Infliximab

Abstract

Over the last several years, a new generation of therapies for psoriasis has been in development. These biologic therapies target the activity of T lymphocytes and cytokines responsible for the inflammatory nature of this disease. In this review, we present an update on the progress of the four biologic agents in the forefront: infliximab, etanercept, efalizumab, and alefacept. The mechanism of each drug will be reviewed, as well as the most recent efficacy and safety data.

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Psoriasis is one of the most common chronic skin diseases, affecting 1.5-2% of the population in western countries. The recent implication of an immunologic phenomena in the pathogenesis of this frequently debilitating disorder has led to new research for possible treatment options over the past few years (1,2). The result has been the birth of biologic therapies, those drugs targeting the activity of T lymphocytes and cytokines responsible for the inflammatory nature of this disease. The aim of these therapies is to provide selective, immunologically directed intervention with the hope that such specificity will result in fewer side-effects than traditional therapies. Of interest and importance, these pharmaceutical interventions also act as a form of investigational tool in psoriasis. Their relative efficacy in the psoriatic process provides useful insights into the hierarchical importance of immune events in the disease process, and recent evidence suggests that innate rather than acquired immunity has a key role. In this review, we present an update on the progress of the first wave of biologic agents, those either under review at the FDA or closest to FDA submission. These agents include infliximab, etanercept, efalizumab, and alefacept (Table 1).

Infliximab (Remicaide)

Infliximab (Figure 1) is a chimeric (mouse-human) IgG1 monoclonal antibody that binds to tumor necrosis factor a (TNF-a). It also inhibits production of other pro-inflammatory cytokines, reducing cell infiltration and eventually keratinocyte proliferation. The drug is currently approved for rheumatoid arthritis and Crohn's disease via intravenous infusion. Because TNF-a is thought to play a role in the pathogenesis of psoriasis, investigations have been performed to determine the efficacy and safety of infliximab as a potential therapy.

[FIGURE 1 OMITTED]

Chaudhuri et al. (3) reported the results of a double-blind, randomized trial to assess the clinical benefit and safety of infliximab in psoriasis. Thirty-three patients with moderate-to-severe plaque psoriasis were randomly assigned either intravenous placebo (n=11), infliximab 5 mg/kg (n=11), or infliximab 10 mg/kg (n=11) at weeks 0, 2, and 6. Patients were assessed at week 10 for the primary endpoint (score on the physicians' global assessment [PGA]).

Nine of 11 (82%) patients in the infliximab 5 mg/kg group were responders (good, excellent, or clear rating on PGA), compared with 2 of 11 (18%) in the placebo group and 10 of 11 (91%) in the infliximab 10 mg/kg group. When evaluating improvement in the psoriasis area and severity index (PASI), they found that 5 mg/kg resulted in 82% of patients showing at least 75% improvement in the PASI (PASI 75), while 10 mg/kg resulted in 73% with at least 75% improvement in the PASI.

The placebo group had only an average 15% improvement in the PASI score. The median time to response was 4 weeks for patients in both infliximab groups. There were no serious adverse events, and infliximab was well tolerated. The authors concluded that patients receiving infliximab as monotherapy experienced a high degree of clinical benefit and rapid time to response in the treatment of moderate-to-severe plaque psoriasis compared with patients who received placebo (3).

Schopf et al. (4) treated eight patients with severe psoriasis in an open-label clinical trial in which they received infliximab 5 mg/kg, intravenously at weeks 0, 2, and 6. The PASI score was used to monitor disease activity at weeks 0, 2, 4, 6, 8, 10, and 14. Week 10 was the end point of the treatment phase, and week 14 was the follow-up end point.

Between weeks 0 and 10, they documented a nearly 85% reduction in the mean PASI score. At week 14, two months after the patient had received the last infliximab dose, the mean PASI score was dramatically reduced by 67% from baseline (4). Pruritus decreased from 2.5 +/- 0.26 at week 0 to 0.43 +/- 0.2 at week 10, and to 0.83 +/- 11.3 at week 14. Furthermore, epidermal thickness (acanthosis) tended to normalize from 0.41 +/- 0.06 mm at week 0 to 0.14 +/- 0.02 mm at week 10. No adverse effects other than fatigue during infusion on some occasions were reported (4).

