Overcoming ankylosing spondylitis, the current treatment of new progress

Axial spondyloarthritis (axSpA) is an immune-mediated inflammatory disease primarily affecting the axial skeleton, but also peripheral joints, tendon terminals, and extra-musculoskeletal organs such as the eyes, skin, and gut (Figure 1).
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AxSpA primarily affects young adults and is associated with chronic symptoms such as pain, stiffness and fatigue, leading to impaired quality of life and disability
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Substantial progress has been made in the diagnosis and treatment of axSpA over the past two decades
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With the advent of the International Society for the Assessment of Spondyloarthritis (ASAS) axSpA classification, clinicians are able to identify patients with early disease (non-imaging axSpA, nr-axSpA), as well as patients with radiographic sacroiliitis (known as ankylosing spine) inflammation (AS) or imaging axSpA (r-axSpA))
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The therapeutic goals of axSpA are to improve signs and symptoms; control inflammation and delay imaging progression; prevent complications; maintain physical function, work, and social participation; and ultimately improve health-related quality of life
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Figure 1: Pathogenesis of Axial Spondyloarthritis Although there are no laboratory biomarkers other than C-reactive protein (CRP) and HLA-B27 to aid in the diagnosis, it increases the risk of abnormal lesions on MRI of the sacroiliac joint and spine.
Identification and interpretation facilitate early diagnosis of axSpA
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Regarding drug therapy, in addition to NSAIDs and TNF inhibitors, IL-17 inhibitors have been approved by the FDA and EMA for the treatment of AS and nr-axSpA
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Janus kinase (JAK) inhibitors have also shown promising efficacy in phase III studies in AS, which led to EMA and FDA approval of tofacitinib for AS and EMA to upadacitinib for AS
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Three biologics DMARDs (bDMARDs), certolizumab (a TNF inhibitor), secukinumab, and ixekizumab (both IL-17 inhibitors), have been FDA-approved for nr- axSpA, while all TNF inhibitors (except infliximab), secukinumab and ixekizumab are EMA-approved for nr-axSpA
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Nonpharmacological Treatment of axSpA Arguably, in axSpA, physical therapy and regular exercise are just as important as drug therapy in improving symptoms and function through maintenance of posture and spinal flexibility
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Consistent with the ASAS–EULAR recommendations, the 2019 ACR–SAA–SPARTAN guidelines strongly recommend that patients with active and stable axSpA receive physical therapy
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A systematic review of 24 studies found that regular exercise improves physical function and disease activity, but there is less evidence for improvements in pain, stiffness and spinal mobility
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Uncertainty remains about the most effective exercise program for axSpA; however, supervised group exercise provides more benefits than unsupervised home exercise
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A 2020 study from the United Kingdom showed that AS patients with sedentary behaviors had worse exercise capacity and quality of life than patients with active life>
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In general, patients with axSpA should be strongly encouraged to do regular strengthening exercises
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Pharmacotherapy of axSpA NSAIDs NSAIDs are the initial drug of choice for axSpA
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They work by inhibiting cyclooxygenase 1 (COX1) and COX2 enzymes
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Various NSAIDs are equally effective, and there is currently no preferred NSAID for the treatment of axSpA
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About 25% of patients have adverse reactions that are not tolerated by NSAIDs
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Caution should be exercised with long-term use of NSAIDs because they are associated with several comorbidities of axSpA, including hypertension, peptic ulcer disease, worsening of underlying IBD, chronic renal insufficiency, and cardiovascular disease
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Conventional synthetic DMARDs Trials of conventional synthetic DMARDs (csDMARDs), such as methotrexate and sulfasalazine, for the treatment of AS have shown disappointing results for axial symptoms, especially spinal pain
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In a 16-week open-label study, methotrexate did not improve axial manifestations of AS, but signs and symptoms of peripheral arthritis did; therefore, csDMARD may play a role in the control of peripheral inflammatory arthritis
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Evidence is more favorable for sulfasalazine compared with methotrexate for axSpA peripheral arthritis
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Retrospective cohort studies of csDMARDs (especially methotrexate) combined with TNF inhibitors to prolong drug survival (ie, treatment continuation rates) in AS patients have produced conflicting results
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The 2019 ACR–SAA–SPARTAN guidelines recommend against co-administration of methotrexate with TNF inhibitors
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Biologics DMARD1.
TNF inhibitor TNFα is a pleiotropic cytokine that promotes inflammation by activating leukocytes, triggering the downstream production of pro-inflammatory cytokines by immune cells, stimulating inflammatory cells to migrate to the intercellular matrix, and inducing fibroblast proliferation.

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Early translational studies reported increased TNF mRNA and protein in sacroiliac joint biopsy specimens from AS patients
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Based on the results of subsequent clinical trials, TNF inhibitors have become the mainstay of management in patients with axSpA who have an inadequate response to or intolerance to NSAIDs
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Initial RCTs of the TNF inhibitors etanercept, infliximab, adalimumab, and golimumab in AS patients showed that approximately 60% of patients treated with TNF inhibitors achieved ASAS20 responses, and 40% achieved ASAS20 responses.
