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Updates in Pharmaceutical Therapy for Ankylosing Spondylitis: Incorporating Evidence-Based Guidelines and New Biologics to Improve Patient Outcomes
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.
Table 1. Pharmacologic Recommendations for the Treatment of Adults with Stable and/or Active AS9,10 |
Recommendations |
Level of Evidence |
Active AS |
• Treatment with NSAIDs is strongly recommended over no treatment with NSAIDs* |
Low |
• Continuous NSAID treatment is conditionally recommended over on-demand treatment |
Low to moderate |
• No particular NSAID is recommended as a preferred choice* |
Low to moderate |
• For those with an inadequate response to NSAID therapy, sulfasalazine, methotrexate, or tofacitinib are conditionally recommended over no treatment with these medications. Clinicians should consider sulfasalazine or methotrexate only in patients with prominent peripheral arthritis or when TNFi are unavailable |
Very low to moderate |
• For those with an inadequate response to NSAID therapy, TNFi are conditionally recommended over tofacitinib |
Very low |
• For those with an inadequate response to NSAID therapy, TNFi therapy is strongly recommended over no TNFi therapy |
High |
• No particular TNFi is recommended as a preferred choice |
Moderate |
• For those with an inadequate response to NSAID therapy, secukinumab or ixekizumab therapy is strongly recommended over no secukinumab or ixekizumab therapy |
High |
• For those with an inadequate response to NSAID therapy, TNFi therapy is conditionally recommended over secukinumab or ixekizumab therapy |
Very low |
• For those with an inadequate response to NSAID therapy, secukinumab or ixekizumab therapy is conditionally recommended over tofacitinib therapy |
Very low |
• For those with an inadequate response to NSAID therapy and TNFi contraindications, secukinumab or ixekizumab is conditionally recommended over sulfasalazine, methotrexate, or tofacitinib |
Low |
• For primary nonresponders to TNFi therapy, secukinumab or ixekizumab are conditionally recommended over treatment with a different TNFi |
Very low |
• For secondary nonresponders to TNFi therapy, treatment with a different TNFi is conditionally recommended over treatment with a non-TNFi biologic |
Very low |
• For those with an inadequate response despite initial TNFi therapy, switching to treatment with a biosimilar of the initial TNFi is strongly not recommended |
Very low |
• For those with an inadequate response despite initial TNFi therapy, the guideline conditionally recommends against the addition of sulfasalazine or methotrexate in favor of treatment with a new biologic |
Very low |
• Treatment with systemic glucocorticoids is strongly recommended against* |
Very low |
• For patients with isolated active sacroiliitis despite NSAID therapy, locally administered parenteral glucocorticoids are conditionally recommended over no treatment with local glucocorticoids* |
Very low |
Stable AS |
• On-demand NSAID treatment is conditionally recommended over continuous treatment. |
Low to moderate |
• In patients receiving TNFi and NSAID therapy, continuing TNFi treatment alone is conditionally recommended over continuing both treatments. |
Very low |
• In patients receiving TNFi and a conventional synthetic antirheumatic drug, continuing TNFi treatment alone is conditionally recommended over continuing both treatments. |
Very low |
• In patients receiving a biologic, the guideline conditionally recommends against biologic discontinuation. |
Very low to low |
• In patients receiving a biologic, the guideline conditionally recommends against dose tapering as a standard approach. |
Very low to low |
• In patients receiving an originator TNFi, continuing treatment with the originator TNFi is strongly recommended over mandated switching to its biosimilar. |
Very low |
Active or Stable AS |
• In adults receiving a TNFi, the guideline conditionally recommends against co-treatment with low-dose methotrexate. |
Low |
Abbreviations: AS, ankylosing spondylitis; NSAID, nonsteroidal anti-inflammatory drug; TNFi, tumor necrosis factor inhibitor.
