Biologic Therapy for Psoriasis: The New Therapeutic Frontier
Singri P, West DP, Gordon KB
Arch Dermatol. 2002;138:657-663
Objectives: (1) To develop a clinically useful model with which dermatologists can understand the potential uses of biologic therapy for psoriasis and understand the potential differences among these novel drugs, (2) to discuss the process by which recombinant DNA technology is used to develop rationally designed protein medications along with the potential benefits and difficulties of therapy with biologic agents, and (3) to provide a short review of the medications under development for psoriasis.
Data Sources: The pertinent literature was reviewed with particular emphasis on published, randomized, and placebo-controlled trials. Phase 1 and early phase 2 trials were also included in our review when more stringent studies were not available. Studies presented as peer-reviewed abstracts at major conferences were also reviewed.
Conclusions: With the development of recombinant DNA techniques, it has become possible to develop new biologic therapies that can be designed to specifically alter physiological responses. These new drugs are in use in many different medical fields and will soon be available for the treatment of dermatological diseases, primarily psoriasis. Dermatologists should be familiar with the potential benefits and risks of these therapies to make rational decisions concerning their use in the treatment of their patients with psoriasis.
Novel Therapies for Psoriasis
Cather J, Menter A
Am J Clin Dermatol. 2002;3:159-173
The T cell-driven immunopathogenesis of psoriasis has been well recognized since cyclosporine first revolutionized the treatment of psoriasis 20 years ago. Almost all investigative and clinical research subsequently, has concentrated on elucidating the specifics of antigen presentation, T cell interaction and the production of specific cytokines. The role of the keratinocyte, previously thought to be the primary target cell in psoriasis pathogenesis, has been relegated to a secondary role and the mechanism of action of systemic methotrexate in psoriasis has been challenged, the primary role of the T lymphocyte is now well known. While psoriasis has traditionally been treated "ab initio" with topical medications (corticosteroids, vitamin D(3), and retinoid derivatives), either singly, in combination, or with ultraviolet B (UVB) or psoralens and ultraviolet A (PUVA) therapy, the role of systemic medications has assumed greater prominence. Thus, three systemic medications currently are approved worldwide for the treatment of moderate to severe forms of psoriasis, namely cyclosporine, methotrexate and acitretin. The first two are likely to give significant clearing (greater than 75%) in the majority of cases, whereas acitretin is significantly less effective as monotherapy, but may approach methotrexate and cyclosporine in efficacy, if combined with PUVA or UVB phototherapy. The main limitations of these three drugs remain organ toxicity, especially hepatic toxicity with methotrexate, hypertension and nephrotoxicity with cyclosporine, and teratogenicity and mucocutaneous toxicity with acitretin. Thus, the need for more specific systemic therapy, targeting the T lymphocyte. This has become the major area of clinical research interest over the past 5 years, with the promise of longer-term disease control (improved remissions) and less organ toxicities. Currently, there are over 15 of these "biologic" drugs in various stages of development and clinical trials, either by the subcutaneous, intramuscular or intravenous route. The three main variables are the rapidity of onset, percentages of improvement and remission rates. Without exception, these new systemic agents appear to be remarkably free of systemic organ toxicities (liver, renal, bone-marrow, etc.), with adverse effects being limited to mild flu-like symptoms with the anticipated increase in infections (e.g., herpes simplex) being either equal to placebo or only marginally increased. Not all these agents under evaluation give clinical responses equal to methotrexate or cyclosporine (75% or greater clearing in 75% of cases). In addition, response rates may be slower with some therapies versus others. However, the need for intermittent administration even by the injectable route, longer remissions, lack of systemic organ toxicities and the potential for safer usage in females of child-bearing age, make a compelling argument for widespread acceptance by both patients and the dermatological community. Other modalities under clinical evaluation include vitamin D and retinoid drugs, topically and systemically, with effects on nuclear receptors, as well as more specific wavelengths (308 to 311 nm) of UVB phototherapy with application for more localized forms of psoriasis. For the 2 to 3% of the worldwide population of patients with psoriasis the future has never looked brighter.
Novel Immune-Based Therapies for Psoriasis
Kirby B, Griffiths CE
Br J Dermatol. 2002;146:546-551
The primacy of the immune system in the pathogenesis of psoriasis is a well-established concept to the extent that psoriasis has been classified as a T-cell-mediated, autoimmune disease. An explosion of knowledge concerning immunological events in psoriasis and the clinical efficacy of immunologically directed therapies, such as cyclosporin, support this concept. Armed with this understanding and modern biotechnology, novel interventions have been developed to treat psoriasis. 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. This article reviews recent developments in immune-based therapies for psoriasis.