Ogilvie et al. (5) described treatment with infliximab in six patients with both psoriasis and psoriatic arthritis (5). All patients had long-standing disease that was refractory to several treatments with methotrexate, and received infusions of infliximab at 5 mg/kg at weeks 0, 2, and 6. They also continued to receive the same doses of methotrexate or sulphasalazine during the study period. At 10 weeks after the initiation of therapy, all patients had experienced a dramatic improvement in their arthritis, as well as a dramatic and rapid improvement of their skin lesions, with a decrease in their PASI score by as much as 80% (5).

Infliximab has also been shown to be effective in pustular psoriasis. Newland et al. (6) reported a rapid response to infliximab in a 44-year-old Caucasian woman with a 26-year history of severe, generalized, pustular psoriasis of the von Zumbusch type. (6) The patient had failed to completely respond to various anti-psoriatic medications and treatments including topical steroids, UVB, acitretin, PUVA, cyclosporine, and dapsone. She was hospitalized for worsening psoriasis, and was started on infliximab 5 mg/kg, infused over 3 hours, with rapid improvement (6).

O'Quinn and Miller recently reported the effectiveness of infliximab in treating two cases of recalcitrant psoriasis. Two patients with recalcitrant psoriasis that was unresponsive to multiple topical and systemic therapies were treated with a single infusion of infliximab over 3 hours (7). The first patient, a 52 year-old white male with a 17-year history of psoriasis, noted a decrease in pruritus and erythema of the skin within 2 days. A 4-week follow-up examination showed complete resolution of all psoriatic plaques, erythema, and scaling. A follow-up biopsy specimen taken 10 days after treatment showed a resolution of psoriasiform epidermal changes. The second patient, a 33 year-old white woman with a 8-year history of psoriasis and psoriatic arthritis along with concomitant inflammatory bowel disease, reported decreased erythema in the psoriatic plaques within 24 hours of receiving the infusion. A follow-up examination after 2 weeks was significant for complete clearing of all plaques with residual macules and patches of hyperpigmentation with minimal overlying scale (7). These cases further demonstrate the potential utility of this drug in psoriasis.

Infliximab has been associated with a number of adverse events (8). Infusion reactions have been reported in 19% of patients in clinical trials, consisting of fever or chills, or more rarely: chest pain, hypotension, hypertension, and dyspnea. Neutralizing antibodies are formed, and patients can develop a serum sickness reaction days after administration of the drug. Infection is an issue of major concern, and there have been multiple reports of reactivation of latent tuberculosis (9). Infections are common in patients treated with infliximab, most likely because many are receiving other immunosuppressive therapy. In controlled trials, however, there does not appear to be an increased risk of serious infection in infliximab-treated patients (8).

Etanercept (ENBREL)

Etanercept is a 100% human TNF-receptor, made from the fusion of two naturally occurring TNF-receptors (Figure 2). It binds to TNF with greater affinity than natural receptors, which are monomeric. The binding of etanercept to TNF renders the bound TNF biologically inactive, resulting in significant reduction in inflammatory activity. Etanercept is currently approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Etanercept is administered subcutaneously by patients at home.

[FIGURE 2 OMITTED]

Mease et al.10 reported the results of a randomized, double-blind, placebo-controlled, 12-week study, which evaluated the efficacy and safety of etanercept (25 mg twice-weekly subcutaneous injections) compared to placebo in a study population comprised of 60 patients suffering from psoriatic arthritis and psoriasis. Psoriatic arthritis endpoints included the proportion of patients who met the Psoriatic Arthritis Response Criteria (PsARC) and who met the American College of Rheumatology preliminary criteria for improvement (ACR20). Psoriasis endpoints included improvement in the PASI and improvement in prospectively-identified individual target lesions. In this study, 26 (87%) of etanercept-treated patients met the PsARC, compared with seven (23%) of placebo-controlled patients. The ARC20 was achieved by 22 (73%) of etanercept-treated patients compared with four (13%) of placebo-treated patients. Of the 19 patients in each treatment group who could be assessed for psoriasis ([greater than or equal to] 3% body surface area), five (26%) of etanercept-treated patients achieved a 75% improvement in the PASI, compared with none of the placebo-treated patients (p=0.015). The median PASI improvement was 46% in etanercept-treated patients versus 9% in placebo-treated patients; similarly, median target lesion improvements were 50% and 0, respectively. Etanercept was well tolerated in this study. The authors concluded that etanercept offers patients with psoriatic arthritis and psoriasis a new therapeutic option for control of their disease (10).

