A closer look at the US guidelines for managing axSpA
In August 2019 the ACR, Spondylitis Association of America, and Spondyloarthritis Research and Treatment Network issued updated recommendations for the management of axial spondyloarthritis (axSpA), including both ankylosing spondylitis (AS; also known as radiographic axSpA) and nonradiographic axial spondyloarthritis . medwireNews speaks to lead author Michael Ward, from the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Maryland, USA, about why this update of the 2015 guidelines was needed, and how the guidelines might be used by rheumatologists.
The emergence of new treatment options
“The update was prompted primarily by the recent availability of new medications to treat ankylosing spondylitis: secukinumab and ixekizumab,” says Ward. He explains that “data on the efficacy of these medications became available after the publication of the 2015 treatment recommendations , and we wanted to keep the recommendations current.”
Indeed, secukinumab was the first interleukin (IL)-17A inhibitor to be approved for ankylosing spondylitis in the USA, with the FDA approving the agent for this indication in January 2016 [3,4], following European approval in 2015 .
The approval of secukinumab was based on the results of four phase III, double-blind, randomized controlled trials investigating various doses of the agent versus placebo in patients with moderate-to-severe AS despite treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
The MEASURE 1–4 trials tested secukinumab at doses ranging from 75 mg to 300 mg every 4 weeks with and without loading doses, and based on these findings the US FDA recommends a dose of 150 mg every 4 weeks, either with or without a loading dose of 150 mg/week at weeks 0–4 .
The second IL-17A inhibitor to be approved for the treatment of AS was ixekizumab. The FDA expanded the indication for ixekizumab to include AS in August 2019, based on the results of the COAST-V and COAST-W trials, which demonstrated its efficacy in biologic-naïve patients and those with an inadequate response to tumor necrosis factor (TNF) inhibitors, respectively [6–8].
In light of these approvals, “[t]he new recommendations regarding the use of IL-17 inhibitors is the major addition” to the latest US guidelines for managing axSpA, says Ward. He explains that “[f]or both secukinumab and ixekizumab, the [present] recommendations [are] in favor of treating with the medications,” and “the question then becomes how to sequence them in the course of treatment for individual patients.”
Ward explains that for “almost all patients” with active AS despite NSAID treatment, for whom biologic treatment is considered, “the recommendations are to use a TNF inhibitor as the initial biologic, with a few exceptions for those with selected comorbidities.” He adds that a second TNF inhibitor should be used “for patients who have a good initial response to a TNF inhibitor but that wanes over months to years,” whereas an IL-17A inhibitor is recommended for patients with an inadequate response to the first TNF inhibitor.
Addressing new topics
As well as creating the new recommendations for IL-17A inhibitor use in people with AS, “we took this opportunity to revisit some of the previous recommendations to see if these should be modified based on new data, and to add recommendations on some topics not addressed previously, such as de-escalation of treatment and imaging,” remarks Ward.
For example, he points out that while treatment tapering was not addressed in the 2015 recommendations, the updated guidelines “conditionally [caution] against tapering or discontinuing biologics for patients who were in remission while taking these medications, due to the likelihood of relapse,” whereas tapering can “be considered in selected patients in sustained remission in agreement with the wishes of the patient.”
Similarly, magnetic resonance imaging (MRI) was not addressed in the 2015 guidelines, but the 2019 update includes “a conditional recommendation to obtain MRI of the spine or pelvis in patients on treatment with a biologic when it was not clear if inflammation was contributing to symptoms and if the MRI results would reasonably prompt a change in treatment,” as well as “a recommendation not to perform scheduled X-rays of the spine on a periodic basis to monitor for the degree of spine fusion,” he says.
What about nonradiographic disease?
“The new recommendation topics for AS were also addressed for nonradiographic axial SpA,” says Ward. Although there has been some progress in understanding nonradiographic axSpA in recent years – with the FDA approving certolizumab pegol as the first treatment for this specific indication in March 2019 – he cautions that there are “limited studies” involving patients with nonradiographic axSpA, and therefore “most recommendations parallel those for AS.”
