What alternative medications can be considered for a patient with ankylosing spondylitis (AS) who is unable to take Disease-Modifying Antirheumatic Drugs (DMARDs) due to frequent urinary tract infections (UTIs)?

Treatment Options for Ankylosing Spondylitis When Conventional DMARDs Are Not Tolerated

For a patient with ankylosing spondylitis unable to take conventional synthetic DMARDs due to frequent UTIs, you should proceed directly to biologic DMARDs (TNF inhibitors or IL-17 inhibitors) or JAK inhibitors, as conventional DMARDs have no proven efficacy for axial disease and are not required before initiating advanced therapies. 1, 2

Why Conventional DMARDs Are Not Necessary

The patient's inability to tolerate conventional synthetic DMARDs (sulfasalazine, methotrexate, leflunomide) is actually not a barrier to optimal treatment:

• Conventional DMARDs have no proven efficacy for axial manifestations of ankylosing spondylitis and are strongly recommended against for purely axial disease. 1, 2
• There is no evidence supporting obligatory use of DMARDs before initiating biologic therapy for axial disease. 1, 3
• Sulfasalazine may only be considered for patients with active peripheral arthritis, not for axial symptoms. 1

First-Line Pharmacological Treatment: NSAIDs

Before advancing to biologics, ensure the patient has had an adequate trial of NSAIDs:

• NSAIDs are the mandatory first-line pharmacological treatment for AS patients with pain and stiffness. 1, 2
• Continuous NSAID treatment is preferred over on-demand dosing for patients with persistently active symptomatic disease. 1, 2
• The patient should trial at least two different NSAIDs at adequate doses before being considered for biologic therapy. 1

Biologic DMARDs: The Appropriate Next Step

If NSAIDs have failed, are contraindicated, or poorly tolerated, biologic DMARDs should be initiated:

TNF Inhibitors (Preferred Initial Biologic)

• TNF inhibitors are strongly recommended as first-line biologic therapy for patients with persistently high disease activity despite NSAIDs. 1, 2
• Approved TNF inhibitors include: adalimumab, etanercept, golimumab, certolizumab pegol, and infliximab. 1
• All TNF inhibitors demonstrate comparable efficacy for axial manifestations in the absence of extra-articular features. 1, 3

IL-17 Inhibitors (Equally Valid First-Line Option)

• IL-17 inhibitors (secukinumab and ixekizumab) are equally valid first-line biologic options alongside TNF inhibitors, with no prioritization between the two classes. 1, 2
• The 2023 PANLAR guidelines note more extensive long-term data exists for TNF and IL-17 inhibitors compared to JAK inhibitors. 1

JAK Inhibitors (Reserve for Specific Situations)

• JAK inhibitors (tofacitinib and upadacitinib) should be reserved for when TNF inhibitors and IL-17 inhibitors are contraindicated or unavailable. 1
• This recommendation is based on increased cardiovascular and malignancy risks observed with tofacitinib in rheumatoid arthritis patients ≥50 years with cardiovascular risk factors. 1
• For patients ≥65 years with smoking history or cardiovascular/malignancy risk factors, JAK inhibitors should only be used if no suitable alternatives exist. 1

Important Considerations Regarding Infection Risk

Given this patient's history of frequent UTIs:

• Biologic DMARDs do carry increased infection risk, but this must be weighed against disease morbidity. 4
• Screen for latent tuberculosis before initiating any biologic therapy. 1
• Consider whether the UTIs are related to the underlying inflammatory disease or other factors that could be addressed.
• TNF inhibitors and IL-17 inhibitors have different infection profiles—discuss with the patient which risks are most acceptable.

Treatment Algorithm for This Patient

1. Ensure adequate NSAID trial (at least 2 different NSAIDs at therapeutic doses). 1
2. If NSAIDs fail or are contraindicated, initiate biologic DMARD:
   • First choice: TNF inhibitor or IL-17 inhibitor (no preference between classes unless extra-articular manifestations present). 1, 2
   • Consider IL-17 inhibitor if concerned about infection risk, as theoretical infection profile may differ from TNF inhibitors.
3. Reserve JAK inhibitors for situations where both TNF and IL-17 inhibitors are contraindicated or unavailable. 1

Critical Pitfalls to Avoid

• Do not delay biologic therapy waiting for a trial of conventional DMARDs—they are ineffective for axial disease and not required. 1, 2
• Do not add methotrexate or sulfasalazine to biologic therapy for axial disease—combination therapy is not evidence-based. 1, 2, 5
• Do not use systemic glucocorticoids for axial disease—they are not supported by evidence. 1
• Consider local glucocorticoid injections only for specific sites of musculoskeletal inflammation. 1

Monitoring During Biologic Therapy

• Assess disease activity using validated measures (BASDAI or ASDAS) at 3-6 months after initiation. 3, 5
• Monitor CRP or ESR every 3-4 months. 3, 5
• Screen regularly for infections given the patient's history of recurrent UTIs.