steroidal anti-inflammatory drugs (NSAIDs) remain first-line for symptomatic control, the advent and maturation of biologic disease-modifying antirheumatic drugs (bDMARDs) such as TNF inhibitors (TNFi) and IL-17 inhibitors, and the recent introduction of targeted synthetic DMARDs (tsDMARDs; JAK inhibitors), have expanded therapeutic options and complicated decision-making for clinicians [1,4–7].

 

Guideline recommendations have been updated to reflect these changes; the ASAS-EULAR 2022 guidance provides practical escalation criteria (persistent activity despite optimized NSAIDs and non-pharmacological measures → biologic/targeted therapy) and emphasizes individualized choice based on extra-articular disease and comorbidity [1,8]. TNFi agents (infliximab, etanercept, adalimumab, certolizumabpegol, golimumab) remain a well-established class with robust randomized controlled trial (RCT) and long-term extension evidence for axial symptom control, function, and MRI inflammation reduction [9–11]. Over the last decade IL-17A inhibitors (secukinumab, ixekizumab) demonstrated efficacy in phase-3 programs and are accepted alternatives to TNFi, particularly in TNFi-intolerant or non-responsive patients [12–15]. More recently, IL-17A/F dual blockade (bimekizumab) produced highly encouraging phase-3 results, broadening therapeutic options [16,17]. Parallel development of oral JAK inhibitors (upadacitinib, tofacitinib) offers effective non-injectable options with meaningful clinical responses in RCTs, but long-term regulatory guidance reflects vigilance regarding safety signals (infections, thromboembolic risk) reported in broader JAK inhibitor programs [18–20].

 

Comparative effectiveness work including network meta-analyses and indirect comparisons suggests broadly similar efficacy across major biologic classes for axial outcomes, with TNF monoclonal antibodies and IL-17A/F agents often ranking high for efficacy while safety and extra-articular efficacy (particularly IBD/uveitis) modulate choice [21–23]. Structural (radiographic) modification as an outcome remains challenging: radiographic progression in AS is slow, requiring long observation, and evidence that biologics alter long-term structural outcomes is evolving and not conclusively established for all classes [24–26]. Safety remains a central concern in selection: infection risk (including TB), candidiasis with IL-17 pathway blockade, and cardiovascular/thrombotic signals with JAK inhibitors require individualized assessment [10,16,18,27].

 

This review synthesizes RCTs, long-term extensions and pooled analyses, guideline updates, and comparative studies published over the last ~10 years (2015–2025), focusing on efficacy (ASAS20/40, BASDAI, ASDAS, MRI), radiographic progression, safety, treatment sequencing, and future directions.

 

The aim was to provide a comprehensive, evidence-based synthesis to inform clinicians, guideline developers, and researchers. Key questions include: (1) What is the comparative efficacy of current pharmacologic options for AS? (2) How do safety profiles differ and how should they guide agent selection? (3) What evidence exists for structural modification? and (4) What are the critical knowledge gaps and research priorities for the next decade?

 

MATERIAL & METHODS

Search strategy

A structured search of PubMed/Medline (via NCBI), ClinicalTrials.gov, and major journal sites (Annals of the Rheumatic Diseases, Arthritis & Rheumatology, Rheumatology (Oxford), The Lancet Rheumatology) was performed for the period of 10 years Search terms included combinations of: “ankylosingspondylitis”, “axial spondyloarthritis”, “axSpA”, “TNF inhibitor”, “secukinumab”, “ixekizumab”, “bimekizumab”, “interleukin-17”, “JAK inhibitor”, “upadacitinib”, “tofacitinib”, “randomized controlled trial”, “phase 2”, “phase 3”, “long-term extension”, “radiographic progression”, “ASAS20”, “ASAS40”, “BASDAI”, “ASDAS”, “safety”, “infection”, “tuberculosis”, and “candidiasis”.

 

Search filters: randomized controlled trials, phase-2/3 trials, clinical trials, systematic reviews, meta-analyses, guidelines, and observational long-term extension studies. Reference lists of identified key reviews/guidelines (ASAS-EULAR 2022) and major RCTs were manually screened for additional eligible studies. Where necessary, conference abstracts (EULAR/ACR) and regulatory press releases were consulted to capture the most recent approval/long-term data (e.g., BE-MOBILE extensions). Key load-bearing guideline and RCT sources are cited inline.

