What are the disease-modifying antirheumatic drugs (DMARDs) of choice for a patient with ankylosing spondylitis?

DMARDs of Choice for Ankylosing Spondylitis

Conventional synthetic DMARDs (sulfasalazine, methotrexate, leflunomide) have NO proven efficacy for axial disease in ankylosing spondylitis and should NOT be used for this indication. 1 The only effective disease-modifying agents for axial AS are biologic DMARDs—specifically TNF inhibitors and IL-17 inhibitors. 1

First-Line Treatment: NSAIDs Before Any DMARD

• NSAIDs are the mandatory first-line pharmacological treatment for AS patients with pain and stiffness. 1
• Continuous NSAID treatment is preferred over on-demand dosing for patients with persistently active symptomatic disease. 1
• Only after NSAIDs fail or are contraindicated should biologic DMARDs be considered. 1

Biologic DMARDs: The Only Effective "DMARDs" for Axial Disease

TNF Inhibitors (First Choice for Biologics)

For patients with persistently high disease activity despite NSAIDs, TNF inhibitors are strongly recommended as the biologic DMARD of choice. 1

Approved TNF inhibitors include:

• Adalimumab 1
• Etanercept 1
• Infliximab 1
• Golimumab 1
• Certolizumab pegol 1

Critical selection consideration: All TNF inhibitors have equivalent efficacy for axial and peripheral musculoskeletal manifestations, so there is no preferred agent based on AS symptoms alone. 1 However, if the patient has concomitant inflammatory bowel disease (IBD), TNF monoclonal antibodies (infliximab, adalimumab, golimumab, certolizumab) are strongly preferred over etanercept, as they have proven gastrointestinal efficacy. 1

IL-17 Inhibitors (Alternative First-Line Biologic)

IL-17 inhibitors (secukinumab and ixekizumab) are equally valid first-line biologic options alongside TNF inhibitors. 1, 2

• The 2023 PANLAR guidelines make no distinction in prioritization between TNF inhibitors and IL-17 inhibitors for initial biologic therapy. 1
• Ixekizumab is FDA-approved at 160 mg at Week 0, followed by 80 mg every 4 weeks for ankylosing spondylitis. 2
• Secukinumab is also approved for AS treatment. 1

JAK Inhibitors (Reserve for When Biologics Contraindicated)

JAK inhibitors (tofacitinib, upadacitinib) should be reserved for situations where TNF inhibitors and IL-17 inhibitors are contraindicated or unavailable. 1

• This recommendation is based on the longer track record and more extensive observational data for TNF/IL-17 inhibitors compared to JAK inhibitors. 1
• In patients ≥65 years with cardiovascular risk factors, smoking history, or malignancy risk, JAK inhibitors should only be used if no suitable alternatives exist due to increased cardiovascular and malignancy risks observed in rheumatoid arthritis populations. 1

What About Conventional Synthetic DMARDs?

For Axial Disease: NO ROLE

There is absolutely no evidence supporting the use of sulfasalazine, methotrexate, or any other conventional DMARD for treating axial manifestations of AS. 1

• Multiple guidelines explicitly state that DMARDs including sulfasalazine and methotrexate are ineffective for axial disease. 1
• There is no evidence to support obligatory use of conventional DMARDs before initiating TNF inhibitors for axial disease. 1
• Co-treatment with low-dose methotrexate alongside TNF inhibitors is conditionally recommended AGAINST in AS (unlike in rheumatoid arthritis). 1

For Peripheral Arthritis: Limited Role for Sulfasalazine Only

Sulfasalazine may be considered ONLY in AS patients with active peripheral arthritis, not for axial symptoms. 1

• This is the sole indication where a conventional synthetic DMARD has any role in AS management. 1
• Methotrexate has no proven benefit even for peripheral arthritis in AS. 1

Treatment Algorithm for Active AS

1. Start with continuous NSAIDs for pain and stiffness 1
2. If persistently high disease activity despite NSAIDs: Initiate biologic DMARD 1
   • Choose TNF inhibitor OR IL-17 inhibitor as first-line biologic 1
   • If concomitant IBD: Use TNF monoclonal antibody (not etanercept) 1
   • If biologics contraindicated/unavailable: Consider JAK inhibitor 1
3. If primary non-response to first TNF inhibitor (no improvement at 3-6 months): Switch to secukinumab or ixekizumab over switching to another TNF inhibitor 1
4. If secondary non-response to first TNF inhibitor (loss of response after initial benefit): Switch to a different TNF inhibitor over switching to non-TNF biologic 1

Common Pitfalls to Avoid

• Do NOT prescribe methotrexate or sulfasalazine for axial symptoms—this is ineffective and delays appropriate biologic therapy. 1
• Do NOT require a trial of conventional DMARDs before biologics—guidelines explicitly state this is not evidence-based for axial disease. 1
• Do NOT add methotrexate to TNF inhibitors in AS—unlike RA, combination therapy is not recommended. 1
• Do NOT discontinue biologics in stable patients—60-74% will relapse, often within weeks to months. 1, 3