*These recommendations were in the original 2015 AS guideline and were not reviewed in the 2019 update. |
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
Table 2. Dosage and Administration of Available FDA-approved Biologics in AS15-24 |
Biologic
|
Recommended Adult Dosage Regimen
|
Comments
|
Adalimumab
(Humira®)15
|
40 mg SC every other week
|
• Methotrexate, other non-biologic DMARDs, glucocorticoids, NSAIDs, and/or analgesics may be continued during treatment
• Available as single-dose prefilled pen, glass syringe, and glass vial (for institutional use only)
• Patients may self-inject in thighs or lower abdomen; rotate injection sites
|
Certolizumab pegol
(Cimzia®)16
|
400 mg (given as 2 injections of 200 mg each) SC initially and at weeks 2 and 4, followed by 200 mg every other week or 400 mg every 4 weeks
|
• Available as a single-dose prefilled syringe and vial for reconstitution
• Patients may self-inject in thighs or abdomen; rotate injection sites
• For the 400-mg dose, the 2 injections of 200 mg should occur at separate sites in the thigh or abdomen
|
Etanercept
(Enbrel®)17
|
50 mg SC once weekly
|
• Methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics may be continued during treatment
• Available as single-dose prefilled syringe, prefilled SureClick® autoinjector, Enbrel Mini® single-dose prefilled cartridge for use with AutoTouch® reusable autoinjector, and multiple-dose vial for reconstitution
• Patients may self-inject in abdomen, thigh, or outer area of upper arm; rotate injection sites
|
Golimumab
(Simponi® ; Simponi Aria®)18,19
|
Simponi® : 50 mg SC once monthly
Simponi Aria®: 2 mg/kg IV at weeks 0 and 4, then every 8 weeks
|
• May be given with or without methotrexate or other nonbiologic DMARDs; corticosteroids, NSAIDs, and/or analgesics may be continued during treatment
• Available as single-dose prefilled syringe or SmartJect® autoinjector (Simponi®); available as a single-dose vial (Simponi Aria®)
• Patients may self-inject Simponi® in back of upper arm, thigh, or lower abdomen; rotate injection sites
• Dilute the total volume of Simponi Aria® with 0.9% sodium chloride or 0.45% sodium chloride to a final volume of 100 mL
• Infuse the diluted solution through a 0.22 µm or less filter over 30 minutes
• The efficacy and safety of switching between IV and SC formulations have not been established
|
Infliximab (Remicade®); Infliximab-dyyb (Inflectra®); infliximab-abda (Renflexis®)20-22
|
5 mg/kg IV at 0, 2, and 6 weeks, then every 6 weeks
|
• Available as lyophilized powder for reconstitution
o Reconstitute each vial with 10 mL of sterile water
o Dilute the total volume of the dose to 250 mL with 0.9% sodium chloride; resulting infusion concentration should range between 0.4 and 4 mg/mL
• Infuse the diluted solution through a 1.2 µm or less filter over a period of no less than 2 hours
• Adverse effects during administration have included flu-like symptoms, headache, dyspnea, hypotension, transient fever, chills, GI symptoms, and rash
• Anaphylaxis may occur at any time during the infusion
• Premedication (eg, antihistamines, acetaminophen, and/or corticosteroids) may be administered
• For mild-to-moderate infusion reactions, slowing or suspending the infusion may improve the reaction; upon resolution of the reaction, reinitiation at a lower infusion rate and/or premedication is recommended
|
Ixekizumab (Taltz®)23
|
160 mg SC (two 80 mg injections) at week 0, followed by 80 mg every 4 weeks
|
• Available as single-dose prefilled autoinjector and syringe
• Patients may self-inject in upper arms, thighs, or any quadrant of abdomen; rotate injection sites
• Administration in the upper, outer arm may be performed by a caregiver or healthcare provider
|
Secukinumab (Cosentyx®)24
|
Loading dose regimen: 150 mg SC at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
If an inadequate response, consider 300 mg SC every 4 weeks
|
• Available as a single-use prefilled syringe, Sensoready® pen, and lyophilized powder for reconstitution (healthcare provider use only)
• Patients may self-inject in upper arms, thighs, or any quadrant of abdomen; rotate injection sites; vial for reconstitution is for healthcare provider use only
• Reconstitute lyophilized powder with 1 mL sterile water; use immediately or store in refrigerator for up to 24 hours
|
Abbreviations: AS, ankylosing spondylitis; DMARD, disease-modifying antirheumatic drug; FDA, Food and Drug Administration; GI, gastrointestinal; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; SC, subcutaneous. |
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).