 

 Inclusion and exclusion criteria

Inclusion: adult patients with radiographic axial spondyloarthritis (AS) or axSpA; randomized, placebo-controlled (or active-comparator) phase-2/3 trials; long-term extension studies reporting clinical or radiographic outcomes; meta-analyses and guideline documents. Observational safety registries and pharmacovigilance reports were included for safety synthesis.

 

Exclusion: pediatric studies, case reports, non-systematic narrative reviews not adding trial data.

 

Data extraction and synthesis

From each eligible trial, we extracted study design, sample size, patient characteristics (bDMARD-naïve vsTNFi-experienced), intervention and comparator, primary and key secondary efficacy endpoints (ASAS20/40, BASDAI, ASDAS, MRI SPARCC scores), duration, radiographic outcomes where available (mSASSS or similar), and major safety signals (serious adverse events, infections, TB, Candida, thromboembolism). Trials were narratively synthesized and grouped by drug class (TNFi, IL-17A, IL-17A/F, JAKi). Network meta-analyses and systematic reviews were used to contextualize comparative effectiveness.

 

RESULTS

NSAIDs and first-line management

NSAIDs remain first-line symptomatic therapy for axial symptoms and stiffness; they provide meaningful symptom reduction in many patients and are recommended as initial therapy before escalation to biologics unless other indications exist [8,16]. Continuous NSAID use may modestly affect radiographic progression in selected patients in some studies, but evidence is conflicting and must be balanced against cardiovascular, renal, and GI risks.

 

TNF inhibitors (class overview and long-term data)

TNF inhibitors were the first bDMARDs to demonstrate convincing benefit for AS. Multiple RCTs and meta-analyses show TNFi agents (infliximab, etanercept, adalimumab, certolizumabpegol, golimumab) produce rapid clinical improvement (ASAS20/40), improved function, and reduction in MRI inflammation [9,14,15,21]. Long-term registry data and extension studies show sustained symptom control, but rates of radiographic progression vary and depend on baseline risk factors and imaging follow-up duration. Safety: TB reactivation risk (necessitates screening), infections, and injection/infusion reactions. Biosimilars have maintained efficacy and improved access.

 

IL-17A inhibitors — Secukinumab&Ixekizumab

 

Secukinumab: The MEASURE trials (MEASURE 1–4) demonstrated significant improvements in ASAS responses and sustained benefit through 52 weeks with an acceptable safety profile; pooled analyses and real-world studies support these findings. Secukinumab is effective in both bDMARD-naïve and TNFi-experienced patients.

 

Ixekizumab: The COAST program (COAST-V, COAST-W etc.) showed ixekizumab produced statistically significant improvements versus placebo with durable benefits to 52 weeks in both TNFi-naïve and TNFi-experienced patients. Safety profile is consistent with IL-17A blockade (mucocutaneouscandidiasis increased modestly).

 

IL-17A/F dual blockade — Bimekizumab (recent evidence)

Bimekizumab, an IL-17A and IL-17F neutralizing monoclonal antibody, demonstrated strong efficacy in the BE-MOBILE phase-3 program (parallel BE-MOBILE1 and BE-MOBILE2 trials) with significant ASAS outcomes and MRI improvements; 52-week pooled analyses showed sustained efficacy and an expected increased rate of mucocutaneouscandidiasis compared with IL-17A selective agents. Regulatory approvals for axial spondyloarthritis indications were announced recently (2023–2024), and longer safety and head-to-head data are accruing.

 

JAK inhibitors (upadacitinib, tofacitinib and related)

 

Upadacitinib: SELECT-AXIS trials (nr-axSpA and AS) demonstrated clinically meaningful improvements in ASAS and ASDAS endpoints. Longer follow-up analyses (up to 2 years in some extension cohorts) report durable responses and low radiographic progression in some cohorts. Safety concerns follow the JAK inhibitor class profile: infections, herpes zoster risk, and the broader class-level regulatory attention to thromboembolic and cardiovascular events — patient selection is important.

 

Tofacitinib: Phase-3 trials indicated efficacy vs placebo for AS symptoms with acceptable short-term safety; however, class-wide safety monitoring remains necessary.