In a phase II clinical study assessing the efficacy and safety of this biologic therapy, 112 patients with moderate to severe plaque psoriasis were randomized evenly to receive 25 mg of etanercept or placebo subcutaneously twice a week for 6 months (11). The primary end point of the study was the proportion of patients achieving a PASI reduction of at least 75% after 12 weeks. At 3 months, 30% of 57 patients on etanercept achieved a 75% reduction in PASI, compared with 2% of 55 patients on placebo (P<.0001). Fifty-six percent of patients treated with etanercept achieved a 75% reduction in PASI at 6 months compared with 5% of patients receiving placebo. Additionally, at 6 months, 21% of patients receiving etanercept achieved a 90% reduction in PASI compared with none of those patients who received placebo, while 77% of patients receiving etanercept achieved a 50% reduction in PASI compared with 13% of patients receiving placebo. Side effects seen were mild infections including mild upper respiratory infections and sinusitis, and injection site reactions (11).

Similar findings were seen in a report of six patients, ages 33-57, with severe, residual psoriasis (three also with psoriatic arthritis) who had been unresponsive to systemic treatments and phototherapy (12). The PASI scores of these patients before etanercept and, in some cases, combination therapy averaged 24 with the highest score being 29, while the scores following treatment with etanercept had a mean of 9 with the highest score being 14. In addition, no toxicity secondary to the treatment was noted. In the patients where etanercept was added in combination with other systemic and topical medications, resistant disease became more responsive to treatment and permitted the usage of lower doses of systemic agents. The authors concluded that etanercept appears to be a promising immunomodulatory agent that can be used in combination therapy for the treatment of psoriasis (12).

Like infliximab, etanercept has also shown utility in the treatment of pustular psoriasis. Kamarashev et al. (13) reported a 50-year-old male patient with a 15-year history of psoriasis, including mutilating psoriatic arthritis, in whom the withdrawal of cyclosporin A induced a generalized pustular exacerbation and an aggravation of the joint condition. Two weekly injections of 25 mg of etanercept led to a rapid improvement of his psoriatic arthritis, as well as regression of the pustular eruption, while residual erythema was still present. The clinical response was reflected by an increase in circulating IL-10 and a decrease in IL-6 and IL-8 serum levels during treatment. The authors concluded that etanercept may be a safe and effective therapy not only in severe psoriatic arthritis, but also in cases of pustular rebound after withdrawal of immunosuppressive agents (13).

Etanercept has been used safely over the past few years. Injection site reactions are the main adverse events noted. There have been rare observations of demyelinating disorders such as multiple sclerosis, allergic reactions, and aplastic anemia (8). Because etanercept has been available for rheumatoid arthritis for several years, it is developing an ever-increasing positive track record in regards to the risk of malignancy and infection. Results from 1272 patients (3706 patient-years) in North America demonstrate continued safety of etanercept for over 5 years of therapy (14). Overall, the rate of adverse events remains low. The frequency of infections requiring hospitalization or intravenous antibiotics was 0.04 per patient-year in the total population, which was the same as the rate in the control group in controlled trials. The incidence of malignancies was not increased in the etanercept group compared to the expected number from the NCI SEER database (35 observed vs. 35 expected) (14). In addition, from 1993 to 2001, reports of tuberculosis in patients receiving etanercept were rare (20) and reporting rates were comparable to background incidence (15). Importantly, there was no apparent temporal association of onset of clinical tuberculosis with introduction of etanercept therapy.

