Study of Psoriasis with Infliximab Induction Therapy

The SPIRIT trial was a multicenter double-blinded, placebo-controlled phase 2 trial that randomized 249 patients to receive IV infusions of infliximab or placebo. Selected patients had plaque psoriasis for at least 6 months, Psoriasis Area Severity Index (PASI) ≥12 or more, and 10% or greater body surface area (BSA) affected. The primary endpoint was the proportion of patients who achieved PASI-75 at week 10. Patients were randomly assigned in a 1:2:2 ratio to infusions of infliximab 3 mg/kg, 5 mg/kg, or placebo and were treated at weeks 0, 2, and 6, and followed to week 30.

Responses were seen after the first infusion of infliximab. By week 2, 34% and 40% of patients in the infliximab 3 and 5 mg/kg groups had achieved PASI-50, compared with 4% in the placebo group. At week 10, 72% of the 3-mg/kg group and 88% of the 5-mg/kg group achieved PASI-75 compared with 6% of placebo. These results correlated with Physician’s Global Assessment (PGA) findings, with 72% and 90% of the infliximab 3- and 5-mg/kg groups, respectively, achieving PGAs of minimal (PGA = 1) or cleared (PGA = 0) psoriasis by week 10. Improvements in quality of life were also noted–the median change in Dermatology Life Quality Index (DLQI) from baseline to week 10 was −8 and −10 for the 3- and 5-mg/kg groups, respectively, compared with 10 in the placebo group.

To assess the safety of re-treatment, patients with PGA ≥ 3 were eligible for a single IV infusion of their assigned treatment at week 26. A month after re-treatment, 38%, 64%, and 18% of patients in the 3-mg/kg, 5-mg/kg, and placebo group had a PsA less than 3 (considered mild, minimal, or clear psoriasis).

Patients were followed up to 20 weeks to assess the duration of response. The maximum response was achieved at week 10 for both the 3- and the 5-mg/kg groups. The response began to decline at week 10 in the 3-mg/kg group and week 14 in the 5-mg/kg group.

In summary, SPIRIT demonstrated that infliximab induction therapy resulted in significant improvement in psoriasis for most patients in the study. After 3 doses of infliximab, the response rates in this study were similar to those seen with cyclosporine, and greater than those achieved by other biologics. The response seen at week 4, with about one-third and one-half of patients in the 3- and 5-mg/kg infliximab groups, was only seen after 12 or more weeks of therapy with other biologics. The improvement in quality of life, as measured by DLQI, was also greater than other biologics or hospital-based treatment ( Fig. 9.2 ).

Efficacy data of SPIRIT trial.

European Infliximab for Psoriasis Efficacy and Safety Study I

The EXPRESS I trial was a multicenter, double-blinded, phase 3 trial that evaluated the efficacy of infliximab induction and maintenance therapy for moderate-to-severe psoriasis. The primary endpoint was the percentage of patients achieving PASI-75 at week 10. The secondary endpoints were PASI-50 and -90 at week 10. Selected patients had moderate-to-severe plaque psoriasis, PASI ≥12, BSA ≥10%, and were candidates for phototherapy and systemic therapy.

In the EXPRESS I trial, 378 patients were randomized to infusions of infliximab 5 mg/kg or placebo. Infusions were given at weeks 0, 2, 6, and then every 8 weeks up to week 46. Patients in the placebo group received placebo infusions at weeks 0, 2, 6, 14, 22 and then crossed over in a double-blinded fashion to receive infliximab 5 mg/kg at weeks 24, 26, 30, and every 8 weeks through week 46.

At week 10, 80% of patients achieved PASI-75 and 57% achieved PASI-90 in the infliximab group. Only 3% and 1% of the placebo group achieved PASI-75 and PASI-90, respectively. This response was maintained at week 24. By week 50, PASI-75 and PASI-90 had dropped to 61% and 45%, respectively. Similarly, 83% of patients attained a PGA of clear or minimal psoriasis by week 10, which dropped to 53% at week 50. This decline in clinical response was associated with low infliximab serum concentrations due to the development of anti-infliximab antibodies. Within the group of patients who achieved PASI-75 at week 10, only 39% who were antibody positive maintained this response through week 50 versus 81% and 96% of the antibody-negative and inconclusive patients, respectively. Being antibody positive did not preclude those patients from having a clinical response, although fewer antibody-positive patients achieved PASI-75 or a maintained clinical response.

