Biologic and targeted synthetic therapies in ankylosing spondylitis: a pharmacological review

Ankylosing spondylitis (AS) is a prototypical axial spondyloarthritis (axSpA) defined by chronic inflammatory back pain, progressive spinal stiffness, and frequent extra-articular manifestations such as acute anterior uveitis (21%-33%), inflammatory bowel disease (5%-10%), and psoriasis (4%-13%). Management has shifted from non-steroidal anti-inflammatory drugs (NSAIDs) to highly targeted biologic and synthetic disease-modifying antirheumatic drugs (DMARDs). This comprehensive review focuses on the current evidence for biologic and targeted synthetic therapeutics in the management of AS, emphasizing mechanisms of action, regulatory approvals, dosing regimens, and clinical efficacy. Three major therapeutic classes are identified: two biologic DMARD classes, comprising tumor necrosis factor-alpha (TNF-α) inhibitors and interleukin-17 (IL-17) inhibitors, and the targeted synthetic DMARDs, namely, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors. TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, certolizumab pegol) typically achieve Assessment of Spondyloarthritis International Society 40% improvement (ASAS40) rates of 40%-58% at 12-24 weeks versus 13%-24% with placebo, and maintain clinical benefit in many patients over 5-8 years. IL-17 inhibitors (secukinumab, ixekizumab, bimekizumab, brodalumab, netakimab) yield broadly similar ASAS40 responses (30%-50% versus 10%-20% placebo) and are particularly useful in patients with concomitant psoriasis with substantially reduced risk of tuberculosis reactivation. JAK inhibitors (tofacitinib, upadacitinib) represent the newest class, offering oral administration with ASAS40 responses of 40%-52% versus 13%-26% for placebo in both biologic-naïve and biologic-experienced AS, though cardiovascular safety considerations necessitate careful patient selection. Therapeutic selection should consider comorbidities (uveitis favors TNF monoclonal antibodies; psoriasis favors IL-17 inhibitors), safety profile, route of administration, and sequencing after non-steroidal anti-inflammatory drug failure. Understanding these pharmacological distinctions enables personalized therapeutic decisions based on the specific molecular pathology and risk profile of the individual patient.