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This article, the second in a 2-part series, will review interleukin 10 (IL-10) administration, the T-cell receptor mimic peptide, and CTLA4Ig. We also will review 4 of the most promising therapies currently being investigated for the treatment of psoriasis: infliximab, etanercept, efalizumab, and alefacept.
A 33-year-old man with generalized vulgar psoriasis type I and psoriatic arthritis was admitted to the Naftalan Special Hospital on February 21, 2000. He was immobile and complained of severe pain in all his joints. Since the patient had suffered from the disease for 10 years without showing any improvement after different therapies, his cutaneous and joint lesions gradually worsened and eventually resulted in generalized psoriasis and mutilating arthritis. Nevertheless, the patient was discharged from our hospital in better condition. To avoid such severe consequences of psoriatic arthritis, we believe that patients with either type I or type II psoriasis should undergo locomotor system screening. It would significantly decrease the number of unrecognized and undiagnosed cases of psoriatic arthritis and allow their early treatment, and prevention of more severe forms. Administration of new therapeutic agents, e.g. Alefacept (IgG1 fusion protein), Etanercept (inhibitor of TNF activity), and Efalizumab (monoclonal antibody that blocks the leukocyte integrin CDIIa/CD18(LFA-1), could provide successful management of the disease in future.
Psoriasis is a common cutaneous disease that can have a profound effect on an individual's life. New biologic drugs--proteins that are synthesized using recombinant DNA technology to mimic naturally occurring molecules and that selectively target the immune system--have changed the paradigm for treating this disease. We review 4 biologic drugs that are either currently FDA approved or in phase 3 studies: Alefacept (Amevive) and efalizumab (Raptiva), which are T-cell modulators; etanercept (Enbrel), a soluble TNF receptor; and infliximab (Remicade), an anti-TNF monoclonal antibody.
Alefacept, efalizumab, etanercept, and infliximab are currently approved for the treatment of adults with moderate to severe plaque psoriasis, and phase 3 trials for adalimumab are ongoing. The high level of evidence from large randomized, double-blind, placebo-controlled clinical studies for each of these biologics allows high-grade recommendations and helps define uncertainties, one of which is longterm safety. For tumor necrosis factor-a blocking agents, safety profiles are available from clinical experience in other indications. In general, biologics are safe and effective in the treatment of psoriasis, with potential to address unmet medical needs. Their distinct profiles allow dermatologists to match the biologic agent to individual characteristics of patients who are candidates for systemic therapy or phototherapy. In this evidence-based review of the literature, we assess the effects on psoriasis of induction therapy with 5 biologics and provide preliminary treatment guidelines.
In addition to corticosteroids, dermatologists have access to an array of immunomodulatory therapies. Azathioprine, cyclophosphamide, methotrexate, cyclosporine, and mycophenolate mofetil are the systemic immunosuppressive agents most commonly used by dermatologists. In addition, new developments in biotechnology have spurred the development of immunobiologic agents that are able to target the immunologic process of many inflammatory disorders at specific points along the inflammatory cascade. Alefacept, efalizumab, etanercept, and infliximab are the immunobiologic agents that are currently the most well known and most commonly used by dermatologists. This article reviews the pharmacology, mechanism of action, side effects, and clinical applications of these therapies.
A 75% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI 75) is the current benchmark of primary endpoints for most clinical trials of psoriasis. Many consider this endpoint to be too stringent as it places potentially useful therapies at risk of failing to demonstrate efficacy. We hypothesized that a 50% reduction in the PASI score (PASI 50) represents a meaningful change in a person's life and thus is a better primary endpoint. To test this hypothesis, we analyzed PASI scores, quality of life (QoL) data, and desired re-treatment scores from a number of clinical trials in addition to studying individual elements that make up the PASI. This analysis shows (1). the PASI score is not linearly reflective of psoriasis severity (eg, a reduction in area of 95% without a change in redness, scaliness, and induration translates to only a 66% reduction in PASI); conversely, a drop in erythema, scale, and induration from an average of 3 to 1 would not lead to a 75% reduction in PASI; (2). treatment with methotrexate, an effective psoriasis therapy, more frequently reaches PASI 50 than PASI 75 as evidenced by a recent open trial in which 63% of patients achieved PASI 50 versus 26% achieving PASI 75; (3). improvement in QoL exists at PASI 50, using the Dermatology Quality of Life Index, as documented in several recently completed large clinical trials; (4). patients achieving PASI 75 frequently defer therapy until they are well below PASI 50; a clinical trial where retreatment was patient initiated showed patients did not re-treat until their PASI dropped to an average of 20% improvement from baseline; and (5). effective, meaningful therapies are consistently differentiated from placebo at PASI 50 as evidenced by histologic and photographic parameters of clinical trials of alefacept, efalizumab, and etanercept. We conclude that PASI 50 equates to a clinically meaningful improvement in psoriasis and represents a discerning primary endpoint.
