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Contemporary Management of Moderate to Severe Plaque Psoriasis
Jashin J. Wu, MD

Contemporary Management of Moderate to Severe Plaque Psoriasis

Jashin J. Wu, MD
Recent trials investigating biologics for the treatment of moderate to severe plaque psoriasis have set primary end points as the achievement of PASI 90.59-61 PASI 90 and complete skin remission measured as PASI 100 in response to treatment may be a reasonable goal, given the increased rate of response seen with newer biologic agents.58 In phase 3 trials of the interleukin (IL)-17 inhibitory agents secukinumab, ixekizumab, and brodalumab, PASI 90 was achieved at Week 12 in 59%, 71% and 70% of patients, respectively.57,62,63 As a measure of reference, European and Canadian guidelines have adopted PASI 100 as the standard treatment goal for psoriasis.64 According to the NPF, treatment targets for psoriasis an acceptable response at 3 months after treatment initiation is achieving BSA 3% or less, or BSA improvement of at least 75% from baseline. Clinicians and patients should strive to achieve a target response of BSA 1% or less at 3 months after treatment initiation and at every 6-month evaluation with maintenance treatment.6

The etiological role of chronic inflammation is another important consideration in targeting treatment goals. The chronic inflammation found in psoriasis is also thought to play a causal role in its comorbidities, including obesity, metabolic syndrome, atherosclerosis, and depression.8,21 Treatments for psoriasis help address aspects of this inflammation, and achievement of higher PASI 75, PASI 90, and PASI 100 may reflect better controlled systemic inflammation overall. Targeting a higher therapeutic PASI goal may positively impact these comorbidities through decreasing overall systemic inflammation. However, there is insufficient consolidated data to state this definitively at this time.8

Current Agents in the Treatment of Moderate to Severe Plaque Psoriasis

Recent systemic treatment options for the management of moderate to severe plaque psoriasis fall into 2 classes of agents: biologic and nonbiologic. Biologic agents compose the majority of the most efficacious drugs to treat psoriasis (Table 452- 57, 59, 60-62, 64-74). Classes of biologic agents used to treat plaque psoriasis include TNF inhibitors, IL-12/23 inhibitors, IL-17 inhibitors, and selective IL-23 inhibitors.

TNF Inhibitors

Etanercept

TNF alpha (TNFα) is an inflammatory cytokine believed to be a key mediator of inflammation in the pathogenesis of psoriasis.53,54 Etanercept competitively binds to cell-surface receptors and inhibits endogenous TNF-mediated receptor activation. Etanercept is indicated for the treatment of moderate to severe plaque psoriasis in patients who are candidates for systemic or phototherapy.65 In an early phase 3 trial, patients with clinically stable plaque psoriasis were randomized to treatment with high-dose (50 mg) etanercept (N = 164) or placebo (N = 166). The primary efficacy end point was the proportion of patients achieving PASI 75 at Week 12. In the etanercept treatment group, 49% of patients achieved PASI 75 and 22% achieved PASI 90 at Week 12 compared with 4% and 1% of placebo treated patients, respectively. Patients treated with etanercept continued response at the 24-week assessment; 59% achieved PASI 75 and 30% achieved PASI 90.53

Infliximab

Infliximab is indicated for the treatment of adult patients with chronic severe plaque psoriasis who are candidates for systemic therapy when other systemic treatment options are not deemed medically appropriate.66 Infliximab is a monoclonal antibody that binds and neutralizes the biological activity of TNFα.54 The phase 3 EXPRESS trial evaluated the safety and efficacy of infliximab in patients with moderate to severe plaque psoriasis. Of the 301 patients randomized to treatment with infliximab, 80% achieved PASI 75 and 57% achieved PASI 90 at Week 10 compared with 3% and 1% of placebo treated patients, respectively. Although patients maintained response to infliximab at Week 24, after 50 weeks of treatment, the proportion of patients that achieved PASI 75 and PASI 90 decreased to 61% and 45%, respectively.54

Adalimumab

Adalimumab is an anti-TNFα monoclonal antibody indicated for the treatment of patients with moderate to severe plaque psoriasis.1 The long-term efficacy and safety of adalimumab was investigated in the REVEAL phase 3 trial. In the REVEAL trial, 71% of the patients receiving adalimumab achieved PASI 75, 45% achieved PASI 90 and 20% achieved PASI 100 at Week 16.68 Week 24 data shows there was a slight increase in patients that achieved PASI 90 and PASI 100 (49% and 22%, respectively).68 The ESPRIT Registry is an ongoing, 10-year postmarketing surveillance registry that is tracking the long-term safety and efficacy of adalimumab in the real world environment outside of a clinical trial. The results from the 7-year interim analysis shows the as-observed effectiveness has either increased or remained stable through the 7 years of the registry thus far.75

Some evidence suggests TNF inhibitors may have a positive effect on depression that may be attributed to mediation of anti-inflammatory effects. The results of a phase 3 trial of etanercept showed that patients treated with the drug had less fatigue and depression as assessed by the Beck Depression Inventory (BDI), the Hamilton Rating Scale for Depression (HRSD), and the Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-Fatigue).76 Similarly, a trial of adalimumab found that the drug seemed to reduce symptoms of depression in patients with moderate to severe psoriasis.77

Biosimilars may lower the cost of treating moderate to severe plaque psoriasis. Biosimilars of adalimumab and etanercept were approved for chronic moderate to severe plaque psoriasis and biosimilars of infliximab were approved for chronic severe plaque psoriasis.78-82

