The IL-17 Superfamily: What Future for PsA?

Mar 18, 2014

Can drugs that target the shared interleukin 17/23 pathway improve on existing options for treatment of psoriatic arthritis? A brief overview discusses the options now in testing, and preliminary results.

The discovery of the pro-inflammatory cytokine interleukin-17A (IL-17A) two decades ago led to better understanding of the pathogenesis of psoriasis and psoriatic arthritis (PsA), as well to some new therapeutic options.

The hope is that a range of newer agents against the interleukins will provide alternatives to the tumor necrosis-alpha (TNF-α) inhibitors shown effective in clinical trials against active, persistent PsA. The latter don’t work for all patients and may not improve the entire broad range of PsA symptoms (including enthesitis, joint inflammation, nail abnormalities, and sacroiliitis). Some of them even (albeit rarely) produce psoriasis-like skin lesions.

In a recent phase 3 clinical trial, a fully human monoclonal antibody against the shared IL-12/23 pathway, ustekinumab (Stelara), significantly improved symptoms of PsA .1 Other recent research has produced a number of experimental drugs that selectively target the IL-23 and IL-17 pathways, including secukinumab, the first anti IL17-A agent tested in PsA.2

A review from the University of Glasgow, newly published online in Current Rheumatology Reports, describes recent results from this new class of drugs and challenges to testing new agents for this highly variable condition.3

Crossed Paths

A subset of helper T cells, Th17, preferentially produce IL-17, which plays a major role in orchestrating inflammation in psoriasis.4 Members of the IL-17 cytokine superfamily, designated A through F, share some structural resemblances but have distinctly different activities during adaptive and innate immune responses.3

IL-17 crosses paths with IL-23, sharing the same “axis.” IL-23 sits upstream and is partially responsible for driving IL-17 production by many cells.. Thus they may share functional profiles to some extent. In psoriasis, levels of both are increased in skin lesions. In PsA, the IL-17/IL-23 axis is believed to stimulate overgrowth of synovial fibroblasts, resulting in inflammatory processes that create excess synovial fluid, which may divert key nutrients away from cartilage.3

[[{"type":"media","view_mode":"media_crop","fid":"23493","attributes":{"alt":"IL-17 interleukin-17","class":"media-image","id":"media_crop_4357490747794","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1863","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 399px; height: 184px;","title":" ","typeof":"foaf:Image"}}]]Signals from both IL-17A and IL-17F also activate metalloproteinases and other proinflammatory cytokines, including IL-6. (One agent that targets IL-6, tocilizumab [Actemra], has been FDA-approved to treat rheumatoid arthritis and juvenile idiopathic arthritis.) Its role in PsA is unproven.

Several agents against IL-17 show some promise in PsA:

Secukinumab

Mixed results so far: No significant differences at six weeks in the primary outcome, ACR 20 (20% improvment in American College of Rheumatology indicators) in a small double-blind, placebo-controlled, randomized trial of patients with moderate to severe PsA who met new PsA diagnostic criteria.5 However, the secukinumab group showed significant reductions in C-reactive protein (CRP) and erythrocyte sedimental rate (ESR), as well as improved quality of life and other clinical outcomes.5

Long-term safety and efficacy are now being evaluated in larger phase III studies.4Ixekizumab

Another experimental IL-17A-blocker, ixekizumab improved clinical symptoms of psoriasis in a phase IIIb dose-ranging trial reported in 2012.6

The trial randomized 142 psoriasis patientsto one of four doses of the active drug or to placebo. After 12 weeks, the drug had achieved at least a 75% reduction in the The drug achieved a reduction in the psoriasis area-and-severity index (PASI) score for a large majority of patients (82%), compared with only a small percentage (8%) of those in the placebo group.6

At the highest dose of ixekizumab, patients reporting PsA also showed a significant reduction over baseline in the joint pain visual analogue scale (VAS) at 12 weeks compared with baseline.3

A phase III study in active PsA is now underway.3Brodalumab

The investigational agent brodalumab, a fully human monoclonal antibody that targets the IL-17 receptor (IL17-RA), has also met with success in efficacy and safety trials among patients with active psoriasis.3,7

In a phase II double-blind clinical trial of 168 patients, presented at the 2013 American College of Rheumatology (ACR) meeting, between 37% and 39% of patients (depending on dose) on brodalumab achieved ACR20 by 12 weeks, as against 18% of those on placebo. ACR20 responses increased to 64% by week 24 in the open-label portion of the trial.7

In an earlier dose-ranging phase II clinical trial, reported in 2012, a majority of patients (mean 86%) had a 75% improvement in PASI score at week 12.