Efalizumab (Raptiva)

Efalizumab is a humanized monoclonal antibody against the CD11a molecule. CD11a and CD18 comprise subunits of leukocyte function-associated antigen-1 (LFA-1), a T-cell surface molecule important in T-cell activation, T-cell migration into skin, and cytotoxic T-cell function (Figure 3). The binding of this drug to CD11a on T-cells blocks the interaction between LFA-1 and ICAM-1, its partner molecule for adhesion. The blockade is reversible, and does not deplete T-cells.

[FIGURE 3 OMITTED]

Gottlieb et al. (16) explored the immunobiologic and clinical affects of treating moderate-to-severe psoriasis vulgaris with a single intravenous dose of humanized monoclonal antibody against CD11a (hu1124). This was an open-label study with a single 0.03- to 10-mg/kg dose of hu1124. Clinical (PASI) and immunohistologic parameters (epidermal thickness, epidermal and dermal T-cell numbers, and keratinocyte intercellular adhesion molecule-1 expression) were followed.

It was found that treatment with hu1124 at doses higher than 1.0 mg/kg (group 3) completely blocks CD11a staining for at least 14 days in both blood and psoriatic plaques. At 0.3 to 1.0 mg/kg, T-cell CD11a staining was completely blocked; however, blockage lasted less than 2 weeks (group 2). Only partial saturation of either blood or plaque cellular CD11a was observed at doses between 0.01 and 0.1 mg/kg (group 1). This pharmacodynamic response was accompanied by decreased numbers of epidermal and dermal CD3+ T cells, decreased keratinocyte and blood vessel expression of intercellular adhesion molecule-1, and epidermal thinning. Statistically significant decreases in PASI scores compared with baseline were observed at weeks 3 and 4 in group 2 patients, and at weeks 2 through 10 in group 3 patients. No significant decrease in PASI scores was observed in group 1 patients (16).

Adverse events were mild at doses of 0.3 mg/kg or less and included mild chills, abdominal discomfort, headache, and fever. At a single dose of 0.6 mg/kg or higher, headache was the most common dose-limiting toxicity observed. The investigators concluded that targeting CD11a may improve psoriasis by inhibiting T-cell activation, T-cell emigration into the skin, and cytotoxic T-cell function (16).

Papp et al. (17) reported the results of a double-blind, placebo-controlled, phase II, multicenter study with anti-CD11a, in which 145 patients with minimum PASI scores of 12 and an affected body surface area of 10% or more were enrolled sequentially into low-dose (0.1 mg/kg, n=22) or high-dose (0.3 mg/kg, n=75) groups. The patients were then randomized to treatment or placebo (n=48) in a 2:1 ratio. Intravenous infusions were administered at weekly intervals for 8 weeks. Fifteen percent of placebo patients and 48% of those receiving the high-dose of the drug achieved a more than 50% improvement in physician's global assessment after one week of receiving the final dose. The physician's global assessment of excellent (>75% improvement) was greater in the 0.3 mg/kg group (25%) compared to the placebo group (2%). PASI scores were also lower in the group receiving the drug (10.9 +/- 8.4) versus those in the placebo group (13.9 +/-7.5). The overall treatment was well tolerated and the most common adverse events were mild to moderate flu-like symptoms. The authors concluded that anti-CD11a antibody administered intravenously in 8 weekly doses of 0.3 mg/kg was well tolerated and induced clinical and histologic improvements in psoriasis (17).

Gottlieb et al. (18) examined the immunobiologic and clinical effects of treatment with multiple doses of efalizumab. In an open-label, multiple-dose, dose escalation study, 39 patients with stable, moderate-to-severe plaque psoriasis (>15% body surface area involvement and a PASI score >15) were treated with efalizumab (18). The subjects received infusions of the following dose levels for 7 weeks in an ascending dose escalation paradigm: 0.1 mg/kg every other week or 0.1 mg/kg weekly (category 1), 0.3 mg/kg weekly (category 2), 0.3, 0.4, then 0.6 mg/kg or 0.3, 0.4, 0.6, then 1.0 mg/kg for the remaining weeks (category 3). The median baseline PASI score was 23, ranging from 15-42. Because of early discontinuations or damage to some biopsy samples during transit, histologic analyses were conducted only for 32 subjects. Skin biopsies were performed on days 0, 28, and 56 (18).

