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Introduction

Spondyloarthritis (SpA), also known as spondylitis, is an umbrella term for a family of closely related chronic inflammatory diseases that share common clinical, genetic, and pathophysiological features.^1-3 These conditions are broadly classified as predominantly axial- or peripheral-dependent upon primary disease manifestations.^3,4 Axial SpA is associated with inflammation of the sacroiliac joints and/or spine; peripheral disease commonly involves joints in the extremities (eg, hands, wrists, elbows, knees, ankles, feet).^1,3 Axial SpA affects an estimated 2.7 million adults in the United States;⁵ patients with this condition may be further categorized into those with or without radiographic evidence of disease.^1,6 Radiographic axial SpA is another term for ankylosing spondylitis (AS).

AS is best known as an arthritis of the joints of the spine, but it frequently affects other joints (eg, shoulders, hips) and occasionally affects other organs such as the eyes, skin, and intestines (ie, uveitis, psoriasis, and inflammatory bowel disease, respectively).^1,6 The etiology of AS is unknown; however, environmental and genetic factors may play a role in its occurrence.^6,7 Human leukocyte antigen-B27 (HLA-B27) is the primary gene associated with an increased risk for AS; the presence of interleukin 23R (IL23R) and endoplasmic reticulum aminopeptidase 1 (ERAP1) may also increase risk. Symptom onset commonly occurs in late adolescence or early adulthood (17-45 years of age) with unilateral or alternating low back and buttock pain or stiffness that improves with activity and worsens with rest.^1,4,6 The pain is usually dull and diffuses and progresses gradually over weeks to months.¹ Bony tenderness may also be a presenting symptom, and up to 35% of patients have hip arthritis.⁴ The pain eventually becomes chronic and bilateral in nature and advances to neck pain and stiffness months to years after initial presentation.¹ Of note, symptoms of AS may initially manifest in a peripheral joint in a minority of patients, more commonly in children, which may lead to the potential for an incorrect diagnosis.

There is no “gold standard” diagnostic method for AS.⁶ However, the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA may assist clinicians in diagnosing the condition in patients 45 years of age or younger with back pain 3 or more months duration.⁸ The ASAS criteria include evaluation of an individual’s analgesic response to nonsteroidal anti-inflammatory drugs (NSAIDs), family history of AS, HLA-B27 testing, imaging for sacroiliitis, and identification of SpA features such as inflammatory back pain, elevated C-reactive protein arthritis, enthesitis, dactylitis, anterior uveitis, psoriasis, and Crohn’s disease or ulcerative colitis.

Current Evidence-Based Guidelines

In 2019, the American College of Rheumatology (ACR), Spondylitis Association of America, and Spondyloarthritis Research and Treatment Network published an updated guideline for the treatment of AS and nonradiographic axial SpA. Per the guideline, the overall goals of AS management are “to alleviate symptoms, improve functioning, maintain the ability to work, decrease disease complications, and forestall skeletal damage as much as possible.”⁹ This document provides recommendations, following ACR and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, for pharmacologic therapy, rehabilitation, surgery, comorbidity management, disease monitoring, patient education, and preventive care for patients with active or stable disease.

As noted throughout the 2019 guideline, biologic agents have a significant role in the management of active and stable AS. Any tumor necrosis factor inhibitor (TNFi), such as infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab, is a strongly recommended treatment option for adults with continuing active AS despite chronic NSAID therapy.⁹ This recommendation is based on the results of 24 randomized controlled trials that revealed improvement in patient-reported outcomes, composite response criteria, and spine and sacroiliac inflammation on imaging. The anti-interleukin-17A (IL-17A) antibodies, secukinumab and ixekizumab, are also strongly recommended in adults with continuing active AS despite chronic NSAID therapy; however, TNFi are conditionally recommended over secukinumab or ixekizumab in this patient population based on availability of long-term safety and toxicity data and clinical experience with their use. Secukinumab and ixekizumab are also conditionally recommended over sulfasalazine, methotrexate, or tofacitinib therapy in adults with active AS despite NSAID therapy and TNFi contraindications. Specifically, the anti-IL-17A antibodies are preferred in patients with heart failure or demyelinating disease as these agents are not associated with worsening these conditions. Of note, sulfasalazine is preferred over secukinumab, ixekizumab, and tofacitinib if the contraindication to TNFi use is tuberculosis, other chronic infection, or a high risk of recurrent infection. Tofacitinib should be considered over secukinumab or ixekizumab in patients with coexisting ulcerative colitis if TNFi therapy is not an option. Table 1 details recommendations and corresponding levels of evidence regarding pharmacologic management for adult patients with stable and/or active AS from the 2019 guideline.

