Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

65th Annual Meeting of the American Academy of Dermatology

Washington, DC / February 2-7, 2007

A series of major multicentre trials presented here at the 2007 AAD annual meeting have greatly expanded the data supporting the routine use of biologics in the control of psoriasis. The validation of biologics in the new group of studies is based not only on large improvements in PASI (Psoriasis Area and Severity Index) scores but also in potentially more important outcomes from the patient’s perspective, such as improved quality of life (QoL) and overall productivity.

Biologics in Maintenance Therapy

One of the most important questions addressed in the new findings is whether biologics can be used in maintenance therapy. A new study has evaluated continuous vs. discontinuous therapy with a biologic over 120 weeks. As a biologic also approved for use in rheumatoid arthritis and inflammatory bowel disease, infliximab has demonstrated very high response rates with manageable side effects in data collected over two years. There were no controlled studies evaluating efficacy and safety beyond one year of treatment. For agents like infliximab, which has demonstrated a high degree of efficacy even in psoriasis highly refractory to conventional treatments, there have been no data to guide long-term use. The goal of this study was to compare the efficacy and safety of this biologic in a group of patients who were maintained on therapy to those who discontinued treatment after 22 weeks. Each group contained 15 patients, and the differences in efficacy over the course of 120 weeks favouring maintenance were progressive.

According to Dr. Sergio Chimenti, Department of Dermatology, University of Rome Tor Vergata, Italy, “After 120 weeks of follow-up, no severe adverse events [AEs] or hypersensitivity reactions were [seen] in the group on continuous therapy. When compared to the group that discontinued therapy after 22 weeks, the major difference was in regard to efficacy.” Commenting on a study led by colleague Dr. Alessandro Giunta for which he served as a co-author, Dr. Chimenti concluded that in patients with persistent plaque-like psoriasis, infliximab “seems to be more effective in a continuous than in a discontinuous regimen.”

He reported, “In the maintenance group, patients received infliximab in a dose of 5 mg/kg at weeks 0, 2, 6, and every eight weeks thereafter up to 120 weeks.” Although the same dose and schedule was used for the first 22 weeks in the comparison group, no further treatment was given after this point until there was a loss of response, defined as a decline of 50% or more in the initial PASI improvement. A single infliximab re-treatment was permitted at this point.

Study Findings

While a PASI 75 (75% improvement from baseline) was achieved in approximately 80% of both groups by the end of week 22, control of psoriatic lesions diverged at all scheduled evaluations after this point. In the maintenance group, the proportion of patients who achieved or maintained a PASI 75 fluctuated over the 120 weeks from 66.7% at week 46 to 87% at week 120. In contrast, less than half of the patients had a PASI 75 at week 48 of the re-treatment period, and five patients had withdrawn from treatment by this time point because of lack of response. The median time to relapse in the group that discontinued therapy after 22 weeks was 187 days. In the maintenance arm, median time to relapse was not reached because almost 90% of patients maintained or reached PASI 75 at the end of the study.

The most common AE in either group was headache after infusion. There were no serious AEs attributed to therapy and no evidence of immune-related complications, such as serious infections or lymphoproliferative disorders. Dr. Chimenti told the audience, “Toxicity seems to be a minor concern and seems not to correlate with the duration of treatment.” Although he called for larger randomized studies to confirm these results, he indicated that the efficacy and safety observed in this group provides reassurance for those who require maintenance treatment to achieve sustained psoriasis control.

Measuring Quality of Life

PASI scores are an important method of objectively confirming benefit, but the devastation of psoriasis is perhaps best measured in QoL, which has been found to be similar or worse than many life-threatening diseases such as cancer and advanced cardiovascular impairment. New data generated from the multinational EXPRESS II (the second Evaluation of Infliximab in Psoriasis in an Efficacy and Safety Study) associated the biologic with profound and persistent improvements in QoL relative to placebo. This translated into other important measures of daily living such as productivity.