The main outcome measures included serum efalizumab levels, levels of total and unoccupied T-cell Cd11a, T cell counts, epidermal thickness, cutaneous intercellular adhesion molecule 1 (ICAM-1) and keratin 16 (K16) expression, as well as PASI scores. Results showed that category 1 failed to maintain detectable serum efalizumab or T cell CD 11a down-modulation between doses. Category 2 achieved both, as did category 3 which also maintained sustained T-cell CD11a saturation between doses. Clinically, the mean decrease in the PASI score was 47% in category 3, 45% in category 2, and 10% in category 1 (P<.001). Epidermal and dermal T-cell counts, epidermal thickness, and ICAM-1 and K16 expression decreased in categories 2 and 3, but not in category 1. Circulating lymphocytes count also increased in categories 2 and 3. Therefore, intravenous efalizumab at a dose of 0.3 mg/kg or more per week produced significant clinical and histologic improvement in psoriasis, correlating with sustained serum efalizumab levels and T-cell CD11a saturation and down-modulation (18).

Recently, two phase III trials with subcutaneous (SC) efalizumab, enrolling nearly 1100 patients, showed promising results in treatment of moderate to severe plaque psoriasis (19). The major endpoint was achievement of 75% improvement in PASI score; other efficacy endpoints were achievement of an overall lesion severity (OLS) score of minimal or clear, and a physician's global assessment (PGA) score of excellent or clear. Included subjects had moderate to severe plaque psoriasis (body surface area [BSA] 10% and PASI 12) and were candidates for systemic therapy. Treatment regimens were identical in both trials. Subjects were randomized to treatment consisting of an initial conditioning dose of 0.7 mg/kg in Week 1, followed by 11 weekly doses of either 1.0 mg/kg or 2.0 mg/kg of efalizumab or placebo (19).

In comparison to those on placebo, patients receiving efalizumab showed marked improvement on all efficacy measures. More subjects treated with efalizumab achieved 75% PASI improvement in comparison to those on placebo (19). For the 1.0 mg/kg/week group, 29.2% achieved PASI 75, and 55.6% achieved PASI 50; for the 2.0 mg/kg/week group, 27.6% achieved PASI 75, and 54.5% achieved PASI 50. For patients in the placebo group, 3.4% achieved PASI 75, and 15.1% achieved PASI 50 (19).

Combined results from both trials show the PASI improvement for both efalizumab groups was improved over that of placebo after only 2-4 doses (P<0.005). Approximately 25% of patients in both efalizumab dose groups obtained an OLS score of minimal to clear (24.6% and 22.5% in the 1.0 and 2.0 mg/kg dose groups, respectively) as compared to placebo (3.1%). Approximately 29% of patients in both dose groups received a PGA score of excellent or clear (29.2% and 29.1% in the 1.0 and 2.0 mg/kg dose groups, respectively) as compared to placebo (4.1%). In addition, subjects in both efalizumab groups showed marked improvements on the remaining 2 efficacy endpoints: decrease in plaque thickness on the pruritus scale and in psoriatic BSA; and improvement on quality-of-life scales. These findings from nearly 1100 subjects indicate that 12 weekly doses of SC efalizumab improve signs and symptoms of psoriasis in patients with moderate to severe plaque psoriasis (19).

Efalizumab has been used safely in nearly 2000 patients. Most have been treated from 12 to 24 weeks, with a small number treated up to 1 years (8). Importantly, there have been no opportunistic infections, no clinical signs of immunosuppression, and no hepatotoxicity or nephrotoxicity associated with the use of efalizumab (8).

