Editors' Note: Psoriatic arthritis (PsA) is a chronic inflammatory disease affecting multiple organs that impacts patients from a pain, quality of life and functional ability standpoint. A major focus for patients is analgesia, but also the ability to function and return to a normal life without the fatigue and psychological distress associated with chronic painful disorders. The review below examines PsA and newer treatment options including biologics (DMARDs), conventional synthetic (csDMARDs), targeted synthetic (tsDMARDs), and the most recent to market, the interleukin-17 (IL-17) inhibitors. The latter include secukinumab (Cosentyx), ixekizumab (Taltz), and brodalumab (Siliq). Our rating focuses on the IL-17 inhibitors – the speed with which these newer agents with pharmacological nuances are becoming available is quite exciting. Considering the improved tolerability of the IL-17 inhibitors, the novelty, risk-benefit ratio, clinical utility, and scientific rigor of studies, we assign a 4.5/5 STARS.
–PPM Editors-at-Large Jeff Gudin, MD, and Jeffrey Fudin, PharmD
Diagnosing Psoriatic Arthritis
Psoriatic arthritis (PsA) is an inflammatory disease that compromises joint integrity and functionality. PsA decreases the overall quality of life (QoL) in those diagnosed by significantly impacting mobility,.¹˒² Simialr to plaque psoriasis (PsO), patients present with physical discomfort and concomitant extra-articular manifestations.³ While prevalence has not been precisely identified, estimates of PsA in the United States provide a relative rate of 250 people per 100,000.⁴
Unfortunately, no single test is available to diagnose PsA, and workup includes physical examination of skin and affected joints as well as additional laboratory workup.⁵
Treating PsA with Disease-Modifying Drugs
Treatment for PsA involves therapies that target and disrupt the inflammatory pathways causing joint damage. While agents like NSAIDs and steroids may be helpful in mild disease, alternative agents are often needed in more advanced or active disease.
Disease-modifying anti-rheumatic drugs or, DMARDS, are preferred in active disease and can be classified into three main categories:
biologics (bDMARDs) – biologics
conventional synthetic (csDMARDs) – including oral small molecule agents such as methotrexate (MTX) and cyclosporine
targeted synthetic (tsDMARDs) – such as those which inhibit Janus Kinases (JAK) or phosphodiesterase-
DMARDs are particularly beneficial overall in active disease because they alleviate symptoms by reducing complex disease progression.
Evaluating PsA Treatment Response
When evaluating treatment response, the American College of Rheumatology score (ACR) is used to assess symptom improvement to medication therapy.⁶ The ACR20 is a validated scale that measures the improvement in symptoms of PsA, with accepted criteria of 20% improvement in the number tender and swollen joints, and 20% improvement in three of the following five criteria:
patient global assessment
physician global assessment
functional ability measure
pain
acute phase reactants (ie, ESR or C-reactive protein)
The ACR50 and ACR70 are the similar to the ACR20, however the accepted percentage improvement is increased to 50% and 70%, respectively.
According to the 2018 ACR consensus guidelines, the subclass of bDMARDs- tumor necrosis factor-alpha inhibitors (TNFα-i), are recommended over csDMARDS and other bDMARDs in medication naïve patients with active disease.⁷
PsA Treatment Side Effects
However, bDMARDs use can be limited by tolerability and adverse events, commonly upper respiratory infection (17%), headache (12%), rash (12%), and gastrointestinal side effects (7-9%).⁸ It has been estimated that up to 10% of PsA treatment regimens utilizing TNFα-i are discontinued due to intolerability, further highlighting the need for alternative therapies.³
Emerging Treatments for PsA: Interleukin Inhibitors
Numerous cytokines have been identified in the PsA inflammation pathway, and Interleukin-17 (IL-17) serves as a novel target of the pro-inflammatory cascade by activating osteoclast precursors and acting on synovial cells and keritoncytes.⁴ The recently FDA approved bDMARDS secukinumab (Cosentyx), ixekizumab (Taltz), and brodalumab (Siliq) have demonstrated improvement in joint inflammation and pain by modulating the IL-17 pathway.⁵ Table I describes the FDA-approved IL-17 inhibitors available at the time of this writing.
IL-17 Inhibitors for Psoriatic Arthritis Aim to Reduce Pain and Improve Function and Treatment Adherence
Secukinumab
FDA approved secukinumab in 2016 based upon the FUTURE-2 and EXCEED trials. The FUTURE-2 trial compared secukinumab to placebo, finding that secukinumab improved ACR20 at 24 weeks.⁹ An ACR20 was achieved in all secukinumab cohorts – 300 mg, 54% (P<0.0001); 150 mg, 51% (P< 0.0001); 75 mg 29% (P=0.0399) – when compared to placebo (15%).
In the EXCEED study, secukinumab was an effective treatment alternative when compared with adalimumab as monotherapy in patients who were bDMARD naïve.¹⁰ While secukinumab failed to demonstrate superiority of improving ACR20 response at 52 weeks, secukinumab had a higher proportion of medication adherence compared to adalimumab, with discontinuation rates of 14% and 24, respectively at week 50. Discontinuation of therapy was primarily due to intolerability (7%) and lack of efficacy (7%) for adalimumab, compared to (4%) in both secukinumab cohorts.
Adverse drug event (ADE) rates for secukinumab 300 mg were similar to adalimumab with nasopharyngitis (19%) and upper respiratory tract infections (10%) being most prevalent. Injection sites reactions occurred at a lower rate for secukinumab (1%) when compared to adalimumab (7%).