Table 3. Management Strategies for Biologic-related Adverse Reactions27 |
Adverse Reaction |
Preventive or Therapeutic Measures |
Infection-related |
Severe bacterial, opportunistic infections |
• Identify any pre-existing foci of infection and past history of severe infection
• Avoid concomitant administration of immunosuppressive medications
• Monitor CD4+ T-cell count and initiate appropriate prophylactic antibiotic therapy as necessary
• Vaccinate against specific pathogens (Streptococcus pneumoniae) prior to biologic administration |
Tuberculosis |
• Screen for latent Tb and administer appropriate prophylactic antibiotic therapy if necessary |
Herpes zoster |
• Vaccinate prior to biologic administration
• Administer appropriate antiviral therapy as necessary |
Hepatitis B |
• Screen patients at risk
• Monitor viremia
• Vaccinate prior to biologic administration
• Administer antiviral prophylaxis for chronic HBV |
Hepatitis C |
• Screen patients at risk
• Consider treating patients with effective HCV medications prior to biologic administration |
Noninfectious-related |
Immunological |
• Discontinuation of the biologic agent usually leads to resolution of the adverse reaction (eg, lupus-like syndrome, peripheral neuropathy, autoimmune hepatitis, demyelinating disease) in the majority of cases |
Hematological |
• Mild cytopenias are not a reason for interruption of biologic therapy
• Persistent or progressive cytopenia should result in prompt biologic discontinuation |
Cardiovascular |
• Biologic therapy should be immediately interrupted
• Use particular caution in patients ≥ 60 years of age with pre-existing heart failure, especially when using TNFi |
Pulmonary |
• Regularly assess lung function with clinical examination and, if indicated, pulmonary function tests and radiological exams
• Discontinue the offending biologic if a noninfectious pulmonary adverse reaction is suspected
• Use particular caution in patients with pre-existing interstitial lung disease |
Gastrointestinal and metabolic |
• Reduce biologic dose (if applicable) or discontinue biologic therapy |
Cutaneous |
• If a blistering skin reaction occurs (eg, TEN or SJS), immediately discontinue and do not restart the offending biologic |
Neurological |
• PML is a concern, avoid extreme immunosuppression (CD4+ T-cell count < 0.2 x 109/L) • Biologic therapy should be immediately interrupted and an alternate class of biologic or DMARD should be used, if necessary |
Malignant |
• Regularly assess for skin and systemic malignancies
• Biologic therapy should be immediately interrupted upon malignancy detection and an alternate class of biologic or DMARD should be used, if necessary |
Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; PML, progressive multifocal leukoencephalopathy; SJS, Stevens-Johnson syndrome; Tb, tuberculosis; TENS, toxic epidermal necrolysis; TNFi, tumor necrosis factor inhibitor. |
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
Table 4. Clinical Trial Data for Secukinumab and Ixekizumab in AS. |
Reference |
Study Design |
Results |
Secukinumab |
|
DB, PC, MC, RCT
Duration: 104 weeks
Subjects: 350 adults with active AS with prior documented radiological evidence fulfilling the modified New York criteria for AS
Interventions:
Secukinumab 150 mg SC at baseline, weeks 1, 2, 3, and every 4 weeks starting at week 4 (loading dose; n = 116)
Secukinumab 150 mg SC at baseline, placebo at weeks 1, 2, 3, and then 150 mg SC every 4 weeks starting at week 4 (no loading dose; n = 117)
Placebo (n = 117)
At week 16, all placebo patients were switched to secukinumab 150 mg SC every 4 weeks
|
Primary endpoint:
There was a nonsignificant improvement in the proportion of patients achieving an ASAS20 response with secukinumab compared to placebo at 16 weeks (59.5% with loading dose vs 61.5% with no load vs 47% placebo; P = 0.057 and P = 0.054, respectively)
Others:
Secukinumab, with or without a loading regimen, was not superior to placebo at week 16 for any secondary endpoint
