Biologics target T-cell responses in psoriasis

Anti-T-cell therapeutic agents treat psoriasis by interfering with the immune responses involved in the generation of psoriasis.

Two such anti-T-cell agents, alefacept and efalizumab, are currently indicated for moderate to severe psoriasis in patients who are candidates for systemic therapy or phototherapy.

"I generally use these drugs when the tumor necrosis factor (TNF) inhibitors are either ineffective or contraindicated," notes Bruce Strober, M.D., Ph.D., assistant professor of dermatology at the New York University School of Medicine in New York City. "However," he adds, "some dermatologists have a personal preference that may lead them to use T-cell inhibitors with the same frequency as TNF inhibitory drugs in patients without psoriatic arthritis."

Dr. Strober explains, "Efalizumab acts by inhibiting the ability of immune cells to leave the vasculature and enter into the skin. Additionally, it is believed that the drug may alter T-cell activation by inhibiting the ability of antigen-presenting cells to activate T-cells."

Alefacept (a leukocyte function-associated antigen-3 [LFA3]-IgG1 fusion molecule) binds to CD2 present on activated T-cells. The agent is administered intramuscularly by the practitioner as a weekly 15 mg dose given for 12 consecutive weeks. Alefacept likely alters the immune response by deleting memory effector T-cells that are relevant to the genesis of psoriasis. Like efalizumab, it may also affect the ability of antigen-presenting cells to activate T-cells.

EFFICACY OF AGENTS

In a 2003 phase 3, double-blind analysis involving the pooling of data from multiple studies, 556 patients with moderate to severe plaque psoriasis were randomized to receive a 12-week course of weekly efalizumab at 1 mg/kg (n = 369) or placebo (n = 187).

At week 12, 27 percent of patients treated with efalizumab achieved a 75 percent or greater improvement in Psoriasis Area and Severity Index (PASI-75), compared with 4 percent in the placebo group (P < .001) (Gordon KB et al; JAMA. 2003;290:3073-3080). In a subsequent open-label analysis, 516 of these patients received an additional 12 weeks of 1 mg/kg efalizumab. Among patients in the efalizumab arm, the proportion of patients experiencing PASI-75 increased from 27 percent at week 12 to 44 percent at week 24 (Menter A et al; Arch Dermatol. 2005;141:31-38).

Alefacept has also demonstrated responses in clinical trials. In a phase 3, double-blind, parallel group study, 507 patients with chronic plaque psoriasis were randomized to receive weekly intramuscular alefacept (10 mg or 15 mg) or placebo. At two weeks after the last dose (week 14), 21 percent of patients receiving 15 mg alefacept achieved a PASI-75, compared with 5 percent of the placebo arm (P < .001). (Ortonne JP; J Eur Acad Dermatol Venereol. 2003;17 Suppl 2:12-16).

SAFETY PROFILES

Adverse events with efalizumab may include flare and rebound, primarily worsening of psoriasis while on drug or severe worsening of psoriasis after abrupt discontinuation of drug.

Dr. Strober notes, "This may involve plaque psoriasis worsening or altered morphology like pustular or erythrodermic variants of psoriasis occurring while patients are receiving the drug."

He estimates that approximately 0.5 percent to 3 percent of patients experience severe flares or altered psoriasis morphologies while on the drug and 14 percent have severe flares or rebound after abrupt discontinuation of the drug.

A mild adverse event seen with efalizumab treatment is a transient (24- to 48-hour) flu-like syndrome involving headache, fever and myalgia that generally occurs after the first two injections and subsequently dissipates with each future injection. Other rare safety issues with efalizumab include thrombocytopenia and hemolytic anemia. Furthermore, rare cases of infectious side effects of the drug have been reported in post-marketing events.