Alefacept in Combination with Methotrexate: New Data in Rheumatoid Arthritis

Based on data presented by Gerald G. Kreuger, MD, University of Utah, Salt Lake City, Utah

In a double-blind, placebo-controlled study conducted in patients with rheumatoid arthritis (RA), the combination of alefacept and methotrexate demonstrated substantial improvement in symptom scores. The study demonstrates the safety of combining alefecept with methotrexate.

In this study, for which results were presented almost simultaneously at the International Psoriasis Symposium in New York and the European League Against Rheumatism (EULAR) in Lisbon, 36 patients on stable dosages of methotrexate (12.5 to 15 mg/day) were randomized to no additional therapy, 3.75 mg of weekly alefacept, or 7.5 mg of weekly alefacept. Both alefacept doses were administered with continued methotrexate. Joint symptoms were compared using the ACR (American College of Rheumatology) scoring system at 6 months, which was 3 months after the last dose of alefacept.

In both alefacept groups, there were significant reductions in joint tenderness and joint swelling compared to baseline and to those treated with methotrexate alone. Three months after the last dose of alefacept, more than 40% of patients in the alefacept group achieved an ACR 20 versus 10% of those who remained on methotrexate alone. More than 25% of patients achieved an ACR 50 versus none of those on methotrexate alone.

A reduction in memory T cells, a mechanism by which alefacept exerts benefit in psoriasis, were also found to be reduced in the RA patients receiving alefacept but not in patients receiving methotrexate alone. This is the first data to support a pathogenic role of memory T cells in RA, and it suggests that the mechanism of action of alefacept may be relevant to a variety of T-cell mediated autoimmune diseases.

The rates and types of adverse events were balanced between those receiving methotrexate alone versus those receiving methotrexate plus either dose of alefacept, suggesting no influence on tolerability from the addition of the immunobiologic.
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Remittive Therapy: Duration of Benefit with Alefacept

Based on data presented by Kenneth B. Gordon, MD, Director, Chicago Psoriasis Center at Loyola University, Maywood, Illinois

In an extension study of the phase III intramuscular (IM) efficacy trial, alefacept has demonstrated prolonged remission following treatment in patients with chronic plaque psoriasis. Like the initial phase III trial, benefit continued to accrue in patients after last dose.

Ninety-four patients entered into the extension trial at an alefacept dose of 15 mg weekly. In those who achieved at least a 75% reduction in PASI score during the initial phase III arm, the duration of response before entering the second course (maintenance of a >50% reduction in PASI score from baseline) in the absence of any systemic therapy or phototherapy was 7 months (209 days). In the subgroup of 40 patients who achieved a clear or almost clear rating on PGA, the duration was 8 months (245 days) off treatment.

This duration of response exceeds that of other immunobiologic or systemic therapies. The improvement in PASI score over time after last dose suggests remittive activity, a benefit defined by favorable clinical change after discontinuation of therapy.
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Keynote Address

Biological Change in Psoriasis

Based on data presented by James G. Krueger, MD, PhD, Professor and Laboratory Head, Rockefeller University, New York, New York

As a result of the advent of immunobiological agents in the treatment of psoriasis, there is now substantial information about the relative pathogenic contribution of different cell types. The next set of studies is expected to define the pathogenic interaction between specific genes and cellular signaling processes.

There are more than 50 growth factors, cytokines and chemokines elevated in psoriatic lesions relative to normal skin. Of 2500 genes expressed in psoriatic lesions, 159 have now been shown to be consistently turned on in diseased versus normal skin. When these genes are organized by transcription factors, STAT1, which activates interferon gamma, has been upregulated to the highest level. The consistency with which interferon gamma is upregulated in psoriatic versus non-psoriatic skin completes a picture in which both STAT1 and interferon gamma emerge as key factors in pathogenic signaling.

Molecular signaling in psoriasis is complex and probably redundant, diminishing the likelihood of distilling the pathogenesis of psoriasis to a single molecular event, but immunobiologics has initiated an evolution that is expected to reveal this disease in a quality of detail that had been until recently difficult to envision.
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Combination Therapy: Alefacept and Narrowband Ultraviolet B Light

Data Presented by Barbara M. Mathes, MD, Senior Director of Medical Affairs, Biogen Inc., Cambridge, Massachusetts

Alefacept achieves a substantially more rapid control of psoriasis when combined with narrowband (NB) ultraviolet B (UVB) light, according to results of a trial that randomized 30 patients to alefacept 15 mg weekly with no NB UVB, 6 weeks of NV UVB, or 12 weeks of NB UVB. The dose of NB UVB at the start of treatment was 70% of the minimum erythematous dose (MED) with dose increments of 15% of MED.