 

Comparative effectiveness and network meta-analysis summaries

Network meta-analyses (NMAs) summarizing multiple biologic and tsDMARD options suggest TNF monoclonal antibodies and some IL-17/IL-17A-F agents rank high for axial efficacy; IL-17A/F agents may present an improved trade-off between efficacy and safety for some outcomes, though NMAs are limited by between-trial heterogeneity and differences in patient populations (bDMARD-naïve vs experienced). Direct head-to-head trials remain scarce; where available, they are valuable to inform sequencing.

 

Radiographic progression (structural outcomes)

Radiographic progression (mSASSS) is slow and requires long follow-up; some long-term TNFi registry data suggest slower progression in patients treated earlier and continuously, but randomized evidence proving disease-modification for structural outcomes remains limited and inconsistent across studies. Recent upadacitinib and bimekizumab extension analyses report low rates of progression over 2 years in treated cohorts, but longer and comparative radiographic trials are needed.

 

Safety synthesis

Infections & TB:TNFi and JAKi increase infection risk; TNFi require latent TB screening and monitoring. JAK inhibitors add herpes zoster risk.

· Candidiasis: IL-17A blockade modestly increases mucocutaneouscandidiasis; dual IL-17A/F blockade shows higher candidiasis rates compared with IL-17A selective inhibitors.

· Cardiovascular / thrombotic risk: Regulatory concerns for JAK inhibitors (class signals) require individualized risk assessments.

· Extra-articular disease impact:TNFi monoclonal antibodies are preferred when active IBD coexists; IL-17 blockade may be neutral or detrimental in IBD, hence careful choice is required in patients with IBD’

 

Summary of principal findings

Over the past decade the evidence base for pharmacologic treatment of ankylosingspondylitis (AS) has matured substantially. Randomized controlled trials (RCTs), long-term extension cohorts, network meta-analyses and guideline updates confirm three practical points: (1) NSAIDs remain first-line symptomatic therapy but many patients require escalation; (2) TNF inhibitors (TNFi) are well-established and effective for axial disease with long-term data supporting sustained symptomatic and MRI benefit; and (3) newer targeted agents — IL-17A inhibitors (secukinumab, ixekizumab), dual IL-17A/F blockade (bimekizumab), and JAK inhibitors (upadacitinib, tofacitinib) — provide alternative or subsequent lines of therapy with comparable axial efficacy in RCTs but differing safety and extra-articular effect profiles [1–11,14–18]. Network meta-analyses generally rank TNF monoclonal antibodies and IL-17/IL-17A-F agents among the most efficacious for axial endpoints, while highlighting the limits of indirect comparisons [15,21].

 

DISCUSSION

This expanded discussion synthesizes the last decade of evidence (2015–2025) and places findings into clinical, mechanistic, and research contexts. It is organized into topical subsections so you can pull relevant paragraphs for a manuscript discussion section or use the whole text as a standalone in-depth interpretation.

 

Summary of principal findings

Over the past decade the evidence base for pharmacologic treatment of ankylosingspondylitis (AS) has matured substantially. Randomized controlled trials (RCTs), long-term extension cohorts, network meta-analyses and guideline updates confirm three practical points: (1) NSAIDs remain first-line symptomatic therapy but many patients require escalation; (2) TNF inhibitors (TNFi) are well-established and effective for axial disease with long-term data supporting sustained symptomatic and MRI benefit; and (3) newer targeted agents — IL-17A inhibitors (secukinumab, ixekizumab), dual IL-17A/F blockade (bimekizumab), and JAK inhibitors (upadacitinib, tofacitinib) — provide alternative or subsequent lines of therapy with comparable axial efficacy in RCTs but differing safety and extra-articular effect profiles [1–11,14–18]. Network meta-analyses generally rank TNF monoclonal antibodies and IL-17/IL-17A-F agents among the most efficacious for axial endpoints, while highlighting the limits of indirect comparisons [15,21].

