Promising Results from Adalimumab Study
Results show improvement in disease and quality of life.
Phase II study results of adalimumab (Humira) in patients with moderate to severe chronic plaque psoriasis showed that patients achieved significant and continued improvement in disease activity and quality of life over 24 weeks of treatment, with nearly half of patients experiencing a 90% improvement in disease activity.

A double-blind study was conducted to measure the effectiveness and tolerability of adalimumab after a total of 24 weeks of treatment. This study, led by Kenneth Gordon, M.D., was the continuation of a 12-week trial in which 148 patients with a diagnosis of moderate to severe chronic plaque psoriasis for at least 1 year and an affected body surface are of >=5% were randomized to receive adalimumab or placebo administered by subcutaneous injection. Patients completing the first 12 weeks of the trial (n=137) were eligible to continue. Patients who had been receiving adalimumab 40 mg every other week, and patients receiving adalimumab 40 mg weekly continued with treatment at the same dosing for the additional 12 weeks. Beginning at week 12, patients in the placebo arm received 12 weeks of therapy, with an initial dose of 80 mg of adalimumab followed by 40 mg every other week beginning at week 13. Patients and physicians remained blinded to dose until week 24 when patients were evaluated.

The primary efficacy endpoint was the percentage of patients achieving at least a 75% reduction in disease activity after 24 weeks as measured by PASI compared to the baseline value at week 0.

Results at 24 weeks showed:
• 64% of patients receiving adalimumab 40 mg eow achieved PASI 75.
• 72% of patients receiving adalimumab 40 mg weekly achieved PASI 75.
• 55% of patient who switched from placebo to the 40 mg eow regimen beginning at week 12 achieved PASI 75 after 12 weeks of therapy.

Quality of Life Results
Patients receiving either dose of adalimumab reported significantly greater improvements in Dermatology Life Quality Index (DLQI), a measure of patient-reported outcomes in dermatology. The improvements were reported to continue over 24 weeks and showed:
• 40% of patients receiving adalimumab 40 mg eow reported a DLQI of 0, meaning they were “not at all” affected by their psoriasis.
• Almost 55% of patients on weekly dosing reported a DLQI of 0.
• 26% of those on placebo reported a DLQI of 0.

Understanding the Causes of Psoriasis
Scientists have made breakthroughs in what causes the condition.
A team from Leicester University discovered detailed genetic differences in people who suffer from psoriasis, according to a report on BBC News. The researchers, led by Professor Richard Trembath, believe their work could lead to new, more effectively targeted drugs. Professor Trembath told BBC News that past studies have shown that a small region of chromosome 6 contained at least one psoriasis susceptibility gene. He went on to say that closer examination of this genetic interval identified a gene called CDSN, responsible for the adhesion and shedding of skin cells. And researchers found that a CDSN DNA variant is found much more frequently among psoriatic patients compared to those without the disease.

“This variant may confer susceptibility to psoriasis by causing an accumulation of CDSN protein, which in turn could contribute to the inflammatory response observed in the skin of patients,” Professor Trembath told BBC News.

Methotrexate and Birth Defects
Study shows methotrexate in early pregnancy may not cause defects.
A small study, published in the December 2004 issue of the Journal of Rheumatology, looked at the risk of major malformation of the fetus among pregnant women who were treated with low-dose methotrexate in the first trimester of pregnancy. Secondary outcomes included the rate of miscarriage, birth weigh and gestational age at delivery. Data from the French network of 31 pharmacovigilance centers and two teratology information services were analyzed. A total of 28 cases were reviewed for this study.

Methotrexate exposure ended before 8 weeks of gestation in 26 patients. Miscarriages occurred in four patients, and five patients had elective termination of pregnancy. There were 19 live births, of which three were premature. Birth weights in full-term children were within the expected range and one baby who had been exposed until 8.5 weeks of gestation had minor anomalies (metatarsus varus and eyelid angioma).
Researchers found that although no definite conclusion could be drawn, the results and analysis of the study support the conclusion that no strong teratogenic risk is associate with low-dose methotrexate as long as the drug is discontinued as early as possible in the pregnancy. n

Methotrexate Medication Errors
The causes and effects of common medication errors.
A recent study published in the July 2004 issue of the American Journal of Health-System Pharmacy looked at all the medication errors reported to the FDA as adverse events in which methotrexate might have been involved. Researchers, Thomas J. Moore, Christopher S. Walsh, and Michael R. Cohen, examined adverse-event reports submitted to the FDA from November 1997 through December 2001. They analyzed the medication errors involving methotrexate to determine the indication for use, the type of error and the point in the medication-use process where the error occurred.

Researchers looked at reports that listed methotrexate as a suspect drug and that contained a Medical Dictionary for Regulatory Activities (MedDRA) term suggesting a medication error may have taken place. These terms included medication error, drug maladministration, drug interaction NOS (not otherwise stated), drug level NOS above therapeutic, accidental overdose, accidental exposure and drug interaction potentiation. The researchers then put each report into one of four categories — death, disability or birth defect, serious outcome (nonfatal), and other or none stated. Researchers then requested full reports for possible cases of medication errors from the FDA under the Freedom for Information Act.