ASAS40 response rates at week 16 were nonsignificantly improved with secukinumab loading dose (38.8%) and secukinumab no loading dose (35.9%) vs placebo (28.2%; P = 0.188 and P = 0.356, respectively)
Increases in response rates achieved with secukinumab for ASAS20 at week 16 were sustained through week 104
The safety profile of secukinumab, with or without a loading dose, revealed no new or unexpected safety signals
|
Pavelka 201734
EASURE 3 |
DB, DD, PC, MC, RCT
Duration: 52 weeks
Subjects: 226 adults with moderate-to-severe AS fulfilling the modified New York criteria for AS
Interventions:
Secukinumab 150 mg SC every 4 weeks (n = 74)
Secukinumab 300 mg SC every 4 weeks (n = 76)
Placebo (n = 76)
Patients in both secukinumab groups received a 10 mg/kg IV dose at baseline and weeks 2 and 4; SC dosing was initiated at week 8
At week 16, all placebo patients were re-randomized to secukinumab 150 mg or 300 mg SC every 4 weeks
|
Primary endpoint:
There was a significant improvement in the proportion of patients achieving an ASAS20 response with secukinumab compared to placebo at 16 weeks (60.5% 300 mg vs 58.1% 150 mg vs 36.8% placebo;
P < 0.01 and P <0.05, respectively)
Others:
ASAS40 response rates at week 16 were also significantly improved with secukinumab vs placebo (42.1% 300 mg vs 40.5% 150 mg vs 21.1% placebo;
P < 0.05 for both comparisons)
The majority of secondary endpoints were also met in both secukinumab groups
ASAS20 and ASAS40 response rates seen at week 16 in both secukinumab groups were sustained through 52 weeks
Increases in response rates achieved with secukinumab for ASAS20 at week 16 were sustained through week 52
The most frequent TEAEs through week 16 were nasopharyngitis, diarrhea, headache, and cough
During the entire treatment period, pooled incidence rates of Candida infections and grade 3-4 neutropenia were 1.8% for each AE in patients administered secukinumab
|
Baeten 201528
MEASURE 1 and
MEASURE 2 |
Two DB, PC, MC, RCTs
Duration: 52 weeks
Subjects: 371 (MEASURE 1) and 219 (MEASURE 2) adults with AS fulfilling the modified New York criteria
Interventions:
MEASURE 1:
Secukinumab 150 mg SC every 4 weeks (n = 125)
Secukinumab 75 mg SC every 4 weeks (n = 124)
Placebo (n = 122)
Patients in both secukinumab groups in MEASURE 1 received a 10 mg/kg IV dose at baseline and weeks 2 and 4; SC dosing was initiated at week 8
MEASURE 2:
Secukinumab 150 mg SC at baseline, at weeks 1, 2, and 3, and every 4 weeks starting at week 4 (n = 72)
Secukinumab 75 mg SC at baseline, at weeks 1, 2, and 3, and every 4 weeks starting at week 4 (n = 73)
Placebo (n = 74)
At week 16 in both studies, all placebo patients were re-randomized to secukinumab 75 mg or 150 mg SC every 4 weeks
|
Primary endpoint:
ASAS20 response rates at week 16 (MEASURE 1): 61% 150 mg vs 60% 75 mg vs 29% placebo (P < 0.001 for both comparisons)
ASAS 20 response rates at week 16 (MEASURE 2): 61% 150 mg vs 41% 75 mg vs 28% placebo (P < 0.001 and P = 0.10, respectively)
Others:
In MEASURE 1, all predefined secondary endpoints were met in both secukinumab groups
ASAS40 response rates at week 16 (MEASURE 1): 42% 150 mg vs 33% 75 mg vs 13% placebo (P < 0.001 for both comparisons)
In MEASURE 2, all predefined secondary endpoints except ASAS partial remission were met with secukinumab 150 mg; responses with secukinumab 75 mg did not differ significantly from placebo responses
ASAS40 response rates at week 16 (MEASURE 2): 36% 150 mg vs 26% 75 mg vs 11% placebo (P < 0.001 and P = 0.10, respectively)
Clinical responses observed at week 16 were maintained through week 52 in both studies
Pooled exposure-adjusted incidence rates of grade 3-4 neutropenia, Candida infections, and Crohn’s disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients
|
Ixekizumab |
Deodhar 202040
COAST-X |
DB, PC, MC, RCT
Duration: 52 weeks
Subjects: 303 adults with an axial SpA diagnosis who fulfilled ASAS classification criteria and had a treatment history for axial SpA for at least 12 weeks
Interventions:
Ixekizumab 80 mg SC every 2 weeks
(n = 102)
Ixekizumab 80 mg SC every 4 weeks
(n = 96)
Placebo (n = 105)
Patients in the ixekizumab groups were also randomly assigned to an 80 mg or 160 mg starting dose at week 0