 

Mechanistic interpretation and why different classes matter

AS pathophysiology is driven by innate and adaptive immune activation at entheses and the sacroiliac joints, with a prominent role for TNF and IL-17 pathway signalling as drivers of inflammation and tissue damage.TNFi broadly neutralize TNF-α and reduce downstream inflammatory cascades; IL-17A inhibitors target a central effector cytokine produced by Th17 and innate lymphoid cells implicated in entheseal inflammation. Bimekizumab’s dual neutralization of IL-17A and IL-17F appears to deepen cytokine suppression and may account for the robust ASAS and MRI responses observed in phase-3 programs [8,16–17]. JAK inhibitors block intracellular signalling for multiple cytokine families (including those relevant to Th17 differentiation and type I/II interferons), providing a mechanistically distinct, oral route to modulate the inflammatory milieu [10,18]. These mechanistic differences explain both the overlapping clinical efficacy (because multiple cytokines drive common inflammatory pathways) and class-specific safety/extra-articular patterns (e.g., IL-17 blockade and candidiasis; TNFi and IBD efficacy; JAKi and viral reactivation/thrombotic concerns).

 

Comparative efficacy — what the data say and their limits

Pivotal RCTs for TNFi, IL-17A inhibitors, bimekizumab, and JAK inhibitors consistently report clinically meaningful improvements in ASAS20/40, BASDAI and ASDAS scores compared with placebo. Network meta-analyses suggest modest ranking differences but generally show several agents deliver high response rates. Important caveats:

· Heterogeneous trial populations: Trials differ in proportions of bDMARD-naïve versus TNFi-experienced patients, baseline ASDAS/BASDAI severity, and concomitant csDMARD use. These differences bias indirect comparisons.

· Endpoints and timing: Primary endpoints (ASAS20/40) capture short-term symptomatic changes; MRI outcomes provide objective inflammation measures but do not directly equate to long-term structural change.

· Power for rare outcomes and head-to-head data: Most comparative assessments rely on indirect (network) methods; few large head-to-head RCTs exist to definitively rank agents on efficacy and safety.

Thus, although several agents can be considered similarly efficacious for axial symptoms, clinical choice should be personalized using extra-articular disease, comorbidities, route preferences, access/cost and risk profiles [15,21–23].

 

Structural outcomes — does suppressing inflammation prevent progression?

Preventing radiographic progression (ankylosis) is a central, unresolved question. Key points:

· Time scale and sensitivity: Radiographic progression measured by mSASSS is slow and requires multi-year follow-up; small changes over 1–2 years may not reflect longer trends.

· Observational signals: Registry and long-term observational data suggest earlier and continuous control of inflammation (often with TNFi) may slow progression in some patients, especially those with high baseline inflammation and risk factors for progression.

· RCT evidence limited: Randomized trials with radiographic endpoints and sufficient duration are rare. Recent extension data for newer agents (e.g., upadacitinib, bimekizumab) show low short-term progression but are insufficient to establish disease modification conclusively.

· Mechanistic plausibility but complex biology: Inflammation reduction plausibly limits osteoproliferation through modulation of the inflammatory microenvironment, yet osteoproliferation in AS may proceed by partly independent mechanisms involving bone morphogenetic pathways—hence inflammation control alone may not completely prevent new bone formation.

In pragmatic terms, available evidence supports early effective suppression of inflammation to likely reduce (but not guarantee prevention of) structural progression; definitive disease-modifying claims require longer and comparative radiographic trials [24–26].

 

Safety trade-offs and how they should shape practice

Treatment choice must weigh efficacy against class-specific harms:

· Infections and TB screening:TNFi and JAK inhibitors increase infection risk; TNFi importantly require TB screening and prophylaxis where indicated. JAKi carry heightened herpes zoster risk.

· Candidiasis with IL-17 blockade: IL-17 pathway inhibition increases mucocutaneous Candida infections; dual IL-17A/F blockade increases this risk further. Most events are mild–moderate and manageable, but clinicians must counsel patients and treat promptly.

· Cardiovascular/thromboembolic signals with JAKi: Regulatory caution (and labeling) reflects signals observed in broader RA populations; individual cardiovascular risk assessment is essential before initiation.

· Extra-articular disease considerations: When active IBD coexists, certain TNFi (infliximab, adalimumab) are preferred; IL-17 inhibitors may worsen or be neutral for IBD activity and should be used cautiously where IBD is active or suspected.

These safety differences make individualized, shared decision-making essential (vaccination optimization, latent infection screening, baseline risk assessments, and ongoing monitoring) [10,16–18].

