IL-17A Inhibition: A Treatment Option for Psoriatic Arthritis With Axial Involvement

Psoriatic arthritis (PsA) is among the subset of seronegative autoimmune rheumatic diseases collectively referred to as spondyloarthritides (SpAs). This subset also includes ankylosing spondylitis (AS), which is the radiographic manifestation of axial spondyloarthritis (axSpA). A heterogeneous inflammatory musculoskeletal disease, PsA is the most common comorbidity of psoriasis, affecting 30% to 33% of people with psoriasis.1,2 

These statistics suggest a subset of patients with psoriasis who are at increased risk for progression to PsA, an erosive disease affecting peripheral and axial joints.5

Progression to axial involvement has been reported in 25% to 70% of patients with PsA, potentially leading to fusion of the vertebrae, with pain, structural damage, and significant functional limitation.5 Data from the Consortium of Rheumatology Researchers of North America registry reveal that compared with patients who have PsA without axial involvement, patients who have PsA with axial involvement exhibit characteristics of significantly worse overall disease activity. This is reflected in their higher scores on the Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index, an elevated level of C-reactive protein, and more significant impairment of quality of life.6 

The mechanism by which psoriasis, an inflammatory skin disease, progresses to PsA with axial involvement is unknown. It is thought that interleukin (IL)-17 is a critical cytokine, and that elevated levels of IL-17 in patients with skin psoriasis with arthralgia are at increased risk for PsA. Therefore, targeting IL-17 inhibition is a reasonable strategy to prevent progression of psoriasis to PsA.
 
This strategy was demonstrated in a small-scale study of 20 patients with psoriasis who presented with arthralgia, inflammatory lesions on magnetic resonance imaging, and synovitis or enthesitis.7 The study found that treatment with the IL-17 inhibitor secukinumab over 24 weeks resulted in significant improvement in symptoms of arthralgia and synovitis. No progression in joint erosion or enthesophytes was reported; there was significant improvement in bone mass.7 This study suggests that targeting IL-17 inhibition might effectively treat psoriasis and prevent both progression to PsA and axial manifestations. The demonstrated pathophysiological relationship between psoriasis and PsA suggests that dermatologists can play a critical role in preventing the progression of psoriasis to PsA; therefore, collaboration with rheumatology has the potential to improve patient outcomes. 

What is the evidence for the role of IL-17 in PsA?

Animal models of chronic inflammation and studies of patients with radiographic axSpA support a role for overexpression of the IL-23/IL-17 pathway in chronic inflammatory disease. IL-23 is essential to promoting IL-17 production; although inhibiting IL-23 in patients with axSpA had no significant effect on clinical manifestations of disease, inhibiting IL-17 did significantly alleviate axSpA signs and symptoms8,9—suggesting that IL-17 is a critical player in the pathophysiology of axSpA.

A proinflammatory cytokine, IL-17 plays an essential role in acute inflammation by stimulating macrophages, fibroblasts, and epithelial and endothelial cells to release cytokines and chemokines involved in promoting inflammation and osteoclastogenesis.7,10 Evidence supports the complex role of IL-17 in enthesitis, neuropathic pain, and bone modulation, including bone formation and erosion—all common in axSpA.9 Given that PsA is a subset of SpA (to which axSpA also belongs), it is reasonable to speculate that IL-17 also plays a vital role in the axial manifestations of PsA. Elevated levels of innate and adaptive cells thought to be involved in IL-17 production have been identified in the blood and synovia of patients with PsA.9 An increased level of these cells has also been found in skin lesions and the blood of patients with psoriasis. Furthermore, IL-17A receptors are expressed on the surface of skin keratinocytes, providing a rationale for progression to PsA.7 Understanding the relationship between IL-23, IL-17, and the role of IL-17 in early PsA provides a rationale for targeting IL-17 in the treatment of PsA.

Why is IL-17 an essential therapeutic target in PsA?

IL-17 targets various cells, including endothelial cells, fibroblasts, and macrophages that promote chronic inflammatory disease, including PsA. IL-17 is, in fact, a superfamily of 6 isoforms (IL-17A to IL-17F). Although the etiology of PsA in patients with skin psoriasis is not well-defined, some evidence suggests that IL-17A is the critical isoform common to both psoriasis and PsA, and is involved in recruiting inflammatory cells and stimulating the innate immune system inflammatory response that leads to clinical manifestations of PsA.11,12 IL-17A involvement in the pathogenesis of PsA has been demonstrated in randomized controlled trials of the effectiveness of IL-17A inhibition in improving clinical outcomes in patients with plaque psoriasis (PsO) and PsA.13-17