IL-12/23 Inhibitor

Ustekinumab

IL-12 and IL-23 have been shown to play an important role in psoriasis pathogenesis, and several available products modulate the levels of these cytokines.52 Ustekinumab is an monoclonal antibody which binds to a subunit shared by IL-12 and IL-23.52 Theresults from the phase 3 PHOENIX-1 and PHOENIX-2 trials demonstrated that at Week 28, 79% of patients with moderate to severe plaque psoriasis achieved PASI 75 in both trials; 54% and 55% achieved PASI 90 and 29% and 30% achieved PASI 100 at the highest dose (90 mg) in PHOENIX-1 and PHOENIX-2, respectively. Patients that discontinued ustekinumab treatment due to unsatisfactory therapeutic effect were deemed treatment failures.52,70 Analysis of the phase 3 PHOENIX-2 trial also showed that ustekinumab treatment improved symptoms of anxiety and depression as measured by the Hospital Anxiety and Depression Score (HADS) and the DLQI.83 Five patients experienced AEs of depression which later normalized.83

IL-17 Inhibitors

Recently developed biologics target IL-17, a pro-inflammatory cytokine whose production is closely dependent on the production of IL-23.45,58 Secukinumab and ixekizumab are agents that target the IL-17A ligand, while a similar drug, brodalumab, targets the IL-17RA receptor subunit which is thought to be shared by several other ligands in the class.58  

Secukinumab 

The phase 3 ERASURE trial of secukinumab found that at Week 12, 82% of patients receiving secukinumab 300 mg achieved PASI 75, 59% achieved PASI 90, and 29% achieved PASI 100.57 The phase 3 FIXTURE trial of secukinumab found similar results, with patients achieving PASI 75, PASI 90, and PASI 100 were 77%, 54%, and 24%, respectively.57 Missing data were imputed conservatively as nonresponses regardless of the reason for missing data.57

Ixekizumab

The safety and efficacy of ixekizumab in patients with moderate to severe psoriasis were evaluated in the UNCOVER-1, UNCOVER-2, and UNCOVER-3 phase 3 trials. The UNCOVER-1 trial compared ixekizumab with placebo. In the group receiving ixekizumab every 2 weeks for the first 12 weeks followed by every 4 weeks, 89% of the achieved PASI 75; 71% achieved PASI 90; and 35% achieved PASI 100.55 At Week 60, the proportion of these patients that achieved PASI 75, PASI 90, and PASI 100 were 80%, 73%, and 55%, respectively.55 The UNCOVER-2 and UNCOVER-3 trials compared ixekizumab with placebo and an active comparator, etanercept. The 2 respective trials showed that 90% and 87% of patients achieved PASI 75, 71% and 68% achieved PASI 90 and 41% and 38% achieved PASI 100 at Week 12 in the group receiving ixekizumab every 2  weeks compared with the relative rates of 42% and 53%, 19% and 26%, and 5% and 7% in the etanercept group.55,62

Brodalumab

Brodalumab is a human IL-17 receptor antagonist indicated for the treatment of adult patients who have failed to respond or lost response to other systemic therapies.69 The safety and efficacy of brodalumab were studied in the phase 3 trials, AMAGINE-1, AMAGINE-2, and AMAGINE-3. The AMAGINE-1 trial compared brodalumab with placebo and showed that 83% of the patients receiving brodalumab achieved PASI 75, 70% achieved PASI 90, and 42% achieved PASI 100 at Week 12.73 Brodalumab was compared with placebo and an active comparator, ustekinumab, in the AMAGINE-2 and AMAGINE-3 trials. In the 2 respective trials, the proportion of patients that achieved PASI 75 at Week 12 were 86% and 85% in the brodalumab groups versus 70% and 69% in ustekinumab groups.64 The proportion of patients that achieved PASI 90 at week 12 were 70% and 69% in the brodalumab groups versus 47% and 48% in ustekinumab groups.64 Patients that achieved PASI 100 at Week 12 were 44% and 37% in the brodalumab groups versus 22% and 19% in the ustekinumab groups.64 At Week 52, the proportion of patients in the brodalumab groups that achieved PASI 75, PASI 90, and PASI 100 in the AMAGINE-2 and AMAGINE-3 trials were 80% in both trials, 75% and 73%, and 56% and 53%, respectively; compared with the respective rates in the ustekinumab groups of 62% and 63%, 48% and 50%, and 29% and 30%.64

Concerns for psychiatric adverse effects have also been raised for brodalumab. Four completed suicides (including an indeterminate one) were reported during the brodalumab psoriasis trials, which was higher than expected.84 However, it is uncertain whether there is a true association between brodalumab and increased rate of suicide due to the presence of confounding variables during the trials. The brodalumab trials’ exclusion criteria did not exclude patients with mental health comorbidities as rigorously as most clinical trials evaluating systemic drugs in patients with moderate to severe psoriasis. The exclusion criteria were designed to mimic the general psoriasis population more accurately.85 Baseline psychiatric disorders, including depression and anxiety, were present in 18% of the patients.85 Furthermore, no increase in suicidal behavior events was seen during the trial in the brodalumab treatment group.84,85 The investigators also found that a greater proportion of patients in the brodalumab group  had improved anxiety or depression symptoms, based on the HADS criteria, compared with patients receiving placebo.85

 
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