ASAS40 responds
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All TNF inhibitors were shown to improve spinal and peripheral musculoskeletal manifestations, such as enthesitis and dactylitis, as well as CRP levels and MRI-detectable inflammation in the sacroiliac joints and spine
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All TNF inhibitor monoclonal antibodies, but not the TNF soluble receptor (etanercept), are effective against uveitis and inflammatory bowel disease
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Figure 2: ASAS40 Responses in AS Clinical Trials In RCTs of nr-axSpA patients, certolizumab was superior to placebo in achieving major improvements in ASDAS at weeks 12 and 52 (47% of patients at week 52).
7% of patients in the placebo group)
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Based on the results of this trial, certolizumab became the only TNF inhibitor approved by the FDA for the treatment of nr-axSpA in the United States
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All TNF inhibitors except infliximab have been approved in the EU for the treatment of nr-axSpA since 2012
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Figure 3: ASAS40 Responses in the nr-axSpA Clinical Trial Can improve clinical signs and symptoms of AS
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Both were associated with improvements in spinal symptoms, peripheral arthritis, dactylitis, enthesitis, and psoriasis, as well as improvements in spinal mobility, physiology, health-related quality of life, and work productivity
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In a phase III study, ixekizumab demonstrated superior ASAS40 responses (25-30%) over placebo (12.
5%) at week 16 in AS patients with prior intolerant or inadequate response to TNF inhibitors )
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Both drugs have completed studies in patients with nr-axSpA and have shown similar efficacy, leading to FDA and EMA approval for the treatment of nr-axSpA
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Brodalumab is an anti-IL-17 receptor A (IL-17RA) monoclonal antibody
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It inhibits several cytokines of the IL-17 family, including the IL-17A–IL17F heterodimer, IL-17C, and IL-17E
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In a phase III study involving patients with axSpA, brodalumab was associated with ASAS40 responses in 43% compared to 24% in the placebo group
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These results are comparable to those of IL-17A inhibitors
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IL-17 is an important cytokine for maintaining the integrity of the gastrointestinal mucosa
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New-onset IBD or exacerbations of underlying IBD have been reported in patients receiving secukinumab and ixekizumab
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It is recommended that patients with IBD should avoid IL-17 inhibitors and closely observe patients for signs and symptoms of IBD
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The use of IL-17 inhibitors has been observed to increase the incidence of fungal infections, especially nonsystemic candidiasis
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JAK inhibitors Currently, tofacitinib and upadacitinib have been studied in phase III RCTs of AS patients
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Both were associated with significantly better ASAS40 remission compared to the placebo group
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The FDA recently approved tofacitinib for the treatment of AS, while both tofacitinib and upadacitinib have been approved by the EMA for the treatment of AS
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Notably, the manufacturer suspended two Phase III trials of the selective JAK1 inhibitor filgotinib in AS and psoriatic arthritis (NCT04483687) due to FDA concerns about the drug's risk-benefit profile
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Additionally, in September 2021, based on a review of RCT data, the FDA concluded that tofacitinib use resulted in an increased risk of major cardiovascular events (such as heart attack or stroke), cancer, blood clots, and death
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Because upadacitinib has the same mechanism of action, the FDA requires the same boxed warning for all 3 JAK inhibitors and advocates for clinicians to consider TNF inhibitors before JAK inhibitors
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The IL-23 inhibitors Tildrakizumab, risankizumab and guselkumab are IL-23p19 inhibitors that are effective in the treatment of psoriasis and psoriatic arthritis
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IL-23 and IL-12 share a common p40 subunit, and ustekinumab is an IL-23p40 inhibitor
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The first RCT of ustekinumab in TNF inhibitor-naïve AS patients failed to meet the primary endpoint of ASAS40 response; therefore, two other phase III studies were terminated early
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In a phase II study, risankizumab failed to meet the primary endpoint of ASAS40 response in patients with active AS, suggesting a limited role for IL-23 inhibition in the management of axial inflammation in AS
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The reasons may be as follows: First, the number of IL-23-secreting myeloid cells is reduced in the axial skeleton compared to the peripheral skeleton
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Second, IL-23 may be important in disease development, but not in continued immune-mediated inflammation in the axial skeleton or in the presence of IL-23-independent sources of IL-17
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Conclusions Since the approval of TNF inhibitors for axSpA, the field has been developing rapidly
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Although individualized therapy remains a significant unmet need, there has been substantial progress in the management of axSpA over the past decade
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In addition to TNF inhibitors, bDMARDs that block IL-17A and JAK inhibitors have been approved, and phase III trials of dual IL-17A and IL-17F inhibitors are underway
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Treatment options are also evolving with the advent of many new therapeutic agents
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It's safe to say that the field of spondyloarthritis treatment is experiencing the same boom in rheumatoid arthritis treatment 10 years ago
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Reference: Danve, A.
, Deodhar, A.
Treatment of axial spondyloarthritis: an update.
Nat Rev Rheumatol 18, 205–216 (2022).
https://doi.
org/10.
1038/s41584-022-00761-z