Ixekizumab
FDA approved ixekizumab in 2017 based upon the SPIRIT-P2 trial and the SPIRIT-H2H trials. SPIRIT-P2 examined ixekizumab versus placebo for the management of PsA in TNF-α-i treatment failure cohorts.¹⁷ The primary outcome was the percent of patients achieving an ACR20 at 24 weeks. Both treatment cohorts, ixekizumab every 4 weeks (53%) and ixekizumab every 2 weeks (48%) reached statistically significant improvement at 24 weeks compared to placebo (20%). The effect size of ixekizumab compared to placebo for the primary ACR20 outcome was 33.8% (95% CI 22.4% - 45.2%) in the ixekizumab every 4 weeks group, and 28.5% (95% CI 17.1% - 39.8%) in the ixekizumab every 2 weeks cohort. These effect sizes demonstrate that the outcomes are clinically significant and not solely statistically significant. The proportions of patients who met the ACR20 and ACR50 response were significantly higher in both treatment groups when compared to placebo. Injection-site reactions (18%), upper respiratory tract infection (9%), nasopharyngitis (5%), and sinusitis (5%) were the most common ADE’s identified.
SPIRIT-H2H demonstrated ixekizumab’s efficacy in improving symptoms in patients with both PsA and psoriasis when compared to adalimumab·¹⁸ The primary endpoint was the proportion who achieved combined ACR50 and PASI 100 responses. The Psoriasis Area and Severity Index (PASI) is a method of quantifying disease severity and extent by examining clinical manifestations of psoriasis, such as erythema, scaling, and lesion development.¹⁹ The accepted 50% and 100% improvement in ACR and PASI were statistically significant in the ixekizumab (39.7%) monotherapy group when compared to the adalimumab (20.2%) monotherapy group (p = 0.002). Ixekizumab had similar proportion of patients who met the primary outcome regardless of MTX use.
Brodalumab
Brodalumab is currently FDA approved for psoriasis and not PsA.¹³ Phase 3 trials for PsA were terminated in 2015 due to brodalumab’s sponsorship terminating the co-development of the drug. This decision came after reports of a serious safety concern for suicidal ideation and behavior (SIB). After termination, however, pooled data of the AMVISION-1 and AMVISION-2 trials were examined for ACR20 response comparing brodalumab to placebo.²⁰
ACR20 rates at Week 16 were significantly higher in both brodalumab treatment arms, 280 mg, (47.9%) and 140 mg (45.8%), (p< 0.0001) when compared to placebo (20%). Only 962 participants of the 1,125 goal were enrolled at the time of termination.
The SIB risk that lead to early termination of the PsA trials were reported in 34 of 4,464 (0.8%) patients during the psoriasis trials.¹³ Of the 10 subjects who attempted or completed suicide, eight had a history of depression or SIB, and four died by suicide during the trials.¹³˒ ²¹ In the AMVISION trials, one patient reported SIB by Week 16, which was determined to be non-treatment related and resolved promptly.²⁰ Although there is no causality between SIB and brodalumab use, the drug was approved with a REMS requirement for patient safety and monitoring. Due to these safety concerns, use in clinical practice and accessibility are currently limited.¹³
IL-17 Inhibitors to Treat Psoriatic Arthritis: Clinical Use
Both secukinumab and ixekizumab demonstrated significant improvement in ACR20 response compared to placebo in patients with PsA. While secukinumab failed to demonstrate superiority over adalimumab, a lower discontinuation rate was identified and may improve treatment adherence. When compared to adalimumab, ixekizumab monotherapy demonstrated superiority over adalimumab in improving articular and extra-articular outcomes. These trials reveal IL-17 inhibitors as an optimistic alternative to TNFα therapies, as efficacy was similar in joint outcomes and patient tolerability improved. In addition, ixekizumab demonstrated superiority over adalimumab at improving both joint and skin outcomes in patients with PsA and may be preferred in patients with extensive skin involvement. (see also, interleukin inhibitors for rheumatoid arthritis.)
Brodalumab demonstrated significant improvements in ACR20 rates at Week 16, indicating rapid symptom improvement. Despite conflicting safety data between psoriasis and PsA treatment, brodalumab does appear to offer significant benefit in improving disease. Although it cannot be recommended at this time for PsA, further trials are needed to support its use as an alternative for PsA.
EULAR Guidelines Point to bDMARDS
Overall, IL-17 inhibitors have exhibited substantial benefit in managing both articular and extraarticular disease in patients with PsA. The 2018 ACR guidelines were not able to include the newer IL-17 trials into their consensus recommendations and current evidence recommends TNFa-I as the preferred bDMARD, however the European agency EULAR released a 2019 update to address these new studies.⁵˒⁶ In the updated EULAR guidelines, the current recommendation is that all bDMARDs are viable options with no preference for one over the other. IL-17 Inhibitors were elevated to have the same recommendation as TNFa-I and IL-12/23 inhibitors. The EULAR guidelines mention evaluating individual components of each agent on a case-by-case basis, and specifically note that IL-17 inhibitors should especially be considered in those with relevant skin involvement.⁵
Clinical trials support bDMARDs’ respective place in therapy as first-line treatment options to reduce pain and improve activities of daily living due to better toleration in individuals with psoriatic arthritis.
Acknowledgements: The authors thank Ashley Jackson, Pharm D, for her technical editing and clinical expertise in the drafting of this manuscript.