Good progress in psoriasis and implications for IBD

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New Treatment For Psoriasis Is Highly Effective

08 Feb 2007

http://www.medicalnewstoday.com/medicalnews.php?newsid=62563

A new treatment for psoriasis that targets its key inflammatory

mediators (IL-12 and IL-23) is highly effective, according to a study

by University of Utah researchers to be published in the Feb. 8 issue

of The New England Journal of Medicine.

Current treatments for psoriasis include topical medicines and UV

light therapy to treat the symptoms of the disease. Many of these

treatments are messy, time consuming, have cumulative toxicities, and

are not very effective, according to Gerald Krueger, M.D., principal

investigator for the study. Krueger is a professor of dermatology and

a Benning Presidential Endowed Chair at the University of Utah School

of Medicine.

He says the results of the study are especially intriguing because of

what it may mean for other immune mediated diseases that share the

same signaling pathways, specifically inflammatory bowel disease

(IBD).

In 2005 another team of researchers (Mannon et al for the anti-IL-12

Study Group) showed that a different human monoclonal antibody to p40

was effective in the treatment of IBD. " These results suggest that

therapeutics that target the IL-12 and IL-23 signaling pathway appear

to effectively treat both psoriasis and IBD, " he said.

According to Krueger, the story of the link between psoriasis and IBD

gains intrigue by events independent of these reports of treatment

success. In October of last year the University of Utah and Celera

Group of Applera Corporation reported at the American Association of

Human Genetics annual meeting that psoriasis patients carry a common

polymorphism in the gene for p40 (IL12B) more often than control

subjects. Further exploration led to a discovery of a second

polymorphism in the receptor for IL-23 that also associates with

psoriasis. These results were recently published in the American

Journal of Human Genetics (Cargill et al. 2007). Duerr and colleagues

(2006) have reported that the same variant in the IL-23 receptor is

associated with IBD. The common forms of these polymorphisms are

associated with risk of both psoriasis and IBD, while the uncommon

forms are protective, according to Krueger.

" This is really an alignment of the stars. It's unusual that

targeting a new inflammatory pathway in two different diseases

provides patients with dramatic improvement, " he said. " And then,

almost simultaneously, we find disease-associated genetic variants in

this same pathway. "

Krueger and colleagues at Celera predict that refinement of disease

association patterns to specific genetic variants within IL-12/23 and

the IL-23 receptor will play an important role in the elucidation of

the causes of psoriasis, and IBD.

Krueger says that, " Further studies should help determine whether any

of the identified differential risk polymorphisms are also associated

with response to therapy and possible toxicities and thereby help

determine the most effective dosage of these new monoclonal antibody

therapies. "

Researchers from Dalhousie University in Halifax, Nova Scotia; St.

Louis University, St. Louis; Mount Sinai School of Medicine, New

York; and Centocor, Inc. of Malvern, Penn.; participated in the

study. The study published was funded by Centocor, Inc.

About Psoriasis:

Psoriasis is a chronic (long-lasting) skin disease of scaling and

inflammation that affects 2 to 2.6 percent of the United States

population, or between 5.8 and 7.5 million people. Although the

disease occurs in all age groups, it primarily affects adults. It

appears about equally in males and females. Psoriasis occurs when

skin cells quickly rise from their origin below the surface of the

skin and pile up on the surface before they have a chance to mature.

Usually this movement (also called turnover) takes about a month, but

in psoriasis it may occur in only a few days. In its typical form,

psoriasis results in patches of thick, red (inflamed) skin covered

with silvery scales. These patches, which are sometimes referred to

as plaques, usually itch or feel sore. They most often occur on the

elbows, knees, other parts of the legs, scalp, lower back, face,

palms, and soles of the feet, but they can occur on skin anywhere on

the body. About 25% of patients who develop psoriasis go on to

develop psoriatic arthritis.

Information courtesy of:

http://www.niams.nih.gov/hi/topics/psoriasis/psoriasis.htm#1

University of Utah Health Sciences

420 Chipeta Way, Ste 1900

Salt Lake City, UT 84108

United States

http://uuhsc.utah.edu/

_____________________________________

N Engl J Med. 2007 Feb 8;356(6):580-92.

A human interleukin-12/23 monoclonal antibody for the treatment of

psoriasis.

Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y,

Dooley LT, Lebwohl M; CNTO 1275 Psoriasis Study Group.

University of Utah, Salt Lake City, USA.

gerald.krueger@...

BACKGROUND: Skin-infiltrating lymphocytes expressing type 1 cytokines

have been linked to the pathophysiology of psoriasis. We evaluated

the safety and efficacy of a human interleukin-12/23 monoclonal

antibody in treating psoriasis. METHODS: In this double-blind,

placebo-controlled trial, 320 patients with moderate-to-severe plaque

psoriasis underwent randomization to treatment with the interleukin-

12/23 monoclonal antibody (one 45-mg dose, one 90-mg dose, four

weekly 45-mg doses, or four weekly 90-mg doses) or placebo; 64

patients were randomly assigned to each group. Patients assigned to

the interleukin-12/23 monoclonal antibody received one additional

dose at week 16 if needed. Patients assigned to placebo crossed over

to receive one 90-mg dose of interleukin-12/23 monoclonal antibody at

week 20. RESULTS: There was at least 75% improvement in the psoriasis

area-and-severity index at week 12 (the primary end point) in 52% of

patients who received 45 mg of the interleukin-12/23 monoclonal

antibody, in 59% of those who received 90 mg, in 67% of those who

received four weekly 45-mg doses, and in 81% of those who received

four weekly 90-mg doses, as compared with 2% of those who received

placebo (P<0.001 for each comparison), and there was at least 90%

improvement in 23%, 30%, 44%, and 52%, respectively, of patients who

received the monoclonal antibody as compared with 2% of patients who

received placebo (P<0.001 for each comparison). Adverse events

occurred in 79% of patients treated with the interleukin-12/23

monoclonal antibody as compared with 72% of patients in the placebo

group (P=0.19). Serious adverse events occurred in 4% of patients who

received the monoclonal antibody and in 1% of those who received

placebo (P=0.69). CONCLUSIONS: This study demonstrates the

therapeutic efficacy of an interleukin-12/23 monoclonal antibody in

psoriasis and provides further evidence of a role of the interleukin-

12/23 p40 cytokines in the pathophysiology of psoriasis. Larger

studies are needed to determine whether serious adverse events might

limit the clinical usefulness of this new therapeutic target.

(ClinicalTrials.gov number, NCT00320216 [ClinicalTrials.gov].) PMID:

17287478.