Novel Immunotherapies for Psoriasis
Asadullah K, Volk HD, Sterry W
Trends Immunol. 2002;23:47-53
New insights into the pathophysiology of psoriasis have suggested possibilities for targeted therapeutic intervention. Several novel, systemic immunomodulatory therapies are currently in clinical development and results of recent clinical trials are remarkable. These include approaches targeting antigen presentation and costimulation, T-cell activation and leukocyte adhesion, the action of proinflammatory mediators and the administration of anti-inflammatory cytokines. These trials contribute to our further understanding of the disease, indicating which mechanisms play a greater or lesser part in its development. Moreover, they will lead to new therapeutic options. If psoriasis is considered as a visible model disease for T-cell-mediated disorders characterized by a type-1 cytokine pattern these recent findings might have a more general impact on the treatment of autoimmune disorders.
The Immunologic Basis for the Treatment of Psoriasis With New Biologic Agents
Krueger JG
J Am Acad Dermatol. 2002; 46:1-23
Psoriasis vulgaris is the most prevalent T-cell-mediated inflammatory disease in humans. The pathogenesis of psoriasis is linked to activation of several types of leukocytes that control cellular immunity and to a T-cell-dependent inflammatory process in skin that accelerates the growth of epidermal and vascular cells in psoriasis lesions. Critical steps in immunologic activation include Langerhans cell maturation (activation), T-cell activation, differentiation and expansion of type 1 T cells, selective trafficking of activated T cells to skin, and induction of an inflammatory cytokine and chemokine cascade in skin lesions. In turn, each of these steps offers an opportunity for intervention with engineered biologic therapeutics.
Psoriasis as a Model for T-cell-Mediated Disease: Immunobiologic and Clinical Effects of Treatment With Multiple Doses of Efalizumab, an Anti-CD11a Antibody
Gottlieb AB, Krueger JG, Wittkowski K, Dedrick R, Walicke PA, Garovoy M
Arch Dermatol. 2002;138:591-600
Background: Leukocyte function-associated antigen 1 (LFA-1), consisting of CD11a and CD18 subunits, plays an important role in T-cell activation and leukocyte extravasation.
Objective: To test whether blocking CD11a decreases immunobiologic and clinical activity in psoriatic plaques.
Design: Open-label, multicenter, dose escalation study.
Patients: Thirty-nine patients with moderate-to-severe psoriasis.
Intervention: Intravenous infusions of efalizumab, a humanized anti-CD11a monoclonal antibody, for 7 weeks at doses of 0.1 mg/kg every other week or 0.1 mg/kg weekly (category 1), 0.3 mg/kg weekly (category 2), and 0.3 increasing to 0.6 or 1.0 mg/kg weekly (category 3). Skin biopsies were performed on days 0, 28, and 56.
Main Outcome Measures: 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, Psoriasis Area and Severity Index (PASI) scores.
Results: Dose-response relationships were observed for pharmacokinetics and pharmacodynamic measures. Category 1 failed to maintain detectable serum efalizumab or T cell CD11a down-modulation between doses. Category 2 achieved both. Category 3 achieved both and additionally maintained sustained T-cell CD11a saturation between doses. A dose-response relationship was also observed clinically and histologically. 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 lymphocyte counts increased in categories 2 and 3.
Conclusions: At doses of 0.3 mg/kg or more per week, intravenous efalizumab produced significant clinical and histologic improvement in psoriasis, which correlated with sustained serum efalizumab levels and T-cell CD11a saturation and down-modulation.
Treatment of Psoriasis With the Chimeric Monoclonal Antibody Against Tumor Necrosis Factor Alpha, Infliximab
Schopf RE, Aust H, Knop J
J Am Acad Dermatol. 2002;46:886-891
Background: Psoriatic skin lesions in patients with Crohn's disease or psoriatic arthritis have shown improvement during infliximab treatment.
Objective: The purpose of our study was to systematically assess the effects of infliximab in patients with psoriatic skin lesions.
Methods: Eight patients with severe psoriasis were enrolled in an open-label clinical trial. Patients received infliximab, 5 mg/kg, intravenously at weeks 0, 2, and 6. The Psoriasis Area and Severity Index (PASI) 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; week 14 was the follow-up end point. Pruritus was assessed on a scale of 0 to 3. Histologic sections were prepared from biopsy specimens of uninvolved skin and of psoriatic lesions at weeks 0, 1, and 10 to measure epidermal thickness with the use of a microscopic micrometer grid.
Results: The PASI diminished from 21.8 ± 4.2 (mean ± SE) at week 0 to 3.4 ± 2.0 at week 10, corresponding to 10.7% ± 4.3% of the original values (100%); on follow-up at week 14, the PASI was 7.1 ± 2.7 (or still 33.3% ± 11.3% of the values at week 0). 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. Likewise, 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.
Conclusion: Although psoriasis tends to recur beyond 2 months of the infusions, this open study provides evidence that infliximab is an effective treatment.
The Effectiveness of Tumor Necrosis Factor Alpha Antibody (Infliximab) in Treating Recalcitrant Psoriasis: A Report of 2 Cases
O'Quinn RP, Miller JL
Arch Dermatol. 2002;138:644-648
Background: Psoriasis is being recognized as an autoimmune disease in which immunocyte-derived cytokines are thought to drive the development of the altered keratinocyte phenotype. Although the role of tumor necrosis factor alpha (TNF-alpha) in psoriasis is not completely understood, it may underlie many of the key steps that lead to induction and maintenance of the disease. Infliximab is an immunoglobulin monoclonal antibody that binds and inactivates TNF-alpha and has been successfully used in the management of TNF-alpha-mediated diseases, such as Crohn disease and rheumatoid arthritis.