Upon binding to a receptor, IL-17A upregulates inflammatory genes implicated in promoting bone formation and regeneration by facilitating osteoblast differentiation and proliferation.18 The effects of IL-17A are augmented by other inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-α). Synergistic effects of IL-17A and TNF-α on keratinocytes maintain a positive feedback loop for increased production of TNF-α and other mediators, as well as upregulation of genes involved in psoriasis.11
 
Inhibition of IL-17A has been shown in clinical studies to affect several manifestations of PsA, including skin and nail findings, peripheral arthritis, axial disease, dactylitis, and enthesitis,9 suggesting that targeting IL-17A might alleviate symptoms of psoriasis and PsA while preventing progression to axial manifestations. This evidence supports clinical development of IL-17A inhibitors for the treatment of PsA with axial involvement.

Which treatments target IL-17A for PsA with axial involvement?

In the past, treatment of PsA with axial involvement was adapted from studies of AS and based on international guidelines developed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; the European League Against Rheumatism; Assessment of SpondyloArthritis international Society; and the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network.19-21 

MAXIMISE (ClinicalTrials.gov Identifier: NCT02721966) was the first randomized controlled study to investigate the safety and efficacy of a biologic agent in patients with PsA. Patients with axial PsA and an inadequate response to nonsteroidal anti-inflammatory drugs were randomly assigned to secukinumab 300 mg, secukinumab 150 mg, or placebo. Secukinumab provided rapid and significant improvement in axial function and symptoms vs placebo; the percentage of patients achieving an ASAS20 response at Week 12 was 63.1% with secukinumab, 300 mg, and 66.3% with secukinumab, 150 mg—vs 31.3% with placebo (P <.0001).22

The demonstrated efficacy of targeting IL-17A inhibition has resulted in the approval of 2 agents, secukinumab and ixekizumab, for the treatment of psoriasis and PsA, as well as AS.23,24
 
Secukinumab, a fully human IgG subclass 1 monoclonal antibody, selectively inhibits IL-17A. The phase 3 FUTURE5 study (ClinicalTrials.gov Identifier: NCT02404350) evaluated the efficacy of subcutaneous secukinumab in improving clinical signs and symptoms and radiographic progression in 996 patients with active PsA. Patients were randomized to receive secukinumab (300 mg or 150 mg, with or without a loading dose) or placebo. Compared to placebo, secukinumab, at all dosages investigated, significantly improved signs and symptoms and inhibited radiographically observed structural progression.14
 

Similarly, the efficacy of secukinumab in patients with psoriasis was demonstrated in 2 phase 3, double-blind trials: ERASURE (ClinicalTrials.gov Identifier: NCT01365455) and FIXTURE (ClinicalTrials.gov Identifier: NCT01358578). In both trials, secukinumab was superior to etanercept and placebo in achieving 75% or more reduction from baseline in the psoriasis area-and-severity index score.13 A pooled analysis of long-term treatment with secukinumab for as long as 5 years in a total of 7355 patients (5181 with PsO, 1380 with PsA, and 794 with AS—representing, respectively, 10,416.9, 3866.9, and 1943.1 patient-years), demonstrated a favorable safety profile.25 These studies further validated IL-17A as a therapeutic target in both PsA and psoriasis, supporting US Food and Drug Administration (FDA) approval of secukinumab for the treatment of SpA, including psoriasis, PsA, and nonradiographic axial SpA.23

Secukinumab adverse effects
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Secukinumab adverse effects commonly reported include nasopharyngitis, diarrhea, and upper respiratory tract infection.

Ixekizumab is a humanized IgG subclass 4 monoclonal antibody approved for the treatment of psoriasis, PsA, and AS.24 The efficacy of ixekizumab for the treatment of patients with active PsA was demonstrated in the double-blind, randomized phase 3 SPIRIT-P1 clinical trial (ClinicalTrials.gov Identifier: NCT01695239). Overall, in patients with active PsA naive to a biologic, treatment with ixekizumab resulted in improvement in disease activity and physical function and inhibition of progression of structural damage.17 The UNCOVER series of clinical trials (ClinicalTrials.gov Identifiers: NCT01474512 [UNCOVER-1], NCT01597245 [UNCOVER-2], and NCT01646177 [UNCOVER-3]) also demonstrated the efficacy of ixekizumab in patients with moderate to severe PsO,16 including efficacy and safety in long-term treatment extension through 5 years.26

Ixekizumab adverse effects
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Ixekizumab adverse effects commonly reported include injection site reactions, upper respiratory tract infection, nausea, and tinea infections.