|
Primary endpoint:
Proportion of patients achieving an ASAS40 response was significantly improved with ixekizumab compared to placebo at 16 weeks (35% every 4 weeks vs 40% every 2 weeks vs 19% placebo;
P = 0.0094 and P = 0.0016, respectively) and 52 weeks (30% every 4 weeks vs 31% every 2 weeks vs 13% placebo; P = 0.0045 and P = 0.0037, respectively)
Others:
An increased ASAS40 response rate was observed in each ixekizumab group vs placebo as early as week 1
The initial ixekizumab starting dose (80 mg or 160 mg) had no effect on the primary outcome results at week 16 or 52
All major secondary endpoints showed greater improvements in each ixekizumab group as compared to placebo at weeks 16 and 52
Most common TEAEs with ixekizumab were nasopharyngitis and injection site reaction
One case of serious infection was reported in the ixekizumab every 4-week group
|
Deodhar 201938
COAST-W |
DB, PC, MC, RCT
Duration: 16 weeks
Subjects: 316 adults with an axial SpA diagnosis who fulfilled ASAS classification criteria for radiographic axial SpA and had a prior inadequate response or intolerance to TNFi
Interventions:
Ixekizumab 80 mg SC every 2 weeks
(n = 98)
Ixekizumab 80 mg SC every 4 weeks
(n = 114)
Placebo (n = 104)
Patients in the ixekizumab groups were also randomly assigned to an 80 mg or 160 mg starting dose at week 0
|
Primary endpoint:
Proportion of patients achieving an ASAS40 response was significantly improved with ixekizumab compared to placebo at 16 weeks (25.4% every 4 weeks vs 30.6% every 2 weeks vs 12.5% placebo;
P = 0.017 and P = 0.003, respectively)
Others:
Proportion of patients achieving an ASAS20 response was also significantly improved with ixekizumab at 16 weeks
The initial ixekizumab starting dose (80 mg or 160 mg) had no effect on the primary outcome results at week 16
Every 2-week dosing did not result in a clinically meaningful incremental increase in observed efficacy in comparison to every 4-week dosing
The majority of secondary endpoints showed greater improvements in each ixekizumab group as compared to placebo at weeks 16
Most common TEAEs with ixekizumab were nasopharyngitis and injection site reaction
Few serious AEs were reported, with similar rates across arms: 4.8% placebo, 3.1% every 2 weeks, and 3.5% every 4 weeks
|
van der Heijde 201837
COAST-V |
DB, PC, AC, MC, RCT
Duration: 16 weeks
Subjects: 341 adults with a radiographic axial SpA diagnosis who fulfilled ASAS classification criteria previously untreated with biological DMARDs
Interventions:
Ixekizumab 80 mg SC every 2 weeks
(n = 83)
Ixekizumab 80 mg SC every 4 weeks
(n = 81)
Adalimumab 40 mg SC every 2 weeks
(n = 90)
Placebo (n = 87)
Patients in the ixekizumab groups were also randomly assigned to an 80 mg or 160 mg starting dose at week 0
|
Primary endpoint:
Proportion of patients achieving an ASAS40 response was significantly improved with ixekizumab compared to placebo at 16 weeks (48% every 4 weeks vs 52% every 2 weeks vs 18% placebo; P < 0.0001 for both comparisons)
Others:
Adalimumab was also associated with a significant ASAS40 response as compared to placebo at week 16 (36% vs 18%; P = 0.0075)
The initial ixekizumab starting dose (80 mg or 160 mg) had no effect on the primary outcome results at week 16
All major secondary endpoints showed greater improvements in each active treatment group as compared to placebo at week 16
Most common TEAEs with ixekizumab were nasopharyngitis and injection site reaction
Serious AEs occurred in 1 patient in each ixekizumab arm and in 3 patients in the adalimumab arm
|
Abbreviations: AC, active-controlled; AE, adverse event; ASAS, Assessment of SpondyloArthritis international Society; AS, ankylosing spondylitis; DB, double-blind; DD, double-dummy; DMARD, disease-modifying antirheumatic drug; IV, intravenous; MC, multicenter; PC, placebo-controlled; RCT, randomized controlled trial; SC, subcutaneous; TEAE, treatment-emergent adverse event. |
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.
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