Alefacept (Amivieve)

Psoriatic plaques are characterized by infiltration with CD4+, CD45RO+, CD8+, and CD45RO+ memory-effector T lymphocytes. The recombinant protein alefacept binds to CD2 on memory-effector T lymphocytes, inhibiting their activation. It is a fusion protein composed of leukocyte function-associated antigen type 3 (LFA-3) protein and human IgG1 Fc domains (Figure 4). The drug is administered by intramuscular injection or intravenously.

[FIGURE 4 OMITTED]

In a multicenter, randomized, placebo-controlled, double-blind study, Ellis ct al. (20) evaluated alefacept as a treatment for psoriasis. Two hundred twenty-nine patients with chronic psoriasis received intravenous alefacept (0.025, 0.075, or 0.150 mg/kg of body weight) or placebo weekly for 12 weeks, with follow-up for 12 additional weeks. Before treatment, the median PASI scores were between 14 and 20 in all groups (0 denotes no psoriasis and 72 the most severe disease possible). In the study, alefacept was well tolerated and nonimmunogenic. The mean reduction in the PASI score 2 weeks after treatment was greater in the alefacept groups (38%, 53%, and 53% in the groups receiving 0.025, 0.075, and 0.150 mg/kg, respectively) than in the placebo group (21%) (P<.001). Twelve weeks after treatment, 28 patients who had received alefacept alone were clear or almost clear of psoriasis. Three patients in the placebo group were clear or almost clear; all 3 had received additional systemic therapy for psoriasis. Alefacept reduced peripheral blood memory-effector T lymphocyte (CD45RO+) counts, which correlated with the improvement in psoriasis. The investigators concluded that treatment with alefacept for 12 weeks is associated with improvement in chronic plaque psoriasis. Similar responses were seen in a retreatment study in which one-half of the patients achieved more than 50% improvement and one-fifth improved by 75%15. Alefacept selectively targets CD45RO+ memory-effector T lymphocytes, suggesting that they have a role in the pathogenesis of psoriasis (20).

An international multicenter trial randomized more than 500 patients to 1 of 3 arms: intramuscular (IM) alefacept 15 mg once a week for 12 weeks; IM alefacept 10 mg once a week for 12 weeks; or placebo21. Two weeks after the last dose was given, 21% of patients treated with the 15-mg dose achieved at least a 75% reduction from baseline in their PASI score compared with 5% of patients receiving placebo (P<.001) (21). Such results are contributing to an anticipated FDA approval of this drug in early 2003.

In terms of adverse events, patients treated with alefacept have a reduction in CD45RO+ memory T cells, which correlates with improvement in psoriasis. The drug has been studied in over 1500 patients, with some receiving as many as six courses of treatment. To date, no clinically significant signs of immunosuppression or opportunistic infections have been observed, and no increase in malignancy has been observed. The FDA will most likely require monitoring of T cells in patients treated with alefacept.

Conclusion

Biologic therapy research continues to make great strides in the treatment of psoriasis. With continued progress at this rate, it is possible that one or more of these pharmacologic agents will become major therapeutic options for psoriasis. The data from this work is very encouraging (Table 2), but we await further data from many of these medications, as well as the treatments which will follow. Hopefully the next year will continue to bring us favorable reports regarding the safety and efficacy of these new therapies (22).

The authors would like to thank Genentech for the use of figures depicting the structures of the medications.

References

(1.) Tutrone WD, Kagen MH, Barbagallo J, Weinberg JM. Biologic therapy for psoriasis: a brief history, I. Cutis 2001; 68:331-336.

(2.) Tutrone WD, Kagen MH, Barbagallo J, Weinberg JM. Biologic therapy for psoriasis: a brief history, II. Cutis 2001; 68:367-372.

(3.) Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001; 357:1842-1847.

(4.) Schopf RE, Aust H, Knop J. Treatment of psoriasis with the chimeric monoclonal antibody against tumor necrosis factor alpha, infliximab. J Am Acad Dermatol 2002; 46:886-891.

(5.) Ogilvie AL, Antoni C, Dechant C, Manger B, Kalden JR, Schuler G, et al. Treatment of psoriatic arthritis with antitumour necrosis factor-alpha antibody clears skin lesions of psoriasis resistant to treatment with methotrexate. Br J Dermatol 2001; 144:587-589.