Approval of secukinumab and ixekizumab by the FDA supports the role of IL-17A in advanced PsA with axial involvement. These agents’ FDA indication for psoriasis suggests that treating a patient with psoriasis or PsA early might slow or prevent disease progression. In support of this hypothesis, data from the IVEPSA study (an arm of the PSARTROS program; ClinicalTrials.gov Identifier: NCT02483234) suggest that very early treatment of PsA, particularly in high-risk patients, can result in a comprehensive reduction in skin symptoms, pain, and subclinical inflammation.7 It also offers the opportunity for other agents in this class to be used for the treatment of PsA. Indeed, several investigational agents targeting IL-17A are in mid-stage or late-stage clinical development (Table), potentially expanding options for PsA treatment.10

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These preclinical and clinical studies support the role of IL-17A in the pathophysiology of psoriasis and PsA. It is essential that dermatologists and rheumatologists are knowledgeable about the role of IL-17A in psoriasis and PsA pathology and work collaboratively to achieve optimal patient management.

References

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  2. National Psoriasis Foundation. About psoriasis. Updated January 14, 2021. Accessed May 4, 2021. www.psoriasis.org/about-psoriasis/
  3. Johns Hopkins Arthritis Center. Psoriatic arthritis. Updated February 5, 2020. Accessed May 4, 2021. www.hopkinsarthritis.org/arthritis-info/psoriatic-arthritis/
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  5. Gottlieb AB, Merola JF. Axial psoriatic arthritis: an update for dermatologists. J Am Acad Dermatol. 2021;84(1):92-101. doi:10.1016/j.jaad.2020.05.089
  6. Spondylitis Association of America. In psoriatic arthritis, axial involvement is associated with more severe psoriasis.  August 2018. Accessed May 4, 2021. https://spondylitis.org/research-new/in-psoriatic-arthritis-axial-involvement-is-associated-with-more-severe-psoriasis/
  7. Kampylafka E, Simon D, d’Oliveira I, et al. Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation—data from the prospective IVEPSA study. Arthritis Res Ther. 2019;21(1):178. doi:10.1186/s13075-019-1957-0
  8. Sieper J, Poddubnyy D, Miossec P. The IL-23-IL-17 pathway as a therapeutic target in axial spondyloarthritis. Nat Rev Rheumatol. 2019;15(12):747-757. doi:10.1038/s41584-019-0294-7
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  10. Tsukazaki H, Kaito T. The role of the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritis. Int J Mol Sci. 2020;21(17):6401. doi:10.3390/ijms21176401
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  14. Mease P, van der Heijde D, Landewé R, et al. Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study. Ann Rheum Dis. 2018;77(6):890-897. doi:10.1136/annrheumdis-2017-212687
  15. Mease PJ, McInnes IB, Kirkham B, et al; FUTURE 1 Study Group. Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med. 2015;373(14):1329-1339. doi:10.1056/NEJMoa1412679
  16. Gordon KB, Blauvelt A, Papp KA, et al; UNCOVER-1 Study Group; UNCOVER-2 Study Group; UNCOVER-3 Study Group. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356. doi:10.1056/NEJMoa1512711
  17. Chandran V, van der Heijde D, Fleischmann RM, et al. Ixekizumab treatment of biologic-naïve patients with active psoriatic arthritis: 3-year results from a phase III clinical trial (SPIRIT-P1). Rheumatology (Oxford). 2020;59(10):2774-2784. doi:10.1093/rheumatology/kez684
  18. Ono T, Okamoto K, Nakashima T, et al. IL-17-producing γδ T cells enhance bone regeneration. Nat Commun. 2016;7:10928. doi:10.1038/ncomms10928
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  21. 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(2):282-298. doi:10.1002/art.39298
  22. Schreiber S, Colombel J-F, Feagan BG, et al. Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials. Ann Rheum Dis. 2019;78(4):473-479. doi:10.1136/annrheumdis-2018-214273
  23. Cosentyx. Prescribing information. Novartis; 2018. Updated June 2020. Accessed May 4, 2021. www.novartis.us/sites/www.novartis.us/files/cosentyx.pdf
  24. Taltz. Prescribing information. Eli Lilly and Company; 2020. Updated March 2021. Accessed May 4, 2021. https://uspl.lilly.com/taltz/taltz.html#pi
  25. Deodhar A, Mease PJ, McInnes IB, et al. Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data. Arthritis Res Ther. 2019;21(1):111. doi:10.1186/s13075-019-1882-2
  26. Leonardi C, Reich K, Foley P, et al. Efficacy and safety of ixekizumab through 5 years in moderate-to-severe psoriasis: long-term results from the UNCOVER-1 and UNCOVER-2 phase-3 randomized controlled trials. Dermatol Ther (Heidelb). 2020;10(3):431-447. doi:10.1007/s13555-020-00367-x

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Clinical Pain Advisor had no role in this content’s preparation.

Reviewed May 2021

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