Patients in the brodalumab and placebo groups experienced minor adverse events and there were some serious adverse events, including neutropenia.6,7

Safety issues will be examined in a current phase 3 efficacy trial of brodalumab vs. placebo and ustekinumab, as well as a phase 2 clinical trial of PsA treatment.

Treating The Whole Disease

Although the main function of the IL-17/IL-23 pathway in psoriasis and PsA is now well-understood, clinical trials have yet to deliver on this knowledge, in part because PsA has features that are distinctly different both from psoriasis and other forms of arthritis.

Inclusion criteria for most PsA clinical trials are based on disease activity (swollen and tender joint counts), rather than on the extent of skin involvement, so “true assessment of skin improvement in PsA patients is difficult,” note the authors of the review.3

In addition, current PsA clinical trials use ACR response criteria as primary outcomes, even though these criteria were developed for RA and may miss some important joint changes in PsA. Other clinical outcomes important in PsA, such as enthesitis, are often used only as secondary endpoints. And the absence of swollen peripheral joints in some subtypes of PsA excludes these patients from most clinical trials of the condition.3

Use of the Classification for Psoriatic Arthritis (CASPAR) criteria and other new composite outcome measures could improve patient selection and monitoring.2,3 To meet CASPAR criteria, PsA patients must score at least 3 points among the following:

•  Current psoriasis (2 points)

•  A history of psoriasis but no current psoriasis (1 point)

•  A family history/history of psoriasis, but no current disease (1 point)

•  Painful inflammation and sausage-like swelling of finger or toe, dactylitis (1 point)

•  New-bone formation near a joint, juxta-articular bone growth (1 point)

•  Rheumatoid factor (RF) negativity (1 point)

•  Abnormal, shape, texture, thickness of finger or toenails, nail dystrophy (1 point)

But CASPAR alone may not be enough to fine-tune clinical research.

The ultimate goal, say the authors of the review, is to “treat the whole disease entity, rather than just selected currently measured elements.”3

 

 

 

 

References:

1.    Richlin C, Rahman P, Kavanaugh A, et al., Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis. (2014) Jan 30. doi: 10.1136/annrheumdis-2013-204655. [Epub ahead of print] 2014 Jan 30. Open access.

2.   McInnes IB, Sieper J, Braun J, et al.Efficacy and safety of secukinumab, a fully human antiinterleukin-17A monoclonal antibody, in patients with moderate-to severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis (2014) 73:349-356 Published Online First: 29 January 2013 doi:10.1136/annrheumdis-2012-202646.

3.   Frleta M, Siebert S, McInnes IB. The interleukin-17 pathway in psoriasis and psoriatic arthritis: disease pathogenesis and possibilities of treatment. Curr Rheumatol Rep. (2014) 16:414. doi: 10.1007/s11926-014-0414-y.

4.  Genovese MC, Mease PJ, Greenwald MW, et al., Clinical Response To Brodalumab, An Anti-Interleukin-17 Receptor Antibody, In Subjects With Psoriatic Arthritis. ACR 2013 Abstract #817, Arthritis Rheum (2013) 65:S347

5.   Ritchlin CT, Gottlieb A, McInnes IB, et al. Ustekinumab in active psoriatic arthritis including patients previously treated with anti-TNF agents: Results of a phase 3, multicentre, double-blind, placebo-controlled study [abstract]. Presented at ACR 2012, Arthritis Rheum (2012) 64 Suppl:S1080.

6.   Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. (2012) 366:1190–1199.

7.   Papp KA, Leonardi C, Menter A, Ortonne J-P, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. (2012) 366:1181–1189.

x