| Alice Bendix Gottlieb, MD, PhD, professor of medicine and associate chair for research,
Department of Medicine, W.H. Conzen Chair in Clinical Pharmacology, director of the
Clinical Research Center, UMDNJ-Robert Wood Johnson Medical School
The current understanding of the pathophysiology of psoriasis is little more than a decade old. Once marginalized as strictly a dermatologic disorder, funding for research was minimal and progress was slow. While at The Rockefeller University, our laboratory was among the first to demonstrate that immune dysfunction plays a pivotal role in this disease by showing increased numbers of activated T cells and greater expression of a number of immunologic cytokines in psoriatic plaques. We published our findings in 1986 and 1988 in the Journal of Experimental Medicine, and in the Proceedings of the National Academy of Sciences in 1989. Our team then determined that treatment with denileukin difitox, a T-cell specific immunotoxin, cleared psoriasis clinically and histologically, and published this work in Nature Medicine, 1995.
Psoriasis most typically begins between ages 20 and 40, and is life-long. For the seven million Americans affected by it—particularly the two million classified with moderate to severe disease on the basis of either the body surface area involved or significant impact on psychological and/or physical health — quality of life is seriously impaired. Several drugs, among them cyclosporine, that are effective in clearing the disease in many sufferers, cannot be used long-term because of toxicity.
As a direct result of findings on the immunopathogenesis of psoriasis, researchers — including our group at the Clinical Research Center (CRC) at Robert Wood Johnson Medical School — reoriented their approach to treating the disease, and began to investigate the efficacy of biotechnology-engineered immunomodulators. Biologics are medications that are made by living cells. Biological therapy normalizes the immune system’s function. The beauty of biologics is that they target specific components of the immune system rather than dampening down the entire system, and they also appear to be quite safe.
Certainly, we count among our major successes the investigator-initiated, single-site clinical trial that we conducted in 2000 at the CRC that established the tolerability and efficacy of infliximab (Remicade®), an anti-Tumor Necrosis Factor-alpha (TNF-alpha) monoclonal antibody, for treating moderate to severe plaque type psoriasis. These findings were published in Lancet, Vol. 357, 2001. At that time, infliximab was the only biologic agent to clear psoriasis in a high proportion of patients in a manner comparable to cyclosporine, which has numerous serious side effects. Our research showed the pivotal role that TNF-alpha, a cytokine with an important role in a variety of inflammatory processes, plays in the pathogenesis of psoriasis. TNF-alpha recruits and activates lymphocytes and dendritic cells (professional antigen presenting cells), stimulates intercellular adhesion molecule expression as well as neutrophil and monocyte chemotaxis, and induces other inflammatory mediators, such as IL-1, IL-6, and IL-8 in psoriatic plaques. Infliximab, produced by Centocor, Inc, is marketed under the name Remicade®, and is FDA-approved for Crohn’s disease and rheumatoid arthritis, but is prescribed off-label for psoriasis. (It will be approved shortly for the treatment of psoriatic arthritis.)
In the past two years, new developments in psoriasis treatment have held out more hope to those with moderate to severe disease. Studies of two other “targeted biologic therapies” were published in the Nov 20, 2003 issue of The New England Journal of Medicine.
I am the senior author of one of these papers on a study of etanercept (Enbrel), a TNF antagonist, for the treatment of plaque psoriasis. As reported in The New England Journal, in this 24-week, double-blind study, 652 patients either received a placebo or received etanercept by injection at a low dose (25 mg once weekly), a medium dose (25 mg twice weekly) or a high dose (50 mg twice weekly). After 12 weeks, patients in the placebo group began twice-weekly treatment with 25 mg of etanercept. The primary measure of clinical response was the Psoriasis Area-and-Severity Index (PASI).
At week 12, there was an improvement from baseline of 75 percent or more, as measured by the index, in only 4 percent of the patients on placebo, compared to 14 percent in the low-dose etanercept group, 34 percent in the medium-dose group, and 49 percent in the high-dose group.
The clinical responses continued to improve with longer treatment. By the 24th week, there was at least a 75 percent improvement in the PASI in 25 percent of the patients in the low-dose group, 44 percent in the medium-dose group and 59 percent in the high-dose group. Assessments of skin clearing made by physicians and patients confirmed these results, and the side effects were minimal. This drug is the only biologic approved for both psoriasis and psoriatic arthritis. (Our group has participated in clinical trials for both indications.) Etanercept is produced by Amgen.
Our team was the principal investigatory site for a 36-month, open-label, multi-center trial evaluating the safety and efficacy of efalizumab (Raptiva), a T cell-targeting biologic, as a long-term treatment for patients with moderate-to-severe plaque psoriasis. In February 2005, at the 63rd annual American Academy of Dermatology meeting, I presented data on patients receiving continuous Raptiva therapy for three years. These data demonstrated sustained efficacy without increased toxicity for 36 months of continuous treatment. Raptiva is manufactured by Genentech Inc. and Xoma. The U.S. Food and Drug Administration approved the drug for the treatment of moderate to severe plaque psoriasis on October 27, 2003. I was the lead investigator for all three Phase I/II clinical trials with efalizumab. Our data were subsequently published in the Journal of the American Academy of Dermatology, Archives of Dermatology and the Journal of Cutaneous Medicine and Pathology. The existence of the CRC for these early, complex trials was essential to our success.
Recently, I have also been focusing my attention on educating dermatologists to recognize and treat psoriatic arthritis earlier. This form of arthritis affects roughly 20-40 percent of those with psoriasis, and most often develops about 10 years after skin manifestations start. Dermatologists are usually the first to see and treat the disease, and are in a position to prevent or slow down joint damage due to psoriatic arthritis progression.
My own mother, who has been battling psoriasis for more than 50 years, recently developed psoriatic arthritis. It came on suddenly and aggressively, and over a period of six months transformed a very active individual into a crippled one, unable to get out of a chair without assistance. When etanercept was prescribed for her, she was up and running again within one month.
Immune-mediated skin diseases, and in particular, psoriasis, are an area of huge scientific interest, but psoriasis is a field that has been seriously under-funded by the NIH. Collaborations with industrial partners have been pivotal in moving research, clinical care and education forward. The Clinical Research Center’s relationships with Amgen, Celgene, Genentech, Biogen Idec, Centocor and Abbott, among others, have allowed clinical research — and the education of the next generation of medical specialists in this field — to flourish and yield major findings that have led to new and improved care for our patients and better understanding of the pathogenesis of psoriasis and psoriatic arthritis.
Alice B. Gottlieb earned her MD from Cornell Medical College and her PhD in immunology from The Rockefeller University. She completed a residency in internal medicine, and a second residency in dermatology. She also completed a fellowship in rheumatology at the Hospital for Special Surgery. She is triple boarded in dermatology, rheumatology and internal medicine. Dr. Gottlieb, an internationally recognized expert in psoriasis and psoriatic arthritis, has received numerous awards for her research, clinical care and teaching and is chair of the Advocacy Committee of the National Psoriasis Foundation. She is the W.H. Conzen Chair in Clinical Pharmacology and founder of the Psoriasis Center of Excellence at RWJMS. She is also director of the Clinical Research Center (CRC) at the medical school, which is serving as the site for 25 current (and many upcoming) research protocols conducted by the RWJMS departments of surgery, psychiatry, pediatrics and medicine, Rutgers University, Boston University, UMDNJ-New Jersey Medical School and The Cancer Institute of New Jersey.