Interleukin (IL)-17 Versus IL-23 Inhibitors: Which Is Better to Treat Patients With Moderate-to-Severe Psoriasis and Mild Psoriatic Arthritis in Dermatology Clinics?

IL-17 inhibitors

IL-17 and IL-23 inhibitors are highly efficacious in treating moderate-to-severe psoriasis (PsO), but there is more clinical trial evidence demonstrating the therapeutic benefits of IL-17 inhibitors than IL-23 inhibitors in psoriatic arthritis (PsA), as outlined below.

Inhibition of radiographic progression of joint damage in PsA. IL-17 inhibitors inhibit radiographic progression of joint damage in PsA. The SPIRIT-P1 trial showed that both ixekizumab (IXE) and adalimumab significantly reduced radiographic progression of joint damage compared to placebo.¹ Similarly, 84% of patients with PsA treated with secukinumab (SEC) had no radiographic progression after 2 years.^2-5 Given the abundance of data, the radiographic response is documented on the US Food and Drug Administration labels for both SEC and IXE, yet is notably absent on the IL-23 inhibitor labels.^6-9

Efficacy in very early and oligoarticular PsA. Evidence suggests that IL-17 inhibitors are effective in halting disease progression in early and oligoarticular PsA. In the Interception in Very Early PsA (IVEPSA) study, patients with PsO who had erosive or inflammatory changes on magnetic resonance imaging (MRI) or computed tomography but no clinical signs of arthritis at baseline were treated with SEC for 24 weeks. This led to a reduction in signs of joint inflammation, detected by MRI as well as a significant decrease in visual analog scores for pain and Psoriatic Arthritis Impact of Disease (PsAID) symptom scores.¹⁰

Approximately 50% of patients with PsA have involvement of 4 or fewer joints, which is known as oligoarticular PsA.^11,12 Although evidence for biologics in this form of the disease is limited, a study by Ogdie et al found that SEC improved physical function and disease activity in patients with 1 to 4 affected joints. Specifically, 43.5% of these patients achieved complete remission after receiving SEC compared to only 6.7% in the placebo group.¹¹ Additionally, these responses were sustained through week 52, demonstrating the durability of SEC’s effects in oligoarticular PsA.

Efficacy in axial PsA. IL-17 inhibitors work well in axial PsA (axPsA). The Managing Axial Manifestations in Psoriatic Arthritis with Secukinumab (MAXIMISE) trial examined the efficacy of SEC in treating axPsA.¹³ SEC was superior in improving Assessment of SpondyloArthritis international Society (ASAS) 20 scores after 12 weeks of treatment when compared to placebo. Given this data, IL-17 inhibitors were included in the 2021 GRAPPA treatment recommendations for axial disease.¹⁴ Though there is some evidence based on posthoc analyses from guselkumab (GUS) trials suggesting that IL-23 inhibitors may be effective in treating axial PsA, it is important to note that the observed improvement in the outcome measures used (ie, Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) could reflect disease activities in other PsA domains. Overall, the IL-23 inhibitors lack the same quality of evidence as the IL-17 inhibitors, which directly demonstrated their efficacy in axial PsA in the MAXIMISE trial. For this reason, IL-23 inhibitors are not included in the list of recommended therapies for axial PsA in the GRAPPA 2021 guidelines.¹⁴

Analysis from the trials investigating GUS in patients who have had axial symptoms suggests that these agents might be effective in axial PsA. However, it is also possible that improvement in the outcome measures used (for example, BASDAI) could reflect disease activity in other PsA domains. Because these studies included primarily patients with active PsA, and these agents did not prove effective in axSpA, the evidence is currently too limited and conflicting such that these medications cannot be recommended for axial PsA at this time.

IL-23 inhibitors

Despite both treatments being efficacious in psoriatic disease, IL-23 inhibitors may be the preferred option over IL-17 inhibitors in patients with moderate-to-severe PsO and mild PsA, given multiple lines of evidence described below.

PsO efficacy and persistence. Although both IL-23 and IL-17 inhibitors are among the most efficacious biologics in moderate-to-severe PsO, there is growing evidence that IL-23 inhibitors are superior in durability of response.¹⁵ The IMMerge trial comparing risankizumab (RZB) to SEC showed superior sustained Psoriasis Area and Severity Index (PASI) 90 scores of RZB at 52 weeks (142/164 [86.6%] vs 93/163 [57.1%]; P < 0.001).¹⁶ Similarly, a sustained PASI90 to 172 weeks with RZB was shown in the LIMMitless trial.¹⁷ The ECLIPSE trial comparing GUS to SEC showed superior sustained PASI90 of GUS at 48 weeks (451 [84%] vs 360 [70%]; P < 0.0001).¹⁸ Moreover, the potential mechanistic benefits of IL-23 inhibition were shown through data on greater suppression of CD8+ resident memory T cells in patients treated with GUS compared to SEC.¹⁹ In summary, there are reasons to believe that IL-23 inhibition may have superior long-term outcomes among patients with PsO.

PsA efficacy. IL-23 inhibitors have also been shown to be effective in PsA. The KEEPsAKE trials comparing RZB to placebo showed a greater proportion of patients using IL-23 achieving all primary endpoints as well as secondary endpoints, most notably the stringent composite low disease activity/remission endpoint, minimal disease activity (MDA), and that these responses increase over time to 52 weeks and beyond (week 24 patient global assessment of disease activity: odds ratio [OR] 2.0 [95% CI 1.5-2.7]; week 24 pain: OR 2.2 [1.6-2.9]; week 24 fatigue: OR 1.9 [1.4-2.5]).²⁰ In the DISCover trials comparing GUS to placebo, all primary endpoints were met, including a greater proportion of patients using IL-23 achieving American College of Rheumatology (ACR) 20/50/70 responses at week 24, in addition to key secondary endpoints, such as MDA (159 [64%] vs 81 [33%]; P < 0.0001).²¹ A subset of patients in these trials was also determined to likely have axPsA (312 [28%]) based on an approach whereby patients (1) were identified by the investigator, (2) had BASDAI and spine pain ≥ 4, and (3) were diagnosed with sacroiliitis on imaging. Notably, this subset had clinically important improvement at week 24 in axial symptoms as measured by overall BASDAI and BASDAI without the peripheral joint pain question. Further dedicated studies in axPsA are ongoing.²² In the setting of mild PsA where most patients will not have erosive, damaging disease, the relevance of radiographic inhibition remains unclear.

Safety, convenience, and tolerability. IL-23 inhibitors demonstrate additional qualities that make them a favorable option over IL-17 inhibitors. First, they have an excellent safety profile and are well tolerated by patients. Unlike IL-17 inhibitors, there is no increased risk of candidiasis or inflammatory bowel disease (IBD) flare risk.²³ Certain IL-23 inhibitors are even approved to treat IBD.²⁴ Second, they are more convenient with infrequent dosing (4-6 doses a year), no high burden loading doses, and no ongoing monitoring requirements. Importantly, convenience is strongly associated with adherence, which is critical for a chronic condition such as PsO.²⁵