There is a significant amount of severe psoriasis patients who are undertreated with currently available medications. Approximately 77% of all patients and 55% of patients with a Psoriasis Area Severity Index (PASI) ≥20 have never been treated with a systemic drug.¹

Most patients with moderate and severe psoriasis are only treated with topical therapy or no therapy at all.² In fact, only 6% of patients actually receive biologics to treated their psoriasis, while the majority with moderate and severe forms are still not getting adequate therapy.²

Low expectations is a common reason for not visiting a healthcare professional, while other patients think that they don’t have symptoms, even though they would be classified as having severe psoriasis.^2,3 Finally, some patients believe that their symptoms are not severe enough to warrant healthcare professional help.²

The severity of psoriasis often dictates the type of treatment. Mild psoriasis is frequently treated with topical therapy, while moderate to severe forms are treated with systemic treatment (including phototherapy). Genital, face, and nail psoriasis can be considered as moderate-to-severe forms when this localization affects the quality-of-life (QoL) of these patients.

The guidelines for disease assessments differentiate mild and moderate-to-severe psoriasis in terms of intensity for erythema, induration, and scaling (Table 1) ⁴.

However, it is important to note that⁴:

• Psoriasis can be considered mild if the BSA >10 or PASI >10 (indicates moderate-to-severe disease) but DLQI ≤10 (denotes no significant impact on QoL)
• Psoriasis can be considered moderate to severe if BSA ≤10 or PASI ≤10 (indicates mild disease) but the DLQI is >10 (denotes significant impact on QoL).

Actual European Guidelines recommend a treatment target of PASI ≥75.⁴

Improved skin and increased QoL are important to patients and both are reflected in current treatment goals:

• ▲PASI <50% or ▲PASI 50-75% and DLQI >5 indicates an inadequate response: modify treatment (increase the dose, reduce dose intervals, combination therapy or change the drug).
• ▲PASI 50-75% and DLQI ≤5 or ▲PASI ≥75% indicates an adequate response: continue treatment.

(▲PASI = improvement from baseline)

The Psoriasis Group of the Spanish Academy of Dermatology and Venereology proposes biologics as first-line therapy for patients with moderate-to-severe psoriasis, at the same level as conventional systemic drugs and phototherapy.⁵ Moreover, this expert group suggests the following therapeutic goals in the treatment of moderate-to-severe psoriasis:

1. Ideal therapeutic goals

• PASI 90
• Psoriasis Global Assessment (PGA) ≤1, or alternative a minimal and controllable localized involvement with topical treatments (PGA ≤2 and PASI <5)
• DLQI ≤1
• Prolonged remissions without loss of efficacy
• No worsening of comorbidities

2. Criteria for an appropriate response initially and in the long term (more than 6 months)

At least one of the following:

• PASI 75
• PASI <75
• PGA ≤1
• DLQI <5

3. Criteria for the minimum efficacy required

• PASI 50
• PASI <50 if the patient is satisfied with the result
• DLQI <5.

The absolute PASI may be a better therapeutic target for patients than PASI response relative to baseline.⁶ In fact, there is a strong correlation between the absolute PASI and DLQI. Approximately 55% of patients with a PASI ≤2.5 at week 24 had DLQI=0, compared to <5% of patients with PASI >5.^6,7

Topical

Calcipotriol plus betamethasone dipropionate aerosol foam is a valuable therapeutic option that achieves rapid itch relief and is well tolerated in patients with body psoriasis.⁸ This foam showed significantly greater efficacy after 4 weeks, than 8 weeks of treatment with calcipotriol plus betamethasone dipropionate gel, with similar tolerability.⁹

Systemic

There continues to be barriers to the prescribing of some conventional systemic treatment because of both physician and patient concerns. Country specific analyses showed national differences in physician perception of safety aspects.¹⁰ For example, in the United Kingdom methotrexate is considered very safe, while in Spain, Italy, and Canada its use raises strong concerns.

In addition, some countries require the use of a specific first-line therapy before being able to continue to a second- and third-line approache.¹⁰ (Table 2).

PDE4 Inhibitor (apremilast)

A phase III, multicenter, double-blind, placebo-controlled study evaluated efficacy/safety of apremilast at 30 mg twice a day for moderate to severe plaque psoriasis.¹¹ At week 16, significantly more patients taking apremilast (33.1%) achieved 75% or greater reduction from baseline PASI versus placebo (5.3%) (p <0.0001). At week 16, the placebo group switched to apremilast through week 32, followed by a randomized treatment withdrawal phase to week 52. Most patients (61.0%) rerandomized to apremilast at week 32 achieved PASI 75 at week 52 versus 11.7% rerandomized to placebo. Therefore, apremilast resulted effective in moderate-to-severe plaque psoriasis.¹¹

Another study demonstrated that apremilast also reduces the severity of nail and scalp psoriasis.¹²

Biologics

TNFα inhibitors: etanercept - infliximab - adalimumab
TNFα inhibitors have been widely available for many years and the efficacy varies from one drug to another.

PASI responses at week 12 (comparisons not from head-to-head trials): ^13-15

• PASI 75: 34% with etanercept 25 mg, 49% with etanercept 50 mg, 68% with adalimumab 40 mg, 80% with infliximab 5 mg/kg

PASI 90: 11% with etanercept 25 mg, 21% with etanercept 50 mg, 37% with adalimumab 40 mg, 57% with infliximab 5 mg/kg.

IL-12/23 inhibitor: ustekinumab
In 2 clinical trials with 12-week durations, ustekinumab 45 mg and 90 mg showed the following PASI 75 response rates:^16,17

• 67.1% and 66.7% for the 45 mg dosage
• 66.4% and 75.7% for the 90 mg dosage

In another study, 70% of ustekinumab-treated patients completed treatment through week 244, with high proportions of patients responding to the 45 mg and 90 mg doses [PASI 75 (76.5% and 78.6%) and PASI 90 (50.0% and 55.5%), respectively].¹⁸

IL-17A inhibitors

Secukinumab

The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept:

• In the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo

In the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (p <0.001 for each secukinumab dose versus comparators)¹⁹

Ixekizumab

Over 2 years, ixekizumab was well tolerated and showed maintenance of efficacy across all endpoints with high skin clearance rates.²⁰
Two clinical trials (UNCOVER-2 and UNCOVER-3) revealed that 90.5% and 87.0% of patients receiving ixekizumab 80 mg every 2 weeks achieved an absolute PASI ≤5 over 12 weeks compared to 55.9% and 41.3 in treatment with etanercept 50 mg biweekly.²¹

IL-17RA inhibitor: brodalumab

Binding to the IL-17 receptor with brodalumab inhibits multiple pro-inflammatory cytokines.²² The median time to PASI 90 response was shorter in the brodalumab group (6.43 weeks) compared with ustekinumab (12.1 weeks).²³

IL-23 inhibitors

Guselkumab

Greater proportions of patients treated with guselkumab achieved PASI 75 (97.5%) and PASI 90 (82.3%) at 100 weeks.²⁴

Tildrakizumab

Tildrakizumab 200 mg and 100 mg is well tolerated in the treatment of patients with moderate to severe chronic plaque psoriasis and resulted efficacious compared with placebo and etanercept:

PASI 75 at week 12: 66% with tildrakizumab 200 mg, 61% with tildrakizumab 200 mg, 48% with etanercept 50 mg, and 6% with placebo.²⁵

Risankizumab
50% of patients achieved PASI 90 at week 48 after 3 drug doses.²

Based on the safety data of many of the new systemic therapies, the newer drugs are safer than the older ones. However, certain monitoring should be required when using specific treatments (Table 3).