Defining a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm,” researchers determined there were 106 cases. Of these cases,
25 (24%) resulted in death, and 48 (45%) resulted in other serious outcomes. Of the 106 cases, the most frequently involved indication for use was rheumatoid arthritis (44 cases), psoriasis (13 cases) and cancer (9 cases).

The errors analyzed for this study occurred in all four steps of medication use — 37% during prescribing, 19% during dispensing, 17% during administration and 20% during consumption. Confusion about the once-weekly dosage schedule was responsible for 30% of errors. The errors in prescribing were based on contraindications, labeled interactions, dosage errors and the wrong drug.

The researchers found that methotrexate is associated with significant medication errors that could be prevented with better patient safety measures. Suggested measures included written instructions that state a specific day of the week for taking the drug, emphasizing the weekly-dosage schedule, and that explain the possible adverse events associated with dosage errors.

FDA Accepts sBLA for Psoriatic Arthritis Treatment
Two trials show promising results for infliximab.
The FDA has accepted a supplemental Biologics Licensee Application (sBLA) for Centocor’s drug infliximab (Remicade), an anti-tumor necrosis factor alpha therapy. The sBLA for infliximab, already approved for the treatment of rheumatoid arthritis and Crohn’s disease, was accepted based on the results from two, double-blind, placebo-controlled trials, IMPACT and IMPACT 2.
The IMPACT trial showed significant improvements in PASI scores were maintained through 1 year. The IMPACT 2 study showed there was significant improvement in psoriasis and arthritis symptoms in patients receiving 5 mg/kg of infliximab over those receiving placebo. (For more information on these studies, please see FDA News & Approvals.)

Letter of Outreach
NATIONAL PSORIASIS FOUNDATION CAPITAL CAMPAIGN
The development of treatments for psoriasis (topical corticosteroids, vitamin D and A analogues, UVB, PUVA, oral retinoids, methotrexate, cyclosporine and several new biologics) and the application of these treatments to other dermatologic conditions have made this a golden age for medical dermatology. With more new drugs in the psoriasis pipeline, the critical issues facing our specialty are hurdles to getting those drugs approved, patients’ access to those treatments, and regulatory changes that perpetually threaten our ability to give patients quality care.

Over the decades, there has been one large, grassroots organization that has understood the value of dermatology and that has been there to stand up for our patients and for our specialty: the National Psoriasis Foundation (NPF). The NPF has intervened for our specialty on many occasions. When the bulleted documentation guidelines used by Medicare were first proposed, the entire skin exam consisted of one bullet, leaving dermatology visits treated like minor nursing visits. Examination of the entire skin was assigned a level of reimbursement no greater than would have been accorded the simple check of one’s blood pressure or pulse. The NPF, along with American Academy of Dermatology members, complained to Medicare, resulting in our reimbursements being dramatically increased. Also, at one point, Medicare wanted to institute a program that would limit phototherapy reimbursements to 12 treatments per year. Despite many complaints from dermatologists and dermatology organizations, the program was slated to begin, until Gail Zimmerman, Executive Director of the Foundation, intervened. In 2002, the NPF successfully lobbied Medicare to dramatically increase phototherapy reimbursement in order to help keep this treatment a viable option for patients.

Serving Us and Our Patients
The Foundation has served our specialty and our patients in many other ways. Members of the NPF have testified at the FDA numerous times, and Gail Zimmerman has served on panels at the NIH and has led numerous national and international efforts to help our patients. Simply stated, the NPF has become to dermatology what the Arthritis Foundation is to rheumatology or the American Cancer Society is to oncology.

With the challenges ahead, the NPF’s roles will only increase. Advocacy to gain access to medications for our patients will be more important, and lobbying to have patient assistance programs for those who can’t afford the new treatments will be critical. The Foundation already has a track record in advocacy for our patients in Washington and with insurance companies in many of our states. As techniques in molecular biology answer the questions in the human genome, more and more targets for research are identified, but the funding to support that research is not there. The NPF has generated a tissue bank that helped identify the first genes linked to psoriasis, and that work must continue. The Foundation also provides seed grants to many young dermatologists doing clinical and basic research that will help our specialty flourish into the future.

The National Psoriasis Foundation has launched a 5-year, $5,000,000 capital campaign to support research and advocacy in dermatology. At this critical time in dermatology, we can help by supporting the organization that has helped us for the last 25 years. Please make a donation to the National Psoriasis Foundation Capital Campaign. Dermatologists can fully fund the campaign if each of us makes a commitment of $1,000 (just $200/year for 5 years). Recognizing all the NPF does for us, please make a more generous donation if you can. Your contribution will make a difference for our patients and our specialty for years to come.

Mark Lebwohl, M.D.
Chairman, Medical Board of The National Psoriasis Foundation
Professor and Chairman, Department of Dermatology
The Mount Sinai School of Medicine