Although ACR considers adherence to guideline recommendations to be “voluntary,”⁹ communicating management aspects and explaining the related clinical evidence to clinicians regarding appropriate AS care is of paramount importance. Historically, research studies have revealed that clinician noncompliance with practice guidelines is substantial, varying between 33% and 70%.^11-14 In order to improve compliance, continuous real-time education with performance feedback may assist providers in choosing appropriate evidence-based treatment options for individual patients. Bos and colleagues evaluated the impact of a pharmacist-driven educational program on guideline nonadherence in the hospital setting utilizing a prospective before-after design.¹⁴ In the P-REVIEW study, surgical, urological, and orthopedic patients in 2 hospitals underwent usual care with medication surveillance and communication between pharmacists and physicians for a 6-month control period followed by a 3-month introductory intervention period, and a formal 6-month intervention. The intervention consisted of educational programming for physicians on various topics including national and local hospital guidelines as well as medication safety consultation training for pharmacists (ie, medication review plus visits to audit and provide prescriber feedback). The primary outcome measure was the proportion of admissions in which physicians were nonadherent to practice guideline recommendations. Results revealed a significant reduction in the proportion of admissions in which physicians were nonadherent to prevailing guidelines occurred in the intervention period as compared to usual care (21.8% [193/886] vs 30.5% [332/1089]; P < 0.05) and confirmed the positive impact of educating physicians regarding the use of evidence-based guidelines.

The Utilization of Biologics in Ankylosing Spondylitis

The Food and Drug Administration (FDA) has approved various biologics for reducing the signs and symptoms of active AS in adults.^15-24 Table 2 summarizes dosage regimens and administration recommendations for these agents. After appropriate training in subcutaneous administration, patients may self-administer the majority of these agents. Only infliximab and the Aria^® form of golimumab are administered exclusively via the intravenous route.^19-22 Infliximab-dyyb and infliximab-abda are biosimilar, but not interchangeable, products approved for use in adults with active AS.^21,22

There are numerous safety concerns with biologic therapy. Certolizumab, secukinumab, ixekizumab, and infliximab are contraindicated for use in patients with hypersensitivity to any inactive component of the product or to any murine proteins (infliximab only).^16,20-24 Etanercept should not be administered to patients with sepsis, and infliximab at doses more than 5 mg/kg should be avoided in patients with moderate-to-severe heart failure as this dosage regimen is associated with an increased incidence of death and hospitalization due to worsening heart failure.^17,20-22 The TNFi all carry a boxed warning for serious infections such as active tuberculosis, which may present with pulmonary or extrapulmonary disease; invasive fungal infections; and bacterial, viral, and other opportunistic infections.^15-22 Although these are not boxed warnings for the anti-IL-17A antibodies, serious infections are listed as warnings and precautions in the labeling for secukinumab and ixekizumab.^23,24 The TNFi also share a boxed warning regarding an increased risk for lymphoma and other malignancies, some fatal. Other potential serious concerns for biologics in AS include exacerbations of Crohn’s disease and ulcerative colitis (ixekizumab, secukinumab);^23,24 hepatitis B reactivation, heart failure, cytopenias, demyelinating disease, lupus-like syndrome (TNFi);^15-22 hepatotoxicity and cardiovascular and cerebrovascular reactions (infliximab);^20-22 and avoidance of concurrent live vaccine administration.^15-24 More common adverse effects include infusion site reactions, diarrhea, nausea/vomiting, abdominal pain, infections, hypertension, and headache.

As treatment with biologics has become routine, the long-term safety of these agents is of concern due to immune suppression and the potential for serious infections and malignancies. In AS, a meta-analysis of 25 randomized controlled studies with 2403 patients treated with various biologics (eg, adalimumab, certolizumab, etanercept, golimumab, infliximab, and secukinumab) revealed no significant increase in the risk of serious infections with biologics compared to controls (odds ratio [OR], 1.42; 95% confidence interval [CI]: 0.58-3.47).²⁵ Another meta-analysis of 14 randomized controlled trials with 2032 patients treated with adalimumab, certolizumab, etanercept, golimumab, or infliximab revealed no significant difference between TNFi and placebo for overall serious adverse events (OR, 1.34; 95% CI: 0.87-2.05), risk of serious infections (OR, 1.59; 95% CI: 0.63-4.01), malignancy risk (OR, 0.98; 95% CI: 0.25-3.85), and discontinuation due to adverse events (OR, 1.55; 95% CI: 0.95-2.54).²⁶ Although these data support the safety of biologic administration in AS, clinicians should be aware of general management strategies if an adverse reaction occurs (Table 3). For noninfectious-related adverse reactions, management generally involves immediate discontinuation of the offending biologic and switching to another class of biologic agent or disease-modifying antirheumatic drug (DMARD).