The introduction of a number of biologic therapies into the market has revolutionized the practice of dermatology. These therapies include interferons, intravenous immunoglobulin, infliximab, adalimumab, etanercept, efalizumab, alefacept, and rituximab. Most dermatologists are familiar with the Food and Drug Administration-approved indications of these medications. However, numerous off-label uses have evolved. As part 1 of a 2-part series, this article will review the literature regarding the off-label uses of the interferons and intravenous immunoglobulin in dermatology.
The introduction of a number of biologic therapies into the market has revolutionized the practice of dermatology. These therapies include adalimumab, alefacept, efalizumab, etanercept, infliximab, IVIg, omalizumab, and rituximab. Most dermatologists are familiar with the indications of these medications that have been approved by the Food and Drug Administration; however, numerous off-label uses have evolved. To update the reader on more recent uses of the biologics for off-label dermatologic use, this article will emphasize more recent published data from 2005 through the date of submission in May 2006.
As the pathogenesis of psoriasis is better understood, specific targeted therapies are being developed. In addition to alefacept, etanercept, efaluzimab, and infliximab, discussed in separate articles in this issue, numerous other investigational therapies are currently in clinical trials, some of which will likely be approved in the future. We review the most promising of these therapies and their mechanisms of action.
BACKGROUND: Costs and patients' adherence related to biologics are important factors to consider while making informed decisions regarding therapy with biologics in psoriasis management. OBJECTIVE: To examine predictors of adherence related to biologics, total health care costs, and service utilization among psoriasis patients. METHODS: This was a longitudinal cohort study of psoriasis patients (<65 years old) enrolled in North Carolina Medicaid who were prescribed biologics (alefacept, efalizumab, and etanercept). Patients' medication adherence, health care costs, and service utilization patterns in the pre- and post-biologics period were examined. RESULTS: Adherence to biologics was significantly higher compared with the other psoriasis medications (0.66 vs 0.39; p<0.001). Prescription costs were significantly higher in the post-biologics period (3796.77 US dollars vs 11,706.32 US dollars; p<0.001). However, total health care costs in the post-biologics period did not differ significantly from the pre-biologics period (14,662.22 US dollars vs 16,156.10 US dollars; p>0.05). Patients' adherence and health care costs did not differ significantly across the biologics. After controlling for other variables, patients had a significantly lower number of hospitalizations in the post-biologics period (p<0.001). CONCLUSIONS: Although costs associated with prescriptions for biologics were higher, total health care costs did not differ significantly in the post-biologics period. Biologics had a better adherence rate compared with other psoriasis medications.
In this retrospective analysis, the effect of currently used treatments in 26 patients with psoriasis of the palms and soles were analyzed. In general, patients are treated initially with topical medications including superpotent topical corticosteroids in combination with calcipotriene ointment or tazarotene gel or both. If satisfactory improvement is not achieved in 4-8 weeks, systemic retinoids are added, formerly etretinate and currently acitretin, except in women of childbearing potential. If the latter regimen is not effective within two months, soak PUVA is added to the regimen of oral retinoids and topical medications. If improvement is inadequate, or if the treatment regimen is not tolerated, methotrexate or cyclosporine have been added in the past. The availability of the excimer laser has recently modified our approach so that this therapy is used in combination with acitretin before soak PUVA. With the availability of biologic agents, methotrexate is avoided because of its hepatotoxicity and bone marrow toxicity and cyclosporine is avoided because of its nephrotoxicity. If oral acitretin plus topical therapy is not adequate to control the disease and the excimer laser is not an option because of its limited availability, alefacept, etanercept and infliximab are added when possible. Other biologic agents are likely to be added to this list in the future.
PURPOSE OF REVIEW: This paper will review the data published in 2004 on the treatment of psoriatic arthritis, which arthritis affects 6 to 39% of all patients with psoriasis. RECENT FINDINGS: New data from placebo-controlled trials of anti-tumor necrosis factor agents, etanercept, infliximab, and adalimumab continue to show sustained effectiveness of these therapies in their ability to control the symptoms and signs of both arthritis and psoriasis, improve quality of life and function, and inhibit disease progression as measured by radiologic changes. Medications that inhibit T cells have been approved for the treatment of psoriasis and have been studied in psoriatic arthritis. The effectiveness of one of these agents, efalizumab, did not achieve statistical significance in the treatment of psoriatic arthritis. The results of a trial with a second agent, alefacept are pending public review. SUMMARY: There has been a persistent increased focus on the diagnosis and treatment of psoriatic arthritis as newer and more effective drugs than traditional disease-modifying agents have become available.
BACKGROUND: Eruptive naevi have been described to potentially arise in immune compromised patients. OBJECTIVES: We describe three patients with eruptive benign melanocytic naevi during a phase of immunosuppressive therapy. METHODS/DIAGNOSIS: Two patients with Crohn disease were treated with either azathioprine monotherapy or a combination of azathioprine and infliximab, when eruptive naevi arose particularly at the palms and soles. Our third patient with plaque psoriasis developed eruptive naevi during two episodes of treatment: during a course with the biological agent alefacept and during etanercept therapy. CONCLUSIONS: We conclude that treatment with the recently available biological agents might be associated with the formation of eruptive naevi. Although positive evidence for the occurrence of malignant pigmented lesions is lacking, alertness to the development of eruptive melanocytic naevi during treatment with biological agents is indicated.
