J Dermatol. 2017 May;44(5):552-559. doi: 10.1111/1346-8138.13698.

Efficacy and safety of dose escalation of infliximab therapy in Japanese patients with psoriasis: Results of the SPREAD study.

Torii H1, Nakano M2, Yano T3, Kondo K2, Nakagawa H4; SPREAD Study Group.

Abstract

Although infliximab is approved for psoriasis, its efficacy is reduced over time in some patients. The aim of this phase III trial is to evaluate efficacy and safety of infliximab dose escalation in Japanese psoriasis patients with loss of efficacy to standard-dose therapy. Patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis or psoriatic erythroderma who showed loss of efficacy to standard-dose therapy received infliximab dose escalation (10 mg/kg every 8 weeks) from weeks 0 to 32. Loss of efficacy was defined as not maintaining 50% reduction in the Psoriasis Area and Severity Index (PASI 50) after achieving PASI 75. Efficacy and safety were evaluated up to week 40. Fifty-one patients received dose escalation and 43 completed the study. PASI 75 and median improvement rate of PASI score at week 40 were 44% and 70.0%, respectively, showing efficacy in skin symptoms. Efficacies in quality of life, nail psoriasis and joint pain were also obtained. Median serum infliximab level increased from less than 0.1 to 1.1 μg/mL from weeks 0 to 40, showing positive correlation between efficacy and serum infliximab level at week 40. Favorable efficacy was observed in patients with detectable serum infliximab levels (≥0.1 μg/mL) at baseline. Incidences of adverse events, serious adverse events, serious infections and serious infusion reactions were 92%, 10%, 4% and 0%, respectively. No marked difference was observed in both efficacy and safety among psoriasis types. No new safety concerns were observed. Infliximab dose escalation was effective and well-tolerated in psoriasis patients with loss of efficacy to standard-dose therapy, suggesting that dose escalation may be a useful therapeutic option for these patients.

KEYWORDS: Japanese; dose escalation; efficacy and safety; infliximab; psoriasis

PMID: 27882586

 

Supplement:

Background

Psoriasis is a chronic immune-mediated skin disease which affects not only skin but also other organs, such as nails and joints. Although the etiology of the disease is not fully elucidated, it was reported that the level of tumor necrosis factor (TNF)α, a pro-inflammatory cytokine, increased in blister fluid or sera of patients with psoriasis, and this increase was correlated with disease activity.

Infliximab (IFX), an anti-TNFα antibody which inhibits the activity of TNFα, has been reported to show excellent efficacy in psoriasis as well as several other inflammatory diseases such as inflammatory bowel disease and rheumatoid arthritis. However, some patients with psoriasis have been reported to show inadequate response and require a dose-escalation of IFX mainly due to its low serum level.

In Japan, IFX was approved for the treatment of several types of psoriasis including plaque psoriasis, psoriatic arthritis, pustular psoriasis, and psoriatic erythroderma at standard-dose treatment (5 mg/kg at Weeks 0, 2, 6, and 14, and every 8 weeks thereafter) in 2010. However, high-dose treatment (10 mg/kg every 8 weeks) was not approved, and the loss of efficacy was reported in some patients who had initially responded to standard-dose treatment in real-world clinical settings. In order to evaluate the efficacy and safety of dose-escalation of IFX in psoriasis patients who showed loss of response, the SPREAD study, a phase III, multicenter, single-arm, 40-week trial, was conducted.

 

Methods

Patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis, or psoriatic erythroderma who showed loss of response were included in the SPREAD study. Loss of response was defined as once achieving Psoriasis Area and Severity Index (PASI) 75 response (a 75% reduction of the psoriasis area and severity) to standard-dose IFX therapy, but then falling below PASI 50 (less than 50% reduction).

Patients with loss of response received 10 mg/kg every 8 weeks from Week 0 to 32, and the efficacy and safety were evaluated until Week 40.

 

Results

Fifty-one patients with loss of response received high-dose (10 mg/kg) of IFX treatment, and 43 completed the study. The median improvement rate of PASI score at Week 40 was 70.0%, and the response was observed from Week 4 with the median improvement rate of 50.5%. PASI 50 response rate (the rate of patients who attained ≥50% improvement) and PASI 75 response rate (≥75% improvement) at Week 40 were 81% and 44% respectively, and the response rate in Global-improvement at Week 40 was 88% (Figure). The rate of patients who attained Dermatological Life Quality Index (DLQI) ≤1 (no effect at all on patient’s life) at Week 40 was 37%. No marked difference was observed in efficacy among psoriasis types. In addition, efficacies in nail psoriasis, and joint pain were observed.

Median serum IFX level at the start of dose-escalation (at Week 0) was 0.1 µg/ml (below the detection limit of IFX), and that at Week 40 was 1.1 µg/ml, resulting in increase of circulating IFX level by dose-escalation. A positive correlation was observed between efficacy and serum IFX level at Week 40.

Occurrence of adverse events, serious adverse events, and serious infections were 92%, 10%, and 4% respectively, showing good tolerability and no new safety signals.

 

Conclusion

Dose-escalation of IFX showed good efficacy and tolerability in psoriasis patients with loss of efficacy to standard-dose therapy, which provides a useful therapeutic option for such patients. On the basis of these results, dose-escalation of IFX was approved for psoriasis in 2016.

 

Figure. Response rates of dose-escalating IFX at Week 40

 

References

  1. Torii H, Nakagawa H; Japanese Infliximab Study investigators. Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial. J Dermatol Sci 2010; 59: 40–9.
  2. Torii H, Nakagawa H; Japanese Infliximab Study Investigators. Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. J Dermatol 2011; 38: 321–34.