Clinical and Real World Data for Anti-IL-17A Antibodies –Secukinumab and Ixekizumab

Of the biologic agents approved for management of active AS, 5 are TNFi (adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab) and 2 are anti-IL-17A antibodies (secukinumab and ixekizumab). The anti-IL-17A-antibodies were approved for AS recently, 2016 and 2019, respectively. Table 4 summarizes the key AS clinical trial data for secukinumab and ixekizumab in the MEASURE and COAST study series, respectively. Results from the MEASURE 1 trial revealed that ASAS20 and ASAS40 response rates were significantly improved with secukinumab as compared to placebo at week 16 and maintained through week 52.²⁸ The sustained efficacy and safety of secukinumab in AS has been demonstrated at 2, 3, 4, and 5 years of MEASURE 1 follow-up.^29-32 Results from MEASURE-2 confirmed the efficacy and safety of secukinumab 150 mg subcutaneously (SC) as a treatment regimen in AS, while demonstrating no significant difference between secukinumab 75 mg SC and placebo through 52 weeks.²⁸ At a 2-year follow-up, efficacy in the key clinical manifestations of AS was sustained with the secukinumab 150 mg SC regimen.³³ MEASURE-3 revealed that both secukinumab 150 and 300 mg dosage regimens were effective and safe options,³⁴ with sustained improvements through 3 years in the signs and symptoms of AS.³⁵ Secukinumab with or without a loading dose resulted in a nonsignificant improvement in the percentage of patients achieving an ASAS20 and ASAS40 response as compared to placebo at week 16 in the MEASURE 4 study.³⁶ Of note, this result was not due to lower than anticipated response rates with secukinumab, which were similar to those observed in previous trials, but higher than anticipated placebo response rates. Increases in ASAS20 response rates observed with secukinumab at week 16 were maintained through week 104 of therapy.

At 16 weeks, ixekizumab 80 mg SC every 2 and every 4 weeks was associated with a significant improvement in ASAS40 response rates with acceptable tolerability as compared to placebo in the COAST-V (biologic DMARD naïve) and COAST-W (TNFi-experienced) trials.^37,38 This response was sustained through 52 weeks.³⁹ These results were confirmed in the COAST-X trial, which concluded that the proportion of patients achieving an ASAS40 response was significantly improved with ixekizumab 80 mg SC every 2 and every 4 weeks as compared to placebo at 16 weeks (40% every 2 weeks vs 35% every 4 weeks vs 19% placebo; P = 0.0016 and P = 0.0094, respectively) and 52 weeks (31% every 2 weeks vs 30% every 4 weeks vs 13% placebo; P = 0.0037 and P = 0.0045, respectively).⁴⁰

Real world data with secukinumab and ixekizumab in AS are fairly limited. In a cross-sectional, web-based survey of 200 patients with AS, the majority (74%) reported overall improvement (a little to much better) in AS symptoms after secukinumab initiation.⁴¹ Additionally, secukinumab therapy was associated with improvement in individual symptoms such as fatigue, morning stiffness, lower back and neck pain and stiffness, pain disrupting sleep, soreness in areas other than joints, and enthesitis. The vast majority of patients also reported overall satisfaction with secukinumab regarding symptom improvement (99%), speed of improvement (97%), ease of use (93.5%), patient support services (97%), and occurrence of adverse effects (93%). In another study, investigators translated ASAS40 improvements seen with ixekizumab from the COAST-V and COAST-W trials into effects on patient-reported outcomes.⁴² Results revealed that patients who achieved an ASAS40 response in the clinical trials had significant improvement in spinal pain at night, fatigue, and sleep quality. In fact, an ASAS40 response was associated with a 2.6- to 5.3-fold improvement in pain, fatigue, sleep, and quality of life in biologic DMARD-naïve patients and a 5.1- to 18.5-fold improvement in these outcomes in TNFi-experienced patients, compared to patients who were ASAS20 nonresponders in COAST-V and COAST-W.

Conclusion

Ankylosing spondylitis is a chronic inflammatory disease characterized by progressive and irreversible structural joint damage and pain, thereby leading to substantial disability, reduced physical function, and impaired quality of life. Historically, mainstays of AS pharmacologic treatment include NSAIDs, DMARDs, and TNFi. However, treatment can be hindered by a lack of efficacy with DMARDs and lack of response or intolerance to TNFi therapy. The anti-IL-17A antibodies, secukinumab and ixekizumab, are more recently approved agents for adults with active AS. The 2019 ACR, Spondylitis Association of America, and Spondylitis Research and Treatment Network clinical practice guideline provide evidence-based guidance on the role of these emerging therapies in AS management. This guidance is based on results from the MEASURE (secukinumab) and COAST (ixekizumab) clinical trials. Additionally, limited real world data reveal the beneficial effects of both anti-IL-17A antibodies on patient-reported outcomes.

References

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