(6.) Newland MR, Weinstein A, Kerdel F. Rapid response to infliximab in severe pustular psoriasis, von Zumbusch type. Int J Dermatol 2002; 41:449-452.

(7.) O'Quinn RP, Miller JL. The effectiveness of tumor necrosis factor alpha antibody (infliximab) in treating recalcitrant psoriasis: a report of 2 cases. Arch Dermatol 2002; 138:644-648

(8.) Lebwohl M. New developments in the treatment of psoriasis. Arch Dermatol 2002; 138:686-688.

(9.) Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098-1104.

(10.) Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet 2000; 356:385-390.

(11.) Gottlieb AB, Lowe N, Matheson R, Lesback ME. Efficacy of etanercept in patients with psoriasis. Poster presented at: American Academy of Dermatology 60th Annual Meeting, February 22-27th, 2002; New Orleans, LA. Poster 25.

(12.) Iyer S, Yamauchi P, Lowe NJ. Etanercept for severe psoriasis and psoriatic arthritis: observations on combination therapy. Br J Dermatol 2002; 146:118-121.

(13.) Kamarashev J, Lor P, Forster A, Heinzerling L, Burg G, Nestle FO. Generalised pustular psoriasis induced by cyclosporin a withdrawal responding to the tumour necrosis factor alpha inhibitor etanercept. Dermatology 2002; 205:213-216.

(14.) Moreland L, Cohen S, Fleischmann RM, Baumgartner SW, Schiff MH, Burge DJ. Safety and efficacy of up to five years etanercept (ENBREL[R]) therapy in rheumatoid arthritis. Poster presented at: EULAR 2002, June 12-15th, 2002; Stockholm, Sweden.

(15.) Holman J, Wallis WJ, Sabath DF, Viveash D, Burge DJ, Garrison L, et al. Tuberculosis reports with etanercept (ENBREL[R]) therapy. Poster presented at: EULAR 2002, June 12-15th, 2002; Stockholm, Sweden.

(16.) Gottlieb A, Krueger JG, Bright R, Ling M, Lebwohl M, Kang S, et al. Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis. J Am Acad Dermatol 2000; 42:428-435.

(17.) Papp K, Bissonnette R, Krueger JG, Carey W, Gratton D, Gulliver WP, et al. The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody. J Am Acad Dermatol 2001; 45:665-674.

(18.) Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R, Walicke PA, Garovoy M. Psoriasis as a model for T-cell-mediated disease: immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-CD11a antibody. Arch Dermatol 2002 May; 138:591-600.

(19.) Gottlieb AB. Subcutaneous efalizumab (anti-CD11a) is effective in the treatment of moderate to severe plaque psoriasis: pooled results of two phase III clinical trials; February 22-27, 2002; New Orleans, LA. Poster 576.

(20.) Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001; 345:248-255.

(21.) Christophers E, Rizova E, Lebwohl M. Intramuscular administration of alefacept is safe and effective in patients with chronic plague psoriasis: results of an international randomized, double-blind, placebo-controlled, dose comparison phase III study. Poster presented at: American Academy of Dermatology 60th Annual Meeting; February 22-27, 2002; New Orleans, La. Poster 581

(22.) Weinberg JM. Tipping the scales: biologic therapy 2002. Cutis 2002. In press.

ADDRESS FOR CORRESPONDENCE:

Jeffrey M. Weinberg, MD

Department of Dermatology

St. Luke's-Roosevelt Hospital Center

1090 Amsterdam Avenue, Suite 11D

New York, NY 10025

Phone: 212-523-5898

Fax: 212-523-5027

Email: jmw27@columbia.edu

JEFFREY M. WEINBERG, MD, RITU SAINI, BA, AND WILLIAM D. TUTRONE, BS

DEPARTMENT OF DERMATOLOGY, ST. LUKE'S-ROOSEVELT HOSPITAL CENTER AND BETH ISRAEL MEDICAL CENTER, NEW YORK, NEW YORK

Disclosure: Dr. Weinberg is a member of the Speaker's Bureau for Amgen and Genentech.

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