Combination Results in Faster and Sustained PASI Reduction

The addition of NB UVB to alefacept treatment resulted in a faster reduction in PASI than alefacept monotherapy. With the combination of NB UVB and alefacept, 38% of patients already achieved a 50% reduction in PASI after 2 weeks of treatment; 57% of patients achieved a ≥75% reduction in PASI after 4 weeks of treatment. All of the patients treated with alefacept and NB UVB achieved a reduction from baseline PASI of ≥75%, and approximately 76% achieved a PGA of "clear" or "almost clear".

For patients who achieved a ≥75% PASI reduction 2 weeks after the last dose, 100% of the alefacept monotherapy and approximately 80% of the combination treatment arms maintained their response through the 12-week period Alefacept was well tolerated both as monotherapy and in combination with NB UVB. Based on the results of the study, alefacept plus NV UVB was characterized as a safe and effective treatment option for chronic plaque psoriasis. Six weeks of NV UVB appears sufficient as their was no advantage for the 12 week regimen.
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Combination Therapy: Use of Oral Retinoids in Combination with Other Agents

Based on data poster whose senior author was Steven R. Feldman, MD, PhD, Department of Dermatology, Wake Forest University Health Sciences, Winston-Salem, North Carolina

National practice survey data indicate that a minority of psoriatics treated with an oral retinoid receive this therapy alone. This finding was supported by a chart review at an academic medical center conducted to complement the national practice survey. In the 10% of psoriatics treated with an oral retinoid in the academic center, 79% also received a topical therapy, most often a steroid.

34% Receive >2 Additional Therapies

The pattern of oral retinoid prescriptions in the United States was derived from The National Ambulatory Medical Care Survey (NAMCS), which generates information on medication use from approximately 30,000 office visits each year. It is sponsored by the National Center for Health Statistics. Within this data set, oral retinoids (etretinate prior to 1996 and acitretin afterwards) were prescribed alone in 29% of patients, with one additional anti-psoriatic agent in 37%, and with two or more additional agents in 34%.

In the chart review of 518 psoriasis patients at an academic medical center, all received an additional therapy with the oral retinoid. In addition to the topical medications used in almost 80% of patients, these included phototherapy in 26% and methotrexate or another systemic therapy in 19%. Side effects were common, recorded in 75% of patients in the chart review. The most common of these were dry mucous membranes (19%), dry skin (17%), and alopecia (15%). None were serious. Overall, the long-term safety of oral retinoids was characterized as a "strength" by authors of the study.
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Anti-TNF-Alpha Therapy: Current Status

Based on data presented by: Alice B. Gottlieb, MD, PhD, Director, Clinical Research Center, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey; Kenneth B. Gordon, Director, Chicago Psoriasis Center at Loyola University; and Jeffrey M. Sobell, MD, Director of Phototherapy, New England Medical Center, Boston, Massachusetts

Controlled clinical trials with infliximab, an immunobiologic agent targeted at inhibition of tissue necrosis factor (TNF) alpha, suggest that the therapy is effective for reducing symptoms and improving quality of life in patients with moderate to severe psoriasis. In a recently completed phase III multicenter study, the 3 mg/kg dose was associated with a PASI score of 75 or greater in 71.7% while the 5 mg/kg dose achieved a PASI score of 87.9%.

Based on these data and the absence of a significant difference in adverse events, Alice B. Gottlieb, MD, recommended 5 mg/kg for further clinical development. In addition to producing greater clinical benefit, "it seems to reduce the risk of neutralizing antibody formation," a problem associated with this drug.

If continued evidence of benefit leads to regulatory approval, dermatologists will need to familiarize themselves with the specific requirements for the slow intravenous infusion by which infliximab is delivered, according to Jeffrey M. Sobell, MD. While some other anti-psoriatic agents are now delivered intravenous push, the longer administration time of infliximab requires specific accommodations and equipment for patient comfort and safety.