Maintenance of clinical response was related to the ability to achieve stable serum concentrations of infliximab. Of the patients who maintained their PASI response through week 50, median preinfusion serum infliximab concentrations were 1.0 μg/mL or greater at weeks 30 and later. The patients who lost response by week 50 had median preinfusion serum infliximab concentrations 1.0 μg/mL or less. Among the patients who achieved PASI-75 at week 10, 89% of patients maintained this response at 6 months and 65% maintained this response at 1 year. No dose escalation or additional therapy was needed, apart from low-potency topical corticosteroids on the face or groin.

In summary, the EXPRESS trial demonstrated the efficacy, rapid onset, and maintenance of therapeutic benefit of infliximab as monotherapy in moderate-to-severe psoriasis. By week 6, about two-thirds of patients achieved PASI-75 and one-third achieved PASI-90, with proportions of these patients continuing to increase during the course of the study. By week 10, one-fourth of patients reported complete clearing. This study also demonstrated that maintenance treatment with infliximab 5 mg/kg every 8 weeks was effective in maintaining clinical response and well tolerated in most patients ( Fig. 9.3 ).

Efficacy data of EXPRESS I trial.

European Infliximab for Psoriasis Efficacy and Safety Study II

The EXPRESS II trial was a phase 3, randomized, double-blinded placebo-controlled trial that investigated the benefit of regular versus on-demand maintenance regimens of infliximab. The EXPRESS II trial was the first biologic study to directly compare maintenance regimens of continuous, every-8-week therapy versus intermittent, as-needed therapy.

The primary endpoint was the percentage of patients achieving PASI-75 at week 10. Other endpoints were improvement in the PGA and DLQI by week 10, and the average percentage improvement from baseline PASI between weeks 16 and 30 and weeks 16 and 50.

All patients had moderate-to-severe psoriasis, with a PASI ≥12 and 10% or greater BSA involvement. This study consisted of 835 patients who were assigned to infliximab 3 mg/kg, 5 mg/kg, or placebo at weeks 0, 2, and 6. At week 14, patients were randomized again to either continuous maintenance therapy or as-needed intermittent therapy at the same dose as the induction phase. In the maintenance group, patients received their assigned infliximab doses at 8-week intervals (weeks 14, 22, 30, 38). In the as-needed group, infliximab was given when the PASI improvement from baseline dropped to less than 75% at the weekly study visits. If PASI improvement was at least 75%, placebo was given. The placebo group was crossed over at week 16 to receive infliximab 5 mg/kg at weeks 16, 18, 22, and every 8 weeks until week 46.

At week 10, 70% and 75% of the 3-mg/kg and 5-mg/kg group had achieved PASI-75 versus 1.9% in the placebo group. PASI-90 was achieved by 37% and 45% of the 3-mg/kg and 5-mg/kg group versus 0.5% in the placebo group.

Efficacy for the maintenance phase was evaluated from week 14 through week 50. Among the week 10 PASI-75 responders, response was better maintained in the every-8-week continuous maintenance group as compared with the as-needed intermittent group. In the patients receiving 3 mg/kg, the median of the average percentage improvement in PASI was 80.6% for the every-8-week group versus 72.4% for the as-needed group. In the patients receiving 5 mg/kg, the median of the average percentage improvement in PASI was 89.6% versus 76.4% for the every-8-week group versus as-needed group. Among the week 10 PASI-75 nonresponders, 59.0% eventually achieved responder status at some point during the maintenance phase across all groups.

This study concluded that the patients in the 5-mg/kg every-8-week continuous therapy group maintained PASI responses better than the 5-mg/kg intermittent treatment group and 3-mg/kg groups. Of the patients assigned to 3 mg/kg, those who received infliximab every 8 weeks maintained PASI responses better than the intermittent treatment group as well. Although infliximab has been shown to provide excellent initial control, a maintenance regimen is important in sustaining adequate response. At the same time, long-term drug exposure should be limited by choosing the lowest effective dose or least frequent interval of drug administration ( Fig. 9.4 ).

Efficacy data of EXPRESS II trial.