According to Dr. Alan Menter, Baylor University Medical Center, Dallas, Texas, “At baseline, norm-based physical domain scores of the SF-36 [Short Form 36 QoL assessment tool], which measures productivity in work and daily activities affected by physical health, were low. On any infliximab treatment, including crossover after initial placebo, there was significant productivity improvement. The best productivity improvement through week 50 was in the group receiving 5 mg/kg infliximab every eight weeks.”

In EXPRESS II, a study that included centres in Canada, 835 patients with moderate-to-severe psoriasis were randomized to induction doses of infliximab 3 mg/kg, 5 mg/kg or placebo at weeks 0, 2 and 6. Patients in the active treatment groups were then re-randomized at week 14 to receive scheduled infliximab every eight weeks or as needed, at the doses they received during induction. At week 16, placebo patients crossed over to the 5 mg/kg cohort through week 46 after following the same induction period as the original group.

Much like the first EXPRESS study, an earlier multicentre trial with a similar design that randomized 378 patients, EXPRESS II demonstrated the greatest improvement in the QoL outcome among those patients who received the higher active dose every eight weeks. In EXPRESS, the Dermatology Life Quality Index improvement at 10 weeks was 10.3 for infliximab vs. 0.4 for placebo (P=0.001). In EXPRESS II, physical domain scores at week 14 on the SF-36 increased 4.1 for the 3 mg/kg dose, 5.1 for the 5 mg/kg dose, and 0.8 for placebo (P<0.001). At week 50, mean productivity improvements remained above baseline in the groups initially randomized to infliximab, but the advantage relative to placebo was lost because the latter cohort had improved after being crossed over to active treatment at week 16.

Nail Psoriasis

EXPRESS substudy results on nail psoriasis demonstrate another important benefit from biologics. Among the 378 patients randomized to 5 mg/kg or placebo, 80.6 % had nail psoriasis at baseline. All measures of disease in the nail improved in the active treatment group relative to placebo, including a 57.3% vs. a -4.1% (P<0.0001) improvement in Nail Psoriasis Severity Index at week 24.

Remarked Dr. Phoebe Rich, Oregon Health Sciences University, Portland, “These data are promising, because the results demonstrate the efficacy of infliximab in psoriasis patients whose disease is affecting the nails, a difficult-to-treat and chronic manifestation that affects a larger proportion of patients.”

Other Strategies

Other targeted therapies have also been the focus of encouraging efficacy and safety data in psoriasis. In a different placebo-controlled study led by Dr. Menter, adalimumab, another tumour necrosis factor alpha (TNF-a) inhibitor, was evaluated over 52 weeks in 1212 patients (randomized 3:1 to active therapy vs. placebo). At week 16, a PASI 75 was achieved in a significantly higher percentage of patients in the treatment arm vs. placebo (P<0.001). Response was sustained with continued therapy up to 33 weeks, but there was rapid loss of response after therapy discontinuation. Importantly, the rate of serious AEs was 1.8% in both the active therapy and placebo groups. According to Dr. Menter, the agent was both active and safe.

New safety data with the biologic alefacept, as it inhibits lymphocyte activation, were also reassuring. An evaluation of a phase IV post-marketing study of 1200 treated patients revealed no increase in AEs compared to the background rate in patients with psoriasis. Presented by Dr. James M. Krell, Total Skin and Beauty Dermatology Center, Birmingham, Alabama, the study findings provided additional evidence that biologics can be used safely in psoriasis control.

Summary

The body of data testing the efficacy and safety of biologics in the management of psoriasis has been expanded substantially in a series of newly reported trials. Based on encouraging safety even over long-term follow-up, agents such as the TNF-a inhibitor infliximab are now being evaluated as long-term maintenance therapies. In trials out to one year, new findings not only demonstrate improvement in objective measurements of skin involvement but also important changes in measures of QoL such as productivity. Such outcomes are critical to measuring benefit in patients due to the major negative impact this disease exerts on activities of daily living.