Ward notes that of the 2015 recommendations that were reassessed, “the recommendation regarding treatment of patients with nonradiographic axial SpA with TNF inhibitors was changed from conditional to strong, based on new data.”
Indeed, the guideline authors identified “several clinical trials” investigating the use of these agents in people with nonradiographic disease, allowing them to strengthen the recommendation. For instance, C-axSpAnd – the pivotal trial supporting the FDA approval of certolizumab pegol for nonradiographic axSpA – demonstrated that a significantly higher proportion of patients treated with the TNF inhibitor versus placebo achieved a major improvement in ASDAS (decrease of 2.0 points or more from baseline or achievement of the lowest possible score of 0.6 points) at the 1-year follow-up . Patients received the study drugs alongside nonbiologic agents, and these findings led the trial investigators to conclude that there is a need for intervention beyond nonbiologic therapy for people with nonradiographic axSpA.
With the exception of the recommendation to treat nonradiographic axSpA with TNF inhibitors, the remaining 20 recommendations were based on a low or very low level of evidence, highlighting the need for further research involving patients with nonradiographic disease.
Gaps in knowledge
As well as there being limited evidence to support the recommendations for nonradiographic axSpA, Ward says that the main overall challenge encountered by the panel when developing the set of guidelines “was the low level of evidence, or lack of evidence, for many of the treatment questions.” Therefore, “many recommendations were based on the knowledge of the expert panel,” he remarks.
Ward believes that the lack of a cure for spondyloarthropathies “is certainly the largest gap” in knowledge at present, and notes that for disease management “there remain questions about whether any biologic is more effective than any other biologic, and most importantly, whether any treatment, including NSAIDs, can slow or stop spinal fusion.”
“The large number of recommendations with low levels of evidence indicates that much more research is needed,” he stresses.
Nonetheless “we hope that rheumatologists will find these recommendations useful to guide decision making in the clinic,” says Ward, emphasizing that the questions addressed in the guidelines “were selected to be the most common questions that come up in the course of treating patients with axial SpA.”
And he concludes that “while no set of recommendations can address all possible patients and all possible variations in presentation, we hope these will help inform treatment for the most commonly encountered scenarios.”
medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group
- Ward M, Deodhar A, Gensler LS, et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol 2019; doi:10.1002/art.41042.https://onlinelibrary.wiley.com/doi/full/10.1002/art.41042
- Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol 2016; 68: 282–298. https://doi.org/10.1002/art.39298
- Novartis press release: Novartis receives two new FDA approvals for Cosentyx to treat patients with ankylosing spondylitis and psoriatic arthritis in the US. Available at: https://novartis.gcs-web.com/novartis-receives-fda-approvals-for-secukinumab-in-as-and-psa [Accessed 6 September 2019]
- US prescribing information for COSENTYX® (secukinumab) injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125504s013lbl.pdf [Accessed 6 September 2019]
- European Medicines Agency: Cosentyx. https://www.ema.europa.eu/en/medicines/human/EPAR/cosentyx#authorisation-details-section [Accessed 6 September 2019]US prescribing information for TALTZ (ixekizumab) injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125521s016lbl.pdf [Accessed 6 September 2019]
- US prescribing information for TALTZ (ixekizumab) injection. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125521s016lbl.pdf [Accessed 6 September 2019]
- van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet 2018; 392: 2441–2451. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31946-9/fulltext
- Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol 2019; 71: 599–611. https://onlinelibrary.wiley.com/doi/10.1002/art.40753
- Deodhar A, Gensler LS, Kay J, et al. A Fifty-Two-Week, Randomized, Placebo-Controlled Trial of Certolizumab Pegol in Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol 2019; 71: 1101–111 https://onlinelibrary.wiley.com/doi/10.1002/art.40866