Observations: Two patients with recalcitrant psoriasis that was unresponsive to multiple skin-directed and systemic therapies were treated with a single infusion of infliximab. The treatments resulted in rapid and complete clearing of psoriatic erythroderma and resolution of symptoms of arthritis in one case and complete clearing of widespread psoriatic plaques and improvement of symptoms of arthritis and inflammatory bowel disease in the other. The single treatments with infliximab were well tolerated with no immediate or long-term adverse effects noted.
Conclusion: A single infusion of infliximab at 5 to 10 mg/kg resulted in the rapid and complete clearing of recalcitrant psoriatic plaques and erythroderma with a disease-free interval of 3 to 4 months in these 2 patients and improved the symptoms of psoriatic arthritis
Efficacy and Safety of Infliximab Monotherapy for Plaque-Type Psoriasis: A Randomised Trial
Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB
Lancet. 2001;357:1842-1847
Background: Currently available treatments for moderate to severe psoriasis are either incompletely effective in some patients, or are associated with toxic effects. Since tumour necrosis factor alpha (TNF-alpha) is thought to have a role in the pathogenesis of psoriasis, we did a double-blind, randomised trial to assess the clinical benefit and safety of infliximab-a monoclonal antibody against TNF-alpha.
Methods: 33 patients with moderate to severe plaque psoriasis were randomly assigned 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 physician's global assessment [PGA]). Analysis was by intention to treat.
Findings: Of the 33 patients enrolled, three dropped out. Nine of 11 (82%) patients in the infliximab 5 mg/kg group were responders (good, excellent, or clear rating on PGA), compared with two of 11 (18%) in the placebo group (difference 64% [95% CI 20-89], p=0.0089), and ten of 11 (91%) patients in the infliximab 10 mg/kg group were responders (difference from placebo 73% [30-94], p=0.0019). 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.
Interpretation: In this controlled trial, patients receiving the anti-TNF-alpha agent 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. These findings suggest that TNF-alpha has a pivotal role in the pathogenesis of psoriasis.
Etanercept for Severe Psoriasis and Psoriatic Arthritis: Observations on Combination Therapy
Iyer S, Yamauchi P, Lowe NJ
Br J Dermatol. 2002; 146:118-121
Background: The antitumour necrosis factor (TNF) activity of etanercept has been utilized to generate an important and novel treatment for rheumatoid arthritis. TNF has also been implicated in the pathogenesis of psoriasis.
Objectives: To determine whether blockade of TNF activity by etanercept may provide an additional treatment option for patients with psoriasis.
Methods: In an uncontrolled trial, etanercept was added to the treatment regimen in six patients with severe recalcitrant psoriasis (three also with psoriatic arthritis) partially resistant to other ongoing systemic agents.
Results: In each case, the disease activity showed marked improvement on addition of etanercept therapy. No added toxicity was found with etanercept.
Conclusions: Etanercept appears to be a promising immunomodulatory agent that can be used in combination therapy for the treatment of psoriasis, and a prospective controlled trial may be warranted.
Selective Targeting of T Cell Subsets: Focus on Alefacept - A Remittive Therapy for Psoriasis
Krueger GG
Expert Opin Biol Ther. 2002;2:431-441
Psoriasis is an immune-mediated disease in which memory-effector (CD45RO+), skin-homing T cells play a key role in driving the disease process. Available therapies are often poorly tolerated, none are curative and most only suppress disease symptoms without attacking the underlying cause of the illness. Alefacept (Amevive((R)), Biogen, Inc.) is a fully human lymphocyte function associated antigen-3/immunoglobulin G1 fusion protein that targets memory-effector T cells by binding CD2 on the T cell and Fc phi receptor III IgG receptors on accessory cells, thereby preventing T cell activation and proliferation and causing selective T cell apoptosis. To date, alefacept has been studied in moderate-to-severe chronic plaque psoriasis and in a pilot study of psoriatic arthritis. In chronic plaque psoriasis, alefacept produced significant and sustained improvements in psoriasis symptoms. There was no evidence of disease rebound or worsening of psoriasis following treatment cessation. Multiple courses provided consistent efficacy, with a trend for more rapid and greater clinical improvement in subsequent courses. Alefacept reduced circulating CD4+ and CD8+ memory-effector T cells, with relatively no change in naive (CD45RA+) T cells or B cells. Alefacept also reduced IFN-phi-secreting Tcells in lesional biopsies of psoriatic skin. These reductions all correlated with the observed clinical effect. Alefacept was well-tolerated throughout these studies, with a side effect profile similar to placebo. There was no evidence of generalised immunosuppression or increased risk of infection or malignancy. Alefacept did not alter the primary or acquired immune response in psoriatic patients. Clinical data obtained to date support the use of alefacept as a safe and remittive therapy for psoriasis. |