This paper reviews the new biologic agents that selectively block the immunologic steps implicated in the pathogenesis of psoriasis. Four strategies have been targeted: reduction of the number of pathogenic T cells; inhibition of T-cell activation and migration; modulation of the immune system; and blockage of the activity of inflammatory cytokines. There are three classes: monoclonal antibodies, fusion proteins and recombinant cytokines or growth factors. The actions, efficacy and side-effect profile of the biologic agents, alefacept, efalizumab, etanercept and infliximab, are reviewed.
Quality of life studies in patients with cutaneous psoriasis attest to its significant impact on day to day activities and personal social interactions. Up to 40% of patients with psoriasis may develop psoriatic arthritis, usually within 5-10 years after onset of the cutaneous disease, heightening quality of life issues. These data have prompted an increased awareness and interest in more aggressive management of psoriasis; coupled with a better understanding of immunopathogenesis, this has led to the development of new agents targeting specific cells and molecules involved in the development and maintenance of psoriatic plaques. Although non-biological therapies, including methotrexate and ciclosporin, show significant efficacy their side effect profiles have precluded their long term use for moderate to severe psoriasis. This review concentrates on new biological agents, focusing on the three agents approved for psoriasis within the past 18 months (alefacept, efalizumab, and etanercept). Phase II and III trial data on other agents in development (adalimumab and infliximab) are also presented. Surveys show many patients want to be treated more aggressively. It is hoped that the introduction of new agents that are more targeted and that hold the promise of fewer side effects will cause patients and their physicians to reconsider systemic treatment and, as a consequence, stimulate other patients to reconsider treatment for psoriasis. Close cooperation between dermatologists and rheumatologists, particularly in the area of psoriatic joint disease, will enhance these considerations.
Psoriasis is a life-disabling disorder in which 8-10% of patients aged 18-54 actively contemplate suicide because of their disease. Owing to the toxicity and/or inconvenience of current, FDA-approved treatments far moderate-to-severe psoriasis, they are generally used intermittently so that patients experience cycles of remission-flare-remission-flare, etc. The challenge to drug development for moderate-to-severe psoriasis is to provide safe and effective long-term management. Immunobiologics offer the hope for safe, long-term control of psoriasis because they lack targeted organ toxicity. Thus the treatment paradigm may shift from one of intermittent treatment limited by toxicity with resultant flares of disease, to one similar to that seen in diabetes or hypertension in which disease is controlled continuously. Additionally, immunobiologics may alter the natural history of psoriasis. Etanercept, which targets TNF-alpha, controls signs and symptoms and halts joint destruction in patients with psoriatic arthritis. The long-lived remissions observed after cessation of alefacept or infliximab (anti-TNF-alpha monoclonal antibody) treatment lead this author to speculate that these immunobiologics may actually alter the natural history of the cutaneous manifestations of psoriasis.
OBJECTIVES: To provide information regarding the most important properties of the new therapeutic agents marketed in 2003. DATA SOURCES: Product labeling supplemented selectively with published studies and drug information reference sources. STUDY SELECTION: By the author. DATA EXTRACTION: By the author. DATA SYNTHESIS: The 28 new therapeutic agents marketed in the United States during 2003 are reviewed in this article: adalimumab, agalsidase beta, alefacept, alfuzosin hydrochloride, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, bortezomib, daptomycin, efalizumab, eletriptan hydrobromide, emtricitabine, enfuvirtide, eplerenone, gefitinib, icodextrin, laronidase, memantine hydrochloride, mequinol/tretinoin, miglustat, nitazoxanide, omalizumab, palonosetron hydrochloride, pegvisomant, rosuvastatin calcium, tadalafil, tositumomab and iodine I 131 tositumomab, and vardenafil hydrochloride. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. When possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION: A number of the new therapeutic agents marketed in 2003 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.
Psoriasis is a chronic skin disorder characterised by inflammation producing red, thickened areas with a flaky white build-up. Efalizumab is a humanised monoclonal IgG1 antibody that inhibits the binding of T lymphocytes to endothelial cells and their subsequent migration. In patients suffering from plaque psoriasis, there was improvement in 51-52% of the efalizumab-treated patients at week 12, compared with 17% of the placebo patients. Efalizumab caused a > 75% improvement in 22-28% of psoriasis patients compared with 5% of placebo patients. Efalizumab also improved quality-of-life outcomes. Early studies are also showing benefits with other compounds (alefacept, infliximab and etanercept) in psoriasis. Direct comparative clinical trials will be needed to ascertain which of these agents provides the maximal improvement with the minimal incidence of side effects.