Pimecrolimus Identifies a Common Genomic Anti-inflammatory Profile, is Clinically Highly Effective in Psoriasis and is Well Tolerated Klemens Rappersberger,

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Pimecrolimus Identifies a Common Genomic Anti-inflammatory Profile, is Clinically Highly Effective in Psoriasis and is Well Tolerated Klemens Rappersberger, Michael Komar, Leo Richter, Klaus Wolff, MD, FRCP Journal of Investigative Dermatology Volume 119, Issue 4, Pages 876-887 (October 2002) DOI: 10.1046/j.1523-1747.2002.00694.x Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 (a) Median blood trough concentrations of pimecro limus throughout the study. Blood concentrations of pimecrolimus increased in proportion to the dose and steady state as reached after days 5–10. (b) AUCτvs dose on day 28. AUCτ increased in proportion to the dose. Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Clinical efficacy of pimecrolimus is shown for a patient receiving 20 mg twice daily photographed on day 0 (a) and day 28 (b) and for a patient receiving 30 mg twice daily on day 0 (c) and day 28 (d). Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Clinical efficacy of pimecrolimus as assessed by percent PASI change from baseline for the different dose levels. Efficacy is clearly dose-related and reflects as PASI reduction of 60% and 75%, respectively, on day 28 for doses of 20 mg twice daily (40 mg per day) and 30 mg twice daily (60 mg per day). Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 (a) Median serum creatinine levels in the placebo and various pimecrolimus [5 mg, 10 mg, 20 mg, 20 mg twice daily (= 40 mg per day) and 30 mg twice daily (= 60 mg per day)] dose groups. Serum creatinine never increased more than 30% compared with baseline. There are no notable changes in the creatinine levels from screening to end of study (EOS) scr: screening visit, BL: baseline. (b) Percent change of serum creatinine from baseline at day 28 in the different dose groups and placebo. The highest percent change from baseline was seen in the 20 mg twice daily dose group, which exceeded that of the 30 mg twice daily dose group that showed fewer changes than the placebo group. Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Glomerular filtration rates. Percent changes from baseline BL at day 28 for the different dose groups and placebo. There are no differences between pimecrolimus and placebo-treated patients. bid: twice daily. Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Renal plasma flow. Percent changes from baseline (BL) at day 28 for the different dose groups and placebo. There are no significant differences between the 5 mg, 20 mg twice daily, and 30 mg twice daily pimecrolimus group and placebo-treated patients. The increase of renal plasma flow in the 10 mg pimecrolimus group is unexplained. bid: twice daily. Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Skin biopsy of a patient receiving 30 mg pimecrolimus twice daily at baseline(a) and day 28(b). Section stained for the epidermal proliferation-associated keratin-16 (red). Note significant reduction of epidermal thickness, inflammatory infiltrate, parakeratosis, and loss of keratin 16 staining at the end of the treatment period. This is a reversal of the psoriatic phenotype to almost normal. (c) Shows a section stained for proliferating Ki-67+ keratinocytes. Note significant reduction of Ki-67+ nuclei at end of treatment (d) that accompanies the reduction of acanthosis to that of a normal looking epidermis. Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Ki-67 proliferating keratinocytes at baseline (day 0) and day 28 in a 30 mg twice daily (60 mg) pimecrolimus and placebo-treated patient. Note the significant reduction of Ki-67 positive cells (p = 0.02) under pimecrolimus as compared with placebo. Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 9 Reduction of lymphocytic infiltrate and unchanged numbers of CD1a+ cells (Langerhans cells) during pimecrolimus treatment. (a) CD3+ cells in psoriatic epidermis and dermis at days 0 and 28 at dose levels of 20 mg, 40 mg (= 20 mg twice daily), and 60 mg (= 30 mg twice daily). The reduction of CD3+ cells at dose levels of 20 mg in the epidermis (p = 0.009) and dermis (p = 0.04) and of 60 mg (= 30 mg twice daily) in the epidermis (p = 0.05) and dermis (p = 0.006) are significant. (b) CD4+ cells are significantly reduced at day 28 both in the epidermis (p = 0.02) and dermis (p = 0.01) at the 60 mg (30 mg twice daily) dose level of pimecrolimus. (c) Pimecrolimus reduces CD8 cells in epidermis and dermis, at all dose levels. The reduction of CD8+ cells in the dermis at 60 mg (30 mg twice daily) is significant (p = 0.077). (d) Pimecrolimus does not significantly affect CD1a+ cells in the epidermis and dermis at any of the dose levels of pimecrolimus (e.g., 60 mg per day epidermis p = 0.958; dermis p = 0.887). Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 10 Skin tests for recall antigens in the 30 mg pimecrolimus twice daily patient cohort. Numbers in the right upper corner indicate patient number, patients marked with P are patients on placebo; blue bars indicate pretreatment readings, red bars post-treatment readings, A–H refer to antigens tested: (A) tetanus toxoid; (B) diphtheria toxoid; (C) streptococcal antigen; (D) tuberculin; (E) control; (F) Candida albicans; (G) Trichophyton mentagrophytes; (H) Proteus mirabilis antigens. The figures on the ordinate are diameters in millimeters of positive reactions. There are no consistent changes from pretreatment to post-treatment skin reactions to the recall antigens tested. Journal of Investigative Dermatology 2002 119, 876-887DOI: (10.1046/j.1523-1747.2002.00694.x) Copyright © 2002 The Society for Investigative Dermatology, Inc Terms and Conditions