 

Sequencing, switching, and therapeutic strategies

Practical sequencing algorithms that emerge from evidence and clinical pragmatism include:

1. First escalation: For NSAID-refractory active disease, a TNFi or IL-17 inhibitor is reasonable first biologic, with TNFi favored in the context of active IBD.

2. After TNFi failure: Switching mechanism (IL-17A/F or JAKi) is supported by trials showing efficacy in TNFi-experienced populations; switching within class is also an option when immunogenicity/drug levels suggest inadequate exposure.

3. Tapering/de-escalation: Data to guide safe tapering are sparse; de-escalation may be considered in sustained remission with careful monitoring and rapid re-escalation plans.

4. Combination therapy: Routine combination biologic therapy is not recommended due to safety concerns; combinations with csDMARDs have limited axial benefit but may be considered for peripheral disease in select patients.

These approaches must be tempered by local access, cost, and patient preferences. Therapeutic drug monitoring for TNFi (trough levels/antibodies) can help differentiate pharmacokinetic failure from pharmacodynamic non-response.

 

Biomarkers and precision medicine — promise and current reality

Predictive biomarkers to guide agent selection are an active research area but currently limited in clinical utility. Candidate approaches include:

· Clinical phenotyping (presence of IBD, uveitis, psoriasis) to direct agent selection.

· Imaging biomarkers (MRI inflammation burden, fat metaplasia patterns) that may predict progression and treatment response.

· Molecular signatures (gene expression, cytokine profiles) and microbiome studies show promise but lack validation for routine clinical use.

Until validated biomarkers are available, a pragmatic phenotype-guided strategy combining clinical features, comorbidity assessment, and patient values remains standard.

 

Health systems, access and cost considerations

The arrival of biosimilars and multiple agents increases options but also complicates equitable access. Cost, reimbursement policies, and availability shape real-world utilization and can drive suboptimal sequencing (e.g., prolonged ineffective NSAID use while awaiting access). Policy and health-economics research should accompany clinical research to ensure that evidence-based agents are accessible in diverse settings.

 

CONCLUSION

In the last decade, pharmacologic management of AS expanded considerably — TNFi remain an evidence-backbone, IL-17A inhibitors and IL-17A/F (bimekizumab) broaden therapeutic choice, and JAK inhibitors provide effective oral targeted therapy. Agent selection requires nuanced integration of axial efficacy, extra-articular disease, safety profile, patient values, and access. Critical evidence gaps remain in head-to-head comparisons, long-term radiographic disease modification, predictive biomarkers, and optimal sequencing and de-escalation strategies. Focused comparative trials and biomarker research are priorities to move toward precision medicine in AS.

 

Limitations of this review

1. This review is narrative and not a formal systematic review with meta-analysis; although a comprehensive structured search strategy (PubMed/NCBI 2015–2025) was used, the review did not include formal risk-of-bias scoring or pooled quantitative estimates.

2. Rapidly evolving literature (ongoing trial extensions, conference abstracts, regulatory updates) means some late-breaking data published after the search cut-off (15 Feb 2025) may not be captured.

3. Heterogeneity across trial populations (bDMARD-naïve vsTNFi-experienced), outcome definitions and durations complicate direct comparisons and necessitate cautious interpretation of network meta-analyses.

4. Radiographic progression data are limited by short follow-up intervals relative to disease natural history.

 

Practical takeaways for clinicians

1. Start with NSAIDs and non-pharmacologic care; escalate to biologic/targeted therapy if disease activity remains high.

2. TNFi remain broadly effective; choose agents with consideration for comorbid IBD/uveitis.

3. IL-17A inhibitors (secukinumab, ixekizumab) are effective alternatives; bimekizumab (IL-17A/F) offers a potent new option with higher candidiasis risk.

4. JAK inhibitors provide an oral targeted option; assess cardiovascular/thrombotic risk prior to initiation.

5. Monitor for infections, update vaccinations, screen for latent TB/hepatitis, and educate patients regarding infection symptoms.

 

Acknowledgements

I express my sincere gratitude to my guide and co-guide for their support. I also extend my appreciation to my co-authors for their valuable contribution towards the successful completion of this review. Manuscript Communication Number: ID- IU/R&D/2026-MCN0004363

 

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